Jump to:

Product Design

Conference on the Ftc Cigarette Test Method 941205 - 941206 Holiday Inn, Bethesda, Maryland

Date: 05 Dec 1994 (est.)
Length: 250 pages
89289677-89289926
Jump To Images
snapshot_lor 89289677-89289926

Fields

Named Organization
Bw, Brown & Williamson
Conference on the Ftc Cigaret Test Metho
Ftc, Federal Trade Commission
US Court Appeals
Brand
Barclay
Subject
Particle Size (Technology)

Document Images

Text Control

Highlight Text:

OCR Text Alignment:

Image Control

Image Rotation:

Image Size:

Page 1: apt20e00
Conference on the FTC Cigarette Test Method . December 5-6,1994 Holiday Inn, Bethesda, Maryland ~ CER `~ ~ iNSTITUTE
Page 2: apt20e00
TABLE OF CONTENTS Nicotine Delivery Devices ............................................. John Slade Tar and Nicotine in Cigarette Smoke ............................... . H.C. Pillsbury et al. Inter-Individual Variation of Nicotine Uptake Among Smokers ............. G.D. Byrd et al. FTC v. Brown & Williamson--Regarding Testing Results of Barclay Brand of Cigarette, October 14, 1983 FTC v. Brown & Williamson--U.S. Court of Appeals, October 2, 1984-December 18, 1985 The Health Conseauences of Smoking - The Changing Cigarette A Report of the Surgeon General 1981 Selected Bibliography on FTC Cigarette Test Method 1981-1993
Page 3: apt20e00
458 R. H. Deibel, University of Wisconsin, Madi- son, Wis. J. Disikes and G. Sherman, U.S. Department of Agriculture, Chicago, Ill. W. M. Hall, General Foods Corp., Technical Center, Tarrytown, N.Y. D. Horn, Bio-Scan Laboratories, Division of W`ilson Pharmaceutical and Chemical Corp., Chicago, , Ill. F. R. Kronenwett, American Biological Con- trol Laboratories, Inc., Tena6y, NJ. G. K. Morris and J. 0. Wells, National Com- municable Disease Center, Atlanta, Ga. D. M. Murphy and R. Kubista, Wisconsin Alumni Research Foundation, Madison, Wis. R. A. Oleen, Winton Hill Technical Center, The Procter & Gamble Co., Cincinnati, Ohio R. M. Wood and Catherine Powers, Departt ment of Public Health, Berkeley, Calif. The following members of the Food and Drug Administration also served as collaborators: R. L. Ambrose, Buffalo; Jayne C. Beard, Cincinnati; T. H. Burton and N. J. Eltsworth, Los Angeles; R. D. Debo, New Orleans; John Erickson, New York; Ralph Groomes, Division of Microbiology, Washington, D.C.; Virginia Hatsenbeler, De- j(IIIRIiAL OF THE AoAc (Vol. 52, No. 3, 1969) troit; S. A. Keoseyan, San Francisco; J. M. Lanier and L C. Miyasa]uu, Minneapolis; A. J. LeBlanc and F. W. Longbine, Atlanta; J. E. MeCarron, Denver; E. H. Peterson, Kansas City; C. N. Roderick, Dallas; Sam D. Schrivener, Chi- cago; R B. Smittk, Baltimore;, C. F. Thayer and F. A. Stanely, Seattle; T. J. Wasenski, E. Robin- son, and K. Rhodes, Philadelphia;, and F. A. Zaptka and B. MeEachern,, Boston. The assistance of John Van Dyke and hie as- sociates, Bureau of Science, Food and Drug Adiainistrati'on; Washington` D.C., with statisti- cal services is also gratefully acknowledged. RaFSaasncas (1) North, W. R., J. Backriol. 80, 861 (1960). (2) "Changes in Methods", This Journal 50, 231-239 (1967). (3) "Changes in Methods", tbid. 51, 505-306 (1988). (4) Poelms, P. L., t3id. 50, 753-763 (1967). This report of the Ae.ociat. Ref:n.. P. L Poelnu. wu pepmted at the b2ad Annual Meeting af the Asociation of O/lfeitt Analrtical Chemi.t., Oet. 14-17, 106A. at Waahing_ toa. D.C. TOBACCO Tar and Nicotine in Cigarette Smoke By H. C. PILLSBURY, C. C. BRIGHT, K. J. O'CONNOR, and F. W. IRISH (Federal Trade Commission, Pennsylvania Ave. & 6th St., N.W., Washington, D.C. 2fIS80) Cigarettes were conditioned 24 hr at 7S'F and 60% relative humidity prior to being selected and smoked In a random order. Cigarettes were smoked In a Cambridge filterbolder on an automatic smoking ma- chine to a pre-deternained butt length. TPM wet oollection was on a CM113A filter disk and was determined as the net weight gain in the Cambridge filter holder after smoking. The filter pads were extracted with diozane-isopropanol solution and were analyzed for moi.ttue by gas chromatog- raphy. The pads and solvent extracts were ateam distilled and the distillate was anal- yzed spectropbotometrieally for nicotine. TPM dry was calculated as TPM wet minus nicotine and water. The coefficient of varia- tion in tWs method is le.s than 5y(v with a 9596 confidence level. This paper describes a working method for TPM (total particulate matter) and nico- tinet analysis in cigarette smoke based on the consolidation of the methods of Ogg (1), Shults and Spears (2), and Sloan and Sublett (3). This combination provides a standard,, uniform analytical procedure which will give reproducible results within and between labo- ratories and which conforms to the method put forth by the Federal Trade Commission (4). " Nieotise rden to toW altsloid" t6rousbout thie paper. Reeeived SaptemG.r 0. IOGi. 'rhis payer was qesetd st the l2nd Annual Meeting of the Aawoiatiae of Oieid Analytical Chemiete. Oct. 1'4-t7. 1968, at Waehinston. D.C.
Page 4: apt20e00
PILL4nUR] ET AL.: TAR AND NICOTINE IN CIGARETTE SMOKE 459' METHOD Reagents (a) Dioxane+isopropanol solulinn.-One part isopropanol (apectrophotometric quality) to 100 parts'dioxane (distilled in glass); store in brown bottle with drying tube open to air. (b) Sodium hydroside-salt sofution.-Diasolve 300 g NaOH in water and dilute to 1 L; saturate with NaCI and cool. Stir occasionally for several hours and decant supernatant. (c) Hydrochloric acid.-SN; 0.2N, and o.05N HCI. Apparatus (a) Smoking machine.-Philip Morris Auto- mated Smoking Machine designed by Philip Morris Research Laboratories (5) (available from Phipps & Bird, Inc., 6th & Byrd' Sta., Richmond, Va.) (Fig. 1), automatic and capable of drawing puffs according to the following specifications: Puff uol'ume.-35 f 0.5 ml measured as the volume of smoke that will be drawn from cig- arette under actual machine smoking conditions. Measure puff volume by soap bubble manometer attached to port with smoke collection trap in place before and after each smoking run. Puff duration. 2 f 0.2 sec measured under actual machine smoking conditions by soap bub- ble manometer and/or stop watch. PuffJreguency.-One puff per 60 :k 1 sec. Pro- tect cigarettes from drafts and convectional cur- rents during smoking operation. (b) Smoke collection trap: (Available from Ph'sppa & Bird, Inc.) Plastic or aluminum filter holder with threaded inner and outer parts. Filter diska.-Pre-cut filter .dieks 1.74' in diameter from CM113A fiber glass sheets (avail- able from Phipps & Bird, Inc.). Filters must col- lect not less than 99.9% of all particles greater than 0.3 µ in diameter at' 28 linear ft/min flow rate, must have a maximum pressure drop not greater than 93 mm water at 28 ft/min, and must contain not more than 5% acrylic-type binder. Rubber membrane.-Use thin latex tubing similar to that used for surgical drains, ca 8 X 20 mm, or cut square pieces of medium latex dental d'atn, ca 3.5 X 3.5 cm. (Place dental dam between two pieces of rubber tile or other suitable ma- terial and punch hole 4-6 mm in diameter in center of each square with a cork borer;,size of hole depends on diameter of cigarettes.) LuciCe guide.-(Available from Phipps & Bird, Inc.) Required only with dental dam, designed so dental dam will fit over one end which can be inserted into the filter assembly. The other end of the guide is tapered so that the small "0" ring may be passed over it and onto the assembly holding the dental dam in place. Silicon-rubber "0" rinqs, small.-(Available from Linear, Inc., State Rd. and Levick St., FIG. 1-Tw.nty-port automat.d smoking machin..
Page 5: apt20e00
460 Philadelphia, Pa.)' %' id or may be made by slic- ing thin sections of rubber tubing of same inside diameter. Silicon-rubber "t7' rtinps, larye.-(Available from Phipps & Bird.) Large silicon-rubber "0" ringofcs4'2mmid. Cambridge f+ltsr assam6fy. For a detailed de- acription see Wartmaa et aL (6). (Set Fig. 2.) FtG.2-Parts of the Caetbrtd9e filter hetder sssem- bly. (1) Wire wrench, (2) Outer part of filter holder. (3) Threaded Inner part of filter holder. (4) Pre-cut filter disk, (5) Lucite gulde.,(6) Dental dam, (7) Large silicon-rubber "O"ring" and (8) Small silicon•rubber ••O•` ring. Place pre-cut filter disk inside filter holder, making sure that rough side of filter disk is facing toward port through which cigarettes are smoked. Put silicon-rubber "0" ring (large) on top of filter disk inside filter holder. Then screw on threaded inner part of filter holder and tighten it with wire wrench. Place hole in dental dam over small end of Lucite guide. Insert this into eu- tranoe hole of filter holder and push small silicon rubber "0" ring down from other end of guide. This goes over the dental dam and holds it io place on the filter holder. For some cigarettes, i.e., non-filters or small diameter cigarettes, rub- ber tubing may be preferred. Guide rubber tubing into entrance tube of filter holder, leaving some tubing extending beyond entrance hole. Stretch and fold this extension over outside of tube and fasten securely 'in place with small "0" ring. (c) Gas cAromaloyraph.-Containing 6' X ~/s" utainleee steel column packed with 80-100 mesh Porapak Q. Column temperature 200eC, injection Mention of br.od or firm in this paper doea not constitute rndor.ement by the Fderat Trade Commirion o++er othere or a s'vnmi{.r natanx not tmntioned: JUUItNAL UF THE AOAC (VoL 52, No. 3, 1969) port 240°C, thermal conductivity detector 210°C, helium carrier gas 100 ml/min. (d) Spedrophotomrter.-Capable of accurately measuring absorbance from 200 to 300 mp aud having a slit width not greater than 5 mp. (e) Gri~'ttAl disl:Ifalion apparatus.-Available from Consolidated Glass Works, Kingsport, Tenn. Preparation ojSample l're-condition all cigarettes a minimum of 24 hr on mesh trays' at 75 f 2eF and 6U f 2% relative humidity. Select cigarettes randomlyy with care to avoid frayed ends and loosely packed or damaged cigarettes. Pre-caark cigarettes to 2'3 mm butt length or length of filter-overwrap plus 3 mm, a hichever is longer. Gently wipe filter assembly wi:h soft cloth or tissue and weigh assembly to nearest f0.05 mg. Connect filter assembly to smoking machine so that the cigarette and filter assembl.• are held horizontally. Keep volume between filter arsem- bly and smoking machine to a minimum. Test smoking apparatus and filter assembly for leaks. Insert a cigarette through hole in rubber mem- brane until butt end is approximately flush with the inner end of the holder tube, i.e., ca %' depth. Take care that the butt end does not come in contact with filter disk. Withdraw cigarette slightly so that lip of orifice in rubber membrane projects outward and forms a snug- fitting collar surrounding smooth portion of cigarette to provide leak-free seal. Cigarettes manufactured with air vent holes must be in- serted carefully to: prevent covering holes W hile smoking. Light cigarette at beginning of first puff (au electric coil lighter is suggested). Smoke five cigarettes per filter pad. Smoke each cigarette until burning coal reaches mark. With auto- matic smoking machines, a string placed on the mark is burned, releasing a micro switch which discomtects its specific port: (See Fig. 3.) On other types of smoking machines, balance the "overs" with the "unders" for each filter holder (for detailed description see Ogg (1)). ImmcKli- atcl'y after smoking five cigarettes per pad, di+- connect filter assembly from apparatus, Wipv with cloth or tissue, and weigh to nearest 0.05 mg. If pads tend to "wet through" (a brown stain on the reverse side of the pad) indicating that all the cigarette smoke TPM wet is not retained, reduce the number of cigarettes smoked per hatl. Determination (a) TPri (toel).-itecord weight gain of filter assembly as TPM (wet)/pad and dividre by
Page 6: apt20e00
PILLSBURY BT AL.: TAR AND \I(,'Q"fIN@: IN CH3AItliT7.'!r 5MU6L•' Flti. 3-Cetail ot cigarette In smoktnS machine port. (1) Strins placed on ciaarette at pre3et butt lensth, (2) Filter holder In smoking machine port. (3) M1cro switch whkh Is released when string bums throuah, thus stopping smoking of that particular ciga- rette port. uumher of cigarettes smoked for TPM (wet)/ cigarette. Save filter pads for moisture and nico- tine analysis. (b) TADf t,eoisture contenl.-Ilnmediatelyaf ter N•eighing place filter pad in dry, stoppered 25 ml l:rlenmeyer fiask or serum bottle. Wipe filter assembly, including entrance port, with onN quarter unused filter pad which is slso placed in serum bottle. Add exactly 10 ml dioxane-iso- propanol solution. Stopper bottle and shakc 30 miu. (Iu lieu of shakiug, the solution may stand overnight.) A 5 Nl sample is withdrawn through the rubber serum cap and injected into the gas chromatograph. Prepare stalulurds by adding known amouutb of water to dioxat>e-ieopropanol solution. Cou- struct curve by plotting ratio of peak heights of water to isopropanol versus mg of water added to standard after subtracting a solvent blank. The resulting straight line is the standard curve from which the water content of the filter pad ex- tract may be read directly (2). Subtract the value for a sample blank, conaisting of a filter pad aud 10 uil dioxane-isopropanol solution, before read- ing the sample value from the standard curve. (c) Nicoci»e.-Su6stances interfering in the UV analysis are removed by steam distillatiuu from an acid' solution. The remaining solutiou is 461 subiceyuently made alkaline and distilled. The ui:.rotine in the distillate is then determined by ultraviolet spectroscopy: L•xpel the steam condensate from the distilla- tion fl•rtk and add 5 m10.2N HCL Quantitatively tranxfrr dio..auo-isopropanol extract and filter pad to distillation flask of Griffith distillation ap- paratus, rinsing flask with solvent. Steam distill until ca T00 ml distillate is obtained. Discard this distillate. Discontinuc steaming, place a 250 ml volumetric flask containing 10 ml SN HCl under the receiving tube, add ca 5 ml NsOH-NiaCl solu- tion from tttcasuring tubes mounted above the tuiit to distillation ft:.sk, and resume distillation. Remove receiving flask after ca 200 ml distillate is collected and dilute distillate to volume (7). Dihtte an aliquot with 0.05N HCl (1 -1-1), mix, and miasurc+ absorbance at 238, 259, and 282 mr aguiust 0.0511 HCI reagent blank. (If nicotine absorbance at 2.59 mp is below 0.300, read alnwrhsnce of distillate without dilution; if ab:- sorbance at 259 mµ is above 0.800, further dilute olixtillate.) Calculate weight of nicotiuc as follows: A'zas - absorbauce of nicotine corrected for background = 1.059[Aass - (i(Asas + AsasA aud total Noightof nicotine/pad (mg) = A'sse X j/(n X 6) whera a=:absorptivity of pure nico-
Page 7: apt20e00
462 JUC:R\AL OF Tlit \pAC (Vol. 52, Nu. 3. 1!1(Ig) Table 1. Statistical analysis showing within-laboratory reproducibility of the method for TPM and nieotine using control cigarettes Less Than 100 Cigarettes/Sample More Than 100 Cigarettes/Sample - Sample No. Cig. Smoked Nicotine. mQ,/Cig. TPM Dry. mg/Cig. Sample No. Cig. Smoked Nicotine, mg/Cig. TPM: Dry, mg/CiQ. A 90 1.34i-0.02' 20.2t0.3 E 150 L.35t0.0t, 19.7=0.2 8 90 1.34*0.02 20.3*0.3 F 200 1.31t0.01 20.t_0.2 C 85 1.32*0.02 19.9f0.3 G 180 1.36t0.0t 20.8_0,3 D 90 1. 36 i0.02 20.6 f0.1 Statisticss Xx i 95.1200 1440.3000 112.8400 2159.1000 Zx ° 127.5922 29257.0700 192.6544 44056.4400 n 71.0000 71.0000 106.0000 106.0p80 R ' s 1.3397 20.2159 1.3475 20.3716 (} ar) i 9047.3144 2074464.0900 20403.2656 1663008.3500 o 0.0469 0.7499 0.0400 0:7915 Standard error' 0.0055 0.0888 0,003g 0,0768 • 2 x standard error. • W. J. Youden (9). • n- number of entries: number of pads (ports) smoked, five cigarettes smoked per pad. ~ v2 - IEx' - (Ex)=/nl/[n - Ij • Standard error - '~-. . n tine in 0.05N HCI solution - d/(c X b), b- cell length, f- dilution factor, and c= concen- tration of saturated solution of pure nicotine (g/L) in 0.05N HCI. The generally accepted value for nicotine absorptivity is 34.3 (8). Determine mg nicotine/cigarette by dividing mg nicotine/pad by number of cigarettes smoked/pad. (d) TPM dry (far).-Calcul'ate as follows: TPM (wet)/cigarette - moisture/cigaretlc (read from calibration curve) - nicot5ne,.'ciK- arette - TPM dry (tar)/cigarette. Results and Discussion Since there are no known absolute values for nicotine or TPM dry in cigarettes, no recorern• percentages were obtained. A special uniform blend of cigarettes manufactured to be used ass control cigarettes were conditioned and as- sayed' according to the above method alonr w-ith other brands being tested. The statistical' analysis shown in Table 1 is based on the methods of Youden (9). The results shown in Table 1 are typical of the results which have been obtained within our laboratory over the past year. Although Samples A through D are based on less than 100 cigarettes (20 pr,rts), they have a tolerance of Tess than 0.5 mg/ cigarette for TPIt dry an& less than 0.05 mg/cigarette for nicotine at the 95% ct,nfi- dence level. The standard error indicated c_ood precision for this method. (1) (2) REFERENCES t tgg, C. L., Thia Journal 47, 356-362 (1964). Schultz, F. J.,, and Spears, A. W:, To+,nceu Sci. 10; 75-i 6 i'1966). G;) Sloan, C. H., and Sublett, B. J., ibid. 9. 7ti-73' (1965). (4) Fedcral' Trade Commi"ion news rrlea=e, August 1, 1967. (a) (U'lieefe, A. 1:., and Lieser, R. C., Ta!~tcco 146(22), 20-23 11958). (I;) Wartman, W. B., Cogbill, L•'. G., attd'itarln.r, Iti. S., auaL'. Chrnt. 31, 1i(ti 11J5!)). (71 (;riffitlt, it.13.,TobnccoSci.145, 26-3:; Ia.i7-. (ti) 1Cillits, C. 0., Swain, \Iargaret L.. f'uti- nc•Ilr, J. A., and Brice, B. A.. 3nal. Chr.,.. 22; 430-433 (1930t. (9) 1'uudcn, 11'. J., SGrlislical Tcchniqtr•a ior f'oflrrGorntlrc Texls, Association of (tflirial :Iucth•Iical ('Itemists, \1"a=1»ugtoll, 1).t'., VjGi.
Page 8: apt20e00
INTER-INDIVIDUAL VA.RIATION OF NICOTINE UPTAKE AMONG SMOKERS G.1). Byrd, .1. lI. Robinson, W. S. Cnldrvcll, ond.i. D. dcDcthizy R. .1. Reynolds Tobncco Company, Producl C.valus+lion Group, Winslon-Ss+lent, NC 27102. I'oslcr jor Inlernalioiral Syniposium on Nicotine, Montreal, Canada, Jrily 21-24, 1994..
Page 9: apt20e00
INTROUCTION Cigarette smokers have a wide variety of "tar" and nicotine yield hroducts to choose from in /he current market, ranging from 0.5 nrg "tar" and less Ihan 0.05 mg nicotine to 27 ing "tnr" and 1.8 nig nicotine by the Fedcrnl Trade Commission (FTC) method. Nicotine uptake by cigarette smolcers Is commonly thought to be a function of cigarette yield ns determined by the FTC machine cmnking method. Iteccnt notoriety of this issue in the popular rnedin has led to speculation that the FTC method is misleading (Ililts 1994). The current FTC method, adopted by the U. S. gov- ernment in 1967, is bnsed on measurements from a smoking ma- chine following a well-defined regimen (Tillsbury e(al.1969). The reference method was established for product comparison al- tirough prolonged use of F'l'C ratings hns fostered thc belief llsat these dala predict nicotine uptake by individual smokers. Like rrny standar-dizcd machine smoking nrcthod, the FTC method suffcrs from thc fact tlrnt humnni do not necessarily smoke like m:rchincs and predictions of srnoke exposure based on the FTC rncthnd remain rough cstimrtes. Nicotine uptake by smokers Is not only inflrrenccd by lrroduct composition and design, but also by smokcr-controlled parnmcters (priffing patterns, depth of in- h:rlation, numbcr and frequency of cigarettes, c(c.) and physiologi- cal factors such as p1i of nrucosni membranes and metabolism (Kycrcnraten and Vessell 1991; I3enowit7 1988). Consequently, It+rgc inter-individual varinbility is expected nmong smokers with regard to nicotine uptake; however, a standardized method such as that used by the FTC is irnportant for p'roduct comparison. INTRODUCTION, continued Improved understanding of nicotine nietabolisnn in humans has made i/ possible to account for essentially all nicotine uptake over a 24 h period in smokers by monitoring urinary excretion of nico- tinc and Its mebtholi/es. Mcthodologics thnt determine both phase I and phase I[ urinary mctabolites of nicotine and include minor metabolites such ns nicolinc-N'-oxide nncf cotininc-N-ozide ap- proaclr lotnl nicotine accountability (90%) (Curvall et al. 1991). Such high recoveries in urine offer the best means for precise qunntitation of nicotine uptake in humans (Qcnowift 1991). Au»ly- sis of 24 h urine specimens to dclcrmine daily nicotinc ulrtnke by smokers hns the advnntnge of being noninvasivc anrl pernrits nd libihiirr smoking by subjects with minimal impact on their daily routines. This is nn important component in cap/uring an nccu- rnle picture of nicotine uptake in smokers since thc total daily nicotine uptake integrr/e.t any differences in smoking bch:rvior over a 24 It pcriod.. In order to put nrnchinc-laased nicotinc uptnkc prcdictions into perspective, we studied several groups of surokers using rnctlrods to account for daily nicotine uptnlcc. This study reports nicotine ur/akc in 33 smokers that spanned four product groups: I mg "tar" (1MG), ultra-low "tnr" (ULT), full-flavor to%+• "/ar" (rFl;l'), and full flavor (FF) cigarette smokers. Mcasrrrcd nnd predicted nicotine up/akc arc compared for all smokers and far the means of each group. sa3sezse
Page 10: apt20e00
., I?XI'ERIMI;NTAL Su?)iccts. Thirty-three adult snrokcrs, ages 26-50 years, partici-d patcd in this sludy and were compensated. For lite various ciga- re/les smoked by these subjects lite distribution among FTC yield categories was as follows: FTC Nicotine ~.~ _n_ ~Im~1~isL FTC "tar" tang/cia) 1MG 9 0.14 # 0.01 1.0 t 0.1 ULT 13 0.49 * 0.06 5.4 * 0.6 FFLT 6 0.67 t 0.07 9.7 t 0.6 FF 5 1.13 t 0.15 15.5 t 1.1 The subjects were nll male Caucasians except for one Caucasian and one African-American female In the FF group. All subjects were allowed to smoke their usual brand of cigarette (cigarettes were not supplied to the smokers by the experimenters) as much as they desired, and were required to record the number of ciRa- rettes smoked and collect all their urine over a 24 h period. The I MC and ULT smokers recorded the numberof cigarettes smoked daily over a one week period and snbmitted three consecutive 24 h urine samples on the final tirrce days of that week. The FFLT nnd FF' srnokers recorded lite number of cignretlea smoked for one tn three days and collected a single 24 h t,rinc sample on tlrc finnt day. Each subject wns supplied with two 3-Lspccimen bottles stored in a portable cooler. The subjects kept lhe coolers with them during tlte 24 h reriod as they performcd their nor-mal rou- tines. Total 24 1r urine volumc was measured immediately after cach collection. Samples were frozen at -20'C prior to analysis. EXPERjMENfAL, continued Analvsis of samples. Samples for the 1MG, Frl:l', and FF sntnlt- crs were prepared and analyzetl according to a moditicalion (Byrd et a1.1992) of a Publislrcd LC/MS mclhntf (hicManus ct al. 1990). The UI,T smoker samples were analyzed by a modification (Byrd 1993) of a published CC/MS method (Voncken et al.. ]989) shown to give comparable nicotine uptake data to the L.C/MS method. In both methods, nicotine attd metabolite concentrations were summed to produce a total concentration of nicotine equivalents. This value was multiplied by the 24 h urine volume to give lite total nmount of nicotine uptake per 24 h. The daily nicotine un- take divided by the number of cigarettes smoked gave Ihe :tvcr- age nicotine uptake per cigarette. Statistical analysis. Paired t-tes(s were used to compare FTC and measured yields per cigarette for separate groups and all smak- ers together. The groups were also compared with e1ch other using Duncan's Multiple Range Test. Regression analysis was used to test for lite existence of a linear relationship bctwecn F1'C yield and measurctl nicotine uptake. The group means were com- parcd with each other to finc) further significant differences in nicotine uptake that might be expected as a function of FTC TC yicld.. Finally, the correlation between nicotine uPtake and nuntber of cigarettes was determined. Significance was defined as P 0.0-5. 9199sezse
Page 11: apt20e00
Cotnt»risnn of FFC nicotine yicld with Ineasure(1 nicotine uptake for four groups of sblolters 1rr:11igC(I by r('C yicid category. MeassFTC FTC Nicotine Measured Nicotine (mg/24 h) Group N ci 24 h mg/cic„-- mg 24 h_ mg/cig mct 24 h Ratio= 1MG 9 35 ± 16 0.14 ± 0.01 4.8 f 2.2 0.23 ± 0.11. 9.1 ± 7.3 -1.64 ± 0.82 ULT 13 37 ± 21 0.49 ± 0.06 18.7 ± 12.5 0.56 ± 0.23 19.2 ± 10.0 1.18 ± 0.53 FFLT 6 37 ± 14 0.67 ± 0.07 24.8 t 8.3 0.60 ± 0.18 21.8 ± 9.4 0.89 ± 0.28 FF 5 34 ± 15 1.13 ± 0.15 38.1 ± 15.2 1.19 ± 0.43 37.3 ± 14.4 1.04 ± 0.34 Itesults of Dunc:in's Multiplc ltonge Test for comparing the four different groups in this study. Means with (lie sanic lctti arc not significantly different. Comparison of mg nicotine/24 h: Group N Mean Duncan Grouping 1MG 9 9.1 A ULT 13 19.2 A B FFLT 6 21.8 B FF 5 37.3 C comparison of mg nicotine/cig: Gr ,ouP N Mean Duncan GroupiAS 1MG 9 0.23 A 4g9Gezse VLT 13 0.56 B FFLT 6 0.60 B FF 5 1.19 C
Page 12: apt20e00
Nicolino uptake (mg12411) vs FTC nlcotlne yield for group ntoans 60 Linear RegreStlon Y*As8'X Param VsluQ fd r 50 A 4.77446 1.4769 12647 2.09627 v 0 26 . N I FF ` R =099449 . ~ 40 Sn v 1.49597. N= a y P•000551 ~ 70 rz D ULT d 20 1/ T FFLT C ~ MG1 Z t0 ~ 0 0.0 0.2 0.1 0.6 0.8 1.0 L2 1.4 1.6 Average FTC Nicoline (mglcig) Nicotine uplako (mg/clg) vs FTC nlcotine yield ror group means 1.4 . E 1.0 B 0.a n D 0.6 C . p 0.4 U z 0.2 - linear Rayiesslon Y=A•0'X P1ram Va1ue sd A 0.06532 0.08495 0 0.v542 0.120sr R-0.96~91 SO - 0.00604. N 4 P  0.01559 0.04 0.0 0.2 0.4 0.8 0.8 1.0 1.2 1.4 1,0 Average FTC Nicotine (mg/cig) Nicotine uptake (mgf2411) vs FTC nicotine yield far Individuals lke,rr ner7reieion 60 YnA•0'X Pararo V.tua td A 545316 3.20017 50- 0 27.1281 5.16602 q  0.6646t 40 SO  9.69269.11 + »r ~ P - 0.0000 t  .  FTC Nicotine (mg/cig) r  Nicotine uptake (mg/clg) vs FTC nicotine yield for individuais 1.6 - 1.4- 0.0 0.0 Linear negresslon Y- AI 6•X Param Vdue sd A 0.09255 0.07716 E 0.91363 0.12506 a  0.7v534 SO- 0.2»71,Na 33 P  3.1994E.0  0.2  • a r 0:4 oA o:e t:o 1:2 FTC Nicotlne (mgfctg) 1.4 1.6 eessezse
Page 13: apt20e00
RESULTS • Mcan differences in measured mg nicotinelclg compared to FTC yield were insignificant based on n paired hvo-tailed t-. tcst. - Group mcans for nicotine urtake showed a signilicant (1' <0.05), positive linear relationship with Ihe FTC nicotine yield for nlco- line uptake per 24 h and per cigarette. •'ncerc were large inter-.individu>+l varinbilitics In daily nicotine uptake within each group. CV's ranged front 0.39 to 0.80. . Avcrnge rAtios of niensured nicotine uptake to FTC nicotine yield were near unity for FF, FFLT, and ULT smokers, but in- creased to 1.64 for Iltc 1MG smokcrs. • Although IMG smokers as a group tended to excced FTC pre- dictions more than the others, they still received less nicotine on average contpnred 1o the other groups on r per cigarette nnd on a tinily bstsis. • Duncan's Muitiple Rangc'Iest on uptake as mg/cigarc/te avcr- ngcs in each group showed 1MG and FF smokers were different front stll other groups. The 24 h uptake data showed 1 MG snrolc- crn were different from FFLT and FF smokers but not ULT smok- ers. FF smokers were different from all other groups. • Measured nicotine uptake and number of cigarettes smoked were highly correlated for lMG smokers (lt = 0.98) and FFLT smokers (R - 0.91). FF smokers were the least correlated (R= 0.038) followed by ULT smokers (R = 0.369). GS96SZ68 CONCLUStONS • FTC yields are predictive of average nicotine uplalte: luwcr FTCyicid cigarettes result in less nicotine uptake on average per 24 h, and also per cigarette smoked, than higher FTC yield ciga- rcltes for tlte product groups iit this study. • For cncit "lar" cntcgory, di[fcrcnccs bctwcen FTC yields :tnd measured nicotine uptake are not significant; however, ratios of the tivo Indicate that the k"I'C method is not as accnratc prcrlict- ing nicotine uptake for lower yield cigarettes. • Only when smoking more cigarettes do smokers of titc lowest yield cigarct/es (1MG) obtain nicotine uptake compnrahle to Ihc othcr smokers. • While FTC yield cnnttot ahvays predict nicotine ulitnlcc for an individual smoker, H is useful in predicting and conthnring stctual nicotine uptnke by smokers who select cigstreltcs %villt n partieu- lar FTC yield. • These dnta suggest Iltat nicotine uplakc is a C-unction of incli- vidunl smoking bchavior within product dcsign limits. ~ Determination of nicolinc urlake by tnonitoring 24 It nicotinc nnd its metabolites is supcrior to nctt/c laboratory shrclics because it allows unrestricted srnokirtg bchavior, accounts for mc/nbolic variations amongsmolcers by monitoringseveral ntetabolites, and approaches total nicotine accountability.. ACKNOWLEDGEMENT We would like to thank W. T. Morgan for assistance with statis- /ics.
Page 14: apt20e00
1tI;FI':RENCES Ilcnowilx NL (1988) Pharniacokinetics and hharmacodynamics of nicolinc. In: 'fhe Pharmacology of Nicotine, Rand MJ,Thurnu K(cds) IRL 1'ress, Oxford, Washington I3cno«•itz NL (1991) Metabolism in the human biology of nico-. fine. In: Effects of Nicotine on Biological Systems, Adlkofer F, Thuraus K(cds) I3irkhfluser Verlag, IiAsel Byrd GD, Chang KM, Crccne JA7, deBcthizy JD (1992) Evidence for urinary excretion of glucuronide conjugates of nicotine, cotinine, and trans-3'-hydroxycotinioe in smokers. Drug Me- tstlrolism and Disrosition 20:192-197 Byrd GD (1993) Comparison of GC/MS and LC/MS methods for determining nicotine absorption in tobacco smokers. 41st ASMS Conference on Mass Spectrometry and Allied Topics, San Francisco, CA Curvall M, Va1a EK, Engtund G (1991) Conjugation pathways in nicotine mctabolixm. In: Effects of Nicotine on Biological Systems (Adlkofer F, Thuraus, K(eds) DirkhSuscr Vcrlag, Dasel Federal Trade Commission (1967) Cigarettes: testing for tar and nicotine content. Fed Regist 32:11178 Ililts 1'J (1994) Big flaw cited in federal tests on cigarettes, The Ncw York Times, May 2 Kyerematen CA, Vcssell ES (1991) Nicotinc metabolism. Drug Mctabol Rev, 23:3-41 McMnnus KT, deRcthizyal), l:artciz DA, Kyercmalcn (; A, Vcscll ES (1990) A new quanlitatiye thertnospray-LC/MS ntethod for Nicotine anti its motabolites in biological fluids. .1 Chrom Sci 28:510-516 Pillsbury 1IG, Bright CC, O'Connor 10, Irish F«' (1969) .1 Assoc. Off Anal Chem 52:458-462 Voncken P, Schcpers C, Schfi[cr Kll (1989) Capillary gas chromntographicdetermination of lrans-3'-hydroxycotinine si- multaneously with nicotine and cotininc In urine and blood samples. J Chromatogr 479:410-418 069sezse
Page 15: apt20e00
F.T.C. e. BROWN & WILLI:1i<1SON TO)3:4('CO CORP. Cile as Sa0 F.Supp. 991 (1981) duly affected by any drug administered to Mr. Leatherman. Under the cirLumstances of the present case at leatst, it does not appear appropriate for the Court to inter- vene. For the foregoing reasons the Court is of the view that petitioner has not shown a substantial likelihood of success on the ulti- mate issues presented. Nor has petitioner demonstrated' irrep.'trrable injury either to his health or to hi.s opportunity for a mean- ingful 9 301(k) hearing if the Hospital i.~c allowed to proceed with the proposed treat ment. Petitioner's request "for interim re- lief preventing administration of HaWoD iss therefore denied. SO ORDERED. FEDERAL TRADE COMM[SSION. Plaintiff. V. BROWN & WILLIAMSON TOBACCO CO RPO RAT ION. 1)efendant. Civ. A. No. 83-1910. United States District Court. District of Columbia. Oct. 14. 1983. Federal Trade Commission sought to enjoin cigarette manufacturer from adver- tising its cigarette as "1 mg. tar" and "9V tar free." The District Court, Gesell, J., held that: (1) method used by Federal Trade Commission for measuring cigarette tar is not misleading; (2) claim that particu- lar cigarette contained "1 mg. tar" was misleading; but (3) claim that the cigarette was •'99:'~ tar free" was not misleading. Ordered accordingly. 981 I. Trade Regulation a76a Fed'eral' Trade Commission system for measuring tar produced by smoke of vari- ous cigarettes providesJegitimate cornpara- tive infol..tation to consumers and is not meaningless or deceptive; FTC thus may ask for equitable relief against cigarette manufacturer which, it believes to be using the system in a misleading manner. 'Z. Trade Regulation a-i W Cil,~arette manufacturer's advertising claim which made no mention of any partic- udar rating system but stated that its ciga- rettes contained "1 mK. tar" was deceptive in that it led consumers to believe that the cigarette was r.lted at 1 mg. by the Federal Trade Commir.ion, when, in fact, it was not. a. Equitv a63t 11 Failure of Federal Trade Commission to take action against certain cigarette manufatcturerx: advertising their cigarettes :IS containing less than .5 mg. tar, even though the FTC rating system did not give a rating of below .a mg. did not preclude the FTC. under the clean hands doctrine, from taking action against manufacturer which was alle-;edly misleading consumers into i,eliev inX that its cigarettes contained I mg. tar. 3~. Trade Regulation 4-801 Evidence demonstrated that cigarette was improperly rated at 1 mg. of tar by FTC method, because that method could not properly measure the particular ciga- rette, and thus that any claim that the cigarette was a I mg. cigarette was decep• tive.. a. Trade Regulation 4='i6-1 Cigarette manufacturer's claim that its cigarette was "99% tar free" was not de- ceptive so long as it was unaccompanied by any claim that it contained only 1 mg. tar. John H. Carley, Jerold D. Cummins, Ju- dith P'. Wilkenfefd, Joel Winston, Melvin Orlans, F.T.C., Washington, D.C., for plain- tiff..
Page 16: apt20e00
982 .i;to FEDERAL SCPPl.E31F:`T Martin London. Martin Flumenbaum. Elizabeth Kolton, New York City and Washington, D.C., for defendant. MEMORANDUM GESELL. District Judge. This is an enforcement proceeding brought by the Federal Traoe Commission ("FTC") pursuant to section 13(b) of the Federal Trade Commission Act. 15 U.S.C. § 53(b), to enjoin Brown & Williamson To- bacco Corporation ("B & W") from decep- tively advertising the tar content of the Barclay king-size cigarette which B & W advertises as "1 mg. tar" and "99';~ tar free."' The FTC charges that Barclay ad- vertising violates Section 5(a) of the FTC Act, which prohibits unfair methods of competition and unfair or deceptive acts or practices in commerce. 1S U.S.C. 0.fa(a).= After receiving numerous Kffidavryts, hear- ing the testimony of six vitnesses, and considering the briefs and arguments of counsel, the case is now before the Court for final judgment on the merits.3 The Court's findings of fact and conclusions of law follow. - 1. The prescnt suit chalicngcs the "1 mb. tar' and "99% tar frec" claims as used in all Barclay advcrtising. Evidence at trial' focuscd on Bar- clay magazine advcrtiscmcm,. Gos•.E.c. 26 and Atts. 83-86 to Gov.Ex. 3. and advcrtising on the Barclay cigarette package. DcI.Ex. 40L In many instanccs, such as herc. the Court refers the reader to where in the record cvi- dcncc relating to a particular aspect of the case may be found. No attempt is made to cite cvcry portion of the record upon which the Court relics to support the conclusions reached. 2. The panics do not dispute the proper stan, dards to be applied under § 5 of the Act. An advertisement may be dcccpti%r within the meaning of § 5 if it has "a tendency and capaci- ty to convey misleading impressions to consum- en cven though other nonmislcading intcrprcta- tions may also be possible." Chrysler Corp. v. fM 561 F2d 357, 363 (D.C.Cir.1977). The Impression created by the advcrtising, not its literal truth or falsity, is the dcsidcrautm' .tnrerican Home Prodsrcrs Corp. it. FTC. 695 F.2d 681, 687 (3d Cir.1982). 3. A hearing was originally scheduled on the FTCs motion for a preliminary injunction. to be resolved on affidavits and testimony from two expert witncsscs for each party. As the hearing The FTC periodically publishes reports which rate the amount of tar and nicotine of each cigarette sold in the United States.' These ifficial figures, reported in milli- grams, are determined by the FTC using a smoking machine which measures the amount of tar and nicotine the cigarette delivers. The FTC smoking machine does not and is not intended to duplicate actual smoking behavior. Rather, it smokes each cigarette in an identical way, using a stan- dard set of "puff parameters." = Since no smoker can or would smoke exactly like the machine.' this test method does not meas- ure how much tar and nicotine a smoker would actually take into his mouth were he to smoke a given cigarette. It does pur- port, however, to tell a smoker the relative amounts of tar and nicotine he would re- ceive in his mouth if he smoked two ciga- rettes in the same manner. Thus, if a -moker smoked a "10 mg. tar" cigarette in the identical manner as a"a mg. tar" ciga- rette, he would get approximately twice as much tar in his mouth from the former as he would from the latter. For over ten years cigarette companies have publicized these official FTC ratings probressrd each party stated its willingness to proceed to final judgment on the record. Tr. 113. The Court asked to hear tcstimony from consumer research experts from cach side and the case was then submitted on the pretrial briefs after full argument. The Commission presented oral tcstimony from Drs. Fred Bock. Michael Guerin. and Fdward Popper. B & W presented oral testimony from Drs. Gio Gori and Jacques Van Rossum and Mr. Alfred Vogel. 4. The latest FTC Rcport can be found at 48 Frd:Rcg. 13.268 (March 30. 1983). as amended by Notice of April 13. 1983. 48 Fcd.Rcg. 15.953, dari/ied 48 Fcd.Rcg. 22.992 (May 23„ I983). See also Gov.Ex. 18. S. The mcthodology of thc FTC testing procedure is described in Goc.Ex. 5(aff. of Harold Pills- bury) at T°, 2-S. The FTC machine is calibrated to take "puffs" of a certain duration aad vol- umc, and to smoke the cigarette to a certain "butt longth." 6. B & W has made much of the fact that no individual smokes in the same standardized manner as the machine. its own expert conced- ed. however, that such standardiration is ncccs- sarv in order to obtain valid testing results. Tr. 613-614 (testimony of Dr. Van Rossum).
Page 17: apt20e00
F.T•('. v. tiftO11'\ & W1L1.lAJltit)ri TOR:ICCO CORP. Ctteas SSII F.Supp.9lt (t9Za3) in advertising and on some cigarette part:- ages pursuant to a voluntary agreement with the Commission.' Many cigarette smokers note and rely on these FTC rat- ings in making their decision to purchase a particular brand. Cigarettes with low tar and nicotine ratinls are generally con- sidered b}y smokers to be relatively less risky to health and cigarette companies em- phasize low ratinAs to promote certain brands.` B & W undertook a major promo- tional campaign when it introduced its new Barclay cigarette in 1981. emphasizing its then official FTC rating of I mg. of tar and claiming that Barclay was "5):r • tar free." The cigarette tt•as widely accepted by con- sumers.} Jlost "losr tar" cil;arette-, obtain their low ratings in part f.• diluting the smoke which the smoker takes in through the tobacco rod with outside air." Typically this is accomplished. by cent.~ or perfora- tions near the point where th• tobacco rod meets the cigarette filter, ur that the .moke drawn through the rod and the out- side air drawn through the .'entc or perfo- rations are mixed together as they pass through the filter before entering the smoker's mouth. The Barclay cigarette, however, uses a different dilution process based on a unique design. The outside air 7. The voluntary agreement was cntcrcd' into b}- thc major United States tobacco :t maanics aftcr the FTC initiated a Trade Regulation Rule Pro- eceding in 1970 and this proceeding was cvcntu• ally dropped as a result or the agreement. The history uf the FTC testing prugram and the adoption of the agreement arc detailed in Gov.Ex. 3(aff. of Wallace Snyder) at rR 3-11. and the agrccmcnl is rcproduccd' as Att. 3 to Gov.Ex. 3. Neither party to the present pro- cccding contends that the voluntary agreement has legal effect. 8. B & kti attempted at trial to dinpute rcliance on ratings by consumers and cigarette manufac- turcn. In a rcl'atcd proceeding. however. B & W cxplicitlti conceded this noin-. "The public has come to accept and rely upon those num- bcrs, and the cigarcttc companics have molded massive advertising and marketing strategies around those numbers. They havc become a vital part of the industry' Complaint ", 114. Brown & %rilliarnswi Tobactco Corp. %: fTC. hfo. C 82-0373-L(B) (tW:D,Kv.1982`. Att. 75 to t;,ov.Ex. 3. See also :1tt. 76 to Gov.Es. 3 (AfL of 983 is channeled through the filter tip separate- ly from the smoke by means of four sepa- rate, sealed lonxitudinal' vents in the filter itself. This causes the outside air to be d!rawn directly into the smoker's mouth before it mingles with the smoke drawn through the cigarette. Because of this de- sign, the exit holes for the outside air vents are placed in close proximity to the smoker's lips." ln the December, 1981, FTC Report the Barclay cigarette received an official FTC rating of I mg. tar based on the standard test using the FTC smoking rnachine.'= Follow inK Barclay's successful introduction into the market, however, R.J. Reynolds and Philip Morris. the industry's two larg- est companies, complained that in actual smoking the Barclay vents were being "crushed"' by lip pressure and/or blocked by lip "drapage" so that dilution with out- .ide air was being reduced and the tar delivered by the Barclay cigarette to the mouth of the smoker was thus substantial- ly greater than the amount the FTC ma- chine tests refdected. Thereafter the FTC commenced un extensive ineestiKation. so- liciting and examining studies prepared by B & W and by its competitors, and sending these studies to several recognized outside experts for review.t' Seott Wallace. Senior Vice Presidcnt Marketing v( B & W) at L 6: Att. 46 to Gov.Ex. 3(B & 1W submission to FTC datcd' Feb. 16. 1982)' at 20. 9. Dcf.Er. 15 (aff. of Ernest Papplcs) at 1;F 22, 25. 10. A filtcr cigarette consists of a tobacco "rod" which contains the tobacco itself, and a filter through which the smoke from thc tobacco rod must pass before entering the smoker's mouth. 11. Diagrams showing the construction of a con- ccntional filter and of the Barclay filtcr arc found in Att. ll to Gov.Ex. 3. 12. Att. 40 to Gov.Ex. 3. 13. Th,: FTC invcstigation of Barclay is summa- rized in Goe.Er. 3. (bff. of Mr. Snyder) at ''^,13-35. The selection of Drs. Bock„ Gucrin. and' Kozlowski as outsidctonsultants is describ- cd in Gov.Ea. 11 (aff. of Mathccv Myers). B& «"did not object to the selection of Dr. Bock or Dr. Gucrin. but did object to Dr. Kor.lo.cski. /d. at c°.i-6.
Page 18: apt20e00
984 5S(1 l•'1:1)E RAl. St'Ppf.EMF•\T On June 25, 1982, the FTC determined that Barclay was not accurately assessed by the FTC machine method and directed that a Federal Regis.'er notice be issued amending the December, 1981, FTC Report to reflect this conclusion. The same d'ay B & W filed suit in federal district court in Kentucky, and obtained an injuncticn which prevented the FTC from publishing its no- tice in the Federal Register or from initiat- ing any enforcement action. On April 1. 1983, the injunction was dissolved by the United States Court of Appeals for the Sixth Circuit pending appeal, and on April 13, 1983, the FTC announced in the Feder- al Register that its testing methods were inadequate to test the Barclay eiKarette with accuracy, that based on the evidence before it the Commission estimated Barclay was more properh rated from 3 to 7 mgs. of tar rather than 1 mg. as originally re- ported, and that until new testing methods were developed the FTC would rw longer report an official' rating for th- Barclay cigarette." On June 24, 1983, the Sixth Circuit held that the Commission did not act arbitraritt" or capriciously in revoking Barclay's rating.'" In response to the FTC's action, B & W has deleted from its advertising any direct reference to an FTC rating and its adver- tisements now state that Barclay is I mP. tar "by a recognized method used by B & W and supported by independent laborato- ries." t" While conceding the literal truth of this advertising claim, th@ FTC asserts that the Barclay claim is still deceptive because it falsely suggests to consumers that Barclay is officially rated 1 mg. by the FTC and because it leads consumers to believe, incorrectly, that Barclay's tar deliv- 14. 46 Fed.Reg. 15.953 (April 13. 1953). 15. Browrt & Williamson Tobbaco Corp. u FlC 710 F.2d 1165. rehearing and rehearing en banc denied,, 717 F.2d 963 (6th Cir.1983). atG 81 lo Gov.Ex. 3. The FTC is now in the initial stages of an inquiry•y looking toward impro.vment of its testing and rating procedures and has sought comments from the industry and from the pub- lic. Both panics rccognirc that years may pass before a new FTC rating system is in effect. 16. See note 1. supra. ery is comparable to that of other ciga- rettes rated 1 mg. by the FTC. Moreover. while also concedirg the literal truth of Barclay's "99`.4 tar free" slogan, the FTC asserts that this claim is also misleading because it falsely suggests that Barclay is "virtuaily free of tar." In opposing the injunction B & W has vigorously presented' a number of defenses. Despite the longstanding acceptance of the FTC rating system ky B & W and other major U.S. cigarette companies. B & W contends that recent scientific evidence demonstrates that the FTC st stem is soo flawed that it is itself deceptive. Accord- ingly. B&«" urges that the FTC rannot ask for e% itable relief even if its factual assertions are true. As a second major defense. B & W argues that the FTC has failed to carry its burden of showing that consumers perceive Barclay ads in the manner the FTC contends. Finalh, B 8«'' argues that even if consumers do perceive B&«' to be making the claim that Barclay delivers the same amount of tar as other cigarettes rated 1 mg., such a claim cannot be deceptire because it is in fact true. A. The FTC Rating System. The FTC rating system has enjoyed a6 most universal acceptance for over a dec- ade. Recently., however, the system has been subjected to criticism, largely but not entirely in connection with the Barclay con- troversy. Seeking to defeat the present suit by demonstrating that the entire FTC rating system is itself misleading, B&« has presented to the Court several "coti- nine" studies. Such studies measure by indirect means the amount of nicotine a smoker actually inqests."- The principal 17. Cotininc, a metabolitc of nieotine, has a IonL- cr half-life in, the bloodstream than nicotine and thus can be more easily measured. Existing scientific data supports the conclusion that coti- nine is a reliable 'markct' for nicolipF. by determining the lct-cl of cot(ninc, therefore. it is possible to determine the level of nicotine with an acceptable degree of accurac.. See Dcf.Ex. 35 (Aff. or Dr. Renato Galcarzi). There appears to be no dispute on this point. See Tr. 279-280 (testimony of Dr. Gucrin).
Page 19: apt20e00
F.T.C. v. ItKO`•t'` & %1tG1.1AN15U\ TO8.1C('O ('QRP. Clteu 380 F.Supp. "1 (1993) .studies upon: wnich B & W' relies are an "t;00-person" study conducted by Dr. Gio (;ori, a B & W consultant, and a study by Dr. Neal Benowitz.1" The Gori and Benowitz studies undoubt- edly suggest that small differences in FTC ratings may not be as significant as many would believe. The Gori study found that between cigarettes whose FTC nicotine rat inKs differed by a factor of -even, differ- ences in smokers' blood cotininr levels av- eraged only 30-10';." The principal expla- nation offered for this effect is that many smokers "compen,ate"-they change their smoking habits to receive more tar and nicotine from low-rated cigarettes and less tar and nicotine from high-ratt-,l cigarettes than the FTC ratings would auKKest.=" This evidence, however, is not sufficient to I'ead the Court to hold that the FTC system is meaningless or deceptive. First, the Gori study does in fact validate the FTC system at least to a certa'n extert by demonstrating that a positive relationship exists between nominal FTC ratings and blood levels of nicotine.=' Even if the lev- els of tar and nicotine differ bs only 30- -10';. this difference has significant health implications. as Dr. Gori acknowledged in his testimony.22 Exactly how small a dif- ference is of significance is impossible to determine given the current state of scien- tific knowledge,2' and it is possible that even very small differences might account for a significant number of early deaths across the nation.=' Furthermore. because 1d. Gori and Lynch. Smoker lntake From Ciga rettes oJ Different Analytical Yields (draft dated July 27. 1983). Att. E to Dcf.Ex. 13: Bcnowitz. et aL, Smokers of Low-Yield Cigareues Do Not Con- sume Less Nicotirre, 309 N.EngJ..S1cd. 139 (1983). Att. F to Def.Ex. 13. 19. Def.Es. 13 (aff. of Dr. t,ori) at " 39-40. 20. Dc(.Ex. 22 (af(. of Dr. Paul Dacnens) at S 11: Dcf.Ex. 27 (afL of Dr. Paul Dc Scnepper) at !t 8: Def.Ex. 13 (aff. of Dr. Gori) at 110 21. See Gov.Ex. 1(aff. or Dr. Bock) at 0141, 13: Tr. 210 (testimony of Dr. Bock). Thc Benowitz study concluded that 'smokcts or low-nicotine cigarettes do not consume less nicotine." Att. F to Dcf.Ex. 13 at 139. The Bcnowitz study, how- ever. appears less reliable than thr study per- formed by Dr. Gori, and the Court has Ihcrcforc 985 the relatively small difference in nicotine levels between the high and low FTC-rated cigarettes is due in part to the manner in which they are smoked-the •'compensa- tion" effect-a smoker who avoids engag- ing in compensatory behavior would still receive tar and nicotine into his mouth in rough proportion. to the FTC numbers. Even accepting Dr. Gori's results, his study thus fails to discredit the FTC system. A second reason exists for finding that B & W has failed to demonstrate that the FTC system is not of value to consumers. The FTC system attempts onlyy to deter- mine how much relative tar and nicotine a smoker would get in~ his mouth were he to smoke two cigarettes in the same manner. B & W has utterly failed to show that ti.r system does not do this. Nor has it shown that a better method for determining the relative health hazards of' the many differ- ent varieties of cigarettes on the market ix currently feasible. Dr. Gori, while arguing for the use of cotinine studies rather than the current rating system, estimated it would take a study using 40,000 people to test properly the brands of cigarettes no..• rated byy the FTC.2i Moreover, even such a massive and expensive study would leave unanswered questions. The cotinine meth- od measures only the amount of nicotine a smoker ingests. The major health danger to smokers comes not from the ingestion of nicotine, however, but from the ingestion and retention of tar in the body.='t Because accorded the Bcnow•irrz study relatively little weight. See Gov.Ex. L(zff. or Dr. Bock) at'. 31 22. Tr. 557 (tcuimony of Dr. Gori). 23. Tr. 217 (testimony of Dr. Bock). 24. Dr. Bock testified that even accepting Dr. Gon s conclusion that bctwcen high and low tar cigarettes a difference of only 30-40% in actual nicotine intake exists, such, a difference could stili account for 100.000 early deaths a year. Tr. '_i 3-213. 25. Tr. 478-179 (testimony or Dr. Gori). 26. Tar consists of a myriad of microscopic par- ticlcs that are drawn into the smoker's mouth. along with nicotine. When smoke is inhaled
Page 20: apt20e00
986 .iKU FEDF.RAL SUPI ,.1:MErT actual tar ingestion cannot be directly measured'by any known process,r in order to derive tar data from the cotinine experi- ments it is necessary to calculate a "tar/nicotine" ratio for each brand based on independent experiments. How this ra- tio can properly be determined is the sub- ject of scientific dispute?" and the issue has yet to be resolved. (1)i Although serious questions have been raised, it is thus too early to sound the death knell for the current FTC rating system. While the FTC system is in need of improvement, un the evidence before it the Court concluues that the system does provide legitimate cor..parative information to consumers who wish to reduce the health hazards the Surgeon General has some of these tar panicles arc retained in the smoker's lungs and body. Cancer. the health ha7ard smokers most fcar, is auribut.blc to this ingestion of tar. The amount of tar a given smoker ingests and retains depends on a wide variety of factors peculiar to the individual. including the manner and frcqurncy of smoking and the individual smokcrs mctabolic proccss. 27. Tr. 617-618 (tcstimonr of Dr. Van Rossum); Def.Ex. 13 (aff. of Dr. Gori) at 'r 45: 28. See Tr. 64, 86 (testimony of Dr. Bock); Tr. 375-377 (testimony of Dr. Gucrin); Tr. 566-568 (testimony of Dr. Gori). 29. B& W has brought to the Coun's attention several recent ads for different cigarettes which carry both FTC numbers and lower numbers given by the manufacturer. as well as cigarette packages with the lower non-FTC ratings. These citarettes, however. wcrc t ated "kss than .5 mg.; the lowest rating the FTC gisrs, and the manufacturers lower rating numbers arc thus not inconsistent with the FTC rating. The FTC has represented to the Court that it has not brought suit against all such claims because, unlike the Barclay ads, these ads give numbers which the FTC believes may be correct and because relatively few consumers purchase such brands and hence any harm to the public inter- est is not great. Without condoning the FTCs ezercise of its prosecutorial discretion in this respect, the Court concludes that the failure to pursue a possible action to halt such: advertising is not of such significance as to justifa• barring equitable relief in this suit under the "clean hands"doctrine, as B & W would have the Court do. Furthermore„uhcre is no reason to belicve that these isolated' incidents have altcrcd the concluded are inherent in cigarette smok- ing. B. Barclay's "I mg. Tar" Claim. (2,31 Although the 1970 voluntary agreement to publish FTC ratings has no legal effect, as a result of industry adher- ence to the agreement consumers have for years been exposed to only FTC ratings x' and have come to rely upon these ratings on the understanding that they all derive from this one official source.'° B & W's change in the wording of its advertising legend, deleting specific reference to the FTC testing method, is not sufficiE..t tu put consumers on notice that the rating give^ is not an official FTC rating." Furthe-- more, the Barclay cigarette package maues no mention of any rating system at all, but public's general understanding that tar and mil- ligram ratings in cigarette advertisements are official FTC ratings. 30. As B & W points out. and as the FTC con- eedes. Goc:Ex. 10 (afL of Dr. Popper) • 25, there are no studies which consider ho.w consumers pcrcci%r the FTC system. Although such con- sumcr surn•ev ovidcncc would be uscrul. it is not neeessarT in order to establish a violation of §, 5 of the Act. See American Home Products Corp., supra. 695 F.2d at 687 n. 10 (3d Cir.t982), and cases cited therein. The Court finds that the evidence in the present record amply supports the conclusion that consumers arc aware of and rely on FTC ratings. First. B& W has conceded this faa in the related proceedings in fcderal court in Kenttxky. See Note 8, supra. Second: the fae that cigarette companies spend millions of dollars advertising low FTC ratings allows the inference that marketing experience demon- stratcs reliance ky consumers on such informa- tion in making purchasing dccisions. Finallry the Court heard expert testimony supporting this conclusion. Tr. 849 (testimony of Dr. Pop• per)- 31. Dr. Popper testified that after 12 years of exposurc to F'fC ratings consumers have bo come "habituated` to the tar and nicotine 'leg- cnds' in cigarette ad.ertiscments, and hence will only pay attention to those portions of the legend which thcy expect to change from ad to ad--the numerical tar and nicotine ratings themsclccs. A consumer reading the Barclay ad would be likelv either not to read the wording of the Icgend, or not rcal'i7c that the tcrminolo- gy cmploycd' signified a d'cpanurc from the long-utilizcd FTC Rcport numerical ratings. Tr. 830-833.
Page 21: apt20e00
M.T.C. t. BROWN & 1ti'II.LIa%tSUN TOFi:1CCO CORP. 987 Cite as 590 F.supp.9et 11983) only states "1 mg. tar." Const:mers will naturally assume, incorrectly, that this rep- resents an official ratinR " Barclay adver- tising is therefore deceptive in that it leads consumers to believe that Barclay is rated 1 mg. by the FTC. This situation might be cured by requir- ing Barclay to carry a legend which specif- ically states that Barclay does not have an FTC rating. The FTC urges. however, that the "1 mg." claim must be eliminated alto- gether. Since to a consumer a milliQram tar rating has no significance except inn relation to other such ratings. a rating number 3tanding alonr or oased on a dif- ferent rating s^-tle gives no usrful inforrna- tion about rela:ive health risk." It can only be understood in reference to ratings found in other cigarette advertisements. which are FTC ratings. Thus even if con- sumers were informed that Rarclay's ra• ing is not government appro .1 and t:..... indeed, the government haa withdrawn Barclay's rating, they would still take Bar- clay's "I mg." designation to be a claim that Barclay deliver. to the smoker the same amount of tar as those cigarettes rated 1 mg. by the F'I'C. The accuracy of such a claim is the principal dispute under- lying the entire Barclay controversy. 32. Tr. 924-926 (tcstimony of Mr. Vogel). 33. Gov.Ex. 10 (aff. or Dr. Poppcr) at 124. 34. The Philip Morris study was conducted by the United States Testing Company. Inc.. an independent testing laboratory. Au. 44 to Gov.Ex. 3. In the study smokcr- "puffcd" on several brands of cigarettcs, including their reb- ul'ar brand. For each brand the smokcr took puffs first with the cigarette protected by a tip which prevented the smoker from blocking any part of the cigarette filtcr, and thcn without thr protective tip. A testing apparatus attaehcd' tc the cigarette then measured how much the air ith drawn through the tobacco rod was dilutcd' .h air drawn through the venting system. Whi'c the degree of dilution caricd' frum brand to brand, for each brand c.xccpt Barclay it rc- mained essentially unchanecd with or without the protective tip. For Barclay. ho..-cacr, rc- moval of the protective tip resulted in a reduc- tion in ventilation of approximately onc•third. See Table Ii in Pan Ii of CS. Testing Company Repon.id The evidence presented by the FTC dent- onstrates that Barclay delivers to the smoker's mouth significantly more tar than other cigarettes with a 1 mg. FTC rating. The so-called "ventilation" studies sub- mitted to the FTC by RJ. Reynold's and Philip Morris and reviewed by the Commis- sion's independent experts show that, un- like with other cigarettes, dilution of Bar- clay smoke with outside air through the cigarette's ventilation mechanism is greatly reduced in human smoking as compared to machine stnoking." The principal theory relied upon to explain this phenomenon is that smokers unconsciously and ineritably "drape" their lip tissue over the exit open- ings in the Barclay longitudinal vents, thus cutting off or reducing the flow of outside air into the mouth.'s As a result, iht "puff' which the smoker draws into his mouth contains a higher percentage of air drawn through the tar-containing tobacco -od. thLa increasing the net amount of tar in the puff of smoke which enters the smoker's mouth. Other cigarettes, with their more conventional construction, are not susceptible to this phenomenon. B&«.' attacked these studies on the ground that they are merely laboratory experiments and do not provide useful in- formation about actual smoking behavior. Scientific experiments. of course, are often RJ. R#.-trolds conducted a similar test com- paring dilution of the Barclay and Now ciga- rettes. While the Now cigarette had an idcnti'- cal' dilution ratio when smoked with and with- out a protective mouthpicce, the Barclay ciga• rcttc's ventilation dropped almost 50% when the protcctiNC r^•ccc was abscnt. Att. ;i to Gov:Ex. 3. 35. hnthc carl?• stabcs of thc Barclavcontrovers.• both lip drapabr and -crushing" of the vents by lip pressure were suggested as possible causes of the Barclay vcntilatiomrcd-iction phenomenon. B & W has presented evidence that lip pressure is not the culprit. DeLEx. 30 (aff. of Dr. Roger Kamm), and the FTC now rclics onthe lip drapaSc theory. The Court makes no attempt :icrc to ascertain the cause of the Barclay phc- nomcnon with absolute cenainty, but concludes that the existence of the ccntilation•rcduction phenomenon has been demonstrated, and it is apparently attributable to Barclay's unique t•cnt- ing system. Sec Tr. 172 (testimony of Dr. Bock).
Page 22: apt20e00
988 W FI:DEEtaI, SCPP/.EME:NT unable to duplicate real world conditions precisely. The Court accepts the testimony of the Commission's experLs that the venti- lation studies are usef ul and scientifically valid?' No evidence was introduced which demonstrated that the methodology of the experiments significantly biased the results against Barclay n B & W had most of the test data before it, including videotapes of some of the tests being conducted. There was no evidence that B & W's competitors conducted or sponsored other :uch tests which have not been rev ealed.31' B & W presented no ventilation studies of its own. The Reynolds and Philip Mor- ris studi«s were thus the only sil{nificant evidence presented to the Court going di- rectly to the question of how much tar Barclav delivers to the human mouth-the question which the FTC method attempts to answer." The Court concludes that the ventilation studies prov ide strong evidence that Barclay is improperly rat- I mg. by the FTr testing machine. 36. Gov:Ex. l(aff. of Dr. Buck) at « 19-27; Tr. 222-225 (ICstimonv of Dr. Bock): G».Ex. :(. ff. of Dr. Gucrin) at25-26. 37. B & W argued that the studies Nrrr bia.ed because the apparatus uscd' blocked tix pcrfo- rated intake holcs for all ciuarcttcs. a step ncccs- sarv in order to determine the ventilation rcad- ings Thus onlr Barclay could' be `n.mpra mised" through a reduction in ventilation. Ho.vever, even assuming that some smokers would block the air intake vents consciously or unconsciously, this d'ocs not negate the Gact that Barclay, and Barclvv a(one, suffen from the additional problem of blockage of outside air at the filter tip, and that this phenomenon results in a reduction ot ventilation for Rarc(ar as compared to other ciQarcttcs: See Gov.Ex. I (aff. of Dr. Bock) at 123: Gov.Ec. 2 (aff. of Dr. Guerin) at IE 27. 3g. The Court takes notice oC the fact that Reyn- olds and Philip Morris. the initial instigators of th: Batclay controvcrsy, have resistnd disccnrn- in the present case. See Dcf.r-%. 25 (aff. of Martin Klotz). They did. howrvcr. agree to turn over their research materials comr'1'ed specif. ically in connection with the Barclay invcstiga- tion. Id at a 6. There is nothing in the trcord' to establish that these companies are harboring additional related scientific documcnts. As to the scientific data provided by R%nmolds and Philip Morris, the Court has thrrcfipre felt able to accord such rvidcnec significant weight. The B & W points to cotinine studies by Dr. Gori, however, as proof that Barclay deliv- ers into the smoker's body no more tar than other I mg. rated cigarettes. The principal Gori study addressing the issue of Barclay's proper rating was the "288-per- son" study which tested Barclay against other cigarettes rated I mg. by the FTC.10 This study indicated that smokers who smoked Barclay received' approximately 1'/•- to 2 times as much nicotine into their sys- tems as smokers of the other cigarettes tested." Dr. Gori testified that if one ap- plied tar/nicotine ratios obtained for each different cigarette from a separate study . to the nicotine figures obtained in his study, one could conclude that Barclay should also be rated approximately I rnK., as each of the cigarettes tested gave ap- proximately the same amount of tar.'= Two fact,ors prevent the Court from giv- ing much weight to this conclusion. The first is the ongoing controversy over the application of tar/nicotine ratios." The second factor, also related to the uncert,ain- Coun' considers research submitted to the FTC by Reynolds and Philip Morris concerning con- sumcr perceptions of Barclay to be entitled to .rry linlc ..rieht, however. bccausc the Courtt has reason to brlicve that those companies re- leascd only selected portions of such research. 39. The Court was presented with additional cri- dcnec of relatively minor value. These included infrared studies. "butt" studics. taste tests. fiber- optic tests, and others. Much of this evidence was fcwndcd on novel scientific techniques and is subject to significant criticism. SeG e.Y... Gov.Ex. 2(afL of Dr. Gucrin) at 19 29-35. Nei- ther party placed great emphasis on this evi- dence at tltc hearing. The Court find's this cvi- dencc tu be gcncrails inconclusive and of little value in address: ig the issue of Barcla,v s proper rating. 40. Cori and Lynch. Arrali•tical Nieotine Yields As Predictors of S+noker hnake From 1 tnr lVominal FTC Tar Ciearettes (19g2), Att. C to Def.E-,c. 13. Several similar preliminary studies were also condu~-ted. See Dcf.Ex. 13 (atf. of Dr. Goril at 0,'r 20-26. - . 41. Dcf.Ex. 13 (afL of Dr. Cori) at 129. 42. Tr. 368-570 (testimony of Dr. Gori). 43. .Sre Note 28. sapra.
Page 23: apt20e00
F.T.C. v. BROWN & WILLIAMSON TOBACCO CORP. 989 Citc as S!Q F.Supp. 961 (1983) tyy over tar/nicotine ratios, is the possibility of an alternative explanation for the data Dr. Gori obtained. Barclay was tested only against cigarettes rated 1 mg. tar by the FTC and recorded' a higher nicotine content than each of the other cigarettes tested, a result which B & W argues is explained by Barclay's higher ratio of nicotine to tar. It is possible, however, that this difference in nicotine delivery resulted not simply from a difference in tar/nicotine ratios but also, in part, because Barclay does in fact have a higher tar and nicotine content than the other cigarettes tested." A smaller coti- nine study commissioned by Reynolds, in which Barclay: was compared with a 5 mg. cigarette as K ell as with a 1 mg. cigarette, suggests that this latter explanation may be correct." :f so. the Gori M-person data would not be inconsistent with the ventilation studies presented by the Com- mission. [;] The Court conc...des that the hre- ponderance of the evidence demonstrates that Barclay is in fact improperly rated 1 mg. by the FTC method and that any claim, that Barclay is a 1 mg. cigarette is decep• tive."' The ventilation studies presented by the FTC are the only credible evidence which addressed the question of how much tar a smoker receives in his mouth, the 44. See Gov.Ex. 1(aff, of Dr. Bock) +t R 36-37. 45. A.D. Little. Inc.. Report on Pfasnna Cotinine Levels in Smokers o/ Ulrra-Low and Low Yield Cigarettes (1982) at 41-43. Au. 48 to Gov.Ex. 3. 46. B & W has suggested that, regardless of thc validity of the evidcnce pr:scnted by the FCC, a recent modification of the Barclay design now enables the cigarette to achieve a proper rating of I mg. tar. The Court finds, howcver, that this design change does not prevent the filtcr "eompromisc' problem. See Gov.Ex. 2(aff. of Dr. Guerin) at 5° .t0-d5; Gov.Ex. 6(aff. of Mr. Pillsbury). 47. A cigarette with a rating of approximately 5 mg. tar or less wouid' t•"99% tar frcc" by wxight. Dcf.Ex. 16 (off. of M. Lancc Reynolds) at 5% 51-54. 48. Go..Ex. 10 (aff. of Dr. Popper) at " 14-21. 49. In evaluating the '99% tar frcr" claim, the Court gives primary considcration to thc opin. ions of the consumer experts prescntcd by each issue the FTC testing method attempts to determine. These studies provide strong evident. that Barclay is improperly rated as 1 tng. because its vent system is "com- promised" under actual smoking condi- tions, unlike the vent systems of other l'ow- tar cigarettes. The evidence presented by B & W failed to refute the ventilation stud- ies and did not provide significant contrary evidence. C. Barclay's "99r- Tar Free" Claim. Unlike the dispute concerning the 1 mg. claim, no scientific controversy exists over B & W's claim that Barclay is "99:, tar free." 0 The lone issue is how consumers perceive that assertion. The FTC argues that a substantial number of consumers interpret 9913 tar free to mean "virtually free of tar," a claim it considers false."B & W contends that the consumer surve}-s upon which the FTC relies do not support their conteation." (S) The evidence clqarly shows that con- sumers do not perceive the "99'.4 tar free" claim as an assertion that Barclay has a particular milligram rating, even when ac- companied by a specific milligram rating as in the current advertisement. Indeed, con- sumers have difficulty even relating the claim to any milligram number.3' Further- side and to two consumer surv¢ys, one prepared for the FTC and one prepared for B & W. Audits & Surveys, f7ti' Barclay Ad Survey (June 1983). Au. 6 to Gov.Ex. 10; Market Probe Intcr- national. Inc.. Consumer Understanding of Two Print A'dt for Barclay Cigarettes (Januarr 12. 1981). Att. B to f1cLEx. 26. Little weight was given to consumer surveys commissioned by R.J. Reynolds and Philip Morris. See footnotc 38. supra. Soi In the Audits k Surveys study prepared for the FTC. of i03 intcnie+vecs askcd "If you saw the phrase 99% tar free in a cigarette ad. what would that mean to you?", not a single respon- dent answered I mg. tar. Even aftcr being asked to express their answer in terms of milii- Erams, only six respondents out of 203 who were not exposed to the Barclay ad with its I mg. claim answered 1 mg. tar, and only 20 out of 200 respondents who were exposed to the advertisements gave that answer. See questions 5'and 6 in Att. 6 to Gov.Ex. 10. In his testimony the FTCs expert witncss on consumer pcrcep- tions. Dr. Poppcr, acknoavlcdgcd that most pco-
Page 24: apt20e00
990 580 FEDERAL SUPPLEMENT more, there is little support for the FTC's view that consumers understand the claim to assert that Barclay is among the lowest- rated cigarettes. Even the FTC's own con- sumer survey suggests that the over- whelming majority of consumers perceive ••99'i(~- tar free" as a general low tar claim.st Other evidence before the Court reinforces this interpretation.'= The Court concludes, therefore, that the FTC has failed to show that Barclay's "99" tar free" claim, unac- companied by the "1 mg. tar" claim, is deceptive. D. Conclusion. The Court finds that P & W's current advertising claim that Sarc:ay is "1 mg. tar" is deceptive within thr meaning of 15 U.S.C. § 45(a). The Fl`C has failed to show, however, that the "99'x tar free" claim, unaccompanied by the "1 mg. tar" claim, is also deceptive. Accordingly, the FTC's prayer for relief is qranteti in part and denied in part.~ & % must be perma- nently enjoined frorn promoting its Barclay cigarettes by advertising, package layout or other means with any claim of a specific milligram lar content rating, unless such rating is approved by the FTC or derived using a test methodology approved by the FTC for measuring Barclay.`13 Counsel shall immediately confer and present an agreed form of order consistent with the foregoing on or before 0^.:ober 21, 1983. Failing agreement, separate forms of order proposed by each party shall be presented by that date. pie do not freely associate 99% tar free with a I ms. rating. Tr. 769. St. See Audits & Surveys, at 4-5. Att. 6 to Gov.Ez. 10; Dcf.!«:. 24 (aff. of Mr. Charles Sobel) at 98 13-16. S2. See Markct Probe, at 18-20, An. B to DcB.Ex. 26: Def.Ex. 24 (a[f. of Mr. Sobel) at 912: Def.Ex. 26 (aff. of Mr. Vogc!) at IF. 9. WEBB RESEARCH CORP. ROCKLAND INDL'STRiES, INC. Civ. A. No. 83-1161. United States District Court, E.D. Pennsylvania. Dec. 2. 1983. Pennsylvania corporation brought ac- tion against Maryland corporation seeking to recover for alleged breach of contract for purchase of a machine to pleat fabric. On Maryland corporation's motions to dis- miss complaint for lack of personal jurisdic- tion. improper venue, and failure to state a claim upon which relief can be granted. and, in the alternati.e, to transfer action to District of Maryland, the District Court, , Raymond J. uroderick, J., held that: (1) Maryland corporation's contacts with Penn- sylvania were sufficient to support jurisdic- tion; (2) Maryland corporation's motion to transfer breach of contract action to Dis- trict of Maryland from Pennsylvania would be denied in view of failure to make re- quired showing as to how convenience of witnesses would be served by transfer; and (3) Pennsylvania corporation's motion for leave to amend complaint to conform with rule requiring allegation that all condi- tions precedent have been performed or have occurred would be granted. Order accordingly. 1. Courts 4-i2(2.10) When personal jurisdiction is asserted' over a nonresident defendant on basis oth- 53. B & W is thus [rec to advertise Barclay as containing 3-7 mg. tar, the cstitnate which the FTC currently acccpts. B & W is under no oblisati..u to use the FTC estimatc, hovtx.rr. as thc FTC has made no showing of the need for `corrccti.r advertising.
Page 25: apt20e00
F.T.C. v. BRO«'ti & WILLIAMSON TOB:ICCO CORP. 4,tt rs778 F.ld )s ( D.C. Cia 1985) III. CONci..ccMN We find that the FCC's refusal to waive its mileage separation rule and its conse- quent dismissal of the North Texas applica- tion for the FM broadcast facilitt on chan- nel 256 were fully consistent with agency precedent. We therefore affirm the Com- mission's decision. So OrderetL FEDERAL TRADE COMMISSION v_ BROWI~1 & WILLIa\1SON TOBACCO CORPORATION, Appellant. No. 83-2129. United States Court of Appeals. District of Columbia Cir tit. Argued Oct. 2, 1984. Decided Dec. 10. 1985. Amended Dec. 18. 1985. Federal Trade Commission 4ought to enjoin cigarette manufacturer from adver- tising its cigarettes as "1 mg tar" and "99% tar free." The United States District Court for the District of Columbia. Gerhard A. Gesell, J., 580 F.Supp. 981, entered in- junction prohibiting manufacturer from ad- vertising cigarette as containing 1 mg of tar, and manufacturer appealed. The Court of Appeals, Bork, Circuit Judge, held Broadcast Assignments. Report and Order in Docket d0-90, 94 F.C.C.2d 152 (1983). on rscat- sideration, 97 F.C.C.2d 279 (1984). This rule- making created a new class of FM radio facili- ties, C-l, an intermediate rank between class B and C stitions. and amended the mileage sepa- rations to incorporate stations in the new class. However, the rulemaking did not -iodify the allotment structure embodied in the table of assignments. North Texas could have relied on these new rules to validate its mileage separa- tion from other stations only had it invoked the 35 that: I U manufacturer's advertisements were misleading within meaning of Federal Trade Commission, and (2) injunction pro- hibiting manufacturer from advertising any tar number for its product without receiving prior Federal Trade Commission approval w ss broader than reasonably nec- essary to prevent deception. Affirmed in part and remanded in part. 1. Trade Regulation e-800 Presentation of consumer survey evi- dence is not required to support finding that advertisement has tendency to deceive and violates provision of Federal Trade Commission Act (15 [:.S.C.a. § -15(a)) pro- hibiting false and deceptive advertising. Federal Trade Commission Act, § 5(a), as amended, 15 U.S.C.A. § 45(a). 2. Trade Regulation 4-801 District court's finding that consumers rely on tar ratings to make comparative assessment of health effects of cigarettes was not clearly erroneous; vast expendi- ture of advertising dollars on tar ratings strongly supported public reliance and ciga- rette manufacturer that challenged finding had made statement in related proceedings in federal cuurt that customers were aware of and relied on Federal Trade Commission tar ratings. 3. Trade Regulation e-801 District court's finding that disclaim- ers explaining difference between tar rat- ing for one cigarette and'that of another would be ineffective was not clearly errone- ous; there was expert testimony that after 12 years of exposure to Federal Trade Commission ratings consumers had become ruiemaking process to reclassify channel 256 as C-1 rather than C. Further, because of the abolition of the "15-mile" rule in 1983. prior to the effective date of the Report and Order in Docket 80-90, a rulemaking procedure would also have been required' to reassign the channel from Denton to Lake Dallas. Finally, the FCC gave specific notice in its Report and Ord'er tLat.. before the effective date of the new FM rules. any applications which did not conform to the old rules would be returned. 94 F.C.C.2d at 181-82.
Page 26: apt20e00
36 778 FEDERAL REPORTER, 2d .,8RIES habituated to tar and nicotine leg;nds in cigarette advertisements, and would pay attention only to those portions of legend they expected to change from ad to ad, numerical' tar and' nicotine ratings them- selves. 4. Trade Regulation 4-764 Cigarette manufacturer's advertising violated provision of Federal Trade Com- mission Act (15 U!S:C.A. § 43(a)J prohibit- ing false or misleading advertising, where consumers relied on tar ratings to make comparative assessments of health effects of cigarettes, manufacturer of cigarettes delivered disproportionately more tar than other similarly rated cigarettes, and dis- claimers explaining difference would prove ineffective. Federal Trade Commission Act, § 5(a), as amended, 15 U.S.C.A. § 45(a). 5. Constitutional Law 4-90.2 Restrictions imposed on deceptive com- mercial speech can be no broader than rea- sonably necessary to prever : deception and may not place absolute prohibition on po- tentially misleading information if informa- tion also may be presented in way that is not deceptive. U.S.C.A. ConstAmend. 1. 6. Constitutional Law ea90.2 Injunction prohibiting cigarette manu- facturer from making any specific milli- gram tar rating claim, unless ~'ed-aL Trade Commission approved it or manufac- turer derived it from feder..l trade commis- sioner approved methodology was imper- missibly broad prior restraint on manufac- turer's First Amendment rights, where in- junction would prohibit manufacturer from devising new testing method and, in adver tising its results for its cigarette, providing information about competing brands promi- nently enough and in sufficient quantity to allow consumers to make informed deci- sions without confusing figures from dis- parate testing systems. U.S,C.A. Const. Amend. 1. 7. Trade Regulation 4-847 Injunction prohibiting cigarette manu- facturer from deceptively advertising tar content of its cigarettes did not prevent manufacturer from airing publicly its dis- pute with Federal Trade Commission and its methodology for measuring tar, where manufactur. - was free to voice its dis- agreement with Commission in every medi- um except advertisement of specific milli- gram tar ratings which offended Federal Trade Commission Act's [15 U.S.C.A. § 45(a)] proscription against deceptive ad- vertising. Federal' Ttade Commission Act, § 5(a), as amended, 15 U:S.C.A. §45(a),. Appeal from the United States District Court for the District of Columbia (Civil Action lti o. 83-01940). Martin London, New York City, for ap- pellant. Jerold D. Cummins, Deputy Asst. Gen. Counsel, F.T.C:, with, whom Howard E. Shapiro, Deputy Gen. Counsel, F.T.C., Washington, D.C., was on brief, for appel- 1'ee. Before EDWARDS, BORK and SCALIA,. Circuit Judges. Opinion for tne Court filed by Circuit Judge BORK. BORK, Circuit Judge. The Federal Trade Commission brought this enforcement proceeding in the district court to enjoin the Brown & Williamson Tobacco Corporation ("B & W") from de- ceptively advertising the tar content of its Barclay king-size cigarettes. B & W adver- tises these ci'garettei; as being •`1 mg tar by a recognized method used by B & W and supported by independent laboratories." The FTC alleges that Barclay's advertising claim is false and deceptive and so violates section 5(a) of the Federal Trade Commis- sion Act, 15 U.S.C. § 45(a) (1982). The district court agreed and enjoined B 4 W from advertising any tar number for its Barclay cigarettes without receiving prior FTC approval. Because we find the injunc- tion broader than reasonably necessary to prevent deception, we affirm in part but
Page 27: apt20e00
F.T.C. v. IiltUW` & WILLIAMSON TOBACCO CORP. Cite rs 778 F2d 33 ID.C. Cir. 198!) remand to the district court to modify the injunction consistent with this opinion. I. Since at least the mid-1950's the FTC has been concerned about the validity of tar and' nicotine content claims in cigarette ad- vertising. In 1955 the Commission publish- ed cigarette advertising guides advising manufacturers to make no representations about the tar and nicotine content of a cigarette that could not be supported with reliable scientific evidence. By the mid- 1960's the FTC became concerned about the absence of a standard method for test- ing cigarette delivery of .ar wnd nicotine. Accordingly, in 1967 the Commission adopted a testing method and began a pro- gram to analyze the tar and nicotine levels of each brand of cigarettes sold in the United States. The test adopted by the FTC is known as the Cambridge Filter mt •'1od and is used with minor variations throughout the world. The test utilizes a smoking machine that takes a 35 milliliter puff of two sec- onds' duration on a cigarette every 60 sec- onds until the cigarette is smoked to a specified butt leng^th_ The tar and nicotine collected by the machine is then weighed and measured. This provides an objective basis for assessing the relative amounts of tar and nicotine differen` cigarettes will deliver when they are smoked in the same way. The test does not measure the amount of tar or nicotine that any individu- al smoker may receive since that quantit}y will depend on individual gmoking behavior. In 1970, the FTC proposed a formal rule- making in order to promulgate a Trade Regulation Rule requiring disclosure of FTC tar and nicotine ratings in cigarette advertising. Immediately following this proposal, five leading cigarette companies, including B & W, agreed' among them- selves to a voluntary disclosure plan (the "1970 agreement"). This plan provided that the cigarette manufacturers would dis- close the tar and nicotine figures in all advertising for their cigarettes according to the most recently published Commission 37 test results. Upon accepting the 1970 agreement, the FTC indefinitely suspended its rulemaking proceeding: In January 1981, B & W introduced Bar- clay cigarettes to the national market. Barclays are ultra low tar cigarettes with an innovative filter design. B & W heavily promoted and advertised its king-size Bar- clays as 1 milligram ("mg") in tar, which is one of the lowest tar claims made for any cigarette. Pursuant to the 1970 agree- ment, all Barclay advertisements initially stated that the cigarettes were "1 mg 'tar.' 0.2 mg nicotine by the FTC method." Within six months the Barclay brand had captured more than one percent of the do- mestic cigarette market. Shortly after introduction of Barclay, two of B & W's competitors, the R.J. Rey n- olds Tobacco Company and Philip Morris Incorporated, complained to the FTC that the I mg t3r claim was inaccurate and misieading. They alleged that the Barclay filter differs from other filters so that "when the cigarette is smoked between hu- man lips its air ventilation system is inevi- tably obstructed and the cigarette delivers disproportionately more tar and nicotine than other comparably rated cigarettes." Brief for FTC at 6. Because the FTC smoking machine does not reproduce the obstruction caused by human lips, B & W's competitors claimed that it did not accu- rately rate the Barclay. They also argued' that other low tar cigarettes are not sub- ject to this phenomena because they have a different filter design. The Commission undertook a comprehen- sive inquiry to determine whether the Bar- clay cigarette was accurately rated by the current testing method. The Commission solicited evidence from all the major ciga rette companies including B & W. In addi- tion, three consultants were retained-each an expert in the chemistry of tobaccb use- to assist in evaluating the evidence. The Commission did not otherwise engage in independent efforts to gather evidence or conduct studies but attempted to act as an impartial fact-finding body..
Page 28: apt20e00
38 77S FEDEEtAI. 1tEP..A1TEtt. _'d SERIES . R.J. Reynolds and Philip Morris vach submitted studies purporting to show that the tar and nicotine yield of Barclay ciga- rettes is increased when theyy are smoked by humans. B & W submitted contrary studies measuring smoke constituents in human plasma and purporting to show that Barclay's FTC ratings correctly reflected the amounts of tar and nicotine actualiv ingested by Barclay smokers as compared to smokers of competitive I mg, tar ciga- rettes. The three FTC consultants-eti•.alu- ating the studies independently--found that the Barclay cigarette is not prt+lwrh: ranked by the FTC testing method and ; ields substantially more tar than other comparably rated cigarettes when smoked by humans. Asked to estimate what Bar- clay's tar rating should be, the consultants gave amounts ranging from 3 mg to 7 mg. These estimates would still piace Barclay in the ultra low tar range of cigarettes. On June 25, 1982, the Commission an- nounced its determination that th. FTC testing method does not accurately mea- sure the tar and nicotine delivery of the Barclay. The Commission directed B & W to refrain from relying on the FTC m.thod to substantiate advertising claims concern- ing Barclay's tar content. The Commission announced that it would publish a notice in the Federal Register requesting comment on how to modify its test to rate the Bar- clay cigarette accurately. Before this could be done, however, B & W-•.ied to enjoin the Commission from taking its pro- posed action on the ground that the FTC's exclusion of Barclay from its offic:al test- ing and reporting program was procedural- ly and substantively improper. The district court for the Western District of Kentucky granted! B & W a temporary restraining order against the FTC's proposed actions and againat the publication of those actions in the Federal Register. When the district court in Louisville subsequently dismissed B & W's complaint because the FTC's ac- tions were not final or reviewable, it en- tered a stay against the Commission pend- ing B & W's appeal to the Sixth Circuit. The Sixth Circuit dissolved the district court''s stay and subsequentlyy rulec( for the 1•TC on the cnvrit.+. >ce Brown & 16'rl- lr.,i+ison Tobacco C'orp. r. FTC 710 F.2d 1165 (1ith Cir.19b:3), cert. denied. atiS U.S. 1100, 104 S.Ct. 1:iJa. tiU 4..Ed:2d 1'22i (1983): The FTC then published notice in the Fed- eral Register seeking public comment on proposals to modify the present testing method and deleting the values listed for Barclay cigarettes in past reports. The Commission also retroactivelc amended itss official December 1981 and .4arch 198:3 Tar and Nicotine Reports to delete Barclay's ratinKs.. B & W declined the FTC'; suggestion that it alter its advertisements to use an rstimated vield of 3 to 7 mg tar. Instead. B & W continued to label and advertise Barclays as 1 mg tar cigarettes and contin- ued to state prominently that Barclays were "99 1v tar free" with "1 MG TAR." B & W did. however, revise its fine-print tar and nicotine legend to refer to "a recog- nized method used by B & W and sup- ported by independent laboratories" rather than, as previously, referring to "the FTC method." On Jult 7. 198:3, the FTC filed the present action in the United States District Court for the Di.~trict of' Columbia seekingg injunctive rrlief pursuant to section 13(b) of the FTC Act. 15 [;.S.C. § 53(b) (1982). The Commission sought permanently to enjoin B & W from continuing to advertise either that Barclay is "1 mg tar by a recognized method used by B & W and supported by independent laboratories"'or that it is "99% tar free." The FTC's complaint alleged that Barclay's advertising was false and deceptive when considered against the background of the Commission's rating system for tar and nicotine. The FTC claimed that the Barclay advertisements would mislead consumers into believing both that "Barclay delivers approximately the same amount of tar to hnman smokgrs as other cigarettes rated 1 mg tar, when smoked in the same manner, and that Bar- clay's 1 mg tar designation is an official government rating." Brief :or FTC at 16 (emphasis added).
Page 29: apt20e00
F.T.C. v. BROWN & WII.LIAMSON TOBACCO CORP. . C..e a 7SF.. The district court held that B & W's claim that Barclay is a 1 mg tar cigarette i.~ false and deceptive under the FTC act: FTC v. Brown & Williamson Tobacco Corp., 580 F.Supp. 981 (D.D.C.1983). The opinion reviewed B & W's evidence indicat- ing that the FTC's rating system does not accurately reflect the proportionate amounts of tar and nicotine delkered by different cigarettes when smoked by hu- mans rather than machines. The judge found that B & W had raised serious ques- tions about the system's utility. None- theless, the judge found that the system does provide some useful comparative in- formation to consumers who wish to reduce health hazards. Id at 98r86. In addition. he found that,B & W wPs unable to sug- gest a superior alternative method of rank- ing cigarettes for their health-threatening qualities. In evaluating Barclay's "1 mg. tar"' claim, the district judge held that this claim would mislead consumers who over the years have come to rely on the FTC's ciga- rette rating system. 580 F.Supp. :.t 986- 89. He found that "''B & W's change in the wording of its advertising legend, deleting specific reference to the FTC testing meth- od, is not sufficient to put consumers on notice that the rating given is not an offi- cial F'TC rating." Id. at 986.. The judge concluded that the FTC had succeeded n demonstrating that Barclay was 'improper- ly rated 1 mg by the FTC method and that any claim that Barclay is a I mg. cigarette is deceptive." Id at 989. He enjoined further use of the "I mg. tar" claim. In evaluating Barclay's "995; tar free"' claim, the judge concluded that consumer surveys relied on by the FTC did not indi, cate that this claim was deceptive. 580 F.Supp. at 989-90. Because consumers had difficulty "relating the claim to any milligram number; " he found that "99% tar free" was perceived only as "a I-sr.eral low tar claim." Id at 990. Accordingly, the "99% tar free" claim was upheld so long as it was not accompanied by the ' 1 mg. tar" claim. Judgment was entered on October 25, 1983, and the following permanent in- junction was put into effect: 39 C . C1r. 1985) ORDERED, ADJUDGED AND DECREED: 1. Defendant is permanently enjoined from representing in any advertising, in- cluding packaging and labeling, any spe- cific milligram tar yield or content of any variety of Barclay cigarettes, including the representation that Barclay ciga- rettes are l mg. tar, unless such rating is approved or accepted by the Federal Trade Commission, or derived using a test methodology approved by the Feder- al Trade Commission for Barclay. 2. Except as set forth in paragraph 1 of this Order and Judgment, plaintiff's prayer for relief in all other respects is denied Defendant is free to represent in advertisements that Barclay is "99% tar free" and/or "ultra low tar," and defendant shall not be required to adver- tise any milligram tar yield for Barclay cigarettes under the present Federal Trade Commission-approved voluntary rating program now in effect. Joint Appendix ("J.A.") at 61. The district court further announced that it would "re- tain jurisdiction over this action for any such purposes as justice may require." Id at 62. B & W has appealed to this court. II. B & W's principal claim; on appeal is that the district court erred as a matter of law in not requiring direct survey evidence of consumer deception. B & W claims that without such evidence, the district court had no basis for determining that consum- ers are deceived by the "1 mg. tar" claim or for determining that this deception is material. In addition, B & W asserts that the district court's permanent injunction is a sweeping prior restraint on constitution- ally protected commercial speech. B & W asks that the injunction be vacated and replaced by a remedy no more restrictive than necessary to prevent the deception shown. We address each of B & W's con- tentions in turn. A. I11 In considering charges of false and deceptive advertising, "the public's impres-
Page 30: apt20e00
40 77e FEDERAL SEPORTER, 2d SE1tIES sioa is the only trne measure of deceptive- neat." 1A L. Altataa, Callmax's Tke Law of Uhfiair Qompslitio+t. Tmd:ata*ka and ,Kortopottu 4 6A4„ at 5-32 (4th • ed. 1981) (footnote otnitttd). Appellant notes that much of the jurisprudence of fiLe advertis• ine emphaaizea the unportanee of "exam- itliae ... eolutlrner datt<" to determine the consumer's undolstalldine of the advertise- tnent at isstu, tf the language of the advet- tisement is ambignous and the deception not, tflereforeM facialiy apparentt Sa, ay., American Home Products Corp. v. Joka- ma & 1oliKaon, 577 F.Zd 160, 186 (2d Cir. 19T8) (Lanhaat Aat,).= We accept the Qener al desirabflity of 1laving some empirieal evi- deuce of consumer pertxption, but we do not accept appellant's contention that ton- sttmer survey evidetiee must, as a matter of law, be presented to support a finding that an advertisement has a tendency to deceive snd violates section 5 of the F!'C Act. The Laahitm Act falss ad.etWna cases relied on by appe0ant ekirly do suggest 1. We need not decide whether the FDC may be.r a bwer burden of ptoof In f S false and d.oaptt.e advertisiwd ca.es 6tousla before tbe qeocy ltxlf rather tbtat bafore a dbtrlet aourt. Beeauu of tht Comtttlsoron's accumulated et- perti.e In such tnauersm a t+ttrkwlad cotaz may retvas to owrtYra an FTC adJtidi¢.tfott of hLe adwtt.ina wb.rs lt wotdd rrj.a such a finding by a dist:iet eomt relytft est titMtar evidence af daoepdos. S.e. a&. Siwt.at M=aqsmau Cory. v. f7tw 379 F.Zd 11]7.1142 (!t6 Ctr.l97s). T4is doa not. howerer. dtatw the faet that, as an appellate comt sttd% in rs.rlcw af a district toattt'a factual determtntttblts, such a a Ctedft of the Inlta+mt oatdew of tbe "1 et>sm tatr legead to deedft we nttrt apply the Ztrow r'~~„ e<TOa0011e 1Mndafd. ~~~7 iAwr.dera lYbw.a AoiG+ew aad other ea.s re- cw.rt' Radi ~e udc f~a) d the LW Itam Ad, iS [1S.C, f 1125(a) (1952), which atata In rele.rnt prtt Any penon who ibaL ... we ia cotasetlon with any `oodt ... any Ealse deser3ptiea or reprvodatloe, iwcludiag words or ot1Mr sym• bals teadioe fal.eiy to dpcribe or tepresent the stmta. and shall e:me ruell goods ... to ettter tnto eoauneroe ... saall be Ilsbk to a civil aWoat ... by any person wbo beUeves tAat he In or Is likely to be damaged by the u.o of such false d'etaiptlon or raprsxata- that if "the language of the advertisement it not unambiguous," then the ttial judge may be "compelled to exstailw consumer data to detetmine first the ttteseage oon- veyed" See Aszterioan Xome Prodt,trl; 577 F.4d at 164-66. Thus, if the lower court confroats an ad'vertiseatent involving "litardly true or grammatically oortwt° statements, the trial judge cannot make a finding of deeeptireltess unless the parties provide "evidence of subatanoe" about what "the person to whom the drertise- ment is 9dr+Ksed find[*] to be the mes- sage.'° American Browds, !na v R.J. Reynolds Tobacco Co., 413 F.Supp. 1352, 1857 (9.D.N:Y.1976) (Ianham Act). We do not mean that consumer sur.ey data must alwayt tutderlie any Sndiog of tendency to deceive In such aaees. Evf deixx of consumer reaction "tLsual}y [takeej ... the form of market research or eotuumer aurveys: " AfeNdlaA Ina u Atxerieax Xottte Prodrtsts Corp., 501 F.Supp. 517, 62S ($.D.N.Y.195Q), but a trial court may accord other forms of evidence By oontrast. I 5(aXi) of the FPC Act declstw "unlawfur ath '[aIeEair atethods of tompdi- tiott ... stYd untaU or deeeptfMt OraetiCes in or .ffeCtitts eoau>uros.' Ss Id OS.C. f 4S(a)(1) (1982). Both atatutes, Imwever, attack Edie ad- vectislnf, attd, mws importantly for tlte ease at bar. botth addtas advsrtiisntents tLar, while aot "litera/1; Ealic," crote a ap.dty or lendeney to deceive the eonwmar. Contprn+e ANUria.a lfiorsr A'odeati 377 F.2d at 165 ([Anbam Aet) widi Pl1C v. Shrtiwj Dr.& 1tye. 317 F-2d t,bv. 674-75 (2d C1r.14631(FTC Act). T1ms6 owitts 10 eatre ehe paucity of atses iavolvig de aow trial peocosdinas unda tbs FPC /let, we took to i.ata Ium Act eases for auidanoe as to evldentiary reqtiiraaents to atabllth 'teadeacr to dsalre." The FrC arsua that pi~atatnoemeats In Laa. ham Act e..u mpas+~nd the evideattrry value of entpirlait ooasama daq should not apply tn tttis ease Brid for FTC at S4-S1. We disa{rae. AWwuA ~ tlte FPL accurately Aetla~o the [~ ...o Mttavr'y z;ltcaMs luve dtm~tt purposm we 8nd the dlSarettoe not to be tbe tvidcut:ary point u stakr 5cit= The Ls& bam Aet does constitute a pri.atie rsmodhi scheme for the beoefit of diwcuntied eoatpeti- ton wba+eas the F['C Act >we spectfkaly serves the public iaterat and is saferoed by d- FEC: but in both ittrtaaoa, tM facmd prediat+ for the wuse of aetien tssb in deceptba of the pulrlie.
Page 31: apt20e00
F.T.C. v. BRQWN & WILLIAMSON TOBACCO CORP. 41 CNe a. T1'! ssd 7! (m.C. Ctr. 1980 ""substantial weight" If that e.idence ap- pears reliabk. See Amtricu+s JXome Prod- fteM, 97 F.2d at 167. A court may give weight to expert teat9taaty provided by the parties, au id, as long as It Is root friv- olous. See Ameriean Br,atads, 418 FSupp; at 1361 (refusing to credit the testimony of p)aintifPs sales manaQer because it was based only upon "three or four casual con- venations with srnokers"h m s4o 1A 1. Altman, eupra p. 40, f:..16, at b-92 C'Cl"7hoie rrho customarily deal with ... t .. . "asers ... are pualifted to tcstify .vith respect to the buyers' tutdernt-atding of tne words t3Ky hear and use.") (footnote osnit- ted). Indeed, courts and commentators have recognized the inherent weiktteaaes that msy cbaraeterize a consumer survey and its mode of eoastrnetion, aee: Rp:, American Honte Produets, 577 F.2d at 167; Ds><elopmetets in tJke LatP-Dasptive Advertisi:eg, 80 Harv.L.ltev. 1005. 1077 (1967), and a "court treuet [tdso] ... rely on Its own experier.ce and understanding of buman nstate in drawing reasonable Infer- ences about the reactions of consumers to the c)tsthnqed advestieing." McAi'silab, 501 F.Supp. at 525 (emphasb added). The Supreme Court this past Term in Zauderer s O;~''ice of Disciplinary Cottn- se4 - U.S. --, 105 S.Ct. 8265, 86 LEd.2d Bt#2 (1986), suggested that when the aIIepd deception rises to "a cotntaon- plux," s court may itself ftltd the deoeption ".e)fsvident" Id, 106 M at 4288. T6e Court Implied that In sfttitioas Involving "techniesl ... terms," it ma,r beaotne rea- sonstb)e to assume that members of the pubhc may be "unaware of the ... mesn- ings of such terms" and that "ssvbstantial s. Abre Cerpti x Cau.rn.: tlalow of Ueimd &W*$. fac 466 U.S. M% 104 SCt. 1949, 80 LF.d.2d 302 (t4M). dea sot eh.nse the auNd d.rd of reviewr ia deoeotWe advsrti.ins otei In that mae, the Sureene Court (tdd that ap• pellate oourts tntot exetefte independeet jud8- a+-nt and determia whether the record eutib• lskes actual malla" In 9bd e..o. !rL 104 S.CL at 1967. Mad brosdly, this might Imply a nquiconent of a more sesrehina review than exhts ender the •clearly aroacoos' a.pdard whea findinp of tret at isate Implicate th. avsllabiSty of Nnt amendmwt protecdor,. Tlun nndtAp of teAdency to dmadve and inAcr- ent deceptirenes,, which bear on whether corn- numbers" might be misled. Id While the Court did not go so far as to state that a judge may make such a fiadtng without evidence, the -opinion's "aelftrident" lan- gnage seetm to give a court considerabk leeway, and the opinion explicitly ststed that if a court fittds the deception "se)f-evi dent," no survey data sn required. ld Thus, while consumer stsr.eys conducted by independent experts may atgnabiy con- stitute the b.st way to establish consumer ttnderstanding and preference, see Gell- horn. Proof of Cowamsr Deception Be• forC the f'1'C, 17 Kan.LRev. 559 (1968), cited in S. Opperiltetm, G. Weaton, P. Maggs & IL Sebechter, Unfair Trode Proctieei and Cottsuaeer Protection 608, 04 (4th ed. 1983), such surveys sre not the exclusive form of probative evidence of public pereeption. The "conclusions of market researchers" do not bhtd the ttial ooart, which must ultimately taalae a deter- asiaation of public reaction based upon all "the evidence." Sea McNeilab, 501 F'.Supp. at 526. Appel)snt's contention. therefore, that a consumer survey most be provided as a matter of law is ill-founded- Unlras the district court's finding 6 "clearly erroneous"' we must uphold its concluek.a that the "1 mg. tar" lairn. al- tbougb literally true, is inherently decep- tive for Barclay dQuettes. See Fed.B. Ctv.P. b2(a); American Home Prodtuts. 577 F.2d at 169 (Lanham Act,)s The daim of inherent deception reats on three factual premises: (1) consumers rely on tar ratings to make cotapatative aase:sments of the health effects of cigarettes; (2) Barclay cigarettes deliver disproportion><tely more rneroW speech faHs outside the scope of the fwitar.mndroetU, miafit acsuably 411 wishin lbis cateserv requtrfins heightened reviewe we are reludant, 11w-,cr. to estead 8raas to the ..ylnt ot f.1ar and deeepti.e advertisinu. FiESt, the implications of 8oes ace far from elsr. S.e lrlonsjhan, Cowu,Errden.l FAriRr- viewti 8S Cohim.L.lta.. 229. 244-47 (1S16S). More Irnpuetss+ay. 6ots useu wpotsW tl,.t eoft merdal speeob mwkt not tnertt the same W proaeh as set out tbrrein fet libet usea. Sae 104 S.Ct. at t961-62 n. 22. TherrcEorem we appiy the `clearly crroneoue' standard in this esse.
Page 32: apt20e00
42 778 FEDERAL REPORTER. 2d SERIES tar than other similarly rated cigarettes: and (3) disclaimers explaining the differ- ence will prove ineffective. We conclude that the record supports the district court's findings on alll three of the factual predi- cates above, and that none of the findings is "clearly erroneous." First, with respect to comparativ2 assess- ments, we think that the likely public reac- tion is unambiguous, and that consumer survey evidence is not required. `o party disputes that these numbers bear signifi- cance only insofar as they implicate health matters. That consumers rely on • he milli- gram ratings promulgated pursuant to the FTC rating system is supported by the evidence. The trial court fo..ad relevant both a statement B & W made in the relat- ed proceedings in the federal court in Ken- tucky that consumers are aware of and rely on FTC ratings and the fact that ciga- rette companies, including B & W, spend substantial sums of money advertising tar figures. 580! F.Supp. at 986 n: '0. The court also credited testimony by e FTC'y witness, Dr. Popper, who testified about consumer behavior based on his "vast his- tory of research in consumer behavior and social psychology." See Testimony of Dr. Popper, J.A. at 168. (2) We cannot say that the finding of reliance based upon this evidence is "clear- ly erroneous." B & W has had vabt experi- ence in cigarette marketing, and its previ- ous statement regarding consumer reliance must not lightly be disregarded. More- .. over, the vast expenditure of advertising dollars on tar ratings strongly supports public reliance because advertising expendi- tures presumptively have the effect intend- 4. Better Busixets 8areaa v. Aledica! Diretrom Inc., 681 F.2d 397 (5th Cir.19g2) (Lanham Act), suggests that "context" may create inherent con- sumer deception even where an advertisement is facially truthful. [d at 403. There, a defend- ant weight clinic referred to customers who gave the Better Business Bureau ("BBB'") volun- tary, periodic favorable reports on tt e clinic as BBB "spies or "investigators." Techniully, the labels were arguably accurate insofar as the customers had informed the :?3B of their inten- tions to provide information, and. unbeknownst to the defendants, acted on the BBB's behalf. ed. ,+ .llrNeilab„ aQ1 F.Supp. at 530. At least„ those who are paying the money and are most familiar with the market believe that consumers are guided by tar ratings. Finally, Dr. Popper's expert testimony may be credited if reliable, see supraa p. 41, and an appellate court should not second- guess a trial court's judgment as to the reliability of witnesses absent circumstanc- es not present here. On: the question whether consumers use such information comparatively, we find the public's perception to be unambiguous, given the context in which, the information appears.+ Consumers have no innate abili- ty to assess an individual tar claim stand- ing alone. The tar milligram figures have significance only as comparative values. Thus, a consumer can assess Barclay's "I mg. tar" claim as being like other "1 mg. tar" cigarettes and ordinarily less detr . mental to health than cigarettes of higher ratings. _ius, if Lae second finding, that Barclay delivers disproportionately more tar than other cigarettes of "I mg. tar" rating, is not ciearly erroneous, the advertisement is inherently deceptive. Because the district court carefully weighed the implications of ventilation studies by RJ. Reynolds and Philip Morris, as well as defendant B & W's own cotinine studies, 580 F.Supp. at 987-89, we will' not disturb the court's con- clusion regarding disproportionate tar de- livery. Thus the finding of inherent decep- tiveness is well-supported. {3] As for the third' issue-the effec- tiveness of disavowing any official FTC rating as a way '-liminating the decep- tion-we agree with the district court's Yet given the context of the BBB's strong role in "encouraging honesty and exposing deception." the labels used by defendant raised a strong 'inferettce of (an] endorsement" that did not exist. Id. In this ease. twelve years of well-established and relied upon comparative ratings raice a strong inference of the comparability of all mil: ligram tar ratings. Indeed, in this case the inferenee appears even stronger because the rat- ings are meaningless outside the comparative context.
Page 33: apt20e00
F.T.C. v. BROWN & WILLIAMSON TOBACCO CORP. cne a.77a F2d 35 (D.c. ctr. 19851 conclusion that no disclaimer can have that effect. See 580 F:Supp. at 986.5 The "1 mg. tar"' claim appears more visibly than the legend explaining the source of the ratings as being independent laboratories. This fine-print legend, rnoreover, often ap- pears in virtually illegible form. placed in an inconspicuous corner of Barclay adver- tisements. See Brief for FTC at 24. More importantly, however, the lower court ac- cepted expert testimonyy that after 12 years of exposure to F'TC rat- ings consumers have become "habituat- ed" to the tar and nicotine "legends" in cigarette advertisements, and hence will only pay attention to those p)rtions of thz legend they expect to change from ad to ad-the numerical tar and nicotine rat- ings themselves. A consumer reading the Barclay ad would be likelyy either not to read the wording of the legend, or not realize that the terminology employed signified a departure from the long-uti- lized FTC Report numerical ttings. 580 F.Oupp. at 986 n. 31 (citation omitted). We do not find this conclusion to be clearly erroneous. (41 Thus we -hold that the district court's conclusions as to the "l. mg. tar" claim's inherent tendencv to deceive to be supported by the evidence. The trial court's holding that B & W's advertising violates section 5 of the FTC Act must, therefore, be affirmed. B. The Supreme Court has placed commer- cial speech within the ambit of first amend- ment protection. See., e.g., Fn d'ldman c. Rogers, 440 U.S. 1, 99 S:Ct. 887, 59 L.Ed.2d 100 (1979). Both consumers and society have a strong interest "in the free flow of commercial information,". see Virginia State Board of Pharmacy r. Virginia Cit- izens Consu mer Cou nci l, Inc. 425 U.S. 748, 763, 96 S.Ct. 1817, 1826. 48 L.Ed.2d 346 (1976), and it is this interest in ensur- ing the flow of that information essential 5. In fact, B & W did not disclaim comparability with FTC-rated milligram figures per se. It merely deleted reference to the specific FTC 43 to "the proper allocation of resources" and the regulation of our economy that the first amer.dment vindicates in extending its scope to commercial speech. Id. at 765, 96 S.Ct. at 1827. Yet, "[f]dlse, deceptive, or misleading advertising" does not serve, and, in fact, disserves, that interest, and thus the subcategory of commercial speech consisting of false and deceptive advertis- ing "remains subject to restraint." In re R.-til J.. 455 U.S. 191, 200, 102 S.Ct. 929, 936, 71 L.Ed.2d 64 (1982). In fact. "[m]is- leading advertising may be prohibited en- tirelv."' Id at 203. 102 S.Ct. at 937. [5] As appellant has correctly asserted. however, any restrictions imposed on de- ceptive commercial speech can be no "broader than reasonably necessary to pre- vent the deceptinn." In re R.?K.J., 45.i U.S. at 203, 102 S.Ct. at 937. The restriction imposed, moreover, may not "place an ab- solute prohibition on ... po«•nt'ially mis- leading information ... if the information also may be presented in a way that is not deceptive." Id. B & W contends that the district court's permanent injunction against B & W's making any specific milli- gram tar rating claim, unless the FTC ap- proves it ,r B & W derives it from an FTC-approved methodology, constitutes an impermissibly broad prior restraint on B & W's first amendment rights. Brief' of B & W at 50-57. We turn now to this claim. Contrary to the appellant's implication, the lower court did not impose a "sweeping prohibition" or "blanket injunction[]" against any milligram tar claim, subject only to the discretion of the FTC. Brief of B & W' at 51. In fact, the district court explicitly stated that "B & W is ... free to advertise B & W as containing 3-7 mg. tar, the estimate which the FTC currently ac- cepts."' 580 F.Supp. at 990 n. 53. Thus, the injunction merely prevents B & W, absent FTC approval, from advertising Barclay as falling within 1-2 mg tar rat- ings, or from advertising a specific number within the 3-7 mg tar range„- which the testing method in the legend accompanying the numerical rating..
Page 34: apt20e00
44 778 FE[)ERaL REPORTER. 2d SERIES FTC contends and the lower court implicit- ly accepts to be inherently misleading. Be- cause we believe that the 3-7 mg tar esti- mate, an amalgam of three separate ranges estimated by FTC consultants in 1982, is not clearly erroneous, we hold that the district court's injunction against advertise- ment of milligram tar figures below that range is not "broader than reasonably nec- essary to prevent deception." Nor does the possibility of the future obsolescence of this currently acceptable 3-7 mg tar range, vulnerable to ongoing research and advancing scientific knowl- edge, render the district court's disposition of this matter infirm under the first amend- ment. If the FTC changes its position and refuses pursuant to the terms of the in- junction to continue tu allow B & W to advertise Barclay in the 3-7 mg tar range, or if the Commission rejects a claim by B & W that lower or more specific tar ratings have become appropriate, either tep would entitle B & W to judicial review of this agency action. See 5 U.S.C. §§ 7a?; 704 (1982); see also Environmental Defense Fund v. Ruckelshaus, 439 F.2d 584, 589 n. 8 (D.C.Cir.1971) (where agency action "im- poses an obligation or denies a right," this has sufficient finality for "purposes of re- view").4 Thus, a reviewing court will set aside ager.cy refusal to allow a certain i. •t- ligram tar rating to be advert;sed if that refusal is "arbitrary, capricious, ... or oth- erwise not in accordance with the law." 5 U.S.C § 706(2XA) (1982). Thia suggests that unreasonable restriction of B & W's right to non-deceptive advertisen.ent of tar ratings for Barclay would be struck down 6. The review provision of the FTC A4t, see 15 U.S.C. § 21(c) (1982), does not apply to such Commission actlons. That provision applies only to cease and desist orders brought under IS U.S.C. § 21(s) to enforce various provisions of Title 15. The FTC does not have to bring a cease-and-desist action to regulate B & W's ad'- vertisement of tar ruings; the Com,nissioa has explicit veto power over such advertisements under the terms of Judge Gesell's injunction. See 580 FSupp. at 989. Thus judicial' review for FTC refusal under the injunction to allow spe- cific milligram tar advertisements would be ob• uinablr under 5 US.C 1 704 (1932) as "final on appeal of the FTC's refusal to grant permission. The district .•+rt's retention of jurisdic- tion "for any such purposes as justice may require," see J.A. at 62, moreover, further diminishes any danger that the FTC might unreasonably withhold permission for a specific milligram tar rating which is not deceptive. If B & W believes in the future that the FTC has unreasonably withheld itss approval in the face of new scientific evi- dence, it' may petition the court to modify or dissolve the injunction. There is a problem, however,, in the fact that, these safeguards notwithstanding, the injunction places the burden on B & W to justify the advertisement of results from a different system of testing which it con- siders superior to the FTC system, even if B & W includes a prominent disclaimer explaining that the rating comes from a new system not comparable to that used by the FTC and other manufacturers. Be- cat..e the FTC has not adopted its system of testing pursuant to a Trade Regulation Rule under section 18 of the FTC act„ 15 U.S.C. § 57a (1982), one cannot say that the FTC system constitutes the only acceptable one available for measuring milligrams of tar per cigarette. If B & W sought to advertise the results of a different system solely with respect to Rurclay, this objection would be ground- less. If the different system produces re- sults not comparable to the FTC ratings used by other manufacturers, an advertise- ment displaying only that system's results for Barclay would have an inherent tenden- cy to deceive, even witu an explanatory disclaimer.' The sole utility of any particu- agency action for which there is no other ade- quate remedy in a court " 7. In Part 11-K of this opinion. we upheld the district court's finding that no disclaimer could' cure the inherent deceptiveness at stake. See supra p. 42. We unnot, therefore. order the' modification of the injunction to allow the oth- erwise deceptive advertisement of a rating ob- tained under a system not comparable to the FCC system simply because B& W appends a disclaimer explaining the disparity of the sys- tems and results.
Page 35: apt20e00
F.T.C. Y. BROWN & WILLIAMSON TOBACCO CORP. 45 Cltu as 778 F2d 35 (D.C. Clr. 1985) lar milligram, rating is in comparison with the analogous ratings of other cigarettes. Thus, standing alone, the Barclay rating from a new system would tend to encour- age comparison with the inapposite FTC ratings advertised by other manufacturers. This would tend to deceive consumers. (6) The injunction as written, however, would even prohibit B & W from devising a new testing system and, in advertising its results for Barclay, providing information about competing brands prominently enough and in sufficient quantity to allow consumers to make informed decisions without confusing figures from disparate testing systems. Since this would elimi- nate consumer confusion, we believe that the FTC must bear the affirmative burden of demonstrating any inadequacy, and' thus deceptiveness, of the results obtained un- der such a system and advertised in the manner described. We do not wish to leave intact the injunctior ; requirement of prior FTC approval of such advertising be- cause that would enshrine the current FTC system as the sole legitimate testing meth- od, even though it was not passed pursuant to section 18 of the FTC Act, 15 U.S.C. § 57a (1982), and subjected to the possibili. ty of judicial review. Thus we remand this case to the district court with instructions to modify the injunction to allow for the presentation of the resulu of a different testing system, so long as any advertise- ment of such results provides sufficient data to avoid deceptiveness due to confu- sion with the FTC testing system. It hard- ly requires saying that the FTC would re- main free to prove deceptiveness due to the inaae5uacy of the new testing system or the form of the advertisements under sec- tion 5 of the FTC Act. The Commission may, of course„ address the problem by promulgating a Trade Regulation Rule un, der section 18 of the Act. (7) Finally, we find ourselves unable to accept B & W's remaining first amendment claim that the lower court's decision pre- vents B & W from airing publicly its dis- pute with the FTC and its methodology. The decree does no more than prohibit B & W from expressing its dispute in a particu- lar "form" that would be deceptive. See Friedman, 440 U.S. at 10, 99 S.Ct. at 894. B & W is free to voice its disagreement with the FTC in every medium except the advertisement of the specific milligram tar ratings which offend the FTC Act's pro- scription against deceptive advertising. The judgment below is Affirmed in part and' remanded in part.
Page 36: apt20e00
The Health Consequences of Smoking THE CHANGING CIGARETTE a report of the Surgeon General ; U.f. OEPARTNHNT OF HEALTH AND HUMAN iERVIClE ~ PubMO N.MIA s«vk. '~ ONIw M fnoAMO &n0 N..m hir ~I'^sV z~e w trb by IM r~SIM. .M M1~&p. U.B. ON~~wMM hW/M Of/1so. raMNylew. D.C. 30403
Page 37: apt20e00
1Mr/[C.[TAMt a/ WM/NYa M{,MM1(/IYMf . . ..n.www.ac1 n..1 7he Honorabla ihaaaa P. o•MOlll. Jr. Opaakar of the Nouae of kapreaentatlv. Maehiytow, D. C. 20515 Dear /k. spaakor$ I hereby aubadt to yoY the Noalth Con.wa.ncaA of faeklna- Th. Ch.w ln. C ar. te. 1h1e r.pore ~a a raapwne. to two .oagra.o na reqa r.wenta. Tha Public DeaLtk Clqaretta i.okln0 Act ot1fN calla upon thla Dapartn.at to issue fnsnal r.porta on the health eon.oqa.neea et awoRlna and to aYbrlt 1.91alatlve raoa.wwaatlewa. ~ootlow 403 of the Noalth i.rvlaaa and Cantare A.awdrnta of 1976 a.ka for a'atWy er atudlwa o[ (1) the relative health rlaka associated Wlth aaokieg olIarat.a e[ varying lov.la of tar. wleotine, awd earbon .enoaidor awd (2) the health riaks associated with rek1M al0arottaa Contafniwg any ebatawooa ca.wnly .ddad to oo.nre/a1Ly rwutaotrsad al0aratte..• ln propwrinp tAis raport, the .ofentiata and .ctontltle agewolea of this Dapartaont have rovle+ad-all current scientific evtdawee and have coaaluded tkat tho .oarch for lY.o hazardous el~.ratto. Ma. aet ylald.d . prodaet which can be considered •aa[o.' 7ha poraow oYo ahaMea to a cigarette with lowr wa.ured Ylolda .ay redaee eerta/n huards of e.okiM. but the bonarlta - vill be wll aomparad to the benefits of quitting entirely. The aroat 1~pottant conclusion of tht, report lo that yovernaent and tha prlvate aawnity llka wuat lntonaily their .ttorta to ree/wd the public of the hararde of awokin9 and to assist those who do a.oka to quit. Yo nuat atap up our proqraes to persuade yoan9 people not to t.ke up the habit lnrtho tlret place. This report also notoe that we eaat oontlnee to wonltor the changing olqaratto-to insure that M,.w war allar.tte producte appear they deaot bring with thae nw haaarda to lealth. Rhrerqhout this report th.neod to knoy about aubatancaa added to elyarwttoa is stated repeatedly. At preaont. there is no rrchanlab by rhlOh qovarnwent ar the scientific cownlty can reqoira disclosure of these addltlvea, which nu.t obviously be a first etep in aaoaa.inq their health a[[ecta. 7fila needs to be aerrootld byvolawtary action or, 1t necessary, by legislation. oa a nu.bor of ocoaalona previous Lerstarl.a of thle Dapartrnt hava callad for new and stronger health rarnlnya, the aatabliah.ant of nari.nm lovola ot •tar' and niaotlne and the dlaoleoare of .oro intorrtiow about cigarette products. This 1961 rreport eatabliahoa the nead to aiove torvard-oe these raco.ondatlowa.ie partlealar, I believe thornataotarere should llat yields o[ tar•, nicotine and other h.rardous oorpon.nta ow their packages awd in their advertising with appropriata orplanatory in[oratlon on the health .i9ni.tlcanco ot theee wea.arementa. This would be a wlnt.r tlr.t, atep in giving cigarette conaa..ro full awd adaqvate intorn.tloa about the produota they are buying. rely ~~~~ ~~ Patricia bberta Narrl. Ei4sezse saoleaere
Page 38: apt20e00
PREFACE This is the fourteenth report on the health consequences of smoking which the Public Health Service has issued since 1964 and the third to be issued during my term as Surgeon General. By Conge essional directive it considers the relative health effects of cigarettes with varying levels of "tar" and nicotine and the relative health effects of cigarette additives. At the present time, a third of all smokers, some 18 million persons, are smoking cigarettes with measured yields of less than 15 mg "tar;' and this number is increasing by approximately 5 percent per year. Most of these persons have changed to lower yield cigarettes in the expectation that this will somehow reduce the hazards of their smoking. It is in the interest of these persons, and in the public interest, to know to what extent these expectations are justified. In 1966, the Public Health Service held that "The preponderance of scientific evidence strongly suggests that the lower the tar and nicotine content of cigarette smoke, the less harmful would be the effect." In 1979, the Public Health Service confirmed this statement, citing nevw evidence, but was more cautious. "In presenting information to the public," I wrote in the Preface to the 1979 Report, "three caveata are in order: consumers should be advised to consider not only levels of tar and nicotine but also (when the evidence becomes available) levels of other tobacco smoke constituents, including carbon monoxide. They should be warned that, in shifting to a leea hazardous cigarette, they may in fact incresse their hazard if they begin smoking more cigarettes or inhaling more deeply. And, most of all, they should be cautioned that even the lowest yield of cigarettes presents health hazards very much higher than would be encountered if they smoked no cigarettes at all, and that the single most effective way to reduce the hazards associated with smoking is to quit." In thi3 1981 Report, the Public Health Service has reviewed the question again and in far greater depth than before. Overall, our judgment is unchanged from that of 1966 and 1999: smokers who are unwilling or as yet unable to quit are well advised to switch to cigarettes yielding less "tar" and nicotine, provided they do not increase their smoking or change their smoking in other ways. But our
Page 39: apt20e00
new review raises new questions and suggests an even more cautious approach to the issue. Here are the basic findings of this Report: 1. There is no safe cigarette and no safe level of consumption. 2. Smoking cigarettes with lower yields of "tar" and nicotine reduces the risk of lung cancer and, to some extent, improves the smoker's chance for longer life, provided there is no compensatory increase in the amount smoked. However, the benefits are minimal in comparison with giving up cigarettes entirely. The single most effective way to reduce hazards of smoking continues to be that of quitting entirely. 3. It is not clear what reductions in risk may occur in the case of diseases other than lung cancer. The evidence in the case of cardiovascular disease is too limited to warrant a conclusion, nor is there enough information on which to base a judgment in the case of chronic obstructive lung disease. In the case of smoking's effects on the fetus and newborn, there Is no evidence that changing to a lower "tar" 'and nicotine cigarette has any effect at all on reducing risk. 4. Carbon monoxide has been impugned as a harmful constituent of cigarette smoke. There is no evidence available, however, that permits a determination of changes in the risk of diseases due to variations in carbon monoxide levels. 5. Smokers may increaae the number of cigarettes they smoke and inhale more deeply when they switch to lower yield cigarettes. Compensatory behavior may negate any advantage of the lower yield product or even increase the health risk. 6. The "tar" and nicotine yields obtained by present testing methods do not correspond to the dosages that the individual smokers receive: in some cases they may seriously underestimate these dosages. 7. A final question is unresolved, whether the new cigarettes being produced today introduce new risks through their design, filtering mechanisms, tobacco ingredients, or additives. The chief concern is additives. The Public Health Service has been unable to assess the relative risks of cigarette additives because information was not available from manufacturers as to what these additives are. In evaluating the public health significance of the finding of reduced risk of lung cancer, it is important to recognize that the largest component of excess mortality caused by smoking is eardiovascular disease deaths. There is not sufficient evidence to conclude that use of lower "tar" and nicotine cigarettes causes any reduction in this burden. The same is true of the other major diseases caused by cigarette smoking, most notably chronic obstructive lung disease and adverse effects on pregnancy. These findings raise important questions of public policy. Some appear to be easily resolved. It should be possible to work out procedures so that cigarette manufacturers can disclose the additives they use while still protecting their legitimate interest in trade secrets; an effort to accomplish this is now underway.. It should also be possible to develop better methodologies to measure smoke constituents, although no machine will ever be able to duplicate human smoking behavior exactly. And longitudinal surveys are now being carried on in an effort to monitor smoking behavior, and to help answer some of the behavioral questions raised in this Report. Other questions pose greater difficulty. A common thread running through the sections of the Report is that too much reliance in the past has been placed on the nonselective measure of "tar" as a measure of risk to the neglect of other constituents and approaches to risk assessment. Additional epidemiologic and bioassay work is required, as is a better definition of the fundamental mechsnisma of smoking- related disease. Further study is necessary to examine the addictive nature of smoking and its impact on initiation, maintenance, and cessation, especially in light of the recent statement of the National DrugAbuseAdvisoryCouncil that cigarette smoking is addictive.These questions cannot be answered quickly or without expenditure of scientific resources. The questions raised by this Report suggest action in both the public and private sector. In the research community, a research plan is needed to enable us to monitor the changing cigarette and to answer the many research questions put forth in this Report, with special emphasis on the issues of initiation and cessation. New measures and markers of relative toxicity are needed to supplement "tar" and nicotine. As stated, a voluntary disclosure and testing program needs to be developed with cigarette manufacturers to assess the relative health risks of cigarette additives and to protect against new hazards. In the regulatory area, this Report suggests the need to increase the public's access to information about the product it buys. Advertise-s ments and packages alike should display yield figures more prominent- ly, including measures of carbon monoxide and possibly other hazard-s ous ingredients. Marketing terms such as "low-low" and "ultra-low" need to be standardized. In the area of public information and education, much more needs to be done both by the Government and by private health and educational agencies. The overriding objective must be to persuade young people not to take up smoking and to encourage present smokers to quit. Smokers of the lower yield cigarettes should be warned not to begin smoking more cigarettes or inhaling more deeply. Pregnant women should be cautioned that lower yield cigarettes are not an alternative to quitting. SUSSM vii
Page 40: apt20e00
Since 1964, when the first Public Health Service Report was issued, smoking has declined in the United States from 40.3 percent of the population to 32.5 percent. Per capita consumption of cigarettea is now at the lowest level since 1957. There in less smoking by boys than in many years, and smoking by girls has declined from the higher levels of the mid 1970s. This is a tribute to the educational efforts of our teachers, of our health profession&ls, and of our educational and health agencies. There is every reasod to hope and believe theae trends will continue. Yet 54 million Americans continue to smoke, unwilling or unable to quit. This population Is at extra risk of lung cancer, heart disease, chronic lung disease, and other diseases; it is a population with a life expectancy months and years less than the population of nonsmokers. The evidence presented in this Report shows that there is no "safe" cigarette available to these smokers, but that some cigarettes may be less bazardous than others, reducing the risks of smoking In a limited and selective fashion. Julius B. Richmond, M.D. Assistant Secretary for Health and Surgeon General January 12, 1981 ACKNOWLEDGEMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, John M. PinSiey, Director. Medical Staff Director for the Report was Joanne Luoto, M.D., M.P.H. Managing Editor was Donald R. Shopland. Consulting scientific editors were David M. Burns, M.D., Ellen R. Gritz, Ph.D., Jeffrey E. Harris, M.D., Ph.D., and John H. Holbrook, ' M.D. The following individuals participated in working groups at the June 1980 conference on Research Needs on Low-Yield Cigarettea. Except where otherwise indicated, the working group chairperson also au-d thored the corresponding working group report and was responsible for Incorporating comments from other members of the group. Phannaoloyy and Tasieotopy Fred G. Bock, Ph.D. (Chairman), Director, Orchard Park Laboratories, Itoswell Park Memorial Institute, Orchard Park, New York S. P. Battista, Ph.D., Senior Staff Pharmacologist, Arthur D. Little, Inc., Cambridge, Msssachusetta James F. Chaplin, Ph.D., Director, Oxford Tobacco Research Laborato- ry, Oxford, North Carolina 0. T. Chortyk, Ph.D., Chief, Tobacco and Health Laboratory, Richard Russell Research Center, Athens, Georgia Louis Diamond, Ph.D., Professor and Director of the Pharmacodynam- ics and Toxicology Division, College of Pharmacy, University of Kentucky, Lexington, Kentucky M. R Guerin, Ph.D., Section Head, Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Dietrich Hoffmann, Ph.D., Chief, Division of Environmental Carcino• genesis and Associate Director of Naylor-Dana Institute, American Health Foundation, Valhalla, New York Harold C. Pillsbury, B.S., Technical Director, Federal Trade Commis- sion, Tobaeoo Research Laboratory, Washington, D.C. 9Tl,GgZ6B
Page 41: apt20e00
W. S. Riekert, Ph.D., Department of Statistics, University of Waterloo, Waterloo, Ontario, Canada T. C. Tso, Ph.D., Chief, Tobacco Laboratory, U.S. Department of Agriculture, Beltsville, Maryland Cancer Jesse L Steinfeld, M.D. (Chairman), Dean of the School of Medicine, Medical College of Virginia, Richmond, Virginia Lawrence Garfinkel, M.A., Vice President fpr Epidemiology and Statistics, American Cancer Society, Inc., New York, New York Michael Kunze, M.D., Professor of Social Medicine, Institute of Hygiene, University of Vienna, Vienna, Austria William Lijinsky, Ph.D., Director, Chemical Cardnogenesis Program, Litton Bionetics, Frederick Cancer Research Center, Frederick, Maryland Donald H. Luecke, M.D., Chief of Special Programs Branch, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Maryland Marvin A. Schneiderman, Ph.D., Bethesda, Maryland William D. Terry, M.D., Acting Director, Division of Cancer Control and Rehabilitation, National Cancer Institute, Bethesda, Maryland Elizabeth Welaburger, Ph.D., Chief of Laboratory for Carcinogenesis Metabolism Branch, Carcinogenesis Intramural Program, Division of Cancer Cauae and Prevention, National Cancer Institute, Bethesda, Maryland Ernst L Wynder, M.D., President, American Health Foundation, New York, New York Dietrich Hoffmann, Ph.D. (Special Consultant), Chief, Division of Environmental Carcinogenesis and Associate Director of Naylor- Dana Institute, American Health Foundation, Valhalla, New York Card{ouaacular Diseases William P. Castelli, M.D. (Chairman), Medical Director, Framingham Heart Study, Framingham, Massachusetts Poul Astrup, M.D., Professor of Clinical Chemistry, University of Copenhagen, Copenhagen, Denmark Manning Feinleib, M.D., Dr.P.H., Associate Director for Epidemiology and Biometry, National Heart, Lung, and Blood Institute, Bethesda, Maryland William Friedewald, M.D., Associate Director, Clinical Applications and Prevention Program, National Heart, Lung, and Blood Institute, Bethesda, Maryland Robert S. Gordon, Jr., M.D., Special Assistant to the Director, National Institutes of Health, Bethesda, Maryland William R.. Harlan, M.D., Professor and Chairman, Department of Postgraduate Medicine, University of Michigan, Ann Arbor, Michi- gan r.TzsQZSQ Richard J. Havlik, M.D.,-M.P.H., Chief, Clinical and Genetics Epide- miology Section, National Heart, Lung, and Blood Institute, Bethes- da, Maryland John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah, Sa1t Lake City, Utah Stephen B. Hulley. M.D., M.P.H., University of California, School of Medicine, San Francisco, California Henry C.. McGill, M.D., Professor, Department of Pathology, Universi- ty of Texas Health Science Center, San Antonio, Texas Gardner C. MaMillan, M.D., Associate Director for Etiology, Arterio- sclerosis and Hypertension, Division of Heart and Vascular Disease, National Heart, Lung, and Blood Institute, Bethesda, Maryland Douglas R. Rosing, M.D., Senior Investigator, Cardiology Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland Nicholas J. Wald, M.D., LC.RS., Cancer Epidemiology and Clinical Trials Unit, Radcliffe Infirmary, Oxford, England William J. Zukel, M.D., Associate Director for Program Coordination and Planning, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland Chronic Obstructive Lung Disease Philip Kimbel, M.D. (Chairman), Chairman, Department of Medicine, The Graduate Hospital, Philadelphia, Pennsylvania A. Sonia Buist, M.D., Associate Professor, Department of Physiology, School of Medicine, University of Oregon, Portland, Oregon David M. Burns, M.D., Pulmonary Division, University Hospital, San Diego, California Jeffrey M. Drazen, M.D., Assistant Professor of Medicine, Harvard Medical School, Peter Bent Brigham Hospital, Boston, Massachu- setts Eric R. Jurrus, Ph.D., Health Scientist Administrator, Airways Dis- easea Branch, Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland James F. Morris, M.D., Chief, Pulmonary Disease Section, Veterans Administration Medical Center, Portland, Oregon Clifford H. Patrick, Ph.D., Chief, Prevention, Education, and Manpow- er Branch, Division of Lung Diseases, National Heart, Lung, and Blood Institute, Bethesda, Maryland Diana Petitti, M.D., Department of Medical Methods Research, Kaiser Permanente Medical Care Program, Oakland, California Pregnancy and fnfant Health Lawrence D. Longo, M.D. (Chairman), Professor of Physiology and Perinatal Biology, Professor of Obstetrics and Gynecology, School of Medicine, Loma Linda University, Loma Linda, California Heinz W.. Berendes, M.D., M.H.S., Director, Epidemiology and Biome- try try Research Program, National Institute of Child Health and Human Development, Bethesda, Maryland xi
Page 42: apt20e00
William A. Blanc, M.D., Professor of Pathology, Head, Division of Developmental Pathology, College of Physicians and Surgeons, Columbia University, New York, New York Alfred W. Brann, M.D., Professor, Department of Pediatrics, Director, Division of Neonatal-Perinatal Medicine, Emory University School of Medicine, Atlanta, Georgia Charlotte S. Catz, M.D., Head, Pregnancy and Perinatology Section, Clinical Nutrition and Early Development Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, Bethesda, Maryland Eileen G. Hasselmeyer, Ph.D., Associate Director for Scientific Review, National Institute of Child Health and Human Development, Bethesda, Maryland Mary B. Meyer, Sc.M., Associate Professor, Department of Epidemiolo- gy, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland David Rush, M.D., Ph.D., Associate Professor of Public Health (Epidemiology) and Pediatrics, Faculty of Medicine, School of Public Health, Columbia University, New York, New York Zena Stein, M.D., Professor of Public Health (Epidemiology), Sergiev- ski Center at Columbia University, New York, New York. Behatriord A:peeta Charles R. Schuster, Ph.D. (Chairman), Departments of Psychiatry and Pharmacological and Physiological Sciences, Pritzker School of Medicine, University of Chicago, Chicago, Illinois Lynn T. Koalowaki, Ph.D. (Author), Scientist, Clinical Institute of the Addiction Research Foundation, Toronto, Ontario, Canada Roland R. Griffiths, Ph.D., Associate Professor of Behavioral Biology, altimore, School of Medicine, The Johns Hopkins Univerei -ty, Baltimore, Maryland Ellen R. Grita, Ph.D., Associate Research Psychologist, Department of Psychiatry and Pharmacology, University of California at Los Angeles; Research Psychologist, Veterans Administration Medical Center, Brentwood, Los Angeles, California Murray E. Jarvik, M.D., Ph.D., Professor of Psychiatry and Pharmacol- ogy, University of California at Los Angeles; Chief, Psychopharma- cology Unit, Veterans Administration Medical Center, Brentwood, Los Angeles, California Chris-Ellyn Johanson, Ph.D., Research Associate (Associate Professor), Department of Psychiatry, University of Chicago, Chicago, Illinois Sandra Levy, Ph.D., Acting Chief, Behavioral Medicine Branch, Division of Resources, Centers, and Community Activities, National Cancer Institute, Bethesda, Maryland Margaret E. Mattson, Ph.D., Program Scientist, Behavioral Medicine Branch, Division of Heart and Vascular Diseases, National Heart, ng, and Blood Institute, Bethesda, Maryland st4sezsR David M. Monsees, Ph.D.; Program Director for State and Evaluation Projects, Behavioral Medicine Branch, Division of Resources, Cen- ters, and Community Activities, National Cancer Institute, Silver Spring, Maryland Edward J. Roccella, Ph.D., Deputy Branch Chief, Health Education Branch, Office of Prevention, Education and Control, National Heart, Lung, and Blood Institute, Bethesda, Maryland Michael Russell, M.D., Institute of Psychiatry, Maudsley Hospital, London, England The editors acknowledge with gratitude the many distinguished scientists, physicians, and others who lent their support in the preparation of this Report by coordinating manuscript preparation, contributing critical reviews of the manuscript, or assisting in other ways. Henry Blackburn, M.D., Professor and Director, Laboratory of Physio- logical Hygiene, School of Public Health, University of Minnesota, Minneapolis, Minnesota Lester Breslow, M.D., M.P.H., Dean, School of Public Health, Center for the Health Sciences, University of California, Los Angeles, California Benjamin Burrows, M.D., Director, Division of Respiratory Sciences, Arizona Health Sciences Center, Tucson, Arizona Vincent T. DeVita, M.D., Director, National Cancer Institute, Bethes- da, Maryland Donald S.. Fredrickson, M.D., Director, National Institutes of Health, Bethesda, Maryland Maureen Henderson, M.D., Associate Vice President for Health Sciences, University of Washington, Seattle, Washington Norman Kretchmer, M.D., Ph.D., Director, National Institute of Child Health and Human Development, Bethesda, Maryland Robert I. Levy, M.D., Director, National Heart, Lung, and Blood Institute, Bethesda, Maryland Abraham Lillienfeld, M.D., M.P.H., D.S.C., University Distinguished Service Professor, Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Kenneth Moser, M.D., Director, Pulmonary Division, University Hospi- tal, San Diego, California R. L. Naeye, M.D., Professor and Chairman, Department of Pathology, M.S. Hershey Medical Center, Hershey, Pennsylvania Richard Pete, M.A., M.S.C., I.C.R.S., Regius Assessor of Medicine, Radcliffe Infirmary, Oxford, England William Pollin, M.D., Director, National Institute on Drug Abuse, Rockville, Maryland
Page 43: apt20e00
Richard D. Remington, Ph.D., Dean, School of Public Health, Universi- ty of Michigan, Ann Arbor, Michigan Robert Resnick, M.D., Associate Professor, Department of Reproduc- tive Medicine, Medical Center, University of California, San Diego, California Dorothy P. Rice, Director, National Center for Health Statistics, Hyattsville, Maryland Marvin A. Sackner, M.D., Chairman, Department of Medicine, Mt. Sinai Medical Center, Miami Beach, Florida Irving J. Selikoff, M.D., Professor of Community Medicine, Professor of Medicine, Mt. Sinai School of Medicine, City University of New York, New York, New York Jeremiah Stamler, M.D., Chairman, Department of Community Health and Preventive Medicine, Northwestern University Medical School, Chicago, Illinois Ronald W. Wilson, M.A., Chief, Health Status and Demographic Analysis Branch, Division of Analysis, National Center for Health Statistics, Hyattsville, Maryland The editors also acknowledge the contributions of the following staff and others who assisted in the preparation of the Report. Erica W. Adams, Copy Editor, Informatics Incorporated, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Jacqueline O. Blandford, Secretary, Office on Smoking and Health, Rockville, Maryland Tina K. Brubaker, Information Specialist, Clearinghouse Project9 Department, Informatics Incorporated, Rockville, Maryland Betty Budd, Administrative Clerk, Office on Smoking and Health, Rockville, Maryland Marsha Clay, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Martha E. Davis, Technical Illustrator, Informatics Incorporated, Rockville, Maryland Wesley Dean, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Stephanie D. DeVoe, Data Entry Operator, Informatics Incorporated, Rockville, Maryland Steve A. Fairbairn, Applications Manager, Information Processing Services Division, Informatics Incorporated, Rockville, Maryland Rose M. Gerondakis, Secretary, Office on Smoking and Health, Rockville, Maryland st~sezse John F. Hardesty, Jr., Public Information Officer, Office on Smoking and Health, Rockville, Maryland Rebecca C. Harmon, Manager, Graphics Unit, Informatics Incorporat- ed, Rockville, Maryland Reginald V. Hawkins, M.P.H., Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, MarylaGd Linda Herold, Information Specialist, Clearinghouse Projects Depart- ment, Informatics Incorporated, Rockville, Maryland Shirley K. Hickman, Lead Data Entry Operator, Informatics Incorpo- rated, Rockville, Maryland Cindi M. Holgash, Secretary, Clearinghouse Projects Depnrtment, Informatics Incorporated, Rockville, Maryland Robert S. Hutchings, Associate Director for Information and Program Development, Office on Smoking and Health, Rockville, Maryland Barbara Hyde, Editor, Biospherics, Incorporated, Rockville, Maryland Lisa A. Katz, Graphic Artist, Informatics Incorporated, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Assis- tant, tant, Office on Smoking and Health, Rockville, Maryland Julie Kurz, Graphic Artist, Informatics Incorporated, Rockville, Mary- land C. Yvonne Lee, Statistician, Informatics Incorporated, Rockville, Maryland William R. Lynn, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Jacquelene Mudrock, Technical Illustrator, Informatics Incorporated, Rockville, Maryland Judith L. Mullaney, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Marjorie L. Olson, Secretary, Office on Smoking and Health, Rockville, Maryland Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Karen Robinson, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Roberta A. Roeder, Secretary, Informatics Incorporated, Rockville, Maryland Matthew J. Schudel, Editor, Biospherics, Incorporated, Rockville, Maryland Valsala Sekhar, Data Entry Operator, Informatics Incorporated, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Scott Smith, Editor, Biospherics, Incorporated, Rockvilfe, Maryland xv
Page 44: apt20e00
Linda Spiegelman, Administrative Officer, Office on Smoking and Health, R.ockville, Maryland Sol Su, Sc.D., Statistician, Office on Smoking and Health, Rockville, Maryland Carol M. Sussman, Writer-Editor, Office on Smoking and Health, RockviUe, Maryland Selwyn Waingrow, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Melissa L. Yorks, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland . ozz,sezse TABLE OF CONTENTS Preface..................................................................... . V Acknowledgements :..., ................................................ ix 1. Introduction, Summary, and Research Recommendations .................................................... 1 2 Pharmacology and Toxicology,... .................................27 3. C a n cer . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 4. Cardiovascular Diseases ........................................ 111 6. Chronic Obstructive Lung Disease .......................... 131 6. Pregnancy and Infant Health ................................ .153 7. Behavioral liapects ............................................... 173 & Lower "Tar" and Nicotine Cigarettes: Product Choice and Use.............................................................. .. 193 Index ....................................................................... 239 -•.I xvii
Page 45: apt20e00
Section 1. INTRODUCTION, SUMMARY, AND RESEARCH RECOMMENDATIONS T746Sz6S
Page 46: apt20e00
zZLs&zse CONTENTS Introduction Doea-Response Relationship Relative Risks of Lower "Tur" Cigasettee for Specific aseases Methodologies for Assessing Relative Risk Conclusion Summaries Pharmacology and Toxicology C.naer Csrdiovsseular Diseases Chmnic Obstructive Lung Disease Pregnancy and Infant Health Behavioral Aspects Lower "Tar" and Nicotine Cigsrette.: Product Choice and Use Research Recommendations From the worldng Meating "Research Needs on Low Yisld Cigarettes" 3
Page 47: apt20e00
Introduction Great changes have taken place in the cigarette product in recent decades. In 1954, the average "tar" yield of the sales-weighted average cigarette was 37 mg and average nicotine yield was 2 mg. In 1980, the comparable figures are expected to be leas than 14 mg of "tar" and less than 1 mg of nicotine. No cigarette marketed in the United States in 1979 yielded more than 30 mg of "tar."1 Smokers have turned to these new products because of health concerns. In the 1950s, cigarette manufacturers introduced cigarette filters as "health protection" and advertised them widely. The 1964 Report of the Surgeon General's Advisory Committee on Smoking and Health did not discuss cigarette smoke filtration, but in 1966 the Public Health Service reviewed the issue of smoke constituents. That report stated, "The preponderance of scientific evidence strongly suggests that the lower the 'tar' and nicotine content of cigarette smoke, the less harmful would be the effect." Thereafter, Government and tobacco industry seientists conducted studies of cigarette engineering and tobacco cultivation that could_ lead to lower "tar" and nicotine yields. Later, when new products appeared, cigarette manufacturers aggressively promoted them through advertising. The request by Congress for an assessment of the "relative health risks associated with smoking cigarettes of varying levels of 'tar,' nicotine, and carbon monoxide," and "the health risks associated with smoking cigarettes containing any substances commonly added to commercially manufactured cigarettes" has come at an appropriate time. In the 2 years since Congress called for the present study, manufacturers have marketed cigarettes that yield as little as 0.01 mg of "tar" when measured by present Federal Trade Commission technology. The technology of producing lower "tar" cigarettes has progressed well beyond a simple reduction in the amount of tobacco in the cigarette or the removal of a portion of the "tar" by filtration. Present technology has achieved "tar" reduction by alterations in plant genetics, changes in the cultivation and processing of the tobacco leaf, and changes in cigarette paper and filtration of the cigarette. The methods used in testing cigarettes by machine may not correspond to the way persons actually smoke. There is evidence to suggest that the cigarette yields measured by machine are very different from the yields that the consumer actually obtains by smoking the cigarette, due in part to the difference in patterns of smoking between testing machines and Individual smokers. Therefore, "tar" measurements of current cigarettes may not reflect the same rlyr' r Y. o.n d" l• &!. petkd.r n.um at.k.nw rrr. u.l b nW.d by a Q.kkp nMa pe .a...o.rr..t r.~r..d .w.. t. w....oe.% n.1... -w r p...e rr %.wu." wrm u«.aa.i.. wu •l.r' Y rt a dy1....tlprN Y.t..d.fo rf .ry ditw.a etlm1.1 "nN14wb u" eY.m *t awYlwwfa
Page 48: apt20e00
estimate of risk provided by the "tar" measurement of cigarettes manufactured at the time of the 1966 Public Health Service Review. Another closely related concern about lower "tar" and nicotine cigarettes is the use of flavorings and other chemical additives. In order to enhance consumer acceptability, flavoring substances are added to cigarettes; it may be that the lower the "tar" yield, the more flavoring additives are used. It is impossible to make an assessment of the risks of these additives, as cigarette manufacturers are not required to reveal what additives they use. No agency of the Federal Government currently exercises oversight or regulatory authority in the manufacture of cigarette products. Further, no agency is empow- ered to require public or confidential disclosure of the additives actually in use by the cigarette manufacturers. At the same time that changes have occurred in the cigarette, marked changes have occurred in the smoking patterns of the U.S. population that may have substantially altered the risk of smoking lower "tar" cigarettes. Over recent years, smokers have been taking up regular smoking at younger ages, and the number of women who smoke currently far exceeds the number from several decades previously. The multiplicative risks of smoking and oral contraceptive use is an example of bow changes in the population of smokers can make both quantitative and qualitative changes In the nature of the risk. The proportion of the population that smokes has declined, but the average number of cigarettes smoked by each smoker appears to have increased over several decades. Changes have occurred in the environ- ment, dietary habits, and behavioral patterns of the population, which may alter the interaction between cigarette smoking and other risk factors for disease. Thus, we have a continually changing population of smokers who smoke a continually changing cigarette In a continually changing manner. Dose-Response Itelationshlp A clear dose-reaponse relationship has been established between cigarette smoking and a number of disease states; this constitutes a major part of the evidence suggesting that lower "tar" cigarettes may be less hazardous. It is important to understand this dose-response relationship and the limits of the data. The major prospective studies on smoking and disease show that the risk of coronary heart disease and lung cancer increases in a roughly linear manner with incir.asing numbers of cigarettes smoked per day. There is also a marked increase in the risk of death from chronic lung disease with the number of cigarettes smoked per day, but problems in classification of this disease make it unclear whether the relationship is linear. There is no clear evidence of a threshold effect in any of these studies. The relationship between number of cigarettes and disease is strengthened by showing that the risk increases with longer duration R ~~ezse of the smoking habit and with younger age at initiation of regular smoking. Risk is thus closely related to smoke dose as measured by number of cigarettes consumed. The relationship may result from the effect either of repetitive doses or of cumulative smoke dosage. The effect on risk of the time interval between cigarettes has not been thoroughly examined, but there is evidence to suggest that risk is related to the total dose of smoke delivered to the smoker, regardless of the time pattern of exposure.. Overall, disease risk clearly increases with increasing depth of cigarette smoke inhalation. Pipe and cigar smokers who do not inhale have a lower risk of tobacco-related diseases. Thus, it is logical to hypothesize that a reduction in the actual dose of cigarette smoke to the smoker would be accompanied by a reduction in the risk of developing heart and lung disease. "Tar" Is a major portion of the total particulate matter of cigarette smoke. To the extent that the machine measurements of "tar" yield of cigarettes reflect the actual smoke exposure resulting from use of that cigarette, a lower "tar" cigarette should be less hazardous. In order for the measured "tar" yield of a cigarette to reflect smoke exposure, a number of conditions would have to be met. First, changing the "tar" yield should not change the pattern, or style, of cigarette use. If the smoker compensates for reduced yield by increasing the number of cigarettes, the depth of inhalation, or the volume or frequency of puffs, a reduction in "tar" might not result in a reduced smoke exposure. The possible increase in the average number of cigarettes smoked by each smoker and the possibility that the depth of inhalation and puff volume may also have increased as the average "tar" yield of the cigarette has declined raise a real concern that the shift to the use of lower "tar" cigarettes may not have resulted in a proportionate drop in smoker exposure. A second assumption In equating lower "tar" yield per cigarette with lower smoke exposure, and therefore lower risks of disease, is that the reduction in "tar" is accompanied by a similar reduction in all of the constituents of smoke, or at least all of those constituents related to disease. As long as the lowering of the "tar" yield was largely secondary to a reduced amount of tobacco In the cigarette or a €iltration of the smoke, a reduced "tar" yield could be assumed to represent a lower smoke exposure. Prior to 1971, the reduction in "tar" yield was very similar to the reduction in weight of tobacco per cigarette (see Figure 8, Section 8), but since that time the reduction in "tar" has been proportionately somewhat greater than the reduction in weight of tobacco per cigarette, and this difference appears to have increased since 1995. As discussed in this Report, the recent reductions in "tar" yield have been accomplished by altering tobacco growth and processing and by changes in cigarette manufacture. These changes may have produced a "tar" with a different composition from that of 7
Page 49: apt20e00
old higher "tar" cigarettes, and may have changed the concentrations of some of the constituents contained in the gas phase of the smoke. An additional concern is that the production of cigarettes with lower "tar" and nicotine yields may Involve the increaaing use of additives for tobacco processing or flavoring. Some additives available for use are either known or suspect carcinogens or give rise to carcinogenic substances when burned. The use of these additives may negate beneficial effects of the reduction of. "tar" yield, or might pose increased or new and different disease risks. Therefore, the "tar" yield of cigarettes currently being manufactured probably cannot be used as a precise measure of current smoke exposure risk, nor be compared quantitatively with the smoke exposure risk of the older higher "tar" cigarettes. The major prospective studies that provide the data for our assessment of smoking-related health risks examined persons who smoked these older, higher "tar" cigarettes. A third assumption 3n equating "tar" yield with smoke exposure is that the "tar" yield of a machine-smoked cigarette be equal to or at least proportional to the yield of the same cigarette when it is consumed by the smoker. Later sections of this Report dearly establish that the "tar" yield of the current cigarette may vary markedly with style of smoking, with much higher yields being produced by higher puff volumes or occlusion of the perforations in the cigarette wrapper. Thus, the manufacturing changes that have resulted in low "tar" yield measurements may not have resulted in a comparable reduction in the exposure of the individual cigarette smoker. Relative Risks of Iawer "Tar" Cigarettes for Specific Diseases Having examined the nature of the dose-response relationship and some of the limitations of using "tar" measurements as the measure of dosage, we can now examine the evidence available that assesses the relative risk of lower "tar" cigarettes for specific disease processes. An understanding that the different health consequences of smoking may be caused by different smoke constituents is pivotal to these assess- ments of relative risk. Our understanding of the specific etiologic mechanisms by which cigarette smoke constituents cause different diseases remains incomplete at this time.. The individual sections of this Report review in detail evidence on the relative health hazards of lower "tar" and nicotine cigarettes. Assessment of the relative risk of these cigarettes requires the integration of this information; final assessment of the overall relative health hazard of these cigarettes has not been reached. The major issue. is the potential and actual health Impact of the Introduction of these cigarettes into the marketplace. Assessment of this requires under- standing of the changes that have taken place in the cigarette product, the effects of those changes on smoking initiation, cessation, and ~ ~rna of cigarette uee, and the probable health effects of the net s=4sIRzss change in cigarette smoke dose. It also requires an understanding of the changes in risk that occur secondary to switching to lower "tar" cigarettes distinct from the risks of lifelong use of these products. Lung cancer is the disease process in which the relative risk of lower "tar" and nicotine cigarettes has been most clearly evaluated. Approxi- mately 85 percent of the incidence of lung cancer can be directly attributed to cigarette smcking; there are relatively few problems with changing criteria for classification of cause of death, and there is a dear, linear dose-response relationship. Moreover, the "tar" portion of the smoke probably contains most of the carcinogenic activity of the whole smoke. If the reduction in machine-measured "tar" yield is accompanied by an actual reduction in smoker exposure dose, then there should be a relatively proportionate reduction in lung cancer risk. Lower "tar" cigarettes are associated with a reduction in the risk of developing lung cancer, although the proportionate reduction in risk is substantially less than that of "tar" yield.. A smaller percent reduction in lung cancer risk versus that of measured cigarette "tar" yield could result from several factors, including compensation (such as an Increased depth of inhalation or a greater number of cigarettes smoked per day), or from a lack of comparable reductions in other carcinogens. For several reasons, it is difficult to extrapolate these risk reduction data to the current very low "tar" cigarettes. Because the lower "tar" yield of the cigarettes evaluated in the published studies probably was accomplished predominantly by reducing the weight of tobacco in the cigarette and by removing "tar" through filtration, use of these cigarettes might reasonably be expected to result in a lower smoke exposure If compensation did not occur. It is not clear, however, that the alterations in the techniques of tobacco processing and cigarette manufacture that have produced the very low machine-meaeured "tar" yields can be expected to result in similar reductions in actual smoker exposure to toxic smoke constituents. In addition, the potential carcinogenic effect of the substances added to these cigarettes has not been evaluated. The demonstrated reduction in mouse skin tumorigen- icity of "tar" has not, however, been accompanied by a reduction in the Incidence of or mortality rates due to lung cancer among humans. Cigarette smoking is an independent risk factor for coronary heart disease, one that Interacts synergiatically with other risk factors such as hypertension and hypercholesterolemia. The effect of cigarette smoking in coronary heart disease risk is clearly dose related, and cessation of smoking reduces the risk. Estimation of the Impact of varying cigarettes on coronary heart disease risk is difficult, because the exact etiologic agent(s) have not been identified. A number of agents have been suggested to be active In the development of coronary heart disease, including nicotine and carbon monoxide. Any change in risk that might occur because of switching to lower "tar"
Page 50: apt20e00
and nicotine cigarettes might be expected to become evident more rapidly for coronary heart disease risk than for cancer risk, due to the acute effects of cigarette smoke in causing adverse coronary heart disease events such as sudden death. As in the caae of cancer, the expectation that a risk reduction for coronary heart disease would accompany the use of lower "tar" and nicotine cigarettes Is based on the premise that the use of lower "tar" cigarettes results in a reduction of exposure to the responsible smoke constituents. This assumption is reasonable if nicotine is a major etiologic agent, because there is a close relationship between the "tar" and nicotine yields for individual cigarettes. That is, among the cigarettes currently available in the United StAtes, a lower "tar" cigarette is also a lower nicotine cigarette. The variations of the other constituents in the particulate phase of the smoke In relation to "tar" yield is largely unknown, especially in those cigarettes specially formulated to produce very low machine measurements of "tar" yields. Carbon monoxide is one gas In cigarette smoke that may be closely associated with coronary heart disease risk, perhaps through interfer- ence with myocsrdIal oxygenation, enhancement of platelet adhesive. ness, or promotion of atherosclerosis. The relationship between carbon monoxide yield and "tar" yield, however, has not been as thoroughly examined as that between "tar" and nicotine. The factors that influence the carbon monoxide yield are closely related to the manufacturing process (e.g., porosity of the paper, filter ventilation, etc.), and therefore may vary somewhat independently of "tar" yield. In addition, the absorption of carbon monoxide is more dependent on depth of inhalation than is the absorption of nicotine and, if the use of lower "tar" products results in a compensatory increase in depth of inhalation, smoker exposure to carbon monoxide may remain un- changed or actually increase. The reality of this concern is borne out by those studies that show no lowering of carboxyhemoglobin levels in smokers who switch to lower "tar" cigarettes. If carbon monoxide is an active etiologic agent for cigarette-related coronary heart disease, and if significant compensatory changes In the style of smoking occur with .use of lower "tar" cigarettes, then the risk of coronary heart disease with lower "tar" cigarettes may be similar to, or possibly greater than, the risk of smoking higher "tar" cagarettts. Some other agents in the gas phase of cigarette smoke have also been suggested as possible contributors to the development of coronary heart disease. Little is known about the relationship between the yield of the gas phase of the smoke and the "tar" yield. The change in formulation that allows the reduction in "tar" yield of the new lower "tar" cigarettes has not been examined for its effect on the yield of individual gas phase constituents. The potential for creating new aubstances z~6ezse and for increasing the yields of existing gas phase constituents by changes in formulation cannot be assessed from existing data, but may well impact on the risk of coronary heart disease produced by smoking lower "tar" cigarettes. It is not surprising that the studies looking at the relative risk of lower "tar" cigarettes reviewed in the cardiovascular section have not produced a clear estimate of relative risk, given the difficulty in relating a difference In "tar" yield to a difference in coronary heart disease risk and the existence of gapa in our understanding of the etiologic agents in smoke that cause coronary heart disease. Thus, the impact of a reduction in the "tar" yield of cigarettee on the coronary heart disease risk produced by smoking cannot be estimated at this time. Approximately 70 percent of chronic obstructive lung disease deaths are attributable to cigarette smoking. The number of deaths attributed to chronic obstructive lung disease is much smaller than the number of lung cancer deaths. This fact, and the relatively long interval of time between the onset of symptomatic chronic airflow limitation and death from respiratory failure, reduce the usefulness of mortality data from chronic lung disease in assessing the relative risks of lower "tar" cigarettes. Therefore, attention has focused on the level of symptoms and measured reductions in air flow for evaluating relative risk of chronic obstructive lung disease. As reviewed in the section on chronic obstructive lung disease, there are three major aspects of cigarette-induced lung injury: chronic mucous hypersecretion, airway Inflammation and narrowing, and alveolar septal destruction. The causal agents for each type of lung injury may be different, and therefore each type may be affected quite differently by a reduction in the "tar" yield of the cigarette. The mucous hyperseeretion and cough are a response of the lung to the chronic irritant effects of cigarette smoke. To the extent that a reduction in "tar" yield reflects a reduction in smoke exposure, smoking lower "tar" cigarettes should result in reduced cough and sputum production. In the studies that have looked at this question, the expected decrease in cough and sputum production has indeed accompanied the use of lower "tar" cigarettes. Airflow limitation is not produced by mucous hypersecretion per se but rather by airway narrowing and lom of parenchymal lung units. The same studies that showed a reduction in symptoms with the use of lower "tar" cigarettes failed to show a similarly reduced effect on air flow limitation. This finding may indicate that teaG of air flow limitation are not sufficiently sensitive to measure the differences in extent of disease. It could also result from a failure to produce lower exposure to the causative agent(s) with the use of lower "tar" cigarettes, either due to a lack of reduction in concentration of the agent(s) or to compensatory changes in smoking behavior. 11
Page 51: apt20e00
The loss of parenchymal lung units that is the hallmark of emphysema is extremely difficult to measure during life, but there has been substantial progress toward an understanding of how this disease is produced by cigarette smoking. This work is reviewed in detail in the section on chronic obstructive lung disease; it is suggested that alveolar walls are desLroyed by excess proteolytic activity. Cigarette smoke may promote this excees activity through a combination of an increased cellular release of proteolytic enzymes and the oxidative inactivation of the inhibitor of these proteolytic enzymes. Since the airways filter out most of the particulate matter in the smoke, it is felt that the gas phase may be the component of smoke responsible for the changes in enzymatic activity. The gas phase contains a number of agents capable of oxidative inhibition of the enzyme inhibitor alpha,- antitrypsin. Therefore, the risk of developing emphysema may not be related to the "tar" yield of the cigarette smoked. Even if the reduction in "tar" yield results in a reduction In smoker exposure to "tar," a pattern of compensation that produces a deeper Inhalation may deliver a greater dose of the gas phase of that smoke to the alveoli where It produces a pathologic effect. In addition, the techniques used in formulation of the newer very low "tar" cigarettes may result in an increase in the concentrations of etiologic agents In the smoke. Therefore, the relative risk for lower "tar" cigarette usage In the development of chronic obstructive lung disease ia highly problemati- cal. The lower "tar" and nicotine cigarettes may well produce less of the symptomatic component of this disease, but even if they do result in a reduction of total smoke exposure, the pattern of that smoke exposure may negate any reduction in riek. The relative risks for both the mother and the fetus of smoking lower "tar" and nicotine cigarettes during pregnancy are of great concern, both because of the numbers of young women who smoke and because of younger women's more frequent use of lower "tar" cigarettes. The inr,reaaed use of cigarettes with lower "tar" yields has not been investigated for its effect on changes in risk of adverse effects of smoking on pregnancy. Accordingly, no reduction in risk relative to higher "tar" and nicotine cigarettes has been demonstrated. Of particular concern is the potential teratogenic effect of additives and their combustion products. Thus, it In not possible to assume that switching to a lower "tar" cigarette would have an effect in reducing risk during or after pregnancy. It is clear that the only recommenda- tion that can be made to reduce risk In the smoking mother is for her to quit smoking. The ultimate assessment of risk is, of course, overall mortality. One study examined the effect of smoking lower "tar" and nicotine cigarettes on overall mortality. Persons smoking cigarettes with lower "tar" and nicotine yield exhibited a decline in mortality rate from any cause of approximately 15 percent in comparison with that of smokers of higher "tar" cigarettes. Direct extrapolation of these overall mortality results to current smoking exposure is not possible. The lowest "tar" categories in that study included cigarettes that would be considered higher "tar" products today; the mechanisms by which subsequent reductions have been achieved may differ from earlier techniques. There was no evidence available on the duration of use of lower "tar" products in this population. Methodologies for Assessing Relative Risk The task of monitoring the relative risks of lower "tar" cigarettes is complex, but it is not impossible. Four approaches can be used: constituent toxicology, bioassay systems, observational epidemiology, and the study of fundamental mechanisms of disease production. Each approach makes a unique contribution to our understanding of relative risk. Each approach also has significant limitations to its contribution to a complete assessment of risk. It is necessary to combine the information gathered by each of these methods in order to understand the risk. The final assessment of relative risk requires data from each of these four methodologies. To the extent that information from any one area is lacking, the estimation of relative risk is incomplete. The first approach is that of constituent toxicology. A tremendous amount of time and effort has been spent to characterize cigarette smoke and to identify disease-producing smoke constituents. Several thousand individual constituents have been identified. Much has been learned about the effects of cigarette reformulation on the pyrolytic process. Studies have led to a better understanding of human absorption of these substances and how this is influenced by differing patterns of puffing and inhalation. The identification of carcinogens, oxidants, and ciliatoxic compounds represents an important advance in understanding the risks of cigarette smoking. The fundamental strength of this approach is that it might ultimately allow risk to be measured by examining the chemical composition of the smoke and its absorption. Thus, assessment of risk might be made prior to allowing human exposure to the smoke. It could lead to the selective removal of toxic substances from smoke.. The major limitation of this approach is the sheer magnitude of the task. It would be necessary to identify each of the several thousand substances, the site and amount of absorption with different patterns of smoking, and the toxicity for each organ system. It would also be necessary to address the more complicated question of the potential interactions between smoke constituents, environmental and oecupa. tional exposures, and other exposures, such as medications. The monumental nature of this task does not mean that constituent toxicology ia unable to contribute to our assessment of relative risk.. It simply means that it alone cannot solve the problem. The choice of what substances to measure in order to aaseae risk must be guided by r.7%sezse
Page 52: apt20e00
an understanding of the basic mechanisms of disease production and must be correlated with changes in disease occurrence in human populations. In this way the search can be, and is being, focused on those areas and substances that may provide the beat measure of risk. A second method of assessing risk is through the use of bioassay systems. The term "bioassay" is used broadly to Include animal models as well as cellular or organ responsea. This approach can also rapidly provide information on risk without human exposure and has the additional advantage that whole smoke or major fractions of amoke can be tested rather than individual conatituenta. The limitation of this method is that the estimate of risk Is only as good as the bioassay system. Unless the system truly approximates the disease procm of concern, changes in that system may not reflect risk of disease. A number of bkmasay systems exist for the study of cigarette risk. Unfortunately, none of them can be said to exactly duplicate human disease. At the present time, estimates derived from these systems cannot stand alone, but must be interpreted in the light of information derived from other methods. The ultimate "bioassay" is, of course, human ezposure.. The occur- rence of disease in human populations would provide the most accurate estimate of the relative risk of lower "tar" cigarette smoking. An important drawback to this approach is that it permits the develop- ment of that disease In the population prior to measuring risk and taking appropriate public health action. An additional limitation of the observational epidemiology is that the risk being measured is caused by a product and a pattern of use that occurred in the past. Because of the long time lag between regular exposure to smoke and the development of most cigarette-related diseases, and the time lag between develop- ment of disease and diagnosis of that disease, the relative risk determined by observational epidemiologic methods may lag many years behind the current risk. It may take 20 to 30 years before smoking related disease ia observed. With a rapidly changing cigarette product, it is necessary to estimate the risks of current exposures rather than those. of past exposures. This assessment is complicated by the difficulty of defining and measuring any differences in individual smoker exposure resulting from changes or individual variations in styles of smoking. Nonetheless, despite these difficulties, the epidemio• logic method remains the major tool in assessing the relative health risks of differing cigarettes. Some of the limitations of the observational epidemiologic method can be overcome by Incorporating information from the other ap- proaches to risk aeeessment. Information on the toxicology of cigarette smoke might allow epidemiologists to sharpen their measuremept of actual smoker dosage, and might identify earlier tests of toxicity than the traditional end points of disease occurrence or death. Information on the basic mechanisms of disease production could improve the .. ~z~s8zse estimation of relative risk by directed measurement of the basic pathophysiologic processes or their biochemical or metabolic sequelae. An excellent example of this kind of potential interaction is the testing of populations of smokers for the byproducts of elastin degradation suggested in the section on chronic obstructive lung disease. The fourth method of assessing relative risk is the definition of the fundamental mechanisms of disease production. An obvious attraction of this approach is its potential to provide information that would permit the prevention or cure of the disease process. The difficulty with this method of risk assessment is our limited understanding of these fundamental mechanisms. It is important to incorporate what understanding we do have into the risk assessment produced by other methods, and equally important to incorporate information from other methods into the search for disease mecha- nisms. As an example, it would be fruitless to examine the effect of a given substance on the cell function in alveoli if it has been learned from absorption studies that the substance is absorbed in the upper airway and never reaches the alveoli. Once the mechanism of disease is understood, however, an estimate of relative risk might be made, not only by measuring the dose of etiologic agents in smoke, but also those determinants of the disease process pro-existing in a given individual. Conclusion In summary, the final estimation of the relative risk of smoking lower "tar" and nicotine cigarettes must be based on a synthesis of the information derived from several methodologies. Despite the lack of comprehensive and conclusive evidence currently available, the Public Health Service policy on lower "tar" and nicotine cigarettes must remain unchanged The health risks of cigarette smoking can only be eliminated by quitting. For those who continue to smoke, some risk reduction may result from a switch to lower "tar" and nicotine cigarettes, provided that no compensatory changes in style of smoking occur. This Report of the relative risks of lower yields of "tar," nicotine, and carbon monoxide has defined the following more clearly: the conclusions warranted by present evidence; the difficulties and importance of defining and monitoring changes in cigarette yields and actual smoker exposure; and the major questions remaining unan- swered, which constitute the major areas for future research efforts. Summaries of the available data on the relative risks of cigarette- related diseases among smokers of differing cigarettes follow. They are grouped by topic. Following these summaries are the research recommendations from the Working Meeting, "Research Needs on Low-Yield Cigarettes." ib
Page 53: apt20e00
These recommendations are combined, reflecting the common underly- ing concerns among disciplines. Summaries Pharmacology and Toxicology 1. Several thousand constituents have been identified In tobacco and tobacco smoke. Of these, nicotine appears to be the most Important acute-acting pharmacologic agent. Nicotine's physio- logic effects include increased heart rate and blood pressure. Nicotine also can permit the formation of tobacco-specific nitrosamines, which are potent carcinogens, and nicotine itself may be a significant cocarcinogen. The carcinogenic potency of cigarette smoke condensates appears to depend on the nicotine content of the "tar." This relationship may be due in part to the conversion of nicotine to tobaoco-specifie nitrosamines or to the coexistence of nicotine and some other unidentified carcinogen. Whether the carcinogenic effects of nicotine as determined in animal studies are directly applicable to humans is not known at presenh 2In an important study to predict the carcinogenic activity of cigarette smoke oondensate, the amount of available nicotine delivered to the mice was found to be a factor in every term but one of the predictive model. 8. Polycyclie aromatic hydrocarbons and tobacco-specific nitrosa- mines are two prominent classes of tumor initiatora found in the smoke condensates of commercial cigarettes. Of the polycyclic aromatic hydrocarbons formed during combuation, ben- zo[a]pyrene (BaP) may be the most important and has been studied the most extensively. A correlation has been found between benro[a]pyrene levels and the carcinogenic activity of smoke condensates from several types of cigarettes, but other studies have failed to show that carcinogenic potential is significantly dependent on benzo(a)pyrene eontent. However, the Interaction of BsP with nicotine does appear important in carcinogenesis. 4. The tobacco•epecific nitroeamines (TSNA) are formed during curing and fermentation of tobacco leaves and combustion of cigarettes. TSNAs induce cancer in the lungs and trachea of hamsters and may be of particular importance in the induction of human laryngeal cancer. They may be active as contact carcino- gens, or their metabolism at distant sites may produce carcino- gens that are then transported to a target sito. 6. It is not known whether the unidentified mutagens in cigarette smoke are an important cause of lung cancer in humans, but added exposure to any tumor initiators probably carries an increased risk of cancer. 6. Cigarette smoke contains oxidants that have been shown to reduce the activity of alphai-antitrypsin in animals and man. This inhibitory function is distinct from the effect whole smoke has on increasing levels of elastolytic enzymes released by neutrophils and macrophages. 7. The great variety of tobacco types makes it possible to manipu- late the plant genetically to change the content of the constitu- ents of the leaf. The chemical content of the leaf is also affected by agriculturul practices and curing methods. The nicotine content of tobacco, for example, is related to the amount of nitrate fertilizer used in cultivation. Modification of tobacco as reconstituted sheet incorporates substantial amounts of tobacco stems that contain less nicotine than the leaf. The physical nature of reconstituted sheets can be controlled to change their burning characteristics and smoke composition. 8. Vapor-phase constituents of cigarette smoke inhibit ciliary motility and mucous flow in experimental animals. 9. Cigarette smokers metabolize several compounds more rapidly than do nonsmokers. This effect is believed to be caused by the induction of microsomal oxidases, which include aryl hydrocarbon hydroxylase (AHH). Induction of AHH activity appears to be caused by systemic exposure to the smoke compounds themselves or to the metabolites of those compounds. The AHH system may be involved in the metabolic formation of ultimate carcinogens from procarcinogen precursors. 10. In recent years, a number of flavoring additives or cellulose- based tobaooo substitutes may have been included in manufac- tured cigarettes. The nature and amounts of such additives as actually used are not known, nor is it known what influence these additives may have on the chemical composition or subsequent biological activity of cigarette smoke. 11. Cigarette design has a major effect on smoke composition. The filter is the design characteristic that has the most impact on "tar" yield; it can also selectively remove nitrosamines and semivolatile phenols from smoke. The porosity of cigarette paper and the presence of holes in the mouthpiece Influence smoke composition because ventilation reduces the quantity of "tar" and dilutes the gas phase of smoke. 12. Because of the complexity of cigarette smoke, the total impact of any cigarette modification on smoke composition will probably never be fully known. 13. Many laboratory studies of the effects of smoke constituents have been carried out using smoking machines that control puff volume, frequency and duration, butt length, and other factors . sz4sSZSS?
Page 54: apt20e00
according to standardized parameters. However, the most widely used parameters were established in 1967, and the type of cigarettes generally smoked today are substantially different with respect to length, paper porosity, "tar" and nicotine content, and concentration of gas phase constituenta Evaluation of the toxicological and pharmacological properties of smoke from new types of cigarettes requires detailed knowledge of the manner in which those cigarettes are smoked, as well as of how smoking patterns affect smoke composition. Cancer 1. Today's filter-tipped, lower "tar" and nicotine cigarettes produce lower rates of lung cancer than do their higher "tar" and nicotine predecessors. Nonetheless, amokers of lower "tar" and nicotine cigarettes have much higher lung cancer incidence and mortality than do nonsmokers. 2 Smokers of lower "tar" and nicotine cigarettes may tend to smoke larger numbers of cigarettes, to inhale more deeply, to have relatively higher amounts of carboxyhemoglobin than predicted from machine measurements of carbon monoxide yield, and to have higher than predicted carbon monoxide in exhaled air. 3. In attempting to develop a''leas hazardous" cigarette, singular emphasis has been placed on reducing the "tar" yield of cigarette smoke because of the early demonstration of a causal relationship between "tar" and lung cancer. Comparable data on changes in yield of constituents in the gas phase of smoke are not publicly available. 4. The occurrence of laryngeal cancer has been reported to be reduced among smokers who use filtered cigarettes, compared with those who use nonfiltered cigarettes. 6. There is no cpidemiologic evidence to prove or to disirrove a decreased occurrence of cancers of other sites in humans who smoke lower "tar" and nicotine cigarettes. 8 In evaluating the effect of smoking lower "tar" and nicotine cigarettes on histologic changes in the bronchial epithelium, it was determined in one autopsy study that male smokers who died between 1970 and 18?7 had fewer histological changes than those smokers who died between 1900 and 1955. 7.. Even among those who do not develop cancer, histologic changes In the tracheobronchial tree are more advanced at autopsy in smokers of cigarettes with higher "tar" and nicotine than among smokers of cigarettes with lower yields. S. The "tar" content of smoke condensate of today's cigarettes is leas tumorigenic to mouse akin than that of cigarettes of 80 years ago. Levels of the known carcinogen benrro[a]pyrene are lower In oC,4sszse the smoke of today's cigarettes than in that of cigarettes of 30 years ago. Flavor additives used in lower "tar" and nicotine cigarettes produce traces of mutagenic compounds. 9. Although studies point to polycyclic aromatic hydrocarbons in the "tar" of inhaled cigarette smoke as potential carcinogens for humans, additional work is needed to determine whether nicotine playa a major role as a carcinogen. Definition of the role of nicotine in carcinogenesis is necessary prior to advocacy of cigarettes yielding less "tar" but more nicotine. 10. Animal studies have shown that a significant reduction of "tar" and a selective reduction of tumor initiators and cocarcinogenr can markedly reduce the tumorigenic potency of cigarette smoke. Cardiovascular Diseases 1. Epidemiological studies show that the incidence of coronary heart disease (CHD) increases as the daily number of cigarettes smoked increases and that the incidence of CHD decreases among those who quit smoking. These dose-related effects suggest that lower "tar" and nicotine cigarettes might be associated with lower risks of CHD. However, the overall changes in the composition of cigarettes that have occurred during the last 10 to 15 years have not produced a clearly demonstrated effect on cardiovascular disease, and some studies suggest that a decreased risk of f HD may not have occurred. 2. Of the several thousand substances found in cigarette smoke, only a few have been implicated in cardiovascular risk. A number of substances have not yet been adequately assessed. Further, the changes in smoke constituents that have resulted from changes in the cigarette product have not been documented. 3. Linking cigarette smoke yields to cardiovascular disease is complicated by the evidence that smokers of lower "tar" and nicotine cigarettes may smoke more "intensively," although they may not smoke a substantially greater number of cigarettes daily than do smokers of higher "tar" and nicotine cigarettes. The net result could be to decrease the actual intake of "tar;" nicotine, and carbon monoxide less than that expected on the basis of machine measurements. 4. Nicotine stimulates the sympathetic nervous system, producing a rise In catecholamines that in turn increases heart rate, elevates systolic blood pressure, constricts cutaneous blood vessels, and increases levels of free fatty acids. The nicotine-stimulated release of catecholamines has been suggested as the cause of increased platelet stickiness and aggregation, pointing to a potential role in coronary disease. There is somee evidence that these physiological effects may be dose related and somewhat diminished with lower nicotine varieties of cigarettes. 19
Page 55: apt20e00
5. Carbon monoxide has a negative inotropic effect on the myocar- dium of patients with angina pectoris. When combined with hemoglobin in the form of carboxyhemoglobin, carbon monoxide may increase the permeability of the blood vessel walls to lipids, thereby promoting atherosclerosis. 6. Cigarettes with unperforated filters yield lower "tar" and nicotine levels than unfiltered cigarettes, but they yield more carbon monoxide than do unfiltered cigarettes at the same "tar" yield. Carbon monoxide yields are lower In cigarettes with perforated filters, but as the composition of cigarettes has changed, carbon monoxide yields have decreased much less in proportion to the decrease in "tar" and nicotine yields. 7. In studies of patients with angina pectoris, increased carboxy- hemoglobin levels significantly shorten exercise time until the onset of angina pectoris. 8. Myocardial ultraatructural changes have been found in rabbits bits exposed to carbon monoxide. 9, Most cardiovascular studies have focused on nicotine and carbon monoxide rather than on "tar," which has not been shown to have a major acute role in cardiovascular diaease. Even leas is known about other constituents of cigarette smoke. 10. Not all cigarettes that produce a lower yield of one substance necessarily provide a lower yield of other substances. 1L Evidence on the association between CHD and filter cigarettes is somewhat conflicting. One major study showed a reduction of 10 to 20 percent in coronary deaths among persons smoking lower "tar" and nicotine cigarettes as compared with those who smoked higher yield cigarettes, but other surveys have shown a slightly increased risk of coronary mortality in people who smoked filter cigarettes relative to those who smoked nonfiltered cigarettes. Recent unpublished data from the Framingham Study do not show a lower CHD risk among smokers of filter cigarettes. Chronic Obstructive Lung Dieease 1. The relationship between cigarette smoking and chronic obstruc- tive lung disease (COLD) is well documented. The constituents of cigarette smoke that are responsible are currently not known. Whether a difference in risk of COLD has occurred with lower "tar" and nicotine cigarettes as compared with higher "tar" and nicotine cigarettes is currently unknown. 2 Cigarette smoking is associated with the release by alveolar macrophages of an increased amount of the elastolytic enzymes, which degrade alveolar tissue, and with reduced activity of alpha,-antitrypein, the primary elastase inhibitor. This mecha- nism has not yet been directly related to the development of human emphysema. To date there are no published studies that ,cUsezss compare the effectA of higher versus lower "tar" and nicotine cigarettes on elastolytic enzymes and inhibitor activity. 3. Cigarette smoke also contains relatively high levels of oxides of nitrogen. The nitrogen oxides produce lung damage in animals that is similar to that induced in humans by cigarette smoke. The oxides of nitrogen may be responsible for the early lesions of human emphysema. 4 An individual's smoking pattern is one of the most important determinants of the relative concentration of smoke constituents that reach the lungs and of the subsequent response of the airways to smoke Inhalation. Holding smoke In the mouth before inhaling it into the lungs produces lesa response of the airways than direct inhalation, which causes spirometric changes indica- tive of bronchoconstriction. This effect is independent of the "tar" content of the cigarette. 5. Pulmonary mucous hypersecretion and symptoms of cough and phlegm appear to be affected by the "tar" content of cigarette smoke. The development of airway obstruction is closely related to the number of cigarettes smoked. Smokers of lower "tar" and nicotine cigarettes who compensate by smoking more or inhaling more deeply might thereby increase their risk of developing obstructive airway disease. ' 6. Population studies that have examined the rate of decline of lung function in relation to the number of cigarettes smoked have shown variable results, and most of the available data do not relate lung function to cigarette yield. Overall, the mean difference between the rate of decline of FEVi in asymptomatic smokers and nonsmokers is very amall, but there is a subgroup of the smoking population that shows more rapid decline and is apparently more likely to develop significant pulmonary disease. Pregnancy and Infant Health 1. Cigarette smoking during pregnancy has been shown to have adverse effects on the mother, the fetus, the placenta, the newborn infant, and the child in later years. There is no evidence available that lower "tar" and nicotine cigarettes decrease or increase these health risks, relative to those posed by higher "tar" and nicotine cigarettea 2 Problems that have been linked to smoking during pregnancy include placenta previa, abruptio placentae, vaginal bleeding, and reduced average birthweight of newborn infants. 8. Smoking by pregnant women increases the risk of spontaneous abortion, premature delivery, fetal death, and perinatal death. Parental smoking is associated with the sudden Infant death syndrome.
Page 56: apt20e00
4. The fetuses of smoking mothers have higher blood carboxyhemo- globin levels and lower fetal arterial oxygen levels than do the mothers. 5. Children of smoking mothers appear to show a greater suscepti- bility to some adverse health effects, such as bronchitis, pneumo- nia, and respiratory disease, during early childhood. Slight differences in physical growth and other forms of behavioral and Intellectual development may be found in children as old as 11 years of age. 6. Although "tar," nicotine, carbon monoxide, and some other constituents of cigarette smoke produce deleterious effects, the specific etiologic agents and their mechanisms of action for adverse effects on pregnancy are not clearly determined.. Thus, the relative importance of "tar" and nicotine, or carbon monoxide and other constituents of tobacco smoke in the etiology of adverse gestational and fetal events is not known. Behavioral Aspects 1. Nicotine appears to be the primary pharmacological reinforcer in tobacco, but other pharmacological and psychosocial factors may also contribute a reinforcing effect. 2 It appears that some smokers make compensatory adjustments in their smoking behavior with cigarettes of different yields that might Increase the amounts of harmful substances entering the body. The frequency and amount of spontaneous compensatory changes in smoking style with different cigarettes require further investigation. $. Additional information is needed on the role of lower "tar" and nicotine cigarettes in the initiation, maintenance, and cessation of smoking. 4. Rigorous comparative behavioral studies involving animals are needed to provide comprehensive, experimentally valid results on behavioral aspects of smoking. 5. Laboratory techniques developed for study of opioids and alcohol should be adapted for studies of tolerance and dependence on nicotine. 6. Improved laboratory facilities are necessary for more tightly controlled behavioral research. A particular need exists for clinically acceptable cigarettes with standardized ingredients. 7. Smoking machine measurements that more closely simulate the practices of human smokers must be developed. Lower "Tar" and Nicotine Cigarettes: Product Choice and Use 1. Public awareness of the dangers of smoking has steadily increased since 1965. In 1978, more than 90 percent of all Americans helieved cigarette smoking to be hazardous to health. ze~sezse 22 2 Cigarette product choice has shifted dramatically since the 1950n. In 1979, 91.7 percent of U.S. smokers used filter-tipped ciga- rettes, compared with 1.4 percent in the early 1950s. . 3. Lower "tar" cigarettes conventionally have been defined as yielding 15 mg of "tar" or less per cigarette. The proportion of all cigarettes consumed in the United States that are lower "tar" has increased from 3.6 percent in 1970 to almost 50 percent in 1979. In 1979, 58.5 percent of all cigarette brands marketed in the United States yielded 15 or fewer mg of "tar." 4. Since 1968, the "tar" content of the "average cigarette" in the United States has declined by 32.2 percent, and nicotine content has fallen by 25.6 percent. These declines may be partially accounted for by lower tobacco weight per cigarette-down 23.8 percent from 1968 to 1978-and by the greater length of the filter and overwrap of the average cigarette, which could result in a declining number of machine puffs per cigarette. 5. The prevalence of smoking in the U.S. adult and adolescent populations has continued to decline. In 1979, 325 percent of the adult population smoked cigarettes (36.1 percent of men and 29.4 percent of women). However, evidence suggests that the average daily number of cigarettes consumed by those adults who continue to smoke has Increased over several decades. The availability and use of lower "tar" cigarettes have increased over recent yeara.. 6. In 1979, 83.8 percent of adult regular smokers used cigarettes yielding 15 mg "tar" or less. Studies show that women smokers are more likely to use lower yield cigarettes than men are, and white smokers use lower yield cigarettes in greater proportions than do blacks. Smokers of higher income and education also select lower yield cigarettes In a higher percent of cases. 7. A large national survey found that smokers in older aged cohorts choose both the lowest and highest yield cigarettes in higher proportions than do younger cohorts. 8. Although black smokers choose cigarettes of higher "tar" and nicotine in greater proportions than do whites, the lower daily number of cigarettes smoked by blacks suggests that their average daily intake of "tar" and nicotine may be lower than that of white smokers. 9. In 1979, 53.5 percent of adolescent smokers (age 12 to 18) used lower "tar" cigarettes, compared with 0.7 percent in 1974. Boys and girls smoke cigarettes of about the same level of "tar" content. 10. Adult smokers started smoking regularly at the average age of 18 years. One survey showed that the higher the "tar" level of the cigarette currently smoked, the younger the reported age of beginning smoking. 23
Page 57: apt20e00
11. Evidence from a large national survey does not support a correlation between a greater mean number of cigarettes smoked per day by users of lower "tar" and nicotine cigarettes than by higher "tar" users. 12.In a national survey, smokers of lower "tar" and nicotine cigarettes more frequently reported having attempted to quit at least once, and among these smokers, a higher proportion report having attempted unsuccessfully to quit multiple times. The applicability of these data to defining the role of "tar" or nicotine yields of cigarettes in quitting behavior is not clear in the absence of more detailed longitudinal data, 13. Although a greater proportion of unsuccessful quitters reported amoking the lowest "tar" and nicotine products than did recent auccessful quitters In one large survey, interpretation of these data is made difficult by the noncomparability of brand reported (i.e., unsuccessful quitters reported the brand smoked after an attQmpt, successful quitters reported the brand smoked prior to the attempt). 14. In a large national survey, the mean duration of the latest unsuccessful attempt to quit shows no clear relationship to "tar" or nicotine yields. Research Recommendstlons From the Working Meeting "Research Needs on Low-Yield Cigarettes" The following list is an overview of research recommendations submitted as a result of the working group reports from the June 1980 conference "Working Meeting: Research Needs on Low-Yield Ciga- rettes." No attempt has been made to place them in order of priority. • It must be determined whether lower "tar" and nicotine cigarettes change smoking behavior. For instance, compensatory adjustment, such as deeper, longer, and more frequent puffs, may turn a nominally lower yield cigarette into a higher yield cigarette. Studies are needed to determine whether adjustments made by smokers of lower "tar" and nicotine cigarettes may inadvertently increase their exposure to "tar" and carbon monoxide beyond that expected from a less intensively smoked higher yield cigarette. • Because of ehanges in cigarette composition, further retrospec- tive and prospective epidemiologic studies ara needed to assess the health effects of these changes. A primary need is to establish whether there are measurable differences in morbidity between smokers of higher "tar" and nicotine cigarettes and smokers of lower "tar" and nicotine cigarettes. Efforts should include ongoing long-term studies that are adaptable to such epidemiologic inquiry. EUsezse • The increased use of nonhuman primate models might pernut comparison of the effects of lower "tar" and nicotine cigarettes with those of higher "tar" and nicotine cigarettes under controlled conditions. • More indepth studies on the mechanisms of cardiovascu and pulmonary disease are needed to assess new brands of~ower "tar" and nicotine cigarettes. With improved noninvasive tech- niques, scientists will be better able to determine how a particular cigarette affects cardiac function and other physio- logical activities. Genetic markers should be explored as a possible method of identifying high-risk groups who are more likely to develop tobacco-related diseases if they smoke. • Additional emphasis should be given to both human and animal research models for the developmental mechanism of chronic obstructive pulmonary disease and its possible alteration by lower "tar" and nicotine cigarettes. The elastase-inhibitor imbalance hypothesis of emphysema pathogeneais needs confir- mation for human disease. Recently developed tests that measure lung elastin degradation products in plasma and urine need rapid clinical evaluation. • Emphasis should be placed on studies that determine the character and magnitude of the health hazards that lower "tar" and nicotine cigarettes pose for pregnant women and their offspring. Specifically, the smoking habits of pregnant women should be analyzed in prospective epidemiologic studies to determine the effect of varying cigarettes on the course and outcome of pregnancy. Careful laboratory measurements of various physical capacities and functions of newborn infants and pregnant women should be performed in case-control and prospective studies to determine the influence of smoking on pregnancy outcome. Clinical and experimental studies using animals should be conducted to evaluate the effect of individual constituents of cigarette smoke on tissues and physical re- sponses. Direct intervention strategies should be aimed at pregnant adolescents who amoke. • Another research need is routine, frequent surveillance of current and future lower "tar" and nicotine cigarettes for specific chemical constituents and biological activity. In addition to "tar," nicotine, and carbon monoxide yield, new types of cigarettes should be monitored regularly for delivery of other potentially harmful constituents, such as bens,o[a]PyreRe, phe- nols, catechols, nitrosaminea, nitrogen oxides, volatile aldehydes, and radionuclides. More frequently updated ratings of "tar," nicotine, and carbon monoxide content would permit more accurate studies on the potential impact of cigarette components on health.
Page 58: apt20e00
• More data are also needed on cigarette flavor additives and their combustion products. Flavoring agents and additives should be studied by cigarette companies for carcinogenicity and toxicity before their commercial use is permitted, and the results of such studies should be made available. • Research should be done on the distribution, partitioning, and penetration of lower "tar" and nicotine cigarette smoke in the lung, with consideration of potential changes in smoking patterns by those who smoke lower "tar" and nicotine ciga- rettes. Cigarette smoking-mschinea currently in use and the techniques by which animals inhale cigarette smoke in research models may not be representative of the human situation because human smokers are able to take larger, more frequent, and higher velocity puffs. To conduct meaningful assays of cigarette yielda and the biological activity of cigarette smoke, it must be determined how smokers actually smoke various types of commercial cigarettes. When this information is available, it will be possible to design smoking-machines that yield more accurate estimates of human risk. • Controlled studies are needed to determine the role of nicotine as a primary reinforcer in cigarette smoking and to determine whether thero are other chemicals in addition to nicotine that may contribute to or reinforce the smoking habit. By analyzing the mechanisms whereby nicotine reinforces smoking behavior, it may be possible to design more efficacious methods of smoking cessation. • Research should be conducted to define what effects modifica- tions of the physical and chemical properties of leaf tobaccos have on the pharmacology of cigarette smoke. Since tobacco culturing and curing practioes are continually changing, it is important to determine whether such changes as the use of new pesticides also alter the composition and biological activity of cigarette smoke. • Standardized experimental cigarettes have frequently proved unpalatable and unacceptable for behavioral research, Proto- type cigarettes should be especially designed to deliver a wide range of constituent concentrations, particularly those that approximate commercial cigarettes. This would allow research• ers to predict the behavior of smokers of new types of cigarettes more accurately. b~~6ezse 26
Page 59: apt20e00
CONTENTS sC4sezse Introduction Experimental Systems for Assay of Relative Risks of Cigarette Smoking Lung Cancer Animal Models Lung Carcinogens in Cigarette Smoke Polycyclic Aromatic Hydrocarbons Tobacco-Specific N-Nitrosamines Other Mutagenic or Co-.mutagenic Agents Weak Acids Nicotine Polonium 210 Volatile N-Nitrosamines Bladder Cancer Laryngeal Cancer Other Cancers Early End Points Suggestive of Carcinogenic Potential Chronic Obstructive Lung Disease Sudden Death Due to Cardiovascular Disease Animal Models Nicotine Carbon Monoxide Other Agents Complications of Pregnancy and Early Childhood Nonspecific End Points of Toxicologic Significance Reduction of Lung Defense Mechanisms Induction of Microsomal Oxidase Changes in Genetic Status Changes in Immune Status Composition of Smokes From Various Types of Cigarettea Smokinq Machine Design Dependence of Smoke Composition on Cigarette Design Filtees Ventilation Tobacco Variety Agricultural Practice Reconstituted Sheet and Modified Tobaccos
Page 60: apt20e00
Addi tives Variations in Human Smoking Behavior Research Needs Surveillance of New Cigarettes Determination of Paramcters of Human Cigarette Smoking Evaluation of Health Effects of Nicotine The Effects of Smoking-Machine Parameters on Relative and Absolute Yields of Smoke Components From Various Types of Cigarettes Influence of Raw Product Modification on Pharmacology of Cigarette Smoke Physical and Chemical Properties of Smoke From Cigarettes Delivering [.ess Than 10 mg of "Tar" Development and Validation of Analytical Methods Other Research Needs Summary References LIST OF FIGURES Figure l.-Effect of cigarette smoke differing in selected chemical components on pancreatic elastase levels in beagle dogs after a 600-day exposure protocol of 12 cigarettes per day, 7 days per week LIST OF TABLES Table i.-Major toxic agents in the gas phase of cigarette smoke (unaged) Table 2-Major toxic agents in the particulate matter of cigarette smoke (unaged) so 9C4sezse Table 8.-Coeif'icients and standard deviations of coefficients for Prediction Model 10 Table 4.-Comparison of mutagenic and tumor-promoting activity of fractions of cigarette smoke condensate 31
Page 61: apt20e00
Introduction Tobacco and tobacco smoke are very complex mixtures. In 1968, Stedman (155) reported that they contained more than 1,200 clearly identified substances in addition to a number of polymer classes, such as pigments, resins, and proteins, that were not resolved into specific compounds. Since that time, many additional compounds have been isolated; at least a thousand additional constituents were found in tobacco and tobacco smoke in the following 10 years (ey). Cigarette smoke components arise through distillation of volatile and semivola-e tile materials from the leaf and from the pyrolytic decomposition of leaf constituents. In addition, nonvolatile components of tobacco leaf can be transferred to the smoke without degradation. Thus, the components of smoke are very diverse. Many suspected or proved toxic agents have been identified in the gas phase (Table 1) or in the particulate matter (Table 2) of smoke (190). It is not surprising that chronic exposure to such a complex mixture will lead to a variety of pharmaeologic and toxicologic responses. 4C4sszsg TABLE 1.-Major toxic agents in the gas phase of cigarette smoke (unaged)• Anot Biololie C.aamt+aWNdgantte aetiritr npat.d , drae.ttast Dieelhy6itroMaha C 1-20 tq 13 ag EthylmetAyloilrormina C 0.1-10 -s6 1.1 e` DiNbyWir..ai.. C 0-10 nff 1.i nr Ni4e.opyn.fidin. C ?.42 ej 11 a` ol}w alraamlee. 0 a.mporaa.) C 0-Z0 ob 1 Hrdrazie. C 24-4 ec 82 e` Y6q1 diloride C 1-16 sff 12 ar Ufeth.ns TI 10-W eb 30 aff rarndd.Ayds cr, CoC 20.10 rr 30 pC Hydror.e q.nida CT, T W2D0 pC 110 K Aeolein CC 70_1a PC 70 PC Ae.1.Id.Ayd. CT 1s-1A00 pg 800 pg Nitr.ffrn oddo (NU.p T 10-600 K 360 K Ammonla T'N 10-150 K 00 M fyrkie. Tf+ 0-ie K 10 K Cuboo teawdd. T Z-9D aE 17 .s •elp.nw Oq.rW oa.r rh erduer.r as uraS Ha.l e.e.a,yl,..a p.iM. ..rur dIwfa.wa d.ns ar aw...~.n.. •C lsslr.ndatbw;ll, l•r WtlNar CtC~ me.rd.or..; GT. dtla /ads y..R aad t, t.dt y..~ t0{ ar lfr.IM wN6wt fYlw tip 00•a1t a1 tIN Opqa N.eLN lrlt-1YJ0. •Ne•>I/x Noi -110. •lla wsr I. rl..(N.dd U!A ay.atta eanrt Pn <fi, d thw.M sa..d. a•r ry.aaa re pF.,•a .rrrprorUrt.a, SoU[tCC I/yaetr.M Mdha.aa U")6
Page 62: apt20e00
TABLE 2.-Major toxic agents in the particulate matter of eigsr.tte anoke (unaged)• Aj..t DwiNk .dMur RP.w apAla.b 6.na(hwne. Tx $40 .0 a0 .S N[WrylekraM T1 Ob -t a0 oA .ff BsoQXMwr..uuo. Tt 540 .0 10 .g 9.r(a1ntM..... Tt cao .d a .~ othr p.b.odM ,n.aq. .ydeo ..~b... (9V) «mw..d.) T[ T T ~ 4~hata.. T~i tlo s s t s ~iSal~MtoM Tt 0.7 .0 0.706 Pr- cAC ro-ao+ s uo s iWa.au... Cac 60-06. .0 l70 .0 owr- itm.Ne b~ao• coC u-6o .0 OD ,~ rebor (>10 wp..b) CoC T T N&*ksMw CaC 1-10 K { M 1-Y.ugli.ds{r CaC O3-0.0 Pg 91 K 6.Yaaeawb.nlo cbC 00054 3 Pg 9.1 K o16.e nrUd ao.pardr G9C T t atetbd cac +o,bo K ?I0 ,K L a 4WtbAbal.eior CaC Io.ID Fg 72 K otl~e obeMY ~+ ~o.~w.d~) CoC t T U.kno.. pMwir Sad .at& C.C t T N'.NWN.riw.f.qr C l0aiE0 as 760 .C otbW .wwWb lfUw.ir C T T aNwOwwmf• DC aa oC 79 .R ouW L..uk .mir 6C 7 7 Uak.o.. .iM .spw.b sC T T Pdoeis3l0 c QZ-13 pt7 T Nkkd wpor.& C 10a00 .g T CWah. wipo..di C 940 ac T An..ie C 1-ffi K I NbNlr T O.1aA we 16 sg Yi.or Nbs.m sabW T o.01-U .e a1 s0 ee.,a Cr 1oaoo PC af K C.w4 (i aeapamd.) CT IO-Ibo PC 70 K • 1,,".bW r.L 'C awlr.rr..rq OR tl.llr.rd..pr, Tf, (r.r W Wk.; O.C,...ed.y..i Cl..oi. wd..v..k od T. N~-dplMl~ 1il~w{ I{Ma Yp Mq~{ N Ibq.~.r~K M1F1r'K /OUpCS: Ry.d.r wl adtr..(!M1 Experimental Systems for /kssay of RelaUve Risks of Cigarette Smoking Lung Cancer AniTnal Modala The mouse skin carainogenesis aseay is thus far the most fruitful method of evaluating smoke condensates from different types of cigarettes for carcinoQenic potency for the human lung (46, 51, 89,106). 34 91:4sezs9 This model for the development of cancer dates back to 1915 (191). A large body of laboratory experience has provided consistent evidence for the quantitative validity of this relationship. Procedures providing good dose-response relationships are in use in many laboratories. Assays can be standardized to give relatively consistent results within a laboratory, and probably among laboratories (QS, 6d, 64, 65). The assay depends on a number of similarities between the laboratory model and human e:periencx. The epithelium of both the skin and lung is directly exposed to the presumptive carcinogenic agent-in this case, cigarette smoke or cigarette smoke condensate. Rabbit and mouse skin develop tumors after exposure to coal tar, a known occupational carcinogen. Mouse skin assays have predicted occupational induction of human lung cancer by bis-chloromethyl ether (Li8,17T). It is conceivable that the mouse skin carcinogenesis assay may give a misleading measure of the relative risk of various types of cigarettes. Skin is covered with a lipid film, and the pilo-sebaceous apparatus is particularly suited for penetration of lipid materials into the skin. In contrast, the airway surface is covered by an aqueous film and might be less readily penetrated by fat--soluble materials. There is no evidence, however, that such a difference is important. Indeed, the response of mouse skin to different types of experimental cigarettes is roughly parallel to the response of hamster larynx to the same rnaterials (48, 50,189). The hamster larynx has been used for comparative studies of different types of cigarettes (17, b0, 68). Invasive carcinomas of the larynx were induced in 87 percent of inbred hamsters exposed to cigarette smoke for 59 to 80 weeks.. Both the cancer incidence and the incidence of other epithelial changes were dose related. Exposure of rats and mice to cigarette smoke for up to 2% years resulted in a small incidence of respiratory tract tumors, primarily pulmonary adenomas (44, 68, 72). Cigarette amoke produced changes in cultured human gastric epithelial cella suggestive of malignancy (158). Lung Car+cimgeru in Cigarette Smoka Experience in man and with the mouse skin system indicates that two or more distinct classes of carcinogenic stimuli lead to the occurrence of tumors (16, 26, 48). Tumor initiators appear to alter the genetic constitution of the cell; tumor promoters accelerate and enhance the neoplastic expression of previously initiated cells. Both may play a role in the induction of tumors. Other types of cocarcino- gens may also play a role in the induction of mouse skin tumors by cigarette smoke condensate (16, 74, 89,176). If similar mechanisms act in man, it may not be possible to differentiate between a human carcinogen in the conventional sense and a cocarcinogen or tumor 35
Page 63: apt20e00
promoter acting on a diverse population already exposed to low levels of a variety of tumor initiators. Two prominent classes of tumor initiators are found in smoke condensates of commercial dgarettes-polycyclic aromatic hydrocar- bons (PAH) and toba(xo-specific nitrosamines (TSNA). Other carcino- gens or tumor initiators are present in cigarette smoke as well; however, they appear to be lees significant because they either am leee potent or are present at lower concentrations than are PAIf or TSNA. Polycyclic Aromatic Hydrocarbons A large variety of PAH molecules are formed by the pyrolytic process during combustion of the cigarette (87, 105). Of the PAHs, benzo[a]pyrene (BaP) is the most prominent and has been studied moet intensively. Chemical asaays for BaP in smoke condensates are well established, and It has been suggested that such assays can serve as indicators of production of all of the PAH.. This appears to be generally true. Among smoke condensates from 98 experimental cigarettes, the correlation coefficient between BaP and bens[a]anthracene content was 0.78 (15). Although highly significant, the value is sufficiently low to indicate that real differences do exist in the ratios of these cyclic molecules in the various cigarette smokes. Nevertheless, BaP appears to be the most Important single member of this clasa of compounds, taking Into consideration both its concentra- tion and its relative carcinogenic potency. The contribution of BaP or PAH in general to mouse skin carcinogenesis by cigarette smoke condensate cannot be fully mea- sured at this time. Wynder and Iioffmsnn (188) found a correlation between BaP levels and carcinogenic activity of smoke condensates from several types of cigarettes. A much larger series of experimental cigarettes was studied in the smoking and health program of the National Cancer Institute. No significant dependence of carcinogenic potency on BaP content was observed (6t, 6J, 64, 65). The relationship between chemical composition of the experimental smoke condensates and the biological activity of this series was examined extensively by Bayne (15). He employed the linear terms, squared terms, and all interaction terms between any 2 of 10 independent variables. Starting with a 66-term regression equation, he searched for simpler prediction models that would provide useful estimates of carcinogenic activity. The simplest model (Table 3) that retained good predictability contained nine terms. The interaction of BaP with the nicotine term was one that appeared important. BaP and other tumor initiators are particularly important because humans are already exposed. to a number of Initiators in the envtronment. The effect of initiators is cumulative and irreversible. Hence, any additional exposure to initiators such as the PAH might be expected to increase tumor Incidence in smokers. TABLE 3.-Coefficients and standard deviations of coefficients for Prediction Model 10 l tnueeepe s c 0 a 4 pH 6 VWA f N: N T pH z pH e N: pH 1 N s BAl slana.re deriatiem c~erria..(. of awraanu zeaT am -t.TpO Z:-s 02T4 Gi 4.El6 64 0.106 &4 3.IS1 r-1 0.0110 1r.-1 1?.12 &] 0.660 61 U30 E-8 O.EES }}4 1683 LF-4 O.e75 G! -T.OTB 6-4 leb/ E-{ -LT10 &i O,S7T 64 'C-Oftesobetka Lsl&rx vwA-..q ,.mt .da. (Gwgl: N-rs11.. (.Wda .r sAr-e.re(.by,.e. Ws. uacas,y..Gh. TobaccaSpecific N-Nitrosamines During tobacco curing, fermentation, and burning, nornicotine givea rise to N'-nitroeonornicotine (NNN), nicotine to NNN and to 4-(N- methyl-N-nitroaamino).1{3.pyridil}1-butanone (NNK), and anatabine to N'-nitrosoanatabine (NAT). NNN is a moderately active carcinogen, inducing tumors in the respiratory tract of mioe, rats, and hamsters. NNK is a strong carcinogen, inducing lung carcinoma in each of the three animal species (75, 84, 86), The concentration of these carcino- gens in cigarette smoke is very high in comparison with usual environmental exposures, being 1 to 85 ppm in tobacco and 1 to 9 µg in the smoke of a cigarette (57). These tobacoo-eperific N-nitrosamines may play a role in the development of several types of human cancer. NNN is metabolically activated by human liver microeomes (T8) and, together with NNK and NAT, may be formed in vivo from the tobacco alkaloids. Other Mutagenlc or Co-mutagenic Agents It is generally believed that tumor initiators are mutagens that can be detected by one or more short-term biological assays (2, 10J). A number of fractions of cigarette smoke eondensate are positive in the Ames assay system (9J, 101).. The agents responsible for this activity have not been fully identired, but probably Include products of protein pyrolysis (119). Ames test activity, however, does not predict the activity of fractions in the mouse skin carcinogenesis assay. Fractions of smoke condensate that show activity as complete carcinogens (89) or in a promotion assay that would detect akin carcinogens as well as tumor promoters (t4) am not correspondingly active In the Ames system (Table 4). It cannot be determined whether the unidentified mutagens in cigarette smoke are an important cause of lung cancer in seZ,sezse
Page 64: apt20e00
TABLE 4.-Comparison of mutagenic and tumor-promoting activiq+ of fractions of cigarette smoke condensate Y.Up.k AoeotrK .didtV'- .etl.ty- enea~ y4W r . P.a.t.p r . Pr'a..W+ .r .w. .t wt ».. .iu eooe.u.b wbo1k a.d.r.t. saaar (K...c r. (raN (ao& K d. 4u» s~ e.z01% WWMs Bw .ha. h.olYw. 9..u, Wr.okM. D...., ..cr .dVw W..k addI, iroi.bM N..t .dd4 .tlr.da6N si..s .a+.k r.ak,d. ai..& ..ik .u.r .wei. 84w9 .i+ti ..tw ..M" liatnlti sS otlirol .ol.bl. M.rddti qdde.r wbb4 HwtrnY, .iYa.dh... iatd4 21 4 81 11 11 4 I = so s 1 E9 : t <t S <t s : 7 sl 13 ! s •r..M t.r.r b.rwi. Md..Mt r Soa.d..." humans; however, added exposure to any tumor initiators probably carriea an incremental risk of cancer. Weak Acids Cigarette smoke contains weak organic acids that exhibit tumoti promoting or oocarcinogenic activity (84, T;,1 T6). The concentration of very weak acids in cigarette smoke condensates was one of the terma predictive of the skin carcinogenic activity of smoke condenaatea (Table 3). Of the weak acids, catechol appears to be the most important on the basis of concentration and activity (74,176). 1 It is probable that the weakly acidic constituents of smoke act as tumor promoters or oocarcinogena rather than as tumor initiators. This is true for phenols and for catechol (27, 176). There is no reason to believe that tumor promoters or other types of eocarcinogens exhibit either a cumulative or an irreversible effect. Indeed, for tumor promotion in mouse skin by croton oil, clear thresholds for frequency of application and for the amount of promoter In each applied dose are apparent (td). It this is also true for man, the risk of very small doses of weak acids might be negligible. Phenol (1t8, 188), but not catechol (20), can be selectively removed by filters. The extent to which the oocarcinogenic weak acids are reduced by selective filtration cannot be determined at this time. ered. ~..a...~. wo wo RNartialud s lls Nicotine Nicotine exhibits neither complete carcinogenic activity nor tumor- promoting activity. The nicotine content of cigarette smoke condensate did not affect its carcinogenic activity when suspended in beeswax- tricaprylin pellets implanted in rat lungs (43); however, in mouse akin bioasaays, this alkaloid is an important cocarcinogen (20). Not only Is nicotine active in models with other compounds such as BaP and 1Z0- tetradecanoytphorbol-l8-acetate (TPA), but also the measured carcino- genic potency of cigarette smoke condensates appears to depend on the nicotine content of the "tar." Of all of the individual compounds of smoke condensates assayed in the smoking and health program of the National Cancer Institute, nicotine was most closely related to carcinogenie activity (68, 6s, 64, 65). In the simplest predictive model developed by.Bayne, every term but one involved nicotine concentra- tion, pH, or the concentration of crude condensate (Table 3). The availability of nicotine to the tissues depends on the pH and concentra- tion of condensate. Hence, available nicotine was a factor of all but one term of the prediction model. Nicotine may also play a role in the development of oral cancer in tobacco chewers. Aqueous extracts or unburned tobacco exhibit tumor- promoting activity when tested on mouse skin. This activity depends on the presence of nicotine acting together with a fraction having a molecular weight greater than 13,000 daltona (81). In addition, nicotine gives rise to carcinogenic N nitroaamines during tobacco chewing (84). Data of Moroaco and Goeringer (1t8) suggest that nicotine reduced serum alpha,-antitrypsin activity and elevated pancreatic elastase levels in dogs exposed to cigarette smoke. These workers believe that interference with the protease-protease inhibitor balance may be a factor in carcinogenesis (1YJ). It must be pointed out that the relationship between carcinogenic activity of smoke condensates and their nicotine contents may be caused in part by the conversion of. nicotine to tobacco-specific nitrosamines or to the co-occurrence of nicotine and some other unidentified carcinogen. For example, the nicotine level of tobacco is dependent on the amount of nitrate fertilizer used in tobacco culture (16B). High levels of tobacco-specific nitrosamines were found In the unburned tobaecos usually raised with high levels of nitrogen fertilizer (77). The level of volatile nitrosamines In cigarette smoke also depends on nitrate fertilizer (170). One may postulate that the nicotine level of cigarette smoke condensates is an indicator of such nitrogenous carcinogens that were not measured directly. At preeent, however, there is no direct evidence that this is the case. In any event, the carcinogenic activity of mixtures of pure BaP and TPA are enhanced by the concomitant application of nicotine under conditions such that nitrosamine formation would not be expected (20). 39 04sezse «n
Page 65: apt20e00
Whether the eocarcinogenic effects of nicotine are important for man is a matter of speculation. Tumor-promoting activity of croton oil exhibits a threshold both for frequency of application and for the quantity of agent preaent with any given treatment (g6). The animal studies in which nicotine acts as a cocarcinogen employ nearly lethal levels of nicotine administered once or twice a day. In contrast, smokers are exposed to a large number of low doses of nicotine daily. If a threshold amount of nicotine per dose is required for cocarcinogenic activity, human smokers may not be affected in a manner similar to that of the mouse skin system. Polonium 210 There have been repeated suggestions that IMPo might contribute to the carcinogenic activity of cigarette smoke in man (1d7). Polonium levels in tobacco result primarily from the use of phosphate fertilizers that are contaminated with radium demy products, particularly naPb, a precursor of 214Po (168,168). Very little mPo is found in tobacco leaf, but some is transferred to the smoke. Yields of 10 to 15 fCi of alpha emitters were recently reported for experimental cigarettes and 490 fCi/gm for commercial cigarette smoke condensate (s6). Most of the radioactivity was due to insoluble forms of m*Po. Cancer may arise from a single affected oell. It has been suggested that small amounts of insoluble ZWPb concentrated in small arese might deliver an effective carcinogenic dose to a target cell (112). Harley et al. (71), however, found very few "hot spots" in the lungs of deoeased smokers. Based on human experience with radon daughters, they assumed a lifetime risk of lung caneer of 1 x 10= for a dose of one rad/year. At most, the radioactivity they deteeted was estimated to explain only 10 percent of the lung cancers suffered by cigarette amokers. They consider polonium 210 a questionable risk factor in human caMnogenesis. Polonium 210 contamination of tobacco can be effectively reduced by selection of plant types and sources of phosphate fertilizer, and by removal using chelating agents (71,171). Volatile N-Nitrosamines Tobaoco smoke contains a number of secondary and tertiary amines. These amines, together with nitrogen oxides, may give rise to the in vivo formation of nitrosamines. Although the formation of most nitrosamines is favored at low pH (110), a small amount of volatile nitrosamines is found in cigarette smoke and may be formed in the lungs under normal conditions (30, 4 170).. The volatile N-nitrosa- minea are organ-specific carcinogens, which in mice give rise to tumors of the liver and kidney. At present, there is no reason to assume that volatile nitrosamines cause lung cancer in smokers. Nevertheless, it is r-dent to limit the presence of any carcinogen in cigarette smoke. Volatile nitroaamines in smoke can be reduced by selective filtration and by limiting the nitrate content of tobaocos (10,1g1). Bladder Cancer The induction of bladder cancer in animals has been studied intensively over the past several decades. The bladder appears to be a particularly sensitive target for agents that are metabolized in the liver and excreted in the urine. Among the compounds known to produce bladder cancer in both man and animals is P-naphthylamine. The presence of O-naphthylamine in cigarette smoke has been demon- strated (85), along with other carcinogenic aromatic amines (1g9). The yield was so low, however, that they did not believe these agents contributed significantly to the risk of bladder cancer in smokers. The urine of 10 smokers and 21 nonsmokers was examined by Yamasaki and Ames (18g) for mutagens or for substances that were converted to mutagens by rat liver microsomes. Increased levels of uiutagens were found in the urine of seven smokers, but in none of the nonsmokers. If promutagens in urine are responsible for the bladder cancers occurring in cigarette smokers, it is possible that certain individuals are particularly sensitive to bladder carcinogenesis by cigarette smoke. If true, this sensitivity may be exploited for disease prevention. Large quantities of mutagen-containing urine can be collected from sensitive individuals. Isolation and identircation of the promutagens might permit removal of the precursors from cigarette smoke. Lryngeal Cancer Hamsters develop laryngeal cancer after long term inhalation of diluted cigarette smoke (17, 50, 58). The effect is dose related and has been used to compare different cigarettes. Tobacco-specific nitrosa-s mines induce cancer in the trachea and lungs of hamsters and may be of particular importance in the induction of human cancer of the larynx (84). Other carcinogens and cocarcinogens of cigarette smoke that are active in the mouse skin bioassay system may also contribute to induction of laryngeal cancer. Both organ systems involve epithelial tissue directly exposed to the carcinogenic mixture. Other Cancers Cigarette smoking is also associated with cancer of the kidney, panrreas, oral cavity, and esophagus (17J). No animal model of these cancers has been developed to the point where it could be used for quantitative comparisons of different types of cigarettes. Oral cavity and esophageal tumors may be induced by direct exposure to smoke carcinogens. NNN, when given in the drinking water of rate, induces cancer of the esophagus (8.i). This finding suggests that tobacxoo- I UP4sezse
Page 66: apt20e00
specific nitrosamines may be active as "contact" carcinogens. Alterna- tively, the carcinogens might be produced through metabolism at distant sites, such as the liver, and then transported to the target site, where they can be further activated. Pancreatic cancer was induced in hamsters with diisopropylnitrosamine (134). This observation suggests the possibility of a similar action of smoke nitrosamines. Any carcinogen in cigarette smoke might contribute to induction of cancer distant from the exposure site. To this extent, elimination of the carcinogens causing lung cancer or bladder cancer would reduce the induction of cancer in other organs as well. Alcohol usage and cigarette smoking show synergistic effects in the induction of'canoer in the upper digestive tract (11J,17't). The effect of alcohol in this circumstance may result from the induction of microsomal enzymes, which are believed to metabolize carcinogens to their active forms (111). Early End Points Suggestive of Carcinogenic Potential It is generally considered that the induction of cancer requires a specific genotoxic event that may be preceded or followed by ill- defined and less specific epigenetic changes that enhance the manifes- tation of the genetic event (182). In the two-stage carcinogenesis system of mouse skin, the first step-initiation-appears to be genotoxic, and the second step-promotion-appears to be epigenetic.. Several other forms of cocarcinogeneais have been described (1b). Tobacco smoke owes its carcinogenic activity to several carcinogens and cocarcinogens (t4, 87,176,188). Agents capable of producing genetic change can often be detected by mutagenesia assay systems (2). Most carcinogens are mutagens. Conversely, agents capable of inducing mutations are suspect as possible carcinogens. Cigarette smoke condensates and some of their fractions are mutagenic in the Ames salmonella assay systems (0, 119). Theae fractions are clearly of interest because they possess the capability of inducing genetic changes that might lead to tumor formation. Mutagenesis assays may provide a basis for the quantita- tive comparisons of new cigarettes when the relative importance of the genetic and epigenetie factors in smoke-induced cancer is understood. The Ames teat gives poor results for fractions of smoke condensate that appear to be most active In systems designed to detect tumor- promoting activity (Table 4). Furthermore, mutagenesis assays of a aeries of experimental cigarettes have not provided consistent results (189'). The complexity of carcinogenesis by tobacco smoke condensates renders mutagenesis assays of uncertain value for quantitative comparisons of relative carcinogenicity. Several in vitro systems measure the transformation of normal cells Into malignant cells after exposure to carcinogens. These systems are sensitive to both t[enetic and epigenetic processes (90,188). Such assays may prove to be useful short-term indicators of the relative potency of different types of cigarette smoke. The toxicity of moat experimental smoke condensates may interfere with the conduct of such studies, however. Experimental cigarettes that yield smoke condensates with a wide range of carcinogenic activity are now available. It should be possible to determine the usefulness of in vitro systems with this material. For organ-specific carcinogens, the DNA repair test is a good predictor of relative carcinogenic activity (186). Most chemicals that are carcinogenic to mouse skin selectively destroy the sebaceous glands of the treated skin (23). The sebaceous gland suppression assay is a good predictor of the activity of experimental smoke condensates as carcinogens in mouse skin (22).. Chronic Obstructive Lung Disease No animal models for chronic obstructive lung disease are available to measure the potency of smoke from various types of cigarettes. Long-term inhalation studies with hamsters, dogs, and primates have not given rise to disease states comparable to emphyse- ma observed in humans (17, 50, 5t,114). In two experiments, Sprague- Dawley and CD rats exposed to cigarette smoke for 6 to 26 months developed emphysematous changes (104,184). Similar results were not reported in other long-term studies with rats (.K Q8). A number of pulmonary function tests have been evaluated as measures of early lung disease In man (31, 61, 7S, 100, 1J5, 154). Thus far, similar tests have not proved useful as animal assays. They might, however, be useful in comparing the effects of different types of cigarettes on human smokers. Expoeure'of CD rats to whole tobacco smoke for 6 months led to a loa9 of lung parenchymal tissue distal to the terminal airways (124). This was indicated by a 21 percent decrease in parenchymal tissue and 12 percent decrease in alveolar surface area. Recent evidence suggests that emphysema results from a shift in the balance of elastase production and elastase inhibition in the lung (97). A few individuals with genetically determined very low levels of alpha,-antitrypsin, an elastase inhibitor, are particularly prone to develop the disease (53). When purified elastase is instilled Into the lungs of dogs, emphysematous changes appear in as little as 90 minutes (9a, 98). Cigarette smoke can act on this system in two ways. In vitro tests with cigarette smoke condensate show that this material suppressed the antiprotease activity of human serum, pulmonary lavage fluid, and purified human alpharantitrypsin (94). The suppression of protease inhibitors by cigarette smoke is blocked by the presence of phenolic antioxidants, suggesting that oxidanta or free radicals of'the smoke were responsible for the effect (107). In one study, the serum levels of alpha,-antitrypsin in smokers were higher than In nonsmokers (7Q). Another study found, however, that immbdiately after smoking, serum 43 •~ z~~,sezse
Page 67: apt20e00
alphai-antitrypsin activity was reduced in smokers (95). Likewise, the activity of ilpharantitrypsin in lung lavage fluid from Sprague- Dawley rats was reduced by 80 to 40 percent after 3 to 6 puffs of cigarette smoke. Similar reductions were observed in lavage fluid from the lower respiratory tract of asymptomatic smokers (54 Even greater differences were seen between smokers and nonsmokers with idiopathic pulmonary fibrosis. Cigarette smoke also stimulates the release of elastase from nuuxophages in vitro and in vivo and from polymorphonuclear leukocytes in vitro (19,14.t,185). Thus, smoke may increase the elaboration of elastase in the lung and at the same time suppress its inactivation. The techniques used in these studies eould be applied to smoke from various types of cigarettes; they might then serve as short-term end points to evaluate relative cigarette risk.. Dogs exposed to cigarette smoke through tracheostomies for 600 days had significantly higher levels of pancreatic elastase than sham- smoked controls (1t!). The greatest effects were seen in animals exposed to higher nicotine cigarettes, although the blood carboxyhem- oglobin levels were the same for both higher and lower nicotine smokers (Figure 1). The lower nicotine cigarettes in this study were. produced by removal of the alkaloid by a commercial process (65). It cannot be stated with confidence that other constituents were not removed as well. Sudden Death Due to Cardiovascular Disease Animat Modela No animal model permitting the quantitative comparison of death rates due to cardiovascular disease induced by different types of cigarettes is presently available. Long-term Inhalation studies using smoke-exposed rats, hamsters, dogs, and primates have been conducted (17, d.{, 50, 5t, Q8,10.t,11d). None has provided an end point comparable to sudden death observed in human smokers. There are, however, several avenues of investigation whose Intermediate experimental observations might indicate a mechanism for mortality caused by cardiovascular effectaa Much attention has been given to changes induced by nicotine-induced catecholamine release (1J8, 156, lBd). Methods to follow these effects In animala are well eatablished. Other short-term end points being studied include lipoprotein levels (79), alteiation of arterial morphology (9, 10, 18, 111), and changes in arachidonic acid metabolism (1t, 82). These procedures might be adapted for estimation of the relative potency of various types of cigarettea, but there is no direct evidence that any of these changes are either necessary or sufficient indicators of the risk of sudden death due tn 1heart diseaae. CtP4s9zSe W 7 10 s- COCE 32 CooE 13 OONTNOI. FIGURE 1.-Effeet of cigarette smoke differing in selected chemical components on pancreatic elastase levels in beagle dogs after a 600-d.y exposure protocol of 12 cigarettes per day, 7 days per week. $sn indicate mean t$D. Animals exposed to code 32 (high-nicotine) and code 13 (low•nicotlne) cigarettes diffee+ed signiflcantlY (pE005) in pancreatic elastase levels from corresponding .ham4xposed controls. Si:nificant differences were also observed (pC0.05) between code 32 and code 13 cigarette innokera (Student t-test). sovaca w.e...+ o..+.,.r cfM Ni,cotine It has long been known that nicotine elevates blood pressure and heart rate and may increase the onset of angina pectoris attacks. These effects were summarimd. in the 1976 report, 2fie Heatth Conaequenees of Smoking (17b). Nicotine readily passes through biological mem- branes. The level in the breast fluid of smoking women ia similar to that found in the plasma (81}.. The heart rate of fetuses of smoking women is elevated, apparently caused by transplacental passage of nicotine (127, 1J8). Thus, nicotine causes widespread effects in the smoker. An estimate of the relative potency of various cigarettes with respect to the acute cardiovascular effects of niootine can be deter- mined by direct chemical assay of relative levels of nicotine In the smoke.. By measurement of urinary excretion of nicotine and its major
Page 68: apt20e00
metabolite, cotinine, it is possible to estimate the individual smoker's actual exposure to nicotine. Nicotine appears to have measurable effects on performance by smokers (1a9,18J). This may acoount for the apparent role of nicotine in the reported tendency of some individuals to compensate when switched from higher to lower "tar" and nicotine cigarettes (60, 119, 1.i8,1.i8,14y). Carbon Monoxide The effects of carbon monoxide in reducing the oxygen-carrying capacity of the blood are well known. More recently a body of evidence has linked carbon monoxide directly to disease states and to early end points that might be predictive of disease (11,108). Aronow has shown that carbon monoxide, along with nicotine, decreased the duration of exercise achieved before angina (6, 7, 8). In his studies, a non-nicotine cigarette made of Indian herbal leaves was employed. Smoke from these cigarettes was more active than expected on the basis of its carbon monoxide content. Aronow (6) attributed this effect to a "tobacco eomponent" other than nicotine or carbon monoxide.. . The effect, however, could well have been caused by a specific herb constituent. Models using pigeons, rabbits, pigs, and primates have been employed to study early end points for carbon monoxide effects (4, 11, 118). To the extent that carbon monoxide is responsible for cardiovascular disease, determination of the relative potency of various cigarettes In affecting cardiovascular disease can be made by chemical assay of cigarette carbon monoxido yield. Othsr Ayants It has been suggested that agents of tobacco smoke other than nicotine and carbon monoxide contribute to its cardiovascular effects (4,116). Until these agents are identified or an alternative explanation for tobacco effects is established, animal models predictive of cardio- vascular death in smokers will be important. Complications of Pregnancy and Early Childhood A full understanding of the potential effects of smoking on pregnancy and early infancy is still being developed. Most of the current information available was reviewed in the 1980 report, TRs HcalUi Conacquencst of Smoacir g for Women (174). Maternal smoking causes changes in the vascular structure of the placenta and increased fetal heart rate (9,10,1t7,118). Maternal carboxyhemoglobin (HbCO) is elevated in smokers, leading to an elevated fetal HbCO and thus to a reduced oxygen content of the fetal blood (108). Some, If not all, of the smoking-related complications of pregnancy are attributed to nicotine and carbon monoxide (108). The relative hazards of lower "tar" and nicotine cigarettes with respect to these agents can be determined by chemical assays of carbon monoxide and nicotine. Actual disease risk, however, will be affected by the delivered dose of these constituents, which in turn depends upon the individual's style of smoking. Other constituents of smoke might also contribute to complications of pregnancy. Comparisons of various types of cigarettes should be possible through epidemiological study, coupled perhaps with evaluation of the vasculature of human placenta (9,10). Recent reports indicate that cigarette smoke might contain active transplacental carcinogens (S4, 125, 140). The importance of this in human cancer will probably not be determined soon. No animal assays have yet been applied to assess the relairive health hazard of varying cigarettes in tranaplacental carcinogenesis. Nonspecific End Points of Toxicologic Significancs Cigarette smoke and its components cause several conditions that may relate to human disease in nonspecific ways. Using assays with these end points may provide useful measures of potential risks due to smoking. Reduction of Lung Defense Mechanisma Vapor-phase constituents of cigarette smoke inhibit ciliary motility and mucous flow In experimental animals (1J, 14). With ciliary paralysis, removal of other toxic materials from the lung will be inhibited. Animal models suffer some limitations in attempts to duplicate the human situation. For example, many of the ciliastatic agents In the gas phase of smoke are absorbed In the upper airways of man and may not reach areas in the lung where they could affect bronchial cilia (A. Furthermore, the concentration of ciliatoxic agents in cigarette smoke will depend on the ainount of dilution of smoke by air that occurs during inhalation. Accordingly, the interpretation of animal studies requires care. Similar effects occur in humans, however. Clearance of FeaOi dust from the lungs of smokers is dramatically slower than from the lungs of nonsmokers (8y). Induction of Microsoma! Q~cidaae Cigarette smokers metabolize several compounds more rapidly than nonsmokers (38, 39, 89, 18?). This effect is believed caused by the induction of microeomal oxidases, which include aryl hydrocarbon hydroxylase (AHH). The level of AHH itself is much higher in placentas from smoking women than from nonsmokers (1s0, 131, 178). Activation of these enzymes has also been observed in the lungs of rats, hamsters, and mice exposed to cigarette smoke (1, S9). Guinea pigs, in contrast, showed a reduction in pulmonary AHH after smoke exposure (18). Induction of AHH activity appears to result from - VV4sezse `°
Page 69: apt20e00
systemic exposure to the smoke compounds themselves or to the metabolites of theee compounds. Some carcinegens, Including PAH, induce AHH ($8). More important, the AHH system is Involved in the metabolic formation of ultimate carcinogens from procarcinogen precursors (118). Cigarette smoke may play an indirect role in carcinogenesis among smokers through this mechanism. Assay of the inducibility of AHH as a measure of individual sensitivity to cigarette smoke haa not proved useful (116,1t8); however, screening of enzyme activity in tissues of human or animal smokers of different types of cigarettes might prove useful for indicating the relative potency of the different dgarettes. Chang" in Cenetie Status To the extent that an early step of carcinogenesis involves genetic change, one would expect that exposure to cigarette smoke might cause detectable changes in genetic material. It is reported that heavy smokers have higher incidences of chromoeomal aberrations and higher rates of sister chromatid exchange than do nonsmokers (91). Animal models with such end points are feasible, but have not been applied to assays of the toxicity of various cigarettes. Changes in Immu" Statua Recent reports suggest that smoking causes changes in immune function (66, 68, 14.4), but the contribution of theee effects to major disease states is unclear. Man with malignant melanoma who smoke are more likely to develop metastases than are nonsmokers, perhaps as a consequence of impaired immune systems (16.t). Composition of Smokes Fronm Various Types of Ciyarettes Smoking-Machine Design Laboratory smoking machine parameters historically have been standardized to permit Interlaboratory comparisons and to provide reproducible baselines with which modified cigarettes can be com- pared. Somewhat different parameters ara used in different countries (88). In the United States, the most widely used standards are those employed by the Federal Trade Commission (1ss). The machines deliver a$b m1 puff from the cigarette over a 2-second period with a bell-4haped puff profile. The cigarettes an puffed once each minute to the &fined butt length of 23 mm (nonfiltered cigarettes), or to a butt length 3 mm longer than the filter overwrap (filter-tipped cigarettes). The butt length is different from cigarette to cigarette, sooording to the length of the overwrap. . These parameters were established in 1967 when the great majority of -sqarettes consumed In the United States were nonfiltered and 70 or 85 mm in length. They were based, in part, on observed smoking patterns in a limited number of human smokers. The types of cigarettes smoked today are substantially different with respect to length, paper porosity, pressure drop, "tar" and nicotine yield, and the concentration of gas phase constituents. Cigarette smoking machines can be designed, however, to control puff volume, frequency of puffing, duration of puff, the profile of puff pressure over time, butt length, position of cigarette during and between puffs (e.g., horizontal or vertical), and "restricted" or "free" smoking between puffs (i.e., whether the butt end is closed or open). The puff volume can be measured in terms of the air entering the cigarette or the air plus combustion gases leaving the cigarette. Smoking-machines could be designed to change the puff frequency and the nature of the puffs during the course of smoking a single cigarette (41, 4s). Human smoking patterns are diverse and span a wide range from one individual to another (40, y8,189). Some individuals compensate for lower yield cigarettes by changing their style of smoking (80, 1d9, 14.0, 148, 180). These changes can include increasing puff volume, duration, or frequency, or changing the puff pressure profile. In summary, human smoking behavior may be quite different from standard emoking machine behavior. Furthermore, the average smoker may have a different smoking pattern for each different type of cigarette. The chemical composition of smoke is affected by smoking-machine parameters. "Tar" yield per puff depends on puff volume, puff frequency, butt length, and the frequency of puffing at different stages of cigarette consumption (188, 193, 184). The concentrations of several specific chemical constituents of "tar" are controlled by the puff frequency, volume, and duration (Chortyk, O.T., and Schlot• shauer, W.S.S., personal communication). If the human smoking pattern varies systematically with the type of cigarette, the relative yield of various chemical constituents delivered to the smoker may vary substantially from that measured by machine. Accordingly, evaluation of the toxicological and pbarmaeologic potential of the smokes from new types of cigarettes will require knowledge of the manner in which those cigarettes are smoked by the consumer and of the effect of smoking patterns on the composition of smoke. Dependence of Smoke Composition on Cigarette Design The composition of smokes from different types of cigarettes can be described by absolute yields per cigarette or per puff, or by the concentration of constituents per unit weight of "tar" or per unit volume of smoke. Modifications of cigarette design can affect yield (quantitative change) or composition of the smoke (qualitative change).. Information with respect to individual constituents Is avail- able for many modifications. However, modifications affecting the sV4sszss
Page 70: apt20e00
concentration of one substance will also affect the levels of other substances as well. Because of the complexity of cigarette smoke, the full impact of any cigarette modification on the composition of the smoke in either absolute or relative terms can never be ascertained. For this reason, bioassays with appropriate end points are essential to determine the relative toxicities of new types of cigarettes. Several modifications of cigarettes reduce the mouse skin carcinogenic activity of the smoke eondensate,. These include choice of leaf variety, use of reconstituted sheet, and use of tobacco substitutes. Filters The design characteristic of commercial cigarettes that most affects the cigarette yield is the filter. In 1980, the "tar" yield of cigarettes, ss reported by the Federal Trade Commission or by advertisements, ranged from 30 mg for unfiltered, king-size cigarettes to as low as 0.1 mg for some filter-tipped brands (5S). Filters selectively remove nitrosamines and semivolatile phenols from the smoke (88, 110, 126, 188). Thus, not only the absolute delivery of these constituents but also their relative concentration In cigarette "tar" depend on the filter. Ventilattion A second major influence on the composition of cigarette smoke is ventilation of the cigarette by the use of paper with a high degree of porosity or by the presence of holes in the mouthpiece. When more air is drawn through the paper or through the mouthpiece, the amount of air drawn through the burning coal of the cigarette is reduced. This effect will reduce the quantity of "tar." By altering the burn temperature, it will also change the combustion process and thus the composition of the smoke. Ventilation also dilutes the gas phase of the smoke with air, causing a marked reduction in the concentration of gas phase constituents in the smoke (66, 8J,1t6). Tobwco Variety A substantial collection of tobacco lines is available to plant geneticists. These include 63 species related to tobacco and about 1,000 different tobacco varieties (164). The wealth of this material permits genetic manipulation of the leaf, which could be used selectively to enhance or to reduce the content of specific constituents. Among flue- cured tobacco lines available at present, the nicotine concentration varies from 02 to 4.75 percent (34). Among various burley lines the concentration varies from 03 to 4.58 percxnt. The ranges could be extended by agronomists, should that be desired. Changes in yield of many other smoke constituents might be achieved by genetic modifica- tion. Apricultu7+at Pr+aatice The chemical composition of tobacco leaf is also affected by agricultural practice and by curing methods (161, 163). High levels of nitrogen fertilizer Increase nicotine and nitrate levels of the leaf. Growing plants more closely together reduces the nicotine content of the lcaf. Flue-cured tobaocos are harvested, leaf by leaf, as each is ripe, but the entire plant of burley tobacco is harvested at once. Changes associated with leaf maturity depend on the harvesting practice. Enzymatic degradation of leaf constituents is halted by heat during flue curing. In contrast, burley, Maryland, and oriental tobaccos are not heated to this extent, so that more extensive enzymatic changes occur. As a consequence, thec+e is a markedly lower sugar content in burley tobacco along with a markedly higher content of pigment polymers. Homogenized leaf curing (HLC), if commercially developed, could permit better control over these chemical changes. Furthermore, specific leaf constituents such as soluble proteins may be removed during homogenized leaf processing. Cigarettes made with HLC tobacco yielded smoke containing significantly less dimethylnitrosa- mine and condensate having significantly less sebaceous gland sup- presaion activity (165,169). Reeo=titttted Sheet and Modified To6aaooa The composition of cigarette smoke is also affected by the use of reconstituted tobacco sheet and modified tobaccos (62, 61, 64, 65). Reconstituted sheet can contain substantial amounts of the tobacxo "stem," which has a different composition from that of the leaf lamina. The stem is noteworthy for having a low nicotine content. In addition, the physical nature of reconstituted sheet can be controlled to change its burning characteristics and hence the composition of the smoke. In recent years, some cigarette tobacco has been "expanded" or "puffed" Using this material, less tobacco Is required to fill the cigarette. The manner in which the tobaooo is shredded also affects the burning rate and therefore the composition of the smoke (47). Cellulose-based substitutes have been used as a replacement for tobacco (17, 85). These materials cause substantial differences in the total yield and chemical composition of the smoke. Additives Humectants and flavoring agents have long been used as additives in cigarette manufacture. The advent of reconstituted tobacco sheet (RTS) technology expanded the possibilities for the addition of subtances to the sheet during the processing of tobacco for the manufacture of cigarettes (1?',i,188). It is possible to add substances to the tobacco slurry or suspension for extraction of specific constituents, for dilution of the sheet, for burn rate acceleration or retardation, for K, sV4sezse 51
Page 71: apt20e00
ash cohesion, and for enhancement of flavor (smoke aroma and taste) (65,151). Additionally, one process for curing tobacco leaf calL for the addition of exogenous enzymes to tobacco (169), and as noted above, artificial tobacco substitutes are also available. In recent years, cigarette manufactureea' advertisements have focused on the flavor of new lower "tar" and nicotine cigarettes, enhanced presumably by the addition of tobacco constituents or by the addition of new flavoring materials, such as natural or synthetic ehemtcals. The identities and amounts of the additives actually used In the manufacture of U.S. cigarettes are not known. Systematic Information has not been published or made available on the influence of these additives on the composition or biological activity of cigarette smoke. Variations In Human Smoking Behavior It does not appear possible to fully monitor smoking behavior in humans without the subjects' knowledge. Butt lengtha can be mea- sured in a variety of settings, and puff frequency can be observed without distorting smoking behavior. Measnrement of puff volume and duration and of Intensity of inhalation, however, requires instrumenta- tion that may lead to alteration of usual smoking behavior. Neverthe- less, despite these limitations in objectivity, recent studies provide better data than those available in the past. Smoking measurements reported from England, Germany, and Canada differ from those used for smoking6machines in the United S.tates (is9, 141, 1d0). If the average American smoker, as well, is taking larger puffs with a greater frequency than Is the machine, the absolute yields of smoke constituents are under-rhported in the United States. This Is not to say that the relative yield of "tar" between cigarettes is compromised; however, if smokers puff different types of cigarettes in different ways, the relative yields may be grossly distorted.. For example, some smokers block the perforations in the mouthpiece of ventilated cigarettes (102). These smokers receive substantially more "tar," nicotine, and gas phase constituents than would be predicted from machine-amoked cigarette yields. Because this action would affect the yield only of ventilated filter cigarettes, the relative ranking of eigarettes by yields would be affected. Similarly, emokers' behavioral compensation for low nicotine delivery can affect the relative yields of filter-tipped cigarettes (d0,1.tt). R.sZarch Ne.ds Many gape In our assessment of the pharmacological properties of cigarette smoke can be f7led by a coordinated, well-directed research program. In comparison with the economic and medical costs of cigarette smoking, the size of the required program is modest. Rerourees sufficient for implementation of a meaningful program are available. For example, except for assays of "tar," nicotine, and carbon monoxide yield, new types of cigarettes are not being monitored regularly for the delivery of potentially harmful smoke constituents. Scientists currently conducting sophisticated assays of cigarette deliv- ery of various smoke constituents could serve as resource personnel in the design of an appropriate approach to assays of new cigarettes for suspected toxic agents. Other scientists are investigating short-term end points indicative of long-term risk from many diseases. These laboratories could assist in modifying these procedures specifically for cigarette smoke and its conatituents. Surveillance of New Cigarettes The chief research need for the study of redueed'"tar" and nicotine cigarettes Is the routine and frequent surveillance of current and new cigarettes for specific chemical constituents and biological activity. The chemical constituents should include nicotine, benzo[a]pyrene, phenols, catechols, nitrosaminea, carbon monoxide, nitrogen oxidea,' volatile aldehydes, and radionuclidea. The biological assays should include sebaceous gland suppression assays, mutageneais assays, studies of the effects of smoke on airway and ciliary function and on the increase of urinary metabolites related to the activity of elastase, and such other biological assays as may appear predictive of human disease in the future. Inherent in this recommendation is the use of quantitative shortr term end points for various conditions associated with human disoase. We do not have proven animal models for quantitative evaluation of risks of chronic obstructive pulmonary disease, sudden death due to cardiovascular diseaee, or complications of pregnancy and infancy. Emphasis should be given to developing short- and long-term bio&asays aimed particularly at these dieeases. Iktermination of Parameters of Human Cigarette Smoking Smokers may smoke different types of cigarettes differently with respect to puff volume, duration, and frequency, inhalation profiles, and the manner in which the cigarette is held by the fingers and in the mouth. To conduct meaningful assays of cigarette yields and of the biological activity of cigarette smoke, it is important to know how smokers consume each type of commercial cigarette. Only when this Information is available can smoking-machines be designed to yield the most accurate estimate of human dose. We must know both the average and the range of variation in smoking pattern. The available studies eompare smokers' behavior with commercial cigarettes found to deliver different amounts of "tar" or nicotine. Other changes that occur in the product are often unknown. A second type of study should use prototype cigarettes specifically designed to deliver a wide range of concentrations of a desired constituent; for 4V4sezse
Page 72: apt20e00
example, with high or low nicotine to "tar" ratios. Such a study would define the behavior of smokers of new types of cigarettes before or as they are marketed. These studies„ however, would require a particular resource that Is not accessible to most investigators. There are a large number of experimental cigarettes differing widely in several respects (6t, es, 64, 65). Unfortunately, they were developed without concern for smoker acceptability and cannot be used to evaluate human response to design changes. A coordinated program should be estab- lished to develop a series of clinieally acceptable experimental ciga- rettes that resemble a"reference standard" as closely as poesible, differing only in one or two well-defined cbaracteristics. These should then be made available to appropriate investigatoa for the study of human smoking behavior. Evaluation of Health Effects of Nicotine Nicotine has pharmacological significance for man and animals (9t). The alkaloid is suspected of playing a role in sudden death due to cardiovascular disease, to the complications of pregnancy and infancy, and possibly to chronic obstructive pulmonary dieease. Nicotine in cigarettes leads to the formation of tobacco-specific nitrosandnes in the smoke. These are potent cae~einogens. Nicotine itself is a significant cocarcinogen In mouse skin cardnogenesis assays of smoke oondensate. It Is Important to determine whether nicotine aets as a oocareinogen under the conditions of dosage achieved by cigarette smokers and whether the levels of niootinederived nitro.aminea play a role in human malignant disease. Resouroes for such study are available and should be employed in a comprehensive evaluation of the potential carcinogenic effects of new types of cigarettes. Nicotine should be tested alone, and in the presence of other noxious agents such as carbon monoxide, in animal systems designed to serve as models for nonmalignant diseases associated with cigarette smoke. Experimental cigarettes with a range of nicotine content have been produced for studiea of carcanogenesie. Many of these cigarettes are still available. Those experimental cigarettes that might be needed for pharmacological studies of nicotine should be identified and distributed to appropriate laboratories as the need develops. The Effects of Smoking-Maehine Parameters on Relative and' Absolute YieWs of Smoke Components From Various lypes of Cigarettes Smoking-machine assays of cigarettes fulfill two needs. The F'1`C ratings of "tar" and nicotine yields measure an Implied risk to the smoker. Snwking machine data guide experimenters in elucidating the mechanisms of induction of smoking-related disease. Absolute levels of smoke constituents may be very important for experiments, so the experimenter must have reliable information about the comparability R. e641ezse of machine and human smoking. The use of machine data to monitor risk has somewhat different requirements. If the relativa yields of different cigarettes are not greatly affected by smoking conditions, present smoking-machine standards will be adequate to indicate relative risk of new cigarettes. We know, however, that the relative yield of many oonstituents is affected by butt length, puff frequency, and degree of ventilation. We need to determine how the variations In these smoking parameters affect relative yields of the several sub- stances In smoke that are of toxicological interest. Influence of Raw Product Modification on the Pharmaeology of Cigarette Smoke The composition of smoke is determined by the physical and chemical properties of leaf tobacco. Modification of the raw product therefore changes the pharmacology of cigarette smoke. The diversity of available 'tobacoo gerniplasm along with known genetic techniques permits reduction of hazards in cigarettes through plant breeding and selection. Cultural and curing practices are constantly changing in response to market demands and the needs of farmers. Pesticides currently registered for use on tobacco have been teated as eontribu-m tora to the carcinogenic activity of cigarette smoke eondensatea When used as directed, these materials caused no significant change in biological aetivity (65, 166). However, the pesticides used in tobacco farming change from time to time in response to the occurrence of new plant pests; for example, the recent spread of blue mold in tobacco- growing regions has led to the use of a new pesticide. It Is not known whether the use of such materials may result in changes in the hazards of cigarette smoke. Present tobacco curing proeesses'may vary somewhat from farm to farm. Furthermore, marked differenees in agricultural practices such as close spacing of tobacco plants, bulk curing, and homogenized leaf curing might be Introduced in the future. We need to determine the consequences of changes (genetic, cultural, and curing methodologies) on both the chemical composition and the biological effect of cigarette smoke. Physical and Chemical Properties of Smoke From Cig.rettes Delivering Less Than 10 mg of 'Tar" In the past few years, cigarettes delivering less than 10 mg of "tar" by FTC test have been placed on the market These cigarettes apparently employ efficient filters together with various degrees of smoke dilution. The extreme reduction of "tar" and nicotine delivery by these cigarettes suggests signircant differences in combustion processes. Substantial differences In the chemical nature of both mainstream and sideatream smoke might result from such ahanges. 55
Page 73: apt20e00
Some or all of the new lower "tar" and nicotine cigarettes are manufactured by processes that involve the use of chemicals or flavor additives to improve consumer acceptability. The nature of these additives, and their combustion products, that are currently used in marketed cigarettes is not available to the public or to the Govern- ment. Likewise, there are no published data on the biologic effects of these additives or their combustion products. Very low yield cigarettes may add to present eoneerns with respect to sidestream smoke (6, 169', 18.t). While these cigarettes may deliver such low levels of "tar," nicotine, and gas phase constituents that smokers cannot compensate completely, the delivery of sidestream smoke may not be reduced. Indeed, the sidestream smoke might contain more of some substances (e.g., pyrolytic products of flavor additives) than does the sidestream smoke of higher yield cigarettes, For very low yield cigarettes, the risk of the sideatream smoke may equal that of the mainstream smoke. The chenucal and physical nature of sidestream smoke should be determined on new eigarettes. Development and Validation of Analytical Methods Methods for determining "tar" and nicotine yield were developed before very low yield cigarettes were an important segment of the market It Is questionable whether existing procedures can measure accurately the "tar" delivery of the cigarettes yielding 0.1 mg of "tar." Other techniques giving acceptable results must be developed. Prooe-s duree for determining "tar" yields of low magnitude through measure- ment of fluorescence have been recommended (169). These methods must be validated by detBrmining intraw and int$r ]aboratory reproduc- ibility. Furthermore, fluorescence measurements may be compromised by additives that interfere with fluorescenee, either directly or through the behavior of their pyrolytic products. Fluorescence measurements may not be satisfactory for use with new eommercial cigarettes. Analytical procedures must also be validated for a number of chemical constituents in smoke such as aldehydes, nitrogen oxides, phenols and catechols, aromatic hydrocarbons, and nitroeaminee. Several laboratories are conducting such assays with favorable results. However, coordinated comparisons among laboratories to measure the degree of intra- and inter-laboratory variability have not been reported. Othfr Research Needs Ay numbor of other research needs of lesser priority should be addressed• 1. It is necessary to study the Interaction of smoking with occupational and environmental exposure to other noxious mate- rials. The incidence of lung cancer ie greatly increased in asbestos workers or uranium miners who smoke cigarettes (J, r0,117). The risk of using contraceptive hormones is also greater in cigarette smokers (1s8,17;). Laboratory models of oocarcinogeneHis should be used to measure the potential effect of combined smoking and exposure to other environmental toxins. Animal models should be developed to investigate the possible synergism of smoking and the environment in causing other diseases. 2. It is necessary to determine the threshold, if any, for carbon monoxide with respect to cardiovascular effects, pregnancy, and psychological performance. Carbon monoxide delivery of ciga- rettes can be controlled by ventilation (68,1t6), To determine the carbon monoxide risk of lower "tar" and nicotine cigarettes, we need to know whether thresholds for carbon monoxide activity exist and whether these thresholds vary for individuals of different ages, medical histories, or genetic backgrounds. Evalu- ation of risk due to carbon monoxide must take environmental exposure into consideration (152). 3. It is necessary to define the extent of smoker compensation for differences in nicotine delivery of cigarettes. To the extent that smokers compensate for lower nicotine delivery, they will probably obtain more of other constituents from lower nicotine than from higher nicotine cigarettes.. For example, the smoker might take more puffs to obtain the same dose of nicotine, and thus reoeive a greater dose of carbon monoxide (80, 145). It should be determined at what point smokers can no longer compensate for lower nicotine levels and whether compensation is a permanent behavior change of smokers who switch to lower "tar" and nicotine cigarettes. To carry out such studies, standard- ized noninvasive procedures to indicate smoke uptake from cigarettes yielding various amounts of "tar," nicotine, and carbon monoxide should be validated. Analyses of blood, urine, and expired air have been used for these purposes (ts, 179, 181). Analysis of saliva for nicotine might alw be useful. With any procedure, inter-laboratory comparisons using standardized methods are needed. 4. Many gas phase components of cigarette smoke are ciliatoxic in the experimental setting. They may overcome physiologic de- fense barriers against pulmonary toxins. To some extent, the ciliatoxic agents are absorbed in the mouth and upper airways and do not reach the deeper portions of the lung. Experimental systems may not be capable of duplicating the anatomic and behavioral factors that may affect human response to ciliatoxic agents. Nevertheless, short.term sequellae of smoking can be measured in human smokers of different types of cigarettes. Further evaluation of these effects In man should be undertaken. 6. Attention to chemical habituation evoked by cigarette smoking is centered on niootine, which is the most active acute pharmacolog• sb4sezss
Page 74: apt20e00
ic agent in cigarette smoke. It is necessary to determine whether there may be other chemicals present in cigarette smoke that contribute to cigarette smoking reinforcement. 6. A variety of short•term animal models with quantitative end points predictive of the development of tabaacosaaodated dis- easea should be developed. Except for canoer, long-term animal models suitable for quantitative compzrisons of disease risk are not adequate. Even If successful long`tErm animal models are developed, the costs in time and resoucr:es may prevent the timely evaluation of new cigarettes. 7. It is necessary to develop methods for dissemination of informan tion regarding the delivery of various noxious agents by ciga- rettea. The smoke content of "tar," nicotine, carbon monoxide, phenolic constituents, volatile aldebydes, nitrogen oxides, aro- matic hydrocarbons, and nitrosamiaes may all contribute to the risks incurred by smokers. The Federal Trade Commission releases its findings of "tar" and nicotine yields of cigarettes and has announced its intention to assay carbon monoxide delivery. As additional monitoring assays are conducted, it will be necessary to present the new information to the public and to health professionals in a meaningful way. 8. It is necessary to evaluate the health hazard posed by passive inhalation by nonsmokers of the sidestream smoke from new types of cigarettes. Lower "tar" and nicotine cigarettes are designed to reduce the mainstream smoke received by the smoker. There is no evidence that the amount of sidestream smoke or its quality Is improved by these design changes. Indeed, If additives are used to insure acceptability of the cigarettes by the smoker, their pyrolytic products may occur In the sidestream smoke. New types of cigarettes should be monitored for the qualitative and quantitative risks they might impose on the nonsmoker. 8.. It is neceeaary to evaluate cigarettes with lower "tar" to nicotine ratios than are currently found in the market place. Compensa- tion by smokers of lower "tar" and nicotine cigarettes appears to be based on nicotine delivery. The "tar" to nicotine ratio may limit the delivery of smoke constituents to the smoker. A low ratio might be s desirable strategy for lower risk cigarettes. It should be determined whether smoke from cigarettes with unusually low "tar" to nicotine ratios has unusual pharmacologic or toxicologic properties. 10. It Is necessary to develop a low "tar" and nicotine reference cigarette. Several laboratocies will need these refer+ence ciga- rettes as a standard for comparisons of lower "tar" and nicotine commercial cigarettes.. Commercial products cannot serve as a referenoe because design changes are made without announce- °-194G8zse ment and because the identity of additives is not disclosed. Without a stable reference, intra-laboratory comparisons con- ducte<i at different periods of time and many inter-laboratory studies will be compromised. Reference cigarettes are available for a limited range of "tar" and nicotine deliveries. A reference cigarette delivering very low levels of "tar," nicotine, and gas phase constituents is needed. To produce a reference of sufficient quality, large numbers of cigarettes must be made. Because an effort of this magnitude cannot be undertaken by individual researchers, a centralized facility to provide reference cigarettes to appropriate scientists is desirable. Summary 1. Several thousand constituents have been identified in tobacco and tobacco smoke. Of these, nicotine appears to be the most important acute-acting pharmacologic agent Nicotine's physio-c logic effects include increased heart rate and blood pressure. Nicotine also can permit the formation of tobacco-specific nitrosamines, which are potent carcinogens, and nicotine itself may be a significant cocarcinogen. The careinogenic potency of cigarette smoke condensates appears to depend on the nicotine content of the "tar." This relationship may be due in part to the conversion of nicotine to tobacco-specific nitrosamines or to the coexistence of nicotine and some other unidentified carcinogen. Whether the carcinogenic effects of nicotine as determined in animal studies are directly applicable to humans is not known at present. 2. In an important study to predict the carcinogenic activity of cigarette smoke condensate, the amount of available nicotine delivered to the mice was found to be a factor in every term but one of the predictive model. 3. Polycyclic aromatic hydrocarbons and tobacco-specific nitrosa- mines are two prominent classes of tumor initiators found in the smoke condensates of commercial cigarettes. Of the polycyclic aromatic hydrocarbons formed during combustion, ben- zo[alpyrene (BaP) may be the most important and has been studied the most extensively. A correlation has been found between benzo[a]pyrene levels and the carcinogenic activity of smoke condensates from several types of cigarettes, but other studies have failed to show that carcinogenic potential is significantly dependent on benzo[a]pyrene content However, the interaction of BaP with nicotine does appear Important in carcinogenesis. 4. The tobacco-specific nittoeamines (TSNA) are formed during curing and fermentation of tobacco leaves and combustion of 59
Page 75: apt20e00
cigarettes. TSNAs induce cancer in the lungs and trachea of hamsters and may be of particular Importance in the induction of human laryngeal cancer. They may be active as contact carcino-, gens, or their metabolism at distant sites may produce carcino- gens that are then transported to a target site. b. It is not known whether the unidentified mutagens In cigarette smoke are an important cause of lung cancer in humans, but added exposure to any tumor Initiators probably carries an increased risk of caanoer. 6. Cigarette smoke contains oxidants that have been shown to reduce the activity of alphai-antitrypsin in animals and man. This inhibitory function is distinct from the effect whole smoke has on Increasing levels of elastolytic enzymes released by neutrophi7s and macrophages. 7. The great variety of tobacco types makes It possible to manipu- late the plant genetically to change the content of the constitu- ents of the leaf. The chemical content of the leaf is also affected by agricultural practices and curing methods. The nicotine content of tobacco, for example, is related to the amount of nitrate fertilizer used in cultivation. Modification of tobacco as reconstituted sheet ineorporates substantial amounts of tobacco stems that contain less nicotine than the leaf. The physical nature of reconstituted sheets can be controlled to change their burning characteristics and smoke eomposition. 8. Vapor-phase constituents of cigarette smoke inhibit dliary motility and mucous f low in experimental animals. 9. Cigarette smokers metabolize several compounds more rapidly than do nonsmokers. This effect is believed to be caused by the induction of microeomal oxtdaees, which include aryl hydrocarbon hydroxylaee (AHH). Induction of AHH activity appears to be caused by systemic exposure to the smoke compounds themselves or to the metabolites of those compounds. The AHH syetem may be involved in the metabolic formation of ultimate carcinogens from procarcinogen precursoes. 10. In recent years, a number of flavoring additives or cellulow based tobacco substitutes may have been Included in manufac- tured cigarettes. The nature and amounts of such additives as actually used are not known, nor is it known what Influence these q,additive' may have on the chemical composition or subsequent , biological activity of dgarette smoke. iL Cigarette design has a major effect on smoke composition. The filter is the design characteristic that has the most impact on "tar" yield; it can also selectively remove nftroeaminee and semivolatile phenols from smoke. The porosity of cigarette paper and the presence of holes In the mouthpiece Influence smoke composition because ventilation reduoea the quantity of "tar" and dilutes the gas phase of smoke. 12. Because of the complexity of cigarette smoke, the total impact of any cigarette modification on smoke composition will probably never be fully known. 18.. Many laboratory studies of the effects of amoke constituents have been carried out using smoking mer,hines that control puff volume, frequency and duration, butt length, and other factors according to standardized parameters. However, the most widely used parameters were established in 1967, and the type of cigarettes generally smoked today are substantially different with respect to length, paper porosity, "tar" and nicotine eontent, and concentration of gas phase constituents. Evaluation of the toxicological and pharmacological properties of smoke from new types of cigarettes requires detailed knowledge of the manner in which those cigarettes are smoked, as well as of how smoking patterns affect smoke composition. ts4sszse
Page 76: apt20e00
References (1) AILIN, FJ., BENNER, J.F. Induction of aryl hydrocarbon hydeozyiaae In rodent lung by efaarette smoke: A potentlal sbort.term bioary. Tbmioafopy and Apy[ied PAwwwoo[oyy 8d(2): 881-387, May 1976, (t) AMES. B.N. Identifying enaironmental chemicals causing mutations and cancer. Soiena 2Dr(43Da): 687-6Y8, Hay 11, 1979. (l) ARCHER, V.E., WAGONFA J.IL, LUNDIN, F.&, JR. Ue.niunm oioing and cigarette woldas effeots on man. JoKrset y Obeupational X.aie{w ]6(8): 204-211, Msrsh 1qI8. (4) AR1[ITAGFti A.H., DAVIES. R.F., TURNER, D.M. The effecta of carbon monoside on the dsvelopauent of.th.eo.elero.if in the White Cernesu pl8ron. AtA.ro.el.re.(. E8(2): 888, NaicFrAprd 1l76. (5) ARONOW, W.S. Elfeet of passive emqldnr on sn;ins pectoris. Nev AMyiar d Jon+wel oJXrdieiv 29D(1): 21-21 July 6,1978. (e) ARONOW, W.S. Effect of nowniatias eieaestt.a and carbon monoxide on angina. Lltnsuis;io.61(H): 263-266, Febsuaey 196Q (7) ARONOW, W.S., ISBICLL, M.W. Cubo..waozidn efbet on .x.vi..iaduaed angina peetoris. Annals ojbf..wa1 Aledreine 79(8)s BoQ.i96. September 1978. (8) ARONOW, WS., SWANSON, AJ. The dfeot of bw-oiootine elaarsttes on an8ina peetorL. Awtmis oj Iwtersel A[edteiw. T](8): 6rliFe01, September 1969. (1) ASMU8S@i, L Ulhattnucture of the human plaoeats at Wm Obaeevatkws on placentas from newborn ehiklren of smoking and nonsowklnK moUwea Aefs Obd.6deis a Oye.nolqptas Saswdiwaroios 66(2):119-126,1977. (t0) A$MUSSLN, L Ultcasteuctur of human umbilical veios. Observations oa.einn from newborn ohildren of smoking and noasmokinK mothees. Aefa Obdstr-ieia sf Gyaeeoloyias' Saaedinaeioa 67(8): ffiS-PS6,1Y7B. (tt) ASTRUP, P. Carbon nwno:ide as a eoetdbutor to the health hasaeda of ei8aretts smohina. In: Gori, G.B., BoeJc, F.G. (Editon). Banbuty Report 8-A 3afi Cipantte/ Cold Spring Harbor, New York, Cold Spring Harbor Isboesto- ryr 1M, pP. 7b'80. (12) BAHHLE, YB., HARTIALA, J., TOIVONEN, H., UOTILA, P. Effects of cigarette smola on the metabolism of vasoeatire horaones in rat iwlated lung.. BeitisA.lournd oJPAaruwoolopy 66(8): 486-499, March 1879. (13) BATPISTA, S.P. Ct1ia toxic components of cigarette aaaka In: Wynder, F..L, Hoffmnnn, D, Cori, G.B. (Editon). Prooesdin8s of the Third World ConfeF anoa on Smokinj and He.lth, New York, June A.b,1976. Volums I.11[ed{Jyinp tJie Risk Jbr tlie Smoker. U.S. Department of Health. Eduoation, and Welfare, Public Health Senfoer National Institutes of Health, National Canoee Institute, DHEW Publication No. (NIH) 76-1PZ1,1870. pp. 617-684. (14) BATfISTA, S.P. Inhaiation studia of toxicity of tob.coo smoka In: God, G.B., Book, F.O. (Fditoes). $awbr+y R.po.e S-A • Saylir G`pand4! Cold Spring Harbor, New York, Cokl Spring Harbor Laboratory,1980, pp. 61-68. (IS) BAYNE, C.K. AProbebiliq/ Prsdietios 11(od.I e j Xows Sbix 74rson Bard on CAeawioaL Cow,pawRts #I (ltyarstN 8rnolo. CsMdtwrat.s. Oak RidBe, Tennessee, U.S. Department of Energy, Oak Ridge National Laboratoqr, Publication No. oRNidTM-7067, October 1979.38 pp. (ts) BERENBLUM, L A ro-evaluation of the concept of ooeandnogenesis. A+opws. (1T) in &priau+da! 74ww' ItueanJ111: 21-a0,196Y. BERNFELD, P., HONBUBGER„ F, SOTO, E., PAI, K.J. Cigarette smoke Inhalation studies in fobmed Syrian golden hnnrtem Jownnl ef fM National Canoer Indfbwe 6B(8): 676489, September 1979. (18) BILIMORIA, M.H., JOHNSON, J., HOGO, J.C., WITSCHI, H.P. Pulmonary sryl hydrocarbon bydrazyiaae: Tobaoeo.moko+uposed 8uiaos pi8a. Tbariaoloyy and Applied L'ksrmeeaiopr 41(9): 48a-440, AuBuat lY7Z (18) BLUE, M: L., JANOFF, A. Possible mechanisma of emphysema in cigarette smokers. Relew of .lastase from human polymorphonuclear leukocytes by ciaantte smoke wndensata in vitro. Amsrican R.wiew oJ,Rapiratory Dlseo,u 117(2): 817-M, February 1078. (t0) BOCK, F.G. Comrdnoaenie properties of nicotine. In: God, G.B., Bock, F.G. (B'diton). Baxbary Report 8-A S4js flpasdte! Cold Spring Harbor, New York, Cold Spring Harbor Lsboratory,lM, pp.12P-18D. (21) BOCK, F.G., CLAUSEN, D.F. Further fractionation and oo-promotina activity of the large mobeulac weight components of aqueous tob.ooo e=traeta. Car+aisanawaia 1: 817-821, April 1960. (tE) BOCK. F.G., GORI, G.B. StbaaoKs Glawd Supprs..ioK Tists as as Indioular of (M (24) the Ce.uswoDSie Activity of A4ptritstattal Cioantte $w•oke Go.deneatee (3C3) . Proosediege ot the Sixty-Ninth Annual Meeting of the American Association for Canoae Research 19: 48, March 1978. BOCK, F.G., MUND, R. A survey of eomponnds for activity in the suppression of naus sebaosous glands. Cawoe. Rsssas+eA 18(8): 887-89$ Sept.mb.c 1968. BOCK, F.O, SWAIN, A..P., STEDMAN, R.L. Bioasa.y of major fractions of oi8arette smoke condensate by an accelerated technie Canar RsatanA 29(3): 5664567, March li6Y. BORGERS, D., JUNGE, B. Thiocyanate as an indie.tor of tobacco smoking. R.eextia Y.dicin.8(8): 861-867, May 197l. BOUTWELL, Ii K. Some biolo8ical aspecta of ddn arcinoeenesie. Ptinpnas in AF3symsauRtol ?titworR.asatrA 4: J07-7b0,1Y64. BOUTWELL, RIC., BOSCH, D.K. Tbe tumonpromotinB action of phenol and related compounds for mouse skin. <kecsr ReewnA 18: 413-424. May 1960. BRUNNEMANN, K.D., HOFFMANN, D., WYNDER, &L., GORI, G.B. Chemi- cal studies on tobacco smoke. XXXVII. Determination of tar, niootine, and carbon monoxide in dQarat4e smoke. A oomporLos of International smoking conditions. In: Wynder, ILL. Hoffmann, D., Gori, G.B. (Editon). Prooeedin8s of the Third World Confenna on Smoking nnd Hdth,New York. June 2-5, 1976. Volume L Afod4(yiny tAe Riak for t6e Smake.. U.S. Department of Health, Education, and WeUaro, Public Health Service, National Institutee of Health, National Cancer Institute, DHEW Publication No. (NIH) 76-1221, 1976, pp. 441-4r9. (29) BRUNNEMANN, K.D., LI:E, H.-C., HOFFMANN, D. Chemieal studies on tobacco smoke. XLVII. On the quantitnti.e analysis of cateebole and their eaduetioa. Awotyticol Iwttera 9(10): 889-Y66,1976. (SO) BRUNNEMANN. K.D., YU, L., HOFFMANN, D. Assessment of carcinogenic volatile N.nitrosamines in tobnaeo snd In mainstn.m and sklestream smoke from eiQarettee. Canes.lteawek 87(9): 8218-8772 September 1977. (Jl) BUIST, A.S, GHEZZO, H., ANTHONISEN, N.R., CHERNIACK, R.M., DUCIC, 8., 1[ACKLEH, P.T., 1dANFREDA, J., MABTIN, B.R., MCCARTHY, D., RO$9, B.B. Relationship between the sinjl._be+sath Ns test and a8e, aex, and smoking habit in three North American cities. Am.rtoa% R.visv of Rsrpivn- tory Diaean 1E0(2): 806-818, AuBust 1979. BYIACK, A., BONDJER3, G., JANSSON, I„ HANS$ON, H.-A. Surface ultrastnucture of human arteries with special reference to the effects of smoking. Aefa %tAo{oyioa .t lUierobio/oyioa Soandiwavios (Section A: Phtboto. py) 8T(s): Ef11-209, May 1979. (1,t) CARP, H., JANOFF, A. Passible m.chanLms of emphysema in smoken In vitro suppression of aerum elastaae-iohibitory capacity by fersh cigarette smoke and ite pnrentiou by .utioaidants. A+Maiean !l.viev of Reapiratory Disear 118(8): 617-681, Septembtr 1978. ($4) CHAPLIN, J.F. Genetic influanoe on chemical oonstituents of tobacco leaf and smoke. Btitrayr sw TabakJosokwno 8(4):288-240, Deoember 1976. A9 =S8zss
Page 77: apt20e00
(t6) Ci.APP, M.J.L, CONN1NG, D.M., >iPILHON, J. Studiu on the local and ay.temle arr3nogenioily of topically applied .moke eoadenette from a eubetitute emokina material. BriNat. Jorna! oJtbrar 86(8): D69-al1, Murb 1977. (36) COHEN, B.S., 6ISIaiBUD, M., HARLEY, N.H. Alpha radioactivity in dgaretto smoke. RedtatieK RAoarrA 8S(1):190-199, Juiy 11i96. (1f) COHEN, D, ARAI, a.F, BRAIN, J.D. Smoking impairs long-term dust ela.ranea feom the Inne. Seiena.2D/(daY*: a14-617, May 4,1979. (6d) CONNEIf, A.H, LEM, W. C.reJeonn metaboliem in e:perimental animals and man. In: ltontaeans, R., TemaNe. L(ZAitmt). Giieatiest Cercinopewn is E.aaye. Int.enat3onal Agency for Research en Conoor Scientific Publications, No.10,1-K 197'L (19) p00S81.EY, W.G.F., FARRELL, (i.C., CASH, G.A., POWlT.L, LW. The inteaacfiun of ei`entte smoking and chronic drag in`eetiqn on human drug meta6oiY.m. Cliate»i ani Bayeriwentai Phorwmadpr snd PAriioiaylr 6(5): DONTENWIL4 W, CHEVALIER, H.J., HARY$ H.-P., ICLIMISCH, H.J., I{UHNIOK, C., RECKZEH, G., SCHNEIDER, B. Unta.uchungen uber den Effekt der ohroni.ehen ?igarettenrauchinhalation beint eyrisehon Goldbameter and uber die Bedetung des Vitamin A auf die tei Berauchung gefunden Organveranderungen. (Studies on the effect of ehronia cigarette smoke inhaiat3on in Syrian golden hamaten and the import.noe of Vitamin A on morphologieal alterations after smoke espowua) Z.ttsclriJt fur Ksbefqr arbwq rwd XkniaeAo Owketapie 8Y(Z):168-180,1977. (bi) DONTLNWILL, W, CHEVALIER, H.,I„ HARICE, H.-P, ICIJMISCH, II.J, RECKZEH, G.. FLQSCHDRANN, B., SELLER, W. E:perimentells Untenu- ehungen uber die tunorerasugonda Wirkung von U`uMttetvauch-Kosdenea- ten an der Mousetnut. VII.. Mitteihmg: Einoelrugldehe von ICond.en.ten vorechiedener modiffsierter Zigaretten. (F•:periotental investigations on the tumoriganie activity of eiganette smoke condensate on mouse ddn. VII. Comparative studies of condensates from different modified ei`an:tte,.] r.rie.eAriJe Jwr 1Cm6rJbr..aMmy +rni Iainiae6t oai+oiegie e9(2): 146..161, 1977. DONTENWILL, W., CHEVALIER, H.,L, HARKE, H.-P., LAPRENZ, U., RECI[ZKH, G., SCHNEIDER, B. Investigations on the effeeta of chronic dgaretts-anwke Inhalation in Syrian golden hanrters. Journol eJtii. Natiord Canser Inadh* 61(6):1761-183?, Deoemher 1973. ERtKSSON, S. Studies on ewntitryp.in deficiency. Aefa Medics Soandina.ios 177 (Supplement 432): 6-86,1966. EVERSON, RB. Hypothesis: Individuals trampl.aentally expoeed to maternal smoking may be at Increased cancer risk In adult lito. Iawost 7E(919E):123-126, July 19,1960. FEDERAL TRADE COMMISSION. Report of "Tbr" and Nicotine Cantset oJ tAe snMdM oJlff Ysr(stip oJCryontt.,. December 3979. FERSON. M.. EDWARDS, A., LIND, A., MILTON, G.W., HEIt3EY, P. Low natural kiikr-0ell activity and (nuaunogbhulin levels aroeiatod with smoking in hnman niDjeW IntorNatloeai JournoJ of Canar 26: 606-A09,1979. FINE, D.H. An aeeaement of human exposure to N-nitroeo oompounde. In; Walker, F.A., Gridnte, L, Castognaro, M., Lylo, EtE., Davie, W. (Editon). Proceedings of a conference at Durham, New Hamphire, Augu.t. 2?.,2t,19T7. Eboironnwsta! Aepects of N•Nit,ao Counpounde. Lyon, Franoe, International Agency for Raeareh on Canoer, IARC Scientific Publiation No.19,1978, pp. 867-a76. 627-M SeptembeFOatohar 19'N, (40) CREIGHTON, D.>+, LEWIS, P.H. The effod of diffa.at aigantw on human smoking patterne. In: Thornton, RA (6ditor). 9:.ak{+y B.Jlsvier, PAyeioloyi- (5t) aat sni Pbrrbo/oyioei In,/Iwnar.. Now Yorit, Chwchill Ilvin6.teae, 1970„ pp. YB9400. (41) CREIOHTON, D$ LEWIB, P.H. The offeat of smoldng pattern on aeoke deliveries. In: Thornton, R,If:. (Dditse} JDembi+a aeAatdor, PkpidepiooW and (~') PryeAofopfeal l+{/ttienma. New Yort, Chaechill IMnptone,1976, pp. s01-S14. (4!) CREIGHTON, DX NOBLE, M.i., WHEIVEI1L% LT. In.trumrnta to mea.uie, (54) record and duplicate human smoking patterns. In: Thornton, R& (Editor). 8+sokf*0 B.lisoi.r, Pkfn+eiaDieal a+d Ayekoloyiod L1R+iesoea N.w York. Churehill Livint.tone,1970, pp. 3Ti Zb7. (65) (4J) DAGLE, QF., MCDONALD, ILR, SMITH, LG., aTEVICN3, D.L, JR Pulmo• nary aaedeoR.aeda in rate given isplaaq of cigarette enake condensate in (66) Deewa: peileq. Jorraa{ of the Netfonst t7mmerr hwtitwt. 61(3): 906-810, Septsmb.r 1978. (44) DALBEY, W.Tt, N1.79'H8}IE1M, P« G1liffiEMER, R., CATON, J.F., GUERIN, (57) M.B. Chronie inh.Ltion of cigarette amoke by Fal4 rats. Journal of the Nations! Caum In.litrte 61(2): E6a-alb, FabnurY 1980. (45) DALHAMN, T, EDFORS, M.I.,1tYLANDER, R Mouth absorption of varioue compounds in cigarette amoka Areili.ee of blad+v+nsentol If.sIN 16(6): 681- l36, June 196t;. (46) DAY, T.D. Carainopnia action of dgar.tte anwke eondenuto on mouee skin. An attempt at a quantitathre study. BriNalt Jeaswal af taaneer 21(1): 66-d1, March 1967. (47) DEBARDE[.LrBLrNi, M.Z, CLAFLIN, W.IC, GANNON, W.F. Role of cigarette physical eh.raeteei.tle es neoko eompaition. Rea.ht Adroswew iri To6oceo Ssisnoe. Valhalla, New York, Naybr Dana Inrtituts for Diwee Prevention, American Health Foundation, 3ariee 4. 1976, pp. d6-11L (4a) DoLt, R, rSPO, a. Cig.rotte a:eoking and econehia ouefnom.; Doee and time relationships among regular smokers aad lifelong noo-emoken. Joerwat of 1' b'pideaaoiqysad G1vmmMwity HrsitA>X4): »OB-11l, Dee.mber 1978. (40) DONTENWIL4 W. Biological e.aWation of eaedeogen. in tubaaou aad tobacco smoke. In: Wynder, E.L,, Hoffmann, D, Gori, G.B. (Flditots). Proceedings of the Thkd Werid Conference on Smoldng and Hoslth, New York, June S-6, 1976. Volume L lifod{fyi'nD tib JKak Jbr tJb Snrok.r. U3'1. Department of Heahly Eduaatioq, and Welfare, Public Hedth S.nk+% National Instlwtea of Health, National Canear Institute, DHIti1 Publication No. (NIH) 76-1T11, IM pA2004M (bd) GADEIC, J.E, FELLS, G,A„ CRYSTA4 R.G. Cigarette smoking Induces functional antipootease deficiency In the lower reepiratory tract of human.. Science 206(442{):1816-1816, Deoember 1979. (aD) GIE[.EN, J.E., GOUJON, F., SELFi J., VAN CANTFORT, J. Oegan specificity (60) of induction of activating sad inactivating onsymae by cigarette smoke and eigarette emoko condensate. A+eAiwo oI 7beiadogy (Supplement 2): 239-261, 1979. GOLDFARB, T., GRITZ, ER, JARVIK, M.F., STOLTRMAN, I.P. Reactions to eipretta as a function of nicotine and "tar." Ctiriieal PAsnsaeology a*d TMroprutiee 19(6):767-77?, June 1976, (61) GORI, (3.B. (Itlditor). Proceedings of the Tobacco Smoke Inhaiation Workshop on Experimental Methode in Smoking and Health Research, Botlweda, Maryl.nd, June 19-21, 1974. Ao:wdinyr oJ tAe TLdeaeo S4naAr INAaluAion WortsRop on Mep.r{swst.i X.tAodo in SwaNoy end A.aW Raes++ek U.S. Departmeat of Heaita. Eduation, and Welfara, Public Health 8ervio% Natiow) Institutes of Health, National C.naer Inetieutt, Smoking and Health Ptogram, DHEW Publiotion No. (NIH) 76-908,1976, 88 pp. Cs4sezse
Page 78: apt20e00
(6!) GORI, G.B. (Editor). lb:as.d La. hfasardouo Oipprat... TJ4 Fyr.t ,S.t of aip.riwMntat GYpantta. U.B. Department of Haaith. Education, and Welfare, Public Health S.rvia, National Institutes of Health, National Canaer In.titut., 8mokleqland Health Program, Report No.1, DREW Publication No. (NIH) 76-806,1976,148pp. (B,t) GORI, G.B. (Editor). Tbwsnd Lw Hara.dour Gtipontua. Til. S.ooRd &t oj Akpeelraafa! Ciyar.tam. U.3 Department of Hodth. Education, aod Walfare, Public Haalth 8arrios, National Institutes of H.altk, National Canaer Iastituto, Smo13n`and Health Pmgram, Report No. T, DREW Publication No. (NIH)76-1111,1976,15J pp. (84) GORI, G.B. (Editar). Toward Isst flasanTou,t G'yparsttu. T1Ys IAtrd Sat of Espnswaafd aynnlGa. US. Department of H.aJth, Edocatb., and Wolfar% Public Health Saevio., National Institutes of Health, National Cancer Inititutt, 8awkingand Health Pin`ram, Report No. 8, DREW Publication No.. (NIH) 77 1880,1977, ].58 PR (BS) GORI, G.B. (Editor). Toward Isst Hazardous GYAanKta. TMs FmrfA Set of dthporisantel GYBastt+a. U.S. Department of Hoalth, Ednoatioa, and Walfare, Public Health Ser.loe, NatJonal InsHtnt" of H.altb, National C.na.r Institute, S'moldnsand Health Program, Report No. 4,1[areh 1990. (se) CORI, (i.8., ELLISr R.L Reduction of carbon aoaoxid" is eipeutt..nwlco. Frwenqive dbdioino 8(8): >59466,1979. (ef) GEtEFN, C.E. Neutral ourySenstad eompounds In ciYarette .mobe aad th.i' possible preepinws. R.wnt Adra:ws in 2bboooo $eieso.. Valkalla, Now York, Naylor Dans In.tituts for Di..ass Prevention, M.eeio_ an Health Foundation, Seria 3: 94-1M,19?T. (88) GUERIN, U. Tamaurs pulmonaires et cancer buccal el:as Is rat sounds a 1'iahalation da fumes de dSarette. Bullsti+t d. I'Auoeiatiaa J4a*oaiss pow t'and& dti Ca*ai^ 46(2): 296-800, Apri4June 1959. (69) GULSVIK, A„ dAOERHOL, Id.H. Smoking and ImmunoQlobulin lo..ls, Lanat 1(8188): 449, February 54,1979. (Letter) (70) HAMMOND, S.G, SEI.IKOFF, I.J., SEIDIiAN, H. Asbestos exposure, ciQs- ratte smoking and death rates. In; Sdtkoff, LJ., Hammond, E.C. (Editora). Health Harards of A.bestos Exposure. Annafa of tA. N.w York Acads,ny of 3eionaa 11110: 448-4W,1979. (n) HARLEY, N.H., COHEN, B.B., TSO, T.C. Polonium-210: A questionable risk factor in smoking=e.latod aardao6.nsi.. In: Gori. G.&, Boe]:, F.G. (Editon). Banbury R.port !-A Sofe Gtiporrttof Cold Spring Harbor, New Ycrk, Cold Spring Harbor Laboeat9ry,199D, pp.98-10t. (78) HARRIS, RJ.C., NEGRONI, 0, LUDGATE, S., PICK, C.R., CHESTERMAN, F.C., IUtID3tENT, 8J. Tbe inoidonea of lung tunaun In C67BL mios exposed to cigarette aoolamir mixtures for prolonged periods. Iulsrwational Jowrwa! ej Ca+tasr 14(1): I80-1S6, July 16,1974. (7J) HARRISON, QN, MOOR, (31t, IQOHLEIt, J.L, SPEIR, W.A., JR Small airway dis.w: Comparison of tuts in young smaken v.nus nonsmokers. Souflurw lloLiee! JoYrwa171(9):1679.-1081, 8aptomboe 1948, (74) HECHT, 8.8., CARHlr[d.A, S, IdORJ, II., HOFFYANN, D. A awdy of t9baooo aeeinoSeneda. XX Tb. rok of auolwis as a major ooardnoean in the we.kiy.ridie ftaetion. Jon+wat oJt/l. National Cimor. hNtit.v., in press. (fb) IIICHT, 8.8., CHEN, C.H.B„ HOFF9[ANN, D. Tob.oeo4p.c(fk altrasamines:. Oaean.aea, foem.flon, ftednoS.ni:dty, and mstabol(We. Aaeorxt. q/CSnn;ost R...anA 10):92-i6,1[aeeb 1979. (fq HECH'T, $.$., CHEN, C.-H.B.,1[OCOY, G.D., HOFFMANN, D., DO1tl6LLOF, L. .eliydrosy4tioa of N-nitrosopyrevlidirw and N'-niLnsonorniooHae by human liver misrosorna. CbMO.r htf.n !(1): 85-41, November 1979. r>469''Z~•. (Tl) HECHT. 8.8.. ORNAF. RM.. HOFFHANN, D. Chemiwl studia on tobacco ..wk.. XXXIIL N'-Nitewoaorntaotine in tob.oou: Andysis of porible oontrib- utJne factan and biologic Implicationt Jouraai of the Nattoaat Cancsr I+utidds 64(5):1Z87-1249, May 1975. (78) HENNINGFIELD, J.E., GRIFFITHS, Itli. A preparation for the ezporimental analysis of human cigarette smokinF beharior. BsAavior Raea+rA 1lfsthodi and Ix.trxnowtstiow 11(6): ti38-b14, D.etmbar 1979. (7a) IiEYDEN, S, HI789, G., YANEGOLD, C., TYBOLEB, H.A., HAKES, C.G., BARTEIti A.(i., COOPEH, 9. Tbs aombin.d .tl.et of smoking and coffoe drinking on LDL and HDL obolatsnol. Cireul.tios 60(1): 8S-ffi, July 1079. (80) HILIy P.,1[ARQUARDT, H. Planna and urine cbanFw after.mokinH different brands of cigarettes. G7iwiasl P6asnyaaokgy swd TMnapru*a 27(5): 568-ffi8, )day 1980. (81) HILL, P., WYNDER, 91. Nicotine and eotisine in brraat iluid. Cancer Lettsra 6: 261.261,1979. (8t) HIN1[AN, L11., STBVENB, C., HATTHAY, RA., GEE, J.B.L AnQiotenin oonvertas activities In human alveolar a:.eropba6es: Effects of cigarette smoking and a.rooidaais. Soioaa 806(440a): 202-M, July 18,1979. (8l) HOFP7[/tNN, D. ADAMS, J,D., WYNDER, F3L Fmmatton and s:Wyais of carbon monoxide In cigarette nlain.tewn and sidsatram amok.. Pf+wntiv. Xodiciw.8(3): 8444150, May 1979: (8f) SOFFI[ANN, D, CHEN, C.-H.B., HECHT, S.S. The Eole of volatile and nonvol.bls N-nitro.amiewa in tobacco carriaoseoesit. In: Gai, G.B., Bock, F.O. (F.diton). Bawbury Report 8-A Saft G`panWf Cold Spring Harbor, New York, Cold Spring Harbor Labont9ry,19B0, pp.118-127. (eS) HOFFILANN, D,, MASUDA, Y., WYNDER, E.LL rNaphthyl.mino and p-. napbthylamina in r3Qarotte smol:.. Nolwn 22](6177): 264?b6, January 18, 1W. (86) HOFFYANN, D., RAINRRI, R., HECHT, 8.8.,1LARONPOT, R, WYNDER, E.L. A study of tobacco careinoSenais, XIV. Eff.ot of N'-nitsv.onorniaatine and N'-nitrosoeasba.iae In rat.. Jowrval of tAs Nationat Conosr Institute 56(4): 977-979, October 1975. (87) HOFFMANN, D., SCHMELTZ, L, IIECHT, S.S., WYNDER, E.L. Tobaom eaednoQenesia, In: Galboin, H.V., Tso, P.O. (Editoea). PblYeyotie Ilydrocarboiw and CaeoK. Volume 1. Nsw Yaic, Academic Pra.,1978, pp. 85-i17. (88) HOFFHANN, D., TSO, T.C., GORI, G.B. Tbs lr harmful elgarette.. Pnwntiv. Xodiri:a 9(2): 287-296, March 1980. (8D) HOFF7[ANN, D., WYNDER. E.ir A study of tobacco oarelnoFanais. ZI. Tumor initiators. tumor accelerators, and'tumoc promoting activity of oondeaa.ta fvactiona. Csnar t7(4): 8t8-M, April 1871. (90) HoLLBTEIN, H., 1fCCANN, J., ANGELOSANTO, F.A., NICHOLS, R! W. ShortAtarm tests for carcinogens and mutspns. Ihd9tioe SsNaxA 65(8):183- 286„ Soptsmber 1979. (a1) HOPI{IN, J.H., EVANS, IiJ. Ci<aratte.nwka-iaduoed DNA damage and lung canoe'ri.ks. Nature 288(5746): !8&,490, January 24, 101 (9t) HUDSON, R.D. Cantral nervous system responses to eij.retts.nwke inhalation in ths cat. A.uAivr. Iwfor.atioa.f.. do PAa+osaaodyaawde a do TfYenapio ?87(2):191-212, February 1979. (DJ) HUi'TON, J.J., HACICNEY, C. Metabolism of dQarstts sntoko ooadensatw by buoaa and rat bomoFsnatea to foFin mutageas dat.ctable by salraonolla typbLrutium TA IWB. Cauoer R...arrA a6(9): PA61-L/48, 8.ptsmber 1975. (Y;) JANOFF, A., CARP, Ii, Po..r'ble as.eka.i.nr o[ emphysema in smokon. C/Qatrtt..moke oondensat•e suppresses prot..ss in3ibitJoa In vitro. AuurJeas Reris:a oJRsqrinsfory Disease 116(1): 66-72, July 1977. 67
Page 79: apt20e00
JANOFf, A., CARP, IL, I.11K D.IL, DRElI, R?. Clrsrette smoke Inhalation dadswo araatitrypsin aati.ily In rat lung. 8eiewce 206(4424); 1a1s-1a14, December 14,1979. (OE) JANOFF, A, SLOAN, B., WEINBAUM. G., DAMIANO, V., SANDRAUS, R.A., ZLIAB, J, KMBEL, P. Experimental emphysemr h:duoed with purified human neulrophil elsstw• Tl.mw loralis.Noa of the indMed prote.... Aeis n A..isr eJRrsrinsbry Dis..s.11li(6): 461-77,1Gush 1077. JANO:r!', A, I/HTI6, R, CAEP,IR., HABa[, 4 DURING, R., LZE, D. Lunt Injury Induced by leuiroqtie peotese., Aswriess JoKnm1 cJAxNioovr 97(1k 118-1l8,Ootober1979.. (Od) JOHAN$ON, W.Q, JR., PIIILCE, A.K. Elfeatr of efadw, oolisc.nss., and (DO) (100) papain en strustaro and fnnetiss of rat hmp ia vitro. 771. Joww.! oJ at+sko! lnastijeHoa b1(t): 2Ji6-tfS, Tehraary 1911 JJUSKO, WJt. [nll.enoe of afJanstte.moldnt on drug met.boiiim In man. Diwo MstabslinR Rs.iw+s 9ft 821-7H6,1979. KANNER, $.B,, R>CNZ6ITI, A.D., JB,, KLAUBBB, I[.R., $MITH, C.B, GOLDEN, C.A. Vaet.hles associated with elnn`e. (e spirometry in patients with obdiuetive lung disasros. Awwrjosu Jowrnal of Msd+oi+r 07: 44-00, July 1l79. (101) 1[IER, LD., YA1tA8AKI,1., AME.q, B.N. Detactisn of nuta6.nia activity h ei6.rotte anok. aondartes P4aewdi+ps.f 1J1s 1Veti~nul Aosle+ny y3ein~or. eJtlr f7s+bdSlebs ef Anwries 71(10): 410-41611,Oete6er 1974. (1Bl) KOZIAWSIU, LT., p'REQC6R, R.C., KHOUW. V., POPE, MI.A. The misuse ot "lea.-hsude:r" ol6uettr and its det.etioe: Ho1.bloddeB of ventilated filters. As.nieaw Jerr:wi.f A:bdis Re.tM 70(11):1202-1200, November 19l0. (103) LAVOIB, II., BEDENKO, V, HIAO?A, N., HDCHT, $.l., HOFirMANN, D. A aompars.oa ef the nmt.6saicit,f, tumoNinitiatlnB activity and complete are3no6enidpr of pnlpnucleee arvmatia hydroairbon< I.: Jona, P.W., Leber, P. (Lrdit9n).. lbiymideor AroMatie Ifydsoearboas. Ane Arbor, Aaa Arbor Sdenoe,ll7l, pp. 70ti-72L (104) LE BOUFFANT, L, MAIfLZN, J.C., DANIEL, H, HBTRN, J.P. NORMAND, C. Action of iat.:ri.e eiBar.tte smoke Inhalatioas on the rat lung. Role of p.rtJaslate snd r.war ae[eeton. JeK+w.l a/ tA. Nati.ual Csne.r IwsMtvt. 61(2): 275-Z61, February 18E0.. (106) LEE, N.L., NOYOTNY, Dt., BARTidi,1LD. Gr olromatogr.Phy/aur speetroc metrie and .ndeer prseetk easonuroe spsehometric stndies of eae~eMo6ark polynneJear aromatic hyroearbour In teAeeeo and mseijwna smok. conden- sates. wtes. AnaLytissl Qisrisby 4B(2): 466-41q lehrnary 1946. (100) I8$ P.N., ROTHrYlLIL.. K, WHITEHEAD, J.E. Fractionation of mouse skin eandno6enw ia d6aruttt..mske condewata. 9ritlsA Jor+ieat of Csrar 86(6): 730.742,Jua.19?7. (107) LELIQUCE, J., CLAUDLr, J.lt, THNVIaiIN, 11. AIpAs(1)antltrypdne at tah.e, one etade ds 1496 bommee saio0 (Smoking and .erms alpiu(1} antitrypsi. In ltfb healthy men.] aiwia.lal{mios Ada 46(8): l67-048. 1979. (1od) LONOO, LD. Ths bioloriesl effeete of carbon monoxide on the pregnant woman, fet:r, and n.wbsea infant. AmeHssw Journal of O6.esbiea and (' Qynaalepp 1P8(1): 661-100, aepto:.Uu 1,1f77. (10)) LOUGH, J. Cardiomyel+stqp profi~osd by ei6.ratts rooke. UiM..fructur.l obeeevatioas in pdne. pigs. Arahiws .J AUobyy awd lakratay M.dieiw. l0?{7): 5777-MJuy if7l. (110) YAGE6, P.N, IdONTL9AN0, R, PRb[)8S1[ANN, B. N-Nitroso compounds and related cardno6em. In: aearls, C.F. (l7ditor} assw:ioei Ch+e+*vpen.. American CMmial'Jociety Monograph 17d,197a ss,GSgzm (111) MARSHALL, M., HE3,9,,. H., $TAUBESAND, J. Ewpa.imentelle Untasuchun-" aen uber dea BLikofsktor R.uehsn. [Experimente on the risk factor smoking.] Yass; Z.t2akriJ! frr Ctfaessk+o+Jdw{tew 7(4): a8Y-sYT,1978. (tts) MARTELI„ E.A. lisdioeoti.ity of tobacco triehomer and Insoluble ciaarette smoke pasf3eies. N.tY+v 2/9(61b1): 216-217, Hay 17,1974. (113) 1LCCOY, G.D., WYNDER, 1LL Etiolo6ical and pee.entive implications in alcohol esrcinmnesi. Ciweer lPassr+e1189(7): 2644 2660, JdJ 1979. (114) 110GIW., H,C., JIt,1tOGBJtS, W.It, WILBUB, R.L, JOHNSOBI, D.E. Qisrette smoidnBh.Eoon model: Demonstration of fessibility.l4mo.dinpsojtA.Boeidy. Jfor Eh.per{wun(ol Bisffopy and Msdidnt 167(4): 6724176, Apri11978. (116) 1fCLE1d0ItE, T.L, MARTIN, ItR, PICKARD, LB., SPRINGER, B.B., WRAY, N.P, TOPPELL, ILL, MATTOX, K.L, GUINN, G.A., CANTRELL, F.T» BUSBEE, D.L, Analysis of aryl hydrocarbon hJdwxylase aetinltJ in human lung lis.ue, pulmonary m.cnpiuaes„ and blood IJmsepboeyts. Cana+ss 41(6): 2292-260Q,June 1978. (110) 1(CMILLAN, G.Q Evidence for components other th.n carbon nwno:ide and niaotine se etk:lo6kal factors In eaediowscular disa.... In: Wynder, ES., Hoffm.nn, D, Oai, O.B. (Editees). Prooeedinp of the Third World Confen anoe on Smoking and Health, New York, Jun.4-6,1l76. Volame L Modifyi+y tA. Risk Jbr Nu 3+Ndbsr. U.B. Department of Health, Ddueatioo, and Welfn+e, Public Health Service, National Inetitutes of Healtly National Cancer Institute, DI11LW Publication No. (NIH) 76-1221,1Y7Q, pp6 3110467. (119) 1lEURMAN, 1.0, KIVILUOTO, II_, HAKAl[A, M. Combined effect of asbestos exposure and Lobeeao smoking on Finnish aeth)plylrllNe minen and millers. In: 9eiikoff, IJ., Hammond, E.C. (Editors). Health Heraeds of Asbestos Exposun. Anwals ejMs Nw Yor* Aeod.wlr of Seitness 330: 481-486,1978. (11d) MILLER, &C. Some current perspectives on chemical eaecino`enais in 6umans and experimental animals; Peraidential address. Cancer Rsssa*rA 38(6):1479- 1496, June 1978. (110) YIZUBAIII, S., OLtMOTO, H., AICIYAMA, A., FUKUHARA, Y. Relation between chemical eonstituents of tob.ooo and mutqenie activity of cigarette smoke condensate. Mrtatiew RussreA 4i!(3/4): a1s-026, July 1977. (120) 1[ORIN, G.P. 9oleatiw filtration of tobacco smoke eomponents: A erview. Proosedinp of American Chemical Society Brmpo.iam, 173rd Ameelesn Chemical Society Meeting. A6rioultur.l aad Food Chemistry Di.ision, New Oef.w, 1977 . R.awt Adsawas in lJis Ql.n,ie.i G1r+npwition of 9bbooao and TaBoaoo 8saty,1977, pp. 6611-M (111) IdORIE, O.P., SLUAN, C.H. Determlaation of N.nlttosodltnetl~l.min. In the smoke of hi`fi-nitnte tobacco cigarettes. B.itreyu stir 15bphJbrseA+.hp 7(2): 61-46, June 19?E. (It!) 1[OROSCO, G.J., GOERINGER, G C. Panesntic aastase and serum at-antitrypp sin levels In beagle dogs smoking high- and low-nieotine cigarettes: Possible mechanism of p.aereatic c.noer in eigaretb emolws. Jerr*al of Tb:icroloyy a„d Z%wirsnwu„ta! Neeltl, 5(5): i79-890, September 19Ti1. 1[OB09C0, OJ., GOERINGER, O.C. Lifestyle factors and eanoer of the panere.s: A hfpothetiai mechanism. Jfed.aal XypotJlaa 6(9): 971-9Bb, J.PtamOer 1980. (124) NICHOLAS, H., DAVIM P, 80RNBElLGER, C, HUBER, 0. Aitentions in LnB patenebyma following a:perimentsl ehronb Inhalation of fobeoeo smoke. CAed 72(i): 40, SsptemEer 1977. (1ts) NICOLOV, 1.0, CHLRNOZEMSKY, I.N.1umon and hyperplatb lesions In Syrian h.meeers following tiaa.plaeentsl and neoo.td treatment with aisaretb smoke aondensate../ourrol of Gh*oer Rena+oA atd aisfaol Onoolopy s4(12): 2ti1-2a6,1s79
Page 80: apt20e00
(1st) NORMAN, V. The effect of perforated tippins paper on th. yield of varioia .moke oomponenta Bdtrvpc sw Ta6a&/wacAunp ?(6): 28248'l, Septemba 1974. (1s7) NYLUND, L., LUNE4L, N.0., PF•RS,90N, B„ FREDHOLN, B.B., LAGF3i- CRANTZ, H. Acute metabolic and circulatory effects of cigarette smoking in late pregnancy. liynsoctoyic and 0bcf.trie lawatiya{ioa 10(1): 89-46,18't9. (ls8) PAIGEN, B., GURT00, H.L, YINOWADA, J., HOUTEN. L., VINCENT, R, PAIGEN, 1L, PARKER, N.B., WARD, S., HAYNEIt. N.T. Questionable relation of aryl hydrocarbon hydroxylase to lun=-canasr tisk. New Jllstpnd Joxr.al oJXcdieiwc 207(7): E16-a60, Au=ust 18,197 7. (1t9) PATRIANASOS, C., HOFFI[ANN, D. On the analysis of aromatic aminea in dsnstt, amoka /orsaat of AsatyNcoi ?bmlaotoyy i(4):160-1G4, July-AuQust 1979. (1J0) PEL&ONF.N, 0., JOUPPILA, P, KARKI, N.T. Effect of maternal dsarette smokins on EA-ban:pyrane and N-m.ttqrianqiae metabolism In human fetal liver s.d placenta. 4baicoioylr and Ayplicd Pharwwooioyy 28(8): 889-407, Novemker 1072. (Itl) PELKONEN, O, KARKI, N.T., KOIVISTO, M., TUIidALA, R., iCAUPPILA, A. Maternal cigarette smohina, placental aryl hydrotarbon hydroayl.p and neonatal sis.. 7U.icobyy Iwtt.n i(8): 881-886, June 1p79. (tJ!) PETIITI, D.B„ WINGEBD, J., PELLDGRIN, F., IiAMCIIARAN, S. Risk of vascular disease in women. 8mokins, oral contraceptives, nonooatr.oeptive esteo8eos, and other factors. Jouraol of tJYc AmMrioax Xcdiesi Aaxiatioa 242(11):1160-1164, Septsmber 14,1978. (1JJ) PILLSBURY, H.C., BRIGHT, C.C., O'CONNOR, KJ., IRISH, F.W. Tar and nisotine in d8arette snwked dor+wat of tAc Aaseiatton oJ OJ)Seinl Ans2ytioot Chsn(afa 62(8): 468-462, lday i9®B. (11l) POUR, P, Y]tUGER, F.W., CH1:M, D., ALTHOFF, J., CARDESA, A., MOHR, ,U. Caneer of the panen.. Induced in the Syrian golden hamster. American Joa.mi oJlbtAoiopr 4Q(Z):. b49-M, AuBust 1944. (IJS) PRiETO, F., ENGLISH, 1[J., COCHRANE, OJL, CLARK, TJ.H., RIODEN, B.G. Spirom.try in healthy m.o:. A correlation with smoking and with mild symptoms. TAsruo,88(8): $22-527, June 1978. (1JQ) RUIGLBiY, M,B., SHELHAN, IC.L.. WILKES, M.M., YEN, S.3.Q. Effects of (tsr) ma4rnal smoking oa siroulating eateotwlamine levels and fetal beart rates. Anw.iosw Joe*a.i 4l Obrtariu and Gyesootopy la9(A): 686-600„ March 15, 1979. RADFORD, C.P., JR, HUNT, V.R Polonium-210: A volatile radioelement In cigarettes. Se+awos 149(8E08): 247-?.t9, January 17,1964. (1J8) RAEDEEI, E.A., BURCKHARDT, D„ PERRUCHOUD, A., BLUM, P., AM-. REIN, R, HERZOG, H. Effects of smoking and Inhalation of carbon moooxdds on systolic tims intervals and blood presure. Differences between two types of ei8.rettea and a cigar. CJust 76(2):196-140, February 1979. (139) RAWBONE, RG. MURPHY, K„ TATE, x.E., KANE, SJ. The analy.is of smoking parameters, iahalation and absorption of tobacco smoke In .tudies of human anwkina-behavior. In; Thornton, RE (Editor). Smoking B.Aavto., PkycPoicyioal snd Aiydblopical I+y(Ivcwas. New York, Churchill Li.inptose, 1978, pp.171-194. (1{0) RICE, J.11. Prena4l effach of chemical carchwQans and metAods for thsir deteetion.. I: Kimmel, CA, Buelk.,Sam, J. (F.ditms). Asrtopawetat lLaiaity, in prea (141) RICBERT, W.9., ROBINSON, J.C., YOUNG, J.C. Estimating the hssards of "Mr hassedad' cigarettes. L Tar, nieotioe, earbon aaoo:ide, aeroldn, hydrogen ey.ntdei and total aldehyds dell.erkr of Curdiso cigarettes. Journal of 7Wieoiopr and Dkviroxmcntat XmttA d(ZJ: 861-986,1990. 70 9S4seus (142) ROBINSON. J.C., YOUNG, J.C., FORBES, W.F. Low-tar CiQarettd can produce long-term reduetion in nicotine expawoa Canadinx Medical Aa+oeiation Journal 128;. 889-891, Novembee E,1880. (143) RODRIGU$L, RJ., WHITE, R.R, SENIOR, R.M., LEVINE, E.A. Elastase release from human alveolar macrophages: Comparison between smokers and nonsmokees.s Science 198(4814): 818-514, Oetobee 21,19?7. (144) ROMANSKI, B., BRODA, S., SWIATKOWSKI, H, ZBIKOWSKA, M. The immunologic response to tobaooo antihsna in smokees. IIL Type III hypenensi- ti.ity skin reaetioos aad specific uruns pc.ciplUns to four different tobacco extraets in patients wffee'.ps from aoevnary artery disease. AUs.yoioyia ct Im+axaopatioloyia 7(E)s f 87-188, MayJuna 197p. (145) RU68ELL, li.A.H. The ew for medium-oieotiny low-tar, iow.carbon monorode Uas) daarettss. In: Gari, G.B., Boek, F.G. (FAiton} 8anbr.y Rcport $-A Safe Cipa+ctts! Cold 8prin8 Harbor, New York, Cold Spring Harbor Laboratory, 1980, pp.. 2'D'1-H10. RUSSNLL, M.A.H., JARVIS, M., IYEIi;, R, FEYERABIt1ID, C. Relation of niootiae yield of dpuettes to blood niootln" ooac.ate.tions in smokers. British Medical Journal 280: M978, Apri16.1080. (1J7) RUSSELL, MAH., SUTTON, S.R, FEYERABEND, C., COLE, P.V. Addiction Research Unit nicotine titration studies. In: Thoenton, R.E (Edit9r). Smoking B.Jlavior, PhysioloyiaaL and AsycAoioyiaal hy/iucnas. New York, Churchill LiviuBafoae,1978, pp. 5.96.948. (1dI) SAKABE, H. l.ueK cancer due to exposun to bis (chloromethyl) ether. I+iduab+al HcattA 11(3):146-148, lY7& (149) SCHACHTEti„ S. Ph.rmaaolojical and psychological determinant+ of smoking. In: Thornton, RG. (Editor). Smak:npp IScAavior, Physioiopicat awd Ayehotopi- eal Iq/Iucnau, New York, Churchill U.inBstone,1978, PP 209-M SCHULZ, W., SBTrIIOFER, F. Smoking behaviour in Garmany-The analysis of cigarette buttw (KIPA). Ins Thoenton, B.$. (irditorl Smoking BsAavior, PkysioloyiarW sud Aryekoiopioal hy/lwrnew. New York, Churehill LivinSst,one, 19Ti, pp. 240-Y76. (1t+1) SELKE, W.A. Reconstituted tobacco abeet. In: Gosi, G.B, Bodc, P.G. (Editon). Banbwy R.poet !-A Say/b C+Qasett.l Cold 8prias Harbor, New York, Cold Spring Harbor Laborstory,19e0, pp. 206-214. (1SD) BEPPANEN, A., UUBITALO, AJ. Casbo:yYaemoglobin saturation in relation to awidn8 and various ooeupatkmai conditions. Annals of (xiwioal R.wancli 8(6): E61,%68, October 1877. (16J) SHAW, H.1[, MILTON, G.W., MCCARTHY, W.H., FARAGO, G.A., DIL- WORTH, P. Effect of smoking on the recurrence of malignant melanoma. Mcdioo! Jor.wot of Aucbatia 1(6): 20B-M9, MareL 2t,1Y79. (154) SOBOL, BJ, VAN VOORHIES, L., EMIRGILti C. Detection of acuta effects of cigarette smoking on airway dynamia: A critical and oomparative study of respiratory function tests. T7aras S'!(9): 912416, June 18Tf. (155) STEDI[AN, ILL Ths chemical composition of tobsooo and d tobacco smoke. Chsw.iest Rerisw 69(2):166-20't, April 1968. (1be) TACH16jES, L,, FERNANDEZ, R.J., SACKNER, M.A. Hemodynsmic effects of smoking si8arettes of hi8h .ad lorw niaotine eontsnt. Acat 74(S): 245-?A6, SeptAmbee 1973. (167) TAGER, LB., WEISS, S.T., ROSNER, B. SPEIZER, F.E. Effect of parental cigarette smoking on the pulmonary function of ehildr.n.. Amc.uftw Journal of 67ptd..doiopy 110(1):15-Z6, July 1879. (16d) TAYLER, R., PIPBK D.W. The eardnoasnie effeet of eiQsntte smoke. The .ffeat of djwtte smoke on human gastric nuuoosal esBr In organ culture. Caucer 3K0):. 262l-2SZf, June 1977. 71
Page 81: apt20e00
8928975`7 'aopsirdald w'qltuaZ »ns o33w0IJ Jo aopaaa,d. n wl-ltva ROlwsvq0 Ja 41918 1l '6'M 'MMII[ b't 'NOSxIHORt '"JY 'DNfloJL (tQr) aol7u.d.ad v}'IxpI°uOi' P"a vP!"NND usfi-AdX '+PrinoR +a4++b lo vvW°}1iQ su}ptPaH iv j+4L m-vhD -f •++P-*!J +H -Y POo'J wl! B'M'M[JI1I''07'xOSNIa07t "'J7'JxllOx (rsr) 'LL6T WJnY'a998-9496 I81iL v0l-Y I• v+MYa!u!t Mr+ h v~l~slo R+vv-v t v"vlV i» /o vOM!POW 'vvlsa alaasq= o.vq aaqoru..3wa10 mraY]C Na+sviodaoa vql qilr uopdao.p. 6q vulm tnosf .aaftmn jo aoqslaooaap 'x'a '$ZHY '$ 'I]iY6YitY1[ (ser) ST6T Lsaftavt'Bb-T 4T1Q Y-rd +MvbIv tvv+Mt omoapm Jo •pauatoN.d a0 Jo JMP muauil+adSq 'Y 'YdYYIHOt "I 'YMIJYITYx (ter) •6uT'e1 a+drr'ooe-M49Tbo6 W.-Phrlo tumor wvift a+x 'atuRRqP MWM Y Vq7tavq Pav oo°v9os •a 'xxY1NUOli ''i j 'lLsatdJCa (oer) 'OL6I JaquMft 'L84•iL9 :(6)fZ ++ouv0 Iv Iv"+oP Yn)+g 'vlaa.9oupva ooosQol al aasia[t Lv.solq w vy tmoy.ald.as puv >ryandi wLL 'a 'xxYWd30H ''I'H 'NHaNJLM (Qir) 'dd 06L'IA6T'av+d oP~PvsY'+!v~~+~9'J f a7v~*+o~T a} .npiyg •n-v ooooqoa puv -sqaa 'a 'NxYIN+moH ''I'Z 'ffiaaNJLM (8ir) 6L4T Alat b6'•YT -(T)OZ sop+udwaKL pw /IOoloovwr,+aYd tvc+!u}o 'asp*uFurlP uo°.a wIuvitaoPul puv val+ddpus uo laqauv mo+a9P puv 9ulh jo 1-)n 'fl'a 'aNYHS "'IHONY1i8 '7C0 'xOSNI717IM 'Z-d''IYZHHA`rrV 'aooM (<ir) . '6L61 flrf'49Q-L9a '(.lZ9+i+}+vMn rol7dtwy Ivtos(!o /o vaNvloavY M h 1va+*o!` 'vuv6ouio- Ivalmaq+ jo laryoaa- aoJ aladar PWV v2fUvP YNQ UM vmv1.J. 7p1 -iH al Jo w" 'N'D 'SJtYPTriM (air) •6y6T ~aqmaados'661~6~ ~(Q)i6 ~}9!hvlf 1OOtU}ID PaD AOlAC4oT I° t-*"P '•afvqda4.m vu}wuu [q uop- oM.vto ao 040- qiattsya Jo t3wjJN 'Y',d.toNYt''f4UMM'7I r1.LIHM (4YI) '086T'bZ 4'+wPt'aZL-OZL Ul?ZOa'"p.gPep410 >w-/' rv-Aw ouAr `nl«uI o-.qol ol p..ods• /ya- -1uvmRo Lunpum+vv at vopwaJvfP vLvaiFv-UmB 'jI'Ei '63ou '7iY "rLLIHM (tY!) 'pT-TSI 'dd '6LtT'vv*PalAl'I lll4M4J '4vx wx '+J04ix1ful px&1°rAd Pug, tp!"Yd 'joYWaS 6a}qowG'fio7)P3) 38'no3waU :aI 'aorlavslv annnq aodn v1a14vI vapoolv puv 8aqom. .n-~a Jo qaaJJv vyL 'Afa 'Np18ASttYd "H 'HixSHM (rYT) '8QT1'i44 'OQ6I "o'J Salq4lVnd avIDO°vhl'vWJC wx 'uolP!Po WoovB wa!4J I° aw!V vlvvg oqy ;AAqoorytly .,ilaaQ prs Xaav.vO '(Wo1lpH) "0'I[ 'JatauY "aD 'ua.vqx "t'6noa :al •vu.toarassa P4m.q0 'IiT'fl 'Sl1YPPIIM `H'f ''l0fl811$SISN1 (i8r) 'LL6T'T YyvM '90w06 :(8)6fT Rtfda' ,Col-oo fo iwmol` 'Lqdailowmom pablt -uvwoJjad-46lq oilvxro.l Lq w;otus jo auµa .q3 al .uppoo pav aupoola Jo vp8lvaa pldat '(r1 'NOuYM (rpr) mud QIW+v1LL 'o'awv3P Jo w[4'Iun1J!P 3o wnom. auoaiw atqlq sa2RqaI 'Y 'lIS'IIYS `t 'AtYMoa `A VI(II "rH 'aZYM (oai) LL6T vvaf'iW.9f9 xY)L9 YrtavX at?4WIa J-'nOt -alLs-YwDvdza .uaa.fla Jo .aa~ ..pnfQo n.asa.bolqi manv Pav vPRouout aoqasa Jig n04ft •e•s 'x2rTnH "s 'xosMCwatM '•e 'xUMe "x z 'aooA (ur) •6L6T 7m2nY'Q8T6 Lf.T6 :(8)6B YAWWW LaaraO tiamo. oanu Iryuvovld avoinq Lq oalpqvlam oaaxLd(s)oauoq no faqoat. jo iwJJ3 'YJ `lIOJ.`)Oa''1I'aI1H0837''a'N `NH)litYd'"I'H'OOaIl1J''S'f'LH'JIIYA (pLr) 'BS6T IIdY rolt-zlf =(r)ot wrafr PP-+-la+arlo -"vuv V&SW1M Iupvl.Gpv jo oddi rau Y cuvqLopq=vqd1Y 'Y '7IYAI$ "D 'OaYOY{31( ''I 'H7rZ6flNY'I ''D 'ZLYA ''NI'S 'Hld1QSa'iU`J '"I•a 'lIHSlUlQ xYA (w) 'IItT-90T'~'GY6T'~Vv'I ~9wH sW8 Ppo '3pox .aH 'Jawv» Jkwle ploo Jn>MW Ve r-t< pO+ar LrM"vS '(ueIlPit1 'D'a VoH `s't) 'Ho0 roI 'a+va.paos qoau .as-dP al smla1qW +oanq Psv 'wn$a+Waaoo '.w$vapuvo Z ~xl a ~~A (Gir) ~L Oa0)'ex vvnvmnd dn 'ILnwo vvesvFa jaJ m'Ivv'J'p" 'O1vvH ' 1 ollaaa'w*fnM pw *wIviOl6;'mveH Jo s.«Qla.a.a 's•n wow mawirr 1 v-Buwpre Iv +ou+vbaaro vno+X ws 7ntAvn S,itivHS Orlaad 'FrA (fLr) '"st'oset '4IIvvH Pav SvP1O8 ao pIJJO'411MH JOJ 4eOMS 11ROiM 00 Jo p1JJ0 *1"s "H nltqAa `•+amd wv UO1MM 'Mtps P VMWPMba `s'a `I-k) v-A-6 +0 lo i+vd+7f Y•-Jl -WOUR-Blo SN-NbWM YrivvfJ ncL mxvmx aNV 'xo>J.YOnas 'H.twxa so Jmnwvdza vn (ur) '" 9C1T'iUT'Y0009-iL (6SHd) 'ox aoAviA9ad MHHa'q3lvrS Pav S°P[omS no vOWO'41PvH wJ Anpav8 1U""WY 0% Jo vo<1JO 'plANS q1MH v1lVad 'v+vAvM Pav "POMPH VMa Jo OvvQqwlaa 'B'A '1-0-D 11OAaB on Iv t+oft Y Vpvtr Pw &tar-s'aur&mM aKV'xolsYOnax'uwatt ,to LHzxnYaa sn (w) '6L6T ANt'sf4i =prgy .(LlG8vuaasy sMop :moavs Pro Ivqoolv Jo nMlMvppaY'Y'8NJEILL (fJl) 90iT'611f-L10 19)00 ivamat d-0"dY *AIIA+vJ Pov PC 'I vw4o3 al WM oTi•4d puv 0TL-ad Xm-J1o -wJ M-OwsY `B'S'191wi''I'D'BN9rTML8 b'i'OSL (r6r) '9L6t t+vavvt" 4T)Q AM1f•+uWVqqL 41s.layi.g •.VaiW40292a al iaslavo aalm.oollaft.mIP -x 2,+tv»ir ol"9vJ opowAsa «me -wa'xoexHOt *,rr'si'cts Iv,ti'o$s (acr) *M Li.ausf 'T9=w(TIe A-v=-A°m " •eap/se vuarar LrvanalpA .ma pav qvvq mpwavq,y'I'Saiw Jvvl P@q=&v'aH'M'a'flxOt3a'7I %MO'I''J'Z'o$1 (ttr) 'Mi'azmavs*A*x'srorSoT :M mom •ea We"TNMOR"JNIw oTa: -v+nNolod Pav 9ZiCMlI8T Z't `JlHaxY]fil'IY 'Yx 'x3aTIYS `J'l '0U (rar) 'LL6T tvI[ 'L99T aAvlloB Pm+vi vm1m+SY Jo awaa'ISVaW 'a'A '00oo9v.L duoatY ranu0.g r/dlHai( pao wwap"mq o0oaMum vaZ'OBL (L9r) '0o6T alft " Uv IfavvX Pp h9vous8 YMoM wpvw$P InJ+w9 vwl mJ 0ooaqoT lapapaA ol .ar7.M 'J'Z 'oU (Jar) V1T=TQT'w `OB6T 'R+wv+oQv'I +aq+aH hMvi6 P!o N+aJC wN'+v9wH 2uWS IMvJ J+»uol!0 sifv$ v-t mpl+0t A-q'og '(wo=) 'fl i V°8 I" IM :4I vooaqoa aoJ.. • ]ujdol...p aoJ..abloqaa7 pLmprWv RftutIS vb11wlilPo)T'J'Z'0U (4ir) T•L6T'MN=b p1+IWL'0T-): xi)OI A"W Mv!oS I-nm-.Ugv nwala jeja 2up%-W jo: Imav* wz ys 'ost (ra:) TJ ET vaat'6T4T-TTgt :(G)Oi vrvt!1oul -oKV~J pwoAl+nlvt+-Mt'qusaM aovv" Pvl*IvMMvo4 a{ auqlnal8v Jo aM-m}y=pod q9aojp a;W.q~wwW Jvt Jo avRvlndlavl[ "J Z'0U (rir) 'OL6L ~qo1~p•Wqv+v'idv6'1Y~-YDY ~(9JW l~+M~R+~~Y 'solqo•ol tq jeFQ1+vf Pvv tP wwJ.vqd Pov«Ad Jo iv"wu Pv'alusfI,7Z'08,L (i'Jr) •eOaT'!Jg'f09 .WAhI°r4M p"Mj6•tl&IbwP'0a+qai T)',L'08,b (rir) `61~6T vvt'MT-TSI ~(t)f ~1 tv0lv~lo J~+*vP tivodmW '.avmnq dF vPvflol4 J&WWMv+Pv WM vrl3Wlo. Pav a.I1MN.noa nvlpvaI 20IMw swlvva vnwasP 7o•p•fJv ali,waaqv pav iqao.aolpreO ~rN'nSNSLSI!)AO''1',L'NSSaN9A$''3'f 'NSb'1HV'J''t'xHBmu`dYiLL (Oar) a6iT'$P i9 ~fa .''B #-wVZ vps4- I4d.13o.otoovoaoap aoda PMV4 vvi7a+v>ip L-.INP rol Ju+vi al.i +O7 Pv4'w- PqvWnaY W'j '$YAOHL (i9r)
Page 82: apt20e00
Section 3. CANCER ss4sezse
Page 83: apt20e00
Gs4sezse CONTENTS Introduction Epidemiologic Studies Background Epidemiologic Studies Discussion Pathologic Studies Discussion Experimental Chemical Carcinogenesis Tumor Initiation and Cocarcinogen' Organ-Specific Carcinogens Carbon Monoxide in Cigarette Smoke Smokers' Compensation 1ranaplacental Carcinogenesis Flavor Additives Conclusions and Recommendations Summary References LIST OF FIGURES Figure 1.-Lung cancer mortality ratios, by amount of "tar" and nicotine in cigarette smoke 77
Page 84: apt20e00
Introductlon Figure I-Lung cancer mortality ratios, by number of Research indicates that cigarette smoking causes cancer of the lung, cigarettes smoked per day and amount of "tar" and larynx, oral cavity, and esophagus, and is significantly associated with nicotine in cigarette smoke pancreas, urinary bladder, and kidney cancer in both men and women (102, 10s, 10;). This conclusion is based on epidemiologic, pathologic, Figure &--ltelative risks of lung cancer in bng term filter and experimental evidence collected over the past half-century. r smokers (LTF) compared with nonfilter smokers (NF) by A quarter-eentury ago lung caneer, , was found to be relatbi'd number of cigarettes smoked per day, males quantitatively to cigarette "tar" cumulatively inhaled. This finding, Figure 4.--Decrease of benzo[s]pyrene in the smoke of along with much other evidence, led to the prod sction and widespread U.S. nonfilter cigarettes (85 mm) use of today's lower taF" and nicotine eigarettes. The evidence summarized in this section demonstrates that lower "tar" and nicotine cigarettes produce lower rates of lung cancer than Figure S.-Pereent of sections with advanced lesions by do their higher "tar," higher nicotine predecessors, but smokers of smoking habit in two periods lower "tar" and nicotine cigarettes still have much higher cancer morbidity and mortality rates than do nonsmokers, as well as a higher incidence of other diseases associated with smoking. One imporFsnt research conoern is to identify the human carcinogen- ic chemical or chemicals in the particulate and gas phases of cigarette LIST OF TABLES smoke. Multiple metabolic trandormations are available in the human body for the several thousand chemicals In cigarette smoke, a number of which could lead to carcinogenic activity in model animal systems. Table 1.-American Cancer Society Matr.hed Groups Study Another important research concern is that changes in cigarette composition to reduce "tar," nicotine, and possibly even total smoke Table Z-Bnown carcinogenic agents in the gas phase of exposure may inadvertently increase, or fail to decrease, those cigarette smoke chemical constituents still largely unidentified that contribute to cardiovascular and pulmonary diseases, pregnancy complications, and Table S.-Tumor-inf tiating agents in the particulate phasc fetal and perinatal deaths. of tobacco smoke A third area of concern is that the animal model systems used to predict human disease from cigarette smoking require additional study Table 4.-Cocsrcinogenie agents in the particulate matter and correlation with the human situation, if these models are to serve of tobacco smoke as a basis for modifying cigarette composition. When disease-produc- tng chemicals are identified, their reduction or elimination should be associated in the animal models with a decrease in the disease(s) Table 5.-0egan-specific carcinogens in the particulate predicted and without untoward effects. matter of cigarette smoke This section summarizes data on the human cancers associated with lower "tar" and nicotine cigurettes, as compared with the "standard" Table 6.-Carbon monoxide in smoke of cigarettes cigarette of the 1930s or 1940s. In addition, it compares pathologic (autopsy) studies on bronchi of cigarette smokers of a quarter-century ago with bronchi of lower "tar" and nicotine cigarette smokers. Further, the section describes the identification, metabolism, and possible mechanisms of action of certain carcinogenic chemicals in both the particulate and the gas phases of cigarette smoke. Finally, the • srar...l.e tr s..rw.r lu. NaWq a..r r.r..d w..r.do ew.+ypA b..r'1.r; b... Y.11r.ipntlr Lwwr, W ~iW~bw.~.lw•JIW vpwdrMl.w'Y~..Llrtlw~.Mlr~.w~w, W&tl. d Mw'1."W airY.w dpnMr.m aMrd .N.n 10/mY/Od.4 .rK1..n l.w.r •1.r'..1 d..Y.. 09499mg 79
Page 85: apt20e00
section presents a series of conclusions and recommendations for research. Epldemioiogic Studies Background It has been established that cigarette smoking causes cancer of various organs including the lung, oral cavity, esophagus, and larynx, as well as exhibiting a significant association with cancer of the pan- creas,bladder and kidney (102). Epidemiological studies, both retrospec- tive and prospective, have shown a dose-response effect; that is, risk increases with the length of time the individual has smoked and with the number of cigarettes consumed. Such studies have demonstrated that, upon cessation of the smoking habit, risk for developing these cancers declines; the slope of the decline depends on the duration and extent of the former habit. For an individual who has smoked more than 20 cigarettes per day for more than 20 years, no reduction in risk of cancer development is noted for at least 3 years; however, the risk decreases thereafter and, after 10 years of cessation, begins to approach that of one who has never smoked. From these epidemiological observations, it has been predicted that a smoker's cancer risk would be reduced if the "tar" yield of a cigarette were reduced, provided that the individual does not compensate by more frequent and deeper inhalation of lower "tar" cigarettes. The trend toward cigarettes with lower "tar" and nicotine started more than 25 years ago with the introduction of a number of filter brands. This trend continued over the years with a greater number of filter brands on the market. Since the early 1970s there has been a rapid Increase in production of cigarettes with 15 mg or iesa "tar" and 1.0 mg or less nicotine.. By 1980, brands with these characteristics are expected to account for more than 40 percent of total sales (70). In 1950, the average cigarette had 40 mg "tar" and 2.2 mg nicotine. Today's filter cigarettes average about 14 mg "tar" and 1.0 mg nicotine. The downward trend, particularly in terms of "tar" in filter cigarettes, is continuing. There are increasing numbers of cigarettes yielding 10 mg "tar" or less, and these have only one-fourth the "tar" yields common 30 years ago. Although total consumption has increased froni'365 billion cigarett$s in 1950 to 620 billion cigarettes in 1979, consumption per capita by persons 18 years of age and over has decreased by 5 percent in recent years-from 4,148 cigarettes in 1973 to 3,924 cigarettes in 1979 (101), reflecting the 30 million smokers who have quit (75). On the other hand, the proportion of smokers who reported that they smoke 25 or more cigarettes per day increased from ° -cent in 1970 to 28 percent in 19'tR Epidemiologic Studies Three epidemiologic studies-by the American Cancer Society, the American Health Foundation, and the National Cancer Institute- have evaluated the effect of lower "tar" and nicotine cigarettes on lung cancer mortality. The American Cancer Society conducted a prospective study in which more than a million nen and women in 25 States were enrolled in 1959 and traced for 13 years. Subjects completed a questionnaire on smoking habits upon enrollment, and the survivors completed another questionnaire in 1965. An analysis of mortality from lung cancer was made for two 6-year periods: July 1960 to June 1966 and July 1966 to June 1972. The analysis included males and females who, in 1959-60 and in 1965, reported either that they had never smoked regularly or that they smoked cigarettes regularly but never smoked cigars or pipes regularly (J6). On each questionnaire, subjects reported the brand that they usually smoked. From this information and from various reports of "tar" and nicotine published in the years in which the questionnaires were completed, subjects were classified as high "tar" and nicotine (T/N) smokers, medium T/N smokers, and low T/N smokera. In the first period, high T/N brands were defined as cigarettes with 25.8 or more mg of "tar" and 2.0 or more mg of nicotine. Low T/N was defined as brands with less than 17.6 mg "tar" and less than 1.2 mg nicotine. The medium T/N category was between these two groups. By the time the second questionnaire was distributed, there had been an increase in the number of filter brands on the market and a general lowering of T/N levels. Low T/N was defined in the same way as in the first period, but the high T/N category had to be reset at a somewhat lower level. Smokers in the three groups were compared by a matched groups analysis. In this procedure, the groups were matched by age and other factors, including number of cigarettes smoked per day, age at which smoking began, race, urban or rural residence, occupational exposures, education, income, and prior history of lung cancer or heart disease. To be counted in the study, at least one person in each of the three T/N groups had to be matched on all the variables mentioned above. The adjusted number of lung cancer deaths was obtained by dividing the number of deaths in each triad by the lowest number in each of the three groups. The adjusted numbers of deaths were then summarized for each of the three T/N groups. Table 1 shows the number of subjects and the unadjusted and adjusted number of lung cancer deaths in the high, medium, and low T/N groups by sex and time period. In both sexes, deaths were fewest in the low T/N group. Figure 1 shows the lung cancer mortality ratios based upon the adjusted number of lung cancer deaths. The number of adjusted deaths for high T/N smokers was set at 1.00, and the adjusted number of ' 194687.G8
Page 86: apt20e00
TABLE 1.-American Cancer Society Matched Groups Study au Piriod Hio T/N I(.di.r TM Iw.r TIN HdN 19e4.1!!t e1Aa 5000 16,i00 11d. tae4im 10,151 .qpYO {= rwi. lfeaatet .4ut 40.100 14" re..w uesans 324" r,bt f1,ro1 M.1. uM0.1fM ifl 40 ta YaM 1Ni.1l7! .n fi. r.ndo ueO-111" 0 a Is ltimN 111b-1f7= ii ltf N llaN ifa.llM MA 137A 101.0 1LM 1fIF1l7f e" W 90.f /'...r U+a1fw ss 41.4 s1A h.nM lW1f8 0!1 492 $61 N0l111l7Lt Hmrrri.L (Jq. cancer deaths for medium and low T/N smokers was compared with it. The mortality ratio for male low T/N smokers was 0.85 and 0.79 In the two time periods; for females, it was 0.57 and 0.6Z The mortality from lung cancer In low T/N cigarette smokers for both sexes over the combined time periods was 26 percent lower than for high T/N smokers. The mortality ratio for smokers of medium T/N cigarettes was lower than for high T/N, but greater than for the low TlN amokers. Low T/N smokers had mortality ratios considerably higher than men and women who had never smoked. In men, the mortality ratio of nonsmokers for lung cancer was only 9 percent of that of the low T/N smokers; in women, the nonsmoker rate was 43 percent as high in the first 6-year period and 22 percent as high in the second 6-year period. It is Important to note that the T/N level of the brand of cigarettes smoked was not as significant as the number of cigarettes smoked. The adjusted number of deaths in men and women who smoked fewer than 20 high T/N cigarettes per day was compared with those who smoked 20 or more low T/N cigarettes per day. Figure 2 shows the mortality ratioe. The less-than-20cigarettes-per-day high T/N smokers had mortality ratioe from 67 percent to 27 percent iawer than the men. and women who smoked 20 or more low T/N cigarettes per day. A retrospective study of lower "tar" and nicotine cigarettes was conducted by the American Health Foundation (111). Data on lung cancer esses in white malea and females were collected, and interviews were conducted in hospitals in six U.& cities between 19®9 and 1976. Control cases were selected from patients in the same hospitals on the basis of an absence of a bistflry of tobacoo-relatsd diseases.. Z94sezse M N M t M M L °TA/M AND NICOTN/E M) C/dM1lTT! eMOK9 M L FIGURE 1.-Luag cancer snortaUty raHoy by amount of "tar" and nicotine In cigarette smoks IIOTHs H.li&y Y-adl..r, L-1nti •OU3OQ i.rwdii(M). Cigarette smokers were classified as long-term filter smokers (those who smoked filter cigarettes currently and for at least 10 years) and nonfilter smokers (current smokers of nonfilter brands). Relative risks for filter smokers and nonffiter smokers were computed by number of cigarettes smoked per day. Figure 8 shows the relative risk of the male filter smokers as a percent of the risk for nonfilter smokers. The percentages ranged from 61 to 89. Females showed the same pattern, with the relative risk for long-term filter smokers ranging from 38 to 79 percent of the nonfilter group. Only in the heaviest smoking category (a small number of cases) were the relative risks the same. This risk ratio of filter smokers to nonfilter smokers remained low when the data were adjusted for factors such as duration of smoking, amount of cigarette smoking, age, and alcohol consumption. The American Health Foundation study also analyzed the risk of larynx cancer for long-term filter smokers versus that for nonsmokers. There were many fewer cases of larynx cancer than of lung cancer, but the same general pattern was observed. In men, the relative risk for long-term filter smokers was between 50 percent and 76 percent of the as
Page 87: apt20e00
20+ <20 ae+ <20 20+ <20 20+ <m A DAY A DAY ADAY AOAY ADAY ADAY A DAY A DAY LOW NIOM L01M NqN LOW NION LOW HIGH T/N TM T/N T/N T/N T(N TfN TiN FIGURE 2.-Lang cancer mortality ntios, by number of cigarettes anoked per day and amount of "tar" and nieotine in cigarette emoke sollOC@ e.....+ 0t.L (N} risk for nonfilter smokers In various number-of-cigsrettes-smoked-per- day categories. Women showed the same pattern. A third epidemiologk study was conducted in Austria (6S). This project, part of an International study of smoking by the National Cancer Institute, analyzed data on a sample of 4141ung cancer patients and 828 controls. Cigarettes were categorized intfl three groups by T/N level l,Group I, cigarettes with "tar" yielde below 15 mg; Group 11, 15 to 24 nig "tar"; and Group 111, 26 mg or more "tar." These groups were assigned values of 1, 2, and 8, respectively, to indicate average expoeure. The average "tar" exposure In cancer patients (2696) was signifi-y cantly higher than for controls (2026). Scores for total "tar" exposure were computed as the product of the number of cigarettes smoked per • +he number of years smoked, and the "tar" level (1, 2, or 8). LTF NF 1-10 ADAY LTF NI 1M20 A DAY LTF Nf 21-30 A DAY LTF NF 21-40 A DAY LTf Nf 41t A DAY FIGURE 3.-Relative risks of lung cancer In long-term filter rmokers (LTF) compared with nonfilter smokers (NF) by number of ¢trarettes smoked per day, males 20viMMT.1W.d sNO.w (nn, Relative risks were then computed by these scores. Theae risks increased directly with "tar" exposure scores, from 1.6 for scores lower than 600 to a relative risk of 6.1 for scores higher than 5,000. Discussion Cigarette smoke condensate of present cigarettes produces fewer tumors on mouse skin than did that of cigarettes tested some 80 years ago (109). This difference is probably because today's cigarettes contain more tobacco stema and more reconstituted tobaccos and have cigarette paper with higher porosity, all contributing to smoke condensate that is less tumorigenic to the experimental animal.. Changes in chemical composition of the smoke may be a factor. Using just one chemical component as a carcinogenic indiattor, researchers have shown that benzo[a)pyrene (BaP) content Is significantly lower in today's cigarettes than (n cigarettes of 80 years ago (Figure 4) 1''"
Page 88: apt20e00
"tar" and nicotine in the inhaled smoke may be more than indicated by the test procedue ea. Epidemiological studies thus far have only studied cohorts who began their smoking careers with the old nonfilter, high "tar" and nicotine cigarette. Only in the years to come can we determine the lisk of those individuals who began smoking with lower "tar" and niedtine cigarettes, and it is important to study this risk. As the "tar" yields of cigarettes decrease further, it is probable that flavor additives will be increasingly used. Their potential biologic activities need to be investigated and monitored on an ongoing basis. Epidemiological data In addition to chemical and biological findings show the reduced risk among lower "tar" and nicotine cigarette smokers, which was predicted because of chemical and biological data previously known. No such clear demonstration bf effect exists, however, for cardiovascular diso~ chronic obstructive pulmonary disease, or pregnancy. The character and meehanisms of smoke components causing these diseases probably differ significantly from those acting in cae+cinogenesu. FIGURE 4.-Decrease of benzo[a]pyrene In the smoke of U.S. nonfilter cigarettes (85 mm) . Many brauds of cigarettes classified as lower "tar" and nicotine were introduced in the 1970s and had a remarkable growth in sales. The average "tar" in lower "tar" and nicotine brands in 1978 was about 10 mg. Many brands of cigarettes classified as lower "tar" and nicotine in studies reported in the 1960s and early 1970s would be classified as medium "tar" and nicotine cigarettes in the 1980s. . Therefore, it might be assumed that cigarettes with lower "tar" and nicotine yields afford even lower cancer riaks. But this is not necessarily true. Studies of smoking patterns suggest that smokers of the lower "tar" and nicotine cigarettes tend to inhale more deeply (44, 98), have higher amounts of catrbozyhemoglobin than predicted (106), and have higher than expectr ed carbon monoxide In their exhaled breath (S4).. On the other hand, the lower "tar" and nicotine cigarettes of 1980 have a" little as one- fourth the "tar" and nioothte of the cigarettes of 1950, and even if some compensation takes place, actual net smoker exposure is probably much lower. There is evidence that machines that measure "tar" and nicotine content are not suitable for measurements of smoke from lower "tar" and nicotine cigarettes with perforated filter tipe (68) and that the PatholoSlc Studies Histological changes in the tracheobronchial tree in noncancer patients can be observed at autopsy in direet proportion to the number of cigarettes smoked per day during life. Lung cancer patients have the most advanced histological changes in their remaining epithelium (4, 6). Ex-emokers who quit for at least 5 years show greatly reduced histologic changes.. This finding, together with the observation of cells with disintegrating nuclei in the epitheiial lining, suggests that a healing process has taken place In these cases (4 To evaluate the effect of smoking lower "tar" and nicotine cigarettes on histologic changes in bronchial epithelium, male patients who died of causes other than lung cancer in 1970-77 were compared with those who died in 1955-60 (3). None of the men who died in the later period could have, in the last 5 to 10 years of their lives, smoked cigarettes that were as high in "tar" and nicotine content as the cigarettes smoked by men who died in the earlier period. Sections from the tracheobronchial tree of 211 men who died in the earlier period and of 234 men who died In the later period were put In random order for microscopic study. A total of 20,424 sections were read, an average of 46 sections per patient. Histologic changes studied included basal cell hyperplasia, loss of cilia, and occurrence of cells with atypical nuclei. Smokers bad these changes far more frequently than did nonsmokers, and within each group the percent with these changes Increased with the reported number of cigarettes smoked per day. Nonsmokers in both time periods had about the same proportion of these changes. But in each smoking category (adjusted for age), the men who died in 1970-77 " Ps4sezse 87
Page 89: apt20e00
mortem studies of the human lung further support the finding that the filter, lower "tar" and nicotine cigarettes are less oncogenic than the nonfilter cigarettes of 25 to 50 years ago. NEVEn <1 1•4 :. SMOKED PACK PACKS PACKS REO. A DAY A OAY A OAY NeYCQ <1 1-2 :. stAOKEO PACK PACKS PACKS /Ee. ADAY AOAY ADAY FIGURE S.-Percent of gecfions with advanced lesions by Smoking habit in two periods sousce:....rw.L(a4 had far fewer histological changes than those who died In 1965-60. Figure b shows the percentages with the most advanced histologic change recorded (carcinoma-in-eitu) in the 19666-60 and 1970-49 groups. These changes were not found in nonsmokers in either group, and they were found far more frequently in smokers in the 1958-60 eases than in the 1970-77 eases. In two-pack-a-day smoken, 22.5 percent of the 1966-60 group had this advanced change, compared with only 2.2 percent of the twoo-pack-*4ay smokers in the 197a77 group. Discussion Epidemiologic and experimental pathologic studies yield some evidence that f"ilter,lQwer, "tar" and nicotine cigarettes produce fewer neoplaams than the nonfilter cigarettes of 25 to 80 years ago. While it is not always possible to directly extrapolate data on animal experi- mental carcinogenesis studies to man, the data summarized in this section show the predicted lower mouse skin tumorigenesis of filtered, lower "tar" and nicotine cigarette "tar" on an equal weight boeis. Poet- !994s9Ws Experimental Chemical Carcinogenesis While epidemiologic, pathologic, and experimental studies all point to polycyclie hydrocarbons within the "tar" moiety of inhaled cigarette smoke as potential carcinogens for man, additional work is needed to determine whether nicotine plays a major role as a cocarcinogen. Further, nicotine and nornicotine give rise to two carcinogenic nitroaamines that are found only in tobacoo products. Tablea 2, 8, 4, and 5 list known carcinogenic agents in both the particulate and the gas phases of cigarette smoke. Russell (90) recently suggested that a lower "tar," medium nicotine cigarette would be more attractive to amokers and tend to promote their use while minimizing health risk. This action cannot be supported without further research on nicotine's effects in carcinogenesis. Studies should address not only nicotine carcinogenesia, but also the chemical's effects on the cardiovascular, gastrointestinal, endocrine, and central nervous systems. Nicotine has been found to have potent physiologic effects on these systems. The following discussion briefly considers the probable routes of metabolism and binding to eritical cellular components of the chemi- cals in the particulate and gas phases of cigarette smoke thought most likely to be carcinogenic for man. Most proearcinogena are metabolized through a mixed function oxidase system, which is composed of the hemoprotein cytochrome P-. 450, NADPH-dependent cytochrome P-950 reductase, and phospholip- id. Various forms of P4b0 have been characterized immunologically (99), and some have been separated electrophoretically (78). The amino acid composition and partial sequences of some forms of P-450 have been elucidated recently (15). A treatise on the physicochemical characteristics and physiological function of P4b0 has also appeared (78). '!'he different forms of P-450 may have differential effects in the production of inetabolitca (33, 81, 91). Metabolic activation of most carcinogens by the P-450 mediated oxygenases is considered to afford structures that are strong electrophilea and thus prone to attach to cellular nucleophiles, including proteins, nucleic acids, and other macromolecules (21, 7!, 7J). Polycyclic aromatic hydrocarbons present in tobacco smoke are typified by benzo(a]pyrene (BaP). BaP is found in the soil and atmospheric particulates of cities, with relatively high concentrations around highways, airports, factories, and similar inetallations (51). Since it oceurs in pyrolysis products, such materials as soot, tar, and charcoal-broiled or thoroughly roasted foods all have measurable ,
Page 90: apt20e00
levels. BaP also has been Identified in forest soils, in volcano effluents (50), in marine sediments, and even in the deeper layers of soil from the permafrost regions of the earth (52). BaP was among the first polycyclic aromatic hydrocarbons isolated from coal tar and has been used for various experimental purposes for 50 years. On the basis of metabolic studies with phenanthrene, Boyland (16) hypothesized that hydrocarbons were metabolized through arene oxide or epoxide intermediatea.. Such intermediates could account for the identification of phenols, dihydrodiols, premercapturic acids, and mercapturic acids as metabolites of phenanthrene or naphthalene, all depending on whether the epoxide reacted with water or glutathione or rearranged nonenzymatically. The information gathered from various experiments in vitro with metabolites of BaP, DNA adducts, and presumed intermediates led to the conclusion that both the dihydrodiol and epoxide moieties were required for carcinogenic activation of BaP and other polycyclic hydrocarbons. In the case of BaP, the potent carcinogenicity of the 7,8- dihydrodiol IndImted that It was probably an Intermediate toward the final activated carcinogen (5y). A number of studies have substantiated the concept that a "bay" region Is involved In transformation of most polycyclic hydrocarbons to the activated Intermediate (74, 88,108).. The diol epoxide of BaP thus appears to be the metabolically derived strong electrophile that is capable of reacting with critical constituents in the eell. The reaction of this activated intermediate with nucleic acids has been followed both in vivo and in vitr+u (59, 8l, 78). Pi-4b0 is also a component of the enzyme system called aryl hydrocarbon hydroxylase (AHH) (2). The major phenolic detoxification product, 8-hydroxybenzo[a]pyrene, results from nonenzymatic rear- rangement of the Giltial 2,,Upozide formed by the Pr450 (112). The phenols are amenable to conjugation by glucuronyl transferaae or eulfotransferase, leading to solubilization and more rapid excretion. The available evidence suggests that in different strains of mice high AHH inducibility leads to increased susceptibility to hydrocarbon- induced tumors. The genetics of AHH inducibility in mice have been thoroughly discussed (T!', 78, 7t+). Attempts have been made to extend some aspects of the AHH work to humans, despite the variability in results noted in human populations (2). Although there is currently more emphasis on the reactions of the electrophilic species from carcinogens with nucleic adds, the binding of careinogens to proteins had been noted many years earlier (71). More recent efforts have shown that ligandin, a hepatic protein that binds anionic metabolites of glucocorticoids (ey), also binds some carcinogens such as polycyclic aromatic hydrocarbons and aminoazo dyes but not aromatic amides (68).. Aromatic amines are found in tobacco smoke. These compounds are formed during the burning of tobacco, including toludines, 2-naphthyl- amine, and unknown aminofluorenes. These compounds are also activated through the P1350 system similar to that for the aromatic hydrocarbons. Ring-hydroxylated products of aromatic aminesqp par- ently are detoxification products. For most of the carcindgenic aromatic amines or amides investigated, N-hydroxylation apparently was the activation route. Further reaction of the N-hydroxy compounds was found necessary to afford forms capable of reacting with nucleic acids or proteins. Acetate, glucuronide, sulfate, or even phosphate eateri of the N- hydroxy amide had the required characteristics; the products from in vitro reactions with nucleic acid were the same as those isolated from reactions in vivo. In some but not all cases, the carcinogenicity of the parent amide or amine roughly correlated with the enzyme levels in a target organ. One of the most readily obtained of the activated esters, N-acetoxy- N-2-fluorenylacetamide (N-AcO-FAA) has been employed in many model experiments to study effects on the structure and function of nucleic acids. N-AcO-FAA forms a major adduct with DNA where approximately 84 percent of the fluorene residue was linked to the C-8 of guanine by arylamidation, affording N{deoxyguanoein-8-yl)-ir fluorenylaeetamide, which retained the N-acetyl group (88).. An additional means for activation and adduct formation of aromatic amine derivatives has been investigated by C.M. King et al. (58). An enzyme termed N-O-acyltransferase forms derivatives that are quite reactive and readily form adducts with RNA. More recent work points toward attachment by the activated aromatic amines and amidea to still other positions on the bases of nucleic acids (10, 55,56). Numerous model studies with N-AcO-FAA modified nucleic acids have shown a change in function of the altered nucleic acid. However, none has shown the exact role in the process of carcinogenesis; this remains an area for further investigation (9.f).. Although the aminoazo dyes and aromatic amines or amides are activated in a similar fashion and both bind to proteins, the proteins involved differed somewhat (8, 9, 88, 97). Relatively less emphasis has been placed recently on carcinogen- protein Interactions than on carcinogen-nucleic acid interactions. In view of the essential function of the proteins, it seems their interac- tions with carcinogens require more investigation.. N-Nitroeo compounds found in tobacco smoke include those derived from nicotine, nitrosonornicotine and related compounds, N-nitroeo- diethanolamine, and nitraeodimethylamine. Metabolic activation of dialkylnitrosamines is necessary for expression of their toxic and hepatocarcinogenic effects. Oxidative metabolism of dimethylnltroea- 81 20 9s4sSZSe
Page 91: apt20e00
mine, for example, is accomplished by the liver microsomal P450 system yielding an unstable (arhydroxymethyl)methylnitrosamine, which forms formaldehyde and an unstable methylnitrosamine. In turn, this molecular species collapses with release of nitrogen and formation of the methyl carbonium ion, CH,+, which alkylates proteins, nucleic acids, and probably other cellular constituenta. The Intermediacy of the (a-hydroxymethyl)methylnitroaamine is substanti- ated by the potent mutagenicity and outstanding carcinogenicity of the more stable (a-aoetflxymethyl)methylnitrosamine (11). More recent studies suggest that other oxidation pathways may also be involved (66). Tobacco and ita resultant smoke contain two carcinogenic N-nitrosa- mines that are formed from nicotine and nornicotine (Table 2) (46, 47). N-Nitrosonorniootane (NNN) gives rise to a-hydroxy N-nitrosamines, which are unstable and decompose finally to oxocarbonium ions, the suspected ultimate carcinogenic forms of NNN. Most of the oxocarbo- nium ions react with water, yielding a keto alcohol and a hydroxyal- dehyde (19). The other carcinogenic and tobacco specific N-nitrosamine is 4{N-methyl-N-nitrceamino)-i{8-pyrldyl)-1-butanone (NNK), which is also a-hydroxylated. The methyl hydroxylation product gives rise via an oxodiazohydroxide to the same carbonium ion as the 2'-hydroxyl- ation of NNN (42). Alkylnitrosonreas afford alkylating moieties without the need for metabolic activation; spontaneous decomposition occurs at alkaline pH values. However, the organs affected by alkylnitrosoureas may vary, depending on the route of administration and the animal model. Nitrosomethylurea, most widely used in model experiments, can cause tumors In brain, breast, stomach, liver, heart, skin, kidney, Intestinal tract, bladder, trachea, and peripheral nervous system (107); administration to pregnant animals often leads to tumors of the nervous system in the offspring many months later (60). The alkylating moiety (carbonium ion) formed from a nitrvso compound may attach to a variety of positions in the nucleic acids bases, on the phosphate backbone, or on the ribaee portion of the RNA. Environmentally, nitrosamines and related structures represent a problem, since they may be formed endogenously from secondary or tertiary amines, amides, or ureas and nitrite, available from reduction of n trate by bacteria of the salivary plaque. Nitrate has a widespread dist~ibution in dietary vegetables and grains. Although each individual has therefore the capacity to form nitroso compounds, endogenous nitrosation can sometimes be Inhibited by ascorbic acid, propyl gallate, or other compounds that compete with the amine or amide for nitrous acid. This is not a panacea, for ascorbic acid may enhance nitroeation of certain amines (18). Furthermore, innocuous nitroso compounds, such qa nitrosoproline, or even some aliphatic nitro alcohols, can provide a -mo group to form carcinogenic nitrosamines or amides by transni-. trosation (26, 95). Although certain bacteria are instrumental in formation of nitrosamines within the organism (40), bacteria also degrade nitrosamines (89), leading to a balance between endogenous formation and decomposition of nitroso compounds. During the chewing of tobacco, N-nitraeonornicotine is formed in the oral cavity (41). Although it has not been demonstrated, it may be assumed that under certain conditions the carcinogens NNN and NNK can also be formed from nicotine in other organs or sites in man. Another carcinogen, vinyl chloride, has also been identified in tobacco smoke. Metabolically, vinyl chloride is activated through the P- 460 system by formation of a halogenated epoxide (7, ,iS,11S). Such an epoxide may yield halogenated aldehydes or alcohols through rear- rangement rangement (45, 113) or through derivatives of glutathione through S- traneferase (45). In sumtnary, moet of the identified carcinogens found in tobacco smoke are activated through the P-450 system to electrophilic com- pounds, which react with proteins, nucleic acids, perhaps lipids, and other cellular constituents. Since there are many constituents of tobacco amoke, only the activation pathways of BaP, typical aromatic amines, nitrosamines, and vinyl chloride have been presented here. The activation pathways of the other carcinogens found in tobacco smoke may be similar. Although the pathogenesis of several types of cancer, chronic obstructave pulmonary diseases, and cardiovascular diseases is linked to different tobacco smoke constituents, the epidemiologic associations with cigarette smoking are dose related for each of these diseases (d4, $6,17, J8, 10S). Thus, the first goal In production of a"less hazardous cigarette" was to reduce total smoke delivery.. Because the causal relation between smoking and lung cancer was the first established, primary emphasis was placed on reducing the carcinogenic "tar" of cigarette smoke (110). Tumor Initlatlon and Cocardnogens Inhalation studies with Syrian golden hamsters and bioassays on mouse skin, rabbit ears, and the connective tissue of mice and rata have clearly Indicated that the major carcinogenicity of cigarette smoke resides In Its particulate phase (23, 48, 109). Although the presence of volatile carcinogens in the gas phase has been well established (Table 2), the models available at present do not allow detection of a carcinogenic effect of the gas phase because of the low sensitivity of the systems (t1). Extensive fractionation studies combined with bioassays have supported the concept that the concentration in cigarette "tar" of certain polynuclear aromatic hydrocarbons (PAH), which are known human carcinogens (J5, 69, 86), is too low to account for their activity
Page 92: apt20e00
TABLE 2.-Snown carcinogenic agents in the gas phase of cigarette Imoke* oWA.U%w. r ... a4WOU8 R-p iepw4W 1 •00 K 13 OL J,i,! ]0 us Is .g JA+ 0 . 70 Pg Is .g 1,R{ s • 42 ,e 11 as J.es 0 • 2u es 7 JAI U , u v u.c s,t I - Is ,r 12 39 1,7 U - 1s K 10 PC Sa R71 - L!1 K OA Ig 10.11 20 - 0/ u4 36 eC 1;J0 -nr t.w b .A «.pn..r.% u. V.. MW w.r....ar" wr .a..~.... .d..r aw .~ r.rw wwa.wwrwr.wtw..w.q6W1.k ..+.wmwn..ft ••dwa u.. •l,M.r ua.r9 ...~r n..*au..AawP nru n. eaa...i.o w..usr...n..i.. «rs i. u. ".A.. O..w.gu.u...W a.ryWU.W.a.., as complete carcinogens. These PAH, however, are active as tumor initiators and thus contribute to the induction of tumors by tobacco "tar;" which contains an abundance of cocarcinogens (20, 48). Tables 8 and 4 list the tumor initiators and cocarcinogens In cigarette smoke known at this time. Large-scsle model studies on mouse skin and inhalation studies with Syrian golden hamsters have shown that a significant reduction of "tar" and a selective reduction of tumor initiators and eocarcinogens will lead to a significant reduction of the carcinogenic potential of cigarette smoke (13, 23. 84, 29, $0, 81, St, 48). Recently, a study has indicated that nicotine (and possibly other tobacco alkaloids) may be active as a cocarcinogen (14), while another study did not show acrolein to have cocarcinogenic properties (87).. Further detailed inveatigations are required. OrOan-Specillc Carclnogens This approach toward the less hazardous cigarette has been criticized by several groups as one-sided because it has been concerned only with "tar," nicotine, and tumor initiators such as PAFl and with cocarcino- gens, rather than with organ-specific carcinogens (85, 88,108). Table 5 lists the known organ-specific carcinogens. In the case of polonium-210, a recent indepth study raises doubts on the significance of =Po as a factor contributing to lung cancer in smokers. Nevertlle- less, it may be prudent to reduce the mPo content of tobacco products (s9). Among the aromatic amines, certain Individual compounds are known human bladder carcinogens (e.g., 2-naphthylamine, 4-biphenyla- TABLE 3.-Tumor-taitiating agents In the particulate phase of tobacco smoke• wi.u.. .atvy .. Conpamd mmpl.is ord.ocer NVaprW* N &.o(.wr.oe +++ 10-b0 bH.urYYry..r +++ 0,0 D~.{,,,A}.tNo... + + 10 &em(IxWxsthm. + + !0 + + eo ue..w(..~~r... + + pr' + + p,' nm..(v}«~ + + i-10 + 4 e.m[t1~1«r•u,ne. + p' l~a~s}uttinorn + 40-70 Ciq.... + 1 OP~O &..a[,ww. + 1 c-1o L, bXdkVkl+r7..w + T 7 >•. t<it.uqlerryw.. - 10 sM.uYn.a..w.. + U s`r.uy~n.wa.t6en. 7 40 Dib-{,I)y~ (+) Prb Dibpr(.,Alsidi.. (+) 0.1 we.r(v)ut-W (+l at •IIy,~~Lb Nr(~ ~N IbIr~~Y~ YUN Y MIIYr WIIdM N~~M~Ni ..Ydh M.w.e.il. r..wwi i..r iMn1.ry. iwi. alir (1W7Ci/Yi) da; T. .a.y..Ny..Y..w7 (+)`•N1dd Y... Mhn.l.rp. OouRCa:=.Krr.t.L(~. mine, and benr.idine) (83). Doll (22) has discussed the aromatic amines as likely contributors to the increased risk of cigarette smokers for bladder cancer.. These carcinogenic compounds are primarily pyrosyn- thesised from the tobacco proteins (84, 98). Exoept for the development of a process to reduce the protein content of tobaooo (100), no efforts toward the reduction of aromatic amines in cigarette smoke have been reported. A major group of organ-specific carcinogens in cigarette smoke are the N-nitrosamines. The volatile nitrosamines, for which protein and nitrate are precursors, can be selectively reduced by filtration (17). The tobacco-specific N-nitrooamines in tobacco and in smoke are formed during tobacco curing as well as during smoking. So far, N'-nitrosonor- nicotine (NNN), 4-(N-methyl-N-nitrosamine)-1.(8-pyridyl)-1-butanone (NNK), and N'-nitroeoanatabine (NAT) have been identified. These compounds are formed from the major tobacco alkaloids: nicotine (NNN and NNK), nornicotine (NNN), and anatabine (NAT). The total concentration of these three niti"osalDinea varies between 0.7 and 10.0 pg/cigarette (47'). NNN is a moderately active carcinogen in mice, rats, and Syrian golden hamsters, whereas NNK is a strong carcinogen in the respiratory tract of all three species; NAT has so far not been A, 69468Z68 95
Page 93: apt20e00
TABLE 4..-Cocarcinogenic agents In the particulate matter of tobacco anoke• Cen~w.A` C.and.M.d. .d1.W Nt/d11antYS L Nwhal haetle. PYm.. (-) + eal00 1t*6,y"..r (tm 1 a~AOo .,.«..w.. c ) + moaeo 1[.tl1T1l1.oe..lb~.w (+;1) 1 1eo s..~r,~c>~.. (a + m e...{~yryew (+) + fo Ot1e PAAU (~) 1 T N.pAt4Nw (-) + a*=rk= I•r.yYwdW. H + efo Flf-IA I , (-) + 1~0 V-DbNw4d1bws () + tpoo (t>s)' otlwwW.ow...im f 1 IL Ad1fe fea" CAtftbd (-) + amo"b0,000 Lltdlpkd.drl (-) + 11.a7"P00 4YN4iebeM) (-) + 1SA10-2IA00 4460ntaYd 0 4 10p00AAGD 4+.4wnp}IaMdw Itl f - ijooo aLr a4daY nl PMmh (m oun..di8w qeb (f) I 1 T T •L...,i.NrM. n.r+M.n.rw.d..~Mtj....n.+b: (n...t.... N. Pr+Vaw 6+...bwL..r...a Wd." e.. If0 nA in ..mS wqh .d.....w h L... r.... ocT ar aoD M..w L li. ua ~.e.a.. .ou.cc a.rrrr.et(M bioaseayed. Although conclusive epidemiologic data are not available, "NNN should be regarded for practical purposes as if it were carcinogenic to humans" (M. Research programs on the reduction of these tobaooo•epeoific cardnogens In cigarette smoke and their possible in vivo formation in the smoker from nicotine, nornicotine, anatabine, and other tobaooo alkaloids need to be undertaken. A neglected area may be the reduction of other organ-apeciffc carcinogens In eigarette.make, such as nitro-arenet and pesticides that may give rise to carcinogens such as nWeic hydrazide diethanolamine (MH-80). M Carbon Monoxidt In Clganrtla Smoke Until a few yeus ago the reduction of carbon monoxide in cigarette smoke had not been seriously studied. In fact, in 19?6 a report from the United Kingdom demonetrated that unperforated filter cigarettes can deliver higher carbon monozide values (18-18 mg/eig) than nonfilter ss4,sIRzse TABLE 6.-Orgatrr-specUic carcinogens in the particulate matter of dg.rette smoke - Gedee~e. Oa.oqtratia/dprettW dM..Lwfdtr L P.oph.cw NtNkn.e.admtte. U4D K + 1s0-b,400 eN + 0.(N•1[MJqr41~4dw. 0.1-0A pg + tr:arw..o...~.w.. Nlt.w.~IprWle. asa:a Pg + 61aa + U.k.e.. ra.rrMsle.l dVensir 1 n.I..~ Ewed.slo Niekd mmpe..dr C.ilo. eempo.ed. o,oe-Le pd + oenn P4 + 9,40 r4l t u.~.o... IILP..a... NGwnsiss Udnowr Iv. Yfd..Y .a/ W.dd.e aN.aeiy".. f f f + f f 22 K + x-A.LWMweoe + + X-Ambwft- + + aTeld" + + O.kswm womNk .mim 1 T .Nle,aalww v.1.w. dtn aapea.& !1 ee f 1 t uckmrrrua.wI- ou,r .wa..". -+ A.u.w...a.d: t.."j..a.rrm.d soul= u.er.....ea.L.> cigarettes (9-16 mg/cig) (105). This finding has been confirmed in both Germany and the United States (.i9). An increasing number of tho cigarette brands sold in the United States have perforated filter tips, at present amounting to approximately 50 percent. The filter perfora- tion leads to air dilution of the smoke and to changes in the burning profile of the cigarette, and thus, to a significant reduction of the carbon monoxide content of the smoke (Table 6). Filter tip perforation similarly reduces the nitrogen oxides in cigarette smoke (82). Smokers' Compensation Studies by Russell and his group (90, 98) and recently by Hill and Marquardt (44) have demonstrated that many smokers who switch to lower "tar" and nicotine cigarettes will compensate for the loss in smoke nicotine (and possibly other agents) by Intensifying their smoke intake, puffing more frequently, and drawing larger volumes per puff. In the case of cigarettes with perforated filter tips, the occlusion of the filter vents by the fingertips may be an additional compensation
Page 94: apt20e00
TABLE 6..-Carlan monoxide In smoke of cigarettes C.ebo. .ow,zw. (edAgarWo) Fepla P.efmated NoaNtr fOter Nkr us (9n of .. 1YTV19Tf 11.4-rlA 1/A40.0 3s-1Zf »i.)P a+-n a+-ffi1 t"-+1 ux s-16 13-15 - (lM)b M - +1 (N - 14 ci-q 1F$1 16s-na - (IM) (N - 11 (N - n) ss-us cN...y xs-w ..u-uA (WM (K-1W (x-16) (N-9) -A.".p .d.. fv ..AMr .k rNW, IU .Q fr esor /Yl.r igr.p.% 17.1 uKi !w prf.d.d Mr .4.ff+iw.u.w bA.o.p..l... /.r...fOYr.Ipw1M..1lf .4rsfw/W.dp.Yr,1L1.* s -...r..cb...+d rw, sovacst a.rr..~.&.i.(46 technique that smokers may develop either intentionally or subcons- ciously (89). These factors of "smoker compensation" must be consid- ered in the evaluation of lower "tac" and nicotine cigarettes. Filtered, lower "tar" and nicotine cigarettes that are leas vulnerable to increasing the smoke and nicotine deliveries are needed. Such products are envisioned by scientists in the tobacco health field. Attempting to minimize smoker compensation by selectively reducing "tar" and other smoke compounds while maintaining nicotine yield may carry serious disadvantages. First, maintaining nicotine delivery may reinforce physiologic habituation, and interfere with smoking cessation attempts (93). Second, nicotine gives riso to the tobace"pecific cas+cinogenic N-. nitrosamines, NNN and NNIf, and nicotine itself may be carcinogenic (see Experimental Chemical Carcinogenesis within this section). Final- ly, nicotine is suspected to be a major smoke constituent correlated with the increased risk. of cardiovascular disease among cigarette smokers. Transplacental Carclnogenesls The possible transplaoental effect of oigarette smoking on carcino- genesis should be investigated. Recently, it has been shown that cigarette "tar" Is an active transplacental carcinogen in Syrian golden hamsters (80). I+wcthermore, a number of smoke constituents are active as tranaplaeental carcinogens in the experimental animal (yb). These include volatile N-nitrosamines, benzo[a]pyrene, o-toluidine, ethyl carbamate, and vinyl chloride (87). Other major tobacco carcinogens including the bensofluoranthenes, NNN, and NNlf need to be bioas- oa Ol4sv4'6B sayed for their transplacental activity and to be considered with respect to lower "tar" cigarettes. Flavor Additives The development of lower "tar" and nicotine cigarettes hast5bded to yield products that lacked the taste components to which the sMoker had become accustomed. In order to keep such products acceptable to the consumer, the manufacturers reconstitute aroma or flavor. There are several ways in which this can be achieved. Flavor extracts of tobacco can be added to the lower-yield blends. Other plant extracts can be used to supplement the flavor spectrum, synthetic flavors can be added, or a combination of techniques can be applied (64, 83). Powdered cocoa, one flavoring additive that is probably used In U.S.. cigarettes, has been found to increase mouse skin tumorigenicity of the "tar" from a standard experimental cigarette at each of two dose levels (J1). The burning of cigarettes with flavor additives produced increased and perhaps novel types of semivolatile agents, including traces of mutagenic compounds. The mutagenic agents were found in the basic fraction of the semivolatile portion obtained from heating the tobacco mixtures. Chemically, the agents thus far identified were substituted pyrazines and other aza-arenes with and without amino groups (64). The exact delineation of the chemical structure of additives, their pyrolytic products, the possible carcinogenic properties, and the quantities found in smoke of lower "tar" cigarettes is urgently needed in order to assure the consumer that the filter, lower "tar" and nicotine cigarette does not carry additional or new health risks. Conclusions and Recommendatlons 1. Both retrospective and prospective epidemiologic studies in man have shown a doeareaponse relationship between cigarette smok- ing and the occurrence of cancer of the lung, larynx, esophagus, oral cavity, and bladder with a less clear quantitative relationship to canceis of the pancreas and kidney. Smoke dose was measured by various paramet$rs, including numbers of cigarettes (daily or lifetime), duration of habit, depth of inhalation, and number of puffs per cigarette. The highest priority in the field of public health is that individuals who have not started smoking should not begin and that those who currently smoke should quit. 2 Those individuals who start smoking with a filter-tipped, lower "tar" and nicotine cigarette, or who switch after a period of time from high "tar" and nicotine cigarettes to the lower "tar" and nicotine cigarettes, will have a lower Incidence of lung cancer, but an incidence far in excess of the nonsmoker. 99
Page 95: apt20e00
Specifically, high priority should be given to continued and long-term retrospective and prospective epidemiologic studies on a!I tobacco-related diseases, with specific reference to brand of cigarettes smoked, number of cigarettes, manner of smoking, inhalation, etc., along with generation of data on "tar," nicotine, carbon monoxide, and other chemical content, as determined by the most up-to-date scientific methods. This same epidemiologic survey should include studies of individuals in high-risk occupa- tions, of groups such as teenagers, minorities, and people of varying socioeconomic status, of men compared with women, and of different ages at which smoking began. Concern expressed by the group was, because cigarette composition in the United States is changing rapidly, without continued, well-planned, long-term studies, it will be difficult to know what effect the changing composition is having on the health of the American people. S. An administrative mechanism to focus major Interest on tobacco and the diseases caused by smoking tobacco should be established. Such a mechanism should include involvement of basic scientists, epidemiologists, physicians, statisticians, social scientists, and related experts concerned with smoking. There should be a stable source of funding for both new and established investigators to work together on tobacco and health problems over a period of time, since the answers to the questions raised over the past quarter-century will not come quickly, considering the magnitude snd duration of the problem in the United States. Moreover, institutions and progTams should be encouraged to train scientists for smoking research and to maintain a core group of physicians, scientists, and educators to consider various aspects of smoking research Issues. 4 Additional work in carcinogenesis should be performed: a. It should be determined whether nitroaamines are formed from cigarette smoke in the human body and, if eo, whether they are formed in significant concentrations. A key concern is whether nicotine itself forms nitrasamines in biologically significant quantities following reaction with nitrous oxides. The role of nicotine in human carcinogenesis should be identified. b. Tobacco additives and flavoring agents should be studied by appropriate methods for carcinogenicity and other toxicities, ~ before their commercial use is permitted, and study data should M be made available to the appropriate agencies. c. A continuing study of lower "tar" and nicotine cigarettes for carcinogenicity might detect changes resulting from new or different manufacturing practices or from new additives or flavoring agents that might aet synergietimlly. d. The gas phase of cigarette smoke should be examined more fully for carcinogenicity. i44sszse e. Several carcinogens from cigarette smoke should be studied for synergistic, additive, or antagonistic effects on carcinogenesis because tobacco constituents are inhaled or swallowed as a mixture, not individually. f. Further investigations of promoters, cocarcinogens, and initia- tors of cancer in cigarette smoke are necessary. g. New models for careinogenicity should be developed with emphasis on in vitro or short-term experimenta h. Nicotine itself should be investigated for carcinogenic or cocareinogenic action in animals even though it is a very toxic chemical. Similarly, acrolein should be tested for carcinogenic and cocarcinogenic action. i. Anti-carcinogens or preventive compounds, such as vitamin A, retinoids, or other chemicals that may prevent carcinogenesis deserve further investigation. j. There should be a registry for listing all the different chemicals identified in cigarette smoke, along with known properties of those chemicals. 5. Cooperative international epidemiologic studies should examine different tobaccos, ethnic groups, dieta, and smoking habits. Such studies would describe the differences in development of tobacco- related cancers and elucidate the etiologic roles of differing cigarettes. 6. Genetic markers such as I;LA or other indices should be sought to identify high-risk groups prone to tobaceo-related diseases if they smoke. Genetically susceptible individuals should be counseled about their high-risk status. Summary 1. Today's filter-tipped, lower "tar" and nicotine cigarettes produce lower rates of lung cancer than do their higher "tar" and nicotine predecessors. Nonetheless, smokers of lower "tar" and nicotine cigarettes have much higher lung cancer incidence and mortality than do nonsmokers. 2. Smokers of lower "tar" and nicotine cigarettes may tend to smoke larger numbers of cigarettes, to inhale more deeply, to have relatively higher amounts of carboxyhemoglobin than predicted from machine measurements of carbon monoxide yield, and to have higher than predicted carbon monoxide in exhaled air. 3. In attempting to develop a"less hasardous" cigarette, singular emphasis has been placed on reducing the "tar" yield of cigarette smoke because of the early demonstration of a causal relationship between "tar" and lung cancer. Comparable data on changes in
Page 96: apt20e00
yield of constituents in the gas phase of smoke are not publicly available. 4. The occurrence of laryngeal cancer has been reported to be reduced among smokers who use filtered cigarettes; compared with those who use nonfiltered cigarettes. 5. There is no epidemiologic evidence to prove or to disprove a decreased oecurrenee of canoers of other site_ s in humans who smoke lower "tar" and nicotine cigarettes. 6. In evaluating the effect of smoking lower "tar" and nicotine cigarettes on histologic changes In the bronchial epithelium, it was deted mined in one autopsy study that male smokers who died between 1970 and 1977 had fewer histological changes than those smokers who Jled between 1950 and 1955. 7. Even among those who do not develop cancer, histologic changes in the traebeobronchial tree are more advanced at autopsy in smokers of cigarettes with higher "tar" and nicotine than among smokers of cigarettes with lower yields. 8. The "tar" content of smoke condensate of today's cigarettes is less tumorigenic to mouse skin than that of cigarettes of 30 years ago. Levels of the known carcinogen benzo[a)pyrene are lower in the smoke of today's cigarettes than in that of cigarettes of 30 years ago. Flavor additives used in lower "tar" snd nicotine cigarettes produce traces of mutagenic compounds. 9. Although studies point to polycyclic aromatic hydrocarbons in the "tar" of inhaled dgarette smoke as potential carcinogens for humans, additional work is needed to detezinine whether nicotine plays a major role as a carcinogen. Definition of the role of nicotine in cae+cinogenesis is necessary prior to advocacy of cigarettes yielding less "tar" but more nicotine. 10. Animal studies have shown that a significant reductaon of "tar" and a selective reduction of tumor initiators and cocarcinogens can markedly reduce the tumorigenic potency of cigarette smoke. .snnces (1) A1fF5, B.N., SIYS, P., GROVER, P.L Epo=ides of cardoogenic polycydic hydeoearbcw+s are frameshift muttFemt Seisra 176(4080); 47-d9, Apri17,197Z. (t) ARNOTT, H.9., YAI6EAUCIii, T., JOHN$TON, D.A. In: Griffin, A.C„ and Shaw, C.R. (Editon).. ChreinoJe.a tdentyksdon and X.dasisms of Actios. New York, Raven Pras,1979, pp, 145-1b4. (J) AUERBACH, 0., HAltIfOND, &C., GARFINICE[ti 1.. CiunFes in brondrisl epitGsltnm [n rdation to cigarette Wuoldng, 1966-1980 vs. 1970-1977. Afsw 1i`s&%d Joarwed of Abdiaint 800(8): 3B1-i66, Februsry 22,1979. (4) AUERBACIi, 0.. STOUT, A.P, HAMMOND, N.C, GAItFINKEL, L Changes in bronchial apitLdium in . datioa to cisarette smoking a.d in relation to lung e.neer. Nw JWpla+d Jouswa! of ]Wiieine 266(0): ffif, Auput 1A,196L (5) AUERBACH. 0., STOUT, A.P., HAlIMOND, E.C., OARF7NKEG, L Bronahisl epitlrBum in former smoksn. Ne+o DlKdand Jewwai q/ lGdiaine 267(3): 119, July 19, 1962. (e) AUERBACH, 0, STOUT. A.P., HAMMOND, F.C, GAItFINKEt,, L ChanRes in bronchial epitAdium In relation to ss:, age, eaWenos, smoidcg and pnwmonia Nev il6yiawd Journal edAbiieiw. WJ(a):111, July 19, 3982 (9) BANSRJF$ S., VAN DUUxEN, 5.1.. Covalsnt binding of the carcinogen trichloroetbyleoe to hepatic minasomtl proNitr and to exoBenous DNA In ritro. Caworr Rraa.eJl a8(S): 776-780, Y.rels 1978. (M) BARRY, &J., t3iT1'1[ANN, H.R. Pwtbin medif hxtbns by setivat.d cirdnoQens. lowrwel q(B9io(oyiosl (.'AsmiKry 2{8(7): 2780-M, Aprn710,1978. (a) BARRY, E.J., OVDCHKA, C.A., aUTHANN, H.& Jowwal oJ Biolapieal Chewietry 21S: 61-80,196& (10) BELAND, F.A. Nstiows! Cswar r*didd. XoMOynspA, in pnas, (1!) BERYAN, J.J., BIC$, J.H., WENK, Id.L, ROLLER, P.P. Intestinal tumors Induced by a siogl. ints.peritoa..l iN.etJon of msthyl (sostoxymstbyl) nittvsamine in the.e stesiss of rats. Csne.r R.asnoh 39(5): 1KZ-1466, May 1979. (1s) BRBNFBLD, P., HOIdBURGEiiti F., RUSSFIELD, A.B. Ciprette smolce- induad cancer of the l.ryn: in ham.tooi. (CINCH)a. A method to s...y the csranere.teitr of aisaiatl+ smoke. Hvp...s in 1{Yy.dwn.e.i 2laoor R.aancA 21: a1s-1119,1979. (t1) BF.RNFELD, P., HO1[BURGF$ F., SOTO, E. PAI, H.J. (5saretts smoke inhalstion stadies In inbrsd Syrian Bolden hamsters. JoY+xsi of fA. National Cancer rwditde 8a(E): 07G-899, Ssptaaber 1979. (14) BOCK, F.G. Coosndnodenia properties of niaotina In: Gori, G.B., Bock, F.G. (Editon). Bawiury Report J-A SaJe (Jipsrstl.! Cold Spring Hsrbor, New York, Cold Sprin` Harbor I..boratoay.1990, pp.l2i1-189. (15) BOTELHO, L.H, RYAN, DX, LEVIN, W. Amino acid oanpositioas and partial srnino acid sequenoes ol three highly purified forme of liver miiarosomsi eytochrome P450 from nts treated weitk polyohlarinated biplrnyls, phsnobu- bital, or 3-metl:yiebolsnthr.na Jor.wol of Biolqpiool Mmidry ZW(1S): 6E86- 66/0, July 10,19T9. (18) BOYLAND, IL The biological significance of metabolism of polycyclic oorn- pound.. In: Wiliiaw, LT. (Fdito.). Btioloyisai Omfdatiow of A+vwat+e Ri„p.. Biochemical Socisty Symposia No.. b,1960, pp. 40-b1. (17) BRUNNEIiANN, K.D, YU. L., HOFFMANN. D. Aa.ewment of carcinogenic volatile N•nitrasmims in tobacco and in mainstream and sidestram smoke from cljar.ttea (7swo.rJP.aosrc.l'7(9): i'118-8S2f, Septs6er 19'M. (18) CAANG, S.-B., iWiRINGTON, O.W., ROTHSTE[N,11., SHEROALIS, W.A., SWERN, D., VOHRA. S.Y. Aaosleeltisg effect of ssoorbic acid on N- nihassmine formatiou and nttroution by onYyponitrita Cancer &wanclt i9(1o): i671-d874. October 1979. sezse e zse103 102 zr.~ s
Page 97: apt20e00
(lD) CHEN, C.B., HDCHT, S.$., HOFFMANN, D. Metsbolie nlpha-hydro:ylation of the toD.coo.epedfic carcinogen, N-nitroeonorniootine. Cswen RosearrA 88(11): i6SS9-Wd6, November 1878 (id) DAVIS, B.R., WHITEHEAD, J.K., GILIti ILF~, LEE, P.N., BUTTERWOIITH, A.D, ROK J.F.C. Response of rat lung to tobscco smoke eondeneate or fractions derived from it administRred repeatedly by intratracheal instillation. BritisA Journat oJCawotr 81(4): 468-461,1176. (st) DEUTBCH, J., LEUTl, J.C„ YANG, S.g., GELBOIN, H. V„ CHANG. Y.L. VATSIS, K.P., OOON, M.J. Regio- and stsrecealeetivity of various forms of purified eytoebeome P.450 In the metabolism of bense(s)yrene and (-)trnrrr 7,8-dihydromty-7$dihydrobensa[sbyrene as shown by product formation and binding to DNA. Aoaodinge eJ tA. Nationsi Aeedemy of Scienws of Hu United Stafn oJA+nrrlrs 76(T):. E128-8127, July 1978. (!t) DOLL, R. Caonn Re(ofed to SMOktny: Proceedings of the Second World Confuwnes on Smoking and Health, Londen, Pitman Mediesl,1471, pp.10-M (ts) DONTEIJWILL4 W.P. Tnnariganle eftect of cheoola eigsevtte smoke (nhalatjon on Syrian golden hamsters. In: Karbe, ll., Park, JF. (Editen). Intetnatiom) Symposium, 8eatde, June st-86, 1Y74. Bqw*w%ta! Lrng Qopmtr. Gl.mno- 'anssia snd Bioasmlra. New York, 9prleqR.nVerlsg.1974, pp. 8W~-W. (!.Z) DONT$NWILIti W., CHEVALIER. H.J.. HA$M HrP., KLiMI9CH, H.•J., RECKZEH, (i., FLEI$HMANN, B., 1CEII.ER, W. Bcperimentdl. Untrisu- ahungen uber die tumoreeeeugande Wirkue8 ron ?lganttRnraudb-Kondonsa- tsn an der Mausehaut, VIL Mitteilung Fimel.erletrbs von Eondeesaten .ersshtedener moditidsrtar Z'igsnttsn. (E:periment.d in.ro.tig.ttons on the tumoriganie activity of cigarette smok.e eondenrte on maw ddn. VIL Comparative studies of condensates from different modified oigarettes.] Leii.eAr+Jt frr !Crobormhung wnd 1CHni.eAe OnAnfopis 89(2): 145.161,1977. (ts) b'VERSON, R,B. Hypothesis: Individ.als tranplacent.Ry e:posed to maternal smoking may be at inera.sed eanar risk in adult lif.. larart Z(8186):128-126, July 19,1980. (t6) FAN, T.Y., VITA, It, FINL: D.R. C.Nitro compounds: A new rJaw of nitroesting sgentL Tasioclopr L.tfns 3(i): 6-10, Usy 197E. (!f) PERON, V.J., KRUYSSE, J. Effoefs of .xpowur to aeroleta vapor in hamsters amsters simultaoeously treated with bemo(a]pyesns or dimethylnitrosamina Jou +rst of 7brtcofapy awd &nrvnm.ntai IfsitA 8(a):37a494, Oetober 1977. (!d) FUCHS, R.P.P. A"wlytioa! .BiooAntii.lrlt 91: 669-678,1978. (si) oORI, G.a (Fdltor). 2bw.d Luo Xatardons fJtjavta. TA. rYnt 8ee of Ea.pninwntal GVerrtsu. U.S. Dep.rtrnent of Hetlth. Education, and 1Nelfare, Public Health 8+rvioe, National Institutes of Health, National Ceac.r Instituta, Smoking and Health Ptogr.ny Report No.1, DREW Publication No. (NIH) 76•806,1976,14E pp. (s0) (iORI, G.B. (liditar). tbwsrd Lae ffa.xdors GYpontqa 471o Sroond Set of B7epriw.wlal Gtpar.tEa. U.S. Departrnent of Hafth, Dduntbn, and Welfere, Public Health ServNational In.tit.tes of Iiealth, Nationd Cancer Institute, Smoking and Health Program, Report Na ?. DREW Publication No. (NIH)76-1111,197A,168 pp. (s1) GORI, O.B. (Editor). 7bwnl Less Jlasa.toue G7yanet.s. TJ1e Tllird Set of N li•sporinwnt.I (Rpar.tfo.. U.S. Departawnt of Hedth, Hdueation, snd Welfare, Public Health 8scvb% National Imtitrles of Hesltly N.Hond Canoer Institub, Smoking and Health Prageam, Report Na 8, DHEW Publication No. (NIH) Tl-]280,1677,16! pp. (1t) GORI, 0.B. (Fditor). 71»osrd Iwa Ifo+a.dow, Cips.ntfa. 17b FtiwiA So0 of Eiperirnsntai GYpnssEfos, U.S. Department of Heatth. Education, and Wdfare, Public Huhl+ Setwtar National Institut.s of Ilealth, National Cancer In.titute, Office of Cancer OommnnicaUom, March 1980, 210 pp. (JJ) GUENGERICH, F.P. 3eparatlon and purification of multiple forms of micro- wmal eytoebrome P-M . Activities of diffexnt forms of cytochrome P-350 towards several compounds of environmental interest. Journal of Bfatopieai Chnniatry 452(11); 8970-89'19, June 10,1877. (34) HAENSZEE, W. (Editor). Dpidorniolopisal Appnoochss to fJu 3tndy of Cancer and Other CArawie Diaeo+ei. U.$ Department of . Health, Education, and Welfare, Public Health Service, Nstional Institutes of Health, National Cancer Institute Monograph No. 19, January 198q, 466 pp. (Jb) HAMMOND, EC., GARFINKf;rL, L., SEIDMAN, H., LEW, E.A. "Tar" and niootins content of cigarette sawke in relation to death rates. Bkvisonmentai RaaeartA 1Z(8): 268-274, Deoember 1976. (ds) HAMMOND. 4C, (lARFINKEG, L, SEIDMAN, H., LEW, E,A. Some recent findings coneerning cigarette smoking. In: Hiatt, H.H„ Watson, J.D., Wiasten, J.A• (Editors). Oriyins of lfxrtan Gtanoe+: Book A. Ineid.nn of Cawcer in Human.. Cold Spring Harbor Conferences en Coll Proliferation, Volume 4, New York, Cold Spring Harbor Lbmstory, lOT[, pp.101-112 (JY) HAMMOND, B.C., HORN, D. Smoking and death rates-Report on forty-four months of follow-up of 187,788 men. I. Total mortality. Josrnal of tlhs Arnerican Medioal Association 166(10):1160.1175, March 8, i968. (J8) HAMMOND, S.C., HORN, D. Smoking and death rates-Report on forty-four months of fo8ow-up of 187,788 men. II. Death rates by cause. Joarral of th. Anurioaw 7lledioa! A.roeiation 166(11):1?D4-I90D, Mnoh 16,1968. (J9) HABZ.EIC, N.H.. COHEN, B.S., TSO, T.C. Polonium•210: A questionable risk factor in smddng-rolsted eaeeinogene.is. In: Gori„ G.B., Bodt, P.O. (Fditon). Banbury R.pa! f-A SaJe Cigawtlo/ Cold Spciog Harbor, Now York, Cold Spring Harbor Laboratory,19B0, pp. 98-101. (40) HAWKSWORTH, G., HIL1., M.J.. The in vivo formation of N-nitroeamines in lhe rat bladder and their subsequent absorption. BriNak Jou"wl of Caneer 29(6): 8b8-368, )I{y 1974. (4t) HECHT, B.S., ORNAF, RM., HOFFMANN, D. Chemical stadies on tobacco smoke. XXXIII. N'-nitrosenornicotine In tobacco: Analysis of possible contrib- uting faetors and biologic implicationa Journoi of U+e Natiorwl Cancer 1n.tilwEt 61(a): l88?-12N, May 1Y7b. (4s) HDCHT, S.S., YOUNG, R., CHLN, C.B. Metabolism in the F-344 rat of 4{N- metLyl-N-nitraeamine}1{&pyridyl}1-but,anone, a tobacco specific oednogen. Cono.r R.ua+eA 40(11): 814L-4160, November 1980. (4t) HENSCHLNR, D., BONSE, G Adeatiete iw PJta+vnorofapy and TArnsepeedie. 9: 1?3-i80,1879. (44) HILL, P« MARQUARDT, H. Plsama and nrine ehan8es after smoking different brands of dg.rettes. CLiwtoa! PAarnmoolspr and TWsrnpouNea 2?(6): 662ra6Q, May 1980. (46) HILIti D.L., SH1H, T.W., JOHNSTON, T.P., STRUCII, R.F. Idamomolecul.r binding and metabolism of the carcinogen 1,2dibromoethsae. Canar Res.a+ch 88(8): 2488-2L42, Augu.t 1978. (41) HOFFAfANN, D, ADAMS, J.D„ BRUNNEMANN, II.D., H®CHT, 8$, As.eut ment of tobsooo.pedfic N-nItrv.amines in tnh.coo products. Cancer Ressa+cJt 88(7): 2606-260p,19'f9. (J7) HOFF)[ANN, D., CHEN, C.B., HF7CHT, 5.8. The rde of volstpe and nonvolatilo N-nitroeaminea in tobsooo w+cinoeane.ta In: Goei, G.B., Bock, F.G. (Edltors). Banbnry R.pord d-A Bsfe GVpa+rlE.l Cold Spring Harbor, New York, Cold Spring Harbor Isboratory,1o80, pp.113-127. (48) HOFFMANN, D., SCHMELT74 1., HDCHT, SS, WYNDER, 6L. Tobacco eaeeinogeeesis. In:. Gelboin, H.V„ Too. P.O. (Fditan). rblyrpelic Xtd+nea+tone and Canar. New York, Aesdemic Prees,1978, pp. 86-.11T. CF..4sRzVe. I
Page 98: apt20e00
(49) HOFFMANN, D, TSO. T.C.. GORI, G.B. Tbs leu harmful e3QaretteL heventiw Yodieiw. 9(2); 287-M l(u+rh 1980. (50) ILNIT.SKY, A.P, I[49CHENKO, V.S., SHABAD, L.M. Now data on vokanoea u natural .ouror of oansinoasnie substances. Ca*ar Iwtt.n 8(8/6): 227-Zi0, Novambv 19Y7. (51) ILNITECY, A.P., VINOGRADOV, V.N., RLIBCHUN, V.K., MISCHENKO, V$., GVILDIS, V.Y, B&LITSCY, GJL, SHABAD, L1[. Ca+wr Iwwra 8(1): 61-8, Novanber 1879. (52) ILNITSKY, A.P., VINOGRADOV, V.N, RIABCHUN, V.K, 1USCHENKO, V 4., GVILDIS, Vdy CHERNENKY, V.Iy BELITSKY, G.A., SHABAD, L1L Duklady AAr.d.mii Nauk 3.93ft E46: 254-267,187Y. (58) INTERNATIONAL AGENCY FOR RFSEARCH ON CANCER. N-Nitrasanor aioottno. lARC Xonopropll* on the DualyatioK of tJ1. Caciuoyonia Risk of Cbw<uals to llsusanr So+s N-stitrao Cawpowda. Intanationa! Ap..ay for R.a.ar+eA on Cancer Jifonqgraspk 17q 281496, lday 1978. (54) JAFFFti J.H., KANZLER, li., FRIEDHAN, L Studioa of owitAhin` to low tar and nimtlao dyynttti. Ia: Gorl, G.B., Bodc, F.G. (RdiWs). BaKkrry Bsyort 8- A 8gfo Cipur.Ef.1 Cold SpriaK Ilarbor, Now Yark, Cold SpriaE Harbor Irboratory,19B0, p. 81L (55) KADLUBAR, F.F. National Canar Inotitvla l[o.oyro,pA,, In pew. (5t) KADLUBAR, F.F., MILLER, J.A., YILLE$, EO. Guasyl 0karylszoiwtion and Otarylation of DNA by the carcinogen N-hydros,y-1-naphtqylamina Cancer Rtns.vA 88(11): 8628-5636, Novambor 1978. (57) KAPITULNIK, J., LEVIN, W, CONNEY, A.H., YAGI, H., JERINA, D.M. Beoro(a)pyrono 7,8-dihydrodid is aan raerinoy.nio than bensa[a]pyrono in newborn miot. IJaLwo 26E(ba00):378-880,11art:h 24,14Tl. (58) KING, C.M, TRAUB, N.R, LORTZ, Z.1L, THISSEN, Id.R. CaMOer R...wek 30: 8!6lE-337?,1979. (5a) KING, ILW., OSBORNE,1[.R, BROOKES, P. Ci.ulao-BfoleFird Intervetioa+ 24: b46-a,'f9,19'A. (60) KOESTNER, A., $WENBERG, J.A., WECHSLER, W. Experimental tumors of tLo nervous system induood by iororptiv. N-altrooau.a oompound.. AnBnra in Bhpai+iwnMt'l4worRsaarrA 17:. 9-8Q 1a7'8 (81) KOREEDA, ii[, MOORE, P.D., YAGI, H., YEiI, H.J.C, JERINA, D.H. AlkglaNon of polyyuanylie aeid at the 2-amino troup and pbospAao by the potent wutaras (s)-7p,Ba-dihydro:y-ip,lokapory-7,B,A,l0detrabydroben- zo(a]pyrano. Jowwst of tAt A.wrioaw Qhomiooi Society 9®(21): Fl2D-477$ Oclobor 18„ 107& (e!) KOZLOWSKI, LT, FRECKER, R.C., KHOUW, V, POPE, N.A. The misuse of "los"asndar" dsarattas aad Its dot.ation: Hol..bloekieg of ventilated fi7taa. Awerioax Jaarnat of Pfrblic R.a1tA 70(11):1202-120®, November 1890. (8.T) KUNZE, i[, VU'PIJC, C. Threshold of tar expa.uro: Andy.is of walcinr history of nulo lung eanor a..r and aonteola. In: Gorl, G.R., Bor]c, F.G. (FAitorr). Eaubsry Report t-A Say4 Gliponttd Cold Spring Harbor, New York, Cold SprinE Harbor Laboratory, lYBO, pp. 2D-K LAVOI$ I'.J, HECHT, S.S.., HOFF1lANN, D, WYNDER, E.L The less barmful eiaaietto and tobaooo omohe flavors. In: Goei, G.B., Bock RQ (Editon). Ban6ury Report ?-A 3a1. (5par.ttsf Cold Spring Harbor, Now Yorlc, Cold Spring Harbor L.bontory,l9®0, pp.. 261--= (OS) Li:FFIN(iWBLf., J.C, YOUNQ 1I.J., BIIiNASEK, IL TbBacov lMawrirp Jor Synoki,y A+sduota. Winston-Salem, North Carolina, RJ. Reynolds Co., 1972 (6Q) LUINBKY, W, REUBER, Y.D. CarclaoSenkity In nta of nltro9on1othybthybs-s mine. laboled with deutsrium In several positions. Cann. lkworeA 40(1): 19- 21, January 1M (67) LITWACK, G., CAKE,1d.H., FILLER, R., TAYLOR. L Physical mwurementos of the liver yluoooortiooid receptor. Biochsesioal JourMaL 169(2): 445-448, February 1678. (Qd) LIT9VACK, G., KE7TERER, B, ARIAS, I.M. Ligandin: A hepatic protein which bindb ota.oido, bilirubin, aueiaoreno and a number of auasnous organic anions. Nature 2'd4(b3?9): 466-4E7, Dooombor 17,197L r (BD) LLOYD, J.W. Lona-term mortality study of steelworkers. V. Respiratory In coke plant workers. Journal of Cbeupational J[a{ioiw. 18(2): Fotxvary 197L (70) MAXWELL, J.C., JR. Trondo In cigarette consumption. In: Gori, G.B., Bock, F.O. (Editocn). Bawbury Report 1-A Safi C14a..Mf Cold 8priny Harbor, N.w York, Cold Spring Harbor Lboestorjr,l9®0, pp. 3ZS,132. (71) MILLER, B,C., HILLER, J.A. The pro.enoe and significance of bound uainoa sodyeo ia the livan of rate fed p dimsWylamiao.mbeoaona. Cauo.r R.aoa++sA 7; 4611_480,1947. (7s) YILLER, B.C., l[II.I.ER, J.A. In: Saarlo, C.E. (Pditor). CIY.miaal Chreiwopsna. Amniesn Chmniral Soeiety Yonosraph 173,1976, pP. 7>f7-7ft (71 ) 1[ILi.EIt, J.A.,1[ILLER, E.C. Advanaa ix Pharmacology and Therapeutics 9: 8-1T,197A (74) HOSCHS4 RC., BAIRD, W.M, DIPPLE, A. Metabolic activation of the carcinogen 7,1Zdimatl~ylb.n(a)antbraeoes for DNA binding. Biodlemioal and BiopAyiioal R.wsrc4 Coiww.siootiewo ?6(4): 1092--1608, Juno 2D,19TJ. (75) YOSS, A.J. Cbn.pw in Cipnstfs Smoking and C4frrnt Smokiny Rnctioc. Asany Adtiltu flwi6.d Sfah., 1l78. U.S. Department of Hoalth. Educ.tion, aod Wdfara, Pubik Health Servio., National Center for Health Statistics. Advance Data from Vital and Health Statistics, Publkatlon No. 62, September 19,197l,1S pp. (76) NAKANISHI, K, KASAI, H„ CIiO, H., HARVEY, RG., JEFFREY, A.M, JENNETIF,, K.W., WEIIJSTEIN,1.8. Absolute eoafiSuntioa of a ribonucleic add adduct formed by motaboiim boaso[aJpynao. Joarwal q/ tAt American CA#*ioal8oatoty 96(1): 266-M January 5, 1977- (77) NEBEtT, D.W. Genetic control of carcinogen metabolism IoadinF to individual diftarseaa in oanoa risk. DiosAuwio 6D(Y):101Y-102P, Doambar 197a. (7d) NEBERT, D.W., JENSEN, NJ1. The AL loeu.: Genetic regulation of the metabolism of eae+dnoeon4 drugs, and other onvirenm.ntol ehomfeals by oytoehromo P-450-modi.t.d monoo:ys.moM. CRC Critical R.ui.a ix Bio• eAew{" 6(1): 401437. Jups 1979. (f9) NEBERT, AW., LEVITT, RC, PELKONEN, O. In: Griffin, A.C, Shaw, C.R. (Editon). Caretwoyora Idestifiestios and Jl.eMnionw q/ Aetion. New York, Raven Prsa.,1979, pp.167-:186. (80) NICOLOV, LG., C1IERNOZEIiSYY, LN. Tumors and byporpla.tio lo.iono In Syrian banrtsro following tranoplaoental and neonatal treatment with dqr.tto aowk. onaden.as.. Journol oJCsnar Ru.atVk and Qiniool Onaofoyy 94(12):. 2/D-466„ 1979. (81) NORMAN, ILL, 1[ULLER.ESERIIARD, U., JOHNSON, EF. Tho role of eytocLroms P-{SO form. In &aminoanthraoano and baazo[a]pyrene mutayaca- ois. BiocAewioul and BiopAy.ioa! R..oa+aA Co.zwwxiaotioni 88(1): 195-201, July 12,1979.. (BS) NORMAN. V. Tho effeot of perforatd tipping paper on the yield of various amok. euopawtsN. B.iaapr swr nbmkf8raeltrup 7(6): 2ez,?87, September 1974. (e!) PARKEB, H.O. Th..pidemiology of the aromatic amine eanoera. In: S.arls, QI: (Edit9r). Cio+.iOai Gb+ot*o8.~.. American CiMmioal $ocht,Y Monograph 173: 462-480,1976. twt ~p~pe~riSg 107
Page 99: apt20e00
(d1) PATRIANABOS, C., HOFFMANN, D. Chemical studies on tobacco nnoke. L7C1V. On the aaaly.is of aeom.tio amiew In eigarett..nwk.. Jou.riaW of Anolytfoef Taafmkgy a(4); IQa-1b1, Jullr/Auguat 197Y. (db) RADFORD, E.P., HUNT, V,R., LITTLF'1 J.B., WYNDEti, E.L. HOFFMANN, D. Caretnogeaidty of tob.ooo-amoke eonetJtuents. Seiw+w lA6(8880): 512-318, July 18. i96A, (d6) REDMOND, C.S., CIOCCO, A., Li.OYD, J.W., RU9H, Ii.W. Long term mortality of ateelwarted. VL Mortality from maBgnaat eeepla.mt among ooke ovea workers. Jowwe[ ef Oxupatio.al lfedieine 14(6): 6y1-A26, Augu.t 19Ti (87) RICE, l.M. Pnaatal effaep of chemical eardnogaro and method. for their detection. In: Simmd, C.A., BnelkwSam, J.. (Editors). Devaopmsnfal 7lomieity. 1860. (8t) ROF., F.C., WALTFR4,ILA. Sonw unsolved probiemr In hmg cancer etloiogy. A+npra.a {wI(Zwrr+sesta! 7kmorRasrok l:126-827,1DA6. (aa) ROWLAND. LR, GRASSO, P. Desrndatloa of N-nitrownine, by Intestinal bacteria. AlplJed Jlioro6ielopy 2Y(1): 7 1?, January 1976. (v0) RUSSLLL, M.A.H. The ease for msdium-nioatine, low-tar, bw-caebon monoxide eigarett.n In: (iaei, d.B., Boek, F.Q (Editon). Ba*bwY ltepert !-A Sa14 Gips+stbf Cold Spring Harbor, New Yoek, Cold Spting Harbor Laboratory, 111110, pp. Yq'i-S100. (91) SATO, R., OMURA, T. (Edltoa). DyioeMowe 1°R46o Tokyo, Kodaa.ha Ltd.,18TS, 283 pp. (Dt) SCHMELI7., L, HOFP'MANN, D. Nitrog.n-aont.ining eocnpound. in tobaoao and tobaooo amoin. Chen.{eoi R..few ?7(a): 05-M 1, Juna 19??. (YJ) SHIFFMAN, 31(. Diminiahed smoldng, withdrawal qmptomo„ and cessation: A cautionary note. In: Cod, G.B„ Boqk, F.G. (Fditms). BanOrry R.port 1-A Safk dlyoratbf Cdd Speing Harbor, New York, (7old Sptiag Harbor Lborato- . ry.19B0, pp ?113-286, (1{) SINGER. B. N-oltroa aDqtat(ng agents: Formation and peni.tenoe of allql deri.atiws in mamnnliaa nneleia s" as eoatribntin` factors (a mtdnogene- ais. Jounm! ef ths NatioaaJ CsaaslwstitrOs p(A)r 1l.28-1ZMl. Juae 1l79. (!S) SINGER, S.S. XinatJa and mechanism of aKphatia hsnreitraoatiod Jowwat of ChynRie (Rnairt+ry 44?A): 4412-461d, No.+mber t1,19'ls. (os) SLAGA, TJ„ GLEA.90N, (i1., DIGIOVANNI, J., SUKUMARAN, K.B., HARVEY, R.O. Potent tumori.itiatlug activity of the akdiAydrodiol of T,1Z. dimethylben(a)anthraeaae ia mouo. ddn. Cancer Riwar,k a9(6): 19s4-19®6, June 19?Y. (97) SOROF, S., YOUNG, &M., MCBRIDB, RA., OOFFEY, C.B. Cisrar Rsroatrll S0(7): 2D2i1L20a/, Ja1y 197U. (98) SUTTON, S.il, FSY8RAB8ND, C, COLE, P.V, RUSSELL MJi.H. Adjust- ment of nnokas to dCution of tobacco .aroke by veatilated e5gantt. holders. Ainioal P6arwmaetery emd TA.rspsrtiee B1(4): lY6.406, Oetob.e 167l. (99) THOMAS, P.Lr, LU, A.Y.H., RYAN, D., Wg'ST, d.B., l(AWALEK, J., LEVIN, W. Imnnnoehenteal evidence far dx faemr of rat liver eytoehrocna P450 1' obtained a.ing ao!(bodies against purified rat li.er eltoesromar P460 and " P146. JUolisufar P6~aootoyy 18(6k ?46-?6Q, 8aptnnb~r 1f7~6. (i00) TSO, T.C. ModifkatJon through agricultural teo>takuem for developing a safer tobaeoo. In: Goei, 0.8., Boek, F.G. (Edltws). Bonbwry Repoa! f-.t Safr eipmrabt Cold Spriag Harbor, New Yort, Cold Spring Harbor Laboestory. 19®p, pp 1a1-190. (101) U.!!. DII'/l1tTMENT OP AGRICULTURE, Eoonomio Re.eaeobServke. 4b8aooo 9ittistiox 17L 1980. (10!) U.S. DEPARTMENT OF HEALTH, BDUCATION, AND WEI,FARE. 3:nokiay a+id XealtlY; A Rsport of N1s Su+yeon Gewsral. U.S. Department of Health. Education, aad Welfare, Public Health Sarvioe, Office of the As.istant Secretary for Heaith. Office on Smoking and Health, DHEW Publication No. (PHS) 78-b0066,19'J'J,1186 pp. (103) U.S. PUBLIC HEALTH SERVICE. S+aokfnp ard ifealU, Report of tAs Adviaory CoMINtta to the Su+yeon Cwws+ni of t11e Iwbtie IfeallA 8srvier, U.S. Deparb ment of Hea1W, Fdueation, and Welfan, Public Heaith Service, Center for Disease Control, PHS Publieation No.110s,19Q4, 387 pp. (104) U.S. PUBLIC HEALTH SE1tVICE. TAe fl.olfk Conarownew of Smoking. A Rsport to tJ1. Swprsn fissanL• 1971. U.S. lkpartment of Hedth, Edueatbn, and Welfare, Health $ervioes and Mental Health Admini.tration, DHE9Y Publication No. (H$M) 41-7613,10?3, 46s pp. (105) WALD, N. Mortality from lung cancer and aoronary heert.diseaoo In relation to cluage. in sn+oidng habit.. Lanod 1(7961):186-159, January 1976. (!06) WALD, N.J., IDLFti M„ BORIBIAM, J. Inhaling habita among smokers of different types of cigarettes. TAo.as, in p.ww. (107) WEISBURGER, $.IL, Canar RarareA, in pr.r. (108) WOOD, A.W., LEVIN, W., LU, A.Y.H., RYAN, D., WEST, S.B., LEIfR, R.E., SGIfAEFLr6-RIDDER, M., JERINA, D.H., OONNE]f, A.H. Mut.geeteity of met.bolinlly activated benao[a]antlwaoene E,4-dihydrod'ioi: Evidence for bay region activation of caeeinogenic polyoydie 6ydtooarbees. BiorJleneiesi and BiopApiar! Rsaarr,A Qos.mx„iootian 1Z(2): 68Q-686` Septamber ZU,1974. (109) WYNDER, P.' L, HOFFMANN, D. 2bbaooo and Te6eece SwalFt. Shtdies in Fspri,a.wtei CarefnoDsnais. Ne.. York, Academic PPreu,19b7, 4s0 pp. (110) WYNDER, &L, HOFFMANN, D. (Editon), 7btoo+d a Lew ftonnful Oigarotte. U.S. Department of Health, Education, and Welfare, Public Health Service, National Imtituta of Health, National Cancer Institute Monograph No. 28, Juna196a,482pp. (111) WYNDER, E.L, STELLMAN, S.D. Impact of long6teem filter cigarette usage on lung and larynx cancer rl.k: A rame-eantrol study. Joxsvat of tiM National Cawetr lwaflue.68(8): 471. Maeeh 1979. (11t) YANG, S.If., ROLLER, P.P., FU, P.P., HARVEY, ItG., GELBOIN, H.V. Eridenoo for a$b4poxide as an intermediate in the m1Qa.omal metabolism of bmsa[akyrene to b-hydrroxybenaa(alyrsne. Efochsxtical and Biaphysiesi Rs..nrrA ComrMknicationa Tl(4):1176-116Z, Auga.t 82,1877. (11J) ZAJDELA, F„ CROISY, A., BARBIN, A., MALAVEILI.E, C., TOMATIS, L, BARTSCH, H. Caednogenioity of chioroethylene o3dde, an ultimata reactive metabolite of vinyl chloride, and bi.(chloromethyl)etber after subcutaneous adminatration and In iniNatkm-.pranation e:periment+ In mioa. Cancer R.aiank 40(2): SS2-SSR, February 1980. . S&"M
Page 100: apt20e00
Section 4. CARDIOVASCULAR DISEASES
Page 101: apt20e00
CONTENTS Introduction The Relation of Cigarette Smoking to Cardiovascular Risk Factors in Cigarette Smoke Related to Cardiovascular Function Nicotine Carbon Monoxide Other Components Studies of the Impact of Lower "Tar" and Nicotine Cigarettes on Coronary Heart Diaease The Challenge of Future Research Proposed Future Research Descriptive Studies Cohort Studies Observational Studies Clinical Trials Case-Control Studies Studies of Mechanisms Animal Experimentation Technical Resource Center Behavioral Ramifications Summary References LIST OF TABLES Table L-Coronary heart diaease-mortality ratio® Table Z.-.The effect of the cessation of cigarette smoking 113
Page 102: apt20e00
on the incidence of coronary heart dieease (CHD)- Introduction morbidity ratios in ma>es Table &-Filter cigarettes and risk of coronary heart disease in men The expectation that a lower "tar" and nicotine cigarette would be associated with less cardiovascular disease is based on two well-known epidemiological findings: (1) the strong dose-related association be- tween cigarette use and coronary heart disease (CHD)-the largest component of cardiovascular disease; and (2) the evidence that it one quits smoking, the vascular consequences of smoking diminish. Table 1 shows that the more people smoke per day, the greater their risk of coronary heart disease. Table 2 summarizes several studies indicating that persons who quit have s lower risk of CHD. These findings have been challenged (41) because the sample of smokers who have voluntarily quit may be biased through self- selection. Indeed, even prior to quitting, persons who stop smoking differ from those who continue smoking (16); however, their major cardiovascular risk factors do not differ (18). A multivariate analysis of the impact of smoking on CHD that takes into aooount all the major possible oonfoundere shows smoking's independent effect on CHD risk (31). In some studies (18), the quitters were more sick than those who continued to smoke, but none of the known major factors involved in CHD risk (disregarding cigarette smoking) explains the difference in CHD rates between smokers and nonsmokers. None of the factors distinguishing quitters from continu- TABLE 1.-Coronary heart disease-mortality ratios ADMUKJMW s4W.sezse Ber.nee. Ns 10 1aso <so ao >M >D-~o >40 H.o.od ..d sA0 L'A lA 2!D t{1 H««. (S4 Doyl. .t .I. (1{) L00 L00 1.76 8.30 Ddl .ed Pd. L00 L9i L27 LN (13) Pboliam Prej.ai L00 1.Q6 L70 8.00 (SO Ya1. (!!) lA0 LaY L18 1,61 200 No'l'C:N/~?Ln.~Ya TABLE 2.-The effect of the eeasation of cigarette smoking on the Incidence of ooronary heart disease (CHI))- n+orbidity ratios in males 14M Ad.n.a ierktl ..oks 3moY.n H.wnw1 d Q..lLkd (tq L00 Lls LA! Ja.1i...t &L. (lI) L00 ili Lt{ 84apln « d. (M lA0 a9f Lp [wM « d (sOj L00 O10 L70 ,.. 115
Page 103: apt20e00
ing smokers clarifies why the risk of cardiovascular disease declines rapidly following smoking ceasation. The effect of smoking on CHD risk fulfills many epidemiological criteria for a causal association: powerful, independent, dose related, and reversible. When the association of smoking with CHD is adjusted by the other major risk factors, the coefficients are strengthened, rather than weakened (18). At present only a few of the several thousand substances found in cigarette smoke have been implicated in cu<rdiovascular risk; others have yet to be fully assessed. In order to facilitate a complete analysis, a study would have to measure the impact of each substance in cigarette smoke and establish its independent contribution. However, testing large fractions of cigarette smoke for cardiovascular risk might allow the elimination of specific constituents. Currently, one can define only part of the impact of smoking on cardiovascular risk. What factors Isolated in cigarette smoke are known to have cardiovascular consequences? What is already known of the cardiovascular impact of smoking cigarettes with some of these factors removed? In view of the rapidly changing variety of cigarettes found in the market; how can one keep pace with studying the cardiovascular impact of each new lower "tar," lower nicotine, lower carbon monoxide cigarette? The Relation of Cigarette Smoking to Cardiovascular Risk Many exhaustive reviews of this issue exist, and only a brief account of the essential findings is presented here. The chapter on cardiovascu- lar disease in the 1979 Surgeon General's Report on Smoking and Health amply documents that cigarette smoking is a major, indepen- dent coronary heart disease risk factor in Weatern countries (46). There is substantial evidence from autopsies that more atherosclerosis is found in smokers t.han in nonsmokers (44). Hyaline thickening of arterioles in the heart is more prevalent in smokers (6). Experiments on atherosclerosis in animals, however, have not produced uniform reaults. In those parts of the world where serum cholesterol levels are low, especially below 160 mg96„ smoking is not aa strong a risk factor as It is in the United States (JJ). After the age of 65, smoking poees less of a cardiovascular risk than it does in younger age groups (J1). Study reaulf differ on whether smoking Is a risk factor in coronary heart disease following a myocardial infarction (46). The relationship of smoking to angina pectoris is uncertain (g7, J1). It is essential to emphasize theee points because one could plan a study of lower "tar" and nicotine cigarettea in developing countries, with older subjects or with people who have already had a myocardial infarction or angina pectoris and find that the exoess risk of CHD rr.4(;@zsS among smokers had disappeared. To establish that lower "tar" and nicotine cigarettes cause less risk of CHD than higher yield cigarettes, there should be studies of randomly selected American men, 40 to 60 years of age, for the development of sudden death, first myocardial infarction, or peripheral vascular disease-endpointa with which cigarettes are associated at more than double the normal risk. All the other factors associated with CHD risk ahould be measured simultaneously In a multivariate analysis so that any differences caused by quitter self-selection can be eliminated as the explanation of reduced risk. In this way, independent change in risk caused by the change in smoking behavior could be accurately assessed. In addition to its effect on coronary heart disease, smoking Increases the risk of arteriosclerotic peripheral vascular disease. Its impact on cerebrovascular disease is less uniform (48). Factors In Cigarette Smoke Related to Cardiovascular Function Most of the studies on cardiovascular endpoints associated with cigarette smoke have focused on nicotine and carbon monoxide rather than on "tar," which has not been demonstrated to have a major acute cardiovascular effect. Less is known about the effects of cadmium, zinc, chromium, carbon disulfide, carbon dioxide, tobacco antigens, hydrogen cyanide, nitrous oxide, or polonium-210, among other constituents of cigarette smoke. Nicotine Many studies have documented a dose effect of nicotine on cardiovascular function (t, 45). Acute studies in humans indicate a rise in heart rate, an elevation of systolic blood pressure, and cutaneous vasoconstriction. Cardiac output generally rises, but not always. Since stroke volume is generally not affected, or may fall, In patients with angina pectoria (2), the observed rise in cardiac output has been attributed to an increased heart rate. Such changes have been attributed to a atimulation of sympathetic ganglia by nicotine. This stimulation results in a rise in catecholamines, which in turn produces variable degrees of positive chronotropic and inotropic cardiac actions. Other effecta include generalized peripheral vasoconatriction and transient systemic (primarily systolic) hyperten- sion (9'). Levels of free fatty acids rise in niootine-treated subjects, possibly as another consequence of the catecholamine release (n). Whether free fatty acids affect cardiac function adversely, as some researchera have proposed (37), or aid in fatty deposition as others have suggested (10) has not yet been fully established. Nicotine increases the diurnal secretion of cortisol (26). Plasma cortisol levels have been found to be elevated during myocardial 7
Page 104: apt20e00
infarction, but the increase may be an effect rather than a cause of this condition. On the other hand, the cortisol rise has been implicated as a precursor of ventricular arrhythmias (38). Nicotine-stimulated release of catecholamines has also been suggesb ed as a cause of increaeed platelet stickiness and aggregation (24); this and other smoking~related hemostatic effects are potential mecha- nisms by which smoking may contribute to increased rWiovascular disease. Although the evidence is meager, some of the acute effects of nicotine on cardiovascular function, such as elevation of heart rate and blood pressure, are dose related and apparently diminish in some lower-nicotine varieties of cigarettes (t, 4_S). Carbon Monoxide Carbon monoxide is inhaled in the form of a gas in cigarette smoke. Its affinity for hemoglobin is approximately 210 times greater than that of oxygen. The availability of oxygen to the myacardium is further decreaaed by the tighter binding of oxygen to hemoglobin in the presence of carboxyhemoglobin. Carbon monoxide also combines with myoglobin, impairing the availability of oxygen to the mitochond- ria. In addition, carbon monoxide can combine directly with cyto- chrome oxidase to slow the oxidation of reduced nicotinamide-adenine- dinucleotide (65). Carbon monoxide has a direct impact on cardiac function In patients with angina pectoris, including a negative inotropic effect on the myocardium. Aronow (1) demonstrated an increase in left ventricular end-diastolic pressure, with a significant decrease in left ventricular dp/dt and stroke index. Anginal patients with increased carboxyhemo- globin levels also experience significantly shortened exercise time until the onset of angina pectoris (3). DeBias and co-workers (12) have also shown in monkeys that exposure to carboxyhemoglobin lowers the threshold for ventricular fibrillation. Myocardial ultrastructural changes have been described in rabbits exposed to carbon monoxide. Among the changes are myofibrillar necrosis and mitochondrial deg+eneration (S). Aatrup (4) has proposed that carboxyhemoglobin increases hypoxia of vessel wslls. Because this condition may increase the permeability to lipids, Including cholesterol-laden lipoproteins, it may promote the prooess of atherosclerosis. It has been shown that exposure of humans to esri,on monoxide increases the rate of disappearance of radio- iodina4kd serum albumin (4.t). Wald and Howard (49) have shown that the carboxyhemoglobin level is more closely related to the prevalence of coronary heart disease than is smoking history. They emphasize that smokers who are physically active enhance their mechanisms for releasing carboxylurnoglobin and have a much better CHD prognosis than do sedentary smokers. Other Components McMillan (JS) has reviewed studies on a variety of other factors in cigarette smoke and has concluded that much more data are needed. He noted a possible association of cadmium with hypertension. Smoking generally results in an acute rise in blood pressure, but has not been proved to cause chronic hypertension. Whether tobacco antigens play a role in increased endothelial cell damage is conjectural. Finally, IYIcMillwn considered the hypothesis proposed by Benditt and Benditt (18) that atherosclerosis is really caused by monoclonal smooth muscle cellular proliferation. If so, one may be persuaded that "tar," which is mutagenic, is atherogenic after all. Studies of the Impact of Lower "Tar" and Nicotine Cigarettes on Coronary Heart Disease Not all cigarettes that produce a lower yield of one substance necessarily provide a lower yield of other substances. Indeed, research suggests that cigarettes with unperforated filters ("unventilated"), which yield lower "tar" and nicotine levels than do nonfiltered cigarettes, may Increase exposure to carbon monoxide (53) and lead to higher levels of carboxyhemoglobin (52). Cigarettea with perforated ("ventilated") filters may produce lower carbon monoxide yields (6-0). People who smoke lower "tar" and nicotine cigarettes do not generally smoke substantially more cigarettes per day than smokers of higher yield cigarettes (16, 40, 61); however, their intake of "tar," nicotine, and carbon monoxide is higher than would be predicted by data from machine-amoked cigarettes. This suggests that these cigarettes are smoked more intensively than higher yield cigarettes (40, b1). There is evidence from four studies of the association between cardiovascular disease and the use of lower "tar" and nicotine cigarettes. Hammond et al. (tg), in their prospective study of volunteers of the American Cancer Society, have shown reductions of 10 to 20 percent in observed coronary deaths among persons smoking lower "tar" and nicotine cigarettes when compared with those who reported smoking similar numbers of regular cigarettes per day. Hawthorne and Fry (25), in three prospective surveys of over 18,000 persons in west-central Scotland, showed a slightly increased relative coronary mortality in persons who smoked filtered cigarettes oom- pared with persons who smoked unfiltered cigarettes. Dean et al. (11), in a retrospective mortality study in northeast England published by the Tobacco Research Council, showed relative risks of about 0.6 for coronary heart disease and 0.4 for cerebrovascular disease in filter cigarette users versus smokers of unfiltered cigarettes. Unfortunately, smoking habits of cases and controls were obtained from different sources and at different times, confounding the study design. Recent 118 o9zZez-6• 119
Page 105: apt20e00
TABLE 8.-Filter cigarettes and risk of coronary heart dieease In men Ikt.nAe. }t.in nw s..tborn..d rn (M - - i.ao i.a - H.sed d .L (!t) L.~'hi" Paried t ( L00 Qp re~loa t ioo oA i e~rea Lco osi f~r wa s zoo uo u....t,t (!J) ]AO oes cu" kAL ( n < so teo us 00+ . Le0 of6 unpublished data from Framingham (9) have failed to show a lower CHD. risk among smokers of filter cigarettes, and in younger men there was actually a slightly higher rate of coronary disease among smokers of filtered cigarettes (Table 8). This study took into account the other major CHD risk facto:s (cholesterol, blood pressure, and age); the increased risk in filter smokers is independent of effects attributed to these other factors. Overall, use of lower "tar" and nicotine cigarettes has not produced a consistent decrease in risk for cxudlovaaonlar disease; Indeed, In some studies a slight increase in risk has been seen. Additional studies will be needed to assess the actual Impact of any changes In the composition of cigarettes on subsequent CHD rates. Terms like "lower yield" may describe only part of the change; other additives and the overall use of the cigarette might actually increase risk. Wald (54) has shown that, in the United Kingdom, while lung cancer mortality fell in men from 19b0-60 to 1969-73, with the change to filter cigarettes, CHD mortality increased. The author wondered whether the decrease in "tar" accounted for the lower lung cancer death rates, and whether unchanged levels of carbon monoxide might have contributed to the observed continuing rise in CHD death rates. The Challerp of Rufurs Research In the United States, virtually no filtered cigarettes were smoked before 1950; now 90 percent of the cigarettes sold are filtered.. The sales-weighted average "tar" composition per cigarette has decreased fromp over 85 mg of "tar" per cigarette in the early 1960s to under 15 mg"in 1979. Cuntintly, nicotine has decreaaed from over 26 mg per cigarette to about 1.0 mg per dgarette. Ultra low nicotine and "tar" cigarettes are now inarasingiy available, with levels of under lA mg "tar" and 0.1 mg niootine.. Unfortunately, the amount of carbon monoxide delivered by dgarettes has not been studied as intensively as the "tar"' and nicotine levels, although a recent United Kingdom TQs'.68Zfs8 survey of old and current cigarettes indicates that carbon monoxide yields have changed much less than "tar" or nicotine yields. This may be the case in the United States as well. Linking cigarette carbon monoxide yields to possible toxicity is further complicated by the fact that patterns of smoke inhalation for lower "tar" and nicotine cigarettes may differ from patterns for higher "tar" and nicotine cigarettes arettes (51). A technique should be developed to monitor the effect of changes in cigarette composition, particularly in nicotine and carbon monoxide content, on cardiovascular risk. Proposed Future Research Descriptive Studies Continued research into the changes in cigarette smoking is needed. Surveys such as the National Health and Nutrition Examination Survey (NHANES), prospective epidemiological field studies, and prepaid hospital insurance group studies an needed to provide comprehensive information on cardiovascular disease caused by smoking. Such studies should include worldwide data surveillance. Cohort Studies Obseruational Studtei Observational studies are studies of large populations in which a variety of factors related to cardiovascular disease are measured and followed, permitting an independent analysis of variables such as a given cigarette brand. There are now a number of studies that follow a given population over a period of time to assess prospectively the impact of amoking.. Some of these are traditional single-town studies in which a random sample of a given population is followed over varying time intervals, often every 2 to 5 years. Examples of such studies are those in Framingham, Tecumseh, Puerto Rico, Evans County (Georgia), Hono- lulu, and Goteborg and Stockholm, Sweden, where whole populations or samples thereof are followed on a more or less continuous basis. In addition, there are worksite studies, such as the Albany civil servants, People's Gas Company of Chicago employees, Western Electric work- ers (Chicago), Minneapolis business executives, California longshore- men, and British doctors, which call for repeated observations. Questionnaire studies, such as the American Cancer Society's 25-State Study or the 9-State Study, the U.S. Veterans Study, the Canadian Veterans Study, the Swedish Study, the Japanese 29 Health Districta Study, and the Study of California Males, can observe as many as a million subjects. •ii
Page 106: apt20e00
In addition to measuring the risk for cardiovascular disease, most ost of these studies also assms other consequences of smoking. They allow, better than any other studies, the calculation of the independent effect of smoking. The shortcoming of these prospective studies hss been that the average turnaround time has been approximately 10 years. Occasional- ly, a 4-year interval produces enough data for a meaningful analysis, but with the rate of change in the composition of cigarettes, the information could be outdated by the time the data are collected and analyzed. Clinital Trials Several clinical trials of the effect of smoking intervention on coronary heart disesse are in progress. Perhaps the most promising of these is the Multiple Risk Factor Intervention Trial (MRFIT) (t8), in which high-risk men were randomly assigned to a special-intervention group and a usual-care group. The study, now in its 6th year, avoids self-selection bias by contrasting the overall disease experience of the two randomly assigned groups. Unfortunately, the inferences that may be drawn about lower "tar" and nicotine cigarettes per as (which is only a part of the intervention program) ara somewhat limited and do involve self-selection. Another problem is that this study directs its intervention to serum cholesterol and blood pressure control as well as to smoking cessation. Nevertheless, long-term studies like the MRFIT are recommended because the followup of cohorts may provide findings that differ qualitatively from those available in strictly observational studies and because the measurement of other major risk factors permits the estimation of the independent effect of smoking behavior changes. All such clinical trials should incorporate the conviction of the mediaal and public health communities that current smokers ought to quit and that nonsmokers should not begin to smoke. Caa8-Comitrol Studies Caaeoontrol studies have the advantage of relatively short turn- around times and usually are less expensive than other studies. Unfortunately, unless very carefully designed, they can suffer from a partial and therefore lese accurate assessment of the disease under etudy.w*or example, in studying cigarettes, one must assess the death endpoints of coronary disease. The problem In studies of this kind is how to compile an objective .nwking history of the deoeased. Obtaining information from a spouse or close associate introduces a certain amount of error, but this error may be controlled somewhat by interviewii.g close associates of the members of the control group. In studies of nonfatal myocardial infarction, the survival of_ both the cases and the controls allows more precise measures of the variables under study. Despite shortcomings, case-control studies represent the major means for assessment of the relative cardiovascular risk of varying cigarettes. Further, serial case-control studies, similarly designed, performed, and analyzed, could provide information on changes in risk over time. In such studies care must be taken to select appropriate controls, to treat cases and controls alike, to avoid hospital-based rosters, and to study well-defined and documented endpoints. Studies of Mechanisms In view of the difficulties involved in doing large population-based studies and the need to know more about the meehanisms whereby cigarettes cause damage, more studies are needed on the components in cigarettes that affect cardiovascular risk. It may be that nicotine and carbon monoxide are the chief toxic agents, but until more is learned of the other constituents, judgements are based on scanty information. Perhaps the main reason to pursue the study of disease mechanisms is to shorten the turnaround time for assessing any new brand of cigarette; studies could be designed to measure particular constituents of the cigarette smoke and characteristics of the sub ject at risk. With better noninvasive cardiovascular techniques, studies of how a particular cigarette affects cardiac function could be performed in greater depth Such studies would provide better measurement of the biological effect of the cigarette smoke components in individual smokcrs. Measurement of expired carbon monoxide, serum carboxy- hemoglobin, thiocyanate, and ootinine would help resolve not only differences in the composition of cigarettes, but also major differences in the ways individuals smoke (47, 48). These more precise measure-e menta of smoke exposure and dosage of smoke constituents could be correlated with a host of biochemical and physiological parameters. The number of biochemical factors found to be affected by smoking continues to grow. Lower HDL cholesterol levels are found in smokers than in nonsmokers, an effect that is associated with an increased CHD risk (1?). A variety of effects could be weighed to produce a multifactorial analysis of how cigarettes produce atherosclerosis, sudden death, and other cardiovascular problems. Physiological studies using treadmill performance, scintillation scanning-ineluding gated pool studies-and Holter monitoring could provide better clues to the action of cigarettes on cardiovascular function. If such alterations In function could be more certainly tied to later events, they might prove invaluable predict,ors of smoking-. related risk for a given Individual. in ze~sgzse 123
Page 107: apt20e00
Animal Experimentation Most of the animal models used in studies of the effects of cigarette smoke have been designed to teat its carcinogenicity on the bronchial epithelium or the skin of small animals, usually rodents. A few models have been developed to examine the effects of inhalation on the respiratory and cardiovascular systems of rodents, dogs, or nonhuman primates (t0). Very few animal studies have attempted to sasess the effects of different cigarette smokes in inhalation studies of experi- mental atherosclerosis or on the styles of inhalation that may be intervening variables in the pathogenesis of atheroscleroais. It is feasible to induce nonhuman primates to inhale cigarette smoke (sk). Such primates frequently develop many of the physiologic changes related to the atherosclerosis found in human smokers (Je). The further utilization of such animal models would permit a comparison of the effects of proposed lower "tar" and nicotine cigarettes with the . effects of conventional higher yield cigarettes under controlled conditions. Subjects could be assigned randomly to different types of cigarettes to eliminate the self-selection bias, The primates could be examined for effects of smoke from different cigarettes on response variables such as serum lipids and lipoproteins. At this time, the augmentation of experimental atheroecleroeis by exposure to cigarette smoke has not yet been demonstrated; further development of an animal model must occur before definitive studies in atherogenesis will be practical. Technical Reaouree Center In addition to monitoring research evidence on the impact of smoking on health, further activities should focus on developing tools for the conduct of studies on the impact of smoking on health in several areas. A standard questionnaire on smoking should be refined for use by the various studies in the United States and in foreign countries. In addition, techniques for measuring actual exposures to carbon monoxide, cotinine, nicotine, and many other substances could be evaluated to determine the most effective analytic techniques. Where debate continues on the merits of one teat versus another, studies should be designed to resolve the issue. Control of test quality should be instituted and could be ascertained, even from widely disparate grou$ is. Not only could a hierarchy of useful tests be provided, but a quahty-oontrol mechanism should be developed to ensure continued high performance. Finally, frequent updated ratings of "tar," nicotine, and particularly carbon monoxide yields would permit others to conduct better studies of the impact of cigarette smoke components on cardiovascular functions. Behavioral Ramifications It is important to determine the effect of lower "tar" and nicotine cigarettes on cardiovascular disease risk reduction. A key unknown is whether efforts to persuade people to switch to lower "tar" and nicotine cigarettes interfere with other efforts to persuade people not to begin smoking or to quit. Activities to provide a less hazardous cigarette should not Interfere with efforts to eliminate cigarette smoking. Finally, given the limitation in research funds, priorities for research must be drawn. The research proposals outlined above are of high priority. The combination of results from a variety of studies can provide a consensus on the impact of a given innovation in lower "tar" and nicotine cigarette composition. Ultimately, the effect of lower "tar" and nicotine cigarettes will be measured in terms of smoker morbidity and mortality. Summary 1. Epidemiological studies show that the incidence of coronary heart disease (CHD) increases as the daily number of cigarettes smoked increases and that the incidence of CHD decreases among those who quit smoking. These doee-related effects suggest that lower "tar" and nicotine cigarettes might be associated with lower risks of CHD. However, the overall changes in the composition of cigarettes that have occurred during the last 10 to 15 years have not produced a clearly demonstrated effect on cardiovascular disease, and some studies suggest that a decreased risk of CHD may not have occurred. .'.Of the several thousand substances found in cigarette smoke, only a few have been implicated in cardiovascular risk. A number of substances have not yet been adequately asseased. Further, the changes in smoke constituents that have resulted from changes in the cigarette product have not been documented. 8. Linking cigarette smoke yields to cardiovascular disease is complicated by the evidence that smokers of lower "tar" and nicotine cigarettes may smoke more "intensively," although they may not smoke a substantially greater number of cigarettes daily than do smokers of higher "tar" and nicotine cigarettes. The net result could be to decrease the actual intake of "tar," nicotine, and carbon monoxide less than that expected on the basis of machine measurements. 4. Nicotine stimulates the sympathetic nervous system, producing a rise in catecholamines that in turn increases heart rate, elevates systolic blood pressure, constricts cutaneous blood vessels, and increases levels of free fatty acids. The nicotine,stimulated release of catecholamines has been suggested as the cause of CscsRzse1
Page 108: apt20e00
increased platelet stickiness and aggregation, pointing to a potential role in coronary discaee. There is some evidence that these physiological effects may be dose related and somewhat diminished with lower nicotine varieties of cigarettes. 5. Carbon monoxide has a negative inotropic effect on the myoear- dium of patients with angina peeteria. When combined with hemoglobin in the form of carboxyhemoglobin, carbon monoxide may increase the permeability of the blood vessel walls to lipide, thereby promoting atherosclerosis. 6.. Cigarettes with unperforated filters yield lower "tar" and nicotine levels than unfiltered cigarettes, but they yleld more carbon monoxide than do unfiltered cigarettes at the same "tar" yield. Carbon monoxide yields are loaee in cigarettes with perforated filters, but as the composition of cigarettes has changed, carbon monoxide yields have decreased much less in proportion to the decrease in "tar" and nicotine yields. ?.In studies of patients with angina pectoris, increased carboxy- hemoglobin levels significantly shorten exercise time until the onset of angina pecloris.. 8. Myocardial ultrsstructura) changes have been found in rabbite exposed to carbon monoxide. 9. Most cardiovascular studies have focused on nicotine and carbon monoxide rather than on "tar," which has not been shown to have a major acute role in cardiovsscular disease. Even less is known about other constituents of cigarette smoke. 10. Not all cigarettes that produce a lower yield of one substance necessarily provide a lower yield of other substances. 11. Evidence on the association between CHD and filter cigarettes is somewhat conflicting. One major study showed a reduction of 10 to 20 percent in coronary deaths among persons smoking lower "tar" and nicotine cigarettes as compared with those who smoked higher yield cigarettes, but other surveys have shown a slightly increased risk of coronary mortality in people who smoked filter cigarettes relative to tltoee who smoked nonfiltered cigarettes. Recent unpublished data from the Framingham Study do not show a lower CHD risk among smokers of filter dgarettes. ML6g?`.6S Referonces (1) ARONOW, W.S. Carbon monoxide and eardiovucular dian.se In: Wynder, E.L, Hoffmsnn, D., Oori, G.B. (Editon). Proceedings of th. Third World Confer- enoe on Smoking and Health, New York, June 9rb,1976. Volume 1. Modifyiny t8. Riok)br tM S4aokers U.B. Department of Health, Education, and Welfare. Public Health 3ervioe, National Inatiwtea of Health, National Cancer Institute, DREW Publication No. (NIH) T6-1281,19'M, pp. S21-BZ6. (s) ARONOW, W.S., DENDINGER, J., ROKAW, S.N. Heaet rate and carbon (3) (4) monoxdds lavd after smoking high-, lowo.. and non•nioodne dyuetcsa A study ia malo patients with angina pectori.. Asnola of Ixle+nal Modicias 74(b): 6®7- Y02,May 1871. ARONOW, W.$., ROSAW, S.N. CarboxryhemoQlobiA eaund by .moldeg non- nioolias dyaretka. Effects in aayina peetoeia. Cir+awiatioK 44: T82-?88, Novembw 194L ASTRUP, P.. SWdiae on carbon monoxide and nicotine. In: Wyndeq EL, Hoffmamy D, God, G.B. (Editor.} Prooeedlstp of the Third World Confar- anoo on Smoking and Hnlth, New York, June 9-6,,19?6. Volume L Mod;fyiap tAo Ri.k for tJle Smoker. U.$. Department of Health, Education, and Welfare, Public Health Senia, National Institutes of Health, National Cancer In.titute, DHEW Publication No. (NIH) ?b-12Z1,1976, pp. aS1-ML (5) ASTRUP, P, EJEIASEN, If. Model otudieo linking carbon nqnoxide andfor (8) aiootine to arteriacleroais and eardioya.calar diaoa... A'.oenti.o M.dieinm t(S): !Y6-t02, Bay 1979. AUERBACH, Ory CARTB$i. H.Wy GARFINIfEL, 1., HAMMOND, EC. Ciea- retto .mddns and coronary artery disesae. A maaoaoopio and miaeoaoopio study. CAat 70(6): eB7- 7U6, Deoember 1M (7) BALIh 1L, TURNER, R. Smoking and the burt. The basis for action. Laeoet 2(T'sat): (i2t-880. October 6,1s7< (8) BENDITT, L',P, BENDIIT, J.M. Evidence for a monodond origin of human atherosclerosis piaoques. Auoeedirya of N. IVotienol Aoodenyr of Scienees of tbe Unit.d Sta4a a/A+nerioa?(1(d):1?b3-1?56, June 1Y73. (S) CA9TSLGI, W.P., QARRISON, BJ., DAWBER, T.R., 1ICNA][ARA, P.M, FE[NLEIB, H, KANNFI., W.B. Tb. fi)ter etysretts and coronary heart di....e. 27m P1a+niryAam, 9t+idy, In peeparation. CA$T6i.L1, W.P., NICKEBSON, R.J„ NEWELL, J.1[„ RUTSTEIN, D.D. Serum NEFA following fat, carbohydrate and protein ioQa.tloa .pd during fasting as related to intraoellular lipid dapoaitioa. .Iawrn.i of AtA.roal.rori. R..earrA 6: E2&b11,1986. (11) DEAN, G., LBE, P.N., TODD, G.F., WILKEN, A.J. Report on A 3ooond R.tre.Podiso Mortality Study ix NortM&wt Aipisnd. A+rt I.• Fi.etois R.toted fo 11(ortality frms LuW Conwr, B+trMeJli;f+, fiart Dfraae onud Stroke in Cl.aals+d Corwty, xitA Phrticulnr L%pAsd. ow tll. R.iativ. Riak. A..oeiated ~.iL1 Smotinp P2ter ard Plcix OFparstt.R London, Tobacco Research Cou ndl, Research Paper 14,1977, 96 pp. (1t) DEBIA9, D.A., BANERJEE, C.IL, BIRIHEAD, N.C., GRZEN!'. C.H., $COTr, B.D., HARREI; W.v. Effects of carbon monoxide inhalation on mtricuiar fibrillation. ArrAiws of EWvironmentat Hmlth E1(1): 4246, January-February 19'te. DOLL, R„ PETO, B. Mortality (n relation to amolduy: 80 years' observations on mak BritLh doctors. British Mediaal Jow7al 2(6061)t 1b2b-1686, December R6„ 1976. 126 127
Page 109: apt20e00
(li) DOYLE, J.T., DAWBEB, T.li., ILANNEI, W9, HINCH, S.H., KAHN, H.A. The relationship of eiraeette smoking to eooamy h.aet dinaoe. The second report of the combined asperlenea of the Albaqy, New York, and Framing- ham, Maeeachuaettn, atudieo. Jonrn.l of the Anwticaw Afod+eal Aaaaeiotion 190(IO): 8!<6-090, Deeember 7,1961. FRIEDMAN, G,D., 81EGELAUB, A.B, DALL4, LG., SELTZER, C.C. Chanw. ter4tiee pndieWe of coronary b.art dioaa.e in ex+moken before tMy.topped amoting: Comparison with persistent smokers and nonmoken. JoMrnal of GAronie Dieeoae SZ(1/Z):178,1979. GARFINKEI,, L C6ange.ln numbe' of dgaratte..mohed compared to changes In tar and .iootiae eonteet ovec a 1S.year perfod. In: Gori, G,B., Hod:, F.G. (Editoes). Bewbury Repo.! !-A SaJ` Ci'.nrWf Cold Spring Harbor, New York, Cold Spdng Harbor Leboeataqr,1980, pp.19-ES. (1?) GARRISON, RJ, KANNEtti W.B., !'E[NIJCItt,1L, CASTEidJ, W.P.,1[CNA 1[ARA, P.iiE., PADGETT, $.J. Cigarette amoking and HDL ebolmteroL The Framingham Offepeing Study. AtAadeefsratr SO(1):17-ib,11[ay 1978. (1d) GORDON, T. KANNEL, W.B., DAWBEiR T.B., l[CGQ D. Changs amod. ated with quitting cigarette amoldng: The Prandnlh.m Study. Amerioax Ifart Jorr.al 90(8):3=3?B, 9eptembee 1975. (1!) OORIWN, T, SOttLIE, P, 3A.NN1M., W.B. S.etio. ?l. Coeooary 6eaet dieea.e, atherotlnrombotie bnln infanaion, lnteentttentdaudifkation-A multivariate analysis of.onr faeben.elated to their Incidence: llamingham Study,1a-year folbwup. In: tCannel, W.B, Gadon, T.. (Editon). T9io Prsw:iiyAaR SI[wdr As b'pid.m(oloyieo[ Iuvootipotios of Csrd+o.aocrta, Diaau... Waahington, D.C., U.S. Department of Health, Edueatba, and Welf.n, Publio Health Service, National In.tidites of Healtb. May 1971, 42 pp. (tU) GORI, G.B. (Editor). Prooeadings of the Tobaoao Smolw Inhalation Workshop on Experimental Methods In Smoking and Health Itesareh, Bethesda, Haryland, June 1! 81, 1871. Aocwdtng+ of the 1b&aaeo.9nwte In4alatio% Workehep oa lslspvr{wwatal 11[etAoda in Sttaoki+y and BoaltA ReaorcA. US. Department of Health. Edueaiion, and Wdfan, Public Health Servk+e, National Institutes of Healtly National Canoaa Intltate, DHEW Publiotice No. (NIH) 7b-906, Bethesda, Maryland,1976, 8S pp. (s1) HAMMOND, E.C, GARFINKEL, L Corvnary be.rt diwae,.troke, and aortie aneury.na. AnAiwo of 1El:vt.onaeo+Ks! floatfJ119(2):167-18$ Augu.t 1999. (t!) HAMMOND, 14C., GARFINREL, L„ SEIDIQAN, H, LEW, E.A. "Tar" and nbotine content of cigarette amoke in rslation to death rates. Environmental Roora+rA 12(8): t03-g74,1)eatnba 19?6. HAMMOND, E.C., HOttN, D. Smoking and death ratea-Report on forty-four months of fo8ow.up of 187,788 mwn. IL Death rates by cause. JoKrnal of the A*wrioae Jlodioa! Association 166(11):1994-1808, MaerL 1b,1968. (!.i) HAWKINS, ILL Smoking, platelets and thrombosis. Nature 284(8848): 480-462, Apei129,194R (t6) HAWTHORN$ V.II., FRY, JS. Smoking and health. The aa+odation between smoking bah.viour, total mortality, and eudioMpantoely di.ean In we.t (i e.ntrwl8eotland. rarrwol of Apidnnwofcyy ad Coatn.4eity JioaitA 82(4): 290- M 8E0, Deoember 1998. (!e) HILL, P. Niaoiiae: An etiologie.l factor for eoronary heart dheass. In: Wynder, E.L, Hoffmane, D, Carl, G.B. (Editora). Proceedings of the Third World Conference on Smoking and Health, New York, June 8-6, 1976. Volume 1. Modifying tAs R(.4 Jbr t!r Barot+.r. U.S. Departnwnt of Hu1tA. Edueation, and Welfare, PuWk Health Ser.io., National tnNtltutea of Health, National Cancer InadtuLe, DHEW Publication No. (NIH) 76-1t81,1976, pp, S1S-819. (t7) JENKINS. C.D., ROSENMAN, R.H., ZYZANSKI, SJ. Cigarette smoking. Ite rclatianahip to eoronary heart disease and related tiah facton in the Weatern Collaboratlve Group Study. Ctneufation 88(6):11W-1166, Deasmbsr 1988. (td) JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION. Collaborating Investigation: The multiple ri.h factor Intervention ttiaL Jo~ of tJw A+nericas Medioal Association 286: 826-826,1976. (29) KAHN, H.A. The Dorn Study of smoking and mortality among U.SA veterana: Report on 8$A years of observation. In: Hayrosl, W. (Ed'itsor). Dpidemiotoyiea! AppreaeAo# to f1Yo Study of Cancer and OHwr CbenGe Diseases. National Canone Intituto Monograph 19. U.S. Department of Healt,h. Education, and Welfare, Public Health Service, National InotitvG:s of Heakk National Cano" Inatitute, January 1966, pp.1-1Zb. (10) SANNEL, W.B., CASTELLI, W.P., MCNAIKARA, P.M. Cigarette aarol:ing and risk of ooronary heart disease. Epidemiologin dnei to p.tlwjeneds. The Framingham Study. In: Haensel, W. (F.dit9r).EpidsMioiopicat ApproaoAea to t1u Study of Cancer and OtAer Ckranio Dioeaea. National Cancer Inetitute Monograph 19. U.S. Department of Healtly Education, and Welfare, Public Health Service, National Institutes of Health, National Caaoer Institute, January 1066, pp.127-204. (J1) 1CANNEI., W.B, GORDON. T. (Editors). Some characteristics Mated to the inddenee of cardiovascular dbease and de.th: 18 year fellow-up. The FknashwAasa Slludy: An I'Jjvid.uaofoyioa! Inpsdiyation of Cardiow.oeular 1?iseau. U.S. Department of Health. Education, and Welfare, Public Health Service, National Institutes of Hedth, DHEW Publication No. (NIH) 74-699, February 1974. (Jt) EERSHBAUM, A., BT.LI.ET, S., DICESTIaN, F.R, FEINBER.O, LJ. Effect of cigarette smoking and nlootine on serum free fatty adds. Based on a study In the human ouhject and the experimental animal. Circulation R.afsreA 9(3): 681-b3E,1[ay 196L (is) LIFSIC, A.Y. Atheroedero.is in smokers. Bullot{n of tA. World fieoltA Orgaxi.ation 68(bl6): 681-&38,1976. (34) MCGILL, H.C., JR., ROGERS, W.R., WILBUR, R.L, JOHNSON, D.E Cigarette .moking baboon model: Demonstration of feasibility. Avondi+ya of tAe Society for Rper{ewxtal Biology and Medicine 167(4): 672-674 April 19?B. (ds) MCMILLAN, 13.0. Evidenoe for oomponenta other than carbon monoxide and nicotine ae etiologieal factors in aaediovaoealar dleeaae. In: Wynder, EL, Hoffmann, D., Gori, G.B. (Editon). Prooeedinga of the Third World Confer- eaoe on Smoking and Health, New Yosk, June S-ti,19?6. Volume I. Jlodifylnp tA. Risk for tAs $mok.r. U.S. Department of Healtb, Education, and Welfare, Public Health Service, National Institutee of Health, National Canoer Institute, DHEW Publication No. (NIH) 76-1221,1976, pp. 868-867. (36) HOSS, A.T, GOLDSTEIN, S., GREENE, W. Precursors of ventricular arrhytlr mi.s during early pra.hoepital phase of acote myoeardial infuetion. GYmrla- liow 11:44,1971. (37) OLIVER, II.F., YATE$, P.A. Induction of ventricular arrhythmiu by elevation of arterial free fatty acids in enperimental myocirdid infaretion. fardioloyy 66:869-861. 1971r12. (Js) POOLING PROJECT RESEARCH GROUP. Relationship of blood pressure, serum eboleatecol. smoking habit, relative weight and E(:O abnofmalittea to Incidence of major coronary events; Final report of the Pooling Projest Jokraat of Chroaio Diseases 81(4): 2D1-806, Apr111978. (dY) ROGERS, W.R., BASS, R.L, Ilt, JOHNSON, D.E., KRUSKI. A.W„ MCMA- HAN, QA., MONTIEL, ld.id., M01T, G.E., WILBUR, R.L., MC(]ILL H.C., JR. Atheeo.densirrelated responses to elSarette .moktng In the baboon. Circulation 61(6):1188-1195,1980. SR46ezse
Page 110: apt20e00
(40) RUSSELh 1[.A.II., JARVIS, I[, IYER, R., FNYBRABEND, C. Relation of niaotine yield of djuettea to blood niootine concentration in.moken. Bi,4tieA Mad&ast Joarwat RBO(6219): f72-974, 19e0. (41) S6LTZE8, QGt Smoking and ooeonvy heaR disease: What are we to believe? Aaserieax Ifeart, Jorrwa! 100: 27b-280, September 19D0. (.{!) SHAPIRO, S., WEINBLATT, E., FitANIE, Q.W., SAGER, ILV. Incidence of ooronary beut di.eeee in a yopulation ineurod for medical are (HIP). Myoeardial infaretion, angina peetorie, and po.eiWe myocardial infaretion. Aawrk+an Jowwal of AiblielialtA 6Y(9upplement 6):1-101, Jnna 196Y. ({ t) SIGGAARD-ANDESSSN, J., PET61tS1QI, !'.8., HANSEN, T.L, l[Ei.LE![- GAARD, IC Pluma volume snd vascular parmesbWtr during Aypexla and carbon eanozide aspo.nre. Seaodiwavisw Jounut oJ QiwkoW awd laborutory Intutipatiow 22(Supplement 10a): 894a,19A6. (44) SfRONG, J.P, RICHARDS, M.L. Ciaa~ette smoking and stbera.deroas in autopded men. AtJlav.cbrv.ia ?8(d): 461-d76r May/June 197& (45) TACH1[E& L„ FERNANDEZ,, RJ, SACaNL6, I[.A. Hemodpnamia effeeta of smoking cigarettes of high and low niootJne content. (AleA 74(i): t13-ZI6, Sept*mber 1978 (ld) US. DEPARTMENT OF HEALTH, EDUCATION, AND WEiFARE 8isokino and flaaldl• A Repvrt of Glt 9u.yron Qeseral. US. Department of Hea)th, Edueation, and Welfar+, Public Health SeerOffice of the Ari.tant Secretary for Health. Offiae on Smoking and He.lth, DREW Publication No. (PIiB) ?0.6UOQ6,19T9,118e pp. (47) VOGT, T.H, SELVIN, S., HUId.Lr1E, S.B, Comparison of blocbemical and que.tionnaire ertirnstta of tahaooo exposure. Aruentia 3fad+aie. fi(1): 28-85, January 19?9. (48) VOGT, T.ld, SELVIN, S., WIDDOWSON, G, HULLEY, S.B. Expired air carbon monoxide and serum {hioeyanate aa objective mee.ueee of d6.rette exposure. A+snioos Jorrnal of Aiblie XaeMJI 67(Q: 646-619, Juna 1977. (,{0) WALD, N., HOWARD, S. SmoldnM e.rbon maroxide and artrial dLeae.. Annals of OontpaNonal IfYyiene 1s(1):1-14,19?b. (S0) WALD, N, HOWARD, S., SMITH, P.(i., SJELDSffid,1L Association between atLeio.elerotie dieeaees and earbo:7banogiobin )ereb In tobacco unokay. BritieA Dfa{ iosJ Jornw! 1(bQ66): 9a1-766, March 31,1M (51) WALD, N., IDE.F, N„ BOREHAIE, J, BAILlfY, A. Inhaling habits among .aoken of different types of dgarretts. TAorss ffi(12): 9?b-9?E, Deoerober 1980. (b!) WALD, N, ID[.E, M, SMITH, P.G., BAILEY, A. Csrbo3qrhaemoglobin k.ela In tmokers of filter and plain cigarettes. lancet 1(8008): 110-112, January 15, 1977. (at) WALD, NJ. Carbon monoxide Y an setbbgkal agent In aeler(d d(re..a- Some buman evidence. In: WJnder, &L, Hoffmann, D., (iari. O.B. (Edkon), Peooeedinp of the Third World Conference on Smoking and Health. New oYork, Jnae t~, 19'J6. VoMme L XodiJ~yiq tlM Risk JBr tA. 9enokar. U.. w Department of Heaitb, Dduaatioa, and Welfata, Pub11e Health Serriee, National la.tituta of Health, National Qnar Institute, DH3tW Publication No. (NIH) 76-12Z1,197d, pp. SO-86L (54) WALD, NJ. Mortality from lunt ranaar and coronary ha.r6diau In relation to changes In emoldn8 babita. Lsno.t 1(?961):1116-1E8, January 17,19?4. (d6) WHEREAT. A.P: Ie atheradeeoeie a dieotder of inhamitodrondeial respiration? Awnala o/lnterra! N.dieint 73:1ffi-127,1970. Ion 9R14qz(;q
Page 111: apt20e00
CONTENTS The Reeearch Problem Current Research Findings Future Research Approaches Epidemiologic Studies Priorities for Reeearch Recommendations Research Reoommendations Summary References 494SgZSe 133
Page 112: apt20e00
The Research Problem The causal relationship between cigarette smoking and chronic obstructive lung disease (COLD) (chronic bronchitis and chronic obstructive pulmonary emphysema) is well documented (34). However, the possible differences in the effects of higher versus lower "tar" and nicotine cigarette smoke in the pathogenesis of chronic obstructive lung disease are not known. COLD usually progresses slowly; physio- logic and pathologic abnormalities may exist for an extended period of time prior to the development of disabling clinical manifestations. The latter are usually associated with severe lung damage or destruction. It is uncertain which of the many ingredients in cigarette smoke has a role In the production of COLD. Lower "tar" and nicotine cigarettes may have no impact, or indeed an untoward impact, on the develop• ment of COLD. Therefore, it Is urgent that research be carried out to resolve this complex problem. Cigarette-related chronic lung disease may be subdivided into three major components: (1) uncomplicated chronic bronchitis, a disesae of mucous hypersecretion and cough; (2) chronic bronchitis and bronchio- lar inflammation, similar to (1) but with airflow limitation caused by intrinsic airway pathology; and (8) emphysema, a disease associated with anatomical hyperinflation of the distal air spaces and destruction of lung parenchyma. Because cigarette smoking ie associated with all of these conditions, they commonly coezist. The factors causing one or more of these diseases to develop in response to cigarette smoke in some individuals and not in others are unknown. Cough and mucous hypersecretion are common symptoms among cigarette smokers, while evidence of airflow limitation is significantly less common. Recent evidence suggests that the early stage of emphysema is associated with cigarette smoking-related inflammation in airways less than two millimeters in diameter (11). Research on the response to inhaled Irritants is usually focused on one or more of the anatomical components of the lung: the airways, the cellular and biochemical contents of the alveolar spaces, and the contents and structure of the alveolar septa or interstitia. Responses in the airways may consist of alterations in epithelial cell types, mucous gland hyperplasla, hypersecretion of mucus, inflammation, impair- ment of mueociliary function, abnormalities of immunologic factors or other substances, smooth muscle hyperreactivity and hypertrophy, and intrinsic narrowing fibrosis or destruction of small airways. Physiolog- ic responses reflect airflow limitation, early closure of small airways, and nonuniform distribution of inspired air. In the alveolar spaces, free cells (including alveolar maerophages and neutrophils), surfactant (a phospholipid secreted by the alveolar lining cells), enzymes released or secreted by macrophages or neutrophils, and protease Inhibitors and other proteins that reach the alveolar spaces by transudation from the circulation are all under study. The alveolar ....
Page 113: apt20e00
septum or interstit3um, consisting of alveolar lining cells, basement membrane, capillary endothelial cells, other alveolar interstitial eells, and the connective tissue framework composed primarily of collagen, elsstin, and proteoglycans is the focus of much research. Physiologic alterations reflect decreased surface area for gas exchange and alterations in the elastic recoil of the alveolar structuree,. The lung plays an active role in the production and metabolism of various bioactive substances such as angiotensin, proetaglandins, and serotonin. This anatomically, physiologically, and biochemically com- plex organ is exposed to the external environment and its agents, including cigarette smoke and air pollution. Complicating host factors also affect this system: age; sex; inherent reactivity of the airways; genetic factors that predispose to emphysema, such as alphat-antitryp- sin deficiency; childhood infections; and as yet undefined familial factors. The design of experiments to determine the short- or long-term effects of cigarettes on smokers is made difficult because the composition of cigarettes and the population of smokers have been changing over the past 10 to 15 years. Further complicating this problem is the large number of tobacco smoke components with varying solubility and interactive capabilities. There is also a lack of knowledge of the topography of cigarette smoking. Individual differ- ences in the mechanics of smoking such as the volume of puff, holding time in the oral cavity, depth of inhalation, time of retention in the lung, and length of butt significantly influence the composition, distribution, penetration, and retention of cigarette smoke components in the lungs. The topography of smoking may vary depending on the nicotine content. The composition and concentration of the gas phase components that reach the small airways and alveoli may have a significant role in the production of emphysema, while the particulate matter that deposits in the larger airways may be more involved in the development of chronic bronchitis. The target tissues, cells, or ultra- structural components may be different in chronic bronchitis and emphysema. Thus it is extremely important to develop a better understanding of the topography of smoking so that appropriate experiments can be designed to determine dose-response relationehips of pertinent smoke components and the reactions to them in the difffent regions of the lung. The problem is that of assessing the effects of continually changing cigarette products on a continually changing population of smokers. The ultimate concern is for the effects on smokers. For chronic lung disease, this effect can beat be assessed by the combination of epidemiokogic evaluations of popula- tions at risk and laboratory evaluations of the effects of smoke on the -echanism of disease production. se/,Gszse Current Research Findings Recent advances in research have led to a plausible hypothesis for the etiology of pulmonary emphysema: If an imbalance between endogenous elastolytic enzymes and protease inhibitors in the lungs permits active enzymes to exist in the alveoli or alveolar walls, degradation of the alveolar tissue components, primarily elaatin, will occur (t5, 26). The sources of endogenous elastase are polymorphonu- clear leukocytes and alveolar macrophages. The major source of the inhibitor is the serum protein, alpharantitrypsin, which reaches the alveolar space by the process of transudation. This hypothesis is reinforced by experimental data from a variety of sources. Humans with a genetically transmitted deficiency of alpharantitrypsin are prone to develop emphysema (29). The instillation of elastolytic enzymes into the lung, including human neutrophil elastase, will produce experimental emphysema in animals (JS).. Cigarette smoke is implicated in this procesa by mechanisms that may lead to the development of emphysema. Alveolar macrophages from smoke-exposed mice increase in number and secrete significantly greater amounts of elastase than macro- phages from control mice (35). Human alveolar macrophages from cigarette smokers also secrete significantly more elastase than macro- phages from nonsmokers (JS). Alveolar macrophages exposed to cigarette smoke produce a chemotactic substance for polymorphonucle- ar leukocytes (17~ Mild exposure to eigarette smoke also increases the release of elastase from human polymorphonuclear leukocytes (5). Cigarette smoke inhalation decreases the alphai-antitrypsin activity in the rat lung (M, and alveolar lavage from human smokers shows a functional antiprotease deficiency (16). This effect of cigarette smoke on alphai-antitrypsin is related to its oxidant effect (1, 8). The loss of inhibitory activity of alphar-antitrypsin is induced by oxidation of methionine residues at the reactive center of the molecule (23). A chemical oxidant, chloramine-T, administered to dogs, also induces a reduction in the elastase inhibitory capacity of both the serum and alveolar lavage fluid, and the animals develop morphologic changes of mild cmphysema (1J). This animal model simulates the human alphar antitrypsin deficiency state except that the deficiency is functional and not in absolute quantity. Oxidante are also released when polymorpho- nuclear leukocytes are exposed to exogenous elastase (tT). This in vivo and in vitro experimental evidence indicates that cigarette smoke both increases the amount of elastase in the alveolar tissue or air spaces and simultaneously reduces the functional capacity of the primary elastase inhibitor, alpha1-antitrypsin, and links the action of cigarette smoke to the possible production of disease in humans. Although there is general acceptance of the protease-inhibitor imbalance hypothesis, it has yet to be directly related to human emphysema. There are no available studies in which smoke from 137
Page 114: apt20e00
regular and lower "tar" and nicotine cigarettes has been used to determine If there are differences in their effects on elastase or oxidant release or production, or concentrations of cigarette smoke oxidants that could affect the functional capacity of alpharantitryp- sin. Small airway inflammation and bronchiolar inflammation develop much more frequently in smokers than in nonsmokers (11). Findings in the lungs of individuals 40 years of age or older who died suddenly of nonrespiratory causes revealed inflammation, increased numbers of goblet cells, and muscular hypertrophy In small airways. There was also an increase in airways under 400 microns in diameter and in the occurrence of respiratory bronchiolar inflammation in the smokeis. The lungs showing both the largest number of small (under 400 microns) airways and the moet airway pathology had the most centrilobular emphysema, the predominant type found in cigarette smokers. The respiratory bronchlolar inflammstion was characterized by infiltration with macrophages that extended into adjacent alveolar walls. Previous studies of resected lung from smokers showed that the severity of similar small airway pathology in excised human lungs correlated with impsirment in ventilatory funetion (10). The small airway disease and severity of emphysema also correlated with changes in small muscular pulmonary arteries that could be important in the development of pulmonary hypertension (19). These studiea suggest that cigarette smoke produces small airway pathology, which is a factor In ventilatory function Impairment The respiratory bronchiolar inflammation may initiate an enzyme-inhibitor imbalance in the centrilobular regions. The release of elastase from alveolar macrophagea and from neutrophils brought to the alveoli by increased chemotaxis and the impairment of alphai-antitrypein function could be stimulated by cigarette smoke in the alveolar spaces. This leads to destruction of alveolar wall elastin and then to the morphologic and physiologic changes observed in emphysema. The oxides of nitrogen occur at relatively high levels in cigarette smoke and at lower levels as an ambient air pollutant. Exposure of dogs to NOi and NO for 68 months resulted in pulmonary function changes characteristic of emphysema (18) that continued to progress after cessation of exposure. Long-term exposure to oxides of nitrogen results in airway and alveolar epithelial changes and parenchymal damage that suggest an emphysemaarlike disease (14 Evidence suggests that the damage is induced by an oxidant-type mechanism. In addition, the most severely affected tissues are the terminal bron- chioles, alveolaf ducts, and adjacent alveoli, .vhich are infiltrated with inflammatory'4xlh The latter are primarily mscrophsges with other mononuclear cells and occasional granulocytes. Interruption and thickening of elastic fibers in alveolar w+alls were observed. Theae lesions are similar to those induced by cigarette smoke and suggest that the oxides of nitrogen may be one of the agents responsible for the initiation of the early lesions of human emphysema. As an outgrowth of the elastase-inhibitor imbalance hypothesis for the etiology of emphysema, new potential markers or indicators of disease arc being investigated. Since lung elastin appears to be the target substance for degradation, several laboratories are seeking a method to identify products of elastin breakdown that would serve as markers for the development of emphysema. In one studyi peptide breakdown produCte of lung elsatin were identified in the serum ef dogs In which experimental emphywma wr iadylpd 1qr the admini& tratlon of olastase (28). Other inveetigatore are measuring the urinary excretion of deamo- sine, the Qoss-linlring amino acid of elastin that appears as a breakdown product If it can be demonstrated that elastin degradation products are significantly elevated in the blood or urine of smokers who have early emphysema, undetectable by other means, further development and refinement of such tests may provide a sensitive biochemical marker or screening test for the early detection of emphysema. Such a measurement would simplify cross-sectional and other epidemiologic studies In which the results in subjects who smoke regular cigarettes could be compared with those of subjects who smoke lower "tar" and nicotine cigarettes. Studies of acute human responses to the different types of ciga- rettea, which may be important in the pathogenesis of chronic lung disease, are beginning to appear. The type of cigarette and the amount of smoke inhaled Into the lungs, measured by changes In blood nicotine level or carboxyhemoglobin level, are not related to the occurrence of acute airway responses to smoke inhalation (21). The authors found that individual susceptibility is a factor, but even more important is the smoking pattern. Holding the smoke in the mouth prior to inhalation into the lungs reduced the response, whereas direct inhalation from the cigarette into the lungs caused an increased number of smokers to develop spirometrie changes indicative of bronchoconstriction. This was independent of "tar" yield and rein- forces the importance of the cigarette smoking pattern in the dose- reaponse relationship. The study showed that the habitual cigarette smoker avoids the direct irritant effect of cigarette smoke by temporarily storing the smoke in the mouth before inhaling it into the lungs and also demonstrated that the smoke inhalation pattern is important in determining the relevant concentration of the constitu- ents of smoke that reach the lungs. There are few epidemiologic studies, either cross-sectional or longitudinal, that deal with differences relating to the "tar" and nicotine yield of cigarettes smoked. In a survey of over 18,000 civil servants (x0), the "tar" yield and the number of cigarettes smoked daily were correlated to respiratory symptoms and epirometry. Sputum 129 139
Page 115: apt20e00
production and air flow obstruction increased as cigarette consumption increased. "Tar" yield influenced sputum production, but not the degree of air flow obstruction. When subjects smoking lower "tar" cigarettes smoked over 20 per day, their sputum production was the same as that of the higher "tar" cigarette smokers. In this study of asymptomatic men, the air flow obstruction was related to the daily cigarette consumption. Higher "tar" cigarette smokers did not have a greater air flow obstruction than those using lower "tar" cigarettes. If there was a compensating increase In the number of cigarettes smoked by the smokers of lower "tar" and nicotine cigarettes, the advantage of reduced mucous hypersecretion was lost. Ex-emokers had better lung function than current smokers with comparable total cigarette con- sumption. The authors conclude that mucous hypersecretion depends on the "tar" fraction of the cigarette's smoke and that the develop- ment of air flow obstruction depends on the number of cigarettes smoked. They reason that the gas phase of the smoke, particularly the volatile compounds, was responsible for damage leading to air flow obstruction. They hypothesize that "tar" droplets and soluble gases, such as sulfur dioxide and hydrogen cyanide, are more likely to be deposited or absorbed in the larger bronchi where mucus is produced. The smaller bronchi, which are the site of airway obstruction, and the alveoli are exposed to a lower concentration of "tar," but to a full concentration of insoluble gases, such as the nitrogen oxides and ozone. Higenbottam and co-workers (x0) did not differentiate between emphysema and chronic bronchitis as a cause of airway obstruction. The authors conclude that smokers of lower "tar" cigarettes who compensate by smoking more cigarettes or inhaling more deeply may increase the risk of obstructive airway disease. They suggest that more information is needed about the nature and concentrations of irritants In the gaseous phase of smoke and their relation to concentrations of "tar•• and respiratory damage. Another British study (15) indicates that filter cigarette smokers report less cough. The difference between the groups of smokers was relatively small, however, and the filter cigarettes that were smoked are probably dissimilar to those currently smoked in this country. Dean et al. (12) reported the results of two retrospective studies, separated by an interval of 10 years but carried out in the same area, to determine whether the increasing use of filter cigarettes produced leas risk ~X dying of four diseases, including chronic bronchitis. In the seco study, relatives of those who had died were interviewed to obtain the information about the smoking habits of the deceased individuals. The cause of death was determined from death oeetifi- cates. A living population was selected as the control sample. The investigators found that mortality from chronic bronchitis was related to age, to the number of cigarettes smoked, and to the level of '%alation. The estimated risk of mortality from chronic bronchitis of the population who smoked filter cigarettes since 1954 was about half that of the continuing regular cigarette smokers. Many features of this study could cause bias or misinterpretation: information was collected from relatives of deceased individuals; the information on the living and the deceased populations related to different points in time; and changes in air pollution levels and in the population probably occurred during the period of the study. From the epidemiologic standpoint, firm conclusions cannot be drawn from this study. In an ongoing study of a healthy population, the rates of decline of pulmonary function in smokers and nonsmokers show only a very small difference (6). However, 8 to 12 percent of smokers have a distinctly more rapid decline in the FEV,. These are primarily male smokers and may represent the group who will ultimately develop symptomatic obstructive lung disease. In the entire population, the tests of "emall airway function," such as closing capacity, show no lifference in the rate of change between smokers and nonsmokers. These tests tend to be abnormal in those individuals who develop an abnormal FEVi, but at the same time, a large number of subjects with abnormal tests of small airway function will not develop a rapidly decreasing F'EVi. Data about differences in the type of cigarettes smoked were not obtained, but the extremely small difference between healthy smokers and nonsmokers, except for the small group of rapid decliners, suggests that atudiea of large populations with thie objective may not be revealing. Another longitudinal study suggests that a study of approximately 8 years is necessary to identify those asymptomatic smokers who will show a significantly accelerated rate of lung function deterioration (15). This study also finds that, in spite of frequent smoking-induced cough and expectoration, only a relatively small percentage of smokers show a greater than average decline in respiratory function. The authors report that when a group of asymptomatic middle-aged smokers who had subnormal FEVi levels and rapid decline stopped smoking, the rate of deterioration reverted to that of nonsmokers although there was no significant improvement• in the initially determined abnormal lung function. This study did not distinguish between the effects of lower "tar" and nicotine and regular cigarettes. The traditional tests of airflow limitation such as FEVIare thought to reflect changes relatively late in the course of disease. Some investigators have demonstrated that flow measurements taken from the near terminal part of the forced vital capacity tracing are more sensitive, but these are not widely used to date (J0). Newer tests of small airway function such as slope of phaae III, closing capacity, and volume of isoflow with helium and oxygen have not been established for their specificity in indicating the development of significant chronic lung disease (4). .y, ts,GSBZSV
Page 116: apt20e00
A study carried out in two successive decades, in which successively sutopsied airways from lungs of smokers were studied for bronchial epithelial changes, demonstrated a decrease in changes thought to be related to carcinogenesis (2). This favorable change was thought to be related to the increasing use of lower "tar" and nicotine cigarettes. Unfortunately, this study did not examine the lungs for evidence of chronic obstructive lung disease. Future Research /lpproschea Animal models in which emphysema has been induced by elastolytic enzymes have been reported by a number of authors (24), but for reasons that may reflect a combination of factors, such as the shorter life span of animals, the method of smoke exposure, and species resistance, there are no published studies that acceptably show in an animal model that the development of emphysema is induced by cigarette smoking. Thus, a successful animal model has not been developed in which the relationship of different types of cigarettes to the development of emphysema can be studied. One study in which dogs received smoke directly through chronic ttacheotomies reported the development of emphysema (3). The lesions were not conclusive and the results have not been confirmed by others. Therefore, to elucidate more clearly the differences between regular and lower "tar" and nicotine cigarette smoke exposure, it will be necessary to study other aspects of lung function, either biochemical or physiological, that may be altered by the cigarette smoke and that are projected to be important pathogenetic mechanisms in humans. As suggested in the preceding paragraphs, much new Information will be needed before conclusions can be drawn about the effect of lower "tar" and nicotine cigarettes on the development of COLD. Acute and subacute responses could be measured by physiologic studies, although such responses may not be relevant to the develop- ment of chronic, irreversible lung diseaae. The quantity and composi- tion of mucus secreted in the airways in response to different types of cigarettes may be studied in animals or humans. The histology of the bronchial muma may be evaluated In human material from lobes or lungs resected for other reasons, from biopsy specimens, or from poet mortem findings in which changes related to chronic bronchitis or emphysema are specifically quantitated. In autopsy or resected lungs from ynokers of regular and of lower "tar" and nicotine cigarettes, factors in the small airways such as lumen size, number of airways, cell types, goblet cells, muscle hypertrophy, and Inflammation may be evaluated. Enzyme inhibitors produced in the tracheobronchial tree could also be evaluated, as could the secretion of immune globulins. Effects of cigarette smoke on the mueociliary function of the bronchial mucosa is another potential measurement. The response of the alveolar region of the lung could be determined by biochemical, morphologic, and physiological techniques. The cellular content of the air spaces, the functional status of alphai-antitrypsin, the presence of chemotactic factors, oxidant production by neutrophils or macrophages, elastase production and inhibition, and degradation products of lung elastin may be measured in response to amoke expoeure. Human studies would require bronchioaiveolar lavage to obtain these data, although the invasive nature of this technique may preclude its use in large populations lacking other indications. Produe- tion and turnover rates of lung elastin and collagen, the numbers and types of interstitial cells, and the presence of free or bound elastase may be evaluated in the interstitial tissue. Macrophage and neutrophil responses to the whole smoke and selected fractions can be investi- gated. These Include phagocytosis and elaboration of elastasea, chemo- tactic factors, and oxidanta. Surfactant production and alterations might be evaluated. Many of these factors are deemed important in the determination of the protease-antiprotease balance in the lungs. The development of some measurements into standard biologic assays by which the various types of cigarette smoke may be evaluated would be a valuable advance. This research would not only aid in the develop- ment of techniques to assess the response to various types of smoke, but also would add Important information to our knowledge of the pathogenesis of disabling chronic obstructive lung disease in humans. Physiologic measurements of lung volumes, elastic recoil, and diffusing capacity of the lungs may be studied in humans and animals, although in published studies to date, the observed effect is minimal or negative. The question of which fraction of cigarette smoke contains the agent(s) that alter the lung defense mechanisms to Induce chronic lung disease must be resolved. It is not feasible to evaluate each of the several thousand substances in cigarette smoke, but the major fractions that contain the offending agents and the distribution and penetration of these fractions should be studied. Gas phase constitu- ents should be evaluated by category, and the method of exposure must be related to the actual smoking habits of humans. Cigarette amoking machines that produce 35 ml puffs and the techniques by which animals inhale cigarette smoke in research models may not be representative of the human situation. Research techniques must be devised by Individuals who are knowledgeable in the field of aerosol distribution and deposition, in the chemistry of cigarette smoke, and in the biophysics of the distribution of smoke in the airways. Patterns of inhalation for the average smoker must be studied in more detail. If individuala who switch from regular to lower "tar" and nicotine cigarettes undergo a change In smoking pattern, such aa deeper or more frequent puffs, this must be taken into consideration because the contents of the smoke, the size of the particulate matter, and the distribution of smoke in the lung may change with the variations in 142 Z6&Gez6e 143
Page 117: apt20e00
inhalation patterns. Such Information must be applied to dosimetry in short-term iw vivo and in vitro experiments as well as In epidemiologic or population studies, Epldemloloplc Studies Studies of populationss of smokers with well-defined smoking histories are a major tool in determining whether a real difference exists between smokers of regular cigarettes and smokers of lower "tar" and nicotine cigarettes. If, In well-planned epidemiologic studies, there is no difference found In the human occurrence or severity of chronic obstructive lung disease between smokers of different types of cigarettes, more basic research involving humans, animals, or in vitro syst4ma to determine differences between the effects of smoke products would be lees useful. The design of epidemiologic research for this purpose raises a number of issues. Determining the true dose of smoke In cross- sectional, retroepeetive, or proepective population studies is a difficult problem. Most studies rely on patient histories to obtain dosage information. The accuracy of recall, the design of the queationnaire, and the skills of the Interviewer all Influence the accuracy of smoking history. The cigarette itself presents a problem in studying the significance of the lower "tar" and nicotine brands because changes in the content and design of cigarettes have continued over the past 10 to 15 years. This "moving target" makes evaluation of the dose-response in populations diffiault, especially since a large proportion of current smokers began their smoking careers with regular cigarettes and switched after varying periods of time. The comparison of mortality rates is a commonly used epidemiologic tool. There are well-known problema In obtaining accurate mortality data on chronic lung disease, particularly in retrospective studies In which death certificates ob- tained 10 or more years ago are utilized. Morbidity, including hospital days and days lost from work because of respiratory illnessea, might also provide useful Information but is limited beeause of the selective nature of populations (sl). Population studies that investigate the rate of decline of lung function proportionate to the number of cigarettes smoked have shown variable results. Most of the available data apply to smoking without re to cigarette yield. Environmental factors such as air pollution mchange simultaneously, and corrections must be made for these factors. The mean differences between the rate of decline of the FEVi in populations of nondbeased smokers and nonsmokers are very small. A difference between the smokers of higher and of lower "tar" and nicotine cigarettes may be Impossible to detect. However, the subgroup ,f the smoking population that shows a nare rapid decline should receive special attention, since it is probable that this group of smokers, for reasons yet unknown, is most likely to develop significant diseaae. Random variations from year to year in the measured FEVi in individual patients require an extended period of time before valid data can be obtained (7). Biochemical tests that may serve as new markers for chronic lung disease are in the early research stage and should be explored as soon as possible. Under the best of circumstances they could replace the physiologic tests that measure air flow limitation as the earliest practical mechanism to detect lung damage. These measurements should be given high priority to determine their ultimate usefulness. In the meantime, it would be reasonable to collect and store for future use blood and/or urine samples from the screened populations. The lack of specific, detailed information about the human dose- response to cigarette smoke and the mechanism that eausea individual susceptibility to more rapid deterioration of lung function results in difficulty in predicting sample size and the length of tim needed for a population study to determine differences between the smokera of higher and of lower "tar" and nicotine cigarettes. Current data suggest that the time and effort required to mount new epidemiologic studies may delay the acquisition of needed information. However, there are several ongoing studies in which epidemiologic data, both cross- sectional and longitudinal, are being collected with relevance to chronic lung disease. It is appropriate to consider the utilization of these current studies where populations xre already identified. Data on the history of brands smoked could be added. Available information about the "tar," nicotine, and carbon monoxide yield of the various brands offers one measure of dosage. A recently developed radioimmu- noassay for plasma nicotine levels may also be a helpful tool (9), although smoking patterns may be as important as the number of cigarettes smoked in determining the actual dosage. Additional questionnaire material involving brand data and history of morbidity related to respiratory symptoms could be superimposed on ongoing studies. The accuracy of historical data on cigarette smoking must be verified to the best possible extent. If new indicators serving as a screening ttst, such as blood or urine analysis for lung elastin degradation producte, become available, they should be incorporated into the studies. Depending on their diagnostic reliability, it might be possible to study a considerably smaller population than that required for studies of morbidity, mortality, and lung function deterioration. All studies yet to be initiated should include questions on brand history. This would require the revisions In the standard queationnaires of the American Thoracic Society and Medical Research Council of Britain. An ideal longitudinal study will require the enrollment of younger subjects who begin their smoking careers with regular or with'lower "tar" and nicotine cigarettes and continue to emoke them. Changes in a e~9zs1R ~
Page 118: apt20e00
other constituents such as additives will have to be considered as will data obtained on patterns of smoking. If population studies enroll subjects who have switched to brands with varying smoke yields one or more times, the probability of detecting differences in F'EVi or other parameters would be more difficult. Special efforts should focus on observations made of saymptomatic and symptomatic individuals with lung function abnormalities. It will probably be relatively easier to detect differences in the rate of pulmonary function deterioration between the regular and the lower "tar" and nicotine cigarette smokers in this group. Priorities for Reseerch Recommendadons The primary public health concern is the effect of the lower "tar" and nicotine cigarette on the individualb health. The second concern is the mechanism of the effeet„ and the third is the specific agent involved in stimulating the mechanism. The first need is to establish whether there is a measurable difference between smokers of regular and of lower "tar" and nicotine cigarettes. The epidemiologic approach to the problem may yield the greatest amount of valuable information in the most rapid manner, but population studies may not show differences in the development of chronic lung disease, since It Is not known whether the etiologie component of smoke is altered In the currently marketed lower "tar" and nicotine cigarettes. Therafore, parallel research is necessary to a better understanding of the pathogeneais of COLD and identification of the responsible smoke component. A combination of epidemiologic studies designed to answer broad questions and human. animal, and in vitro studies will be required to define the entire problem. The epidemiologic studies will determine whether or not the lower "tar" and nicotine cigarettes have a health benefit or whether a potential beneflt Is negated either by changes In smoking patterns or by ignoring the agents responsible for inducing COLD. Topographic and dose•responae information is rs- quired for the human studies. The final and perhaps niaet beneficial aspect of the research would be the elimination of the offending agents from cigarettes. Investigation of the distal air spaces or lung parenchyma where the destructive component occurs in emphysema has received recent emphasis with new approaches and measurements. Therefore, inveati- gation If this area may offer a greater possibility for significant new data. Tb date, studies of air flow characteristics, airway raactivity, and morphology have provided data concerning the cltronology of the disease but have not pointed to the mechanism by which lung damage in emphysema is produced. Much of the benefit of basic research hinges on a better predictability of the topography of smoking and dose-response relationships. Information learned in the basic studies can be translated into or used in epidemiologic studies, while the data obtained from epidemiologic studies can offer directions for the finer tuning of basic research. All of this would provide more information about the pathogenesis of chronic obstructive lung diseases and their potential alteration by lower "tar" and nicotine cigarettes. The problem of passive exposure to cigarette smoke of different types of cigarettes also needs consideration. However, determination of the impact of lower "tar" and nicotine cigarette smoke on active smoke inhalation presents difficulties significant enough to render to low priority the passive smoking investigation at this time. Future dose-response data, especially determination of thresholds, would offer a lead into the area of passive smoking. Research Recommendations 1. High priority should be given to a study of the distribution, partitioning, and penetration of regular and lower "tar" and nicotine smoke into the lung, including quantitation of and adjustment for any changes in the pattern of smoking by smokers of lower "tar" and nicotine cigarettes. Individuals in the apecial- ized fields of aerosol physics, pharmacology, and toxicology should be involved in answering this question. 2 Parallel priority should be given to epidemiologic studies, prefera- bly by adding to ongoing longitudinal and cross-sectional studies the data necessary to determine brand-related history. Higher and lower "tar" and nicotine cigarette smokers should be compared for differences in symptoms, morbidity, physiologic measurements, and mortality relating to COLD. Special attention should be given to people with identified disease or whose pulmonary function is deteriorating at an accelerated rate. New studies should be started if it is not possible to supplement the ongoing studies. Several ongoing epidemiological studies have been identified: (1) the Tucson Epidemiologic Study of Obstructive Lung Disease at the University of Arizona (Dr. Benjamin Burrows); (2) the Emphysema Screening Center Study of smokers and nonsmokers at the University of Oregon at Portland (Dr. Sonia Buist); (3) the Johns Hopkins University study of. risk factors in chronic lung disease in Baltimore (Dr. Harold Menkes and colleagues); (4) the study of smokers in the Kaiser Permanente Health Care Plan (Dr. Diane Petitti); and (5) the Nurses Health Study at Harvard 'University (Dr. Frank Speizer). Statistical data to be collected by the National Center for Health Statistics, such as the Health and Nutrition Examination Survey, should be oriented to the collection of a detailed history of smoking, and followup studies should include apirometry. Data from the National Health Interview Survey and the National Death Index may also be useful. 146 147 V~9~~
Page 119: apt20e00
3. The rapid clinical evaluation of the recently developed biochemical tests that measure products of lung elastin degradation and that can be detected in the plasma or urine should be carried out. If these prove both specific and sensitive, the time involved in carrying out the human epidemiologic research could be shortened. 4. Human, animal, and in vitro research that studies the mechanisms responsible for COLD and their possible alteration by lower "tar" and nicotine smoke should receive emphasis. Although the elas-w tase-:inhibitor imbalance hypothesis is well supported by experi- mental studies, confirmation of this mechanism is required for human disease. Verified animal models of emphysema induced by cigarette smoke exposure are not available at this time, but if such a model can be identified, it should be exploited. Investigation should involve airway factors, parenchymal alterations, and alterations in defense mechanisms that can be studied in short- term or subacute experiments. Biochemical, histological, and ultrastructural studies are required for oorrelation with exposure to smoke products or components from regular or lower "tar" and nicotine cigarettes. Dosimetry or exposure levels for these studies can be drawn from topographic and epidemiologie studies. Ra search on both animal and human tissue, cells, and lung lavage fluid Is required. Much progress has been made in recent years in the study of the mechanisms of lung damage relating to cigarette smoke. However, chronic bronchitis and emphysema are potentially devastating illneam that have no curative treatment. E(iminatbn of cigarette smoking would significantly reduce their public health importanoe. It is Imperative that we define as soon as possible any differences In the effect of currently manufactured lower "tar" and nicotine cigarettes In the pathogenesis of these diseases. Summary 1. The relationship between cigarette smoking and chronic obetrue- tive lung disease (COLD) is well documented. The constituents of cigarette smoke that are responsible are currently not known. Whether a difference in risk of COLD has occurred with lower "tar" and nicotine cigarettes as compared with higher "tar" and n}ootine dgarettes is currently unknown. 2. (.i"'garette smoking is associated with the release by alveolar macrophages of an Increased amount of the elastolytic enzymes, which degrade alveolar tissue, and with reduced activity of alpha,- antitrypsin, the primary elastase inhibitor. This mechanism has not yet been directly related to the development of human emphysema. To date there are no published studies that compare 56~sezsg the effects of higher.versua lower "tar" and nicotine cigarettes on elastolytic enzymes and inhibitor activity. 3. Cigarette smoke also contains relatively high levels of oxides of nitrogen. The nitrogen oxides produce lung damage in animals that is similar to that induced in humans by cigarette smoke. The oxides of nitrogen may be responsible for the early lesions of human emphysema. 4. An individual's smoking pattern is one of the most important determinants of the relative concentration of smoke constituents that reach the lungs and of the subsequent response of the airways to smoke inhalation. Holding smoke in the mouth before inhaling it into the lungs produces less response of the airways than direct inhalation, which causes spirometric changes indicative of bron- choconstriction. This effect is independent of the "tar" content of the cigarette. 5. Pulmonary mucous hypersecretion and symptoms of cough and phlegm appear to be affected by the "tar" content of cigarette smoke. The development of airway obstruction is closely related to the number of cigarettes smoked. Smokers of lower "tar" and nicotine cigarettes who compensate by smoking more or inhaling more deeply might thereby increase their risk of developing obstructive airway disease. 6. Population studies that have examined the rate of decline of lung function in relation to the number of cigarettes smoked have shown variable results, and most of the available data do not relate lung function to cigarette yield. Overall, the mean differ- ence between the rate of decline of FEVt in asymptomatic smokers and nonsmokers is very small, but there is a subgroup of the smoking population that shows more rapid decline and is appar- ently more likely to develop significant pulmonary disease. „4
Page 120: apt20e00
References (1) ABRAMS, W.R, ELIRAZ, A., KIMBXL, P„ WEINBAUIt, Q Tbs effeet of the oxidizing agents ehloramine-T and eSearett+ saake on dog s.eum piot.inaw inhibitm(s). likp.rieysatal Iwmg R.wah 1('): Z11-PZ3, August 19e0 (t) AUERBACH, 0, HAHMOND, B.C., GARFtNIIEL, L Changes In bronchial epithelk+m in rilstioa to elgatetts rorokiag, 196b-196D va BP70-39T1. N.ro Is`nylani JorrwoL ef N.dteine S00(a): E614E6„ Irebruaey t?,1l79. (3) AUEIt$ACH, 0., HAMffiOND, L.C., IIR1tAN, D, GARFINKEt, 4, STOUT, A.P. Histologic ehaeg.. In beonehiel tubes of d6aratta-.moldng dop. Canar 20: 2006-2006,1f6T. (4) BBCKLAM Ii.R, PELt1tUTT, 8. Evaluation of te.ta of lung function for "screening" for early detection of ebroeie obstructive lung dbeeea In: MaeJdom, PJ., Permntt, 8. (]9diton). T7M IwW {s 1lsweitioR B.lwan IfeoltA a"d Diase+. N.w York, l[ared Dekker, ll7P, pp. iUAIB6. (5) BLUL, 1(.-L, JANOFF, A. Poeeihle nwehaniems of emphp.enn In djacette smokers. Retaee of etastw ftom hnm.n po[Inoepharove.r feukoeJtes by eig.e4tb.moice eondaoeate In vitra. Awwries+.ll.eir+r.JRrrrsb.lr Die.asr 11?(t): s17-aE6, February 197d.. (6) BUIST, A.B. Tbe relative eontdbatton of natwe sad nartyre ls clnaeia obstructive pnlmonarl diaesa Wistern Jowwel .f Jlfadief„. lt1M: 114-121. Au6n.t 187l. (7) BUItROWB, B. Couru and peagnosM of patients with chronio nirwap ob.t:ua tion. (71ut ?7(9uppl.ment 2): 250-?81, February i980. (8) CARP, IL, JANOFF, A. Po.eible mechani.nr of emphyseau In smoken. In vitm • suppeee.ion of seeum dseta..inbiAitary oipseity by fresh eiraeette.moko and (ts peevention by entiosidants.. A+nariesn R.v" of R..pirstay Di..aw 118(s): 617-d$1, 8eptember 1976. (9) CASTRO, A., YONJI, N, ALI. H., YI, M.. B4WHAN, E.R„ MCKENNIS, A., JR. Nicotine antibodis: Comparison of Bg.ud eped8dtios of anttbodies produced MainR two niootina aoq(ugatx Bkrop.au Jor.not ojEtocAerR{stry 104(2): aSL43i0,1990. (10) C09IO, )i., OHEZ?A, H, HOCG, J.C., CORBIN, R., LOVffi.AND, 1A., DO& MAN, J, MACELEN, P.T. TLe relations betweon structural ebanges In small airways and pnlmonser=tuaetIos tests. Nw Skland Jotnral of Medicine 2S8(28):1277-1?91, June a,1Y7'8. (11) C08IO, IL0« HAL!',1LA., NIEWOEHNSR, D.6.1[aepbologio aad noephomet. rln effects of prolonged cigarette emoking on the smaB alrway.. A+a.riasw 14..i.v eJRespi.ee.ry Dieasr 1t2(Z): 2e6-C1, August 1l90. (1!) DEAN, 0, Ll& P.N, TODD, (i.F., WICKEN, AJ. Repo.t on a Seeond RshoOpedise YortaltiLy Stuh in NoriJb9ast Daptand. Fbrt L hLofma Refaki to Xorial{tY Jbm La+y Cswe.r, d+.eollitis, Ifeert Di..a.n and StroA» ie C1eu.[and Cwetr, riN I'hrt(ewfer BnWAseie eR the Jir/slfee R{sb Aaaoeiated ritA Smoking l41tK and Pfain GY6srseta, Londoo, Tobacco Research Council Research Paper 1l, Part I,1477. 66 pp.. (11) 1T.IBAZ, A., ABR/t![S, W.R, MERANZE, D.R, RhIBIIti P., WL[NSAUM, (I. Do.elopeeest of as animal eaodei of fmmdonal alph., antipeotesss defieienq. +~ CMse 77(~ppleawnt 2): 87a, February lUB0. (14) M>6wVAN9, lU, FItL61[AN, G l[oepboloFkal and pathologkal eftecl. of NO~on the rat letq. In: Lee, $D. (Bdtor} N+f.oyrs Osid.e sni T%oir jtraats on B.altJl. Ann ArLor, Michigan, Ann Arbar 8eienee,198Q pp. 448-666. (ta) FLETCHER, C, PSTO, B, TINKER, C., SPEIZER, F,E. TA. Natural H{dory of CA.osie B++o+rAitie and Skp4muwm. A* B(gAI-Y.ar Slu1y of Der(r CAronie Ob.trretiee Lwny Diewsm in Working Men in tadon. Oxford, Oxfocd Univeetlty Pier,,164d, 2TlPP. (1e) CADEK, J.E., FELLS, C.A., CRYSTAL, B.G. Cig.eette saroking Induces functional antiprotesee deficiency in the lower respiratory tLaet of humane, Ssi.ncti 206(4d24):181b-1816, Deoembet 1979. (17) GADEK, J.E., IIUNNINGIIAKE, G., ZIMMERMAN, R, CRY$TAL, R.G. Neebaniams controlling rekase of neutrophil ehemot.ede factor by alveo)ar macrophages. American R.rino of Rspiratory Diawes 117: 66, Part II,1978. (Abstract) (18) GILLFSPIE, J.R., BEIiRY, J.B., WHITE, LI., LINDSAY, P. Effeats on pulmonary function of low level nitrogen dioxide e:pn.ure. In: Lee, &D. (FAitor). Nilropsw Ostd.s aad Their Effecfs on Ifea(fA. Ann Arbor,MSohiaan, Ann Arbor Seknoe,1880, pp. 231-212. (1p) HALF{ H.A., NIEWOEHNER, D.E., CO310, M.Q. Morphologic changes In the muscular pulmonary arteries: Relationehip to cigarette smokina, airxay disease, and empbyeama. Awwerioax Revier of Rspi+vtory Dia.oes 127{Z): Y7b- 278, AuQud 1950. (td) HIOSNBOTTAIt, T., CLARK, T.7.H., SHIPLEY, IA<J., ROSE, G. Lung function and spmptome of cigarette smoken related to tar yield and number of dgarett.s smoked. Lsneee 1(n166): 409-11?, February 2a,1980. (21) HIGIIdBOTTA]l, T, FEY'ERABFIIdD, C., CLARH, TJ.H. Cigarette smoke inhalatkn and the seute airway response. TUras E6(4): ?A6-264, April 1980. (t.E) JANOFF, A., CARP, H., LEE, D.IL, DREW. ItT. Cigarette emoke Inhalation deereaees alphawntitrypsin activity In rnt lung. Soi.eoe 206({f?A): 1813-181d, December 14.1879. (t.t) JOHNSON, D., TRAVIS, J. The oxidative iaactivation of human alphai proteins.e inhibitor. Further evidenoe for methionine at the reactive center. JounaW oJsioioyienl <.7ke+Ki.try 2i1(1o): dU1rL4026, May ffi, ]976. (t4) IIARLIN3KY, J.B., SNIDPl41, O.L Anlnul models of emphysema. Amtrioen R.ri.v oJRsipimdvey Disaar 117(6):1109-11a8„ June 197& (td) KIMBEI4 P. Protsoiytio lung damage. CAat 77(Snpplenxnt 2): 876-Zr6, Februaryr 1980. (!a) KIMBEh P., KUEPPE89, F. The biochenilca) badr of etnphysesia: The oxidant effect of elgaeette smoket Axwal" of Ietnool M.dietn. 92(h: 664, April 19g0. (!7) KTCIOAWA. S., TAKAKU, F., SAXAMOTO, S. Evidence that ptoteasee an inv+olved In sapero:ide production by human polymorphonucleer leukoeyts and monocyta. Joknmt of Cl{wioef Involiyation 66(1): 74-81, January 1980. (!d) KUCICH, U., R09ENBIAOM, J., CHRISTNEIt. P., KIl[BIPJ., P., WEIN- BAU1d,0. Development of a bem.gglutlnaLion ...Y to measure elastin fragments and antielastin antibodies. Clwu! 77(8upplement 2): 278-278, February 1980. (!p) LAUREW., CrB, ERIKSSON, S. The eleetrophor.tic alphat=lobulin pattern of serum In alpharantitrypdn deficiency. Soandiwavian Jow+ral of G1iniwi and Laboratory lssulipation 16(1):132,1968. (do) MORRIS, J.F., LO$Kl, A, BItEffiE, J.D. Normal values and evaluation of foroed-end espintary flow. Anurkan Rmiiar of Rsspinatory Diseo.r 111(e): 766-74 June 1974. (dt) PATRICK, C.H. In: Hemphill, D.D. (Lrditor). Ttivau 9Wb.tswou (n b7laii+on„wn- taI ff.aldl-.LIY. Columbia, ldiroari, Unl.uetty of Miroud,1880. (1t) RODRIOULrZ, RJ., WHITF, R.R., SENIOR, RAt., LEVINE, EA. Elestsee release from human alveolar maceophaces: Compariwn between ueohen and noesmokee.. Ssfe")a 19B(4814): a13-s14, Oatobet 21,1877. (JJ) $ENIOB, RH., TDQNEIf, H., KUHN, C, OB7.ABON, K., BTARCIiER, B.C., PIERCE, J.A. The Induction of pulmonary empblsems with human Ieukoeyte slastaee. Am.riean 12eview of I;Repirotorlr Ilisraw 116: J69-176,19T/. 150 9G1sGe?;se 151
Page 121: apt20e00
(J4) U.S. DEPARTMBNY OF FIEAL_ TH, EDUCATION, AND WLi.FARE. 9nwkt+p and Iieo/tk A R.prt ef the Surj.ow (J." srol. U.S. Department of Health, F.due.tba, aad Ndfan, Pubik Health Smviee, Offke of the Arbt.at 3eeretary for Hedth, Oftice on Smoking .nd He.ltb, DHIlW Puhliation No. (PH3)?f.b0066,1M,11abpp. (16) WHtfE, R. WHM J., JANOFF, A. Effects of drarotta smoke on dut..e seetkn by e.utiao m.erepAOV., Jerrwol of Le6nsterlr and Qinied Af.diedes 99S): 4s9-499, September 197f. 4st,(;ezse 152
Page 122: apt20e00
CONTENTS Introduction Evidence on the Effects of Smoking in Pregnancy Health Effects of Lower "Tar" and Nicotine Cigarettes Research Approachea Recommendations for Human Studies Recommendations for Behavioral Studies Recommendations for Clinical Studies General Studies Placental Studies Autopsy Studies Breast-Feeding Studies Recommendations for Physiologio-Pharmacwlogic Studies Tobacco Smoke Nicotine Carbon Monoxide Polycyclie Aromatic Hydrocarbons Other Substances Priorities for Research Recommendations Summary References 155
Page 123: apt20e00
u,uoducflon Since Simpson (SS) first reported that the newborn infants of women who smoked during gestation were of significantly lower weight than the infants of comparable nonsmokers, the adverse effects of maternal smoking on pregnancy have been increasingly appreciated. In 1979 the publication Smoking and HealtJe: A Report of Eke Surgeon Gerum1q6) documented the considerable body of epidemiological, clinical, And laboratory evidence concerning the role of cigarette smoking in complications for the pregnant woman, fetus, newborn infant, and child. Although many of the effects on a pregnant woman and her child of smoking "regular" cigarettes manufactured during the past three or four decades are well known, possible differences between the effects of higher versus lower "tar" and nicotine cigarettes on the incidence and magnitude of these various complications ara not known. The relative importance of "tar" and nicotine (oommon)y assayed in current cigarettes) versus the importance of carbon monoxide and several thousand other constituents of tobacco smoke (usually not measured) ie not known. In fact, it is possible that compounds other than "tar" or nicotine are important in producing these effects. It is essential to elucidate these issues. Evidence on the Effects of Smoking In Pregnancy The complications of pregnancy aacribed to cigarette smoking may be divided into those that affect (1) the mother, (2) the embryo and fetus, (3) the placents, and (4) the newborn infant and child. The mother, fetus, and placenta constitute an integrated organic unit rather than separate systems or organs. Thus, although separation of effects Into these categories is convenient, it is also somewhat arbitrary. Some effects, such as spontaneous abortion and other reproductive loss, affect both the mother and fetus. Complications in different categories can occur ooncurrently.. Cigarette smoking has been demonstrated to exert effects on each category. Maternal complications of pregnancy that show a greater incidence among women who smoke cigarettes include placenta previa, abruptio placentae, vaginal bleeding during pregnancy, and, possibly, prema- ture rupture of the membranes (1s,1.i). Lifetime smoking histories also affect the occurrence of placenta previa, abruptio placentae, and bleeding during pregnancy (17, 19). The Incidence of amnionitis (infection of the amniotic fluid and its membranes) also is increased among women who smoke (16). The occurrence of the preceding complications appears to increase with the number of cigarettes smoked. For instance, the risk of placenta previa for mothers who smoke less than one pack per day is 25 percent greater than that of nonsmoking women, but is 92 percent greater in those who smoke one or more packs of cigarettes per day (14). Additionally, the risk of 157
Page 124: apt20e00
abruptio placentae is increased 23 percent and 86 percent, respectively, in these two amoking-level groups compared with nonsmokers (14). Virtually all of the more than 50 studies published, involving more than half a million births from many countries and ethnic groups, have been consistent in demonstrating that maternal smoking has an adverse effect on birthweight (25). These newborn infants weigh on the average 200 grams less than babies born to comparable women who do not smoke, and the decrement in birthweight varies with the number of cigarettes smoked (85). In an analysis of data from the Ontario (Canada) Perinatal Mortality Study, the number of newborns weighing less than 2,600 grarns was 62 peroent greater among women smoking less than one pack per day and 130 percent greater among women who smoked one pack or more per day, when compared with the pregnancies of nonsmoking women (it, 11). The contribution of this reduced birthweight to the occurrence of abruptio placxntae or placenta previa is not clear (18). Several studies have shown that the placental ratio (placental weight to fetal weight) is higher for the gestations of mothers who smoke (8y). This increaae in the placental ratio results from a decreased newborn birthweight and from a slight Increase in absolute placental weight in heavier smokers (t6). Preliminary results from the Columbia University study fail to show either smaller weight decreases in the newborns of mothers who smoke lower "tar" and nicotine cigarettes or a return to nonsmoker values in the placental to fetal weight ratios. The risk of spontaneous abortion is 30 to 70 percent higher among pregnant smokers than among nonsmokers and increases with the number of cigarettes smoked (11). Rates of fetal deaths (occurring after 20 weeke of gestation) also increase significantly with the level of maternal smoking (J). The risk of premature delivery is 36 to 47 percent greater in mothers who smoke during pregnancy than in nonsmoking mothers; about 19 percent of all preterm births can be attributed to smoking (1, 1, 9, 13). This is an important factor in the increased risk of neonatal mortality among the infants of smoking mothers. Infants of women who smoke experience a mortality rate ranging from less than 10 percent to almost 100 percent greater than that among offspring of nonsmoking mothers. The excess risk of perinatal mortality varies, depending upon the number of cigarettes smoked and upon the preeenoe of other high-risk factors (e.g., low socioeconomic group, a previous low-weight birth, or anemia) (15). Several abnormalities of infancy and childhood occur more frequent• ly anlbng the offspring of mothers who smoke. Children of women who smoke during and after pregnancy experience higher rates of morbidi- ty and mortality up to the age of 5 years. In Finland, smoken' children had more hospitalizations, more visits to the doctor, and more use of specialized services (20, 21). Significantly more infants of smoking parents are hospitalized for pneumonia and bronchitis (5, 6, 10). The sudden infant death syndrome (SIDS) occurs more frequently among the children of parents who smoke (i, 24). Other long-term sequelae of maternal smoking during pregnancy are also of concern. Several studies suggest that older children of mothers who smoke have slight but measurable deficits in physical growth, intellectual ability, emo- tional development, and behavior (25). For instance, in Great Britain the physical growth of smokers' children remained less than that of nonsmokers' offspring, at least until age 11(4). Associations have been reported between maternal smoking and deficits in neurological and intellectual development of the child. These include minimal cerebral dysfunction and abnormal or borderline electroencephalograms (8), hyperkinesis (7), and abnormal infant behavior patterns (22). These long-term effects of maternal smoking require attention because of their potential seriousness. Thus, an excess risk of several disorders or death face the fetus and infant of the mother who smokes. Although °tar," nicotine, carbon monoxide, and some other constitu- ents of cigarette smoke have been shown to produce various effects, the specific etiologic agents and their meehanism(a) of action are not clearly established for these adverse effects on pregnancy. * Health EHects of Lower "Tar" and Nicotine Cigarettes Although use of lower "tar" and nicotine cigarettes has grown markedly over the past decade, there are no data available that suggest that the developing fetus, the infant, or the pregnant woman are less harmed by cigarettes with lower levels of these constituents. There has been no demonstration of decreased risk of complications of pregnancy. There is no evidence of a decreased risk among smokers of spontaneous abortion or preterm birth, nor of an increase in the average weights of their babies. Newborn infants of smoking mothers continue to have a mean weight of 200 grams less than those of nonsmokers, a relation that is dose dependent. The risk of preterm delivery remains much greater for smoking mothers. Further, there is no evidence to date that maternal smoking of lower "tar" and nicotine cigarettes decreases the risk of perinatal mortality. Most research reports to date have considered only the number of cigarettes smoked per day in quantitating smoke exposure, without adjusting for differences in yield of different cigarettes. Research Approaches Investigation into the effects of maternal cigarette smoking on pregnancy, the fetus, and the young child should include the following types of studies: (1) prospective epidemiologic studies comparing the course and outcome of pregnancy by maternal smoking habits; (2) 159
Page 125: apt20e00
case-control studies of pregnancy complications inc]uding laboratory measurements of various body functions and constituents and a proepective study of pregnancy outcome; and (3) clinical and experi- mental research, often using laboratory animals, in which tobacco smoke or some of its constituents, commonly nicotine and carbon monoxide, are administered to the subject, animal, tissue, cell, or subcellular element, and the response quantified. With numerous systems to be considered (the pregnant woman, the fetus, the newborn, the young child), and with various organs, tissues, cells, and subcellular elements potentially acted upon by a myriad of tobacco smoke constituents, the selection of appropriate study designs is a complex prooess. Further, the design of such studies is complicated by continuous changes in the composition of cigarettes over the past two decades. The spectrum of cigarette types, composition, and smoke yield varies enormously. In addition, the individual smoker's lifestyle, habits, and intake of other substances such as alcohol, caffeine, and drugs must be considered. In view of the multiple variables Involved, the recommendations that follow are those most likely to contribute significantly to an under- standing of the character and magnitude of adverse effects of smoking cigarettes with varying levels of "tar" and nicotine on pregnancy. Research must define the relative importance of the several constitu- ents, the impact of dose variations, and the mechaniams of action of the toxins in cigarette smoke. Recommendations for Human Studies Studies of populations of individuals with defined smoking histories have made an important contribution to elucidating the effects of smoking on various aspects of pregnancy, childbirth, and infant health. To date, no epidemiologic data exist to indicate lower risks of the aforementioned conditions in the pregnant mother, fetus, or infant resulting from the use of a lower "tar" and nicotine agarette.. Present knowledge is sufficient that new, large prospective studies specifically designed to evaluate smoking effects are not necessary; rather, the approach should be, first,. to encourage all prenatal care facilities to record smoking information, preferably with measurement of exhaled carbon monoxide. Second, the major source of information should be centers where continuing prospective evaluation of pregnan- cy is already being carried out in a systematic way, such as the Kaiser Permanente Cohort Study. These centers should adopt a uniform practice of keeping detailed records of their patients' smoking habits, recording at each prenatal visit the number of cigarettes smoked, brands, filters, "tar" and nicotine content, and measured exhaled carbon monoxide (to estimate maternal and fetal COHb). Records of other exposures such as alcohol, coffee, and other drugs should also be kept. These and other relevant 160 TQBSgZGg personal, medical, and demographic factors should be analyzed or controlled in evaluating the outcome of these pregnancies (spontane• ous abortions, later fetal deaths, complications of pregnancy, preterm deliveries, duration of gestation, birthweight, and neonatal and later conditions versus normal, live births). These comprehensive, continuing studies are needed to elucidate the interrelationships of factors already known to affect pregnahcy outcomes. It would be desirable to have several centers with large numbers of births follow a standard protocol for such studies. Within the context of such a protocol, or possibly separate from it, case-control studies of spontaneous abortions, fetal death, preterm births, and particularly abruptio placentae, placenta previa, and premature rupture of membranes should be carried out. Patients who have not delivered at the time of ascertainment should be followed prospectively to delivery, together with their matched controls. Biochemical tests should be included in these studies to elucidate the mechanism of action of smoking in the increased incidence of these events. Any possible modification of these outcomes that accompany the use of lower "tar" and nicotine cigarettes should be examined. A variety of other special clinieal studies to test for differences in adverse pregnancy outcome by use of different cigarettes during pregnancy could be added to these larger monitoring operations or could be set up independently, using infants of matched smokers and nonsmokers. For example, (a) neonatal behavioral assessment (Brazel- ton scale), (b) auditory response testing of newborns, (c) neonatal and poat-neonatal growth measurement, (d) special studies among very heavy smokers, and (e) placental studies could be performed. Several epidemiologic studies now in progress might provide an- swers to some of these questions, for example, the study of spontane-s ous abortion at Columbia University in New York, or the Oakland Kaiser Permanente Cohort Study, which prospectively links smoking history and cigarette brand to all hospitalizations of approximately 50,000 women, many of childbearing age. Studies have indicated that maternal smoking during pregnancy may be associated with impairment of physical and intellectual development byperkinesis, and changes in the infant's responsiveness (25, 26). The hypothesis that alterations in the constituents of cigarette smoke might affect the risk of these conditions needs to be tested. Differences in risk of long tcrm neurological consequences for a child exposed to maternal smoking should continue to be examined in existing data sets insofar as they contain appropriate Information. Data files include (a) the Collaborative Perinatal Project (U.S.), (b) the 1958 and 1970 British Perinatal Studies (U.K.), (c) the Kaiser Permanente Cohort Study (Oakland), (d) the Finnish Perinatal Study (Finland), and possibly (e) the University of Washington Study (Seattle).. Such studies must include consideration of possible confound- 161
Page 126: apt20e00
ing factors such as socioeconomic status, nutritional status, alcohol use, and exposure to legal and illegal drugs. In addition to studies documenting the maternal and fetal risks of varying levels of "tar," nicotine, and other constituents in cigarette smoke, there is need for study of the effect of cessation of smoking at different times in gestation on subsequent adverse events of pregnan- cy, Including measures of birthwelght, gestational agq perinatal mortality, and long term sequelae. It will be important also to discriminate the effects of maternal smoking during gestation from those of parental smoking during infancy and childhood. The combined effect of such studies would be to define any differences by cigarette "tar" or nicotine yield in the incidence of maternal complications or fetal or newborn sequelae, relative to both nonsmokers and smokers of different products. Recommendations for Behavioral Studies The factors and Influences that lead an individual to start smoking and to maintain the habit despite knowledge that it poses health risks are complex. In view of the absence of evidence that lower "tar" and nicotine products pose less risk to pregnancy outcome, the description of smoking patterns among pregnant women and the investigation of motivational factors in this population are critical to the design of appropriate public health programs. Some studies indicate that cessation of smoking early in gestation results in a pregnancy and fetus with risks of low hirthweight similar to those among nonsmokers (". Clinical studies could be conducted of pregnant women who refuse to quit smoking, in order to define the time Intervals during which cessation of smoking results in a risk indistinguishable from those of nonsmokers. In view of the demon- strated effects of nicotine, carbon monoxide, and other tobacco constituents, rapid smoking techniques for cessation are contraindicat-d ed ln pregnant women. Exhaled carbon monoxide should be masured at each visit, and the results used to explain to the mother that her baby's oxygen supply as well as her own te reduced by carbon monoxide from the cigarettes. Further, considerable evidence indicates that the majority of women initiate smoking during their teens and pre•teens. Therefore, behavior- al studies should focus on the prevention of initiation of smoking in this age group. Adolesoents are a high risk group during pregnancy becapse of many factors, such as inadequate nutrition, anemia, iaa uate prenatal eare, and the use of illicit drugs. Adolescents who smoke during pregnancy constitute a particularly important group becewse of the coexistence of smoking and other risk factors. Interven- tion techniques must be found that effectively illuetrate to the pregnant adolescent how smoking affects her body and fetus and that assist in cessation attempts. Such demonstrations might include zdesszse measurement of increases in fetal heart rate and decreases in fetal respiratory rate after smoking. Studies of lifetime smoking experience should describe the role of pregnancy in changing smoking, such as cessation attempts and successes, brand choices, and number of cigarettes smoked daily. A logical extension of this study would define how the techniques of smoking cessation during the course of gestation may differ for pregnant women compared with those directed to smokers in general. The applications of such studies are particularly important for women who smoke heavily as well as for those women at high risk because of other factors. Recommendations for Clinical Studies General Studies The adverse health consequences of cigarette smoking for the individual smoker extend beyond the pregnant smoker. As do the taking of drugs, exposure to workplace chemicals, or voluntary exposures to toxic substances such as alcohol, smoking by pregnant women affecta the health of her fetus. The implications of this extended responsibility cannot be overstressed. The effects of heavy smoking (two or more packs a day) on the pregnant woman, her fetus, and child have not been well defined. If adequate numbers of pregnant women who are very heavy smokers (two or more packs per day) could be identified, a special study should be undertaken to compare them with nonsmokers matched on impor-t tant factors, e.g., time of registration, age, parity, and socioeconomic status. A prospective study should examine heavy smokers, including users of modified lower "tar" and nicotine cigarettes, as well as nonsmokers. For these heavy smokers as well as for light smokers, maternal blood levels of nicotine, eatecholaminee, carboxyhemoglobin, thiocyanate, cadmium, and other suspect compounds should be exam- ined during pregnancy. Such a study should monitor several fetal variables Including cardiac electrical activity, breathing and other body movements, cerebral electrical activity, and periodic measurements of head growth (biparietal diameter). Following birth, placentas would be examined for morphometric and/or pathologk abnormalities. Newborn infants should be completely examined, including measurement of lung volume and brain size and neonatal behavior assessment using the Bratelton scale. Children should undergo long-term followup for neurologie function (e.g., hearing and visual disorders). Alternatively, certain aspects of neurological dysfunction should be examined by case-control studies in which children with abnormalities are compared with normal neonates, matched by such factors as time of birth, gestational age, and socioeconomic status. Prenatal exposure to smoking by amount, type of cigarette, and yield and exposure to other ,AR
Page 127: apt20e00
substances ahould.then be compared to determine associations betweon neurological abnormalitiea and these exposures. The mechanism(a) by which maternal smoking increases eomplica• tions of pregnancy, such as spontaneous abortion, abruptio placentae, placcnta previa, and premature rupture of the membranes are not clearly defined, despite the fact that these complications account for a significant portion of embryonic and fetal morbidity and mortality. Abruptio placenta will continue to result in anoxic fetal deaths. Preterm deliveries attributable to premature rupture of placental membranes will continue to pose the attendant hazard of neonatal death to the newborn infant. Therefore, studies ought to test certain hypotheses about the mechanisms of action of cigarette smoke in these events. Instances of complications should be Identified (i.e., placenta previa, abruptio placentae, premature rupture of the membranes, and probably sponta- neous abortione). Controls should be selected for each case (matched by time of registration, gestational age at occurrence of complication, social status, age, parity, and perhaps other factors), and demographic factors and confounding exposure(s) to other compounds should'be examined. A number of variables quantitating smoke exposure should be measured, including the concentrations of blood hemoglobin, carboxyhemoglobin, thiocyanate, copper, and various vitamins (A, Bu, C, and folate). The subjects should be followed to delivery, and the influence of measured factors related to outcome. Although at birth one could measure variables such as the biomechanical properties of membranes, tissue collagen concentrations, and cell number and size, such measures are not known to elucidate the mechanism of action of smoke conetituents. Biopsies of the cervix from women with premature rupture of the membranes should be examined for concentrations of elastase or other enzymes that might play a role in premature dilation of the cervix. In instances of abruptio placentae and placenta previa (and in matched controls), that organ could be examined for morpho- metric or morphologic alterations. Pta,unf,aL Studiea Placental morphology and morphometry are plagued by a lack of information and understanding of the relation of villous structure to the size (generation) of tho associated blood vessels. Therefore, such morphometric studies of the placenta should be carried .out in a laboratory dedicated to placental structure. The ratio of placental weight to birthweight increases with numbers of cigarettes smoked daily. Ught smokers' placentas may be slightly lighter and heavy smokers' placentas somewhat heavier than those of nonsmokere. The diameter to thickness ratio is also somewhat in- creased for smokers. Signs of "premature aging" are also seen in smokera' placentas, characteriaed by early appearanee of calcium and subchorionic fibrin (27'). The described changes were somewhat smaller in magnitude than those described for high altitude or anemia. These studies did not, however, include consideration of the type of cigarette smoked. The factors that account for these changes and their mechanism of action are unknown. Morphometric studies should be designed to determine what fea- tures of placental archit.ecture are altered by maternal smoking a4 by the type of cigarette used. These studies would include examination of the trophoblast, blood vessels and their interrelations, relative matura- tion of the placenta includipg the presence of calcium and subehorionic fibrin, membrane thickness, relative size of the intervillous space, and evidence of pathologic alterations. In addition, other studies should examine ultrastructural features of the trophoblastic eella and blood vessels. Further studies should examine biopsies of the placental bed, including the decidua and endometrium of women who do and do not smoke. Studies indicate that the blood of smoking women has lower concentrations of certain amino acids and vitamins A, Bu: C, and folic acid, among others, but the mechanism of these changes is unknown. Placentas from smokers of different cigarettes and matched controls should be studied for uptake kinetua and for intracellular to extracel- lular concentration ratios of amino acids and other compounds. Autapey Studies The fetus of the mother who smokes weighs less than the fetus of a comparable nonsmoking mother, and this effect varies with the number of cigarettes smoked. However, the mechanism(s) whereby this change occurs is unknown. No evidence is available on how different cigarettes affect the occurrence of low birthweights. In an effort to determine whether decreased cell size, or cell numbeg or both, account for this change, we recommend that studies examine DNA concentrations (cell number) and DNA to protein ratios (cell size) in infants of smoking mothers suffering perinatal death.. One large study, corroborated by others, showed that, among perinatal deaths associated with maternal smoking, the largest catego- riea of cause of death for stillborn infants were "unknown" causes or "hypoxia." The largest number of neonatal deaths were ascribed to "prematurity" alone. In an effort to elucidate specific causes and possible mechanisms of these deaths and the implications for newer cigarettes, dead fetuses and infants who die near the time of delivery, of smoking and nonsmoking mothers, should be subjected to thorough and careful autopsy by an experienced neonatal pathologiat. Such studies may help elucidate differences in the smoker's infant who dies. Fetal lung weight is decreased preferentially in animals exposed prenatally to carbon monoxide. Infants of smoking mothers experience increased risk of respiratory infections and pulmonary disease, and the 164 165 Caesezse
Page 128: apt20e00
lungs may be altered In Infants of smoking mothers who expire in the "sudden infant death" syndrome. In an effort to determine the morphologic basis and possible mechanism of these changes, the lungs of atiliborne, or of newborn infanta who expire, should be examined for morphologie and pathologic changes related to the smoking status of the mother. Some specific indices to be examined include alveolar type II cells, macrophagea, and microcieculatory vascularization. Fetal brain weight is Increased (probably from edema) in animals exposed prenatally to carbon monoxide. The infants of smoking mothers experience increased risk of "minimal brain damage," hyper- kinesis, and other neurologie disorders. In order to determine the morphologic basis and possible mechanisms of these changes, the brains of the dead fetuses or infants of this group should be examined for morphologic and pathologic changes. Some specific indicea to be examined include neuronsl and dendritic number and architecture. It may be of special importance to examine the brainstem because of altered respiratory control mechanisms, Breast-Feeding Studies Several products of tobacco smoke such as nicotine, ootinine, and thiocyanate are known to be secreted in breast milk. However, little is known about the dose-reeponse relationship of smoking to the concen- trations of these compounds. Breast milk of lactating mothers and the blood of their newborns should be examined for concentrations of nicotine, cotinine, thiocyanate, cadmium, and other toxins. In addition, breast milk from smoking mothers should be analyzed for the concentrations of leukocytes, monocytes, immune globulins, and other immunologically Important factors, in addition to protein, fat, earbohy- drate, and other constituents that affect newborn growth. Again, dose- response relationships should be explored. Finally, breast-fed infants of smoking mothers should be examined for evidence of nicotine addiction and withdrawal symptoms (irritabili- ty, nervousness) at the time of weaning. Some studies have indicated that maternal smoking suppresses lactation. Milk production and ability to nurse should be studied in smoking and nonsmoking women who want to breast feed their babies, including evaluation of the effects of stopping smoking and the use of loweT,"tar" and nicotine cigarettes. M Recommendaqons for Phrsloiogio-Phermacoloylc Studies Laboratory studies in experimental animals have proved useful to test various hypotheses regacding the specific effects of the individual constituents of tobacco smoke, as well as mechanism(s) of action. Such '-boratory studies.hould be carried out in a well-organized and careful manner, and should consider exposure to tobacco smoke per se as well as to its individual constituents. Tobacco Smoke The introduction of modified, lower "tar" and nicotine cigarettes raises several questions regarding the effects of these tobacco products on the pregnant woman, fetus, and infant. Although purportedly lower in their yield of "tar" and nicotine, these cigarettes may still deliver a threshold level or more of carbon monoxide or other toxic products. Additionally, smokers may use certain techniques to increase the yield so that the delivery of "tar," nicotine, carbon monoxide, or other constituents is similar to, or perhaps in excess of, that of regular cigarettes. Further, the possibility exists that there is a systematic difference in the style of smoking depending on "tar" or nicotine level. If smokers of lower "tar" and nicotine products uniformly take more puffs, larger puffs, or inhale more deeply, the actual dose of constituents experi- enoed by the smoker would not be as low as that predicted by machine measurement. In addition, while the relative amounts of smoke absorbed may vary, differences in smoking pattern might also affect the relative proportions of constituents in the smoke inhaled, a fact that might well influence the probability of developing smoking- related health problems. Measurements of smoke constituents and breakdown products in the smokers' exhalations, serum, and other body fluids may provide better estimates of cigarette yield than smoking-machine results. Levels also differ by sex and during pregnancy. Studies of the effect of tobacco smoke in animals present problems as to the dose of smoke actually received by the animal, the specific compound(s) responsible for the changes observed, and the concentra- tion of these substances in blood or tissue. All such studies should include measurements of blood concentrations of nicotine, carboxy- hemoglobin, and perhaps other compounds, as well as tissue concentra- tions where appropriate. Numerous animals have been used for studies on the effects of smoking. Ideally such studies should be carried out in subhuman primates, such as baboons trained to smoke. However, the technical difficulties and expense of such studies make this approach unrealistic. Consideration must be given to whether there is, in fact, a particular animal model that is optimal from the standpoint of relevance to human studies, availability, and expense. As noted previously, an almost universal phenomenon is the decrease in birthweight of infants of smoking mothers. Animal studies must explore which components of cigarette smoke. are most important in reducing the rate of fetal growth. Such studies should determine whether it is the rate of mitosis or cell number that is reduced, and 3?
Page 129: apt20e00
whether the smoking-associated reduction of fetal growth rate is caused by retarded growth of only certain organs or tissues. Following birth, many children of smoking parents are continuously exposed to tobacco smoke. This may be a factor in the higher incidence of sudden infant death syndrome, hyperkinesis, "minimal brain dysfunction," and respiratory disorders in such children. Animal studies should be performed to examine the effects of passive smoking on newborn or young animals. Nicotine Nicotine is an important pharmacologic agent in tobacco smoke. Studies suggest that some smokers titrate their nicotine dose by altering the number of cigarettes smoked, the depth of inhalation, or the degree of occlusion of pores (in the can of low "tar" and nicotine cigarettes). The following major areas of inquiry should be studied: 1. Definition of the role of nicotine exposure during fetal life in birthwelght reduction, behavioral development, and childhood ' growth retardation Z Examination of the effect of nicotine on individual organ growth, including the fetal brain, adrenal glands, lungs, heart, and kidneys 3 Study of nicotine's contribution to neurologic disorders in children 4. Elucidation of the role of nicotine or Its metabolites in carcinogen- esu, alone or in combination with benzc[a]pyreno and other carcinogens in smoke 5. Definition of the effect of nicotine on human fetal blood catecholamine concentrations Carbon Monoxide Carbon monoxide, a product of incomplete combustion of carbona- ceous compounds, is present in tobacco smoke In relatively high concentrations (1 to 6 percent). Hemoglobin avidly binds carbon monoxide as carboxyhemoglobin, decreasing the oxygen transport capacity of blood. Because of the relatively higher affinity of fetal hemoglobin for Osand CO, as compared with adult hemoglobin, a given carbon monoxide partial pressure results in a fetal blood carboxybemo- globin level 10 percent greater than that of the smoking mother, while fetal arterial oxygen tension is only 20 to 80 percent that of the mother. Thus, the fetus experiences higher carboxyhemoglobin levels and a greater carbon monoxide-induced hypoxia than that occurring simultaneously In the mother. Exploration of the following questions should be undertaken: 1. Definition of the major physiological consequences of carbon monoxide exposure on the developing fetus or newborn 2 Elucidation of the dowreeponse relationship of carbon monoxide in disease occurrence 3. Examination of fetal adaptation to low carbon monoxide concen-. trations, and the mechanisms of any such adaptation 4. Definition of the patterns of growth, development, and matura- tion of the central nervous system and other organ systems exposed to chronic low-level carbon monoxide 6. Study of the periods during gestation when the fetus is partic~lar- ly vulnerable to carbon monoxide ' Polycyelic Aromatic Hydrocarbons Benzoja]pyrene (BaP) and other polycyclic aromatic hydrocarbons (PAH) are potent carcinogens. Little is known about the transplauental effects of these substances on the developing fetus. Examination of the following questions is needed: 1. Definition of the transplacental passage of BaP and PAH 2. Description of BaP or PAH distribution in the fetal organs and tissues • 8. Examination of a possible role of BaP or PAH from maternal smoking in the growth and development of the fetal brain and other organs It should also be noted that BaP and PAH are known inducera of the cytochrome oxidase (P,w) system, including aryl hydrocarbon hydroxyl- ase (AHH). Such enzymes are involved in drug and steroid metabolism, among other functions. Thus, the PAH should be investigated for possible metabolic effects beyond those of car+rinogenesis. Other Substanas Numerous possibly toxic substances are present in cigarette smoke, including cyanide and cadmium. Little is known about the role of these compounds in altering fetal growth and development. Studies should examine the effects and mechanism(s) of action of these substances. Priorities for Research Recomm.ndatlons The preceding discussion has presented many research issues that are major and valid questions. The primary emphasis, however, must be placed upon studies that determine the character and magnitude of the health bar.ards posed to the individual pregnant smoker and her offspring by the modified lower "tar" and nicotine cigarettes. Research to define the specific etiologic agents and their mechanism(s) of action must take a priority second to that of defining the risks. It is through epidemiologic research that the answers to the most important questions will be reached. It is apparent that there is a need for refining the measurement of cigarette dosage and the quantitation of cigarette smoke exposure. A more accurate description of dosage must be an intrinsic part of epidemiologic research efforts that deal with smoking exposures. All obstetricians and prenatal clinics should 1 AR saes~~ 169
Page 130: apt20e00
a: be strongly urged to record details of their patients' smoking habita at each visit. Simultaneously, however, laboratory investigation should proceed in parallel to exanlne the specific compounds involved and their mechar nisms of action. Research has contributed some knowledge of tissue, cellular, and subcellular effects. Further studies at these levels hold the promise of elucidating the mechanisme whereby these changes occur. Such studies 'may lead to a greater understanding of specific cigarette hazards by dosage and thereby . suggest dirvotions for epidemiologic studies. Conversely, epidemiologic data will suggest directions and specific questions for laboratory or clinical research.. These approaches should proceed in concert for maximal results in understanding the problems of lower "tar" and nicotine cigarettes in the medical, biological, and social envirOnments. Summary L Cigarette smoking during pregnancy has been shown to have adverse effects on the mother, the fetus, the placenta, the newborn infant, and the child In later yean. There is no evidence available that lower "tar" and nicotine cigarettes decrease or increase these health rislai, relative to those posed by higher "tar" and nicotine eigarettts. 2 Problems that have been linked to smolFing during pregnancy include placenta previa, abruptio placentae, vaginal bleeding, and reduced average birthweight of newborn Infants. 8. Smoking by pregnant women increases the risk of spontaneous abortion, premature delivery, fetal death, and perinatal death. Parental smoking is associated with the sudden infant death ayndrome. 4. The fetuses of smoking mothers have higher blood carboxyhemo- globin levels and lower fetal arterial oxygen levels than do the mothers. 6. Children of smoking mothers appear to show a greater susceptibil- ity to sollm adverse health effecta, such as bronchitis, pneumonia, and respiratoq disease, during early childhood. Slight differenoes In physical growth and other forms of behavioral and intellectual eloplnent may be found in children as old u 11 years of age. 6. Although "tar," nicotine, carbon monoxide, and some other constituents of cigarette smoke produce deleterious effects, the specific etiologic agents and their mechanistns of action for adverse effects on pregaancy are not clearly determined. Thus, the relative importance of "tar" and niootine, or carbon monoxide and other constituents of tobacco smoke in the etiology of adverse gestational and fetal events is not known. References (1) ANDBE4VS, J, MCGAItAY, J.M. A community study of smoking In preCnancy. Jorreal of 06.t.triw and (}ynasaiopy of tAe Briliak Cmnmonwealth 7g(12): 1067-107s, Deoember 1sTL (t) BEBGMAN, A.B., WIESNER LA. Relationship of pwi.e dgarette4moking to sudden infant da.tL syndronme. Ardiatriw 6d(6): 66fL-d68, November 19% (J) BUTLER, N.R, ALBEItMAN, ED. (Editon} PYriwsml pfobteme. T7r ,8eevnd Report of the ilSe Eriti.A AWeatal Moefalilr Bu.roey. London, Ii~ and S. LlvinBston, Ltd.,19E9, pp. ed-84. (4) BUTLER, N.R, GOLDSTEIN, H. Smoking In pregnancy and subsequent child dereloproent. BriliaA M.diaat JoKrna! 4: 673-67b, Deaember S,1!?E. (5) OOLLEY, J.B.T. Rerpiratory symptoms ia children and perentai umking and phlegm produetion. BritiA Medica[ Je.mal Z(8811): 2D1-2D1, April Zl,1fR4. (e) COLLEY, J.RT., HOLLAND, W.W., CORRHILL, RT. Infiuence of passive (7) smoking and parental phlegm on pn.umonL and bronchitis In early childhood. Lnnoot 2('t888);1091-1054, November ?,1974. DlNSON, R., NANSON, J.L, MCWATTSR8,1f.A. Hyperkiooda and maternal moking. t'swodion FlyrAistria Aaoefstion Jaerwa! 20(3):183437. Apti11875, (8) DUNN, H.G., MCBURNEY, A,IL, INGRAM, S, HUNTER, C.M. Maternal (') dganette aeoking during pregnancy and the dhild'a subsequent dwelopment: lI. Neurological and intdlectud maturation to the ap of 6% years. Ghnodins Jowwel of Aiodie fleoltk 68(1): 45-60, Jaanary/Februapr 1977. FABIA, J. Clg.rettes pendant la `eo.aa..a, poicb do safmanoa et mortalU,e perinattle. [Rgarette amoldng during pregnancy, bietL weight and perinatal mortality.] Canadiss Medioal A..oetation Journa1108(11): 1104-1109, Decem- ber1,1913. (10) HAitLAP. S., DAVIFS, A.M. Infant admissions to hospital and maternal smoking. Ianmt 1(7867): 571-.R?,1[erchl0,1974. (11) KLINE, J, STEIN, Z.A., SUSSER, M, WARBIJItTON, D. Smoidng: A risk factor for spontseeats aEorWn. Nw ,l9Yy&wd Journal of Jlfedfdns 297(16)¢ 795-796, october 13,1977. (1!) MEYER, M.B. How does maternal smoking affect birtD wdght and maternal weight gaint EYidenea from the Ontario Padnatal Mortality Study. A+nerican Jounal eJ Ob.tst.iu and Qyneeotopy 181(8): 888-898, Anguet 16,197e. (1J) MEYEI;1d.B., JONAS, B.S., TONASCIA, J.A. Perin.tsi events associated with maternal tmoidn` during pregnancy. Asvr+oen Joar+.at of Dpidentiofoyy 108(8): 46i-d76, May 1978. (14) MEYER, M.B, TONASCIA, J.A. Maternal smoidng. pre`nancy oompliutions, and perinatd mortality. A*w+ican Jouenat of O6.t.tria and Gyneooiopy 12t1(6): 49MSO?, July 1,1977. (15) MZICBJi. Lf.B, TONASCIA, J.A., BUCK, C. The Interrel.tionhip of maternal smoking and increased perinatal mortality with other risk facton. Further analysis of the Ontario pesinatal mertality .tudy, 198D-196L Amsricnn Jouraal oJDpidt+nioieyr 100(6): 4"2, December 1974. (1e) NAEYE, RL Effects of maternal dgaeette.moking on the fetus and pl.osnta B+ritiaA Jouawl of 08rtctrici and Cyn.oefopy 88(10): 73B-781, October 1978. (17) NAB,YE, RL The duration of nut.r.ai dga'.tte aeaktag, total and plaoontd disorders. Fady Hinnan ikatbpment a(i): 2$9-237. SeptemDer 19TY, (Id) NAEYF., R,L Cigarette anaking and pregaaner weight gaia laneet 1(8171): 7Q6-766, Apri16,1Yl0. (Letter) (11) NAEttL, It.L. Abraptb pl.centae aad placenta preria: Frequ.ney, perinatal mortality, and cigarette smokiag. O6.aMies snd Crynwoiopr 66(8): 701-701, June 1o80. &it soesezse
Page 131: apt20e00
(20) .n TALLIO, P. Itelationehip of maternal smoking to morbidity and mo..~lity of the child up to the age of five. Asta Phsdiatrica Scandinavioa 87(5): 621-831, September 1p78. (21) RANTAKALLIO, P.; ICRAUSE, U., KRAUSE, K. The use of the ophthalmologi- aal services during the preschool age, ocular findings and family background. Journal of lidiatrie OpAthalmoloyy and Strnbiamua 15(4): ffi8-~268, July- Augu.t 1978. (pt) SAXTON, D.W. The behaviour of infants whose mother..moke in pregnancy. Early Human Dealopmext 2(4): S68-S89,1978. (tJ) SIMPSON, W J. A preliminary report on cigarette .moking and the incidence of prematurity. Ameriaau Journal of OG+tetric# and Cryneeofoyy 73(4): 8U&515, Apri11957. (24) STEELE, R., LANGWORTH, J.T. The relationship of antenatal and postnatal factors to.udden une:pected death in infancy. Canadiax Medical Aasxiatioa Journal 94:1166-1171, May 29,1866. (.tS) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WQ.FARE Smoking and Heatthc A Rqort of ths 9urp.on Gsneaul. U.S.3 Department of Health. Education, and W.itare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Publication No. 78-50068, lY7sa,1186 pp. (tB) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The Ifealth Caaarquenaa of Smoking lor WoraeK A Repwi oJ tJr. Surpan Cexaral. U,S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Seeretary for Health, Office on Smoking and Health, 1980, 859 pp. (27) WINGERD, J., CHRISTIA2VSON, Ii., IAVITT, W.V., SCHOEN, E.J. Pl.oontal ratio in white and black women: Relation to smoking and ademia. A+eerioan Journal oJObrtstriu and Gye.ootoDy 12f(7): 67i-675, April 1,1978. Section 7. BEHAVIORAL ASPECTS 4oesen3
Page 132: apt20e00
g096IRZ68 CONTENTS Research Priorities Controlled Studies To Determine the Role of Nicotine as a Primary Reinforcer in Cigarette Smoking Animal Models of Nicotine Use The Self-Administration of Nicotine by Animals The Study of Tolerance and Physical Dependence Nicotine Research With Humans Compensatory Behavior in Smoking Voluntary Switching Controlled Switching Additional Comments Natural History of Smoking Along Both Biological and Psychosocial Dimensions Recommendations Clinical Testing Facilities and Standardized Research Cigarettes Clinical Testing Facilities Research Cigarettes Machine-Smoked Yields of Lower "Tar" and Nicotine Cigarettes Toxicology of Nicotine Summary References 17.r,
Page 133: apt20e00
This section outlines the future directions that research L wer "tar" and nicotine cigarettes should take. These are: (1) to.l,,...orm additional laboratory studies under controlled experimental conditions; (2) to conduct additional research on compensatory smoking; and (3) to investigate both the biological and psychological factors involved in s©esszse smoking. M Research Priorities Controlled Studies To Determine the Role of Nicotine as a Primary Reinforcer in Cigarette Smoking Many important questions on the pharmacological importance of nicotine in maintaining cigarette smoking remain unanswered, despite a large number of studies on the topic (1, 2, 19, 25, 36, 44, 46, 49, 65, 69, 73). Nicotine is probably the primary source of the pharmaeodynamic appeal of tobacco, but not enough is known about its exact role in smoking to determine whether it is the only source. (For reviews on nicotine and smoking, see 18, 81, 31, $7, 61.) Tobacco without nicotine appears not to be sufficiently reinforcing to support sustained use (18). There has never been an appropriately designed study with a large number of subjects randomly assigned to smoke flavor-balanced cigarettes of varying nicotine content over a substantial (months) time period. The behavioral aspects of cigarette smoking are of paramount importance in the evaluation of less hazardous cigarettes. Behavior is the interface between cigarette smoking, its pharmacological and physiological effects, and the generation of disease. Compensation for nominally reduced machine- measured "tar" and nicotine yields of cigarettes by increased depth and volume of inhalation as well as proportion of the burning cigarette consumed has been demonstrated. Such a study would be necessary to conclusively support this hypothesis of cigarette habituation. Instead, we can only look at the distribution of smoking by nicotine yield and the experimental literature. In 1979, the percentage of current regular smokers in the United States who smoked cigarettes low in nicotine content (lesa than 0.5 mg nicotine and less than 5 mg "tar") was very small, about 4 percent. Research studies using tobacco cigarettes virtually free of nicotine show these to be rated as aversive by smokers (36, 64). At the same time, it has been difficult to demonstrate that smokers will use nicotine in a nontobacco medium. In one study, lettuce leaf cigarettes injected with nicotine were smoked for 1-week periods at intake levels only approximately 50 percent the rate of the subject's own brand, and with protest of much reduced satisfaction (13). Considered a more direct route of administration, injections of nicotine became a satisfying replacement for cigarettes 177
Page 134: apt20e00
after repeated trials, but this early study was not conducted in a "blind" fashion ($8). . More recent studies of intravenously administered nicotine have contained subjective reports of perceived pleasure (39), but also have included reports of an inability to suppress subsequent smoking to a major extent (J9, 46, 49). Although the results were perceived as only mildly pleasurable, nicotine administered in oral tablet form (35) or embedded in chewing gum (44, 64) has decreased various measures of smoking in individuals not trying to quit. The major problem with giving nicotine in other than inhaled form is that it lacks some of the biological as well as many of the behavioral similarities to smoking. The nicotine bolus, when inhaled, reaches the central nervous system in less than 8 seconda (58). More information is needed to understand the pharmacological, psychological, and situational cofactors that may contribute to the reinforcing effects of nicotine. By analyzing the mechanisms whereby nicotine reinforces smoking behavior, it may be possible to design more efficacious treatments for cigarette dependence or to devise techniques for maximizing the rewards of smoking while minimizing the risks to health. Animal Models of Nicotine Use Animal models have several advantages over human models in studying the effects of nicotine. In the animal laboratory, environmen- tal variables can be controlled to a much greater extent than they can in the human laboratory. History of exposure to the drug can be manipulated in a true experimental fashion. One of the greatest limitations of much epidemiological and behavioral research on human smoking behavior is that the aubjecta are self-selected. Consequently, the research is inherently correlational rather than experimental. Correlational research can describe associations between variables, but it is often confounded by unmeasured variables (J0). Animal models have been used to study the dependence liability and toxicity of many drugs (17, 75). The techniques used in analyzing responses to other drugs should be developed further and applied to the study of nicotine-and perhaps other substances in tobacco. Methods of administration can have a large effect on the pharmaeo- kineticavof nicotine. Oral, intravenous, and inhalation modes of administration should be employed, but since smokers receive nicotine from inhaled smoke, the inhalation route is particularly important. Unfortunately, animals do not inhale nebulized nicotinb or cigarette smoke in ways that are comparable to human inhalation patterns (53). Until reliable inhalation methods for animals are perfected, intrave- noov• administration will have to be used in much of this research. ,n o1e6ezse The Self-Administration of Nicotine by Animals Since people take nicotine on their own, an ideal animal model would be one in which animals take nicotine on their own. Attempts to get animals to administer nicotine to themselves have not been uniformly successful (17, 21). Maintained self-administration has been found in the monkey and the rat in some studies (6, 9S, 47, 50), but not in others (82). Recent work has shown that under some schedules of reinforce- ment, monkeys will self-administer injections of nicotine (12). In order to discover precisely what variables are critical to the reinforcing properties of nicotine, further studies are needed. In addition to studying the parameters of self-administration, toxicity should also be measured. For example, it is important to look at the variables of physical dependence, food and water intake, and morbidity, as well as necropsy findings. The Study of Tolerance and Physical Dependence Both tolerance and physical dependence can develop to nicotine or other ingredients in tobacco (JS, 48, 71, 78). Animal models have been used successfully in research on opioids and alcohol (70) and could prove effective in future research on nicotine and smoking. Appropriate animal models would facilitate the study of the pharmacokinetica of nicotine and would help in the evaluation of pharmacological treatments for dependence. Since tolerance and physical dependence can influence the reinforcing properties of drugs of abuse, animal studies should investigate the extent to which withdrawal phenomena may contribute to the reinforcing properties of cigarette smoke. Methods developed for evaluation of opioid drugs could be adopted for these purposes. Nicotine Research With Huma.na The scientific issues in human and animal research are similar, although not all studies conducted on animals are practically and ethically suitable for research on humans. A great amount of preliminary data already exists on the role of nicotine in human smoking behavior (see the reviews cited above), but the influence of tolerance and dependence on nicotine on the initiation, maintenance, and cessation of smoking behavior are still not resolved (27, 46, 59, 61, 68). Clearly, both biological and psychosocial factors influence human cigarette intake (41), and it is in the human model of cigarette smoking that the interplay of these factors can best be studied. There is no known analog in animal behavior for future orientation and cognitive factors, such as worrying about the risks of cancer or about weight gain upon giving up smoking. Progrese to date in laboratory studies of smoking dependence has been slowed by the lack of standardized test materials, such as 179
Page 135: apt20e00
cigarett aade to research specifications, and of standardized, easily accessible laboratory analyses, such as for plasma levels of nicotine. Compensatory Behavior In Smoking If, in the course of a standard assay for the'"tar" and nicotine yields of a cigarette (54), a smoking machine derives relatively small amounts of "tar" and nicotine, the cigarette can be called lower "tar" and nicotine. Unfortunately the smoking-machine model is limited in accurately reproducing human smoking behavior. The machines take a 2 second, 36 cc puff each minute until a predetermined butt length is reached. Smokers, however, are able to take larger, more frequent, and higher velocity puffs than the machines do.. It appears that such compensatory adjustments often turn nominally lower "tar" and nicotine cigarettes into higher "tar" and nicotine cigarettes (1, 4, 9, 25, 36, 46, 60, 6f).. Even if the compensations made in smoking a single cigarette are small or nonexistent, smokers can increase their intake of "tar" and nicotine by smoking more cigarettes (66). Cigarettes of less than about 6 mg "tar" and 0.5 mg nicotine are also subject to the influences of compensatory smoking. Most of these cigarettes achieve their lower yields as a result of ventilation holes placed in the filters, which cause each puff of smoke to be diluted with air. These air-diluted puffs deliver relatively small amounts of "tar," nicotine, and carbon monoxide to the amoking machines (29). Some smokers have learned to block the ventilation holes with their lips or fingers-or sometimes with tape-and thereby, often unwittingly, defeat the purpose of the holes. If the ventilation holes are blocked, yields of nicotine, "tar," and carbon monoxide can increase by about two, three, and four times, respectively (42). In 1979, ventilated-filter cigarettes accounted for about 25 percent of total cigarette sales (29). Many studies have used estimates of nicotine and smoke intake based on direct observations (44), measurements of smoking topogra- phy by means of special cigarette holders (24, s6), or analyses of residual nicotine in cigarette filters (1, 9, 55). Only a few studies have measured the levels of nicotine in plasma as a function of the nominal smoking-machine yields (1, 61), but research indicates that some smokers do compensate for reduced yields of nicotine. By smoking more to compensate for lower nicotine intake, lower "tar" and nicotine cigarette smokers can inadvertently increase their exposure to "tar" and carbon monoxide beyond what might be expected from a less intensively smoked higher "tar" and nicotine cigarette (57, 67). Because less hazardous cigarettes may require the delivery of moderate levels of nicotine while delivering lower levels of "tar" and carbon monoxide, Russell (57) has proposed that lower "tar" to nicotine ratios should be used to Indicate less hazardous cigarettes. Thesc ratios may direct smokers to potentially loas hazardous ciga- rettes, but the way in which a cigarette is smoked can affect the ratio iso i186Qz68 of "tar" and nicotine entering the body (5, 45). It is not yet cle. w accurately machine-determined ratios can predict human inta. of "tar" and nicotine. Compensatory smoking is central to the question of the public health benefits of lower "tar" and nicotine cigarettes. The frequency and extent of compensatory smoking should be measured in detail in order to determine whether smokers who switch to lower "tar" and nicotine cigarettes actually inhale fewer harmful compounds. TA types of studies of brand-switching behavior are needed: voluntary (naturalis- tic) switching and controlled (experimental) switching. These studies should be carried out over several months and include topographical, pharmacological, biochemical, and physiological measures in order to characterize the degree and nature of compensation. Research should address the question of the acceptability of lower "tar" and nicotine cigarettes and should measure smoker satisfaction with them. A low- risk cigarette serves its purpose only if people will smoke it in a way that truly yields lower "tar" and nicotine. The issues of self-regulation of smoke intake and acceptability have been discussed by Russell (60). Vo[untary Switchiny Little is currently known about smokers who have adopted lower "tar" and nicotine cigarettes, but detailed prospective studies of voluntary switching would reveal how exposures to nicotine and carbon monoxide change as smokers switch to those cigarettes. Data do exist on plasma nicotine levels (62) and COHb levels (79, 80) from lower "tar" and nicotine cigarettes, but these studies are cross sectional. They suggest that lower "tar" and nicotine cigarettes may not be particularly "low yield" to those who have chosen to smoke them. Jaffe et al. (32) used monetary incentives and health messages to encourage switching to cigarettes with lower "tar" and nicotine delivery in a series of studies on female smokers. Croas,sectiona] data on smokers who were already smoking lower "tar" and nicotine brands with substantially reduced nominal carbon monoxide delivery revealed that these smokers had alveolar carbon monoxide levels as high as smokers of higher "tar" and nicotine brands, as well as comparable levels of saliva thiocyanate. Preliminary results from the prospective study of voluntary switching, still in progress, show significant reductions in nominal daily nicotine intake and only a few instances of a significant rise in carbon monoxide upon switching. Epidemiological research on smoking cannot be done rapidly; it will take several years to evaluate possible reductions in the health risks of lower "tar" and nicotine cigarettes. Behavioral studies on voluntary switching, however, can provide estimates of health risks. If further research indicates that exposures to toxic products do not decrease in those who change to lower "tar" and nicotine cigarettes, then a re-. 181
Page 136: apt20e00
examination of the advisability of encouraging people to switch to milder cigarettes should be undertaken. (See Russell (60) for a brief discussion of the possible role of self4election biases in the epidemio- logical finding that filter-tipped cigarettes are less hazardous (3, 81). See Harris (ts) for a summary discussion of behavioral and economic factors affecting the promotion of lower "tar" and nicotine cigarettes.) Coxtroiied Switching Very few studies on controlled switching have employed measures of plasma nicotine (1, t8, 60). No large-scale studies have been conducted that make use of plasma nicotine, carbon monoxide, and physiological measures of smoke exposure. The relationship between smoker satisfaction and compensatory smoking appears to be complex. One forced switching study (74) has shown that, even though the compensation was incomplete and did not change for the few days of the study, satisfaction did improve during the course of the experiment. We do not know if satisfaction with lower "tar" and nicotine cigarettes increases with duration of their use, if it decreases with time if compensation occurs initially, or if nicotine yield alone determines cigarette acceptability. Additional Comments As noted earlier, progress in compensatory smoking research has been hindered by the lack of research cigarettes varying systematically in nicotine, "tar," and carbon monoxide, and by the shortage of laboratory facilities in which to do needed analyses. One byproduct of the proposed research on switching to lower "tar" and nicotine cigarettes might be the development of practical diagnos- tic techniques. Smokers and physicians have not determined whether lower "tar" and nicotine cigarettes have produced "low-yield" smok ing, but simple measures such as expired air carbon monoxide (11, 26) might help supply needed Information concerning smoke exposure. Natural History of Smoking Along Both Biological and Psychosocial Dimensions Since almost nothing is known about the role of lower "tar" and nicotine cigarettes at crucial transition points in a smoker's history, this issue cannot be considered in detail (7, 20, 40, 52, 56). One key unanswbted question is whether lower "tar" and nicotine cigarettes tend to~acilitate taking up the smoking habit Presumably, initiation of smoking is easier for th se who first try lower "tar" and nicotine cigarettes than for those who first try regular cigarettes. Thus, lower "tar" and nicotine cigarettes can reduce averDive physical responses to early smoking episodes that might otherwise deter taking up the habit (41* 'Ts). ztesezse 184 Teenagers generally prefer moderately high-yield cigarettes (77), but 2.5 percent of the boys and 12.3 percent of the girls who smoke use lower "tar" and nicotine brands (here defined as <_ 10 mg "tar"). Research has not addressed the question of what percentage of these smokers may have been helped either in their initiation to smoking or in their shift from casual to habitual smoking by the use of lower "tar" and nicotine cigarettes. The incidence of smoking among teenage girls has increased during the past 10 years (76, 77). Silverstein et al. (72) present data supporting the hypothesis that the increasing availability of lower "tar" and nicotine cigarettes has encouraged this increase in smoking. Analysis of a survey of high school students suggests that girls experience greater social pressure to smoke than do boys, and that they also face greater physiological pressure not to smoke because of their higher sensitivity to nicotine. Girls appear to resolve these pressures by becoming lighter smokers than boys and by switching to lower "tar" and nicotine cigarettes. Perhaps if lower "tar" and nicotine cigarettes were less available, some girls would choose not to smoke rather than to experience unpleasant nicotine reactions. Most research on the initiation of smoking and casual smoking has been psychosocial. No doubt there are practical, if not ethical, constraints on studying biological influences on smoking among teenagers. Whatever the reason, very little is known, for example, about the role of nicotine in early smoking experiences. No one knows how much exposure (days, months, years) to smoking is needed before withdrawal symptoms appear. More balance is needed in research on teenage smoking. Whenever possible, biological factors-both physio- logical and pharmacological-should be studied along with psychoso-l cial factors (f7, 41). There has been little research on the effects of lower "tar" and nicotine cigarettes on maintenance or cessation of smoking. There are studies on the effects of using decreasing amounts of "tar" and nicotine as a cessation or reduction aid (10), but these studies do not include biochemical or physiological measures of change in smoke exposure. It seems plausible that the alternative of a supposedly less- hazardous cigarette might make some smokers less likely to try to abstain completely. By the same token, the example of a satisfied, though perhaps fully compensating, smoker of lower "tar" and nicotine cigarettes might make a former smoker more likely to relapse. The former smoker might view the lower "tar" and nicotine cigarettes as both acceptable and safe (14,15). Answers to these questions can have immediate implications for smoking treatment.. Research in this area should include such crucial variables as gender (72). Both experimental and epidemiological data are needed in these studies. Perhaps large- scale smoking surveys can be expanded to include more questions that would help characterize the natural histories of smokers. , ,QQ
Page 137: apt20e00
Recomr= iatlons Clinical Testing Facilities and Standardized Research Cigarettes There has been an active research effort in this country on the behavioral aspects of smoking. To further its productivity and to refine the scientific questions that this research can address, especially with regard to lower "tar" and nicotine cigarettes, the facilities and research cigarettes described here are needed. Clinical Testing Facilities These facilities should be able to provide biochemical and pharmaco- logical analyses of assays for plasma nicotine, cotinine, carboxyhemo- globin, and salivary thiocyanate. (Jarvik (34) reviews the use of these assays.) Each of these assays can be used to measure a smoker's exposure to some of the toxic and/or reinforcing ingredients in tobacco smoke. Plasma assays for nicotine (8) are available in a few laborato- ries; these assays can require special facilities to avoid problems of contamination. For example, a laboratory that is used part of the time by a worker who smokes may be unaeceptable for the evaluation of plasma nicotine levels. Few behavioral researchers have access to or sufficient control over the needed laboratory facilities. Laboratories of this nature would be a great boon to behavioral research and would help to standardize assays in this area. Research Cigarettes A supply of clinically acceptable cigarettes that vary in nicotine, "tar," and carbon monoxide yield should be made available to behavioral researchers. Although some standardized cigarettes have been available for years from the Tobacco and Health Research Institute of the University of Kentucky, these cigarettes have no filters, and their lack of palatability and acceptability almost complete- ly precludes their use in behavioral research. Cigarette technology has several ways of altering "tar," nicotine, and carbon monoxide yields. Ideally, different strategies would be employed to produce cigarettes with identical machine-smoked yields. Consider two examples. A fast- burning, strong-tobacco cigarette might have the same yields as a slow-burning, mild-tobacco cigarette, but it is not clear how human smoking behavior might change as a function of these modes of yield reduction. A cigarette low in carbon monoxide could be made with either vented cigarette paper or a vented filter. The vented filter can be closed by smokers accidentally or intentionally, thereby increasing the actual yield to the smoker (42), but the effect of porous cigarette papers cannot readily be circumvented by the smoker. Variations in "tar" to nicotine ratios should be of special concern (57). It is important to determine the lowest ratios that still produce a satisfying cigarette. Obviously, identical "tar" and nicotine ratios can xs;ur in cigarettes that have very different standard nicotine yi Research could show if there is an optimum combination of atano,....L yield and ratio that leads to maximum satisfaction and minimal exposure to toxic products. Cigarettes that vary systematically in "tar" to nicotine ratios are needed for this research. Machine-Smoked Yields of Lower "Tar" and Nicotine Cig~rettea . The standard smoking-machine assay of "tar" and nicotine yields provides inadequate information to the tobacco consumer as well as to the researcher (16, 45, 7,6).. The published yields do not indicate how many puffs were taken on a particular brand (45); assays at the Oak Ridge National Laboratory (37) reveal that from 6.9 to 11.5 puffs are taken on different brands of king-size filter cigarettes during standard assays.. The current smoking machine standards are meant to represent an average smoker, but it is probable that the standard puff volume (35 cc) is too small (5, 51) and that the puff interval (one puff per minute) is too long (4, 74). Since compensatory smoking occurs with lower "tar" and nicotine cigarettes, larger and more frequent puffs tend to be taken. Smokers sometimes interfere with ventilation holes on lower "tar" and nicotine cigarettes (45); smoking-machines do not. In addition to the standard assays, there should be maximum-yield assays of "tar," nicotine, and carbon monoxide. These assays would be based on puffing parameters of volume, rate, and duration for the 95th-or even the 75th-percentile of heavy smokers smoking lower "tar" and nicotine ventilated cigarettes up to the tip overwrap. These parameters would be used in smoking-machines, with these same ventilated brands, to derive yields with ventilation holes in both blocked and unblocked conditions. This procedure would produce much higher yields than does the standard assay, and these values would better represent the possible maximum risks of the lower "tar" and nicotine cigarettes to smokers who engage in compensatory smoking. Without access to information about how much the standard yields can change with intensive smoking, there can be only a limited understand- ing of possible reductions in actual smoking exposure. Using research in the British-American Tobacco Company Laboratories in the United Kingdom, Green (16) has argued that intensive smoking can make middle "tar" cigarettes (11 to 16 mg) deliver as much as high "tar" cigarettes (81 to 35 mg). Green could not demonstrate that low "tar" cigarettes (0.4 to 9 mg) can be made to deliver high "tar" levels, but this study did not consider the effect of blocking the ventilation holes on these cigarettes. Toxicology of Nicotine A probable outcome of behavioral research will be that nicotine is the primary pharmacological reinforcer for cigarette smoking. If this 'P` "B6BZ68 195
Page 138: apt20e00
prediction is correct, a lower "tar" and nicotine cigarette that will be used by smokers and that will minimize the exposure to other toxic components of smoke may require substantial yields of nicotine (57, 62). Consideration of the toxicity of nicotine, then, may become crucial in determining whether the benefits of lower "tar" and nicotine cigarette smoking outweigh the costs. Summary 1. Nicotine appears to be the primary pharmacological reinforcer in tobacco, but other pharmacological and psychosocial factors may also contribute a reinforcing effect. 2 It appears that some smokers make compensatory adjustments in their smoking behavior with cigarettes of different yields that might increase the amounts of harmful substances entering the body. The frequency and amount of spontaneous compensatory changes in smoking style with different cigarettes require further investigation. 3. Additional information is needed on the role of lower "tar" and nicotine cigarettes in the initiation, maintenance, and cessation of smoking. 4. Rigorous comparative behavioral studies involving animals are needed to provide comprehensive, experimentally valid results on behavioral aspects of smoking. 5. Laboratory techniques developed for study of opioids and alcohol should be adapted for studies of tolerance and dependence on niootine. 6. Improved laboratory facilities are necessary for more tightly controlled behavioral research. A particular need exists for clinically aooeptable cigarettes with standardized ingredients. 7. Smoking-machine measurements that more closely simulate the practices of human smokers must be developed. ~'~esQZSe References (1) ASHTON, H., STEPNEY, It., THOMPSON, J.W. Self-titration by cigarette smokers. British Medical Joarnol 2(6186): 857,860, August 11,1979. (f) ASHTON, H., WATSON. D.W. Puffing frequency and nicotine Intake in cigarette smokers. Britiah Medical Journal 3(5724): 679-681, September 19, 19?0. (1) AUERBACH, 0.. HAMMOND, E.C, GARFINKEL, L Changes In bronchial epithelium in relation to cigarette smoking, 1955-1980 vs. 1970-1977. New Engiand Journal of Medicine 800(B): 861-86, February 22,1979. (4) CREIGHTON, D.E., LEWIS, P.H. The effect of different eigarettes on human smoking patterns. In: Thornton, R.E. (Editor). Smoking BeAavier, PAysioioDi.l eal and Psychological Influenoss. New York, Churchill L[vingetone, 1978, pp. 289-t00. (5) CREIGHTON, D.E., LEWIS, P.H. The effect of smoldng pattern on smoke deliveries. In: Thornton, R.E. (Editor). Smokirq Bebuvior, PAysiaiapfeal and Ptpehdopieal Influences. New York, Churchill Livingstone, 1978, pp. l01-S1l. (6) DENEAU, G.A., INOKI, R. Nicotine self-administratJon In monkeys. Annals of Uw IVea York Aeademy of Seiends 1lR(Artiele 1): 277-279, March 15, 1967. (9) EVANS, R.i., HENDERSON, A., HILL, P., RAINES, B. Smoking in children (e) (9) and adolescents: Psyehosocial determinants and prevention itrategies. In: Krasnegor, N.A. (Editor). TAe Behaeiora! Aspects of Smoking. National Institute on Drug Abuse Research Monograph No. 26. U.S.& Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, DHEW Publication No. (ADM) 79-88?, August 1979, pp. 69-98. FEYERABEND, C., LEVITT, T., RUSSELL, M.A.H. A rapid gas-liquid chromatographic estimation of nicotine in biological fluids. Jonrnat of Pharrmao y and Pllarwaeology 27(6): 484496, Jun.1975. FORBES, W.F., ROBINSON, J.C., HANLEY, J.A., COLBURN, H.N. Studies on the nicotine exposure of Individual smokers. I. Changes In mouth-level exposure to nicotine on switching to lower niootine eigarettes. Internationnl Journal of the Addictions 11(6): 903-850,1976 (10) FOXX, R.M., BROWN, R.A. Nicotine fading and self-monitoring for cigarette (11) (11) abstinence or controlled smoking. Journal of Applied Behavior Analysis 12(1): 111-125, Spring 1979. FREDERIKSEN. LW., MARTIN, J.E. Carbon monoxide and smoking behavior. Addictive Behaviors 4(1): 21-30,1979. GOLDBERG, S.R., SPEALMAN, R.D. Maintenance and Suppression of Re- spondinp by Nieotine tin Monkcys. Paper presented at the National Institute on Drug Abuse Technical Review on Cigarette Smoking as an Addiction, Rockville, Maryland, August 2S-21,1979. (11) GOLDFARB, T., JARVIK, M.E., GLICK, S.D. Cigarette nicotine content as a determinant of human smoking behavior. PAychopharsmeoiogia 1T(1): 89-93, 1970. (14) GORI, G.B. Low risk cigarettes: A prescription. Setenes 194(4271): 1243--1246, Deoember 17,1976. (15) GORI, G.B., LYNCH, C.J. Toward lees harardous cigarettes. Current advances. Journal of ths American Medieal' Association 240(12): 1255-1259, September 15,19T8. GREEN, S.J. Ranking cigarette brands on smoke deliveries. In: Thornton, RE. (Editor). Smoking Behavior, PAy.iotopicsl and Psychological Inffuenees. New York, Churchill Livingetone,1978, pp. 881-SA8. 186 187
Page 139: apt20e00
(17) ux 'HS, R.R., BRADY, J.V., BRADFORD, 4D. Predicting the abuse Iiabuity of drugs with animal drug self-administration proeedunst Paychomor tor stimulants and hallucinogens. In: Thompson, T., Daws, P. (Editors). Advances in Behaviora! PAa+7naeoioyy. Volume 2. New York, Academic Pneae, 1979, pp.1f3--20B. (18) GRITZ, E.R. Smoking behavior and tobacco abuse. In: Mello, N.K. (Editor). Advances in Substance Abuse. Volume 1. Greenwk,h, Connecticut, JAI Press, 1980, pp. 91-16& (19) GRITZ, F R,, BAERrWEISS, V., JARVIK, M.E. Titration of nicotine intake with full-length and half-length cigarettes. Clinica! Pharnmcolopy and Tberapeutica 20(b): b52-65B, November 1976. (=0) GRITZ, E.R., BRUNSWICK, A., BIERMAN, K.L. Behavioral aepecta of amoking. In: U.S. Department of Heaith. Education, and Welfare. 77m Health Conaeqwenas of S+hokiwy for Wonuw: A Report of th. Su+peow General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Aasistant Secretary for Health, Office on Smoking and Health,1980, pp. 271469. (21) GRITZ, E.R, SIEGEL, R.K. Tobacco and smoking in animal and human behavior. In: Davidson, R.S. (Editor). Modification of Pathological Behavior. Experinwrntal Analyass of Fatioiogy and Behovior Therapy. New York, Gardner Preas,1979, pp. 419-476. (tf) HANSON, H.M., IVESTER, C.A., MORTON, B.R. Niootine self-administration in rats. In: KraaneQor, N.A. (Editor), G4ganstte Smoking as a Drpe„dtnte Process. National Institute oa Drug Abuse Research Monograph No. 24. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, DHEW Publication No. (ADM) 71I`800,1979, pp. 70-90. (tJ) HARRIS, J.E. Public policy issues in the promotion of ler harardous cigarettes. In: Goei, (;.B., Bock, F.Q (Editors). Banbury Report 1-A Safe Ciparate t Cold Spring Harbor, New York, Cold Spring Harbor Laboratory,19B0, pp. 893-M. (!4) HENNINGFIELD, J.E., GRIFFITHS, R.R. A preparation for the experimental analysis of human cigarette smoking behavior. Behavior J4ueareA Methods and Inetrumentation 11(6): 6,98-b44, Deoember 1979. (25) HENNINGFIELD, J.E, GRIFFITHS, R.R. Effects of ventilated cigarette bolders on cigarette smoking by humans. Paychophannasolopy 68(2): 116-119, 1980. (t6) HENNINGFIELD, J.E., STITZER, M.L., GRIFFITHS, R.R. Expired air carbon monoxide accumulation and elimination u a function of number of eigarettes smoked. Addictive BtAarior+ b(8): 26b-278,1980. (!~ HERMAN, C.P., KOZLOWSKI, I...T. Indulgence, excess, and restraint: Perspec- tives on consummatory behavior in everyday life. Journal of Drug Iaevs.9(2): 185-196. Spring 1979. (28) HILL, P., MARQUARDT, H. Plasma and urine changes after smoking different brands of cigarettes. Clinical Pharmaaolopy and Thanapeuutica 27(b): 652-668, May 19®0. (t9) H_ OFFMANN, D., TSO, T.C., GORI, G.B. The leas harmful cigarette. PrevenCive Medieine 9(2): 287-288, Maech 1980. (J0) HULLEY, S.B., ROSENMAN, R.H., BAWOL, R.D., BRAND, R.J. Epidemiology as a guide to clinical decisions. The association between triglyoeride and coronary haart disease. New Degla+u! Journai of Medicine 80Z(2b): 1389-1389, June 19,1990. (31) JAFFE, J.H., JARVIK, M.E. Tobacco use and tobacco use disorder. In: Lipton, M.A., Di Mascio, A., Killam, LF. (Editors). Peyc/bpAnrsaco/opy: A Generation of Anyr.er. New York, Raven Press,1978, pp.186rp-1878, tY) JAFFE, J.H., KANZLER, M., FRIEDMAN, L Studies of .witehing to low and nicotine cigarettes. In: Gori, G.B., Bock, F.G. (Editors). Banbury Rrpt J-A Safe Cigarettet Cold Spring Harboe, New York, Cold Spring Harbor Laboratory,1980, pp. 511-3?A. (1J) JARVIK, M.E. Tolerance to the effects of tobacco. In: Kraanegor, N.A. (Editor). Cigarette Smoking as a Dependence 13aoas*. National Institute on Drug Abuse Research Monograph No.. 28.. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug. Abuse, and Ment4 Health Administration, National In.titute on Drug Abuse, DHEW Publical,ion No. (ADM) 79400, January 1979, pp.160-1b7. (J4) JARVIK, M.E. Biological influences on cigarette smoking. In: Krasnegor, N.A. (Editor). Ths BeGaoiond Aspects of Smoking. National Institute on Drug Abuse Research Monograph No. 26. U.B. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, DHEW Publication No. (ADM) 79-882, August 1878, pp. 7-45. (35) JARVIK, M.E, GLICK, S.D., NAKAMURA, R.K. Inhibition of cigarette smoking by orally adminiN.ered nicotine. Clinical Pharmacology and Tlura- pautica 11(4): b74-678, July-August 1970. (JB) JARVIK, M.E., POPEK, P., SCHNEIDER, N.G., BAERrWEISS, V., GRITZ, E.R. Can cigarette size and nicotine oontent influene_e smoking and puffing rates? Prychopharanaoolopy 68(S): 808-808,1978. (11') JENKINS, R.A., QUINCY, R.B., GUERIN, M.R. Selected Conatitusnts in the Snwku of U.S Commaieial Ciyar+rtd.n "7bv," 1Viootine, Carbcn Monoside and Carbon Dioxide. Oak Ridge, Tennessee, U.S. Department of Energy, Oak Ridge National Laboratory, No. ORNL/TM-6870, May 1979, 42 pp. (S8) JOHNSTON, L Tobacco smoking and nicotine. Lancet E: 742,1942 (J9) JONES, R.T., FARRELL, T.R., III, HERNING, R,I. Tobacco smoking and nicotine tolerance. In: Krasnegor, NA. (Editor). Salf-Adminiatratium of Abused Subdanaar Methods for Study. National Institute on Drug Abuse Research Monograph No. 20. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse,1978, pp. 202-2D8. (40) KOZI,OWSKI, LT. Psychoso¢ial Influences on cigarette smoking. In: Krasne- gor, gor, N.A.. (Editor). T1u B.Aaaioral Aspects of Smoking. National Institute on Drug Abuse Research Monograph No. 28, U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, DHEW Publication No. (ADM) 79-882, August 1979, pp. 97-125• (41) KOZLOWSKI, LT. TAs Rols of Nicotine in the Maintained Use of Cigarettes. Paper presented at the National Institute on Drug Abuse Technical Review on Cigarette Smoking as an Addiction, Rockville, Maryland, August 23-24, 1919, 19 pp. (42) KOZLOWSKI, LT., FRECKER, R.C., KHOUW, V., POPE, M.A. The misuse of "less hazardous" cigarettes snd its detection: Holabbeking of ventilated filters. American Journal of Public Health 70(11): 1202-1203, November 1980. (43) KOZLOWSKI, L.T., HARFORD, M.R. On the significance of never using a drug: An example from cigarette smoking. Journal of Abrwrnw! Psychology 85(4): 483-454, Auguat 1978. (44) KOZLOWSKI, LT., JARVIK, M.E., GRITZ, E.R. Nicotine regulation and cigarette smoking. Clinical Pharmacology and TAerapeutiu+ 17(1): 93-97, January 1975. (4S) KOZLOWSKI, LT., RICKERT, W.S., ROBINSON, J.C., GRUNBERG, N.E. Have tar and nicotine yields of eigarettes changed? Seience 2U9(4184)s 1b60- 1b61, September 26, 1980. 188 stesezsQ 189
Page 140: apt20e00
(4e) KUMAR, R., CUGKE, E.C., LADER, II.H., RUSSELL, Id.A.H. Ie nicotine important in tobacco amoking? Clinioal Pllarmaooiopy awd Tberapeutits 21(5): 620-b28,1[ay 1977. (4t) LANG, WJ., LATIFF, A.A., MCQUEEN, A., SINGER, G. $elf-administration of nicotine with and without a food delivery schedule. P1+a*awoo(ayy, BioeAnRiet+y and BeAavior 7(1): A6-70, July 1977. (4d) LARSON, P$., BILVETTE, H. ToBoooa E+psri+tental and Clinioal Studies. Supplement IIL Baltimore. Williams and Wilkin,1975, 798 pp. (46) LUCCHESI, B.R., SCHUSTER, C.R., EMLEY, A.B. The role of nicotine as a determinant of cigarette smoking frequency in man with observations of certain cardiovascular effects arm3ated with the tobacco alkaloid. Ainicai Plisrnaaoloyy and 17terapertise e(6): 789-796, Novembsr-Deoember 1967. (50) MCGILIti H.C, JR., RGGERB, W.R, WILBUR, RL, JOHNSON. D.E. Cigarette smoking baboon model: Demonstration of feasibility. livaediuge oJtJb Society forltxper#+neatal BioloDy and Medieine 167(4); 672_878, April 1978. (51) MOODY, P.M., GRDrFITH, R.B„ AVERIIT, J.H. Smoking history and puff profiles of hospital patients. In: Praoesdiwpe of tlYe Uwirosrtlty of Kentucky Tobaocs and IleaitA Research InaNtxte, RbAsaao and ReattA Workshop Con/esewce, ConJinMee Report s, Ls]dngton, Kentucky, January 11-13, 19T2, PR a1-{E, (52) PECHACEK, T.F. Modification of smoking behavior. In; Krunegor, N.A. (Editor). TAe BeAaviornl Aepeets of Ssro+kiwy. National Inatitute on Drug Abuse Research Monograph Na 26. U.3. Department of Health, Education, and Welfare, Public Health Service, Aloohol, Drug Abuse, and Mental Health Administrstion, National Inatitute on Drug Abuse, DHEW Publication No. (ADM) 79-832„ Au3u.t 1979, pp..12/-1s8. (5a) PIEPER, W.A., CGLE, J.M. Operant control of smoking In great apea. Behavior ReaearaA MetAafe and Inetru+sentatiow 6(1): 4-d,197s. (54) PILLSBURY, H.C., BRIGHT, C.C., O'CONNOR, ILI., IRISH, F.W. Tar and nicotine In dgarette smoke. Josrnai of the AaaootaNoa of OJ)'Seiat Analytical CMm{rta 62 (E): 458-462, May 1969. ((55) RGBINSON, J.C., YOUNG, J.C. Temporal patterns in smoking rste and mouth- level nicotine exposure. Addiative B.havioss, in pe~ese. (56) RU3SELL, M.A.H. Cigarette amoking: Natural history of a dependence disorder. BriNah Jow,rnis! oJMedioal Ptyelleiayg 44(1):1-16, May 197L (57) RUSSELL, M.A.H. Low-tar medium-niootine dgarettes: A new approach to safer amoking. British Medioai Journal 1(E028):1430.1433, June 12,197& (58) RUSSELL, M.A.H. Tobacco smoking and nicotine dependenoe. In: Gibbins, RJ., Israel, Y., Kalant H., Popham, R,E., S4hmidt, W., Smart, R.G. (Editors). Research Advances in AlcoAol and Drug Plobie+ne. Volume 3. New York, Wiley and 9oea,197a, pp. 1-47. (55) RUSSELL,1[.A.H. Tobacco dependence: Ia nicotine rewarding or aversive? In: Kranagor. N.A. (Editor). Cigarette Smoking as a Dependence I4+oc.we. National Institute on Drug Abuse Research Monograph Na 23. U.B. Depart- ment of Health, Lrdueation, and Welfare, Publie Health Servkea, Alcohol, Drug Aow.., and Meetal Health Admini.tration, National Institute on Drug Abuse, IyliEW Publication No. (ADM) 7g-800, January 1979, pp 106-12Z (60) RUSSELI~, l[.A,H. The ose for medium-niootine, low-tar, low-cwrbon mono:ide cigarettes. In: Gorl, G.B., Boek, F.G. (Edlton). Banbsvy Report S-A Safe Cigarette? Cold Spring Harbor, New York, Cold Spring Harbor Laboratory, 1980, pp. 2p7-S1o. (61) RUSSELL,1[.A.H., FEYERABEND, C. Cigarette mwk(ng: A dependence on bigh-niootiee boli. Drrp Metebolina Reviews e(1): 2o-b7,197& (6t) RUSSELL, M.A.H., JARVIS, M., IYER, R., FEYERABEND, C. Relation of nicotine yield of cigarette to blood nicotine concentrations in smokers. British Medical Journal 280(B219): 972-976, Apri16,1980. (6J) RUSSELL, M.A.H., SUTTaN, S.R, FEYERABEND, C., COLE, P.V. Addiction Research Unit nicotine titration studies. In: Thornton, R.E. (Editor). Smoking Behavior, PAyeioloyicat and Fsyeholoyie+nt IxJiaenoet. New York, Churchill Livingstone,1978, pp. 336548• (Q_4) RUSSELL, M.A.H., SUTTON, B.RL, FEYERABEND, C., COLE, P.V., SALOG- JEE, Y. Nicotine chewing gum as a substitute for smoking. British Medical Jo4+wal 1(8088): 1060-.1063, Apri123,1977. (65) RUSSELL, M.A.H., WIISGN, C., PATEL, U.A., FEYERABEND, C., COLE, P.V. Plasma nicotine levele after smoking ciQarettes with high, medium, and low nicotine yields. British Medical Journal 2(b968): 414-416, May 24, 1076. (66) SCHACHTER, S. Nicotine regulation in heavy and light smokers. Journal of E~psrtwte„tai Payohoioyy: General l0Q(1); 6-12, March 1977. (6y) SCHACHTER, S. Pharmacological and psychological determ(nants of making. Anna(a o/Iwhnnl Medicine 88(1):104-114, January 1978, (6d) SCHACHTER, S. Regulatjon, withdrawal, and nkotlne addktioa In: Krasne- gor, N.A. (Editor). Gtiga..tte Snooki+p as a Dependence Aroaar. National Institute on Drug Abuse Research Monograph No. 2S. US. Department of Health, Education, and Welfare, Public Health Service, Aloohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse, DHEW Publication No. (ADM) 79-800, January 1979, pp.123-13.3. (69) SCHACHTER, S., SILVERSTEIN, B., KOZLOWSKI, LT., PERLICK, D., HERMAN, C.P., LIEBLING, B. Studies of the interaction of psychological and pharmacological determinante of smoking. Journal of hkpePimental Ayehoio- gk General 10E(1): 5-40, March 1977. (70) SCHUSTER, C.R.. JOHANSON, C.E. The use of animal models for the study of drug abuse. In: Gibbin., R.J., Israel, Y., Kalant, H., Poph.m, RE., Schmidt, W., Smart, R.G. (Editors). RsmareA Advances in Alcohol and Drug F4nbtsme. Volume 1. New York, Wiley,1974, pp.1-S3. (71) SHIFFMAN, S.M. The tobaooo withdrawal syndrome. In: Kreanegor, N.A. (Editor). Ciyawffe Smoking aa a Depnndence Prvass. National Institute on Drug Abuse Research Monograph No. 23. U.S_ . Department of Health, Education, and Welfare, Public Health Service. Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publication No. (ADM) 79-800, January 1979, pp.168-161. (72) SILVERSTEIN, B., FELD, S., KOZLOWSKI, LT. The availabllity of low- niootine cigarettes u a esuse of cigarette smoking among teenage females. Journal of flealtA and Social Behavior, In press. (73) STEPNEY, R Consumption of cigarettes of reduced tar and nicotine delivery. BritiaA Joarnat of the Addictions 7s: e1-96,1980. (74) SUTTON, S.R, FEYERABEND, C., COLE, P.V., RUSSELL. M.A.H. AdJu.tr ment of smokers to dilution of tobacco smoke by ventilated cigarette holdets. Cliniaa! Pharnmaoolopy and TAernpertics?A(4): S9b-4U6, Gctober 1978. (75) THGMPSGN, T., UNNA, K.R. (Editora). Predicting Depende+ioe Ziobility of Stimulant and Depreesmit Drxya. Baltimore, University Park Prer,19TJ. (76) U.S. DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE. SMOking and ReeltJk+ A Report of Ue Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health 9erv{oe, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Publicttion No. (PHS) 78-0O0E6,1979,1136 pp. 196 9IRGRZ6e !
Page 141: apt20e00
(77) U.B. DEPAETYENT OF HEALTIi, EDUCATION, AND WELFARIr'. TTw NiaW Avnnpsnaa ajBwaEtap Jbr Wonun: A R.port of tM SwrywK C.r..el. U.S. Dep.r#aest of Healtb, Edurstion, and Wolfan, Public Hedth Sarvia, OIGoe of tL. Assistant 8aor.tary for Health, Offioe on Smoidng and H.alth. IY!B0, 369Pp. (7Y) U.S. NATIONAL INSTITUTE ON DRUG ABUSE. 'haAsioa! R.view ca GYya..tt. Snwiisp ee ax Addiction. Final Report Summarizing Task Force Yasting Sponored by tb. National In.titnte on Drug Abu.., Augo.t 28-2t, 1878. U.S. Department of Health, Ednestbn, and Wdtare„ Public Health Servioa, Akohd, Drug Abuse, and Mental Health Administration, National Institute oe Drug Abu@,1979,14 pp. (79) WALD, N.J., IDLE, I[., BOREHAM, J., BAILEY, A. In6aling habits among .mok.rs of different typr of atgarstts..l7Ymos, in pre.a (Ao WALD. N., IDLE, M., Sl[ITH, P.(i. BAILEY, A. Carbozyhaanwglabin levels in .mok.rs of filter and plain eignattea.. Idsat 1(800g): 110.11?, January 16, Iia77. (81) WYNDER, E.L, HABUCHI, K, BEAITIE, FJ, JR. The epidemiology of lung canoer. ./ornai of fA. Awwrioaw 1l.dieaL AaockWmm 218(13): Z7ZI-~, 3eptqmbar ffi,1970. (82) YANAGITA. T. Brief r.view on the use of .elt-adminbtrstion teehniquea for pesdiatinE drug dnp.od.oa potentid. In: Thomp.os, T, Unaa, II.R (Editors). PA.dioliV D.paJ.ep l,iobility of SYiwwdant and D.pwraaswt lhvpr. Balti- mon, University Park Pras,l9Tl, pp. 281-7A2. Section 8. LOWER "TAR" AND NICOTINE CIGARETTES: PRODUCT CHOICE AND USE 192
Page 142: apt20e00
CONTENTS Introduction The Growth in the Use of Lower "Tar" and Nicotine Cigarettes An Increasing Public Awareness of the Health Hazat+ds of Cigarette Smoking Public Attitudes The Cigarette Profile Cigarette Choice and Smoking Behavior Overview Relationship of "Tar" and Nicotine Yields to Smoking Behavior Consumption Patterns Cessation Summary Addendum: Comparison of "Tar" and Nicotine Yields of Cigarettes in 1978 and 1979 Yields of "Tar" and Nicotine Correlation of Varieties Reported in 1978 and 1979 "Tar" and Nicotine Yields of New Brands in 1979 Applications to the Discussion Referencee LIST OF FIGURES Figure 1.-Market ahare of dollars expended in the U.S. on advertising and promotion of cigarettes yielding 515 mg "tar" compared with total domestic cigarette advertising and promotional expenditures for years 1970, 1975, 1976, 1977, and 1978 195 eigs8z~e
Page 143: apt20e00
Figure 2.-Domeatic market share of cigarettes yielding S 15 mg "tnr,"' 1967-1978 Figure 8.-Sales-weighted averages of "tar" and nicotine per cigarette consumed in the U.S., 1954-197b Figure 4.-Salee-weighted averages of "tar" and nicotine per cigarette consumed in the U.S., 1968-1978 Figure 5.-Ratio of "tar" to nicotine based on sales- weighted averages of cigarettes consumed In the U.S., 1968-1978 Figure 6.-Delivery of nicotine as a function of "tar" of commercial cigarettes, U.S. Figure 7.-Delivery of carbon monoxide as a function of "tar" of selected U.S. commercial cigarettes Figure 8.-Index of average "tar" and tobacco per cigarette, annually, 1967-1979 Figare 9.-Annual per capita consumption of total cigarettes and filter-tipped cigarettes in the U.S., for persons aged 18 and older, 1900-1979 Figure 10.-Annual per capita consumption of tobacxo products in the U.S. (including overseas forces) for persons aged 18 and older, 1925-19T9 • Figure 11.-Annual per capita consumption of cigarettes in the U.S. (including overseas forces) for persons aged 18 and older, 1963-1978 I ' 'LIST OF TABLES Table L-Estimated percentage distribution of current regular smokers by "tar" yield of primary brand of cigarette, by sex, race, age, and education, adults, U.S., 1979 siesezse 196 Table 2.-Mean daily dose of "tar" or nicotine for current regular smokers by race, sex, and age, U.S., 1979 Table 8.-Fetimated percentage distribution of current regular smokers by "tar" and nicotine yield of primary cigarette used, U.S., 1978 and 1979 Table 4.-Eetimated percentage distribution of regular smokers by "tar" yield, adolescents aged 12-18, U.S., 1974 and 1979 Table b.-Percent distribution of adoleeoent regular smokers by "tar" yield of primary. , brand, by sex and age, U.S., 1979 Table 6.-Mean age at onset of regular smoking by "tar" or nicotine yield of primary brand, by age at interview, current regular smokers, U.S., 1979 Table 7.-Estimated percentage distribution of current regular amokers by number of cigarettes smoked daily by approximate quintiles of "tar" or nicotine yield, adults, U.S., 1979 Table 8.-Mean number of cigarettes smoked daily by "tar" or nicotine yield, by age groups, current regular smokers, adults, U.S., 1979 Table 9.-Estimated percent of current regular smokers who have tried seriously at least once to quit, by "tar" or nicotine level and age, U.S., 1979 Table 10: Estimated percentage distribution of recent smokers by status of recent attempt to quit, by "tar" or nicotine yield of primary brand, July 1978 through December 1979 Table 1L-Estimated percentage distribution of current regular smokers by number of serious attempts to quit smoking, by "tar" or nicotine level, U.S., 1979 Table 12.-Mean duration of most recent attempt to quit, by "tar" or nicotine yield of current primary brand, current regular smokers, 1979 197
Page 144: apt20e00
Introduction - Table 18.-Mean yield of "tar" and nicotine of cigarettes, This section discusses changes in cigarette smoking over recent years by type of modifier, all and filtertip varieties, U.S., 1978 in the United States. Currently available evidence indicates that, while and ig79 the prevalence of cigarette smoking is at its lowest point in several decades among both adults and adolescents, there are significant Table 14.-Mean yield of "tar" and nicotine of the differences in the cigarettes being used by those persons w~fo do varieties of cigarette marketed in both 1978 and 1979, smoke, by type of 'modifier, all and filtertip varieties, U.S. The discussion does not attempt to describe comprehensively the patterns of cigarette smoking; such reviews have been published Table 16: Comparison of "tar" and nicotine yield on the previously (Q5, 26). Rather, it focusea on the information that describes varieties of cigarette marketed In both 1978 and 19?9, the cigarette products currently being used by smokers and the role ~ that such modified products may play in the smoking habit. It includes U examination of (1) the growth of the lower "tar" and nicotine cigarette, including social and marketplace activity in recent years, Table 16.-Mean yield of "tar" and nicotine of the new and' (2) cigarette product choice and use by the smoking population. varieties of cigarette marketed In 1979, by type of This consideration of changes in the cigarette is restricted to that of modifier, U.S "tar" and nicotine yields of various cigarette brands, because of the _ availability of systematic measures of these constituents through the Table i7.-Distr[bution of "tar" and nicotine yield of the annual reports of the Federal Trade Commission (FTC)• Note should be new varieties of cigarette marketed in 1979, U.S. taken, however, that the extensive discussion of "tar" yields in this Report ought not to be construed as implying a primary or singular role of "tar-" in causation of all the adverse health effects associated with cigarette smoking. Rather, "tar" yields are used because they are readily available and correlate closely to nicotine levels. No comparable measurements are available for carbon monoxide or other constituents of cigarette smoke, such as acrolein, hydrogen cyanide, or the nitrogen oxides, which are identified as probable contributors to smoking- related disease. Further, there are no systematic data available regarding the effects of commercially used cigarette additives on the yields of any of these constituents. Although the data cited here are derived from multiple sources, much of it represents the first analysis of a large, ongoing national survey. At the request of the Office on Smoking and Health, a smoking supplement was added to the continuing National Health Interview Survey (NHIS) by the National Center for Health Statistics. Begun in July 1978 and continued through 1879, the smoking supplement was designed to provide data on the prevalence of smoking, amount smoked, and attempts to quit smoking. Representing a random one- third subsample of the NHIS interviews of noninstitutionalized peraons aged 17 or older, the 18-month data included approximately 86,000 individuals interviewed. Unless otherwise indicated, the data cited represent analysis of the approximately 24,000 interviews on smoking conducted during calendar year 1979. Lifetime smoking status (i.e., never, regular, occasional, and former smoker), age at onset, d~gEiQ~F`s~ brand choice, amount smoked, and data on the attempt(s) to quit were collected for recent and current smokers. The "tar" and nicotine yields M 199
Page 145: apt20e00
for the 1978 and 1979 NHIS data sets are based on the FTC listing of cigarette varieties, sampled in 1977 and published in May 1978, and updated to include cigarettes identified by the FTC as marketed in July 1978. Three major conclusions can be elicited. First, Government and other agency activities in recent decades have led to widespread public recognition of the health hazards of smoking cigarettes. Second, the marked increase in the use of filter-tipped cigarettes in the late 1960s has been followed by a reduction in the "tar" and nicotine content of the cigarette products actually being seleeted and used by the smoking population. Third, the role of cigarettes of varying levels of "tar" and nicotine in the initiation, maintenance, or cessation of smoking is unknown. The data from the National Center for Health Statistics presented here neither prove nor disprove a role of lower "tar" and nicotine cigarettes in easing initiation, increasing daily consumption among regular smokers, or decreasing the probability of attempting to quit or of succeeding in the attempt. Much further work remains to be done to clarify and define the effects of lower "tar" and nicotine cigarettes on these behaviors, and thus their effect on total lifetime patterns of cigarette smoke exposure. The Growth In tM Us. of Lower "Tar" and NlcoUn. Cigarettes An Increasing Public Awareness of the Health Hasards of Cigarette Smoking The decades since the first medical reports of a link between lung cancer and smoking in the 1950s have seen multiple ehanges in the cigarette products being used by the smoking population (11,14,15,1B, 85). A number of factors may have encouraged these changes. The U.S. Public Health Service (PHS) has been active in assessing and attempting to reduce the excess burden of preventable illness related to cigarette smoking. Its first oomprchensive review of the evidence linking cigarette smoking and adverse health effects by the Advisory Committee to the Surgeon General of the Public Health Service in 1964 was followed by regularly issued reports from 1966 through 1980, each of which continued aua extended the PHS concern. In 1966, the PHS submitted to Congress (.ft) the Teehniasl Report on "Tar" and Nicotine. On the basis of the clear demonstration of cigare" dose-dependent risks of several diseases, the PHS concluded: The preponderance of scientific evidence strongly suggests that the lower the "tar" and nicotine content of cigarette smoke, the less harmful would be the effect. We recommend . . . the progressive reduction of the "tar" and nicotine content of cigarette smoke. 200 iZ96e68 At the same time, Secretary of Health, Education, and Welfare John W. Gardner urged the Congress to require "tar" and nicotine levels on packages and advertisements, with provision for adding to the label any ingredients subsequently identified as hazardous (.t.4). The PHS then began transmitting this information to the public. The PHS policy formulated on the evidence available was that there is no safe cigarette; the single best way to avoid the health hazards of smoking is to quit smoking, but for those unable to quit, a lower "tar" and nicotine cigarette would probably pose lower risks. In 1972, the PHS classified some of the known chemical constituents of cigarette smoke into different risk categories. The compounds classified as "most likely" contributors to health hatards. "tar," nicotine, and carbon monoxide-were recommended as primary targets for reduction (J.t). In 1974 and again in 1975, Secretary of Health, Education, and Welfare Caspar W. Weinberger formally requested legislation author- izing the regulation of cigarettes by formulation of maximum permissible levels of hazardous ingredients (38,39). During this time, a number of health professional societies, volun- tary health agencies, and concerned citizena' groups also conducted public education activities on the health hazards of cigarette smoking. The cigarette Industry's activities during this period probably also influenced changes in cigarette chom In 1852 only L4 percent of cigarettes sold in the United States were filter tapped; by 1956, 29.9 percent of all cigarettes were filtered (27). In 1979, filtered cigarettes represented 89.2 percent of all brands marketed (t.l), and were used by 9L7 percent of regular smokers, according to data from the 1979 Smoking Supplement of the National Health Interview Survey. Advertising probably contributed to this rapid growth of filter-tipped cigarettes. As early as 1954, one brand's advertising slogan read, " . . . filter gives greater protection against nicotine and tars than any other cigarette on the market today. It is the greatest health protection in cigarette history" (27). Another brand advertised the "Miracle of the Modem Miracle Tip" (even while the "tar" yield of that product increased 40 percent and the nicotine Increased 70 percent over the 2• year period after the filter had been introduced) (2?'). During the last decade, when systematic data on "tar" and nicotine yields of marketed cigarettes have been available, lower "tar" brands have been marketed in Increasing proportions. Federal Trade Commis- sion data show that cigarettes yielding 15 rng or less of "tar" constituted 15 percent of all brands in 1968, 20.4 percent in 1972, 30 percent in 1976, and 69.5 percent in 1979 (1, l, J, 5). Over the same time period, the proportion of all marketed brands that yielded 10 mg or less of "tar" Increased from 4.7 percent in 1968, 9.9 percent in 1972, 124 percent in 1976, to $8.0 percent in 1979. 201
Page 146: apt20e00
1no asn u" vW un IM FIGURE 1.-Market share of dollars expended In the U.S. on advertising and promotion of cigaretta yielding 515 mg "tat•' compared with total domestic cigarette advertising and promotionsl expenditures for years 1970, 1976, 1976, 1977, and 1978 NOR: r.wb~. (i.dd.wr) e.f. Vprma.r.ua WLY.d Lr. e0tlIICC DM.d h+.rW..t11.i G..irt..lq. Further, the marked increase in the last 5 years in the proportion of all cigarette sales accounted for by branda yielding 515 mg "tar" coincides with an increased percentage of total dollars spent for advertising and promotion of cigarettes yielding 15 mg or leaa of "tar" per cigarette. Figure 1 shows this increaaing promotional efforC Since 1970, the absolute amount as well as the percent of all advertising dollars spent that went to advertising of "low tar" cigarettes has increased from approximately $87„900,000, or 10.5 percent, In 1970 to ;421,800,000, or 48.1 percent, in 1978 (4).'1his increase occurred over the same period as the greatest increase in the lower "tar" brands' proportion of market eales. Public Attitudes Several surveys have exurnined the opinions of the general public about cigarette smoking. zz$sezsa Public surveys conducted by the National Clearinghouse on Smoking and Health examined the beliefs and attitudes of the U.S. public relative to cigarette smoking (28, 89, 38, $0, 41). These surveys indicated that the belief that cigarette amoking poses health hazards was increasing, not only among the general public but also alnong persons who continued to snwke. For example, in response Ib the statement "Smoking cigarettes is harmful to healtb;' in 1964, 81.5 percent of the persons interviewed agreed and 18.1 disagreed, but in 1975, 84.9 percent agreed and 11.8 percent disagreed, with intersaedi-o ate figures occurring in 1970 (29, ZS, se). Substantial differences were apparent when smoking history was considered. In 1964, former smokers believed smoking to be harmful in 90.5 percent of interviews, while only 69.5 percent of the current smokers believed smoking harmful; only 7.4 percent of former smokers did not agree that smoking is harmful, but 21.9 percent of smokers did not agree (29). This diffet+ence by smoking status in the percentage of interview subjects who believed smoking to be harmful persisted in 1975, but the difference narrowed (78 percent of current smokers agreed and 91.6 percent of former smokers agreed) (39). Very similar results were reported in a large survey in 1978, which found that 90 percent of all persons and 88 percent of smokers believed smoking to be harmful to health (7). The percentage of smokers who agreed that "cigarette smoking frequently causes disease and death" incre,aeed from 52Z percent in 1966 to 70.7 percent in 1975; the proportion of smokers who disagreed declined from 87.6 percent in 1966 to 22.3 percent in 1975. The percentage of the total population who had no opinion on this question and the preceding question declined from 9.1 percent to 5.3 percent and from 4.7 percent to 3.4 percent, respectively. This suggests that educational efforts may have reduced the size of the "undecided" population. Other questions assessed the personal impact of beliefs about the health hazards of cigarette smoking. Although the percentage of smokers who reported being "alightly" concerned about the possible effects of smoking on their own health remained fairly constant from 1966 (18.1 percent) to 1975 (18.9 percent), the proportion of smokers who were "fairly" or "very" concerned Increased from 29.1 percent in 1966 to 47.6 percent In 1975. The number of smokers "not concerned" declined from 52.5 percent In 1966 to 31.5 percent in 1975. For the entire population, the proportion of interviewees who agreed that "smoking (is) enough of a hazard for something to be done about it" Increased from 76.8 percent in 1966 to 84.0 percent in 1975. Additionally, one question asked of current smokers In 1966, 1970, and 1975 provides information on smokers' peroeptions of varying hazards by cigarette type (29, 36, 40). The number of smokers who felt that "all cigarettes (are) probably equally hazardous" declined from I
Page 147: apt20e00
67.8 percent in 1966 to 40.6 percent in 1975, while the number of smokers who believed that "some cigarEtteE (are) more hazardous than others" increased from 29.9 percent in 1966 to 49.1 percent in 1975. Among smokers who believed there was a difference among cigarette brands in health hazard, current smokers who believed their own cigarette brand was fsas hasatdoua than other kinds declined from 69.9 percent in 1966 to 49.7 percent in 1975, and smokers who believed their cigarette brand was nwrs hasardeus increased from 12.6 percent to 20.4 percent. Thus in the period from 1966 to 1975, there was an increasing proportion of smokens who believed different cigarettrm posed varying health rlsks, but among these smokers the proportion who felt their cigarette was more dangerous to health than other cigarettes also increased. Unfortunately, identical large surveys to assess subsequent trends either in smokers' beliefs about differences in health risks or about the role of such beliefs In affecting cigarette product choice have not been published since 1975. The Tobacco Institute, which represents the cigarette manufactue- ers, has also supported periodic surveys of attitudes. Their most recent survey is publicly available. Conducted in 1978 (18), this survey found that more than 90 percent of the U.B, population believed cigarette smoking is hazardous to the health of the smoker. Fully 61 percent believed that any amount of smoking Is hazardous, up from 47 percent in 1970. This is In close agreement with surveys performed by the PHS in 1970. Further, in 1970 and 19?8, 42 percent and 50 percent, respectively, of the population surveyed believed that smoking "makes a great deal of difference in longevity;" a higher percentage than those believing the same thing about fatty diets (43 percent), alcohol consumption (89 percent), lack of exercise (84 pereent), and overweight (24 percent). The proportion of all persons who believe smokers "have" or "probably have" more of "certain illnesses" has increased from 56 percent in 1970 to 62 percentin 1978, when only 11 percent believed that smokers do not suffer more illness. Only 8 percent of people surveyed did not believe that cigarette smoking is a cause of disease, a figure that has not changed appreciably since 1970. The 1978 Roper Survey found that the proportion of the population who believed others' smoking is hazardous to the nonsmoker's health had inc~,lased from 46 percent in 1974 to 58 peroent in 1978. In 1978, the number who believed passive or involuntary smoking to be harmful was 69 percent among nonsmokers; while among smokers It was 40 percent. For the first time, the health effeet of involuntary smoking was cited most frequently as a reason for legislation to ban cigarette smoking in public places. CZesezse The Cigarette Profile The definition of cigarettes as "lower 'tar' " at ~ 15 mg is arbitrary. Nonetheless, this breakpoint has gained general acceptance. The separation of S 15 mg "tar" was meaningful when the vast majority of cigarettes were of higher "tar" yields; now, however, more than half of all the cigarettes sold in this country are at or below the level of 15 mg "tar" per cigarette. Many of the following measures use this break- point (_<15 mg). Special note should be taken, however, of the fact that both "tar" and nicotine yields vary continuously, and groupings by relative yield measurements do not automatically imply differences either in the type or in the magnitude of their biologic effects. As discussed previously, the proportion of domestic commercially marketed cigarette brands that yield 15 mg or less of "tar" has increased over the last two decades to 58.5 percent in 1979 (1, 5). These figures, however, reflect industry marketing decisions and do not directly measure the smoking public's selection of a cigarette product. The market share of unit sales, however, reflects both the "tar" yield of each brand marketed and the smoking population's actual use of that product Figure 2 shows the percentage of all U.S. cigarette sales (the "market share") represented by cigarettes containing 15 mg or less of "tar." Over the lsat decado the market share of sales acoounted for by lower "tar" products has increased consistently since 1971. Cigarettes yielding C 15 mg "tar" accounted for only 2 percent of the cigarette market sales in 1967, but the comparable figure ia projected to approach 50 percent in 1980 (24). This represents an almost 23-fold increase over 13 years. There has been a threefold increase over the last 5 years in the proportion of all cigarettes purchased and presumably consumed that are lower in "tar." Thus, cigarettes of 15 mg or less are not only available in the market, but they are also being chosen by the smoking population. A different measure of cigarette choice is the sales-weighted average of "tar" or nicotine. The sales-weighted average is derived from the "tar" or nicotine yield of each cigarette available in the United States, weighted by the numbers of packages of each brand sold annually. The sales-weighted average values for '"tar" and nicotine thus represent a hypothetical "average cigarette" smoked in the United States. Figure 3 shows the trend over time of the sales- weighted average cigarette's "tar" or nicotine content (43). The yield of "tar" declined from 38 mg in 1964 to 19 mg in 1975, while that of nicotine declined from 2.3 to 1.3 mg per cigarette. The decline In both "tar" and nicotine approximated 50 percent over this 20-year period. Data provided from a single source of continuous measurement as shown In Fignre 4 indicate that the decline in "tar" has continued in recent years, although at a slower rate than that observed from 1954 to 1965. It is projected that the sales-weighted 205
Page 148: apt20e00
np NICOTINE ~~ I :1 w . v ra O P • • FIGURE 2.~Domeetlc market .hare of cigsrettes yielding 51b mg "tar," 1967-1878 noMIn..w......r. lOURCS: L.i.M d.. r.Ird'[rd. C...ri.lA average "tar" and nicotine In 1980 will be leea than 14 mg and 1 mg, reapeotively, Examination of the ratio of "tae'yield to nicotine yield per cigarette in interesting In light of tlw hrpothe.is that nicotine, perhaps in combination with organoleptic eompounde, exhibits a thrwhold value acceptability to the consumer. This threshold may have been 7o~w r~~°'Gs~ FIGURE 8.-$ales-.veighted averages of "tse and nicotine per eigarette consumed in the U.S., 1854-1975 B0u10aNtl"r (4?
Page 149: apt20e00
21 20 m ~ 16 ~ 17 m r1.6 I-1d -1.3 ~ 12 C i i- Z ~ {-1.1 ~1.0 1966 19N 1970 1171 1979 wn 1976 1976 1976 1977 1974 TEMI FIGURE 4.-Sales-weighted averagea of "tar" and nicotine per cigarette consumed In the U.S., 1968-1978 souJtCk D.e/..d L.s hi.l'h.Mao..bi.. (A reached (at 1.4 mg nicotine) in certain countries (e.g., England) (19). In the United States, the sales-weighted average nicotine yield per cigarette has continued to decline below the level of 1A mg (Figures 3 and 4). Figure 5 presents the "tar" to nicotine ratio of the sales- weighted "average cigarette" annually from 1968 to 1978. The "tar" to nicotine ratio has ranged from 16 to 14.3, with a maximum variation of leaa than 10 percent of the ratio's absolute value. There has been no systematic difference observed between the declines of "tar" and nicotine of the average cigarette product over the last decade. The Ocevious discussion has focused on "tar" yields and, to a leseer extent, on nicotine yields. The relationship between "tar" and nicotine is a direct one, as is shown in Figure 6(s;). The correlation coefficient for these two variables is 0.967, based on data from the Federal Trade Commission report (6). 8imilarly, the correlation coefficient reported by the Oak Ridge National I,aboratory was 0.917 (12). The description 208 szesezse 16- ~ 19R6 1969 1970 1971 1972 1973 1971 117S 1976 1977 1976 rEw FIGURE b.-Ratio of "tar" to ntcotine based on sales-weighted averages of cigarettes consumed In the U.$., 1968-1978 9oull(s: D.fwd troe r.i.d A.e. o.nn4d.. (4 - of cigarette products by "tar" yield can thus be assumed to approxi- mate closely the pattern that would rasult from a similar analysis by nicotine yield. There appears to be a similar relationship between "tar" and carbon monoxide yields, as Figure 7 shows. There is, however, a systematic difference between the "tar" and earbon monoxide yields of filtered and nonfiltered cigarettes (12). Filtered cigarettes tend to have a higher carbon monoxide yield than do nonfiltered cigarettes of the same °tar" yield. Nonetheless, there appears to be a strong association between "tar" and carbon monoxide yield by cigarette variety, with a correlation coefficient for "tar" and carbon monoxide of 0.803. Data from the Department of Agriculture describe tobacco weight per cigarette over time (fa). Figure 8 shows tobacco weight per cigarette in relation to "tar" yield, with both values shown as a percent of its value in calendar year 1967. While "tar" content per cigarette declined by 822 pereent and nicotine declined by 25.6 percent since 1968, the weight of tobacco per cigarette declined by 23.8 percent over the same period (t4). This suggests that a significant portion of the 2D9
Page 150: apt20e00
....:.,.,. ...,, .. , ...~. . Hi' 2.5 2.0 1 1.5 -~ ~ 00 404aoO V, 0.5-+ 0 00 U 0 Oo OqpOp • 00~000 ••~~ 0~0 s 0 FlMr oq.r.ue a.na 00 • Mawl...q.r.a. a.na • 5 10 15 20 35 30 "TAp" (0.0/a1121006) FIGURE 6.-Delivery of nicotine as a function of "tar" of conunereid cigaretteI6 U.S. sous= r.r,r,ti.r. a..ww ta decline in the "tar" and nicotine yield in recent decades may have resulted directly from a decrease in the amount of organic material (tobacco) available to be burned in the cigarette. Data available from Canada suggest that the observed decline In that country's officially measured "tar" and nicotine yields per cigarette at least in part results from a decline in the total number of puffs taken per cigarette during machine measurements of smoke yield (1S). Although detailed information on the number of puffs taken per cigarette Is not available for U.S. cigarettes, the FTC reports on "tar" and nicotine yields of U.S. cigarette brands suggest a similar factor may be operating in the decline of "tar" and nicotine yield measurements. The FTC testing method specifies that cigarette "tar" and nicotine yields be determined by smoking the cigarette to a minimum butt length of 23 mm, or to the filter and overwrap length plus 3 mm if in excess of 23 mm, while holding constant the puff volume, duration, and interval. Since 1967, the filter and overwrap length of U.S. cigarettes appears to have incressed. In 1967, the proportion of cigarette brands that were smoked down to a butt length fteeezee .T,W. (11wavarsw) FIGURE 7. Delivery of carbon monoxide as a function of "tar" of selected U.S, commercial cigarettes souacM u.ww o.. J..ds. Wl4 of 23 mm was 26 percent, but in 1979 the comparable figure was only 10 percent. Conversely, the number of all brands tested that were smoked to a butt length 30 mm or longer increased from 21 percent in 1967 to 77 percent in 1979. Thus, the butt and overwrap fengtha of U.S. brands appear to have increased. The absolute contribution of this factor In the total decline in "tar" and nicotine yields over recent years, however, is undetermined. Cigarette Choice and Smoking Behavior Overview Previous examinations of many parameters measuring the patterns of cigarette smoking in the United States have been published (tS, 26). They documented the continuing decline over the laat several decades n11 LJLALIJ rr,rV-T. (z, m c) cXj rvic-n o a . :.,.' ,~ ..;...: .. 0 Q/ 0 6 10 12 11 1e 1• 20 22 21 2. 20 20 72 3/ 2{ 39 40 O Oo • O O • 0
Page 151: apt20e00
fri7 1/N OM 1274 1.I1 Im 1973 ,fT. 1.7{ 1974 1t71 1174 t.7f• rEM FIGURE B.-Index of average "tar" and tobwoo per cigarette, annually, 1967-1979 • stl..lrald.rw..w. IMsr pu 1pr.ms sovsec va eqr1..N.t...MJMn (.4 in the proportion of men who were regular cigarette smokers, from 62.6 #rcent in 1966 to 37.0 percent in 1978. These publications also reported a similar but smaller decline sinee 1965 in the proportion of women who were current regular smokers, varying between 82 and 83 percent from 1965 to 1976, but declining to less than 30 percent in 1978. These trends continued through 1979, with a total prevalence of emoking at 82.5 percent of all adults, or 36.1 percent for males and 29.4 percent for females, according to data from the 1979 Smoking Supplement of the National Health Interview Survey. Interpretation of these cross-eectional data is difficult since changes in prevalence figures represent the net effect of several variables, including the entry of new smokers, the removal of smokers who quit, the reentry of "relapsing" amokera, and the removal of smokers by death or emigration. The data show an increasing proportion of former smokers among the population, suggesting a significant role of cessation of smoking in the observed decline in the prevalence of adult smoking, particularly among males (25). The 1979 prevalence of regular smoking at 32.5 percent of all adults represents the lowest total figure In more than four decades. Accompanying this decline in the prevalence of smoking among adults has been a decrease in the per capita consumption of cigarettes in recent years (Figure 9) and in the per capita consumption of pounds of tobacco In any form or as cigarettes (Figure 10). After peaking at 4,336 in 1963, the consumption of cigarettes per adult decreased (Figure 11) and is estimated to be 3,860 In 1980, its lowest point since 1960 (24). The decrease in per capita consumption of pounds of tobacco began in the 1940s and continues to the present. The relatively greater decrease in total pounds of tobacco consumed per capita in the form of cigarettes than In tobacco consumed per capita in any form since 1978 may result from an Increasing use of tobacco in other forms, such as snuff or chewing tobacco, in addition to the previously mentioned decline in the estimated weight of tobaooo per cigarette. The preceding parameters are aggregate measurements. Other more detailed sources of evidence, however, suggest that the average number of cigarettes smoked daily by regular smokers may, In fact, be increasing. These data include evidence suggesting that the propor-e tionate decrease in percentage of the adult population who smoke exceeds the reported decrease in per capita cigarette consumption for the total population (p5).. Further, when figures on total annual per capita cigarette consumption are divided by the estimated number of smokers in the United States as derived from reported prevalence figures, the estimated average daily intake for regular adult smokers was 11.5 cigarettes in 1936, 26.2 cigarettes in 1955, and 33.3 cigarettes in 1979 (26). These data should be interpreted in light of a strong tendency for smokers to round off their reported number of cigarettes smoked to one pack per day. Of the approximately 24,000 persons surveyed for the Smoking Supplement of the National Health Insurance Survey, fully 85.2 percent of all regular smokers reported smoking one pack, or exactly 20 cigarettes per day. Nonetheless, the proportion of all current regular smokers who consume 25 or more cigarettes per day has increased for both sexes (26). These findings could result from a higher rate of quitting by light smokers, from an actual increase in the number of cigarettes consumed by continuing MI. °'° ~zesezse
Page 152: apt20e00
ToW 1900 11110 uao 1930 1940 rEAa ,950 ,900 DIE 1900 FIGURE 9.-Annual per capita eonsumption of total cigarettes and filter-tipped cigarettes in the U.S, for per.ons aged 18 and older, 1904-1979 snwkers, from the entry of new smokers who consume more cigarettes per day, or from some combination of these factors. A number of sources of information exist on the Issue of the role of nicotine as the major pharmacologic agent in maintenance of smoking, including prospective studies (8, 9, 10) and short-term experimental studies (8q, 21), A more detailed discussion of the possible role oE lower nicotine yields in In<reasing the daily number of cigarettes smoked can be found in the Behavioral Aspects section of this Report. To summarize, the available evidence is consistent with the conclusion that the average daily number of cigarettes smoked by current regular smokers has increaaed. Although a role for "tar" or nicotine yields in this change has been postulated, whether the role is primary and by what mode of action aro not clearly understood. Several surveys in the 1970s examined the percentages of recent smokers who recently attempted to quit and of those who suoceeded. Data from the National Center for Health Statistics indicate that men and women were not only similar in the probability of attempting to quit but also indistinguishable in the probability of quitting sucoessful- l.- r416). ezesezse ,926 30 iu 40 .9 60 66 90 16 70 77 77 79 74 76 7{ 77 79 ti79• FIGURE 10.-Annual per capita eonsimptba of tobacco products In the U.S. (Including overseas forces) for persons aged 18 and older, i9ZS-1979 • 1999"wli)rlYwrY~a souscs:ui owA...t.rArww.. pr.a, a} Relationship of 'Tar" and Nicotine Yields to Smoking Behavior As indicated previously, this section focuses upon the currently available "tar" and nicotine data for adults. The discussion presents (1) a description by demographic eharaeteristics of the current use of cigarettes of different yields, as well as changes over time where available; (2) data on the effect of varying "tar" or nicotine yields on consumption pattarns; and (8) data defining the role of varying yields of "tar" and nicotine in cessation of smoking. The following data are from the National Center for Health Statistics' Smoking Supplement to the Health Interview Survey and include discussion of the Informa- tion on "tar" and nicotine levels of the cigarettes smoked by adolescents, as collected by the National Institute of Education (17). As noted previously, the selection of categories of "tar" or nicotine yields is arbitrary; In fact, both are continuous variables. The categories of yieW used in the following analysis do not imply that the cigarettes within those categories differ either qualitatively or quanti- tatively from the cigarettes in other categories. Rather, the groupings permit convenient presentation of data on a cigarette's yield of "tar" and nicotine relative to other available cigarettes.. 01 a
Page 153: apt20e00
~ TABLE 1.-Estimated percentage distribution of current regular F-~ smokers by "tar" yield of primary brand of cigarette, by ses, race, age, and education, aduits, U.S„ 1979 -r.P .kN ar a+a.e. enee ~ a <10 10-14 16-If >80 .9 Mg .Y mc ~ Total 1i.o 10.3 672 9.4 ~ O sez YaMr 11.1 172 69.1 1i6 ~ r.odo 16.0 Yd.O 66.4 a0 a 4 S4 YW fM Y.4r, whN. 11:! 16.0 67.4 lEb Y.1a, Y.dc at nCl 11.6 15.8 lamd.ti .MI. 1R0 f1.6 6Ai 69 F1 R.enMti Y.dc 7.6 16.0 !Yt 7.6 A6. In rae. 174/ f.0 Zte 6l.f 1.0 li-14 1116 21 6it EA ~V 4b61 Ze6 li f 16.e 1e2 laa I40 6ao 17a lao fi«n af .d.eaeb. 64 7A 14.0 !LO 16A 6`11 6,6 l62 t6.4 9A ~ it 1L0 21.2 $14 a4 i1-16 16.3 flt 49.4 7a ~ 216 t3! !l7 46.0 6.4 ~ sooscc s.»a.. daa h+n u.1s» s.ekl.. sa~i.~.~t.r w ILw.r e.Mr 1.4..W+ smv.n. r r T f The percentage distribution of current regular smokers by "tar" level of their primary brand of cigarettes is presented in Table 1. Although not shown, the same patterns are observed among five arbitrary categories of nicotine yield (based on data from the 1979 Smoking Supplement of the National Health Interview Survey). As noted previously, both 1978 and 1979 data on brands were coded to 1978 FTC values for "tar" and nicotine yield. For this reason, and because the cigarette samples tested in 1978 were obtained in 1977, the data that follow probably report slightly higher values of "tar" and nicotine yields than were actually being nsed during these periods. A further discussion of the differences in "tar" and nicotine yields of cigarette varieties reported by the FTC In 1978 and 1979 appears in the addendum to this section. Overall, 85.8 percent of current smokers use lower "tar" cigarettes (yielding less than 15 mg of "tar") and 66.7 percent use higher "tar" cigarettes. Females smoke lower "tar" GIOMIETTE COMJIJ6M"ION PER CAPITA n- ww- a asW.n..) FIGURE 11.-Annual per capita consumption of cigarettes in the U.S. (including o.erseas forces) for trrsons aged 18 and oWer, 1963-1978 "u. ca us. q 217 ~ ~'zesezse
Page 154: apt20e00
4 cigarettes in higher proportions than do males. This difference in choice of product by "tar" or nicotine level also persists when examined by race. Whites smoke lower "tar" products in greater proportions than do blacks, regardless of sex. For both sexes, white smokers choose lower "tar" products approximately twice as frequently as do black smokers of the same sex. While the percentage of all smokers using cigarettes yielding <10 mg of "tar" increases within age cohorts, there is no clear relationship of age cohort to those smoking cigarettes yielding 10 to 14 mg of "tar." Among smokers of the two highest "tar" categories, there is a olear difference by age; the proportion of smokers choosing cigarettes yielding 15 to 19 mg of "tar" decreaaea with age, but the percentage using the highest "tar" (Z20 mg) cigarettes increases with age. The trend to increasing use of highest yield products among older cohorts is clearer than the corresponding trend to higher proportions using the lowest "tar" yield products. The correlation of older ages and more frequent use of the highest "tar" products could result from a cohort effect among older smokers who continue to use the higher "tar" cigarettes that they used when they first began to smoke. Educational level, as measured in years of education completed, is strongly associated with the percentage of smokers who use low "tar" products. In considering products of 15 to 19 mg "tar" yield, an inverse relationship with educational level in the proportion of smokers using that product is observed, and a similar pattern is observed for the extremely high "tar" products, yielding 20 mg or more of "tar" per cigarette. (This inverse relationship persists even when age is con- trolled, although the data are not shown in the table.) A similar though less clear trend is observed with an increasing proportion of smokers choosing lower "tar" products among higher income groups (data sre not shown). The lack of correlated health endpoint information or detailed data on knowledge and beliefs precludes interpretation of these data as cause or effect, but the data do provide a description of the observed differences in product choice by "tar" or nicotine yields. The percentage of adults of both sexes who use lower "tar" products has increased over time. These increases are observed in both races for the time period shown. This is consistent with the previously cited market data on the sales of lower "tar"products. The finding that only 33.3 percent of adult smokers in 1979 used cigarettes yielding less than 15 mg "tar," although these products accounted for almost 40 percent of the market, does not establish a greater daily number of cigarettes smoked by users of the lower "tar" products, because gross sales figures include purchases by smokers not included in this analysis (e.g., inatitutionalised persons inciuding the military forces, adolescent smokers, occasional smokers, and interviewees whose smoking atatus is unknown). Comparison of changes in the "tar" level of chosen brand is possible for the years 1970 and 1979. The proportion of male smokers choosing cigarettes yielding less than 10 mg "tar" increased from 1.1 to 11.1 percent and females choosing these brands increased from 2.7 to 15 percent. The use of high "tar" (>15 mg) declined from 1970 to 1979 from 89.4 to 71.6 percent for males and from 90.5 to 61.4 percept for females (based on data from the 1979 Smoking Supplement of the National Health Interview Survey and from U.S. Public Health Service (J7)). Analysis of cigarette choice by nicotine yield shows the same patterns by demographic variables, with the proportion of current regular smokers who use lower nicotine products increasing with increasing age and the proportion of smokers using products with higher nicotine yields also Increasing with increasing age. Whites use lower nicotine products in greater proportions than do blacks. A further measure of consumption suggests that the actual toxic exposure of smokers by age, raoe, and sex may, however, differ significantly from that implied by consideration only of cigarette'"tar" or nicotine yield. Table 2 shows the estimated mean daily "tar" or nicotine dose derived from combining the reported yield per cigarette and the number of cigarettes smoked daily by each individual in that group. There is a consistent trend toward higher dose with increasing age of smokers for race and sex groups. Although these figures do not consider possible systematic differences in the style of smoking (e.g., butt length unanwked, frequency and depth of inhalation, etc.), they do illustrate marked differences in an estimate of mean dose of "tar" or nicotine by age, sex, and race. It shows that if all smokers smoked in the same manner, blacks would nonetheless experience a lower daily dose of "tar" and nicotine than whites. Thus, although blacks smoke higher "tar" products in higher proportions, the lower numbers of cigarettes they smoke daily may result in a lower average daily dose of smoke constituents. More recent data on cigarette brand choice reveal changes. Table 3 presents data on the percentage distribution of smokers by "tar" and nicotine yield of cigarettes in the period July through December 1978 versus 1979. These two surveys, each of which represents approximate- ly 12,000 interviews, showed a shift in the percentage of persons using lower "tar" (<15 mg) cigarettes from 28.8 percent in 1978 to 33.7 percent only a year later, a similar downward shift was observed at nicotine yields below the highest category. Such a shift might be caused by either an actual brand change or an involuntary downward "ereep" due to reduction in the "tar" or nicotine yield of the product by the manufacturer. As noted previously, however, the cigarette brands reported were coded in both 1978 and 1979 by the 1978 FTC "tar" and nicotine yield values. Thus, the downward shift observed over this 1- 0eGsezse
Page 155: apt20e00
TABLE 2.-Mean daily dose* of "tar" or nieotine for current regular smokers by race, sex, and age, U.S, 1979•• Wi.. r..m asy ea. ~'ae_ .os (.ria.» .NoaN9._ sn2 II1it. AA Ms 2 17 U1 l6.f 17 fl i~ f43 S6-N 419 0.1 sl.ek IN 11r W.. Z 17 ax tl4 !0! $u ffi.1 211 17dA !M 17.1 ffii1 1M !0.7 ~FN 1!7 9Sb !6# !M 1l1 P.m.M il~ tL0 ~~ AM %a ZH SM - UA 1Ru t!i 1f.1 ss~ rs N I6+ tst aM 4M sco Lls 17, DIr3 M nr 2 17 !N 16! 17-M m/ 11.0 Z6 M so 1710 Y N Jdt 17b ~6a 102 9l.0 •xr.bret egu.Nr wra.l.rdOeMy u.l..d twr'w d.aw ..L. t....~.d....n....h. . lolllOCR aud M YN 9t.n iM 1f79s"WsN 8"plwaNf IM ]AtMd N.m iMwN. s.n+f year Interval In cigarette "tar" and nicotine yield represents an actual change In the brand of cigarettes used by smokers. Similar patterns have been observed in smoking among adoleacents. In a 1979 national telephone interview survey of 2,689 adolescents, the percentage of all adolescent smokers who seleeted brands of lower "tar" (516 mg) had Increased from 6.7 percent observed in 19?4 for both sexes (Table 4) to 33.5 percent In 1979. Direct comparison of the percentage distribution of "tar" yield among adolesoents with that observed-among adults is complicated by different groupings of "tar" level and by different definitions of "regular" smokers in the two surveys (after having smoked 100 cigarettes, "regular" smokers were defined for adolescents as "smoking regularly each week"; for adults, as anr positive response to "when did you start smoking tegularly?"). Nonetheless, a similar trend toward incressing use of lower "tar" products is observed among adolescents and adults. Table 6 presents data on brand ehoice by "tar" level among adolescents of different ages from the largest recent smoking survey of. adolescents. The amall numbers of smokers, and the relatively large numbers of individuals who are unclassifiable, make interpretation of TABLE g.-Estimated percentage distribution of current regular smokers by "tar" and nicotine yield of primary cigarette used, U.S., 1978` and 19790 `TAe ffeld Paontyt. i. 1l76 Pac.,tas. 1. 1979 Ss .K 4.2 ..o 64 nK 7a sA 10-14 mg 17.1 20.7 16-ti q 61.4 ai.E Zm sK U 9.0 Nkatlm 9idd ruaenuy. I. Mi raeat.p 1. 1979 <OS aff 41.2 _ _ 12 . O.W.9 .K ri7 tL7 1,0-u .K 41.1 87.7 1J-U mg ffi7 }b,9 Zt7 .e 1.t U • trt l.L.a.. q.M... e.y. 9pURCS: s...a ....1. M1.w IY If7f ss.kl.e Spyb..H.t tM Ndls.d N." t.t..dn. l.n.y . TABLE 4.-Estimated percentage distribution of regular smokers by "tar" yield, adoleacents aged 12-18, U,8„ 1974 and 1979 P.eeants. eoys Paa.nts. g41s P"amtyr both .e:. 'Td_- t~eN 1Y74 1979 1974 - ~- 1M4 197i y 10 eC oa ii oa 121 03 72 11-14 .K S.0 aS ae 129 0.4 20 10-.19 stt 73.T QOE W LOS 7l0 00.1 290 aK ma '1.4 1l.1 U 1" 62 9ouuCe x.u..a t..aaft w s...w.. U rlM product choice among adolescents by age group difficult. Thus, a clear definition of the relationship of the adolescent smoker's age to choice of cigarette smoked Is not possible from this series. In Table 6, the mean age of onset of smoking cigarettes for all current regular smokers is 18.2 years. Although most of the data in the National Health Interview Survey Smoking Supplement involves recall, the mean age at onset Is perhaps the most subject to bias, whether in remembrance or in reporting preference. Nonetheless, the reported age at onset of smoking is higher among older age groups. This might reflect (1) a real change in recent years in the age at which younger cohorts start to smoke, (2) the addition of a few late-starting smokers during the extra years "at risk," causing a higher reported age at onset among older cohorts, or (9) an effect of different mortality rates for early versus late beginning smokers. The demonstration that the average age at onset of smoking among females has declined from 86 years among women born prior to 1900 to 16 years among women 99' TEesezs@ 221
Page 156: apt20e00
TABLE 5.-Percent distribution of adolescent regular smokers by "4r" yield of primary brand, by sex and age, U.S, 1979 -r.r ~~r ~r br.ea 516 .g >1b M Ury.dCwd Dv.'t imw H.7. .4r iioup f a % a % a S  ll-11 1L1 s 66.i 10 02 f U 16-14 2" 16 ILI Is 7.I 4 17-1s li.4 19 6it 49 161 11 lf 8L1 ls Y.f IM{ l!7 7 NieseSM rLN ef ui , lA IMA~ M. ~ , ~ S21 ,[ >1s .r Ur9dfW Do.'t luar CGY ap poup ~  %  'i a Ti  liall 76.0 • 701 17 41 1 1L14 !i! 11 fi.i !s 12.8 4 U i u li iLt 31 fZ0 51 112 1: Lo 1 u i0.i Is IOi 40 la{ 11 souact 11.w.r Lrtwadsarlw u~1 born between 1951 and 1960 (26) explains a portion of the observed differences in age at onset by cohort. Older cohorts may not fit the assumption that the survivors within that cohort are representative of all individuals within the original cohort. The amount and direction of the effects of (1), (2), and (8) remain to be defined. However, there is a general trend that, for each age cohort, the higher the "tar" level of the cigarette currently smoked, the younger the reported age of onset of smoking. The same observation is also found in the relationship between nicotine yield and age of onset, except that an older age of onset is indicated for those smoking the highest nicotine yield (]1.7 mg) cigarettes, which value is based on a small sample size. Consumption Patterns In attempting to define the role of "tar" or nicotine yield on the daily number of cigarettes smoked, adult regular smokers were divided into three levels of daily consumption by approximate quintiles of "tar" and nicotine yield of primary brand (Table 7). This Table shows that the percentage distribution of smokers by number of cigarettes per day does not "bit an association with "tar" or nicotine level of cigarette used. This Table provides evidence that there is not a significantly greater proportion of "heavy" smokers among smokers of the lowest "tar" and nicotine cigarettes than there is among smokers of the highest "tar" and nicotine cigarettes. It does not, however, disprove the theory that individual smokers may increase their daily number of eigarettes smoked when they switch to a cigarette with lower "tar" or nicotine yield. That is, the absolute number of cigarettes ZVesszse TABLE 6rMean age at. onset of regular smoking by "tat•' or' niootine yleld of primary brand, by aga at interview, current regular smoker16 U.S., 1979 Ap .t it.ri.. •ttir *u -- -- -4 - IWd 31aa ~1 AM lEr7d as 3 ffi3 <i .e luI liS ul lf.b M,i 1!s as " sV Its lOJ lti lti tl.G 30 3L1 1Q14 .S lti 1t! ILI 1t.7 192 !0.{ !L4 11~lf .C 1tA 16a 1M Iti I9A 1fJ ls.f 2l0.S l7A 16.7 17.1 17O 17.1 ILI fU TaW 1s] 1" 17j 1L4 ltll 1RT lL.f NbNi.. *a <U .S 1l.7 lf.i If1 lfi 2.i 19i !d l 4i-Of .g 1L7 lti 1i1 Ilf lS.i n.1 a.i LS-1f .K I60 10.7 lt= Iss ILI W ri.7 1.8-1.A ag • 17.7 161 1tA 17J 17.4 ILI lU 2L7 wC 1!J 31.0 lti 17.i 1!A sl.f 2" TNW l!3 16.5 17a 1L4 ILI u.7 223 fovlCS ,a,.d..4w tn. w af. /..ri~s~rr.t w xuwr a.w lasi..s~nr. smoked by individuals at low "tar" and nicotine yields may, in tact, be higher than the number of cigarettes the same itutividuais smoked at high yield leveL, even though there is no cross-sectional difference. The relationship of "tar" or nicotine yield to the number of cigarettes smoked daily can also be examined by the average number- of cigarettes smoked in various age groups, as presented in Table 8. After grouping smokers by age at interview, it b still observed that neither the level of "tar" nor that of nicotine demonstrates a definite association with the mean number of cigarettes smoked daily. CeMation The role played by cigarettes of varying "tar" and nicotine yields in cessation has been widely discussed (B,S, 26). Present survey data have not sufficed to define the role for varying "tar" and nicotine yields in cessation, largely because of the laclt of longitudinal surveys of cigarette consumption prior to attempting to quit or after an unaucoessful attsmpt. A longitudinal study of smoking patterns by both cigarette product choice and number smoked daily to determine their relationship to cessation is being conducted by the NCHS for the Office on Smoking and Health during 1980 and 198L Table 9 examines by cigarette "tar" or nicotine yield the percent of current smokers who report ever having seriously tried to quit smoking. Overall, there is a clear inverw relationship between the "tar" or nicotine yield of the cigarette and the percent of amokers who have ever tried to quit. The group of lowest yield smokers shows a
Page 157: apt20e00
TABLE 7.-Fetfsaated pe:+oentage distribution of current regular amoken by number of cigaretEes smoked daily by approld.mts qnintiks of "tar•' or niootine yieki, adults, US, 1979 Slo W9 PMae.t .t Yt.l Pood.tla 1l.1 D* .rnlee d dpnttr <u 10-Z/ 9s aT srj 'bld. 101.1 'Td' .YN at duawd. f01de1001. 11-1s *-1T li-U >K off MIC 1/.1 as 1!A rrs 1L1 t7.0 461 M 422 n. Uu ss Us f1A 100.1 xV.x...Wa .. d.u.be. rpa,ur., SRT W101 L00_Lp L101A1 Mf mf SK we PWant .F 1oW pphtLs n3 fo1 1l.T II.t c.q ...b..r <li s3 f1s !s.! 212 16 !4 422 Ms tlA Os Zs Ta" ss 100A KA 100A IoA iooA ss uaS "iABLE 8.--Mean number of cigarettes saiolced daily by "tar" or nicotine yield, by age groups, current regular smokers, adults, U.S., 1979 .1e1 d Isevudn imd 323f ts:W a=u !~F! ls:AJ ffit 21f <S ee !1s 10 10s t=A 2Lt 212 16A 6-0 ne0 7D.T 1TA 0 7 !19 ySA }20 ne 1a11.e0 2" 143 . >ID2 ?a.1 if.T 19.6 1" 10J1 16-10 aff s.0 ]TA AA 87 212 12.1 10.4 2m q !Ei 152 aA 20 Ed.f SA 1W ToW 7D.7 1T.1 1>D 2z$ }d,{ !Lb 172 96 f , m ~ . Us <0A se Z1d 1R0 1!s 1Z0 36A !1A 1t.T 100A 0.60.f rff flAt 102 IDA su 21.7 elA uA 1A-11 as riA 17.7 E1! 21.1 >7A 80 16,/ 1A-40.g 21.2 1TA f0.1 stA AT !27 173 2LT sC 1!s 6b 1!, SU 1!i as 17 0 Z1At of ToW lG.7 17.1 90A !2! lf.1 IIA . 172 1l.4 roU.cC a,.d w bu t~ u.1s10 Ss.kr,T e.ppMsnt.t tu.ll.u.rl 11.nl1 Id..rw ar.q. iL0 al TABLE 9.-Estimated percent of current regular smokers who have tried seAousUr at teast once to quit, by "tat" or nicotine level and aM U.S., 1979 sss «r.r +ud d .dn... .,aN. taae SDl1101a 1ooiM W.6w W q10 s.skYO iqpM.ra d tM 11.tYr11W10 YM.Lw [fewT, higher proportion of persons who have ever tried than those groups smoking higher yield products. This relationship was found for both "tar" and nicotine yields for all age groups except those 66 or more years of age, where the sample siLe was considerably smaller and the pattern was less clear. The finding that greater proportions of current smokers of lower "tar" or nicotine products report ever attempting to quit than do smokers of higher "tar" produets could result from (1) a higher rate of attempting to quit (but with a similar failure rate) for more health- conscious Individuab who may also t]lerefore choose lower yield cigarettes; (2) a differeaos in the addictive qualities of lower "tar" or niootilp products, causing a higher probability of relapsing after attempting to quit; or (8) the choice of a lower "tar" and nicotine cigarette product after failing to stop smoking: Selection between these alternatives would require comprehensive data on brand choice both prior to and following an attempt to quit smoking, as well as health status measurements that might affect brand switching or quit attempts. Such Information Is not availsble from this data set. 224 MG@ZE'sB Ar O+wP <0 we H ss 10-u . K 1F10 s0 2q1 00 17-24 6t! 61.1 P1A st! W 26-M 7" !QE eli Ns 040 sbit TlA Ol0 01.1 OSS OlA 206 00.0 ODA qA Ou tl.T A11 .0.. !OA 062 t1A Dd! OL6 ulMUM 1~l .r ~.....~e ~03 Ob-QO 1A-1= 1W,0 ZLT AP grasp ~[ W[ s0 ot as 1v 2/ OD.7 6!0 N.0 4.1 60.4 tt•N 7U 0&1 {L! 16.1 M! asa~ 7q1 ea0 !!.{ y10 493 bti ODA 67i 663 0!0 All s.. as Ot1 i6.t its i0A lOUOC! On.O.. i1. fwal.ltt7f i.ati.0lVp%..a d a. N.Yw111.." INwr+Y. f.nq. Table 10 shows a comparison of the frequency distributions of recent smokers by "tar" or nicotine level of the primary cigarette brand smoked by those who either did not try to quit, those who tried but failed to quit, and those who succeeded in quitting smoldng within the 2L5
Page 158: apt20e00
12 months prior to interview. In this analysis, "success" in quitting was arbitrarily defined as persons who had recently been regular smokers who bad attempted to quit within 12 months and who had not smoked for at least 6lnoaths prior to interview. Persons who smoked regularly within 1 year prior to the intsrview and who had attempted to quit during the last year but had been off cigarettes less than 6 months are excluded from oonsideration in this analysis. Unsuccessful quitters were defined as regular smokera at the time of interview who reported having attempted seriously to quit at least once within the 12 months prior to interview date. Interpretation of theee data is complicated by the fact that the primary brand reported for successful quitters represents the brand smoked prior to a quit attempt, while unaueoeso- ful quittere' brands are those smoked after a quit attempt. Thus, clear distinction cannot be made between the possible explanatione. The data show that higher proportions of smokers who use the two lowest "tar" or nicotine cigarette products are found among the unsucoessful quitters than among successful quitters. The proportion of recent regular smokers who use cigarettes yielding <5 mg of "tar" is lowest for persons who did not attempt to quit (8.8 percent), internle(iiats among those who succeeded in quitting (4.6 percent), and highest among those who failed at an attempt to quit (4.9 percent). Grouping these smokers into larger categolies by "tar" level (e,g, the percent smoking cigarettes yielding <10 mg or those smoking cigarettes yielding <15 mg "tar'7 shows that a lower proportion of recent smokers who successfully quit used lower "tar" products than do recent smokers who did not attempt to quit, while smokers who failed In an attempt to quit reported smoking lower "tar" products in the highest proportions. Conversely, a lower proportion of unsuccessful attempters currently smoke higher "tar" products (66.8 percent) than is found among either nonattempters (69.0 percent) or successful quitters (72.2 percent).. A similar relationship was observed by nicotine yield: the proportion of peraons choosing the lower yield products (<1.0 mg) was highest for unsuccessful quitters, intermediate for nonattempters, and lowest among successful quitters. Thus, these data are consistent with the postulated tendency of smoker, to switch to lower "tar" and nicotine eigarettes following an unsuccessful attempt to quit smoking. The relationship between number of serious attempts to quit smoking and the "tar" or nicotine yield of the primary cigarette smoked is shown in Table 11. Note should be taken that the table includes only current regular smokere who have tried at least once to quit. For the lowest categories of "tas" and nicotine yields, there is a suggestion of a shift in the population toward a greater number of cessation attempts. No significant difference is observed in the frequency distributions of .mokera of other "tal" and nicotine products. TABLE 10.-Estimated percentage distribution of recent smokere by status of recent attempt to quit, by "tar" or nicotine yield of primary brand, July 1978 through December 19794 eUw..t "~+' yJel~dt+dm~nr_lo~ ~ t.." aaept t. <6 .g H aK lalA .~ 14-1f as Z9D .~ ~`CoW qolt ..oH.W S(a) 7i W S(a) 74 (a) S W % (•) suer.[Y( " (uA U (1a) 17A (60y iM (IM u(?b) t3 Z9/ Ur....rhl l! (lM 1s (sQ SU (MQ M.7 (iW) s.S (17i) ffi.i =Yt Ns .W.pt tt (X6) ss (7Y1) MO (748) N.1 (d070) 10! (UO) Tt1 C181 Tdal 4.1 (600) a1 (1025) IAi (N1) /as (7m1) fs (1u0) Ni0.! 1Mu )IlooWt ~ ~ idmrCr ~ _ <" .e OA-0 .K LA-tf te U-1.6 .4 ?-L7 M{ S (.) S (s) B~awtul l{ (13) fIJ (71) ur..erdd 6,0 (u6) i22 (WY) No .Wnpt lA (af1) US (966i) 7W1 " (Slf) i0A (sW S (a) S (.) S (.) 4tI (17) U0 (71) 0.T (!) 7.3 !at s0.t (1fO) ' Eti (em a1 (!i) s6,t 10®8 11.7 (fiW) t91 (ZM) LA (11f) 7i1 Slal t{.T (Ml) 5,{ (f1111) Ls (111) 100A 1315 •u.-asb.a+r. .00X& wd...wa.d w 1q.a..rLS•7ll•n••t.r u.IbWrl s«NilN.,L.,i.wi,. TABLE 11.-Edimatsd percentage distribution of current regular aaok,ern by number of seriow attempts to quit .mokint, by "tu" or niootine level, U.B., 1979 meJad *d <6 s nA sil 1C.{ iA lf.l H 16.7 faf 1Li u 16t 1o-1u US s71 Il~ f.i (S.f 1i-1f ai{ su 1L7 if uA 2s rrs sf.7 lLf U Iti 1'ata( US s7.1 1lf U 16.7 Moo(ioLJml (s) <os su 2!A 1112 s.7 tTJ ~0! WA K{ 14.9 LI 11.1 1A-1s a+S fU u1 LA 14.7 1J1-L6 16J US 1L7 61 11.0 2L7 11A sL1 21.1 ts laf Tw1 sr.3 ;f.1 14s iJ 16.7 SouNCi: @..d..41.h.. w 3M/rYm/.ppin.K.f IY N.WrI n..M1M.+lwr wrny. The relationship of cigarette choice to the duration of the most recent unsuccessful quit attempt is shown in Table 12 for current regular unokcra./llthougll there are large variations in the individual durations within each "tar" or nicotine gr+ouping, the alean durations V~', , '@zG19 2Z?
Page 159: apt20e00
..:- ~- aa"`°`".~ r~ 4er' e ONTO sIS! .us o c+f 0 Lt u as _. .i V toW Ls xkdk..Ma <Ob .K t4 os4s as i.a.u .K u l.i-.L{ .C i.f 20 .f U rOW Le m...lg.add" ewaM s...! «..Y h.. w m. a+diq SuppLr.t.rtM I/.u.r a.hM t.w.l..s..q. do not exhibit a relationship to either "tar" or nicotine yield. The higher mean duration of quit attempt among the smokers of highest yield products must be interpreted in light of the small numbers of individuals within those yield groupings. Summary 1. Public awareness of the dangers of smoking has steadily increased since 1965. In 19?8, more than 90 percent of all Americans believed cigarette smoking to be hazardous to health. 2 Cigarette product choice has shifted dramatically since the 1950s. In 1979, 91.7 percent of U.S. smokers used filter-tipped ciga- rettes, compared with 1.4 percent in the early 1950s. 8. Lower "tar" cigarettes conventionally have been defined as yielding 16 mg of "tar" or less per cigarette. The proportion of all cigarettes consumed in the United States that are lower "tar" has increased from 8.6 percent In 19?0 to almost 50 percent in 1979. In 1979, 68.5 percent of all cigarette brands marketed in the United States yielded 15 or fewer mg of "tar." 4. Sineq, 1968, the "tar" content of the "average cigarette" in the Unithd States has declined by 32.2 percent, and nicotine content has fallen by 25.6 percent. These declines may be partially accounted for by lower tobacco weight per cigarette-down 23.8 percent from 1968 to 19'fa-and by the greater length of the filter and overwrap of the average cigarette, which could result In a declining number of machine puffs per cigarette. ~,,,be prevalesoe of smoking in the U.S. adult and adolesm populatwpe has continued to decline. In 1979, 32.5 percent of ~ adult population smoked cigarettes (36.1 percent of men and 29.4 percent of women). However, evidence suggests that the average daily number of cigarettes consumed by those adults who continue to smoke has increased over several decades. The availability and use of lower "tar" cigarettes have increased over recent years. 6. In 1979, 83.3 percent of adult regular smokers used cigarettes yielding 15 mg "tar" or less. Studies show that women smokers are more likely to use lower yield cigarettes than men are, and white smokers use lower yield cigarettes in greater proportions than do blacks. Smokers of higher income and education also select lower yield cigarettes in a higher percent of cases. ?. A large national survey found that smokers in older aged cohorts choose both the lowest and highest yield cigarettes in higher proportions than do younger cohorts. 8. Although black smokers choose cigarettes of higher "tar" and nicotine in greater proportions than do whites, the lower daily number of cigarettes smoked by blacks "suggests that their average daily intake of "tar" and nicotine may be lower than that of white smokers. 9. In 1979, 33.5 percent of adolescent smokers (age 12 to 18) used lower "tar" cigarettes, compared with 6.V percent in 1974. BBoys and girls smoke cigarettes of about the same level of "ta_r" content. 10. Adult smokers started smoking regularly at the average age of 18 years. One survey showed that the higher the "tar" level of the cigarette currently smoked, the younger the reported age of beginning smoking. 11. Evidence from a large national survey does not support a correlation between a greater mean number of cigarettes smoked per day by users of lower "tar" and nicotine cigarettes than by higher "tar" users. 12. In a national survey, smokers of lower "tar" and nicotine cigarettes more frequently reported having attempted to quit at least once, and among these smokers, a higher proportion report having attempted unsuccessfully to quit multiple times. The applicability of these data to defining of the role of "tar" or nicotine yields of cigarettes in quitting behavior is not clear in the absence of more detailed longitudinal data. 13. Although a greater proportion of unsucoes~ful quitters reported smoking the lowest "tar" and nicotine products than did recent successful quitters In one large survey, interpretation of these data is made difficult by the noncomparability of brand reported W SEgseZse
Page 160: apt20e00
(i.e., unsuccessful quitters reported the brand smoked after an attempt, successful quitters reported the brand smoked prior to the attempt). 14.In a large national survey, the mean duration of the latest unsuccessful attempt to quit shows no clear relationship to "tar" or nicotine yields. Addendum: Comparison of "Tar" and Nleotlne Yields of Cigarettes In 1978 and 1979 The Federal Trade Commission (FTC) has conducted tests of eommercially available cigarettes in the United States since 1968. The FTC measures "tar" and nicotine yields of approximately 99.5 percent of the branda available in the United States and issues annual reports on these measurements. This discussion examines the changes in cigarette yields from 1978 to 1979 as published by the FTC. The following should be helpful in estimating to what extent the coding of NHIS brand data for 1979 by the "tar" yields measured in 1978 might influence the results presented above in this section. Yields of "Tar" and Nicotine The cigarettea tested in 19?8 (sample collected in 1977) had a mean "tar" yield of 15.4 mg and in 1979 (sample collected in 1979) the mean "tar" yield was 18.6. The corresponding mean yields of nicotine were 1.02 and 0.97 mg in the 1978 and 1979 FTC reports (Table 13). These reductions in yields occurred regardless of the different parametera of cigarette type (length, menthol/plain, package type, and fil- ter/nonfilter). If only filter-tipped cigarettes are considered, the mean nicotine yield declined from 0.95 to 0.90 mg. For all 1979 varieties, there was a significant difference in "tar" yield between filter and nonfilter cigarettes, and between menthol and nonmenthol varieties of cigarettes. Examining filtered cigarettes only, the length of cigarette was the only parameter that showed a significant difference in mean "tar"leveL Correlation of Varieties Reported in 1978 and 1979 There were 144 varieties of cigarettes marketed in both years (1978 and 1979) that were unchanged, as defined by exact variety name, length, menthol and filter status, and package type. Despite the identity of all five parameters, the mean "tar" level of varieties declined over the period mentioned (Table 14). The mean "tar" level declined from It.3 mg in 1978 to 14.8 in 1979; for filter-tipped cigarettes only, the mean "tar" level declined from 13.8 to 13.3 mg. These decresses, although slight in absolute terms, are statistically significant. The change in nicotine yields for these same brands of cip 'tes over the same period is negligible. i I t%l- ~ ~ x pIgs; rxa sM an -P Ella ~ I R p R8 at8 G 1198 1~ Ig 5M 9 t%l 1I;; ;xi ;"n g; ; 1!~ gI I '~, 'z vni aai,~ ~ 230 231
Page 161: apt20e00
's x ~ is a . 1151 - - in 31 1 11112 ' ' !1 51 1 11h; - - ~~ AA ~ Alai .. 0;1;a ~ ~ ~ dl no 1a or. 38 s gill 11 11 BI I Alga 01 ag 3S a ~ "A~ I~ ~GN II ~ I TABLE 15.-Comparison of "tar" and nicotine yield on th% varieties of cigarette marketed in both 1978 and 1979, U.S. 'T.r' rwd x..a w.r YYC 1MOOtSN xo. OL Ie ye.r dilfewnoe (nK) diffneea (mg) ..rietka IM - IM • d.ola4 7 1i7s < IM -0.06 -0.US2f 66 IM > IM l.a9ee a0/7t a Ta.i 0.69 4.0052 144 eotracs: s.e..i n.e. c...d.I.. M e. Further examination of the changes in the "tar" and nicotine yield occurring in the same varieties of cigarettes over this period is presented in Table 15. Of the 144 brands reported on in both periods, only 7 showed no difference in mean "tsr" level. Fifty-five brands showed a slight increase, with the mean difference being less than 1 mg. Eighty-two brands, however, showed a decline from the 1978 reported yields to the 1979 yield. Once again, however, the mean decrease was small, only 1.3 mg. "Tar" and Nicotine Yields of New Brands in 1979 There were 32 varieties of cigarettes defined as new in the 1979 FTC report (Tables 16 and 17). A "new" variety was defined as a different name (such as a varietal name change by addition of the word "lights"), or by a change in one of the other four varietal parameters of filter, length, package type, or menthol status (e.g., a nonfiltered cigarette changing to filtered). The average "tar" and nicotine yields for these 82 new brands in 1979 were 8.5 and 0.67 mg, respectively. Except for a single new variety, the new varieties yielded less than 15 mg of "tar; " with two-thirds of them yielding less than 10 mg "tar." A similar examination of new 1979 varieties by nicotine yield showed a similar trend toward lower yields, with 81 percent of them yielding less than 0.9 mg of nicotine. Applications to the Discussion As noted in the body of this Report, all NHIS variety data on the Smoking Supplement collected in interviewa during 1978 and 1979 were coded to the FTC 1978 "tar" and nicotine yields. Since the cigarettes reported on in 1978 were collected in 1977, and since the updated measures of yield for 1979 were not available in time for their use in coding the 1979 smoking data, the described distribution of smokers by "tar" and nicotine yields of their cigarettes is conservative and underestimates to some extent the proportion of smokers who use. lower yield products. 232 4CIRbi9,z" 233
Page 162: apt20e00
TABLE 16.-Mean yield of "tar" and nicotine of the new va ieti s of ci k arett t d I 1979 b References r e e mar g e e n , y type of modifier, U.B. (1) FEDERAL TRADE COMMISSION. Report to Coagnws Purauant to t!u Federal t7ipantt. Labeling and Advertisiny Act. Washington, D.C., Federai Trade ZYpo Of weak '94r' br] NienHe. (emd Mn.~yi~ ~Lft Commission, June 80,1968, 62 pp. (2) FEDERAL TRADE COMMISSION. Report on "Tar" and Nicotine Content of Soft U 0.A6 so the Smoko of 148 Varictie, of 6Yyarettu. Washington, D.C., Federal Trade Hud 1L7 0.lZ 2 Commieeion, July 1972. F9tar !.b 0.67 (3) FEDERAL TRADE COMMISSION. Report on "Tar" and NiaoN+u Content of NooMksr <100 mm OA 17 tAe Smoke of 1N Varieties of Ciyarette.. Washington, D.C., Federal Trade Commieeion, November 1976. (4) FEDERAL TRADE COMMISSION. Report of tho "Tar" and Niooti„e CoKtent of 2100 mee lOd 1S fAe Smoke of 167 Varietisa of Ciyarettes. Washington, D.C., Federal Trade Menthol 7.0 0.67 11 Commission, May 19?8. (5) FEDERAL TRADE COMMISSION. Rspowi of "Tar" and Nicotine Content of tht ReBul.e f.4 0.72 21 ToW &6 0.67 32 Smoke of 17t Varieties of Cigarotta. Washington, D.C., Federal Trade Commission, December 19?9,12 pp. (e) FEDERAL TRADE COMMISSION. Report to Cor"u licrsuant to tAo Public lOUHOIL r.d.W T4.d. Ga,.I k. (6 Q. Xeala Cigarette Smoking Act Jbr tho Yrar 1878. Washington, D.C., Federal TABLE 17.-Distribution of "tar" and nicotine yield of the new Trade Commission, December ?A,1979, 82 pp. (~) GALLUP OPINION INDEX. Smoking in America. Public Attitudes and varieties of cigarette marketed In 1979, U.S. Behavior. Gattup Opixion Index 166: 1-W, June 1978. (8) HAMMOND, E.C., GARFINKEL, L Changes In cigarette smoking. Journad of "T.r' .ieN terl the Nationa! Cancar Institute 83(1): 49413, July 196{. <5 f,-0.! 10.0-14A 16.0-19.Y Total (9) HAMMOND, E.C., GARFINKEL, L Influeaoe of health on smoking habita. In: 7 14 10 1 S't Haenacel, W. (Editor). Apido+niolo8ie.w! Appnses6or to the Study of Cancer and 21.9 4t3 S1.! f.1 100.0 Othar Chronic Diseases. National nal Cancer anaer Institute Monograph No.19: 269-285, January 1966. NienNne .ield teirl (10) HAMMOND, E.C., GARFINKEL, L. Changes in cigarette .making 1959-1966. <aw o.ao-mer 0.70-O.Ei 0A0-1.00 1.10-1.l8 To1a1 Ameriean Journal of Pubtic Health b8(1): 8b-46, January 1988. N f 4 13 4 2 32 (11) HAMMOND, E.C., HORN, D. Smoking and death rates-Report on forty-four % 2R1 1tb 40.6 126 !3 100.0 months of follow-up of 18?,78A men. II. Death rates by cause. Journal of the American Medical Aisoefatiox 186(11):1294-1808, March 1b,19ti6. OOURCZ: r.d.el74.d. drl.ie. c/. A. (18) JENKINS, R.A., QUINCY, R.B., GUERIN. M.R. .Sel.cted Constituents in the Smoket of U'& Canmenial Ciyarettc.r "Tisr,"1Viooti+io, Car6on lifonoside and Carbon Dioxide. U.S. Department of Energy, Oak Ridge National Laboratory, Publication No. ORNIJTM-6870, May 1979, 42 pp. (18) KOZLOWSKI, L.T., RICKERT, W.S., ROBINSON, J.C., GRUNBERG, N.E. Have tar and nicotine yields of cigarettes ohanged" Science 209(4464): 1b50- f3QeS8zse 1661, September 26,1980. (14) LAVOIE, E.J., HECHT, 3.8., HOFFMANN, D., WYNDER, E,L The leee (1S) (17) harmful cigarette and tobaooo smoke flavors. In: Gori, G.B., Bock, F.G. (Editors). Banbary Report 1-A Safe Ciyarrttol Cold Spring Harbor, New York, Cold Spring Harbor Laboratory,1980, pp. 251-260. LEVIN, M.L., GOLDSTEIN, H., GERHARDT. P.R. Cancer and tobaooo smoking. A preliminary eeport Journal of the American Medical Aaaxiatfon 143(4): 886-538, May 27,1950. MILLS, C.A., PORTER, M.M. Tobacco smoking habita and cancer of the mouth and respiratory system. Cancer Research 10: Q,49-b42,1950. NATIONAL INSTITUTE OF EDUCATION. Tetnape SmokinW Immediate and Long 7brrn Fatterna. U.S. Department of Health, Education, and Welfare, National Institute of Education. November 1979, 259 pp. (18) ROPER ORGANIZATION. A Study of Public Attitudes Touard Cigarette SmoAiwg and f1u Tobacco Indxatry in 1978. The Roper Organisation, May 1978. 234 35
Page 163: apt20e00
(18) -- LL, M.A.H. The ease for mediutn-ntaotlne, low-tar, low4arbon monoxide cigrrettea: Ina'Cori, d.B., Boek, F.(3. (FAitc+I Baxbnry Report 1-A Sa,/e Ciyor.Ebt Cold Spring Harbor, New York, Cold Spriag Harbor Laboratory, 19M pp. 2l7=B0& (EO) SCHACHTER, & Pharmaoologieal and psyeholoskal determinants of smoking. Annals of lwhrwal Medicine 8S(1):104-114,1998. (11) SUTTON, S.R,, FLrYLRABEND; C., COLE, P.V, RUS3ELL, M.A.H. Adjuat. ment of smokers to dilution of tobacco smoke by ventilated cigarette bolden, Clinical Pllarmeaoloyy and TAoeperlia 81(4): l05-406, Oetober 197a. (t4 U.S.& DEPARTMENT OF AORICULTURE. Tobacoe.9itvation. U.S. Department of Agriculture, Eoonomie., 3tstietie, and Cooperatives 3ervioe, September 1964. (ss) U.S. DEPARTMENT OF MiRiCULTURLr Tobaeeo 9ituation. U.S. Department of Asriculture, Economia, Statietin, and Cooperatives Service, September 1911 (t4) U.s. DEPARTMENT OF AaRICULIURE. 7bbaeee Situation. U.S. Department of AQrieulture, Economin, Statietioa, and Cooperatives Servioe, September 1900, 47 pp. (t6) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND W ELFARE. Smoking and Flsaifk A R.port of as 9u+qeow (',..eraL U.S. Departmsnt of Health, Education, and Welfaee, Public Health ServOffice of the Ari.WnL Seeretary for Health, Offioa on Smoking and Health, DHEW Publication No. (PHS)'19-60066,1979,1156 pp. (ts) U.S. DEPARTMENT OF HEALTH, I:DUCATION, AND WELFARE. TAe BeaitA Cvnnquenoa eJ9ieokstq)br Womsw A Report off t11a,9u+peon Ce+wai. U.S. Department of Health, Edueation, and Welfare, Public Health Servios, Office of the Aa+ietant Secretary for Health, Office on Smoking and Health, 19®0,359 pp. (!7) U.S. HOUSE OF REPRESENTATIVES. Aoari+ys BsJbn a 3u6ooewaitts on the Committee on CowrK+nefit Operations. Piai.r end Jlideadiwp Advertising (1Wer Tip Glyareaes). July 18,19.23.24.25, and 26,195T,?9b Pp- (t8) U.S. PUBLIC HEALTH SERVICE. S+aalei+y and Realtb. Report o/t11. Advisory Committee to the 84+y+ow Ceneral of the Pu6lte Health Saroioe. U.B.. Depart- meat of Health,. Education, and Welfare, Public Health Service, Center for Disease Centrol, PHS Publication No.1109,196t, L87 pp. (29) U.S. PUBLIC HEALTH SERVICE. Ua of Tobacco, Practices, Attitudss, Knowledge, and Bet,*eJs, United Sates-Faf! 1lQ4 and Spri+q 1061. U.$. Department of Health, Education, and Welfare, National Clearinghouee for Smoking and Health, July 1969, 807 pp. (10) U.S. PUBLIC HEALTH SERVICE. T1Ya Health Conasquenam of Smokinp. A Acblie Health Service Reviep: 1off. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Adminietratioo, DHEW Publication No. 1E®6, Re.ised, January 1968, 227 pp. (J1) U.S. PUBLIC HEALTH SLRVICE. The EealtA Cvnssquenon oJ9moki+a,196d. Supplement to the 1M7 Asblia Health Ssreior Review. U.S. Department of Health, Education, and Welfare, Public Health Service, Health $ervioeo and Mental Health Administration. DHEW Publication No. 1696, 1M, 117 pp. (32) U.S(,PUBLIC HEALTH SERVICE, 17b XeolfJl C'snwqwnees oJ9mokinp, 1iQD. ."drppienwut to the 1M7 AaEKe Health Service Review. U.S. Department of Health, Education, aad Welfare, Publie Health Service, Health Services and Mental Health Adminiefration. DHEW Publication No. 1l6K 1969, 96 pp. (33) U.S. PUBLIC HEALTH SERVIC& T)re BaltJt (1Mepuenoes ef Smoking. A J?spont of the Smg.ow Ce+wnR 1971. UU.S. Department of Health. Education, and Welfare, Public Health Service, Health Ser+doea and Mental Health Administration. DHLW Publication No. (HSM) 71-751E,1971, 46E pp. (J4) U.S. PUBLIC HEALTH SERVICE. The IfeolfA Consequsntes of Smokinp - Report of the Susyean GeneraL• 187t. U.S. Department of Health, Edueatk., and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. (H3M)?Ir7516,1972,158 pp. U.S. PUBLIC HEALTH SERVICE. 4bewape Smoking, National Phtferns of Cigarette Smoking, Ayes I! Tkrnuyh 18, in 11Ad and 1D70. U.S. Department of Health, Education, and Welfare, Public Health Service, National In.titutea of Health, DHEW Publication No. (H81f) ?t=7506,1M U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1870. U.S. Depart- ment of Health, Education, and Welfare, Public Health Serviee, Center for Disease Control, National Clearinghouse for Smoking and Health, DHEW Publication No. (HSM) 48-8727, June 19?&,1P9 pp. U.S. PUBLIC HEALTH SERVICE. 7Ae Health Qonseqwnron of S+nokieg. A Raport of as Su+gtaa Cener»L• 197t. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Admini.tration. DHEW Publication No. (HSM) T8$701,1978, 249 pp. U.S. PUBLIC HEALTH SERVICE. The Health Cohwqwnae of Smoking. A Report of as 3urDsoa Censroi: 1i74. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Servioet and Mental Health Adminietration. DHEW Publication No. (CDC) 74-3704,1974,124 pp. (Je) U.S. PUBLIC HEALTH SERVICE. The Health Cen.equences of Smoking. A (40) Report of the Su:yeon CenereL• 1075. U.S. Department of Health, Education, and Welfare, Public Health Service, Health Services and Mental Health Administration. DHEW Publication No. (CDC) 96-8704,1975, 286 pp. U.S. PUBLIC HEALTH SERVICE Adult Use of Tobacco, 1l7f. U.S. Depart- ment of Health. Education, and Welfare, Publio Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health, June 197Q (41) U.S. PUBLIC HEALTH SERVICE. The Health Cowsequenoes of Smoking. A R.Jer.noe Lifition. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Dieeaee Control, DHE1V Publication No. (CDC) 76- SS5T.1996, 667 pp. (4t) U.S. SENATE. H.arings Bejone the Consumer Suboommitloe of as Committee on Commerce. Reviewing f'ftyrsu Made Toward fAe Dewlopment and Marketing of a Iwss Aamndoui Cigarette. Serial No. 90-b$ August 23-Z5, 1967, 829 pp. (43) WAKEIIAM, H. Sales weighted average tar and nicotine deliveries of U.S. cigarettes from 1957 to present In: Wynder, E.L., Hecht, S. (Editors). Lung Cancer. International Union Against Cancer, U1CC Technical Report Ser-iee, Volume 25,1976, pp.151-152 236 SegsSzSe 237
Page 164: apt20e00
INDEX ABORTfON. BPONTANDOUB ANGINA P®C7ORI8 affect of matere.l smoking on risk, 1b8 ACIDS oirdnop.iaty, 88 eonrdnogenkity, 8S ACEOI.EIN coearebormicity. 94 ADOLEBCENTB peroant distribution of araolura by tar yiald, 42O-42Z role of lower tar and niootine oi8ae- ette. Ia Initiation of smoking he- bi; 183 use of lower ter eod nieoRine eigar- attM in male..a females, 188 uas d lower tae eitanetta, 2a0-2?Z ADRENAL CORTE= HORMONEB effect of oiootlne on ooRiaol serie- tion, 117-118 ADYER179W1i market trends for lower tar dgu- .tt.a, 8D2 Aee ereee. Sra DRMOORAPHIC YARRLIBLRS AGRICULTURAL PRACTICES (S.. olao G6NEZICB; TOBACCO CURING) affect on ei8arette smoke pherms- eolopr, nseueb recommendations, 55 affect on emoke oompeaiition, 51 ALCOHOL CON9UMPCION intnsetiw affect with smoking in etioiop of upper digestive trsat eeoplYINs, 42 ALKALOID CONTSNT (Sw d.n NICO'PQRS CONTENT) in dpu.tte smake, 97 • AiEAL0ID8 (Su afio NIC0IIIYL) rardna8enidtf, 97 A1OiS CONTENT In gas phase of dprette smoke, 94 reie of carbon wionoxide in exer+cisad induoed an8ina, 46 ANIMAL MODELS (Sw al.o BIOA3SA7) In a..erannt of health risks of lower tar .nd nicotine d8arette., 1U bladdec neopt..my 41 eaudioveseulee efGeta of carbon mwAA0. 46 ehronie obstructive lang dinase, 43- 44 effect of maternal nnokins on preg- nancy, 167 emphyeena4 142 Moph.BeaW e.oplasma, L2 d9 krynged neopi..ms, 41 lung neopl.er, 8H0 niaodne tolerance end physical deo- peadenoe, I79 niaotlne use, 178-179 oral nsopisams, 42 penoewtio naopiaaaea, 41-d8 reduced woinooenkhy of cigarette smoke, 94 srnoldng and cardiovascular diseaaes, 124 sudden death due to cardbrsecular disesse, 44. 46 fo6saoo-eebted diseesa, research rs oommaWIatioos, 58 transpleeentsi earainogeneafa, 47 AN3T11tYP8W affect of eigarstte emoke on actiri- ty. 1b7 138 AN11YZtYPBIAi DS!'ICIffiiCt in emphysema stiolopr, 187-198 AROMATIC A1QD88 binding te nnclde neids, 91 metnbolla eatiratlon aod eueino8en- idty, 91 AROMATIC AMIIN! CONTEN[' in ei8aeotte smoke, 97 °Ve6ezse
Page 165: apt20e00
INDEX INDEX AROMATIC AMINE CONTENP-Con. BEN'LO(a)PlRENE CONTENT-Con. Caoar Set NFAPLA3i1S CARCIINOGENFSiS-Con. reduction of is eiSar.tt..mok., 96 in tobacco smoke, 96 CARBON MONOXIDE vdue of wboooous gland suppression AiW1dA1iC Al@IES BENZO(o)P7RF.NB (S.. at+o CA1tBOJCYBENOGLOBIN) am4y in prediction o~ 43 biadio~ to ouelde acik 91 aardnoganidty, es anin6 mudels of e.rdiovueular et . CARCINOGENS bladd.r aeopi..ms and, 94-96 ooarcinogenieity, 9E fact., 46 (SeW ai.o COCAIOCINOCBNS; Ml3- In bladder neopl.m etiolopr, 41 in tobacco .moke, 96-86 In cardiovascular direaw atioloQy, TAGffidS) m.tabolio asti.ation and e.rdno=en• BIOASSAY lla ben*a)pyoene, 86-57 ieity, 91 (S+r ai.o ANDIAL HODEI$) in coronary boart disea.. .tioloeY, binding to prot.in., 90-91 AttOl[ATIC HYDROCARBON CON- in a..ermsnt of health eiiin of 10 formation and activation In vivo, TENP lower tar and niootino aQarette., effect on brrt function, 118 ~-90 In tobacco smoke, 96-06 14 afbet on myae,acdiwa, 118 in ps p1we of eiQaretto smok., 98- AROMATIC HYDROCARBONS et2.eetta smoke components no• effect on pngnanay, 46-47 94 "bay" r.gion tb.xy of wdnoQ.na , warch r.oomm.ndatioa. 68 ox.rel..induad anSina and, 48 lung oueinogsns in ciQantt..moke. d., 80 , e.earch reoommend.. h lth affeot . 86-41 aed loit o t6$7 95-96 mane .kia wsy for luaB neo- ea + , e n y, pa , P1.mu b4a tio.., 67 matrnai-f.td e:chaags of cigarette eardaog.nidty of artaboiie in- , BISTH W81(iH'1' health .ffocta in fotu., research rf smoka aospotrsts, 9~6-99 term.di+ta„ 90 .ffeet of lower tar and nicotine ci 6 oosmeadatioa.. 1QS-100 metabolic activation by adzsd func- aa'areiaopnie(ty. 96 & CARBON ]lONOI1D8 CON?ENT tion oiida...y.tam. M M.Itti .ffost. In fetus research re- .ratta., 15Y , , commendati 119 effeat of matrn.l amokin& 1b8 (Sro a!a CwRBOZYHEiROGLOBIN nieotGw, !9, 91-05 ons, BLADDER NEOPLASMS LEYEIB) oitroumiaa, 37, 40 ABTL HYDROCARBON HYDRO7CY aaimd models 41 In alwoli, effect .f lower tar and or=an•specitic a;ent. ia particulate LASE , 181 aiootia, djaretta Phase.K 97 offoot of oiQ.r.tts ia.oke on activity aromatic amGw and, 41, 9f-96 , 211 BD9 correlation with tar yield in partkulato pbane of tobaooo in miao.mse. , 47-48 carcinogens and mut.jena in siQac- , , faetors influ.ndns yiold In maia- .mok., 94-96 , role in m.tsbolic activation of ae r otto .awk., 41, 97 dn.v .mok. 10 polodum.23a 40 ntatk hydeoaebons, 90 BLOOD CHEMICAL ANALYSIS , In filtered ... aonffltend eiQarotta, polycyclic .eoraatis hydcvcarbon., A raoommandatioas for clinical tastin2 96-97 119-120 86i7, 9`-04 eolr of cigarette tta, 119 facilities, 184 , reduction of In aigarett.o. Public pe.diotion of activity by mutaQene- BLOOD PLA9ELB18 Health Srrvia r.mmmudation., si. assay .y.t.m., 42-48 BEHAVIOR effect of niootin., 11s 201 peediction of activity by ..baaaous effect of matoraal "oking on eEil- BLOOD PRZ3SIJRE CAItBOYYIiEIOGLOBIIV gland .uppr...ion trt, 43 dne, 160 effect of abotin., 117 (Sa a!o CARBON MONOXIDE) tobacco flavor additiva., 99 BEHAVIOR ANIHAL BLOOD YESBEIB in oardiova.eular diL..a. .tiology, weak iddr; 88 wlt-addai.testioa of niootine, 179 affeet of niootina, 117 11a CARDIOVASCULAR DISEASES BENZ(.)ANPI>nACBNBS .ff.et of tobacco antig.ns on on- CARBO1fTHEHOOLOBIN LEVELS (Sa a(ao CORONARY DISEASE) eanciaogsnidty, 96 dotLelium, 119 (.S.w aa CARBON MONOXIDE .nim.,i nwd.ls of sudden dealh, 44, ia t4D.eeo amoke, 96 BREAST FEEDING CoNrENT) 46 B6NwRLUOxANTii1NES (Sw o!w LACTATION) effect of lower tar .nd nicotine da- carbon monoiddo in atioloo of, 118 -erino4.nktty. 96 fr00mn1lnded research on maternal matta, 1a1-182 effect of lower tar and nwotine ei- in tab.eeo smoke, 95 .mokinff and, 166 CABCIIRO(i8NE8iS pnttr on risk, summary of BENZO(s.kOPZKTLZNB BraneWl epiWeH.a S.r TRACHEO- (.4.s sis lstlPA(iENES1S) fiadinp, 19-M, 126-.126 oooaraiao~.aklRy, 96 B80NClDAL ZPr11ML1[UI[ "bay" region tbwr7, 90 affoct of smoking on risk, 116-117 In tobaaoo umolu, Od BRONCBTIffi Induced by lower tar and niootiss research noomwndation., 124-.126 BPNZ0(e)i'HWAIPPBMNY (Sa efao CHRONIC OB$I'R(J(.1TVE 41161W.tt.16 " CARDIOVASCULAR SYSTEM eardaos+aidtp, 96 LUNG DIS6ASB) noommasdatloop fr ewareh on (.4.r ai.o HEART FUNCTION; ia tobacco .moko, 96 .ff.et of filtrad dawttea on ma.- lower tar aod niootins aiEaretta., BSAAT RATE) B6NZ0(.)PYBSN6 tality ri.t, 140-141 90-101 effect of carbon monoxide, 48 eorcbopokity, t4-i7, 96 .moldng and, 12i~186 rolu of niostLw, 91-i8 effect of lower nioottas aiQanttes Laaltti .tfoat. Ia foto., research co- role of atwk.indne.d miaa.omal on funRbn, 118 eoms""tbr, 1!0 CADIOUN "Ww activity, 48 effect of niootino on fundlon, 117- metabolic arth^atloa, i0 Lyp.rtewbn and, 119 tranapl.oontd eudno`.ned., 9S-A9 118 9EAiZO(a)PrJtEfiB vOMrslPr CADl64I)Id CONTENT .aluo of awtai+nuls arays in prar CATI9CHOL CONTENT In ei<.rkt.. (1Y6e••19e0), l6.ae in dgwats smok., 97 dieHon of, 4t-48 is tobacco anok., 96
Page 166: apt20e00
INDEX INDEX CAT6CHOL9 CHRONIC OaSTRUCTIYE LUNG CIGAREITFS-Con. CIGARETPES, LOWER TAR AND carinoQenkity, 78 DI3EA8E-ConL tar yields of U.3& bnndi (197li- NIC077NB-Con. aocaronegenieity, 88, 96 lov.ar tar and nieotine ei=seettes ie 197!), 280-7d4 determination of physical and ehem- CATFCHOLA>11INR L6VE[8 etiology of, research reoommends- tronda in daily consumption, 218-.214 ical propertiee of emoko, research affect of niootins, 117-118 tiom, 142-148 trends in per eapita consumption, recommendations, 66-66 CEIt1iBItOTA8CI1LAIt DI80RDE1t9 .moking ehsiactaeletiea ssd, 139 218 Y16 development of research cigarettes, (8+t alae CARDIOVASCULAR DI- .moidng In etioiopr of, 11-12, 126- CIGARE'iTffi, FILTERED 68-b9, 184-186 88A81S) I86 (Sa ofao F11.TER8) effeet on antitrypdn activity, 187- affect of fOta.d eijnr.tt.e on mor .anoldrW in etiology of, enmmary of carbon monoside contest, 96-9W 188 tality, 119 ffsain8., 2064 -1.8-1.9 effect on bronchitis mortality risk, effect on birthwoight, 168 CFSt#ATIOBI OF BMOEIIYG CIDtYSEPiE 140-141 effect on eaedlov.eeuiar dleow ri.k, (S.. das 61[4HOMRA- REDUG eardnopnidty 94 affect on eardlo+ra.cui.r disease risk, re.e.reh raamnmendations, 12a- T10N OF SIfOMNM , CIfltYBENE CONTW1T summary of find;np, 20, 128 >zs affect en aoroasey bent di.esw is tobseos spwker 96 affect on cerebrovascular disorder effect on aaediornculer disease risk, riek, 118-116 CIGA1tL1T6 PAPER maefality, 119 summary of finding., 19-20, 12b- 80 affect en neopl.eot riek affect of porosity on enolu aompoei- effect on coronary heart di.easo 128 , 119-120 morbidity and mortality effect on chronic obstructive lung M.lee .a fas.lr 214 601650 , „ reeonomended proseanr for pngnant CI(3AR. Cigarette e.oks 300 dl[OKII effect on cough prevalenoe, 140 disease rbk, 11-12 , effect on laeyn`eal nooplaan riek effect on chronic obstructive lung women 1A8-168 EPI'E , , 8S~ diena.e tiat summary of findinQs recommended research on pregn.ney Cigae ette s.eke, gas Pbsee $u GAS 82-BS effect on lung neopl.em risk , , 20-21 148-149 and, 16t-lel PHAlEti CiGARME !lIfO1<E , nicotine yislds of U.S. brands (1978- , effect on coronary heart dieea.e relatios.hip of tar end nkrotine yield Cis.eetle mseby Partierlate pLew Set 1999) M-284 mortality. 119-180 to ew.tion attempta, =-2JJ8 PARTICULATE PHASE, CIGAIt- , 97 nitrogen omude content affect on coronary heut disease role of Iower ta' and nicotine dQar- iE.'ITE SIIO)rE . reoanmendationm for research cigar- 116-117 eide 9-11 etter, ]88, 223--= Ctgaretto w.ekl.g Se. lill0l=G ettee, 181 , , effect on elaetan activity, 187-188 rolo of lowee tar eed nieotine eisar Cfpeetee ten 8w TARB, CIGARE7IE tar yields of U.S. brands (1978- effect on lung funotion, research re- ettet, summary of ftndings, 21, CIfiARLTI'6 YENTII.ATION 1979), 280-281 - commendations, 144-146 22iL280 effect on emoia eompo.ition, 50 use tresd., 201 effect on lung neoplaem morbidity CHILDREN CIGAItis'T[S8 CIGAREITZ% 1IIdH-NICOTINE and mortality nta., 79 (Sw ofro NEONATE) benoo(s)pyrew content (1966-1980), demographic characteristics of users, effect on lung neoplasm mortality effect of maternal enwldng an 86-a6 219 rirk, 81415 healtb, ib8-160 consumption hands, 80 effect on pancreatic elaetaee levels effect on mortality rate, 12-18 effect of maternal smoking on phy- eorrelatSos between carbon nwnox- ia dog1, N-46 effect on prsgnaney, 12, 16® .ie.l, int.lleetusl, and emotional ido ytdd and tar yield, 209, 211 CIGABSITEB, 1QGH-TAR effect on peegaanoy and infant dewlopawnt, 16i onrralation between aiootine yield demographic characteristics of users, health, research reanmmendation., effect of maternal smoidng, nus- asd tohoseo wetght, 209-210 217-21II 160-162, 169-.17v mary of f(ndin8s„ ?,1 22, 170 correlation between tar yield and use tn®da in mala vs. femaleti offeet on pregnancy and Infant affect of pwalal emohlng on niootine 7ieid, 206, 206-210 217-,219 health, summary of findinge, 21- hedth, 1b8-1b0 eorrelatf" e.tween tar yhW and CIGA1Ht1TE8, LOWBR TAR AND YY,17o CIUtOHO®OMB tobseoo trdght, M"0, 212 NICOTINE effect on traebeobronchial epitheli- (Sw aJao MTCAGUiESIi3) development of optimum tar to ni- ammement of telatire bealth rieks, um, 87-88, 7142 aberrations in smoken vs. nonmok- eotins ratioe, 184-186 8-16 market trenda, bfl, 198-212 as, 48 affect of butt asd oveewrap i.esthe behavioral and economic facton af- product aholos and u.e, summary of CHRONIC OB81RUC17YE LUNG DI- on tar and niesUno yidW 211 feoNng use, 182 findin8e, ?S-?A, 22&?80 aEASlI affect of product dedp en saroke earcinogenidty, 88419 reoonmendatioos for aareioogeneeie (So••lep RxoxCMTlso sas• eompoeitfon, " aareinogenieity, summary of find- eaeeareh, 99-101 r11919MsA) fedvsi ng.lation at a 201 innp, 18•-19, 101-102 research eeovmmesa.tions from the animal nmdAe, ~44 monitoring .mokI aompwneta is in chronic obstructive lung disease Working kieating on lav.-Yield effect of iower tar dprettes en new prod»eta, 83 etiology, research rooommenda. (igarettea (June 1980), 24-26 tLk, 11 12 niootin. yields ef U.BA branda (19T8- . Nos1, 142-148 role in oeuation of emoldng, wm- affect of loMer tar and oieotine dt+ 19Ta) ?a0-,Ll1 eompenrefary emoldng Eebavlor, 7-6, mary of fiodings, 2t, 229-290 s arettas on eisk, sunnmry of find- , e.eonnMndations for :.e.umh oigar 62, 57. 86, 9T-A8, 119, 117, 180Q. role in oemation or reduction of (ags, 2D-21, 14d-1d9 ottea, 184-.185 182 emoldng, 188 zbesezse
Page 167: apt20e00
2NDEX INDEX CIGARETfF$ LOWER TAR AND CIGARETIT$ IAW TAR-Con. CYANIDE CONTENT F.ndotrsiium 3.. BLOOD YFSSEIS MCOTIIVB yieid of non-t.r constituents, 7-8 in ciQantte amokq, 94 ENYIRONIi<ENTAL POLLUTION role in Idtlatbn maintenaoo. and CIGAREi7FA lbTBDIUM•NICO1iPfE (S+s al.o OCCUPATIONAL BxPO- , , eessafJon of .ookins Nmmary of , recomakndations for use 96 180 DFJfOGRAPHIC YARIASLFS SURE) N , fiodinQ., 2Z 186 , , research rseommendations 68 (Sa ef.o SEX RATIO) intenction with .moking, reu4ch . role In initiatfon of amddng h.bi1, , CIGARETlF& NON-NICO'I'IINE hieM n. bw-nioofine cigarette nconm~sadatfons, b6-b7 189-183 attitudes of amokees 177 uwrs, 219 ENZYlD3 ACTIVITY role In maint.nance of smoking ka- , CIGARBTlEB,NONTOBACCO 6igh- va low-tar ci`.eatts users, (Su afao ARYL HYDROCARBON Mt, in effect of .iaokins content on pvo- 21T-218 SYDROZYLASB= ELASTASE; uss In male va femais adolesosnts, duct use, 177 mean daily dose of tar and niootine OZIDASE ACI7YTYY) 183 - CIISA1tY AC1iYlTY in smokers by raoe, .ex, and age, effed of dguette amoke on ela.- use trsad., 199-22E ($ee aieo PUhNONARY CLEAR- 219-22D t+.a, 184-188 CIGAIIBTP11% LOW NICOTIIdE ANCL) use of high- va low-tar cigarettes affect of ajarette amoin on miero- aootpenutory amoidng bekavioq 177, detmnination of aiiato:ic smoke In smokers by educational level, .oroal o:Wa.e., 47-48 180-192 eomponsats, 57 218 effect of 6igh-niootine dgarette demognpbia eb.r*derLlio of users, effect of cigarette smoke, d7 use of hiah- vs. low-tar cigarettes smoke on dutass kvel. In dogs, 219 COCARCINOG8M in smokas by ineome level. 218 44-46 effect on eaediovuwlae function, (8.w ut+o CARCINOGENS: lLUTA= DIBC:NZACRIDINES role In metabolic .eUvatiat of mna- 118 GENS) «rdno94oidty, 96 neYtn., !9 compensatory smoking eeeaviae, re-. atecLol, 89 in tobsa+o nnoke, 95 role of elaatau in empbysema etiol- .eare1 r.ooefinenaatkn., a7 nicoHus, l", 94 DIHENZ(AA)ANTHBACENE ogy, 4s-K zarl-lss role In cessation of .moking, 225- in particulate phaee of tobacco au~c~cinogenicity, 95 ESOPBADEAL NEOPI.ASMS ?Z$ amoke, 91, 96 In tobaeoo anoirR, 96 animal models, lZ-48 trends in s.lerweiQhted arerase, Pi>eol•. 38 DIBENZO(e,s)CARBAZOLE carcinoEsns in particuiate matter of 7A6-,208 weak ada., as «uoinoconkaty, 96 dgarette amoke, 97 u.e trendr, 177, 219-M Cq.p.rtoq emold.g Sss SMOKING In tobaeco smoke, 95 induced by nitrosonoeniooane in CI(LIHBITEB, LOW•TAB ~CS DIBEN7.OYY6RMF8 nts, 41-42 compensatory smoking be4avioc, 7-8, CORONARY DISEAdE cucinogealcitlr, 96 snwkins and aiookoi consumption in 1?7, 180-1dt (.Sw ofao CARDIOVASCULAR DI- in tob.coo amoke 05 etiology of, 42 defioition, 206 SEASHE) , EX-SMOKER$ demoaraplik eL.eaaeeialin of users, carbon moooxide in etiology of, 10 Eduwtio.al Ievel S.. DEMOGRAPHIC (S.u ai.o CESSATION OF SMOK- 21T-218 effect of filtered cigarettes on moF YARIABLLS ING) effect of compensatory smoking on bidity and mortality, 119-120 ELASTASS coronary beart disease risk, 115-116 dwnio ob.keuctiwlung diseaw affeet of lower tar aed niootine dy- effect of dgantte sinohe on kvde, FAT1Y ACIDS tisk, 140 arattM on moltaltt,y, 119-1J0 137-138 effect of niootins on levels in blood effect on duonie ohdruetJve lung effect of lower tar and niootine dr. effest of higb-oiaoiina cigarette , 117 dis.ese ridS 11-12 .ntts on ri.k 9-11 116-117 moke on leveb 1n do s 44-46 ' ' effect on ooroeary ieatt disease , , sffect of lower tar and nicatins dg- . g , role In emphyeewa etiokigy, 48-W, I FETAL iM10RTA11 Y (Sw a4o PERINATAL KORTALI- risk, 9-11 uettes on risk, summary of find- 177-1a8 TY) effect on lung function, 189-1d0 ic4., 19-A 126-126 EMPHYSEMA effect of waternsi smoking Ib9 effect on Iwg neopla.m risk, 9 efted of lower tar cigarettes on (Ss aia CHRONIC OBSTRUCTIYS , FSTUS effeet on asoplasm eisk, e0 risk, 9-11 LUNG DISEASE) effect of lower tar and nicotine cig- effect on sputum peoduetion, 189- effect of smoking on risk, 9-10, animal modeL, 142 arettes 169 140 115-117 bioohemiod markers In early deteo. , 167-169 effest of maternal amoidng Lealth effects of ddrti..m smoke, Multiple Risk Factor Intervention tbn of 139 , off.ct of mateensl aaokinE research research eaoomm.adatioo. 66 Trial (11RFM 112 , , , market tnnds 901-wir 906.1i06 11b-11e risk in e:+moken eisnrette enwke in elaoioQy of, !$.t4 raeomnnndationr, 169-170 , , , 43A la?-lae etiology P1ltud dpncts. Sa CIOAREr= role in a..tion of amddnQ, z2~ 828 Coronary brrt dl..au 8w CORO. NARY DISEASE , Induced by smoke Inhalation in ani-. FILTERED treuds in eales-vnigbtad av.raM COUGH maL, 43, 142 F13.TBRS 2O6-l08 (Ss. .iso RESPIRATORY SYIdP- nitropn oxddes in etiology of, 1fY- (Sss .Iw CIOAREPPE$, use tread. in adoieeo.ntti l80-2~ TOM) 189 IrII.1aR8D) use tiend. In ni.IeN vs, fwnele., effed of filtered cigarettes on poe- smoking aed. 1ffi-186 effect on oaebon mono:ide delivery, Y17-2Y1 valena, 240 smoking in etiolop of, 187-189 119-1m • erY~VGi4f?8
Page 168: apt20e00
INDEX FILTERS-Con. Infant, newborn (0-1 month) See NEO• LUNG NEOPLASMS-Con. effect on smoke composition. 50 NATE effect of lower tar and nicotine cig- perforated type, 97 Inhalation See SMOKING CIIARAC. arettes on morbidity and mortali- Forced reed expiratory .ohurw Set LUNG TERISTICS ty rates, 79 FUNCTION; RESPIRATORY INIELLE(.TUAL DEVEIAPMENT effect of lower tar and nicotine cig- FUNCTION TF.81B effect of maternal smoking on chil- arettes on risk, summary of find- Forced vital capacity See LUNG dren, 159 ings, 18-19, 101-102 effect of lower tar cigarettes on FUNCTION;RESPfRATORY KIDNEY NEOPLASMS risk, 9 FUNCTION TEST9 carcinogens In particulate phase of effect of smoking on risk, 9 GAS PHASE, CIGARETI'E SMOKE cigarette smoke, 97 effect of tar and nicotine content (See oLe SMOKE, CIGAREI'TE) 81-85 on mortality risk LACTATION , 98-94 carcinogens LUNGS , (Sn alro BREAST FEEDING) 88 toxic components small airway pathology in smokers, , recommended research on maternal GENETICS 188 smoking and, 166 effect on cigarette smoke pharma- LARYNGEAL NEOPLASMS MATERNAL•.FETAL EXCHANGE colo`y, research recommendations, animal models, 41 animal models of transpiaoental car- 66 effect of filtered cigarettes on risk, dnogenesis, 47 use In modification of cigarette 8844 cigarette smoke cardnogena, 98-99 smoke oompositkm, 50 induced by dgarette smoke Inhala- Mateena[ smoking Sae SMOHING, tion In hameters, 41 MATERNAL HEALTH EDUCATION induced by nitro.amines In ham- Ma:im.m suidezpiratory flow nea- public awarenees of health hazards sten, 41 aurement. Sa LUNG FUNCTION; of smoking, 200•.-202 LEGISLATION RESPIRATORY FUNCTION HEART )wUNCTION federal regulation of tobacco indus- TESTS effect of carbon monoxide, 118 try, 201 Mixed funetlon esidase. Sa OXIDASE effect of nkrotine, 117 Lower niootlne cigarettes See CIGAR. ACTIYITY HEART RATE ETTES, LOWER TAR AND NICO- MORBIDITY effect of niaotine, 117 TINE; CIGARI+:ITES, LOW-NICO- dose-rasponse relationship between HETEROCYCLIC NITROGEN COM- TINE smoking and disease, 6-8 POUNDS Lnwer tar eiga.ettea 8,e CIGAR• MORTALITY carcinogenicity 97 ETPES, LOWER TAR AND NICO- (3ee also FETAL MORT.1LiTYp IN- , 94 97 in cigarette smoke TINE; CIGAREPTL.+'g, LOW-TAR FANT MORTALITY; PERINA- , , HUMECTANTS LUNG FUNCTION TAL MORTALITY-) (3ee al.o TOBACCO ADDITIVFS; (3es also PULMONARY CLEAR- cardiovascular diseases, effect of fil- . ANCE; RESPIRATORY FUNC- tered cigarettes on risk, 119-120 TOBACCO FLAVOR) . TION TESTS) effect of lov• er tar and nicotine cig- in cigaeettes, 51-52 effect of lower tar and nicotine ejg arettes, 12-18 HYPERTENSION arettes, research recommends- MUTAGENESIS cadmium and, 119 tions, 144-146 (See also CARCINOGENESIS; IbIDiIJNE SYSTEM effect of smoke Inhalation in rats, CHROMOSOMES) 48 siste.r ehnsmatid exchange in smok- effect of amoking, 48 effect of smoking, 188 ers vs. nonsmokers, 48 INDOLES affect of tar ykld, 189-140 value of assays in prediction of car- cocardnogenielty, 96 smokers vs, nonsmokers, 141 dnogenic potential, 42-43 in tobjoeo smoke, 9a LUNG NEOPLASMS MUTAGENS INFANT MORTALITY animal modsls, 54-40 (See also CARCINOGENS; COCAR- (Sss aiso PERINATAL MORTALI- eardnogens In cigarette smoke, 8b-. CINOGENS) Tn 41,97 In dgarette smoke, 57-M effeet of maternal smoking on sud- cigarette tar in etiology of, 79 tobacco flavor additives, 99 den Infant death syndrome risk, effect of filtered dgarettes on risk, in urine In smokers vL nonsmokers, 168-1a9 41 INDEX MYOCARDIUM effect of carbon monoxide, 118 N in bladder neoplasm etiology, 41 NEONATE effect of maternal smoking, 158-169 effect of maternal smoking, research recommendations, 1b9-170 effect of maternal smoking, sum- mary of findings, 21-2?, 170 NEOPLASMS effect of cessation of smoking on risk, 80 effect of lower tar and nicotine cig- arettee on risk, summary of find- ings, 18-19, 101-102 effect of lower tar cigarettes on risk, 80 smoking In etiology of, 79-M NICKEL CONTENT careinogeiddty, 97 in cigarette smoke, 97 NICOTINE animal models of toleranoe and phy- sieal dependence, 179 animal models of nicotine use, 178- 179 cocardnogenidty, 89-0, 94 effect on blood platelets, 118 effect on eaediovascular function, 117-118 effect on catecholamine levels, 117 effect on cortisol secretion, 117-118 effect on fatty acid levels in blood, 117 effect on pregnancy, 48-/7 evaluation of health effects, re- search reeommendations, b4 health effects in fetus and child, re- search reoommendations, 168 intravenous and oral exposure in smokers, 177-178 role in c"nogenesia, 39, 91-93 role in maintenanoe of smoking ha- bit, 177-180, 188 self-adminietration in animals, 179 NICOTINE CONTENT in blood, effect of lower tar and nicotine cigarettes, 181-182 cessation of smoking attempts and, 225-?26 In cigarettes, development and vali- dation of analytical methods, 56 246 "RGSZGS 247
Page 169: apt20e00
INDEX NICOTINE CONTENT-Con. cigarettes In the United States (1978-1979), 2$0-294 cor'elation with tar yield, 208, 208- 210 correlation with tobacco weight per dgantte, 209-210 effect of puffing profile on yield, 210-211. effect of smoking characteristics on yield, 210-211 effect on daily cigarette cunsump- tion, 222-??1i affeet on lung neoplasm mortality eisk, 81-8,5 mean dally doee in smokers by race, sex, and age, 219-MD percentage distribution of smokers by nicotine yield, 219, 221 relationship to nitrosamine content in tobacco smoke, 89 NICOTINE REDUCTION Public Health Ser.ioe reoommends- tions, 2"1 NPfttATE CONTENT 2-niteopropaae in cigarette smoke, 94 NITROGEN OXIDE CONTENT In cigarettes with perforated filter tip., 97 NITROGEN OXIDES In emphysema etiology, 188-139 NITROSAMINE CONTENT in cigarette smoke, 87, 94-95, 97 In tobacco, 87 reduction of In cigarette smoke, 40, 96-96 relationship to nicotine content in tobacco smoke, 89 NITROSAMINES eaednogenicity, 87, 40, 91-92, 97 earcinogenkity in animnls, 95-98 in coophageal neoplum Induction in nte, 41-a2 formation in cigarette smoke, 40 formation In tobacco and tobacco smoke, 95 formation In vivo, 40, 92-93, 9b-96 In laryngeal neoplasm Induction In hamsters, 41 in pancreatic neoplasm induction in hamsters, 42 NITROSOlrIETHYLUREA °- -opla.m inductian In animals, 92 ,,,, sUssezse NUCLEIC ACIDS binding of aromatic amides and amines, 91 Obstructive airway di.asee See BRONCHITIS; CHRONIC OB- STRUCTiYE LUNG DISEASE; EMPHYSEMA OCCUPATIONAL E7i;POSURE (3e" aiw ENVIRONMENTAL POL. Ltl'1'ION) interaction with smoking, research recommendations, 68-b7 ORAL NEOPLASMS animal models„ 42 smoking and alcohol consumption in etiology of, 42 OXIDASE AQfIVTI`Y effect of ciganstte smoke on micro- somal oxidaw, 47-48 role in cae+cinogenesia, 48, 89 PANCREATIC NEOPLAS1fS animal models, 42-48 cueinogau in particulate phase of cigarette rmoke, 97 induasd by diisopropylnitroeamine in 42 Parentnal~.aoktag S.. SMOHINiG, PA- RENTAL PARTICULATE PHASE, CIGAREITE SMOKE (3er alao SMOKB, CIGARE'PfE; SMOIO; TOBACCO; TARS, CIG- ARETTE) carcinogens, 94-96, 97 oocarcinogens, 94, 96 toxic components, 89-94 PASSIVE SMOKING (S.. also SMOKE STREAMS) health effects of lower tar and nico- tine cigarettes, research recom- mendations, 68, 58 public attitudee toward bealth ef- feets, 2D4 Peak ezpintory flow mea.aeemeats Sw LUNG FUNCTION; RESPIRA. TORY FUNCTION TESTS PERINATAL MORTALITY (Sa aia INFANT MORPALFtY) effect of lower tar and niootine cie anttes on risk, 169 effect of maternal smoking, lb6 risk factors, 158 PHNOLS carcinogenicity, 38 coc.er,inogenicity, 88 PLACENTA effect of maternal amoking, 1b7-168 affeet of maternal smoking, research recommendations, 164-165 POLONIUM,216 cardnogenicity, 40, 97 formation in cigarette smoke, 40 formation in tobacco, 40 POLONIUM-210 CONTENT in dgaeette smoke, 97 reduction of in tobacco, 40 PoVcyclk aroautk 4ydeoarboaa See AROMATIC HYDROCARBONS PREGNANCY (Seo also FETUS; NEONATE) animal models of maternal smoking and, 167 effect of lower tar and nicotine cig-. arette., 1$ 159 effect of lower tar and nicotine cig- acettr, re.earch reoommenda- tions, 100-182, 169-170 effect of maternal amoking, 46-47, 167-169 effect of nutternal smoking, sum- mary of findings, 21 2'l, 170 effect of maternal .mokiug, research recommendations, 1iS9-170 per-lnatal projects, 161 reoommended research on smoking cessation and, 16'1-i63 P6EDiATUR1TY effect of maternal smoking on risk, 158 PROTEINS binding of carcinogens, 90-91 Puffing parameter. Sc. SMOKING CHARACTERISTICS PULMONARY CLEARANCE (Sw also CILLARY ACPIVITY; LUNG FUNCTION) effect of cigarette sawke, 47 Pulmonary function Ses LUNG FUNC- TION Racial groups 3.. DEMOGRAPHIC VARIABLES REDUCTION OF SMOKING (Sa else CESSATION OF BMOK-. ING ) INDEX REDUCTION OF SMOKING-Con. role of lower tar and nicotine cigae- ettee, 183 RESPIRATORY FUNCTION TESTS (Sw ai.u LUNG FUNCTION) In early detection of lu* di.ease, 43, 141 RESPIRATORY SYMPTOMS (Su also COUGH) effect of tar yield, 189-140 SEX RATIO (Ses oiao DEMOGRAPHIC VAB1A, BLES) cessation of smoking, 214 smoking habit in the United States, 211-214 use trends for high- and bw-far cigarettes, 217-219 use trends for lower tar cigarettes among adolesoents, 222 SMOKE, CIGARETTE (Sw a7.o GAS PHASE, CIGAR- S1TE SMOKE; PARTICULATE PHASE, CIGA1tE1TE SMOKE; SMOKE STREAAIB; SDiOKE, TOBACCO) analysis of oomponenfs, research re- commendations, 62-b3 animal modds of reduced carcino- genicity, 94 bioawys of selected components, re- search nmnommendations, 53 in ehronic obstructive lung disesse etiology, 143-144 determination of tozicity, rese:reh reoommendations, " development of analytical methods, 56,124 effect of agricultural practices on wmpoeition, 51 effect of cigarette design on compo- sition, 49-60 effect of filters on composition, 50 effeet of tabaooo additives on com- position and activity, b1-52 effect of tabaooo curing on oomposi- tioo, 51 effect of tobaoeo processing on oom- pos{tbey 51 affect of tobacco varieties on com- position, 60 effect of ventilation on composition, 50 2l9
Page 170: apt20e00
INDEX INDEX SMOKE. l7GARE7TE-C9n. SMOHIIIG-Con. SMOKING HABIT-Con. SMOKING SURYEYS-Con. effect on ciliary activity, 47 effect on coronary heart disease trends in per capita cigarette and National Health Interview Study effect on pulmonary clearance, 47 risk, 115-117 tobaoco consumption, 213-216 (NH1S), 199-201 In emphysema etiology, 43-44 SMOKING AND HEALTH trends In use of lower tar and nico- public attitudes toward health ef- formation of components, 33 dose-rasponse relationship between tine products, 199 fects of smoking, 202-204 lung carcinogens, 35-41 smoking and morbidity, " trends in use of lower tar and nico- public awareness of health effects metabolism of caeoinogenie compo- public attitudes toward health ef- tine cigarettes, summary of find- of smoking, 200-202 nents, 894E fects of smoking, 202-204 ings, 22-2/, 228-290 Roper Survey on smoking and monitoring components in new pro- public awareness of health effects SMOKING MACHINES health, 204 ducts, 53 of smoking, 200-202 accuracy in reproducing smoking be- use of filtered cigarettes, 201 monitoring relative vs. absolute recommendations for clinical testing havior, 49, 180, 185 Spirometrie measurements Sts LUNG yields of components, 54-55 faeilities for smokers, 184 design parametere, 4849, 58 FUNCTION mutagenic vs. carcinogenic compo- Smoking behavior Sa SMOKING monitoring relative vs. absolute SPUTUM PRODUCTION UCTION nents, 87418 CHARACTERISTICS yields of smoke components, 54- effect of tar yield, 139-140 aum- harmacology and toxicology SMOKING CHARACTERISTICS 65 p , TAR CONTENT mary of findings, 16-18, 69-a1 accuracy of smoking machines in re• recommendations for improvement, cessation of smokin attem t d yield of constituents in lower tar produetion of 49, 180 185 185 g p s an , products 7-8 , , compensatory smoking behavior with recommendations for maximum yield 223-228 , SMOKE INHALATION lower tar and nicotine cigarettes, assays, 185 cigarettes in the United States 43 In emphysema itduction in rats 97-98, 119, 177, 86 7-8 b2 57 SMOKING, MATERNAL (1978-1979), 230-234 , in laryngeal neoplasm Induction in , , , . 18D-182 behavioral studies of pregnant wom- correlation with carbon monoxide yield 209 211 hamsters, 41 compensatory smoking behavior, en, research recommendations, , , eorrelation with nicotine ield 206 SMOKE STREAMS summary of findings, 22, 186 162-163 y , , 208-210 (See alio SMOI[E, CIGARETTE; effoct of compensatory smoking be- effect on birthweight, 168 correlation with tobacco weight per SMOKE, TOBACCO) havior on obstructive airway di- effect on fetal mortality, 158 cigarette, 209-210 212 health effecta of sidestream smoke seass risk, 140 effect on health of offspring, 158- , development of analytical methods from lower tar and nicotine eig- effect on aeute airway response to 159 , 66, 124 .rettes, bs, 58 smoke inhalation, 139 effect on perinatal mortality, 158 effect of puffing profile on yield SMOKE, TOBACCO effect on tar and nicotine yields, effect on physical, intellectual, and , 210-211 pharmacology and toxicology, aum- 210-211 emotional development evelopment in chil- effect of smoking characteristics on mary of findings, 16-18, 59-61 effect on yield of dgarette smoke dren, 159 yield, 210-211 SMOKERS VS. Ex-SMOSEI.iS constituents, 49 effect on placenta, 157-158 effect on daily cigarette consump- atticudes toward health hazards of research recommendations, 53-54 effect on pregnancy, 46-47, 157-159 tion, 222-225 smoking, 209 SMOKING HABIT effect on pregnancy and infant effect on lung function, 139-140 SMOKERS VS. NONSMOKERS age at onset by tar and nicotine health, research recommendations, effect on lung neoplasm mortalit attitudes toward health effects of yield, 221-223 159-170 y risk, 81-85 passive smoking, 204 behavioral aspects, summary of find- effect on pregnancy and infant effect on respiratory symptoms chromosomal aberrations, 48 ings, 22, 186 health, summary of finding,3, 21- , 139-140 coronary heart disease risk, 115 effect of alternative nades of nico- 22, 170 effect on sputum production 139- lung function, 141 tine exposure, 177-178 effect on prematurity risk, 158 , 140 mutagens in urine, 41 effect of tar and nicotine yield on effect on spontaneous abortion risk, mean daily dose in smokers by race sister chromatid exchange, 48 daily cigarette consumption, 222- 158 , sex, and age, 219-220 small airway pathology, 138 22S effect on sudden infant death syn- percent distribution of smokers by tracheobronchi.l epithelium, 87-88 males vs. females in the United drome risk, 158-159 tar yield, 219-222 SMOKING . States, 211-214 SMOKING, PARENTAL TAR REDUCTION (Sss also SMOEB. CIGARETTE; role of lower tar and nicotine eigar effect on health of offspring, 158- effect on coronary heart disease 84b1[E INI[ALATION; 9MOKE, ettes in initiation of, 182-183 159 riak, 9-11 TOBACCO; SMOKING, MATER- role of lower tar and nicotine cigar- SMOKING SURVEYS Public Health Service reeommenda- NAL; SMOHING, PARENTAL) ettes in maintenance of, 183 attitudes toward health effects of tions, 200-201 in chronic obstructive lnng disease ede of nicotine In maintenance of, smoking in smcken vs. ex-smok- TARS, CIGARETTE etiology, 135-136 177-180, 188 ers, 209 (See also PARTICULATE PHASE, effect on cardiovascular disease risk, trends in daily cigarette consump- National Clearinghouse on Smoking CIGARETTE SMOKE) 115-117 tion, 80, 218-214 and Health surveys, 200 atherosclerosis and, 119 „u, 9Ves~zse 251
Page 171: apt20e00
INDEX TA$8, CIGARF:7TB-Con. in lung neopl.em etiokogg, 79 TOBACCO ADDITIVE3 (Su e/ao HUHJWANTB; TOBAC- CO FLAVOR) a..wmsat of bealth rirks, 6, 8 eardaotanieitr aad mut.g.oieity of fiavorta8 agents, 96 effeet oa inwke composition, 61-62 flavoring aaents, 61-SZ humectanta, 51-62 TOBACCO ANTIGENS etteat on endothelium, 119 TOBACCO CURING (Sa eln AGRICULTURAL PRAC- TICES) affeat on d8arette smoke pharma- eoio8,y, reeearch recommendations, 66 effect on smoke oomposition, 51 TOBACCO FLAVOR (Sa aleo HUNMANTBp TOBAC- CO ADDITIVES) enrdno8enicity snd muta8enidty of additive., 90 TOBACCO PLAVOii-Con, flavoring aBeatL in eiQae+ettes, 61-b2 TOBACCO INDUSTRY fedaeal regitiatioa of, 6, 201 TOBACCO PROCFS9ING effeet on smoke composition, 61 TOBACCO VARi$PIZIl smoke oompwitioA, 50 TRAC1iEOBRONCBIAL EP1TIiELi- 11K effect of bwer tar and aiaotine cig- seettes, 87-88, 142 effect of smoking. $740 'ltimor feiti.ti.B agents S.e CARCi- NOGSNB Tumor promoting agents Sw COCAR. CIP1O(i@IS UABTSANli9 content in ei8arette smoke, 94 VuvYl. CHLoBIDs content In cigarette .moke, 94 metabolic aetivation, 93 Vitd tap.dtt S+. LUNG FUNCTION 4bagqzss~ 26`
Page 172: apt20e00
SELECTED BIBLIOGRAPHY ON FTC CIGARETTE TEST METHOD 1981-1993 AN:0031721 SN:841635 AU:Adams, J.D., Lee, S.J., Hoffmann, D. TI:(TO:) Carcinogenic Agents in Cigarette Smoke and the Influence of Nitrate on Their Formation. JN:Carcinogenesis PG:5(2): 221-223 PY:1984 PD:February 1984 LA:English AB:The nitrate level of nonfilter reference cigarettes was elevated from 0.52 percent to 1.2, 1.8, 2.4, and 3.05 percent, respectively, by addition of sodium nitrate. Data from mainstream smoke analyses showed that yields of carbon monoxide and carbon dioxide were not significantly altered by nitrate elevation. Tar, nicotine, benzo(a) pyrene (BaP), and catechol in mainstream smoke were reduced, while yields of nitrogen oxides (NO(x), volatile N-nitrosamines (VNA), and tobacco-specific N-nitrosamines (TSNA) were significantly increased. On the basis of previous bioassays with smoke condensates from high-nitrate cigarettes, it was expected that the cutaneous tumorigenicity of these tars would be reduced because of lower levels of BaP (and other carcinogenic polycyclic aromatic hydrocarbons) and catechol. However, the total carcinogenic potential of whole smoke from high-nitrate cigarettes is considered to be significantly increased owing to elevated yields of NO(x), VNA, and TSNA. Nitrosamines are regarded as a major group of carcinogens in tobacco smoke, and nitrogen oxides are the most important precursors for the endogenous formation of N-nitrosamines upon smoke inhalation. Findings support the recommendation that the nitrate content of tobacco products should be reduced.. (Auth. Abs.) AN:0039983 SN:90-0513 AU:Adams, J.D., O'Mara-Adams, K.J., Hoffmann, D. TL•(TO:) Toxic and carcinogenic agents in undiluted mainstream smoke and sidestream smoke of different types of cigarettes. JN:Carcinogenesis PG:8(5):729-31 PY:1987 PD:May 1987 LA:English AB:The mainstream and sidestream smoke of four types of popular U.S. cigarettes were analyzed for toxic and carcinogenic agents. The cigarettes included one without a filter tip, and one filter cigarette each with medium, low and ultra-low smoke yields. The analyses clearly demonstrated that 12 toxic agents determined in this study were significantly reduced in the mainstream smoke of filter cigarettes, as compared with smoke yields from the nonfilter cigarette. In the case of the ultra-low yield cigarette, mainstream smoke emissions were reduced by about 90%. In contrast to this finding, the emissions of the same toxic and carcinogenic components into sidestream smoke of the filter cigarettes were not greatly reduced. Sidestream smoke is the major contributor to environmental tobacco smoke, to which both smokers and non-smokers are exposed. Although the exposure of the smoker to mainstream smoke components is decreased due to proportionally greater consumption of low and ultra-low yield cigarettes, and lower rates of consumption of cigarettes with high smoke yields, the carcinogenic potential of indoor pollutants originating from tobacco products is not diminished. AA: (Auth. Abs.) AU:Adams, L., Lee, C:, Rawbone, R., Guz, A. TI:Patterns of smoking: Measurements and variability in asymptomatic smokers. JN:Clinical Science PG:65:383-392 PY:19$3 I
Page 173: apt20e00
AB:There is little doubt that cigarette smoking is associated with an increased incidence of respiratory and cardiovascular disease. However, clincial experience reveals that many life-long smokers suffer no such impairment of -health. Some of these individuals attribute their freedom from smoking- related disease to an absence of inhaling. The objective of the present study was to ascertain to what extent a group of healthy smokers adopted a reproducible pattern of smoking that might contribute to long-term risk over and above that due to the total number of cigarettes smoked per day and the number of years of smoking. The genuine no-inhaler clearly should be less at risk than his inhaling counterpart. This study has therefore attempted to measure the ventilatory events associated with smoking and their reproductibility on different occasions. The objective has been to look at all the ventilatory factors that might contribute to deposition and absorption of tobacco smoke constitutents within the lung. The results of this study have been presented in a preliminary form. AN:0040300 SN:90-1014 AU:Armitage, A.K. Alexander, J. Hopkins, R. Ward, C. et al. TI:(TO:) Evaluation of a low to middle tar/medium nicotine cigarette designed to maintain nicotine delivery to the smoker. JN: Psychopharmacology PG:96(4):447-53 PY:1988 PD:1988 LA:English AB:A specific objective of this 6-week crossover study was to determine how 21 regular smokers of middle tar cigarettes changed their smoking behaviour and uptake of smoke constituents, when switching to either lower tar cigarettes capable of delivering amounts of nicotine similar to a conventional middle tar cigarette (maintained' nicotine product), or to conventional low tar/low nicotine cigarettes. Subjects visited the laboratory every 2 weeks for detailed assessment of their smoking behaviour. Weekly per capita consumption was similar for all three cigarettes. They were smoked with variable intensities (low tar greater than maintained nicotine greater than middle tar), the tendency being for larger puff volumes, faster puffing and increased puff duration with the low tar cigarettes. The maintained nicotine cigarette was preferred to the middle tar cigarette, although acceptability ratings of the three cigarettes only differed marginally. The nicotine absorbed from the maintained nicotine and middle tar cigarettes was similar and significantly greater than the levels achieved from the low tar cigarettes. Intake of carbon monoxide into the mouth and absorption into the blood stream was lower for the maintained nicotine cigarette than for the middle tar cigarette, with the low tar cigarette occupying an intermediate position. Derived estimates of tar intake suggested reduced intake of tar into the respiratory tract (around 25%) from the maintained nicotine product relative to the middle tar product. The possible advantages of switching to maintained nicotine cigarettes is discussed. AA:(Auth. Abs.) AN:0030580 SN:840491 AU:Aronow, W.S. TL•(TO:) Carbon Monoxide and Cardiovascular Disease. JN:Comprehensive Therapy PG:9(10): 21-26 PY:1983 PD:October 1983 LA:English AB:Carbon monoxide exposure from heavy smoking or heavy atmospheric carbon monoxide pollution contributes to the increase in nonfatal and fatal myocardial infarction and sudden death from coronary artery disease through carboxyhemoglobin (1) interfering with myocardial oxygen delivery, (2) depressing the pump performance of the heart muscle, (3) reducing the threshold for ventricular fibrillation, and (4) increasing platelet stickiness, thereby increasing a thrombotic tendency. In addition, data indicate that high smoking or occupational exposure to carbon monoxide contributes 2
Page 174: apt20e00
to pathogenesis of atherosclerotic disorders, aggravates anginapectoris and intermittent claudication of the calf or thigh, and increases myocardial ischemia in patients with clinical and subclinical coronary artery disease. Patients with chronic obstructive lung disease, cerebrovascular disease, and anemla-are also more susceptible to adverse health effects from low levels of carbon monoxide exposure. Pregnant women, fetuses, and newborn infants are particularly sensitive. (Auth. Abs. Mod.) AN:0026052 SN:791394 AU:Ashton, H., Stepney, R., Thompson, J.W. TI:(TO:) Self-Titration by Cigarette Smokers. JN:British Medical Journal PG:2(6186): 357-360 PY:1979 PI7August 11, 1979 LA:English AB:An 11-week crossover study was carried out in which 12 subjects smoked high-nicotine (1.84 mg standard yield) and low-nicotine (0.6 mg) cigarettes after an initial period of smoking their usual brands with a medium-nicotine yield (mean 1.4 mg). Plasma and urine nicotine concentrations, carboxyhemoglobin (COHb) concentration, puffing behavior, 24-hour cigarette consumption, and butt nicotine content were measured. The changes in plasma nicotine and blood COHb concentrations showed' that the smokers compensated for about two-thirds of the difference in standard yields when switched to either high- orlow-nicotine cigarettes. Thus, compared with the medium-nicotine brand, the intake of nicotine and carbon monoxide was only about 10 percent higher when subjects smoked the high-nicotine cigarettes, which had a standard yield 30-40 percent higher than the medium brands, and only about 15 percent lower when they smoked the low-nicotine cigarettes, which had a standard yield about 50 percent lower than the medium brands. Butt nicotine content and urine nicotine concentrations followed a similar pattern. Changes in puffing behavior and in 24-hour cigarette consumption were only slight. The results show clear evidence of both upward and downward self-titration of nicotine and carbon monoxide (and tar) intakes when smokers change to cigarettes with standard yields that differ over the range studied. (Auth. Abs.) AU:Ashton, H., Telford, R. TI:Smoking and carboxyhaemoglobin. JN:Lancet PG:2:(7833) PY:1973 LA:English AB:It is known that, for smokers whose puffing is not controlled, puffing-rate is greater when they are smoking low-nicotine cigarettes than when they are smoking high-nicotine cigarettes, and that the nicotine obtained from the two types of cigarettes does not differ significantly. People appear to smoke for a given dose of nicotine and to alter their puffing rate unconsciously in such a way as to obtain this dose from different types of cigarette. Since the amount of CO obtained from a cigarette depends, like nicotine intake, on puffing-rate (and depth of inhalation), a greater rise of blood-COHb will occur with mild (low-nicotine) cigarettes in natural conditions-the opposite of what Dr.-Russell and his colleagues found in controlled conditions. AN:0026619 SN:820438 AU:Auerbach,, 0., Garfinkel, L. TI:(TO:) Myocardial Mural Arterial Fibrosis and Cigarette Smoking: A Comparative Study 1955-1960 Versus 1970-1977. JN:Bulletin of the New York Academy of Medicine PG:57(9): 759-775 PY:1981 PlrNovember 1981 3
Page 175: apt20e00
LA:English AB:Cigarette smokers who died between 1955 and 1960 showed far more advanced fibrous thickening of the blood vessels in the heart wall than did those who died between 1970 and 1977. Differences between the two increased with the number of cigarettes smoked during life. Nonsmokers had the fewest advanced changes, and about the same percentages were found in both the earlier and the later groups. Results suggest that the reduction of advanced f ibrous thickening in smokers who died in the later period may be due, at least in part, to the reduced tar and nicotine content of the cigarettes they smoked for the last 5 to 10 years of their lives. No American cigarette mass produced during this period had as high a tar/nicotine content as the brand with the lowest tar/nicotine during the earlier period.. The data are consistent with the epidemiologic findings which have shown a 14 percent decrease in coronary heart disease in low tar/nicotine cigarette smokers when compared to high tar/nicotine smokers. (Auth. Abs. Mod.) AN:0025042 SN:790378 AU:Auerbach, 0., Hammond, E.C., Garfinkel, L. TL•(TO:) Changes in Bronchial Epithelium in Relation to Cigarette Smoking, 1955-1960 Vs. 1970-1977. JN:New England Journal of Medicine PG:300(8): 381-386 PY:1979 PD:February 22, 1979 LA:English AB:To test the hypothesis that the reduction in tar and nicotine content of cigarette smoke that began in the 1950's should be reflected by the histologic changes in the bronchial' epithelium of cigarette smokers, 20,424 sections taken at autopsy from the bronchial tubes of 445 men (non-lung cancer deaths) were examined microscopically in random order. There were 211 men who died in 1955-1960, of whom 154 smoked regularly, and 234 men who died in 1970-1977, of whom 181 were regular smokers. Changes studied included basal cell hyperplasia, loss of cilia and occurrence of cells with a typical nuclei. In both periods studied, these histologic changes occurred far less frequently in nonsmokers than in cigarette smokers and increased in frequency with amount of smoking, adjusted for age. Sections with advanced histologic changes in those dying in 1955-1960 occurred in 0 percent of the nonsmokers, in 2.6 percent of those smoking 1-19 cigarettes a day, in 13.2 percent of those smoking 20-39 and in 22.5 percent of those smoking 40 or more cigarettes a day. In those who died in 1973-1977, the percentages were 0, 0.1, 0.8, and 2.2, respectively. (Auth. Abs.) AU:Bgttig, R. Buzzi, Nil, R. TL•Smoke yield of cigarettes and puffing behavior in men and women. JN: Psychopharmacology PG:76:139-148 PY:1982 LA:English AB:Puffing behavior (number of puffs, puff interval, puff duration peak pressure latency to peak pressure, average and total puff volume) was measured in 67 dependent male and 43 dependent female smokers when they smoked two cigarettes of their habitural brand under laboratory conditions. Test-retest reliability for the two cigarettes was high, and factor analysis showed that puff shape, puff volume, and puff frequency accounted for about 50% of variation obtained with the different puffing variables. Expiratory tidal CO levels increased with the number of cigarettes smoked before the tests and with the intensity of the smoking habit, but pre- to postsmoking tidal CO differences were similar for smokers of all types of cigarettes (U.1-1.7mg standard machine smoking nicotine yield). Volume compensation for differences of smoke yield of the cigarettes was getterally more pronounced in women than in men and, additionally, it was more pronounced for cigarettes withh standard smoke nicotine yield below 0.9mg than for cigarettes with standard smoke nicotine yield above 0.9mg for both sexes. Only for women, partial correlation procedures suggested that nicotine 4
Page 176: apt20e00
might be more important in determining puffing behavior than CO and condensate yield, but there were also no women smoking the strongest cigarettes (1.3-1.7mg nicotine). For both sexes, no compensation by adjusting the number of cigarettes smoked daily was obtained. Personality ratings, pulnTonary functions, and cardiovascular functions were not, or only in consistently, correlated with puffing behavior or type of cigarette. AU:Benowitz, N.L. TI:The use of biologic fluid samples in assessing tobacco smoke consumption. JN:NIDA Monograph PG:6-26 LA:English AB:In summary, the source, absorption, metabolism, and disposition kinetics of several compounds that are potential markers of tobacco smoke consumption have been reviewed. Kinetic considerations have been applied to discuss specificity and sensitivity of various compounds as markers of cigarette smoking status, usefulness as quantative indicators of tobacco smoke consumption, and optimal time for sample collection. One cannot, however, escape the conclusion that selection of a biochemical test must be linked to the hypothesis being tested. If only smoking is being assessed, then carbon monoxide and/or thiocyanate are inexpensive measurements that provide adequate information. If self-administration of nicotine or toxic effects potentially related to nicotine exposure are being studied, then measurement of nicotine exposure and consumption required. Measurement of blood concentration of nicotine per se is necessary to document nicotine exposure; blood concentration of cotinine may be a better measure of daily nicotine consumption. To study potentially carcinogen consumption must be developed and validated. AN:00301 10 SN:840019 AU:Benowitz, N.L., Hall, S.M., Herning, R.I., Jacob, P., III, Jones, R.T., Osman, A.L. TI:(TO:) Smokers of Low-Yield Cigarettes Do Not Consume Less Nicotine. JN:New England' Journal of Medicine 39-142 PG:309(3): 139-142 PY:1983 PD:July 21, 1983 LA:English AB:Contrary to suggestions that low-yield cigarettes reduce tar and nicotine exposure of smokers, it was found that smokers of 1ow-nicotine cigarettes do not consume less nicotine. The actual nicotine content of commercial cigarettes with different nicotine and tar yields was determined with smoking machines, while actual nicotine intake was determined by blood cotinine levels in 272 subjects smoking various brands of cigarettes. Low-yiebd cigarette tobacco did not contain less nicotine; in fact, the nicotine concentration in tobacco correlated inversely (ra-0.53, p<0.05) with the concentration measured by machine. Blood cotinine concentrations correlated with the number of cigarettes smoked/day but not with the machine measured nicotine yield. Only 3.8 to 5.0 percent of total variance in blood cotinine was contributed by nicotine yield. (Auth. Abs. Mod.) AU:Benowitz, N:L., Jacob 111, P. TI:Daily intake of nicotine during cigarette smoking. JN:Clinical Pharmacology, Therapy PG:35(4):499-504 PY:1984 LA:English AB:Intake correlated stronglky with cigarettes smoked per day (r=0.59) but not with machine- determined yield. Nicotine intake per cigarette averaged 1.04mg (=0.36) but did not correlate with machine-determined yield. 5
Page 177: apt20e00
AN:0036830 SN:870870 AU:Benowitz, N.L., Jacob III, P., Kozlowski, L.T., et al. TI:(TO:) Influence of Smoking Fewer Cigarettes on Exposure to Tar, Nicotine, and Carbon Monoxide. JN:New England Journal of Medicine PG:315(21): l 310-1313 PY:1986 PD:November 20, 1986 LA:English AB:As daily cigarette consumption was reduced, smokers increased intake per cigarette of nicotine and other toxins. Smoking was reduced to about 5 cigarettes/day among 13 volunteers who had averaged 37 cigarettes/day for 21 years. Intake of tobacco toxins increased roughly threefold while daily exposure to tar and carbon monoxide declined only 50 percent. As cigarettes were smoked to shorter butt lengths, the delivery of tar and carbon monoxide increased logarithmically and nicotine delivery increased arithmetically. Exposure to nicotine and carbon monoxide was reduced by 30 to 40 percent when intake was 15 cigarettes/day and by 60 percent with 5 cigarettes/day. Urinary mutagenic activity increased' concomitantly with smoking restriction. The greatest reductions in exposure to toxins were found among smokers who had the highest nicotine intake per cigarette during unrestricted smoking, presumably because they normally smoked cigarettes intensely and had less potential for increasing their intake per cigarette. -It is concluded that smoking fewer cigarettes may reduce exposure to toxins and related adverse health consequences. Consistent with a tendency to maintain intake of nicotine, the magnitude of the benefit is much less than expected. A N:0035971 SN:87001 I AU:Benowitz, N.L., Jacob III, P., Yu, L., et al. TI:(TO:) Reduced Tar, Nicotine, and Carbon Monoxide Exposure While Smoking Ultralow- but Not Low-Yield Cigarettes. JN:Journal of the American Medical Association PG:256(2):241-246 PY:1986 PD:JuIy 11, 1986 LA:English AB:Ultralow-yield cigarettes deliver substantial doses of tar, nicotine, and carbon monoxide, but smoker exposure to these compounds is considerably less than for other cigarettes. Exposure to tar (estimated by urine mutagenicity), nicotine (estimated by blood cotinine levels), and carbon monoxide (estimated by carboxyhemoglobin levels) was measured in habitual smokers who switched from their usual brand to high- (15 mg tar), low- (5 mg tar), or ultralow-yield (1.0 mg tar) cigarettes. No differences in exposure were found in comparing high- with low-yield cigarettes. Tar, nicotine, and carbon monoxide exposures in ultralow-yield cigarettes were reduced by 49, 56, and 36 percent, respectively. In 248 subjects smoking their self-selected brand, nicotine intake was 40 percent lower for those who smoked ultralow-yield, compared with those who smoked higher yield brands. (Auth. Abs. Mod.) AN:0045255 SN:92-1126 AU:Benowitz, N.L., Porchet, H., Jacob III, P. TI:(TO:) Nicotine dependence and tolerance in man: pharmacokinetic and pharmacodynamic investigations. JN:Progress in Brain Research PG:79:279-87 PY:1989 ~~ PD:1989 LA:English 6
Page 178: apt20e00
AB:A chapter investigates nicotine tolerance and dependency in humans, examining pharmacokinetic and pharmacodynamic characteristics. The pharmacokinetic and pharmacodynamic characteristics necessary to produce drug dependence include effective absorption into the blood stream, rapid entrance into the brain, and psychoactivity. Studies compared the concentrations of nicotine in the blood after tobacco use with concentrations achieved after subjects received it intravenously; the average dose of nicotine delivered to the circulation is about'lmg after smoking a cigarette and 3 to 5mg after ingesting snuff or chewing tobacco.A study of 22 cigarette smokers who smoked an average of 36 cigarettes daily showed an average daily intake of 37 mg of nicotine. With regular use of tobacco, nicotine accumulates in the body all day and is present in significant concentrations overnight. Nicotine is well absorbed into the blood stream from all tobacco products. Studies also show that nicotine rapidly moves from blood' into the brain faster after smoking than after intravenous in jection. Findings suggest that the effects of nicotine track brain concentrations overtime and that psychoactive effects are greater when nicotine is dosed more rapidly. In the cycle of a smoker the day's first cigarette produces pharmacologic effects, primarily arousal, but tolerance also begins to develop. With more cigarettes, there is a greater level of tolerance but also more pronounced withdrawal symptoms. Euphoric effects from cigarettes tend to lessen throughout the day; overnight abstinence produces resensitization to nicotine's actions. Habitual smokers need to smoke at least 15 cigarettes and consume 20 to 40mg nicotine per day to achieve the desired effects of cigarette smoking and minimize withdrawal discomfort throughout the day. AN:0039823 SN:88-1913 AUrBenowitz, N.L., Porchet, H., Sheiner, L., et al. TI:(TO:) Nicotine Absorption and Cardiovascular Effects With Smokeless Tobacco Use: Comparison With Cigarettes and Nicotine Gum. JN:Clinical Pharmacology and Therapeutics PG:44(1):23-28 PY:1988 PD:July 1988 LA:English AB:The extent and duration of nicotine absorption and cardiovascular effects of oral snuff and chewing tobacco use were compared with smoking cigarettes and chewing nicotine gum among 10 healthy male smokers. Maximum blood levels of nicotine were similar for smoked and smokeless tobacco, but because of prolonged absorption, overall nicotine exposure was twice as large after single exposures to smokeless tobacco than after cigarette smoking. All tobacco use increased heart rate and blood pressure, despite development of some tolerance to smokeless tobacco. Lower nicotine levels and reduced cardiovascular response were observed with nicotine chewing gum. The adverse health consequences of smoking related to nicotine can be expected to be paralleled in smokeless tobacco use. AN:0044074 SN:91-4501 AU:Boren, J.J., Stitzer, M.L., Henningfield, J.E. TL•(TO:) Preference among research cigarettes with varying nicotine yields. JN:Pharmacology, Biochemistry and Behavior PG:36(1):191-3 PY:1990 PD:May 1990 LA:English AB:Cigarette smokers (N = 18), primarily women, chose, under double blind conditions, among three research cigarettes with nicotine yields of 0.17, 0.89 and 2.02mg. Choices were made daiff for 12 days following an initial 24-hour forced exposure to each cigarette type. Each subject developed a clear and stable preference for one cigarette type. Of 211 total choice opportunities analyzed, 46% were for the highest nicotine yield cigarette, 29% were for the medium yield, and 25% of the total dose selections were for the low yield cigarettes, suggesting a weak effect of dose. Across subjects, however, the preferences which developed were not significantly related to nicotine yield: low and 7
Page 179: apt20e00
medium yield cigarette were each preferred by 5 subjects; the remaining 8 subjects came to prefer the high yield cigarette. There was no consistent relationship between nicotine yield of the preferred experimental cigarette and that of the subjects' usual brand. In general, the cigarette choice data are consistent with the behavior of smokers in nonlaboratory settings who also tend to develop stable brand preferences. Specifically, within the range of cigarettes evaluated in this study, nicotine yield is not a strong determinant of cigarette type/brand preference. AA: (Auth. Abs.) AN:0044474 SN:9 l -0502 AU:Borgerding, M.F., Hicks, R.D., Bodnar, J.E., Riggs, D.M., Nanni, E.J., Fulp, G.W.. Jr, Hamlin, W:C. Jr, Giles, J.A. TI:(TO:) Cigarette smoke composition. Part 1. Limitations of FTC method when applied to cigarettes that heat instead of burn tobacco. JN:Journal - Association of Official Analytical Chemists PG:73(4):605-9 PY:1990 PD:Jul-Aug 1990 LA:English AB:The design of a new cigarette that heats rather than burns tobacco calls for modifications to the Federal Trade Commission (FTC) method for analytical smoking. These changes include eliminating sample conditioning at 75 degrees F and 60% RH, exercising greater care in lighting cigarettes, and smoking cigarettes to self-extinguishment rather than to a predetermined butt length as a measure of complete consumption. By several gross analytical measures, smoke condensate from the new cigarette differs substantially from that of tobacco-burning cigarettes. This is inferred from the lack of coloration of smoke condensate collected on Cambridge filters. Elemental analysis demonstrates reduced carbon and nitrogen content concurrent with increased hydrogen. Thermogravimetric analysis shows almost quantitative weight loss at Tmax = 220 degrees C. Ultraviolet (UV) spectrophotometric analysis shows greatly reduced levels of tobacco-derived smoke components and qualitative differences in chemical entities being measured. By design, the heat required for smoke formation is supplied by a carbon heat source embedded in the cigarette tip. Tobacco contained in the cigarette is not burned and is exposed to temperature less than 300 degrees C. Thus, it is apparent (l) that smoke from the new cigarette contains little or no "tar" as tar is classically defined, and (2) that the FTC method even as modified to account for cigarette design differences is appropriate only for determination of nicotine and carbon monoxide yielded from this cigarette. AA: (Auth. Abs.) AN:0030581 SN:840492 AU:Borland, C., Chamberlain, A., Higenbottam, T.W., Shipley, M.J., Rose, G. TP(TO:) Carbon Monoxide Yield of Cigarettes and Its Relation to Cardiorespiratory Disease. JN:British Medical Journal PG:287(6405): 1583- l 586 PY:1983 PD:November 26, 1983 LA:English AB:Estimates of the carbon monoxFde yield of smokers' cigarettes were obtained for 4,910 subjects. (68 percent of all smokers) in the Whitehall study of men aged 40 to 64. In the 10 years following initial examination, 635 men died. When men smoking cigarettes with high carbon monoxide yield were compared with those smoking cigarettes with a low yield (after adjusting for age, employment grade, amount smoked, and tar yield), the risk of death was 32 percent lower for coronary heart disease, 49 percent higher for lung cancer, and 10 percent lower for total mortality; these differences were not statistically significant. Among men who said they inhaled, the risk of fatal coronacy heart disease was 51 percent lower in the high carbon monoxide group (p<0.01), while the risk of lung cancer was 75 percent higher. Re.sult.c provide no evidence that a smoker can reduce the risk of death by smoking a brand with a low carbon monoxide yield. (Auth. Abs. Mod.) 8
Page 180: apt20e00
AU:Bridges, R.B., Combs, J.G., Humble, J.W., Turbek, J.A., Rehm, S.R., Haley, N.J. TI:Population characteristics and cigarette yield as determinants of smoke exposure. JN:Pharmacology, Biochemistry and Behavior PG:37:17-28 PY:1990 LA:English AB:Although the nicotine yield of the cigarette correlated significantly with plasma cotinine and marginally with plasma nicotine, the reduction in plasma nicotine and cotinine was not proportionate to the reduced' yield of cigarettes, suggesting that smokers partially compensate for the lower yields of their cigarettes. AU:Bridges, R.B., Combs, J.G., Humble, J.W., Turbek, J.A., Rehm, S.R., Haley, N.J. TI:Puffing topography as a determinant of smoke exposure. JN:Pharmacology, Biochemistry and Behavior PG:37:29-39 PY:1990 LA:English AB:Puffing topography variables were measured in a well-characterized, male population their own brand of cigarette. Of the puffing topography variables, interpuff interval appeared to be the primary determinant of blood concentrations of smoke constituents; however, preliminary data in a homogeneous population according to the nicotine yield of their cigarette suggest that total puff volume per cigarette may also be a significant determinant of blood levels of smoke constituents. Smokers of low nicotine yield cigarettes partially compensated for these lower yields by increasing the total volume puffed per cigarette. Observed differences in puffing topography associated with increased daily cigarette consumption and cumulative smoking history were consistent with a higher smoke exposure per cigarette. Further, although both alcohol and coffee consumption are associated with present and cumulative smoking history, coffee consumption is uniquely associated with differences in puffing topography consistent with a higher smoke exposure per cigarette. However, by multiple regression analyses, neither coffee nor alcohol consumption histories added significantly to the prediction of blood concentrations of smoke constituents over that obtained by smoking history and puffing topography. AN:0039941 SN:89-4576 AU:Bridges, R.B., Humble, J.W:, Turbek, J.A., Rehm, S.R., et al.. TI:(TO:) Smoking history, cigarette yield and smoking behavior as determinants of smoke exposure. JN:European Journal of Respiratory Disease PG:69(Supplement 146):129-37 PY:1986 PD:1986 LA:English AB:The effects of smoking history, cigarette yield, and smoking behavior on smoke exposure as determined by smoke constituents and metabolic products in peripheral blood were examined in 170 male smokers and 170 age- and sex-matched controls. Smokers, who were recruited without regard to the nicotine yield of their cigarettes or their smoking history, smoked their own cigarette brands ad libitum, including I cigarette 5 min prior to bloodsampling. Elevated serum thiocyanate, blood carboxyhemoglobin, and plasma nicotine and cotinine values were noted in all smokers (p-0.0001) and were correlated with past 24-hr cigarette consumption. The nicotine yield of the cigarettes correlated with plasma cotinine concentrations and with smoking behavior variables. Smokers consuming lower nicotine cigarettes exhibited an increased total puff volume/cigarette, suggesting that smokers of low-nicotine cigarettes compensate for low yields by their smoking behavior. Lower plasma cotinine concentrations detected in smokers of low-nicotine cigarettes indicate that this compensator.Xbehavior is incomplete. Plasma nicotine and mean puff interval were correlated in the total population and in a subpopulation smoking a single brand of cigarette. These data suggest that smoking history, nicotine yield, and smoking behavior are all determinants of smoke exposure. If tobacco-related 9
Page 181: apt20e00
obstructive pulmonary diseases are associated with increased smoke exposure, a lesser degree of lung injury may be expected in smokers of low-nicotine cigarettes. AA: (Auth. Abs. Mod.) UI:92176890 AN:0022364 SN:811319 AU:Brown, K.S., Cherry, W.H., Forbes, W.F., Thompson, M.E. TI:(TO:) Carbon Monoxide Yield of Cigarettes. (Letter). JN:British Medical Journal PG:280(6227): 1323 PY:1980 PD:May 31, 1980 LA:English AB:Several readers respond to an earlierpaper by P.N. Lee (British Medical Journal 2(6204): 1584, December 15, 1979) which suggested, among other things, that the tar reduction in British cigarettes came about prior to the British publication of the first tar table in 1973, and that this reduction was done on the initiative of the industry and' not as a response to the tables. It is suggested that the publication of tar tables in Canadian 1969, and similar actions in the United States around that time, prompted the British cigarette industry to act. The carbon monoxide yields of cigarettes are also commented on. The potential role of carbon monoxide exposure in coronary heart disease is noted. in response to this hazard, several countries now require CO yields of individual brands be identified (Canada, South Africa); and' others, such as the United States, are considering the requirement. See also 80-1288. AN:0042326 SN:91-451 Z AU:Burling, T.A., Lovett, S.B., Frederiksen, L.W:, Jerome, A.,, Jonske-Gubosh, L.A. TI:(TO:) Can across-treatment changes in cumulative puff duration predict treatment outcome during nicotine fading. JN:Addictive Behaviors PG:14(1):75-82 PY:1989 PD: 1989 LA:English AB:The smoking behavior of 10 male and 15 female smokers was assessed weekly during a standardized nicotine fading program to examine the relationship between compensatory smoking (i.e., increases in the number of cigarettes smoked per day, expired air carbon monoxide (CO), or the frequency and duration of puffs) and posttreatment abstinence from tobacco. Subjects who continued to smoke or relapsed immediately following treatment (Nonabstainers) smoked significantly more cigarettes per day during the program (p less than .05) and exhibited greater across-treatment increases in the time spent puffing a cigarette (i.e., cumulative puff duration) (p less than .05) than subjects who successfully quit smoking (Abstainers). Both Nonabstainers and Abstainers exhibited across-treatment decreases in expired air CO (p less than .001). Similar analyses conducted between subjects who were abstinent versus relapsed 3-6 months following treatment revealed no significant differences in smoking behavior, although both groups exhibited similar across-treatment decreases in CO (p less than .001) and time spent smoking a cigarette (i.e., time alite) (p less than .05). The findings are discussed in reference to their relevance to (a) the development of differential assessment procedures to match smokers to appropriate treatments; (b) the determination of appropriate procedural modifications in the nicotine fading protocol; and (c) nicotine regulation research. AA: (Auth. Abs.) 10
Page 182: apt20e00
AN:0U29089 SN:831051 AU:Buriing, T. A.,, Lovett, S. B., Richter, W. T., Frederiksen, L.W. TI:(TO:) Alveolar Carbon Monoxide: The Relative Contributions of Daily Cigarette Rate, Cigarette Brand, and' Smoking Topography. JN:Addictive Behaviors PG:8(1): 23-26 PY:1983 PD:1983 LA:English AB:The alveolar carbon monoxide (CO) levels of 60 smokers were significantly correlated with the topographical characteristics of the smoking style, the(self-reported) depth of inhalation, the CO yield of the brand of cigarette smoked, and the time since the last cigarette. Higher CO levels were found for individuals who reported inhaling more deeply, who had smoked more recently, who smoked each cigarette for a longer duration, and who smoked cigarettes with higher CO yields. The subjects were 23 men and 37 women who had volunteered for a community-based, stop smoking program. The average age was 38.2 years, the mean number of years spent smoking regularly was 19.7, and the mean estimated daily cigarette rate was 31.8. The average tar and nicotine content of the cigarettes smoked was 10.5 mg and 7.8 mg, respectively. The interpuff interval and cigarette duration, the amount of time since the last cigarette, and a self-rated estimate of depth of inhalation were significantly correlated with alveolar CO. A forward stepwise multiple regression analysis also yielded a three variable equation (interpuff interval, the CO yield of the brand of cigarette smoked, and daily cigarette rate) which was highly predictive of alveolar CO (p<.001) and accounted for 36 percent of the total variance. These results support earlier arguments that the CO levels of smokers are determined by a variety of factors in addition to daily cigarette rate. (Auth. Abs. Mod.) AU:Burling, T.A., Stitzer, Bigelow, G.E., Mead, A.M. TI:Smoking topography and carbon monoxide levels in smokers. JN:Addictive Behaviors PG:10:319-323 PY:1985 LA:English AB: Factors which effect the expired air carbon monoxide (CO) levels of smokers were examined in matched'subject pairs who smoked an equal number of daytime cigarettes but had different CO level (x difference = 15.4ppm.) Measures of puff number, duration, and spacing, as well as the amount of CO increase per cigarette (CO boost), were assessed while subjects smoked a single cigarette in daily laboratory sessions. Subjects with relatively high CO levels had larger increases in CO after smoking a single cigarette than did individuals with low CO levels (p. < .005) but did not differ on any other smoking topography measure. These data suggest that simple topography measures of puff number and duration may not contribute to between subject differences in tobacco smoke exposure, and that greater attention should be given more refined measures such as puff volume and depth of inhalation. These data also suggest that the measurement of CO boost per cigarette may provide useful information regarding tobacco smoke intake. AN:0037462 SN:871502 AU:Chapman, S., Wilson, D., Wakefield, M. TL•(TO:) Smokers' Understandings of Cigarette Yield Labels. JN:Medical Journal of Australia m PG:145(8):376, 378-37 C09 PY:1986 ~ PD:October 20, 1986 LA:English Oy AB:Of 498 smokers, only 2 percent were able to state correctly the tar content of their cigarettes from ~ cigarette pack labeling in a survey of smokers' understandings of cigarette yield labels. On a scaled 11
Page 183: apt20e00
range of tar levels in all cigarette brands available in Australia, 69.1 percent of smokers underestimated the level in their cigarette brand (p<0.0001); 56 percent placed randomly chosen tar levels in the wrong category. Of 500 smokers sampled, 40 percent said that they did not know where to obtain information on the yield of the cigarette brand that they smoked; 49 percent named the pack as a source of information and very few smokers named various other sources. It was agreed by 72 percent that comparative tar yields should be displayed at all points of tobacco sales. In order to receive a license to retail tobacco, tar, nicotine, and carbon monoxide yield information for all national cigarette brands should be displayed prominently to the consumer by the retailer. AU:Chortyk, O.T., Chamberlain, W.J. TI:A study on the mutagenicity of tobacco smoke from low-tar cigarettes. JN:Archives of Environmental Health PG:45(4):237-244 PY:1990 AB:A series of 16 low-tar cigarettes, yielding from 1 to 10 mg of tar, were smoked on a modified cigarette smoking machine that collected both mainstream (MS, inhaled) smoke and sidestream (SS, between puffs) smoke. The SS smoke is the major contributor to environmental tobacco smoke. The collected MS and' SS smoke condensates were evaluated for mutagenicity by the Ames test and compared with MS and SS smoke condensates from a high-tar cigarette. Both MS and SS condensates of7ow-tar cigarettes (LTCs) were tested' with the Salmonella strains TA 1538 and TA 100. Except for three cigarettes, the MS smoke mutagenicities of the LTC smoke condensates were significantly reduced (about 30%) when compared with a control, high-tar (23-mg) cigarette. Opposite results were obtained for the SS smoke condensates, which were more mutagenic (about 20%) than the SS smoke condensate of the high-tar cigarette. Thus, LTC mainstream smoke may be less hazardous to the LTC smoker, whereas LTC sidestream may emit more mutagenic compounds into environmental tobacco smoke, which, through passive inhalation, could affect both smokers and nonsmokers. AN:0032955 SN:850898 AU:Chortyk, O.T., Schlotzhauer, W.S. TI:(TO:) Increasing Selenium in Cigarettes and Smoke: Transfer to Smoke. JN:Archives of Environmental Health PG:39(6):419-424 PY:1984 PD:November-December 1984 LA:English AB:Selenium (Se) content of some American tobaccos and transfer rates of added Se were examined for several commercial and experimental cigarettes of varying tar levels. For high-tar cigarettes, as much as 10 percent of added Se was found in mainstream smoke, while low-tar cigarettes delivered about 3 percent of added Se. Transfer rates correlated well with tar values; addition of Se (1 mug/cigarette) yielded transfer rates of 7, 5, and 4 percent for 24, 17, and .9 mg tar cigarettes, respectively. About 60 to 70 percent of Se may have escaped via sidestream smoke, with the remainder deposited in the butts. Analysis of 9 American tobacco varieties and 13 brands of cigarettes showed a range of 0.010 to 0.085 ppm Se, with an average of 0.04 ppm~, 10 times lower than in cigarettes from countries with low lung cancer incidence rates. Field fortification of tobacco was also investigated. Addition of Se had no effect on yield of other smoke components. The rationale for use of Se fortification in producing safer tobacco products is discussed. (Auth. Abs. Mod.) AN:0049217 SN:93-0052 AU:Chortyk, O.T., Schlotzhauer, W:S. TI:The contribution of low tar cigarettes to environmental tobacco smoke. JN:Journal of Analytical Toxicology PG:13(3):129-34 PY:1989 12
Page 184: apt20e00
PD:May-Jun 1989 LA:English AB:A series of low tar cigarettes(LTC) were smoked and' the quantities of condensable mainstream (inhaled) and sidestream (between puffs) smoke compounds were determined and compared to those produced by a high tar, nonfilter cigarette. It was found that the LTC produced large quantities of sidestream smoke condensates, about equal to the high tar cigarette, and contained very high levels of toxic or cocarcinogenic phenols. On an equal weight basis, the LTC emitted more of these hazardous compounds into sidestream and environmental tobacco smoke. Higher smoke yields of a flavor additive and a sugar degradation product indicated addition of such compounds during the manufacture of LTC. It was concluded that, compared to a high tar cigarette, smoking LTC may be better for the smoker, but not for the nearby nonsmoker. Information should be developed to allow smokers to choose LTC that produce lower levels of hazardous compounds in their environmentally emitted sidestream smoke. (AA: Auth. Abs.) AN:0051582 SN:93-2417 AU:Cohen, J.B. TI:Research and policy issues in Ringold and' Calfee's treatment of cigarette health claims. JN:Journal of Public Policy and Marketing PG:11(1):82-86 PY:1992 PD:Spring 1992 LA:English AB:This article discusses two papers by Ringold and Cal'fee. The first paper published in 1989, presents a content analysis of cigarette advertising from 1926-1986, together with critiques of both the analysis and its implications. In their subsequent paper published in 1990, they (1) argued that the evidence supports their exclusion of mildness and most filter claims from the health claims category, (2) defended their exclusive focus on coding of explicit advertising content rather than the likely interpretation of such claims, and (3) presented a lengthy and speculative analysis to the effect that regulation of tar, nicotine, and related health claims, particularly by the Federal Trade Commission (FTC), was ill-advised. The author of this article asserts that many industry-sponsored consumer surveys and advertising recall studies clearly demonstrate that cigarette companies do not view "mildness" as distinct from health and safety claims. He argues thatRingold and Calfee have provided an inadequate empirical foundation with little direct relevance, and that their public policy views and implied recommendations are inconsistent with the FTC's mandate. Sections of this article include (1) Mildness and Filtration Claims, (2) Validity Issues in Content Analysis, (3) Market Forces and the Reality of Marketplace Behavior, and (4) Ignoring Regulatory Responsibility. AN:0022765 SN:811725 AU:Cole, P. TL•(TO:) Smoking Habits and Carbon Monoxide. SO:In: Greenhalgh, R. M. (Editor). Smoking and Arterial Disease. Bath, Great Britain, The Pitman Press PG:pp. 74-83 PY:1981 PD:August 1981 LA:English AB:Among the potentially toxic components of tobacco smoke, carbon monoxide is believed to be one of the most important causal agents in peripheral vascular disease. Inhalation of tobacco smoke produces high levels of carboxyhemoglobin (COHb) in the circulating blood, and measurement of these levels can provide an objective assessment of the degree of pulmonary absorption of other toxic agents of tobacco. It is therefore important to know and measure any other contributors to &e COHb level, so as not to confuse them with COHb test levels from smoking only. One endogenous source of CO is the breakdown of hemo-containing compounds in the body, shown in one study to result in 13
Page 185: apt20e00
a mean level of only 0.68 percent COHb. Air pollution is another endogenous source, but even in a study conducted in downtown London it contributed no more than a 0.29 percent COHb level. Inhalation of tobacco smoke by nonsmokers (passive smoking) in a London office resulted in a low COHb reading of 1.12 percent. Smokers in that same office, by contrast, registered a 5.5 percent level. Although cigarette smoking appears to be the largest single source of COHb in the body, the relationship can be affected by several variables. One is the degree of inhalation; with greater inhalation leading to greater intake of CO. Another variable is the source of tobacco, since pipe and cigar smokers tend not to inhale unless they have previously been cigarette smokers. The greater the physical activity of the subject, the greater the excretion of CO from the body. Finally, the time of sampling is important, for the COHb level in a smoker tends to follow a cyclical up and down pattern during the day, hovering around a mean level for each individual. AN:0021013 SN:801757 AU:Creighton, D.E., Lewis, P.H. TI:(TO:) The Effect of Different Cigarettes on Human Smoking Patterns. SO:In: Thornton, R. E. (Editor). Smoking Behaviour. Physiological and Psychological Influences . Edinburgh, Churchill Livingstone PG:pp. 289-300 PY:1978 PD:1978 LA:English AB:Frequent measurements of the smoking patterns were recorded for 16 subjects who were changed from a control brand of cigarettes to either a higher or lower delivery brand. Each cigarette brand was smoked exclusively for about 4 weeks. Representative smoking patterns (including puff volume,, puff duration, and average butt length) for each subject were duplicated by machine to measure deliveries of total particulate matter (TPM), nicotine, and carbon monoxide (CO). Analyses of these data showed that on average smokers increased the intensity with which they smoked the lower delivery brand and decreased the intensity of smoking the higher delivery brand when compared with the control brand. The number of cigarettes smoked per day did not change significantly. The amounts of TPM, nicotine, and CO taken from the medium- and high-delivery brands by the smokers were similar, although the deliveries of these two brands differ considerably when smoked by machine under standard conditions. Although they smoked the low-delivery brand more intensely, the smokers did not equalize the deliveries taken from the low- and medium-delivery brands. A further analysis showed that the modified smoking patterns adopted to smoke the brands with changed deliveries were maintained for the period of smoking those brands. The smokers reverted to their former smoking patterns during the last phase of the experiment when they again smoked the control brand. (Auth. Abs. Mod.) AN:0021014 SN:801758 AU:Creighton, D.E., Noble, M.J.,, Whewell, R.T. TL•(TO:) Instruments to Measure, Record and Duplicate Human Smoking Patterns. SO:In: Thornton, R. E. (Editor). Smoking Behaviour. Physiological and Psychological Influences . Edinburgh, Churchill Livingstone PG:pp. 277-288 PY:1978 PD:1978 LA:English AB:Thispaper describes the structure, functions, and operation of a smoking analyzer and data logger designed to monitor the way human subjects smoke cigarettes, and a puff duplicator which smokes cigarettes to the recorded smoking patterns. The data may be displayed in numeric fora_and stored in digital form on magnetic tape. The magnetic tape may be read in several forms so that printoutss of the pressures, flows, volumes, durations, and intervals between the puffs may be made in a number of ways. Paper tapes are made to control the functions of the puff duplicator which smokes cigarettes 14
Page 186: apt20e00
in the same pattern as the human smoker, enabling the tar, nicotine, and gas phase components to be collected for analysis. This instrument was used to duplicate the smoking patterns of a number of subjects who participated in a study of the effects of brand changes. It was found that the accuracy of volume duplication is generally within 1.0 percent, and the timing of both puff durations and intervals between puffs is within 0.02 sec. AN:0021323 SN:810236 AU:Creighton, D.E., Noble, M.J., Whewell, R.T. TL•(TO:) A Portable Smoking Pattern Recorder. JN:Biotelemetry Patient Monitoring PG:6(4): 186-191 PY:1979 PD:1979 LA:En:glish AB:An instrument has been developed which can be used to record the smoking patterns (e.g., puff volume and duration) of human smokers in almost any location. The smoker is required to smoke thee cigarette through an orifice plate cigarette holder connected to the recorder. The smoking pattern data are recorded onto a standard audio cassette as pressure and flow signals together with timing impulses and speech. The instrument is battery-powered and can be built into a small briefcase. The four channels of data are decoded on a separate instrument, which uses the timing signals to synchronize a data logger, thus making the whole system independent of tapespeed errors. The speech channel is used to identify the smoker, cigarette,and location. Comparisons have been made of the performance of the portablerecorder and a laboratory smoking analyzer and data logger. It was found that data decoded from the portable recorder are generally within 1 percent of the values recorded directly on the laboratory instrument. (Auth. Abs.) AN:0051501 SN:93-2336 AU:Crooks, E.L., Lynm, D. TI:Measurement of intrapuff nicotine yield. JN:Beitrage zur Tabakforschung International PG: I5(2):75-86 PY:1992 PD:April I992 LA:English AB:Time-resolved measurements of intrapuff nicotine yield in mainstream smoke have been investigated using a specifically designed intrapuff smoking apparatus (ISPA). The ISPA-filter traversing mechanism collects mainstream particles on a rectangular filter pad that move at a constant velocity perpendicular to the direction of smoke flow at the mouth end of the cigarette. Filter pads were assayed by two analytical techniques. Standard gas chromatographic (GC) methodology was used to quantify nicotine mass in five equal time segments per puff. A second method, using a Berthold TLC-Linear Analyzer, measured total radioactivity across the pad for samples from (2'- 14C)-nicotine labelled cigarettes. Intrapuff nicotine concentrations were determined from puff flow-rate profiles and the collected masses of nicotine on the filters. GC nicotine concentration measurements correlated well with total activity from the scanner measurements. Studies carried out with filtered full-flavor cigarettes revealed that nicotine concentrations in the smoke vary significantly during a puff. This work provides a new technique for studying time-resolved yields of mainstream smoke components. It may potentially be used to explain mechanisms controlling the yield of nicotine and other mainstream smoke components. AA: (Auth. Abs.) AN:001 1221 SN:010043 AU:Dalhamn, T., Edfors, M.L., Rylander, R. TI:(TO:) Retention of Cigarette Smoke Components in Human Lungs. 15
Page 187: apt20e00
IN:Archives of Environmental Health PG:17(5): 746-748 PY:1968 PD:November 1968 LA:English AB:The pulmonary retention of certain volatile compounds and particulate matter in cigarette smoke was studied in humans. A smoke-dosage apparatus delivered a standard puff which was inhaled and subsequently, exhaled into cold traps. Acetaldehyde, isoprene, acetone, acetonitrile, toluene, particulate matter, and carbon monoxide were measured and compared with the amounts found in noninhaled smoke. An 86 percent to 99 percent retention was found for all compounds except carbon monoxide of which 54 percent was retained. These findings stress the importance of using methods which approximate actual smoking conditions when evaluating the biological effect of tobacco smoke. AU:Dalhamm, T., Rylander, R. TI:Tar content and ciliotoxicity of cigarette smoke. JN:Acta Pharmacology, et Toxicology PG:25(3):369-372 PY:1967 LA:English AB:The cilkiotoxic property of cigarette smoke with varying tar content was examined in short-term exposure experiments using animal in vivo preparations. An increased toxicity was noted when the tar content increased. The possible significance of this finding in connection with human exposure to tobacco smoke is discussed. AN:0040572 SN:90-0522 AU:Darrall, K.G. TL-(TO:) Smoking machine parameters and cigarette smoke yields. JN:Science of the Total Environment PG:74:263-78 PY: 1988 PD:Aug 1 1988 LA:English AB:The relationship between smoking machine parameters and cigarette smoke yields of tar, nicotine and carbon monoxide has been investigated. It is concluded that the order of ranking of brands for tar does not alter substantially when machine parameters are used which differ from those in the present standard international methodology. Corroborative evidence is presented documenting the variation in the value of a number of cigarette design features with alternative smoking machine parameters. AA: (Auth. Abs.) AN:0041980 SN:90-0514 AU:Davis, R.M., Healy, P., Hawk, S.A. TI:(TO:) Information on tar and nicotine yields on cigarette packages. JN:American Journal of Public Health PG:80(5):551-3 PY 1990 PD:May 1990 LA:English AB:We examined information on tar and nicotine yields on the packages of 160 cigarette brands, 58 percent of the 275 brands for which tar and nicotine yields were listed in a recent Federal Trade Commission report. The tar yield was indicated on 14 percent, the nicotine yield was iadicated on 11 percent. As tar yield increased among brands, the yieid was progressively less likely to be shown on the package and was not disclosed on the package of any cigarette yielding 1 l mg or more of tar. AA: (Auth. Abs.) 16
Page 188: apt20e00
AN:0049657 SN:93-0492 AU:DeGrandpre, R.J., Bickel, W.K., Hughes, J.R., Higgins, S.T., et al. TI:Behavioral economics of drug self-administration. lii. A reanalysis of the nicotine regulation hypothesis. JN:Psychopharmacology PG:108(1-2):1-10 PY:1992 PD:1992 LA:English AB:The maintenance of a characteristic level of nicotine in a smoker's body is referred to as nicotine regulation. Considerable research has examined this question of whether smokers regulate nicotine intake. This is because nicotine regulation raises the question of whether smokers who, to decrease their intake of tar, switch to low tar/low nicotine cigarettes wiliincrease the number and/or intensity of cigarettes smoked. Although the results of studies examining nicotine regulation are reported as generally consistent, considerable variability exists across these analyses such that the health hazards of smoking low tar/nicotine cigarettes remains uncertain. In the present analysis, these studies were analyzed to ascertain whether a behavioral-economic interpretation could better quantify the effects of changing nicotine yield on individuals' nicotine and smoke consumption. Specifically, 17 nicotine-regulation studies were reanalyzed using a unit-price analysis (i.e., cost- benefit analysis). The reanalysis showed less variability across regulation studies than previously reported; a positively- decelerating demand curve was found across most studies, consistent with previous unit-price analyses of food- and drug-maintained behavior. The benefits of this reanalysis versus the traditional regulation interpretation are that the behavioral economics approach:l) brings unity to a variable set of data, 2) shows a nonlinear relationship, previously considered to be linear, between nicotine consumption and nicotine yield, 3) shows that nicotine yields higher,and not lower, than the smoker's usual brand decrease smoke consumption and thus decreases consumption of the harmful agents in tobacco, 4) better quantifies the data and provides a more parsimonious interpretation that generalizes to other drugs and' food-maintained behavior in humans and nonhumans and, 5) integrates behavioral and pharmacological factors that control the consumption of reinforcers. These results suggest the value of behavioral economics in the study of consumptive behaviors and clinically suggest, in agreement with the studies contained herein, that decreasing the smoker's usual nicotine yield can have potential health risks for smokers who are unable to stop smoking. AA: (Auth. Abs.) UL87164685 AU:Diding, N. TI:Mach,ine smoking results compared to human uptake of cigarette smoke. SO:International Journal of Clinical Pharmacology Ther Toxicology PG:25(3):143-7 PY:1987 AB:Studies of plasma concentrations and the application of pharmacokinetic parameters in human smoking published during recent years are reviewed. It is clear that this approach contributes to better understanding and to the quantitative evaluation of many problems related to human smoking, such as: first, smoking behavior, second, self-regulation and compensation when switching between different brands and third, relationships between in vitro machine smoking yields and actual human uptake. The reviewed articles show that the widely believed opinion that cigarettes with low yields, when in vitro tested, are less hazardous, must be questioned. For the majority of cigarette brands there is no defensible correlation between in vitro analytical machine yields and actual uptake and bioavailability. Based on these findings suggestions are given to modify the use of tar and nicotine yields obtained by in vitro machine testing methods for classification purpose. A N:0050280 SN:93-1113 AU:Domino, E.F., Riskalla, M., Zhang, Y., Kim, E., et al. TI:Effects of tobacco smoking on the topographic EEG II. 17
Page 189: apt20e00
JN:Progress in Neuro-Psychopharmacology and Biological Psychiatry PG:16(4):463-82 PY:1992 PD:JuI 1992 LA:English AB:Tobacco smokers are well aware of the long term hazards of tobacco smoking,yet they continue to smoke. Presumably people smoke because of short term gains due to nicotine. The mechanism by which nicotine is a drug reinforcer still needs a great deal of study. The specific aim of the present study was to determine the effects of tobacco smoking on the topographic EEG of 12 hr deprived heavy tobacco smokers. Seven normal' adult tobacco smokers of mixed sex were recruited into the study and compared with six normal nonsmokers of similar age and sex. A Grass Model 8-24D EEG and 16 different scalp monopolar electrodes were used to record the EEG using both ears as reference before and after smoking. EKG lead II was recorded on channel 17.Blood pressure was measured by auscultation. Exhaled CO, was measured' using a CO detector. Computer analysis of the EEG data was run of line on a Zenith 386/25 microcomputer using RHYTHM 7.1. The same system was used to store the EEG in digitized form. The maximum number of 4 sec artifact free epochs in a 3 min recording period with eyes open and' then closed was used before and after low and high nicotine tobacco or sham smoking. The hypothesis of this research was confirmed, i.e., that tobacco smoking of high nicotine cigarettes (about 2.0 mg/cigarette) would cause a shift in EEG alpha rhythm to higher frequencies in more diffuse midline cortical structures. In other studies an increase in alpha rhythm has been correlated with an awake relaxed behavioral state. A heart rate increase was a more sensitive index of tobacco smoking than an increase in arterial blood pressure. Exhaled smoking CO levels correlated with the nicotine and tar content of the cigarette. AA: (Auth. Abs.) AN:0021015 SN:801759 AU:Dunn, P.J. TL•(TO:) The Effects of a Reduced Draw Resistance Cigarette on Human Smoking Parameters and Alveolar Carbon Monoxide Levels.. SO:In: Thornton, R. E. (Editor). Smoking Behaviour. Physiological and Psychological Influences . Edinburgh, Churchill Livingstone PG:pp. 203-207 PY:1978 PD:1978 LA:English AB:Smoking parameters and alveolar resting carbon monoxide (CO) levels were measured in seven heavy smokers when they switched from smoking their normal brand of cigarette to cigarettes with 30 percent reduced draw resistance. There were no trends or significant changes with regard to butt length, puff number, or interval between puffs. The smokers, however, took puffs of 9.5 percent shorter duration and of 20 percent greater effort, which resulted in an increase of 28 percent in relative velocity. An average increase in relative volume per puff of 9 percent was observed for six of the seven smokers studied. An increase of 7 percent in total relative volume per cigarette was noted for five of the seven smokers as a result of changes in puff number. These changes in smoking parameters resulted in a significant increase of 56 percent in mouth nicotine intake. Despite the substantial increase in nicotine to the mouth with the cigarette of lower draw resistance, the alveolar resting levels decreased by an average of 16 percent, which is markedly (29 percent) less than the level predicted using mouth nicotine as an: indicator of total smoke concentration. This difference is quite possibly due to all smokers inhaling less deeply with the increased nicotine concentration in the mouth. The ease of availability of nicotine with the cigarette of lower draw resistance (more nicotine per unit effort) did not cause a decrease in total amount of smoke taken from the cigarette; in fact the smokers appeared to show increased effort when smoking this cigarette. There was nonsignificant change in total daily cigarette consumption or other smoking parameters. In experimms designed to measure how a smoker responds to cigarettes of different types or to cigarettes smoked under varying experimental conditions, it is essential to estimate inhalation. 18
Page 190: apt20e00
AN:0021016 SN:801760 AU:Dunn, P.J., Freiesleben, E.R. TL-(TO:) The Effects of Nicotine-Enhanced Cigarettes on Human Smoking Parameters and Alveolar Carbon Monoxide Levels. SO:In: Thornton, R. E. (Editor). Smoking Behaviour. Physiological and Psychological Influences . Edinburgh, Churchill Livingstone PG:pp. 195-202 PY:1978 PD:1978 LA:English AB:A study was conducted to test the assumption that smokers modify their smoking to regulate nicotine intake. A change in inhalation is one means of smoke compensation, i.e., a smoker unconsciously inhales cigarette smoke of higher nicotine concentration to a lesser extent than smoke of lower nicotine concentration, resulting in a lower body carbon monoxide (CO) level. Four subjects who were heavy smokers were presented with cigarettes of higher nicotine delivery and were monitored for alveolar CO levels and smoking parameters. The study found no direct relationship between the cigarette smoke yield of CO obtained under standard smoking conditions and the actual alveolar uptake of CO during smoking. The resting levels of alveolar CO were significantly lower for all smokers when cigarettes of unchanged CO yield but 30 percent higher nicotine yield were smoked. The smokers did not compensate for the 30 percent increase in nicotine delivery by significantly altering puff number, interval, duration, or butt length. No decrease in total daily cigarette consumption was noted with the increased nicotine availability: With the nicotine-enhanced cigarette, all smokers reduced, to varying degrees, the amount of smoke inhaled, as evidenced by the lower alveolar CO resting levels. This greater availability of nicotine to the smoker may be an effective means of reducing the intake of tar and CO. A N:0030470 SN:840379 AU:Ebert, R.V., McNabb, M.E., McCusker, K.T., Snow, S.L.. TI:(TO:) Amount of Nicotine and Carbon Monoxide Inhaled by Smokers of Low-Tar, Low-Nicotine Cigarettes. JN:Journal of the American Medical Association PG:250(20): 2840-2842 PY:1983 PD:November 25, 1983 LA:English AB:In 76 smokers, correlations between plasma nicotine and alveolar carbon monoxide (CO) levels of the individual smoker and the nicotine and CO yields of the cigarette were very poor. In 24 smokers of low-nicotine, low-tar cigarettes,, mean alveolar CO levels did not differ from those of smokers of regular cigarettes. Mean plasma nicotine levels were lower in smokers of low-nicotine cigarettes, but a wide overlap of individual values occurred. The implication that an individual shifting to ultra-low-tar cigarettes reduces risks of cardiopulmonary disease is unwarranted. (Auth. Abs.) AN:0026493 SN:820309 AikFairweather, F.A., Carmichael, I.A., Phillips, G.F., Copeland, G.K.E. TI:(TO:) Changes in the Tar, Nicotine, and Carbon Monoxide Yields of Cigarettes Sold in the United Kingdom. JN:Health Trends PG:13(3): 77-81 PY: 1981 ~s PD:August 1981 LA:English 19
Page 191: apt20e00
AB:The tar, nicotine, and carbon monoxide yields of most cigarette brands on sale in the United Kingdom are regularly determined by the Government Chemist, and have declined progressively since the early 1960s--those of carbon monoxide more slowly than those of the other two. The incidence of lung cancer, bronchitis, and heart disease is strongly related to cigarette smoking. Evidence suggests that the recent decline in mortality rates from these diseases in men is related to the decline in the amounts of substances yielded by cigarettes. Greater experience of smoking low-tar cigarettes is needed to determine the extent to which the health risks are reduced. It is better not to smoke; but for those unable to stop, and particularly those at greater risk, it would be prudent to smoke only cigarettes in the low-tar band,, those being generally lower in carbon monoxide as wel'l., However, the mortality risks for lung cancer, bronchitis, and coronary heart disease, even for low-tar smokers, are greatly in excess of those found among lifelong nonsmokers. Reduction of this toll of sickness and death represents one of the greatest challenges to preventive medicine. (Auth. Abs.) AN:0043045 SN:91-1228 AU:Fielding, S., Short, C., Davies, K., Wald, N., Bridges, B.A., Waters, R. TI:(T(Y) Studies on the ability of smoke from different types of cigarettes to induce DNA single-strand breaks in cultured human cells.. JN:Mutation Research PG:214(1):147-51 PY:1989 PD:Sep 1989 LA:English AB:In this paper we report preliminary studies using alkaline elution to examine the incidence of DNA-strand breakage in human lung cells exposed to smoke/phosphate-buffered saline generated from cigarettes of different tar contents and filter status. The majority of the DNA breaks induced were abolished by catalase indicating a role for active oxygen species. The incidence of breaks did not correlate with the tar content of the cigarettes. The presence of a filter in the cigarette reduced the TPM concentration of the mainstream smoke but did not reduce the number of single-strand breaks occurring in DNA after exposure to smoke/PBS. This last parameter was however reduced if the filter was ventilated. AA: (Auth. Abs.) AN:0045534 SN:92-9163 AU:Fischer, S., Spiegelhalder, B., Preussmann, R. TI:(TO:) Influence of smoking parameters on the delivery of tobacco-specific nitrosamines in cigarette smoke-a contribution to relative risk evaluation. JN:Carcinogenesis PG:10(6):1059-66 PY:1989 PD:Jun 1989 LA:English AB:The influence of the smoking parameters (puff profile, puff duration, puff volume, puff frequency) on the delivery of tobacco-specific nitrosamines (TSNAs) in mainstream smoke was investigated for six different cigarette brands, including filter cigarettes with very low to medium smoke yields and non-filter cigarettes with high and very high smoke yields. The puff profile did not influence the TSNA yields. The puff duration also had no remarkable influence on the TSNA delivery with the exception of a non-filter cigarette made of dark tobaccos. The puff volume and the puff frequency significantly influenced the TSNA yields. Increasing puff volume and frequency resulted in increasing TSNA values. The total volume drawn through a cigarette was calculated. The dependency of the TSNA delivery on the total volume was almost linear at least up to a total volume of approximately 500 ml/cigarette. The TSNA yield was the same for the same total volume no matter whether the to: l volume was due to a changing puff volume or a changing puff frequency. The total' volume drawn through a cigarette is the main responsible factor for the TSNA delivery in mainstream smoke. Total volume data from smokers of low- and medium-tar cigarettes are used to 20
Page 192: apt20e00
calculate TSNA intake. The different smoking behaviour observed for smokers of low-tar and low-nicotine cigarettes as compared to standard smoking conditions is discussed with respect to the TSNA dependency on smoke parameters. AA: (Auth. Abs.) AN:0048468 SN:92-0522 AU:Fischer, S., Spiegelhalder, B., Preussmann, R. TI:(TO:) Tobacco-specific nitrosamines in commercial cigarettes: possibilities for reducing exposure. JN:IARC Scientific Publications PG:( I 05):489-92 PY:1991 PI71991 LA:English AB:Tobacco-specific nitrosamines (TSNA) are powerful carcinogens found in tobacco and tobacco smoke in relatively high concentrations. Tar delivery, which is generally accepted as an index for the carcinogenic potential of cigarette smoke, must be declared in most European countries. In this investigation of more than 170 types of commercial cigarettes from several European countries and the USA, no correlation was observed between tar delivery and mainstream smoke concentration of N'-nitrosonor nicotine (NNN) and 4-(N-nitrosomethylamino)-I-(3-pyridyl)-1-butanone (NNK). Therefore, although crucial, tar delivery alone is not a sufficient index for the carcinogenic potential of cigarette smoke. It is proposed that TSNA concentrations be determined for characterization of the carcinogenic potential of cigarettes with; liow and ultra-low tar yields and that these be declared by an additional and adequate parameter. The mainstream smoke concentrations of NNN and NNK are given by the amounts of preformed compounds in tobacco, which is dependent on the nitrate content of the tobacco and the tobacco type. A further important determinant of the exposure of smokers to TSNA is the total volume drawn through a cigarette while smoking, which is dependent on puff volume and puff frequency and which directly influences TSNA transfer. Smokers inhale higher volumes when smoking low-nicotine cigarettes, so that low NNN: nicotine and NNK: nicotine ratios result in decreased exposure to TSNA. Reduction of exposure to TSNA can be achieved by selecting tobaccos with low levels of preformed TSNA (low nitrate content, small amounts of burley tobaccos and stems) and by manufacturing cigarettes with low NNN:nieutine and NNK:nicotine ratios. AA: (Auth. Abs.) AN:0010052 SN:770740 AU:Forbes, W.F., Robinson, J.C., Hanley, J.A., Colburn, H.N: Tl:(TO:) Studies on the Nicotine Exposure of Individual Smokers. I. Changes in Mouth-Level Exposure to Nicotine on Switching to Lower Nicotine Cigarettes. JN:International Journal of Addictions PG:1li(6): 933-950 PYA1976 P171976 LA:English AB:Twenty-four subjects smoked two brands of filter-tipped cigarettes delivering different amounts of nicotine, on the following 4-week schedule: smoking their usual brand for I week; smoking another brand similar in size, but delivering less nicotine, for 2 weeks; reverting to their usual brand for I week. The amount of nicotine entering the mouth,, defined as the mouth-level exposure, was estimated from a determination of the amount of nicotine trapped in the filter of each cigarette smoked. The results indicate a substantial variation in mouth-level exposure for the subjects studied, even among smokers of cigarettes that deliver similar amounts of nicotine when smoked on a machine under standard conditions. For the majority of subjects, however, changing to a lower nicotine cigarette reduced the total daily mouth-level exposure to nicotine and, therefore, presumably the total tar intake. AA: (Auth. Abs.) 21
Page 193: apt20e00
AN:0019482 SN:800150 AU:Garfinkel, L. TL•(TO:) Changes in the Cigarette Consumption of Smokers in Relation to Changes in Tar/Nicotine Content of Cigarettes Smoked. JN:American Journal of Public Health PG:69(12): 1274-1276 PY:1979 PD:December 1979 LA:English AB:Over a 13-year period, 59 percent of 28,561 smokers decreased the tar and nicotine (T[N) level in the cigarettes they smoked without changing the number of cigarettes smoked to any important extent (34 percent smoked the same number of cigarettes, 32 percent increased, and 34 percent decreased their cigarette consumption). On the other hand, more than 54 percent of the "less than one pack a day" smokers as compared to only 25 percent of the "one pack or more a day" smokers increased the number of cigarettes smoked. Nicotine dependency plays a minor role in determining the smoking habits of those who continue to smoke on a long-term basis. (Auth. Abs.) AN:0085525 AU:Gerstein, D.R., Levison, P.K. TI:Reduced tar and nicotine cigarettes: Smoking behavior and health. JN:National Academy Press PG:137-321 PY:1982 LA:English AB:Smokers who want to reduce the health hazards from their cigarettes are best advised to quit smoking entirely. For continuing smokers, exposure to the constituents of smoke and attendant risks depend not only on the content, construction, and number of cigarettes but also on the way they are smoked. Therefore, the T/N yields may or may not correspond well to the actual hazard exposure of different smokers. Thus, the evidence for switching to lower T/N cigarettes is doubtful. In our judgement, the degree of benefit most smokers can expect from switching to lower T/N brands, if any, is small compared with the benefit of stopping completely. AN:0049384 SN:93-0219 AU:Goldsmith, R.J., Hurt, R.D.,, Slade, J. TI:Development of smoke-free chemical dependency units. JN:Journal of Addictive Diseases PG:11(2):67-77 PY:1991 PD:1991 LA:English AB:Until recently, the country's chemical dependency units (CDUs) have not addressed nicotine dependence in a meaningful way for their patients. Most CDUs have accepted exemptions to the smoke-free hospital requirements enacted around the country. Twenty-nine CDU's have been identified which have developed progressive smoke-free policies and begun to treat nicotine dependence in the substance abuser. These CDUs cite three factors--concern for the smoker's health, concern for the health effects of involuntary smoking, and the strong opinion of a key leader--as motivations to implement these policies. Because of the significant resistance to these policies, the strong opinion of a key leader was considered one of the most important factors. Once the policy was in place, these CDUs were surprised that the programs ran so smoothly, including normal census counts. The CDUs used a variety of interventions to help smokers quit. There is considerable need to develop effective interventions sti;tabie for CDUs ir, the treatment of nicotine dependence. AA: (Auth. Abs.) 22
Page 194: apt20e00
AN:0009318 SN:770006 AU:Gori, G.B. TI:(Tf34 Low-Risk Cigarettes: A Prescription. JN:Science PG:194(4271): 1243-1246 PY:1976 PD:December 17, 1976 LA:English AB:Low-toxicity cigarettes hold significant promise in the prevention of diseases related to smoking. Since 55-60 million Americans smoke, and the habit appears to be increasing among teenagers and women, it is important to protect those who continue to smoke despite all warnings. The hazards of cigarettes can be reduced by a simultaneous reduction of tar, carbon monoxide, nitrogen oxides, hydrogen cyanide, acrolein, and other undesirable toxic components, and by an ad justment of nicotine levels and protonation of nicotine conducive to consumer satisfaction. The limits of cigarette and smoke composition: that may approach relative safety should thus be defined as smoke intake doses at which the risk of disease in smokers approaches that of nonsmokers. Present low, average, and high values of selected smoke components are, respectively: tar (mg)- -65, 86, 151; nicotine (mg)- -4.5, 6.0, 10.5; COHb (expressed in terms of the percentage increase of COHb in the smoker's blood)--2.6, 3_2, 4.8; nitrogenoxides (in micrograms)--405,540, 945; hydrogen cyanide (in micrograms)--492, 820, 1435; acrolein (in micrograms)--156, 260, 455. The above figures represent critical values of daily intake of selected smoke components based on data (tabulated in this article) associated! with all causes of disease mortality for current smokers. The feasibility of less hazardous cigarettes raises the question whether there are such limits that would indeed approach relative safety. These limits can be defined as the smoke intake doses at which the risk of disease in smokers approaches that in nonsmokers. Such values can be estimated by dose--response analysis of several epidemiological studies and by extrapolation of blood concentrations at different rates of intake for certain smoke components, such as carbon monoxide. Critical values determined by these methods should not be interpreted as indicators of safe smoking levels; they do imply, however, that a rapid shift in cigarette consumption habits toward the proposed range of values will make possible a substantial reduction in the current epidemic proportions of smoking-related diseases. A N:0044460 SN:91-1133 AU:Gori, G.B. TI:(TO:) Consumer perception of cigarette yields: is the message relevant? JN:Regulatory Toxicology and Pharmacology PG:12(1):64-8 PYa990 PD:Aug 1990 LA:English AB:Over 1200 randomly selected subjects from the U.S. and key European countries were interviewed by telephone, to establish how consumers perceive the meaning and relative value scale of tar yields of commercial cigarettes. Some 50% of respondents interpreted numerical tar yields as being precise quantitative predictors of intake related to health effects. A less precise quantitative intuition is shown by 20-30% of respondents. The remaining respondents had little or no interest in, or understanding of, tar yield meaning. Despite local differences, the aggregate responses from the U.S. were analogous to European responses and were not significantly affected by age, sex, or socioeconomic status. The results show that consumers expect a cigarette grading message predictive of actual intake from different brands. The current message based on standard analytical yields does not meet this requirement and needs modification. Cigarette ratings based on the tar-to-nicotine ratio of standard yields could offer the basis for an acceptable message. AA: (Auth. Abs.) 23
Page 195: apt20e00
AN:0044577 SN:91-8520 AU:Gori, G.B. TI:(TO:) Cigarette classification as a consumer message. JN:Regu~latory Toxicology and Pharmacology PG:12(3 Pt 1):253-62 PY:1990 PD:Dec 1990.. LA:English AB:Cigarette yields of tar, nicotine, and carbon monoxide, obtained by standard smoking machine procedures, have been adopted as official consumer information throughout the world. However, real-life dynamics of cigarette puffing and inhalation are not standard, but follow widely fluctuating individual behavior. In addition, smokers inhale after puffing, an event that standard smoking machines do not address. Clearly then, analytical cigarette yields alone are insufficient as quantitative predictors of smoke intake valid for all smokers. Bioavailability studies show that virtually all cigarettes, regardless of analytical yield, can satisfy the nicotine demand of any smoker. On the other hand, tar intake and nicotine intake are related according to the tar-to-nicotine ratio of the smoke, which varies with brands. Thus, while a generalized message predictive of quantitative individual intake is not feasible, tar-to-nicotine ratios of standard analytical yields tell any smoker about expectations of proportional tar intake from different brands, and should be adopted as the preferred consumer message. AA: (Auth. Abs.) AN:0037607 SN:871647 AUGori, G.B., Benowitz, N.L., Lynch, C.J. T1:(TO:) Mouth Versus Deep Airways Absorption of Nicotine in Cigarette Smokers. JN:Pharmacology Biochemistry and Behavior PG:25(6):118 l -1184 PY:1986 PD:December 1986 LA:English AB:Mouth vs. deep airways absorption of nicotine was studied in 41 male and 52 female smokers who smoked more than or equal to 20 American cigarettes/day for > 1 year and in 15 nonsmoking controls under normal ventilation and smoking conditions or under high ventilation and controlled smoking conditions that restricted intake to the mouth only with no inhalation. There is virtually no nicotine intake through the buccal mucosa while smoking American cigarettes. Plasma nicotine and carbon monoxide (CO) levels were not correlated with the analytical yields of nicotine and CO of the cigarettes smoked. Within the highly ventilated environment, nicotine and CO levels were not significantly changed' in nonsmokers. Within the normally ventilated environment, both substances increased minimally. Nicotine may be a better indicator of exposure to passive smoke than CO. AN:0025033 SN:790369 AU:Gori, G.B., Lynch, C.J. TL•(TO:) Toward Less Hazardous Cigarettes. Current Advances. JN:Journal of the American Medical Association PG:240(12): 1255-1259 PY:1978 PD:September 15, 1978 LA:English AB:Increased interest in the role of cigarette constituents in tobacco related disease has prompted the compilation of critical levels of selected cigarette smoke constituents. Levels are expres$g,d in terms of maximum numbers of pre- i 960 cigarettes that a smoker may consume daily without increasing his mortality risk substantially above that of a nonsmoker. Tar, nicotine, carbon monoxide, nitrogen oxides, hydrogen cyanide and acrolein content of 27 popular commercial brands are given; these levels 24 i%
Page 196: apt20e00
are also tabulated in terms of reduction in yields compared with pre-1960 cigarette yields. Reductions range from a high of more than 98 percent (Stride - hydrogen cyanide yield) to a low of 24 percent (King Sano Menthol - nitrogen oxide yield). On the average, the brands under consideration have had the greatest percentage reduction in tar yield (86 percent) and the least percentage reduction in carbon monoxide and nitrogen oxides yields (69 percent) compared with pre-1960 cigarettes. In addition, the yields of these selected constituents concomitant with the yield of I mg of nicotine are provided as a guide for the smoker who titrates or adjusts his smoking pattern to accommodate a fixed daily intake of nicotine. AN:0029792 SN:831776 AU:Gori, G.B., Lynch, C.J. TL•(TO:) Smoker Intake From Cigarettes in the 1-mg Federal Trade Commission Tar Class. JN:Regulatory Toxicology and Pharmacology PG:3(2k 110-120 PY:1983 PD:June 1983 LA:English AB:Plasma cotinine levels, analyzed as a marker of intake as smokers of I mg U.S. Federal Trade Commission (FTC) tar class cigarettes switched brands, spanned a similar range of values from nondetectable to about 800 ng/ml in all brands tested. Pharmacokinetic considerations suggest that smokers of these brands generally intake actual nicotine levels exceeding posted FTC values, with aggressiveness of personal behavior as a main determinant. Both mean values across smokers for each brand and brand differences in individual smokers were closely proportional to the analytical differences of FTC nicotine yields for each brand smoked.V1+hile standard FTC analytical values may not predict absolute smoke intake, they indicate the relative intake that smokers can expect from different brands in the I mg FTC tar class. (Auth. Abs. Mod.) AN:0047573 SN:92-6085 AU:Gori, G.B., Mantel, N. TL•(TO:) Mainstream and environmental tobacco smoke. JN:Regulatory Toxicology and Pharmacology PG:14(1):88-105 PY:1991 PD.Aug 1991 LA:English AB:Environmental tobacco smoke (ETS) is derived from cigarette smoldering and active smoker exhalation. Its composition displays broad quantitative differences and red'istributions between gas and respirable suspended particulate (RSP) phases when compared with the mainstream smoke (MSS) that smokers puff. This is because of different generation conditions and because ETS is diluted and ages vastly more than MSS. Such differences prevent a direct comparison of MSS and ETS and their biologic activities. However, even assuming similarities on an equal' mass basis, ETS-RSP inhaled doses are estimated to be between 10,000- and 100,000-fold less than estimated average MSS-RSP doses for active smokers. Differences in effective gas phase doses are expected to be of similar magnitude. Thus the average person exposed to ETS would retain an annual dose analogous to the active MSS smoking of considerably less than one cigarette dispersed over a 1-year period. By contrast, consistent epidemiologic data indicate that active smoking of some 4-5 cigarettes per day. may not be associated with a significantly increased risk of lung cancer. Similar indications also obtain for cardiovascular and respiratory diseases. Since average doses of ETS to nonsmoking subjects in epidemiologic studies are several thousand times less than this reported intake level, the marginal relative risks of lung cancer and other diseases attributed to ETS in some epidemiologic studies are likely to be statistical artifacts, derived from unaccounted confounders and unavoidable bias. AA: (Auth. Abs.) 25
Page 197: apt20e00
AN:0026973 SN:820792 AU:Griffi~ths, R.R., Henningfield, J.E. TI:(TO:) Experimental Analysis of Human Cigarette Smoking Behavior. JN:Federation Proceedings PG:41(2): 234-240 PY:1982 PD:February 1982 LA:English AB:A laboratory setting that permits relatively unobtrusive measurement of naturalistic cigarette smoking behavior in humans was used for studies in which volunteer subjects participated in daily sessions lasting up to 3 hours. The first study showed that the intervals between consecutive cigarettes were relatively stable, both within and across sessions. An analysis of puffing for a single cigarette revealed that as the cigarette was smoked, i~nterpuff intervals tended to become longer while puff durations became progressively shorter. The second study showed that cigarette deprivation increased the tendency for subsequent smoking as reflected in latency to smoke and number of cigarettes and puffs. In the third study no change in smoking behavior was detected when subjects were informed that they would subsequently be exposed to a period of cigarette deprivation. The final study demonstrated the responsiveness of cigarette smoking to a form of dose manipulation: decreasing the concentration of tobacco smoke delivered by using ventilated cigarette holders produced increases in the rate of puffing and total numbers of puffs. These studies demonstrate the sensitivity of this preparation and suggest that it may be valuable for exploring a range of pharmacological and behavioral variables that control human cigarette smoking. (Auth. Abs.) A N:0026974 SN:820793 AU:Griffiths, R.R., Henningfield, J.E., Bigelow, G.E. TI:(TO:) Human Cigarette Smoking: Manipulation of Number of Puffs per Bout, Interbout Interval and Nicotine Dose. JN:Journal of Pharmacology and Experimental Therapeutics PG:220(2): 256-265 PY:1982 PD:February 1982 LA:English AB:In a residential research ward, cigarette smoking was studied during 12-hour daily sessions in 7 volunteer human subjects with histories of regular smoking. Puff-to-puff delivery of cigarette smoke was held relatively constant by instructing and monitoring subjects in taking uniform puffs and by specifying and timing the duration of holding the smoke in the lungs (5 seconds) and the duration of the interpuff interval (25 seconds). When a modest response requirement of riding a stationary exercise bicycle for 1 minute was required before each smoking bout consisting of 8 uniform puffs, stable patterns of smoking emerged in which smoking bouts were evenly spaced within and across sessions.. When the number of puffs per bout was experimentally manipulated both across and within sessions, increases in puffs per bout resulted in increases in interbout intervals. When the interbout interval was experimentally manipulated both across and within sessions and the number of puffs per bout was free to vary, increases in interbout interval' resulted in increases in puffs per bout. When both nicotine dose (0.2-1.6 mg per cigarette) and puffs per bout were varied across sessions in the same experiment, changes occurred in interbout interval in response to manipulation of puffs per bout but not nicotine dose. Although nicotine dose did not influence interbout.interval or puffs per hour, subject ratings of cigarette strength tended to increase with dose. (Auth. Abs.) AU:Gritz, E.R., Rose, J.E., Jarvik, M.E. TI:Regulation of tobacco smoke intake with paced cigarette presentation. JN:Pharmacology, Biochemistry and Behavior PG: 18:457-62 PY:7983 26
Page 198: apt20e00
LA:English AB:Smoking behavior in response to an increased presentation of cigarettes was investigated to determine whether compensatory changes occurred in order to maintain a constant intake of tobacco smokeJ The lighting of each cigarette was paced at both twice and four times that of subjects' baseline smoking rates in a three condition repeated measures design for eight smokers. Puff topography-number of puffs per cigarette, puff duration, volume peak flow and interpuff interval-was monitored continously. Results showed that subjects titrated smoke intake, as summarized by three smoke compensation indices based on number of puffs, puff volume and puff duration. Compensation was virtually complete in the double rate condition, and substantial in the quadruple rate condition. Results of this experiment do not support the view of a bimodal distribution of smokers, "compensators" and "noncompensators", since a continuous range of compensatiuon ratios was obtained. The measures of individual puff topography were only modestly correlated, and were generally highest for volume x duration. Volume would appear to be the most accurate measure of tobacco product consumed. AN:0033970 SN:860002 AU:Grunberg, N.E., Morse, D.E., Maycock, V.A., et al. TI:(TO:); Changes in Overwrap and Bu2t Length of American Filter Cigarettes. An Influence on Reported Tar Yields. JN:New York State Journal of Medicine PG:85(7):310-312 PY:1985 PD:July 1985 LA:English AB:Tar and nicotine yields of cigarettes, determined by official government assays and used by the public and by health professionals to evaluate and compare cigarette brands, have proved to be misleading in 18 percent of the 161 American brands examined. Reported tar yields and changes in physical characteristics (overwrap length and butt length) of 29 filter brands showed an inverse relationship, indicating that the reported tar yields maybe inaccurate. Smokers can compensate for reduced tar and nicotine content of cigarettes by taking more puffs or by blocking ventilation holes, thereby self-administering substantially more tar and nicotine from each cigarette than official reports indicate. To improve the meaningfulness of the reported tar and nicotine yields, the number of puffs taken on each cigarette by smoking machines should also be included. (Auth. Abs. Mod.) AN:0028626 SN:830588 AU:Gust, S.W., Pickens, R.W. TI:(TO:) Does Cigarette Nicotine Yield Affect Puff Volume? JN:Clinical Pharmacology and Therapeutics PG:32(4): 418-422 PY:1982 PD:October 1982 LA:English AB:The smoking behavior of four women and two men changed in a systematic way when they were presented with cigarettes of varying nicotine content. Three doses of nicotine cigarettes were used: 0.32-, 1.25-, and 2.50-mg average nicotine yield/cigarette. Tar and carbon monoxide content and burning characteristics were similar for all three cigarettes. Total smoke exposure was found to be inversely related to nicotine content. As nicotine yield decreased, puff volume, puff duration, number of puffs, and carbon monoxide boost increased. The evidence lends support to the suggestion that smoking low-nicotine cigarettes may increase exposure to other harmful smoke constituents. (Auth. Abs. Mod.) AU:Gust, S.W., Pickens, R.W., Pechacek, T.F. TI:Relation of puff volume to other topographical measures of smoking. 27
Page 199: apt20e00
JN:Addictive Behaviors PG:8:115-119 PY:1983 LA:English AB:Puff volume, puff duration, interpuff interval, cigarette interval, puffing rate, and number of puffs per cigarette were recorded n eight normally smoking subjects during five daily one-hour laboratory sessions. Topographical measures showed wide variability across subjects, but measures were relatively stable within subjects. Puff volume was significantly positively correlated with puff duration for five subjects. As the cigarette was smoked, puff duration remained relatively constant, while puff volume decreased systematically and interpuff interval increased initially and then decreased. AN:0039867 SN:89-0503 AU:Gutenmann, W.H., Lisk, D.J., Shane, B.S., Hoffmann, D., Adams, J.D., et al. TI:(TO:) Selenium in mainstream and sidestream smoke of cigarettes containing fly ash-grown tobacco. JN:Drug and Chemical Toxicology PG:10(3-4):181-7 PY:1987 PD:1987 LA:English AB:The quantities of selenium, tar and nicotine present in mainstream (MS) and sidestream (SS) smoke of machine-smoked' cigarettes was studied. The cigarettes were prepared from tobacco purposely cultured on fly ash-amended soil so as to increase its selenium concentration. Selenium concentration was found to be the same in the gaseous phase of both MS and SS smoke, but its concentration was significantly higher (p less than 0.05) in the particulate matter of the MS smoke. Tar was higher in MS smoke and nicotine in SS smoke. Factors affecting selenium concentrations in tobacco and its possible environmental significance are discussed. AA:(Auth. Abs.) AN:0042817 SN:91-4546 AU:Guyatt, A.R., Kirkham, A.J., Baldry, A.G., Dixon, M., Cumming, G. TI:(TO:) How does puffing behavior alter during the smoking of a single cigarette? JN:Pharmacology, Biochemistry and Behavior PG:33(1):189-95 PY:1989 PD:May 1989 LA:English AB:We examined changes in puffing behavior during the course of a single cigarette in 76 subjects seen on 6 occasions each (456 cigarettes). The puff volume fell on average by 33% during a cigarette and puff duration by 39%, the interpuff interval rose by 75%, but the pressure drop and the maximum flow and pressure achieved during puffing hardly changed. There were highly significant differences between subjects but not between sessions, or when subjects were grouped according to tar yield of the cigarette or by sex. Individual puff volumes with a single cigarette were highly correlated with puff duration (except in a few individuals with irregular puffing patterns), but not generally with maximum flow rate, suggesting that most smokers reduce volume by taking shorter puffs. This is unlikely to reflect mechanical factors or smoke temperature, and may be a response to changing smoke composition. Variation in puffing patterns between individuals may reflect differences in sensitivity to smoke components and individuals who show little fall in puff volume also show small responses on switching to cigarettes with different tar and nicotine yields. The individual' response to smoke might be assessed by an analysis of puffing on a single cigarette. AA: (Auth. Abs.) 28
Page 200: apt20e00
AU:Guyatt, A.R., Kirkham, A., Mariner, D.C., Baldry, A.G., Cumming, G. Ti:Long-term effects of switching to cigarettes with lower tar and nicotine yields. JN:Psychopharmacology PG:99r.90-86 PY:1989 LA:English AB:On switching to cigarettes with lower tar and nicotine yields,, most individuals smoke more intensively, but it is not clear if this effect persists over a long period. Smoking behavior was monitored in 10 male and 18 female volunteers at five monthly visits, smoking commercially available cigarettes (tar yield > 10mg), then for six more visits at 6-week intervals after switching (mean reduction of 5.9mg tar and 0.45mg nicotine). Puffing behaviour was monitored with a flow sensing holder, and measurements were made before and after smoking plasma cotinine, carboxyhaemglobin and alveolar carbon monoxide. After switching, cotinine levels only fell 40% of that predicted from the fall in nicotine yields, and there were no systematic trends for the rest of the study. Puff volumes rose (reflecting perhaps the reduced draw resistance of the lower yield cigarettes), and remained higher thereafter. The number of puffs per cigarette appeared to rise on switching, but then decreased again. In conclusion, most effects of switchiing to lower yield cigarettes appeared' to persist for at least 36 weeks, suggesting that the strategy of reducing exposure to cigarette smoke lowering tar and nicotine yields may be of limited value. AN:0009534 SN:770222 AU:Hammond, E.C., GarfinkeD, L., Seidman, H., Lew, E.A. TI:(TO:) "Tar" and Nicotine Content of Cigarette Smoke in Relation to Death Rates. JN:Environmental Research PG:12(3): 263-274 PY:1976 PI}December 1976 LA:English AB:More than 1,000,000 men and women were enrolled in an epidemiological study in 1959-60 and were followed, with few exceptions, for 12 years; all answered questionnaires on cigarette smoking and other factors upon enrollment; survivors answered three repeat questionnaires. Cigarette smokers were classified' by the amount of tar and nicotine (TIN) delivered by the brand they usually smoked at the start of each of two 6-year periods (Period I and Period 2): high TIN (2.0-2.7 mg nicotine and 25.8-35.7 mg tar); low TIN (less than 1.2 mg nicotine and, with few exceptions, less than 17.6 mg tar); and medium TIN (intermediate between high and low). Among those who smoked the same number of cigarettes/day, the total death rates, death rates from coronary heart disease, and death rates from lung cancer were somewhat lower for those who smoked low T/N cigarettes than for those who smoked high T/N cigarettes. Total number of deaths were 4,735.5 for high T/N smokers, 4,299.9 for medium and 3,991.1 for low; corresponding numbers of lung cancer deaths were 318.4, 285.5, and 235.2, respectively. The differences between high and low were statistically significant in both cases. Lung cancer mortality ratios of low TIN smokers were lower for women than for men (0.57 and 0.83, respectively, in Period I and 0.62 and 0.79, respectively, in Period 2). Corresponding figures for coronary heart disease (1616.8 in high, 1483.3 in medium, and 1392.7 in low) also show a statistically significant difference between the high and low groups. In an analysis comparing subjects who smoked many low T/N cigarettes with those who smoked fewer high T/N cigarettes, there was a statistically significant difference in coronary heart disease deaths (670.6 for subjects smoking 1-19 high cigarettes aad 736.6 for those smoking 20-39 low cigarettes). There was also a difference in lung cancer deaths (75.8 for those smoking 1-19 high and 129.5 for those smoking 20-391ow); for each of 4 individual sets of comparisons (men and women in Periods 1 and 2), the number of lung cancer deaths was lower in those who smoked 1-19 high than in those smoking 20-39 low. Another analysis compared low T/N smokers with nonsmokers; death rates were far higher in the low T/N group than in the nonsmoking group (total deaths were 4,670.3 and 3,099.0, respectively, coronary heart disease deaths 1,674.3 and 1,008.3, respectively, and lung cancer deaths 258.0 and 39.4, respectively). It was 29
Page 201: apt20e00
concluded that a reduction in the tar and nicotine content of cigarettes did not make cigarette smoking "safe" for the men and women in this analysis, all of whom were over the age of 40 in 1959. AN:0041748 SN:90-4593 AU:Hatsukami, D.K., Morgan, S.F., Pickens, R.W.,, Champagne, S.E., et al. TI:(TO:)~ Situational factors in cigarette smoking. JN:Addictive Behaviors PG:15(1):1-12 PY:1990 PD:1990 LA:English AB:Situational factors related to smoking behavior in the natural environment were studied. Six subjects smoked all cigarettes over 10 days with a portable, electronic recording device which measured a number of frequency and time-based features of smoking. Subjects also coded activities and internal states associated with each cigarette smoked. Across subjects, there were considerable differences in the distribution of cigarettes smoked across the activity and internal states categories. Within subjects, all subjects showed variation in measures of smoking topography (number of puffs/cigarette, mean puff duration, total puff time/cigarette) as a function of situational variables. It did not appear that pharmacological factors could fully account for the substantial situational differences found. The results suggest that different factors may be involved in the control of different aspects of smoking topography. AA: (Auth. Abs.) AN:0042999 SN:91-9148 AU:Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., Rickert, W., Robinson, J. TI:(TO:) Measuring the heaviness of smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day. JN:British Journal of Addiction PG:84(7):791-9 PY:II989 PD:Jul 1989 LA:English AB:Two simple self-report measures have been used to assess the heaviness of smoking, 'number of cigarettes per day' (CPD) and 'time to the first cigarette of the day' (TTF). Little attention, however, has been given to the precise method' of scoring this information. Using biochemical indicators of heaviness of smoking (alveolar carbon monoxide and cotinine), we explore the optimum data transformations for regression analysis and categorical' analysis. We suggest a four category scoring scheme for both time to the first cigarette of the day (less than or equal to 5, 6-30, 31-60 and 61+ min) and average daily consumption of cigarettes (1-10, 11-20, 21-30, 31+ cigarettes) as the most powerful and practical categorical scoring of these variables. Due to possible ceiling effects on biochemical measures, we suggest using logarithmic transformations of CPD or TTF for regression or correlation analyses. AA: (Auth. Abs.) AN:0030654 SN:840568 AU:Henningfield, J.E. Tl:(TO:) Measurement Issues in Cigarette Smoking Research: Basic Behavioral and Physiological Effects and Patterns of Nicotine Self-Administration. SO:In: Grabowski, J.; Bell, C. S. (Editors). Measurement in the Analysis and Treatment of Smoking Behavior. U.S. Department of Health and Human Services, PHS, ADAMHA, NIDA Research Monograph 48, DHHS Publication No. (ADM) 83-I285 ~_ PG:pp. 27-38 PY:1983 PD:1983 30
Page 202: apt20e00
LA:English AB:Data collected from studies that utilized two general nicotine self-administration strategies provide an experimental basis for assessing the role of the multiple factors involved in cigarette smoking. The two strategies were a cigarette smoking paradigm and an intravenous nicotine self-administration paradigm. Some of the factors discussed are: (1) problems of measurement in tobacco research, e.g., the nature and quantity of constituents in any given puff of smoke as a function of multiple factors, including cigarette constitution, puff topography, and inhalation characteristics; and (2) the equivalence of i.v. nicotine to tobacco smoke,a factor in determining the role of nicotine in the dependence process. Results suggest that measurement issues can be surmounted by systematically applying the methods of behavioral pharmacology and biological assay procedures. The use of multiple measures help resolve issues arising from any single measure. It is concluded that cigarette smoking is appropriately categorized as an instance of drug dependence in which nicotine is the key pharmacologic mediator of the behavior (but only one of the many components involved in the acquisition, maintenance, and elimination of the dependence process). AN:0021615 SN:810552 AU:Henningfield, J.E., Griffiths, R.R. TI:(TO:) A Preparation for the Experimental Analysis of Human Cigarette Smoking Behavior. JN:Behavior Research Methods and Instrumentation PG:l 1(6): 538-544 PY:1979 PD:December 1979 LA:English AB:A preparation for the experimental analysis of cigarette smoking is described in detail. The preparation, which consists of a comfortable naturalistic, experimental environment equipped with a cigarette monitoring system, permits the intensive study of cigarette smoking in individual subjects under controlled laboratory cond'itions. A variety of behavioral and physiological measures used i'nclude rate and pattern of puffing, duration of each puff, time spent smoking cigarettes, expired air carbon monoxide levels, cigarette butt weights, and subjective rating scales of various aspects of smoking. Sample experiments with 19 heavy smokers were run to test the validity of the preparation. It was found that the preparation was reliable and permitted relatively unobtrusive monitoring of smoking performance. Cigarette smoking was found to occur in orderly patterns within subjects; it varied as a function of number of cigarettes provided and hours of smoking deprivation. AA: (Auth. Abs. Mod.) A N:0021023 SN:801767 AU:Henningfield, J.E. Griffiths, R.R. TI:(TO:) Effects of Ventilated Cigarette Holders on Cigarette Smoking by Humans. JN:Psychopharmacology PG:68(2): 17 5-119 PY:1980 PD:May 1980 LA:Engtish AB:Heavy cigarette smokers individually attended daily 3-hour test sessions which were run in specially designed cigarette smoking evaluation rooms. Subjects were required to use the cigarette holder provided and to extinguish each cigarette 4 min after the first puff on the cigarette. Other than these restrictions, subjects were allowed to smoke ad libitum. The concentration of delivered tobacco product was varied from 100 to 10 percent across sessions by using graded commercially available ventilated cigarette holders. As concentration of tobacco product was decreased, rate of puffing and' total number of puffs showed robust compensatory increases (pc0.01) Number of cigarettes increased only moderately in response to decreases in tobacco product concentration. There was little change in subjective ratings of strength on smoking satisfaction. Finally, expired air carbon monoxide values and cigarette butt weights were relatively stable across the four ventilation 31
Page 203: apt20e00
conditions. These later findings suggest that a significant degree of compensation had occurred in response to the concentration manipulations. (Auth. Abs.) AN:0021159 SN:8 10062 AU:Henningfield, J.E., Stitzer, M.L., Griffiths, R.R. TI:(TO:) Expired Air Carbon Monoxide Accumulation and Elimination as a Function of Number of Cigarettes Smoked. JN:Addictive Behaviors PG:5(3): 265-272 PY:1980 PD:1980 LA:English AB:Eight heavy cigarette smokers smoked varying numbers of cigarettes during sessions of approximately 8 hrs in length. Expired air carbon monoxide (CO) levels were determined every 10 min during sessions using a portable breath analyzer. Under these conditions, orderly patterns of CO accumulation and elimination were revealed, both within and across subjects, although absolute rates of accumulation and elimination varied considerably across individuals. Peak CO values and the duration of elevation of CO level were directly related to number of cigarettes smoked. In general, the findings support the potential utility of this measure for smoking research and treatment. (Auth. Abs.) AN:0021331 SN:810244 AU:Henningfield, J.E., Yingling, J., Griffiths, R.R., Pickens, R. TI:(TO:) An Inexpensive Portable Device for Measuring Puffing Behavior by Cigarette Smokers. JN:Pharmacology, Biochemistry and Behavior PG: l 2(5): 811-813 PY:1980 PD:1980 LA:English AB:A device for counting discrete puffs by cigarette smokers is inexpensive, easily constructed, and fully portable. The device consists of a plastic cigarette holder which is connected to a miniature pressure sensor via 18 gauge polyvinyl tubing. The pressure sensor has two electrical terminals which provide access to a normally open circuit which is closed following a pressure drop produced by puffing on the cigarette holder. The pressure sensor is wired to a common pocket calculator in such a way that each puff is counted by the calculator. The device has been shown to be reliable, and the puff measure is sensitive to a variety of experimental manipulations. The device may serve in either the laboratory setting or may be carried by a smoker to monitor his behavior in his natural environment. (Auth. Abs.) AN:0009535 SN:770223 AU:Herson, J., Simpson, C., Kennedy, J., Kapoor, S. TI:(TO:) A Theoretical Approach to the Evaluation of the Mortality Effects of a"Low Tar" Cigarette. JN:Journal of Chronic Diseases PG:29(12): 747-758 PY:1976 PD:December 1976 LA:English AB:Receat smoking and health controversy has centered around the likely effects on human mortality of a federal policy sanctioning only the sale of low-tar cigarettes. At present, very little-data are available to document the mortality effects of prolonged smoking of cigarettes at various tar levels. Moreover, ethical and practicality considerations preclude the possibility of a controlled clinical trial being performed to estimate these effects. The objectives of this paper are thus to develop various 32
Page 204: apt20e00
mathematical models to: (1) Estimate the variation in various measures of mortality by daily smoking frequency and cigarette tar content. (2) Discuss implications of the mortality results in terms of public health policy that would encourage the use of low-tar cigarettes and/or encourage smokers to lower-4aily smoking frequency. The two parameter Gompertz hazard function is shown to fit Hammond's 1960 American Cancer Society life tables which depict survivorship of men aged 25-100 years for five levels of smoking frequency. Using data on tar levels of cigarettes on the market during the period 1960-65, various models are proposed to estimate the covariation of the Gompertz parameters by smoking frequency and tar content. For each model, estimated life expectancy and age specific death rates are presented for various smoking frequency/tar groups and the mortality consequences of a low tar and low frequency public health policy are discussed. Multiple regression analysis is used to summarize the mortality findings and to provide a quantitative assessment of the relative importance of tar content and smoking frequency in determining life expectancy and death rate. Evidence from the models favors a low-tar policy over a low frequency policy but considerable benefits can be obtained from a combined policy. (Auth. Abs. Mod.) AN:0020954 SN:801687 AU:Higenbottam, T., Feyeraband, C., Clark, T.J.H. T1:(TO:) Cigarette Smoke Inhalation and the Acute Airway Response. JN:Thorax PG:35(4): 246-254 PY:1980 PD:April 1980 LA:English AB:The acute airway response to smoking varying numbers (1-4) of identical cigarettes in rapid succession and smoking single cigarettes of differing tar (low to high)/nicotine (0.70 to 3.39 mg) yields was assessed repeatedly in 13 healthy smokers. The airway response was variable, indicating airway narrowing consistently in only three subjects. There appeared' no difference between forced spirometry and measurement of airway resistance in detecting the airway response. No relationship was observed between the airway response and amount of smoke inhaled into the lungs as measured either by changes in venous blood nicotine or percentage carboxyhemoglobin. When five smokers inhaled smoke directly from a cigarette, acute airway narrowing was consistently observed. A normal smoking pattern consisting of an initial drag of smoke into the mouth, followed after a pause by inhalation of smoke diluted with air, did not consistently cause airway narrowing, although similar amounts of smoke as the direct drag were inhaled as assessed by changes in venous blood nicotine. The manner of smoke inhalation affects the relative concentrations of the different constituents of smoke reaching the lungs and also appears to be the main determinant of the acute airway response to smoking, which was unrelated to the number of cigarettes smoked or the tar content of the smoke. This suggests that patterns of smoke inhalation may influence the pathogenesis of bronchial disease associated with smoking. (Auth. Abs.) AN:0030128 SN:840037 AU:Hill, P., Haley, N.J., Wynder, E. L. TI:(TO:) Cigarette Smoking: Carboxyhemoglobin, Plasma Nicotine, Cotinine and Thiocyanate Vs Self-Reported Smoking Data and Cardiovascular Disease. JN:Journal of Chronic Diseases PG:36(6): 439-449 PY:1983 PD:1983 LA:English AB:Results showed a plateau of plasma nicotine and cotinine concentration at levels above 20 cigarettes/day, with progressive increase of carboxyhemoglobin and thiocyanate corresponding with increasing consumption. Absorption of tobacco smoke constituents was determined by comparing self-reported cigarette consumption and nicotine availability with carboxyhemoglobin and plasma 33
Page 205: apt20e00
thiocyanate, nicotine, and cotinine levels in 450 smokers. Smokers of low-yield brands (<1 mg nicotine/cigarette) had lower plasma levels of nicotine and cotinine, but comparable levels of carboxyhemoglobin and thiocyanate. Plasma nicotine bore no relationship to smoke inhalation, while the number of cigarettes consumed/day showed a weak correlation to smoke inhalation. Despite lower nicotine yields, modified behavior enabled smokers to derive similar amounts of carbon monoxide and thiocyanate from both low-yield and high-yield cigarettes, thus counteracting the advaatage of low-nicotine brands. The relationship of these parameters to the risk of coronary heart disease is discussed. (Auth. Abs. Mod.) AN:0049509 SN:93-0344 AU:Hofer, I., Nil, R., Battig, K. TI:Ultralow-yield cigarettes and type of ventilation: the role of ventilation blocking. JN:Pharmacology, Biochemistry and Behavior PG:40(4):907-14 PY:1991 PD:Dec 1991 LA:English AB:Habitual smokers of perforation-ventilated cigarettes and of channel-ventilated cigarettes (18 male and 18 female subjects each; nicotine yield 0.1-0.3 mg, 0.2 mg, respectively) were compared with respect to different smoke exposure indicators and puffing behavior. The role of ventilation blocking was assessed by comparing normal lip contact with smoking through a cigarette holder. The presmoking concentrations (plasma nicotine, cotinine, respiratory CO) were higher for channel-filter than for perforation-ventilated cigarettes, as were the pre- to postsmoking boosts (nicotine, CO) with normal lip smoking. Holder smoking resulted in lower boosts than lip smoking for the channel filter cigarettes, although the puffing behavior was considerably intensified. The boosts for perforation-ventilated cigarettes remained unchanged and were reached with only moderately intensified puffing behavior. The results indicate the importance of ventilation blocking in everyday lip smoking for channel-filter cigarettes, but not for conventional, perforated cigarettes. AA: (Auth. Abs. Mod.) AN:0051459 SN:93-2294 AU:Hofer, I., Nil, R., Battig, K.R. TI:Nicotine yield as determinant of smoke exposure indicators and puffing behavior. (Erratum: I. Hofer, R. Nil, and K. Battig, "Nicotine yield as determinant of smoke exposure indicators and puffing behavior," Pharmacology Biochemistry and Behavior, Vol. 40(1): 139-149, 1991). JN:Pharmacology, Biochemistry and Behavior PG:41(2):465-468 PY:1992 PD:February 1992 LA:English AB:The authors present corrections to data that originally appeared in I. Hofer, R. Nil, and K. Battig, "Nicotine yield as determinant of smoke exposure indicators and puffing behavior," Pharmacology Biochemistry and Behavior, Vol. 40(1), pp. 139-149, 1991. The data in Table 1 were not properly represented in the original publication.In addition, the correlation of taste with yield, as indicated in Table 5, is not significant. Results generally support the hypothesis that lower yield cigarettes are associated with reduced smoke absorption, although to varying degrees across the different smoke indicators. For the reader's convenience, both tables are correctly reprinted. AN:0020839 SN:801565 AU:Hoffmann, D., Tso, T.C., Gori, G.B. TI:(TO:) The Less Harmful Cigarette. JN:Preventive Medicine 34
Page 206: apt20e00
PG:9(2): 287-296 PY:1980 PD:March 1980 LA:English AB:Risk assessment shows that the adverse effects of cigarette smoking on human health are clearly related to the total consumption of cigarettes. Such dose--response is evident from data on the incidence of lung and larynx cancer and is also supported by results from bioassays with Syrian golden hamsters and mice. The concept of a less harmful cigarette, therefore, involves primarily a reduction of the quantities of tar and nicotine in cigarette smoke. The identification of tumorigenic and toxic tobacco smoke constituents and the study of their formation during smoking has guided the development of products with 40-60 percent reduction of sales-weighted tar and nicotine levels in most western countries. These changes have been effected mainly through development of efficient filter tips, selection of specific tobacco types, and modifications in tobacco blends, including the technology of reconstituted tobacco preparation. This presentation discusses details of the development of cigarettes with reduced levels of tar, nicotine, and carbon monoxide. It is emphasized that the risk for diseases associated with tobacco usage can be eliminated only by abstention from smoking, but that a risk reduction through product modification has been achieved and may be further improved. (Auth. Abs.) AN:0025656 SN:790995 AU:Jaffe, J.H., Kanzler, M.B. TI:(TO:) Tobacco and Nicotine Self-Administration in Humans: The Evolution of a Methodology. SO:In: Krasnegor, N:A. (Editor). Self-Administration of Abuse Substances, Methods for Study. National Institute on Drug Abuse Research Monograph Series, No. 20 PG:pp. 209-220 PY:1978 PD:July 1978 LA:English AB:The self-administration of nicotine by humans was examined in a laboratory study. Preliminary experiments were done to investigate how smoking varies as a function of response cost. Subjects performed simple tasks and were rewarded with a cigarette. Results showed that consumption went down as response cost increased and then rose again, but not to the starting point,as response cost was lowered. In the main test, the relationship between overall response costs and nicotine content of the cigarette purchased was examined. The 23 smokers (16 women, 7 men) were asked to save cigarette butts during a 2 week baseline observation period and each time the subject changed brands. Estimates of daily nicotine intake were made. Results indicated behavioral differences between the men and the women. Fewer men than women volunteered for the study and only four of the seven completed the 12 week study. The men who finished showed substantial reductions in nicotine and tar consumption. Twelve of the 16 women completed the study. All showed a rapid drop in the intake level of nicotine in the first 6 weeks and the decline continued more gradually for the rest of the study. Economic incentives did not seem to influence the subjects to switch to low nicotine and tar cigarettes. Subjects tended to consume more of the cigarette as the nicotine content decreased. The tendency to inhale more did not result in higher carbon monoxide levels. Results indicate that social factors, coffee or alcohol consumption and health concerns may play a role in determining the number of cigarettes smoked per day. Possibilities for innacurate measurements in the test were noted. AN:0026226 SN:820040 AU:Jaffe, J.H., Kanzler, M., Friedman, L., Stunkard, AJ., Verebey, K. TI:(TO:) Carbon Monoxide and Thiocyanate Levels in Low Tar/Nicotine Smokers. JN:Addictive Behaviors PG:6(4): 337-343 PY:1981 35
Page 207: apt20e00
PD:1981 LA:English AB:The purpose of this study was to compare carbon monoxide (CO) in expired breath and thiocyanate (SCN) in saliva of smokers who had spontaneously switched to lower tar/nicotine cigarettes with those same variables in nonswitchers and nonsmokers. CO was measured in 200 smokers and 28 nonsmokers; SCN in 150 smokers and 52 nonsmokers. CO in breath correlated significantly and positively with number of cigarettes smoked but did not vary significantly across a wide range of tar and nicotine deliveries. Smokers' SCN levels were far in excess of those of nonsmokers but were not significantly related to tar or nicotine levels of their brands. While there was no substantial decrease in CO among smokers of the lowest tar/nicotine brands, neither was there an increase. For most smokers the risks of switching with respect to CO and SCN appear minimal. AN:0031886 SN:841800 AU:Jarvis, M.J., Russell, M.A.H., West, R., Borland, C., Chamberlain, A., Higenbottam, T., Shipley, M., Rose, G. TI:(TO:) Carbon Monoxide Yield of Cigarettes andTts Relation to Cardiorespiratory Disease. (Letters). JN:British Medical Journal PG:28 8(6416): 566 -567 PY:1984 . PD:February 18, 11984 LA:English AB:The validity of the data base used in a study of the risk of fatal coronary disease ( British Medical Journal 287(6405): 1583-1586, November 26, 1983) is questioned, noting that data on carbon monoxide yields from the Government Chemist's report could not be reconciled with yields shown in the earlier report, derived from the same source. Other fundamental discrepancies in the data, which was used to show that in men who inhaled, the risk of fatal coronary heart disease over a 10-year period was 51 percent lower in smokers of high carbon monoxide cigarettes are discussed. The original authors justify use of brands outside the years 1967-1970 by noting that within a given brand, yields changed little between 1965 and 1972. The close agreement between the tar values quoted by the Tobacco Research Council and the Government Chemist suggests support for the cigarettes being of similar composition and thus probably of similar carbon monoxide yield.lt is claimed, therefore, that it is unlikely that laboratory errors in classifying an individual's exposure to carbon monoxide could have produced the positive results reported. See also 84-0492. UI:89022357 AU:Kabela, E., Andrasik, F. TI:Behavioral and biochemical effects of gradual reductions in cigarette yields in pregnant and nonpregnant smokers. JN:Addictive Behavior PG:13(3):231-43 PY:1988 AB:Smoking-related risks have been well-documented for both the smoker and the pregnant smoker's unborn child, but the risks associated with low tar/nicotine cigarette smoking are still controversial. The present study examined some of the behavioral and biochemical effectrof gradual reductions in tar and nicotine yields in six pregnant and six nonpregnant smokers. Over four sessions spanning a 6-week period, smokers switched to cigarette brands progressively lower in tar and nicotine. Examination of the topographical variables assessed both during (cigarette frequency, puff frequency, and cigarette duration) and between sessions (daily cigarette rate and nicotine intake) revealed significant decreases in both pregnant and nonpregnant smokers' cigarette duration and nicotine intake. Also observed were significantly lower and less variable carboxyhemoglobin (COHb) levels among the pregnant smokers when they smoked the lowest tar and nicotine brands. However, even the pregnant smokers' low:,r mean. COHb /evels did not drop below the 3% minimal cardiovascular risk level. The pregnant smokers also tended to have lower and less variable salivary thiocyanate 36
Page 208: apt20e00
(SCN) levels, but these differences were nonsignificant. The results were discussed in terms of implications for controlled smoking treatment programs for pregnant smokers. AN:065b186 SN:93-1021 AU:Kaiserman, M.J., Rickert, W.S. TI:Carcinogens in tobacco smoke: benzo(a)pyrene from Canadian cigarettes and cigarette tobacco. JN:American Journal of Public Health PG:82(7):1023-6 PY:1992 PD:JuI 1992 LA:English AB:We evaluated the benzo(a)pyrene (BaP) content in the smoke from 35 brands of Canadian cigarettes and 5 brands of Canadian tobaccos for roll-your-own cigarettes. For the cigarettes, mean values of BaP ranged from 3.36ng to 28.39ng per cigarette, roughly in proportion with declared tar values. The relationship between declared tar and yields of BaP, however, does not allow accurate prediction of one from the other. For the tobaccos, mean BaP values ranged from 22.92ng to 26.27ng (average, 24.7ng) per cigarette. The implications of these findings are discussed with respect to overall exposure. (AA: Auth. Abs.) AU:Kaiserman, M.J., Rickert, W.S. TI:Handmade cigarettes: It's the tube that counts. JN:American Journal of Public Health PG:82(1):107-109 PY:1992 LA:Engiish AB:Thirty-one Canadian brands of fine-cut tobaccos for roll-your-own cigarettes (RYOs) were evaluated under standard conditions using mandated tube and filter combinations. Results indicate no evidence of a significant difference in the amounts of tar, nicotine, and carbon monoxide produced by the 31 brands. ln addition, the data emphasize that it is primarily the tube and filter combination that determines delivery of toxic constitutents. (AA: Auth. Abs.) AN:0030592 SN:840503 AU:Kaufman, D.W. TI:(TO:) Constituents of Cigarette Smoke and Cardiovascular Disease. JN:New York State Journal of Medicine PG:83(13): 1267-1268 PY:1983 PD:December 1983 LA:English AB:Although the risk of fatal and nonfatal myocardial infarction was higher in smokers than nonsmokers, the magnitude of risk was not correlated with carbon monoxide and nicotine levels of cigarette brands in three studies. This implies that either (1) nicotine and carbon monoxide are not the constituents in smoke that contribute to coronary disease; or (2) that smokers are absorbing more of these compounds than indicated by Federal Trade Commission-established ratings. A growing body of data suggests the latter reason may be valid, since several studies have shown that smokers of low-nicotine cigarettes take in as much nicotine as smokers of higher-rated products, and also that carboxyhemoglobin levels do not correlate with cigarette yields. Although it is possible another substance may be responsible, other biologic evidence indicates that nicotine and carbon monoxide are the risk-increasing factors. Smokers of low-yield brands should be warned that these products do not reduce risk of coronary heart disease. 37
Page 209: apt20e00
AN:0028903 SN:830865 AU:Kaufman, D.W., Helmrich, S.P., Rosenberg, L., Miettinen, O.S., Shapiro, S. TI:(TO:) Nicotine and Carbon Monoxide Content of Cigarette Smoke and the Risk of Myocardial Infarction in Young Men. JN:New England Journal of Medicine PG:308(8): 409-413 PY:1983 PD.February 24, 1983 LA:English AB:To evaluate whether the nicotine and carbon monoxide content of cigarette smoke is related to the risk of nonfatal first myocardial infarction in young men, 502 cases (356 smokers, or 71 percent) were compared with 835 hospital controls (430 smokers, or 54 percent), all aged 30-54. Results show that men who smoke the newer cigarettes with reduced amounts of nicotine and carbon monoxide do not have a lower risk of myocardial infarction than those who smoke cigarettes containing larger amounts of these substances. As expected, the estimated risk of myocardial infarction increased with the number of cigarettes smoked; overall, the relative risk estimate for current smokers was 2.8 (95 percent confidence interval, 2.0 to 4.0). The overall age-adjusted relative risk estimate increased from 2.1 for the lightest smokers (<25 cigarettes/day), to 4.0 for the heaviest (more than or equal to 45 cigarettes/day). Multivariate estimates were considerably higher among men under age 45 than among older men; for the heaviest smokers, the estimates were 7.5 and 2.6, respectively. The risk did not appear to vary according to the amount of nicotine or carbon monoxide in the cigarette; the mean amounts of both substances/cigarette were similar for the cases and controls. (Auth. Abs. Mod.) AN:0041371 SN:$9-2085 AU:Kaufman, D.W. Palmer, J.R. Rosenberg, L. Stolley, P. Warshauer, E. Shapiro, S., et at. TI:(TO:) Tar content of cigarettes in relation to lung cancer. JN:American Journal of Epidemiology PG:129(4):703-11 PY:1989 PD:Apr 1989 LA:English AB:Although it is generally considered established that the risk of lung cancer is directly related to the tar content of cigarettes, an examination of the results of previous studies does not yield conclusive evidence in favor of the hypothesis. The authors evaluated this issue in a study of 881 cases of lung cancer and 2,570 hospital controls who were 40 to 69 years of age; data were collected by interview in hospitals in the United States and Canada from November 1981 to June 1986. For each year of smoking, cigarette brands were classified according to their tar content as published in regular Federal Trade Commission reports (from 1967 to 1985) or the Reader's Digest (from 1957 to 1966). Tar values for years for which there was no published information were estimated by interpolation. Smokers were divided, according to the tar content of their cigarette brands averaged over a specified period, into low (less than 22mg/cigarette), medium (22-28mg/cigarette), and high (greater than or equal to 29mg/cigarette) tar smokers. When the average tar content was based on cigarettes smoked at least 10 years previously, the relative risk estimates for medium and high tar smokers compared with low tar smokers were 3.0 and 4.0 after control for potentially confounding factors, including the number of cigarettes smoked per day. The trend was significant (p = 0.002). The tendency for the risk of lung cancer to increase with increasing tar content was consistent among men and women. The results provide further support for the hypothesis that the tar content of cigarettes is directly related to lung cancer risk. However, the data were limited in that there were very few subjects whose lifetime tar exposure averaged less than 10mg/cigarette. AA:(Auth. Abs.) ~~ 38
Page 210: apt20e00
AN:0042525 SN:91-9158 AU:Knott, V.J. TL•(TO1 Effects of low-yield cigarettes on electroencephalographic dynamics. JN:Neuropsychobiology PG:21(4):216-22 PY:1989 PD:1989 LA:English AB:Previous research had indicated that the smoking of medium tar and nicotine (T/N) yield cigarettes produced a psychostimulant action on electroencephalographic (EEG) activity which was apparent after a single cigarette and was evident as early as the fourth puff. The present study adopted the identical' smoking and recording procedure to examine whether low-T/N yield cigarettes produced qualitatively similar EEG profiles as previously observed with medium-yield cigarettes. Although the results indicated similarities in post-smoking EEG profiles of low- and medium-yield cigarettes, discrepancies with several EEG components and temporal (puff-by-puff) EEG features suggested that low-yield cigarettes may exert less impact on brain electric activity. The results are discussed in relation to motivational theories of smoking behavior. AA:(Auth. Abs.) AN:00S0114 SN:93-0949 AU:Kolonen, S., Tuomisto, J., Puustinen, P., Airaksinen, M.M., et al. TI:Effects of smoking abstinence and chain-smoking on puffing topography and diurnal nicotine exposure. JN:Pharmacology, Biochemistry and Behavior PG:42(2):327-32 PY:1992 PD:Jun 1992 LA:English AB:Effects of chain-smoking, a 15-h smoking abstinence, and the nicotine yield of cigarettes on puff indices were studied in eight healthy smokers by using a controlled crossover study design. Puff parameters were measured puff by puff with a portable measuring device when 10 or 20 cigarettes, with nicotine yields of 0.3 and 1.0 mg, were smoked per day. The interval between sessions was I h, and the 20 cigarettes per day were chain-smoked 2 at a time. Serum cotinine indicated that smokers compensate completely for the lower nicotine delivery from the 0.3-mg cigarette. Smokers almost doubled total puff volume per cigarette and per day mainly by taking more puffs from the low-nicotine cigarettes and slightly prolonging puff duration. However, nicotine deprivation and chain-smoking had a relatively minor effect on puffing indices with both brands, a fact that agrees poorly with the nicotine titration hypothesis. However, in the course of every single cigarette of the day smokers significantly reduced puff duration and puff volume toward the end of the cigarette, which probably involves satiation of the nicotine crave but may also be due to changes in taste of the smoke. (AA: Auth. Abs.) AN:0049874 SN:93-0709 AU:Kolonen, S., Tuomisto, J., Puustinen, P., Airaksinen, M.M., et al. .TL•Puffing behavior during the smoking of a single cigarette in a naturalistic environment. JN:Pharmacology, Biochemistry and Behavior PG:41(4):701-6 PY:1992 PD:Apr 1992 LA:English AB:The 36 participants in this study were habitual low-yield cigarette smokers, medium-yield cigarette smokers, and switchers from medium- to low-yield cigarettes. All participants smoked both low- (0.4 mg) and medium-nicotine (0.9 mg) cigarettes during the study. Puffing indices were 39
Page 211: apt20e00
recorded during the first two cigarettes, after an overnight abstinence of smoking, by a portable flow meter processor unit in a naturalistic environment. The puff volumes per cigarette and per day were significantly lower while switching to higher-yield cigarettes, mainly due to a decrease in the number of puffs and longer interpuff intervals, but also due to a decline in puff duration and flow rate. However, the down regulation by puff volume was incomplete, at most two thirds, as calculated by machine smoking yields. Within the course of smoking a single cigarette, the flow rate was quite stable, puff duration and puff volume decreased toward the end of the cigarette, and interpuff interval was longest during the middle of the cigarette. Total puff volumes per cigarette were similar in the first two cigarettes of the day after an overnight abstinence of smoking, with no significant differences in other puff parameters. Diurnal cotinine excretion revealed' that nicotine titration in switching situations was very accurate among switchers and medium-yield cigarette smokers, but not among the low-yield cigarette smokers, and so called over smoking was found with the higher-nicotine brand. Preferred cigarette type had little effect on the puffing patterns of smokers in single cigarettes. (AA: Auth. Abs.) AN:0048016 SN:92-4756 AU:Kolonen, S., Tuomisto, J., Puustinen, P., Airaksinen, M.M., et al. TI:(TO:) Smoking behavior in low-yield cigarette smokers and switchers in the natural environment. JN:Pharmacology, Biochemistry and Behavior PG:40(1): l 77-80 PY:1991 PIrSep 1991 LA:English AB:Urinary cotinine and puffing parameters were studied in 36 smoking students. Three smoking groups, formed according to the tar content of their preferred cigarette, were compared. Eighteen students had always smoked low-yield, 10 medium-yield and 8 were switchers from medium- to low-yield cigarettes. The subjects smoked their preferred brand (the first week),, low-yield cigarettes (the second week) and medium-yield cigarettes (the third week). Day urine samples were collected for cotinine analysis during the two last days of the test weeks. Puffing indices were reported on the last day of every test week with a portable microcomputer assisted analyzer with flowhead cigarette holder. Urinary cotinine concentrations were rather constant within the groups, but lower among the low-yield cigarette smokers as compared to the switchers (p less than 0.05). Also the female smokers had lower cotinine concentrations than the male smokers (p less than 0.05). The compensatory behavior seen in every smoking group while they were smoking low-yield cigarettes was based on up-regulation in single puff volume, puff duration and total smoking time when compared to values with medium-yield cigarettes. The correlation between cotinine concentration and diurnal puff volume (1/day) was poor. It is concluded that the benefit possibly gained with low-yield cigarettes is not long lasting. AA: (Auth. Abs.) AN:0022977 SN:811939 AU:Kozlowski, L.T. TI:(TO:) Applications of Some Physical Indicators of Cigarette Smoking. JN:Addictive Behaviors PG:6(3): 213-219 PY:1981 PD:1981 LA:English AB:Since abstinence may be an unrealistic goal for some smokers, the use of presumably less hazardous, low-yield cigarettes has been recommended. A cigarette is called low-yield if it delivers small amounts of tar and nicotine in a standard smoking machine assay. Unferxunately, machine-smoked yields are poor predictor s of a smoker's exposure to the toxic ingredients in tobacco. Many smokers who smoke low-yield cigarettes are not actually low-yield smokers, in that they use any of a number of compensatory smoking techniques to increase the yields of their cigarettes.. 40
Page 212: apt20e00
Compensatory smoking often takes place without the awareness of the smoker and can be very difficult for the smoker to monitor, even if trying to do so. Physical indicators of tobacco use should be appiied by smokers who are trying to reduce their exposure to tobacco. The application of information to be found in heart-rate changes and in changes in the appearance of spent filters should be considered. The physical indicators have the advantage of placing the responsibility for less hazardous smoking on the individual smoker, who potentially is the primary benefactor of low-yield therapy. The smoking of low-yield cigarettes should be recommended only when low-yield smoking has been confirmed in the individual smoker. (Auth. Abs. Mod.) AN:0021761 SN:810701 AU:Kozlowski, L.T. TI:(TO:) Tar and Nicotine Delivery of Cigarettes. What a Difference a Puff Makes. JN:Journal of the American Medical Association PG:245(2): 158-159 PY:1981 PD:January 9, 1981 LA:English AB:Variations in tar and nicotine delivery of cigarettes are discussed along with the difficulty involved in changing the yield and the effect of number of puffs on yield. A study of king-size filter cigarettes on standard smoking machines in 1978 produced the following results: 1.2 mg of nicotine and 18.6 mg of tar after 8.7 puffs. Similar cigarettes delivered 12.4 puffs in 1958. A decrease of 3.7 puffs was found from 1958 to 1978 (p<0.001). It is suggested that this decrease, which is controlled by burn-time of the cigarette, may be the actual cause of the lower yields claimed by low tar and nicotine cigarette manufacturers. With the same brand of cigarette, the tar yield varies as a function of number of puffs; 6 puffs, 13 mg; 8.7 puffs, 18 mg; 10 puffs, 21 mg; and 14 puffs, 30 mg. It is suggested that lower tar and nicotine intake can be better controlled by the smoker than by the cigarette. - AN:0022379 SN:811334 AU:Kozlowski, L.T. TI:(TO:) Smokers, Non-Smokers, and Low-Tar Smoke. (Letter). JN:Lancet PG:82'18(1): 508 PY:1981 PD:February 28, 1981, LA:English AB:Concern is expressed over the health implications'of exposure to the sidestream smoke from increasingly popular low-tar, low-nicotine brands of cigarettes. As noted, many smokers have turned to these less hazardous brands to reduce their tar and nicotine intake from smoking. This reduction in tar and nicotine content is achieved primarily through air dilution of the main smoke stream by using perforated paper or ventilated filters. Mainstream smoke may be diluted with up to nearly 80 percent air. However, sidestream smoke is subjected to no such dilution and thus provides no benefit to nonsmokers subjected to passive smoking. Moreover, since smokers of low-tar, low-nicotine cigarettes may, in some cases, increase the number smoked, the nonsmoker may even be at a greater disadvantage. AN:0026980 SN:820799 AU:Kozlowski, L.T. TI:(TO:) The Determinants of Tobacco Use: Cigarette Smoking in the Context of Other Forms of Tobacco Use. JN:Canadian Journal of Public Health PG:72(6): 396-401 41
Page 213: apt20e00
PY:1981 PD:November-December 1981 LA:English AB:All forms of tobacco consumption deliver nicotine to the central nervous system (CNS); however, the effect of the form of tobacco use on the chemical senses, and its social convenience, influences the choice of how the nicotine is delivered. Chewing tobacco and cigarettes may differ in their CNS effect and taste, but may be equivalent in their biological rewards. The current unfortunate bias for cigarettes (possibly the most toxic means of tobacco use) may be a result of cultural and psychosocial considerations rather than the nicotine bolus effect. Modes of tobacco use have changed over time; the antispitting laws of the late 1800s and early 1900s reduced the convenience of chewing tobacco, the then-preferred form. The ease of accommodation, such as cigarette use in an industrial society (faster than pipes), and the improvement of a portable source of fire influenced the popularity of the cigarette. The cigarette is the "fast food" of tobacco, and while cigarettes may not produce stronger addictions, their convenience has made it easier for more individuals to become addicted. It is rare to find tobacco used as an intoxicating drug in industrialized societies; thus, the "greater addictiveness" of cigarettes due to the nicotine bolus-delivery theory as opposed to sociocultural considerations is unlikely. AN:0030657 SN:840571 AU:Kozlowski, L.T. TI:(T0:) Physical Indicators of Actual Tar and Nicotine Yields of Cigarettes. SO:In: Grabowski, J.; Bell, C.S. (Editors). Measurement in the Analysis on Treatment of Smoking Behavior. U.S. Department of Health and Human Services, PHS, ADAMHA, NIDA Research Monograph 48, DHHS Publication No. (ADM) 83-1285 PG:pp. 50-61 PY:1983 PD:1983 LA:English AB:Problems inherent in the currently used' standards of average smoking patterns and the deficiencies of smoking machine assays are explored. These problems center around interindividual variability and interpersonal inconsistency in puff number, puff duration, puff volume, and vent-blocking behavior. As an alternative to the standard assay for determining smoke exposure, analysis of the tracks of tar stains left in cigarette filters is suggested. Photographic examination of stain patterns reveals hole-blocking, and color-matching techniques to grade stain intensity would indicate tar yield. The origins of the standard regimen, in the laboratory of the American Tobacco Company in the 1930s, are traced. AN:0041204 SN:89-8001 AU:Kozlowski, L.T. TI:(TO:) Evidence for limits on the acceptability of lowest-tar cigarettes. JN:American Journal of Public Health PG:79(2):198-9 PY:1989 PD:Feb 1989 LA:English AB:The sales of the lowest yield cigarettes (1-3 mg tar) seem to have been particularly resistant to the effects of promotion and advertising, while the sales of other low-yield cigarettes (4-9 mg tar) seem to have been increased by promotional efforts. This finding is consistent with the existence of a boundary of tar and nicotine acceptability below which consumers in general are not prepared to go. Use of lower tar cigarettes may be helpful for those who cannot stop smoking, but, sin'ee< 1979, the percentage of cigarettes under 16 mg tar has changed little. AA: (Auth. Abs.) 42
Page 214: apt20e00
AN:0049198 SN:93-0033 AU:Kozl'owski, L.T. TI:Rcrftction of tobacco health hazards in continuing users: individual behavioral and public health approaches. JN:Journal of Substance Abuse PG:I(3):345-357 PY:1989 PD:1989 LA:English AB:For those smokers who will not stop using tobacco, methods are discussed for reducing the risks to health of continued tobacco use. Overall, tobacco users are encouraged to reduce their exposure to tobacco toxins as much as they can tolerate. The boundary model of nicotine regulation implies that it is practical to prevent so- called needless excesses of nicotine intake. For continuing smokers of cigarettes, fewer cigarettes per day and very-low-tar cigarettes are encouraged, provided filter-vents are not blocked by the smoker. Better yet would be a switch to smoking one or two non-inhaled pipes or cigars each day. Even better would be a switch to use of the minimum acceptable amount of smokeless tobacco or nicotine- containing gum. Of course, the best course would be abstinence from any form of tobacco or nicotine use. Since relatively few tobacco users voluntarily engage in substantially less hazardous ways of using tobacco, public health measures (e.g., social restrictions, differential taxation, changes in package size)may be the most important means of bringing about less hazardous tobacco use among continuing users. AA: (Auth. Abs.) AN:0021333 SN:810246 AU:Kozlowski, L.T., Frecker, R.C., Khouw, V., Pope, M.A. TI:(TO:) The Misuse of "Less-Hazardous" Cigarettes and Its Detection: Hole-Blocking of Ventilated Filters. JN:American Journal of Public Health PG:70(1 l ): 1202-1203 PY:1980 PD:November 1980 LA:English AB:Smokers of 1!ow-yield, ventilated-filter cigarettes sometimes defeat the purpose of the smoke-dilution holes by including them with fingers, lips, or tape. Blocking the holes is shown to have large effects on the delivery by these cigarettes of toxic products (nicotine, tar, and carbon monoxide). Techniques for detecting this misuse of "less hazardous" cigarettes by smokers are discussed, with particular emphasis on the distinctive signs of hole-blocking which are left in the spent fidters. (Auth. Abs.) A N:0043100 SN:91-4665 AU:Kozlowski, L.T., Heatherton, T.F., Ferrence, R.G. TI:(TO:) Pack size, reported cigarette smoking rates, and the heaviness of smoking. JN:Canadian Journal of Public Health. Revue Canadienne de Sante Publique PG:80(4):266-70 PY:1989 PD:Jul-Aug 1989 LA:English AB:Three distinct samples show that pack size is highly associated with individual reports of daily cigarette intake, confirming an earlier report based on aggregate data. Those who report smoking 25 cigarettes per day (or who buy packs of 25) are heavier smokers than those who report smoking 20 cigarettes per day (or who buy packs of 20), as evidenced by greater likelihood of starting smoking earlier in the morning and by higher average levels of alveolar carbon monoxide. Categorizations based on number of cigarettes smoked per day should not assume that "one pack of twenties" is 43
Page 215: apt20e00
roughly the same as "one pack of twenty-fives." No conclusions can be drawn about whether the availability of larger packs promotes heavier smoking. AA: (Auth. Abs.) AN:0043209 SN:91-1429 AU:Kozlowski, L.T., Heatherton, T.F. Frecker, R.C., Nolte, H.E. TI:(TO:) Self-selected blocking of vents on low-yield cigarettes. JN:Pharmacology, Biochemistry and' Behavior PG:33(4):815-9 PY:1989 PD:Aug 1989 LA:English AB:Blockers of vents in ultra-low-yield cigarettes had higher levels of carbon monoxide (CO) and salivary cotinine than did nonblockers. None of the blockers reported that they blocked vents. Exposure differences seemed not to be due simply to vent blocking, but also to be the result of syndromes of heavier (blocking, more cigarettes per day, and starting earlier in the morning) or lighter smoking (not blocking, fewer cigarettes per day, and starting later in the morning). The results are interpreted in light of the boundary model. Cigarette smoking and brand selection should be studied as they occur naturally, as well as in experimentally contrived studies. AA:(Auth. Abs.) AN:0020842 SN:801568 AU:Kozlowski, L.T., Herman, C.P., Frecker, R.C. Tl:(TO:) What Researchers Make of What Cigarette Smokers Say: Filtering Smokers' Hot Air. JN:Lancet PG:1(8170): 699-700 PY 1980 PD:March 29, 1980 LA:English AB:Because of pervasive attention concerning the smoking habit and its health effects, it is not surprising to find that many smokers lie about their habit. For this very reason, withdrawal clinic researchers often use biological assays to confirm the patient's claim of stopping smoking. In one group of heart patients, for example, self-reports indicated that 63 percent no longer smoked, but urine assays indicated that 16-20 percent of these were still smoking, even 18 months after a heart attack. These misleading self-reports are not limited to smokers. People who are overweight, or who are guilty of other usually correctable behavioral sins are also likely to give similarly misleading self-reports. Apparently both smokers' statements and what researchers discern from these statements should be viewed with skepticism. AN:0039400 SN:88-1490 AU:Kozlowski, L.T., Pope, M.A., Lux, J.E. TI:(TO:) Prevalence of the Misuse of Ultra-Low-Tar Cigarettes by Blocking Filter Vents.. JN:American Journal of Public Health PG:78(6):694-695 PY:1988 PD:June 1988 LA:English AB:The prevalence of behaviorally blocked air dilution vents in ultra-low-yield cigarettes was evaluated using tar stain patterns in 135 cigarette butts discarded in public areas. Extreme air vent blocking was noted in 19 percent of filters, some degree of blocking in 39 percent, and no blocking in 42 percent. Hole-blocking did not differ for various tar yields. _ 44
Page 216: apt20e00
AN:0027949 SN:821768 AU:Kozlowski, L.T., Rickert, W.S., Pope, M.A., Robinson, J.C., Frecker, R.C. TI:(TL):) Estimating the Yield to Smokers of Tar, Nicotine, and Carbon Monoxide From the "Lowest Yield" Ventilated Filter-Cigarettes. JN:British Journal of Addiction PG:77(2): 159-165 PY:1982 PD:June 1982 LA:English AB:Results of interviews designed to assess the extent of blocking the holes of low-yield, ventilated-filter cigarettes, and results of a modified smoking machine which better estimates the yield of such cigarettes when they are smoked intensively, are presented. Interviews with 46 low-yield smokers show 52 percent admitting to having blocked the ventilation holes on these cigarettes at some time with either lips, fingers, or tape. Although only three smokers admitted blocking the holes at the present time, 41 percent (of the 39 who were observed smoking) gave evidence (by direct observation and by inspection of characteristic stain patterns on the filter) of currently blocking the holes. A modified smoking machine assay (a 24 sec, 47 ml puff, with a 44 sec interval, vent-holes blocked) demonstrated how much tar, nicotine, and carbon monoxide (CO) an average smoker might derive from the lowest yield cigarettes in the United Kingdom, Canada, and the United States. Compared with standard assays, tar yield increases from 15- to 39-fold, nicotine from 8- to 19-fold, and CO from 10-to 43-fold when ventilation is stopped. It is suggested that smokers be advised of the risks of blocking the holes of ventilated-filter cigarettes and taught how to detect whether they are doing it. The construction of low-yield cigarettes that will ensure low yields to smokers requires careful attention to the behavior of smokers (Auth. Abs. Mod) A N:0021427 SN:810344 AU:Kozlowski, L.T., Rickert, W.S., Robinson, J.C., Grunberg, N.E. TI:(TO:) Have Tar and Nicotine Yields of Cigarettes Changed? JN:Science PG:209(4464): 1' 550-1551 PY:1980 PD:September 26, 1980 LA:English AB:In official assays of the tar and nicotine yields of 12 popular brands of Canadian cigarettes, smoking machines took fewer puffs, on the average, in 1974 than in 1969. The decline in puffs appears to have been a major cause (p<0.01) of the reported reductions in tar and nicotine yields during this period. Two U.S. cigarette brands that were included in some or all of the surveys also showed significant correlations between puffs and tar (p<0.01). (Auth. Abs. Mod.) AN:0044131 SN:91-2604 AU:Kuller, L.H., Ockene, J., Meilahn, E., Svendsen, K.H. TI:(TO:) Relation of forced expiratory volume in one second (FEVI) to lung cancer mortality in the Multiple Risk Factor Intervention Trial (MRFIT). JN:American Journal of Epidemiology PG:132(2):265-74 PY:1990 PD:Aug 1990 LA:English AB:For men participating in the Multiple Risk Factor Intervention Trial, the authors evaluated the relation between the baseline forced expiratory volume in one second and lung cancer mortality among smokers between the third and tenth years of follow-up (1973-1974 to 1!984). This measure of ventilatory function was a powerful predictor of lung cancer deaths, with rates that increased' from 45
Page 217: apt20e00
3.02 per 1,000 person-years in the lowest quintal of forced expiratory volume to 0.43 in the highest quintal. This relation was not weakened by adjustments for smoking dose, including number of cigarettes smoked' per day, tar and nicotine content, duration of smoking, or age at onset of smoking. Nor was forced expiratory volume related to time between its determination and lung cancer death. If these observations can be verified in other studies, the forced expiratory volume in one second may identify smokers at very high risk of lung cancer and, hence, in need of more aggressive preventive approaches. AA: (Auth. Abs.) AN:0007860 SN:751258 AU:Llewellyn, O. P. TI:(TO:) Carbon Monoxide Yield of Cigarettes. (Letter). JN:British Medical Journal PG:3(5981): 487 PY:1975 PD:August 23, 1975 LA:English AB:In response to an earlier article reporting the results of carbon monoxide (CO) content analyses of several brands of cigarettes, the CO content of Planet cigarettes is discussed. Tests using an infrared' gas analyzer showed that Planet cigarettes give less CO than commercially available natural tobacco cigarettes used as controls. It is argued that the contribution of tar, nicotine, and CO to the health effects of cigarettes should not be allowed to obscure the effects of other substances present in tobacco smoke, such as cadmium, hydrocyanic acid, phenols, and aldehydes. In another comment, the use of Cytrel, a tobacco supplement, to lower tar, nicotine, and CO content of cigarettes is described. AN:0013506 SN:007785 AU:Lucchesi, B.R., Schuster, C.R., et at. TI:(TO:) The Role of Nicotine as a Determinant of Cigarette Smoking Frequency in Man With Observations of Certain Cardiovascular Effects Associated' With the Tobacco Alkaloid. JN:Clinical Pharmacology and Therapeutics PG:8(6): 789-796 PY:1967 PD:November-December 1967 LA:English AB:The effect of intravenously administered nicotine upon smoking behavior was studied in smokers who were unaware of the nature of the administered drug and the true purpose of the study. Smoking behavior was not altered significantly when nicotine was administered in a dose of 1 mg per hour for 6 hours. A significant decrease in smoking frequency was obtained when nicotine was administered at the rate of 2 to 4 mg per hour. Recordings of systolic blood pressure, heart rate, and the electrocardiogram indicate that the physiological alterations in these parameters produced by smoking can be reproduced by parenteral nicotine. AU:McBride, M.J., Guyatt, A.R., Kirkham, A.J., Cumming, G. TI:Assessment of smoking behaviour and ventilation with cigarettes of differing nicotine yields. JN:Clinical Science PG:67:619-631 PY:1984 LA:English AB:Nine established cigarette smokers were each studied four times, smoking two identical cigarettes on each occasion. After an acclimatization study, they smoked one of three types of cigarettes, either their usual brand or one of two types of special low tar cigarettes. These latter both ha8`tar yields of about 8mg with nicotine yields of 0.55 (LN) and 0.90 (MN)mg respectively. The test order was randomized between individuals and before using the special cigarettes the subjects were given a pack 46
Page 218: apt20e00
to accustornize themselves. While smoking each cigarette, magnetic tape recordings were made of puff rate, ventilation measured by respiratory inductive plethysmography (RIP) and nasal airflow measured with a modified oxygen cannula. The data were then processed digitally off-line. Salivary nicot ne and alveolar carbon monoxide levels were measured before and after smoking each cigarette, and the cigarette butt was analyzed for nicotine. While smoking behaviour varied considerably between the various subjects only small differences were seen between the different cigarette types in puff volume and duration and shape of the puff profile. Some changes in smoking behaviour occurred during the course of smoking a single cigarette, Ventilatory patterns showed consistent inter-subject differences but there were no apparent variations due to the various cigarettes. Most subjects puffed during an expiration with the buccal cavity closed off, and then took a slower, deeper inspiration breathing through the mouth. Others, however, took puffs at any point in the respiratory cycle. The different nicotine yields of the cigarettes produced marked changes in the butt and salivary nicotine measurements, but neither these, nor the changes in alveolar carbon monoxide, were closely related 'to ventilatory measurements. Possible explanations for these discrepancies are discussed. AN:0030100 SN:840009 AU:McCusker, K., Hiller, F.C., Wilson, J.D., Mazumder, M.K., Bone, R. TI:(TO:) Aerodynamic Sizing of Tobacco Smoke Particulate From Commercial Cigarettes. JN:Archives of Environmental Health PG:38(4): 2'15-218 PY:1983 PD:July-August 1983 LA:English AB:Aerodynamic sizing of smoke particulates was performed on a variety of commercial cigarettes using a single particle aerodynamic relaxation time (SPART) analyzer. Five cigarettes with filters and five without filters were tested from each brand. Smoke particles from all cigarettes were less than 0.6 mum mass median aerodynamic diameter (the particle number/puff increasing as the cigarette shortened). Filters on commercially available cigarettes reduced smoke particle concentrations by 20 to 96 percent for the cigarettes tested. After filtration of 96 percent of the particles in mainstream cigarette smoke, the concentration of smoke was 10**8 particles/cm**3. Some cigarettes rated as low-tar by the Federal Trade Commission had smoke particle concentrations in the range of those rated as medium-tar. Thus, tar content is not a measure of puff by puff smoke concentration_ Also, the ultimate respiratory tract deposition site of smoke particles is not affected by filters, since particle size was not altered by passing smoke through cigarette filters. Findings suggest that estimation of tar delivery to smokers from cigarettes should include puff number information. (Auth. Abs. Mod.) AN:0027956 SN:821775 AU:McManus, I.C., Weeks, S.J. TI:(TO:) Smoking, Personality and Reasons for Smoking. JN:Psychological Medicine PG:12(2): 349-356 PY:1982 PI7May 1982 LA:English AB:Contrary to the usual findings, smoking did not relate to extraversion but to psychoticism in this study of the relationships between smoking, reasons for smoking, and personality in 98 cigarette smokers. It is suggested that this relationship is the true one, and previous findings have been due to a contaminated measure of extraversion. Correlations were also discovered between extraversion and' tea and coffee intake as well as alcohol consumption:. Neuroticism was related to the amount smoked, and particularly to a willingness to give reasons for smoking. There was no relationship between the Reasons for Smoking Questionnaire results and attempts or success at giving up smoking. 47
Page 219: apt20e00
Smokers who rolled their own cigarettes were more introverted than others. No measure showed any significant relationship with the nicotine or tar content of cigarettes. (Auth. Abs. Mod.) AN:0010183 SN:770871 AU:Meade, T.W., Wald, N.J. TL•(TO:) Cigarette Smoking Patterns During the Working Day. JN:British Journal of Preventive and Social Medicine PG:31(1): 25-29 PY:1977 PD:March 1977 LA:English AB:The rates at which people smoke cigarettes during different periods of the day were obtained from three occupational groups. Group I consisted of those working at the main London production site of a food processing factory, Group 2 consisted of those in the administrative offices of the same company; there are smoking restrictions at both. Group 3 consisted of workers in the offices of a London borough where there are no smoking restrictions. Replies were received from 3,174 people, or 88 percent of those approached. There was a higher proportion of nonsmokers (over 70 percent) among the two groups of office workers than among the food processing workers (about 55 percent). Smokers in Group 3 recorded somewhat higher average cigarette consumption than those in Groups I and 2. During different periods of the day, the maximum hourly rate of cigarette smoking was about three times the minimum rate. For Groups I and' 2 the maximum rate occurred consistently during the interval between leaving work and going to bed.. In contrast, the maximum rate for Group 3 was consistently during the afternoon, while at work, and the rate between leaving work and going to bed was similar to the rate for the day as a whole. Results will help in deciding the time of day at which blood' for carboxyhemoglobin estimations should be taken. (Auth. Abs.) AN:0051701 SN:93-2536 AU:Meyer, J.A. TL•Cigarette century. JN:American Heritage PG:72-80 pp. PY:1992 PD:December 1992 LA:English AB:This article discusses the history of the cigarette and the increasing prevalence and treatment of lung cancer in the United States. In 1919 lung cancer was exceedingly rare. Until World War I, cigarette production remained stable. After the United States entered the conflict in 1917, millions of free cigarettes were delivered to the troops in France. The author states that this started a growing habit and that physicians began to notice the consequence of this habit by the 1930's. In 1932 it was postulated that the probable cause of this new epidemic of lung cancer was cigarette use. In 1930, the death rate from lung cancer among men was less than 5 per 100,000 population per year. By 1950 it had quadrupled to more than 20; today it is above 70. The death rate continues to rise, but there are definite signs that among men the rate of increase is diminishing as more men give up smoking. However, women's lung-cancer death rates are increasing and it is estimated that by the year 2000 more women than men will be dying of lung cancer. The 1964 Surgeon General's Report marked the beginning of stricter tobacco legislation regarding tobacco advertising and warnings labels on cigarette. The author concludes that (1) lung cancer remains the number-one killer among cancers; and (2) despite all the high-technology treatment methods, less than 10 percent of all lung cancer patients can be cured. Reproductions of actual advertisements from 1918 to 1936 are also presented in this article. ~~ 48
Page 220: apt20e00
AN:0020797 SN:801520 AU:Moody, P.M. TI:(T0:) The Relationships of Quantified Human Smoking Behavior and Demographic Variables. JN:Social Science and Medicine PG:14A(l): 49-54 PY:1980 PD:January 1980 LA:English AB:This study, based on a sample (na517) of adult medical patients at a southeastern medical center who were current users of cigarettes, reports the quantified aspects of smoking behavior and their relationship to sex, race, age, education, income, and socioeconomic status of these patients. Patients from lower socioeconomic groupings had a greater number of puffs, shorter intervals between puffs, longer puff duration, shorter cigarette butts, and more daily tar and nicotine intake than the subjects from upper socioeconomic groupings. Males and older patients had longer puff duration, greater puff volume, and more daily tar and nicotine intake than their counterparts. Implications of this and related studies upon the development of a social policy toward smoking and health are discussed. (Auth. Abs.) AN:0034844 SN:860876 AU:Moody, P.M. Haley, J.V. TI:(TO:) Quantified Human Smoking Behavior Among Various Disease Categories. JN:International Journal of the Addictions PG:20(5):751-761 PY:1985 PD:May 1985 LA:English AB:Patients with cancer and respiratory disease patients had longer puff durations and cancer patients tended to have higher tar delivery/cigarette than patients with other diseases, according to a smoking behavior study of 244 patients in, seven diagnostic categories. Patients with circulatory problems took longer to smoke a cigarette than patients with other diseases. Endocrine patients had the highest level of nicotine delivery/cigarette and cancer and respiratory patients the lowest. Patients (51 percent men and 49 percent women) ranged in age from 21 to 75 years (82 percent white, 18 percent nonwhite) and were classified as neoplasm (32), endocrine (31), blood problem (23), circulatory (66), respiratory (26), digestive (45), and genitou:rinary (21). Smoking characteristics for each diagnostic category are tabulated for cigarette puff duration, puff volume, puff interval, number of puffs, smoking time, number of cigarettes/day, tar delivery, and nicotine delivery. More detailed research is needed to determine if the relationships between smoking behavior and smoke deliveries have any cause--effect properties. (Auth. Abs. Mod.) AN:0050332 SN:93-1167 AU:Moreyra, A.E., Lacy, C.R., Wilson, A.C., Kumar, A., Kostis, J.B., et al. T1:Arterial blood nicotine concentration and coronary vasoconstrictive effect of low-nicotine cigarette smoking. JN:American Heart Journal PG:124(2):392-7 PY:1992 PD:Aug 1992 LLA:English AB:Low-nicotine cigarettes have been, advertised to the public as less harmful to the cardiovascular system. We studied the effects of smoking two low-nicotine cigarettes on arterial and venous blood nicotine levels, hemodynamics, and coronary vascular tone in 12 patients referred for diagnostic coronary arteriography. All were chronic smokers as evidenced by their elevated baseline arterial and 49
Page 221: apt20e00
venous cotinine blood levels (139 +/- 30 ng/ml and 155 +/- 34 ng/ml, respectively). High-resolution coronary angiograms were evaluated blindly before and after smoking. An electronic caliper was used to measure the diameter of disease-free coronary segments of the left anterior descending and circumflex arteries. Arterial nicotine levels rose from 5 +/- 1 ng/ml at baseline to 37 +/- 7 ng/ml (p less than 0.01) after the first cigarette was smoked and to 45 +/- 8 ng/ml (p less than 0.01) after the second cigarette. Yenous nicotine levels rose from 8 +/- 2 ng at baseline to 15 +/- 3 ng/ml (p less than 0.05) after the first cigarette and to 20 +/- 3 ng/ml (p less than 0.01) after the second cigarette. After the first cigarette heart rate increased 8+/- 2 beats/min(p less than 0.003) and double product 1229 +/- 400 beats/min x mm Hg (p less than 0.02). Compared to baseline values, after the second cigarette heart rate increased 9+/- 1 beats/min (p less than 0.001) and double product 1767 +/- 486 beats/min x mm Hg (p less than 0.01). Systolic, diastolic, and mean blood pressure did not change significantly after either the first or second cigarette. AA (Auth. Abs.) AU:Nil, R., Battig, K. TI:Separate effects of cigarette smoke yield' and smoke taste on smoking behavior. JN:Psychopharmacolog PG:99:54-59 PY:1989 AB:The purpose of this experiment was to compare independently the influence of different cigarette smoke taste categories and different machine standard smoke yield values on cigarette smoking behavior and related subjective measures. In six separate sessions 15 regular smokers were presented with a medium and a low smoke yield cigarette of each of the three taste categories, mentholated, dark (Gauloises) and blond (Muratti) tobacco. Each session included a"natural" and a"forced" smoking procedure of one cigarette type only. Forced smoking consisted of smoking 30 puffs whereby a new half-length cigarette was presented after every third puff. During the seventh session, habitual brand cigarettes were smoked as a reference. The sessions followed in weekly intervals, and the subjects became familiar with the test cigarettes during the last 5 days preceding each test session. Although general acceptability of the cigarettes, smoking satisfaction and pleasantness of taste were clearly lower for all test cigarettes as opposed' to the habitual brand reference cigarettes, these measures remained unaffected by taste or smoke yield of the test cigarettes. Harshness of smoke was higher in the dark tobacco category and' general'ly decreased with the lower smoke yield cigarettes. Independent effects of taste and smoke yield were obtained for total puff volume, inhalation time and CO absorption, suggesting a compensatory intensification of smoking behavior for low yield cigarettes and an independent increase of smoking intensity from mentholated to dark tobacco to blond tobacco. The results suggest therefore that factors which affect cigarette smoke taste have effects on smoking behavior which are separate from those obtained by comparing smoke yields. A N:0050916 SN:93-1751 AU:NiC, R., BAttig, K., Ney, T., Gale, A. TI:Smoking behaviorr a multivariate process. SO:In:Smoking and human behavior. Ney, T.; Gale, A. (Editors). New York, New York, John Wiley and Sons Ltd. PG:199-221 pp. PY:1989 PD:1989 LA:English AB:This chapter examines smoking behavior as a multivariate process. Multivariate assessments of smoking behavior reveal low levels of interrelationships between single measures. This suggests that multiple modes of control operate to determine smoking behavior. The authors of this chapter assert that smoking behavior is a process involving several steps: (1) Selection of the type of cigarette, (2) frequency of smoking, (3) intensity of puffing, (4) intensity of inhalation, and (5) atgiorption of smoke constituents into the Wooa. They suggest that interindividual variance in smoking behavior reflects individual differences in the relative importance of the several determinants of smoking. Apart from nicotine, which seems to act in a differential way depending on the route of 50
Page 222: apt20e00
administration and dose, and individual sensitivity (tolerance effects), the authors conclude that non-nicotinic smoking motives deserve more attention in future research. Sections in this chapter address (1) measures of smoking behavior, (2) measurement of respiratory inhalation; (3) biochemical markers of smoke absorption; (4) regional deposition of smoke particles in the respiratory system; (5) physiological responses to smoking as a measure of smoke uptake; (6) interdependence of different smoking behavior variables; (7) determinants of smoking behavior and regulatory mechanisms of smoke intake; (8) multivariate attempts to separate effects of cigarette nicotine, tar, and carbon monoxide; (9) ratios of nicotine, tar, and' carbon monoxide; (10) the role of nicotine in the maintenance of smoking behavior; (11) individual variability in smoking behavior; and (12) future research trends. AU:Nil, R., Buzzi, R., Battig, K. TI:Effects of different cigarette smoke yields on puffing and inhalation: Is the measurement of inhalation volumes relevant for smoke absorption? JN:Pharrnacology, Biochemistry and Behavior PG:24:587-595 PY:1986 LA:English. AB:Puffing patterns (number of puffs, puff volume, puff duration, puff interval, peak pressure, peak flow, peak latency), respiratory smoke inhalation (postpuff inspiratory latency, volume and time and postpuff expiratory volume and time), and the pre- to postsmoking boost of tidal air CO concentration were analyzed in 117 regular smokers. They smoked both a cigarette of the habitual brand and a second cigarette of a brand with about 40 to 50% lower machine standard yields and the most similar taste quality. The pre- to postsmoking CO boost remained unrelated to the smoke deliveries of the cigarettes in both comparisons (interindividual and switching). Estimated mouth intake of nicotine was strongly dependent on the smoke yield variables of the cigarettes but remained uncorrelated' with CO absorption. The discrepancy between mouth smoke intake and alveolar smoke absorption could be explained by the volumes or durations of the postpuff respiratory cycle. Multiple regression analyses suggested differetial modes of control for the daily number of cigarettes smoked, for the patterns of puffing, for respiratory inhalation, and finally for alveolar CO absorption. The results are discussed in relation to the dynamics of puffing and inhalation and their possible relevance for tobacco-related diseases. AU:Nil, R., Woodson, P.P., B3ttig TI:Smoking behaviour and personality patterns of smokers with low and high CO absorption. JN:Clinical Science PG:71(5):595-603 PY:1986 LA:English AB:The present experiment describes an attempt to select differentially nicotine dependent smokers by means of an objective and non-invasive measure of cigarette smoke CO absorption. Toward this goal the differences in expiratory tidal air CO concentration before and after smoking a single cigarette (tidal CO boost) were measured in three experimental sessions. The selection criteria were tidal CO boosts greater than 3.5 p.p.m. and less than I p.p.m. According to these criteria 19 out 171 subjects were consistently found to be high CO absorbers and 20 were found to be low CO absorbers. Puffing behaviour was measured throughout all three test sessions by the flowmeter method and respiratory inhalation by thorax impedance plethysmography. In addition, heart rate was continuously measured during smoking. These data were used to assess for specific differences between the two extremes of inhalation behaviour. High CO absorbers differed from low CO absorbers by more intensive patterns of puffing and respiratory inhalation, by higher daily cigarette and coffee consumption, by lower alcohol consumption, by shorter latencies to the first cigarette in the morning, by greater subjective need for smoking and by lower scores for healthy eating habits. No intergroup differences were observed for smoking induced heart rate acceleration. The high CO absorbers were significantly older than the low CO absorbers; however, no evidence was found that any of the differences in smoking style between the two extremes might be related to their differences in age. 51
Page 223: apt20e00
No differences were seen in cigarette strengths, in personality or in coronary prone behaviour as assessed by means of standardized questionnaires in all subjects. It is concluded that nicotine plays a more important role in smoking motivation among the high than among the low CO absorbing smokers. The role of nicotine and the individual dosage absorbed by the smokers, however, remain to be analyzed further and are discussed in the light of nicotine tolerance effects. AU:Ossip-Klein, D.J., Martin, J.E., Lomax, D., Prue, D.M., Davis, C.J. TI:Assessment of smoking topography generalizatikon across laboratory, clinical, and naturalistic settings. JN:Addictive Behaviors PG:8(1):11-17 PY:1983 LA:English AB:A three-study series was conducted to examine smoking topography across clinical, laboratory, and naturalistic settings for 24 smokers who were patients in an alcohol treatment program. Experiments I and 2 included surreptitious observation of smoking in group therapy sessions (naturalistic), and obstrusive observation of smoking in a smoking clinic setting. The third study added a laboratory smoking condition to the clinic and group conditions. Puffing patterns in clinical and laboratory settings tended to be similar, and both differed from smoking in the naturalistic setting. Subjects generally took more puffs, longer puffs, and had shorter cigarette durations in clinical and laboratory settings than in the naturalistic setting. The implications of these findings for assessment of intake and health risk are discussed. AN:0042496 SN:91-1320 AU:Pomerleau, C.S., Majchrzak, M.J., Pomerleau, O.F. TI:(TO:) Paced puffing as a method for administering fixed doses of nicotine. JN:Addictive Behaviors PG:14(5):571-5 PY:1989 PD: 1989 LA:English AB:Smokers' ability to regulate nicotine intake by varying topographical parameters such as depth of inhalation and number of puffs makes it difficult to administer standardized doses of nicotine as delivered from smoking. A number of studies have claimed to control these parameters without confirming the effectiveness of such procedures by measures of plasma nicotine. The purpose of the present study was to determine whether specifying onset and duration of each puff would result in accurate dosing. Plasma nicotine boosts for five paced puffers were compared across two sessions and with similar data for five free smokers. Neither between-subject consistency nor within-subject reproducibility was improved by this paced puffing procedure, despite apparent topographical control. AA:(Auth. Abs.) A N:0049646 SN:93-0481 AU:Pomerleau, C.S. Pomerleau, O.F. TLEuphoriant effects of nicotine in smokers. JN:Psychopharmacology PG:108(4):460-5 PY:1992 PD:1992 LA:English AB:Two studies were conducted to replicate and extend previous demonstrations of smokinginduced, dose-related reports of euphoria, r.r.W to confirm this relationship using measures of plasma nicotine. In experiment 1, overnight-deprived subjects, in three different sessions, smoked ultralow-, high-nicotine, and usual-brand cigarettes. In experiment 2, ultralow-, medium-, and high-nicotine 52
Page 224: apt20e00
cigarettes were used, and plasma nicotine was measured. In both studies, subjects were asked to depress a button during euphoric sensations. Number of sensations for the ultralow-nicotine cigarette was significantly lower than for the high-nicotine cigarette in the first study, and than for both the mediuta-and high-nicotine conditions in the second; a significant linear trend was observed for number of sensations as a function of plasma nicotine level in the second study. For the high-nicotine cigarette, 19 of 22 subjects experienced at least one sensation (mean around three), starting around 2.5 min after lighting up. Together, these studies support the existence of a dose-response relationship for nicotine-induced euphoric sensations; suggest that they are more pronounced following overnight abstinence than following minimal deprivation, and in more dependent smokers; and characterize in detail the temporal features of these sensations. AA: (Auth. Abs.) AN:0032745 SN:850688 AU:Pomerleau, O.F. Pomerteau, C.S. TI:(TO:) Neuroregulators and the Reinforcement of Smoking: Towards a Biobehavioral Explanation. JN:Neuroscience and Biobehavioral Reviews PG:8(4):503-513 PY:1984 PD:Winter 1984. LA:English AB:On the basis of the neuroregulatory effects of nicotine, a unified hypothesis to explain the persistence of smoking behavior is formulated. Because nicotine alters bioavailability of several behaviorally active neuroregulators (including acetylcholine, norepinephrine, dopamine,, beta-endorphin, and vasopressin), it is proposed that nicotine is "used" by smokers to produce temporary improvements in performance or affect. Under this formulation, a potentially large number of exteroceptive and interoceptive cues unrelated to the nicotine-dependence cycle may serve as discriminative stimuli for smoking, over and above smoking to terminate or avoid withdrawal. The rapid action of nicotine, and its diverse neuroregulatory effects, renders it particularly effective as a"eoping response" to the demands of daily living. Of special interest is a biphasic pattern of arousal/alertness during smoking followed by calming/tension- reduction after smoking, which may result from cholinergic/catecholaminergic activation followed by cholinergic blockade or beta-endorphin release. Apparently smokers can adjust nicotine intake to selectively enhance the effects, which may add to the appeal of smoking. (Auth. Abs. Mod.) AN:0027325 SN:821144 AU:Prue, D.M., Krapfl, J.E., Martin, J.E. TI:(TO:) Brand Fading: The Effects of Gradual Changes to Low Tar and Nicotine Cigarettes on Smoking Rate, Carbon Monoxide, and Thiocyanate Levels. JN:Behavior Therapy PG:12(3): 400-416 PY:198'1 PD:June 1981 LA:English AB:When smokers gradually and progressively reduce the tar and nicotine intake of their cigarette, it is demonstrated that there are corresponding decreases in the poisonous gas intake as indicated by decreased carbon monoxide (CO) and saliva thiocyanate (SCN) levels. The effects of progressive reductions in the tar and nicotine content of cigarettes consumed by individuals in a smoking treatment program were examined in nine smokers (five males and' four females) by monitoring CO levels, SCN levels, and consumption rate. Reductions were made by changing the smokers' brands of cigarettes every 2 weeks until smokers were consuming cigarettes with 3.0 mg or less of tar and 0.4 mg or less of nicotine. The data show that, although smokers occasionally had higher levels of CO or SCN during brand fading, no smoker sustained increases over baseline levels while smoking cigarettes with less than 3.0 mg tar and 0.4 mg nicotine. The change in mean level from baseline to final brand change condition represents a 46 percent decrease for CO level and a 44 percent decrease 53
Page 225: apt20e00
for SCN level. Even smokers who showed increased rates of cigarette consumption had decreased levels_of these poisonous gases. AU:Puustinen, P., Olkkonen, H., Kolonen, S., Tuomisto, J. TI:Microcomputer-aided measurement of puff parameters during smoking low- and medium-tar cigarettes. JN:Scandanavian Journal of Clinical Laboratory Investment PG:47:655-660 PYa 987 LA:Finland AB:A portable microcomputer-assisted flow transducer was developed for analysing puff parameters during smoking of low- and medium-tar cigarettes. Smoke flow was determined by measuring pressure difference between two sites within an orifice flowmeter. According to the Bernoulli equation, the pressure difference is proportional to the square of flow. For calibration of the method, various sizes of air volumes were puffed through the flowmeter by a pisto syringe. The calibration curve, which consisted of the flow as a function of the square root of pressure difference, was linear (r=0.98). The automatic microcomputer analysis consists of the following variables: mean flow and mean volume of inhaled smoke gas, puff duration, time interval between two puffs, number of puffs and' total volume inhaled. Eight volunteers smoked 10 low- and 10 medium-tar cigarettes during the cross-over experiments. The investigation indicated that the total inhalation volume of smokers in the case of low-tar cigarettes is twice as large as in the case of medium-tar cigarettes. AN:0032381 SN:850324 AU:Rawbone, R.G. Tt:(TO:) Switching to Low Tar Cigarettes: Are the Tar League Tables Relevant? JN:Thorax PG:39(9):657-662 PY:1984 PD:September 1984 LA:English AB:In an attempt to verify the relevance of British tar league tables as a guide to tar exposure, 134 middle-tar and' 134 low-tar smokers responded to a questionnaire concerning smoking habits and returned 24-hour butt collections for analysis. Tar delivery, measured indirectly by butt nicotine analysis, was compared with league tables. Analyses confirmed partial compensation by low-tar smokers relative to middle-tar smokers, resulting in 32 percent lower tar delivery rather than the 46 percent expected from the standard smoking machine values. Middle-tar smokers (98 percent) achieved an estimated tar delivery within or below that of the league table middle-tar band, while 70 percent of low-tar smokers had a mouth intake of 10.49 mg or less, within the low-tar band. Results support the tar league tables as a guide to the smoker in selecting a lower delivery cigarette. (Auth. Abs. Mod.) AN:003615:1 SN:870191 AU:Rawbone, R.G. TI:(T(Y) The Act of Smoking. JN:Ettore Majoraha International Science Series. Life Sciences PG:17:77-91 PY:1984 PD:1984 LA:English AB:Cigarette smoking is a complex activity that can be studied in terms of detailed measprements of smoking characteristics (e.g., puffing parameters and inhalation) -as well as in terms of the delivery and uptake of smoke components. Measurement of human smoking profiles has demonstrated that different products may be smoked differently. In particular, low-tar cigarettes are smoked more 54
Page 226: apt20e00
intensively than medium-tar cigarettes, thus offsetting reductions in tar delivery expected from standard machine smoking values. Differences in smoking patterns have been attributed to smokers' needs, but evidence is presented indicating that individual smokers smoke to a constant amount of work.,This suggests that the type of cigarette may have an important role, with pressure drop characteristics inversely related to puff volume during smoking. Whatever the interaction between the smoker and the product in determining smoking behavior, the resulting tar intake of low-tar smokers remains significantly lower than that of medium-tar smokers. (Auth. Abs. Mod.) AN:0027960 SN:821779 AU:Rawbone, R.G., Guz, A. TI:(TO:) Cigarette Smoking Among Secondary Schoolchildren 1975-79. JN:Archives of Diseases in Childhood PG:57(5): 352-358 PY:1982 PD:May 1982 LA:English AB:Smoking patterns found among schoolchildren; in the London borough of Hounslow suggested that awareness of several smoking-associated health risks was not altogether effective in reducing smoking. A questionnaire relating to smoking habits, respiratory symptoms, and health attitudes was administered to schoolchildren aged I I to 17 throughout a defined geographical area in both 1975 and 1979, with a valid response from 10,498 and 12,002 young people, respectively. Each cohort was almost entirely different. The results suggest that although the prevalence of regular smoking has decreased in boys from 16 to 13 percent, it has increased in girls from 13 to 14 percent, and that at all ages more girls smoke than boys. However, despite the fail in the prevalence of regular smoking in boys there has been an overall increase in cigarette consumption. Young people who are regular smokers predominantly smoke middle-tar cigarettes while among experimental smokers there is a high incidence of low-tar smoking, which might suggest that suchcigarettes facilitate the taking up of the habit by children. The previously described relationships between smoking and respiratory symptoms were confirmed. During the 4-year study period young people's knowledge of the association between lung cancer and smoking remained high. Their knowledge of the associated links between smoking and heart disease and stroke increased appreciably. For "chestiness" and bronchitis, the reported knowledge remained steady. It is suggested that specific health education during the years 1975-1979 has not been successful, and there is the need for research. (Auth. Abs. Mod.) A N:0021040 SN:801785 AU:Rawbone, R.G., Murphy, K., Tate, M.E., Kane, S.J. TI:(TO:) The Analysis of Smoking Parameters: Inhalation and Absorption of Tobacco Smoke in Studies of Human Smoking Behaviour. SO:In: Thornton, R. E. (Editor). Smoking Behaviour. Physiological and Psychological Influences . Edinburgh, Churchill Livingstone PG:pp. 171-194 PY:1978 PD:1978 LA:English AB:The techniques that may be used to determine how people smoke and what constitutes smoke uptake and retention, and the relationship between them, are discussed. The results of experiments to study differences between habitual middle-tar and low-tar smokers are described, as well as the effects of switching between middle- and low-tar products. Various smoking parameters are measured, including cigarette characteristics, puff parameters, inhalation, and' carbon monoxide (CO) in expired air. It was found that there was no correlation between the dose of tobacco smoke presented to the smoker (estimated from butt nicotine analysis) and the amount of smoke absorbed by the smoker (measured by increments in alveolar CO levels). A significant correlation (p<0.05) was found between the amount of smoke absorbed by the smoker and the smoke exposure index derived 55
Page 227: apt20e00
from the volume and time periods of inhalation following the puffing of a cigarette. No demonstrable differences in inhalation patterns were found between habitual smokers of middle- and low-tar cigarettes. Some evidence was found in switching studies that smokers adjust their smoking to maintain a constant dose of cigarette smoke. The smoker can and may modify smoking parameters and hence modify the quality and/or the quantity of smoke when smoking a particular product. AN:0027514 SN:821333 AU:Rees, P.J., Higenbottam, T., Clark, T.J.H. TL•(TO:) Responses to Cigarettes of Various Tar Contents. JN:British Journal of Diseases of the Chest PG:76(2 ): 143-146 PY:1982 PD:Apri1 1982 LA:English AB:When airway resistance measurements are made 3 to 10 min after smokers have smoked a cigarette in their usual fashion, significant broncho constriction has been found to be uncommon. Specific conductance was measured before and within 10 min of smoking a cigarette in 36 smokers on 210 occasions. Five types of cigarettes were used including the equivalent of a 1956 uunfiltered cigarette. Cigarettes were smoked in the smokers' usual fashion. Significant decreases in specific conductance occurred on only 19 occasions in 13 subjects and were most frequent with the cigarette with the highest tar content currently available. Examination of the overall results shows the only significant change to be an, increase in specific conductance in the control, nonsmoking period. It is concluded that irritant qualities of tobacco smoke increase with tar content but airway narrowing lasting up to 10 minutes is an uncommon event when cigarettes are smoked normally. Most smokers adapt to or avoid any sustained acute airway response to tobacco smoke whatever its tar content: (Auth. Abs. Mod.) AN:0030512 SN:840423 AU:Rickert, W.S. TI:(TO:) "Less Hazardous" Cigarettes: Fact or Fiction? JN:New York State Journal of Medicine PG:83(13): 1269-1272 PY:1983 PI7December 1983 LA:English AB:While smokers of low-yield cigarettes may be at reduced risk of death from lung cancer, myocardial infarction risk is not lower and overall health risks are reduced far less than anticipated. Low-yield cigarettes are often as hazardous as higher yield brands due to the tendency, ascribed to nicotine dependency, to block filter vents (a practice admitted by half of Iow-tar cigarette smokers) and to increase puff volume and/or depth of inhalation. Furthermore, air dilution devices reduce mainstream yields to the smoking machine, but not sidestream yields to the environment. In addition,, human smoking behavior is so variable that it is doubtful whether a single set of conditions for machine smoking can provide reasonable values for smoke constituents such as hydrogen cyanide (HCN). The range of constituent levels for a single cigarette brand is greater than the range recorded for all 115 cigarette brands tested. Nevertheless, response of health conscious consumers to low-tar brands has been extraordinary, with the low-tar (less than or equal to 15 mg) segment in the United States tripling from 17 percent in 1976 to 59 percent in 1982. A similar pattern has been observed in Canada. Changes in cigarette yields from 1969 to 1982 are described, and health effects of CO, carboxyhemoglobin levels, nicotine, aldehydes, and HCN, are discussed. 56
Page 228: apt20e00
AN:0035657 SN:861647 AU:Rickert, W.S., Collishaw, N.E., Bray, D.F., et al. TI:('IFCf) Estimates of Maximum or Average Cigarette Tar, Nicotine, and Carbon Monoxide Yields Can Be Obtained From Yields Under Standard Conditions. JN:Preventive Medicine PG:15(1):82-91 PY:1986 PD:January 1986 LA:English AB:Average yields of tar, nicotine, and carbon monoxide per liter of smoke and per cigarette were determined for 10 brands of cigarettes smoked under 27 different conditions (l standard, 26 nonstandard). Per cigarette yields were highly variable across smoking conditions owing to differences in total volume of smoke taken for analysis. The results of a simple linear regression analysis indicated that up to 95 percent of variation in tar yield per cigarette could be explained by variations in total volume of smoke produced per cigarette. Per liter yields for tar, nicotine, and carbon monoxide were almost constant over the conditions investigated. Since most smokers inhale less than this amount, yields per liter provide a rough estimate of the maximum amount to which a smoker might be exposed. Yields per liter, taken over all 26 conditions, were highly correlated with per cigarette yields under standard conditions. Consequently, values on one scale can be converted to the other, at least for the 10 brands investigated. The average conversion factor for tar, nicotine, and carbon monoxide is 2.5 when, proceeding from milligrams per king-size cigarette under standard conditions to milligrams per liter. This relationship is true for both vented and nonvented cigarettes when ventilation holes are not blocked. (Auth. Abs.) AN:0022407 SN:811362 AUiRickert, W.S., Robinson, J.C. TI:(TO:) Estimating the Hazards of Less Hazardous Cigarettes. IL Study of Cigarette Yields of Nicotine, Carbon Monoxide, and Hydrogen Cyanide in Relation to Levels of Cotinine, Carboxyhemoglobin, and Thiocyanate in Smokers. JN:Journal of Toxicology and Environmental Health PG:7: 391-403 PY:1981 PD:1981 LA:English AB:Yields of chemical constituents such as tar, nicotine, CO, and HCN, defined by smoking machines, are commonly assumed to provide a reasonable indication of the relative hazard associated with smoking a given brand of cigarette. Results reported here suggest that this assumption should be carefully reexamined. A total of 240 subjects, representing a wide range of smoking and brand characteristics, were recruited for an investigation of possible relationships between brand yields and exposure (levels of carboxyhemoglobin, breath CO, plasma cotinine, plasma thiocyanate, and saliva thiocyanate). Exposure was highly correlated with consumption (number of cigarettes per day), but there was no correlation between any estimate of exposure and brand yield when level of consumption was held constant. In addition, a comparison of levels of carboxyhemoglobin and plasma thiocyanate for 16 smokers of "low-hazard" and 15 smokers of "high-hazard" cigarette brands revealed little difference between the two groups, even though average cigarette yields differed as much as two- to three-fold. A possible explanation for the results may be that current values for average puff volume, duration, and' interval differ significantly from those used in programming smoking machines, particularly in the case of brands with low-nicoti~ne delivery. (Auth. Abs.) 57
Page 229: apt20e00
AN:0022406 SN:8l 1361 AU:Rickert, W.S., Robinson, J.C: TI:(TO:) Yields of Selected Toxic Agents in the Smoke of Canadian Cigarettes, 1969 and 1978. A Decade of Change? JN:Preventive Medicine PG:10(3): 353-363 PY:1981 PD:May 1981 LA:English AB:Canadian sales-weighted averages of cigarette carbon monoxide (CO) and tar have been evaluated for the decade ending 1979. Virtually no change occurred up to 1976; between 1976 and 1979 the sales-weighted average CO dropped from 21 to 16 mg with a much smaller decrease in the corresponding values for tar (16.1 to 1'4.4 mg). Thus, changes in CO deliveries did not take place at the same rate as changes in tar deliveries. If standardized smoking machine yields are related to the risk of smoking-related morbidity and mortality, the low correlation and the 8-year lag time in the curves describing the decrease in two of the major toxic constituents of cigarette smoke may be of importance in helping to explain a lower impact of less hazardous cigarettes on coronary heart disease (CHD), rates. Assuming that exposure to CO is a risk factor for CHD, the relatively recent reduction insales-weighted CO yields might have the effect of decreasing CHD rates among smokers in the future. In addition to CO yields, HCN, acrolein, and total aldehyde yields of 25 brands of cigarettes manufactured in 1969 were compared with yields of the same cigarettes manufactured in 1978 to assess changes which may have occurred in other gas phase constituents. Significant decreases were noted in the yields of all constituents other than CO; the average decrease per brand was HCN, 69 mug; total aldehydes, 114 mug; and acrolein, 5.2 mug. AN:0033972 SN:860004 AU:Rickert, W.S., Robinson, J.C., Bray, D.F., et al. TI:(TO:) Characterization of Tobacco Products: A Comparative Study of the Tar, Nscotine, and Carbon Monoxide Yields of Cigars, Manufactured Cigarettes, and Cigarettes Made From Fine-Cut Tobacco. JN:Preventive Medicine PG:14(2):226-233 PY:198S PD:March 1985 LA:English AB:Tar, nicotine, and carbon monoxide yields of selected Canadian brands of manufactured and hand-rolled cigarettes and small and large cigars were compared. To control for varying volumes of smoke delivery, standardized comparisons were made in milligrams of toxic substance per liter of smoke.Mean deliveries of smoke and tar, nicotine, and carbon monoxide were highest for small cigars, followed by hand-rolled and manufactured cigarettes. Large cigars had the lowest yield per liter. However, the mean number of puffs varied from 108 for large cigars to 9.3 for manufactured cigarettes. Mean yields of tar per unit smoked were 38.1 for small cigars (standard error (SE)=5.3), 17.5 (SE-2.4) for large cigars, 21.1 (SE-A.57)for hand-rolled cigarettes, and 9.4 (SE-1.9) for manufactured cigarettes. Five out of six brands of cigarettes handmade from fine-cut tobacco delivered significantly more tar, nicotine, and carbon monoxide per cigarette or per liter than did the identically named manufactured brand. (Auth. Abs. Mod.) AN:0030456 SN:840365 AU:Rickert, W.S., Robinson, J.C., Collishaw, N.E., Bray, D.F. TL•(TO:) Estimating the Hazards of "Less Hazardo+ls" Cigarettes. 111. A Study of the Effect of Various Smoking Conditions on Yields of Hydrogen Cyanide and Cigarette Tar. JN:Journal of Toxicology and Environmental Health 58
Page 230: apt20e00
PG:12(1): 39-54 PY:1983 PD:July 1983 LA:Ehglish AB:A cigarette brand with, nominal tar and nicotine yields (4.0 mg and 0.4 mg, respectively) was examined under various machine-smoked conditions reflecting the wide range of human smoking behavior. Three levels of each of five smoking parameters (butt length, puff duration, puff interval, puff volume, and ventilation occlusion) were examined. The effects on puff number and total particulate matter (TPM) as well as gas phase, particulate phase, and total hydrogen cyanide (HCN) yields were estimated. Yields of HCN (a ciliatoxic agent) and TPM varied significantly under different smoking conditions. Ventilation occlusion had the most pronounced effect, accounting for 34 percent of the response variation of TPM yields and 42 percent of the response variation for total HCN yields. Testing of 115 brands produced total HCN yields from 2 to 233 mug/cigarette(a range less than that observed for a single brand smoked under various nonstandard conditions), providing a possible explanation for the previously noted lack of correspondence between HCN yields under standard conditions and levels of thiocyanate in samples of smokers' plasma and saliva. In addition, HCN yields and efficiency of filters in removing HCN were examined under standard smoking conditions. Acetate filters, the most common variety, were found to remove an average of about 14 percent of the HCN from mainstream smoke. (Auth. Abs.) AN:0031089 SN:841003 AU:Rickert, W.S., Robinson, J.C., Collishaw, N: TI:(TO:) Yields of Tar, Nicotine, and Carbon Monoxide in the Sidestream Smoke From 15 Brands of Canadian Cigarettes. JN:American Journal of Public Health PG:74(3): 228-231 PY:1984 PD:March 1984 LA:English AB:Sidestream smoke yields for 15 brands of cigarettes were determined under conditions where mainstream yields were approximately equal to those used to determine the values that appear on packages of Canadian cigarettes. Sidestream yields of tar, nicotine, and carbon monoxide were much higher than mainstream yields for all brands tested. The average sidestream-to-mainstream ratios for the 1!5 brands were 3.5, 6.6, and 6.8 for tar, nicotine, and carbon monoxide, respectively. The highest sidestream yields were obtained from brands with the lowest mainstream yields. (Auth. Abs.) AN:0020876 SN:801603 AU:Rickert, W.S., Robinson, J.C., Young, J.C. TI:(TO:) Estimating the Hazards of "Less Hazardous" Cigarettes. I. Tar, Nicotine, Carbon Monoxide, Acrolein, Hydrogen Cyanide, and Total Aldehyde Deliveries of Canadian Cigarettes. JN:Journal of Toxicology and Environmental Health PG:6(2): 351-365 PY:1980 PD:March 1980 LA:English AB:The tar, nicotine, carbon monoxide (CO), hydrogen cyanide, total aldehyde, and acrolein deliveries of 102 brands of Canadian cigarettes have been determined. On the basis of these deliveries, 15 brands (9 percent of sales) were categorized as low hazard, and 9 brands (10 percent of sales) as high hazard. All six constituents were used for the classification as tar was a poor indicator of gas phase deliveries for most brands. As a result, smokers who indiscriminately switch to a brand with a lower tar delivery may inadvertently increase their exposure to gas phase constituents such as CO and increase their risk of smoking-related pathology. With respect to Canadian cigarettes, the choice of a 30-mm standard butt length may result in omission of some of the available tobacco from 59
Page 231: apt20e00
the testing procedure, reducing the value of tar level as a guide to choosing a less harmful cigarette. (Auth. Abs.) AN:0031410 SN:841324 AU:Rickert, W.S., Robinson, J.C., Young, J.C., Collishaw, N.E., Bray, D.F. TI:(TO:) A Comparison of the Yields of Tar, Nicotine, and Carbon Monoxide of 36 Brands of Canadian Cigarettes Tested Under Three Condi±ions. JN:Preventive Medicine PG:12(5): 682-694 PY:1983 PD:September 1983 LA:English AB:Although the trend toward cigarettes with low average deliveries of toxic substances may result in reduced health risks for some people, switching to low-yield cigarettes may not reduce the risk for smokers who smoke these products intensively. Thirty-six brands of Canadian cigarettes, including 28 with ventilated filters, were tested under standard smoking machine conditions and two other conditions to determine how yields of tar, nicotine, and carbon monoxide change when cigarettes are manipulated to increase smoke intake. While the rank order yield of tar, nicotine, and carbon monoxide was preserved, the average yield of all three substances more than doubled when cigarettes were smoked intensively in comparison with standard smoking. Findings emphasize the need to consider the dependency of tar--nicotine ratios on smoking conditions when assessing the proposed advantages of a medium-nicotine, low-tar cigarette. (Auth. Abs. Mod.) A N:0022245 SN:811198 AU:Robinson, J.C., Forbes, W.F. TI:(TO:) Studies on the Nicotine Exposure of Individual Smokers. II. An Analysis of Smoking Habits During a One-Week Period. JN:International Journal of the Addictions PG:15(6): 889-905 PY:1980 PD:1980 LA:English AB:The smoking habits of 30 smokers, consisting of monozygotic and dizygotic twins, were investigated to check whether a subgroup of these smokers exhibited a pattern which could be associated with addiction to nicotine. The results showed that smoking patterns varied in the course of a day, although no consistent pattern emerged which indicated that a significant subgroup of smokers was addicted strongly to nicotine. Moreover, on the basis of the associations of mouth level exposure obtained from a specific cigarette, and the time intervals when a cigarette was smoked before or after a specific cigarette was smoked, it appears that the subgroups of smokers which self-titrate nicotine to any appreciable extent is probably small. (Auth. Abs.) AN:0022642 SN:811600 AU:Robinson, J.C., Young, J.C., Forbes, W:F. TI:(TO:) Low-Tar Cigarettes Can Produce Long-Term Reduction in Nicotine Exposure. JN:Canadian Medical Association Journal PG:123(9): 889-891 PY:1980 PI7November 8, 1980 LA:English ~_ AB:The smoking habits of 10 smokers were followed for a 10-week period, during which the mouth. level exposure from every cigarette smoked was estimated, to determine whether the relatively low mouth level exposure found with the low-nicotine cigarette used in an earlier study ( International 60
Page 232: apt20e00
Journal of Addictions 11(6): 933-950, 1976) would be maintained while the subjects were smoking this type of cigarette for a longer period (6 weeks). Three dizygotic and two monozygotic twin pairs were the subjects smoking their usual brand for I week; smoking another brand similar in nicotine delivery during the second week (to obtain data on whether smoking habits were modified appreciably with a different brand); smoking a lower nicotine delivery cigarette during weeks 3 through 8; reverting to the substitute brand higher nicotine cigarette during the ninth week; reverting to the usual brand during the tenth week. The amount of nicotine entering the mouth (mouth level exposure) was estimated from the amount of nicotine trapped in the filter of each cigarette smoked. The results suggest that most of the subjects smoked the low-nicotine cigarettes more intensely, presumably inhaling more deeply in an: attempt to compensate for the reduced amount of nicotine. Although two subjects appear to have obtained similar amounts of nicotine regardless of the type of cigarette smoked, the subjects as a group decreased their estimated intake of nicotine by about half what would be predicted from the lower nominal amount of nicotine smoked in weeks 3 through 8. The data suggest that when smokers change to a cigarette delivering relatively less tar and nicotine, their actual exposure to these substances is appreciably reduced. There is, however, considerable variation in the way smokers react to such a cigarette. A N:0029345 SN:831307 AU:Robinson, J.C., Young, J.C., Rickert, W.S. TI:(TO:) A Comparative Study of the Amount of Smoke Absorbed' From Low Yield ("Less Hazardous") Cigarettes. Part I: Non-]nvasive Measures. JN:British Journal of Addiction PG:77(4): 383-397 PY:1982 PD:December 1982 LA:English AB:Noninvasive measures of smoke exposure (average number of cigarettes/day, daily mouth level nicotine intake, butt length, expired air carbon monoxide, and saliva thiocyanate) showed that significant smoker compensation (increased consumption, puffing intensity, and depth of inhalation) accompanies the switch to low-yield (less than or equal to 12 mg tar) cigarettes, offsetting the assumed health advantage. Twenty-two smokers (more than or equal to 20 cigarettes/day, 0.96 mg average nicotine delivery) were randomly assigned to treatment (n=16) and control (n=6) groups. During the first 2-week period, all subjects smoked their usual brands. For the next 3 weeks, the treatment group switched to a cigarette averaging 0.64 mg nicotine, while the control group switched to another brand within plus or minus 0,1 mg nicotine of their usual brand. During the last 3 weeks, the treatment group switched to a still lower-yield vented cigarette (0.38 mg nicotine), while the control group switched to another brand again having a nominal delivery within plus or minus 0.1 mg nicotine of their usual brand. Cigarette consumption in the control group increased by 16 percent and 11 percent for periods two and three, respectively. Despite further attempts to compensate (hole blocking, a tendency to smoke lowest-delivery cigarettes unusually close to the overwrap), dissatisfaction with substitute brands was expressed by both the treatment and control groups (probably due more to the act of switching cigarettes than to decreased yield). (Auth. Abs. Mod.) AN:0032704 SN:850647 AU:Robinson, J.C., Young, J.C., Rickert, W.S. ~ TI:(TO:) Maintain Levels of Nicotine but Reduce Other Smoke Constituents: A Formula for "Less-Hazardous" Cigarettes? JN:Preventive Medicine PG:13(5):437-445 PY:1984 PD:September 1984 LA:English 61
Page 233: apt20e00
AB:Vol'unteers (n=22) who smoked >20 high-nicotine (0.8 to 1.2 mg) cigarettes/day participated in an 8-week study designed to determine whether smoking cigarettes with a constant level of nicotine but reduced deliveries of tar,carbon monoxide (CO), and hydrogen cyanide (HCN) leads to a decrease in smoke absorption. All subjects smoked their usual brand for the first 3 weeks(P1), and absorption of smoke constituents was determined from thiocyanate and cotinine levels in saliva and serum, levels of CO in expired air, and blood carboxyhemoglobin (COHb) levels. During the final 5 weeks (P2), the treatment group (16 subjects) switched to the "light" version of their usual brands (similar yields of nicotine but reduced yields of tar, CO, and HCN); the control group (6 subjects) smoked their usual brands for the duration of the study. Average levels of cotinine for subjects who switched during P2 were not significantly different from those of the control group. Slight reductions were noted in average expired-air CO levels, blood COHb, and saliva thiocyanate, but reductions were smaller than anticipated from brand characteristics. Results suggest that the ratio of smoke constituents is different when individuals, rather than machines, smoke cigarettes. Yields determined under subject-defined conditions are necessary to properly evaluate the role of nicotine in the design of less-hazardous cigarettes. (Auth. Abs.) AN:0029126 SN:831088 AU:Robinson, J.C., Young, J.C., Rickert, W.S., Fey, G., Kozlowski, L.T. TI:(TO:) A Comparative Study of the Amount of Smoke Absorbed From Low Yield ("Less Hazardous") Cigarettes, Part 2: Invasive Measures. JN:British Journal of Addiction PG:78(1): 79-87 PY:1983 PD:March 1983 LA:English AB:Levels of blood carboxyhemoglobin, plasma thiocyanate, and' serum cotinine in 22 smokers who switched to lower yield brands suggest that the current practice of ranking cigarette brands based on smoking machine yields provides little information about the relative risk of smoking-related diseases that may result from smoking one brand instead of another. The smokers (>20 high nicotine cigarettes/day, 0.8 to 1.1 mg) were divided into two groups and'switched to lower yield brands in two stages over an 8-week period. The control group (n=6) switched to brands with nicotine yields within plus or minus 0.1 mg of their usual brand, while the treatment group (n=16) smoked reduced yield brands (first stage, 33 percent reduction; second stage, 61 percent reduction). Overall averages for levels of blood carboxyhemoglobin, plasma thiocyanate, and serum cotinine were found to change significantly from week to week, but there was no discernible difference between the treatment and the control group in week to week patt