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` BACKGROUND MATERIAL FOR WORKING MEETING : RESEARCH NEEDS ON LOW-YIELD CIGARETTES June 9-11, 1980.

INTRODUCTION This material is divided'into two areas: Bibliography of re- ferences and full reprints of the major individual studies which relate to various aspects of low-yield cigarettes. I The Bibliography is compiled'from published research (1970-19'79) available to the Office on Smoking and'Health's Technical Information Center (TIC). It is subdivided!into 3 categories: "Biomedical Ftesearch", which primarily involves studies on the epidemiological issues of low- yield'cigarettes; "Chemistry, Pharmacology and Toxicology'", which is self-explanatory and describes low yield cigarettes and their individual constituents; and "Behavioral Research", which Lists studies-that examine the pharmacolog,ic and psychologic issues of'the use of these products in the smoking,habit_ The TIC has reproduced'a ser3ies of abstract cards which contain a complete bibliographic citation. For reprints of full articles, the user is referred'to the Table of Contents. The Bibliography is arranged aliphabetically by author within subject classifications. Twenty-two full-length articles are presented,, coverinqthe general areas of'biomedical effects, toxicol'ogy, and behavioral research. This material is-provided to assist considerat'ion_of all aspects of the low-yield cigarette issues. Accordingly, it is not presented as a comprehensive and exhaustivez'eview, nor as~representingan official position. Rather, it attempts to provide an overview of the currently available evidence, in order to encourage f'ree-ranging discussion. May 1, 1980

RESEARCH PAPERS TABLE'OF CONTENTS :'Tar"' And' Ni.cotine Content of Cigerette Smoke in Relation to Death Rates, E.C. Hammond, L. Garfinkel, H. Seidman, and E. A. LPw Some Recent Findings Concerning Cigarette Smoke, ELC'. Hammond, L. Garfinkel, H. Seidman, and E.A. Lew Socially Tolerable Cigarette Smoke?' (Letters)~ F. Homburger, G.B. Gori. and K. W?raer. Less Harmful Ways of Smoking, E.L. Wyndier and D.Hoffmann C.J. Lynch Toward Less Hazardous Cigarettes Current Advances, G.B. Gori, Heart Rate and Carbon Monoxide Level After Smoki'ng,Higtn-, Low-,, and Non-Nicotine Cigarettes, W.S. Aronow, J. Dendinger, 3nd S. N. Rokaw Smoking, Carbon Monoxide and Arterial Disease, N. Wald and S. Howard ,.W.S. Aronora . A:.. ' . . .... ' . . . ' . .. i.. - . " . ' . . . .. . .. .. ;Effect of Non-nicotine Cigarettes and Carbon Monoxide on Angina, w;,,Content, L. Tachmes, R. J'. Fernandex, and'M. A. Sackner Hemodynamic Effects of Smoking,Cigarettes of High and Low Nicotine Significance ' of Nicotine, Carbon Monoxide and Other Smoke. Components in the Development of Cardiovascular Disease, W.B:. Kannel and W.P. Castelli :P.V. Cole, M. Idle and C'. Feyerabend "Extra-Mild" and "Non-MiLd"'Cig4rettes, M.A.H. Russell, C. Wilson, Comparison of Increases in Carboxyhaemoglobin Atter 5motcing . GI.Bi. Fieldl. The Epidemiology of Lung Cancer, E.L. W}mder,, K. Mabuchi, and, .E.J. Beattie, Jr. ' Effects of' Smoking Modified Cigarettes on Respiratory Symptoms and Ventilatory Capacity, S'. Freedman, C.M. Fletcher, and! APPENDIX .. . . yT:~•.. APPENDIR B' SECTI©N L SECTION 2 SECTION 3'. SECTION 4

TABLE OF CONTENTS (Continued) Changes in BSronchial Epithelium in Relation to Cigarette. Smoking, 1955'-1960. Vs. 1970-1977, O.Auerbach, E'.C'., Fammond: Cigarette,Smoking-and Fetal-Breathing,Movements, F.A. Manning, and L. Garfinkel E. C. " Cooke, M.H. Lader, and M.A.H.' Russell. _ Is Tobacco Smoking A Form of Nicotine Dependence?, R. K. Murphy, M.E. Tate, and S.J. Kane.. .of Tobacco Smoke in Studies of Human Smoking Behavior, R.G. Rawbone, Kumar, The Analysis of- Smoking ~~ Pa~rame~ter~s:~ Inhalation and Absorption Pharmacological and Psychological Determinants of Smoking, .S. Schachter. Changes in the Cigarette Consumption of Smokers in Relationito Changes in Tar/Nicotine Content of Cigarettes Smoked, L. Garfinkel Tobacco Dependence: Is Nicotine Rewarding,or Aversive?„M.A.H. Russell. C. .Grunwald' editor, et al. * Proceedings of the Tobaccd and FHOalth Conference, February 24-25,1970, ~j . ::Iu__NIDA_I+tesearch Monograph 23 •' II. Experimental Approaches,, D. Hwffmann and E.L. Wynder :Selective Reduction of'Tiumori'genicity of Tobacco Smoke. SECTION Selected papers from Banbury Report #3 entitled "A Safe (:ig.3rette?", sponsored by Cold Spring Harbor Laboratory's Banbury Center. SECTION'8

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71-0"7: Aronow, W. S., Dendinger,,L„Rokaw, S. N. Heart Rate and CarbonNionoxide Level After Smoking High.„Low-; d an lion-IYicatine Ci;arettes, A Study in hlale Patients Nith Ang'sna Pectori3. Annals of InternalibYedicine 741S)cb97-70Y ;~ , . May 1971. . ~ ~ . .. .. . . _ .. .. . _ ' . . . . . . Y~ .lf.'W l.. .11Jit-i. Ten, cigarette smokers with angina pectoris had blood pressure, heart tate„and expired-air carbon tr.onoxide measure meats before and after smoking each of'fve high-, low-, and non~nicotine cigarettes. There was a significant increase in n systoiic and disstolic blood pressure after smoking each higff- and low-nicotine cigarette, with a significant increase in peak systolic and diastoiic blo.od l pressure frora cigarette 1 to cigarettr S. There was a significant increase in heart rate afrcer anokinD each high- and Iow:nicotinr cigarette but no si, titicant incresse in peak heart rate from cigarette I.' to cigar.tte 5. There was no sipif~icant increase in blood pressure or heart rate after smoking a non-nicotine cigarette. There was a' s. significant increase in carbon monoxide Ievel after smoking each high-, low,, and non-nicotine ciguette,,with a sigttificant iacreasa in e l: 5 d p a car on monoxi e from cigarette I to ciaette 5 (Ath Ab) levelsr.u.s. 7'4-02b01. lshton, H. ; Telford', R. Blood Carbozphaeaoglobin Levels in S'aokers. (Letter) . British !ledical. Journal tt (5894) : 74i0, December 22, 1973, E'nglishi.. Neasnrements of the increase in calrbozyhemoglobin, (C0Hb) in smokers smoking a single low-, intermediate-, or hig;h-nicotine- cigarette showed that the increase was greatest for the low- and least for the high- nicotine cigarettes.. This difference was accompanied by a tendency nicotine vas in fact delivered. - Thus the sublects were able to obtain a toward a low puffing rate for the high-nicotine cigarettes, though more smoking, COHmi rapidly decreases; the rate of. decrease then levels off to a very slov.value in fa.4e.to 25' dinutes. ' Eztrapolatioa of the data gives a half life for CDHIb of approxiaatelg 2.0-2.51 hoars, agreeing with the findings of Enssell.: See Ilbstract 74-0045., that aI Isafer' I cigarette .ight be one that- coabines' a lov yield of carbon onozidie and tar with a relatively high yield of nicotine. . lyeasurement of the rise in CbH'b while saoJting shoved that the greatest rate of increase occurs at the start. of' the cigarette, foll'oyed'~ by a leve2ling, off or fall toward the end. , In the first five minutes after over five-hour periods. The present findings- agree with the suggestion high- compared with the low-nicotine cigarettes. ,- The intermediate- nicotine cigarettes occupied an intermediate position.. These findings are in general agreement Yith. those of the longer-tera study by Russell in, which it was shown that. cigarette consumption and COHb rise diminished in sub jects changing from their usual brand to. high-n.icotine cigarettes `.relativelp high dbse of nicotine with a smaller increase in COilib from the 1005052807

79!-037'8 AuerDacn, 0.; l:aamond, E. C'.; Carfinicel, L. Changes in 3ronchial Epit'hel'ium in heiation to Ci7arettz Smoirin3, 1'955'-1960 Vs. 1917n-1977'. Niev. England .Iournal of medicine 300(3),: 3a1-3d6, Februari 22, 1979. Englishi. To test the hyFpthesis tnat the reduction in tar and nicotine content of cigarette smoke that began in the 1950 •'s shculd ce rzflected cy the . histologic changes in the bronchial epithelium of ci'yarettz smokers,, 20,424, Fercentages were 0, 0.1, 0.8, and 2.2, respectively. (Auth. hos. ). atypical nuclei. In coth periods studied, t.hEse nistolagic crnangts occurred far less frequently in nonsmoicers tnan ini ciyarettz s.aoiccrs anu incrEaSed in freque:ncy with amoun't' of smoking, 3d justed'i for age. Sections wit;a, ad!vancsa histologic chanyes in tnose dying in 1955-1960 occurred in U percent of tne no~nsmakers, in 2.46 percznt of tnose smoking 1-19, cigarettzs a day, in 13.2 percent of' those smoking 20-39 air;d in, 22.5 rercent of th.ose smoKing 40 or more cigarettes a day. In those wno died in 1973-1977, the incluced basal cell hyrerplas~ia,ia, loss of cilia and'occurr_nca of'cells with who dieb in 1970-1977, of: w'hora 1d1 were regular smoKers. Cnangies stuiaiza •_ cancer'deaths) were-examined microscopically in random order. There~were 2'111 men, wino died in 1955-19:60,*of' whom 154 sMoKea regularly, and! 234 men ~s sectionis ta~~k~en~ at~ autops~y~ f~~roiml_the~ bronchial tub~~es~ of~ 4'~u5' men ( npn-lung.

7'8-0261' L'ear, G'.; Lee, P. tt.; Todd, G. F.; W_cksn, l. J.. Report on a S3conc3' EetrospEctive aortal::ty Study in H'orzL-fast lagoand'. Part I: Factors 'a'elatEd' to C.ortality From I:ung Cancer,• fironcatis, Heart Disease a:,d' Stroke ~ u Clevelar.d' Courty, :ith Particular Lsphass on the nelativ_ Risks ' 7, '*obacco , Zssociatad. Wh S'Woki.:g, Filter and Pia+a Cigarettas. 95 pp. 197 7nj 'li s'~' Rcsearch Council fics=6 IAL^dlo~ rcG! P3er 1!n rart l . , ~ , , 0/V 1111, In 1963, a.rttrospect_ve study was connucted in Cleveland County, ' . Faglatd. Zbis report is the result of a s+mllar ratrospactivE study af' th.' ~ same area carried o'ut 10 years' 1St°r I"' thc lntcrv_ning y3'ars a marked ciange in thb smoxing habits in Ergl3na~occurred. Zn 1!9b3', 33 perce:.t of `~r: -e the cigarettes smoked were filtered. 1n 1973, 83 percent were f_ltar.d. 4A~k .Tables prEsatted showing tresds in tar yzeids show the marxed drop in b'l' avErage tar level by 1973. The first on3=ctlva of the study r•as to find the' effect of filter cigarette usage oc mortality rates for lung cazc€r, -, chronic broachitis, coronary heart d+saase &.d cereDrovascular diseasa- The second ob jective was to relate any o,csarvEd chazges to smoking habits 3nd W: r air po:llu tion le vels. liortality figures bY ag e, s2x, social class and a1*~,w ~ d+str::ct are given as well as ia_ornat+oa ot descezdents. Discusszor. is '. Mad4 of the statistical method usEd iL analysis. Relative risk of' mortality from the four smok`n g related' dis€ases are also presa.^.tad by ag-::, social class, and d-strict. Sclative rjsk or aortality by inhajing ha;t;ts and ag.e of beginning-to smoke are also given. Calcuintion oL the relativE rysk of mortality for men and women who smok_d f.:lteraa or regular cigarettes is , _ made. These data are further expanded to show mortality risk based' on the siz_ of the filtered or regular cigarEtttsw other risk factors assoc;ated vith tae four dis_ases were investigated, in ordsr to deteryise the effEct. attributable to smoking. Relative r:sx oz aortaiity, aiter standard_zatiow for age and smoking group, was calculaten consider+ag coffee, tea and ;:;r alcohol consumpt_or, e=ercise lEvEls, obesity, morrizg coug,y and close association with a relative dEad froW ote- of the four diseases. Tabular data on thesa risks are presented. Occupat+ozai exposure to dust, f'untes or, pollution are kr,oun to co found the obsErvat_on of effects due to ci•3arette smoking. Cortality risks based on enviror.meatai exposure to air pollutants are givan•- Among persons who had diaa trom lnag cancer, a survey of' tho:r - smoking h abits based on hospital recores was made. l rElaticushipi betr2en ,:smo;cin!a habit and lunq tumor histolo,ical type :as made. Th=_sE data includE tnaoz call types or pi.ps, cs.gar azd &z-smQ4ars and manuf3cturEd vs. haaa- y+r_rolled cigarette smokers. !lortality nroa all four diseases studied was Psignificaatly associated both.vith izcreasing age and v.th the smoking of manufactared cigarettes. The associatioL Lita cigaratt2s was strongest for = ltaag cancer and caronic bronchitis waats tbera was a clear trend both wi tw . tme number or cigarettes smoked azda ylth the ltvel of -zhal:}tlon. It was .:; , waikEr for coronary heart disease and carebrovascular disease where neith_r"": a significant doseiresponse relationsaij nor a significant effect of , inhalation was seea. T:~a smoking of' rilter cigarett,s was less associ~atEd with mortality from all four diseases thai was the smoki.zg of plain . eig,arettes. The advaLtage of smoking filtEr cig,arettes Y3s statisticallr sig,rif'icart for all the diseases ezce f,t cErebrovascular disease. The' Zor:c4r filt_red cigarettes had been sgoked the less mottality was associatad with > these diseases. Those rhol had smoked filter cigarettes since 1954 had aL estimated risk of mortal'ity, from eacL af' the four diseases which was about a half' that of continuing, plain smokersh bltLough this estimate . has bee:n eorractedr for the- fact that the information on the living and the dece3er:t populations related to diffsrEnt poa,Lts in t:me, further study is still needed in view, of' the possibility of' othitr biassing, factors that arE discussed. .

~^ 72-0451- EIson; L A., Betts, T. E. Sugar Content of theTobaeco and pH'1 of the Smoke in Relation to Lung Cancer Risks of Cigarette Smoking. Journal of the Ya[ional Cancer Institute 48(6)s 1885-1890, J>ane 1972. Some preliminary results are presented of an investigation on the relation between sugar content.of the tobacco and pH' of the srnoke of a range of cicarettes drawn from differenrcountrries. Tltrinvestigation is attempting tolascertain whether the differences in lurte<,•trtcer deatrh rates in different countries have any connection with, the predomutattt type of oigarettessmokediinthese countries. 78-1132 Feyerabe3d, C.; Russell, Effect ofl Urinary pH and Nicotine. Excretion Bate on Plasma Nicotine During Cigarette Smoking and Chewing Hicotine Gum. British Journal of Clinical Pharmacology 5('4) : 2I93'-2'97, Ap~ril-. 1I978. English. _ ~ . Plasma nicotine levels prodiuced' by chewing nicotine g~m were compared with those obtained by cigarette smoking under conditions of control'Zed nrinary pzi. Although absorption was slower, plasma levels comparable to ci;zrette smoking were buzt t up on 4 mq (but not 2 mg) nicotine gum. Urinary excretion of nicotine was influenced markedly by' pH an& therate of urine flow. Plasma nicotine was higher under alkaline compared to acidic conditions (p<0.0101) but the rate of urinary nicotine excretion appeared to aave little effect on the plasma level. (A'uth. l,bs.) z.72-0457. Freedman, S., Fletcher, C. M., Field, G. B. Effects of Smoking Modified Cigarettes on Respiratory Symptoms and Venulatory Capacity. Journal of the NauonaliCaneer Institute 48(6):1805-18!10, June 1972. Lung function, sputum production; and cou¢h frequency were measured' in, 225 men to determine the effects of smo3ang,modifed' cig.uetrtes on the symptoms of'bronchitia: The men were asked to s7noke exclusively special cigarettes designed' for the experiment. Three types of cigarettes were used. All delivered about 1.65 mg of nicotine. Type A delivered about 22 mg of tar and types B and, C' abou!t 17' mg. Type C had approximately a 50' percent reduction in the - vapor phase constituents as compared with the otlier two types. After about four months, men,smol:ina type C cisarettes. began to have lower average cough frequency scores than men smoking, the other two types. An analysis of varixrtce Indicated that this difference was significant and' it became more marked when the results were adausted tor dttterences in s`'"' :garette consttmption There were no si¢nitlcant diffierences between the groups for sputum prodluctionlor lung function. ci. '' The results showed that modification of the composition of cigarettes and their filters can reduce smokers' cough, an early symptom of bronchitis. r~:..

79-0369 uori, G. 8'.; Lynch, C. J. Toward Less Hazardous Cigarettes. Current Ad'vances. Journal of' the American Medical Association 240( 12 ): 1255-1259, September 15, 197fi, English. Iracreased interest in the role of cigarette constituents in tobacco related disease has prompted the compilation of' critical Ievels of selected' ci garette smoKe constituents. Levels are expressed~ in terms of maximum numbers of'pre-1960 cigarettes that a smoker may consume daily without increasing,his mortality risk substantially, above that of a nonsmoker. Tar, nicotine,.carbon monoxide, nitrogen oxides, hydroaen cyanide and acrolein content of 27 popular commercial brands are given; these levels are also ta3ulatEd in terms of rPduction in yields compared with pre-1960 cigarette yie2cis. idecuctions range from a high of more than 98 ' percent (Stride - hydrocen cyanide yield) to a low of 24 percent (King Saino lSenthol - nitrogen oxide y'ield). On the average, the brands under consideration havee had'the greatest percentage reduction in tar yield (86 percent) and the -least percentage reduction in carbon monoxide and nitrogen oxides yields ('69' percent) ccmYa ed with pre-1960 cigarettes. In addition, the y,ield's of these selected constituents concomitant With the yieldof .1 msof nicotine are provided as a guide for the smoker who titrates or adjusts his smoking pattern to accomodate a fixed daily intake ofl ni!cotine. =75-0696. Gray, Di.; Sill D. C'igarette Snoking Tar Content and Death- , , , __'~8~ate~s F'rolo Lung Cance~r in Auistr~ali~aa~i !len. ~ (Letter) • Lancet 1 (79T8) : 1252- ~ 1253, ~May ~ 31 ,~ 1'97~51,~ B~n~gl,ish. sar~v~~ey~ of~~ 6,637 a~ustralian~ aen over th~~e~ p~ast~ decade h~as~~ sh~o~~wn~ that the percentage of smokers decreased with age; 46 percent of' meni 20-29' years old were smokers vs. 33'percent of' men 60 years or older. From. 1969 to 1974, high-tar cigarettes virtually disappeared from the Australian market. ,ge-specific lung cancer death rates showed a decline since 1970 for men, aged 5'5-59' and 61d-64 years. The increase in the number of ez-smokers who g,ave up smoking five or aore years ago is considered the primary factor affecting, miortality. &eductions in N cigarette tar content probably had a lesser effect. Q _ . O CA O C11 2V 0~

75-023u. Guillers, 8.; tiasurel, G'.; Broussolle, B. ; Hyac,inthe, 8'. ; S'i3og, h new low-nicotine cigarette, Gallia (GA) , was developed and testEd.in ~ B'ronches 24 (4) : 209-23'.T, 1'974, French. Hiabituelle Dans un Groupe de Grands Fumeurs. [C1'inical and, 8espiratory Function Effects of' the Substituti'on of' a Cigarette With Lov Irritant SmoJce in Place of the Habitual_ Cigarettz in a Group of Heavy S'mokers. ] a. ; Bee, J. Effets Cliniques et Fonctionnels $espiratcires de la. Substitution d*une Cigarette: a Fumee Pea Irritante a la Cigarette phase and particulate phase, respectively. Chemical compcnents are reported. The subjEcts were 72 men and three Yomen (25-60 years of age), ; in good! health. They had smoked Gauloise filtered, or nonfiltered cigarettes for an average of' 310 pacJc-ye rs. Some of the subjects had : - difficulty with the regime and, were irritable; by the end of five Yeeks, cigarette consumption hiad increased i'n 45 percent of the subjlects, and, charcoal, and cme part cellulose acetate, to filtar components of tbe gas from loWer positions onthe~ stalk, mized', xith, humectants, rzapped in porous paper, and' equipped Vith a, double filter, one part activated a five-week trial., The cigarette was composed of, tobacco lzalves taJcen: decreased in nine percent (meanincrease., tyocigarettes pier day).. ~ Regressions were observed in symptoms. of cough (B6 percent of patients . improved), exp.ectorations ('77 percent improved), pharyngitis, and dy_paea ; of carbon monoxide.. g smoking or, improvedi alveolar functioning, which allowed' more absorption content in, the GA cigarette. This may have beenthe result of mcre rapid Carbozyhemoglobin levels increased in spite of lover carbon monoxide ('911 percent isproved) .. Lung function tests were adainistered before and af ter the five-week period and results are tabulated. liiost parameters were improved to the same level of' improvement noted~ in ex-smo,kers, except for vital capaicity and expiratory volume in one second. , ,

77-QC66 Guiller3, R.; Eroussolle, 8.,8esaltats-an Plan.TesFiratoire de la Substitution d'nne Cigarette a Fusee Fea Irritante a.la Cigarftte. Hahitnelle Chez de Grands Fuaenrs. ,[Bespiratory Results. Ftca Substituting a: . ."' Stand'ard Type Cigarette 1ith a Less Irritating One. in HEaviy.S'ao3cers. ] Boaaon et le Cceur 31- (5) : 277-2'81!, 1975, Prench.. . • 1 g 1 Las a slight, increase (froa 3.78 to 7.43), in blood. canccxyheso lobin 68 Fercent; ezp,ectoration disappeared. in. 33 percent, yas reduced. in 47 Fercent; FharyngeaS irritation subsidedi in ao_t sub jects; and. in aost ' suhj'ects.,, the clfactory capabilities ha4e- iaproved and the appetite has increased'. There Yas a slight iaprove4ent in the: pulaonary f'anction Yithh the folScYing statistical significance: vital ca:ma1city--p:0,GC1; saxiaaa expiraticn--p:C,02; r,esid'ual voluae--p:0,0_j'. Oa the nEg;atiye side, thez$ resn~lts were ebserved: canghing disapFearEd. in, 210 Fercent, sas reduced' in the initial stage of' chronic bronchitis. kfter• the test, the folloying ' ...The substitBtion of a standard French cigarette- of; the Gaulcise type (!G0) by G'allia (GA), the new reciently sarketed cig rEtte with less irritating , constituents, has, been t.ested for 36 days on 80 heary stckers to assess its effect on the :resFiratory tract. She. ccaFcnents of' the gasecus phase cf GO . versus GaA are (per one! cigarette) :.canccn dioxide--3'2.5- vs. „24.5 agi;; carbon, nionoxide--17.'s vs. 11'.4 ag; acrolein--7•1.5 Ts..36' sicrcgrais; nitrogen . cxid'E/Litzcger dicZid!e--390 vs. 3118 aicrcgra°is. CcsFcterts. of the : particulate phase are: tar--28'~.8' vs.vg; alkalcids• (tctal)--1.7 vs~.. .a.7 mg; indclE--505 vs,. .12'6' aicrograms; phienol--168 is. .69 aicrograas. „All. saokers, before smbaitting to the test, had, the usual sicker's sya.g,toas: _ nasal; con}estion, bronchial :intolerance to tcbacco- sackE, coaghing, expectoration, dyspnea, irritated Fharynx, and,.inc sose.instances, were in. _. EvE S.

77-u222 FJlammonid. E. C.: Garfinkel, L: Sei'4:aan, H.; Lew, %. A. "!"Tar"' and Nico*_ine Content of Ciciarette Smoke in Ee.stioa to Weath Rates. Env:;ronment:al 8ese3rch 12 (3): 2'0 3-274, Gecember 1976. Enqlish. Il3re than 1',00r7,000 man and womeni w2rz turolled in an ecidemioloctical stu.lv in 1959-60 and were followed, with i3w exceptions, for 12 years; all ansiered auestioncaires on ciqarette ss+okanq and other factors u!Don e.nroila-z~nt; survivors answered three reneat q.uzstior.naires. Civarette smoRers vere cLassified by the:amount of zar and nicotinie ('T/N) delivered bv the brand they usua119' saoke3' at the stdrt of each, of two 6-year peroids (Paroid 1 and Peroidi 2) : hiah T/K (2.0-27 i mo nicoti,ne and' 25.8-35.7 mq tar) : low TIN (less ttaa 1'.2 ma nicotine oaci, with few exceptions, less than 17'.6 mc tar) : and' mledium T/N' ('intarmi:uiate bptVPen hiah and lav) Aman:1 those who smoked the~samm number or ciararettes/3'ay, the total death ratas, death ratts from coronarv heart nisdasa, and death rates~from~ lun:7 c3nlzJr Y,3re somevcat lorer' for those who aaloked low T/N ciq'arettes than for tho:aL v:ao smo ed hiaa T/'!t ci!qarettes. T'otai number of deaths were 4,735.5 for hliah T/N smokers, 4.299.9 for meuium ond' 3.9191.1 for low; cor_eWvondinq~ numoars of luna cancer deaths were 310.4, Ad5.5', and 235.2, respectively. The diffarences between hioh and low W2xe atatisticallv siqnificant in, both c3ses.., Luno cancer mortalitv ratios oz to. T/N smokers were lower for women th3a for men (0.57 a.^.d' 0.43', rzsoectivelY, in Period' 1 and 0.62 and 0.719, resuactivaly.. in Period 2). GorrssponaiLa ticures for coronary heart disease (1616.d in hiua. 1483.3 in medius, an& 1392.7 in lov) also show a szacisticallv sianificant dilferencz bezti*zzn the hiqh and loy Qroups. In an: an3lvsis commarinc subiiects who smol:a4 adwY low T%`I ciqar2ttPS with those _ who smoked' f:wer hiah :/ti ciyarettes, the&e was a statistically siqnificaut dif=erence in coronary hiPart disease aeatos (670.& for sub!ects smokinQ 1- 11S uiah ciuarettzs and 713o.ti i'or those smw4ir.Q 20-39 low civiarettes). There was also a differe¢rce iz luulc: cancer deatja (75.6 ior those smoking 1-1'9 hici and 129.5' for tr.ose smokina 20-3'y lo:1 : for each of 4 ind!ividual sets of comnariscns (men and women in Periods 1 and 2), th e number of lung canc,tr deaths was lower iz those who sr-okea 1!-19 hivh than iu those snokimQ '_20-39 low. Ar.other analysis compared low i/N smokers with nonsmoKers: death - =~r~"~' ,.,ratas were far hiaher in the low T/N' ©zou~;~ than in the nonsmokinct. Qroup LTG aths vprp 4 3 3 099' 0 ectzvel rY °- lt tal d r s corona h t , . . , . C aa y ,, o e r~r mar disease oeazhs 1,674.3 and 1, Oiln.3, resaectively, ana, Iun(4 cancer deaths ,2158. 0 and 39.4,: respectivel'v). lt was conc.juided that a red'nction in the tar and nico±ine content of ciaalrettes did not maice ci(7a'rette smokinq "'"safe' I for the mea and women in this acalvsis, m.Li of whcm vera over the aQe or 40 in 1959. _

78!-1250 Ha.mmond, E. C. ; Garfinkel',, l. ; Seidman, PH. ;, Lew, S. 1. Some Hecent. Findings Concerning Cigarette Ssoking. pp. 107-T12;. 1977, In• Hiatt, Hi. H.; Hatson, J. D,- ; ainstea, J. a. (Editors) .©rig,ins of guman Cancer. B'ook A. Incidence of'Cancer in Humans, Cold Spring, Harbor Conferences.on Cell P'roL•'feration,. Yolume 4, New York, Cold Spring Harboa Laboratory, E'ng,lish. The preponderance ofl scientific evidence strongly suggests that the lower 0 studies have shown that material cond'ensed from cigarette smoke (tar), is -carcinpgenic when applied to~ animals. The known acute effects~ of nicotine . upon the heart and circulatory system suggest that the nicotine content of cigarette smoke is partly, if' not entirely, responsible for the fact that age specific death rates are higher among cigairette .mokers than among nonsmokers. The reduction in the tar and nicotine content of cigarette smoke did not make smoking safe for the men and women, in this analysis, all of whom were over the age of a'A pears. Cigarettes srith, reduced tar and nicotine were not introduced until the mid 195IO1's,. dlmost all of the male " cigarette smokers and the great majority of the female cigarette smokers in increase with degree of' exposure to c;'garette smoke. Sany experimental f~ `= effects. Death rates from lung cancer and cancer of' several other sites the tar and nicotine content of cigarette smoke the less harmful are the , pro ucing, cigarettes with ex.remely little tar and nicotine. some future health of those who make this youthful decision would be at least .-sooewhat reduced if high T/N cigarettes were removed from, the market- In this study began smoking cigarettes long b!efore. Therefore, the sub jects classified here as low tar/nicotine ('T/N) cigarette: were, with few _exceptions, persons who smoked high T/N or vediam T/N' cigarettes for many years and the3, switched to loti T/N cigarettes. It appears that by so doinq, they somewhat reduced the serious risks incurred by smoking. The switehinq from high T/N' to low T/N cigarettes was at least a small step in the right ` direction for those who continued to smoke cigarettes.. lfter all warnings, many thousands of young people take up the smoking habit. The threat to the the additI9es and the tar should be tested, for carcinogenicit9 before such vanutacturers ay use additives for flavor or for some other purpose. Both : `eigarettes are put on tae aarxet.

77'-u1223 Herson. J.: Simpson: C.: Kennedy, j.: K&poor, S. A Theoretical Aporoach to the Evaluation of the Corta.Lizv Effects of a""Lov. Tar" C:zirette. Journal of Claronic Diseases z94112' : 7v7-75a1, Deceaber 1976. Wuolish. Recer,t smof:ina and healza controversv hss centered around the likely the sale of effacts on human aoytslitY' of a federal UL.~i'cq sanetioniaq only low-tar cigarettes. At mresent, verv lit"a data atm available.to documenz the tiortalitv effects of vrolonqed smoi.iny of civarettas at various tar levals. cfiureovmr, ethical and Qracticmlity considiarations preclude the aossibilitv of a controlled clinical tria.L beirna verflormed' to estimate theseefrects. The obtectives or this vap".r are thus to davelov various matzc=aticaL mo&eis to: l1J Estimatc tnm variatiou in various measures of mo`r~3litv by daily saokine f'rzcuencY and civarette tar conzent. (2) Discuss ioplicdtions of the mortality results in taz=s of' public health volicv that Yoinld enicouiraQi3 the US'2 of Zoii!-L9L ciziaL.3Tt2s a;3'.3,/or eZco'uraQe smoiCers' to lo.:r daily sc,ot:ina Erevuency. The tYU ndA.aaeter Govrortz hazard function is aho:jn to fi•.. t1d©moaai"s 1ylo0 American C:oucc~r Socicty life• tables rhich demict survivorstrio of men aceci 25!-1'OG yaars for f ive lovels of smokinq frezuaacv. UsiaJ data on tar, levels oz cic,arettes on the market durinq the period' 13o0-65, various aodels are prooosad to esti'm3te the covariation, of . 'the .7oimrn-~%rtc vardm_t3rs bv smokina freuurucv and tar content. For each molai, ms tima*_ar3 life expectancv and aciE zgijeclfic death rates arp pr.esentvi" fnc_ various smo.:ina treruaBcy/ta'r croups' autd tha mortality coitseane,nces of al law tar and lou freauencv v!ublic hcalth uolicy are discussed. FlultiFle recression analYS'ss.is nsed to summarize tup mo**alitv findiaas and to croviae a auantitative assess,neut ot tne reiative imoortauce of tar content and srruklnq frzcvmmncy, in deteranini,nc lize exvectancy and death rate. E7ijaace froa the models favors a lov-tar, uoticw over a low freetrt:emcy mal=cv but coasi&er35le benef'its can be o6;.ained from a combined' volicY. (Auth. A os. M'od'. )

76-11Id1 Hill, P. Hicotiae: kn Etiological F.actor for Coronary Heart Liszase. pp. 313-319. 19761, In: Rynder', E. L. ; Hoffmann, D. ; Gori, G. 8. (c:iitors) . Modifyinq the Risk for the Smo;eer, Volume 1. Proceedings of the 3rd Horld Conferenca on S'moking and Health, New York, June 2-5, 1'975. Dfi?.;i ' Publication .bo. (NIH) 76-1221, EhNlish. Although the relationship of nicotine to, atherosclerosis is unclear, nicotine may be a major factor in sudden death and be responsib le f or the increase in CE'D in women. Concerning the need' to smoke, the environmental coadiLi,ons~ initiatiaq low or hig,h arousal situations may, control the nicotine intake in smokers and the ease of smoking; vithdlrawal. Thus the physiological andibiochzaical changes on smaking withdraval may qive leads on the nicotine "I'demand"' and its relation to, CHD6 Investiq~ation of the daily, patterns of nicotine intake~ an3'i changes in plasma nicotine, cotinine, catecholamines, cortisol and carboxyhemo4lobin (C©Hb) levels in smokers and ex-smokers, shoJed initia:l rapid increase in serum adrenaline on smoking which is not maintained, iiut a prolonged elevation of' cortisol, which was maintained throughout the day in a heavy smoker. These changes were - depenuent on the content and rate of intake of nicotine. 3:apid clearance of plasma nicotine occurres, but a, hiq,h plasma cotinine content was maintained from day to, day. Similarly, smokers maintained an elevated~ COHb throughout the day; a, level independent of' the nicotine content of the cigarettes smoked. One week after stopping smokinq, these biochemi:cal parameters are similar to those in nonsmokers. Since smoking withdrawal decreases the risk of CHU1, the effects ot nicotine and C'Ofib, vnich are indeflendent risk factors, appear to be reversible. Although less harmful cigarettes can be develooed only smoking VithdraVal will remove the hazard. (Auth. Abs, ) -79'-o5E@ Hoim-burger, F.; Gori, G. E.; Lynch, C, J. Socially Tolerable Ciq,arette Stoke? (Dettezs) . Jourr.al of the Aaerican nedical Association. ~~2v 1(Zm) : Z'142-21u3, "aY 1s, 1979. Frglish. 100'S052$17' ~This'letter eodments on a study by Gio H. Gori reported in the Wall Street. Journal Xovember 1, 1578,, p. 18' which Lef t the public with the i,pression that some cigarettes are relativelJ safe to! sLcke~ in limited quantity. Results of that study were based on, tar and nicotine values extrapoLa:ted II'rom pre-1960 cigarette smoke. This extrapolation would be justified' only if tfie eompcsiticn of the diliuted smoke remained basically the saae.. The complex naniFulaitioas necessary to obtain lower yields of the six substances studied bi Cori ar,d coworkers aay change the biologic activity of smoke or new sm~oke coc?.onents maY be introduced by addition of flavorings or adaitives not reculated in the United States. Only a, valid lf' c'scrisinate betv h d fl i ee n azar ous saoke. A bioassay of smoke ca previously Fubl'ishedi assay for seasuring the cancer causing potency of various cigarettes is advocated, In his reply, G', 8, Gori.emphasizes that todaY's cigarette pr'eceszina reduces known toxic constituents quantitatively. There is no evidence that the red'uction, of' these constituents is accompanied by an incre3se' in other suspected toxic constituents, Fu'rthezmiore, there is evi3'ence that toda7•s cigarettes produce less tumorigenic tars than Fre-19160 cigarettes, There is no evidence that present flavor addi'itives increase the toxicity of cigarette smoke. Gradual reduction in exFesure to tcxic coastituents remains the reasonable approach until. bi'oassar dat3, are availabl'e fro., onqoiaq buman studies.

76-1250 Kannel, i. B. ; Castelli, W. P. Siqniiicance of Nicotine, Carbon Monoxine and otaer Smoxe Comiponents in the Development of Cardiovascular Disease. pp. 369-381. 1976, Ia; iyndar, B. L.;, Eioifmaan, D.; Gori, G. g., - (zditors) . nodifying the Bisk for the Smoker, qolume 1. . Proceedings of' the 3rd .orld Conference on Saoking and Bealth, New York', 3.une 2-5, 1975. . D(iE'W Publication do. (.VId) 76-1221, Eaqlish. , There is now, ample evidence to show, that nicotine absorbed from inhaled tobacco has acure, transient effects on the circulation which could explain many of tne observed epidemioloqic faaturzs of tae relation of' cigarette. smokiagi to the d'evelopment of cardiovascular disease. Its actions are comparable with a transient, noncumulative and! reversible triqqerinq effect operative in persons with an already compromised coronary circulation. The hiyh carbioxyh,emoqlobin values qen3rated by cigarette- smokers. also fits this pat:.oa1enetic! conceptualization by causinq further impairment of oxyqen utilization; by isctanic tissues supplied' by critically narrowed' vessels and' catechol stimulated by nicotine. In addition, etfects of nicotine on, -piatelet adhesiveness and other clottinq factors could impair flow in the microvasculature or proaote thrombosis in, near occluded arteries. Evidence which incriminates ciqarettes in the process of atherogenesis is less substantial- and does not explain as well the epidemiological relatioashipss of the cigarette habit to the~occurrencz of cardiovascular disease., altaoulqh, it is quite likelq that severe exposure to carbon, monoxide _pzouotzs ath_rosclerosis in the heavy smoker, it is more. likely that the acute precipitatinq effects of' nicotine an& carbon monoxide are~ responsible for the excess risk in the cardiovascular disease-prome smoker. Giving up smoicinq has been shown to red'uce risk by about half so there is muchl to be qained by abolishinq the use of ciqalrettes or, in reducing their nicotine ana car5on, monozide content. (Auth. Abs.) ~.-.=7'9-1v13 K'och, A.; Roffmann, K',,; Siteck, W,; Horsch, A.; Hengen, 11,,; nberl, H', Einffluss von 2igarettenrauchinhalationi aluf Kreislauf- und' :-,S'toffrechselgrossen. [ Ef'fect of' Cigacette Saoke Inhalation on Circulatio,-, -,and netalbolism, ] Yerhandl'uagen, der Deutschen Gesellschaf t fur Innere redizia 84; 1397-1I400, 1976, G'erman. 10il 52 5 0 ~918. Biochemical and b1!ood circulation parameters were eas.uredl in. a g,roup of six healthy men, 20 to 30 years old before and after they smoked' txo 6.5 ca. lona cigarettes, each in 12 iin, Nicotine content of one saoked cigarette was either 1, 54 (hig,h-nicotine) or 0!.08 mg (""nicotine-f ree "') . A .""shamsmoking'" test was also d!one. The aeasuresents were made 1!, 10, 20, 45, and 120 aia after smoking. Pulse rate was directly proportional to thie nicotine variations in plasma after smoking either two high-nicotine or two "'"nicotine-free''' cigarettes, The spstolic Fressure increased considerably with the high-nicotine cigarettes and to a smaller extent with "'"nicotine- free" cigarette.s, The pulse wave velocity decreased significantl7, with high-nicoltine cigarettes. The blood flow through the calf increased slightly for a short time with hish-nicotinle cigarettes but retained unchanged with "'"nicotine-f'ree''' eigar'ettes, The acral flow decreased ;ignificantly with high-nicotine cigarettes and less so with: ""nicotine- '' ; f t Th 2' i ' ` ~ ree acta e c giarettes. e to ppruvaite ratio and blood sugar Iievel increased significantly and continuously with high-nicotine cigarettes, but onlr slightly with ""nicotine-free" c'igarettes.

7'6-1 2'66I M'aaaing, P. A. ; Feyerabend, C'. Cigarette Smoking and F'etal : 3reathinq !lovements, Obstetzical and Gynecoloqiical Survey 3'1 j10) : 7'1I6-71d', October' 1976. Enqlish. The present study investigated the factor in cigarette smok;e responsible for tae depression of fetal breathing. Ultrasound recordings were mad'e of' ' the fetal chest wall movement. Fetal breathing movements were measured before and after smoking two consecutive cigarettes in 19 vomen Vith normal pregnancies, 10 rrith Preeclampsia, 12 with diabetic pregnancies, and 6 vcmen who ultimately delivered small-ior-date babies. In the normal preqnancy group fetal brea.thing movements were present for 69.7 percent of the time before smoking. There was a significant reduction in the. proportion of time d:urinQ which fetal breathing movements were present within 5 minutes after the start of smoking. The reduction was progressive rea :hinq a nadir of 5!0 percent at 3'0 minutes. Plasma nicotine level rose from an initial value of .6' nq/ml to 15'.1' nq,/nl after, the second' ciqarette. There was a siqniticant correlation between the rise of pLasma nicotine 'i-i after simoking and the fall in the amount of fetal breathinq,. This correlation was also evident in, the diabetics and small-for-date preqinain:.ies.. T'hie preeclamptics showed no reductionl in fetal breathing moveaents. Correlations between fetal breatainq movements and' chalnqes in blood sugar or carbozyhemoqlobin levels were not observed. Hence, nicotine appeared to be the ractoz in cigarette smoke responsible tor the reduction, in the incidence of fetal breathing movements. 7'9-1v78 Rabinovitz, B'. ID.; T'horpi, 1t.: Huber, G„ L.; Abelnann, W, H. Acute i ".:-Sixteen healthy, sub jects, ages 18-351 rears,' were studied in the supine. .: HemocTnamic Eff''ects of Cigarette Simok,ing in Can Assessed by Systolic Time , Intervals and EchocardiograFhi. Circulaition 60 ('u) : 75Z-76'0, October 19719. ~--k':'aad after smoking a hi'gih-nicotine cigarette (2.5 mg nicotine) and a lov- :'f+?9''posi'tion by means of systolic time intervals and echocardiography before ;•~ nicotine cigarette (<0.02 mg nicotine) to assess and comFare the immediate effects upon left ventricular function. Smokers (a-12) and nonseckess (n=4) behaived alike. Righ- and low-nicotine cigarettes both caused significant i'ncreases in heart rate, systolic and diastolic blood pressure and the triple product (systolic blood pressure x left ventricular ejection, (LVET) x heart rate) , prolonged LY'ET, and decreased the pre-eji,ection period ('PE'P). and FE'P/LV'E:. In add'ition, smoking a aicotine reference cig,arette increased the eehoeardiographicallr-derived' LV enid-diastolic volume by 7.5 percent and augmented ejection fraction by u percent, while significantly enhancing meaa normalized circumferential fiber shortening by 12.5' percent and mean . normalized posterior wall relocity by 91 percent. Smoking a tobacco - cigarette of ultra-Zow nicotine content resulted in comparable inczeases in ejection fraction and mean circumferential fiber shortening, albieit on the basis o-f a significant decrease in end-systolic volume without alteration in end-diastolic volume. These data suggest that s3oking, a high-nicotine cigarette Mhile in the supinie position acutely increases venous return and augments the principal determinants of myocardial oxygeni consumption. (i.e.,, heart rate, contractility, preload and afterload) and that cigarette smoke ma7 contain inotropic and chronotropic substances other than nicotine. (Auth. Abs.) 1005052819

6-068'.4 &awbone, 3. G. . Closing Volume. The Effects~ of' Acute Exaosure to Tobacco and Tobacco~ Substitute dixtures. (Su©olement y5) - 9'1-916, 1976. In: l Closiaa YoLume. Phvsiolomy, tilethodolovy, c,pideaiolo4v and Clinical Invastiaacioas. An International Svmposium fdeLd' in: od'ense October 20-21, 1975. Scandinavian Journal of' Respiratory Diseases Eaglishi. Tae ef'fects of tobacco cigarette smokina on oulmonary function vere. comioared to the eftects of ciaa~rettes containinq tobacco-substitute material. Twenty-nine male snbiects were aivided into 4 studv crouvs: nonsmokers, normal ciuarette smokers, (whose averaae consumption was greater than 20 middle tar cicarettes containing 17-22 mq tar, per day), substituta simo7cers A and substitute smokers B. Twenty-four hours before , Jarette smokers did exist.,y . attending the laboratory s!ubj~ects (,who~ were smokers) were given a supply of unmarked cigarettes to sAoke for the intervening neriod. Otaon arrival all subiects were aiven a pulmonary function test. The~ test groups ta11 sumiects except nonsmokers) were then asked to t''chain-smoute" five cigarettes followinc which the pul- monarv function test was reajainistered'. All cic:arettes were filter tipped and idl ntical in apoaaranca. Control cigarettes contained'1010 percent flue-cured tobacco while the test cigarettes contained one ot two substitute materials in a mixture of 4 0~ percent sub•szitute to 60 percent control tobacco. Both nitroQen and araon closing volumes were measured to indicate pulmonarY funntioa. The subiect coefficient of' vari3tion •ras nreat: u~c to 3© percent in zonsmakers~ and up to 50 Percent in smo,cers. For the nitroQen closing volume no sicnificant_ d.ifference existed between the 4 groups; hovever, for 'i3 arvon•test a sianificant difference between nonsmokers and the control 7,3-095'9. Russell, xilson, C'. , Cole, P. V., idle, !i. , Feyerabend', r Comparison of Increases in Calrboxy'hiaemoglobia After' Smoking "Extra.- Lancet 2(7831) : 687-694, Septem er , arettes ld" Ci - d "H " ' . ai g on an mild ~. ; ~ T~*nk1973',.. English. carbozyhemoglobin (COH'b) after smoJting, "extra-mild'' and "'nonmild" cig'arettes. The mean increase after smokingi a single nonmild cigarette A"c'ross-over, comparison was aade, in 22 smokers, of increases in , yas 1.45 percent for the standard-size brand (ten puffs) and 1.091percent ~' for the small-size brand (seven puffs) . The meanincrease after a, single extra-mild cigarette was 01.64 percent for the: standard and 0.75 percent for the small brand',. The low Co, absorption from the standard-size mild cigarette was less than half the amount absorbed~ from the similar-sized nonmild cigarette. . This low CO brand' also has a. low tar and nicotine yield. CoHb increases after smoking were g,reatere in tae women than in the men, and there was an inverse! relation betYeen C'D8b increase and hemoglobin level.. The health implications of variations in CO yield of cigarettes are probablp as iaportant as those of' differences in tar and nicotine yield; the C0lyield'f of cigarettes should thus be pubsished! together with tar and! nicotine yield. See Abstract 73-G9©7. ,(Auth. Abs.) 1-110050'52820

75-0788. Eussall, lY.b.H.;' ~ilson, C.;' Patel, U'. R.; Fryerabi:r.d, C.;~ Cole, P. v. Plasma Niicotina Levals After SmcJcizg Cigarettes Uith Hiyh, and Low Nicotine TiElds. British Cedieal .Icurnal 2(5'y168): 414-416, Cay 24, 1975, English. which have been saoked over the preceding few hours. (,Ault:h. Abs.) v_y the cigarette is smoked than on its r.icotine yield' or the number showed mark_d individual variation. The findings suggest that the Flasm3 nicotine level occurring j',usit after cigarette snoking depends more on the morning and afternocn while smoking usual or high-nicotine cigarettes 3ropped to an average of 52.4 nnol/i (8.5 ng;/'ml) . The changes between . respectively) were not siguificantly, hhigher than the morning levels, but after switching to lov-nicotine cigarettes~ (0.14 mg) the plasZa nicotine with their carboxyhemoglohin levels. After ccntinutng~ to saoke their usual brandi or switching to a high-nicotine b_and (3.2' m3 ) avbrage afternoon levels of 185.6 and 180.0' nimol/1 (30.1 and 2'9.2 ng,/m1, Plasma nicotine occurring three minutes after smoking a cigarette was measured in ten sedentary workers in sid-morniiig and five hours latzt on four typical workir.g days. The averagie mid-tcorning level after they had baen smoking, their usual cigarettes (dean nico ina yield 1.34' mg) was 150.4 nmol/1 (;24.4 ng/dl) (range 95.6-236.7 nmol/1 ('15.5-38.u ng,/ml))- t Diespite great variation betwczn smokers the ctid-morni'nig levels of each ' smoker were fairly consistent over the four mornings and cozrelatcd 0.62 72-0575. Sclunahl, D. Review of Current Research in Gerntany on Less Harmful Ways of Smoking. Journal' of the National Cancer Uutitute 48(6):1'77S-ITl7, June 1972. Research et7brts of the German cigarette rttanufacturers'to reduce the tar and nicotine levels in cigarettes are briefly reviewed. Fractions from cinrette smoke condensates are being tested on mouse skin to define and eliminate those fiacriona in which tumor initiators are eonr~entrated. Smoke condensates frorn ci¢arettes modified by various procedures ~j to reduce or eliminate their turnorigenicirty are being tested' on mouse skin and in the subcutaneous tissue of rats. To titnd ~' °' out whether tumori8enicity could also be reduced in the total smoke, a new expertmentall technique has been develboe,l' by which the total smoke of cigarettes is inhaled by hamsters. A:s a resuat of pressure on the German tobacco industry too reduce the yield of total eondensate and nicotine per cigarette, the condensate pe cigarette was 36 percent less and'the' nicotine 31 percencless in 1970 compared with those in 1961. '79-1ta23 Spohr, 0,; Hofraainn, K.; S'teck, Harenberg, J.; walter, E.; 'Athier'osclerosis 33 (3)' : 2'71-28'3, July 1979, English, Evaluation of' Smoking-Induced Eff'ects on Sympathetic, H'erod'ynacic and H'etabolic Variables with, Respect to Plasma Nicotine and COHb Levels, He'ngen', X'.,; llugust'in, J'.,; lSoerT, H.; 1CocA, A.,; F:OrSCls, A.; xeber, E. per cigarette and of shiam-saoking was studied in six healthy habituall smokers,. Levels of •carboxThemog7obin (CO'Hb) and plasma nicotine were measured sicultaneously• vith heoodynamic variables, such as heart rate and blood pressure, and with the metabolic parameters, plasaia dopasine-beta- liydr'oxylase (IDBH) , cortisol, bl!ood glucose, lactate, and free fatty acids. All variables, with the exception of COHb, were dose rellated, to Flasca nicotine levels. Blood pressure, heart rate, and' lactate showed simultaneous peaks together with oaximal nicotine levels, vhi,le DEH and cortisol', blood glucose, and free fatty acids shovedl a del'alyed' reaction compared to nicotine concentrations. No effects of' COHibi, even 'With levels up to 5.6plus or, miaus0,5 peFcent, were observed on the varialbles investigated. Results demonstrate that it is nicotine that induces considerable hemod'ynaeic and metabolic alterations after smoking. (Auth, A' bs.~ the effect of smoking cigarettes containingi 1.5 mg and' 0,08' mg nicotine 1005052821

7'9-0291 Tachmes, L.; Pernandez, E.J.;* Sackae.r, a. 3. Hemodynamic Effec;s of Smoking Cigarettes of High and Lov N3cotine Content. Chest 7 4(3!) : 243- 24'.6 , Sep tember 1978. Eaglish The heaodynamic effects of smoking cigarettes with high and lcv, contents f of nicot iRe in young smokers free! of corona ry arterial disease were studied'. The sample consiste& of fivemen and, three women, ranging in a~ge from 18 to 30 years, with a smoking history of 2-15, pack-y,ears. The smoking . of', one cigarette with a high content of nicotine produced a pea.k rise in cardiac output of 32 percent above baseline values, and the effect pers_sted f~or1 hour. Smoking, a cigaretteyith~ a low cont~en~tof nicotine,. . produced a peak rise of' 13 percent above ba-seline values, Yith a duration of' 5 minutes. T'he, rise in cardiac output was almost, entirely att_;'butable to: tachycardia,, since stroke volume remained relatively constant. Smoking a cigarette with high nicotine content also caused greater and more sustained elevation in systemic, blood prEssure- than smoking a cigarette with low n,icotine cfontent. After smoking, there were no statistical]:p significant changes in consumption of', orygen, diffusing capacity,, volume of~ blood in pulmonary tissue: plus capillaries, functional residual capacity,, 'or flow of' bloodl in calf. Thus, there vas a responsiveness to the, dose of nicotine in cigarettes smoked bT yomng. smokers~ free•of cprona.r7 a~rterial disease, in heart rate and blood pzessare. (Auth. lbs. Bod. ) 10050528022. - 74-1312. Turner, J.1.2l.; Sillett, 8. W.; Ball, K. P. Some Effects~ of Ch.anging to Lor-Tar and Lo!Y-Eicotine Cigarettes. Lancat 2(7'883) : 737-739,. Saptember 2,8, 1974, English.. . Cigarette consumption and biood carboxyhemoglo.bin. (CpHib), levels were maasured during three consecutive periods of one week in ten volunteers smoking ciga.:ettes of prngressivelY lower tar/nicotine content (from 20 mq tar~/1.5 mq. nicotine to 4 mg tar/O. 14 mg, aicotine) . Cigarette consumptioz inc_eased'significantlp (P < 0.01) d'uringthe lov period and vary low period compared with the medium, period. The mean COt[b levelsfzll from 6.34 percent in the medium period', to 6.25 percent in the low p2riod and to 3.80'percent, in the very 1'ow period (low to very low, P<. 0.01). There was a decrease in butt 1'ength from 8.84m mm in the medium period to 7.20 mm in the low and. 4.54 msin the very lov period' (low to very loY, P < 0.01). , There vas~ a rise in the obsarved!/ezpected filter- nicotine ratio fro.m 0.62 in the medium to 0.7'7' in the low and 1.23 in the vary low period. These~ results suggest a change in: the smoking pattern. The fall in CoHb lev_l's did not correlate with the fall in the expected' carbon monozida (C0) dose as predicted by the smoking machine. When the- Co dose Yas corrected for changes in the smokiag pattern the values obtained: showed a close correlation with COBb levels., It is~ concluded-- that, on, changing to very low tar and very low nicotine cig,arettes, consumption increases, smoking patterns change, but COfHb levels fall. (Auth., Abs.)

79'-1i114 Yu2uc, C,; Kuinze, !!'. Aauclagewohnheiten von BSasenkrebs-Patienten: Versuch zur Quantifizierung der Schadstoffexposition. (Smoking Habits of' - Blaid3'er Cancer Patients: Am AttemFt to Quantif'7 Tar Exposition. ], aktue2le ' Orol ogie 10 (3) : 159-16,2, C:aY 197a:, German. There were significantly more cig;3rette smokers among eale bladder cancer patients than in the corresponding population g'ro~up, rhe tar expiosure of' =' _the average smoker in Jlustria has gone down as a result cf the decrease in sales of' nionfiltere3 cigarettes anithe decrease in tar content of cigarettes, Bladder cancer patients di3 not follow this trenid: 96 percent had' coasumeC' cig,arettes Yith high tar contents most of the tive; 52' percent saoked only high tar cigarettes. The iapSeaentation of a maximur limit of tar'content per cigarette would be of aajor iaportance for'the prevention :of,,.tobacco-assoc'iate3'.cancers and other diseases. (Aluith, Abs.,) 75-1252'.*W31d, N.; EHolward, S. ; Smita, P. G. ; Bailey, A. Use of. Carboxyhaemoglobia Levels to~ P.edict the Development of' Diseases Assoc_ated with Cigarptte S,aoking,. Thorax 30: 133-140, 1'97,5', Eng'lish. Carhoxyhecoglobin(CC1ib) levels in tobacco smokers vary thrcughout the day accordinig to the pattern of cigarette consmmFtion and the rate at which CCEb is eliminiatedl. A method is described whereby a single COSibt measuremer.t together with a recent ssoking history may be ased to est:mata the average C0Hb increase produced by each cigarette, the tctal dlaily carbon aoncxide (C'0), uptake from smoking, and the mean COr7b level throughout the day. These three indicas of tobacco! smoke absorFtioa ve.rr estimated in nz'nc healthy cigarette smokers on different days. The indices were reasonably reproducible withia the same person, and the differzmces betwefnl people were statistically sig,nificaat (p < 0.0011).. Thee s timat~esof ineand'aily C0Bb level resultin3~ from sm~ok~ingraniged f~rca; 0.7 to 9.3 percent in smckzrs yho sm~oked 15 to 40 cigarettes per day. These difie_er.ces are suf'ficiently large to distinguish possible differeacros iL the risk of developing' diseases such as iscfiemic heart disease~ which may result fzcm the inhalation andi absorrtion~ of tobacco saoke. ( AutS . Abs. Nod'. ) 100Si052823

76r011i9. L'a1d, N.; Howard, S. Smoking, Carbon Honoxide and' Arterial @isease. Annals of Occupational Hygiene 1'S (1) : 1~-1u, 1975, English. .. The role of carbon monoxide (CO) as a measure of' tobacco smoke absorption and as a possible cause of arterial disease in man is reviewea. Smoking is thie most important single source of exposure to Co, and, ~' frequently leads to carboxyhemloglobin (CO11b) levels above eight percent. liiost filter-tipped cigarettes produce more CO' than plain cigarettes. The miain factors affecting the uptake and elimination of CO are considered; a single COHb mleasurement combined with a recent smoking and, exercise history can be used to estimate the CO'Eb*derived from each cigarette. In one study in a factory population in Copenhagen, the proportion of' sub jects with coronary heart disease and/or intermittent claudication increased not only with tobacco consumption (11 percent among heavy, smokers and one percent among light smokers) but also with CClilo level (18 percent among heavy smokers with a CoHb level of eight percent or mcte). C0 exposure from smoking has been shosrn to be harmful in persons who already have coronary heart disease or intermittent cLaudication. The evidence that CO is also harmfulin persons without arterial disease is inconclusive, but animal data suggest that this may be the case. Some implications relating to the use of "'smoking tables'" and thE odification of cigarettes are corsidered. (guth. bbis. ltod.) 70-if149: Wynder, E. L„hiabuchi, K., Beattie, E. J. (7r.) The EpidernioloMr of Lung Cancer. Journal of the American. Medical Association 213(13):2221-2228, September 2'8,197CD. A retrospective epid:atiologie investig3tion of 350 lung cancer patients of the Memorial Sloan -Kettering Cancer Center observed between Noszmber 1'966 and August 1969, confirmed the close association between ci;arette smoking and lung eancer,, particularly of the squamous and oat cell types. New trends in this'stntdy show that, there is a decrease in relative risk for those patients developing lung eance'r ten years after they have switched to fi7ter cigarettes, possibly due to the lower "tar" content in fdter cia3rettes smoked by theu patients. The risk also deciunes after complete cessation of smoking snd appears to approach the level!of nonsmokers after 1'3'years of not smoking. It is su,;;ested that further efforts to produce less harmful tobmcco products be continued and' expanded' aPthou,lt no smoking or cessation of smoking is the most effective prevention av,ietsc lung cancer. (Auth. Abs. Mod.) ~_~e,. . . . 72-0578. Wynder, E. L., HotTmann, D. (Editors)' Less Harmful Ways of Smoking, A Workshop of the Second, World Conference on Smoking and Health, London„ September 20-24, 1'97'1. Journal of the Nationai' Cancer Institute 4'S(6):1739-1891, June 1972. This workshop was condttczed' to deI'ine what constitutes a less harmful tobacco product and'less harmful smoking habits and to seelc the cooperation of the scientific community and the tobacco industry toward further progress in this area. The pzpers presented cover international'research in tobacco and health, epidemiolo}cal'znd biochemical'studies on tobacco and liealth,and'model studies in tobacco czrcinogenesis. 72-0579. Wynder, E. L., Hoffirrtartn, D. Less Harmfuli Ways of Smoking. Joutnal' of the National Cancer Instiiute 48(6):1749-1758, Jur3e 11972. This communication sureests introducing ways of smoldngtha!t may be less harmful and that are based on the principle of bringing less smoke in contact with lung tissue which wi.tl result in less absorption of tobacco smoke. The discussion shows that cig3r and pipe smoking is generally amsocinted' with a lower risJc'for smoke-related disease, larD ly becatts', ci:zr and' pipe smokers rarely inhale deeply, and that certain types of cigarettes are less instrumennal' in the induction ot' ;ung cancer than others and' are also likely to offer a Iower risk for' other to'bacco-related diseases. Continuous mt:nitori:.g of human smoking habits is vital to the appropriate evaluation of tobacco products presently avaiInblz as well'as chanc:rt tnd. modified' products that may be offercd in the future. This information sliould provide appropriate guidelines anti incrn- tives for tobacco, industnes and governments interested in producing prmdlucts dtrsigricd to make tobacco smoking as hsmless 3s possible by scrting maximum permissible levels of the diffierent harmful components in the smof::. While in some countrics the tobacco industries are already movin;, in, this direction on their own, appropriate goverttm<tttal, directives to accontplish this end are favored where necessary.

Y_ F„0*"ih~ 41 V.-lall .

74-1215. aviado, D. tl.; Watanabe, T. Functional aad' Biochemical Effects on the Lung Follotiring Inhalation of Cigarette Smoke an~d Constituents. I. High- and Lov-Hicotinz Cigarettes in H.ice. Toxicology 3nd! gpplied Pharmacolo3y 30 (',2) : 185-2'00, xovembez 1974, Eng,lish!. If cigarette saoke causes pulmonary e-mphysema and chtonic bronchitis in man, then pulmonary impairment should be noticeable on lu.ng~ function t,sts. Sviss and I'CE 9ouse strains were used, to test this relationship. Daily inhalation of cigarette smoke for five or taa veaks~ elicited an n increa se . in pulmonary compliance, a decrease in fuacticnal residual capacity, a decrease in pulmionary compliance, m.decreasa in tidal volume, no changa in phospholipid content of the lung, and an increase in vet weight of the lung relative to, body weight, which was reduced. The iscrease in pulmonary resistaince and' the decrease in functional residual capacity were elicited by nonfiltered smoke as vell as by the vapor phase, and their appearance was related to the nicotine content of' the -'igairettes and the d'uration of exposure. Thiese results ind!icate:that these two effects are elicited by a combination of the nicotine contained : in particulate material and constituents of the vapor Fhase. The d!ecrease in pulmonary compliance aras elicited by inhalation of nonfilt_red smoke but not by the vapor phase,, indicating, that the causative Sactor is in the particulate matter, probably nicotine, because the appearance of decreased compliance depen&ed' on the: nicotine content.. The~ decrease in tidal volume as Yell as the increase in: pulmonary' resistance, or, bronchospasm, occurred more readily in ICB strain mice than in the Swiss strain. Both strainis developed, tolerance to broachospasm after ten weeks of exposure. There tiras' no incraase in fuactional residual capacity and, hence, no functional sign of pulmonary emphyszma in mice that had been erpos2& to cigarette smoke for five or . ten veeks- ( A'uth. Abs. Codl. )

79-13148' B'ernf'eld,, P'.:' 8omburcer, F, : Soto, E'.: P3i, R, J. Ci'g,arette Saoke. Inhalation Studies in Inbredl Syrian Golden Mazsters, Journal of the National Cancer Institute 63 (;3) : 675-689, September 1979, English. Invasive carcinoma of' the llaryr.x was induced in 36~,8' percent of i'nbred Syrian golden haasters from strain E10 15,1'6, susceptible to this type of , cancer when exposed toismoke from reference filter cigarettes for 59 to 80 weeks, xear'ly: half the animals (u7,u percent) shored laryngeal cancer, inc3udling noninvasive carcinoma and carcinoma, in situ, which occurred with daily smoke exposures (twice a day for 1'12 min each time, for 27' sec out of' each a,in) 7'days a week at smoke concentrations of 22 percent. Yhen the smoke concentration was reduced to 111 percent, the number of induced lesions was reduced'Froportionately, when a portion of tobacco was replaced in the cigarettes by a tobacco supplemens (Cytrel) a reduction of -carcin.ogenesis proportionate to the Cytrel content of the ciqarette took place. Smoke from, cigarettes cor.taining only Cytrel and no tobacco induced no carcinomas under the conCitiocs used. Other dose-related changes observed were laryngeal paFilloe+as, laryngeal epithelial hyFerplasia, . tracheal epitheliall hyperplasia, and metaplasia and accumulation of a1!veol'ar macrophages. Tar deFosit,ion in lungs and larynges was determined ina a separate study by means of a marker (d'ecachlorobiFhe.nyl) added to the cigarettes, Admixture of Cytrel to cigarettes reduced ta€'deposition in the respiratory tract, vhich: paralleled the decrease in the incidence of laryngeal earcinoma, However, the amounts of tar d'eposiied' in the larynx when 100 percent Cytrel was ssoked: were still signlif'icant, eventhouich no earcinoaas wer-e observed. Thus, smoke from Cytrel tobacco~suppleuent may be less carcinogenic than equal amounts of tobacco smoke, (Auth. Abs,)

79-11I2& Bozall, 8. B.; Field, E. 0. Substitute-Tobacco Tar Toxicity. (Letter') . Lancet 1(a!Oo7):: 773, 1pri1 8,, 197'8. Eng,lish. I'nvestigatioa of' the mutagenicity of cigarette condensate from ""Silk Cut" both with and without tobacco substitute material revealed' that both types exhibit mutagenlicity (Ames test). However, only 7 percent of the~ total tar is derived' from the substitute material. d'ouse skin painting tests have shown, a significant reduction (1p<0.05) in tumorigenic activity in cigarettes containing 50 percent ""1Cytre2" (contributing, 19 percent off the total tar) compared with all-tobacco cigarettes. The use~ of substitute materials facilitates reduction of' total tar content in less hazardous cigarettes, with resulting' health benefits for those who continue to smoke. 76-0974' Brun,aemana, if. , D. ; Hoff maaa, D. ;, Wynd'er, E. L. ; Gor'i. G. . 8. Chemical Studies on T'oba~cco Smoke. . XXXVII. Determination of Tar. Jiicotine, and CarWon Conoxide in Cigarette Smolce. , A Comparison of Iater'natioaal Smoking Conditions. pp.. 44 1-449. 1976, In: Vynder, E~. L. ; fioffmaan, D.;. Gori, G. B. (Editors)',. 8odlifyinq the &isk for the S'moker, Volume 1. Proceedinqs of the 3rd World Conference on S'mokin4 and Health, Dtew York, June 2-5, 1975. DdE:iP'ublication No. . (NIH) 76-1221, English. A U. S. non "ril ter cigarette and a U. S. f ilter cigarette were smoked under the various sm1okinq conditions that are declared standards of' sevea countries and one l~n:ternational organization. The values, as reported for the methods of different countries, varied for the noafilter cigarette betveeni 29.4 and 42.6 md for tar, and 1.73 and 2.09 mg for nicotine, and for the filter cigarette between 18.1 and 21.9 mq for tar and 1.31 and 1.42 mq for nicotine. These siqnificant differences must be considered when tar and nicotine data for cigarettes of various cou~ntries are evaluated. This study also emphasizes the need for standard smokinq, procedures to be used internationally. A correlation was found toa tar and, CO of 3'2 exper'imental nonfiltar ciqarettes made with the same cigarette paper and of 68, UT'.S'.. comne.rcial filter and nonfilter cigarettes. The correlationi coefficient for the commerciall cigarettes was less significant (r=0.o1) thaa the correlation c'oefiicieut of the experimental cigarettes (r=0~.81) indicating, that cigarettes can be marketed with some selective reduction of CO in the smoke. This finding, of differences in the smoke CO of commercial U. S. . cigarettes and the possible selectiva CO reduction support the concept that in addition to tar and aicotine. CO values should' be reported. (Auth. Abs. ) 1005052828

70-0533. Burton, H. R. The Pertinence of Tobacco Product Modil:cation to Chemical Composition and' Biolo¢_ical Activity. In: G~ciffith, R..B'. (Director) Proeeeding; of the Tobacco and' Hezltfi Conference, Conference R~eport • 2: February 24, 25, 1970, Lrxington, Kentucky. University of'Kentucky,, Tobacco and Health Research Institute, 1970; pp. 21-28. On the basis of research at the University and results reported in the literature, data are presented which show significant alterations in smoke composition as a result of add'ung, compounds such as sodium nitrate, sodium molybdate, sodtum stannate, ammonium vanadate, and potassium chlorate to tobacco before cigarette manufacture. Smoke yields and composition are aiso affected by product changes involving the type of cigarette paper used„fi7ters, and inclusion of reconstituted tobacco. Moisture content of the cigarette afFects smoke yields and composition. Biological activity of'smoke condensate as measured by tumor production oni mouse backs is affected by chemicai' additives ~ to tobacco, the inciusion of reconstituted tobacco, moisture content of cioarettes, and extraction of tobacco with organic solvents. Acute toxicity of smoke as measured by inhalation techniques is also affected by some or all of these product modifscat2otu. In some iastances mouse skin activity may be reduced but acute toxicity increased, indicating the need to conduct more than one kind of bioassay before eoncluding tsut a given modification resttlu in a , "safer vroduct" (Auth. Abs.) 78!-0763 Pyckiing, E. Ontersuchung der FiitErYirksazkeit des IaDncstraz.gies bei Cigaretten verschiedener fiarte iz lbaanyi3ftit votl der a'n,csuchlazga. [Filter Effectiveness of the Tobacco hod of Cigarettes of DirraraLt Bensities ir fielation to the Smoked :.enyta. ] aeitraege zur Tanioxforschung 8(6') : 3'82'-3'57,, June 1976, German, with cigarettes of diff.ering density tae smoke condensats aua nicotiWe yields in re2'ation to the smokedi length ot' tne cigarette Verii aaterminad. The aacunts cf these substances QuriLy tz2 saoxistg of the first third are generally saal.ler in cigarettes Lith Liyh dlrnsa.ty, about the sama in tae second third aina only in tae last thsrd' are taey greater than .:L cigarattes with low, density. The iilter efficiency ot the tobacco rod' ria~ mctermzzed by smoking equal lengths of rcd cf tne normal and the shortenas cigartttes. The coef'ficiEnt of filtratioa was caiculatEfl. TLe coefficiezt or t3.itration . (mu), is, for condensatE, independent of the iangth of the fil.tar+ng tobacco rod. For the nicotine retention, on the other hand, a clear cLduye ir, the coe f'ficient cf filtration is shoca. The ss"tration power of tLa tobmcco, rod declines vita, decreasing lengthi. The causes oi' this haYe nct Y,at be<n investigated in detail. These results aprly vottt to,filter ana pias.n cigarettes. The coefficient of' filtr3t+oL ('$u) increases in tr.,;. area investigated almost linearly with the aeLssty. The median ccezr;.cieLt of filtraticn for nicotine is nearly 60 percent of' the coezficiez,t ofl filtration fcr, connensate. I further iZvestigaticn was condactii isto, the influence cf the puff freguency on tae couaensate ana nicotint a,aounts. With a ccnstant p.uf.,60 numoer, cigarettiis Vare smoked with changca puff frequencies and the smoking values for s&oka coa&ensate and nicotine content were ccmFared' riith each cther (j.,&r c:.garette and pier rus=) .(duth. Dbs.). 100 5052 8 ~9

7~5-0159'4 Dontenrrill, W.; Chevalier, S.-J.; Harxa, Ii.-P.; 1Climisch, H.-~I.; ~, •irig,k, C.; Reckzeh, G.; Schneider, Bi. untersuchungea uber don cffEkt der. d kb `1~_ronischen Z:igarettenra chl.ahalatioa beiz syrsschen Goldhaaster un, m er die Bedetung des Vitamin A auf die bei b'eraucauag gefunden Orgaaveranderung2n. .[Studies on the Sffi:ct of' Chronic CsgarEtte Smoke Inhalation in Syrian Golden Hamsters ana the Imr.ortaaca of vitamin A on C.orpholog'ical Alterations after S'moke B,xFosure. ]', ZEitschrift icrensforschua und Klinische 0'nkologie 89' (2') : 1'53-1 cs0, 157'7, Gteraan.. Chronic inhalation of cigarette smoke fromi reference cigarettes and modified cigarz~tes induced different stages ©f leuxoplaxias and carcinomas in the larynx oi' Syrian Golden Hamsters. Incydence and intensity of alterations were distinctly dose- and tise-depiEndent; moreover, they were '' dependent on cigarette type or its tar ccateat. Laryngeal changes were less in the group exposed to smoke flrom c.Lgarettes vith, a low tar content. C1odified cigarettes were made from 50 percent ot the tobacco, mixture froa reference cigarettes and 50 percent of' pufiEd tobacco, tobacco sheets or ~' new smoking material. Smoke exposure reductd' oody weight and' increased iaflammations of the nasall•and' oral cav;.ty as well as the nuimfer of pt7alcliths and the incidence of "'"saoxe-cslls" in the lung. The nnmber of spoataneous tumors and iindings in the iuver, spleen, kidney and adrenal glands as well as vascular diseases yare not dependent on treatment. kd'3itior.al chronic treatment of 9itam.:n A inauccd a considerable increase of laryngleal papillary leukoplakias ana a d'istizct decrease of verrucous leukopZakias. An increased incidence of cares.aomas could not be observed. inimalls treated with Vitamin A and smoke more oiten, showed tumors in the thyzoid' gland. The survival time was reduced. llniaals treated only with ~ ttamin A showed an increased' rate oi dysplasias and carcinomas in-the `--~ .igestive tract- (gluth. Abs. )

74-©6T5. Gordon, B'. l.; Wiseman, $..F.; Pesti, L.; Bruckner, G.. ,Germfree lnimals. Proceedings of the University of Kentucky Tobacco and Health Research Institute, Tobacco and Health Aorkshop Conference , Lexingtoa,, Kentucky, pp.:360-38'6, !Sarch 26-28, 1973, English. Investigations on the Effects of Tobacco Smoke on Conventional and The purpose of this work was to studly the effects of' tobacco smoke and .of the airway flora on respiratory and related;, fnnctions in rats; . developaent of'a bioalssay on acute tobacco smoke exposure was also ~: :• type isolators nader conditions ranging from conventional to near- successfully tested, and routinely used outside.and inside of geraifree- 'consider-ad.. An apparatus for smoke exposure studies in rats was built, .steriLity. !leasurements of arterial blood pressure and regional blood distribution, total numbers, and composition of the flora s!uggested that subacute smoke exposure intensified' the penetration of the flora into deeper, normally sterile portions of the airYays; (2) on snoking, the d ele9ated in the hich nicotine g,roup.. A study on the regional depressed in low or intermediate cigarette nicotine groups, an& was episodes (particularly in abd~oainal organs) was normal or, slightly . via the release of catecholaaines; and (3) blood flow, .following these reversible on discontinuation of smoking, upito a threshold of approsimatel:y 3 mg nicotine/cigarette, and above this level either marked' depression or excitation phenomena.occurred; (;2) on using, specific blocking d'rugs it appeared'that these effects were indirect, mediated paralleling ''smoke puff/air breathing" cycles were fairly unifocm and flow in various organs of rats thait were exposed to acute, graded' nicotine-content sm3ke inhalation indicated that hyperteasiYe spikes, pred'ominantlT D.- paeumoniae type flora of normal rats shifted to a fora ,°in which fiemophilns Sp. , was sost f=eqnent; and (3) -exposure to low- or " hihiii g-ncotne content cgarettes did not particularly vodify these ., resnlts. , (Auth. . Abs. )

79!-0187 Go ri,, G. B. (Editor)!. Report No. 3. Toward Less~ Haza rdo cs Cigarettes. The Third Set of Zxperi2ental Cigarettes. 152 pp. 1 S77, U.S. Department of Health, Education, and Welfare, Public H~ea3th Service, National institutes of' HeaLth, National Cancer Institute, Smoking and Health Program, DHEW Publication No. ('SIH) 77'-1128'©. English. Experiments conducted since the earlT 11950!•s have indicatEd that certain modificaticnis of ciqa.rettes can influence tte chemieal comiposition, and tumorig,enic actiYity of the resultinq! saoke a3d! condensate. During 1!9b8' and : 19619, the Tobacco vorking Group andi the National Cancer Institmte reviewed -experiments, consulted vith doaestic and' fo rei'gn. ezperts, ainid f craulated a: set of experimental cigarette aodels for sntseqnent stndy in the search for the characteristics of' a less hazardous cigarette. The third' cigarette ezperisent• was begun in .1974, based, on- results from: first two series, on agronomic factors, and on-additionaZ industrial consideratiozs~. Erperimental variables in the third ezp.eris Ent consisted of: (1), tobacco additives that affect the flavor and chemistry cf the smoke; (2) tobacco addit; ve variations (sugar, cocoad and hnmectant) that affect the burn rate of, the cigarette, the flavor of' the! saoke, and the tumorigenicity cf the coadensate; (3), variations in paper porosity to evaluate the relationship, betveen this factor, and the tnaoriqenic.ity of the condensate; (4) filter var;ations to test the effects of'filtratior on the tumoaigenicity of•the, smoke ; and ('S) variations in artificial tob acco substitutes (AT S) andl physical characteristics to compare their relative tuaoriqeaicity. This .report details the ezperimental conditions, 2aterials and'Imethods e.ployed, including procedures of tobacco anialysis, ccndensate! preparatioln and bioassays, and presents the results obtained, in order to qualify andi support the cverall conc3usion. The resnlts can-be sumaarized as follovs: Comparisons aaonq the additive variabZes indicate that .agnesinf nitrate rednces the tnmorigenicity of cigarette condensate. itihen the adcitives. sugar, humectant and cocoa are compaxedl, ne3ther sugar nor humectant see~-s to affect the tnmorigenicity of the tobacco smoke at lover (12. 5 aq) dose levels bmt may contribnte to tumorigenidtq at- higher d'ose! levels. Powdered coc.caappea,rs to increase the- tumorigenicity of' the saoke at both dose levels. There were no significant differences, amonq the paper pcrosit7 variables or between these variables and Standard Ezperimental Elend III >' of the two artificial tobacco- substitutes (denoted by kTS-b1 and 1TS-B), 0 included, in this experiment, the 1TS'-3 cigarette fared ve1S Yith respect to redncingi cigarette tumorigenicity, whereas- the ITS-B cigarette fared poorly. EzperiAental difficulties arose- rith 1TS-B regarding th e solvent used in the second and' third ezperisents. Tt.is cigarette is beiIIg retested': dinrin4, the foarth ezperiment with. & dilfere=t soivent. (lnth. llts. Hod. )

79-018'8 Griest, W. 8'.; Quincy, H. B. ; Guerin, H. 8. Selected Constituents in the Smoke of' Domestic Low Tar Cigarettes. 20 pp. December 1977, Oak 8.id!ge National Laboratory, Analytical Chemistry Divisi=, Tobacco Smoke Research Program, Oak Ridge, Tennessee, 0&IN I/T:!-b 14w/P 1, Englis& C The Director of the National Cancer Institute Smoking and' Health Program has recently reported the practicality cf p roducing low risk ci garettes and' suggested that a ""critical number"• of' cigarettes might exist tihich, d'efines safe smoking, practices for each disease state. The ""critical number" of' cigarettes may be related to the quantity of saoke ;roduced by the cigarette. Tar, nicotine, carbon monoxide, oxides of 4troqen, hydrogen, cyanide and' acrolein were chosen as biologa.cally significant constituents of smoke vhich may serve:as markers of smoke production related to various disease states. Thirt7-txo brands of domestic, commercial cigarettes have been analyzedi for their production of the mzrker constituents and carbon dioxide. Cigarettes were smoked under standard smoking canditions by a smoking machine. 3esults were ezpressedl: as the average delivery per cigarette including, standard deviations. Tar de 'ivery ranged frcm 14.5 ' mc to 1.2 mg per cigarette, -Yith the nicotine delivery ranging! fro Q 1.03 tg to 011,14 mq per cigarette. Cigarettes of high tar and nicotine deliveries also produced relatively larqer amounts of'the other, constituents. High delivery iroducts considered, in the report are lcwer in delivery than most popular ,zoducts and therefore are still considered lov deliver7r: Results of the study are compared with Federal Trade Ccmmission data on tar and nicotine and vith the F.D. Snell Laboratory data for carbon monoxide, hydrogen cyanide and ozides of nitrogeni. levels in ci garettes. The data,  ay serve as an input to the computation of' ""critical aumbers## for currently availablee name' brands. -

72-04,64'. Hoffmann, D., Wynder, E. L SeIective Reduction of Tumorigenicity of Tobaccw Smoke. IL. Ezperimental Aipproaches. Jourrtal of the Macional Cancer lnstitute 4'8(6).1I855-I86i8, June 1972. Tobaceo smoke contains tumor in7tiators, tumor a+ccelerators, tumor promoters, volatile carcinogens, and bladder car• einogensi Most tumor initiators were identified as poi,vnuclear aromatic hydrocarbons (P?.H) and nioroa_encontairting heteroaromaticsi Tumor accelerators have comparable polarity, witlt the PAH' and are uiactive as tumor initiators andi tumor promoters. They increase, however, the activity of carcinogens and tumor initiators. So far, tumor acr.elerators have been identitied as Y.al!}.yl indoies, u-aihyl carbazoles, and 4,4'dicalorostilbene. Wolatale phenols and'some saturated rtd ttrtaaturated fatty acids, contribute to the tumor•promotiag, activfty of the the particulate mattex of tobacco smoke. However, most tumor-promoting,agents in tobacco smoke remain tobe identofed. It is suspected th'at the vofatile pirase of tobacco smoke contains trace arnounts of several twpes of eareuto, ns. Until' now; only some voiatile V-nitrosamvoes have been identifiicd. Thr only bladder carcinogens so far found in tobacco smoke are traces of ;3-rtaphithylamine and uf an ami'noQitorene: At present, however, enzymatic ehan;es ihdi7ced by inhaled cig3rette smoke are more likely cor^elbted' with. the higter risl: of the c9;anette smoke to induce bladdkr cutcer than the presence of traces o'f bladdzr carcirtogetis ut tobacc o smoke: Since the First World' Conference on Smoking and Healtih, a considerable number of studies reported on the reducti4n of the tumorieenicity of tmbacco srnoke.l'hese inclwzde reditction by changes in the agricultural practica off growing and harvesting tobacco, ehanges in the selectios of tobacco types and tobacco leaves according to stalk positiona utd' nitrate content, tlte modifacation of the curin¢ and ferrttentacion processes, andi the preparation of' reconstituted tobacco sheets. Modei studies with additiives contributed' to an understanding of uhe met:hanisms of the pyrofotmation ot the tumorigenic agenu in the smoke. Chemicali analyt2cal data and bioassay results are preseztted for the smokr tiom ci¢arettes made From tobacco stems and from different types of reconstituted tobacco sheets. I1he particulate matter t'rom tobacco sterrts was signii'icarttlv less tumorige;tic attd had'a si¢niuicsntly lower tumor.oromoting 2ctivity than that from thee latruna portinn. From tihe various types of reconstituted tobacco tested, t;he foamed sheets g3ve the mosc encouraging results with respect to selective reduczibn of total tumorigeniciry and~ with it, selective reduction oi tumor-initin:inY activity: Tlie possible imnortance in tobaccp carcinogenesis of tlte various types ot'components in the wax layer of tobacco leaves is also d'ucusved. (Auth. Abs. 41od.) ' 7'9-C77tt Hudson, &, D. Central Nesvous S7stem B'esponses to Cigarette Smcke I'nhalation ia the Cat, Archive_ Internatiotrales de P'harmacodYnaaie et de Therapie 2I37(2) . 19'1-212, F'el:rttar7 1979, English, Intaet, pentobarbital anesthetized rats (trith and vithout brainsteri stimulating electrode imFl nts) and unanesthetized S'herimgton (gamma- d'river) decerebratE cats ""saoked'' cigarette:s of varying nicotine content (D,2-2,5 ma) via a tracheaL catheter. Nicotine-free lettuce leaf eigarettes vere used as eontrols, "Smokina doses'" of' nicotine base (iD-2'5 mug/kg) vere ad!ainistesed intravenouslr for comparison. Smoke inhalation p€oduced mator ref'ler d'epression vhich paralleled' the nieotine content of the eigarettes ""smoked'',,Batellar reflex facilitation due to meseneepbalie reticular stimulation trac reCuced by doses of' nicotine and cigarette snoke, Cigarettes (2.5 mg nicotine) and doses of nicotine ('25-50 mug/kg, i,v,) significantl7 reduced rigidity and patellar reflex amplitude in the ganma- decerebrate cat, Ditsydiro-beta-errthroidine reduced the nicotine and' cigarette smoke induced patellar refl'ex depression but not the diminution in the riqidit7. Smoking doses of nicotine suppressed' pentobarbital-induced EE't; spindles in acutel7 prepared cats, Nicotine (1!)-25 mug,/kg) prod'uced EEC aad behavioral arousal in cats Yith chronic deep electrodes. It was concLuded that c'i5'zrette sQoke Froduces its pharmacolog,ical eflfec'ts via its nieotine cotztent, (Auth. Abs,) 10O5452834

0 llnalyses of the saoke of 2'20 brands of foreign cig'arettes frolm 11 nationss for tar ('T)i, 'nicotine (tt'), carbon sonoxide (CO) and carbon dioxid!e (C0(2)) are summarized„ The study zs part of an effort to compare the patterns of tobacco smoke related disease in the Onited States vith those in other' countries, in an international epideaiologic study of' the relationship betYeen tobacco usage an3 health,. The brandidescription and physical characteristic's of cigarettes purchasei ir. Anstria, France, Italy and the United' Kingdom are listej and compared, for T, N, C0 and C0 (,2) , Similarities and differences in the delivery of eonstituenits of the smoke of cigarettes for home delivery or for export are noted'. Cigarettes purchased' in Kenya and South africa are listed with brand descriptions and physical ch3racteristics. T and I content of the sane brand cigarettes var'y vid'ely in some calses. Filter, cigarettes often have particulate phase deliveries the saae or larger than nonfilter cigarettes of the same brand, Cigarettes . Furchase3 in Hong Kong, the Philippines. Sri Lainka and mialaTsia are listed' . with brand descripticn and physical characteristics. Cigarettes purchased in Scng Kong have high :' dleliveries and are iarorted from Japan andl China. Cigarettes from the Philippines and Sri Lanka and tSala7sia have high T'and I deliver'ies, Brazilian cigarettes are listed' with brand d'iescription, physieal' characteristics and smoke constituent deliveries. The T', l(, aind C0O deliveries from cigarettes of the same brand bot pmrchased in d'ifferent nations are also compared. Except for cig,arettes produced in Europe for consumption in Austria, most cigarettes with United Kingdom or United States brand nia.ies produced in smaller nations have ucb hig,her smoke constituent deliveries than their U,7C, or o.S, counterparts, ;,x~~;_75-1T'29 Jler.kins, B. h.; 4vincy, E'•. E.; Guerin, r„ R. Selected Cor:stituents • 79-106'4 J'enkins, R, Al,; 4ui'nc7, R. B,; Guerin, L, R. Selected Constituents in the Smokes of Foreign Commercial Cigarettess ""Tar,'• Nicotine, Carbon ttonoxide, and Carbon Dioxide. 56 pp, tlay 19'79', U.S. Department ofl Energy, Oak Ridge National Laboratory, Analytical Chemistry Division, Tobacco Ssoke. Besearch Prograa, Eng,lish,, tt.e Scokes of U;,S,, Ceamezcial C'icarettes: "I"Tar," );icctine, Carben, Rcnoxide and Carbon Lioxide, << F p., ndr 1979, Oak Rid©e National Labcratory, Publication ao„ CEKL/'T:'.-6270, Eng lish, . T'hF delivEries of selected sQck e constituents from 121 do¢estic cicarette brands were reported, Ecth filtered ' and nonfiltered cigarettes were ~ includ'ed' in the saa,:linc,.. The cig arettes were s'aroked throu5h standard Cambrida,e filter assemhlies, ur.der standard saoking condi'ticns. F.ounded values for tar, nicotine, cart-on convxide, and carbon 'dicxide deliveries were sudcarized. There r3s a stscna correlation betweer carbon coroxide and tar deliveries in filter eicarFttes, but nonfiltered cigarettes tended to produce less carLon monoxid'e trar. +roul'd' have been predicted f'roc. their tar deliveries. The adolur.t of ni'rotine was determined by gas ehromatcgiraFhT. There was a cood correlatior. bet.een carbon monoxide and either tar or niroltine for lower tar cigarettes (less than or equal to 13 mig per ,cigarette), but a poolrer correlatian fo: the hicher tar, cigarettes (>13I ag per cilgarette), In gener3l', there was no significant correlation between cig,arette physical cf:aracteristics and smoke constituent deliveries. 1005052835

76-01514 Leuchtenberger, C.;' Leuchtenberger. R.; Zbi'nden, I.; S'chEeA„ E. SM Reactivity of Ci'garette Smoke and Its Correllation with Carcinoglenic Effects high, N0 content of the gals vapor phase and malignant trans{ormation. T'here was no positive correCation for the other analyzed components o{ the smoker smoke from 7 types of cig,arettes containing variable amounts of parti;cutate and gas vapor phase components, atypical growth aradlor malignant cett : transformation were observed wtthin a period of 3-6 months. A. plosi'ti-re corretatiion, was demonstrable between hitigih nercaptan tSHI realctiivity aind . English af ter hamster tung ruttures were exposed repeated[y to puffs of tresh on Wlaaaster Lung Cuttures. Sozilal-urnd Prarrentirmedt'zin ZI611:' 47-50, lanuar i'nclud'ing tar content.t'Auth. Abs.l Health Service, National Institutes of Heal*_h, National Heart, Luzq, asid Blood Institu te, National Cancer Insti tute, Division of' Cancer Cause and December 1977, U.S'. Department of Health, S'dscalt,ion, and Welfare, PubLic ~ 78-1i25'3 National Cancer Institute. Smoking and Health. 1 Program to Reduce ',= the Risk of Disease in Smokers. Status 8erort--Diecember 1977. 128 pp. Prevention, English. developaezt of' the less hazardous c3garet te have been identified: high, porosity paper wrappers; reconstituted tobacco sheet b,lends; tobacco extracted with r:ater, hexane, or detergent; inert tobacco extenders; tobacco varieties d'evelopedl by new culture and curing techniques; filters; and flavor additives. The proposed future plans of the Smoking and Health Program involve expansionlof these studies, with further research into, individual susceptibility to disease, role of nicotine and other cofactors in etiology of tobacco related disease, marketing, of less hazardous ciqarettes and development of epidemiologic surveys to determine the effectiveness of the less hazardous cigarette. Program publications, .-ontract research, workshops, conferences and program ac'.ivities are listed un the appendices. ?,palmiozary functioa tests in doqs have been re:'ined, so as to be useful tools in pulmonary physiology research. Pharmacological approaches are based! nrnec the hypothesis that smoking represents a form of drug dependence (i.e., nicotine add:iction) , and that cessation programs and clinics must deal with the prob llem of' withdrawal. An inno vative approach involving the use of nicotine aerosols as a substitute for smoking has been studied. The dose response effects oflthe most hazardous cigarette smoke constituents for several diseases have been estimated. rar:y factors contrj buting too successf'ully implemented. Protocols for determining the effects of smokinQ on atheroqenic processes in doqis and pigeons have been, developed aad ,I program to reduce the risk of disease in smokers, sponsored bp the National Cancer Institute"s Smoking and! Health Program, has established three primary objectives: (1) identification of individual.s at high risk developing tobaccoirelated diseases; (2) development and evaluation of' pharmacologic and behavioral intervention approaclies toward smoking cessation; and (3) development of less hazardous cigarettes. Several accomplishments in the identification of' ha.gh risk indsviduals halve been of' made thus far. An extremely accurate dosimetry system to measure smokinq trends has been developed, and' a method for collecting epidemiological data on cbanginq smoki'nq patter^s throughout the world has been designed and 100505283G

. j~ 7h-1'291u Ovenl, T. B. Tar and !;icotiale From U.S. Ciqarettes: Trend's 0'ver the Past 2's+zaty Years. pp. 73-50. 1976, In: wyndEr, E. L. ; E3offmann, D.; Gari,. G. B. .(Eaitors) . Hodifyinq the Risk for tae S'.moker, Yolume 1. Proceedings of the 3rd '.or13 Conference on 5'aokinW ana Health, New York, .ilune 2-5, 1975. flaiEr Publication No. ('RZE) 7b-1'221I, Eng'lish. In 1955, American ciqarettes delivered aba ut 43 ' mg of' tar and 2.8& mg of'f nico tine. These values, dropped to 18 mq ot tar and 1.2 mq of nicotine in 137'S'. Tar and nicotine content of four izadinq nonfiltar and five leading filter brandls, weiqh*_e3 by sales volume, are used for trend analysis over the 20-year meriod'. Tar and nicotine received by Q.S. smokers were reduced' by a su!bstantially greater factor because oz the malrked~ trend to filter ciqarettes, and 80 percent of sales Yere in 20 brands deliverinq less than 25 mq, of tar Per ciqarette. Prospects for f urther reduction in tar and nicotine content, and the problem of consumer acceptability or' such brands are discussed. (Auth. Afls. ) ~ 75-0950. fobinson, J. C.; Forbes, 'J. F. The Role of Carbon aonoxide in Cigarette Smoking. Archives of Environmental Fiealth 30 (9)i: u25-43v, SEptember 1975, English... The carbon monoxide (C'0) delivEries of 20 major Canadian brands of cigarett_s, deterained by gas chromatoqraphy and asing standard'smoking zonditions, were estimated' and found to vary by a factor of about tyo. rhe CO yields were found'~ to, increase with puff volume and tobacco - moisture, decreasz vith increased, paper porosity, but remalia essentialSy constant with puff duration. The data suggest that reduced CC deliveries can be achieved by increasing, the cigarette paper porosity. Cbmbustion tamperatura presumably also influiences CO deliveries, but the relative role ascribed' to dilution and! combustion is not clear. It may be concludei, ta!3t smokers can lol+er their C'0 exposure by reducing, their p!uss volume, smoking cigarettes ma:aufactured from high porosity paper, taking, fewer puffsy anid decreasiBg their tendency to, inhale. . Since C0~ and tar ieliverias are correlated, these measures vould also tend to decrease a saoker's exposure to: tar. (Auith. lbs.) 100505283'7'

75-0y51. Russell, C'ol2, P. v'.; I3!le, B. S'.; kdams, h. Carbon Monoxide Yields of' Cigarettes and Their Relation to ;ticotime Yield and ry'pe of' Filter. British Cadicall .iournal 3(5975) : 7'1'~-73', July 12, 1975, Eaglish. Carbon monoxide (CO) yields of 1'1 popular brands of British cigarettes, two types of' cigarettes containing totacco-substitutes, and one brand of' c:gars were measured under standardized conditions. Yields~ of the canventional cigarettes ranged from 5.0 to 20.2 mg per cigarette (1.3 to 4.7 ' percent by volume) . The cigar yielded 81.71 mg (10.0 percent) Co and' the tvo semi-synthetic cigarettes 17.2 (4.2 percent) and 28'.2 mg (6.2 percent) Co. Puff'-hy-puff analysis. shoved an increase in CO concentration as a cigarette is smicJced. In btand's with nicotine yields over 1.0' mg no relatioaship was apparent between nicotine yield and CO yield, and the filters of cigarettes in this category did not appear to r_du,:.e thi_ Ca yield. In the low nicotine cigarettes with ventilated filters there appeared to be some correlation between nicotine yield and Co, y+e13, ain3 thase filters were highly effective in reducing C'o yield, oving mainly to the vantilation. (auth.. Abs. lSod'.) 79-0361' Sa mpson, C. ;Wynder, E. L. ;&of:xan.n, D. Perforated Fil ter-Tip Cigarettes: 'cffect on Tar:, Nicotine, and'iChirbon !lonozide Intake. ('Letters). Journal of the American Medical Associatioz 241 (3) : 295, January 19, 1979. Eag,Lish. _ Several brands of cigarettes use a: perforated' filter to air dilcte the smoke, which resuhts in very low levels of inhaled tar, and' nicotine. The question vas raised whether this technique could be duplicated by punching holes iZ standard cigarette filters, resulting in, a""safer" cigarette, and also aiding in smoking cessation. Another benefit derived from the filter perforation is reduced velocity cf the air drawn throug,h the bcrninq cigarette duringi snoking which increases the completeness of'coabustion.. 8ed'uction in tar and'nicotine content can ezceed 60 percent; reduction inn carbon monoxide is even greater. Hole punching devices are already or- will soon become available so that people who desire to per'orate, their ciqarettes may choose! t,hie deqree of air dilution of' the smoke. T$sts of one such device result in tar rednctions of up to 90 percent,, nicotine red!nctions of up to 80 percent, and carbon monoxide reduc.tions c.f upf to 95 percent. 8ovever, a practical consideration is that smckers may compensate for the change in draw resistance by inhal; rg puffs of qreater volume and velocitT thian those taken from an unperforated filter ciqatrette. 1005090-2838,

76-0195' Spears, A'. W. Pactors AffectzLI SmoJce Delivery of' Nicotine and Carboc !lozozidz. p:p. 12-18. June 1977, lz. 1975 Symposium N:cotine azd Carbat Mozozida, Proceedi:.gis-I, Qaivars_tY of kantucky, Le=ingtoa,. Kentucky, E:.31ysh. Nicotine and' carbon monozide ar=_ two of tae major ind'_v_da3i compoterts o.6' tobacco smoKe. !$owever, tile M_chaLisC.s t,hrJuyh 4Ythey cccur i» sao:3o are _u=te di_ferezt. Further, the abunnaLc€ of each is det_rn~!..-Ed' by some re' atiYeli :ndepend:nt variables. T'hNE;se var:.ables are briefiy rEvieved s:g ow- r.g tha t t:.e n:cotin e yi 6i d of' a c4g arEtt a;.s deter m:n0,d ry the ; nicotine contEnt of the tobacco; the static bur:. rate or amouLt of' tooacco , consumed~ during puffing; the prsssmrir drop of tLe tobacco column; poros;ty of the Y,r',apQer' aLd/or YeII.t'ZZtion at taE f.:.it_r; the pressllre drop of, tk3 filter, the filter ma't,er'iall; the surface arca of' the filter mater'iand ttc ,affinit'y' of tILe flllt6r material Zor L2COtiZ,~', particularly a's' a fur.ct_on of smoke pH. Through the coc.,ulLation of tLese v3riarias, pl_nt y'. g=Letics, ar-d commercial processes to remove a+cotire from tctaccoi, it is possible tomaw:pulatE the y= eld of r.z:cotiaE from about 0.11 a5 to 4 mg p=r . c sarette. Carno- moz.oxidE yield is aei~i&Ldect on tobacco burned during pu:f+: g and on tLa puff volume at th: aurLing c0n=_. Var_at,ons~ in tobaccoo compos:t' oa, as mediated by genetics zz.a comm~.rci31 process_s, are zot sign:f;.caInt with r_spect to carbou mor,oxide y.eld, except as they mediate th_ amount of tobacco burn ed durir.g ruzfiny. lmLiplulatiot of tte acount of tobacco burnEd' atd mWr.ipulatioL oz' tae kuff volume at ty= cone ssrfaca tI ver:t_Iation can prod!uce pra1cticml var-,at+ons in carbon moaoz:de yield froW aboat 5' mg to 25 a;g p=r c:garette. (buti. ADS. nod.) ;' 7'ti-1163 Tso, T. CI. : Gori, G. d. ; Hoifzmann, D. aeduction of tiicotine and' Ta= ' V; in Tobacco and in Ciqarattes ihrouqih Aqricultural Teenni.;,ues. pp. 35-48. ' 1,976, I n: Wynder, E. L.;, Hoffmann, D.; Gori, G. B. (z.iitors) . Codif'yinq the Eisk for the Smoker, Voiume 1'. Proceedinqs of the 3rd iorld' Conrerence on S'moucing, and E:ealthi. :iec York, June 2-5, 1975. DIiEW Publication No. .(NIIli) 76-1221 , caglish. . Recent advainces in aQricultural tecaniques in tobacco productioa havee made it possible to reduce nicotine ana tar content in ciqarette smoice. Low alkaloid 'oreedinq lines with 0.2 percent nicotine content have become avaiiable. Various production Practices are beinq, developed' for red!ucinq; the total tar content as well as for reducing the specific activity of cigarette smoke conaensate. The identification, of leai markers for a theoretical model, the dievelopment of homogenized leaf curing, the potential advantaR'e of hiqh density plantinq, and many neV approaches for post-harvest treatment aay all contribute toward tne production of safer toba cco. (Auth. ADS. ). ~2 10050'839

73-0920. Wald, X., Smith, P. G. Smoking Tables for Carbon Monozide2' ('.Letter). Lancet 2'(7834): 9'107-9,08, October 20, 1973, E'nglish:.. Regarding the publication of tables of the carbon monozide (CO) content of cigarette smoke, the authors argue that there is no direct evidence that CO is a cause of arteriosclerosis in huimans; CO has been: implicated as a cause of' this disease only in animal stud!iesl other substances present in tobacco smoke are inhaled together with the Co and also could. .be responsible for the increased incidence of arterial disease in smokers. CarSozyhemoglobin levels may not have a causal relationship with arteriosclerosis in smokers, but may be only a measure of inhalation -depth. A filter containing Hopcalite, a catalyst for the reduction of C0O concentration in tobacco smoke, is~ now being, studied in order to test the hppothesis of a causal relationship in a clinical trial on patients who are unable to stopismoking,. The study of Russell et all. on the effects of controlled rates of smoking on CC yield of' cigarettes is discussed.. See Abstract 73'-095'9. ,

BEHAU'IORAL ABSTRACTS

7'2-04I07. Ague, C. Nicotine Content of Cigarettes and the Smoking Habit: 'Iheir Relevance to Subjective Ratings of' Preferences in Srttokets. Psychophatntacologa 24(2)326:33I0; March 16, 1972. , . One tettuce4eaf and three tobaceo1 cigarettes with different nicotine content were smoked by 24 habitual' smokers in the course of' four successive sessions. Their previous srnoking habits were found to be scgrticicantly reil<ted to their preferences for the various ciprettes. 1Vhile the heavy smokers (more than 10 cigarettes per day) preferred, only the tobacco cigarettes and stroneely disliked the lettuce-leaf, light smokers disliked mostly the highest nicotinecigan:tte. These r,atings were also relat.ed to differences in the nicotine intake. These Finditugs support the importance of nicotine in the smoking habit, although other factors may be related to the likibleness of tobacco smoking. The relesrance of'this type of' study isdiscuxse.d. (Auth: Abs. Mod.) i 79-0629 ltnderson, u. H. liultifactrrial A'spects of the Chronic B'sonehitis-- EnphYsema C'omplex, pp. 327-3i42. 1977, In: Clark, :1', A, (Editor) , Pulmonsrr Disease• Defense ri'echan'.sms and F'opulations alt Risk, Proceedings of the Tobacco~and' •H'ealth Research Inistittste Symposium 2, Lexington, Kentucky, 7CFri1 12-14, 1977, Tobarco and Health Research Institute, English. Quantitative smoking characteristics were eoapared in a group of' 2016' individuals without cardiopulmonary disease and in a group of' 114 subjects with evidence o'_ airways obstructior, as a measure of ehronic obstructive puleonarp disease (CaPD), lto d'iff erences in such eharacteristics as to number of ci?arettes smoked, puff volume or nutnber, nicotine and tar exposure, an3 smoking ti®e were deronstreated. Therefore, the fact that one. group hiad' CCPD and the other did not must be explained by something other than the qualitaitive and quantitative o.anner, of smoking cigarettes. Studies of airway function were done in chronic cigarette smokers before, S minutes after and 15 inutes afte= smoking either a cigarette with more than 25 mig of tar and 1.5 mg of nicotine or a 2otr tar and nicotine cigarettte containing less than 5.g of' tar and less than 0.5 sq of nicotine. Those who smoked the low tar and nicotit:e ciyarettes smoked more insofar as the volume, duration of puff' and total volume of smoke from each, cigarette was eoneerned. Iieither the smoke from the high- nor the 1oV-tar cigarettes changed the F'rY 70-1144. Ashton, H., Watson, D. W. Puffng Ftequency and Nicotine Intake in Cigarette Sznokers British Medical Journal 3(5724):b7!9-6S'1i, September 19, 1970: , The smoking behavior of 36 subjects szttokin, cigar:ttes with different filter retentionieffciencies for nicotinewas, studied. Subjects were observed while performing vardou.s tasks on a driving simulator and also durin; a, resting period after the tasks. Smokers of cigarettes with high-retention filters took more frequent puffs and obtaine& nearly the same amount of nicotine as smokers of cigarettes with low-retention GIters; both while performing the tasks and'during the resting,period. Smokers of both types of'cigaret!tes took significantly more pu6fs and obtaitted more nicotine per unit time during the resting period' than during the tasks: The resuUta are compatible wit;h, the possibility that smokers automatically adjust the nicotine dose obtained from a cigarette to sornc "optiaturn" level which may vary withi different activities. (Auth: Abs••.) ~' 1005052842.

73-0925. Ashton, S'., Telford', 8. Smoking and Carbozyhaemoglobin. (Letter). Lancet 2(,7833) : 857-858, October 13', 1973, EEnglish. In response to the assertion of Russell and colleagues that an extra- mild (low-nicotine) cigarette causes a smaller rise in blood i carb!oxyhezoglobin (COSb) than a nonmild cigarette when both are' puffed at the same controlled rate, the authors claim that this is unlikely'to be trne for smokers smoking in their natural manner. For smokers whose '" puffing is not controlled, puffing rate is greater vhen they are smoking low-nicotine cigarettes than when they are smoking, high-nicotinie cigarettes, and the nicotine obtained from the two types of cigarettes does not differ sig,nificantly. People appear to smoke for a given dbse - of nicotine and to alter their puffing rate unconsciously in such a way as~ to obtain this dose fron different types of cigarettes. . Since the amount of carbon monoxide obtained from a cigarette depends, like nicotine intake, on puffing rate and depth of inhalation, a greater rise of COEb vill occur with mild cigarettes, the opposite of 8ussell's results in controlled conditions. To publish Co yield as well as tar and nicotine content of different brands of cigarettes, as suggested by Russell, could thus be misleading.. See Abstract 73-09591. 73•3:23 british Hedical Journal. Do People Snake for Nicotine? Erit~'.ish ~r: iedical .lcurral 2,(6094) : )©41- tQU2,. October 22', 1977. English. •~~ . . I Euaber of Fublished studies on the possible, role of nicotine im determinisg smoking behavior are- cited. Peeli=gs of deprivation uiponcessaticn of.nicotin!e injection have been reported, but recarded nicotine .abstinence syndromes may have more accurately been tobacco-abstinence .syndromes. Although puff frequency and propcrticn of nicotine absorbed' fron i': a cigarette appear to increase as cigarettes of__lomer nicotine yield are `_smc]ced, lou-nicctine cig;are.ttes also ha.e. low yields of other constituents ttat,ccntribute to taste and satisfaction; difficultl in. liqhtiag• and snoking some loti,-nicotiae cigar Ettes may be acre. responsible than nicotine for increased' depth of inhalation -or rate of Fuffing...A'lthough gun chewing ccnsinerably reduced cigarette consumption. in one study, chewing gus containizg nicotine: led to. little more reduction than. did. chewing n"'ptacebo"' gum. In other studies, a. limited red'ucticn in- smoJcing! folloeing i,r..tusion cf nicotine supports. the hypothesis that nicotine has a def iaiti ve, b nt small, role in the smoki8g habit.. I'nother: study polnt ed up differences in the diegree to Yhicb inhalation of' saoke _and intratemous nicatine affect the subject's subsequent desire to smoke.. Although nicotine content ct cigarettes has declined by about halE in.the Onited States and Great Britain in the last 15-20 years, -cigarette.consuoption has not doub2ed. The suaaar7 concludies by noting that. tcbaccole dependence is a complex Fhenomenon; ia addition to nicoti3e,•contribating factors likely include the ritual ef sanipuLating cigarettes in the'_ hand and' lips, the pleasures of taste and smell, the relief of ten_ion, and the enhancement of sociabilizY. 100505284'3'.

,- , 76-1291 Cherry, V. h. Recent Studies on Less fiarmfdl Cigarettes at the uiniversity of xaterloa, Ontario, Canada. pp. 1'03-11i0. 1976, Ia: aynder, E. L.; H'ofimann, D.; Gbri, G. S. (,Ed'itors). tiioliifying the Risk for the Smoker, Volume 1. Proceedinqs of the 3rd World Conference on Sdokinq and Kealtih, choiogical addiction as a function of nicotina content of cigarettes smoked was examined. There appears to be some Fs y telationshap, although it is not the most prominent dosagF factor, between nicotine and pslrchological addiction to eigarettes. Investi;ations of phy,siologicaU or pharmacological addiction to ci;arett~es have concentrated upon the primary ortance of nicotine in the addictive process. Results of the analyses performed sug;est the independence of' int p psychological' addiction to ci; zettes from thrunvalidated concept of physolo;icai' or pharrnaeolagical add'iction. (Auth~. Abs. Mod.) . vhica affect these dialiveries. Finally, tae possibility of using increasedd cigarette prices, brouqst about by increased taxes, is discussed, as a method os' discouraqisq cigarette soioKinq, particularly amonq the lower- income group or younq people, where there is evidence of'increasinW use ot cigarettes in Canada, especially by girls. 8vidence for the feasibility of tais approach is presented, including uorb usinq econometric models, andd some of the difiiculzies are also discussed. (Auth. Abs.) studies on individual smokers are described!, which indicate that the majority o,i' smokers can sxitch to a cigarette deliver~'inq less tar and nicotine without a marKzd attempt to coapeasate for the reductions by smoxiaq more intensely. Thirdly, vays oi modifying nicotine and carbon monoxid!e deliveries are discussed in terms of the cigarette c@aracteristics nicotiae deliveries o:: Canadian cigarettes is discussed' as a factor in the trend' toWards cigarettes with decreasing deliveries over the last few years in Canada.In addition, data are presented vhich indicate that this trend has not markedly affected the relative share of the market devoted to specific brands. It is hoped that the puDlicatioa of tar and nicotine deliveries on the cig,arette packages, starting on July 1, 1975, will further promote the trend to lower deliveries, since there is a continuinq slotr increase in Canadian per capita cigarette consumption. Secondly, Work is described oa several methods ot rzducinq the health hazards associated vith cigarette smoking. First, ta2 publication of tar and New York, June 2-5, 1975. DH-*-:*i Publication :io. (hii2i) 76-1221!,, Euqilish. 7'I-1077. Eisin,er, RA.Nicotine and Addiction to Cigarettes. British JourRtal of Addiction 66(2):1S0-156„ 1!971.

! 1 C C 78'-'J0'17 Eaal_, J. F. Pharmacology of b- cotize. pp,. 561-567. 1577', Ia: StainfEld, 3. ;~ G_iffiths, W. ; Ball, !i. ; iallor, H. ti. (Lait crs) . Health Consaqlien'ces, Ed'QCat'ion, CEssat-on Ac'ziv'1t:.as, aII,3' GJvcrnmental Action, . oluae II. Proctedli::gs oi the Third iorld Co:tErea'c- on Szoking and Health, New York, Jure 2-5, 1975. DSEW ' &ublicatiou No. (NIFO 77-1C13', English. The cliLicmS Fuar.t3colog,i'cal effects oz LicotinE as it is present in the main saokE s_ream d'2aand on the phy'sjo..oy;ical state of the subject,a the degree of' nicotine absorption, the eitent of thc habit, and the psychoiog'ical p_eaisposition of' the sWoxer, to mention only a' feVl coLtributing factors. It is to be noted also taat the poarnzcoloqicaS effects ot smoucir:g are not solely relalted to nico:.ine but are the end result of' the sWoka pE'r se and all oI its piarLlclllate matt'et. Tle' pcarmacology of r.i:.otine.als it bears airtc..iy on the smouing habit and' th= pha:macological inter9er.tion in, smoki.ng cessation are rEvieLed. There are, of c'aursa, many factors which itflu_Lcz tWe ansorptioa of nicctin'e from smoking. . A'mWng these are the form of tobacco, the contact time of' tobacco smok:ag with mucous membranes, the pii oi the boay fluial with which the ' smoke comes in contact, the degree and aepth of inhalation, the dEgree' of ha!":ttla_lon of th3 sGCJk=z, the ni'cot;:le con':.Bat ot tnle toba,ccosII'ok'ed, the moisture cron:en't of th= tobacco s'auokca, the l'1's2' of', a filter, the alkal:nitj or acidity of th= tobacco smokE and tn_ ru=f fr~quency. The human system rapidly develops a tQiiErance to nicoL-Ine. Zmr eic:tation, nausea, salivation disappesr. on the other soma smoxers aLa hy,pers.nsitive to n_cotine and exuibit increased blood prEssur_, pulse rate and decreased sr.-,;n temperatIIze aLter smoking a siL"41;z c;.yarette. N_cot'ine produces a nailtituae of Efi'ects re3atedl to behavioral caanges, cardiovascular =esponsas, a:.d pulmonary actions, efieczs vhiich are pr_dlictatle for the most part but whica are also in'+ luencEd by tnle backqrolu:.d, t-Jo;log:'cal and ,sych olog ical activity of tn e smoker. , I z is. tnis ulbiquitous nat ure of nieo_ine which coazouz3's phairmacological intervention oi its aeti,on in smoking behavior. 7T-J134'5 Freedman, S. ; FLetcher. C. tS. hicstine, Tobacco Substitutes, and' SmoKina Babits. (Letter).. British dedicall Journal 2(61032) • 419, AuaUst 14, 1970. Enc711sh. Tnis is a comment on Dr. . Ba'wbone 's articAe in British bedical Journal (Jnly 17, 1976) . The authors do not beliewe that svitchinq to low-nicoitine ci:v3rettes should!necessarily lead to a m'arked increase in ciQarette cons!umption4 Previous data are cited in w"ch the con'sumDtion increasedd from mean 32 to mean 3u. Th_y also aqree tiith the observaltion that when nen accustomedl to a low-nicotine intake svitc'L back to hiqher nicotine ' ciq3ret'tes they trY to keec the consuaption lov. Studies conducted by the alutnors show that estimalted nicotine dei.iviaries may differ from the macnine-smokinQ delivarTbq as nuchl as 01.4 mq. They snqge'st that reQular measure'ments of carbiorvhemoalobin levels c:ould be a, useful indicator of total szoke inhalation. See also Abstract 77-0357. , 1005052845

71-0327. Frith, C. D. The Effect of Varying t;he Nicotine Content of Cigarettes on He::aan Smoking Behavior. P,ycho- pbarrnacolo;ia 19("?):1I8S-192, January, 21D, 1'9711. Nine subjects were given: cigarettes to smoke contrinin;, three dif -rent amounts of nicotine. It was found that the laroer the cont:nt of nicotine in the cigarettes offered tHe srnaller was the number, smoked during tlte eight-hour periiod.A linear relationship between nicotine content and'time to smoke a single~cigarette was found such that the more.nicotinee there was ia a cigarette, the longer a subject took to smoke it: (Auth. Abs:) i 70-0495. Goldfarb; T: L, Jarvdc, 141: E., G1ick, S. D. Cigarette Nicotine Content as a Determnnant of. Hur;iaaSmoking Bzhavior. Psirchopharmacologia 17(1):39-93, P970. bSeasures of smoking rate and psychologicall effects of cigarettes with varying nicotine content were made in IS subjects. While subjects did perceive differences in strength and quality -of the experimental lettuce cigarettes as compared to their own brartds, their smoking,rates did not decrease diffrrcntially over the nicotine grad'uent•. The decrement in: smoking due to the eXperimental cigarettes persisted when subjects resumed smoking their own cigarettes. However, the smoking that did occur in the absence of ' both tobacco and nicotine indicates that the habit iuelf often exhibits functirDnal autonomy from the physiological effecLs of nicotine. (Aut~h~ Abs.) 76-0576 Go I dfarb, T.; Gr i tze E. R.; Jairv i k, H. E.; Sto t eratan, I. P. Reactions to, Cigarettes, as a Function of Acotine and ^Tar''. CtinicaC P'harmaco I ogy and Therapeut i cs 19t b),: 767-772, June 1976. Engt i sh. ExveriRents-were carr'ied out to exatci'ne the, effects of ntcotine and' tar"' on the extent of, and! stibJect i've reactions to e i garette sznok i ng. It was conf i'rmed that sir.okers rate commerciat , low-nicotine cigarettes as less ""'strong" and, less "°satisfying•' than their usual brands. Since such cigarettes deliver reduced amounts of tar as wetl as of nicotine, an experiment to di.stingui!s!h between the two was c.arr iett out with speci'al cigarettes~. Ratings of ""'strengthr'' were directly rel'ated to nicotine: but were not af'fiected by tar. The numbers of c igarettes smoked fel'.1 sl ightliy, as their estimatedl del iveryc of' nicoti'ne Increased, but tar had no effect om this i'ndex. The ur inary excretion of n1coti'ne was corre.l!aited wiiit'h the rated yiletds of nicotirie toc the ditferent c1g'arettes, but there was also evidence that s'ubjects tended to! adjust their manner of smok1ng~so as to titrate their doses of, nicotine. The results are fnterpretedr as i'ndi'cating a role for nieotine, but not for tar, in the maint enance of cigarette s.a.oking behavior, and as support for the v lew that less harmful cigarettes should have a high: yilelld of nicotine relative to tar.iJ,'uth. Abs.lt 100505284& ~~.

\1 0 7'6-1!1d0l Gritr. E. B.; Baer-.eiss, V.; iarvi's, h. Z. Titration oi Sicotine. Intake ;iith r'ull-Leaqthl and Ba1f-Lenqth Ciqarettes. Clinical Pharmacology ind Theralpeutics 20 (5) : 552-556, aolvember 1976. Eaglish. Titration, tae selt-raqulation of' nicotine intak2, vas studied in 12 smokers by gals chromatoqraFh assays of urinary nicotine levels. Results demonstrated that excretion of urinary nicotine in the proximal condition (',half cigarette closer to the filter) did not differ significantly from the whole cigarette coudi tion; ho+:ever, less nicotine was excreted in the distal condition (half cigarette farther from the filter) because oi' a rod filtration eiiect. 3ubjActs extracted proportionately morz nicotine from % the hai,cl than from tua vhoLe cigarettes; titration was approximately the same in both half-ciqar=tte conditions. On scales of strength and satisfaction, fu11-1ength cigarettes Yere given the highest rating, followed by proximal and then distal cigarettes. It was suggested that in future studies of the various parameters of' puifinq, such as number of puffs,, depth of inhalation, and duration of puff, these parameters shouldd be co@pared among tae proximal, distal, and ful11-length cigarettes. (Auth. Abs. . C!'od . )' . 79-0516 Gritz, E. R. Patterns of Puffing, in Cigarette Smokers. National Institute oi' Drug Azuse Researcn Monograph Series 20: 221-235. July 1978'. English. An initial attempt to assess some of the parameters of puffing are presented. Paid volunteers wh!o normally saoked an average of one pack of cigarettes per day were ask:ed!to smoke cigarettes through a modifiedd plastic holdlEr containing a thermistor which was activatedd whenever air passea over it. ln some experiments, volunteers used smoke screens and - subjiects need only turn~ their heads to take a puff of a cigarette. Puf fing seconds or greater) and short (less than 5 seconds) puff to puff' (',P-P) intervals and a grouip who had almost exclusively long,P-P intervals. The former, were, on the average, heavy smo&ers (mean=30 cigarettesJday ) and were older (mean=5w years) compared to the latter group who were, on the average, lighter smorers (',mean-1l8 ci garettes/day ) and younger (mean=30 years). Light smoKers did not increase the number of'P-P intervals even when given quadruple the baseline number of cigarettes. However, heavy smoaezs increased' the number of' both long and short P-P' intervals when, the baseline cigarette number was doublecz or quadrupled. Smoking was depressed in the opaque screen ccnditi'on for all subjects. Puff duration and volume was significantly smaller when subjects had'abst3ined from smoking. Nicotine content of cigarettes affected only maximum rate of inhalation, or peakediness of the puff. Nicotine-free cigarettes vere inhaled' more sharply. when subjects were deprived, the maximuim rate of innalation was greater on the nicotine-free than on the nicotine cigarettes. by puffing pattern were revealed: a group who had a mixture of long (5 - :s.conditions of deprivation or no deprivation. Two Qistinct types of smokers T'parameters were also analyzed using nicotine-free tobacco cigarettes under 100'505284'7

75,-(5°S Jaff'e, J. F.: C.arzler, ". E, Tozacco~ and Nicotine Self- A'-'rir.istratioW ir. Mu.ans: '"he Eve1!Ltion of a nethoidolocy, pp. 2^i-22C. July In: Krasne_cr, i~,P, (',T_ditor). Self-Ad'sinistration of Abuse Su:atalces, aEt:.::ds fcz Study. t~~.ticn_1 Znstitute on Drug Abuse Research ?!cnec'r3'ph S'e'rles, Fo. 2., °_irelis::'. .::e, sElf-_':mtnist=_ti,on of nicctir.e by human.s vas exaoined in a latcrstory _tudy. "reii'rin-ry ezceric.en~ts were done to investigate how sroking varies as a ftncticr: of resroase cost. Sufl jects performed simple taskr and ti=re rewardeW r;:tF: a cicarette. Results showed that consumFtio~n .ent down as re_-or.=e Ccst i'rcreased aa'_ then rose again, but not to the st=rting pci'nt, a_ rez_zn_e cost was lowered. Ir, the mai!n test, the relationsbif betwee.n cveczil re_Fense costs and nicotine content of the ei.;arette purcras_a ::as ex_c,ire~, The 23', ss,okers (1'.5' wo©er., 7 men), were asxed to save ci.._rette buttr dL_inc a 2' veek b,aseline observation period ani each tiae the =urject cha*ced' bran3s. Isticates of daily, nicotine intake were y3Ce, Results 1rGi,c2ted b^havlCral differences between the'men, ar.d thp wozEr. Fewer ¢err trar. va;en_voluntEered f'or the study and only, four of tx~e severd coc::lEtec the tl2 yetk stu3y, The oPn who Aftnished shored sl7[uSCaS.t2'al r'e:llIIct.Qt'.s' 1'n,nlccflr.e and tar consumDtion,, Ttielve of the 16 vomen crrrleted' the study. All =~cre3 a rapid drop irn the intake level of nicotine in the tir3t E weeks and the jecline continued' aore 3,radua117, foLr the rest of t^e =tu'y. Pcortrric incentive_ did not seem to influence the sutjects to ss+itct. tc lox niccti: E ar.3 tar cigarettes. Subjects ter.ded to coasuGe sore o:' the cicaret'tP as the nicotine content decreased,. The teadenc} to inc,ale cere did not result in higher earbon monoxide Ievels. F.:esu:t= indicate that cci_1! factcss, coff'Ee or alcohol consumption aindi health eon:ce:as Qay tiay a rcl'e in deter:.ining the nuaber of cigarettes smokeC per day. Pcssitilitie_ for icaccuzate measurements in the test Yere actei

Jaffe, J, F, ; t;ar,rler, r, P*; alyinic Wh'at We iCno'v From other ltaaictionsc ?'27-?`.7c. In. 5_chw.,rt2 - 1 - . J. L. (rditor) , Proctess 1n' 5'mo'siay Cessatioc, f•rcceed'ic cs af Intzrnaticnal Co'r.ferencE on Smoking Cessation, New Yorx, J'une 21I-2., 1575, :nerican Cancer Society, Eaglish, Sicilarities and d_.':erer.cES between snoking and other forms of druwc use a're ex;lcre:, vi~to:ic=1'lp, cruS use in the United States and Great Eritalin has been suhject to the so'c-L&l cliGate, the cost and the availability of ,i the drug, ~s- t:ze _ocial e'siEZte ctarge's with re'g3ir3 to the aeceptability of , a 3rue, the characteri:tics cf the u'szr chances. Cass p'rodu'ced cigarettes of.Er2d a cheap, o:.ur.da: t sucr?y c: tobaece for the Fublic. Drug and' -._ t-0lo_cco c€?v,L,ny' is ittCnsif,iFW !2 sight of the subs't3nc'$. Patterns o',f ulse' for tobacco and c'ruc_ v_ry and the im_3et on health and social behavior may nct ccrrelata Ri'th the intake cf the 3'.I'ictive substanee, It is Fossible th_t d'ru;s or nicct:r;e have s;ecial a3aptive value for some individuals. Of the 3:, nill'ion z:or.ers vho have storpe3l smickina since 196,4, about 95 percent Qt3'Tt' on thEir o,wn. SCestici.'s '1r',ei ra2Seld about th!o'se who do not stop l1siL-, to'b3c'c?' or :ErC1ri hut s6::t,lt'ute lAwEr' t'ar' and'' nicotine cigarettes or, methadlome in an ef:'ctt t.' use less h.r_rdous substances, l compensatory increase in tt.e Frc; ortier~ er nucter of cigarettes smokeC was not generally otserved aesong, tncse whose ssitci:ed' to lover tar and, nicotine ciaare'ttes ' an_ rratev Er increases tterE werE were not suf'ficienit to offset the decrease in tzr sn d r.icetin e, In of' the lowered tar an3 nicotine romtf;;t, iil but t;:e' very lc.est had equal carbcn monoaide d'eliver7. Studies indicate the f.rezt cb;:acitv of the dr',ule user to deny the pos_ibili!ty of' aeverse effects ar:c de,:'ay, cFang,in'q beha'vior. Smokers, oore th'3fr, alcoholics acd cri_te u'sers, rasist c,haag,e.

75-CE54 Jaffe, J. P,; Kanizler, r, Seokiag as an Addictive Disorder, pp. 4- 23I. January 1979, In: Krasneccr, F, A,. (Editor). Cigarette Smoking as a De;endecce Process, National rnstitute on Drvg, Abuse Research !lonograph. Series, Ko. 23, DkE,w Publication Fo. (AD1) 79-$'00, English. This overview of the ad'dictive nature of' the smoking habit points out se1'ected sir•ilarities ar.d' d'ifferFnces between tobacco usaae and the drug u_ing behavior comdcnlr viewed as addiction in our societT. Speculation on the nature and extent of tobacco consumption in the future ils also made. Fsychol'ocical parallels related' to initial use are: (1)', exFeriaentation and, recular use beSinninc in youth;, (2) tendency for users to have extro.erted personalities; and (?) tendency of the majority of new users to quit eventuallY. A survey of studies on pharaacoloqical factors affeeting ' continued use cor.cer.trates or. the reinforcing role pla7ed by nicotine. Biolocical factors,, such as eEnetic predisposition, raT also affect smoking, haibit. Wi:thdratial symptom:s caused by cessation of'smoking are chiazacterizpd'. Titration and ni'cctine manipulation experiments revealed that a perfect eorrelaticn betveern nicotine levels and smoking levels does not exist, vhich, is still consistent with classic add!i!etions. Cessation, studies revealed that recidivism rates are identical for heroin, alcohol and ciearette users. Tobacco addiction differs from other types in the absence of toxicity due to overd¢sace, lox cost, and high degree of social acceptability. Chanqes in tetacco consumption predicted'for the future include: rrduction, but not elia:inatioa of' the smoking, habit; changes in characteristics of'the Forulation that smokes; and continued reduction inn tar az3 nicotine content in cicazettes. Concern is roiced that widespread use of less hazardous cicarettes vil'1 undermine t1ie ef:fo=t to deter sackinq in younq people, 79-0323 Jarvik, B. E. ; Popek, P. ; Schneid'er, , g. ' G. ; Baer-Weiss, 9. ; Gritz, E. E'. Can Cigarette Size and Nicotine Ccntent InflIIence S3oking, and Puf_ing Rates? Psgchopharaacology 58 (3) : 303-306, 1978. Eng,lish. The stimuli controlling the rate at vhich people smoke ciqa,rettes have not been clearly def ined'. On the hypothesis that smoking is bas icallp nicotine seekingi behavior, nicotine avaflable tc the smb ject was experimentally manipulated through controlling cigarette size and nicotine content. In Elperiaent I, sub jects given their osra, cigarettes in whole, half, quarter, and eighth lengths, increased' the number of cigarettes smoked and number of puffs to compensate for reductions in-size. Satisfaction ras directly related to cigarette length. In Experiment II', sub jects given special cigarettes deli9erin g 0. 2' or 2.0 ag nicotine/cigarette smoked s3gnificantZj more of the low than, of' the hig'hh nicotine cigarettes and took significantZy :ore puffs. ls in EzFeriaent I, signi',ficantly- more quarter length than fall length cigarettes were smoked, but total number of puffs did not differ. These results support the hypothesis that nicotine controls smoking behavior. (huth. lbs. ) 100505-2850

79-0519 Jarvik, M. E. Self-Administrat,ion of, Cigarettes With Varying designed to examine these variables. Paid volunteers were tested using A smoker can control his nicotine intake by varying th~e rate at which he lights cigarettes or by, modifying his puffing rate. Experiments were . . Tobacco and Nicotine Ccntent. National Ins.titute of Drug Ablise Atesearca Monograph Series 20: 236-243. July 19'75. English. trendi (F = 1!8.30, p<0.03 ). T-tests performed bet:reeni all p~ossible, pairs of occasions these same brands were given in whole, half, quarter and one eighth lengths in random order. As the cigarette length decreased, the number of ci'gatettes smoked increased (F = 14.85, p<0.001 ) with a linear .. d'ay, volunteers smotced' their own brand of' cigarettes and on successive special cicarette holders which recorded puffs against time. On the first = means for number of ciQarettes were si3nificant at the .01 level except 0 .betWeen half and quarter lengths. The number of puffs was greater for shorter ci5arettes and the differences were significant ( F= 3.9'1 , p<0 .01) and linear ( F=6.33, p<0.03 ). Differences between whole and quarter, half and quarter, and half and eighth, were significant by t-tests. The average numoer of puffs per cigarette decreased with decreasing lengtn.. Satisfaction was inversely proportional to lengtn, i.e., shorter cigarettes were less satisfying. These changes were also~highly significant. The seconc experiment was designed to examine the effects of varying both nicotine content and length of cigarettes. Experimental cigarettes delivering 0.2 mg or 2.0 mg nicotine per cicarette were used. Suojects smoiced ainC puffea more: on low-nicotine than on hich-nicotine cigarettes. S1,milarl'y, subjects smoked more quarter length tnan full lenigth cigarett'es. All of these differences were highly siignificant. The subjects puffed proportionately more on the short cigarettes. The number of puffs per cigarette remained constant in the face of crnanging, nicotine content. This indicates that number of cigarettes smoked and not puff'ing rate was, used too compensate for cnarnge in nicotine content. The satisfaction ratios were low and approximately equal for noth nicotine content and length. There is a suggestion that subijects dis3iked'all of these experimental cigarettes ... since their satisfaction rating, ranged around' 4.0 or lower, wnereas subjects rated their own cigarettes in the previous experiment about 5.2.. It is very likely, that the nicotine deliveries were either too hich or too: low,.certairaly not the middle range of 1.0 to 1.5 that the smOieers were accustomed: to.

n ~ ~J. 75-0190. Kozlovski, L. T. ; Jarvik, n. E. ; Gritz, E. R. Nicotine Regulation and Cigarette Smoking. Clinical Fharmacology and Therapeutics 1!7 (1) : 93-97, January 1975, English. , study was conducted to determine +rhether there is nicotine re!gulatioui in cigarette snoking. Both cigarettes- and a chewing, gum ccntaining nicotine were administzred as '•1prelaad's''. Since tar comsuimption covaries with nicotine in cigarette preloads, the purest test of a regulation effect is found by looking at the effect of nicotine level in all nicotine gum.conditions combined. The 56 subjectsin the blind study had a m~ean average daily cigarette consumFtion of 20.75 cigarettes and had smo~ked on the average 5.9 years. The results shoved! evidence of nicotine regulation. digh, nicotineprelload vithcigare~ttes (1.3 mgi nicotine, 191 mig tar) produced a significantly, lcnger latency period to the next cigarette than low nicotine loading (0.3 ag nicotine, 1u ag ta=) . With chewing gum, high nicotine prelolading (4 mg nicotine) significantly shortened the total puff-time duraiticn compared' to a low nicotine preload (1 mg nicotine). The different ef.ects of nicotine in cigar,ettes versus nicotine in chewing gum are discussed. 7'9-0592' Lader, M, Xicotine and Sr.cking 3iehaviouir, 9'ritish Journal of depeadeace, A potential major contribution to, the stud7 of nicotine andd szokinig in the recent dIevelopeent of techniques for estimating nicotine and' its eajor aetabiolite, cotinine, in body fluids. The significance of studies on.nicotine excretion, in the urine is also discussed. It is noted' that the route of' nicotine adcinistration is of si'gnificant i!aportance, since inhaling produces more pleasurarle effects than ingestion or injection. N . Q Q. CJ1 ~Q • AI ~ M electroenceFhalogras ac.cificatioir., assessaent of effects of nicotine.on behavioral tastes are also evaluated, and incl'ude observations of changes in smoking characteristics and task performance when the nicotine content in eiaarettes is aodified,. In a series of dif'ferent experiments, it was found that smokers vary their hatits onlY, slightly to adjust to nicotine content. Tobacco dependence aFgears to involve nore than nicotine ;depression of spinal reflexes; respiratory stimulation; and Clinical Pharmacology 5(v.): 2P°-292, April 1978. English,. In this editorial, evidence that nicotine is the habit maintaining agent in cisarette smoking is reviexFd. The physiological actions of nicotine which are repilicated by cigarette szokinig are described'. These include: stimulation and deFression of chclinoceptors in autonomic ganglia and neuromiuscular j'unctions; catectolamine release from adrenal aedulla; ~

77'-3357' Hawbone, B. G. Hlirotine. ;ooacco >,Lbstitutes, and Smokinv H'abits. (Li= _a_Y. British !!ad'ical Journal 2'(1E0,-o) . 177, .dulY 1'7', 1970. EnuLish. Dsirica 1975 the author inv=_stiQated sub3ects smoking the tobacco su!bstitutes hSM (new smokina material)' aL,;. Cvtrel. Subjects smoked both 3 p;oiurt containinai 40 merceat substitute ai.d a matchzd control containinu .10i0 percent tobacco oroduct. each for 24 aours srith an intervening period of seven days. Follo:inaeacro sm'okinQ oer.od five cigarettes were clhain- smoxed and the butts collected! and anaiyzt_s in terms of length and filter nicntine. An estimate of tLa smokers' aost of nicotine (observed nicotine) was calculat:ed'froim the filter nicotinea..,s ""filterretention fact:or: "' I • for each sublect an indication of the m3nLar in which the ciaarettes had bean smoked' may then be obtained by consiaeri,nq the ratio between the obse=ve3 nicotine and the nicotine viaL3 c,s machine smoking (expected, aicotine) . The results indicate: (1) tLat the HSH product was smoked to a :siqxificantlv shorter butt length than thw control: (2) that all subjects received sianif icaintly less nicotine LaEn smoJciac the substitute prod'ucts: (3) that the substitute croducts vere beiLu sianificantlv ""overssoked,'''' rrhizh miQht su!acest an attempt to comm~=E,snte for the reduction in nicotine.. See also Abstract 77'-03W5. - 7'u-0422'. Russell, !!. ~. H. Realistic Goals' for S'moking and' &ealth. -A Case for S'afer Svoking.,S.ancet 1(17'851') : 254!-25,8, February 16, 197'4, English. ,. Evidence is preseated' demonstrating the-crucial role of' nicotine in the generation and maintenance of cigarette dependence, the potency of srhich ensures that almost anyone who smokes at all becomes dependent. It is suq'qested' that this high d'eaendence-oroducina flotencv and the nniversal - : a eal of the eflfects of nicotine lie behi d th t fail f ki ,,~ k pp n ures o e pas smo ng ,control programs.. Zn this cuntezt, the goal of abstinence and thee abolition of all smoking is unrealistic and d'oomed to fail. The more realistic goal of safer smoking is explored. It is argued that the carbon ~•-` sonox'ide (iC0) yield of' cigarette brands should be, adde& to the official .tar and nicotine tables and that the safer cigarette is likely to be the one with low tar and CO yields -but a high, rather than low, nicotine yield!. However, the nlti,ate goal of acceptably safe, light to moderate, controlled smoking will probably require the virtual elimination of cigarette smoking in favor of noninhaled smoking of pipes or sediQm to larqe cigars. With the combined effects of health education coupled too selective taxation directed at this more realistic goal, success is not only possible but probable. O1uth..Abs.)

75-1i2 41. Eussel1, Y:A.S'. Safer Cigarettes. (Letter),. British If_d'ical laurnal 3(,5974) ; 41 , July 5, 1975, English. The int:oduction of safer, cigarettes is commemdable as a me.asure' to reduce smoking-'related diseases. Efforts in this area are more likely to be productive than tr dlitional antismoking methods. Filtered cigarettes were the first measures in safe smoking. Ventilated filters made it possible to red'uce tar, nicotin'e', and carbon monoxid''e yields. The' disadvantage apparen't here was that smokers ccmpensat2 fcr lover nicotine intake by inhaling a greater volume of smoke~ and eventually changing to high-nicotine cigarettes. This evidence sugg;ests that the ideal cigarette would have a medium nicotine yield, approximaltely 1.0 mgi, and low yiel'ds of ta: and carbon monoxide. While~ such cigarettes would nat h'e completely safe, thiey roul'd satisfy smokers who require nicotine, and reduce both lung cancer, which is associated with tar, and cardiovascular disease-, vhich' is associated with carbon monoxide. C 79-1'^3 P.ussell, r..3,li, To}acc'Q Ilecen'_ence: Is NicotinE F'ewarding, or Aiversive?' -F, 1:~s'-122. January 1!97'S, In: K'rasnecor, 1!. A. (rlitor). Ci.;arette 5':cokir.g as a r.eper.d'Ence ?rocess, F_tional I'nstitute on Drug Abuse R ESe?rch' l10CD'crLph Series, SG, :2 , ::1Y11St1. The role of' nicotine in totacc.c deoe'n3er.ce is discussed''.. Peview of thee data availatle irn tse literature raises many questions but provides fev, answers bleycnd the :cl~lcvir.c crrclusio'ns• (1) r~harQacolocical reinforce~sen't is not a'n essential fe-turE of ac?'ictive~behavior; (2), There are many nonc;arc3colioaical factors involvec' in tobacco sWokin,, and these ap'gear to be sufficient to generate strong decenlence in =::okers who do not inhale; (3') The low acce, ta:,ait}° of 1c.-r.icctine ciya'rettes is not necessarily du'.e to the reduced nicotine conttr.t, aor.phac:acologica'1 factors are a1so, involved:. (,n)' Smok'ers yllio i.atale iii~Qem to, tolerate a decrease in, nicotine intake better' than an increasE;, (,S) Simply, because nicotine has many pharc~acological effects in sccl:ir.c cosesi, i't does not follow that these effects are reinforcing rcther thar. aversive; ('6): E'vidence is scanty that~ ar.ir.als will' self'-inject nicotine as avid'l'v as they, do otf:er addictive drugs; (7) Rpart :roQ circur.startial histoiricall evi-d''emce that people have never shown, a str'on; ir:clin:: ticn to iatiale smok'e tr.at does not contai'n a psychoiactive druc,, there is no direct exFerimental study which shows that nicotine is pharmacclocic3lly re+a.:diny, or reinforcing' in hiumans; (8) k'hzther or r,ot nicotine is p'tarr:ecoloqically rE4arding' in optimal dose's, it seems to become averrive vhE* these doses are exceer:'ed; (~9)i The hypothesis that people smoke and inF._le for ner.ohararaeological rewards, including thee taste and irritatcy of nicoticQ itsel'f, bu't are inhibited'from smoking more because they finic excessive r.;cctir,e pharmacologically aversive, has not yet b'eer, disproved; and! (1,) Tf;p ir.Flicaticns for safer cigarettes remain the same aoi matter wFethtr nz'cotir.e is rewardi:na or aversive, The sa'fer cigacette s~hould have a low-tar, lov-earbon monoxide eontent, but medium to hi_h (rather th'ar, low) nicotine yie13', 100'50528'S4

4. , 78-0719 Schachter, S. Studies of the Interactioa of Psycholcqxcal and Pharaacological Oeterminents of Smokzng. 1. Hilcotine BegalatioL in Heavy and Light Smokers. Jou!rnal of E'zFerimental Fsychoiogy 1'06 (1) : 5-12, 1977. Eb g,li sh. The resQ1'ts oi a research program concerned wyth the interaction of pharmacological and' psychological determinants of cigarette sacx.ing are presented. The hypothesis that smokers rrguliate nicotine intake is tested' by having surj~ects smoke cigarettes of aiym or low nicotine content on alternating weeks. Longtime heavy smoxars ao, regulate because they consistently smoke more low than high, nicotine cigarattes. GivEm this indication tnat heavy smokers ad just taaa,r saoxing rate to xeep nicotine at a roughly ccnstant level, the hypothesis that the rate of' saaxing depends on the etabolic fate and excretion rate of nicotine is ezaQined. Pharmacological evidence indicates that although most nicotinb is rapidly metabolizad, a fraction of nicotine Escates datozicatioa and is eliminated in the urinie. The proportion of nicotine tnat escapes metahciism depends on the acidity oi the urine. The 'ore acid the urine, the greater the excretion cf unmetabolized nicotine.-(huthl. abs~.) 78'-0552' Schmidt, F. Sind Z+Qarmtten mit her3bqe_etztem 8ikotin- und Teeraehal t veaiaer qasundi:_itsschaldlichL f Are Lcw-Tar and aicotine Ciqar_ttes Less Hazardous to alialth? ) tied_zinische Va1t 28 (,27) 1180-11 83, .- Ju19, 8. 1577, German. . 'The decision wheth_r smoxinQ of low-tar and nicotine ci'qarettes is less decreases the number of' smakan ciqarattes. The civarettes of varyinW nicctine content (1. 5l mq, 1.0 i6q, 0.5 mQ) and the so-called nico t.ine-fres. eiaarsttes were tested. Fo:tr-seven smokers sackad 45,0'00 test c:qarettess in 1.400 days. :hle smioki'nq raLe did' d'ecrease 15 pe=cent, in smokers of 1.0 aq ciQarEttes. A alueztiott:,d-':a administe,red to s!mckeLS of' ciaarette's with filters troved that those smo,.trs do inhale less. The sn'Ckinq of ciqarettes r,ith filters did not, hotaver, prove to be less damaqinq to health. The nicotine deficiency is also ba..LancEd by the s,mckers cf lo ti-tar/nicotinE ciaarettes by' deecer inhalaticx,. the nicotine def.~'c:ency. Oc tnt colatrary incrsased' nicotine content . ,,.. usually the danaer the consumation of cigar_ttes will increase to balance ~`-• danaerouls is ccn_rovarsial. IL loNerinq the content of n~cctine there is 1U05452855

7b-1200 Silverstein, cs. An Addiction, Explanation of Ciqarenr.z-induc.ed celaxation. 68 pp. 13,761, boctoral Dissertation, Columbia lDniversity, New Yor~k, NewYorY, EaqIlisa,._ sypotheses based: on an addiction model of ciqiarette smokinq were tested in two experiments. Botn involved the use of a sh ocK-endurance anxiety me3sure as the depen:ent variable. In the first experiment, comparisons wers made between aonsmokers, smokers waol ware allowed to smoJce! a ciqarette wit.h either a high or a low nicotine content and smokers who were not allowea to smoke a cigarette. Results were consistent with the hypothesis- taat the calminq efszct attributed to smoking a cigarette is due to the action of nicotine in preventinq*withdrawal; rather than to, a tranquilizinq, property ot ciqarette smokinq. In the second experiment, the urinary pff of': some of the sublects was maintained' al;caline. Results indicated that smosers with high urinary ph will not extibit withdrawal as soon as saokers with low urinary pii'. Zmalications of these finda.nqs for an explanation of ci4,arette smokinqi were discussed. (Auith. Ams.) 77-0713 Wyatt, T. Classification, of Cigarettes. (Zetter) . British Medical Jouraal 2(6032): 4201, l'uigust 114, 1'976'. EWqlish. _ ,. tl T'he author' agrees yith n.1.8. Russell's suggestion (J'uae 12, 1976) that aokers. cbange their brand of cigarettes toi gain a satisf ying nicotine `' s intake for the.least iatake of tar. The author carries the idea a step further by suqq,esting taat smokers may be better able to make such, a change in brands ii' the tar, and' nicotine yields were printed on the cigarette pacYets~. A.s the situa tion, in the IInited' Kingdo 4 exists: no w, only the cateqorT (i. e. , A"low tar, ""'"low to aiddle: tar'"')' is printed o'n the ci4arette packety as opposed to the exact figures for the tar and nicotine yields. The range of yizld!s for each category is relatively large:. For example, in the "'"low tar'' category the range is from 1..25 to 9.58 mig per cigarette, With this type of system, it is impossible!for a smoker to detergine how much difference in exposure a: change in brands wiould make, especially, if the brand change is within thz saae cateq,orq. It is concluded that at a tise when increasing quantification of, tar (and aicotine) values are souqht, the present systes of classification is outdiated. 1oosos,28ss

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..E\"ViRt)hMEATAL RESEARCH~ 12, '63-274(i1976)' 'Tar" and Nicotine Content of Cigarette Smoke in R'edation to Death R'ates' E. CUYLER HiAM.Mt)ND,Z LAWRENCE CiARFIXb:Eii,3 HERBERT SEIDMA.Y,s ~- MJD EDWARD A. LEtWs Department of Epidemiology and Stotiatics; American Cancer Siociety, New Ynrk, New York 10017 Received September 10, 1976 Over 1,t100t000~menand women whoenrolted in an epidemiological study in 1'939-1960were (rovith few exceptions) traced for 12' years. They all answered' questionnaries on cigarette smoking and various other factors at time of enrollment: and survivors answered repeat questionnaires on three later occasions: Inithis analysis. cigarette smokers were c3assiHed by the amount'of tar, and nicotine delivered by the brand they usually smoked at the start of each of two 6.year periods. Among subjects who smoked the same number ofcigarettes a day, total' death rates, death rates from coronary heart,disease; and death,rates from lung cancer were somewhac:lower for those who 1 smoked "low" tar-nicotine cigarettes than for those who smoked "high" tar-nicotine cigarettes. The:death rates of'subjects who smoked! "low"' tar-aicotinr cigarettes were far higher than the death rates of subjects who never smoked regularly. INTRODUCTION .. Many years have passed since the following, was firrnly established by a large number ofepidcmioliogical studies carried o'utby independent investigators in this country and'abroad (U.S. Public Health Service, 1964): First, and most important, death rates are higher'in smokers than ininonsmokers and' increase with degree of exposure to tobacco smoke. Among the diseases involved in this relationship are: (Y) lung cancer and cancer of several other sites, including the Iip, tongue, mouth, larynx, pharynx, esophagus, and urinary bladder; (2) coronary heart. diszase,. : stroke, and aortic aneurysm; (3) chronic bronchitis and emphysema; and (4) several' . other diseases including peptic ulcers. Thz agz-speeiFc Iun'g cancerdeath rates of men whosmoked cigarettes regularly was found to be about ten times as high as the lung cancer death rate of men who never smoked; and this ratio was considerably higher among men who smoked 40 or more cigarettes a~ day. Expressed in the same terms (i,e., mortality ratios), the coronary, heart disease death rates of male'cigarette smokers were found to be about. 1.5'to 3.0 times as highidepending,uponage and'arnount of smokirngas the coronary heart disease death rate of nonsmokers. From this it might be concluded that lung "From a paper given at the Conferenee, on the Origins of Human Caneer at Cold Springs I°arbor Laboratory, P1ew York, September 14, 1976, I Sc:D.. Vice President 3 Nt A'., Assistant Vice President. • M.B.A., Chief of Statistical Analyses. s F.S.A:,,Consultant: Copyriqhc'y'. 1976 brArademie Press. tnc. AU ingius of hrpra/uction iin any. form resernM. 263

HAk41io1V D' ET AL. " cancer is far more highly associated with cigarette smoking than is coronary heart .'disease. While this is true, it tells only half the story. . Lung cancer is a rare disease in nonsmokers, whereas coronary heart disease iss the leading,cause of death among male nonsmokers in the.United States. luluitiply- ing the high CHD death rate of nonsmokers by 1.5' results in far more "excess deaths" than multiplying the very low lung cancer death rate of nonsmokers by 110. Thus in terms of reduction in life expectancy the association between cigarette smoking and coronary heart, disease is far more important than the association between cigarette smoking and lung cancer. While such information is of scientific interest, it is of no value to the public unless it can be utilized to protect health and extend life expectancy. At the outset, several possible ways of putting, the knowledge to practical! use were discussed. Among these were: (1) Simply acquaint the public with the facu. According,to the proponents of this idea; knowledge of the facts would be sufficient to persuade people not to smoke cigarettes. (2) Conduct extensive public education prognams to persuade people not to smoke cigarettes. (3) Attempt to develop a new type of cigarette which would have no harmful effect&(or at least~ greatly reduced harmful effzcts) and yet would be pleasurable to smoke. All three of these things have been, done. Presumably, due to application of'the first two ideas, a great many erstwhile cigarette smokers have given up1he habit (U.S. Public Health Service, 1976). However, millions of'adult cigarette smokers have continued to smoke and each year, tens of thousands of children and youths take up the habit. Many attempts have been made to develop a'"safe" or'"less hazardous'"'type of cigarette which smokers would! find satisfactory. The only procedure along these lines which has as yet gained wide acceptance among cigarette smokers is reduction in amount of tar and nicotine in the mainstream smoke of cigarettes. Cigarettes with considerably reduced tar and nicotine (ofteni referred to as "low" T/N ciga- rettes) have now been available for many years. We are concerned here with the question as to whether or not such cigarettes are actually "less hazardous" than, are '"high." T/N cigarettes. ,< Some years ago, a small committee of experts on the subject came to the conclusion that "the preponderance of scientific evidence strongly sug~ests 'that the lowerthe'tar' and'nicotine contenUofcigarette smoke the less harmful would be the effects" (U.S. Public Health Service, 1968). (A short, time later this was reported by the then Surgeon-Generali of' 'tlte U.S. Public Health Service.), Their reasoning was about as follows: (1) Death rates from lung cancer, cancer of several other sites, coronary heart disease, and several other diseases increase witih degree of'exposure to cigarette smoke. (2) Many experimental studies had shown that material condensed from cigarette smoke (usually called "tar") ") is carcinogenic when applied to animals. ('3)The known acute effects of nicotine upon the heart and circulatory system suggested thatthe nicotine content of cigarette smoke was partly if not entirefy responsible forthe fact that age-specific death rates are higher among cigarette s suppose tt the harm ( The tern conclusior (1) If th, smoke mc turned out T/N to "!c Hammonc (2) Smc inhale the their effec exposure (3) It cc harmful tls that, in cc certain ga might incr Therefc in age-spe Since t. stuoiies (B that, peopi people wh panied by disease) lG Betwee can Canc epidemiol a lengthy for 6 year raaire cont during the questionn series, Q4 after June The So I!96+t„ and traced in dIscontim eighth an. Durine by Divisir

"Te#R" AND NLCOTI\iE CONTENT OF eLGARETTES' 265 cigarette smokers than amo'ng,nonsmo'kers: (4) Therefore, it'seerned'reasonable to suppose that if the tar and nicotine content of cigarette smoke were reduced, then the harm done per cigarette smoke'd' would be correspondingly reduced. The term "'strongly suggests'"' included in the above statement iniplied that the conclusion might be intorrect. The major counter speculations were: (1) If the tar and nicotine content of'the smoke were reduced most smokers might smoke more cigarettes per day and thereby cancel the benefit. (This speculation turned out to be incorrect wheniit was found that, smokers who switch from "high" Tlli`N to "'low" T/N cigarettes do not usually increase the number smoked per'day; Hammond and Garfinkel, 1'964.) (2) Smokers of "'low" T/N cigarettes' might (consciously or unconsciously) inhale the smoke more deeply than smokers of''"high" T11`1' cigarettes. If'so, then their effective exposure to tar an'd'i nicotine might not be reduced while their exposure to the gases in cigarette smoke would be increased. (3) It couldibe that gases contained in cigarette smoke are as harmfttl'if'not more harmful than the''tar" and nicotine content of the smoke. Furthermore, it, could be that, in certain circumstances, reduction in TIN is accompanied by' an increase in certain gases, most notably' carbon monoxide. An increase in carbon monoxide _tnight increase the risk of coronary heart' disease. Therefore, ifal7 this is true, the net effect ofreductiion inT/N mightbe anincrease in age-specific death rates. Since that time, published, evidence from two retrospective epidemiological studies (Bross and Gibson, 1968 and Wynder et at.. 19'10)' was such as to indicate that people who smoke filtertipcigarettes have lbwer lung cancer death, rates than people who smoke nonfilter cigarettes. Concern lest this desirable effect be acco'm- panied by an increased' risk of some other disease (especially coronary heart disease) led~ us to carry out this investigation. MATE R'IAL I can Cancer Society enrolled over 1',000,00b' men and' women in a prospective epidemiological study (Hammond,1964),. Upon enrollment, each subject answered a lengthy questionnaire (hereafter referred to'as'Ql),. Once every 2 years thereafter for 6 years, surviving subjects were requested to, answer a brief repeat question- naire containing questions on cigarettesmoking, hospitalization, diseases incurred during the interval between ques'tionnaires, an'diseveral'otherfactors. Tttese repeat questionnaires will be referred to as Q2, Q3, and Q4. The last' questionnaires of this series, Q4, were distributed on October 1, 1965; but some were not answered until after June 1, 1966. The Society successfully traced 99.6% of the subjects through September 30,. 1'964', and 98:4G''o through September 30, 1965. Of those who were still living,wheni trace& in the sixth annual follow-up, 94.9%, answered Q4. Annual tracing was' discontinued after the sixth follow-up, but was resumed on October 1, 1971. The eighth and last' tracing was started on October 1, 1972. During the first 6 years, enrollment and tracing of the subjects was administered by Divisions of'the Amenean Cancer Society in 1121 counties in 25 states. When Between October 1, 1959, and ;viarch 3'1, 1960; volunteer workers of the Ameri-

,/itaalt QM aa 0 © OPP a 0 a X . •= rY !] tE 266 HAMMOND ETAL. tracing was resumed in 1971, 3' of these states dropped out for administrative reasons; and we decided'not to attempt t+a trace those few subjects who were "lost" in the sixth follow-up. Thus, on Oictober 1,197'U, we set out to trace 897,825 subjects who had been traced in the sixth follow-up and who were stilUliving as of'September 30, 1965. We traced 98.4% through September 30, 1971, and 92.8575 through September 30, 1972. This report is confined to experience dt2ring two 6-year periods of time: Period 1, July 1~„ 1'960-June301 1966; and Period 2, July 1, 1196'6-Jiane30,1972: It is further eonfnedito subjects 40 years of age or older as of July 1, 1960, who on Q!1' said that they were currently smoking cigarettesregtalarlyand had never smo~kedpipesor cigars regularly; and who on Q1 stated', the number of cigarettes they currently smoked per day and their usual brand of cigarettes.6 Experience during Period2 is further confuned'to subjects who answered Q4 and who on that questionnaire said that they were currently s~moking! cigarettes, stated the number they smoked per day, and the brand of cigarettes they usually smoked' at that time. METHODS Information on the tar andinicotine content of the smoke from various brands of cigarettes was obtained from several sources." On the basis of this information, each subject was classified according to the tar and nicotine content (H, "' high'"; M4 'amed'ium'"; or L, "low") of the cigarettes he usually smoked arthree points in time as indicated in Ql, Q2, and Q4. This was relatively easy for Q1, since atthattime, although some manufacturers marketed two ormore types of cigarettes under the same brand name they could bee distinguished by presence or absence of aflter or by menthol. For purposes of this report„we d'efined"high" Th1 as 2.0'to2.7'mg of nicotine and 25.8'to 35.7 mg of'tar. "'Low" TlIN was defined! as less than 1.2 mg of' nicotine; and with very few k exceptions, cigarettes which meet this qualification also delivered less than 17.6 mg ' of tar. "Medium" IN, was simply defined as intermediate between "high"" and' "low."" _. Insofar as possible, we used. these same definitions for later years. However, some manufactureres marketed, under the same brand name, two or more types of eivrettes.vhica differed in tar and nicotine content. Forthis reason, it is likelythat some of the subjects who were placed in the "a'high" TLP<1 category probably belonged in the "medium"" TINI category and vice versa. There was far less difficulty of this sort in distinguishing the "low" T7N smokers from the other two groups. For the period 1966-i'972,, the three sets were distinguished as follows: (1) "High""' was defined as subjects in the "'high'" category in the 1959-1!960 question- • One additional analysis includes subjects who had never smoked regularly. t Tar and nicotine content of smoke:from various brands of cigarettes in various years waa obtained from analyses madt by Foster D. Snell; Inc.. and!pubtished in the November 1959 issue of Readers Digest; in the July 1961 issue of Readers Digest; and for 1965, interpolated from the Readers Digest August 1963' issue and the Federal Trade Commission ratings published in November 1967. " }•'P T'i~r( ~L•TL+ S -+>I~~T .t:vS. ' _ ~ ..,,~ ~ '11_.~t" ~~;_ ~ dividee all ' of : (white '`.or40+ at tieu fumes ~~. wome - schoo Q34or Q2: Q Thi Ptrioc numb= smoki' srnok, Wit three discarr least' c of sub adjusi was tF L) to smullI less tt corre~ subgr : . 6-yea factot to risl alive : up to the st Ha subje • Pat of the they t inClUv ~..~x;,r,~+c. S*t4Y337~+ww•.~a at••+~r}-t P'n

'"'rAR" AND NICOTINE CDIYTEXT OF CLGARETI'ES 267 subgroup, Likewise, the sum of the person-years of exposure to risk (during a "corresponding,adjiustrnent factor to obtain the adjusted number of deaths in that less than 1.00! ) The number of deaths inleach subgroup was then multiplied by the - srrtallests bgroup is 1.00; and for each of the otherttivo subgroups iris either 1.00 or ~: L) to obtain three adjustrnent factvrs. (By def nition, the adjtrstmertt factor for the Q3, or Q4 (yes or no); (9) history of heart disease as reported on Q 1 or as reported on Q2, Q3, or Q4 (yes or no). This matching procedure was carried out' separately for men and women in Periods I and 2. For Period 11 the amount of cigarette smoking was taken as the number smoked per day as specifed on Q1. For Period 2 the amount of cigarette smoking was taken as the higher of these two numbers: the number of cigarettes smoked per day as reported on Ql and the number per day as reported on Q4. Wirthin each matched group, as defined above, the subjects were divided into three subgroups according to tar and nicotine (HI, M, or L). The entire group, was discarded if it did, not contain at least one H subject, at least one M subject, and at least one L subject. Otherwise, the subgroup (H, M, or L) with thesrraallest number of subjects was identif ed. This smallest number will hereafter be referred to as the adjtisted'number of subjects in a specifned group. The adjusted'number of subjects was then divided by the number of subjects in each of the three subgroups ('H, M, or fumes, gases, chemicals, X rays, or radioactive materials (yes or no) (men but not women were matched on this factor); (7) education (no high, school! vs some high school or above); (8) history of lung cancer as reportedon Q1 or as reported on Q2, at time of enrollment (urban or rural); (6) history of occupational expoxure to dust. or40+); (4) age began cigarette smoking (<15,15-24, or 25+); (5) place of residence "low" or "'medium'`on the 1'965-1966 questionnaine (Q4), or as "low" on both Q2 and Q4. "Matched groups'"' analysis was utilized. As a first step, the subjects were divided into groups such that within each group the subjects were alike in respect to all of the following factors: (1) age (same 2-year date of birth cohorts); (2) race (white ornonwhirte); (3) number ofcigaretrces smoked per day (1-9;10-19; 20, 21-39 (2)'"Low" was defined as "1ow""'on the 1959-1960 questionnaire (Q,1), and as either naine (Q 1) and as either"'high" or "medium" on the 1'965-1966 questionnaire (Q4). 6-year period) for each s!ubgroup was multiplied by the corresponding adjustment factor to obtain the adj,usted number of persvn-years. The person-years of exposure to risk of a subject during,a 6'-year period is (a) 6 years if the subject is known to be alive at the end of the 6-year period; or (b) elapsed time from the start of the period up-to the tiime of death if the subject diediduring the period; or (a) elapsed time from the start of the period up until the time the subject was last traced. Having carried out the above procedure separately for each matched group of subjects, the findings were summarized. RESULTS. Part 1 ofTable I shows the number ofmale and female subjects at the start of each of the two time periods classified by the tar and nicotine content'of the cigarettes they usually smoked. Part 2 ofTable 11 shows the number of these subjects who were included in matched groups as previously defined. The difference bztween these on

268 HANiDtOiti D FLtL. TABLE' I TOTAL <tiiuM/nER OF S'CBJECT4,ST. SW.RT~~. OF~ EACH1 oF~Ttti'U~~PERi10Ds., NIaIBE~R'~. LN ~ tf3TCHED CROVPs, Axn~. AnjUSTiED~ 1!tC-WBER~~OF PERS@N-YE4,RS'.OF~~ E:CPOwRE TO. RI5K (BY'"TAR" AND NICOTI\E~ CO%TF--,•T'of ~C[cARE'rrE). "1High" '"il3edium"" "Low" Period' tar-nicotine tar-nicotinc tar-nicotine Male Male Female - Female Male Male Female Female Male Male Female Female' 1. Total'numb,er of'subjeet3 at start of period 1 63,063 54,999, 15,360 2 29,157 40,090 6',832 1 44,137 59,750 32,703 2 22,909 49,193 16,803 2. Number of'subjects in matched groups 1 57,346 50;698' 14,897' 2 25,459 35,112 6,5641 1 43,062 58,538' 32,357' 2' 22,153 47;679' 16,550, 3 1 Adjusted person-years of espoiure to risk 1 82,428' 82:898 83,072 2 35',974 36.051 36.435 1 174;619 175,038 175,7414 2 83,639 89,027 89,129 • Period I: July IL 1960-June 3W. 1966; Period'2: July 1, 1966-June'30, 19%'1. 6'Includes cases which wereditticult to classify. two sets of numbers indicates the number of subjects who were excluded because'e some oroups did not contain at least one H, one L'v1', and' one L subject. The adjusted number of subjects was: 14,688 for males, Period 1; 6175 for males, Peri od 2;,30,176 fbrfemaIes, Period 1; and 15',342'forfemalzs, Per'pd 2.Sint:e a large proportion of'the ""Iow'"' TIN subjects were matched, the adjusted number of matched subjects was only slightly less than the number of "low"'T!N'subjects in matched groups. On the basis of the adjus.ted numbers of subjects, the mean ages of the subjects were: 53.6 for males and 51.6 fo'r females at the start of Period 1; and '`'58.4 for males and 56.7 for females at the start of Period 2. Fart 3 ofTable I shows the adjusted number of person-years of exposure 2o risk as previously defined. .-As shown in part 1 of Table 2, the adjusted' nttmber of' deaths was 4735.5 for "high" TIN srnokers; 4299.9 for "mediinm" TIN smokers, and 3991.2 for "low'"' TIN smokers. The difference between! the "high'"' group and the "low" group is statistically signiificanC(P<0.0001). Furthermore, for each offiour sets ofcomipari- sons (male, Period 1; male, Period 2; female, Period' 1; and female, Period 2), the adjusted nutnberofdeathswas~hiphest for the "high'"TlN smoker~s and Io~westforthe "1mw"" TLI^l smokers. In each of these four, sets, the difference between the "high" T/N' and the ""low'" TIN groups is statistically significant ('P<D.01005). As also shotivn in part I ofTable 2, the adj usted number of'lung cancer deat'hs was 31'8! 4 for "high'"' TLN' smokers, 285.5 for "medium" T1iV smokers and 235.2 for "'lbw"'T1N smokers. The difference between the'"higtt'"'T/Nigroup and the'"low" TIN t , COm''f ~ canc( TJTI : Pa1 numl: adjus the r Comb mort€ ; forfe Perio ' 1VSk "met: TIN : Adju: ofd'e: to ris Tal numb 14'S3.- ence. signif and f: Se Male Male Fem, Femal, Tote Male Male Femal, Femat, . Tot:;

4'`TAR" AND NICOTINE CDNTFN'T OF CIGARETTES 269 TIN smokers. Part 2 of Table 2 shows 'mortality ratios calculated by dividing the adjusted number of deaths in the "medium" T/ht'and"low" T/Nigrowp by the corresponding adjusted number of deaths in the "`high'" T/N group. As shownon, the bottom line, the mortality ratio for the "low" TIN group was 0.84 for all causes of de'ath combined and 0.74 for lung cancer deaths. It is of interest thai' the lung cancer mortality ratios of "low" TIN smokers were lower for females than for inales (0.57 for females and 0.83 for males in Period 1 a'nd! 0:62 for females and 0.79'for males in Period 2),. _. Mortality ratios were alsoicalculated by dividing the adjusted death rates of t'he "medium" TIN and'"'low" TlN smokers by the adjusted death rates of the "high" T/PJ smokers. These mortality ratios were very close to, those shown in Table 2. Adjusted death rates, if desired, may be calculated by dividing the'adjusted number, of deaths (part 1 of Table 2) by the corresponding adjiusted'person-years ofexposure to risk (part 3 of'Table 1). Table 3' shows corresponding figures for coronary hearG disease. The adjtastedd number of coronary heart disease deaths was: 1616.8 in "'high" TINI smokers, L483.3' in "medium" TIN smokers, and 1392.7'in "low" N smokers. The differ- ence between the "`higia'"' T/N group and the "low" TIN group is statistically significant (P<0.000'li). For each of the four individual sets of'comparisons (males and females in Periods 1 and 2), the adjusted' number of coronary heart disease TIN groupi5 stat'isticallysignificanr(P<0.ID005)L For each of fourindividual sets of' comparisons (males and females in Periods I and 2), the adjusted number of lung cancer deaths was highest for the "high'"'T1'i`N smokers and lowest for the "'low"" TABt:E' 2 /AD3UETF.D i lIU~7BER OF~ IDEATHS ~I(TOTAL A1tiD~ LUNG~. CANCER) '~ AND ~:YIfDRTALITY~. RAIIOS ~ DUR7\G~EACH OFTWO:PERIODS~OF~TiJtE~ BY~SEX'AND~BY~"TAR " AND~. NICO1rirE CO:YTENT OF~. C(GARETTES USUA'L'LY~ SdtO.KED -Total . Malb 1 Malb 2 Female i Female 2' Total Total deaths "High" ..Medium.. ..Lou,., Lung cancer deaths ••Hish•• T/N T/N 1VN T/N "Mediucti "' "Low'"' T/N T/:t i. Adjusted! numoer of'lenths 1.543.0 1,394! 4 1.351.7 1L:4 1'17.4, 101.01 935,.2' 913:7 759.4 89.6 84.5 70.61 1,253.6' 1„117:P 1.053.9 48.3 41.4' 27.4 1,003.7 874!7 826'.2' 58.1 42.2' 36.2' 4,735.5 4,299.9 3:99L._' 318.4 285.5' 23'5.2'. 2. Mortality ratios 1.00 0.90 0.88' 1L001 0:96' 0.83 1.00 0.98 0.81 1100 0:94 0.79 1.00 0.89 0.8+>'! 1'L00 0.86 0.57 1.00 0.87 0.82' L00' 0:73' 0j62 1.00 0.91 0:84I 1100' 0:90 0:7d.

. HA1'(SDt]NID'ETAiL. Period' Male 1 Male 2 Female 1 Female 2 Total "High" "Medium" • tar-nicotine tar-nicotine ••L.ow ' tar-nicotine ll Adjusted number of CHD deaths 696.5'' 632.5 - 6!45.6'. 336:0 345':6 274:2' ~ 318.7' 277.5 237.4'. 265.6' 228:0 215.5' 1,616.8 1,483.3, 1,39'2.7' 2. Mortality ratios 1.00 0.91 0.93 1.00 1603 0.82 1.00 0.87' 0.81 1.00 0.86 0.311, 1.00 0.92 0~86 deaths was higher for the "'hight' TIN group than, for the '"low" TIN group: J' As shown on the bottom line ofTable 3, zhe coronary heart disease mortality ratio for "low" TJN s(nokers was 0.86. ADDITIONAL ANALYSES Coronary Heart Disease As a further test of the hypothesis as related to coronary heart disease, a second Inatched~groups analysis was carried out including,additional factors of significance or possible significance in relation to that disease. In this analysis, the subjects within each matched group were alilCe with respect to age (same 5-year date of birth cohort, with respect to alI'the other'eight factors included in the first analysis (as previously described), andlwitfi respect to all of ttie folowiiog factors:(l'0) history of stroke (yes or no); (1I) history of diabetes (yes or no); (12) history of highbliood pressure (yes or no); and (as reported on Q1l~~('13)usualarnount ofex~ercise~(idone, slight vs moderate, heavy); (14) obesity (?0~'0 or more over average weight, yes or no); (15) coffee-teal (six + cups a day, yes or no); (1I6)' whiskey, gin, etc. (none,, occasional vs dailydrindcing); (1'7) aspirin(oftzn vs not often); and (18) occupation (doctor, lawyer, teacher, nurse andi other professionals vs other). Because of the larger number of factors on which'the subjects were matched,, there were fewer matched groups containing at least one H, at least one M', and att least one L subject. The ad'justed numbers of subjects were: 11,599 men, Period 1; 4996 men, Period 2; 23,584 women, Period 1; and 11,450 women, Period 2. Since these adjusted' numbers of subjects were less than the corresponding adjusted numbers of'subjects in'the first analysis (as previously described) there were fewer TABLE 3 AD)uSTED'NU:IIBER OF DEAT'HS'(COROTA'RY HEART'DtSEASE) AYD'.%YCDRTALITY Ft.ifflOS ~ ~ DCRoC~EACH OF~Two ~PER'tODS OF T(SYE.BY~S~EX~~AX~D~~By~**T'11~" AYD~ 1HtCOTtxE' C.OYTE.VT~OF, CItwIMETriE3 U'SUALLX~ S?tOKED~. ~ adjust result! . The was: 1 for "k group compz naryh 8roup. 0;83. Select III c distritt than o couldd ofsub Pe rioc there4 therez very c up sm Many As cance `''1o„r• nttttcf: vari© t' studie cigare subje, or hig cigare tions cigare able r subje carrie were factoi befor time. Perio Th

' "'TaR~' AIID NIICDTtNE CONTENT OF CIG'.iRETPES ,271 adjitsteddeathsd Nevertheless, the results of this second analysis were close tothe results of the frst analysis. :-Tho ; adjusted number of coronary, heart disease deaths (in this second analysis). was: 1007:5for'"high" T/NI smokers, 92'9.31for"rnediiam'"T/N smokers, and 834.5' for "'low" T/N 'smokers: The difference between the ""higtt'" group and the ""ibw'"' group is statistically significant (P<pi001). For each of the four individual'sets of' comparisons (males and females in Periods 1 and 2) the adjusted number of'coro- -nary heart disease deaths was higher in the"high" TINgroup than inthe "low" TIN 'group. The coronary heart disease mortality ratio! for the "low" TlN group was 0.83. Se lecttve Ejjj "ect of Giving Up Snlnking, In comparing smoking habits as reported on Qi', Q2, Q34 Q4, and Q5 (which was distributed in 1972), we found that a larger proportion of the "'Iow'"'TJN smokers than of'the'"high" TIN smokers gave up the habit at a~laterdate. Conceivably, this could have accounted forthe difference between the death rates ofxhese two groups of subjects.To check this possibility, wemade anothermatched'-groups analysis for Period 1. In this analysis, subjects who were not smoking as reported on Q2 weree thereafter excl>aded; Likewise, those who were not smoking as reported oniQ3 were thereafter excluded. The results of this analysis (in terms of tnortal'ity ratios) were very cliose to the res uits shown in Tables 2 and 3: Fromithis, we conclbde that giving up, smoking did'not account for the findings as shown on those two tables. Many "Low" TIN Cigarettes versus Fewer "High" TIN Cigarettes As shown.in Tables 2 and 3, the adjusted numbers of deaths (total deaths, lung cancer deaths, and coronary heart disease deaths) were consistently lower among -"low" T1N smokers than among "'high"' TIiV smokers when the subjects were matched on number of cigrzrettes smoked per day (as well as being matchedi on various other factors). There is abundant evidence fromithis study and, many other studies (U.S. Ptbblic$ealth, Service; 1971) that death rates increase with:number of cigarettes smoked' per day. For this reason, we wished to determine whether sinbjects.who smoked a relati'vely large number of "'low" T/v cigarettes had as higlnh : or higher death rates than persons who smoked a, smaller number of " "high" TIN cigarettes. Because of linlitations in the number of subjects with varipuscombina- tions of number of cigarettes smoked per day and tar and nicotine content of thee cigarettes smoked„ we were unable to make fine distinctions. However, we weree able to compare subjects who smoked, 1 to 19 "high"" T/h( cigarettes a day with subjects who smoked 20 to 39 '°low'"'Tml cigarettes a day. For this purpose, we carried out atnatched groups analysis such that the subjects in each matched group were alike with respect to age (same 5-year date of birth cohor2) ~and all of the other factors used in the first analysis exceprfor number of cigarettes smoked per day. As before, this was done separately for men and women inieach of the two periods of' time. The adjusted number of subjects was: 7971 males, Period' 1; 2785 males, Periqd 2; 12,275 females,, Period ll; and 484'1 females, Period 2. The adjusted number of deaths (all causes of death combined) was U826'.3' for

aais;r_~, . r i r :.t . 272 HAMMOND ET.#G. subjects smoking 1V to 19 "high" TIN cigarettes a day and 1923.9 for subjects smoking 20 to 39 "low" TJN cigarettes a day (mortality ratio 11.05), This difference ,; isnotstatistiaallysignificant.Theadjusted'inutnbero'fcoronaryheartdiseasedeaths was: 670.6 for subjects smoking I to 1'9 "`high'"'T/N cigarettes a day and 736.6 for subjects smoking,20 to 39 "1ow""T ~lY cigarettes a day(mortadity ratio I.10). This difference is statistically significant (P<0:05). The adjusted' number of lung cancer deaths was 75:8'for subjects smoking l to 19'"higb'"'TLN cigarettes a day and 129:51 for subjects smoking 20 to 39 "lnw'"'TIN cigarettes aiday(rnortal'ityratRo 1.71). This difference is statisticall signifucant(P<0.000t). For each of the four individual sets of comparisons (males and females in Periods I and 2), the adjusted number of lung cancerdeaths'waslower in subjects who smoked, 11 to 119 "high" TlY cigarettes a day than in subjects who smoked 20 to 39 "low"' T/N cigarettes a day. "Low" TlaV Smokers versus Nonsmokers ; The next question which we posed was whether the death rates of subjects who. smoked "low'"' T~l~i cigarettes were appreciably different from the death rates of'f subjects who had never smoked regularly. To this end, we undertook a, match'edd groups analysis matching,on age (2-year date of birth cohort) and all of the factors included in the first analysis except number of cigarettes smoked per day and age subjects began smoking. Since subjects who hadi never smoked greatly outnum- bered "low" TIN subjects, all but a very few of the latter subjects were matched. ,The adjusted numbers of subjects were: 15,346 men, Period, 1; 6822 men, Period'2; ;. 32,702 women, Period 1; and 16,803 women4 Period 2. On the basis of the adjusted' ' numbers of subjects, the mean ages were 53.81for men and152:3 fo'rwomen at start of Period 1 and 58.7'for men and 57.3 for women at start of Period 2: The results are shown in Table 4. The adjusted number of deaths (all causes of ti-.`death combined) was 4670.3 for'low" TIN smokers and 3099.0 for subjects who never smoked regularly. This difference is statistically signiificant'(P<0:00'0i1). The adjusted number of coronary heart disease deaths was 1I674'.3' for "low" T ~l .~, smokers and 1008.3 for subjects who never smoked regularly: This difference is statistically significant (P<0.000i1): The adjusted'number of lung cancer deaths was 25'ff:0 for low T1N smokers and 39.4 for subjects who never smoked regularly. This difference is statistically significant (P<0.0i001). For each of the fmurindividual sets of comparisons (males and females in Periods l and 2) for all causes ofdeath combined, for coronary heart disease deaths and'for lung cancer deaths; the adjusted number of deaths was higher for "low" TlN smokers than for subjects who never smoked regularly and each of these differ- ences is statistically significant. (The value of"P'"ranged from <0.01 to <0:0001). As shown on the bottom line of'1'abie 4, the mortality ratio (adjusted number of deaths of subjects who never smoked regularly divided by adjusted nurnber of deaths of "low" TIh1i smokers) was: 0.66 for'all'causes'of dea'th combined, 0.60 for coronary heart disease deaths, and 0.15 for lung cancer deaths. s..^.. Male =' D+tsle Femal Fema1, Tot_ . bfate 3tale Feasal, ... Fetnat Tot: . Nt It smok anal} Cir, (folio 1952; majo befor smo, "meL rettes incur incre to sa step quit W Tr, man• heal; cigar

6, TAR'" AND NICOTINE Cb:YTENT OF CICAR'F:T'rPS 273 TABLE 4 MO~RTALITY~R.CTIOS DtiRt\IG~E.ICH OF~Two~PERiODS~OF~TIl1E~~ B7~SEX', -Lour- T/:I~~ ~ SltO1:ERS; AN~D~ SR'.BJEICTS wwo~. NEVER S?lOKED ~ REGULA'RLY ° ApJUSTED~. NU>tBER~~ OF' DEATHS~(TOTAL. CORONARY HEART DISE.ALSE, AND, ~. LUNG CANCER):.a\~D~~ Total deaths Coronary heart disease I ung cancer Male . _: 1 l1522.3 Male 2 - 853.0 Female 1 11288.0. Female 2 1,007.0 Total' 4,670.3 !! I100' 2 1L00' 1 i 1:00 2 1.00 1.00 Never smokedp ••'Low" T f Y Never smoked* "Low° T1N Never smoked• I. Adjusted number of deaths 86,u 8 742.3 399.11 107.0' 9.8' 542.11 3I111i.0 238:4 77,0 7.1 979.0 343.0' 205:6 30.0 12.8' 713:1' 273.0 165:2 44.0 9.7' 3,099.0 1,674.3 1.008;31 258.0 39.4 2. Mortality ratios 0:57 1:00 0!54' 1.00 0.09 0i64! 1.00 0:77' 1.00 0.09 0:76I 1.00 0.60 1.00 0.43 0.71 1.00 0.59 1.00 0.22 0:66I 1.00 0.60 1.00 0.15 • llever smoked cigarettes, pipes, or cigars regularll+. CONCLUSIONS ' It is quite apparent that reduction in the tar and nicotine content of cigarette. smoke did not make cigarette smoking "safe" for the men and women in this analysis, all of whom were over the age of'4I0 in 1959. . .- Cigaret'tes with reduced tar and nicotine were not introduced until the mid 1950s . `((following the retrospective studies of Wynder and Graham, 1950; Dolll and Hill, 19521; Levin er at., 1950). Almost alI' of'the male cigarette smokers and the great majority of the female cigarette smokers in our study be;an'smo'king cigarettes long . before that date. Therefore, the subjects here classified as "low" TINI cigarette smvrers, were, with few zx'ceptions, persons who smoked ""high" T.';?i or "medium" T/N cigarettes for many years and then switched to "low" TIN ciga- rettes. It' appears that by so doing they somewhat reduced the serious risksthey int:urred by smoking. (This does not'apply to the relatively few who aCthe same time increased the number of cigarettes they srnokediper d'ay.) Therefore, we think it fair to say, thatsw'itching from "high" T7N to "'low" TIN cigarettes was at least a srnau' step in the right direction for those who continued to smoke cigarettes. Those whoo quit smoking fared considerably better. W'hat' of youths who have not yet taken up the habit of cigarette srnoking?' They would be welI'advised never tio do so. However, in spite of all the warnings, many thousands ofyoung people do in facttake up tihe habit. The threatito'thz future health of those who make this youthful decision would be reduced' if "high" T/N ' cigarettes were remov'ed from the rnarket. Manufacturers may be willing,to'db so

E.V vitRO?. HA41MONID ETAL voluntarily in the light of'the fact that long-term trends have been in this di'rectimn.. We will end with a word of caution, ' In producing,eigarettes with extremely little tar and nicotine, some manufactur- ers may use additives for flavor or for some other purpose. In our opinion~ both additives and the cigarette smoke condensate (tar) should be tested' for car- cinogenicity before such cigarettes ~ are put on the market. Brossi L D. J:, and Gibsonl R. (1968). Riaks of lung cancer in smokers who switch to filter cigarettes. Amer. J. Pub. Health 58, 1096. Doll. R., and Hill. A. B. (1952). A study of the aetiology of carcinoma of the lung. Brrt. Med. J. -2 127t. Hammond, E. C. (1964). Smoking inxelationito mortality and morbidity. Findings in first thirty-four, months of follow-up in a prospective study started' in 1959. J. Nat. Cancer lnst. 32. 1!161.. Hammond. E. C:, and Garfnkel L. (196a). Changes in cigarette smoking.J: Nat. CancerInst. 33, 49. Levin, M. L.. Goldstein. H.. and Gerhardt, P. R. (1950). Cancer and tobacco smoking. A preliminary report. J. Amer. 1+lyd. Assoc: 143, 336. U. S. Public Health Service (1964). "Smoking and Health Report of the Advisory Committee to the Surgeon-General of the Public Health Service:" Public Health Service Publication No. 1103. U. S. Dept. of HL E. W., Washington. D.C. U. S. Public Health Service ('196,3). Public health service technical report on "tar" and nicotine. In "'Hearings before the Consumer Subaommitterof the Committee on Commerce," United States Senate.,August 23-25. 1967; p. 7. U.S. Government PtintingAffice. Washington. D.C. U.S. Public Health Service ('197'1): "The Health Consequences of'Smoking. A Report of the Surgeon- Gtneral," DHEW Publication No. 714513. U.S. Dept. of H.E.W. Washington, D.C. U.S. Public Health Service (1976). "Adult Use ofTobacco-1975." U.S. Dept. of H.E.W.. Bethesda, Md. Wynder, E. L., and Graham. E. A: (1950). Tobacco smoking as a possible etiologic factor in bron- chogenic carcinoma, 1. Amer. Med. Assoc. 143, 329. Wynder, E. L.. Mabuchi. K:, and Beattie. E. J.,,Jr. (1970). The epidemiology of lung cancer. J. Amer. AYed: Assoc. 213, 2221. . REFERENCES M H m. . In ,'. Iran. pests about. Garg: )mver. detec the f' po'llu Sana~: Tt: provi samF Pahic after tion Prep, Th meat resu, cont. pow soxli Acet . Ti in a of'p:

Some~~ Recent Fi~nd6~ngs, Concerning, Cigarette Smoking © • l t E C. Hammond, L Garfinkel, Hh Seidman and E. A. Lew Department of Epidemiology and Statistical Research American CancerSociety, New York. New York 1i00'1'7' © * .Vg~w I m ~ ."r.' .YN. ri L. An enormous amount of research on the effects of smoking has been carried out by.' many izadepend'ent inHestigators in many different countries. The epidemfioiogic findings have been so similar in' various studies-especially prospective studies-that data from any one of' them can be used to illustrate the major results. The literature has been reviewed so often and so well that we will not repeat the process' here. However, we will start by dis- cussing a few salient points. First, and most important, death~ rates are higher in smokers than in non- smokers sutokers andl they increase with degree of exposure to tobacco smoke. Among the diseases involved in this relationship are (1) lung cancer and cancer of several other sites, including the lip, tongue, mouth, larynx, pharynac, esophagus, and urinary bladder; (2) coronary heart disease, stroke, and aortic aneurysm; (3) chronic bronchitis and emphysema; and (4) several other diseases, including peptic ulcers. The latter was most elegantly investigated in a clinical trial carried' out by Sir Richard Doll and his associates (Doll et a1. 1''958) . Figure 1 is based'upon data from one of'the prospective studies and shows' lung cancer mortality ratios in relation to types of smoking. Note that althoughh death rates from this disease are considerably higher among pipe and cigar smokers than among men who never smoked' regularly, they are far higher, among cigarette smokers. This appears to be due to the fact that the majority of pipe and cigar smokers do not inhale the smoke or inhale it only slightly, whereas the great majority of cigarette smokers (especially heavy cigarette smokers) inhale the smoke to a moderate or deep degree. Among those few pipe and cigar smokers who consciously inhale the smoke, litng cancer death rates (as well' as death rates from coronary heart disease) are as high as the death rates for cigarette smokers. On, the other hand, death rates from cancer of the lips, tongue, mouth, and esophagus are as high or higher among pipe and' cigar smokers as among cigarette smokers, regardless of degree of inhalationof'tlle smoke.. 73-1Z50. Hammond.' E C.; Garfinkel.,Li.: Seidman, H.: Lew. E A. Sotrte Recent Findings Caonoertting C7gtrette SawkirtG In: Hiatri H. H.; Watson. J. D.; Winsten,!! A- (Editors). Origjnr of Hwtmr Canoe. Book'A. Jneidenct of Canrer in Huni Cold Spring Harbor Conferences on, Cell Proliferation, Volume 4. New York, Cold Spring Harbor [iboratory. 1977, pp. 1 U1«111II: Yoticr. This matenal may bepr<otected byoopyright laov. (Tide 17 WS code) 1r 1D1 ~ mi I. t , IJ l m © ~ ~ t<4 a It t r r. ~ .,.5- l'a. ~-~~d1k~. t ~'«`? . ~, Q ... ,,..... J~ 'w ® lyr" r-..::.+~4~ a ~ ~~-~•~ ^.~ ? 4 Y

1 l:24 lioe r,.-.:-... - N.S1R P1PE'.. qGeR : pGARETTE GGGRET7FONLY ONLY. ANDoNL1f t1rHER' Figure 1 Lung cancer mortality ratios in relation to types of smoking. Lifetime smok- ing,history' (including ex-smokers). Figure 2' shows mortality ratios ( al! causes of' death, combined) in relation to both number of' cigarettes smoked per day artdl the age at which cigarette smokers began to smoke. Death rates increase with the number of cigarettes smoked per day, and, among men who smoke the same number per day, death rates are considerably, higher in those who begani under the age of' 15'than in those who began after the age of 25. - These two variables and'' degree of inhalation are all interrelated. Men who began to smoke at an early age tend, in later life, to smoke more cigarettes per day and! inhale the smoke more deeply than those who begani at an older age. Note that on, this graph no point is shown for the mortality ratio, of' menn who smoked only 1-9 cigarettes per day and began to smoke under the age of 1'5.11ias is because there were so few such men-and, conseqtzently, so few deaths in this category-that their death rates could not be estimated reliably. The remainder of this report is based upon new an& previously unreported data. 0 1-9 1 qHi 20•39. CfOJ1RETTES PER DAY Figure 2 40s. Mortality ratios in relistion to number of cigarettes smoked per day and, age smoking began. Total deaths are shownifor men of age 55-64. _rntiee: This material may be Proteoted byoop,,vrigNt law. fTWe tT'tDScode ..--~ --~•--

. Smoking 103: Dose-Response At the present time there is consid'erable interest in the shape of dose-response curves for human beings exposed to various noxious agents. The principal question is whether in attempting to estirttate the effects of very low dosage from the known efl;'ects of relatively high dosage it is valid to assume that the dose-response curve is Iinear. Figure 3 shows age-standardized death rates for coronary heart disease in relation to l the number of cigarettes stnoked'i per day, for each of three attained age groups. The points certainly do not fall along al straight line for any of the three age a oups. For men in attained' a;e group 70-79, the coronary heart disease death rate was lower for those who srrtoked 40' or more cigarettes a day than for those who smoked 21 to 39 cigarettes a day. This may have been due to selective mortality. These figures are based upon the mortality experience between July 11, 1966: and June 30, 1972 among a large number of, rnen who were enrolIed' in 1959-1960 in a prospective study by volunteer workers of the American Cancer Society. All of the subjects included here answered a follow-up ques- tionnaire between October 1, 1'96S' and June 1966. Alli o[l the smokers were currently smoking cigarettes at' the time they answered the repeat question+- FigWre 3 Age-standardized death rates for coronary heart disease. #Maie. TSir matenial may be protected brcopyright law. (Title ! 7 US code) .

104 E. C. Hammond et al. e a (NJ1 I12J (29.21 0"f CICAtiETTES PER DAY F+4 4N 20 tl~-39' 40 sls ~~ .. Figure 41 Age-standardized death rates for lung cancer. naire, and' none of them had ever smoked pipes or cigars regularly up to the time they answered the first questionnaire. They were classified according to the higher of the following two numbers: the number of' cigarettes they were currently smoking per day aG the time they answered the first questionnaire and the number they were smoking per, day at the time they answered the 1965-1966 questionnaire. Figure 4 shows age-standardized' hnng cancer death rates for the same sub- jects. The shapes of the curves (if they can be so~called') are quite different from the shapes of the curves shown in Figure 3 for coronary heart' disease.. It should be noted that the death rates indicated by some points on' this chart are very unstable statistieally due to smalPnumbers.. As described previously, the effective degree of'exposure to cigarette smoke depends upon the age at which a person begins to'smoke as wel!1' as upon the number of cigarettes he smokes per day. We are undertaking a further analysis taking both of these exposure variables into consideration. Tar and Nicot'ine. Some years ago a small committee of experts on the subject (U. S. Congress 1967) came to the following, conclusion: "The preponderance of scientific evidence strongly suggests that the lower the 'tar' and nicotine content' of ciga- -.rotier. T1his material may be protected bY,copyright law. (Titte 17 US code) w~y,

Smaking i 105 rette smoke the less harmful would be the effectsA (A short time later this was reported by the then Surgeoni General of the U. S. Public Health Service.), Their reasoning was roughly as follows: (1) Death rates from lung cancer, cancer of'severaliother sites, coronary heart disease, and severaI, other diseases increase with degree of exposure to cigarette smoke. (2) Many experimental studies have shown that material condensed fromi cigarette smoke (usual0y, called "tar") is carcinogenic when, applied to anitnals: (3) The known acute effects of nicotine upon the heart' and circulatory system suggest that the nicotine content of cigarette smoke is partly, if not entirely, responsible for the fact that age-speci'fic death rates are higher among cigarette smokers than among,nonsmokers. (4) Therefore, it seems reasonable to suppose that if'the tar and nicotine content of cigarette smoke were reduced, then the harm, done per cigarettesmoked wouldibe correspondingly reduced. ' The term "strongly suggests" included in the statement by the committee cited above iniplied'that the conclusion might be incorrect. The major counter- speculations were: 1. If'the tar and nicotine (T/N) content of the smoke were reduced, most smokers might smoke more cigarettes per' day and thereby cancel' the benefit. (This speculation turned' out' to be incorrect when it was found that smokers who switch from high TIN to low T/N cigarettes do not usually increase the number of cigarettes smoked per day. ) 2. Smokers of'lpw T/N cibarettes might (consciously or unconsciously)i in- hale the smoke more deeply than smokers of high TIN cigarettes. If so, then their effective exposure to tar and nicotine might, not be reduced and their exposure to the gases in cigarette smoke woul&be increased. 3. It could be that gases contained in cigarette smoke are as harmful, if not more harmful, than the tar and nicotine content of the smoke. Furt;hermore,, it could be that, under certain circumstances, reduction in T/N is accom- panied by an increase in certain gases, most notably carbon monoxide. An increase in carbon monoxide might increase the risk of coronary heart disease. Therefore; if all' this be true, the net' effect of reduction in tar and nicotine might be an increase in age-specific death rates. c~c . .. Since that time, published evidence from two retrospective epidemiologic studies (one by Bross and' Gibson [1968] and' the other by Wynder et al.. ['1970]) has indicated' that people who smoke filter-tip cigarettes ha lung cancer death rates than people who smoke nonfilter cigarettes. Concernn that this desirable effect migttt be accompanied by an increased risk of some other disease (especially coronary heart disease ) led us to carry out an iib- vesti;ation which we will'now report. The prospective study referred toi previously consisted of over 1,000,000 men and women in 25 states who were enrolled by volunteer workers of'the American Cancer Society between October 1, 1959 and March, 31, 1960 and' upon, enrollment answered a detailed', questionnaire. Appromiinately9'8'.4~%. of them were ttacedi througk September 30; 1'965; and of those still alive at that time, 94'.9'% answered a relarcivelyshort follow-up, questionnaire. All'but a few of'these had also answered one or both of two previous repeat ques- tionnaires. Tracing,was then discontinued for 6 years. On October i', 1'971, we began what amounted to a new study. The subjects were 897,825 men and women in 23' states who had' been subjects of the first Notien This material may De pnotected ItiycoP,yrnght law, Mtie l7'US codb) I

P study and who~ were still alive as of September 30„ 1965. Of these; 98,4%~ were traced through September 30, 1971, and 92.8% were traced through. September 30, 1972. This report is confined to experience during two 6-year periods: Period 1, July 1, 1960 1 through June 30, 1966; Period 2, July 1, 1966 throughiJune 30, 1972. For both periods, it is confined to people who never smoked! regularly and people who were smoking cigarettes daily at the time of initial enrollment and had never smoked pipes or cigars regularly. For the second period, the report is further confined to people who answered the 1965-1966 question- naire and who were either still' nonsmokers or were stilli smoking cigarettes daily. In each questionnaire, cigarette smokers were asked, among other things,, to name the brand of cigarettes they usually smoked. Since the tar and nicot2nee content' of the mainstream smoke of'various brands of, cigarettes has been re- ported' from time to titne, we were able to divide the subjects into three sets, which we refer to as high TIN, medium TIN, and low T/N smokers.. This was relatively easy for the first period, since even though some m.anu- facturers marketed two or more types of cigarettes under, the same brand name, they could be distinguished by the presence or absence of a filter or by menthol. For the purposes of this report, we defined "high" T/N as 2.01 to 2.7 mg of nicotine and 25.8 to 35.7 mg of tar. "Low"' T/N was defined' as less than 1.2 mg of nicotime, and, with very few exceptions, cigarettes which met this qualification also delivered less than 17.6 mg of tar. "Medium" T/NN was simply defined as intermediate between high and low. Insofar as possible„we used these same definitions for later years. However, during this later time period, some manufacturers marketed under the same brand' name two or more types of cigarettes, which differed in tar and' nicotine content. For this reason, it is likely that some of the sub9ects who were placed in the high TIN category probably belbniged' in the medium T/N' category, and vice versa. There was far less difficulty of' this sort' in distinguishing the low TIN smokers from the other two groups. For the period 1966-1972, the three sets were distinguished as follows: (T)i "Higb"' was defined as subjects in the high category in the 1959-1960 questionnaire and as either high or medium in, the 1965-1966 questionnaire. (2), "Low" was defined as low in the 1!959-1960 questionnaire and as either low or medium in, the 1965'-11966' questionnaire or as low in both the 1961- 1962 and 1965-1966 questionnaires. (3) "Medium" was defined as all other smokers. Matched-group analysis was utilized. This process is similar to age standardization of'death rates except that the standardization is based'on age plus a number of other factors. Male cigarette smokers were divided into~groups, each group consisting of men who, at the start of a periodi were alike with respect tio age, race, number of cigarettes smoked per day, age they began to smoke cigarettes, place of residence (urban or rural), occupational exposure to dust, fumes, chemicals, etc., education, prior history of lung,cancer, and prior history, of heart disease. Female smokers were divided, into groups on the basis.of' all~ the above-named factors ~except occupationaexpbsunes: A group, so defined, was discarded if it did not contain at least one low 3'Ilotkr. This macerial may be protected by oopyright la w.,(Title 17'US code) ~

.~ w .. . ~~. s c±7± J- Smoking 107' High hledirein Low Sex Period TIN TIN TIN Table 1' Total Number of Subjects at Start of Period'. Male 1960-1966 63,063 ' 54,999 115:3601 Male 1966-1972 29,157 40.090 6832 Female 1960-11966 44,137 59,750 32,703' Female 1966-1i972' 22,909 49,193' 16,80.3' a ~ , ~. ~ ~ " ."l.r ~ TMM - ~I'h 4 4 ~ =.E . ~ . T/N, one medium T/N, and one high T/N smoker. Most groups containe& fewer subjects of one type than another type. For example, a group might consist' of 50 low TIN, 200 medium T/N, and 150 high T/N smokers, the ratios of these numbers being, 1, 4, and' 3, respectively. The ad jtated number of, subjects was in this case 50, this being the number of subjects in the type with the fewest subjects. The adjusted numbers of deaths were (in this case) computed by dividing the number of d'eaths in the low T/N subjects by 1, dividing the number of deaths in medium T/N subjects by 4, and dividing the number of deaths in high T/N subjects by 3. After similar caleulations were carried out for each group, the adjusted numbers were summarized over all groups. The logic of this procedure is similar to the logic of an experimentalist who first makes sure that the animals in his experimental sets and the animals in his control sets are as alike as possible and then makes an adjustment for any difference in the number of animals in various sets.. RESULTS Table 1 shows the unadjusted number of'subjects at the start of each of the two time periods by sex and by tar and nicotine. There were fewer low T/N smokers than medium T/N and high T/N smokers. Table 2 shows the ad- justed number of'subjects, which by definition was the same for smokers of' high, medium, and low T/N'cigarettes. -The adjusted number of deaths is shown in Table 3. For both men and women, in both time periods, the adjusted number of deaths was lowest in the low TIN category and' highest in the high TIN category. Figure 5 shows thee same data in terms of' mortality ratios. The adjusted number of deaths in low Table 2' Adjusted, Number of Subjects . ~ Sex Period Number Male 1960-1966 1'4,68'8 Male 1'966-1972 6475 Female 1960-1966 30„L'76 Female 1966-1972 15,342 r .Yntiee: Ttiis material may beprotaeted bineopyright law.,(Ttle 17'NS code) » . ~ - _ . . .r t r . : ~ ~... .: r: .`. Y .... , 0 ®

Table 3 Adjusted' Number of' Deaths (Total' Deaths ). , Ser Male Male Female Female Total, Period' I3isJt TIN Medium T/N Low TIN 1960-1966' 1543.0 1394.4 1351.7 1966-1972 935'.2' 9'13'.7' 759.4 1960-1966 12534 1'117.1 10519 1966-1972 .1i00.3'.7 874.7 826:2' total 4'735.5' 4299.9 3991.2' TIN smokers ranged from 81 ~'o to 88 % of the adjusted number of deaths inn high, TIN smokers. Table 4 shows the the adjusted' nunzber of deaths from coronary heartt disease (C.H.D.). The numbers are reasonably large in each category. Figure 6 shows the same data in terms of' mortality ratios. In i both periods of time and in both men and womenj the adjusted number of C.H.D. deaths for low T/I*T'smokers was lower than the adjusted number of C:H'.D, deaths for high T/N smokers. . Table 5 shows the adjusted number of deaths from lung cancer. In both periods of'tizne and in both sexes, the adjusted number of deaths was highest for high T/N smokers and lowest for low T/N'smokers. Figure 7 shows thee same data im terms of mortality ratios. The adjusted number of lung cancer deaths of Iow TIN smokers ranged from 57'% to 83'% of the adjusted number of deaths of'the high T/N smokers. Obviously the amount of'tar and nicotine taken into the body per day de- Tl1'R;/NIC©T1NE'IN CIGARETTE SMOKE Figure 5 Total deaths in terms of' mortality ratios for high, medium, and low T/N cigarette smokers. .Notkr. This nnaterial may be protected br cooyrf ght law. (Ttle I7'(7S code)

' _ Table 4 Adjusted Number of' Deaths from Coronary Heart Disease Smoking 109 fJLi;lt Afedurnt Low = Sex Period TIN TIN TIN Ma1e 1'960-1966 69,6.5 ' 632.5 645.6 Male 1966-1972' 336.0' 345.6 274.2 Female 1960-1966' 315:7 277.5 257.41 Fem ' a1t 1966-1971 y 263 6 228 0 2'1S 5 Total totai, 1616.8 1483.3' 1392.7 pends upon the number of cigarettes smoked per day as well as upon the tar and nicotine content of each cigarette. To obtain some information on the relative importance of t'hese' two exposure variables, we carried out a second matched-group analysis (Table 6). This analysis was confined to two sets of subjects: (I ) subjects who smoked I to 19 high T%i~1' cigarettes a day and (2) . subjects who smoked 20 to 3'9 low T/N cioarettes a day. As shown in Table 6, the adjusted number of lung, cancer deaths was greater in subjects who smoked 20''to 39 low T/N cigarettes a day than in subjects who smoked 1 to 19 high T/N cigarettes a day. This was true also for total deaths and for C.H.D! deaths, but to a far lesser degree than for lung cancer as shown here. . Finally, in still another matched-group analysis, we compared low T/N smokers with subjects who had never smoked regularly. As shown in Figure 8; death, rates (ftom, all causes of death combined) were considerably higher in subjects who smoked!low T/N cigarettes than in subjects who never smoked' regularly. Figµre 9 shows~ that the lung cancer death rate was far higher in. low T/N' smokers than in subjects who never smoked! reguIarly.. MEN PERIOD I PERIOt1 2 I n. .W M L N M L N' M L H M L TA'RJNICOTINE IN CIGARETTE SMOKE Figure 6' Coronary heart disease mortality ratios. ~oticr. This matetiat tnay be'protected IbycoPynigbt law. (Title l7'US code) w. p

Table 5 Adp"usted'Number of Deaths from Lung Cancer Ser Period' 11F,p11 TIN Mcdirrnt TIN Low TIN Male 1960,-1966' 122.4'. 117.4 1101.01 Ma1tr 1966-1972 89.6. 84.5' 70.6 Female 196iD-1966 43.3' 41'.4'. 27.4 Female 1966-1972' 58.1 42.2 3i6:2 Total total 318.4 285.5. 235.2 1b TAR/N160T1NE IN! CIGARETTE SMOKE' Figure 7 Lung cancer mortality ratios for high, medium, and low T/N cigarette staokers.. Table 6' Adjusted Number of'Deaths from Lung Cancer 1-19 20-39 N Srs Period High Low TIN TJN cigarettes cigarettes ~ Male 1960-1966 363 63.9 ~ Mile 1966-1'972 24:7 33!8' ~. Female 1960-1'966 103 118.0i N Female 196i6-1!972 4 5 1313 ~ Total total . 75.3 129.5 UD Q 110, •Plaiee: This materrtal may taeprotectedl"pyrighclaw: (Title l7 US'code) «

I n's~x.a t, t I r,i! LOW N•SJR LOW N.S.R. LOW NS'.R. LOW N:S1R: TJ'N' T/N T/N T/N Smokdng 1111 R.S•R.*HEVER SMOKEOR(GULARLr Figure 8 Total deaths in terms of' mortality ratios for low TIN' smokers and subjects who bad never smoked regulariy. N:S:R. = never smoked regularly. It is quite apparent that' reduction in the tar and nicotine content of cigarette smoke did not make cigarette smoking safe for the men and women in this analysis, all of whom were over the age of 40 in 1'959. Cigarettes with reduced tar and' nicotine were not introduced untill the mid - ~.: 195i0's (following the restrospective studies of Wynder an& Graham ['1954], ``'DoIl and Hill ['1952], and Levinet ai. ['I9501). Almost all of the male cigarette smokers and the great majority of the female cigarette smokers in our'study began smoking cigarettes long before that date. Therefore the subjects classi- 6ed.here as low T/N'cigarette smokers were, with few exceptions„persons who. 5tnoked'high T/Normedium, T/'N cigarettes for many years and then switched to lomrTjN! cigarettes. It appears that' by so doing, they somewhat reduced the serious risks they incurred by smoking. (Thi's does not apply to the relativcly few persons who at the same time increased the number of cigarettes they smoked per day.) Therefore we think it fair to say that switching from high T/N to low TIN cigarettes was at least a small step in the right' direction fmr' those who continued to smoke cigarettes. Those who, quit smoking fared con- siderably better. W'hat' of youths who have not yet taken up the habit of cigarette smoking? They would be well advised never to do so. However, in spite of a11'the warn- ings, many thousands of young people do in fact take up the habit. The'threat tb~ thefuture~ healthofthos.ewhomake'this youthfui'd'ecision wouldi be at Ieastsomewhat reduced if high T/N'cimarettes were removedifrom the market. We wiil, end with a word of cautiont In prodtacing cigarettes withi extremely .Yotier. This material may be arotaated brcooyrixht law. (TiMe 17 UJS code) 1

LOW N.S.R. LOW N1S.R. LOW N.S.R: LOW N.S.R. T/ N T2 N T/'N Ti/ N N:S:R.-NEVER SMOKED R'EGUILA'RLY' Figure 9 L,ung, cancer mortality ratios for low T/N smokers and subjects who had, never smoked regularly. I*I.S.R. = never smoked regularly,: lit'tle tar and, nicotine, some manufacturers may use additives for flavor or f or some other purpose. In our opinion, both additives and the cigarette smokee condensate (tar) should be tested for carcinogenicity before such cigarettes: are put on the market. Acknowledgment L. Garfinkel; H. Stidman and E. A. Lewassisted in'thisstudy. REFERENCES Bross, I.D.J. and R. Gibsom 1968, Risks of lung cancer in smokers who switch to filter cigarettes. Arn.1. Public flealah 58:33®6. Doll, R and A.B. HiIL 1952. A study of'the aetiology of carcinoma' of the lung. Br. Med:1. 2:1271. N 0 Do11, R., F.A. Jones and F. Pygott. 1958, Effect of'smoking,on the production and 0 maintenance of gastric and'duodenal ulcers. Lancetc657. Levin, M.L., H. Goldsteim and! P.R. Gerhardt. 1950. Cancer and'tobacco smoking: ~ A preliminary report.l. Am. Med. Assoc. 143:336. ~' U.S. Congress. 1967. IHearings before the Consumer Subcommittee of the Com+ mittee on Comrnerce. Senate, 90th Congress, August 23, 24, 1967, p. 7. N ~. Wynder, E.L and E.A. Graham. 1950, Tobacco smoking as a possible etiologic ~ factor in bronchogenic carcinoma. l. Am. Med. Assoc. 143:329. ~ Wynder,, E.L.,, K. Mabuchi and! EJ. Beattie, Jr. 1970. The epidemiology of lung cancer.l. Am. Med: Assvc. 213:2221. i i4ntiee: Thia rtuteriat may be protected Ibrco ~ . PYdShtltw: ~tlr17 US code) P

SECTION 2

Toward Less Hazardous Cigarettes Current Advances Gio Z. Gori, P'hD„ Cornelius J. Lynch, PhD _. 0 Ctitical levels of'. setectedl cigarette smoke constituents have beeni txpressed Im terms of maximum numbers of pre-1960 cigarettes that a, simoker'mayconsurne daily without increasing his mortality risk substantially above.that of'a nonsmoker. T1his could sti111impiy an important'risk, although It may be difficuitto detect. We relate these leveis to the y,ieids of 27'current fow tar andl nicotine commercial cigarettes, as measured at the Oak Ridge, C. atlonal Laboratory: in additioni the yields of these selected constituents concomitant with the yield of 1 mg ofinicotine are provided as a guide forthe smoker who titrates or adjusts his smoking pattern, to accommodate.a fixed daiiy, intakwof' nicotine. . (JAM,A!240s1255'*1259, 1978) STFICE' the Surgeon General's report' on smoking andi health,' considerable " attention has been focused on ciga- 1 1 . rette smoke constituents implioated ~y in the cause of tobac¢o-relat'ed dis- '' ~ h t h ave i eases: any suc eomponen s, been considered, the most frequently For edltorJal comment see p 127'1. cited being total particulate matter (tar), nicotine, carbon monoxide (CO);, nitrogen oxides (NO',~,; hydrogen cya- nide (HCN), and acrolein. Several' investigations document the contribu- tion of these components to cancer, chronic pulmonary disease, or cardio+ vascular impairment-y"' Many studies also: indicate that there, is ad'ose response beta+een the number of ciga- rettes smoked and disease: incidence and morbidity.""" Since publication of'the Surgeon General's report, aver- age tar values of' commercial ciga- rettes have decreasedi by 29%, and nicotine yields have decreased by 21.°0, indicating a continuing preoccu- pation toward reduced ha¢ard." Evaluation of health benefits re- sudting, from these reductions would be premature because of the long latent periods involvedl Available data suggest that, for the present; smoking-related diseases have not abated substantially,,, with the possi- ble! exeeption: of' cardiovascular dis+ eases. However, factors contributing to the decline in these latter diseases are not y,et cib.a,r. On the other hand, From the National Cancer lnatitute; BethesdYl Md (Or G,ony, and Enviro Control, Inc; Rockviil* „ )6Vd (Or Lynch). Ths v4ws axprsssed herein are those of the authors andldo not,necssaarily reflect the views~ or polkiss of the Natlonai Canoer InstlriAe. Pub1i0. Naalth Sisnnes. / Reprint rnQualtl to DNriston of CYne.r Causa, d Prevention, Nstional Cancar Instituls. BldO ~ .i„Room.11AO3, esthesda, MO 20014 (Dr Gon). Jr\INA, Sept 15, 15A8r-Vol1240, No. 122 mortality from tracheal; bronchial, and lung cancer hascontin:zad to rise; projections for the immediate future indicate: that further increases may be expected. This probably is because smokers now in the age groups in which cancer is most likely to develop have spent a~ considerable part of their smoking, history using high tar and nicotine cigarettes. As younger smokers who are exposed to lower tar and' niicotine cigarettes approach cancer-susceptible ages, a reduction in, morbidity and mortality rates could be expected. However, consider- ing tar an& nicotine: alone may give an incomplete and misleading,picture of hazard reduction: the full'impaet of low tar and nicotine cigarettes on health effects should be evaluated in Table i.-/Averape Critical Levels of Pre~L960 Ci9arette Consumption'' 04sssv No. oR Pre-i8eo Clparettss Cancer of the oral eavily 6.8 Pharyp0eal csncsr 2.5 EsopnaQeel cancar 7.3 Penueatic cancer 9.0 Laryngeal canc« a.s Lung cancer 6.7 Blsdder and kidney caneer 9.5. Coronary artery diseasr 4.2 Coronary heari d4eaae 3.5 Aorttc aneuryare 4.3 Emphysem., brorxhitls, or Iwtln . 10.0 AII causes for current smokers 2.0 Less FNUzardous Clqarettes-Gori & Lynch 1255 '

terms of all ' the major toxic smoke eDmponents mentioned previously. Critical levels of daily smoke inhal- ation have been discussed recently in terms of the maximum number of pre-1!960 cigarettes' that may' be smoked daily without detectable' in- crease to the average smoker's risk off mortality beyond that of a nonsmok- er.n'These are by no means safe levels' but merely imply that„ for a smoker' whose daily consurnption does not exceed these levels, any attendant t'obacco4elated mortality risk may be epidemiologically indiscernible from : that of a nonsmoker. This could still imply a substantial although less readily apparent risk. '`For instance, if' the smoker's risk of developing' lung cancer could': be reduced from the present level of approximately 10:1 to some value less than 21, this risk, while considerable; cDuld'i be difficult to establish epide- miologically. The inability to verify this reduce& risk might lead to. its' being considleredI socially tolerable. Average critical levels relative to diseases'tD which smokers are partic- : nlarly susceptible are listed in Table "1, expressed as daily numbers of pre- `19I60 cigarettes: The last entry in Table 1, "Alli causes for current smok- : ers," is -a comprehensive category ^` representing the effect of cigarette i~` tonsu'rpt'ion on mortality in generaL These values are based on, typical yields per cigarette of pre-1!960 ciga. w-: i'retzea 43 mg of tar, 3.0 mg, of nico- -s ,., , tine, 23 mg of CO, 270 jig of hi4„ 410 ' ~'.'~ig of HCN, and 13iD'Kg of'acroleiia." ->'COMMERClAL CIGARETTES '-': Most commercial brands' today '•~ have yields_that are below the typical pre•1'960' levels;, with' particular inter- est in lowered tar and nicotine yields. A recent publication from the' Oak Ridge' Ida'tional Laboratory' lists the yields'of'the six constituentsi referred to previously for 32 brands of com- mercial low tar and nicotine ciga- rettes. Twenty-seven of these brands have measured tar: yields' that do not exceed 10.0 mg, by more than two SEs. Results of testing for these 27 brands are suRne;narizedl in Table 2. The lowest' measured tar yield is 12 mg, and the highest is 10.3 mg (SE; 0.40 mg). Table 3' presents' the percentage. T'able 2:-Melytical Data for SefectedlLow Tar and!Nicotine Ciparettes "' Bhnd Carbon Nit'oqen Nydro9ea Tar, Nlbotlne, Monoxide, Oxidas+;' Cyanid.,Arxolahi, te9/clgt' mq.Yctq- mp/elq a9/rlg aq/cl9 s9ye/q eiensann & HWqes Lights 1a1i 0.8t 12.1 13S 1/e et i Carlton 115' 0.15 2:6' 34 18 18 Carlton Menthol 13 0.14 2.0 12 12 10 Decade 5.5' 0.48 4.3' 67 49 38 Decade Mentholl 646 ' 0.69 4.4 61 60 47 Iceberg 100'!. 3.1 0.32 &7' 44 44 42 Kent Golden Liqhts 8A' 0.711 9:2' 81 6'1 47 Kent Golden Lights Menthol 8:3' 0.68' 8.3 71 62 37 King Sano 6:8 0.29 11.6 195 79 35 King Sano Menthol 5.3 035' 13.6 205 102 44 LdM FlbvorLiqhts (King) 7.2 0.80 4.8 40 65 30 L3M Long Liphts (100'a) 6.5 0:67 5.5 41 69 47 Lark 11 7.5 0J61 7.3 • 83 84' 44'. Lucky 100 3.1 0:28' 5.3 88 34 28 Merit 8.8 M80 12.1 188 161 49 Merit Menthol 8.4 0J61 10.2 172 140 BZ'. Newport Lights Menthol 10.3 0J85' 12.5 88 133' 57' Now 1.9 0:19, 2.4 25 te' 1S'. Now Menthol 1.8 0:18' 2.1 30 9 13! Pall MaI1 Extra Mild 5.1 0:47 6.8 78 65 38' Rea/ 10.2 1.0 1 12.9 99 155 76 Real Menthol 7.9 0.181 10.2 84 105 44 Stride 3.3 0.38 118 66 <10 12 Tarsyton Liqhts 7.8 OA2 2.8 85' 75 ' 31 Tempo e.9 0.56 10.1 168 98 31 True 4.8 0.46 5.2 72 34 29 TrurMenthol: 5.2 0.42 5.7 84 43 31 'Data analyzed by Oak Ridge National Laboratory. tAbbreviation cig indicaterciqarette. *Total oxides ot nitrogen. Table 3.-Reduction inYieids as Percent of Pre-1960 Cigarette Yields Brand: Tar, m9/clq1 Carbon. Nicottne~ Monoxide. mq/clq mq/cldi Nltroqrtn Hydroqen. Oaides, Cyanide, u9/ciq uq/clq IAcroieln, Kq/ciq Benson 8 Hledpes Liphts 77. 73, 47 50 72 53' Canton 97 96,. 89 e7' 96 88. Carlton Menthol' 97 . 95 91 98' 97 921 Decade 87 85 81 79 a8 71 Decade Menthol 86 77 at 77' 88 64 keberq 100's 93 89 75 84 89 68' Kent Golden Lights 79 78 e0 77 88 64 Kent Golden Liphts t:lentho/ 8II 78 54 74 85 72' Kinq Sano 87' 90 50 27 81 73 King Sano Menthol 88 92 41 24 75 88 L8M Flavor Lights (Kinq) i 83' 73 79 65 84 77 LdM Long Lights (L00's) 85 78 70 BS 83 84 Lark ll 83 80 88 69 80 88 Lucky t00 93 91 77 75 92 78 Merit 80 80 47 38 63 62 Meri1 Menthol i 80 80 56 38 68 60 Newport Liphts Menthol 76 72 46 88 88 56 Now 96 94 90 91 9e a6 Now Menthol 9S 95 91ti 89 98 90 Pall Mall Extra Mitd 86 84 75' 72 84' 7'1 Real' 78 Be 44' 63 82 42 ReallMenthoh 82 73 58' 89 74 98 Stnde 92 Btl 92' 98 >98 91, Tareyton Lights 82 76 89 69 82 78 Tempo 84 8t 58 39 76 78 True 83 85' 77' 73' 92' 78 True Menthol 88 8tt 75 78' 90 76 Averaqe 88' 63 69' 64' 83 71 •Ylbbreviation clg indicates ciqerette. 1258 JAMA, Sept 15; 1978'-Vol 240, No. 12' -1005052885 Less Hazardous Ctqarettes-Goni & Lynch

Table 4,-Critica! Levels of Selected Smoke Constituents' ~ Btand Tar Nfcotine• Carbon Monoxide No. of G4ar.ttes Requlred' NitropenHydro9en Orldee Cyanlde Atuoleln Lowest Row'Entry Hlqheat Row Entry 8enson &Hedges Lights' 9'' 7 4t 4tl 7 4t' 4 9 Cadton 57'•' 40 t6 t6t, 51 17 t6 57 Carlton Menthol 72' 43 23t 45 89 26' 23 72' Decade 16 13 11 9 171. 7t 7 17 Decade Menthol 13 9 10' 9 16"' 8t 6 16' Iceberg 100's 28" 19 8 12 19 8t 6 28' Kant'Golden Lighta'. 10 a St 9 18"' 6: 5 16'. Kent Goldentights Menthol 10 9 8t a 13" 7 6 13' King Sano 15. 21' 4 3t' 10 : 7 3 21 King Sano Menthol 16' 24' 3tl 3t 8 6 3 24 L&M Flavor Lights (Kinq)i 12'. 8t 10 14" 13: 9 8: 14 LdM Long Lights (100's) 13' 9 8 13" 12' 6t tY 13 Lark ll tt• 10 8t~ 7 10 8t 6 11 Lucky 100 28' 2!t', 9 8R 24' 9 8 2& Menf 10, 10" 4 3$ 5' 5 - 3 10 Merii Menthol 10' t0' 6 3t 6 5 3 t0', Newport Lights Menthot' 8f 7 4!tr 6' a 5 4' 8 Now, 45 32' 19 22 51' 17'tI 17' 51 Now,Menthol 48'. 38 22 1811 91' 20 18 91 Pcll Ma11 Extra Mild 17' 13' 8, 7t' 13' 7} 7' 17 Real af 6 4 51 5~ 3t 3! 8 Raal Menthol 11 • 7' st 8'. 6 5I 1 t Stride 28 1Tt' 26 108p >82' 22 17' 108 I TareytonLiqhts, 11 8! 18"' 8t' 1/ 8 tli 18 Tsmpo 12' 11 5' 3t 8i 8 3 12 True 16 13' 9 8t 24-' 9 8 24 I True,Menthot 17 14 sif Bt 19? 8t 8 •19 tLowesttow entry. > '1(lghest row entry. Table 5:-Yieldsof Selected Constituents Concomitent With Yleldlof' f mg Nicotine• Brand No: oR'Ctgaratter Necsssary to Yield I mg Niootine• Tar, m9 Nicotlnr m9 Carbon I Monoxlde. mq Nitrogen lDxldes, p9 HYdfogan Cyanide, µy Acroleln, Ya' Benson & Nedges LigMs 1.2 12.11 1.0 14:5 182' 139 73: Canton e.7 10.1 1:0. 17.4. 22a 107 101 Carlton Menthol. 7.1 • 8.5. 110 14.2 85 85 71 Decade 2.2 12.1 1!0 9:5' 125 108 84 Decade Menthol- 1.4 9.2 ti0 6.2I 85 70 666 keb.ng 100'a 3.1 9.6 L0 17.7' 138 135 130 Kent!Golden Lights 1.4 12.3' t:0 12:9 83 7'1 68 Kent'Golden Lights Minthol 1.5 12.5' 1.0 12.5 107 93 56 King Sano; 3.4 19.7' 1.0 39.4 688t 269 119 Kinq Sano Menthoi 4.0 21.2' 1.0 54.41 820f1 408 17e L&M Flavor Lights (Kin9) 1.3 9a 1.0 BJ2" 52 85' 39- L3'M Long Lights (100's1• 1.5 9.8 1.0 &3' 82 , 104 ' 71 Larx u 11e 12:0' 1.0 11.7 133 134' 70 Lucky' 1001 3.6 11.2 1.0' 9.1 245 122 101 Ment 117 15.0 1.0' 20.8 288 257' 83 Ment Menthol 118 13.4 1.0 18.3 275 224 83 Newport LighH Manthol i 1,2' 12.4 1.0 1'5.0 103 160 ®8 Now 5:3' 10.1 1.0 12.7 133 85 80 NowMenmhol. 8.3. 11.3 1.0 13.2 189: 57 82 Pan.Mail ExtraiMild 2.1 10.7 1.0. 12,2 160: 137 80 Real 1.0' 10.2 1_0 12.9 99 155 7e Real MenthoU 1.2I 9.5 1.0 12.2 101 126 53 Sfnde 2:8~ 9.2 1.0 5.0 14 <28 34 Tareyton Lights 1.4 10.9 1.0 3.6 119 105 43 Tempo 1.8 12.4. 1.0 18.2 299' 170 58' True 2.2 10:8 1.0 11141 15& 75 84 Tiue Manthol 2:4 12.5. 1.0 13.7 154 103 74 Critlea/1V.luec Not'Applicab0a 86.0 e1.0 46.0 540: 820 260 ~= 'Eaeh ealumn also gives eonstituentVnicottne ratio~,For esamp0e; entrles under column headed "Tar" phre tarlmicotine.:ratio.. tEtcceeds critical wehte. JJ1M11'. Sept 15. 1978-Vol 240. Nta.. 12 L'ess.FFazardbus: Cigarettes- Gori & Lynch 1257'

reductions in yields of these b'rands mmpared' with yields of'typical pre- 1980 dgarettes Reductions range from a,high of more tban i9g°,'e (Stride HL4 yield) to a low of 24% (King ;~ Saao Sfenthol'NQ; yield). On the aver- age, the brands under consideration bave bad the greatest percentage : reduction in tar yield (68%) and the least,percentage reduction in CO and N0, yields (69%')'oompared with pre- 1960 cigarettes. The numbers of' these cigarettes smoked daily withont exceeding eriti-. eal levels have been calculated from the data in Tables l and 2, as in the following example: since the eritical -'- level' for all eanses is ; two pre-1960 dgarettes: eath;yielding 48mg of'tar, the number of Bensow & Hedges Lights (101 mg:of tar,each) with the equivalent tar yield is g.S. Thus, g.5 Benson & Hedges Lights have a total tar yield equal to the critical level for the "All causes for current'smokern"' category. a-- Similar values for all of'the b'rand! ~` and constituents considered in this article~are given in Table 4, rounded oS' to the nearest integer. Critical levels were calculated under the assumption of a smoking pattern ttniformly distributed over a ten-hour period for any,gives day. Deviations from such a smoking pattern could' alter some critical values, such asi those associated with CO effects." The lowest entry in each row of' t!j1Table 4 represents the maximum number of cigarettes of that brand that if smoked daily would not exceed thecritical':level forany of'the smoke 'eonstituents considered. The highest row entry represents the maximum number of cigarettes of'thaY brand tliat'if smoked daily would Inot eaceed! at least one of the smoke constituents considered. The range,from highesttoo lowest row entries provides the smok- er with,intermediate goals for grad- aally reducing his smoking habit through progtxssively less hazardous smoking, suges proceeding, in this manner; he would gradually reach the lowest row entry as a daily ma omum cigarette consumption level. At this point, the smoker is likeiy to be more receptive to taking, the final step toward totalicessation." Similar con- siderations apply to brands not'ez- plicitly addressed in this article. If' the majority of smokers proceeded along these lines, it' would be reason- able to predieYa substantial decrease In tobaroo-related morbidity and mortality.. It should be noted from Table 4 that the highest row entries for 14 brands are for tar yields, whereas the lowest row entries for 13 of the brands are for N0; yields. In addition, lowest row entries for nine brands occur for CO and aerolein. These values suggest that the cigarette manufacturers should,coneentrate on the further reduction of ND, yields, while still attempting to reduce further the yields of'other constitu- ents, particul4rly C0'and'acroiein. QV'ith the,introduction of'relatively low nicotine yields, it bas been suggested that' some smokers may compensate by increasing, the total number of ugarettes,smoked to main- taiw a fixed daily level of nicotine intak'e.° The daily intake of' otherr constituents for such a person would depend on the nicotine compensation rate.Table 5' lists the yields of selected smoke constituents eoncomi- tant with the yield of 1 mg of nicotine for the brands under consideration:. For example, for Benson: &' Hedges Lights;,about 1':2'cigarettes yield l,mg of nicotine_. This same number of' cigarettes yields 121 mg of tar, 14.6' mgofCCD;162kgofN0,139agof HCN, and 73 Ng of acrolein. Thus, a smoker compensating to I mg of nico- tine would bei exposed also to these yields of'other smoke constituents: Compensating,to other nicotine val- nes would affect associated yields~ proportionately. Table 5' allows a smoker to estimate his smokeiconstit- nent' intake, depending on his own nicotine compensation rates; The 1 mg,of nicotine yield (one sixth or 17% of'the critical'value)'is aecompanied by an NO, yield that exceeds the criti• cal level for two brands and by a CO yield that exceeds it Sor one of these brands. For the remaining brands, the nicotine intake can exceed 1 mg before eoncomitant yields of other constituents exceed critical values. COMMENT' Prr19i60' cigarettes have contrib- uted most to the current epidemic of tobacco-related diseases„ and epide- miologic studies show a relationship between number ofcigarettes smoked daily and the risk of the development' 1258: JAMA.Sept. 15. 197e-V6i 240. No. L2 ofdisease.,From these studies, we can define the critical Idaily smoke intake that would not appreciably increase the risk of the smoker over that of the nonsmoker. Because different cigarette brands '' deliver different amounts of smoke of' different compositions, this critical smoke intake can be met by smoking ' different numbers of cigarettes, de- pending on brand. Today, cigarettes baving toxic con- " atituent yields considerably below : pre-1960 cigarettes atx feasible, and s== forerunners of such cigarettes are commercially available. Twenty sev `= en brands that: fall into this category i were tested at the Oak Ridge National I-::t,.'j Laboratory, andithe,numb'ers of thesei cigarettes smoked daily without ex- ceeding critical values have been esti- -~~ mated for six major toxic smoke .~_ eonstituents. These critical values : may serve as intermediate goals for a_ smoker who is intent on redhcing his ! smoking habit through progressively ~; less hazardous smoking stages. These calculations are based on ~the assump. -s r tion that the smoker of'the low tar . and nicotine cigarettes will not change his smoking habita in terms of , depth of inhalation, frequency of puffing„ and butt length. Findings of ' recent'studies support this assump- tion." Although the yields for the 27 brands are considerably below the , yields of the typical pre-1960 cigar._,: _ rettes, additional reductions are war- ,_ ranted, particularly with respect to NO., C©, and acrolein. Otherwise, smokers who compensate for fixed e, levels of nicotine intake, even thougb these levels do not exceed vitical' values for nicotine, may be subjecting, themselves to daily intakes of'other toxic smoke constituents in excess of their estimated critical values. Methodslor further reductions in .. yields of toxic smoke constituents have been developed th'rough,research ~ such as that conducted by the Nation- al' Cancer Institute's Smoking, and Health Program:'''One of'the princi- pal objectives of this program is to identify those characteristics of ciga- rettes that leadi to toxic and other adverse effects and to develop rneth- ods forreducing,or eliminating such factors. Progress has been made thus far in improving methods for reduc- ing tar yields ~ through the usa i of Less Hazardous Clparattes-Gori 8 Lynoh.

t . recongtituted tobacco sheet and in reducing nicotine yiel'ds through to- bacco extraction processes and re- I 1/~blending. Other sr.ioke yields have ~, been adjusted through selected cotn- binations of' &lters and' smoke-dilu- tion devices, the use of high-porosity paper, the use of'tobacco blends rich in nitrates, and the adjustment of the eigarette's, burning, rate. Further in.- corporation of'these and other state- of-the-art advances coupled with fta- vor acceptability characteristics can improve commercially available ciga- rettes to the point where they may properly be termed less hazardous. The rationale for developing less, hazardous cigarettes rests on the fact that despite the publicity given to the health risks associated with smoking,, more tha'n 50 million Americans still' smoke. While programs to discourage smoking should continue, these edu- cational efforts should be coupled with others directed' toward reducing the risks to persistent smokers. References ( 1. Smoking and HealtkReport of the.idvimry, Experimental' emphysema: Effects of chronic, Committee to the Surgeon General'of.'tJe'e Public nitrogen dioxide exposure and papain in normal Health Sem.aces, p,ublication,1103. Public Health and pneumoconiotic lungs. Arch Enriron Health ' Service,1'974: 16:51-58:1968: Z' Anderson E1v, Andelman EJ, Str.tuch JM, 9. Hammond' EC: Smoking in, relation to the at aL• Effect of low-level,earbon monoxide expo- death rates on 1 million men and women, in sure on onset and!duration iof, angina pectoris:.A Haenszel W, (edh Epidentioiogicaf .ipproachesYo study in ten patients with ischemic heart the Study of Cancer and Other Diseases, mono• disease..4nn lntern Med 79i46-50, 1973. graph 19.1 Bethesda; Sld, Public Health Serviee, 3. Auerbach 0, Stout:IP, Hammond EID, et aL• National Cancer Institute, 1966, pp 12'1 -204. Histologic changes in esophagus in relation to 10. Kahn HiL The,©ornstudy of smoking and smoking habits. Arch Environ Afealth 11:4-1!5, mortality among US veterans: Report on 8 % 19,65.years of observation. in Haenssel «' (edl: 4. Aronow W& Smoking, nrbon, monoxide, Epidemiological Approaches to the Study of and coronary heart disease. Circulation 46:11i69- Cancer and Other Diseaaes, monograph 19. 1172,1!9?3i Bethesda, Md, Public Health Serviee, National 5 Aronow WS, SWanson, AJ: The effect of' Cancer Institute, 1966. low-nicotine cigarettes on angina pectoris. Ann 1L Krain LS: Crossing of the mortality curves lwtkrn Dfed'fIl:599-601, 1969: for stomach and pancreatio carcinoma.,Lnt,Saro & Doll R, Hill A& Mortality in relation to 57:307-310,1972 smoking: Ten yean' observations of' Bhitish 12 Morrow RC, Suarex G: 3lucosal: changes ' doctors:BrSYedJ1t1460-1467;196LL: ; - and,cancerip:intraoralemoklhg:Laryngoscope, ~ 7. Frautneni JF Jr. Cigarette smoking,°anar ' 81:102A-1028, 1!971: ' 8 Gross P, de Trexilla RTP, Baby.k SiA, atal 14 mat xJC The 19lG'~(a:cwetl repont eanaers of the urinary tsact Geographic varia, 13. 3Vyader.,E~ d!labuehi:K; M7ruehi Zf, et aL tion in the lTaited States.~,J Natl'CancersTmat ;• Epidemio~ogirLOf~'caileer of the'pancreas: :Vatf u:1205-1211. 1968 t': !.•'~tCer° Inat 50:645s 7. 1473.,,• ;- .. Persuading the smoker to wean himself to progressively less hazard- ous cigarettes may provide an alter- native w smoking cessation that is perhaps more effective than the self- denial approaches of current anti- smoking messages. Although this would not eliminate the risks tolthe smoker, it is an approach that has the potential to reduce the current epi- d'emic of smoking-associatedi diseases'o to a considerably less serious'publfic healith, problem. Tobacco,Rep 103:16'-17„ 1976: 15:, Gori GB: Low risk cigarettes: A prescrip. tion Science 194:1'243-1246, 19'+6. 16. Griest WH,- Quincy RB;, Guerin JiW: Selected Constituents in the Smoke of Domestic Low Tar Ciparettes, Oak Ridge National Labora- tory, technical memorandum No. 6144; part 1. Oak Ridge; 11enn, Oak Ridge National Labora- tory; 1971 17: Harris RtiY: How To Keep on Smoking and' Live Lincoln, ylass, Chestnut Publications, 1976. 1'8. Russell r1AH, Wilson C, Patel VA, et aL• Comparisoa of effect on tobacco consumption and carbon monoxide absorption of chang;ng, too high,and,low nicotine cigarettes. Br Al-d J 1:51Y. 1973. 19. Weber KH: Recent changes in tobacco products anditheir acceptance by,the consumer. Ptroceedings of'the 6th International Tobacco Conference, Corestn. Tokyp, 1976, pp 47-63. 20.,Gori G'B: Snwkinp and'IPeatth Prroyramr National Cancer Institute Statua,Rrpont;,Decem. ber l9TJ. Bethesda, 1Id, Public Health Service. National Cancer tnstitute, 19771 JAMA, Sep1 1s, 1978-Vol. 240', No. 12 Less Hazardous Ciqarettes-Gori't{ Lynch 1259.

.eY .:,.r;. :.. t~ , .4 Sociaily Tolerable Cigarette Smoke? To the Editor.-The Wio1l Street Jour-nat'(Nov 1, 1978, p 18) suggests that "because of news aocounts of a' study 4 by Gio B. Gmrf... much of the public A - [was left] with the impression that some cigarettes are'relatively safe to smoke in limited quantity." The arti- cle reports that because of' this, "Smok'ers of extremely low-tar ciga- rettes, who ~ were once largely igllored by' the industry, are the targets of' intensifying market competition." This calls for a' close look at the arti- cle by Gori and Lynch ('240:1255, 1978), who conclude that smokers who would' not exceed certain levels of intake of tar, nicotine, carbon monox- ide, nitrogen oxides, hy,drogen cy a- nide, and acrolein would subject themselves to a risk which could be considered "socially tolerable."' Before 1960; smoking two cigarettes per day exposed the smoker to amounts of the aforementioned sub- stances, which were tolerated without demonstrable epidemiologic effiect: G'oril and Lynch calculated the num- ber of today's cigarettes that could expose the smoker to similar amounts of these same substances. Such num- bers of modern cigarette& were assumed to be' permissible without adverse health effects. This was corrected for the low nicotine content of some contemporary cigarettes, which could lead to the smoking of a greater number of cigarettes by those smokers who unconsciously titrate their smoke intake. ,_ . Such, extrapolation from pre-1960 cigarette smoke to today's smoke of low tar and low nicotine cigarettes would only be justi'6ed if the composi- tion of the diltited' smoke remained basicallyy the same. However, the complex manipulations necessary to obtain lower yields of the six sub- stances studied' by Gori and Lynch alter the' proportions of other smoke ingredients and thereby may well change' the biologic activity of the smoke, not to mention the possible introduction of new smoke compo- nents that may conceivably result from addition of' new flavoring agents or other new tarbacco, additives or ingredients that are not regulated in the United St.atess Only a valid and' practical in vivo bioassay of smoke itself, as it is inhaled by human smokers, can discriminate between hazardous and less hazardous smoke:. Bernfeld et al' described the induc- tion of leryngeall cancer in 20% of carcinogen-susceptible inbred Syrian hamsters exposed to cigarette smoke, an incidence twice as high as~ previ- ously reported by German workers in randomly bred Syrian hamsters, but too low, for comparison of' different cigarettes. More intensive exposure' caused laryngeali cancer in 47% ' of smoking animals. With smoke dilu- tion, laryngeal cancer incidence 2142' JAMA. May 19,, 1979+-Vul 241~ No. 20 dropped' in a dose-related fashion. Cigarettes made of a cellulose-based tobacco supplement, causedl no can- eers. Various proportions of this m'aterial' mixed with tobacco reduced smoke carcinogenesis. The cancer-causing potency of'vari- ous cigarettes can thus be measured, and' commercially available smoking products must be b'sologically evalia- ated before conclusions are drawn on theirrelatfive hazards. Only such smoke inhalation studies could estab- lish whether the carcinogenic effects of'smoke have indeed been reduced, as impliedl by Gori' and Lynch. P. r+ou««,oe.. 110 - e1p,Rqeeran MaUWU Gmsndm.. wea 1:Bernfeld P...HomburIIerF: Ruasfiela.AB,strai. ditferenees in the response of'inbred IS)ran hamsnre,to eiqaretta smoke inhal.ation.. J. Natl Casxer hut!S&s7_K 1974. iBernfeld P. Hcmburger P C;Qarette.smoke iehasr• tii.nstudies'fniinhred.3vrian hamstert 1. Methods and dosimetry:. Tuaieoi,App1Pltara.eeat 45:784,1Y$In Reply.-The first issue raised, by Dr Homburger on our recent article . in Txe JouttNat, is the possible altera- tion in the proportion of toxic smoke constituents of today's cigarettes compared with pre-1960 cigarettes. The formulation of today's low tar and, low nicotine cigarettes is carried out by processes that reduce quanti- tatively, and largely nonselectively, the amount of smoke produced' in both the particulate phase (which contains tar, nicotine, and water) and the gas phase (which contains the other smoke constituents). Table 3'of' our article suggests this overall quan- titative reduction, in that the sixx constituents addressed'l are reduced for each ofthe'cigarette brands listed. The constituents considered were cho- sen because these have been impli- cated in human d'isease'incidence. These and other constituents have D; been addressed by the National Can- O, cer Institute's Smoking and Health CA Program, where over 130 types of' Q experimental cigarettes have been ~ tested forpotentiall~+ lower toxicity. Results to date confirm that today's ~ cigarette processing reduces known toxic constituents quantitatively. ~ There is no scientific evidence that (~ the reduction, of these constituents is accompanied by an increase in other suspected!toxic constituents. Further- more, there is evidence that today's cigarettes produce not only lower quantities of' toxic constituents, butt less active ones as well. For example, on a grarn-to-gram' basis, the tar of certain present-day cigarettes is less :' tumorigenic than pre-1960 tar.' The reader is referred to chapter 14 of the 1979 Surgeon General's Report on

Smoking and Health for a detailed description ~ of ' cigarette smoke" Dr Homburger also raises the issue of flavor additives, some of which he ' suggests may not have been present in pre-1960 cigarettes. We know, of no scientific evid'ence that today's addi- tives increase the t'oxicityof'cigarette smoke, and' we have uncovered' no such evidence thus far in, ongoing analyses of the Smoking and! Health Program. However, this remains a possibility that future investigations may qualify. Dr Homburger states that only an in, vivo bioassayy of smoke itself, as inhaled by human smokers, can diseriminate between hazardous and less hazardous eigarettes. We agree. This is why the Smoking and Health Program conducts studies of human smokers on, an international basis.. However, it takes 15 or more years to accumulate sufficient applicabie data for meaningful anallyses. In the mean- time, we believe that a gradual reduc- tion in, exposure to toxic constituents, as suggestedlin our paper, is a reason- able approach for the millions of smokers who persist in, their habit despitp its known adverse health effects. aao e. cw.. a,a li,eNe Maamh's.a.o. I . . . Na1qM1 MflautH o11W1Mn {anNSAc ,11A I Co.raius J. Ls.o-. VR.O (ro/ro ConYOl..h10. _... ' - -... . . /leeav,w. Md L Hoffmann D: Sehmrltz,4 Hecht SS. et aL• To6aeco . nrainoRaneaia, ieGeldioa iHV, Ti 0 PtD (eder. Po(yeydae' Npdtcearbonu a.d Caweer. L• Eaoiro+.e+t, CAa,.utry *, po lYaebotisse. ha- Yort; Ae.damie Pn.n,' 1M pp i sius: L S.roiY.p ar1', hldalrk d ReOD" of' Gr SYryeos' F i`G.aral. , public.tion 1979 281-109/5618. Public Hnlth ` s...;n.,m. challenge the validity of their conclu- sion. Here I' will note only two such assumptions. First, the vast majority of current regular (eg, pack-a-day) smokers in- hale. Hence, for a' meaningful com- parison between present-day low tar and nicotine cigarette smoking' and the pre-1960 ingestiarn of smoke con- stituents, the latter must be associ- ated with inhalation. Yet, assuming inhalation, as the authors implicitly have done, seems unreasonable. Smokers of one or two cigarettes per day, often, do not inhale. Many off those who do soon become regular (ie, heavier) smokers and hence drop out of' the two-a-day class. Consequently, their increased risks also drop out of the data the authors have examinedi For a meaningful comparison, a necessary (although not sufficient) ; condition is that the authors study a cohort of smokers who (1) smoked for a long,period'(preferably lifetime), (2) never deviated substantially from I their two-a-day habits, and (3) always izlhaledi From correspondence with the authors, I' know that they have not met this necessary condition. The second problem also relates to' smoking histories. Many current low tar and nicotine cigarette smokers have switched' from lengthy histories of high tar and nicotine cigarette' smoking. If many of the pre-1960 two- cigarettes-a-day smokers were never heavier smokers; are the relativee health risks ofithe two groupsAirect- ly comparable? The authors' implicit assumption is that they are; bbth, scientific evidence and, logic suggest otherwise. It is important to note, as Dr Gori observed in a personal communica- tion, that the authors were "address- ing the general smoking population, not specific subgroups. The effects of smoking, on an individual depend ... on several factors " Thus, even if one believed the authors' analysis, it says Gori's continuing efforts to develop and' promote less hazardous smoking materials and behaviors. And I recog- nize that throughout his work, he is careful'i to'avoid the term "safe" ciga-' rettes and that he and Dr Lynchh acknowledge that even the "critical' levels" of'smoking, "could still1i!mply an important risk,"' although they believe "it may be difficult to detect."' Like the authors, I regret the Iay' media's predictable misinterpretation of the research, which may conceiv- ably induce potential quitters to adopt an alternative smoking behav- ior having deleterious healt'h, conse- quences. I also regret that, for their professional audience, the authors failed to qualifyy their findings ade- quately by emphasizing their critical dependence on highly questionable assumptions. The Gori-Lynch article offers some interesting calcula'tions, But it does not provide any' scientifi- cally meaningful evidence that cer- tain present-day smoking behaviors will' result in statistically nondetect- able health, risks. I hope that physi- cians will keep this in mind as they counsel their patients on the conse- quences of cigarette smoking. -_ Kn..rn E: w..r.: P+ounn.ron ut W4nw.n selwol of Vuane:W.nn AM ArDat ln Reply.-We appreciate Dr War= ner's perceptive comments on our recent article in 'IHE Jourtt.*1A[.. Dr Warner states that it is unreasonable to~ assume that' the majority of two- a-day smokers inhale. Scientific data on itlhalationi practices of two-a-dayy smokers are sparse, because of rela, tively few' such smokers in the gener- al population. However, an ongoing epidemiologic study sponsored! by the National Cancer Institute's Smoking and , Health Program in eight US ci'ties"has found'that of 2741two-a-day smokers, 157 (577r) inhale. A' similar study in, Western D'urope' has thus far identified only 47 two-a-day smokers, but 29 (62%) of them inhale. Although the sample sizes of these studies are small, we believe they represent some of the most compre- hensive data available on the inhala- 1*n :practices of two-a-day smokers. ~Yqrt#er, respondents to tobacco ques- 3~in~lres frequently understate'. eir tobacco consumption practices„ so the actual percentage of'iinhalers is. likely to be larger than the aforemen- tioned values. We believe these data supparrt' our assumption that the majority of two-a-day smokers in- hale. Toward Less Hazardous ClgareRtes To the Editor.-In a recent issue of' THE Jou~x.*rA4 GIo Gori, PhD'; and Cornelius Lynch, PhD, report on "[c]ritical levels of selected cigarette' smoke constituents ... expressed in terms of' pre-1960 cigarettes that a smoker may consume without' in- creasing his mortality risk substan- tially above that of a nonsmoker." These critical levels are tr'anslatedl. into equivalent numbers of present day low tar and nicotine cigarettes ln I order to provide information to help "the smoker to wean himself to.~', progressi vely less hazardous ciga- rettes." While the authors' motivation is bey,ond' reproach, their analysis is predicated on some highly' question- a!ble assumptions that, if' wrong, JA'MA. May 18. 1979-VoI 241, No. 20 nothing about the relative risks, of' certain high-risk groups, such as women who are pregnant or taking j birth control pills, asbestos workers, I and persons with histories of'cardia vascular problems. - - My .puq)ose i~l ;,rsrsitjpg is1 pqt, ~'. _ questiot tha: Yl'aslci kesnzse.-P, that,, 'und'eiiie Ae'authors' study,-tba;' -sntak.i''ng[ tn~ t;ar~sn~?~'cn~e~~'4 'gw' retti~es is pro~ablj*-l+L~•'K~ardoes `Go' health thanvrpey<cigth~ sa tm num- ber of highei ta!td and nica',in~ ciga- rettes and that encouraging the former may be the most effective health-enhancing strategy for a cer= taim group ~ of' smokers. I applaud Dr.

*1). ` • • . 0 ,., -a$7f ~,. Less Harmful Ways of' Smoking l Ernest L. V'b'ynder; M.D., and Dietrich Haffneann, Pb.D:, Ameriran Healt~h Foundotibn, New York, New York 1C1C)1'9 , all forms of smoking, therefore, we need to ac- IN THE 4R,EA of smoking, it is our hope that someday we will be a society of nonsffiokers.. Obviously, from a look at the social, pplitical„ and economic behavior patterns of today, such a perfect society is not within isiilnediate sight. So,, while keeping the ideal in front of us:as the ultimate objectiti•e, there is much that can and, should be done abong, the road we are following. Concurrent with our eftioru to achieve a society that rejects celerate our efforts to find and encourage less harmful smoking products. If successful, this approach would be particularly pertinent, to the problem because any improvement in the product at its source involves al!'smo}:ezs and will tend to ameliorate the: injurious efl'ects of smolcing, on the broadest possible spectrum. Numerous epidenziologic studies have shown a higher mortality rate for smokers-especially eigarette smokers-compared with nonsmokers (1);. For most diseases and conditions relatedl to 'smoking, the evidence is based on so many ,epidemioliogic and' experimental studies that it is belleved' no.further documentation need! be offered to:confirm the conclusions. In fact, fbr lung cancer, the case against cigarette srrtoking, was clear as early as 1950 when Wytd'er and Graham, (2) and Doll and Hfill (3) published their, fiist reports (texr-figs: 1, 2). More recent evidence continues to point to tobacco, usage as the major contributor to death and incapacity from a variety of cancers, cardiovascular disease, and chronic pulimonary• disease (1). There seems little doubt that, in the absence of slnoking, life expectancy would be significantly prolonged~ What can we do about this major public health problem? This cmm- aiunic3tion attempts to deal with the various facets of the issue. II I , . ~i.s ~ ~j;: ~ ill LIGMT MGCEAATELY MtAVY EDICESSfVE CNAIM qEAVr iCDNTROL iR1 LUMG Ci1NCER (MYNDER• E:L. AMD lGRAMAM. La. 14301 . TtxT-r7ctrnE 1.-Percentages for amount of smoking among, 605 1 malr patients with lung cancer and, 780 men without cancer. Ropnoduad,from Joarnal o/Uu .tmofine dYEdh mt.ltiocoalion 143:924-336,1950 (2). .ranr Cr..o..cco l a~1 . 1Q..®w A.K,W..R.[S I Tkcr-etcuRS 2.-Percentagr of patients smoking different amounts of tobacco daily, Reproduced!from BriarA ldfe+diaal Jownal,2:'34. 745; 19J0.(d). t Presented ara workshop of thrSecond World Conference on Smoking and Health{ sponsored by the United Kingdom Health Education Council, held in London, Septern- ber 20-24, 1971 L 1749 1005052891

.. 1750 WY2IDLR ANtY Ht)FFtitANN HEALTH RISKS FOR' EX.SMOKERS While we know the risks incurred by those who smoke and those who have never smoked, the dam on individual$ who have stopped! smoking are less well documented. Appropriate analysis of ' ex-smokers is made more difficult because the risk for disease depends on the duration and amount of'smokirng of' each individual. For the individual who gives up tobacco after many years of heavy smoking, the risk for lung cancer appears to remain the same as if he was still smoking, for about 3' years (4•6) (text-fig. 3). For the next 14 years, the risk gradually declines to the 1eve1 of'risk for those indiwiduals who have never smoked. Clearly, certain irreversible patho- logic changes remain in, the lung of long-term, heavy smokers. ....~a,. l.. m TrxT-ncuxx 3.-Relative risk of lung cancer by number ; of years of ex-smoieing, male Kreyberg, I lung cancer (ineiudes epidermoid carcimomas ~ and "oat"' cell earcinou mu of the lung): 196b-71. t. For sufferers from chronic cough; cessation of smoking results in a significant improvement of the cough afiter 4 weeks, but this does not appear to change the degree of emphysema praenr (1, 7) (text-fig. 4). This suggests that the effect of smoke on both productive and' nonproductive persistent cough is relatively acutq and thus reversible, while the damage to parenchymal lung, tissue which leads to emphysema is largely iirevezsible. The effect of cessation of smoking on myocardial infarction has not been investigated in much depth. Evaluation is complicated by the additionall important etiologic fiunction of blood lipids andl hypertension in this disease. Data from the Na- Tsxr-F=nx 4:-ChangF in eough, among ex-cigarette smokers from va:nous firms and hospitals, New York, New Forit. tional Heart and Lung Institute's study in, a controlled population: in, Fraaninghatn, hlassa- chtuetu, suggest a relatively quick reduction of risk among ex-smokers (8) ;the study by Hatnmond! (4)' indicates that, among long-term; heavy cigarette smokers who cease to smoke,, the risk of death from myocardial infarction is reduced by 1 year, but that the low rislk level of those who have: never smoked is only reached after 10 yean (text-fig. 5). If these data are confirmed, they cYllMt smWeTS' cq,retlK smttb 104.4 ~ 1 • t1 p l~,-sl.a... 1164 S109 101014 20. hon• ranuiE.-smaen suwtrrs I Nimmond I{fdrtnpL 1NEV1 , TaxT-rsctrna 5.-Mortality ratios ftoas coronary heart disease in men. 40-79 years old; by smoking stattu: , JOURNAL OF ' TFM NA3IONAL CA'NCZR' L*7S4TrUTE . 10050'S2892

. f LESS' I'IiAR!MFWL WAYS OF SMPJKllVO suggest that cigarette smoking, has both a chronic and acute effect on myocardial infarction rates. The chronic effect is perhaps due to the influence of' smoking, on atherosclerosis, while the acute effect tmayy be due to the possible influence of' smoking in the induction of arrh.,thmia and thrombus formation (1). Understanding the occurrence of smoke-related diseases among ex-smokers is essential for the proper evaluation of'less harmful tobacco products. At the same time, it is reasonable tu assume that any beneficial effect such products may offer is unlikely to be as rapid' or as definite as occurs whem an individual stops smoking entirely. HEALTH RISK AFTER SWITCHING TO~ C1GAR' AND PIPE SMO'K'ING The risk of disease to a smoker who switches from cigarettes to cigars and/oi pipes has never been fully investigated. Here, in addition to considering the duration and quantity of cigarettes smoked before the change-over, the amount of cigar and pipe smoke inhaled by the individual who used to inhale cigarette smoke needs to be evaluated. Individlnals smokirng more than 4 cigars andjlor 8' pipes per day have an appreciable risl: for lung cancer even if they claim not to inhale the smoke (9, 10). In any case, cigar and pipe smokers are known to have a relatively high risk for cancer of the upper alimentary tract (11, 12). While 11 or 2 cigars or, pipes after dinner do not seem to be associated with any appreciable increase of lung cancer risk and their effect on cancer of the ozali Catity is also limited, excessive cigar and' pipe smoking does represent a serious health hazard. IDENTIFY'ING' THE HARMFUL AGENTS V1''hen discussing, the work area of less harmful smoking, products-a subject summarized by us. previously (1.3) and' also reviewed in the proceed= ings of'a similar workshop at the First World Con- ference on Smoking and Health (14)-accuratee identification of the most harmful components: within tobacco smoke ia obviously vital. VOL. 48, NO. 6, JIUNE 1972' 1751 NEOPLASIA - Large -scalt fractionation experiments have shown 3' types of tumorigenic components in tobacco smoke: a) Tumor initiators.-tTostly in terms of poly. nuclear aromatic hydrocarbons (PAH); they reside in the neutral fraction of the smoke. The precursors of'the PAH and the alkvlated PAH are believed'to be present to a significant extent in the wax Iayer of tobacco leaf, primarily in the fbrm of'terpenes and phytosterols. [See text-fig. 2 in (15).] b) Tumor accrlrrators,-Tumor accelerators (such as 1'-methyliradole, 9-metltvlcarbazole, and' 4,4- dichlorstilbene) are also present in the neutral fraction. [Sae text-fig. 5 in (15).] They -are not cancer-producing in themselves but tend to enhance the effect of a carcinogen when given jointliy: c) Tumor jiromotns: -Tney reside largely in the tc•ea11y acidic fraction of tobacco smoke. While phenol! itself'is a weak tumor-promoting substance in this garoup, other acidic components still remain to be identif ed. CHRONIC BRONCHlTIS/,E1w1PHYSE'MA Some of the components of' the particulate matter are ciliotoxic, particularly the phenols, as is also true of a number of the volatile components, especially certain volatile acids, -aldkhydes, and hydrogen cyanide (HCN~ ', (16). Conceivably, smoke components which destroy the defensive characteristics of'the respiratory system may play a role in the induction of lung,cancer by destroying, or changing the cilia and mucus, thereby permitting the absorption of'tumorigenic components into the bronchial epitheliuffi. It remains to be shown that the componenm contributing to cilia destruction and mucous stagnation are thus - also responsible for chronic bronchitis and emphysema, Such a sequence of events appears to be a strong likelihood. CARDIOVASCULAR DISEASE Due to its effect on the catechoiamiior reitasee mechAnecm,nicotine is believed to have a chronic effect on atherosclerosis by increasing free fatty acids (17). It may also have an acute effect on thr. 10050528~3

1752 W'YA'DE.R A21D HOFP34ANN induction of heart attacks because of the relation- ship of catecholamlines to arrhythmias and thrombus formation. .. Aznong individuals who smoke, the carbon monoxide content of the smoke they inhale increases the level of carboayher.iogiobin in the blood. It has been suggested that a relatix•e!state of hypoxi& in heavy cigarette smokers accelerates atherosclerosis and also ~ adversely af3'ects, an already atherosclerotic coronary system (18). At. present, our investigations have led us too indict nicotine as an important culprit in athero- sclerosis, but more ! worh in this vital area is neces- sary to establish whether nicotine or carbon monoxidc has the greater infiuence. EXPERIMENTAL STUDIES TumoriqRnicity In the biologic setting, it goes without saying that,, if one n:duces the amount of tobacco-smoke condensate (tar) given to Ian experimental animal, the tumor yield will! also be reduced. This has, been exiensively proved in studies producing skin tumors I in mice with tobacco-smoke condensate ~ .(19-16). Findings in: the experimental situation, therefore, support the data from dose-response studies conducted on man in terms of d utation amdd amount of smoking (text-fig• 6). On the: strength~ of the combination of both human and experi- mental data; therefore, it is reasonable to advocate the lowering of the totali dose available in a given ; tobacco product. Ttx'r-t'tovm 6'-Tumor respnnse to difCerent doses of' eigarctae-smoke condensate in acetone, 1959 and 1'960: It, has been shown that, if natural tobaccos relatively high in nitrates are selected, tumori- genicity of the resulting tar can be lowered, which is apparently secondary to a reduction of' the initiating carcinogens iun the tar (14). It has also been shoti.m that, witen mad'e into cigarettes, tobacco stems practically free of terpenes yicld a smoke condensate with little : tumor-promoting activity (text-fig. 7): raem.: 1so.v arro. . .: - . hanaer: 30%SawmeuoW.nor., ;Eecn oraw , 50% •Si.PW cone.raaa . 9f3..r. 33ec,Sronaero tEeM prao - 37%'Stmi 'cano.raan J 3G nrc. a0 50% Sanaore r- x. ® 30 i x 5 0 wRarrom / - ~ % ,_. ~-r so x Sr«n eone.mer. % 0 ~~ . ¢. % aax'5,..~ ,. e 10 12 ' 14 , MOWM b/,owame18raooNCnran iwW oofMw+W Taxr-rtouu 7: Tumor-promoting activity of smoke condensates fromicigarettes made with standard tobacco . and, tobacco stems. DMBA ~, 7,12,dirnethylbenz[al ~ ` anthracene. Extensive experiments with tar obtained from cigarettes made entirely from reconstituted tobaceo, sheets have shown that the lessening, of complete carcinogenic activity (13, 14, 19) was primarily due to a reduction of' tumor initiators. This finding is eonsistent, with another experimental fiading that tumor-promoting activity is not noticeably reduced in the tar when reconstituted tobacco sheets are used [text-fig. 1I1 in~ (1S)]. We have also been studying tobacco substitutes. In gcneral, products with a high cellulose content give a: tar with low tumorigenic activity. For instance, cigarettes made of hay can deliver a, tar with low total tutnorigenic and, particularly, JOURNAL 0F' TFfE NATIONAL CsANCER IIV5TITtTTE 100505ZS94 .

.. . LESS xAPMFtQt: wr.Ys oF sMOt:mc! 1753 a tumor-promoting, activity. Sirnilarly, our current long-ter= biologic studies with a tar obtainedl from cigarettes made exclusively from oxidized celltalose suggest a significant reduction in total tumorig;nic activity to mouse skin, a finding which we believe to be due to a trductv.oni of tumor promoters [text-fig. 12I in (l.i)1''. We consider the addition of h such materials to tobacco products as another promising,approach to the reduction of turnorigenic activity of tobacco smoke. As these various experimenm have shown, thee ttunor-initiating, and tumor-promoting capacity of . eigarette smoke: ean be selectively redinced by various methods. ~ Cardiovascuiar Disease Ftelati.-ely little experimental work has been done om the effect of'd'ifi'erent types~ of' cigarette smoke on card'iovascular factors. A study by Kershbaum a at. suggested that smoke ~ from filter . cigarettes compared with smoke! from regular cigarettes was not beneficiall in terms of a reduced effect on catecholamines or free fatty acids (17), ` Similarly, studies on thrombus formation with, the use of different types of,cigarettes proved incon- clusive (20). Certainly, more work in this vital area is necessary. i . '-Chronic Pulinonary Disease Extensive experimental' studies on cats, rats, frogs, and clams have : shown that a reduction of particulate: matter and volatile components-in articular acrolein, formic acid, and HCN-will reduce ciliotoxicity of' the: smoke (1, 16). Con- clusive epidemiologic studies relating the effect of such: a reduction in the smoke to a reduction of chronic pulmonary diseases in man have not yet been conducted. . The identification of' substances im tobacco thought to adversely affect man is obviously a prerequisite for designing less harmful tobacco products to be smoked by man.. EPIDEMIOLOGIC STUDIES . ProductlvSiodificati on No amounu of knowledge based' on laboratory findings alone can replace that gained from VOL. 48, NO. 6,, JxJNE 1972' humans. Therefore„ individuals must be contin- uously monitored to assess the value of modi- fications introdidced' irs smoking products. These! studies are vitalc to achicve proof for prodiuct modi- fications introduced in smoking products and for product modifications suggested in the laboratory in: terms of'their effect on diseases in man. Needless to say, to expect a change in risk for a disease, one must have had a change in the tobacco product. Indeed, a significant alteration has taken piace in American cigarettes mainly because of more effective filters, the increased use of reconstitured' tobaccos, the use of tobacco varieties with rela- tiiveNy low tar andi low nicotinecontent, and the usee of paper which enhances the combustibility of the tobacco column. These changes have led to a reduct2om of tar andl nicotine levels in American cigarettes over, the last 16 years (text-fig, 8). Similar modifications are reported from Gerrnany and indeed throughout most of the world (21, 22) (text -fig. 9). ~ i r i ra ~ i ~120 C r Y' r = t r i i t 23 L I_10 1958 160 '62 'di''66 '66 - 1970 Yeor T=r.ncznes B.-Tar and nicotine content of'best,selling American cigarettes (8090 of totall sales: 7,20 brands), 1958-70., I'he average nicotine content of tobacco grown in tlie United Siates has not changed significantly in itself (text-fig. 10),. However,, the increased use of tobacco sterns and sheet in the blends used primarily for manufacturing filter cigarettes (text- fig. 11), has resulted' in a lower nicotine yield as a whole,, decreasing as much as 40% on a, sales- weighted basis between 1958 and! 1969 (text-fig. 8).- 100'505259S

s t 1754' 1.7 1.6 \ ~1-5 °`1.4 1: Year WYNDER' AND: HOFFNtANN 19M 25 fJ TiExT•nouRL 9:-rluerage wet total particulate matter (TA\i) and nicotine content in the mainstream smoke of' 6erman eiRarettes (90C,'e of'totalf market), 1961-70. _.~..~~.- . _ . ..\.. ...... 1961 1!96a1 1961 0t t ii11i i 19541 '56 '58' '60 '62 '64 '66' '68 1970 Ye2 r : uo-'..;.. ,- Tztr-ncmta 110.-Nicotine content of a tobacco blend (671a fine-eured; 33I~"'p' Biiuley ) and of ' the fil'ler in the best selling American, cigarettes ('80t,'-o of total sales:, 7-20 braads). During the same period; the tobacco industry reported a! 30 7c decrease in tar on a sales-weighted' basis and' pointed out that the sales of filter ciga- rettes increased from, 10~-80 7, ' of the total du'ring, the: period' 1954-70. Piedicted Rctes To the exent that tar is associated with the deveDopment of' cancer in manj we should expect a re'duction of cancer among individuals who have smoked! low-tar cigarettes for at least 110 years: We Stlms ~.~.-'+ _M-0- I 1I I I C 1 l ! 1 1! 1961 '62 '63 '64 '6S '66 - '61 '68 '69 1970 Year TExi-ncuRZ 11'. Use of tobacco sheet and stems,in A'meri- ean 1 cigarettes. mayy well not observe any significant difference before that time, jpdg4ng from'the results obtained among ex-smokers. If nicotine does indeed afl'kct cardiovascular disease, to the ~ extent I believe possible, then we should observe some redinctionin risk for the disease within 1 year of the stnok'er'S changing to filter cigarettes, based' on studies by Hammond (4). If' cardiovascular disease relates primarily to carbon monoxide,, no changes would, be observed after the smoker shifts to: filter cigarettes, since the carbon monoxide content of filter and nonfilter cigarettes generally does not vary significantly. If the par- ticulate matter is responsible for chronic bronchitis and' emphysema, we should' observe reduced rates of these conditions antong filter cigarette smokers; but if these diseases are due primarily to volatile acids and aldehydes, then' any reduction observed would only be noted among individuals smoking cigarettes with charcoal filters. Current data suggest a correlation between edia- eat2on, socioeconpmic status, and smoking habits (23),. In any population, the higher the educational and' socioeconomic status, the greater the number of nonsmokers and ex-smokets. Data also indicate that low-tar and lbw-nicotine cigarettes are smoked more by individuaIS in the higher socioeconomic: groups and are smoked more by women than by men, We can, therefore, predict that smoke- related diseases wU increasingly become conditions of' persons in the lower socioeconomic strata (text- figs: 12, 13). The continuing surveillance of the. JoURhAL OF THE ?LATIIDNAL CANCER IIds4IIUTE

.. LESS H,ARHFtJL wAYS' OF SMOKING 1755 smoking habirts of Btitish physicians, and habits concerned with cancer of the lung (25, 76)L Cur- noted noted among our own cases, shows tliat this is no longer jusra prediction (24). me r- Y " .L AO=CAftl1 tDnV 14111 t7n lYl . /01 (7n =) ,"a"~ = , °ou:ras . TExT-rteunx 12. Percentages for nonsmoker, ex-smokeryd and filter cigarette smoker by educational level: 436 male eonmoli patients, Memorial' Hospital, New York, New York. , - MQ~.0/N6f./131) uU PM 4171 = -0, = Wo ta/ Tixr-rzcuRt 13.-Percentages for, nonsmoker,, ex-smoker, and filter cigarette smoker by educational, level: 328 female control! patients, Memorial Hospit.t4 New York, New York: RISK AMONG FILTER C1GAR'ETTE S1w10KERS Studies that have investigated the risk of diseases among, smokers of different types and brands of' cigarettes are limited and at present have only been VOL. 48, N01 6, JU'NE 1972 rent studies by the American Hiealth Foundation are.evaluating the effects of all types and' brands of tobaccos on cancer, chronic bronchitis, and!emphy sema. These studies have now, been extended to include myocardial infarction, cerebral thrombosis, and peripheral vascular disease. The information required by these studies includes the different brand names, cigarette lengths, and other para- meters which contribute to:the total exposure to cigarette smoke. At this time, we shall limit our report to a com- parison of the risks ~ among filter and nonfilter cig- arettes as they relate to, cancer of the lung. The findiisgs reveal! that, compared with regular cig- arette smokers, filter cigarette smokers of at least 10 years' duration have lowei risks of developing lung cancer. These data are: strengthened by the evaluation of an additiona188 11ang,cancer patients (text-fi'g: 14). Of 82' patients who, smoked filter cigarettes for 110 years or more, 73.5% smokedl more than 20 cigarettes a day compared with, 63.610 , of the lung: cancer patients who smoked, regular cigarettes only, as reported previously (26). The liang, cancer patient who smoked filter cig.-, arettes for more than 110 years will have to have smoked 'more of them than the lung cancer pauentt who smoked only regular cigarettes. V1re.have: nott observed a similar finding, among the controls. Thus the smoking, of filter cigarettes for 110 years or more: tends to reduce the risk of linng, cancer by Tc=-nouxc 14.-Reliative risk of lung cancer by number of dgarettes smoked per day, ma1e,,Kreyberg I„196fi-7l. 100505289'7

f 175'fi' .• WA^.vDER' AI+fID HOFFMANN about one-thirdL Our data suggFst that indiaiduals smoking filter cigarettes with a very low-tar yield have an even greater reduction of' lung cancer risk after 10 ~ yeats. I Ald eurrent smokers of filter cigarettes began smoking before the time filter cigarettes were widely availablk, and consequently alll started with non- filter varieties. The data suggest that individuals smoking 20 or less of r'lmerican.ry-pe filter ciga- rettes a da'y from the beginning of their smoking, eareers'would have a relatively lower risk for cancer of the lung (text .-fig. 15), ?Lxr-ftotJxz~ 1 S-PeKentages of patients by number of eigarettes per day and filter versus'l nonfiltcr. In agreement with data reported by Bross and~ Gibson (25), these findings indicate that it is the tar that is carcinogenic to: man, since volatile components are not significantly reduced by f lters'. com¢uonly in use at the present time. RISK AMONG CIGAR AND PIPE SMOKERS Results suggest that smoking of'eigars and pipes exelIIsively carries a lower risk of lung cancer than: smoking of cigarettes. However, very heavy cigar an& pipe smokers, even if they do not~ inhale, incur an enhanced risk (9, 10),- The risk for such smokers to develop cancer of the upper alimentary tract is at least as great as that for lung cancer, and most studies suggest that cigarette smokers have a somewhat greater risk for this cancer (Il, 12). The effect of cigarr and pipe smokiitg, on chronic pulmonary and cardiovascular diseases appears to be relatively low, except when cigars and pipes are smoked inn excess. The differences in risk for lttng cancer, chronic -pulmonary disease, and myocardial infarction between cigar' and pipe smokers and cigarette smokers appear to be reiated! mainly to differences in depth of' imhalation (1). The nicotine content of cigar and' pipe tobacco is higher than that of cigarette smoke, and the fact that the carcino- genic potential of the smoke is strong is well e%idenced by its effect on the oral! cavity (3). LESS HARMFUL SMOKING HABITS~ It is unlikely that there is any component inhaled less harmful to the human system than unpolluted air. We are therefore referring, to less harmful ways' of' smoking in relative rather tltann absolute terms. Less harmful ways of smoking would include the following: . Ioninhalatipn Fewer puffs Longer butts Low-tar/'low-nicotine cigarettes Moderate use of! cigars and;/or pipes Definitely,,one less harmful wayof'sxnoking is to inhale: the sm'oke as little as possible. Other ways include puffing on each cigarette less fteqtnently, extinguishing, thC' cigarette with a long butt, the moderate use of cigars and/or pipes instead of cigarettes, and'the switching to low-tar/1ow-nicotine cigarettes from those with high values. Some of the differences in lung cancer risk among various' population groups relate to the frequency of puffs and length of butts to which cigarettes are smoked. For example, the English smoker, who has tio, pay a high' price for his ~ tobacco„ smokes his cigarette far shorter and puffs more frequently than his Americancounterpart (27). JOU6tNAL 0'B TPTE IifATIONAII CANCER LYS'rMTrE 100Si052t598'

I LESS HARbiFTJI. WAYS OF SMOI:INiG. To encourage better smoking habits, therefore, our task is an ob%ious but not an easy one. Firsty we need to improve and widen our efforts to prevent young people from starting to smoke and to persuade: current smoken ~ to give up the habit. Secondly, we need, to instruct individuals on how to smoke in the, least harmful manner, if they cannot stop altogether. Thirdly, and from a public health, point of view,, perhaps the most effective approach overall is to make certain that all smoking products on the market are rendered as harmless as possible. In concik2sion, this communication has suggested introducing ways of smoking that may be less harmful than ever before-ways primarily base& on tlie principle of bringing less smoke in contact with lung tissue which wili', result in less absorption of'tobaccq smoke. We have shown that cigar amd'd pipe smoking is generally associated with a: lower risk for smoke-related diseases, largely because cigar and pipe smokers rarely inhale deeply. Whaty from a total point of view, scems to be most im- portant and most practical is that we have shown that certain types of cigarettes are less instrumentaSl in the induction of'lung, cancer than others and are also likely to offer a liower risk for other tobacco- related diseases. Continuous monitoring of human smoking habits is v3ta1 to the appropriate evaluation of :-tobacco producu presently available as well, as changed and modified products that may be offered in the future. This information should provide appropriate guidelines and incentives for tobacco industries and governments interested in producing products designed to make tobaccoo smoking,as harmless as possible by setting maximum, permissible levels of the di(ilerent' harmful com- ponents in the smoke. ~1"hile in some countries the tobacco industries are already moving in this direction on their own, appropriate governmental directives to accomplish this end are favored where IIeceiSary. As stated at the beginning„we need'to be practical in ~this life as well as idi:alistic. The gwal of physicians is to profect the healith of the public. Since tobacco, usage has such an adverse effeevon health, we see VOL. 48, NO. 6, JUNE 1972 1757 ini the reduction of this risk one of the greatest ehallenges in, the area of public health. We need to overcome the scientific, legislative, and social obstacles for the sake of' the people who have placed their, faith in the hands of research and medicine. REFERENCES (J) ULS. Public Health.Scrviee: The Health Consequences of 5moking, A Report of 'the Surgeon General: 1'971. Washington, ULS. Public Health Serv. PA:bL No. 71- 75'13, 1971, 458 pp _. . ., _ (2) WYNars EL, Gm"wsc EA: Tobacco smoking, as a possible ctiologie factor in bronchiogeaie caneinom& A study of 684 proved cases. JAMA 143:329-336, 1950 (3) Dot.L R, F3tu. AB: Smoking and carcinoma of the lung; Preliminary report. Brit Med J 2:739-748,,1950 (4) H..kxoxu EC: Smoking in relation to the drath~rates of one million men and womem Nat Cancer Inst Moooqr 1!9r127-204, 1966'. (S), hAm HA: The Dbrn.study of smoking and,mostality among U.S. veterans: Report'on 8yj yean:of obser- vation. Nat Cancer Inst Momogr 19:1-125, 1'966 (6), Dot:r. R, HtLL AB: Mortality in relation to smnring. Ten years' observations of Btniish doctors. Brit Med J 5395:1399-141Q; 1964 (7), Wrnaast EL, Kwvrcm PL, Lzssast RL: A short-term follow-up study on e:.cigarctte smolten. With special emphasis on persistent cough, and'' weight gain. Amer Rev Resp Dis 96:645'-G55, 1967 (B) DovLz J1T, Di.waxx TR, Kwr+NtL WB, ct al: The reiadonship of',cigarette smoking to coronary heart disease. The second report of the combinad expetd- ence,of the Albany, NX. and Framingbtm, Mass. studies. JAMA 190:886-890, 1964 (9) 9mLiN T,, GQU. OR: Relative risk of pulmonary cancer in cigar and pipe smokers. Cancc, 20t1288- 1296, 1967 - (10) Wrnezst EL, M,asumu K: Lung eancer, among cigar, and pipe smokers. Prev Med. In press (11) Wvxmr.n EL, Baoss IJ, FcLnxAx R:.M: A study of the eriologocal factors in cancer of the mouth. Cancer 10t1300-1323; 1957 (17), Wrnnrx EL, Buoss Ij,: A study of'eriologjcal factors in eaneer, of the,esophagus. Cancer 14:389~-4',113, 11961 (13) Wrrroest EL, Horrvmx~ IDt Reduction of tumori- geaicity of cigarette, smoke: An experimestal a~ppnoacii. JAD4A 192:88-94, 1965. (1! )~ Wsrt.ror.m , EL, Hsa rnwx D, eds.: Toward a, Lesa Harmful Cigarette. Nat Cancer Inst Monogr 28,, 1968, 282 pp (15) HorrxkNN D, Wmntse EL: Selective reduction of tumorigenicity of tobacco smoke. Experimental ap- proaches: II. J Natl Cancer Inst 48:1i855-1868,;1'972 1005052899

e ' 1758 WYNDER AMD I3/9P'F!'IANN (l6)~ WrnDrat EL, HornaTtx D: Tobacco and Tobacco Smoke. Studies in Experimental Circinogenesis. New York, Academic Press Inc., 1967, 730 pp (17) KERSas,a,nt A,: Btt.raT' S, HneoawrASSt' r1, et al:' : Regular,,Sl!ter.-tip, and modified cigarettes. Nicotine exeetion, free fatty acidimobilization, and catechol- amine excretion. Ji',\La 201:545-546, 1967 (18) Asratur P: Effects of hypoxia and of carbon monoxide exposures on experimental atherosclerosis. Ann Intern Med 71:+26--427, 1969 (19) DoNTLxNaL' W„EtxeYHORsr H, Ha'Rrs HP, et aI: Experimentelle, Untersuchungen Qber die: taimor- eaeugende Wirking voD. Zigarettenraueh-Kanden- saten, an der AI'3usehaut. II. Einzelvergleiche zNi.chen den Kondensaten,modi6zierter Zigaretten. Z Krebsforsch 73:285-304, 1970 ('I0.). SCHOLNDDRrTH,, WILR'DYtN4J,. CLtrrfoN EE: In9itence of'cigarette smoke on some blood coagula- tion. JI Tled' 1!:'117-128„ 1970 1 (?1) Ttuu J: Einige Tiendanal.ysen zuta Problem, des Zigarettearauchens in der Bundeaepublik Deutteh, land fur die Jabre 1961-69. Beitr Tabakforseh 5:193-197; 1970 (22) Ttsut Jj MtsrEtD JI: TrendanalyseD1 zuta Problem des Verbrauches an Iitikotin und Rauehkondeasat in der, Bundesrepublik Deuraehland fur die Jahre 1961- 1970: Beitr Tzbakforsch 6:5 1-55, 1971 (23) HznRSa Ja.: Facts on Smoking, Tobacco and Health. Washington, D.C., U.S. Govt Print Off, May 1968, 134 pp : (?l)' Royal College of Physicians: Smoking and Health, 1Wow.,Londoa, Pitman,Dirdical and Scientific PubL Co. Ltd., 1971„ 148 pp (?.9)BAoss IDJ, GmsoM R: Risks of'ltsag cancrr'in smokers who switch to filter cigaretteu Amer J Public Health . 58:1396-1403+ 1968 (26) WyxDrx EL, MASucm K, Bzwrrn: EJ!Jn: The epi- demiology of lung cancer. Recent tncnds. JAMA 211:22211'-2228; 1970 (27) WYxDEa EL, Fwztecass;D P: Unpublished data

SEICTZON 3'.

7/-o-el 61 Reprinted from ANNALS o'F'IiNTEAtNAL MEDICINE'Vol. 74, No. 5 MYy 1971 Printed'in US.A. Heart Rate and Carbon Monoxide Level After Smoking High-, Low-, and' Non-Nicotine Cigarettes A Study in Male Patients with Angina Pectoris , WiLB'ERT S. ARONOW, M.D., F.1#:iC.P., JAMES DENDINGER, B.S.,,andISTANLEY N. kOFfAW, N1.D:, Irvine and Los Angeles, California . Ten cigarette smokers with angina pectoris had bloodd pressure, heart rate, and expired+air carbon monoxide measurements before and after smoking each of five high,, low-, and non-nicotine cigarettes. There was a significant increase in systolic and diastolic blood pressure after smoking each high- and low-nicotine cigarette,,with a sigtlificant'increase in peak systolic and diastolic blood pressure from cigarette 1 to cigarette 5.11here was a significant increase inn heart rate after smoking each high- and low-nicotine cigarette but no i significant' increase in peak heart rate from cigarette 1 to cigarette 5. There was no significant increase in blood pressure or heart rate after smoking a non+nicotine cigarette. There was a significant increase In carbonmonoxideJevel after smoking,each hig11-, low.,, andlnon-nicotine cigarette, with a significant increase in peak carbon monoxide level from cigarette 1 to cigarette 5. S tuoKINt; one high-nicotine cigarette (1) aad, one low-nicotine cigarette (2) caused a significant increase ia systolic blood' pressure, diastolic blood pressure, and heart rate inipatients with angina pectoris caused, by corondry artery disease. Thene was no significant change in systolic or diastolic blood1 pressure or in heart rate after smoking one non-nicotine lettuce leaf cigarette (3). 'This study was pertormed to determine the effects on blood' pressure, heart rate, and' expired-air carbon b- From the Cardiology Seaion. Medical Ser+iae. Long Bearb Veter- am Adnumstracion Hospltal; the Tuberauloafs and ReaQarasorr Diaeans AasociaUon of, Los Anaetes County; and the Udvenit7r of Calitormia Colk;e o!' Jfadlcine; Ir.ins, Calit. monoxide level before and after smoking each of five high-nicotine, low-nicotine, and nonnicotine cigarettes every 30 min. Materials and, Methods Ten men between the ages of 40 and 56 (rneani age, 51')-alli of' whom smoked 20 to 30 cigarettes daily- were subjects. Each subject had, a classical history of ex- ertional angina pectoris. Five subjects had a previously documented myocardial infarction at least 1 year ago; the other five subjects had coronary artery disease docu- mented, by previous coronary angiography, with, 50%, or greater narrowing of the lumen of at least one major vessel. The patients were brought to the laboratory and'famil- iarized with the equipment and the procedure before the study was performed. No patient smoked a cigarette for at least 8 hr before the three consecutive mornings of this study. In a statistically randomized order each, sub- joet smoked on three consecutive mornings either stand- ard nonfilter high-nicotine cigarettes, standard filter low- nicotine cigarettes„ or standard non-nicotine lettuce leaf cigarettes. The high-nicotine cigarette contained 2:0' mg of' nicotine andl 28 mg of' tar;, the 1ow-nicotine cigarettee contained' 0.3' mg of nicodne and 7 mg of tar, and the non-nicotine lettuoe'leaf' cigarette contained 24.7 mg of' tar. The patients did' not know which cigarettes they' were smoking. The patients remained in, the same room under constant, observation during, the entire study period. Heart rate was recorded during each observation pe- riod, with an electrocardiograph using lead II. The same observer recorded blood pressure in the right arm of r each patient in the sitting position during each observa- tion periodi using a mercury sphygnnomanometer. After 20-sec breath holding (4, 5) an expired-air sample was collected in a rubber breathing bag,d'uring each observa- tion period by the same technician and, immediately an- alyzed' for carbon monoxide content, using a Beckman Annals of InUmal Medlnin. 74:697-702. 1971' 697

Table 1. Mean ExplredAlr Carbon Monoxide Level Befbre and Atter Smoking Eachi of Fve High-,, law+, andi Non-Nicotine Cig; arettes' t Measurement Average Expired-Air Carbon Monoxide Level . Period High-Nicotine Low-Nicotine Non-Nicotine Base 14.6 t 7:6' 13.6 t 6.3' 13.2 t 9.1 IA 1'9:4t8:0 18.9t6:3' 18.2t9:0 IB 18:0~7:0 17.3 6.0 0 1. 16.6 9.1 2A 214 7.1 1 22.6 6.6 6 21.2t 818 2B 21.9~6.'41 19.9t6.2 19.6,± 8:5'. 3A 27:2t8:1 25:4t6:2 24.3 t 9:0 3B 24.8 t 7:0 23.4 ~ 6:3' 22.6 ± 8.6 4A 29:3't8:2 28,2~7:0 28.0t9:0 4B 27.2 t 7:5' 26.1 t 6:2 25.9 ± 8;1. $A 32:8t 8.1 31.7 ± 7.7 31.8t9:4' . • Ia p,pm = 1 so. Base - baseiine; IA - immediately after smoking dprette 1; 1B - immediately before smoking maarette 2; 2A - isa, mediately after,srnoi:iaa,cigarette 2; 2B - immedlaaely'before srnokiat' dgarette 3; 3A - iisunediately' after smoking cigarette 3; 38 - lmmed, lately before smoking ci{arette 4; 4A - immediatelr ' after smokinf dgarette 4;, 4B - immediately before amokici' cigarette S; JA = thr mediately after smoking daarette s. IR-215' nondispersive, infrared, carbon monoxide ana- lyzer (4, 5)'. At &AM each morning the blood pressure and heartt rate of each patient were recorded in the sitting position, and then an expired'-air sample for carbon monoxide contentt was obtained. At' 8:05 AM, 8:35 AM, 9:05' AM, 9r3S AM, and L0:05 AHt each patient smoked one ciga- rette in the sitting position at his normal pace, inhaiing the smoke. Immediately after smoking each cigarette and 1 min before smoking the next cigarette, the blood pres- sure and heart rate were recordedi in the sitting position,, and then an expilI sample for carbon monoxide content was collected and immediately analyzed. An analysis of variance tests for factorial design was used to analyze the data (6). Results Table 1 shows the mean expired-air carbon mon- Us. •-• Hig~ nicotlna icigarettK o--m loanicotineciWanat o-.u No,nicotine ciq4r.ttes. ® 7A In ' 3A MNauranal irrlads oxide level in parts per million i- 1 standard, devia tion for the 10 patients before and immediately after smoking, each of the 5 high-, low-, and non-nicotine cigarettes. An analysis of variance test showed' a sig- nificant increase in mean carbon monoxide leveli after smoking,each cigarette (P < 0:01)and a significant increase in peak mean carbon monoxide level from cigarette 1 to cigarette 5(P' < 0.01). 'There was no significant difference between the high.-nicotine,, low- nicotine, and non-nicotine cigarettes. Figure 1 illustrates the mean expired-air carbon monoxide level in parts per million for the 10 patients before and immedlately, after smoking each of' the 5 high-, low-, and nonnicotine cigarettes: 'hable 2 indicates the mean heart rate in beats per minute ± l standard' deviation for the 10' patients be- fore and, immediately after smoking each ofl the S high-, low-, andi non-nicotine cigarettes. An analysis of variance test showed a significant increase in mean heart rate after smoking each of, the high-nicotine and low-nicotine cigarettes (P' < 0.01) but not after smoking,the non*nicotine cigarettes. There was no sig- nificant increase in peak mean heart rate after smok- ing the first high-nicotine or the first low-nicotine cig- arette. There was a significantly higher mean heart rate after smoking a high-nicotine cigarette compared with a low-nicotine or a non4-nicotine cigarette (P < 0:01')- There was a significantly higher mean heart rate after smoking & low.nicotine cigarette compared with a non-nicotine cigarette (P <' 0.01). Figure 2 illustrates the mean heart rate in beats per. minute for the 10 patients before andlimffiediately af- ter smoking each of the 51 high*, low-, and non-nico- tine cigarettes. _, 3e 4A m 1oos0s29Q31 Figure 1. There was a significant ' increase in mean expired-air carbon monoxide level after smoking eacA, of the high-, low-, and noanicotine cigarettes, as wellias in peak meani carbon monoxide level' from cig+ arette 1 to, cigarette 5. Base = baseline; 1A = immediately after smoking cigarette 1; 1!B = immed- lately before smoking cigarette 2; 2JA' = immediately' after smoking cigarette 2: 2BI = immediately be- fore smoking cigarette 3, 3A' _ Immediately after smoking cigarettr 3: 38 = immediately before smok+ Ing cigarette 4; 4A = immediately after smoking cigarette 4: 4B = Immediately before smoking, ciga- rette 5: 5A = immediately after smoking cigarette 5. SA 0 t' MayI971 • AnnI lnternrl Medicine •Volume 74 -NumberS 698

- High nicotine cigarettes a-3'Low nicotine cigarettes No nicotine cigarettes INean heart rate for 100 patients in beats per minute. 0.0! : V; T Base --r lA 1B' 2A 21B' 3W. ~-~ 3'B __V4A 4181 -,- 5A Measurement Periods r Rgure~2: There was a significant increase in.mean heart,rate after smoking each oft thei high-nicotine and, Iow-nicotine: cigarettes but not' after smoking the non-nicotine cigarettes. There was no significant increase in peak mean heart rate from cigarette 1 to cigarette 5. For explanation ofimeasurement periods,,see Figure 1 legend. Table 3 1 shows the mean, systolic blood pressure : in millimeters of inercury, ±1' standard deviation for the 10 patients before and immediately, after smoking each of the 5 high-, low-, and'' non-nicotine cigarettes. An analysis of variance test showed a significant rise in! mean systolic blood pressure after smoking each of~ the high-nicotine and low-nicotine cigarettes (P <' 0.01) but not after smoking the non-nicotine ciga rettcs. There was a significant increase in~ peak mean systolic blood' pressure after smoking, high-nicotine and Iow-tticotine : cigarettes from cigarette 1 taciga- rette 5 (P < 0:011), The mean systolic bloodipressure was significantly higher after a high-nicotine ciga- rette compared with a low-niaotine, or a non-nicotinee cigarette: (P < 0.01). There was a significantly higher mean systolic blood pressure after smoking & low- nicotine cigarette compared with a non-nicotine ciga- rette (P < 0.01). Figure I illustrates the mean sys- Tablei2. Mean Heart Rate Beforrand Aftar Smoking Eaeh of Flve. High-• Loww and Non.Nicotine Cigarettes Measurement Average Heart Rate+ Period High-Nicotine : Low-Nicotine Non-Nicotine Beae 7ll0It11.0 72:4t11.1 72:2t9:1, 1A 86.8 t 9.2 81.0 t 9.4 74.9 t 9:3' IB 79.1' t 12.0 75.7' t 10.5 70.5 ~ 8:3 2A . 87.2 10.5 5 8'Z.0t10.0 8 71.7 8.8 2B $0.6 11.4 4 76:3t12:0 70.9 7.6 6' 3A 87:8 t 9:5 83.6 t 10.6 73:8 t8.5 . 36 ` 80.0 11.0 0 76.6t11.1 70.6't7:6 4A 87.6 t 11.3 83.0 t 9.8 73.4 y 7:4. 4B 820 t 11.2 77.6 t 10.1 70.T t, 8.1 SA, 89.4 11.2 2 83.2t 9.9 728t7:9 • In bean/mis ± I so. For ezpiaaatlon ot measutement' puiods;, srr Table Ii tolic blood pressure in millimeters of mercury for the 10 patients, before and'immediately after smoking, each of the S high-, low-, and non-n'tcotine cigarettes. Table 4 indicates the!meam diastolic blood pressure in millimeters of mercury ± 1 standard deviation for the 10 patients before and!iizlmediately after smoking each of the 5 high-, low-, and: non-nicotine cigarettes. An analysis of variance test showed a,significant rise in mean diastolic blood pressure : after, smoking each of the high+nicotine an& low-nicotiae cigarettes (P < 0.01) but' not after smoking the non-nicotine ciga- rettes. There was a significant increase in. peak mean diastolic blood pressure after smoking high-nicotine and low-nicotine cigarettes from cigarette 1 to ciga- rette 5 (P < 0:0!1i). There was a sigmificantly, higher mean~ diastolic blood' pressure after, smoking a: high- nicotine cigarette compared with a low-nicotine or a non-nicotine: cigarette: (P < 0.01)as well! as after, Tabie 3. Mean Systolic Blood Pressure Before and,AYter Smoking Each of' Fve High., 4ow-,, snd! Non-Nicr4tine Cigarettes Measurement Average: Systolic Blood Pressure' Period High-Nicotine Low-Nicotine Non-Nicotine Base 121.4 20.5 5 121.0 20.4 4 7 121.4 21.7 IA 135:0t1'9:9 128.0 21.2 2 1224~22.3 1B 128!4 y 19.8 123.8 t 20.6 120.6 ~ 21.7 2A 137:2t20.0 129.2 21.1 1 121.0 21.0 0 2B 130.4 t 1!9:1 125:8 +; 20.1 121.4 t 21.5 3A 138!6i1'9:9 130.2 21.7 7 123.0 21.5 5 3H 13Z6t20:0 126:8t20.5 121.2t20.7. 4A 140:2±21.0 131.6 y21.6 121.8 t 20.0 4B 134:5 t 20.5 128:6 t, 20.8 121.6 t 21.4 5A 141.4'± 22.6 132:6~21.6 1226~21.6 • In mm Ht = I so. For e:ptanation of', measurement periodl. ter Table 1. Aronow at al. •'Heart Rat., Co RerN. and ISmokint! 699 80. 0 ~ 75: 0 -

142. 0 140.0 ~ Mean sllstolic biood'pressure for 10 patients ini mmHg '- High nicotine cigarettes tT--a Low nicotine cigarettes" oNNo No nicotine cigarettes r ~ ~ ~% %ii. le r / Nb` i % ~ ~ f~ o . .o... " N•,•.,.N.o ~',,N'"~,,. I.ti,/N,•/1/./ .N•••~~"""•"" ••/h1j••I... .N,N.NNNN.~/NMNNNN.N(yNN~ N..N --I Bbse p pNN.NNNNNpN. 1A 18 2A 28 3A, Measurement Periods Figure 3. There was a signiflcant increase In mean systolic blood pressure after smoking each of'the high-nicotine and low nicotine cig- arettes but not after smokingthe non•nicotine cigarettes. There was also a significant increase in peak mean systolic: blood pressure from cigarette 1 to cigarette 1 5 after smoking, the high-nicotine and and low-nicotine cigarettes. For explanation of' measurement peri, ods, see Figure I legend. smoking, a Iowrnicotine cigarette: compared with a non-nicotine cigarette (P < 0.01). Figure 4 illustrates the meatl, diastolic blood pres- suredn millimeters ofmercury for the 10 patients be- fore and immediately after smoking each of the 5 high-, low-, and non-nicotine cigarettes. Occasional premature ventricular systoles were pre- cipitated' in 2 of, 10 patients (20% ) after smoking the high-nicotine cigarettes, in 1 of 10 patients (10% )i after smoking the low-nicotine cigarettes, and in none of the patients (0% ) after smoking the non-nicotine cigarettes. No ischemic ST=segment depression was precipitated after smoking hig.li-nicotine, Iow-nicotine, = or non-nicotine cigarettes in any of the 10 patients. Discussion Rehder and Roth (7) found that normal subjects who smoked:ini successioni two thirds of each oftwo . - r :. .. . . Tabla4. Mean miastolic Blood Pressun Befon and After Smokln` Each of Five High-, Low-, and Non,Nlcotine Cigarsttes Measurement Average Diastolic Blood Pressure!' Period H'igh•Nicotine Low-Nicotine Non-Nicotine Base 79:6 ± 9.7' 80!0 t 9.01 80.~8' ±10:3 IA 87:4! ± 8.6 84.1 t9.0 81.0 t 110.2 1B 83.0 t 8.7' 81.6 t 8.8 8(14' ~ 10.3 2A 88.2 t 8.1 ' 84.2 t 9.0 80.16' t 10.0 26 3A 84,6' t 8.7 890 t7.7 82.2' t 8.4 84.8 8.8 80.16 t 1118, 81.2110.4 3B 8119.0 828t8.7 79!8t110.3 4A 89:8 t 8.91 8&0 t 8.9 804t 9.01 48 86:6 ~9:8' 84.0 t 8.3 80.161 t 9.6 3A 91.2t9.21 86:2t8.3 81.0t110.7 • to mm H¢ = 1 so. For explamuon of measurement perunds, sue Table 11 filtered cigarettes had, during smoking, an increase in mean systolic bloodl pressure of 21 mm Hg; an in- crease in meani systolic blood pressure of 16 mm Hg, and an increase in mean heart rate of 23 beats/min. Aronow, Kaplan, and Jacob (1) previouslly found that patients with angina pectoris caused by coronary artery disease had after smoking one standard non- filter high-nicotine cigarette an increase in mean sys- tolic blood pressure of 16 mm Hg, an increase in mean diastolic bloodl pressure of 9 m¢n Hg, and an in- crease in meaa heart rate of 17 beats/min: After smoking one low-nicotine cigarette their patients had an increase in mean systolic blood pressure of 8 maa Hg, an increase in mean diastolic blood pressure of 4 mm Hg, and an increase: in mean heart rate of 9 beats/min (2). After smoking one non-nicotine ciga- rette their patients had no significant increase in mean systolic blood pressure„mean diastolic blood pressure, or mean hearti rate (3),. - Our results iitdicatedi a: significant increase in mean heart rate after smoking each of the five high«nicotine and five.low-rlicotine cigarettes but not after smoking the non-nicotine cigarettes. These results also showed no significant increase in peak mean heart rate after smoking the first high-lnicotine: or, low-nicotine ciga- rette. Our data; also showed a si_nificant increase in mean systolic blood pressure: and in mean diastolic bloodi pressure after smoking each of the five high-nicotine and five low-nicotine cigarettes bu!Cnot after smoking the non-nicotine cigarettes. The peak mean systolic blood pressure and peak mean diastolic blood'presstlre were also significantly increased from cigarette 1 to 700 Nliy 1971 •/Annals of Internal Medicine • Volume 74 • Number 5 100,5005290105

Measurement Periods - Fguoe 4. There,was a significant increase in mean diastolic blood pressure after smoking',each of the high•nicotlnrand low-nicotine cig- arettes but not'after smoking,the,non-nicotine cigarettes. There was also a significant increase, in peak mean diastolic bloodl pressuree from cigarette 1 to cigarette 5 after smoking',the high-nicotine and low-nicotine cigarettes. For explanation of ineasurement, periods, see Figure 11 legend. ' Mean diastolic. 9Z0-q ~ 90.0-I «--• High nicotine cigarettes a--a Low' nicotine cigarettes a-10 No nicotine cigarettes blood pres's'ure' '~ for 10 patients ~ im mm Hq 85„0 ~ ,' cigarette 5 after smoking the high-nicotine and low- nicotine cigarettes. The increase in heart rate and blood, pressure caused by smoking high-nicotine and Iow-nicotime cigarettes is based on the : known increase ini catechol- amine discharge from the adrenai medulla and from chromaffin tissue in the heart that occurs during', smoking (8-10). Nicotine also acts on chemorecep-. tors in the carotid andi aortic bodies, refleziy, causing, acceleration of the heart rate and an increa5e in blood pressure (11). In addition, low concentrations of' nicotine can stimulate sympathetic ganglion, cells: Our data also indica2ed' a significant increase in mean expired-air carbon monoxide level after smok- ing each high+nicotine, low-nicotine, and non-nicotine cigarette, with a significant increase in peak mean carbon monoxide level from1 cigarette 1' t,o cigoLrette-5. There was no significant difference in mean carbon monoxide level after smoking high-nicotine, low-nico- tine, and non-nicotine cigarettes, as has also recently been found by Cohen and associates (12). Carboxyhemoglobin determinations may be ap- prpximated from expired-air carbon monoxide levels (4, 5)1. The equation, Carboxyhemoglobin % =-0.5 + 0.2 (carbon! monoxide in' ppm), may be used~ for estimating carboxyhemoglobin levels (4),. Using this equation, it can be calculated from our data that the mean carboxyhemoglobin concentratiotr ia our paL tients was 7.105 after smoking the fift;h high-nicotine' cigarette, 6.8% after smoking the fifth, low-nicotine cigarette, and 6,95'o after smoking the fifth non-nico- tine cigarette. The levels of carboxyhemogl,obin (as approximated from expired-air carbon monoxide levels) producet, by repetitive cigarette smoking in our study did not have any significant effect on the systolic or diastolic blood pressure or on the heart rate. The principal noxious eBects of carbon monoxide inhalation on the organism are'caused by the recognized interference of this gas with oxygen delivery, related to competition for hemoglobin transport'capacity' and inhibition of oxyhemoglobin dissociation in the presence of car- boxyhemogIobin (13-16). Current research also indi- cates other significant effects of carbon~ monoxidc in- haiation on the organism' (17)-for example, inter- ference with central nervous system functioning, at low level concentrations (18 ),, and facilitation of ex- pernmental athetosclerosis (19, 20)'. The effects of increased carbon monoxide levels produced by smolcing,cigarettt~s need to be further in- vestigated. We are currently investigating the effec2ss of increased' carboxy'hemoglobin levels prodiaced by smoking many non-nicotine cigarettes on exercise performance in patients with angina pectoris caused by coronary artery disease. AC1:NOWLEDGMEIY'1'St The authors express their appreaa- tionito Donald C. Butler, Ph.D.. Biostatistictl Consultant;,Western Research Support Center, and to Emiko J. Nalcamura, M!S. Statistician;, Western Research Support Center, Sepulveda„ Calif., for biostatistical consultation and biostatistical analysis of' the data. Received 23 November 1'970; revision accepted 22 December, 1970. Aronow.t at. • H.art Rate. CO Levei. and'Srnoklng7~01 Y . ~. . -- . ~ . i N % - le ~ % .y/ Id Q' ,f~....... N.o....... .,,1µ..IQN.M.......... 0 NM.MN...N...•i0 .NN WO M. ....Oa.ua...... +N' - W'~'o~ - O"' + i i I r 0.0 Base 1A 18 2A 28 3A 38' 4A 4!B - 5A

r geqnests, for reprints should be addressed to W'tbert 3. Arononow, M1D, Cardiology Section, Veterans Administration I$ospital, Long Beacb, Caiif. 90801 References LA'aoNOw' WS, KAPLAN MA, JACOw D:! Tobacco: aprecip- itating factor im angina pectoris. Ann Intern Med 69:529-536, 1968 2 AaoNow WS„ Sw,t'NsoN AJ: Ime effect, of low-nicotine cig- arettes on angina pectoris. Ann Intern Med 71 r599-601, 1969 3. A'aoNow' WS, SwANsoN Al: Z;lon-nicotiniaedl cigarettes and angina,pectoris. Ann Intern Myd 70:1=7, 1'96'9' 4. RtNaota A, GoLOSIKt1nt JR, HeLwto HL, et al: Estimating recent carbon monoxide exposures. Arch Enviran i Health (Chkago), 5:308-318, 1962 S. JIDNES, RH,. EL'L'ICOTT. MF, CADIGAN JB, et'. alt Thee relation• ship between alveolar and blood, carbon, monoxide con- centrations during breathholding: simple estimation of' COH''B saturation. I Lab'Cl&e Med 5'1:553-564; 1958 6. WINaE BJ: Statlsrical'Principles in Esparimental'Desigrt. New York, McGraw,HiB Book Co., Inc-, 1962 7. Raxnme K, Ro rN GM: Effect of smoking on the fasting bloodisugar and pressor aatines. Circulation 20:224-228, 1959 8. W.rrs DTi The effect of nicotine and smoking on' the seaetion of epinephrine: Ann NY Acad Sci',90:7480„ 1960 9. KEASxas'UAI A, KHORSANDIAN R, CAPLAN RF, et al: The role of catecholamines in the free, fatty acid response to cigarette smoking. Circulation 28:5Z-57, 1963' . 10. BtIItN JH: Action of nicotine on the heart. Ann NY Acad Sc1 90:70-73, 1960. 11. Cotsaoe 7H Ja: The pharmacological' actions of nicotine. Ibid :, , pp. 48-51. 12. CoxeN SI, PeaxtNs NM, UaY HK, et al: Carbon monoxide uptake in cigarette smoking. Arch Environ Health (Chica`o)- 22:55-60, 11971 13., GoLDSUCtrtt', JR: Carbon monoxide and coronary heart disease. Ann Intern Med 71:199-201, 1969 1'4., AYxes SM, MUet LEr HS, GaeeoaY J1, et al: Systemic and, myocardial hemodynanlic responses to' relatively small con- centrations of carboxyhemoglobin (COHiB'). Arch Environ Health (Chicaga) 18:699-709, 1969 IS. BraxsTlNOL M, CoLa P, HAwoczNa L: Variations, in oxy4 haemoglbbin dissociation with age, smoking, and Buerger's disease. Brdf 1 Surg 54,:615.619, 1967' 16. Asrttur P: Carbon monoxide and peripheral' arterial disease. Scand I ClLI Lab Invesr19(suppl 99'):193-197„1967 17. GoLnsmumt JR; LANDAw SA: Carbon monoxide and human . health. Science 1162:135II=1359, 1968' 1'8- BE;tan RRy WERrtte7at GA: Behavioral impairment associated with' small doses of' carbon monoxide. Aimer l Pftblic, Health 57:2012-2022, 1967 19. Arro<uP P:, Effects of hypoxia and ot'carbon monoxide ex- posures on experimental atherosclerosis. Ann Intern Med 71:426-427, 1969 20. WnExFAr AF: Is atherosclerosis a disorder of intrnmito. chondrial respiration? Ann lntrrn Med 73:125-i26, 1970 702 May 1971 •/IJnnals of Internal Medlcin• •' Volumr 74 • Number6

d'NT7ALS OF CCCLRPATIONAL:, ffEDIDCINE, V.18', 1975. `1; ~ -w. HY,P: VoL IlI. pp. 1,14. Perganson a 1993. .^rincM in Grcit' Britnin, SMOKING, CARBON MONOXIDE ANti7 A RTERIAL . . . DISEASE N. 11VAr:D! and S. HOWARD t -~....---...,r, DHSS Cancer Epidctniology and' Clinical Trials Unit, Department of the Regius Professor of Medicine, Radcliffe In6r.aary,, Oxford O?CZ 6HE A'bstraet-This paper reviews the role of carbon monoxide (CO) as a measure of, tobacco smoke absorption, and as a possible cause of'arterial'disea,se in man. Smoking is the most important'sinS'lcsource of'ex'posure: to CO; and freiquently lead's t'o carboxyhaemoglobin (COHh) lcvels above 8%: Most filter-tipped cigarettes' produce more CO''than plain' cigarettes. The main factors alTccting the uptake and elimination of CO aree eonsidered and itis shown'thata single COY.b measurement combined with a recent smoking andlex'ereise history can beused'to estimate the COf;ib derived from each cigarette. !n a cross-seetional stttdy COI•Ib lbvels weremore eloselyassociated with the preva:cnce of'eoronaryf heart disease (CHD)'than was smoking hutory. CO exposure from smoioing has been shown to be harndul in persons who aitx~ady have CHD or intermittent' claudication. The evidence that CO is also harmful in persors without arterial disease is inconclusive, but animal dzta suggest:t'hat this may be the case. Some implications reiating to the uae of 'Smoking Tables' and the modification of.cigarettes are considered. I'NTR 0DU!CTION RECENTLY,, considerable interest has been fucused on carbon monoxide (CO)' as a measu're of tobacco smoke absorption and also as a toxic constilcucnt in tobacco smoke which may be responsible for the development of arterial disease. In this paper we review these aspects of Cb and consider some of tlte imrntpiicatiars of modi- fying cigarettes in order to make them safer. . The association between smol:ing and coronary heart' disease (CHD) is now well established (DoYLE et af, 1964, Mottms et ah„ L'9C6; Kir:-,NEL et al:, 1968; STAstLt:aR er al.,, 1968) and many prospective studaes have shown that middle-aged men who smoke 20 cigarettes al day have 2'-3' times a non-smoker's' risk of'd3•iio; of CHID (DOLt, and HILL, 19641; BEST, I'9Cc6; 1C.n'rtN, 1966; HAa0,toNlD; 1972), making CHD nurrteriaaily' one of the most, important diseases associated with smoking. CARBON MONOXIDE AS AM.1RfiER' OF' TOII'A'CCO S.MOI:E ABS©RPTION . II!tar, is exposed .o' CO from many sources, and t:hese have been wcll revicwed (GOLDSMITti and L1:.wt)AW, 1968; U.S. DEPARTIIENT OF 1`MGa LT!kfi, 1:DUCATIOI & WELrAttl:, 1972). CO is absorlied tdirouglh the lungs t'o form carbo:C,ilaelTog'lobin (COHb) and'' Table I summarises' the approximate levels of COHb that various sources of exposurc can pr'odtice. Data in this table r'e'ating to environmenta: and occupaticunaC exposure were obtained from non-smokers. TlpYnI~ / R~ l~,.~aJ1 ~,1~Y7 ~, "'-•..4Y. _II' 1'I

. 1 2 A1: VfhLc and S. HowMRa TABt.B 1. T1GP!cA7: CARBON MOt.OxtIDE Arm CARBOACYHAEmOll, LEtisELS AS50C•7a1'ED wl:H,vAR1OUII'. SOURCES OF' EXPOSURE TO CARBON NIOltiOkInE - Approx.mean Approx. mean. Source of'CO' CO (ppm) COHb (iZ Source of COHb dam Metabolism - Environment (non-smokers) Los Angeles commuters London taxi dnvers Occupation (non-smokers) Motor car repair shops (Canada) Parking attendants Border inspectors QvIexico-U.S.). Blast furnace workers Smoking 22 80 80 1'14 0-3 S36sTw+.w (1949) 2-5 DEANE and PERtctVS~(Unpub:). 1-6' - Jo.rFS et a!. (1972) S BUCHWALD (1963) 7 RAmslar (1967), 4 Cbttl:rF,et al. (197'1) 4 BtttT, er'al. (1974). 2 Gownwrrtt and U',DAhv '(1968) 61 WALD (unpublished) 2 CAvtnEr andCot•E (1'973) S': CowtE'er a!. (1973) Pipes (difelong; U.S. & U.K.) I6;000 Cigarettes 40.000! Cigars (lifelong US. & U.K.): 70,000 Pipa+cigars (ex-cigarette smokers) - (i) CO 1 irt tobacco smoke Smoking as a source of exposure to CO dtivarfs all others. For most types of cigarette the concentration of CO in the smoke averages about 4°,; by voliume. Cigarettes deliver about 12 ml CO percigarette when: tested on al smoking machine under standard cond"at'ions as,specified by the Tob'acep: Research Council (P(oTHwfit.L andGtaA, T;,1'972),(35m1 puffsof 2~ sec dtuationatarate of I puff per minuta smolked'1 to: a stan8rd butt length). As ~a cigarette is smoked andi becomes shorter, the quantity of air enterir•.g through the porous cigarette paper is reduced, and so the CO concentration increases with each puff. Since the paper surrounding the filiter of filter-tipped cigarettes is relatively non-porous less air can enter to dilute the CO, producinm a high'er'CO yield in a, filter- tipped cigarette than in a plain one. Thi's surprising, result has been conflnmed on, several brands: ciQarette (EVANS, personal communication). Figure 1 which shows the CO concentration per putT ~ of four brands of cia rette illt:strates this. Two o'F these, °aenior Service Filter and Players i`!a. 6 Filter, have non-porous filter tips, an& one is a typical plain cigarette, Senior Service Plain. The fourth, Silk Cut Extra, i I 1 t'. 3 J)1!{. ~10 llRUFF M.. Fta. 1. Carbon monoxide yields per puff of four brands of cigarotte: Silk Cut Extra Mild has a ventilated filter. ^--.~•--• Ilay.rs rp_6Fil4.r~{'-Seni.r S.rHce-.PI+in -SYnier f.nicr~~Riiter~ N ~ s i ~ 0 ` 'r s .,....-.~-. ,.,.. . :--~...-- . ,._ ~ . .. ~ -~. , r, ~ .._._.. _. . _.. t

I', rH vAwoUS s a t t!)I tb data ~ ttys~~') :d t`rr--ava (Unpub ) rl. (11,', 2)) e(1~;:c) t7it7) at: (l • 7'l) t. (11971 :) ' ti'an4' t.AtvnAw (1968) tpabG- hcd)' v and I ;:otE(1!973) al: (l'.1731 C For most typcs of , ::t 4by voDumr. :Il s'tnok-ing machine :ouncil (R'OTFtwELL per minute srnoked' air en!tcring through t inc;r-es si'th each :arcll~___ is' relatively Cn!yic!d in a filter- bccn confirmed on, xure I which shows -rates chis. Two o'f.' cous lilter tips, and' rtl~, Silk Cut' Extra k Ci:t Extrs hlild& has a 1 Stttoking, carbon monoxide and arterial'disease. Mild, has a"ventils!ted" filter, which differs fronl, conventional filters in' having perforations in the paper surrounding, the filter tip. With this last type of cigarette, air entierin'g,through the perforations dilutes the sm!oke, thereby reducing the quantity of Cb' per puff, and'' this can result in a CO yield even lower than that, of plain cigarettes. When the perforations are artificia'lly'sealed the CO }ieldi of the cigarette increases to levels which are more typical of conventional filter-tipped cigarettes (W/ALD and S,%tm-l, 1973). ' (ii) Uptake and loss o~ CO by smokers Thcuptake of CO from tobacco smoke and the rate of elimination of'COHb frotni the'body depend on several factors which are listed in Tablr2': Apart from'the type' and! quantity of'tobacco smoked, the main factor affiectin!g, CO uptake is the method TASIz 2. TEIE PRINCIPAL FrAE'rOttS INFLUENCtNCu THE'RATES OF, UPTAKE AND EiINQNATIONi OF CARBON MoNoX1IDE BY SMOKERS - CO Uptake Concentration of CO in tobacco smoke No. puffs, puff volume,,puff ftbw rate Depth of inhalation Pulmonary transfer factor for CO' Total haemoglobin+myoglobin mass CO Loss Initial COHb icvel!and!ambient CO levels Alveolar ventilation (physical exercise) Pulmonary transfer factor for CO Total: haernoglobin+myoglbbin, mass Cardiac output . of smoking-that is, the'size and frequency of the'puffs as well as how, deeply each puff is inhaled! The rate of loss of'CO is determined chiefly by alveolar ventilation, which is itself dependknt on physiaal'~ exercise. Figure 2, derived'' from' data published 144 vao ua w u pAERING! SIeM/lY FqatrAEt' 1 I I l ~ tt 16, t? Zu i! YENEILATIq'N RIRi~6 I 11a{el~ FIG.Z. Half-life of,CO'Hb in relationtoalveo,larven'tilation rate. This SFurcwas produced from data published by ConUev er at. (19651. Adjustment has beenrn.zde for the increase in trnsfcr factor for CO with activity, taking avadua firomJ0 mt nrin-' nvi l!1;-' at rost to .0inT1!min- TTuTO FII,;-' with Strem.tous exercise such as foutball. Thc energy expenditure for each activity sh'o:%n'was taken from PxssMoxE and DuRszrr (1955), aud converted into alveolar ventilation rates using 3-4'5 mI oxygen per calorie (Boon<tart et at., 1936), a respiratory quotient of 0•82 and a mean alveolar CA, concentration ofl5•6%. It has been assumedithat the inspired air contains nb CO. sutG/r1RG. STUDMING~ TYRING'

~ 'll 4 eoqe% by COBURN er a!. (1965), shows the considerable eRut that level' of physical activity has on the half-life or COHb, ranging,from 4 hr during sleep to 1 hr dUring vigorous exercise. COHb levels in, smokers normally show a diurttaL rhythm witlt ltvels rising durin,g, the day, and' declining during sleep. The Wye diurnat' variation in CO'I=Ibb level makes a"random"'level difficult to interpret. Figure 3 shows how the pattern of .~ t fr _F IA'CKGt011'N'0 OLOf N. Watm and S. HnwARD i-- . xee ttML'tlrJ ' - FtG. 3. Examples of COHb patterns in'2 smokers. Both sttxtke 20 cigarettes daily but at different times: ney both eliminate COHb atthe'same rate (half-life of4 hrwhile aslecp from OD 00 to 08 09 hr and a half-life of 2 hr while awake from oB-0D to 24 0o hr). Vertical fines represent the increase in. COHb level produced' by each cigarette; this COHb "boou" has been taken as l% COHib ,xr cigarette for both smokers. For simplicity, each cigarette has been shown to have been smokcd instantaneously. The "background" COHb leveUdue to endog=ous CO production and atmospheric CO exposuro has been taken as t;;, recent smoking can affect the daily COHb levels of two hypotli~tetical cigarette smokers, 'A' who'smokes mainly in the evening and B' who smokes steadily through- out the day. Both `A'' and 'B' smoke 20 cigarettes a day, inhale to the same extent (that is, produce the same rise in COHb level per cigarctte), eliminate CO' at the same rate.but smoke their cigarettes at different times of the day. Thus ':4' and 'B' have thersame exposure to tobacco smoke but their COHb levels are the same only at 09.00 and' 119:4©, and at any other time their COHb' levels would be misleading inn suggesting that one smoker was bcing,esposed to more CO than the other. However, if instead of simply comparing COHb level's, the CO uptaAe were measured from cach cigarctte smoked by each of the two persons. it would be demenstraued .hat the two were, in fact, being exposed to the same tota.l quantity of CO. On^ problem of this approach is that the CI0' uptake, and henc: the amount of CO'lib derived ftom'a single cigarette (the COHb 'boost' per cigarette), is likely to vary considerably frotrr cigarette to cigarette according to the circumstances of smoking, even for a,ivtin individual. However, it is reasonable to 'suppose that a smoker's acera;e COHb boost per cigarette is likely to be a characteristic of'that particular person. In fact, this measure can be estimated' from a single CO'idb measurement and a smol;ing and exercise history covering thc previous 24 hr (N1YAtrD et aJ.,,in press). Such estimates have been shown to vary much less within an individual smoker from one day to another than bc;t%scen ditTerent smokers. A smoker's COHb pattern can be I+iott:d as in Fig. 3, and the mean daily COMb can be calcultitedl Figure 4 shows the csti- mated mean COHh levels on sevcral diiTerent days for each of S suojeccs who smoke 15 25' cigcrcttes dhily„ and one (P'H)who smoi-es 40 a day. Alt;iouglr th:.re is a day-to-day variability, somc subjects are consis>,ently and' substataiadly different from others. • ,. +wrsww~.+~^o'.~"'. -- . . ,

:al activity :u t'tttring vigorous ar.dith levels risin'g, ariation itt COHb how the pattern of X:aUKn%ar=.=a Smoking, carbon rnouoxide and arterial distase 5 .y' •. ts r . 9 / r . . / f ~. / /!./o u dlt,,,, but at difTerent' c.•p from 00•00 to 08!00 rarescnt t.he increase in +kcn as 1'„ COi{b per ' I to, have bcen' smokcd tuction and'atmospheric •pothctical cigarettc :es stcadily through- : to tt~e same ettent nat( ) at the sam.e +.•h `V and' `ii' have •c tlic same only at •'tl N- misleading in •he ot•nr: Iloo•erer, -c-. n-cn,urcti, from • d,::noastratcd that ~~. Onc problem ~•r4.~~ CO1'Ib dcrivcd to s•ary cans'id:rably kintg, cvvn for a given :er'scu•cra,e COE,Ib dr,r, p:rson. In fact, ~ and c, smoking and s). F-1ai cstirnates Cr' frctin one Lln)r to •+terni.-un inc plotted !r; 4 >.awti:s lt:c esti} <t.,i,;. + c Nk ho Sn1DiCe: AltltotIr,l1 tiicre is a, .ubsta'nti;ully diAcrcnC w 1005052~12 ,~.. ...._..- . •.,._._.. __-__..._.__~,.~..,.~... _.... ..T.~ _~~,.T_ .........,__.~......_..Y......,... I 4 I 3 _ / • /r Fl1 al WM~Yr MS~1C'~.w~.t6 ts. Fio. 4. Estimated mean daily COHIb levels (above the "background"' level due to endogenous CO production and atmospheric CO exposure) for nine smokers. For each subject, the points represent estimated! values for several ditTcrent days, based on a single CO'Hb messurement. ASSOCIATI~ON BETWEEN CARBOXYHi'AEN4OGLOBM AND THE' PREVALENCE OF ARTERIAL DISEASE The association between COHb' levels in smokers and'' the.prevalence of arterial disease has been studied in a factory population in Copeahagen (WAtD et at., 1973). Satisfactory data were obtained frotn1 950 subjects of whom 53 had either CHD or intermittent claudication: All the subjects were classified into four categories according to the estimated' weight of tobacco s'moked. Blood was taken for COHb measurement after lunch, the subjects having smoi:ed' as usual that day. The COHb level was not corrected for times of smoking or level! of physical activity. Table 3 shows that the proportion of subjects affected by at least one of these disorders increases not only with tobacco consumption (11 °; among heavy smokcrs) ; but al5c, with COHb levcli (13% among smokers with a COH'b lev.et of S"/, or more). A multiple regression analysis using a logistic model showcd tllat the only' factors found to be significantly associated with CHD or intermittent claudication TA'OI:F 3. YStOPORTIt9PIS OF StJB7F.Cf5 wIT't4, CORONARY HEART n15E'1SS' AND/OR nNTERMITrENr CLAUDtIGCTION: GROUt"EID BY'COHb t_ENt1.,ADtD SMOKING CATEGORY. PsRCEtvrAGts IN PARI:vMFSts (TAxla« FwK WAt.D ct aL', 1973) • Smoking COHb % category' 0- 4- ST Totat Nil 21,180 (1) - - 2JQS0 (1) Lighr 0j90 (0) 1127 (4) 0iA (O) 111112111 (I1J~ iVtoderate 4a06~ (2) 15117,3(B) 13j5Q(25)321u35(7) Heavy 5160 (8) 10/95 (1'1'): 8/59 (14) 23,1214 (UI). Total 1,11536 (2) 2K;t3001 (9) 2U1114 (18) 55;950 (6) Definition of smoking ;categories:: Light: 1-14g tobacco per day: Miodarate: 15-24t_ tobacco per day; hte3vv: 25g or more tobacco per day (assuming that each cigarette providcd l g of tobaceo, and each cigar 3g): :

..ni.~r..L... ` 1' N. tiWA'Lo and S. HowAxn - .~-...+-..!`.a~.~,.,.r . were COHb level, age and serum cholesterol (iP<0!00I for each). After allowing for these factors there was no significanc association with the other factors investigated, namely sex, years of past smoking, amount smoked and type of tobacco smoked. Similar results were obtained' among persons who smoked only cigarettess or only cigars. After matching for sex, age and' smoking, history tlie relative risk of having CHD or intermittent claudication with a COHb level of 5 ja, or more was about 20 times that of a person with a COHb level less than 3'y(lower 95 % confidence limit 3-3). The data from this study demonstrated that the COHb level' was correlated with the prevalence of arterial disease independently'of the amount smoked, and suggest that COHb may, in prospective studies, predict such disease more preciseiy than the smoking history. Moreover, the magnutude of the risk associated with an increased! COHb level' indicates the importance of the COHb level as a risk factor for CHD and must at least raise the possibility of a causal relationship. - Two points should be borne ini mind in interpreting these findings. Firstdy, there is the possibility that as a result of'having these diseases persons ini the study al'tered their exercise or smoking habits so as to leadi to higher COHb levels for a given cigarette consumption. This might occur, for example, if cigarettes were inhaled more deeply to compensate for a reduction prompted! by medical advice, althoug' this is unlikely to account for the magttitude of'the observed effect. Secondly, the study cannot incriminate CO as a cause of atherosclerotic disease, as CO'Hb may merely reflect' more accurately than the smoking history the absorption of other constituents of tobacco smoke such as nicotine, which themselves may cause the disease. CARDIOVASCULAR EFFECTS' OF CO In considering the toxic eflfects~ of CO in relation to arterial disease it is helpfull to distinguish the effects of CO in, patients who already have vascular disorders from the effects in subjects who are free of disease. (~ i E,Q"ects of CO on patients with artzrial'disease There is evidence that it is harmful for subjects with coronary heart disease to bee exposed to CO at ia:v levels notl yet shown to be toxic to healthy pco,t:;.. Angina pectoris is aggravated by exposure to CO at concentrations which result in COHb : levels of 3-4 */;, as has bcan, shown by two studies ( ANMttsoN et al:, 11973 ; ARow©uv attd LsnELt, 1973). In each study 10 patients were exposed to air andi CO on different days without either paticnts or investigators being aware of which gas was being administered. Table 4 shows data from these two studies demonstrating that patients with CHD who are exposed to 50ppm and 100ppn} CO for 2-4 hr, have significantly reduacdi exercise tolerance and increased duration, of'ansinai pain as coripared! withl the control group„ althoughi there was almost no, difference in exercise tolerance between ilae two levels of CO exposure. Electrocardiographic changes ;ug.gcstivc of' CHD (imcreasedi ST'ile7ression} were noted durino,CO exposure at rest i¢: one study (ANDexsoN ct al., 1'973), bur oniy during cxercise after CO exposure in the oaher. (f\uOtiow and' Isnraa, 1973). ARON©w dnd RoKAW (19'71) sltovecd' that these cardiac cfTccts were not, caused by nicotine, by investigating, Fatients •xith, CHD who had smoked'8 nicotine-free cigarettes in 4 hr and had, on average,, raistd'tCieir COhi'b levels by 6 %b. ' Ti. ti'. A• I`:' prt FI: dii alli . n:i ~ p C; in t i r u on• i Wr ex.c, ; ~ .. . . . . ...... ..,._._.. .. . ~.-..R,_.......•... •,~ • _ . ~ .. ...._.. ~_ . ~ ....._..,. . ~ . iwY :~

: Smoking, carbon monoxide and arterial disease After oUter factors and' iype of tobacco ~oked only cigarettes -,- thc relative risk of of 5°„ or morre was ower ?5 % conftdence I was correlatcd with -moF •d. and suggest ;re prt:ciseiy than the :d wi i h an increased' risk fictor for CHD r,diite-~. Firstly, there .. s in the stud1r altered c!s for a given S- tcs' were inhaled tcal advice, althoughi. afect: Secondly, the ,zasc, as COi11b may absorption of other •4lves tnay cause the ;e it is helpful' ~ctrla~ disorders from -Y' hcs ric disease to be 'th;v 1,•:ol+lc. Angina 3iicir result in COHb c , 1973;; ARONOw n d CO on ditTt:rent which gas was being 'itrati;tg that patients :' Itr ha c significantly ta as roniparcd with :a excixiFe tolcrancc sraucstive of r at re t in m.ne studyy ivl.ur,- iit thc other 'thm,: A t lt,1t these '~nu v iiih CHU who raisctl thcir CbHbi Air 50 ppm CO 1q0 1ppm CO Before After Before After Before After Andexsort er el. %,COHb (4-hr exposures) Mean 1F6 1-3 1-4 ?.-9 1-6 4+5 S:D. 0-6 0+4 017' 0•7 0.6 0'8'. see Timo to onset=of angina Mean 309 265• 26t'' Duration of angina Mean 242 285NS 3l'St' Aronow et a1 %COHb (2-hr exposures) Mean 1•t M ' 1 10 . 2-7 S.D. 0a3 0•2 0-3 0-2 sec Time to onset of angina Mean 223 188. •P<M5, tP<0-01, ;R<0-001. CO vs air. NS~=Not significant. Much work has been done on the physiolo;ical effects of'CO exposure and on the mechanisms by whic;v CO might aggravatie CHD (Ct3~tnltT~[- o~ EFFeCTS OF , ATMOSPttERIC' CONTAMINANTS ON HUMAN HEALTH & ' tiVELFARE, 1969 ;, COB(JRN 1970). Haemoglobiin combined with CO is not available for carrying, oxygen and the presence of COHb reduces the release of' oxygen carried by the remaining hacmo- globin to the tissues (DoLCt,.ts et aL, 1912; RQUtcEtroN'and DARLING, 1944). Under such circumstances a healthy heart can supply extra oxygen to the myocardium by dilatirtg,the coronary arteries and increasing coronary blood flow. However,,coronary, arteries occluded by atheroma may not be able to dilate sufficiently to prevent myocardial hypoxia. Evidence for this is somewhat inconclusive but AYRLS et al. ('1'970) have demonstrated that coronary blood flow increased' less in patients with Chi'U exposed to CO (10iD0ppm for S-1S mini producing a mean COHb of a%) than in' normai subjects similarly exposed. Whereas the role of CO in precipitating angina inpaticnts witltCHD is reasozably clear, the role of nicotine has not been demonstrated. 1it is kriown that nicotine stimulates the heart both' directly and by the release of catechula'mines Whicl: incrazse the heart rate and blood pressure (GtceEVSPAV et aL, 1969). Such effects increase the demand for oxygen bytlte heart and it is possible that in patients with, CHD coronary blobd flow cannot increase, with consequent myocardial ischacmia. In, addition there are theoretical grounds for expecting the catecholaniit:e-release produced by nicotine to cause cardiac arrhythmia, particularly in a disessed heart. Although these actions of nicotine might explain the cardiac effects of smoking there is little evidence to indicate that they are; in fact, responsible. Ncverthele;s it would be unwse to dismiss nicotine as harmless in people with coronary discase until more data are avai:able. CO has bcen shown tp, aggravate pcrir±heral arterial d'iscnse as well as CiTIU. ARONoW etal: (1974) performed "double-blir+d"CO exposure studh'es on, 10 patients with intermittent claudication rExposurc to S'0ppmi CO for 3!ir raised the rrcan COHb le%-ell from 1•1 °r;; to 2•8'"; and decreased the exercise tolerance before the onset of leg pain by 17,0 (P'.'0 COl) whereas thcrc was no corrasponding change in exercise tolerance after breathing,colnpressed air. ~ 1005052914 .~~.._., _.~...~-_ ~_...~:_.,.~.-...._,. TABIF 4. EkACLQaA7toN oF .1I:CrT.`iA IN PATIF`TT5 EXPOSED TO CARnON NONO)QDE' (TAi:Eti FRO2W1 ANDERSON et al., 1973; AROr'cow et cl., 1974) .. . . ...~~ .. .. ~ + _ . .. .~ . , . r..w.. ..-..IM....Y..-_.... i.... . _ ,__ _ _ . ._ .. .. .. . , _ . .. .. . . . ~ . . . . ..^+~.~~...r_...~.~.~..~„^nr.-..~.1..1w~.+~~~.~-+.r...-i. ~~._~'_

4 t I , 3 N. `Vatn and S. HowAM (ii)i Effects of CO on normal arteries ' The effects of CO or, normal, arteries are~ less clear than those: on a diseased arterial systernL There is good' evidence that exposure to CO encourages the develop- ment of atheroscltrosis in animals, but no dite~ct evidence that it has this effect in man. AsTRUrn ('1'973) has suggested a mechanism whereby CO causes atherosclerosis by reducing the delivery of'oxycen by the blood to the intimal and mediai layers of arterial walls cau.sing,hypoxic damage. This results in an increase in the permeability of the arterial walls to lipi ds, including cholesterol. The combined effect of hypoxia and increased cholesterol entry into the arterial wall initiates or promotesithe process of atherosclerosis. Increased serumi cholesterol and raised blood pressure„both well- established nisk factors ;n CHD; .vi1l obviously exacerbate this pat'hul'ogical process: (a) .4trima!' experinrents. Animal studies have shown th :t exposure to CO causes the deposition of cholesterol in the walll of the: aorta in rabbits and in the: coronary arteries of prirnates, withi electron-microscopic changes suggestive of, early atheroma. Because of the importance of'this work and because the experimental conditions need to be considered before interpreting.the results, it is usetul to consider the relevant experiments in some detail. In the early experiments by AsrxLP et al, (1'967) on cholesterol-fed rabbits exposed to CO (16-18%,COHb) for 8-10~wee.ks„therewas increased' depositiion of choiesteroi in the intima of'the aorCa, compared wit,h control' animals exposed to compressed airr and fed on the same diet and, kept under the san:e conditions. In later experiments (iK.tst:DSEN et al., 1968; 1969) the etFect was found to be greater with intermittent CO exposure than with continuous exposure; moreover, hypoxia (16 % oxygen) pro- dticed the same lesions andi these were reversed by exposure: to. 28%, oxygen. TIz7ss reversal of the atherosclerotic lesions may have useful therapeutic implications in man and suggests that regttlar, oxygen administration in the treatment of CHD might prof'itablw be investio ted. WAtasTxUP et al. (1969), exposed_rabbits fed on; a aormal diet to CO for 3 months, producin, COHb levels ofabout Thc rabbits;develbpcd cha'nges ir the aorta identified by light microscopy as atherosclerosis which were not seen in control animals. There were, howzver, no macroscopic intimal changes seen. KJELDSEN er a!. (1'972'; 1974), using the electron microscope, demonstrated lbca4l areas of partial or total necrosis of myofibrils, intirnal and subintiinal oe3cn;a and' fibrosis in rabbits fed oni a normal' diet exposcd to 180ppm CO (15-1'7 °; COHb) continuously for 2'weeks: Coaorol rabbits kept in atmospheric air did not show these: changes. WEBSTER et al: (1'968)i demonstrated that . CO could cause arterial dama,e in primates as well as in rabbits. Excessive lipid was deposited in the coronary arteries of choltsterol-fed squirrell monkeys exposed to CO (20„ COHb) for 7' months coniparedi to control animals on the same diet and breathing air. Electr©cardio- graphic changcs of right bundle branclr block and T wa.•e dc¢ressian Nvere noted in the CO-expos.:d nnanl:e.rs. Tiiosts,:` (1974) exposed munlecys fed: on normal diet tc CO (producing 21 '.h COHlb), and found af:a.:mcs indicative of atheronia in the coronary arteries when exposure was continuous but only minor changes were seen v.•itli inuermittenC exposure to tfne sanne ini of'CO. lit is interesting to, note that in rabbits tlse lesions causcd by CO were fountd in the norta, whereas in priniates athcroma was restricted to the coronary artemes. The signi'.i+canuc of this difference between the two,species is not known. I . i ti ..r~.'-r-.+.. ~.*e}-...Y~;....~.- .R. .. .~ ..~.:.~-.~.: ~r ... .

n diseased thc devclbp- t~his : ~T1e~t in man.- Ithcroscicrosis by ntctiial lnyers of a the ;-crmcability, !.'ctio:+ of'hypoxia •;notr: the process essu:; -, both well- It:olopical~ process. •un: tti> CO causes 4' in the coronary ,*t'ca7:y athcroma. ;ncntsl conditions s1 ( onsider the ;-d rabbits exposed •:ion oCcholcsterol to conipressed'' air f later experiments !a intcrnti2tcnt CO~ t6°; oxy,bi:n) pro- _3 i, o:.ygen. This -.ic tmallications in ..nti( ;HD might ?:: •°cd-on a normal : raabi:3 devc!ol.^.ed •:ir.%Oira were not. :tit;tl1c%at:,,s se.en. •mntvrra'tcd lhcal •imal tvdcma' and -1 ! "; COH'b)) ntDt' Show, these :rtcrial damage in ^ caronary arteries fftr 7, months 'r. E'.-ctrccardio- -iott rt•:•rc notcd in •in ne;c Imal diet to : tltcrf,lna in the ~•Suznv-, n•cric scen CO wcrc found in •mary artcries. The •. n. SmokinY. carbon monoxide and arterial disease 9 (b) i Nu»ran studies. There is at present only indirect evidence that CO may be a cause of atheroma in man. It is difficult to test this hypothesis directly for two reasons. Smokers who have high COHb levels are also simultaneously exposed to other toxic substances in tobacco'smoke, making it difficult to identify a cause and effect relationsluip, while COHb values in occupationally exposed (non-smoking) groups rarely reach such high levels. However, certain data are at least consistent witlt the hypothesis that CO is atherogenic in man. StGGA.aRD-ANOE'RSEN ec aL (1'9G3)'have demonstrated a significant increase in leakage of plasma proteins, including lipoproteins, through the vascular wall during Cl'J~expoiure in both humans and dogs. The epidemiological study of' Danish factory workers described above demonstrated that atherosclerotic disease was better correlntedi with COHb than with smoking; history, and while it is nott possible to axclude any role nicotine, or any other absonbed' constituent mf'tobacco smoke, may have, the evidence is nonetheless consistent with thehypothesis that CO, is causative. Since exercise has a marked effect on the elimination of CO1 from the body, but probably only a slight effect on the elimination of most other constituents of'tobacco smoke, it might be expected that smokers who exercise vigorously have a smaller excess risk of CHD1 from smoking than those who do not: A study by Moxttts er a!. (1'973) demonstrated this effect (Fig. 5), althought the difference did not reach statistical significance. Nicotine may be involved in aggravating existing CHD but, there is. very littlee evidence to' suggest' that it'' causes atherosclerosis. Most experiments whiclv have investigated this have produced negative results and the few studics that haveshow'n a link between nicotine adniinistration and increased, atheroma only occurred in animals which were fed' on a cholesterol diet (US. DEPAttT'1vtfiD1T ©'F' HEALTH+ EDt1C:A- •rto*r,wt7 WEt.> ARE, 1'971), .~ ' YIIjOriOYf fiefCl6e Nelia0f0YS'.tiefGi3N' iaien nrem. Merntc.1491111, OetH ea.27i uf.svM N/ maltnet eentrUtl . Fio. 5. Relative risk of developing coronary heart disease in smokers and norr-,mokcrs in two exercise groups. Mtonsst'those who did not exercise vi;orously, smokers hnvc 2•5 tintes tite r'ssk of non-smokers; whereas in those who took vigorous cxcrcise the relative risk of smokers as compar~.-d to non-smokers was only 174. (Taken from ivtoaxis er al., 1973, based on 23S'cases and 476 controls.) -„6 . -_..,~,.,.-,-~..... ..,-.~-.-~...,.....,,,-.-«.. ,:. --r----- . •t.

10 N. wA't.n and S. HoavA,tm TRENDS IN MORTALITY FROM CHD AlY'D LUNG' CANCER Relating the changing, mortality from two smoking-associated diseases, lung cancer and CHD, to changes in the composition and!consumption of cigarettes r.;ay, provide some cl.ues to the aetioliogy of these two diseases. Since 1955 there has been a dramatic change in cigarette sales from the'plain to the filter-tipped' varitst-, ' (Fi& 6) which have lower tar and nicotine yselds. During Pleln~ uq+f@NU >r 31 .. L.. , fiiler~tipe!'. Ellilte/1ef: 10 10`~0 ID001O10 1924 1h30i 11148 11150 1964 . 1910 .j Fto.6. Cansumptionofplainand'filter-tippedcigarettes'intheU/.Kfrom1'890'tm1970i(TocD,1!972)n this period the number of cigarettes smo3ced- by men has not changed greatly, but there has been a clear increase in the numbers smoked by women (TooD, 1972). Lung cancer mortality, has been falling',arll'ong men aged less than 60 years but has in- creased in, women, while mortality from CHD has riser, in both men and woaten, (Table 5). Since conventional filter-tipped cigarettes have a higher CQ y,ield, than plain cigarettes, the increase in, CHD mortality is consistent with the hypothesis that Cp is a contributory cause of this disease, although tlte rise could'well be attributable to other factors. TABtB'S. PERCETiMTAGY CHANGES IN'DEATH RATES flROSS LUMG'.CA'NCER.AND CORONARY HEART D[S87SG' IN ENGLAND A.1M NWAt.es FROM :'956--60 To 1966-70 CHD Lung cancer Women Men Women s e .o: 90% i `. e/ e confidence confidence confidence confidence rl.ge % liniits % limits % lim,its % limits 23J- +17 -L18' +67 f52 -17' ±23' 01 1-43 30- +16 ~ 9 +29 ~ 16 -31 ±13 -21 f22. 35- +26 ~ 5 +93 118 . -20 = 8 0. -L1i6 40- +52 ~ 4! +72 s-1G S +35~ ~12 45- +44 = 2 + 42 = 7 -1l ~3 +51 = 9 50-- +26 -2 -L3l - 4 - 31 ~ 2 -6G 1 7 55- +20 ~ 1 + 16' = 3 -41 =2, -41L (4-4 +21 f 1 + 13 = 2' +13 ' ~ 2 +55 = 5 The figures fnr corouary heart disca;c are taken from Table I and Taole 17, of thc ;tqistrar Ctncra9's Sta'ristical Review Part 1, Tabics 'acdiaral; using ICD eoRics 420!and 422.1 until 1967, andl ICD codes 410-414 for 1968 onwards. The :a'tes for lung,tJncer are obt:tincdi from Case (personal communication), and from Table 17' of the R'ogisDtar Generai's Statistica! ILeview„ Part I, :'ables Medical, using DCD codes 162-3.

. < Stnoking, carbon monoxide and arterial disease i'l 1 ; C'E''R /k .t Jiscascs, lun,g, cigarettes may ,1_s frotn the plain to :otiit. yields. During 390 to 1'9'l0i(TODD, 1972): eftar.ged greatly,, but romen (TOtDta„ 1!97Z).. 160 years but has in- oth men, and women tiglyr CO yield than h t~_.,ypotihesis that :d be attributable !T,**+ART I IE,\RT ~ DCSEASE~ '.~ :ktir Wbmcn. '~~ + JYMA,, O i.kn,.~e . confidence 0 nitc '; limits :2T 0 f43 13 -21 .-22 R 0 r16 . S 1-35 ±12 9. ~, -lxS, - 7 2 -4t - 5 2 .t' 53 _ 5 t"-: f1e,;xtrar uatll 1967. and es.d fro;n Czce: (personal I Rlew•'Aav„ ?art T, Tablts present, no comparable data on CHD. While it is necessary to be cautious in interpretiing secular changes in national mortality figures, the dissociation in death rates from lunm cancer and C:3D among, men over, the la5t 15 ' years is striking. There are no prospective d'ata published to indicate that either change in;death rate is due to'the change from plain cigarettes to filter-tipped, but retrospective data from WYNDEtt et al: (1970) suggest that the risk of developing lung cancer among smokers of filter-tipped cigarettes (for at least 110 years) was about 40% , less than among smokers of plain cigarettes. There are, at DISC'UTSSIOhI (i) On'smoking tables and'CO In February 1973 the Department of Health published Smoking Tables showiing the amount of tar and nicotine produced by' different brands of eigarettes. The reason for publishing this information was to encourage smokers to avoid brar.ds with high tar or nicotine and to change from plain to filter-tipped cigarettes. There, was some presumption of benefit implied in the recommendations, particularly regarding nicotine, for which the evidencaoftoucitywasmuch, less'seeurz than it wass for tar. However, since the tar and nicotine yields of cigarettes tend to vary in, parallel this was'not of great 'significance. Little was known of the effect of changing to low tar andi low' nicotine cigarettes on the absorption of other constituents of tobacco smoke,, such as CO. More recently it has been' suggested' that CO should also appear in the smoking tables (RvssFla, et al., 1'973) on the grounds that the circumstantial evidence incrimi- nating CO was sufficient to encourage the seleetion of brands witlt low CO yiclkLss. However, since, with the exception of cigarettes with ventilated 6llters, there is a negative correlation between the tar andi CO yields of cigarettes, tables listing both sets of figures wouldi be confusing. btoreover, some brands that produce less CO than average are inhaled' more deeply (WALD and Snlrrtt{ 1973). It would, taerefore, seem unwise to publish, of6cial tables of the CO yields of cigarettes until the implica- tions of smoking "low CO" cigarettes~ are understood and it is certain that other toxic constituents will not be absorbed in greater quantities as a result. (ii) On cigarette modiftcation The possibility that the change from plain to filter-tipped cigarettes may account, at least in part, for the rise in national CHD mortality empha:sises' an important problemi arising from the use of filters or tite use of tobacco substitutes. The reduction of one harmful constituent of tobacco'smoke, such as tar, may' result in tlie mcrease of another,,such as CO„and the net egect on rnorbidity and mortality may be just as serious: This problem, may unfortunately not be completely soluble and wiili rc:nain a source of concern to those engaged in the deve[oprvent and testing of safer forms of smoking. (iii) On CO and arteriai cliscaae For many years nicotine has been thought to be involved in the association between smoking and cardiovascular disease. More recently, data have become awailablt; on CO, and while nicotine cannot be regarded as altogether harmdess. 1005052918 .-.,.. ~..,._..~..,_,...~~ ~ ~.._..,......_.......,, •_._.... ' ~ Y. ~ .. .. .

, l2 N. WALD and S. Howiutm (particularly in patients with heart disease),,, the evidence implicating CO would, now seem to be stronger. CO exposure from tobacco smoking can exacerbate angina pectoris and intermittent claudication, which affect about 15: _C9 i; of men aged 55-60 years. Whether CO1 exerts this acute effect on coronary or peripheral arteries directly, by for example inhibiting cytpchrome P-350 (CooPElt et ol:, 1970); or indirectly through hypoxia is not:of great practical importance. It would be of interest however, to repeat the studies by ANDERSON et al. (1'973) and ARoNow and ISBELL (1973);,but exposing patients with CHD to air containing oxygen at a reduced partiai pressure instead'of exposing them to CO. The level of'liypoitia that would'correspond' to a given COHb level could be determined empirically by rneasuring the shift in the oxygen dissociation curve. CO may be a cause of'human atherosclerosis, although before this conclusion is accepted more data are needed from experiments on primates exposed' to lower levels of'CO'than have usually been administered hiilierto, and with both continuous and intermittent exposure, as is typical of the human situation. Atherosclerosis iss also related to many factors such a$ diet, family history, hypertension, and physical activity„ and assessing the role of another factor such as CO is dill'iculit. Prospective studies in which COHb levels are measured and the brands of cigarettes used, are recorded may help provide an answer. From such studies it wi1U be possible to see whether CHD is more closely associated with the nicotine yields of the bratids. of' cigarettes smoked, or with the CO yields. Even then the matter would still, not' be settled because the CO and! nicotine yields as measured by the smoking machine would not reflect any systematic differences in the way different brands of cigarettes are smoked. If it became practical to measure blood nicotine levels accurately and at the right time in relation to smoking, many of the difficulties -would' be solved. For the present, however, it is necessary to reserve jjud;Qment on whether CO is a cause of arterial disease, while at the same time suspecting that it may be the principal agent in tobacco smoke. drkotowfedqetrtent--We thank MrJohn Evans of the National Coal Board, Edinburgh, for deter- mining the CiJ yields of the cigarettes. We also thank Profts:sorSir Richard Doll, Professor Vlartin Vessey and ,4tr Peter Smith for tlieir 'hcipful' advice, and Cathy Harwood for her assistance in the preparation of the manuscript and 6gur+es. REFERENCES t#rmetesonr„ E. W., ArtnEt.+wnt; R. J., Srtwttcx, J. lvi., FoRnttrt, N. J. and Kr>a,sotv, J: H. (1!973) Ann. iatern. Med. 79, 46. Axortow, W. S: and Isnu.L, MLW.,(1973) Antt.,intern. Aled:79, 392. Aaotrow, W. S. and'Rbt:Aw,,S. N. (19711) Circulation 44, 78Z tAROavow, W. S.,,STL%istEte, E. A. and I3BELL, M. W. (i1974) Circulation 49, 415. A1TeutP, P. (1973) Circulation 48. 11,67: Asrntur, P:, K.Et.asrrt; K. andi WAmrRUP; J. ('1967) !. .ltluroscfer. {tes. 7, 343. r,YxFS. S. M., GtrwELU, S. Jr., and MUrLLeR„ H. (1970) ,(vue. ,V: Y. Aond. Sci. 174, 263. BrJT, E. W. R. ('t96i6) A Canadian St:rd,v of Srnnking anrl'ldealth. Deparrtmenrof Nutional licalth and Welfare, OttaM1Sa. &x)r¢isr, W. Ni., BsuKSOV, J. and Dtr:v„ H. L. (1936) .dm. J: P1tysiof: 11'S, 463. IIUCHAVALtt, Ei. (1963)riPn. hd.bfy'r'.J: 29~,57U~. Burrm, J., Dnsirs, G: M.. Jor*ES. J. G. and StNcLatx; A. (19'r4),Ann. occup. Fl)•s. 17.57. Cnszietae*+, C. M : and CpLS. P. V. (1973) Lancer2, 21. Conutatr„ R. F. (Editor) (1970) Biological effects of carbon monoxide. Auut. 11.Y. Acad. Sci: 1174, 1-430. 1005,105.2919 ...^...__.,...__

. , . / r. wuuld now batc aI ,ina '' _tr",; of rncn' aged ,.r Nri(+iteta[ arteries •tixa a al., 1970),, oc tt would be of interest _(, Axt~.ow and IsBELL. :n at a reduced partial :inatv :uuld correspond the shifc ia the +nr..t7+is conciusion is .':cs' cr posed uo Iower t nrith lnoth continuous utt. eillterosclerosis is :rtensi.nn, and physical ~ult. Prospective of`ctelrettes used are ri!11' bc possiblc to see ieltis of tlae brands of ~ter would still not be'e thc sraokin; tnachine ut brands of cigarettes :Lvcls accurately and at would be solved. For alyt'r:(a) is'a cause of ; prinL•ipal agent •S Fd:::hur~lt, for deter- •d pi;t.. Prui~.csor biartin • ic*n cen assistanc ~ in :he . 3;3'. . Sri: t' I.6 2oL R ,:io:•taf'Ftealth and .443. Llpr•. 17: 57. :ar. N: Y. Acad. Scf. 174, . ..~~..~ Smokinr, carbon monoxide and arterisl distase 13 CotttrRNi IL F.,,FoRstER, R'. E. and KAtvE. P. B. (1965)1. cCGn. lnvest. •3;4, 1899. Cotll rt, S:1., DoRtoN, G':, GoLDSaaTh, J. R. and PE.'ttiturr, S. (1971) iArchs. envfr. fJfdth 22, 47: (~,oMMrl?rEE ON EFFECis oF AmtosPttF.Ric CONTAMIttAI+iTS o1c HLli1tAI t' HEAi.7tE d"dID \1rELFAR.?: (1969) Egects'of Chronie Ezposure to Low Letels of Carbon 14fonoxfde on Hummr'Health, Behaviour, ortd Performmme. Nat. Acad: Scii, Nat. Acad, fing;, \Vashington, D:C. CooPEx; D. Y., SCHLEYER. H. and ItosExRltAt. 0: (1970) Alut. iX. Y. Acad: Scl. 174, 205: Cowte, J., Stt:LETr; R. W: and BAt t, K. P. (1!973) Lancer 1„ 1033. DEAnre„M. and PERtclNs, N. (Unpublish.ed) Presented at the 7oh Internationat'Scientitic'Yteeting of' thalnternational Epidtmiological Associationi BrightDn. August 1974. ' DoLt., R. and'Htta., A. B. (I1964) Br, mcd:l: 1, 1399; 1450. -- Doual:#.s, C. G., Hitt.oANE„J. S. and HAtDAhz, J. B. S. (1912)1. Pltysfof: 4.1, 273. DrDYt:E, J. 'P., DAwsER, T.,R., K~rraret., W. B., KtNclt, S'. H. and KAttN, H. A. (1964) J. Arn. tned. Ass:190, 886, Got:DSMarx„J. R. and [1AtvDAw, S. A. (1'968) Seience 162, 1'352. GREE3LSPAN, K.,,EDMANDS, K. E., KNoEBEL, S. B: and Ftscrr, C. (1969) Arclts: fttrern. Mcd. 123; 707. H.wtMotvD; E. C. (1972) Proceedin;s of tlte Second ii''orld Conference on Smokurg ond'fifealth, 1971. (Edited by RicttARDsort, It. G.) Pitman, London. JtttvEs, R. D., Coatattxs, B: T. and Can.itc; A. A. (197'1) Lmtcet 2,302. KAH•t, HL A. ('1966) i.b'atn. Canaer Itet. Monogr. 19, 1. K.trrtvF.u., W. B.,,CASaES u, W. P. artd McNAatARA, P: M. (1968) Marn. Cancer litst. ,Noaogr. 28, 9: -KJE1 asFSV, K., AstRUP, P. and' WA'NsrRt P, J. (1969)1. Atheroscler. Rea. 10, 173'. 1GEwsetv{ K., AsrRUP„P. aad W;.~tsrRtur„Ji (1972) A'rh'erosclerosLS 16, 67: KJtzosErq K., TrtDNSEN, H. K. a'nd A'szxuP, P. (1974) I'Circu/atfon Res. 34,.339. KIEt.nsEN, K:,,WANssatuP, J: and AsrtttrP, P. (1968)!..(theroscler. Res: 8, 835k MoRxts; J: N:, CitavE, S. P. W., ADAdt, C., StREx, C:, EesrEnc, L. and! SHEEIaA t, D. J. (1973) Lancer 1, 333: MoRRts: J. N!, KAaAx; A., PArr1soN, D: C., GARDNER, M. J: andi R~FFZ:E, P. A. B. (1966) Latrcet 2, 553. PnssMoRE, R. and DttRNtN,J. V. G. A. (1955) Phpsiol: Rev:35, 301. RAnysEY , J: hi. (1967) Archs envir. liLlth 1'5, 580. Ror~twElt, K. and GRANr, C. A. (Editors) ('1972) Tobaaco Rrseanch Council, Lond'on. Research Papcr IL RoucrtroN„F. J. W: and DARLruo,,R. C. (1'944) Am. J: PbysioL 131, 17. RussEtt, St. A. H., Wttson+, C., CoLE, P. V,, IDLE, Vl. and FEYERAHEND, C. (1'973) Lcncer'2, 683; SIGGAARD+ANDERSEN„J:, BoNIDe PEtERSEN, F:, Hnt:sEn+, T. 1. and MEt.tFwaAARtD;,K. (1968) Scand. J. clta. Lab. Invest. Suppl 103'22, 39. _ SsosrltAt+D, T: (1949) Saand.l: clin. Lab. Irtvest. 1, 201. STA1`a.Ex, J., BERtcsoN, D. wt., LEvrrnoN, M; 1., Moto.t+TER, L., EksaEtY, ,Lt. 1i!. Hi.u., Y., BuRUCEY•, F.. SoxucENc; l*;. and'A.woELStAN, S: L. (1'968) Ann. N. Y..-1cad. Scf.149; 1022. THOMSEat, H. K. (1974) .9tJrerosclerosis20, 233. ToDD, G. F. (Editor) (1972) Tobacco Research Council, Lo,-sdon. Rcseanch'Paper'I.. ZJ.$.. DEPARl'MENToF HEALTIH,.EDUCATIIo1i al:D.WELFARE (ISI1'):The Hcaltlt CUnJQQaencesof S/nok'i1tg,., A Report to the Surgron Gucncra:. Table A23, p.1:0-12°_.' iJSDHEtiY, \ti'ashington, D.C. U1S. DEPARTMEtIS OF HL:~LTkt; EDuCATION A6tD WELFARE (1'972). Occaputionrd Erposare to Carbon Monoxide, USD'HEW, Washington, D:C. WAU),,N., HowARD, S., Sar'rx, P. G. and BAILEr; A. (in Fress) 77wrax. WALD, N., HowARDi S., SMtTH. P. G. and K~ELDSEN, K: (1973) Br. med: J: 1, 7ti'I l WALD, N. and SnaRtt, P: G. (t973)'Lancer2; 907. WAtasrRuP, J., KJEtDsta;t,,K. and AsTRuP; P. (1969) Abta path: microbiol.,scarrd:75,,353. WEasnER, W. S., Ct.ARxson , T. B. and LOFLAtaD, H. Bl (1968) fxp. 6rmo1: Pat/toh 13, 36. WnaDEx, E. L., NLA'eucltr, K: and BEArrIt:, E. J: (1970)!. Am. med: Ats. 213; 2221. DISCUSSIO'N Dr P: CoLE (St Barrholomew's Hpspital. London): I do r.otagrccahatit wowdbeunvfise to )nublish the'CO yields of eigarettes along .vit)r the tar and nicoiinc y,ields: P1:blicatien aL tar attd' nicotine yieldfr pre-supposcs that both these substances are harmful ; in fact; thc evidence that nicouine is barmful is very slim. There is very strong evidcnce that crbon monoxidt3 is harmful, and 1 would sugbest thar publication of'CO tablcs would thereCore lead to /ess public oonfcsioa as to tiie real harrtn from tobacco smol:in'g. Dr \V~,tr~: I have albeady given my reas'ons for disagresiag with Ds CJIe. Although I agrcc that the evidence that nicotine is harnnful!is not Yrea2, I'do not thinlC that it can be conside:ed harJnless. 1005052920 :r.; ,.. ..,--r~ .

A'. 1 ,. 14 N. Wkt.m and S. HowAten Also, I' do not th;nk that the evidence thai the carbon monoxide exposure from tobacco smoke is harmful is as compelling; as Dr Cole believes. Therefore, I think action on this matter should be postponed until, satisfactory information is available. There is a further practical point. At present, cigarettes wibh low CO yiclds have ventilated fiitcrsS which are often, unacceptable to heavy smokers. Promotion of cisarettes with low CO yi-.lds is therefore unlikely to have an appreciable impact on smokers who have the highest risk of diseases associated with smoking. Mr VMDtn (Analysis Automation, Oxford): is tfiere a major difference between the elfects of tar and carbou monoxide, in that thesmoker alone suffers from the effecrof tar, but that others will be affected by the smoker's production of earbon monoxide? Dr Wu:n: It is true that there will be passive smoking by persons in close proximity to a smoker. However, at present the evidence suggests that passive smoking is not of inedical'significance. In one study, the rise in carboxyhaemogiobin among non-smokers in, a smoke-filled room was only equivalent to smoking one cigarette or less. Therefore the difference referred to by Mr Verdln is probably nor great. --~-.~..-..... - .-.~......._ .. .. ,--.--._-._.~.-

~I:~rEMALs n.-rn Mrraons Subjects Five men and three women (ages, 18 to 30 years ) with a smoking history of 2 to 1S pack-years comprised the group under study. 'I'hi ey were free of' cardiopulmonary symptoms and hadl normal findings on physical examinations; spirome- •From the Jane and Edward Shapiro PuItnonary Suite Division of Pulmonary Disease, Department of InteQ! Medicine, Mount Sinai Medical Center,,MSami Beach, Fla. Supported in part by grant. HL.-10822 from the National Heart, Lung, and Blood Imstitute. Manuscript received January 30: accepted Febntary' 9. Reprint'reqeiestss Dr. Saeknrr, 4300Akon Road, Miarni Beach 33140 CHEST, 74: 3,, SEPTEMBER, 1978! lYoNee:Ilhis muerial may be protected bycopyrieht law. (Gtle 17 US code; VtRMAL Dt RST1A.7A11O1`!iS Hernodynamic Effects of Smoking Cigarettes of H igh and Low N icofiine Content* Leonard Tachmes; Roberto J: Fernandez, B.S.;, and biarvin A. Sackner, Nt.D:, F.C.C.P. We studied the hemodynamic effects of smoking cigar- ettes with, high and low contents of nicotine in young smokers free of coronary arteriati disease; The smokine, of one cigarette with a high content of nicotine produced a peak rise in cardiac output of 32 percent above baseline values, and! the effect persisted for one hour Smoking a cigarette with a low content of nicotine produced a peak rise of 13 percent above baseline values, with a duration of five minutes. The rise in cardiac output was almost A s a result of absorption of nicotine, the smoldng of cigarettes produces a rise in heart rate, am elevation of systemic blood pressure,,and cutaneous vasoconstriction. In some smokers, cardiac output is Increased, while in others, it is unchanged. Possibly this variability is related to the failure to control the 1 ~ In a t of nncotune in the cigarett snlokdl contenee. study of smokers wi th angina pectoris, the sznoking of cigarettes with a high content of nicotine ('2:00 mg), effected a greater elevation of' heart rate and' _.systemic blood pressure than satoldng, cigarettes with a low content of nicotine (0.3 mg).° The smok- Cing; of cigarettes with a high nicotine content was associated with a significant fall in stroke volume ": because the rise im heart rate took place without a change in cardiac output.' The dose-related hemo- dynamic effects of'srnroldng cigarettes with low and' high nicotine contents have not been investigated in y;oung;smokers free of'cardiac disease and constitute the basis of this report. entirely attributable to tachy,cardia, since stroke volume remained relatively constant The smoking of a cigarette ..dth high nicotine content also caused greater and more sustained!elevation in systemic blood pressure t5an smok•, ing,a cigarette with low nicotine content.'hhos, there was i a responsiveness to the dose of nicotine in cigarettes smoked by young, smokers free of' coronary arterial! dis- ease. trie testing, and resting electrocardiograms. AD gave in- forrned consent and received' financial remuneration for theirr participation in the study. Methods A modification of a previously described technique of rebreathing was utilLzed.s.' Briefly, the subject rebreathed 2 L of the tested mixture of gases at 24 breaths per minute from the i position for functional residiial' capacity ( FRC').. The mixture consisted of '013 percent radioactive 2sorygen- labelled carbon monoude,, U percent acetylene, 10 percent helium; 21 percent oxygen, and the balance nitrogen. Arsaly- sis of gases was performed'.vith a mass spectrometer (Perkin- Elmer.%{GA 1100), ancIthe analog signals were processed on- line by a digital computer (Digital Equipment Co. model. PDP-12). Diffusing capacity of carbon monoxide was calcu- lated from the curve for the disappearance of carbon monoz fde: 'I'he latter was also used to adjust the intercept of the curve for the diaappearance of acetylene to zero time, in order tor estimate the combined volume of blood in the pulmonary tissue plus capillaries. The curve for the disap- pearance of acetylene, together,.vith the absorption of acet+y- Iene in the tiasve andi blood, was used' to: calculate the flow of blood'an the pulmonary capillaries. ln normal subjects, where intrapuimonary shunting of blbod is negligible, the flow of' blood in the pulmonary capillaries can be considered to be equivalent to cardiac output The curve for helium equi- libration provided data for calculation of FFIC, and the curve for disappearance of oxygen provided data for calculating the consumption of; oxygen. The flow of' blood in the calf was determined by aa plethysmographic technique utilizing a mercury-in-Silastic strain gaugea0 Heart rate was estimated from a sing)b-lead. ECG, and blood pressure was estimated by auscultation after ' obliterating the brachial arteriall pulse with an occluded cuff. Procedure The subjects omitted lunch and refrained from smoking at HEMODYNAMIC EFFE4TS' OF SMOi(INl6' CIGAREI7ES 243

Bas.lin. 15 60 90 1210 . . ume - minutes FYcvaa L Flow of' blood in pulmonary capillaries (equivalent to cardiac output in normal subjects where intrapulmonary shunting of biood is negligible) after smoking one cigarette with high nicotine content (solid circles ), one cigarette with low nicotine content (open cir- cles), or one cigarette in sham fashiow (triangles). There was dose-relatecI increase in flow off blood in pulmonary capillaries. Significant differences of means from baseiine (IP < 0.05) are designated with asterisks. ~ least four hours prior to the study, which was' performed in intervals of time when the analysis of'variance was statistical- the middle of the afternoon. They first rested on a cot in a darkened' quiet room for 45 minutes. Then the procedure of. rebreathing was performed every ten minutes untiI' values for the consumptfow of oxygen became reproducible, a factor :: which generally took an additional! 30 to 60 minutes. Thee baseline values were measured' in duplicate, along wit;h, the - heart rate, blood pressure, and flow of blood in the calf, On each of three separate days, the subject smoked' a cigarette of high or low nicotine content in his usual' fashion -. : or feigned smoking a cigarette as a controi. The order of the different types of smoking was randomized. Cigarettes with a content'of nicotine of 2:4 mg (Players cigarettes) and,with a content of ' 0:1 mg, ( Cardeton ) were chosen as the cigarettes with high and low nicotine confents, respectively.1z Hemo- • dynamic measurements were repeated in duplicate and were averaged at 5, 15,, 80, 90, and' L0 minutes after the end of smokiagwhile the subject remained in the supine position. Data were tested for statistical'significance by means of an analysis of'variance and aNewman-Keu1s testl1='Stud'ent's i• • test was used to test differences from baseline at selected . C, Bcs.line 15 Tirrne - minutes i 90 12'0 F~cmz 2. Heart' rate after smoking one cigarette with high nicotine content (solid circles), one cigarette with low nicotine content (open circles), or one cigarette in sham fashion (triangles). There was dose-related increase in heart rate. Sigaificant differences of ineaas from baseline (P < 0.05) are designated with asteriaks. 244 TACHMES, FERN1A'NDEZ,' SACKNER •,lorkK 7`" ,+ ser-11 •,t be proteetad by capycight la+.. (rit,le 17'U1Seode).:;` ly significant. IRtsvzTS Sham srnokiitg of'a cigarette did not significantly affect any of the measurements. Smoking of the cigarette produced a graded increase in the flow of blood in the pulmonary capillaries (cardiac output), with~ the cigarette with the high nicotine content effecting a peak increase of 32 percent and the cigarette .vAh low nicotine content affecting a peak increase of 13 percent five miisutes after smoking (Fig,1) (P < 0.05). This increase persisted for 60 mihutes after smoking the cigarette with high nicta. tine content, with a subsequent decline to baseline. In contrast, the increase lrut'ed only five minutes after smoking the cigarette with low nicotine con- tent. The heart rate rose in a similar pattern (Fig 2), CHEST, 74: 3; SEPTEMBER, 19T&

. a Btu.lin. 15 ; ~0 90 120 . ~.,, . Tume - minutes ? FtcunE 3. Systolic (top) and diastolic (Fiottam) blood presaures: after smoling one dgarette with low nicotine content (solid circles);,,one cigarette with low nicotine content (opencircles)', and' one cigarette in sham fashion (triangles). Significant differences of ineans from baseline (P < 0.05) , are designated with esterislu. : such that it was the major factor in accounting for the increase in cardiac output„ since stroke volume remained nelatively constant. Systolic and diastolic blood pressures; increased according to the nicotine: content of the cigarette ( Fio 3). The eievati= of systemic blood pressure lasted' 15 minutes after smoking the cigarett'e with high nicotime content andi five minutes after smoking thei cigarette with low nicotine content. After smokino, there~were no statis- ticalliy sigqificant changes in the consumption of oxygen, the diffusing capacity, the volume of blood in the pulmonary tissue plus capillaries, the FIdQ, and the flow of blood in, the calE. Di=ssio:r - The present study dlemonstrated that' cardiac out> put increased immediately aftersmokimg in habitual young cigarette smokers, who were free of cardiac disease. Furthermore, the magnitude: and duration of this increase was directiy, related to i the : nicotine content of the cigarettes smoked. Heart rate and systemic blood pressure rose concomitantl'y, while stroke volume remained, relatively constant. These observations were qualitatively similar to those of Regan et al,s who foundl an increase in cardiac output of'1'4 percent by Fick's principle, and to those of' Kerrigan et al,4 who, reported an increase of' 1'5 percent by dye dilution after the smoddng, of ciga- rettes with an, unspecified nicotine content. In smokers with angina pectoris, smoking cigarettes with a lbigjn nicotine content of1'.8 mg; caused aa significant increase in systemic blood pressure and CHEST, 74: 1 SEPTEM'BER, 1978 r. . -r • r ~., , - 'bv' tir - Ttl heart rate but no change in, cardiac output becausa stroke volume decreased' In such, patients, eleva- tion of the carbon monoxide c•ontent of blood from the coronary sinus by breathing,carbon monoxide at 150 ppm, (.vhich1was comparable to Ievels achieved after smoking three cigarettes) increased the left ventricular end-diastolic pressure and decreased! the stroke volume." Thus„ the heart with coronary ar- terial disease mighf be more sensitive to the nega- tively inotropic effect of carbon monoxide than the normal heart. The increase in cardiac output,produced by smok- ing in our young smokers may be related'to a greaterr stianuSation: by nicotine of the ganglia of the sympa- thetic than the parasympathetic system. The former would lead to: the release of cstecholamiiaes from postganglionic fibers and the adrenal medulla, caus- ing variable degrees of positively cbaonotropic andl inotropic: cardiac actions, prednminant'vasoconstric- tion, and systemic hypertension,2' The diffusing capacity~d'zd not change in our sub- jects wdth the modest elevatiom of cardiac output ' after smoking. This is not surprising, since it has~ been shown that an elevati= in cardiac output of' 113 percent over baseline prodtirced by infusion of a combinatimn of norepinephrine and atropine does not alter the single-breath diffusing capacity. In con- trast, exercise sufficient to cause a~ comparable in- crease in casdiac output is associated with a 20 percent rise in diffusing capacity. The reason for the difference in the response of the diffusing,capacity to drug-elevated and exercise- HEMDD7NAMIC EFFECTS OFSMOKING CIGARETTES 245

administration of 0.5 mg of epinephrine, which caused greater hemodynamic effects, increased the flow of blood'in the calf. R$FERE.Y(ES I Thomas CB,, Bateman JL., Lidberg EF: Observations on the individuaL effects of' smoking on the bloimdl pressure, heart rate, stroke volume and cardiac output of healthy young adults. Ann Intern Med 44~8u4-892„1958. • 2' Comroe JH Jr: The pharmacologic actions of nicotine. Ann NY Acad'Sci'90t48+i1,1960 3 Regan TJ, Frank MJ, McCinty JF, et ali Myocardial response to cigarette smoking in normal subjects and patients with coronary disease. Circulation 23:316a469, 1981' '"4' Kerrigan R; Jain AC, Doyle JT: The circulatory response to cigarette smoking at rest and after exercise. Am J'Med Sci 255:113 -119, 1968 S Shepaniijt Physiology of the C'uculation1n Human Limbs In Health andi Disease. Philadelphia, NTrB Saunders Co, 1963,•.pp 381-389 . 24t TACHMES, FERNANDEZ, SACKNER N!ottacTfiii material maybe protcetrd by eopyr+giu law: (rde 117 US code) :' elevated cardiac outputs might be related to a fall in pulmonary arteriall pressure with administration of adrenergic agonHstsi+ and a rise with exereise.'s A1- though cigarette smoldng, produces cutaneous vaso- constriction,s the effects on the $ovc of' blood in the < muscles have been inconsistent Both Rottenstein et al1e and our group found a tendency towards an ~ Ancrease in the flow of blood' in i the muscles or to a - nediatribution of the flow of blood to the viscera. Sackner et a114 previously found that subcutaneous injection of 0.25 mg of epinephrine, which produced sLp elevation in cardiac output comparable to smok- img cioarettes with~ a high content of nicotine, did not affect the flo!w of blood in the calf, whereas 6' rlronow WS;, Dendinger J, Rokaw Sh:: Heart rate and carboa monoxide level after smoking high., low- and non. nicotine cigarettes. Ann Intern Med 74:697-702, 1971 7' Aronow WS,, Coitlsmith JR. Kern JC,, et' al: Effect of smoking cigarettes on cardiovascular hemodynanmics. Arch Environ Health 28:330-332, 1974 8' Sackner \4A; Greeneitch D, Heiman \fS; et ala Diffusing capacity, membrane diffusing capacity;, capillary bloadl .`;' ' volume, pulmonary tissue volume, and cardiac output' measured by a rebreathing technique. Aur, Rev Respir Dis 11i: i57 -1!6a,1975 91 Sackner MA, Friedman M; Silva G, et aI: The pulmonary hemodynamir effects of aerosols of Lsoprottrrenol'l andi a^ ipratropiurn in normal subjects and patients with revers- ible airway obstruction. Am Rev Respir Dis 116:1013- ible '' ;` 1022, 1977 10 Slason DT, Braunwald' E: A simplified pletlrysmognapbic system, for the measurement of systemic bloodl pressure, and peripheraI blood How. Arn Heart J' 64:79ta-804; 1962. 11' FederalTrade Commission, 1978' 12 BMD, Statistical Package: Health Sciences Computing, Facility, Department of Biomathematics, School of \'tedi- cine, University of California at Los Angeles, University ' of California Press, 1973 13 Aronow WS, Cassidy J, Vangrow JS, et aI: Effect of' cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics in anginal patients. Circn-, lation 50:340-347, 1974 14 Sackner MA, Dougherty R, Watson H, et a1: Hemody- namic effects of epinepltrine and' terbutaline in normal man. Chest 68:616-624, 1975 1'5' Bevegard S, Holmgren A, Jonsson~B: The effect of body position on the circulation, at rest and during exercise, with speciai' rekrence i to the influence on the stroke volume. Acta Physiol Scand'49:2779-298, 1960 16 Rottenstein H, Pierce G, Russ E, et al: Influence of nicotine ou the blood flow of resting'skeletal muscle and of the digits in normal subjects. Ann ; IY rlcad Sei 90:102- 110.5;,1B6o CHES'J•, 74: 31 SEPMBER, 1978 . "V

.._....L- Isi Effect of Non-nicotine Ciga~rettes anid Carbon Monoxide on Angina WILBERT S. AROtVIp'w„ M.D. SUMMARY The effect of smoking fire non-nicotine cigarettes andl of breathing carbon monoxide on exercise-induced angina was evaluated in 13' patients withi angina: Smoking increased venous ear- box.•hemoglobin from, 1.7'1 to 535176, decreased exercise duration until angina 45%, increased ischemic S'F- segmentdepression at angina fromil.33'to 1S2 mm, andldecreased systolic blood pressure times heart rate at angina. Breathing earboni monoxide increased venous carbox}'hemoglobin from 1173 to5.379e, decreased exer- cise duration until angina 35fio, inereased ischemic ST-segment depression at angina from 1.31 to 1.50 mm+ and decreased systolic bloodlpressure times heart rate at angina. Greater decreases in exercise duration until angina and in systolic blood pressure times heart`rate at angina (p < 0.0011) wereobsersed after smoking than after breathing carbon monoxide. Tobacco comportents other than nicotine or carbonimonoaide are responsi- ble for a small decrease in exercise performance until angina. PATIENTS WITH ANGINA PECTORIS develop ar.ginal pain sooner after, exercise follmwin3,cigarette srrtokine for at leasL two reasons: 1) nicotine increases the mvocardial oxygen demand'j" and 2) car- box:.nerno2lobini decreases oxygen delivery to the r.ryoca~rdium!'"` Smoking high-nicotine cigarettes" z°tzravates exercise-induced angina pectoris more thatt smoking low-nicotine cigarettas.? Smoking low- nicotine ciearettesz ' aggravates exercise-induced angiita pectoris more than smoking non}nicotine e:garettes: u Tobacco fmokie contains more than 4000 known c:.c:pounds.1° In addition to carbon monoxide and' nicotine, tobacco smoke cont'ains' oxides of' nitrogen, h-vdrogen eyanide and carbon disulfid'e that may play a role in, asgravating ca!rd'iovascula riovascular dlisease:'"'"' T,~serefore, I ii:vestigrted the effect of smoking five ` nannicotint:garettes and of breatfiing enough car- •,,:- ci bon monoxide to produce a carbon:cyhernoglbbin level similar to that after srnoking on the duration of'exer- cise until! the onset of angina pectoris. The data, from this study are reported below. Materials and Methods Twelwe men, mean age 52.1 ± 5.1 years (± slD), all of whom smoked'one package of cigarettes daily, were subjects. Each, subject had classic stable exertional angina pectoris and angiographic evidence of coro- nary artery disease with > 75% narrowing of at least one major coronary vessel. After careful explanationi of the risks iitt•olved, wri'tten informed consent was ob- tained from ail'1 12 men. The 12 subjects were familiarized with the equip- ment andi the procedures and practiced' exercising up- right on a Collins (Warren E. Collins, Inc., Braintree, Massachusetts) constant-Ioad bicycle ergometer From the Cardiovascutar Sectlon, Long Bcach Veterans Ad- ntinistration Nlw:dical Center and the University of California„Ir- rine. Address fur aurrespondence: 1Vilbert S. Aronou•, M :D., Chicf. Cartlitu•a,wculur Sc4tioni Veterans Adminiztration \tedical Cunter, Lan_ Hcath. Cairornia 90822. Rei :1'pril 26'. 1979: revision accepted Juhy 27; 1979., Ci'rtiulution i61. No. 2: 19AU. 262 before the study began. The study was performed on two consecutive mornings. Smoking was not per- mitted for at least 12 hours before the study each morning and was not' permitted during the study periods except by protocol. The subjects remained in the same area dluring the study periods andi were carefully observed' to ensure adherence to the protocol. On two successive study niornings, at 8' o'clock, with the subject in the fasting state, venous blood was drawn and analyzed for carboxyhemoglobin and' 'hemoglobin levels with a 282 Co-Oximeter ('Irt- strumentation Laboratory, Inc., Lexington, Massa* chusetts). Then„ leads 2 and V, were simultaneously recorded with am electrocardiograph with the patient sitting on the bicycle ergometer. The resting'heart rate was obtained from this ECG. The resting, blood pressure was then ' measured wi!th, a mercury sphygmomanometer. Each subject then, exercised upright on the bicycle ergometer with a progressive work loadt' until the onset of anginal discomfort, and'the durationof'exer- cise was recorded' with a stopwatch. The work load was increased' 25 watts every 3 minutes. The initiall work Ibad' was chosen so that angina pectoris wou!ldd develop 180-360 5econds after exercise in the control periods. The patient was monitored by telemetry with leads 2 and VS throughout exercise. An ECG with leads 2 and V, was simultaneously recorded at the onset of angina pectoris. The heart rate was obtained from this ECG. The blood pressure was record'ed, at, the onset of angina pectoris, with the patient con- tinuing to exercise until the blood pressure was recorded'. Within 2 hours on the first morning, the subject' smoiked five non-nicotine Mint Bidis cigarettes purchssed' frona a tobsccoshop in Los Angeles. These cigurcttes were made from Indian herbnlf leaves. Immediately aftcr smoking the fifth cigarette, the patient sat on the bicycle cr-omcter and an ECG with leads 2 and V, was simultaneously recorded. The heart rate was measured from this ECG. Then, the blood' pressure was recorded with a mercury sphyg- momant7meter. Next, venous blood was drawn and 1005052926

a TOBACCp~COMPONENTS AND ANGINA/Aronow nrlyied for carboxyhemoglobin and hemoglobin. levels. ~ Then, the patient exercised upright on the bicycle ergometer until' the onset of angina pectoris, and the duration ofexercise was recorded with a stopwatch. An ECG with leads 2 and V, was simultaneously recorded at' the onset of angina pectoris. The heart, rate was recorde& from, this ECG. The blood pressure was recorded at the onset of angina pectoris„with the patient continuing to exercise until the blood pressure was obtained. On the second morning„ the subject breathed 1100 ppm of carbon monoxide untol the rise in venous car- boxyhemoglobin level' was identical to that after he had smoked five non-nicotine cigarettes. The patient C them sat on the bicycle ergometer andl an ECIG with leads 2 and V, was simultaneously recorded. The heart rate was measured from this ECG. The blood pressure was next recorded with a mercury sphygmoman- ometer. The patient then exercised upright on the bicycle ergometer untif the onset of angina pectoris, and the duration, of exercise was recorded with a stopwatch. An, ECG with leads 2 and V, was simultaneously recorded at the onset, of angina pectoris. The heart rate was obtained from this ECG. The blood pressure was recorded at the onset of angina pectoris, with the C wtient continuing to exercise until, the blood pressure . was obtained. - THe ECGs were coded and analyzed! in a, blind manner afiter the study was completed. The data were analyzed using the t test for correlated means. 'i`;Table I indicates the duration of exercise until'the . onset of angina pectoris for each patient and the mean exercise duration in the two control periods, after smoking five non-nicotine cigarettes and' after breathing carbon!monoxide. Table I also presents the statistical analy,sis of the differences shown. Table 11 shows a reduction in mean exercise duration until angina pectoris after smoking non-nicotine cigarettes and after breathing carbon monoxide (p < 0.001). The decrease in mean exercise duration until angina was grcater after smoking non-nicotine cigarettes than after breathing carbon monoxide (p < 0.001): Table 2 shows the resting mean heart rate, systolic and diastolic blood pressure, product of systolic blood pressure times heart rate/100, and venous car= boxyhemoglobin level in the two control' periods, after smoking five non-nicotine cigarettes and after brerthingcarbon monoxide. Table 2also presents the statisticall analysis of the differences shown. Table 2 indicates no change in mean resting,heart rate„systohc or diastolic blood pressure or resting product of systlolic blood pressure times heart rate/1100' after 'snooking non-nicotine cigarettes or after breathing carbon monoxide. Table 2 also shows equivalent, in- creases in mean venous carboxyhemoglobin level after smoking non-nicotine cigarettes and after breathing carbon monoxide (p < 0.001), TaBur. 1. Duration of'Ezcrcfae Unhif Angina in the Control Periodtr, A/ter Smoking, and AJter Breathing Carbon.tlonoside Durat6on of exercise (see) Carbon After Pt Smoking control After xmoking, monoxide csrbon control monoxide 1 289 155 281 177 2 203 117 186 123 3' 359 1187 372 238 4 243 134' 254' 165 s 232 135 ~ 219 153 8 210 119 225 148 7 251 145 264 18m 8 246' 121 237 144 9 224 136 212 152' 10 239 124 250• 147 11 220 118 209 138 12 211 107 226 141 Mean 243.9 133 .2"t 244.6 139.0' + sn + 43.0 21.6 47.9 ~ 29.4 •p < 0.001 after smoking compared' with respective eoatzol' and after carbon monoxide compared with riespectixe oontzoL fip < 0.001 after smoking minus respective control com- pared with after carbon monwode minus respective eonumL Table 3' indicates the mean heart rate, systolic and diastolic blood pressure, product of systolic blood pressure times heart rate/100 and the amount of exercise-induced ST-sesment depression at the onsci of angina pectoris in the two control! periods, aP.=r smoking five non-nicotine cigarettes and aftrr breathing carbon monoxide. Table 3alsb presents the• statistical analysis of the differences shown. All 12 pa- TASZE '_' Restvaq Mean Huut Rate, Systolic and Diastolic Blood Pressure, Product of S_vstolie Blood Pravure X Heart Rate/100, and Venous Carbozyiurmoglobin in the Conitrol Periods, .lftor Smol,•ing, and ditv Brcathinq Carbon Monosidr Meaetuement Smoking control After smoking Carbon mono!dde control Mter cartton monoxide Heart rate 68.0 69.6 67.4 67.9 (beats/min) +5.3; -5:4 -3.6 -3:7 SBP ,122.1 123.8 121.2 121.4 (mm Hg) +7.1 -6.3 w- 52 -4:7 DBP 79.2 80.1 78.3 78.4 (mm Hg) •+4.9 -4.3 +3.9 -3.8 Heart ntie X 83.1 50.2 81.7 82.5 S8P/100 -8i6 -8.9 -6.0 i5.4 Ckrboxy- hemoglobin 1.711 5.35' 1.73 3.37• (%)1 -0.16 +0.16 -k0.14 -0.19 Valiies are mean - sn. •p < 0.001, aftersmokingcompared mit;hire.cUcetave control and after carbon monoxide compared with re+rcetive contzol. Abbrevintions: SSP' - systolic blood pressure; DBP - diaatolic blbod pressure.

non-nicotine cigarettes and! after breath'ing, carbon monoxide. The reditction in mean heart rate at the onset of angina was greater after smoking non- nicotine cigarettes than, after breathing carbon monoxide:(p < 0i001'): The decrease inimean systolic blood pressure at the onset of angina was greater after smoking nomnicotine cigarettes than after breathing carbon monoxide (p < 0.005). The reduction in mean product of heart rate times systolic blood pressure/' 100 at the onset of'angina was greater aftersmoking non-nicotine cigarettes'than after breathing carbon monoxide (p <0.00I). Similar increases in the mean amount of exercise-inducedi ischemic ST-segmenrt depression at the onset of' angina, occurred after breathing carbon monoxide and after smoking non- nicotine cigarettes. Dis[ussion The data from this study show that smoking five non.nieottnC: ctgarettes caused ai rise in venous car- ~ boxyhentoglobin from IL7i1 to 5.35% an& a 45% ~ i decrease in exercise duration until angina pectoris. A'fter, breathing sufficient carbon monoxide to raise ~ ~ _ ..,,..y.rr..•.~:~ :., ~ ....,.. ...,.. - . . ,, .. . . _. 264 CIiRCULATI©N Vot. 6l(. No 2; Fi:xttcAav 1980 ' .. Twata 3. .tleoa Xeart Raty Syuol"u and Diaato(fe Btbod Prtawt; Prodod I of Sy"io . Bldod Pr•etar¢e XArart Rare/ 100, ond. E:eroi,e-indrtnd' STrepntentDeprrition at Oiud . of Anyiaa in, the Control' Perior4, Aykr Smo+kiraq, , and Ayrtr Brtothinp, Carbon aYonosfdt b'feasurement Heart rate (~tata/min) SBP - "' y:-... . (tttm HC) . DBP i~ (ttun Hg) Hesrt rate X - SBP/100 ST-se3tmnt depression , (xm) Smoking oonttoli After smoking t.'arbon' monmide tontrol efter. tarbon monoxide 129:1 10.i.4•,1' 129.3 110.4• r8.'9 _6.0 +4.9 .83 155.2 1a8.6-,5' 154.9. 1K8.0• r 10.2 .10.8' -9.7 r i10.4' 81.7 82.8' 81.0. 81.8 .4.2 +4.0 +3.8. .4.4. 200.4 ISt.9•,1 200-s 163.r +1a4 -13.4 +1'5.8 -17.4 . 2.33 1.324 1.31. 1.50( -0.19 -0:31 -024. ~ 0.38 Valoea.us mew~.-so. •p <'0.001 atteramokiag eompared with respective control a.mrl aftesea.-bon.monoaide compared mith~reepeetive,oonttoL tp < 0.00U alter emoking'minus reypeetive 6ontrol' aom- pRd with after carbon atonoride mintt.i respective eontroL , :~, . <8.003atter amoking'nsinus respeativeoontrolI com- pated with atter earbon monoxide minus repeotive mntroL iy. <0.02i after smolting:compared with respective contml' aad aiter'urbon monoxide camparsd with respective aontrnL Ebbreviatiena: SBP - aystatic blood ptemure;, 1DBP' ~ &atcoue blood pressure. „ . . - teau developed at least 1.0'mm of exercise-induced is:iiernic ST-segment depression at'the onset of angina pertoris during the four study periods. Table 3 indicates a reduction in mean heart rate (p <'0:00I).systolicbloodpressure',(p<0:001)„product oC heart rate times systolic blood' pressure/ 100 (p <' ••, - 0.001) and exercise-induced ST-segment dep,ression i(p < 0.02.5) at the onsgt'of angina pectoris after smoking the venous carboxyhemoglobin level from i 1.73 to-~_~ 5.37%. the exercise duration until angina'; decreased =' 35°5. Th'erefore, the dataishow th'arcarbon monoxide ` is:the major eomponenc in non-nicotine cigarettes re-"_'•' ' sponsibic for the decrease in exercise: duration until r." angina pectoris. The'greater deerease,iniexercisedura `4-= tion until angina pectoris after smoking the non-.±'-" nicotine cigarettes than after breathing carbon ~ monoxide (p <'01001') is a(tributable to components of' ` tobacco smoke other than nicotine or carbon monox- V ide. +:r.'r Smoking non-nicotine cigarettes'did not affect the resting product of systolic blood pressure times heart rate and, therefore, did not increase the myocardial .:r•Y-'• oxygen demand. This observation is consistent with~4 previous data.'- e- ta The product of systolic blood pressure,times heart :'+a rate at the onset ofangina'is a good index of myoear- ~: dial oxygen delivery.!a•" I found a reduction in - product of'systolie blood!pressure times heart rate at the onset of angina after smoking, non*nicotine ., cigarettes and after, breathing carbon monoxide, find, .: . ings consistent with previous data'- `-'° The greater --i reduction in product of systolic:blood pressure times heart rate at angina after smok'ing', non-nicotine -, cigarettes than after, breathing oarbon monoxide (p <; 0.001) is attributable to components of tobaceosmoke other than nicotine'oncarbon monoxide. The data also show' that carbon monoxide is the major component in non-nicotine cigarettes responsible for the decrease in product of systolic blood pressure'times heart rate at angina~and; therefore, probable decrease in oxygen supply to the myocardium . More ischemic ST-segment depression iat the onset ,~ of angina occurred after smoking non-nicotine ,, cigarettes and after'breathing carbon monoxide than in the control periods. The increases'in isehemic ST- segment depression at exercise,indUced angina pee- .: toris after smoking non-nicotine cigarettes and after breathing carbon monoxidrwere similar (p "NS). Finally, although this study shows that tobacco eomponents other'than nicotine or carbon monoxide cause a small decrease in exereise performance until angina pectoris'add a small'.probable decreasein oxy- genisupply to the myocardium, this study does not ' clnrify which components of tobacco smoke are responsible. Further studies must be performed to in- vestigate the effects of concentrations of oxides' of' nitrogen, hydrogen'i cyanide, carbon disut5de, andl - other components inhaled in tobacco smoke on the cardiovascular system. Acknowledgment 1'.am iinde:bocd Ito Clifford Roueae.e.,Kdthi Murdocl-.,and Hklen Mithonond fnr tcchniaat assiuance andto Mary Ellen Dunnhak for secret'adall asskunct. " Reftrenttt'. 1. AronoWwS. Kapfan MA.:Jacbb,D•.Tobacco,, e prcripitating, faunniniancina tmctoria.,Ann Inoern RIed69: 519;.196a'. 2. .4ronrrN•S. Sl-annon AJ: Thretfcct ofd6w.nicodne eiprettet on anrina ta•etoris. Ann Intern Bted2lk 599: 1969 '

TOBACCO COi41PONENTS AVD A~4CilNAlAronosv 3. Aronow WS; Dendin er J Rok-w SN: Heart rate and carbon g . monoxide level after smoking high-, low.,, and non-nicotine i eigarettes: a study in male patients with angina pectoris. Ann lhtern Aled 74: 697; 1971 i. Aronow WS. Cassidy J. Vangrow IS. March H. Kern 1C, Goldsmith JR. Khemka M. Pagano J, ViN,tor M: Effect of cigarette smoking, and breathing atrbon, monoxide on car, diovascular hemodynamics in anginal patients. Circulation 50: 340. 1974 S. Aronow WS1,Cassidy Jc Effect of'smok'ing man'huana versus aa high*nicotine cigarette on angina peetoris. Clin Pharmacol Ther 17: 549, 1975' 6., Ayres SM, Mueller HS; Gregory JJ, Giannelli S. Jr. Penny JL•. Systemic and myocardial hemodynamic responses to relatively small concentrations of carboxyhemoglobin (CO H B), Arch Ett- viron Health 18: 699, 1969 7. Ayra'SM, Giannelli S'Jr: Mueller HS: EfTieetof'low concen- trations of carbon monoxide: myocardial and systemic responses to carboxyhemoglobin. Ann NY Aad Scii 11A4:Z68; 1970 g. Aronow WS,, Rokaw SN: Carbozyhemoglobin caused by smoking non,nicotine cig;ncttes: effecu in,angina pectoris: Cir- culatioc 44: 782, 1971 9. .#ronow WS. Harris CN, Isbell MW. Rokaw SY; Imparato B: Eftect of freeway travel onangina pectoris. Ann Intern Mcd 77c 699. 1'972, 10. Anderson EW, Andclman RJ, Strauch JMi Fortuin NJ, Knelson JH:,Effect'of low•-level carbon monoxide exposure,on onset andiduration oGangina peetoris: a study in•ten patients with ischemic,heart'disease. Ann Intern Med'79: 46. 1973 11. Aronow WS„Isbell MV1'; Carbon monoxide effect on exercise- induced angina pectoris. Ann Intern Med 79: 392. 1973' 12. Aronow WS. Swanson AJ: Non+nicotini¢ed cigarettes and angina pectoris. Ann, lhtern Med 70: 1227, 1969 13, Constituents of Tobacco Smokc, Smoking and Health: A' report of the Surgeon Gcneralf 1979. Pteprint. Washington, DC. Government Printing,Offiice. 1979; pp 33-70. 14, McMillan GC: Evidence for components other than carbon monoxide and nicotine as etiologial factors in cardiovascular disease. In Proceedin¢s of the Third World Conference on Smoking and Health. New York, June 2-5. 1'975': Volume 1. Modifying the Risk for, the Smoker, edited by Wy,nder EL, Hoffmann D, Gori GB. US'Department of Health, Education,. and Welfare, Public Healthi Service. National Institutes of Healthl National Cancer Institute, DHE1V Publication No (NIH) 76-122!1', 1976. pp 363-367 15. Aronow WS: Introduction to smoking andlcardiovasculardis- eased ln Proceedings of theThird WorJdiConference on Smok- ing andlHealth, New York. June 2-5, 1975. Voluma l. Modify- ing the Risk for the Smoker, cdited'by Wynder E1., Hoffmann D, Gori' GB. US Department of! Health. Edttcation, and Welfare. Public Health Service„National Institutes of Health4 National Cancer Institute, DHEW Publication No (TtIIH); 76- 122'I, 1976, pp 231-236 - 16. Aronow WS: Efrect of, passive smoking on angina pectoris. Ni Engl J' Med 299: 21, 1978 17. Redwood DR. Rosing, DR, Goldstein i RE. Beiser GD. Epstein SE: Importance of the designi of an exercise protocol in the evaluatiomof I+atientaK ith angina pectoris. Circulation •L3:b18. 1971 18. Amsterdam E4., Hughes Jh. Demaria AN. Zelis R. !slason DT: Indirect assessment of myocardial oxygen consur..;,tjot: in the-e*•aluation off mechanisms and therapy of angina p=oris. Am I Cardiol 33: 737. 1974 19. Gobel' FL Nordstrom LA. Nelson RR: Jorgensen CR. Wang Y: The rate-pressure product as an index of myocartEal oxsc.a consumption during eser.:sa in patients with angina ;=oris: Circulation 57: 5;9, 1978

, , 1 . i The Lancet.Saturday z9 September 1973 COMPARISON O'F INCREASES IN CARBO'XYHR.MOGLOBIh?' AFTER' SMOKING "EXTRA-MILD"' AI+TD "NOht-MILD" .'. Al Q1\7ARk=J' ' . M. A. M RvssELL C. WlrsoN Addiction Atrtcarch Unir, lnstiiute of Prycfiiatrq, London' SE3 8AP '' . P. V. C©LE' M: IDLE Anatthrric RbssarcA' Lab'oratory,, St. Bartholomew's Idospiial, London EC7 ` C. F'E1rERA:BEND' Poisons Uvtir,,I1lew Crou Ffotpital, Lottdon'SEl4' Summary A cross-over comparison' was made, in twent~two smokers, of iacreases in carboxyhaznoglo-6in (COHb)' after smoking " eatra~ anild ° and " non-mild "' cigarettes. The mean increase after smoking a single non-tuibdi cigarette' was 1'43'' o for the standard-size brand (ten puffs) ; andi 1-09'g'„ for the smald-siie brartd' (seven puffs), The mean increase after a single eatra-nlil& cigarette was 0-64 p for the standard and 0'75'°J,' for the smail brand. The low CO absorption from the standard. size mild', cigarette was less than half the' amount absorbed from the sitnilar=sized' non-mild'' agazet2e. ; This low CO btand' also' has a low' tar and nicotine yieid. COHb increases after smoking were greater in the women than in the men, and there was an inverse relation between COHb increase and hamo- g(obin leveL The health implications of variations ia CO yield of' cigarettes are probably as important as those: of differences in car and nicotine yield. It is suggeste& that the CO yield of cigarettes should' be . published together with their tar and nicotine yieldl Introduction MEAStntss to reduce the harmfulness of agarettes are directed mainly at decreasing their tar and~ nicotine yield: Many countries now publish " league tables " of' tar and' nicotine yields of different brandb of cigarette 1 Manufacturers are competing to pro- duce mild'' cigarettes with~ low tar and' nicotine yields, and' expert bodies have': advised those : smokers who cannot abstain to'sw'itch to tifie milder and supposedly safer brands.23 ' But is it only'the tar and nicotine yield of cigarettes that is cause for concern ? What about carbon monoxide ? Evidence is beginnittg to actxue that it is the carbon monoxide (CO) in tobacco smoke 7831 which may be implicated in the' increased risk to smokers of' arteriosclerosis, ischaemic heart-disease, and fetal damage.' ' Should we' not, therefore, be equally concerned about a' cigarette's CO yield ?' In 1922 Armstrong showed that the CO content of tobacco smoke varied with the brand of cigar or' cigarette and the rat'e at which it was smoked! We have' attempted to explore the variation' in carbon monoxide yield of four brands of manufat:tured, cigarette by comparing the rise in the carboxy- hasmoglobin (COH'b)' level' in venous blood before and after smoking a single cigarette. Materials and M'ethods Twenty-eight, students and hospital staff volunteered to take part in the experiment. All were tobacco smokers who said that they could inhale. The experiment was not restricted to heavy smokers, and the volunteers represented a fair aoas-section of smokers (see table t¢). Unfortunately, a few blood specimens were partially clotted an atffival' at the'laboratory and had to be discarded. This was possibly'due to a faulty vial of heparin. This happened with specimens from six of the volunteers, and the analysis was confined to the twenty-two for whom the data were complete. Each' volunteer was used as his own' control for' eom- parisml of' the COHb increase after smoking' an " extza- mild "' cigarette and'' a' popular brand, of "'non-mild "' cigarette. With half the volunteers the' eomparison was made, between two standard-sited cigaretttes, one " eattra- mild "' (A) the other "'non-mild "' (B): Wit'h! the other half the comparison was between two sma11-sized dgarettes, one extra-mild (C) and the other non-mild (D). A'll'' four brands were filter-tipped: details are giwea in table I. The two standard-siied'' brands were fairly well matched for' size, as were the two sma!I1Lsized braada' The volunteers each smoked two cigarettes of similar size, one extra-mild and one non-mild. To control for a possible' influence due to the order in which the two cigarettes ~ were smoked, half' smoked, the extra-mild cigarette first and the non-mil& cigarette second, while TABJ= t--DL+fA[t.l Os ffl[1a' aRD1ltt/s OF CtoAAEL7R sAto!® nT mamtUAMM ' V ~ Brand t3 ~' 6 e.... 41 B e. 4 x, w z ~ A' ' Silk Cut B:at Mild' " ' 4 c0;9' 0•0- ' i 7-00 ' 231 I B Hmbasy Filter 20 1-j' 1-n:' 709 2 SZ~ C "P1sye'a Mild Milfotd' e <0+9' ~h7o ' 649 ' 2-26' D 'Plnet. No. 6 Filtv' 20 I 1-2' 0•77 6•!7 2•3'7' N

688 for the' other half this order was reversed: To achieve this balanced design, seven voliti were randomly assigned to each of four schedules (see table it), but the exclusion of six of the twenty-eight volunteers resulted in some loss' of sytnmetry. The laboratory workers responsible for the COHb analyses were not aware of these smoking schedules. The volunteers did not smoke for at least 20 minutes before the start of the experiment. Venous blood- samples were collected before' and' precisely 1} minutes after the first cigarette and again before and precisely 1} minutes after the secondcigarette. Thus four samples were taken from each volunteer. Between the first and second cigarettes there was a' 20-minute interval which was, spent sitting quietly. Each agarette was smoked to instruction with a puff every 40 seconds to a~ total of tea puffs for standard-sized cigarettes and seven puffs for small-sized cigarettes. The volunteers were encouraged! to inhale every puff as deeply as possible. The purpose of the 20-minute interval between cigarettes was' to allow the volunteer sutEcient time to recover from the first cigarette to enable deep, inhalation of the second one. The venous blood-samples' were drawat, steadily over 30, seconds, with the scheduled' time, falling in the middle of the 30-second interval. They were collected' in heparinised' syringes which were capped and stored in ice. The analysis for CO13b was done using an IL. 182 "CD-Oumeter'. This is an accurate' method with reproducibility having 95a0 eonlfidentu limits within 0•1°'o CO13b! Statiatical'' analysis was by Student's r test. Results The' mean increase in CI"J'Hb level after smoking a singde' cigarette was about 1%, the mean increase THE tantcar, sErl'mBelt 29, 1973 sADLa ltt-tNQaARi tNCt]M t:In[S'~.AITls: SVNO!<txo DtRmaM altAtJ'DS OF ctOAasTTI 11to. of puR~ increase in tncreue in Brand of ciaerette to complete COHb per COHb per cigarette cigarette (mcan t f.a.) puff (mean x ua:) (~:d ( :I Extra mild A 10 0•64It0-40 0•064t0+040 Non-mild8 10 143 to-l7 0•143 t0+037. Extra mild C 7 0•73 t0•47 0•108 t0i067 Non-mild D 7 1•09 ±0•61 O 136 t0+088 One grottp smok'ed an A and is B while a dllrerent group smoked e'C and e D:Tlhurthe eomperiretts A a: B utd'C'e: 0 sre within etbieaas whiteotheteomperison sre bet~een rubiecte. being much the same' for the first and second dgarettes (table li). There was, however, a signifi- cant tendency for the COHb to increase less after the milder cigarettes (table' tll, 6gs. I and 2). This was most striking in the Case of extra mild A, which caused less than half as, much' increase' in COHb as that produced by non-mild B(P<0^001). The difference between mild C and non-mild D is not statistically significant, but mildi C produced signifi- cantly less elevation of COHb than non-mild B (P<0-01). When allowance is made for the difference in cigarette size by calculating the rise in COHb per puff (table tu), the difference' between C and B is no longer significant and the difference between' A and! D becomes sigaificant (le<0•01). None of the other differences between the brands' of cigarette are significant. , - . 7J1ffis t1-•C7iANGES~~.IN~COFIb r39IQ:s IN 22 SMOt®Lt aat+ONEAND AFrdA SMO[m0: ASntGrJa aTOtA-MIIIDANDASntGli ttOtt-MIIAQGA'7lallni vohmteer BloodCOHb leee1L ( ;) No. ot Claer~ Hb Utud'dalt' cigarettes stttokedin Ftrstdpretts, Cbenp after Saeoedaaareta eeqaeryce ~fo. Ses '~te (t 1100 to1)' ap~e consumpnon morning r 20-min. (Tr.) befon icta+el i t between ezper mett Before After DiRereneei °garmO Before After DilTercttee Bme mild A 1' M' 18 13•7 20 S 6-3 6-9 +0•6 -0•3 6•6' 7•8 +1-2 followed by 2 F 22 11-2 10 4 1•6 1•9 +11 -0•8 2-1 4•3 +2-2 aeo-muld B 3 F 18 12 8 12 6 3•0 5•3 +OrJ', +0-2 5•7 7-6 +1•9 4 F 50, 12•7 20 6 3•4 19 +0•1 -0-3 5•6 7-4 +1-8 s F 24 12-8 20 1 2•7 34 +1~2 -0•5 3•4 5•2 I+1•8 6 M ', 41 14.1 00 0 09 1•4 +04' -0-1 1•3 2-4 B tollowed by A 7 F 21 12-9 30 3 5•2 7-0 +14 , -0 S 6 3 6,9 +0-4 8 F 20 13-2 1.S S 0•7 1•7 +160 -0-2 1-5 2•0 +Ws 9 E 18 12-0 10 4 2-5 4-4 +19 -0-5 3•9 S-0 +1-1 10 M 49 I 13•3 J 3 Od 1•3 +0.8 -0-3 1-0 1.0 +04 11 M 44 14-9 10 6 1-0 14 +0-4 +0,2 1-6 2'0 +0•4 Bztrrmild C 12 M 36 13•3 18 3 9-0 6-0 +I-0 -1•0 1-0 6-7 +1•7 followed by 13 F 19 11•9 1S 2 2•9 4-0 +1•11 -0•3 3^7 4,9 +1,2 noa-mildID 14 F 37 11-4 20 1 2•3 44 +1•6 -1•1 3-0 41 +14 15 F 19 13,8 3 0 0.7 1-3 +0•6 -0-1 1^2 1-7 +0+4' 16 M 31 14•7 17 10 3-3 +3 +1•0 -0-4 3,9 5,0 +i•1 17 M ZT 13-4 10 7 0.8 0•8 +0•0 +0-1 0-9 1-0 +0 1 D followed by Cl 18 F 23 12•9 10 4,4 5-7 +1-3 -0+6 7.1 6,3 +i,2' 19' 'F 17 13,8 23 I3 816 10-9 +2•3 -1-3 9-6 9+8 +0•2' 20 F 23 14-6 20 12 6-3 7-1 4.04 -0•3 6,8 7•3 +0•5 21 M 22 13'0 31f 0 9+9 10•18 4-0.9 -1-1 9-7 10•.3 +0•6 2II' M 34 15-4 is 12 $10 5-8 +0•8 -0-4 54 $+9' +03 MenfiD 27•6 .. 15•It6,.5) 3+5f311 3-70 4-69 0-99 -0•46't 4•35 5+23 0•98 +30+7 t2-661 f2-86' t019 t0'38 f2,62 f'340 t0;65 ;i~-•;; . 1 • Rzeriotu cigarette smoker, now an oecaeionsl ctpr smoker. tOetaeiond'eiprettes, regular eiprsabout 6 perdi7. t'tbe three Voluntats who rhowed an " inaase •• were aoonted as sera. S Bsotudina the two cigar tmotete.

: ; / ~ i ~ M t.ANesr, SEPrEMasx :29, 1973 3 0 Standard Smclll A b C 0' ~ • C A I y ~ Ifl ~ • • y A A . ~. • .~ • ~ ~ A . I •• • A..@~~ A. ~ .• . . A A MWe • fenwle. Fig. 1-tacrease In CtD}tb levels after emoklns dUferent brande of 'elsaretto. 'hhe ! average initial COHb level for all volunteers was only 3.7%, confirming that as a group they were not unusually heavy smokers. The initial COIib level was relatedi to usual cigarette consumption (r=049; P<0-01) and to consumption on'the morning of' the experiment (r=0-SI8, P<0-01'). There was no relation between' the increase in COHb after one cigarette and usual, cigarette consumption (r=0-41, N.S.) or between increase in COHb and initaal' level of COHb (r=0-13, N.s.); but there was an: inverse relation between haxnoglobin level' andi increase in COHb1 after smoking (r=-0-69, P<0-01'). The average fall in CDRb % during the 20-minute interval between cigarettes was 0-46, (table II). As expected, this was reiated' to the level of COHb after smoking the flrst', cigarette (r=0-65, P<0•0l): :, Though there was a slight predominance of women among the.volunteers, the random assignment ensured that any sex differences would be reasonably balancedl The women were younger than the men (mean age 24 years v. 33' years, P<0-03'). They also showed a much greater' mean, increase in' COHb than the men after smoking the non-mild cigarette (1-32 ~, compared with 0-90 ;, P<0+02), but the difference after the extra-mild cigarette (0-82% ' compared' witlt 0+S'1'a,) was not statistically signifiiant. Discussion The average rise in the COHb % of'ven!ous blood after smoking a mild cigarette A was only 0-64 com- pared' with 1-43 after a non-mild cigarette B of'equiva- lent size. This comparison was made in the same individual, and each cigarette was smoked in an identical manner, one puff every 40 seconds to a total of' tew puffs per' dgarette. The difference in COHb increase produced by these two cigarettes is very consistent (fig. 2)! and highly' significant (P<0-001). This suggests : that the CO yield of A is very much~ less than B. Indeed it would' take two A cigarettes to produce as great an increase of COHb as one B cigarette. In addition, therefore, to its low tar and' nicotine! yield the remarkably low 689 3, ' Standard Q non-mild ( 81 n 0 mild (Al , 0 u:'r uar- I,t M Z n~ t l il' S 4 7' 1 0 0 1!0 11 Small Q non-mlld (!0) o mild (ic) ~ V 1 : I 't , r.. t: Q 19 12 14 1E 13 1e 21! 22, 20 15 17 Volunteer N! Plr. 7.-C'•omperleen of lnoresea In COHb lerels of indlridu•' eublectrafter senolilhe mild end non-mlld,eitllfeltt6 CO' yield woultd seem to indicate that extra mild cigarette A may, be an even Iess harmful cigarette than has previously been assumedi It' is not evident from this study whether the lower' CO yield is due to differences in the filter or in the tobacco, and we are inNestigating this aspect: With the two sma'il-sized cigarettes there was again a tendency for the COHb to increase less after the extra-mild cigarette, but the difference is not statistically significatu: CO yield per cigarette is determined by the CO yield per pu$' and the number of' puffs which it is possible to take from the dgarette: When a compari- son is' made between a11l four brands in terms: of increase in COHb per puff (table iu)' the differencee between C and B' loses its significance while thee difference between A and D gains significance. Thus ; the mild brand A is the only one of the ! four with a significantly lower CO yield per puff and lowez CO yield per cigarette. Furthermore, it seems thai the differences in CO yield are ! to some extent independent of tar and nicotine yield. Despite atternpts to' ensure that each' dgarette was smokedi in, a sim'slgr way it is possible that systematic differences did occur. Some volunteers may have inhaled the extra-mild cigarette more deeply. If, this were so, the finding of' reduced CO absorption from the exm-mild cigarettes is even more striking. Be- cause of'the exclusion of six volunteers (see above) thee symmetry of the design was slightly upset, and twveivee extra-mild cigarettes were smoked first compared with ten, non-mild. Some participants may have found the 20,minute interval between cigarettes too short, so that they inhaled less deeply at' their second cigarette. If'this were so, the imba'lance:of the cross- over would tend to: reduce rather than enhance the differences. In any case the order of smoking the cigarettes had! no effect on the amount of CO absorbed! The women showed a greater rise than the men in' CORb level after smoking; This happened after exara-mild and non-mild cigarettes. It cannqt' be explained by the fact that the women were younger, because age had no relation to the increase in COHb after smoking. In', view of the inverse relation i f+ 0 0 ~ 0 ~ ~ cc w N ~ f ~ ~ i !

between Hb level and increase in C0'Hb-after smoking, it is possible that' the lower Hb levels of' the women (mean 12•.8' g~ per 100 ml. compared with 144 g. per h i l r smad e tr 100 ml. for the men) together with t blood volume accounts for' their greater COHb increases after smoking. This' relation between sex, Hb level, and COHb uptake has not as far as we know been reported previously. It is certainly not generally appreciated. It may have especial implica- tions for those women who ismoke in pregnancy and who are anamic. 'I'he findings indicate that besides variation in tar and nicotine yield, commercial! brands of cigarette vary greatly in their CO yield. Direct measurement of the CO concentration of ' mainstream smoke presents no more of' a technical problem than the measurement of its nicotine or tar content. Indeed, it is likely that the tobacco manufacturers already know the CO yield of their agarettes~ and cigars. Because the health implications are' probably as important as is the case with~ tar and nicotine, the CO ~ yield of all commerciaily available' cigarettes should' be published' together with their tar and nicotine yield. Furthermore, this should be done' soon. We thank Upendna Patell of the Addiction Research Unit for checking the statistical calculations, Pauline Beattie for ' seeretarial' help, and the Medital Researeh Council, the Depar2ment of Health and' Social Security, and the Joint Research Board of I S6 Bartliolomaars liospital for financial support. Requests for reprints should be addressed to M. A. H. R. 1EPERENCES 1. fanctr„ 1473. ;. 974, 2' Wynder, B: L!w Seeoad World Conferenca on Smokiag and! Health (edited by R. G. Rich.rdson);'p. 197. London, 1971. 3. RoyR1! College of', Physicians. Stoobns aod Health Now; p. 134. Londonj 1971. {: Surgeon General. The Health CConsequenoes of Smoling. U.S: Departrnent of Health. Education and We1Lre, 1972. !. Astrup, P. Br. rnsd. ]. 1972, iv, 447. 4. Astrap. P., Tmlla,D , Olsen. H. NL, Kleldsm, K. Lancrr, 1972. il, 1220. 7. W.IdJ,1+t,,Howsrd, S., Smith, P. G., Kiddien,St. Br: n.d.1.197D; 1, 7at. 6. Atmsuong, H. E. ibid 1942, i, 992: 9. Rus.cll:,.ti1. A. H., Cole, P. V,, Btowo, H: Lewca,1973, l„37b. ° The Malrhusian nightmare, thatmaas storwtion,will be the ultimate population contr+ol, is only one, and that the most distant, of several specters. Beyond' the immediate question of whether, this year's aops willi produce enough food, to avoid major, price disturbances, poiititxl innrabiiitics, and' famines, therr is concern tbat the' present alarms and scarcities may teflect not just last year's badi weather, but a fundamental deterioration in the world food situation.. Already there are those who foresee a period of food sarcity,, in which those with food to sell will have a usr~fsil ptolitiaal weapon in their hands. Governments of developing countries will find this year that thee soaring prices of',food grains and freight rates have driven their imported food bills up by 60 percent or roughly $2 billion, a drain on foreign reseroea which, should it continue, threateans to retard economic development and make the gap between rich aations aad poor grow faster still. Much besides the threat of' famine,,therefore, hinges upon the ability of developing aountriea to make aop,yields grow futerthan people."-Ntt>losyas WAD., Soiatae, 1973, 181, 63+l. T118 IaMCBT, SEPTPJN'BER 29, 1973 DETECTION OF HEPATITIS•B ANTIGEN BY RADIOIMMUNOASSAY IN CHRONIC LIVER DISEASE' AND HEPATOCELLULAR CARCINOMA IN GREAT' BRITAIN W. D. REED A. L. W. F. EDDLESTON R. B. STERNi ROGER, W'ILLTAMS Liver Unit, King't Collegt Hospital assd'Mtdical'Sefi'ool; London SE5 A. J. ZUCXERMAN A. BoWES PAMELA M. EARL Hepatitis Research Unit, Department of Microbiology, Londtrn School of K'ygienr and Tropical Medicinr S„mrsary Itl, a series of 264 patients with chronic liver disease or hepatocellular car- cinoma, a sensitive radioiinmunoassay technique showed 37 cases to be positive for HBAg. 201of these 37patients were HBAg negative by immunodiffusion and electrophoresis. In active chronic hepatitis 1811,11 of the 94 patients were HBAg positive. Comparison of these cases witih HBAg.-negatdve cases showed' a higher frequency of HBAg, in males and those born overseas. There were no significant differences between HBAg positive an& negative patients for clinical maaifestations, immunoglobuiins, autoan'ti- bodies (after allowing for differences in sex ratio)+ cell-mediated immunity, or prognosis, and' in some cases the progression of tissue damage in this con- ditiom may,beunrelated to, the continued presence of circulatiilg, HBAg: HBAg, was found in only 1 of 45 patients with primary biliary cirrhosis, and coincidental infection following bloodLtcansiusion was a possibility in half of' the HBAg-positive cases of eryptogenic cirrhosis. However, blood-transfusions could be' implicate& in only two of the six HBAg- positive patients with alcoholic cirrhosis. In primary hepatoceilular carcinoma„23 °', of the 38 patients were' positive, the fsequenry'being higher in those born overseas (56 ; compared with 15 0), showing that thee reported' geographical variation, in this association cannot be due entirely to differences in technique for detecting HBAg. . Introduction AN association between:viral hepatitis and active chronic hepatitis' was recognised in one of the earlicst reports'of this syndtome, in which it was' called "aaive chronic infectious hepatitis " 1' However, the sub- sequentobservation of a,positiNe lupus.erythematosus (s,.E:) cell phenomenon; hypergamraaglobulin'a:mia,' and the presence of autoantibodies in the' senun ` led to the concept of a primary autoimmune patho- genesis.s More recently, the detection of' hepatitis-B'B antigen (HBAg) in the serum of some patients " has renewedi interest in a viral atiology. The pro- portion of HBAg.-positive cases varies from 51 % in Italy s to 3% in Australia.10i In Great Britain, HBAg was present irl 8% of patients with active chronic hepatitis but all of' the 6' positive cases had come from abroad." A pronounced geographical variation in the frequency of HBAg has also been reported in hepatocelluiar carcinoma.'&u t. l I

William B. Kannel and William P. CosteUl There is.now ample evidence to show that nicotine absorbed from inhaled tobacco has acute„transient effects on the circulation which could explain many of the observed epidemiologic features of the reiation of cigarette smoking to the development of, cardiovascular disease. Its actions are eompatabte with a transient, non-cumulative and reversible triggering effect operati ve in persons with an already compromised coronary, circulation. The high carboxyhemoglobin values generated by cigarette smokers also fitsthis pathogeneticconceptuali¢ation by causingiiurther impairment of oxy,geniudlization by ischemic tissuessupplied by critically narrowed . 76 1250 369 SIGNIFICANCE OF' NICOTINE, CARBON MONOXIDE AND1 OTHER' vessels and catechol stimulated by nicotine. In additioni efifects of nicotine on platelet adhesiveness and other clotting factors coutd, impair flow in the micro- vasculature or promote thrombosis,in near occludedl arteries. Evidence which in* criminates ciprettes in the process of atherogenesis isiess substantial and does not' explain as well'the epidemiological relationships of the cigarette habit to the oc- currence of cardiovascular disease. Ailthough it is quite likely that severe exposuree to carbon monoxide promotes atherosclerosis in the heavy smoker, it is more like- ly that the acute precipitating effects of nicotine and carbon monoxide are re- sponsible for the excess risk in the cardiovasculardisease-prone smoker. Giving up, smoking has been shown to reduce risk,by about,half so there is much to be gained by abolishing the use of cigarettes or in reducing their nicotine and carbon mon- oxide content. There should no, longer be any lingering doubt that cigarette smoking is as- sociated with an, excess rate of occurrence of cardiovascular morbidity and mor- tality (11-3). Because the relationship is independent of adl the known contribu- tors to cardiovascular disease and since giving up the habit is associated with a substantial reduction in risk,:a causal relationship seems likely (4-7),. A number of'pathogenetic mechanisms have been postulated toexplain how cigarettesmok- ing induces cardiovascular illness (4, 8, 9)L The action of cigarette-induced acute and chronic nicotine and carbon monoxide poisoning has been most prominent- ly incriminated by investigators (2, 8, 9;10),. Mechanisms postulated to explainihow cigarettes promote cardiovascular dis- ease must be consistent' withi the known facts aboutthe relation of'the cigareite smoking habit to the development of the atherosclerotic cardiovascular diseases. These facts may be illustrated fromiFrarninghartt data and summarized as follows: The risk is dose related to the number of cigarettes smoked per day (Fig. 1) . Althoughi there is some evidence to suggest otherwise (6, 1'2) the risk may not be related to the duration of the cigarette habit (Fig. 1!). ~~SIV10'~KE~~CIO'MiPO'NENTS IN THE DEYELOP~MiE'NT'O'~F~ CARDIOVASCULAR DISEASE I

KANNEL A(WDCASTE'Llll. ~. ..ra..,a ue i... .. ~..1 ~. yRrAY~~~ m~~~~ ~ I ,,..,........,... .e .,..a ~~ ~~f~Yll1{yIAV. ~IN~. ItN ® f IG. 1. Risk of wronary, attacks according to number of cigarettes smoked pen day vs. dura- tfon of ci=arette habit-Fiunlngham Study. ._.._ ,_ - The risk of coronary heart disease in the ex+smoker may be as low or lower than that of'ttiose:who never smoked (4). Giving,up the habit is associated with a, prompt reversal to lower risk, although some contend that the benefits acuue more gradually (9, 11,,12)',. In any event, those who quit the habit have been found to have only haif'ttie risk of those who continued to smoke (Fig. 2). The :o Is I I sWoMMa. w.ar RtK!!OM Oo0*. snwow trwoe O.HO o.Po. o.ar, o: m. OJ P6' 0229 Tr~IU[' l.lt :..T 107 .T I ; 1 FIG. 2. Incidenee of'eotonary attacks among ciyaretta smokers accordfn; to subsequent clt- arette habit-h1ee~45-74 at exam: Framingham Study-1S yeariollow-ip.

SMOKE COMPONENTS AND CVD 371 benefits of' quitting wane with advancing age and no longer accrue beyond age 65' (7);. The contribution of the cigarette habit to coronary risk in women is feeble (Table I) and in both sexes diminishes with advancing, age (Table I I'). In men ciga- rettes are significantly related to all cardiovascular endpointsexcept possibly con- gestive heart failure. For women in the Framingham cohort only in brain infarc- tion is there no apparent association (Table IIl). TABLE I Average Annual Incidence of Coronary Attacks Per 10,000 Persons at Risk According,to Cigarette Habit. Men and Women 45-74 Framingham Study: 18 Year Follow-Up „ Men Rate ot Coronary Attackt No.ol'Ggorettes Per Dny Person- Yrs. At Rlah No.oLNtw Coronary Attakcs Crude Smoothed Actual Age-Adjusted Age-Adjusted None 11552 85 ' 74 70.6 67.0 Uhder 20 3938 40 1102 90.7 98.3 20 S3'24 71 133 116.3 137:1 pver 20: 5096 59 Women 116 148.8 125.6 None 22802 70 311 27.4 27.6 Under 20 6986 22 31' 3IIS 35.4 20 3754 10 27 38'.6 33:5 Over 20, 1610 5' 31 452 29.3 T-Vaiue-For age:adJusted rate: Men = 4.77 Women = 1.50 Source: Framingham Monographi#30,. TABLE 11 Cae ucient forthe Regression of Incidencrof'Coronary Attacks"'on Number of Cigarettes Smoked Daily According,to Age in Each Sex. Meniand Women 45-74 Framingham Study: 18 Year Follow-Up Men Women 45-54' 33-64 65-74 45-54 SS-64 65-74 Regressfbn Coetflcients. .342' .227 .039 .313 .123 -.142 T-Values 3.73 295 .0-27 1.54 0.76 -0.47 N:umberofEvents• 92 121 45 22 SO 36 'Goronary attacks: Manifestations of coronary heart disease other than angina pectoris. Source: Framingtiam Monograph #30.

,. 372 KANINEL AND CASTELia TABLE' 111 FRegression of Incidence of Major Cardiovascular Diseases onPlumber of' Cigarettes SmokedlDaily: Men andlWomen 45-74 Framingham Study: 18 Year Foqow-1Jp ' Msn Regression Coronary Brain Intermittenr' Congestlve Totol Coehrcient Attacks Infarction Cloudlcation Fallure C: V 0lteast Bivariate• .255 .318 .375' .080' .209 Multivariate~ .300 .373 .41i0 .148' .237 Multixariate ThValues 5.48 3.OOI 4.67 ' 1.61 6,27 Women. Bivariate• .173 -.096 374I .253' .063 Niultivariate" .227, -.0'1'3 .S'07 .314! .134 Multivariate T-Values 193 ~OAO 3.43 2.46 1.41 •Bivariate: Number of cigarettes and age. •=Muitivariate: Number of cigarettes andageplus-systoiic biood pressure,serum cholesterol, glucose tolerance, ECG LVH. - Source: Framingham Monograph `TM`301 The impact of the cigarette habit is stronger for some cardiovascular end- points (9) (such as occlusive peripheral arterial'disease) ttian otihers (sucfi as coro- gestive heart failure) (Tables II„I11): In coronary heart disease the nelationship iss strong, for sudtlen deattt„ modiorate for myocardial infarction and nnn-existent for angina pectoris (Table IV'): , TABLE IV Incidence of 5pecified'Clinical Manifestations of Coronary Heart Disease According,to Cigarette Habit at Each Biennial Exam. Men 4'564 Ftarningham Study: 18'Year Foll'ow-Up N'o.,ofCigarettes AverogeAnnual,LnaidemcePer1G1,000-Age-AdJusted Per Day Euch Coronary Myocardia/ Coronary Sudden Angina Biennia/ fzam. Attocks•' InfbctJon"' InsuffJcitncyt Dleath• PectorJt* None S0 32 8 , 8 43 Under 20 83' 53 10 25 35 20 118 ' 81' 7 20 35 ~ Over 20 1106 68 14 22 51 tNotstatisticaiiy signifcant at P=<.05. •P=C.05 '~T~1 •sP 3<.01 . ~ Source: Framingham Monognaph #30. ~ ~ V1 . The relationship of the cigarette habitto cardioHascular disease is independ- ent of the other majwr contributbrs to risk and it is most orninous in those pre- ; disposed by other risk factors (Tabie I llly Fig. 3)

SMOKE COMPONENTS AND CVD 373' 1 ~. ~ .. W Y >,0 t: 4 O O c ~ 1s9 sx M 0 70.e I" 333 t • FIG. 3. Probability of, developint, cardiorascular ditsase in,a'. years--clPrette smokers vs. nonsmokers accord(ng to Ibvel of'other risk factors-40 year oldlmen: Framineham Stud!y- 1E year, followwp. SYlfOtlC Iu000: rllcseNRl0g .1!I! I.ssWrol4OLtaRCna' rs1M. 3311' . QilUWtaNfOl[wIK9 0' O. 0 tc0-lx" 0 0 0 SO{ACG YOMO0IWM M0. a~' T0 so so. 40 30 20 10 There is littVe$, if any, increased risk associated with cigar and!pipe smoking,, presumably because the tobacco is not inhaied (4). While there is a strong association in most' affluent' societies, there is a, lack of'demonstrabie effect of cigaretrtes in some low coronary incidence populations (Fig. 4). . = M. • E l / ' ~. i ~. ._ FIG. 4. Probability of'CHO occurrence In two years according to amount of cigarette unok- ing-Framin2ham„Monolulu and'Puert'o Rlco-Men 45-65.

374 KANNEL A~MD CASTELLI The postulated pathogenetic mechanisms must' be consistent with these facts. They must therefore. explain what appears to be an independent, transient non- cumulhtive,,reversible triggering effect that appears to operate impersons with ani already compromised arterial circulation in a fashion tharfavors sudden occllrsionn of the circulation to the head, heart or limbs or promotes lethal cardiac dysrhyth- mias (4; 8, 9) rather than one which primarily promotes the underlying athero- scierotic process. TOXIC PROPERTIES OF' THE CIGARETTE The awesome number of'toxic substances have been isolated from the ciga+ rette (13; 14). Among the gaseous and'particulate substances released when ciga- rettes are burned and inhaled are some which have been, demonstratedlto at least acutelif affect card'iovascular, metabolism, function, and physiology (8,9,,13;14). Foremost' amongst those identified are nicotine and carbon:monoxide (!8, 9, 1i0). Apparently of lesser importance are heavy metals,,trace metals„nitrogen dioxide and substances whichi provoke autoantibody and non-specific inflammatory re- sponses (15). Cigarette smoke contains in the mainstream of the gaseous phase- not only CO; but 2'50 p:p.m. ofnitrogen dioxide (or dinitrogen tetraoxide) sub+ stances of concern, to environmental' protection agencies. The safe level of this gas (5' p.p.m.) is easily exceededby many cigarette smokers. Although this noxi- ous gas has been incriminated in lungdisease,,no connection with cardiovascular disease has been demonstrated. Pernicious adverse mechanisms affecting, the cardiovascular system, which can be invoked from the known properties of inhaled cigarette smoke include: hemostatic effects, cardiodynamic influences, atherogenic results, and vasculo- toxic or inflammatory responses (8, 9)',. These are: among the known cardiovas- cular effects of nicotine and carbon monoxide which must brconsidered. Nicotine From 0:3-3.0 mg, of nicotine can be recovered' from smoke taken into the mouth from a cigarette. The amount absorbed wilUvary from 5% in thosewho do not inhale to 10096lin!the deep inhaler. A heavy smoker who inhales is subjecting himself to the influence of 50-100 mg of nicotine daily ('8).The principal effecrof this absorbed nicotine appears to be to stiinulatrcatecholamine production and release of noradrenaline from local stores (8, 9),. This prodwces sympathetic over- activity provoking cardiodynamic effects manifeste&by a rise in heart rate„blood pressure, cardiac contractile force, cardiac output and; as a result, rnyocardial oxygen demand ('8; 9). Inihealthy persons this is compensated for by a compensa- tory increase in coronary blood flow„but in those with atherosclerotic stenosed coronary arteries this may not occur and ischemiaresul!ts (I8). Indeed,aftera myo- caidial' infarction, smoking may cause cardiac output and stroke volume to fall' ('1 G)'. The high myocardial oxygen consumption of the cigarette smoker may-not be entirely explained on the basis of the 'nicotinc-catecholamine induced enhance- ment of inechanical' activity of_' the heart and about half; may result from the metabolic stimulation oPthe high concentrations of free fatry acid's generated!(17).

SMOKE COMPONENTS AND CVD 375. In contrast tioi these eardiodynatnic effects, few atherogenic effects of nico- tine have beeni convincingly demonstrated. Even when adfninistered'in amounts relatively. higher thanithe nicotine uptake of a human smoker, no atherogenic ef-' fects have been shown inianimals ('18)', Some,, but no't' all studies, have foundia il rise in serum cholesterol in cigarette smokers (8), On the other hand, an increas+e li in circulating free fatty acids has been consistently demonstratedlwhich may later result in increased triglyceride, or possibly, cholesterol levels ('1'9)'. Such athero+ ~ genic effects as there are seem minor, reversible and the findings arenoz consis- ~i tent. More importantly, either as a consequence of the rise in free fatty acid or ' i as a direct effect of noradrenalin, myocardral irritability is increased which may I, predispose to sudden death (8, 9, 20). ,. •' IIIII Nicooine-inducedl release of catecholamines also has hemostatic effects and can increase platelet stickiness and aggregation thereby accelerating thrombus I formation in damaged vessels, possibly contributing to the development of athero- mata andl enhancing thromboembolic sequelae in personswith advanced athero- sclerosis (9, 2'1'),. The~smoking of a cigarette has been shown to increase the plate- (et's' response to a standard aggregating stimulus. This phenomenon,, which is i specifically related to the inhalation of'tobacco smoke is not' related to carbon monoxide or to the particulate : matter in the tobacco smoke. Nor does it' appear dependent on the rise in plasma free-fatty acid provoked by cigarette smoking (22'): Evidence to date suggest that thys platelet response is a direct consequence of either the niiaotine itself or the catecholamine response: it elieits (22): This smoking-induced potentiatuon of platelet aggregation could' go a long, way to- wards explaining premature occlusions of stenotic arteries in cigarette smokers. Other hemostatic effects claimed in about 100 papers since 1963 include: de- creased fibrinolysis, decreased clotting time, change in the rateoPinitiaV clot for- mati©n, maximum clor tensile strength andiclo't'retraction (23)s In the brain,,nicotine as well as smoking,inereases cerebraliblbod flmw while at the same time decreasing the arteriovenous oxygen difference, leaving the cere- bral metabolic oxygen rate unchanged (24). - . i Cor6o Nl de l n onnxr Cigarette smoke, in addition to nicotine, also contains from 2.7-6.0% carbone monoxide which when inhaled exposes the smoker to 400-500 p.p.m. of CO, a, level eight times that permitted ini industry (I8). The hazards of CO have been recognized for many years, but only recently connected with the cigarette habitt which now appears to, be the chief cause of chronic CO intoxication. The CO levels encountered in city traffic range from 20-200 p.p.m.exposingnpn-smokers to a T,3'S o carboxyhemoglobin content. Such an exposure is trivial compared to that self-induced by smoking. Because of its greater affinity for hemoglobin than ozygenj CO converts from 3-1596 of smokers' hemoglobin to carboutyhernoglobin. Carboxyhemoglobin not only decreases the-0i capacity of the blood but also al!ters itsoaryhemogliDbin dis- sociation curve so that oxygen is released'more reluctantly to the tissue because of tighter binding,(25, 26). Carbon monoxide may aVso interfere with tissye oxy- gen metabolism because of its high affinity to myoglobin (27,28) which normally t

376 KANNEL AND CASTELLI takes part in the transfer of oxY$en from hemoglobin to tissue mit+achondria and'o also plays a role in storageof oxygen. Through hypoxia CO acts to increase the permeability of'the~ end©theliumi allowing deposition of cholesterol (29). No sig- nificant change! in arterial lipid synthesis has been observed (30),. Thus by mecha- nisms different than those inditced by niicotine„CO may also adversely affect the cardiovascular system. The vessel' damaging effecu of carbon monoxide and hy poxia which allow deposition of cholesterol in the vascular in!tima has beernex- perimentallydemonstrated in animals (31I„32). All the atherogenic changes'attributed to carbon monoxide-increased endo- theliali permeability, accumulation of lipid in the vessel wall and anatomical changes-can be produced by hypoxia alone. Severall investigators have found increased'hematocrits in bothi experimental animals and man as a result of cigarette smoking (33,, 34', 35). This has been shown to result from an increased!eryt'hrocyte mass.(3~6) and may at times reach polycythemic proportions (37). This smoker's erythrocytosis is evidence that. chronic carbon monoxide exposure results in significant tissue hypoxia. In the Framingharn cohort, within the normal range of hemoglobin, valltes,,risk of cere- bral infarction was found to be proportional to blood hemoglobin concentratiom in both sexes ('Fig; 5),. Higherfiemoglobin valuerwere also foundito beassociated withi higher, diastolic blood pressures (38): Eff.ects of carbon monoxide on the brain, other than lethargy and obtundedlsensorium are notwell described. ® ! IN i FIG. S. Risk of cerebral lnfarctlon (9!6 year follow-up) according to antecedent hemoglobin and blood pressure status-Men andlwomen3l0-6II at entry; Framingham Study. More important than its atherogenic effects, the carbdn monoxide inhaled with tobacco smoke reduces the amount of oxygen available to vital.organs such as the heart at a time when its work and demand for oxygen has been stimulatedd by nicotine (25): In, normal persons carbon monoxide will increase coronary blood flow as nicotine does. On the other hand, like nicotine it may produce myocardial hypoxial in the presence of severe coronary atheromatosis: This has been demonstrated clinically in humans by Aronow who showed ttiat'lessezercise is needetd to induce angina after smoking (39). This effect is'very likely a, conse- quence of'CO, induced impaired oxygen utilization in the presence of'critically l

SMOKE COMPONENTS'ANiD CVD 377 narrowed vessels which cannot dilate inia heart'which at the same time has beenn stirmuiated by nicotine. V1laldletol have provided some epiderniologicai data directly connecting,car- boxyhemoglbbin levels: and the frequency of coronary heart disease (40)L It is hard to adduce! from this whether the risk is actually related to the CO per se or to the daily dose of other substances simultaneously inhaledlwithtobaccosmoke. Hmwever, experimental studies show that smoking•induced elevation of car- boxyhemoglobin may adversely affecrcardiac work performance, induce ischemic ECG changes and dysrhythmias in persons with clinical or subclinical coronary disease: The carboxyhemoglobin value may also be a more objective means of determining risk in relation to smoking,thana personal history of cigarette use. A maximum of'about 15% carboxyhemoglobin has been recorded in heavy cigarette smokers. Most pipe and cigar smokers who.presumably do not inhale, achieve a 1-2% carboxyhemoglobin level. However, converted cigarette smokers who take up cigars often continue to inhale and may indu+ae carboxyhemoglobin: levels of: 20% or more, a level capable of prodtacing symptomatic acute and chronic effects (41). PATHOGENETIC IMPLICATIONS Thus, there is ample experimental evidence w show that' the nicotine ab• sorbed from inhaled tobacco has acute„transient effects on the circulation which could explain many of the observed epidemiological features of'the relation of cigarettes to cardiovascular disease. Its actions fit fairiy wellff with a transient, non-cumuliitive, reversible triggering effect operative in persons with an already compromised coronary circulation. The observation of high carboxyhemoglobin values in cigarette smokers also fits this pathogenetic.conceptualizatipn since this could further impair oxygen utilization by ischemic tissues supplied by critically narrowed'vessels and catechol,stimulated by nicotine. Likewise,,effects ofrico- tine on platelet' adhesiveness andi other clotting parameters could'inflWence flow in rnicrovascul~ture or promote thrombosis in near occluded'vessels precipitating vascular catastrophes. Evidence which incriininates cigarettes in the process of atherogenesis (lin- volviing nicotine and carbon monoxide)~ seems to, these reviewers Iess substantiaV and does not explain as well the known relationship of'the cigarette habit to the occurrence of cardiovascular disease. It is qµite:likely that severe exposure to car- bon monoxide (in the very heavy cigarettesrnokeror inhaling cigar smoke) pro- motes at'herosclerosis, but it is more likely that the triggering or precipitating ef- fects of nicotine and carbon monoxide are responsible for the bulk of'the excess risk in the smoker. It is more reasonable at' this point to interpret the cigarettee habi't as playing,a contributory rather than a primary roie in cardiovascular'dise'ase. This is not the case in emphysema and lung cancer.

. N 378 KANNEL AND CASTELLI' THE'RAPEWT'IC~~ AND PREVENTIVE IMPLICATIONS Aside from abstention, soJutions to the cigarette health problem may be sought in producing, a safer cigarette-i.e., one with~less nicotine and tar and one! which generates less carbon monoxide. The possible beneficial effect of a less harmful cigarette or of giving up the! habit is difficuh to estimate precisely in the absence of data from a eqntrolled clinical trial. If one examines the attributable risk for cigarettes (i.e., incidence of C-V' disease in smokers minus non+smokers divided by incidence in smokers) we would attribute as much as 33% of cardla .vascular cases to the cigarette habit (Table V). If the effect were cornpletely in- dependknt (as it seems to be) and ?otally and permanently reversible (as it may be) one would expect a 33% reduction in~cardiovascular mortality from cessation of smoking. While there is no secure basis for making such predictions data, from Framingham seem to indicate that the estimated benefitsmay not be unrealistie. TABLE V Attributable Risk for Cigarette Smoking,in.Cardiovascular Disease. Men 45-74'. F'ramingham Study: 18 Year Fo(lowJJp. 1 t CardlowscuJar Dlfcase Cigonttts Awerogr Annual'Jncidencr Per 10,000 Per Day' 45-54 SS:-64 6d+74' All Aqa (yl djusted) None 79 203' 293 150 20 172 3'37' 3011 223 Difference 93 134 . E 73 A'tuibutable Risk (%) S4' 40' 3 33 Coronary Attacks Gqoretres Averoge Atinual'lncidence Per 10,000 Per Day 45-54 55-64' 65-74 AJI Agu (Adjusted) None 33 90 ": 14S'1 71'. 20 109 169 163' 116 D(fference 76 79 1d' 4S' Attributable Risk (96) 70 47 11 39 For coronary attacks one would estimate from the attributable risk (Table V) a 399o reduction should occur and this is in fact close to what was observed (Fig. 2). Thus; this is not a triivial'. issue and there is something substantialito be gained in identifying,the harmful!ingredients in cigarettes and removing them or abolishing cigarette use. The problem of devising,a safer cigaretteisapparently'tecFinologicalVyachiew able without great, difficulty. Getting the public to use them may be a more dif-flicult matter since the harmful ingredients may weil'be the ones that give the habitual smoker his satisfaction. Turner eto/ fiound thatonichanging to-very low I • . t

SMIOlKE`COMP+ONENTS AN© CVfl 379 tar and niratine~cigarette consumption increases (41). However; despite this, car- boxyhemoglobin levels fall as a result of a change in smoking,pattern.Smoking behavior is evidently related to nicotine intake and achange to low tar and nico- tine. cigarettes generally results in an increased number of cigarettes smoked, a discouraging state of affairs. Fortunately, to maintain the!same nicotine intake, with some very low nicotine cigarettes requirestoo high a daily consumption for the smoker to achieve (41)i Carbon monoxide content can be reducediby dilutung the smoke, which is achieved by using more porous or perforated paper and tips. Unfortunately, smokers rate low tar and nicotine cigarettes unsatisfactory and evidently not many heavy smokers would voluntarily elect to use them. However„ cigarette manufacturers have in recent years been gradually reducing the tar and nicotine yield of cigarettes with little reduction in sales. This suggests that gradual changes in the :cigarettes' tar and nicotine may be acceptable.Similar gradual changes in the carbon monoxide content should be encouraged. Another alternative is a change toicigars: This is evidentdy not algood alter- native for the inveterate: cigarette smoker. J'udging from carboxyhemogiobin values, such converts continue to inhale and unfortunately the carbon monoxide concentration in the smoke from pipes and cigars is approximately twice that of cigarettes. The nicotine content is also higher. Thus there is little hope that the reformed' cigarette smoker diverted to pipes and l cigars will' acquire the Iow risk of'the non-inhaling inveterate pipe!or cigar smoker (4). Regarding the: nicotine: effects of cigarette smoking, it is possible that these may be controlled in the high risk cigarette smoker by counteracting,the sym+ pathomimetic effects with an1 agent such as propanalol. While the: acute effects cani be corrected in this~way, it remains to be shown whether the long-term car- diovascular consequences can likewise be uountered. Pharmacologic solutions to the cigarette problem in general, would seem less desirable tliani either altering the cigarette:to make it safer, or abstention. Because it is so much ~more common and so highly lethal, the most alarming cardiovascular consequence of smoking is an enhanced risk of lethal coronary at- tacks. It seems highly likely that coronary disease in particular can besubstantia!- Iy affected by deniccstizing, cigarettes, reducing their carbon monoxide or popu- lariaing non-inhaling practices. Since the impact of cigarettes is part~icularly per• nicious in persons already at high risk because of a bad cardiovascular risk profile: (Fig. 3) one might argue for efforts foeused especially on this segment of the population. However, the general risk is so high and so~many people.smoke thatt public health measures for the whole popuVation seem to be tequired. Substantial increases in mortality seem concentrated in those smoking more than one-half packagelday but this is about one-third of'the male smokers. The six year coro- nary mortality in these men 3'S-74 in Framingham is 17/1i000 in contrast to 5S/ 1000 in non-smokers (7). Perhaps when we have a "safe cigarette" (without much nicotine and'carbon •monoxide) we can iassess t'he mortality in those who use it againstthose who3on''t and'i in this way complete the fnall link in the chainiof evidenee in humans con- necting nicotine and carbon monoxide per se to cardiovascular mortality. •9

380 REFERENCES KANNEL AND:CASTELLI 1. Roya) ICollegp of Physicians. "Smoking and Health Now," London, 1971. 2. The Health Consequences of' Smoking, 1967-1973. U.S. Dept. Health Education and Welfare„Washington. D.C. 3. Fletcher, C.M. and Horn„D. Report to World Health Organization, 1970. 4. Kannel, W:B., Castelll, W.P., andl McNamara, P.M. Ciguetrte smoking and risk of coro- nary heart disease. Epidemiologic clues to pathogenesis. The Framingham Study. Nat. Cancer /est. Mnnogr. 28:9-20~ 1968. S. Intersociety Commission for Heart Disease Resources. Atherosclerosis' Study Group. Primary prevention of atherosclerotic diseases. Clrculation 42!(Suppl. A):5'Si,1970. 6, Hammond,, E.C. Smoking in relation to the death rates of one millionmen,and women. Nat. Cancer lnst. Monogr. 19:127-2p4,1966. 7. Gord oni T., Kannel, W.B., and IMcGee, D. Death and coronary attacks in men after giv ing,up cigarette smoking. A report from the Framingham Study: Lancet 1:L345-13'53, 1974. 8. Ball, K: and Turner, R. Smoking,and the heart. The:basis for action. Lancet 2:822-826, 1974. 9. Rose, G. Smoking andkardiovascular disese.,Anmotations:Amer. Heart/. 85r838-839, 1973. 10. Astrup, P. Carbon monoxide, smoking, and', atherosclerosis. Post-Grad Mtd./: 49C6'97- 706,19731 1'1. Hammond, E.C. and Garlfnkde; L Coronary heart disease, stroke andlaortic aneurysm., Alrch: Environ. Nealth, 119:167-1182, P969. 1'2. Kahni H.A. The Dorn Study of smoking,and mortality among US. veterans. Report on BAyearsof observation. Nat:,Cancerlnat Monogr. 19:1-1'25~ 1966. 13. James, G. and Rosenthal, T.'•Tobacco and Health;"'CharJes C. Thomas, Springfield, 111., 1962: 14. Wynder„E. and Hoffmann„D. Towards ailessharmful cig}rette.Not. Cancerlmrt Monogr , 2qi:a9'68. 1LS,. Keast, 0. and Hblt P. Smoking and the immunaresponse. New Scientdtt 61:806-807, 1974. 1i6i Pentecost, B. and Shiilingford, J. The acute effects of smoking on myocardial perfbrm- ancein patients with coronary, arterial disease. Brit. Xeart%: 26:4'22-4Z9;11964. 17. Mjoes,,O.D. and Ilbekk„A. Effects of nicotine on myocardial metabolism and perform- ance in dogs:Scand: J, C1ln. Lab. Invest. 32:75-810,1973. 18: Schievelbein, H., Londbng, V:, Londong, W., Grumbach, Hi, and Remplik, V. Nicotine and arteriosclerosis.,An experimental conudbution to the influence of'nicotineon fat metabolism. Z' klin: Ch'em. u. klin. Blochem. 8':190-196„ 1970. 19. Carlson, L.A. and Bottinger, L.E: Eschaemic heart disease in relation to fasting values of'plasma triglycerides and cholesterol. Stockholm ProspectivrStudy: Lancet 1':8I65* 8168, 1972. _ _ 20. Oliver„M.F. and Yates, P.A. Induction of ventricular arrhythmias by elevation of arterial free fatty acids ini experimentallmy,ocardiallinfarction. Cardiology 56:359,364', 197'1. • 21. Murphy, E.A. and Mustardl J.F. Smoking and thrombosis. Nat. Cancer Inst. Monogr., 28:47-55, 1'96i8. 22: Levine, P:H. An acute effect of cigarette smoking,on platelet function. A possible link between smoking and arterial thrombosis. Grculation 48:6'1!9-623, 1973. 23. Hawkins, R.i. Smoking platelets and thrombosis. Nature 236:450-4'S2; 1972. 24. Shinhj, E., Olesen, J., and'Paulson, 0:8. Influence of smoking and nicotine on cerebrall blood flow and metabolic rate of oxygen in men. f. Applied Physiol. 35:820422; 1973. 25: Astrup, P., Hellung-Larsen„P.,,Kieletsen, K.,,and Mellemgrard„ K. The effect of tobac+ co smoking on the dissociationi curve of oxyhemoglobin. Ihwestigations in patients with occlusive arterial' diseaae in nonmal'subjects. Scond. /. Clin: Lab. lhvest. 1I8:45'0- 4'57, 1966: -

SMOKE COMPONENTS ANIDCVD 38t' 26. Goldsmith, J.R. Carbon monoxide and coronary, heart disease. Ann. 1nt: Med. 7'1I:199- 201:,19i69. , 27. Ayres, S.M., Gianneili„ S., and Muller, Hl Carboxyhemoglobin and access to oxygen. Arch. Envlron. Health 26:8'-15, 1973., - 28. Coburn, R.F.Carbon monoxide body stress.Ann. M:Y:'Aud. Srl.' 174:1'1-22,1970. 29. Pauli, H1Gi, Ttuniger, Bi, Larsen„J.K:, et al: Renal functionAuring prolonged exposure to hypoxia and CO.Scand. /. CJIn. La6anvett, 22:(Suppl) 103:61-67„1968: 30. Sarma„ JS.M., Tilluranus, kl:, Ikeda, S~, et al. Lipid meubofism in perfused human,and dog,coronarry arteries.Amer. /. Cardiol. 35:579-587, 1975. 31.. Astrup, P., Kjeidsen,l.C:, and Wanstrup, J.The effects'ofexposureto carbon monoxide, hypoxia and hyperposia on the development of experimental atherosclerosis in rab- bits. In: "Atherosclerosis. Proc. 2nd Internat.Symp."'(James, RIJ. Ed.) pp. 1I08=1'11. Springer-V/erlag, Chicago,,1970: 32. Astrup, P. Some physiological and pathological effects of moderate carbon.monoxide exposure: Brit: Med /.,4:44'7+452; 1972. 33. Goldsmith, J,•R. Carbon monoxide:Scienct 15'7:842•844', 1967. 34. Eisen, M.Ec and Hammond, E.C. The effecrof smoking on packed cell volume, red cell' cour,ts„hemogiobin and platelet counts. Canad. Mtd. Assoc. /. 15:520423, 1956. 35. Isager, Hi and Hagerup, L. Relationship between•cigarette smoking and high packed cell volume and hemoglo;bin lev~e!s. Scond: J. Hoemetol.' 8':24'1•244, 1971. 36. Sagone, A.4., Jr., Lawrence, T., and Balcerzak, S.P. Effect of smoking;on tissue oxygen supply. B'lood 4T:845-831, 1'973. 37. Sagone. A.L., Jr. and Balcerzak, S.P. Smoking as a cause of erythrocytosis. Ann. Int. Med 82:512-S1S1 1975. 38. Kannel, W.B., Gordon, T:, Woif, P.A., and McNamara. P.MI Hamoglobin and'risk of cerebral infarction: The Framingham Study. Stroke 3:409-420, 1972. 39. Aronow„ W.S. and Isbell, M.W, Carbon monoxide effect on exercise-induced angina pectoru. Ann. lM. Med. 79:392-39S, 1973. 40. Waldl N.,Howard„S1,Smith,P:G:,andlKjelsden,K.Associationbetweenatherosclerotic diseases and carboxyhemoglobin levels in tobacco smokers. Brit. Med. /. 1i:761 165, ' 1973. 441. Turner, J.A. McM., Sillett„R.W.,;and Ball, K.P. Some effests of changing,tts lonvtarand low-nicotine cigarettes. Lancet 1:737-739, 1974.

SECTION 4

THE JOURNAL OF THE AMERIiCAN'MEDIICAL ASSOCIATION September 28, 1970 Vol 2113, No 13 Recent Trends Ernest L. Wynder, 11~ID; Kiyohiko Z?'abuchv, TVID; and Edward' J. Beattie, Jr., MD A retrospective epidemiologic investigat'io'n o f' 350 lung cancer patients confirmed the close association between . cigarette smoking and lung cancer, particularly o f the squamous and'oat cell types. New trends in this study ' kl. _% _' show that there is a decrease in relative risk f or those - patients developing' lung' cancer ten years a fter they have switched to filter cigarettes, possibly due to the lower "tar'''content in filter cigarettes smoked by these patients. ;~YS The risk also declines a f ter cornplete' cessation o f smoking d thh llfh an appearso approac teevie o nonarr~o'ers a4ter 'k` 13 years of not smoking. ~'ucrther efforts to produce less .number of cigarettes smoked per day. If''•tar" is the principal harmful ut- gredient4 then it would be sufficient to reduce the concentration of' the tar. The Hammond study on ex- smokers aged S0 to 69 years who had smoked 20 or more cigarettes daily, shows that after ten years of nott smoking they have a death rate sim- flar to that of nonsmokers.' These two pieces of evidence taken y•'z together suggest the following hy- ' harm f'ul tobacco products should be continued and expand ed although no smoking or cessation o f smoking is the most effective prevention against lung cancer. W ith a wealth of' epidemio- ibgic' studies on the etiol- ogy of' lung cancer in the literature,,it may not seem worth the effort to report yet' again on the en- vironmental background of a group of lung cancer patientg.'1 ' However, such a study is of value if it cart show evidence of changes, particularl{y in time trends, in the epidemiological background of these patients. From the Division of Environmental Cancerigenesia, SSoan-Kettering, Inatitute for Cancer Research. and' the Division of Epidemiology, American 13ealth~ Fbaada- tioa (Dts Wynder and Mabucbi) and,the JY1MlA. Sept 28. 1970 e Vol 223, Mo 13 Ih a great many epidemioiogic studies, it has been found that, among cigarette smokers, the risk of lung cancer increases with the num- ber of cigarettes smoked per day.'" In other words, there is a dose-re- sponse relationship. This suggests that reducing dosage by means of reducing the concentration of the smoke from each cigarette might have the same effect as reducing, the Department of Surgery, \'demorial'Hoapital for Cancer & Allied Diseases, New York (Dr. Beattie). Reprint requests to 2 E End Ave. New York 10021' (Dr. Wynder). pothesis s If tar is the principal lung-cancer in- ducing faetarr then people who have switched from high tar cigarettesi to low' tar cigarettes should have lower rates of lung cancer t'han those who , continue to smoke high tar eigarettes- ~ this taking place tien or'more years a'f> ter the switch. The present study was undertaken to test this hypothesis. Methods of' Study Lun!g, cancer patients admitted to the ,1~lemorial Sloan-Kettering Can- cer Center in New York City are interviewed routinely about their background and social habits. Each patient included in this re- port has a histologically-proven lung cancer andl was interviewed between November 19% and August 1'969. The study group consisted of 210 men and 30 women with Kreyberg Lung Cancer-Wynder et al' 22211 -A• .. 11 .

Table 1.-Type of'Smoking and!Number of Cigarettes Smoked by Lung Cancer Patients and•Contral's. Totatt. . IVO. - (1/.)~. Pla~ (Y.). 210' (73.9): 30 (45.5) 7:00:1, 74 (26.U/ 36' (54.5) 2.06:1 234 (100) 66 (100W ' . 4J0:1 group' 1 cancer of the lung (squa- that subclass and let m, and m, stand rnous and oat cell types), and 74 men for the number of nonsmoking cases arld 36 women with Kreyberg, group and' controls. Then the relative risk 2(glandular)' cancer of the lung. The control group interviewedl at Mlemorial~at the same time was twice f+art'he subclass= the size of the cancer group and tnat ehed' by sex and age to the male n, nr m, m.. Kreyberg 1 patients and all female Thus, for those smoking 41 or more cancer patients. The criterion for in- filtered cigarettes per day, n,=25, dzwidua'I's in the control group was n_-7; firom Ta'ble 1, mt-3; rn.-$8t that t'hey' should have no known to- and thezel.ative risk is 104'.8: bacco-related diseases," Tht: risk for any subclass relative: Results to that for nonsmokers was computed Sex Ratio and Hrstofogy:-When in a standard fashion,° as follows: the sex ratio of patients with the Let n, and n} stand for the number different histological types of cancer ,\ J of cases and controls respectively in was examined, the'Kreyberg,11 group >aa1. K'r.yberg 1 Kreyb.rg•'2 - '` Control -" r e ~ ' Nonsmokers 3 (1.4) N o. 6I ( (8.1) No~ 88 ( /,) (21.0) Current smokera •L exemokers (I•9 yr) C7g#rette smokers' 191 (91.0) 61' (82.4) 199 (47.4)' Pipes and/or cigars only 10 (4.8)' 3 (4:1): 64 (1'5.2) Essmokers (1'0 + yr) Cigarettes 6 (2.9) 3 (4.1) 65 (16:5) Pipes and/or cigars only 0 (0) 1 (1•4q 4 (1.0). Total Mal. Patients • 230 (100) 74 (100) 420 (I00)'. No. of cigarettes por day 1to9 7 (3.6) 1 (1.6), 42 . (15.9) 10 to 20 ~ 57 (28.9) 20 (31.3)', 114 (43.2) 21'1 to. 40 ~ . 74 (37.6) 34, (53.1')' 82 (31.1) 4t,- 59 (29.9) 9 (14.01 26 (9.8) Tota( C)garett..5moken 197 (100) 6x (100) 264' (100) Femate Nonsmokers 5 (167)i is (41.73 76 , W•6) Current smokers + eIISmOkers (1•9'yr) CigareRe serokers 24 (80.0) 21 (58.3) 53 (40.2) Easmokers (10~+ yr) 1 (3.3) 0 (0) 3 (2:3) Total Fetnaa Patients 30 (100) 36' (100) 132 (100) No. o! oiganttas per day, 1'to 9 11 (4,0) 2 (9:51 19 (33.91 10 to 20 13: (52.01 11' (52:4) 24 (K¢19) . 21,to 40 g' (32•0) 7 (33.3). 10 (17:9),, 41+ 3 (12.0) 1 (4.8)' 3 15A) ~ Total Cfgsrett. Smokers' 25 (100) 21 (1!00) 56 (1i00) Table 2:-Histologacal Type and Sex' Ratio oflung,Cancer Patients AAali ~ Ftmate 5e. Ratio I W F. ' (I a Y: matd K'reybird group. 1'K'r.yberg, group 2 had a greater predominance of men than, the Kreyberg 2 group (Table 2). Age Diatribcction.-Niale Kreyberg 1 cancer patients were somewhat' older than the male Kreyberg 2 pa- tients a'nd' both groups of wotnen,, though the •dif{erence between thee male Kreyberg 1' and Kreyberg 2 groups was ~ not ~ sig'nifirant (t'-1.19, 0.15'>P>0AD)'.(Tab~le 3).ReligirJn.-T.he male Kreyberg 1. cancer group included a significantly lower percentage of Jews than' both Kreyberg 2 cancer (,1'-3.6a; dii-1, 10>P>0.105) and control groups (t' =25.65; df-1, 0.005>P) (Table 4). The female Kreyberg 2 cancer group also contained'a lower propor- tion of Jews than the eontrols, but the difference was not statistically significant. Smok'ing,-Ainong the' men in thee study there was a signnficanttyg'reat- er percentage of smokers in both his- tolog'icalF groups than in the'controls; and greater in Kreyberg 1 than in Kreyberg 2' (Table 1). (kGeyberg 1 and control: X'-41.61, df=1. 0.005 >'P; Kreyberg 2 and control: X'= 5.93, df-_ 1, 0.05>P>0.10; Kreyberg 1 and Kreyberg 2: Y'-5:93; d'f =1, 0.05>P>0:01). The female Krey- berg1 group also: contained! a, sig- nificantly higher percentage of ciga- rette smokers than the controls'(X"_ 14!77; df~-1, 0:05>P). Tlie' differ- ence in srnokers, between the female Kreyberg 2 and control group was' not statistically significant W_ 223idf,'1', 0.25>P>0.1~0). Arrtount an'd Type ot Cigarette Smoked..-Data on amount smoked refers to the number of' cigarettes smoked daily during the Iest five years of'smoking. Any patient who had' smoked at least one cigarette a day for 20 years or more was defined as a cigarette smoker and, was in- cluded in this analysis. If, a patient smoked for less than 20 years, a dailyy number of' cigarettes' smoked was ca'lculated as follows: (daily number of ci garettes )_( the average number of cigarettes per day for past &years) 2222 JAMA. Sept 28, 1970, • Yo( 213, No 13 Lung Cancer-Wynder at at

1 r Table 3.-Age Distribution of Lung Cancer Patients Maie Female Kreyberg 2 Krsyberg li Kreyberg 2 ~- I No. (y.) No. No. 6 (8.1) 1 (3.3) i 4 (11.1) 7 (9.5) 4 (13.3)1 2 (5.6) 23 (31.1) 14 (46:7)' _ 1s (41.7) 32 (43.2) 9 (30AT 12 (30.6) 6 (8.1) 2' (6:7): 4 (12'.111 0 (0) 0 MY „ 0 (0) 74 (100) 30 (1o0), 36 (loo) , 67.8 56J6 56.7 Age at Kteyberg,l DiaRnosit (YN No. (!%.Y 30-39 31 (1.4) 4049 31 (14!8) 50-59 56' (26.7) 60-69 63! (39.5) 70-79 331 (15.7) :. ac+ 4' (1.91 Totaii 210 (100) M.aa Age 60:2' Religion Male Table 4.-Religious Distribution of Lung Cancer Patients and Controls. Jews CathoNbs Protestants Totals F.ma(e . Jews ''Tathoiics Protestants Totals Kreyb•rg,1 Kreyberg 2 Control' Ne (•!•) No. (9•) i Na (Y•)' 29 (13.8) Ii6 (24.3) 139 (33.A 116 (55.2) 33 (44.6) 18+t (43.8) 65 (31.0) 23 (31.1) 97 (23.1) 210 (100) 74 (100), 420 1100) S (L6.7) 14 (3&9)', 38 (28.8) 1!S (50.0) 13 (36J1') 56 (42.4) 10 (33.3) 9 (254) 38 C18.81 30 (100) 36, (100) 132 (100) Table 5: Numberand'.Ty,pe of Cigarettes Smoked by Ma1e Lung,Cancer Patients andiCo'ntrols Regular No. ' - Krsyberg 1 Control Cigarettes i p.r oay I to 9 4 (4.9) 6' (9.7) ~ 6 3150 10 to 20, 24 (t9.) (:0) 21 to 40i 30 (37.0) 21 (33:9) 41 + 23 C18.4) 4 (6.5) Totals 191 (1''00), 62 ' (100). Filt.r' Kreyb.rg 1 Controi No. (•/.) No. (y.). 2 (3.0) 11 17 (25.8) 36'. 22 (33.3) 28 25 (37.9) 7' 66 (100) 82 (13.3) (43,9) . (34.1) (81S). (100) •P.rsans who smoked'. Nlt.rs for ten or more years aft.r switching from r.guiar cigantt.s. Table 6.-Duration,of'Exsmoking in Ma(e Lung Cancer Patients and Controls. Knyberg.1 Kr.yberg2. No. Y.ars Since ~---~ Stopping 5moking, Na (*/.) Nb. (°/,), 11 to 3 18 (50i0) 3 (25:0) 4 to 6l g (22:2) 3(25:0) 7 to 12 g (22.2) 3 (25.0) 13 + 2 (5.6) 3 (25.0) Totals 36 (100) 12 (100) x (years of snnokingJ20 years). T"hus, a patient smokin'g, 20 ciga-, rettes, daalyfor'tew years! was classi-fi'ed as' a ten-per-day cigarettee smoker. However,, such ad'p'ustments' were rarely necessary. Aalnng, cigarette smokers there was' a significantly greater percent- age of inen.who smoked' in excess of JAMA. Sept 28, 1970 • Vol 213, No 13 .r~. Controi I No. (Y•)i 22 (1'7.6) 17 (13.6). 31, (24.81 55 I (44.0) 125' (100) two ~ packs of cigarettes a day in the. Kreyberg 1 group than inboth Krey- berg 2 and control groups, (Krey- berg 1 and, 2: (X'=5.a3, df=1,, 0:0'5>P>0:0b; Kreyberg 1 and con- trol: X"=29.00, df _ 1I, 0:005>P) (Table 1). A similar, but not sta- tistically sigpificant, trend was noted, for men between the Kreyberg 2 group, and controls, and' for women between I+Creyberg, 2 group and con- trols. For the purpose of testing the hy- pothesis presented in the beginning of this communication, the reiative risk for' Kreyberg 1 lung cancer was cal+culated,by the method stated, be- fore for nonfilter (regular) vs filter. .. cigarette smokers. The former group included persons who smoked non- filter cigarett'es on1y. The latter, onn the other hand, comprised individ- uals'who changed'to filter cigarettes and had smoked! them for at least ten years. In the preliminary analy- sis, it was found that persons who had quit smoking for a long periodof' time had smoked more non'fiSter' cigarettes before stbppin'g than either current or recent exsmokers; as'.. might be expected because there. were, of course, fewer filter cigarettes on the market ten, years ago than, today. In~addition, the con'troli group contained a sigtdificantly larger per- centage of' exsmokers of long dinra- tion (Table 11). Therefore„ for a sta- tistical comparison of'non'ftdter andfilter cigarettes, an arbitrary ten- year period of e)csmoking was chosen and anyone who had not smoked for at least ten years was excluded from, th'is,pa'rticular analysis. The results showed that the rela- tive risk increased in proportion to the greater number of eigarettes ~ smoked for both long-term filter and ~ nonfllter smokers, and that the lower' Q. relative risk noted for filter'srnokers Q. . as a whole (Fig 1) was' similar for all subclasses of smoking, atalmurlts' Q (Fig 2). The ratio of nonfiiter to ~ filter cigarette smokers was 1.22:1 for the Kreyberg 1 and 0:76:1i for the (~ control pa'tients, indicating more ~ nonfilter cigarette smokers inthe. Q liing, cancer' group than the contro'1, group (:Y'-3.76, df=1, 0:10>P> 0.05), (Table 5). Ttie, data also showed' a greater percentage of 40 ' plus-per-day filter cigarette smokers' in, the lung cancer group (37.9%)compared with nonfilter cigarette smokers (28.4%), a trend not as

~~ Current smokera & L.J ex-smacers II-9yrsJ' Q u-smokers t UD+yrs./ Case N' Control 6' 3' 6v g$ • (10+veirs) niaes L10+yearsl 1. Lung cancer risk by type of smoking, in men, Kreyberg groap1. . 1100 Filter cigarettes (10+yrs.) Nonsmoker risk • I Case N '' ConQrol' 10 - 20 21- 40 41 or more Cigarettes per Day 2. Lung cancer risk by number of cigarettes smoked, daiiy, in men, Kreyberg,group 1. 2 3 55 88 r~--Nonsmoker 4-6 l-1x 13• Years ol,Ex+smoking, 22241 JJ4'N1k1. SePt 28, 1970' • Vol 213. No 1T 1=-----r"'..~---- -~---Nonsmoker Ri!gular Filter Cigars ~-smater cigarettns cigarettes andlor, 3. LrYng cancer risk by years of exsrneking, in men, Kreyberg group 1.. Lung Cancer-VNynder et at r. ~a ~... . x,.

:f. -. apparent im the control group. . The data were examined in rela- tion to religion (Jewish and non- . Jewish), but only 22 of the patientss were Jewish men and this was too few toi a'ttempt an analysis in rela- tion to the type of 'cigarettes smoked. However,, removing Jews, from the .:, data 'showed~ . the relative risk to ~ be 462 2 for nonfilter smokers (74 cases, 5I0~controls) andl 26.8'for filter smok- ers (51 cases, 59~ controls), thus showing similar differences as found for the total group: Although the original matching of study to control cases was made by age, the data were eacamined by age group because when it was broken down by stnok- ing category it was possible ~ that the age distribution might be unbal- anced: While a: higher relative risk was consistently noted for regular, or nonfilter, cigarette smokers, in both the under 59 and over 60~age groups; the greatest difference in the relative risk for nonfilter and fil- ter smokers tended to be seen in the younger age group. A meaningful comparison of the groups smoking filter cigarettes for fe ..-: less than ten years by: amount smoked is not possible because onNy ` 23 patients with Kreyberg 1 lung cancer had smoked filter cigarettes~ for one to four years, and 21 for fiive to nine years. Cigar and Pipe Smokers.-Al- t'hough cigarette smoking was shown to be closely related to lung cancer, it must' be rernembered'i that cigar and pipe smokers also have a higher relative risk for lung cancer than nonsmokers (Fig 1) . Among pa- tients who smokedi cigars or pipes or both, in this stud{y, the amount con- sumed by the male Kreyberg 1 can- cer patients was greater than by the controls. Of seven Kreyberg 1 ran- cer patients who smoked cigars only, three smoked ten or more per day ; compared with four of 55 in the con- trofs: Among those who smoked pipes only, two of four cancer pa- tients and ten of 35~controls smokecl teni or more pipes daily. One can- JAMA, Sept 28, 1'970 9 Vol 213. NO 13 . 1958 '59, '60 '61 '65' '66 '67 '68 '69 Year of Report 4. Filter and nonfiYter "tar" yiields in the United States, 19Si9=1969. These data~are compiled reports in Consumer's, Report, Reader's Digest', Federali'1`rade Commission Reports, Wooten Reports, and Maxwell Report's. The results have been converted to correspond'to the standards employed by the Federal Trade Comrniission."° cer patient and' 26 control§ smoked both cigars and pipes. Of three Kreyberg 2 male cancer patients, one smoke& seven cigars daily, another 5 pipes daily, and the third smoked ten cigars and U pipes per day. Essmokers.-An examination of the men who had given up smoking at' least one year before hospital ad- mission showed that the lung cancer patients stopped smoking more re- eently tharn the controls (Table 6). The F{Creyberg 1 male group includedd a significantly higher percentage of' persons who stopped smoking less than, three years prior to diagnosis than the controls (1°-22:32, df=1, 0!Op5 >P ) ~. Thoughthe data seem to be based on a rather small number-of cases, ,the relative risk for Kreyberg I lung cancer was found to declane steadily after cessation of t'he smoking habit (Fig, 3'). The relative risk for those who stopped smoking up to three years previously was the same as for current smokers, but after 13 yearss the risk appearedl to be nearly the. same level as that of nonsmokers. Further analyses of exsmokers by age and different exposure to tobae-,

, co could not'be carried out because of' the paucity of'cases after such cross- tabulation. A review of the environmental his- tory of lung cancer patients who were Iong-tercn exsmokers might be f of' interest in view of determiningg probable exogenous factors that might be related to t'he etiology of' the cancer. The study contained; six lung cancer patients who had given up smoking at least ten years prior to diagnosis. Of'these six cases,,t'he only one to have smoked for Iless than 22 years had, a most unusual, epiderniolbgical history which, sug- gested his lung cancer could have been related to factors other than smoking. Between t'he ages of eight and ten years, the patient was treatedd for psoriasis with potassiumiarseniie. At' 27 years of' age, he had a lymph node tumor removed from his groin and received x-ray therapy. At the age of 37' years the patient hadi an epidermoid carcinoma of the scrot- urn as well as a squarnous cancer of the buttock. The present cancer of the lung was diagnosed the follow- ing year and seven months later yet another prirnary,, this time adeno- I earcinoma of the kidney, was detect- 'ed. There is a possibility that these multiple primaries, particularly of the skin surface, may be associatedi with high doses of potassium arsen- .ite°'' and that t'he effect of this med- ication is also related to, the lung cancer: Of interest in this respect is the report by Robson and Jelliffe of' six patients who developed'lung can- cer after the therapeutic administra- tionof'arsenic." Cahan made a siin- ilar observationand suggested a pos- sible synergistic action of the arsen- ical compound and cigarette smoke: (oral communication fromlDr. Wil- liam Cahan, Aug 181 1969)' A me- tastatic spread of'the scrotal lesion to the lung, although ai rare occur- rence, is also a possibility,° One exsmoking patient had given up 1'S'years previously after smoking heavily for 22 years. Another patient who had given up smoking 20 years prevsously was a carpenter by trade, an occupation often associated withh lung cancer in nonsmokersl'O 1Nonsmokers With LuRg, Cancer: The fact that Kreyberg 1 lung can- cer can develop in al nonsmoker, though it' is quite rare, needs to be consideredl One of the three non- smokers in the male Kreyberg 1 group was a house painter, I:ike al carpenter, this is an occupation, more common than could be ex- pected among smokers with epider- moid carcinoma of the lung.'° The seeond'nonsmoker was a 54-year-old physician who received excessive nitrogenand sulfur mustard gas ex- posures while working in the Chem- ical Warfare Service in 1942-1946. Really adequate protective elothing ' and' gas masks were not considered very important in those days and on many occasions he suffered blisters and burns on the skin after visiting fields where these gases had been used. The increased occurrence of lung cancer among poison gas work.; ers in Japan is of interest in respect to this case." 'T'he& third' nonsmoker with epidermoid lung cancer was an archaeologist. Comment The findings of the present study in respect to filter cigarettes are con- sistent.with the hypothesis presented in the beginning of the communica- tion. Figure 4' shows the decline in! tar content in~leading filter and nonfilter, brands' of cigarettes: 1958 as well as the increased share of the rnarket taken by filters in this period. These are interesting observations since at the beginning of the 1950's, filter cigarettes represented only a very small fraction of the total con- sumed in the United States. Conceptually, lung cancerdeveI-ops when the cumulative tar dose has reached a certain level: If the dose in a singie cigarette is reduced by 20%, it would be reasonable to assume that to achieve the criticali dose level, the individual would'have 2226I J,AMA, Sept 28, 1970, • Voi 213. No 13 to smoke more cigarettes. The Hammond study on, ex- smokers aged 5o,fi9 years who had smoked 20 or more cigarettes daily, shows that after ten years of not smoking,, the individual§ have a death rate frorn lung cancer similar to that of nonsmokers.' After five to nine years, when Hammond's study shows a decline of 50% among ex- smokers, a similar change as found for filter smokers in the present study, can be expected if smokers change to a lower tar cigarette. On the basis of Hammond's study and our hypothesis, no change would be expected among heavy smokers aged'50-69 years who shifted to filter cig-, arettes and smoked them for five •years or less. 'I'he Hammond study showed'also that exsmokers who had been light smokers (1-19 cigarettes per day) already had a reduced lung cancer risk one to four years after stopping relative to those who had continued smoking. Similar findings were observed by Doll and Hill' The present study did not contain suf- ficient exsmokers to carry out a sep- arate analysis of those who had smoked less than 20 cigarettes' per day and who were under 50 years of age. As none of the lung cancer patient5 in: the present study started out smoking filter eigarettes, the relative risk for individuals who smoked only filter cigarettes could not be deter- ~y mingd. O From an, experimental point of O view, few of the longrterm filter ~ smokers in the study - usedi filters Q that would have selectively removed N components toxic to the cilia from ~i the gas phase, such as hydrogen ~ cyanide andi volatile aldehydes. Cellulose acetate fibers from which ~ , the vast majority of' filters are W made; tend to remove selectively some acidic components ~fromismoke. Since available filter materials gen-, era'lly do not selectively remove car- cinogenic agents from the particu- late matter and the tar from filter cigarettes has the same tumorigenic

activity as tar from nonfilter ciga- rettes when compared on a gram-to- gram basis,!" the decreased risk for filter smokers shown by the present' stvdy appears to relate primarily to the reduction in the total tar con- tent obtained by using filter cigar- ettes: There isa a considerable range in the tar yields of' different filter cigarettes. Therefore, the decreased risk for filter smokers is likely to be in direct proportion to the tar con- tent ~ of various brands. This aspect -_; will be explored in subsequent studies. Through manufacturiisg changes, the tar content of regular nonfilter cigarettes has also been reduced' in recent years so that the present-day nonfi4ter cigarettes should also: be '. relatively less harmful, than they were in the past. This fact may ac- count for the finding that liung, can* cer patients who smoked' nonfilter cigarettes only in the present study tended to have smoked'more of'them than lung cancer patients in the per- lod 194840:' In the study by Wyn- der and Graham in 1950, 220.3% of' • _ : male patients with squamous cell ~ carcinoma of the lung smoked, 35 or more cigarettes or equivalent per day (in these calculations, the data on pipe and' cigar smoking was translated into cigarette equivalents and added to1 number of' cigarettes smoked), while in the present study 49.4%; of nonfilter smokers with Kreyberg 1' lung cancer consumed 35 or more cigarettes daily. It is still unclear, however, wheth- er the decreased relative risk of lung cancer for smokers of contemporary cigarettes compared with 20, years ago is related exclusively to differ- ences in tar yield or also to a reduct- ion in carcinogenic activity of the tar. Animal studies ~ suggest that the latter may also be~a factor. Through the increased use of lower tar yield- ing and homogenized tobaccos, and tobacco st'ems, the tar yield can be diminishedl partly by enhancing combustiom Su& practices haven been shown to leadi to a deerease in. tumorigenic activity of the resulting tars:01 It is to the further, reduction of t'he carcinogenic materials in to- bacco smoke that future researeh ef- forts should be directed.. I3istolog,icGonsiderations.-In, view of' the varying histological in- terpretations of lung cancer sections by different pathologists, a precise evaluation of epidemiologic back- ground for two groups of lung cancer patients is difficult even when the data has been collected and reviewed at only one hospital. However, the results of this study are consistent with previous publications suggest- ing that though both Kreyberg 1 and 2 lesionsi reiate to cigarette smoking. there are certain epidemiological differences between the two groups. In a Kreyberg group, the male to female sex ratio is greater, the sub- jects smoke significantly more and there are fewer nonsmokers. A male Kreyberg 11 group, also tends to be older and includes a lower percent.e age of Jews than a male Kneyberg 2' group. These differences may bebe- cause the cells that convert to Krey- berg 1]esions have a greatersensitiv- ity to exogenous carcinogens than the cells involved in Kreyberg 2 lesions and alsobeeause of't'he great- er tendency for the latter type of lesions to arise in the absence of exogenous infit7ences. It is suggested: that epiderniologic studies on lung cancer should continue to separate Kreyberg I and 2 lesions.'o Epidemiologic Considerations.- As in all epidemiologic studles„ one must consider a possibility that a person's, reply to questions ma be influenced by bias or error iia recalli Individuals in the present study tended to recall well the brand or brands predominantly smoked. While there was some: switching from, one nonfilter brand to another, or from one filter brand to another, or from nonfilter to filter cigarettes, there were no individuals who, changed back to: nonfilter cigarettes after more than one year on filters.. There may be come error in rerall. of the precise dhration of' filter smoking but' in general we assume that no difference exists in the ac- curacy of recall between the study and control! patients. There is a po- tential bias, however, in smoking histories reported by liing cancer patients because the general popula- tion~ is obviously far better acquaint- ed with the association of smoking and cancer than ten years ago. A Gallup Poll described in the New York Times found, the majority link cigarettes andi cancer (18, 1969). The present study should be re- garded as a preliminary report on continuing efforts to monitor the epidiPmiologic background of' lung cancer patients. However, the find- ings ~ of this study in respect to filter cigarettes are being reported-because they are not only biologically reason- ablw and in line with other findings reported' in a retrospective study in the literature," but also becnuse the results could be of practical! value and justify further efforts to produce less hazardous cigarettes. ©f'course, as in all' epidemiologic investiga- tions, the possibility that an un- known factor or factors, which cor- relat'e with use of filter cigarettes actually provide the correct explan- ation of the difference, cannot bee excluded. For example, those who switch to, filter cigarettes may alsoo inhale less and it may be the reducedl inhalation rather than the decreased, tumorigenic activity of filter cigar- ettes t'hat accounts forthe difierence. Only further investigation can clari- fy. t'hese. issues. Subsequent epidemiologic investi - gations in this area will have to con- tain a far larger number of subjects so that the risk by various types of cigarettes, ie, cigarettes made of dif- ferent kinds of tobacco and with different types of' filters, can be as- sessed. Tar and nicotine levels in any one brand of'cigarettes usually remain parallel so that the risk for smokers of' d'ifferent types of cigar- ettes to develop a variety of diseases, in addition to lung cancer, must~be 0 Lung Cancer-Wynder et al 2227 J0.MA. Sept 28. 1970 r Vol 213, Mo 13

considered. It' is: well known, that cigarette smokers have an increased mortality and morbidity rate~ for myorardial, infarction especially among men under the age of 50 years."' Ih the final analysis, th'ee judgement of' whether one cigarettie's is less harmful' tio man than another cigarette can only be made by mea- suring its long=term effect on man himself. Preven'tive Cons'iderrztions.- ClearIy, the most successful way to reditce the risk of lung cancer is not to smoke cigarettes in the first place or to give up smoking as early in life as possible. While individual motivation to cease smoking, can and has accomp- lished much, the great number of Americans who still smoke cigar- ettes suggests that the large-scale educational efforts against smoking are not likely to be entirely effective. Fon this reason, we must implement deliberate managerial' measures ofthe type classically so successful in solving public health problems im the past to do their share in reducingg the 'risk of lung cancer and'! other' ` tobacco-related! diseases. While in, dividual motivation should be en- couraged more than ever, manager- ia1 preventive measures affecting the entire population of' smokers must be expanded. The undertaking of effective prevention in this area is the responsibility of'all-the gov- ernment, the tobacco industry, the health professions, and the general public. With the burden to effect change placed on the shoulders of society as a whole, it is society thatt will reap the harvest of its actions in years to'come.. Concllusions This study was based'on 3'50 liang, cancer patients seen at the Memor- ial Sloan-Kettering Cancer Center betweenNovember 1966 and August 1969. As in previous studies, cigarette smoking, is strongIy' associated with cancer of'the lung. This association is greater for the squamaus and oat cell tl!pes t'han for the glandular type even though the latter is also related to cigarette smoking, A lower relative risk of lung cancer (Kreyberg, 1 groupY was foun& forr individuals who had smoked filter cigarettes for at' least ten years after switching, from nonfilt'er cigarettes' than for those who continued to saaoke nonfilter cigarettes. Since fil- ter cigarettes tendi to be lower in tar than' nonfilter cigarettes, the results suggest that a reduction in tar yield ofia given strength wilPbe associated' with a'decreased risk for 111ng cancer unless the smoker compensates for the lower tar dosage by smoking more cigarettes." The lung cancer risk for ind'ivi= duals who slnoked' only filter cigar= ettes cannot be determined aC this time. The relative risk for lung, cancer among exsmokers continues to be' high for at least three years' after cessation of smo4ing: Thirteen years after an individual has stopped smoking the relative risk appears to be close to that of individuals whoo never smoked. Further efforts to produce less: harmful tobacco products should' be continued and expanded although not smoking, or cessation of smoking is the most effective prevention against Uung cancer. This studN was supported bv the Ameri- ean Cancer Society urant Ep-i andi in part' by Public Health Service research grant. CA-08748 from the National Cancer, Insti- tute. E. Cuyler Hammond. ScD. and Jerry Comfieid provided statistical adMice in the preparation, o6 this communication. References. 1. Wynder EL Graham EA': Tobaeco smoking as a possible etiologic factor in bronchogenic cancinoma: A study of 684 proved cases. JAMA 143l329a3i8. 1950. 2 Hammond' EC: Smoking in relation to the death rates of 1 million men and women. Nat Cancer Inst .Vlonogr 19:127- 20;t: 1966. 3. Doll R, Hill,AB:, Mortality in rela- tion to smoking; Ten years obeervation ot' British doctors Brit Ued J' 1t1399-1410, 1964. 2228 JAYNA: Sept 28; 1970: • Vol 213, No 13 4..Smoking and Health. Report of the Advisory Committce to the Suraeon Gen- eral of' the f ublic Health Service. Public F$ealthiService. Bulletin 11034 1964. 5. Cornfield J: A method' o( estimating comparative rates from clinicaii data: Ap- plications to cancer of the lung, bremst'andt cervix. J Nat Cancer Inst 11:1269-1275; 195L 8., Montgomery Hi Arsenic as an etiolo- logic aqent: in certain types of'epithelioma. Arch Dernt Syph 32h218-236; 193.5. 7. Neubauer 0: Arsenical'. cancer. A' re- view: Brit J Cancer 1r192-251-19d7. & Robson AD. Jelliffe AM:' Medicinal' arsenic poisoning and' lung cancer. Brit' Med J 2i207-209. 1963. 9. Dean AL: Epithelioma of scrotum. J Llrol 6065f)8-518. 194& 10: Wynder EL. Berg .IW: Cancer of the lung among nonsmokers: Special reference to histologic patterns. Cancer 20:11i61-a172, 196'7. 1'1. Wada S. Yamada A. rlishimoto Y.. et eL• Neoplasms of' the respiratory tractt among poison ttas workers Hiroahima Igaku 16:5fi-7:1. 1963., 12. Wynder E'L Hoflman De Tobacco and Tobacco Smoke: Studiea in E:peri= mental Careinagenesia. New York. Aca- demic Press: Inc, 1967, p 730. 13. Kreyberg L.: Fliutologie Lung,Cancer TYpea:'a Morp4ological and Histological Correlatien, Oi+lo., Norway. I1lotweguan. Glniversit3r, Prese, 1962. 14. Btrosa IDJL Gibson R: Risk of long ancer in smokers who switch ~ to,filter ciga- rettes. Amer J Public HealtA 58:1396.1403, 1968. r' 15. Hyams L Loop A: The epidemi- ology of' myocardial infarction at two age levels. Amer J Epidem 90:93-102, 1969. 16. Pillsbury HC,, Bright CC. O7Connor 1CJ; et al: Tar and nicotine in cigarette smoke: J Assoc Office Agr Chemiata 52: 458-462. 1'969.

I .r 0% Effects of Srnoking, 1Nloditied' Cigarettes on Respiratory Symptoms~ and Ventiliato,ry Caipacity'-1 ' S. Freedrnan, Pb.D., M.R.CP., C. M: Fletcfier, CBE, F.R.C:P. ond G: B. Field,s Department of'Medicine, RbyaJlPostgraduate Medical Scliool; HamrnenmithHrsspitol, London, England IT IS' well established that cigarette smoking is the primary factor in the pathogenesis of'disabling chronic bronchitis. Despite the large amount of recent publicity about this and! other dangers to health which arise from cigarette smoking, most cigarette smokers, even, those with symptoms of bronchitis, continue to smoke., _ _ . We were therefore interested to see if we could detect any difference in the symptoms of bronchitis in a group of men who changed to smoking, modi- fied' cigarettes. We have been conducting a study on this quest2on~ for the past 22 months. The men were recruited from lists of 6 general practitioners in the London Borough of Hammer- smith. Short questionnaires: about smoking, habits, cough, and expectoration were sent to 6f000 men. Of these, about 600, men fulfilled the following criteria for inclusion in the trial: 1') age 25'-34 yeats;, 2), smokers of at least 10 cigarettes per day; and 3) a persistent cough and expectoration as dtfined by affirmative answers to question 10 in the Medical Research Council's questionnaire on. <. respiratory symptoms. Men with a, history of chest disease other than bronchitis were excluded~ as were those with other conditions which might have affectedl the results. Over 300 of these men who said they were willing to cooperate in! the study were visited by trained field workers twice danring the summer of 11969: On these: visits, the: field workers administered a detailed questionnaire about smoking habits, respiratory symptoms, and' other illnesses. They also measured one second forced expiratory volume (F.E:V.t) and vital capacity (V'.C.), using a portable dry spirometer, collectedl & sputum specimen (the subject having previously been ptovided with a container in which he ~ was ~ asked to collect all the sputum he: coughed up in the first hour of the day), and measuredi cough fre- quency by a technique described below. On each visit, the field worker tried to persuade the man to stop smoking; 45 ' men did so. Those of the remaining men who indicated their willingness to continue being visitedl regularly by the field workers were then asked to smoke ex- dusively cigarettes~ provided by us for a miniinum, of a year. This was the first occasion on which cigarette supply was mentioned. Tlie.men were placed into 75 groups of 3 each. Each group consisted of individuals closely matched for age, cigarette consumption, cough frequency, andi F.E'.V.t. Each, member of a group was ran- domly allocated to I of 3 test cigarettes. The cigarettes were specially manufactured and were identical in appearance and in packaging. They were designed to, provide a standard nicotine content with varying amounrcs of tar and of con- stituents of vapor phase. The clgairettes were designated "A," "B,11 and °`C:" All delivered about 1.65 mg nicotine. "A" delivered about 22 mg "tar'° and "B" and "C" about 17 mg. In addition,, "°C"' had approxi4. mately a 50% reduction in the vapor-phase con. t Presented' at a woricshwp of the Second World Con- ference on Smoking and Health+ sponsored by the United Kingdom Heasth Education Council, held in Londbn,. September24-24, 1971. = Supporned by the Tobacco Research Council. = Prsssnt addresa: Prince Henry Hospital, Little Bay., New South Wales, 2036; ,Australia. 1805 A r7•-t : ..

MEEDMLAN,, FLETGFIEA, AMID F1ELD order. For each card, he was' asked to indicate which statement was closest to his own experience on that day. The answers were marked in on a proforma. The number of'the card on which the answers changed from the more severe to the less severe statement indicated the "cough score" (text-fig. 2). The cards were presented' twice, and ':~' the results accepted! only ' if the answers were ° consistent. Each man was asked to collect the butts of all ~ the cigarettes he had smoied' in 24 hours in a box specially provided. These butts .were analyzed aR the 'T1obacco Itesearch' Council's laboratories to estimate nicotine dose. Of the original 225 men, 30 dropped out for ::, various reasons: 2 died, 3 were told to stop smoking by their doctors, 5 failed to cooperate, and! 20 moved away. Of the 45 lex-smokers; all but 12 started ..,„a smoking again wirchin 3 months, and we have therefore not included any data from this group in, the results. Consumption of cigarette "C" 1~. ~ T~. CYI ~~. WRT ADmOa'..ODOKKIp A, ODQlfi ot ~~ TDR!'.20G47 .6 I~~.. CLI ~. oA1LI~ tLlDan '.000®q Otl= 20Mt , ~wM FwO~~M 1l! 2 t 1 2 7 {I {' ) • • t 1 1 112 2 ! f<' DA'TA CODE SMEET' . stituents that were measured, as compared with the other 2. The trial began in November 1'9169 and ended in September 197'1i. Every month since the trial began, each subject has been visited' by a field worker'wlto administers a questionnaire and' makes the same measurements as on the pre-trial visits. Cough frequency was measured with a special -m form of questionnaire (text -fiig. 1) based on a technique devised by Dr. J. G: Inghazn of the Medical Research CouEicil; Fneumoconiosis' R'e+ search Unit. The questionnaire was placed on 1'1 cards. Each card contained 2 statements about the frequency ofcoughing: One of these statements indicated a greater fixqueney than the other. The statements indicated a progressiwely greater frequency of cough from cardil to card 11„ and on each card the more severe' statement was alternately labeled 1 or 2. The subject was first presented wit;h, card' 3', 6, or 7 and'then with all the other cards ira tandom. OW.y r~r Q Ta~cr-rteuRz 2.-A completad cough fre+ queney prolbrma. Co„y, fma..,,y tl II 21 2 a f. I ~I 2 ! I o toi ~~tt _' I t ? 1 2, IX'I }CI X1 IX IXi J6 X~.IXI X'X~ x~ 1' t 2~ n [ 2T Dat. i 2' / JOtl¢LUAL OF THE YATIONAL CANCER LYSTPPUTE

EFFECTS OF' SMO1=G increasedi sharply at the start but then leveled off (text-fig. 3). Consumption did not change in' the , other 2' groups. Of course, this does ~ not neces- sarily indicate the dose to the smoker of various constituents for, although the original composition of'the cigarettes was known and we could measure nicotine concentration in' samples of butts each month, wewere unable to:quantify any differences or changes in the way in which the cigarettes were smoked, (text-fi'g: 4). , We could, however, make some sort of estimate. : of'dose of nicotine to eachiman, and t,tiere were wide ;'differences between individuals smoking the same cigarette. Cough frequency varie& markedly with the seasons (text-fig. 5). The average scores were N 0 J a01 r M A M J J~ A~ •~. O~. N~ 0'~ J~. I M~ A' Mi J~. JI A N70 HA VOL. 48, NO. 6, JLPNE 19n JYOD[FMD' QGARE1TE5 1807 higher in' the wiiater than in the summer and were higher in the winter of'1969-70 than in the excep- tionally mild'winter of I97U-71. This supports the validity of'the technique. After about 4 months, men smoki'ng cigarette. "C" began to, have lower average cough frequency scores than the others, and on several individiaall months their scores were significantly lower. These differences were clearer if the results were displa}•ed' as deviations from the mean value (text- fig. 6). An analysis of variance of the mean scores for each man throughout the trial indicated that this~ dili'rnsnce, was significant; this significance became more marked when the results were adjusted for differences in cigarette consumption, The results for sputum~ volume were disappoint-' TszT-stcuxz 3:-Averagr consumption of'eaeh of' the 3 types of,cigarette between the start of the arial,(November, 1969) and May 1971. TtxT-nczzxt 4:-AveragF nicodne con- tent of cigarette tips of 60, men; 20 smoking each type of cigarette.

1808 FREEDMAN, FLETCfiER, AND FIEL.D TtxT-natrnz 5.-Average coug#s frequency scores on the types of eigarette: DEVIATItDNS'. F4OMMEAN -08 -O• 00 J L A N O~ J F~ M A' Mi J J. A. S' o~ N o~ J F~ M1A M J. Ji 1969'' 1070 19711 ing, (text.fig. 7),. First, the 3 groups had d'ifferentt initial values, though we had hoped that these values would be similar once the men had been matched so closely in other ways. Second, there was a gradual decline in, mean vabues with no seasonal! variaition. By comparing, individual results wich the.answets in the monthly questionnaire, we concluded that this decline in volume of sputum representedl the increasing, failltre of the subjects to produce the specimens- There was no signifiicano difference between the groups for F:E.Va or F.E.V./V.C- ratiio, (text-fig. 8), A recent large-scale survey of over 7 years showed& that the difference in the annual rate of decline in F:E.V., between smokers of over 15 cigarettes per day and nonsmokers was only about 30, ml/year. The trial would have to be continued for much longer laefone differences between men smoking only slightly modified ciga- rettes couldi be detected. JpURNrtL OF THE NATIONAL CANCER L"VSTrrU'rE 1005052'95~9

.- I -4 7 tFFECrs oF sstoxtNtS UOD2FMa ctaiARE2*rEs We ended this trial in September 1971. VMany problems are: involved in trials such as the one we conducted'. The first and foremost problem is the ethical question. In this regard, none of' the cigarettes used in the experiments exceeded in tar and nicotine content the brands commercially available, and about half the men smoked cigarettes of lower strength, during the trial than they had' been smoking previously. Secondy two-thirds of the men showed little or no change in consumption of cigaaettes during the trial. One-third 'uncreased cigarette consumption, and we estimate from VOL, 48, , NO. 6, JUNE 1972 r8 1809 TuT-Ftctras 7:-Average, sputum production (measured as mm on an,arbitrary7inear seale). 'I'Ex2-novna 8: Average values,of F.E:V.I. chemical analysis of the butts that the dose of nicotine and tar to the smoker was unchanged. Thirdi since, at the start of the triau all the men were advised to stop smoking, we think that few, if any, of' the subjects would have spontaneously given up cigarette smoking if they had, not been included in the trial. The: second probiem is the measurement off response: Few of our subjects ha& objective evidence of airway obstruction as assessed by spirometry, and they were abnormal only by virtue 1005OS2960

1 ~J. I'81i0 FREEnMe\N; FLETCHERy A,YD F'IEL•D of their symptoms of' cough and production of sputumi These symptoms are di 'fficult to quantify, as our experience with measurement of sputum production showed. However, our method of assessing cough frequency is valid and sensitive, as shown by the seasonal changes, though this still awaits validation by some independent means of counting coughs. We have had limitert success with several methods tried. It is now becoming well recognized that spirom« etry is not a sensitive method for detection of early airway obstruction and that newer tech- niques, such as measurement of closing volume, flow-volume curves, or radi©active gas distribution at different speeds of'inspirat4on, are more sensitive. As yet, these techniques are unsuitable for use in targe•scale epidemiologic or field studies, for they must be further simiplifiedL Iat conclusion, we have shown that modification of the composition of cigarettes and their filters can reduce smokers' cough, an important and earl sym tom of bronchitls y p . ~~~,^^~+ry~ ` '~ ~~ ~y • *, ~.: , ~- ~I ~

The New Engla~nd .Journal of Medicine eCopyright, 1979. by the Massachusetts Medical Society t'olume 300 FEBRUARY 22, 1979 Number 8 CHANGES IN ' BRONCHIAL EPITHELIUM IN RELATION TO CIGARETTE SMOKING, 1'955-1960~ VS. 1!9'70-1'97'7 OscAR AvERBacx,, M.D., E. CuYLER hIAMhtoND, Sc.D., A.vD I.AwREticE GARfltixEL„ Ivf.A. I ( Abstract 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 cigarettie srnokers; 20,424 sections taken at autopsy from! the bronehial"tubes of 445 men (non-lung-cancer deaths)i were examined microscopically ini random order. There were 211 men who diedd in 1955-19'80, of whom .154 smoked regularly,, and 234' men who died in 1I970- 1977; of whom 1i8't were regular smokers. Changes studied included basal-cell hyperplasia, loss of' cilia and' occurrence of cells with atypical nuclei. In both IN ai set of studies published some years ago,''' we ~`- found that several types of histologic changes inn bronchial epithelium occurred far more frequently ira. cigarette smokers than in nonsmokers, increased with amount of cigarette smoking and, among cigarette smokers, increased with~ advancing age. The same changes were found tess ft•equentl~ in former tlian in continuing cigarette smokers. The changes studied in- cluded basal-cell hyperplasia, loss of cilia in some areas and occurrence of cells with atypicad nuclei. These histologic findings paralleled' epidemioiogic findings nhat rates of death from lung cancer are many times~ higher among cigarette smokers than among nonsmokers, increase with amount of cigarettesrnok- ing and„ among persons with the same smoking histories, increase with advancing age.'-' Among former cigarette smokers, the rates~ decline with the length of time since giving, up the habit,`-' In a later study, we had beagle d'ogs inhale the smoke from filter-tipcigarettes and from cigarettes of the same brand but without' the filter.' The filter removed about half'of the total tar and sornewhat less than half of the nicotine contained in the smoke. Fewer pulmonary neoplasms were found in dogs thar smoked fiDter-tip cigarettes than in those tharsmoked non-filter-tip~ cigarettes. Invasive pulmonary tumors were found only in non-filter cigarette smokers. Two /~ From the Veterans Administration Medical Center„Eat Orangc. NJ:,the. ~ =ollege of Medicine and Dantistry of New Jcrsay, New Jersey Medical \~Sehoal, Newark„NJ, and the Department of Epidemiology and,Staustica, American Cancer Society. Inc.. New Y;ork.,NY (address reprint requests to Dr. Awerbach at 15 11% Veterans Adminisuation Mediuli Center, East Orange. NJ 07019). periods studied these~histblogia changes occurred far less frequently in nonsmokers than in cigarette smok- ers~and increased in frequency with amount of smok- ing, adjusted for age. Sections withd advanced histo- logic changes . in those dying in 1955*1980 oc- curred in 0'per cent of'nonsmokers, in 25per cent of, those smoking one to 19'cigarettes a day, in 112 per cent of those smoking 20 to 39 and in 22.5 per cent of those smoking 40+ cigarettes a day. In those who: died in 1970-1977 the percentages were 0, 0.1, 0:8,, and 22, respectively. (iN Engl J Med 300:381-386,, 1979) . of these were early squamous-edl~ bronchial car- cinomas, the.others being invasive bronchioloalveolar tumors. In a retrospectiivetpidezniolbgic.study„itwas found that lung cancer occurred less frequently in men who smoked filter-tip cigarettes: than in those whosmoked non-filter cigarettes,' In a prospective epidemiologic study, three groups of cigarette smokers were matched oni the basis of age, current number of' cigarettes smoked per day, age at which, they began smoking, race,, education,, residence (urban, vs. rural), oc- cupational exposure or non-exposure to dust, fumes and chemicals, and, past h~istioryoflheart di'sease! and lung cancer.30 The three groups were as follows: (A), men who smok.:d high tar/nicotine cigarettes; (B), men who smoked medium tar/nicotine cigarettes; and (C), men who: smoked relatively low tar/nicotine cigarettes. In subsequent years, death rates from lung cancer were highest in Group A and lbwesi in INA Group C. 0 Since 1954, when effective filters were first i!n- C trodut:ed„ there has been a large and continuing drop O in the tar and nicotine content of' the! mainstream stnoke of cigarettes consumed in the United' States.t't ~ .Even non-filter cigarettes deliver considerably less tar ~ and nicotine than those sold' in previous years - this cio ' reduction being achieved by selection of tobacco, the Q~ use of homogenized tobaccoiand various other means. jV. Indeed, the highest tar/nicotine brarlds on the markt:t today deliver less tar than the lowest tar brand of American cigarettes on the market before 1954. Thus, everyone who has been a habitual cigarette smoker for 25 years or longer must be smoking cigarettes with

. 382 THE NEW ENGLAND JOURNAL OF'MEDICI:NE' less tar and nicotine than, those formerly'smoked, and a large proportion of smokers have deliberately selected brands with reduced tar and nicotine.. This study was undertaken to determine whether the drop in tar andi nicotine has been reflected in less extensive histologic changes in the bronchial epi- thelium of cigarette smokers. Men who died in 1955'- 1960 were compared with men who died in 197CD•1977. M'A1IERIALS' AA D N1 E7H Ot)S During the period 1955-1960, we obtained a portion of the traehea and the lungs of e.ery person who died and came so autopsy at the 4 eterans' Mcdical Center of East Orange, New Jeney, and, during'a part'of this period, we also obtained''lungs from persons .who died!in several hospitals in upstate New York. We obtained in- fortnationon the,smoking histories and'occupations of'these sub- jects by interviewing members of their famtlicss lhis step provided material for our earlier studies of bronchial epithelium.''s'Collection of lungs from the same hospitals was resumed in 1970 and con• tinued through 1977'to obtain additional material for this study. Exactly the same technical methodi wex used in the two periods. They have been described in detail." Briefly, they, are as follows: As soon after death as possible, the specimen was removed ar autopsy and fixed by instillation of formalin solution down' the trachea. Later, the entire tracheobronchialtree was dissected'out and divided into 208 portions;,which were then embedded in paraf- fin."A thin histologie section was eue from each portion, mounted on a slide and stained with hematoxylin and eosin. In this study, as in some of our other studies, we examined sections from just 55 of' the 203 portions, which t.ere selected from the lower trachea or the main lobar or'segmentallbronchi according,to a set plan' (Fig. 1). S'ELEt:rIOK AND MA?CHT~C OE SUBJECTS We decided to confine this investigation to male subjects of just two sorts: men who had never smoked regularly and men who had smoked cigarettes regularly up to the time of their terminal illness. (Some of the latter had also smoked pipes or cigars.), Those who died of lung cancer were excludedl Alsoo excluded were men for whom we could' not obtain reliable information on smoking, and men whose oc- cupations were such that they may have been Figure 1. Schematic Diagram oEthe Tracheo'bronchial Tree. The circles indicate the locations from which 55' sections were selected for study. Feb. 22, 1979 Table 1. Distribution of Matched Pairs of Subjects According to Age at Death and Smoking Habits. Aoc 6awn(Y.) No. or' WATeneo IPAIRs TOTAL Nivtl S,WKID. f?eOK[D. S910[lDt?AOKED <1 FACI- 1-31ACx- 1F,P4OL-RIOtiURLT' AG[/DAY AGlS(DAT, . A6ltIflAlr «o S' 2' 2 1 0 40:-td 61 0 2 3' 1 45-49 18' 1 5 9 3 1 50+44 ' 11 2' 2 4 3 55-59 28 5~ 7 13' 3 60=64' 35 10' 4 10 11' 65-69 31 6 1II, 12' 2 7044' IS 61 41 S 3 75-79 16 6 3' 5 2 80i84' 12 7 31 2 0 85+ 2, I 0 I 0 Total pairs 182 46 43' 65 28 Total subjects 364 92 86I 130 56 exposed to dust or fumes that are said to have an ef- fect on pulbnonary tissues.. Presumably because of technical difficulties (but possibly because of pathologic alterations in some cases) some of the sections from the 1955-1960 cases were completely or almost completely denuded of epitheliutn; such sections were useless for a study of this sort. Therefore, all the sections were screened microscopically for denudation. Forty-fiive to 55 satisfactory sections were available for a majority of the subjects, and at least 35 were available for most of the others. We excluded cases with less than, 20 satisfactory sections. The age at, death, cause of death and, smoking habits of each of the potential subjects were put on - computer tape together with, identification of' the groupito which they belonged: "A" for those who die& 1'955-1'960 and "B" for those who died 197011977. For each, Group A subject, we'sea'rched for'a GrouplB sub- ject who had smoked the same number of cigarettes'a day and' was within the same five-year age group at time of death. In, most of the final matched pairs the two men were within one year of the same age at the time of death. Where two or more B subjects were found to match, an, A subject, the one closest in cause of death was s+dected'as the match. By this procedure we found 182 matched pairs of subjects, each pair consisting, of one A (1955-1960) subject an& one B (1970-1977) subject. Table t shows the distribution of these subjects according to age and smoking habits. It will be noted that some of the spaces in, Table 1' contain no subjects or only a few subjects. This setup is because the age-by-smoking-habits distribution of subjects who died' im 1970-1i977 was considerably dif- ferent from the distribution for those who died'l in, 1955-1'960. To build up numbers and achieve a better distribution according to age and smoking habits, wee supplemented the matched-pair cases by including, an additional 81 subjects; 29 from Group A and 52' from Group B, Thus a tota'1' of 445 subjects (364 ito matched pairs plhs 81 others) were included in the 1005+05296%11'

Vol. 300 Xo. a' SA'tII AND BRONCHIAL CH.1NCES - rAVERBACH ET AL 0 procedures described beiow, Their distribution ac- `%t:ording to age at death and by smoking habits is shown, in' Table' 2. In all, there were 20,424 sections that contained enough epithelium for evaluation, an average of 45.8 per case from the 445 subjects. A computer record containing the identification number was made for each of these sections, the 20,424'records were put in random order by random numbers, and while they were in this order, a serial number was addea to each record. A label containing, the serial number of each record was placed on the corresponding glass slide, after which the 20,424' slides were put in order by ' seriall nunnber.T,hus; the slides: were, put in ran'dom' order. While still in this order they were micro- C scoplcally examined by one of us ('l7. A.) who was. given no clue to whether a'slide was from the Group A or Group B and no clue to the smoking habits and age of the subject. Normal bronchial epithelium, as' seen inl a cross- section, consists of one row of basalU cells lying on the basement membrane and a single roM1V consisting of ciliated' columnar cells and goblet cells; no cells with atypical nuclea are present. Sections in which the en- tire epithelium fits this description were classified' as "no changes found." Many sections contained one or more areas in which was a change of some sort (i.e., hyperpiasia, loss of ciliai cells with atypical nuclei or a, eombination of these alterations). We called such, an ' " ' area a Two'or more lesions of different types lesion." were found in some sections. Each lesion, was described according to presence or absence of cilia, number of cell rows and proportion of cells with <40 3' 2 40~ c 6' 0 45-49 I8I 1, 50-54 11 2 s3-59 28' S' 60-64 49 13' 65-69 46 14 70-7a 18 6' 76-19 16 6' 80-84 12 7' Totals t 1 Si7 All 1970-1977 subjects (Group B): <x0 , 6 2 4o-s,t 7 0 43-.t9 20 3 50-54 37 3 3*r54 36 6 60-64 3s lo 65-69 34 6 ` 70l 21 6 75-79 21' a 80-8t 12 7 8s+ 5 2 Totals '154- 33 Table 2. Distribution of MumberofSubjects Aucording,to Age •.; at Death and Smoking, Habits. - TorAL M[vlR Srocap RIGULAt6Y All 1955-1960 subjects (Group A,k S}1oKdD <1 Pncc- .oeyDAY Stactn. 1-2 Pucc. ,ou/D.,r SroK[D 2+ PAc.• AaEsyDwY 2 1 0 2 3' I 3 9 3 2 4 3 7 13 3 12 13 111 111'. 12' 9 4 5 3 3 5 2 3 2 0 0 I 0 SII 68 J5' 2 1 1 2' 3 2' 3 9 3' 13 9 12' 7 13 10 4 no u 14 12 2', 7 5 3 3 8 2 3 2 01 1 1, I 1 3 i7 383 atypical nuclei. Additional information was also recorded - for example, the f nding of mitotic figures or unusual cells of any sort. For purposes of this report, we use two terms. The furst is "ba'sal-cell hyperplasia" - a lesion with cilia present but with three or more rows of basal cells. All, the cells may have normal nuclei or'sorne may hawe a''typicall nuclei. The second' is "lesion with eilia absent"t such lesions lack cilia. They m'ayy be norma'!' in other respects, or they may have a few or a great - many cells with atypical' nuclei. They may or may not fit, the description' ofst~ratification: or metaplasia. Photomicrographs of'such lesions have appeared inn published reports:'" As shown in Tables 3 and 4, basal-cell hyperplasia was subdivided according to degree of' hyperplasia (i1e., a total with three or more rows of'basad cells andd those'with six or more rows of'basal cells) and also ac- cording to percentage of cells with atypical' nuclei. Sections containing a lesion with cilia absent were further subdivided according, to percentage of cells with artypicalI nuclei. All the above information was recorded and trans- ferred'to computer tape together with information on the identity of the subject (GrouplA or B);, number of' cigarettes smoked per day and' age at death. FINDINGS IN AI:L SuBJzQ?s'. Table 3 shows the findings for all of the 445'subjects (211 in Group A and 234 in Group B)n including un- matched cases as well as matched cases. The results are presented in terms of percentage of sections con- taining lesions of each of'various types: Since the age distribution vaciedl in different amount-of-smoking categories, the percentages were'standard'ized, for age on the age distribution of'all the subjects in the study. 8aeal1CeII Hyperplasia As shown on the first line of Table 3„ in both Croup A (1955-1960) and Group B(r270,1977) the percentage of sections withibasal-cell hyperplasia was far higher in cigarette smokers than, in nonsmokers and increased with amount qf' cigarette smoking, Among nonsmokers,, Group A had somewhat fewer sections.with basal-cell'hyperplasia than Group B (3.8 per cent vs. 5.8 per cent). Among cigarette smokers the percentage of'sections with basal-cell hyperplasia was higher fbr Group A than for Group B. Relatively few sections had a, basal-cell hyperplasia to the degree of six or more rows of' basal cells. The percentage of sections with this finding,increased with •amount of cigarette smoking, and among, cigarette smokers, the percentages were far higher in Group A than in Group B. The next fbur lines in Table 3 show the percentage of sections with lesions defined as basal-cell hyper- plasial further classified according tio the proportion of cells with atypical nuclei. Basal-cell hyperplasias with as many as 110 per cent of the cells having atypicall nuclei were rarely found inisections from nonsmokers.

e ~; but were found in a large proportion~of'sections from cigarette smokers. The' percentage of sections with such' lesions increased with amount of cigarette smok- ,ing, and among cigarette' smokers was greater in, Group A than in Group B. Basal-cell hyperplasias with 70 per cent or more of the cells having a2ypicall nuclei were found in none of: thesections from nonsrnok'ers and in only a very small proportion of the sections from Group B cigarette. 'smokers. They were found in 0.1 per cent of sections from, Group' A subjects who smoked one to 19 ciga- rettes a day, in 12.2 per cent of sections from Group A subjects who smoked 20'to 3'9 cigarettes a day andlin 66:6' per cent of Group A subj ects who smoked 40 or more cigarettes a day. . . Lesions with Cilia Absent Sections having,lesions with cilia absent were found more frequently in, cigarette smokers than in non- smokers and increased in frequency with amount of' ; cigarette smoking. They were fbund''' more frequently in' sections from Group' A cigarette smokers than in sections from Group B cigarette smokers. Lesions lacking cilia and wit'h, 10 per cent, or more of the cells having, atypicall nuclei were found in 0 per cent of the sections from Group A nonsmok'ers and in <0.1 per cent of the sections from Group B non- smokers. smok'ers. They'were found in an appreciable percent.- age of' sections from cigarette smokers, and the percentage increased with armount, of' cigarette stnok- 109:.+ aalls'with atypinnnuclci -. •Tab1e 3. Percentage of Sections with Each of Several!Categories of Histologic Change, Classified Aecording, to Smoking Basal-csll hyperplisir. ~ : Total _ i 6+ rows 30%+ cells with atypical inuelei SO'8r:+ cclls with atypictl nucld 70%+ cella with atypical nuclei THE NEW ENIGLrluliD JOIJRD1n1L OF NtED'tt:IIYE Feb. 22, 1979 '~'r Y ing. Within each smoking class, more such lesions were found in Group A than in Group B subjects. Lesions lacking cilia and with 1100''per cent ofthe" s cells having atypical nuclei were foundlin none of'sec- tions from nonsmokers. Among, Group A cigarette smok'ers; the proportion of sections with such' lestonr rose with amount of smoking from 2.6 per cent (one to 19 cigarett'es ~ a day)~,. to 13~.2~ per~ cent (20 to, 39 ciga- rettes a day) to 22.5 per cent (40 or more cigarettes a day). Such lesions were found far less frequently in sections from Group B cigarette smokers but rose from 0.1 per cent (one to 19' cigarettes a day) to 0.8 ''.' g per cent (20 to 39 cigarettes a, day) to 2 2 per cent (40 . or more cigarettes a day) (Fig. 2). Four, of the lesions with cilia absent andi with 1100' per cent, of the' cells having atypical nueld' gave evidence of invasion (i.e., very early bronchial carci- -',l noma). Three of'these sections were in the Group B> subjects and one was in a Group, A subject. FINDINGS tN i1r1XTCHE'D PAIRS In this study, 364'of the 445 subjects were matched in pairs according, to age at death, but it is possible that the inclusion of 81 unmatched cases could have introduced some bias in comparison of findings in Group' A vs: Group, B. To avoid'! such bias, we under- took a matched4pair analysis confined to the matched'' subjects: Table 4 gives a summary of findings ineach of twoo sets of mat'chedi pairs: the 46 matched pairs of non- Habit:•' A'D/tnTto ~~ . ADNSTeD \tvan~sMoKm. S.MOCaD 1-191 RtastJ.at:r GwaEmTS/ DAr 7 kn.- . ADiusrto S ADrtnnn. % . SKO:ec -,0-39 S4ohw 40+ GwRrrrea/ GwriTTU/' OAT DAY A 8 A 8'A f. A 8. 3.81 5.9 ' 87.8' 63.11 93;2 76:2. 0 0.1 2.1 0.4 5.7 0.5 0.1 03' 87,6' 62.4 93.2 75:0' 01 0:A 77.2' 53.9 92.6 7II:5 0 0.1 56.7' 9.6' 8,t.1 26.3 0 0 0.1 0 12Z 0:1 ~ 0 Ls:ion with cilia abscnt 98:8' 86.3 13.0 0:8 98.8 86J 98.8' 85:1 98.6 56.1' 66:6' <0.11 Totall 53 4.2 118 8:8 22.5 10.i3 ~ 30.3 11.7 ' I0R,+ cells with 0' <0.1 13.8 8!S 22.3 9:8 30.3 1'1.7 atypical nuclei 30'7e+ ceits with 0 <0.1 12.9 7.6 22J 9.3 30.3 111.7 atypical nuclei r~ 10Si+ ceils with 01 0 10.0 2'? 21.9 6.0 -' 30.3 9.3 ' atypical nudei' 70qi+ celli with 01 0 2.6 0.11 14.6 0.8 28.6 2.2' atypical nuctei' 100% colls with 0 0 2.6 0.7 131' 0.8 22.3 2-1 ' atypialinuclci' Mo: of seetions No. of subjacts 2,:80 2.623 2~~,208 3,026 2:$S I I - 3:47I 57 53 S'II 61 68 73 1,413 35 2;217 47 •'Peteenu8eaadjustedforaptotliedianbuuono(a{sudc.thotalllsubjsasinilhestudy.Adsnotusubjaets.hodiedi nI9S5-19Mt;t8 subjaxs wheidied ie 197tk1977,

Vn1: 300 \o. 8 S\lOK211G 'A.`DI BRONCHIAL CHANGES -AL'iER'BiACH ET'AL 385 !,~Table 4. Comparison of M'att:hed Pairs of Subjects for Each of Several Categories of Findings: 46 Pairs Who Never Smoked ~{ , 'Reguiariy and 136 Pairs of Cigarette' Smokers. _ ~>. Fmm.e Tfnrta S.eoKla Rket twu•r Cie.am Smocas A- 8'-100R, A• 81• 0!i A-8' A>8 A<8 A'- 8-d00R A- 8'-0!f A-8 A>8 A<8. BaswGuell Ih'yperptasia: Total 0 9 0 6+ rows' 0 4i 0 Ir.+ eells with 0 35 0 atypicai nuclei 3046+cellsw'ith 0 36 0 atypical nuelei SO^e'+ ceils with' 0 43 0 atypical nuclei " 70'b+cellswith 0 46 0 uypioal nuclei Lesion with cilia absent Total 0 14 10°c'+ cells with, - 0 4~t 0 atypical nuclei 30'd+ tells with i 0 44 0 atypieal nuclei 5r.'+eelltwith' 0 416' 0 atqpical nuclei 70%+ cells with 1 0 46' 0 atypical nuciai I001ioccllrwith 0 46' 0 atypicai nuclei 100=collswith 0' 46 0 aty'picrl nuclei & invasion, •A daaoce+ wbjaus who dicd in 19b3+1960, A' B subjects who died in 19741977. l _. k ` ' smo ers and the 136 rs of cigarette matched pai smokers. Each subject was classified according to the percentage of' his 20 to 55 sections that shonved! a par- ticular change. This figure could vary from 0 to 1000 per cent. If all the sections oE both subjFcts showed that particular change, this pair was entered under 'A=B=100 per cent. If none of the sections in' either ". subject of a pair showed' a particular type of change,, r' this'pair was entered under the heading,A=B=0 per cent. Otherwise, if.the samepercentage'was found in. Group, A and Group B, this observation was entered under A=B'. If the A subj ect, had more changes than the B subject, this fact was entered under A>$. If B had more changes than A, this increase was entered under A<B. Nonsmokers For basal-cell hyperplasias A>B' in 118 ' pairs and A<B in, 1'9 pairs, and' for lesions with cilia absent, A> B in 15' pairs and A<B' in 1'7 pairs: Very few of the sections fromi the nonsmokers had' lesions with as many as 10 per cent or more of the cells having atypical nuclei. However, atypia was'somewhat more common in Croup B' than in Group A. For example, in the category, "basalLeell hyperplasia with 30 per cent or'rnore of the cells having atypical nuclei,'" A> B' in oniy one pair, and A<B in nine pairs. This dif- %rence between the two groups was not sufficient to (J.iraav a firm conclusion that the frequency of atypia in the' bronchial epithelium of nonsmokers increased with time from, 195'5-196& to 1970-1977. 16 19 6 0 0 112 18 0 2 0 52 0 72 12 2 9 6' 0 0 112 Iit 1' 9 6 1! 1 108 20 0 3 1 7 0 122 6 0 0 0 ' 6E' 0 47' 1' Cigarette Smokers For basal-cell hyperplasia, A>B' in 112 pairs and A<B in only 18 pairs, and for lesions with cilia absent A>B in 92 pairs and A<B' in 42 'pairs. These dif- ferences were statistically signi'ficant6 A large proportion of the sections Erom the cigarette smoker had lesions with 10 p'er' cent or more of the cells h'aving, atypicall nuclki„ and' atypia was more common in Group A than in Group B. For exampde, in the category "basal-cell hyperplasia with 10 per cent or more of cells having atypical nuclei," A>B in' 112 pairs and A<B in, 1 8,pairs; in the category"le- ~' xs~ 20' ~1, 15 0 0 0 2`~o_i A 81 A B gNEV~EgRp SM'OqK~EOx REGULArZLY tA PtMY 0.8 " B A SMOKED hI P~1_cyX3 Figure 2. Percentage of Sections withi Advancedl Lesions (Cilia Absent andiAll Nuclei Atypical) According to Smoking Habit imGroup A(1955-1960 Deaths) and Group B(1!970-1977 Deaths). The 95 per cent confidence limits for these percentages are as follows:' <1 pack, A 1.9-3.3. B 0.0-0.2: 1-2 packs, A 11.9- 14.5, B'0.5-1.1; andi2+ packs„A 20.3-2+4.7, B 1.6-2.8.

THE NEW ENGt11ND JOURNAL OF \'tEDICINE' sions with cilia' absent and 10 per cent or more of the cells having atypical nuclki," a'>B' in 93 pairs and' A<'B in 40! pairs. These differences were statistically significant. More' advanced lesions were found' far more frequently in Group A than in Group B. For ex- ample,, im the category "lesions with cilia absenr and 100 per cent of'thecells h'aving'aty.pical''nuclei;"A>'B in 84 pairs and A<B in only fiire pairs. In examining the thousands of sertions from cigarette smokers,,.+•efound just two eputhelial'lesionss of microscopic siiewith evidence of invasion of the un. derlying' tissue (i.e., very early carcinomas). One of these was in a Group' A subject and the other was in a Group B subject. Because of their very small size, they had' not been found at routine autopsy. DgscusszoN As described abose,, histologic changes of various sorts were found far more frequently in the bronchial epithelium of cigarette srnokers'w,ho died in the period 1955-1t?60 than, in those who died in, the period' 1970- 1977: The changes ranged from slight basal-cell' hy- perplasia withifew if any cells having atypical nuclki too lesions with cilia absent and a'lll the cel'ls having, atypical nuclei. Basal-cell hyperplasia, a reversiblk change, is pre- sutnably a reaction to some de!t:terious' factor; it is~ probably protective rather than harmful. Loss of cilia, a reversib'lechange, presumably results from the pres- ence of some deleterious factor; it is harmful' in that it destroys one of the mechanisms by' which foreign : material is ordinarily removedl from, the lungs. In our opinion, the occurrence of atypical nuclki is the first definite step along a road that' may eventually lead to carcinoma in, situ and from there to invasive carcinoma. This'statement is not to imply that all cells Ty with nuclei havec pttial th is , atypical neoplastioen;ere evadence" that lesions containing a great many ~ atypical cells are still generally reversible. Epitheliali lesions consisting, entirely of cells with atypicali nuclei (and lacking cilia) are nt-oplasrns by definition. Perhaps all such neoplasms, or~ perhaps~ only some of'them, have the potential of invading un- derlying tissues at some later date. Thosewirch suchah potential may properly be callkd carcinoma in situ. Presumably, the neoplasms in which atypia appears to, be most extreme are those with the greatest poten+ tsal for invasion. However, t~hisopinion is~ based upon _ subjective impressions rather than upon conclusive evidence. We are strongly of the opinion that the patho- genesis of bronchogenic carcinoma is a continuum starting' with the occurrence of a few cells with atypical nuclei, the number of'such cells gradually in- Feb. 22, 1979 creasing until all those in a small mass have atypical nuclei„ and from there some' eventually invading un- derlying tissue. At every step' along th'is' road, the process is reversib'le.' There is even evidence thatt some invasive' carcinomas may' disappear spon- taneously, though this is probably an extremely rare event.'= Alllthe evidence suggests that the'progression~from. a' few cellls' with atypical nuciei to lesions consisting entirely of cells with atypical nuclei' (neoplasms) oc- curs over a period of' many' years; it seem likely that carcinoma in situ usually'remains in situ for a, long time before invasion oceun: If so, the decline over time in the proportion of cigarette smokers with large numbers of atypical nuclei in their bronchial epi- thelium should presage a decline in the deathirates of' cigarette smokers from lung cancer at some' future date. The evidence from this study is consistent with evidence from epidemiologic studies'•1D' indicating, that: death rates from lung cancer are lower among men who smoke low talr/nicotine cigarettes than among men who smoke the same number of'hi'gh tar/' nicotine cigarettes per day, and with the fact that dur- ing the last 25' years, there has been algreat drop in thee tar and nicotine content of the smoke' from cigarettes consumed in the United States. R>:remNcFa 1. Auerbach O: Stout AP. Hammond EC, et ab Changes in bronchial epithdium in relation to ci;arette smoking, and in relatioa to lung cancer. N Engl J I Med 263:253-267; 1961 Z Auerbach o; Stout AP, Hammond' EC, u a17 Changes in bronchial epithelium in,relation to sea, age, residence,,smoking and pneumoniy ' N EngIIJ'Med:67:1'111-11d, 1962 3:, ATierbach O. 5tout AP, Hammond EC, et al: Bronchial epithelIum in former smokers. Nl'Engl J Mod 267:11!9-12Si 1962 4. Hammond EC„Horn D: Smoking and death rates - reporTon fony- four months of follow~up of1'37,783 mea.lrAMA 166:1159-1'172,•,I'29X- 1308. 1958 S5. Report of the Advisory Committee to the Surgeon General of the Public Health Sarrica Smoking and health (DHEW Publication No. 1103). Washington. DC. Government Printing Office. 1964 6 Kah'n,HA: The Dortt study of smoking,and mortality, among U.S. veterans: report on eight' and one-half'years of' observation: epi- demiulogial study of cancer and other chronic discases: ,llatl!Cancer Inst Monogr I9sl-1'2b4 1966 7. DoII R, Hill .AB: Morulity in,relation to smoking:, ten _vearsl'observa- tions of British doctors. Br hlbd J I:1'399-1410. 1964 8. Hammond EC. Auerbach 0. Garfinkel, L, et al: Effects of cigarette 9. smoking,on dogs. Arch Environ Health1 ?1:741D.768. 1970 Wyndtr EL, Mabuchi K. Beattie El 1rt The epidemiology of lung, ancerr recent trends: JAMA 213:2221-2228;,1970 10. Hammond EC. Garfinkel L Sridman iH. et ali "Tad' and nicotine con- tent of'eigareue smoke in relation to death,ntes. En.iron,Res 1'2:263- 274„ 1976 11. Wynder EL, Mushinski M;,Stellman S: The epidemiology of'the less' harmful eigarette, Smoking and Health. Part I(D;H!EW Publication No. (NIIHI 76-1I221); Washington. DC. Government Printing Office. 1976 12 Everson TC. Col! WH: Spontuteous Rezr_.,sion of'Canoer: Phila- delp,hia, WiB'Saunders, 1966 i' 10105052"96`~

ti 11 716 OBSTETRICAL AND GYNECOLOGICAL SURVEY C.iGARETTE SMOKING ' AND' FETAL BREATHING ' MOVEMENTS F. A: M.a\NI1+1G AND C. FEYEFtABEt1D The Nuffreld Institute for -tYedical Rssearch, Univenityof O,rford. Ohford„E,tgJand' BriL J. Obsr. & Gynec. 83: 262. 1976I The: present, observations: were undertaken too study the effect' ini high risk pregnancies and! to detetminethe factor in cigarette smoke responsible for the depression off fetal breathing. Continuous records of fetal chest wa1C' move• ments in utero were made using the A-scan ultrasound method. Fetal breat!hing movements were measured before and after smoking two consecutive tobacco cigarettes irr. 19 women with notmal' pregna'ncies; 10 with prceclampsia; f2'with diabetic pregnancies and 6 women who were ultimately delivered of an infant weighing less than the 5'thicentile for gestational age and sex: FetaL breathing movements were present for 69;7 t, 2.66 per cent' of the time before smoking. There was a significant reduction, in the proportion of time during which, fetal breathing movements were present within 5' minutes after the start of smoking. The reduction was proeressive: reaching a nadir of 50 = 4l3'5 per cent at 30 minutes (Table 1). Recovery was not complete until 90 minutes after the onset of smoking. The mean plasma nicotine concentration before smarkin¢, was 2.6 *: 0.6' ng./ml. By the time the next:sample was taken (90'seconds after the second cigarette was finished)~ there was a highly significant elevation ir. plasma nicotine to 15.1 * i ng./ml. The conccntration felt over the nexthour it was still above control'values 60 minutes after the end ~ of smoking (g.42' * 13' . ng:/ml.j significant correlation was observed be- tween the rise of plasma nicqtine after sntoking and the fall in the amount of fetal urcathing movements~' The mcau carboxyhem'og?oLin con- oentration in 13 womcn with normal pregnancies rose from 1.64 * 0.38'percentbeforc: smoking'to 2.74 * 0.31 per cent at' 30~minutes after the end of smoking. ln 10 women with precclampsia tQtere was no signilicant reduction imfcta'1 breathing after smok- ing (Table I'). The plasma nicotine concentration before smoking, was 1.7 t 0:5 ng./ml., similar, tw the pre-smtnking value in nbrmal patients. A, significant rise to 14 t 2.3 ng./ml. was observed 90 seconds after the secondI cigaret'te was smoked. ~ The levelithen fell progressively over the next hour. it remained significantly elevated at 60' minutes~~. TABLE 11 Fetal breathins movements in normal'and abnormal'prcgnancits before and nftersmoking tobacco cigarettes Proportion of time that fctai'breathing movementrwerrpresent (per cent) Mean * SE Time, Normal pregnancies (n - 19) Pre-eclampsia (n - 10) • Diabetesv (n - 12) Smail-ftirr dates (n - 6) Pre-smoking control 69.7 = 2.7 77.2' t 31 74.8 * 2:8 56.0 * 6.8!1' 5 minutes smoking 59 . 4'• 70i0 t 41;'5 66.5 * 5 40.2' * 1Z:4 l01minutessmoking 58'•3 _ s.6~ 63:8 t 7.24 66.0 t 5:3 34.6' ~ 12"' 15 minutcs smoking 56.6 = 5.6" 67:3' ~ 5.9 56.2 t 6' 24.6 = 111 L4's 301minutes SO _,4.351'• 71.3 6.2 :2 59.7 7.8 8 35.0t,1+42 .0 . 45 minutes 53.9 3 5.6' 73:8' t 4 70:8' t 4.5 40l0 t 8 60iminutes 59.8 = 4:6' 63:8' ~ 6.5 59:1 t 6.,1tJ'• 56.5 *, 7.7 75'minutes 54 s 5.1•' 74L7t:6',lD, 73:6t 3.5 57 * 10.4 90lminutes 64.7 = 5 • p < 0.05 as compared to control. •• p < 0.01 as compared'.to control. t p < 0.001 as compared to the norrnal' pregnancies., 100S0S2ngg .... _.~_ __...._... ., .....~ --- -_. . P v 'C-,

(_~) MANAGEMENT'OF'NORMAL PREGNANCY. LABbR ANO PUERPERIUM The, pre-smoking blood' sugar levels were ! signifi- eantly greater in the preeclamptic patients.than in the normals. There was a small fall inibloo&sugar observed after smoking. - The proportion of time that fetal breathing, movements were presient before smoking in 12, diabetic women was 74.3 t•2.8 per cent. After smokine there was a fail in~ the amount of fetal breathing which, reached statistical significance 15 and 60 minutes after the onset of smoking (Table 1')•. The mean plasmanir,.otine before smoking. 3.2 * 0:75 ng:/ml., rose to a peak of 18.6' * 2.2' ng./ml. at' 90 secondfr after smoking ended. It feff C gressively over the next hour, remaining sig- antly elevated above control values at 60 minutes. There was a, significant correlation be- tween the rise of plasma nicotine after smoking, and the fall in tht: amount of fetal breathing. The mean blood sugar before smoking,was 101.2 t 9.5 mg./dl..,signiGcantly higher than thrpre-smoking levels in the normal group. There was a faU in blood sugar aftKr smoking. In fetuses subsequently identified as small-for- dates, fetal breathing movements were present, for 56.0'* 6.8 per cent of the time before.smoking; significantl'y.less than the pre-smoking values in th( nna4 the diabetics and the preeclamptics: There was a progressive fall in the amount of fetad breathing within five minutes after the onset of smoking, to reach a nadirat, lS minutes. Reeovery was complete by % minutes, (Table 7'1'7 I). In 1 of 5 fetuses,, 10 minutes after the onset of smoking,. intermittent low frequency (10 to 15 minutes)) large amplitude chest wall movements apliearedd interspersed among normal fetat breathing move- ments. The plasma nicotine concentration rose to a peak of'1'7:3 * 1L8 ng./ntl: 90!seconds after the second!cigarette was smoked and then fell progres- sively overthe nezrhourt It remained significantly elevated at 60 minutes. There: was a signi'ficant relationship between the change, in plasma nico- tine and! fetal breathing during, smoking. No sig- niGcant change in blood!sugar was observed after smoking. Sinoking non-nicotine~(herbal)~ cigarettes pro- duced increases in carboxyhemoglobin concentra- tions similar to those observed after smoking, tobacco cigarettes, and was not associated with.a fall in the incidence of fetal breathing movements. Chewing,gum containing,nicotine produced riserin plasma nicvtine concentration similar to those . isbserved after iirnoking tobacco cigarettes andlwas associated with a significant reduction in the incidence of fetal breathing movements. Hence nicotine appeared to be the factor in cigarette smoke responsible for the reduction in the inci- dence of fetal breathing movements. Nicotine was present in the cord blood of infants whose mothers smoked. `jC ;:,(1lytore scientific evidence isaccumul'ating,to prove that nicotine is harmful to the developing fetus. Apparently nicotine causes a, decrease in uteroplacental circula- tion which results in snraln-infants-for-gestatimnal-age. ~ The work of'Mannin&and Feyerabend shows that fetal breathing is reduced soon +' after a mother smokes a cigarette., The reduction in rate! of fetal respirations per minute a!ppears not to be related to int:reaaed'rnaternal levels of ca~rboxyhemo} globini so com!mon in cigarette srnokers but, is caused, by nicotine in maternall and 'fetal bloods. The American Academy of'Pediatrics has recently sent an officesign, to all of its members~ so that each can post one in his reception, room which, reada "For the Health of Our Children, Please Don'r Smoke." Obstetricians could weili post the same sign in their offices: The Comtrtittee on Environmental Hazards of the Academy has published an editorial in Pediatrics. 57. 411, 1976; which details the many hazards of smoking by the mother and byothers.tolthe developing fetus. It is thought that maternal smoking adds~ not only to the increased incidence of small-for-gestational>agc infants but causes increased fetal wastage (Report of aV1/'HO Committee:~ Smoking and Its Effect on Health, Technicali Reports Series 568, Geneva, WHO, 1'975). Second handd smoke inhaled from the smoking of others is also a hazard to health. S. Harlap and A. M. Davies found' tHat infants of mothers~who smoked had i

~ ,~ 718 OBSTETRICAL AND G'1"NECOLOGICAL SUFtVEY signif0cantly more admissions to the hospital for bronchitis or pneumonia diaringg the first year of life'~ than did children of non-smoking mothers (Lancet, 1: 529, 1974)l =Iga ' Last but not least, it has been shown that children of smoking parents smoke eariierand,' more frequently than children of nonsmoking, parents(IliliealtihServidcs~+t ;' and Mental Health, Administration: Teenage Smoking: National' Patterns of Cigarette Smoking, Ages 1'2-1B, in, 1968-70, Rockville, Maryland, publication (HSM) 72-7508, 11972'). It has been my expcrience that most pregnant women can be encouraged to cease ; smoking for the benefit of'their children. Obstetricians now have the scientific infiormation available to explain to patients why smoking is harmfial'tolmotheran3 ~' child and should' include this advice in prenatal care.-Ed.)

SECTION 5

&umar, R.; Cooke:, E'.CL; Lader, M.H.; Russell, M.A.H., Is Tobacco Smoking a Form of Nicotine.Dependence? In: Thornton, R.E. ('Edi'tor). Smoking Behaviour. Physiological and Psychological Influences. Edinburgh, Churchill Livingstone, 1978, pp. 244-258. In order to determine whether smoking is a form of nicotine dependence two experiments were performed. In the first experiment the doses of nicotine were given by inhalation of tobacco smoke and in the second experiment, aboutt a month later, roughly comparable doses of nicotine were given to the same subjects by intravenous injection. The dependent variable in both experi- ,ments was the amount and rate of ad libitum puffing at medium-strength, filter-tipped cigarettes (nicotine yield 1.3 mg - normally extracted by about L01puffs) during the three 40-minute sessions which followed each dose:. These cigarettes were regularly replaced, therefore a lit cigarettee was continuously available to the subjects. Smoking behavior was monitored by a pressure transducer connected to the cigarette holder which gave a continuous record of the number of puffs taken and 'the interpuff intervals. In addition, the duration and depth of each puff gave an estimate of the. .vol'ume of smoke sucked through the holder. Various physiological measures (i.e., heart rate, skin temperature and conductance, electroencephalogram (EEG), were also continuously recorded. The subjjects were 12 paid volunteers, seven male and five female, aged between 24 and 38 years; all the subjects were moderate/heavy cigarette-smokers (between 25 and 60 cigarettes daily for at least two years previously). Inhaled "doses" of smoke systematically postponed and reduced subsequent puffing and this was a function of the content of the smoked doses. The intravenous doses were without effect on smoking,behavi'or. -However, the physiological tests sbnwed that the . doses of nicotine clearly modified the heart rate-and the EEG with comparabTe effects in both experiments. These negative findings re-open. the question of whether physiological dependence on nicotine is the basis for the tobacco smoking habit,

19.1s tobacco smoking a form of nicotine dependence? R KUMAR, E C COOKE. M H LAIDER ANO M A H RUSSELL Inrtrod'uctlon The pharmacologicalibasis of the tobacco-smoking habit remains surprisingly obscure, although it is generally assumedi that nicotine plays sorrte part in this bizarre and widespread!compulsionto burn dried leaves. An average-strengCh cigarette: delivers slightly over l mg of nicotine in its mainstream smoke, most of which can be rapidily, . absorbed into the blood-stream following inhalation (Armitage:eta4 1'975),. Such 'smoking doses"of the alkaloid produce many effects in the brain and peripherally ('Agwe, 1i974;,Brown, 1973; Coffman, 1969; Friedman, Horvath andMeares, 1974; Russell, 1'976);, but the:psychological actions of nicotine arevariable and there is oniycircumstantial evidence that tobacco-smoking is a form of nicotine dependence. Smokers can partially regulate their intakes of nicotine whenofferedicigarettes of varying strengths (Ashton, and Watson, 1970;'Finnegan, Larson and Haag, 1945; Frith, 1!971; Turner, Silletrand Ba11, 1'974),,,but other constituents of'tobaceo smoke such as tar, covary in arrtount with nicotine (Atussell eta{,1973), and factorssurh as the taste and 'quality' of the smoke can markedly influence the amounts of smoking, (Goldfarb, Jarvik and'Click, 1'970). Recent tests (Goldfarb cral, 1976)'inwhich tar and nicotine yields:of cigarettes were independently varied do, however, ilnplicate nicotine as a reinforcer of smoking. This view is also supported by the observation (Stolerman et a4 1973)~that smoking,inereases when subjects are given mecamylamine, whic4 is, among,ot'her things„a central antagonist of nicotine. Other evidence for the nicotine hypothesis comes frocnistudies of the effects of nicotine-eontaining chewing-gum upon smokirng~(Btantmark, Ohlinand Westling, 1973; Kozlowski, Jarvk and Crdtz,,1'975),, but'the most direct tests have been done with injected doses of t'he drug.. In 1942 Johnston commentied'i that when habitual smokers were gii+en hypodiermic injections of nicotine they `almost, invariably thought the sensation pleasant, and,, given an adeqtaate dose, were disinclined to smoke for some time thereafter'. The same aut'hor, also injected'himself repeatedly with nicotine and came to prefer the injections to inhaling cigarette smoke; he1ater experienced feelings of deprivation when the injections were discontinued. Thesearc all hallmarks of a dependence disorder and it can be argued that habitual smokers are physiolosically dependentt upon nicotiine and, that they repeatedly self-administer this drug in order to ward! off the onset of withdrawallsymptiorns: There is some evidence fora nicotine-abstinence syndrome compr~ising psychological responsessuclias craving, tiension, irritability, restlessness, impaired!attention and performance, as well as a number of minor 244 1005052973

IS TOBACCO - SMOKING A FORM OF NICOTINE D'EPENDENCE?' 245 cardiovascular and neurophysiological changes (Finnegan et al, 1945', Hail et ai: 1973; Knapp, Bliss and Wells, 1963; Uletr and! Itil, 1970). There seems to have been only one studyof the effects of intravenous dosesof nicotine upon smoking behaviour. This is one of the most direct ways of examining the possible reinftbrcing,actions of the drugand t'heexperinnents were done by Lucchesi, Schuster and Emley (1967) who demonstrated small, but significant, redltctions in the numbers of cigarettes smoked following continuous slow intravenous infusions of nicotine bitartrate: In order to try and confirm these fitndingsand extend the assessment of the role of nicotine in smoking, we devised a laboratory test which permitted the continuous and!automated recording of'ptrffing and also of severall physiological measures. The units!of ineasuremenrwere thus obtained from individual puffs rather Uhan'from counts of cigarettes that were smoked. Because nicotine has a relatively short hall life (iBeckett; Gorrod and Jenner, 1971; Isaac and Rand, 1'972), it was possbie to examine the effects upon smoking of different doses of this drug during,a single: session. An important feature of the design of the study was that it covertly reduced'the possibly over-riding,influences of the habits an& rituals of cigarette smoking. Somewhat unexpectedly, our results do not, support' the hypoth- esis that smokers are dependent upon and hence need regular doses of nicotine. Methods . Subjects Thesubjects were 12 paid vohrnteers; seven male and five female, aged between 24 and 38 years; theirweights ranged between 44 andi83 k:g, They were all screened as fit on the basis of a medical history and physical check, including,ani electro- cardiogram. All the subjects were moderate/heavy cigarette-smokers; they reportedl smoking between 25 and 6®' cigarettes daily for at least two years previously: Count!s of smoking during three days before one of the!tests confirmed these estimates. Procedrrre Each subject was required to attend the laboratory three times. The first, occasion was for famiiiarisation with the apparatus and': procedure and with the `ainrts"of the study. The actual purpose of the.experiments that were to hedone was concealed and the subjectswene told! that'habituation' ofsevtiral important, -physioloeical measures differed in smokers and non-srnokers. It was:explained thatthese measuress had never been recorded while subjects smoked'norinally', nor had the effects of intravenous nicotine on: habituation been studied'inthis way. They were toid! that, in order to obtain adequate recordings from the various electrodes, they would not be able to move about freely, nor to light nor handle cigarettes. In order to circum- vent this probiemia shieldedl holder. containing,a permanentiy lit and regularly replaced cigarette, would!be placed very near their mouths while they sat in a comfortable chair for the duration of each experiment (approximately three-and'-a- hallf hours) in a smailsemi-isoiated test room. They could thus take a puff whenever they wanted. All subjectrwere asked to bring their own reading,matter: A glass of orange drink would be available tltroughout. Excessive hand movements would bee discouragedl as wetli as conversation. It was ex'plained that during the first experiment they would be asked atl intervals to take a number of deep puffs, so that their'habituation' responses to thesecould

246 SMOKING BENAWIOtIR' be compared withithe results of the second test ai few weeks later when, instead of puffs, they would receive pulsed injections of corrtparab9e doses of nicotine through an intravenous infusion which would be running into an arm vein through- out the session. The final requirement was that they shoulditake a total of nine grammes of enteric-coated tablets of arnmonium ehlbridie at set intervals duringg the:24 hours preceeding',each of the!twoltests. The importance was stressed'of acidifying the urine to reduce variations in t'hturitoary excretion of'nicotine; a weak base (Beckett et ai. 1!971): There were no restrictions upon the subjects' smoking or diet prior to the tests. Dn+gs' The plan of the two experiments is outlined in Figure 119.1. In tihe first experiment the doses of nicotine were given by inhalation of tobacco smoke and inithe second experiment, about a month later, roughly comparable doses of nicotine were given to the same subjects by intravenous injection. Two doses o'f'the drug and a control were tested in each experiment; the order: in which they were given to individual subjects was counterbalanced according to a Latin square design (Cochran and Cox, 1957). No r.Nriofiam an rmoklng' tiyl+f, IYndi Urine acidU'wd' pNt'3r5' oeso aar. oe.o ch.akliil ch.cklilr ch+.ckti+t dt.cklist t°m I 1 1 t +Y Ad smok:q ~ . ~ra+ li EMO 40 mins 40 m.na 40 1 miiu 40 M.r I 1A.arurfTfntM1.. Siee4inq: Rr.pu.ncyof'puttiny, I6t.rvala b.rnv..n puffr Aunplilud.e o!' pyfhs phy.iokapical: Shin condwctanc. Shin t.mp.rarvr., W.arr rat. IECGI EEC'.' : a' wore bonds hTclwlo9ico1; . Ch.okliu5 of' mood and bodily. ,pmploms Figure 19.1 Sum'mary, of'the~ proced~ure~~ ad'op~tc:,d,fo~r bothiex~per~im~~entY~~ Experirrtent 1 The independent variable was iithaVed smoked', containing three 'doses' of nicotine. Each dose consisted of 12 deep puffs that were inhaled and held, for 3-5 seconds; the puffs were spaced at' one-minute intervals. Dose '0' consisted of u puffs at'a nicotine-free, herbal cigaretrce, and! dose `2"was 12'puffs at the equivalent of a strong,cigarette (six puffs from eachlof two sm'all'i cigarettes with a machinesmo'ked delivery of 1.3 mg of nicotine • the totttl!intake was thus about'2.brng)', The intermediate dose "U''wasobtained b~yalternatin& puffsat the herbal and: the st~rong,cigaretrce. In all cases, immediately after the last puff of

V_ n r TOBA'CCO-SMOKIIVC A FORXOF NICOTINE D'EPENDENtCE?', 247 eachidose had beenitaken,,a med'aum-strengt'h cigarette was placed in the holder and the subject was told he could resume puffing whenever he wanted. Experiment'3 The procedure for ad ldbrtum puffing,remained the same; but here the doses were administered by intravenous injections through, a saline infusion whir:h ran continuously into an arm vein. Each dose was made upin distilled water oo a wlume of 50 rnL and was given in ten five-second pulses'(5 mil)'at one-minute intervals. The injections into the infusion were made via a two-way tapisituatied behind the subject and each -'bolus" was flushed in by the infusion, thus ovcncoming,'. possible errors due to the dead space. Dose '0' consistiedlof distilled water alone,, dose `7"contained 0:035'mg lkg of nicotine bitartrate in distillediwater, and dose '2' contained 0:07 mg.lkg. of nicotine bitartrate. Thus, dose'2' for a 70 kg: man comprised'an absolute amount-of nearly 5 mg of the bitartrate, which is equivalent to about 1.7' mg of the alkaloid. The subjects were allowed to puff whenever, t'hey wanted during the ten-minute periods of intravenous dosing. Measures of smo king behaviour The dependent variable in both experiments was the amount and rate of ad labrtum puffing at medium-strength, filter-tipped cigarettes (nicotine yield 1.3 mg - normally extracted by about tien!puffs) during theithree forty-minute sessions which followed each dose. These cigarettes were regularly replaced and thus a lit cigarette was continuously available to the subjects. Smoking behaviour was monitored by a pressure transducer connected to the cigarette holder which gave a continuous record of the number of puffs taken andlof the intier-puff intervals. In addition, the duration and depth of each puff gave an estirnate of the voltune of smoke sucked through the holder. Calibration tests with known volumes (range 10-50 m1l), confurmed! the: validity of the volumetric:estintates: The amounts of smoke actually inhaled could not be measured. Physlological'rneasures 1 The~foilowingmeasures were recorded cpntinuous~ly.. Heart rate: wrist'and ankle: electrodeswere usedL Skin temperature: a.therrrtistor was strapped to the middle finger of the! dominant•'hand. Skin conductance: the recording and earth electrodes were attached to the thumb and forearm of the non-dominant hand and,measures of'basal conductance and its variance (an estimate of the flwctuations)were obtained. EEG: two scalp leads (vertex and left parieto-temporal)were used and t'he output was analysed via broad wave-band filters. The mean recti'fied! i'ntcgratcdl vnltage of the EEGIin the 6„9 , or and y wave-bands was recordcdl cuntinuously (i.e. 2.3-4.0 Hz; 4.04.5 E9z; 7.5-13.5 Hz; 13.5 -26L0 Hz respectdvely):. The physiological measures were averaged over one-second periods and then further processed by eomputer (PDP1?) and stored on tape together, with the smoking scores. Polygraph recordings of the ECG; skin conductance and'puffs.wene also taken. Prychological measures Linear analogue scales (Bond' and Ladt:r, 1974) covering a range of it'crns currespunding 1oo5o5291476

248 SMOKING BEHAVIOUR to mood! and to somatic symptorns of'anxiety were administered twenty minutess after the start of the experiment an& twenty minutes after the endlof each dose of' the airug; these were completed by the subjects within two to~five minutes. Analysis of resulrs The scores for puffing and for the physiological measures were fust averaged over ten-minute blocks and this gave four consecutive scores for each measure after every dose. Multivariate analyses showed thaU the scores for the first ten minutes after the inhaled doses ('Experimea 1) were significantly different from, the scores over subsequent ten;minute blocks and it appearedl that the main effects due to doses had occurred' during the first ten-minute block. Further analyses of variance.were then done on the data for the first ten minutes after the doses iniboth experiments and also for selected measures that were taken during the times that the doses were being given (12 mihutes.in: ExperimenU I and tenmirtutes in Experirnent 2). Results and discussion Figure 19.2 illustrates segments of the polygraph, records for two of the subjects;; it shows how, once they had settled down, these subjects tended to pufl"in a regular way. Subjects differed considerably between themselves in their rates of puffing, but, individual rates tended to remain broadly stable during the test session. Further- more, there was a relatively good correlat2on between the overaDl rates of puffiutg by individlual subjects~across the two experiments which were about a month apart (r = 0.66 df 10 p <0.02): These puff-by-puff recordings are reminiscent of behavioural research into drug dependence in anirnala where drugs may be self-administered according to simple schedules of reinforcement. In this study the schedule canibe described as fiiced ratio - 1, i.e. one response (suckutg,at holder) producing one reinforcement (dose of smoke). It was not possible to measure the:amounts of'smoke actually inhaled and we elected'in this experiment not to disturb the smoking behaviour of'our subjects by taking repeated blood samples for nicotine and carbon monoxide estimations. Puffing and inhalation seem closely related, but our conclusions must remaut, tentative until the.method is further developed to incorporate estimates of smoke inhaledL This technique does, however, improve on studies in which either numbers of cigarettes smoked or numbers of puffs arrcounted. Estimates of the volume puffed add greatly to the sensitivity of the measures and the validity of these scores was checked by correlating them with estimates of nicotine remaining in the fiIter-tips. The falters firom Experiment 2'were pooled in batches of four correspondirtg to each forty-minute period; two batches were lost and, there werre therefore 46'possible comparisons (r = 0.88' d!f 44 p<0.00'1). The filter nicotine measures give a good indication of'the smoke that has passed througit the filter-tlp O and, this result confirms the validity of the puff voliame scores. ~ Effects of inhaled and intravenous doses of nicotine upon smoking, Q Figure.19:3'shows the average rates of puffing by the subjects after each of'three ~I doses of inhaled or intravenous nicptine. After t'he inhaled doscs (Esperiment 1) there were no overall differences during the full forty-mnnute periods (F <1)„ but (~ comparisons of'puffung scores over the successive ten-minute blt7cks shtuwed that, j

TOBACCO~-SNUOKdNG A FORM OF NICOTINE D'EPENDENCE?' 249 EICG', GSR Tim. (minsi C .. .. 7.•. . . .. ... ..__. .. ., . .. . Puffs- GSR' Tim. lmins 1 U I l D ~ l 101 , io1' .c3 104 ~oS K Iw~ W L~ Figure 19:2. Sections of polygraph records of twn: subjects, The measures in, each case are of the heart-rate, puffdng, skin conductance and a time-ma!rirer indicating one*minute intexvals. lhdividual,puffs have:been numbered on the tracings. the rates at which puffing changedi were a linear functionlof the doseswhich had, previously been: inhaled'(F = 13.01 dl' 1,20 p<0.002'). For example, there was a marked initial'reduction al'ter the 1arge inhaled dose which was then followed by a gradual recovery. RougHly comparable doses of nicotine were given intzavenously in Experirnent 2 and it can be seen in Figure 19.3 that puffing rates remain unaffected over the! forty minutes (F G1). The subjects did, however, tend to puff more frequently irrespective of thcdose which, had been injected. 10050%532978

250 SbtIOKIMG'BEHAV'IOIJR Siaek'in0afN..g inAak.d d.r.s .1 Nk.rin.(E.p.rin,.n/. II. 0 • I. a s • e f. 0L Siwskii.l aH.rintra..n.vc d..rs d N:eerin. i( E'aNr iw.nt: 21 o---o OYs. 0 ~+ Oa.. l ~-+ O.u. 2 2 3 Sycc.s.i..: kt.cks 001 10'. iwiwvrs~ Figure 19.3. Inhaled tobacco smoke deprcesses the subsequent rate of pu!f'fing in a dbse-related wa'y (Ezperiment 1) and the biggest effect is'seen during the first ten minutes. Com'parable intravenous doses of nicotine (Explcrimlent '2) do not alter subsequent rates of pufSng: The crosses, indlicate the average!nurnber of puffs taken by the subjects during the last teniminutes of the inirtial settling,down period, i.e. just before any doses were given. Smoking aPo.r inhal4dl dos.s Smoking o(t.rin/rov.nowsr dos.s of Nicolin.: (Experiment 11 of ' Nicolino (IEap.rim.nM 21 p'.____.0 •------• mis. 4'0 10 4'O. 3 i0~ X 210 C X loC 11 ~2 3' 4 1 2 3, 4 Succassir.btock's of 10 ieinvtas. Figure 19:4. The average size o'f~ each puff is'reduced by bo'th inhaled doses of'tobacclo smoke to a similar extent and this effect persists throughout the forty minutes after the doses. Intravenous dbses of nicotine do not change the size of'puffs, butAn' Experiment 2 thle subjects take much smaller puffs througholut„cven before any doses are given.(as illustrated'by the two crosses).

t. : doses of tobacco smoke the subjects took smaller puffs and this effect persisted ; The average volumes per puff are'shown in Figure' 1!9.4L After both the inhalcd - TOBACCO-S1v1oK1Nt7 A FORM OF NICOTINE DEPENDENCE? 251 throughout the forty minutes (F = 4.54 df 2,2D p<p105): The~siz'cs of the puffs that were taken, after the intravenous doses didlnot'd'iffer significantly from cach, other (F < 1), but, there was a strtking gpneral!rcductioni in the volumes per puff even before any doses were injected. 3nwk'inq elsaiekoLd dsars~ smekieaa+f/.riel.aroeeVS, dbs!.s, of Hicel7oo (E.p.rilw.n: I) - of NiceNn. (IEap.niin.es 21 nJw 700' E'. ^ 200 , e. a O. . ~CI 100 > r I i' 300 200 100 0 o ---o Dosr 0 r.--r~. Dew~ 1~. ~-+ Deso 2 2 3 4 Syec.ssi.o . bbck~s~ of 10 /einr1s Figure 19:S. Inahled doses of tobacco smoke:reduce the amount of smoke th'at is subsequently pu!ffed in a!dose-related way (ExpKriment' 1) and this effect is greatest during the first ten m'invtes after the doses. Comparable intravenous doses ofhicoaine have no eflfectupon the volumes that areipuffed,in Expernment,2: Althouighithe subjects are puiffing',more often (',see Fig. 19.3), the fact that they take smaiter'puiffs (see Fig. 1,9:4) resubts in a genKral fa/t in the volumes puffed in Experiment 2; this', difference betweenithe two experiments, whiich is evident before any doses are given, is also shown,by the crosses indicating the volumes'.pu!ffed during the',last'ten minutes of the settting-down, period. ~ The average volumes of smoke! puffed in successive ten-minute blocks are plotted in Figure 1'9,5; these scores are, in effect, the product'of the two previous measures (numbers of'puffs and volumes per puff). The i,nhaled doses reduced the vo'lumes subsequently puffed in an orderiy manner (F = 8.78 df 1,20 p<0101) and the clearest effect was seen in the first ten minutes after the doses. As might be expected (see Figures 19.3 and 19:4) the intravenous doses did not modify the amounts of' stnokesubs'equently puffed (F' <21),. The total votumes puffed were smaller in Experiment 2'inspite of the increased rates of puffing; perhaps this was a response to the more stressful conditions produced by the intravenous infusions„but a number of observations fail to support thiss interpretation. In Experiment 2 the subjects"check-iist scores showed that they were JL005052980

252 StwbxtNG 'BEHwlouR not feeling more tense or anxious or experiencing somatic symptoms of anxiety to any greater degree than in the test with the inhaled doses! The physiological measures (see below) were consistent, with the self-reports. Finally, if the altered patterns of smoking in the intravenous test had'been caused by increasedianxiety,, the scores might have shown signs of'habituation as the experiment progressed'over successive sessions of fortymartutes; this was'not thacase (F =<1, F= 1.90 and F = 1.43 dfZ,20, for numbers of puffs„volume per puff and volume puffed respect- ively). Thus, while there is no satisfactory ezplanartion for the differences in patterns of puffing between the two experiments, an effect of intravenous nicotine should, inprutciple, have been possible either through al reductzon1nthe:numbers of puffs taken or by a further depression of the volumes puffed. Pitffing during the fust ten rnirrutes after doses Since the main.etfects seemed to be confined to the first ten minutes-of each period the analyses of variance were restricted to this inirtial block and tested for dose-response relationships in the fiorm of linear trendfr. The two experiments were analysed separately, but the results obtained from within each, experiment are, however, presented and discussed side bysidie. Figure M :6 sununarises the scores for four measures of puffing which are plotted against increasing doses. In Experiment' 1 there was clear evidence: that, dqses of inhaled tobacco smoke reduced subsequent puffing in a dose-related manner: there were significant linear dose:trends for the volumes puffed'(F = 15.24 df 1,20, p40.001), the numbers of puffs(F = 6= df 1,20 p<0:025) and the volume per puff (F = 7.20 df 1,20 p<0:02). In Experiment 2, the:doses of intravenous nicotine failed, to affect the volumes puffed (iF<1){ the numbers of puffs (F<1J) and the volurne per puff (F = 1.3), df 1,20inleach case. In order to check for possible short-lived effects of intravenous nicotine the latencies to thet fusr puff afxer the end of each dose period were compared by the Friedman two-way analysis of variance; this non-parametric test (Siiegel, 1!956) was used because of the non•normal nature of the scores. Inhaled doses of'smoke signiQicantly altiered the latencies (xr2= 13.50 df 2' p 0:01) while intravenous doses were withput effect (aCr)= 1.17 df 2): However, since this was the only measure which suggested that' intravenous doses might be affecting smoking (see Figure 1i9.4); the scores were further checked by tests for linear trends following, reciprocal transformations. While inhaled d'oses systiezoatically reduced the speed' to the first puff (F = 13.19 df 1,20 p<0.002) intravenous nicotine did not (F<1). ~ Fticff¢ng during the periods of'dose administration Q The average volumes of smoke that were puffe& for doses 0;,1 and 2 were 473 ml:, Q 491 ml. and 478 ml. respectively and!, as these values did not differ significantly O (F<11), it seems reasonable to assume that any subsequent effectron smoking were due to t2ie content of the doses. ~' In Experiment 2 the subjects were allowed to puff ad.lrbirum during the ten- (M17~ minute periods of infuston This procedure was adupted because of the greater ~ likelihood of detecting very short-lasting,effects of intravenous nicotine upon ~ smoking. As it happened there were no d'ifferenccs due to the doses in any of the smoking measures, i.e. number of 'puffs(F<'1). volume per puff (F<1) and initheir

TOBi#CCO-SWOKINC h1 FORM OF NICOTINE IDIrPENDENICE" Smoking during the first ten aniinut'es after each of three doses of nicotine misi. 300 200 ~ ~ 100 0' mis. 40 - 30 ~ a E 20. a X 10 0. F----- Expt 1 Doses given by inHolotion -------- Expt 2' Doses given by introvenou,s injection tii D 1 2' Oose ~ -, '~---"---~ ----------------- No, 12 10 ~ 0 0 8 0 i 8 4~ OT sees_ 800. ~ a w 600 0 410'0 a : 200 0 1 Oose . _--r r' - .~ 0 -~ 1 2 0 1 2 Dose Dose Figure 19.6. Dose-response effects of inhaled smoke and intravenous nicotine are compared. The three doses of smoke were roughly matched ini terms,of potency with,the doses of intravenous nicotine and both are expressed on the arbitrary interval scale - 0, 1 and 2. Four smoking measures show that inhaled,doses of tobacco smoke depress subsequent ad llbitum smoking,whereas comparable intravenous doses of nicotine are without effect. Three of the measures, volume puffed, the number of puffs, and'the volumeper puiff, are presented as average scores over the first ten minutes after each dose. The fourth variable is the average delay before taking the first puff and after the end of each dose. product, totallvolume puffed during the ten minutes (F<11); the scores are shown in Figure 19.7. Had any such differences been detected, they would, of'course; have had to be taken into account in comparisons of the periods after the doses. I ~ ~ ~ I ~ Q ~ ~ ~

254 SMOKING BEHAVIOUR Mopsuro• of smoking d4rinp, tha intro..nou, in/usien o1 thr.e do.es of' Nicotine (E:ptL 21 M.on numb.r, oof pufft Mean rolum./puff: Total .olumo puffed tnlt. ml.. 10r = ]0r 200r i 4 2 o, ts 10 s u. 130 100 1 so oL 0. 1 3 0 1 2 Dos.s oF' Nicotine 2 Figure 19.7. The subjects were allowed to puff ad LiburLm during the:tcn minute periods in Experiment 2 when theintravenous,dosesi of'tf!icoaine were being,in!fused. This diagram shows that there are no very short-lhsoing effects due to nicotine. The rates of puffing, the:volum!es per puff and the total vo(umes,pu!ffed during the ten minutes when each dose was infused are very similar. Physiological rrleas~rres Heart rate: Inboth experiments the heart rate was' systematically altered by doses of the drug. Ttje average rates in the ten minutes after the'inhaled doses were 75:9; 77.2 and 79.3 beats per minute for dose 0, dose. 1 and dose 2'respectiveIy (F = 110.22 df 1,20 p<0.005). Intravenous nicotine produced very similar effects; the corresponding,awerage rates were 73.5„76.0 and 78.2 beats per minute (F = 23.85' df 1,20 p<0.000'1). These results are consistent with previous tests of the effects of'inhaled and intravenous nicotine (Ague, 1974; Coffman; 1969). Skin conductance: No dose-related effects of nicotine upon this measurewere found' in either experiment. Skut, temperanure: As a resultl of apparatus failure several measures were: lost and the remaining data were not analysed. EEG mean nectifed, integrated voltage: Inhaled doses of nit:iotine were without a clear effeet on any of the bands although there was a tendency for~ actGvityto be systematically increased by the drug both during,(F'= 2.91 df 1',2b p<D110)) andiin the ten!minutes after the dose (F = 3.37 df 1,20 p/~0.08). A similar and significant effect was seert!during (F = 5;37 df l,'_0 p<0.03) and after thedntra- venous doses of'nicotine:(F =21.0 df 1,20 p0.0002). The mean, scbres for js activity after the inhaled doses were 1.92, 1'.94 and :.07'rV andl in the ten minuties after the intravenous dose the corresponding scores were 1.57, 1.70 and'1.80,crV. The mean~! values during the last ten minutes of the settling-down periods, i!e. before any doses were given, were 1.87 r V andl 1.56rV in, Experiments l and 2 respectively. y" . ..~._.r/.

TOBACCO-SMOKINGA F©R.Vt'0'F NICOTINE DEPENDENCE?' 255 Psych'oiogfcal'measures Analyses of the!self'•••ratings made inboth~the mood check list and the anxiety symptom scale failed to show any consistent effects after doses of'inhaled smoke:or intravenous nicotine. This may well'have beeni due to the fact thatthese ratings were not made until twenty minuteshad elapsed after each dose. The ratings were not done sopner, as they took two to five minutes to complete and this,would have disrupted the principal measure, i.e. smoking. There was, however, a significant trend inthe infusion study for subjects to rate themselves as more drowsy and morerelaxed as the experiment progressed. Paradoxi+eally, they alsoreported feeling more energetic andl this somewhat complicates interpre- tation of the data. Conclusions The realiaim of the experiment was successfully conceale&and this meant that subjects puffed freely and'as naturally as possible. Intervals between lighting-up the mannerof'lighting, handling, puffing,and extinguishing,eigarettes all tend to follow firmly ingrained patterns. By allowing,only the terminal response of puffing it was hoped'to,obtainmeasures ofad libirum smoking which were as free as possible from such habits and' were thus more sensitive to pharsnacological manipulations. I?le physiological, measures provided parallel assays of t'he potency of nicotine itt the two experunents.' Acidifying the urine reduces variations in excretion of nicotine and t'hus itnproving control over circulating levels of the drug. Another important element wastlie use of dose-response analyses without which it is extremely difficult, to draw meaningful conclusions'about the effect' of drugs on bioltDgical systems. Experiment 1 showed that inhaled'`dbses' of smoke systematically postponed and reduced subsequent puffing,and that this was a function of the content of the smoked doses. The second experiment took the analysis a stage further by directly examining thexole~of'nicotine as theputtitive reinforcer. Contrary to expectation, the intravenous doses were without effect on smoking behaviour. The physiological' tests showed that the doses of nicotine clearly modified the heart-rate and also the. EEG (A activity) and very comparable effects were seen in the two experiments. Thus; the lack of effect of intravenous nicotine on smoking,cannot be ascribed' either to inadequate dosage or to a failure of the drug to enter the blood and'.the brain. Same of the subjects did complain of some aching and painin their arms at the time the doses were injected into the infusion, but:neither they, nor the experimenters, were able to guess which doses were active andl which were not, at levels better than chance. Finally, the failure of intravenous nicotine to modiify smoking cannot be~ascribed to an insensitivemetho&(cf: Experiment 1). Our negative findings, therefore, re-open the question whether physiological dependence uponnicotinexeally is the basis fort'he tobacco smoking habit. Is itt possible that there is some other rewarding constituent, of tobacco smoke? Alternatively, if'relief'or aivoidance of nicotine-abstinence.is uniirtportant„could the drug be acting,as a primary positive reinforcer rather in t'he way that amphetamine and otherstimulanG drugs are thought to sustain self-ad'ministration behaviour? (Pickens and Thompsm 1971). Iif'this~were so, one might, expect that, wirhin lirnirs, increasing the nicotine content of cigarettes would result in increased rein- I

256 SMOKING BEHAVIOUR forcement and more smoking; if anything, the opposite seems to be the case (Goldfsrb eral, 19fi6). Although there is now an immense literature on intravenous, self-administration behaviour in animals relating to drugs of depcndence (Kumar and Stolerman, 1'977)„there seems to be only two brief reports (Deneau and [noki, 11967;, Lang,et a!, 1977) that nicotine can serve as a reinforcer in this way. Much money and' effort are being spent on attempts to reduce tobacco smoking and to make the habit less damaging to health: Some recent suggestions and devel- opments include nicotine-containing chewing-gum, cigarettes made from tobacco substitutes, cigaretties with low nicotine andi tar yields, or cigarettes with high nicotine and low tar yields. The ! rationale for such measures is lacking since the role of nicotine and the mechanisms of pharmacological reinforcement in tobacco smoking remain virtually unexplored. Acknowledgements We thank Dr. M.V. Driver for screening the electrocardiograms of our subjects,. Mr. B. Aschkenasy for preparing the nicotine solutions for injection and Dr. Griffith Edwards for his advice and support. This is an expanded version of a paper entitled''Is nicotine important in tobacco smoking?' reproduced with permission from CTinicalPiiarrnacoloSy artd'Therapeurics, 21, 5201529 (1'977); copyright The:C.V. Mosby Company, St. Louis, Missouri; lJS'.A. References Ague, C. ('1974) Cardiovascular variables„skin conductance and time estimation; ehanges after the administration of small'doses of nicotine. Psychopharrnacologia, 37, 109-125. Arrrtitage, A.K., Dollery, C.T., George, C:F., Houseman, T.H., Lewis, PJ. & Turner, D.1y1. (1975) The absorption and metabolism of nicotine from cigarettes. Brirish Medlcal Journal, 4, 313-3 I 6. Ashton, H. & Watson; D.W. (1970) Puffing frequency and nicotine intakeIn cigarette . smokers. British ~lledical Jourrta4 3, 679-681. Beckett, A.H., Gorrod; J.W: & Jenner, P. (1971)i The analysis of nicotine-1'-IN-oxide in urine, in the presence of nicotine and cotiinine,,and its application to:the studjv , -:, .t . of i,ir vivo nicotine metabolism in man. Journal of Pltannacy and Pharmacology, ~ 23 Suppl. „5'5S:61S'. ' O Bond, A. & Lad'er, M. (1974) The use of analogue scales in rating subjective ~ feelirsg;. Brihish Jourrral 'of iVedical Psycltwl uSy, 47, 211-218. ~ Brantmark, B1, Ohlin, P. & Westling, H. (1973) Micotine-containing,chewing-gum ~ as an anti-smoking aid. Psychopharmacolugra. 31, 191-200. ~ Brown, B.B: (1973) Additional characteristic EEG d'ifferences between smokers GO, and non,smokers. In Sinoki,ng,Behavior: Afwtives and'lncenr•ives, ed. Dunn, W.L. ~ pp. 6741_ Washington: V.H. Winston & Sons. Cochran, W:G. & Cox, G.,W. (1957) 8xperirnrntalDesrgps. 2ndl tidirtion. New York: - Wiley. Coffman,* J.D. (1969) Effect of propranoloi on blood pressure and skinbloud flow during cigarette! smoking. Journal of Clitrrcal'PharrtaacolcoV, 9, 3944.

I TOBACCO-SMOKING A FORM OF NICOTINE DEPENDENCE? 2S7 Deneau„G:A. & Inoki, R. (1967) Nicotine self-administration in monkeys. Annals of the New York Academy of'Sciences, 142, 277=279. Finnegan, J.K., Larson, P.S. & Haag, HIB. (1945) The role of'nicotine in the cigarette habit. Science,1V Y., 102, 94-9b'. Friedman, J., Horvath, T. & Meares,R'. (19'74)' Tobacco smoking and a`stimulus barrier'. Nature, Londom 248, 45S-4'56. Frsth; C.D. (1971) The effect ofvarying the nicotine content of cigarettes on human smoking behaviour. Prychopharrnacologia, 19, U88•192. Goldfarb, T., Gritz, E.R., Jarnl, M.E. & Sltolbrman, LP: (1976) Reactions to cigarettes as a function of nicotute and! "tar". CTinical Pltannacology and Thera- peutics, 19, 767-772. Gpldfarb; T:L., Jarvilc, M.E. & Glick, S.D. (197% Cigarette nicotine content ara determinant of human smoking behavior. Psychopltarrnacolog,ia, 17, 89-93. Hall, R.A., Rappaport, M., Hopkins, H.K. & Griffin, R. (1973), Tobaccosrnoking and' evoked potential. Science,lN. Y., 180, 212-214. Isaac, P.F. & Rand, MJ. (1972) Cigarette smoking and plasma levels of nicotine. Nature, London, 236; 308'-310. Johnston, L.M. (1942)' Tobact:o smoking and nicotine. Lancet, 2, 742. Knapp, P:H., Bliss, C.M. & W ells, H. (1963)! Addictive aspects of heavy cigarettee smoking. AmericanJournaTof Psychiatry, 119, 966-972: Kozlosvski, L.T., Jarvak, M.E. & Gritz, E.R. (1975) Nfcotine: regulation and cigarette smoking. G,TinicalPharrnacology and'Therapeutics, 17, 93-9'7. Kumar, R. & StolerQnan, LP. (1977), Experimental and clinical aspects of drug dependance. 1n Handliook of PsycJrwpharmacology; Volume 7, ed. Iversen, L.L., Iversen, S.D. & Snyder, S.H: pp. 321-367. New York: Plenum Press. Lang, W.J., Latiff, A.A., McQueen, A. & Singer, G: (i'977) Self administration of nicotine with: and without a food delivery sehedule. Phar»tacology. Biocluemistry aaid Bphaviour, 7, 65.70. Iyucchesi', B.R., Schuster, C.R. & Emley„C.S. (!1967): The role of nicotine as a determinant of'cigarette smoking freqFSency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid. CTinical Pharmacology and Therapeutics, 8, 789-796. Pickens, R. & Thompson„T. (1971) Characteristics of stimulant drug reinforcement. In Stimulus Properties of Drugs, ed. Thompson, T: & Pickens, R: pp. 177-192. New York: Appleton-CenturyCtofts. Russell, S+lIA.H. (1976) Smoking and nicotine dependence. In Recent Advances in Alcohol and Drug,Problents, Volume III„ed. Gibbins, RJ. et!al, Niew York: Wiley & Sons. Russell, M.A.H., Wilson, C., Pate1, U.A.. Cole, P.V. & Feyerabend, C. (1!973) Comparison of effecron tobacco cotuumption and carbon, monoxide absorpti©n of changing,to high andllow nicotine ciganettes. British .ifedical.llvisntal, 4, 512-5116'. Siegel, S. (1956) Non-parametric Statistics fbr tlie Behavioral Sciencer, Ntw York:, MrG'raw-Hi11. Stolernian, I.P., Gmldlfarb, T., Fink, R. & Jarvik, iv1:E. (1973), Influencing,cigarette smoking with nicr7tiine antagonists. Ps~~chophannarolu~gia, 28, 247 ?59. Turner„J'.A.McIN., Sillett, R.W. & Bail, K.P. (1974) Some effects of changittg to

258 SMOKING BEHAVIOUR low-tar and low-nicotine cigarettes. Larrret, 2, 737-739: Ulett, J:A. & 1til, T.M. (1970) Quantitatflve electroencephalogram in smoking and'smokingdeprivatimn. Science. N Y., 164, 969-970. 9 ~ C 0 CA 0 CA N CD Q)~ .%I

Rawbone, R. G.; Murphy, K.; Tate, M. E.; Kane, S. J. The Analysis of Smoking Parameters: Inhalation and'Absorption of'Tobacco Smoke in Studies of Human Smoking Behavior. In,: Thornton, R.E. (Editor). Smoking Behaviour. Physiological and Psychological Influences. Edinburgh, Churchill hivings'tone, 1978, 'pp. 171-194. .that: (1) There is no correlation between the 'dose' of'tobacco smoke presented, to the smokers and the amount'of'smoke absorbed by the smoker. (2) There is =a significant'correlation between the amount of smoke absorbed by the smoker and the smoke exposure index derived from the volume and time periods of'in- halations following the puffing,of a cigarette. (3) There are no demonstrable differences in smoking behavior between smokers of different product types for habitual smokers of'middle and low tar products and the dose of cigarette smoke presented to a smokers is dependent upon the cigarette specification. Differences in absorption of smoke inhaled are dependent upon the pattern of inhalation but f©r any given inhalation pattern differences in smoke absorp- tion are again dependent upon the cigarette specification. (4) In switching, -j ust their smoking to maintain studies there is some evidence that subj,ects ad a constant 'dose' of cigarette smoke but the possibility of changes due to organoleptic factors has not been ruled out. andid'escribes the results of experiments to study differences between habitual .midd'le tar an&habitual low tar smokers and to study the effects of'switching between middle and'low tar products. Quantitative measurements of'the smoking profile made are the number of'cigarettes smoked,, cigarette butt'lenght, puff. ~parameters (puff volume, puff duration, number of'puffs and inter-puff inter- val) and'the inhalation pattern.. Smoke uptake and retention are measured by alveolar carbon monoxide increments and nicotine butt analysis. Results show 'P,ow do people smoke?' andi'What is:the smoke uptake and retention?'; it explores some of the relationships.between smoke uptake and'smoke retention This paper desdribes techniques.which may be used to answer the questions

14. The analysis of smoking parameters: inhaliation a'.nd absorptioni of tobacco smoke ini studies of humm s mokingi behaviour : ROGER G RAWBONE. K MURPHY, M'ETATE AND S J KANE Introduction Aniearlier conference on Smoking Behaviour, held in 1972, dealt exclusively with the question.`what are the motivational mechanisms sustaining,cigaretre smoking behaviour?', considering this from both the psychological and pharmacological points ofview. During that conference it was suggested by Armitage (1973), however, that an important question, frequently inadequately considered, was that of (nicotine): dosage. Ashton and Watson had shown in 197~0.t'hat the human smoker, can'and does adjust the dose (of'n'icotine) he takes into the mouth by adjusting the size of'h'is puffs and''the rate at which he puffs when smoking. Furthermore, as A'rmitage stated, the smoke can be inhaled very deeply, moderately deeply,,slightly, or not at all. Since that time many reports have con'sid'ered questions which relate to how people smoke and'to the srnoke uptake:and retention, but, apart frornia study'by Guillerm and Radziszewski (1975), there havrbeen no published studies exploring the range of, techniques available and their application in the study of such questions. This paper will describe techniques which may be used to answer, the questions 'How do people smoke?' and 'Wliat is the smoke uptake and retention?';, it will explore some of the relationships between smoke uptake and smoke retentiioniand finally describe the resulks of experiments to'study differences between habitual middle tar and habitual low tar smokers and to study the:effects of sh+vitchirtg, between middle and low tar products. 'How do people smoke?' In:the analysis of this question we are concerned with the physical smoking profile. The dose of tobacco smoke constituents available to the smoker will depend upon the cigarette specification (Table 14.1), However, for any given cigarette, it is the smoking profile.which willia'ffect how much of the dose is dtlivered to the smoker and how much is absorbed. Table 14.1 Factors deterrnining,the charaeteristies of'a cigaret¢e product.. Cigarette Specificaition i)' Filler - Tobacco based Additives DKllienrts / Substitutes ii) Configunatioin iii) W'rapper iv) Filter - Type Ventilation v)' Misc. - Pressure,drnn...

172 ~ SNtoK1NG BIiHAV~IOtUtt~ Quantitative measurements of the smoking profile which can be made are thenurnber of cigarettes smoked„cigarctrte butt length, puff parameters (puff volume, puff duratiran, number of puffs and inter-puff intKrval) and'the inhalation pattiern. ' 'IVfutr is the smoke uptuke and'netention?' Here we are trying,to quantifythe smoke uptake and dose absorbed as a result of the smoking profnle. IWosf approaches to this question attempt to estimate the dose of'tobaccq smoke fro'm an analiysis of certain smoke components or Uheir markers - commonly carbon monoxide or nicotine. It should be noted however that carbon monoxide is a measure o'f th,e gas/vapour phase of the smpke whiQst' nicotine is a reflection of'particulate matiter and it' is possible that these two phases of the tobacco smoke bchave di'fferently in terms of their pulmonary d'istribution and absorption. Carbon monoKide may be measured in the blood or in exhaled air whilst nicotine is usually measured in the bloodiorin theurine: Asomewhat different approach is the estima2ion of nicotine intake from that retained in the cigarette butit'. Measurement of'puff'parameters Methcid Puff parameters canbe obtained' from measurements of the pressure drop across a' small resistance inserted between the cigaretite and'the smoker. In this situation, when there is air flow dursng puffing, the pressure drop created across thesesistance will!be related to thegas flow. The relationship will d'epend upo'nwhether thee airflow is turbulent„whenithe flow rate will be proportional'to the square root of the pressure drop; or laminar, when the f7ow will be direct'ly proportional to the pressure drop: In either case puflvolume canbed'erived'by integratianof the flow signal against time and puff and intierpuff intervads can be measured direetly. Specialised cigar.tte holders haHe been diesigned incorporating devices tio prodiace a pressure dbop with eitherrurbulent flow (orifice piate) or; as used inthepresenC experiments, laminar tlbw (filter insert). )$oth types of dkvice have theiu advantages and disadvantages but' it is not appropriate to d'iscuss these in detail in this paper. Tt; is necessary, however; to outline some of the problems associatedi with the lilter insert type of hmlder as emplbyed in the studies tb be described. Tlie hold'er is shown in' Fig, 14.1. It contains a replaceable 6mm ce!lulose acetate filter across which the pressure drop can be measured using a differential' pressvre guage: The assumption is'that t'his pressure drop is lineurly relarted to the flow of gas through it, i.e. that the flbw is laminar and Q=Kp -(1!) where Q is the Plow rate; p is the pressure dbop and 1C is a constant: Fig: 14., shows the pressvre drop versus flow rclationship of the holder far air over thee rangg of flows found dirring normal smokang. Ik can be seen that the relationship is curvilinear indicating that thebasic assumptuo'n!regarding flow derivation is not currect, Nevertheless, the degree of curvature is relativel~ slIght and the uverall error introduced in computiing puff vollume from the flbw signallis aecordingly small. This relationsitip between pressure and tlteflow hzs bcenobtiained by drawing air througlt the liluer holder at room temperaturesi The exact relationship between . 1o05o52990

INHALATION AMD ABSIDdZF'T1ON( OF TOBACCO SMOKE 173' Fig. 14.11 Thefiitier insert cigarette holder with, a king-size filter tipped cigarette. Two of the 6mm cellulose acetaoe:filttr inserts„across which the pressure drop is measured d~uring smoking, are shown alongside the hoddkr: Fig. 14.2 The relationship between pressure drop across the filter insert and,flouvd arf air throu!gh the hoider:over a range of flows found du!ring normal smoking. 2000 3000 . F4OW (inllminl 4000 5000 100~5~529~~

174', SbiOK1MG'BEHAV'IIDtJR the pressure drop and lamittar flow is given by the equation of'F9agen-Poiseuille: , Q a s(p r4 -(2) 8 nll where r is the radius of thed'evice, I is the tength of the device andin is theviscosity of the gas. Although therefore flow may be proportional to pressure drop the constant in equation (1) is dependent uponthe-viscosity of'the gas whichlinits turn will'be. influenced by temperature. [n the present situation therefore any calibrations of the fibter holdecshould'..be carried out using tobacco smoke at the temperatures found in mainstream smoke. Measurement of the temperature within the filter insert diuring normal smoking is not constant, rising during puffng and falling between puffs. An overall'l rise of about 60C has been recorded smoking to approximately 8mm from the cigarette filter, after which the tempenature rises steeply. r#n es•a!luation of the characteristfics of't'he filter insert holder using tobacco smoke at a temperature 3-5°C'above that of ambient air was found to give results within 3% of those using air. There is one further, question which has ~to be considered when using the filter insert holder- does the deposition of tobacco smoke condensatie within the filter insert, which inevitably occurs during smoking, affect its characteristies2' In practice no differences eould1be detected'in the pressure drop: versus flow relationships of filterr inserts studied before and after the smoking of a cigarette through, the holder. It should be noted that wheni performing butt nicotine analysis (vlde irrfra) the filter insert should be included to take into account the condensate (nicotine) deposited within it. The analyses described indicate that the tulterrinserthoider; calibrated with air at' room temperature, givesan approximation of the flow rate and hence the volume of tobacco srnoke passing through it as a eigaretteis smoked. The filter insert requires renewing foreach cigarette smoked and the calibration shouIdthus be! perforrned before each study: As thederivedif9ow sigrnal'.is only being used to calcuIat~e the puff volume, cadibration.can more readily be carried out by passing a series of'known volumes through the holder and reeording,the appropriate signal. As a final check of'the system a volume calibration of the filter holder was performed using bozh air and tobacco smokc when; over a rangaofbolumes (10-6om1), the results were within 5%'0 of each other. This technical evaluation enables the limitaiions of the calibratlioniprocedures and the precision of our measurements to be known: However, one musL then consider the effect on the puff parameters of smoking with such a holder. There is the intro- duction of the holder changing the weight and feel of the cigarette; the added dead space (1'.6ml)wiith stagnation of'smoke between.puffsaffecting,taste; and the added draw resistance caused by the fibter insert. The latter is in fact relatively small whenn compared to an unventilated kimg,size Gilrcer-tippe& product as showmin Fig. 143 but may become of importancewiith different product designs: , In addition to these factors t'here are the differences in smoking pattern whiichimay result 6rom a subject being studirdiin an experimental situation. This is discussed by Comerand Creighton (1978) but our ownobservations; relating,to butt'analyses (vide infra);,would confirm signif9cant differences in, the.smoking profile between individualssmoking wit'hout'the ciearettie holder in a relaxed atmosphere to srrtoking, 1005052~92

0 INHALATION AND ABSORPTION OF TOBACCO SMOKE 175 with the holder in an experimental laborato'ry situation. 1000 2000 3DOo FUOW fml/ minl Fig. 14.3 The relationship bctween pressure drop and air flow across a king siZe flter-tipped,cigarette andiacross th¢ eigarentrplus filter insert. The relationship for the filter insert (see Fi¢: 14.2) and the cigarette minus 50mim: tobacco rod are!also shown for comparison. Comparison of'meastrred puff pararneters with standa,rd'maehine smoking parameters Despite the limitations of'the modified cigarette holder descrabedl in measuring,puff volume, direct measurements of puff duration and interpuff'interval can be accurately made. We have measured all'these parameters in twenty subjects during the smoking of 100 cigarettes covering a range of product types. Anaiysis of' the average result for each cigarette gives an overall meam puff volume of 47'.5nt1( standard deviation (S.D.)± 6:42mi), mean puff duration of 2.28 sec (S.D. 0.3 sec) and mean interpuff interval of 351 sec (S.D. 9.2 sec). The 959o confidence intervals for the means of our data are puff volume 44.96•50.04'rrtl„puff duration 2:16•2.40 sec and interpuff'ii9terval 3'1i.27=38.53'sec and for each of these parameters the mean result is thus significantly different from the standard (T.R.C.) machine smoking parameters of one 3Sni1 puff of 2 sec duration with aniinterpuff'intervallof5&secs. It is not onlyposstble; using the modified cigarette holder, to make quantitative rneasurernents of'puff'parameters but one may also observe the puff flow profile: In anyindividual,,this profile tends to remain constant and a ciassificationlof smokers on the basis of their puff flow profile has been proposed ('A'dams, 1966): Measurement' of inhalation Metfiod. 1005052993- Depth of inhalation has been measured by recording movements of the chest wall using a mercury strain, gauge chest pneumogram. This consists of a thin, eli+stic+walled tube containing mercury which is held under tensimn across the upper part of the

176 SMIDKIItty BEHAVi0U6t' anteniorchestwall by a strap passing around the subject. As thethest expands with, inhalation the mercury-fIDed tube.is stretched, thuschanging its length and cross- sectional'area, and hence its electrical resistance. This change inielectrical resistance can be displayed o'n a recording device. in order to relate the change in resistance to a change in hing volume a callbration must be performed simultaneously measuringg the chest pneumogram deflection and lung,volurne!changes. The lung volume changes cam conveniently, be recorded at the mouth using aspirometer. It will be apparent that this calibration must be carried out each timr.the chest' pneumogram is applied to or adjusted on a subject.and must therefore be performed at the beginning of each smoking study. A typical calibration for one subject study is shown in Fig. 14'.4 where the linear regression line for volume change versus pneumogram deflectio'n: is shown both over.ar large volume range (0-5 litres) and a smallen volume range (0-2 litres) as.might be, expected'in smoking studies. I I I I I ' I 10 20 30 40., 50 P'NEUMOG'RA+M, D'EFLEC'TION (mm), r-0:96 (vol' 0-5 I itres ) r - 0. 911 (vol 0-2 litres) Fig.1'4'.4 The chesrpneumogram cal'obrartionfrom onesubject,study. Correlations between the pneumogram dkf7ectiimn andlsimulRaneous measurement of lunig volume changes aa measurediby spir,ometry at the mouth. The correlation coefficients and Gnea!r, regressima lines are shown over the total (i0-5 litre) volume range and a smaller (0-2'litre) volume range asmight be found in smoking studies. In all experimental studies we have, performed,, the cmrrelation;coefEiaient, over, the ranga:0+2 litres'for the albration procedure, has been grearter than 0.90. 1005052994

INHALATION AND ABSORPTION OF TOt1ACC'O SMOKE 177 amparison of ineasured inhalation with a szrbject's subjective assessment This technique for evahtatiing inhalation may be used to investigate whether a person"s subjective analysis of his inhalItlon correlates with the volume of gas which he actually itthales. In a preliminary study, 1 S subjects have been presented with a 140mm analogue scale with the extremes'do not inhale"to'inhale maximally'. They were asked'to place a mark along the line in a position between the two extremes which corresponds as closely as possible to the way in which you smoke'. As a validity check subjects answered this question ontwo occasions with an intervening period of at least 24 hours. Analysis of'the data, using a paired t test ga ve a mean difference of -1 mm with a standard deviation of the difference of'19mm (p=0.9, N:S.)i Subjects then smoked a cigarette with the chest, pneumogram in position and the mean smoke inhalation volume for that cigarette calculated. The results of the relationship between the analogue scale recording and!the mean inhaled volume are shown in Fig. 14.5. Maximal 140 120 x x. x x x 20 Nil I 1 0.5 LD 1.9 2.0 NtfA'NI INSPIRE!DIVOUIIME Ilitresl Fig: 14.5' Comipariso,mbetween a subjective measurernent of inhalation as recorded on an analogue scale, and'an objpctave measurement of inhalation - the: mean inhaled volume as measured from the chest pneumogram. The linear regression line for the data,(r-0.65, p<O:D1) is shown with its esrtrapalation. indicating tham the initerce,pt is not zero. Artapparenttlinear rela2ionship exists over the range of inhalation studiedi(r=0.65, p<0.0'1); There are however few observations over the lower range of subjective inhalation andithe linear regcessioil line for the data does not,,as shown, extrapolatee towards the origin. It would therefore seern hkeHy that a linear relationship does ,,

17$' SMOKING BEHAVIOUR -,r . not hold gpod over the full range mf'inhalation. It is over the lower range of' '° inhalation, notcovered in this experiment, that much interest lies - do people who state that they are non-inhalers really not inhale when smoking? It rnaybe argued!that the actval inhalation volume should not be expected to ~• correlate with a measure of subject'iveinhalat6on, because what is regarded'as a minimal inhalation in a'large' subject may be regarded as a maximal inhalationlin.a'small' subject. In order to correct for this the mean inhaled-smoke volume of each subject has been related: to theu vital capacity, this being used as a measure of lung,'size': The resultwas surprising and is openito speculatoonifor it was.found that in all casess the mean inhaled volume was approximately 25% of'thevital'capacity(26qo ± 1(S.D.) ), Smoke exposure indes : . , As in the case of the: puff flow profile the chest pneumogram tracewill give aiquah itative indicat2on of the form of the inhalation. Two examples are shown in Fig: 14:6; in: the.6rst, of these the subject has taken a deep inhalation with immediate exhalation whilst in the second'example a more shallow inhalation is foilowed!by a period of breathholding prior to subsequentexhalation, _. . .;. , I'I!I l l l l l l l'l l l l l l l l!I I I I( I'I!!'l I I I I I I Ll'191 l l l ll'l l f!! I'I I'l l l l l ll !( I I I!I l l l l l l 5M Pneumogram Trace 1' Pneumoqram Trace;?' Fig. i4:6 Two examples of the chest pneumograim tra!cinig showing different patterns of inhalarcion. In each:exaunplt: the inhalation of'tobacco smake is ind6ated' by the arrows and, fos one inhalaaion, the area from whith, the,smoke exposure indbx,is calculated has been shaded. The exposure of'the lungs to tobacco smoke during smoking,will thus not only C) depend upomthe depth of inEtalataonof the srrtokebut alsoont~he tirne,whictithis~i smoke remains in the lungsi In order to take this into account a;srnoke exposure 0 index has been derived' from the chest pneumogram trace by summing the area under f h i h la N~ or eac the curve n a tion of smoke. The areas were measured by planimetry ~ and representative examples are indicated in the traces shown ini Fig. 14.6. . , CD (M `

. 1PdPdA1.A'T10TA'AMD ABSORPTION OF TOBACCO SMOKE 179 The relationship between puff'and inhalation profiles Derivationof'the puff flow profile and the inhala!tion profile have been described separately but useful infiormation maybe gained by combining,these techniques. In Fig. 14.7 are shown two examples. 5ecsI'I'11 I I I I I I I II'I ( I I I I I I II I 11 I I I I I I Il I I l l ll' I'I'UI I I I I I I Il ll l I I I I I I 1 I I q I I I 1 I I I I pneumogram Trace. Puff Profile ~ Fig. 14.7 ' The pneumogram, tracing andi the puff flow profile from two smokers during normal smoking to illustrate: i)~the relationship of the puff to the inhalation and ii) the:pattern of chesYwatl monemenidhrring,puffing and preceeding the inhalation of smoke. The time relationships of puffing from the cigarette and "uiltalation of't'he smoke can be studied1whenit is observed that'the puff is taken into the mouth from thrcigarettee before being inhaled into the lungs. This has important implications in terms of dose exposure for it means that the whole of'the smoke bolus is potentially available to be taken deeply into the lungs at, the beginning of inhalation rather than being distributed throughout the total inhaled volume of air. Recording both puff and inhalationprofiles.it is also possible to note:any gross movements of the chest walt'durirtg puffing. In the majority of subjects studied Q, the patternishowrrinthe first example of Fig. 114.7 is observed where virtuallyno, 01 movement of the chest wall takes~place. However, in a few subjects, most' notably UT smokers of high tar, prodi?cts, there is an apparent active exhalation following the: Q puff prior to the subsequent inhalation. This is sh6wn: in example 2' Fig. 14.7. ~ The implication of this pattern of'smoking,is that the bolus of tobacco smoke has ~ been blown from the mouth andi very litt'lt, if a!ny„is available at the subsequent inhalation (presumably this is also the pattern in cigar smokers)i ~ Measurement of carbon, monoxide Method Tobaccoismoke conta!ins carbon monoxide and'studies have shown that the venous carboxyhaemoglobin saturation (IHbCO`9o) of `inhaling'.' cigarette smokers is signif- icantlly higher than that of non-smokers. Measurement of venous carboxyhacmoglubin, with the necessity of obtaining,a blood sample by Einger prick,or venepuncture, was not considered satisfactoryfor, (large scale) studies ina'normai"populationn lt was therefore decided to measure carbon monoxide in mixed eapired'anr and tio deriive the partial pressure of carbon, monoxide in.alveolar air using the Bohr cquatian.

i 1'$b SMOKING BEHAVIOUR This equation u based, upon the law of conservation of matter which, [or this example, states that the volume of carbon monoxide iniany expired'breath.(fractiwnallconcen- tration oflcarbonmonoxide x tidal volume)'eqaals the vol>flme corning,frorrt the alveoli' plus the volume coming from the dead space. Substituting and rearranging the equation will give the fractional concentratiionlof carbon monoxide in alveolar air (F h1CQ):- V~.Fe C0'- VD.Fi CO {3) FAC~O = VT • VD where FeCO is the fractional concentration, of carbon monoxide in mixed expired gas„FiCOlis the fractional concentration of carbon monoxide in inspired gas, VT is the tidal volume and VID is the.dead space. Ihe details of the method have been published in detail elsewherc(Rawbone, Coppin and Guz, 1976) where it: is also shown that the results for: alveolar carbon monoxide partial pressure obtained correlate with the simultaneous measurement of venous HbC0% (HbCl7~lo = 240 PACO ~(mmHg) - 0:26; r= 0:96; p<b;001): A comparison ojalveolar carbon monixde between smokers antd non-smokers and the cfianges in alveolar carbon monoxide occurring during the day withsmokrng, As an initial evalinationof the technique the alveolar carbon monoxide partial pressure (PACO) was measured at random times throughout the day im 35 non-smokers and' 35'~smokers: The smokers, who had not smoked itir at least'twenty minuties prior too study, were unselected on the basis of'cigarette consumption or tar yield of their regular brand. The results are sliown, in Fig. 14.8 as a simple histogram. 8 25 c c eo 8 0 0 0 o'. 0 c., o' c 0 ~ ar o 0 0 0 ' o c o 0 e., v 10 00 0 0 o g 0 o c c 0 0 0 0 0 0 0 0 0 0 Alveolar Pt:oimm Hlgi Fig. 14.8 Histogram showing rhedistriblurtion of alveolar carboim mnnnvidp n...i.1

INFNiALATIONiAND ABSORPTION 0'F TOBACCO SMOKE 181 Non-smokers fell within ai relatively narrow range (mean PACO 0.004 mmHg; S.D. 0.002 mmHg) whilst the rangF for smokers was mueh greater(mean,PACO 0:016 mmHg; S.D. Qi008' mmHg). The two populations are significantly different (unpaired t test, p<0.001'). In order to evaluate the suitability of the technique for more detailed studies of' smoking;behaviour the changes in PACO with smoking,were followed over a 12-hour peniod'intwo volunteer, regular smokers of ten to twenty middle tar cigarettes per day. Neither subject had smoked for at least 12 hours prior to the commencement of t'he study period during which they were allowed, tb smoke without restriction: Both smoked the same brand of cigarette whichlyielded 25mg,carbon, monoxide/ cigarette under standard (TRC) machine smoking cond'itions: Before smoking each cigarette and exactly 15 minutes after, measurements of PACO were obtained and the results, from both subjects areshown in, Fig: 14.9. It can be seen that t'hePACO increases with each cigarette smoked (mean increase 0:0036 mrnHg, subject A; mean increase 0.0027 mmHg, subject B) and fell between~smoking, The overaff pattern in both subjects is a rise iim PACO~during the early part of the day with a tendency for the level to plateau after 14.00 hours. In subject B, who.was~asked to chain-smoke four cigarettes at the end of the study period, there was a further increase in the level of PACO. Cigarette butt nicotine analysis The characteristics of a filter cigarette can, by machine smoking the product using standard!(TRC) smoking parameters, be definediin terms of the measured!mainstream smoke nicotine and'a derived filter retention efficiency. The filter retientioniefficiency is calt:ulated from measurements of the mainstream smoke nicotine and the filter, nicotine: NR Filt~er~r~etention effaciency~~(F), = ---- -(4)~~ Ns+NR where NR is the filter nicotine and Ns is the mainstream smoke nicotine. If it is assumed that the filter retention efficiency is a constant for any given product specificatiorrthen, knowing,tihe amount of nicotine retained in the filter after human smoking„it' is possible to estintate the amount of nicotine presented to the smoker (mainstream smoke nicotine). ' N,R(I-F). Na = F .(5) Once the amount of nicotine presented to the smoker has been determined, an index of the way in which the cicarettc has been smoked may be obtained by ~ calculating the ratio of't'he smoker's mainstream smoke nicqtiine value to the main- 0' stream smoke nicoitine measured on machine smoking. We have calltd this the ~ nicotine coimpensation ratio whichL because it relates the.smokers value to the O standard machine smoking fiigure, may be compared both betwecn subjects and across product ty v 1 pes , . tN .~s~ ~'

S Venous HDCOSaturation .o w ., ~ w. ~.. ~~~ 1 1 r l r r ~ N \ r 1 m r W_ m ~ ~. < ~ m w ..: :::.:. .::. :. . . .:. .....:.; . .: .. . ..... ~::::.:.. .. .... . . .. ... ... .. O .. ...::.: ~ ~.:.. ; . '. ^ i~, Fig. 14.9 Variatioins in alvuol2r carbon monoxide parrtiai1pncsaunc with cigarette smoking throughowt a 13'•hour period in two subjccas (A ana BD1 The verticaa bars indicaae periods of ciearetue smnk;n.. 1005053000

IN1tALATIbN AND .aBSOAtI'TIION OF TO&ACCD SMOKE 181 A comparison between the increment in alveolar carbon monoxide and butt nicotine analysis Two indicators of a, subject's'dose of tobacco smoke' have now been described - measurement of the increment in alveolar carbon monoxidie from smoking a single cigarette reflects the 'dosc" absorbed whilst the derivation of mainstream smoke nicotine reflects the'diose"presented to the subject. It is of'interest to compare these two measurements. Forty-seven subjetts took part in a study where each wass asked' tochain-smoke frve cigarettes. Carbon monoxide measurcmcntsmere made before and 15' minutes after the smoking period andl each subject's cigarette buttss were collected'and pooled for nicotine! analysi's, in this way, min'inaising,errors due to analytic technique. Bothithe increment in carbon monoxide and the nicotine presented to the smoker have been related to machine smoked values to allow irsterr subject and inter-product comparisons and the results are shown in Fig. 14:10 as a scattergram i 1.0 0.5 0 . .~ .1 • • . ® I 0 . • .. • . . •~ . 0 • .. .. 1! •~, •~, 0 0.5 1.0 1.5' 2.0 NICOTINE PRESEMtED TO SMOKER I MACHINE' NIICOTINE; Fig. 14.10 A scattergrarn of the increment inialvcoGrrcarbon monoxide parrtial! pressurrJmachine smoked carbon monoxide yield versus the dk•rived nicotine presentedtiolthe smokerl'machine smoked nicptine value (nicotine eompensatio,n ratio) in 48 suibjects (k0:28, p)0:05'):

184: SMOKING BEHAWIIt)U6i' lt can be seen that there is no significant ref ationship between the two measurements, (r-0.28,,p 0.05).. The'dose' of tobacco smoke presented'to the smoker (as measured by butt nicotine) is not therefore equal to or even proportional to tihe'dose' of tobacco smoke absorbed by the smoker (as measured by the carbon monoxide increment)'and themajor factior inidetermining the differences is probably related to: inhalation.of the smoke from the mouth into the lungs. The relationship between the abveolaresrbon monoxide! increment and the smoke exposure index If inhalationiis the major determinant of differences between the 'dbse"of tobacco smoke presented to a subjiect during the smoking of a cigarette and the 'dose' absorbed duritog,smoking; then a relationship might be expected between the smoke exposure index (reflecting the depth of inhalation of smoke:and the time which this smoke remains in the llangs) and the increment inialveolar carbon monoxide (reflecting the. 'dose' of smoke absoribed). Habitual middle tar smokers In Fig. 14.11 the carbon monoxide: incretmenr has been pl'otted against' the smoke exposure index for ten habitual middle tar smokers smoking one cigarctte of their usual brand. x Normal smoking ® Defined smoking Fig: 14.11 The relationship bctween the incremenrin alveolar carbon monoxide partial pressure and tihe smoke exposure indez in haibitual'middle tar smokers. x, normal smoking;, ®, defiined unoiking,einher witih, maximal inhataition and!breathhplding or no in'hal'a4ion. Thle tinear'rCg!fessiolfliliil'e for ailllmeasuTemienila i4t ahn+vn lir.A O6

IN1iALATION AND ABSOR'PTION'OF TOBACCO SMOKE 1185 There is amapparent linear relationship between these two measurements (r--0.65,, p<'0.05). In order to define the rclationship further the range of inhalation was extended by instiructing,one subject to smoke with d'eep inhalatimn and, breathholding, and three subjects to smoke.wit'hout inhalation. When these defined-smoking measurements are added''to the measurements obtaine&on normal smoking the linear regression line is as shown in Fig. 14.11 and the correlation coefficient for the data is 0.96 ' (P <0.001). [t should be noted that when there is no inhalation there is no measurable increment in'carbommonoxide suggesting,no significant buccal absorption; this is different to the situation found with nicotine when absorption through the buccal'mueosa ean be readily demonstrated. Hab i tual l o w tar smok ers A similar linear relationship between the increment in alveolar carbon monoxide and the smoke exposure index to that found in middle tar smokers has been dernon- strated in five habitual low tar smokers ('r=0.94, p<0.05). The linear regressiwn line is shown with the data in Fig. 14.12. 10 20 30 40 50. 601 Io, 8o 90, 100 E7cP05URE' INDEX uitre secl Fig.,1'4.12 The retatiotrship between the incremtnt in alive,olar carbon, monoxidr partial pressu!re and,th~e smoke exposure ind'ex ini habitual low tair smokers.., normal smoking,Ll, defined smokirtg without inhaiation. The tinear regression line for the measuremsnts is shown (r=0.94, p<b.0'S) togethcr with the:predlicted regression lina- see text. For comparison t!hr linear regression lint: ot' middlt: tar smokers is shown.

186' SFCOK'ING BENA'V10t1iR' s A comparison between habitiual middle tar smokers and habi'tuai low tar smokers Inhalation Fig; 14.12'shows„inadidition to thc Iinear. regression line for ltDw tar smokers, the regression line for the middle tar smokers prcviously discusscd and shown in Fig. 14.11. These two lines are significantly different at the 5'7eJcvel. The significant relationships between the increment in carbon monoxide and the smoke exposure index for both middle~and low tar smokers is pcrhaps surprising; for within each, tar group there is a range ofi products of differing carbon monoxide yietd! Nibre important however. is the implication of the demonstrated relationship, that all smokers of the satne product type inhale an amount of carbon monoxide which falls within relatively narrow limits, such that the inhalation pattern is the major determinant of the carbon monoxide increment. Although the 'dose' of tobacco smoke presented to srnokers differs widel'y from subjqct tiolsubject, the 'dose' inhaled and available, for absorption tends towards~a constant. Ifs in Fig. 14.12, the slope of the middle tar regression line is set toirepresent thee relationships between inhalation pattern and rise in alveolzrcarbon monoxide :or an average middle tar product: containing 20mg carbon monoxideper cigarette„ then the relationship for an average low tar product, which contains 110mg carbon monoxide, can be predicted. The predicted line for such a product is as shown in Fig. 14.12 and it is not, significantly d'ifferenr from the actual line obtained itorn habitual low tar smokers (p )0;05); Furthermore, as can be seen from.Fig;. 14.11 and' 14.12; the values~for the smoke exposure index of the middle tar, smokers overlap the values for the low tar smokers and statistically there is no difference between the two groups (p )'0.05): One must therefore conclude thart there.is no difference between the inhalation patterns of habit~ual middle tar and habitual low tar smokers, and, at any given level of,smoke exposure index, diflferences in carbon monoxide increment can be accounted fpr by the differences in carbon monoxide content of the d'ifferent product types. Alveolar carbon monoxide increments Itt ttie previous studies investigating the relationships of alveolar, ccarbon monoxide increments with the smoke exposure index, subjects were studied at randbm times during the working day. IU is possible that the increments in carbon.monoxide with smoking may show a changing pattern;' other than rand'om variation, during, the day. Pn order to investigate between-product differences therefore, measure- ments of carbon monoxide were made in relation to the first cigarette of the day. Nine middle and nine low tar smokers were studied before and after their first cigarette of, the day on three separate days over a period of tltree weeks. The results are shown in Table 14.2 as the mean group levels~i Table 14.2 The mesn,alveolar carbom.monoxide partial pressures before and after smoking the firsicigarette of'the day in groups of habitual!middle and low tar smokers:, Wliddle Tar Group Low Tar Group L'evclio[ Sitnifirance Pre s!moking .0I06'3I + .0068 t NS IcveHmm1Hg) .000669 .001045 t ~ Post smoking .01094 t .0086 `- NS L ' Ievell(mmfH6)' Increment .0I00840 nnlt ± .001085 nntT t

INHALATION AND ABSORPTION OF TOBACCO S!t'tt)tCE' 197 ~ " The ineremenL in carbon monoxide for the group of middle tar smokers is significantly higher than tha forthe group of low tar smokers (p<0:1); the magnitude of this r difference is approximately two-foldiwhich is as predicted frunt the average carbon monoxide deliveries of the two product groups. More interesting however is the observation that the pre•smoking level'of'carbon. = monoxide in the two groups of subjects is the same. This mieht, be accounted for by ~ Proximation of'initially different values to within the limits of measurement ,v the a k p capability as the levels of carbonimonoxide decay, cxponentially during the night (period of no smoking), The other possibility to be considered is that, despite the o£smoking parameters during the day or the influence of carbon, monoxide back they eventually plateau at the same average level of carboni monoxide. This may be a re#lectio'ni of differences in cigarette consumptbon, or pattern of'smoking, modificatimn fact thatimiddle and! low, tar smokers appear to smoke onlavenage in an identicallway„ '4ti Smoking parameters As a separate study of habitual middle tar and habitual low tarsrnokers,,cigarette butt length, butt nicotine and puff'parameters were measuredl Seven middle tar and five low tar smokers entered'the study and'response parameters a. pressure trom the blood which increases as the day progresses. were recorded twice in, each subject with an intervening period of seven days. Puff parameters, butt length and filter nicotine values were all derived from the smoking of a single cigarette on each of the two occasions. For the present analysis thrmean, value from the duplicate measurements in each subject have been used to calculate the group statistics on which analyses have been performed using the unpaired ti test. 'Ihe results are shown in Table 14'.3' Table 1'4.3' Puftparameters, butt nicotine and butt length in groups of habitual middle and low' tat smrdkers Test Low Tar Smokers N-5 Middle TarSmukcrs N'= 7 Level of Significance Puffduration secs 1174 ±' 0.028' 1.92 '- 0.205 NS Puff iaterval sea 43.6' ± 5.430 38.8 ± 4.873 NS Number of puffs 9.8 + 1.07' 10.9 + 0.77' NS Nicotine to smoker mg/cig 0.53' '- 0:033 0.78 ± 0.052 p<.001 Nicotine compensation ratio 0.70 ± 0,04',3 0.70 • ± 0.047 NS I Tobaccn butt length mm 12.1 ± 2.081 10.2 ± 0.856 NS Mean level'+ standard crror NS not signiriicant No significant differences are apparent between the middle attd'low tar smokers for puff parameters, butt length or the way in which the cigarettes have been smoked as judged from'the nicotine compensation, ratios. There is aisicnificanrt difference in the amount of'nicotine presented to the smokers but'this is merely a reflzctaon of

I8'8' SMOKING BEHAVIOUR the atr2erences tn, nicotine ytela!ot ttte two proauct groups. Habitual middle tar and habitual low tar smokers ;' _ .., ._. Both the studies of'inhalation partterns and'smoking parameters presented would appear to suggest that there are no differences between habitual middle and low tar smokers in the way iniwhich they smoke and inhale theu respective products. ~.. '' Differences in carbon, monoxide, nicotine and presumably tar presented to smokers are merely a reflection of the differences between the products and not modified by smoking. This conclusion would appear to be contrary to a lot of published experience but such studies are predominantly switching studies where middle tar smokers are studied smoking low tar products and, vice versa, comparisons being made between the two sequential smoking periods. Smoking, paramerers Cigarette switching,studies An experiment, to examine the effects on smoking parameters of subjects switching from middle to low tar cigarettes was conducted in nine habitual middle tar smokers. The original experimental designwas for the subjects to smoke their own middle tar product' for the first two weeks of the study and then switch to a defined low tar product for four weeks. Following this second period, on a low tar product, subjects were expected to switch back to their middle tar product for the third study period which would last a further four weeks: During,the study however„at the completion of the second period, fsve subjects declined to switch back to thcir original middle tarproduct„electing to remain at the low tar level. This is presumably a reflection of the bias of subjects volunteering for such smokingstvdies! As a consequence, the original study population consists of two potentially different groups and for the analyses presented here these groups have been treated separately. Group1A are those subjects who, in the thirdl period, switched back to their original middle tar prodtzct ('n=4) whilst group B are those subjects who elected to remain on the low tar product(n=5): Response measurements were obtained weeklyduring,the ten week study period.. Smoking parameters were recorded Crom the smoking of a single cig3rette, butt' lengthiand butt nicotine analyses were the average from a?4 hour butt collection and cigarette consumption was the mean daily consumption from a weekly record.. For the summary results presented the mean response for all subjects in each of the two groups is given for each of the three smoking periods. Examination for differences between the groups has been carried out using the unpaired t test. Tablk 14.4 presents the results from Group A where subjects have switched''back to the middile:tar product for the final smoking period! There are no significant differences for any parameter betweenithe first and third smoking periods when subjects were smoking the middle tar products. The nicotine compensation ratio would indicate however that the low tar product is being significantly'oversmokrdl when compared! to the middle tar product and from the puff parameters this would seem to be the result of taking larger puff vollrmes. Despite this `oversmoking' of the low tar product, compensation, in terms of nicotine, is nut complcte. Althuughithe decrease in nicotine presented to the smoker is not significant when switching to the low tar product, t'hereis a significant increase wheni switching,bzck to midrllc tarin the third

I Table 14.4 A comparison of smoking parameters between the three stages of a cigarette switching study. Subjects In Group A (n-4) who switched back to a middle tar product for the final smoking period. Experimental Stage Level of Significance 1 Middle Tar 2 Low Tar 3 Middle Tar 1 v 2 1 v 3 2 v 3 Puff Duration — secs 2. 01 17 2.4 # 0.10 2.4 ± 0.09 Puff interval secs 32.1 ~ 4.92 34.1 ± 3.65 37.0 ± 2.30 Puff number 10.0 ± 1.07 10.2 ± 0.66 9.4 ± 0.46 Puff volume cc 44.1 ~ 3.94 53.3 ± 2.85 46.3 ± 2.31 p (.05 pE.05 Nicotine to smoker mg/cig 0.96 ± 0.08 1 0.83 ~ 0.029 1.00 r 0.031 p E.001 Nicotine compensation ratio 0.79 ± 0.07 8 1.00 ± 0.035 0.84 ± 0.034 pC.01 p4C.01 Tobacco butt length mm 8.1 ± 0.52 7.7 ± 0.60 7.3 ± 0.50 Cigarette consumption daily 25.3 ~ 2.96 25.8 ± 1.44 29.9 t 2.09 Mean level ; standard error F.1004SQSOoT v > ~ 0 X 4 0 z ~ S 0 X n I i

Table 14.5 A comparison of smoking par•rmetcrs between lhe three stages of a cigaretle switching study. Subjects in Group U(ns5) who elected to remain on a low tar Product for lhe final smoking period. Exner'unental Stage Level of Significance I 2 3 Middle Tar Low Tar Low Tar I v 2 1 v 3 2 v 3 - - -- - - Wtf duratlon secs 2.1 - 0.20 2.2 ~ 0.10 2.5 ± 0.12 P(•05 W ff interval sees 37.1 i 4.3 34.3 ± 4.60 , 34.7 ± 4.90 Puff number 9.3 ± 0.54 10.1 ~ 0.64 10.5 ~ 0.84 Puff volume cc 41.0 ~ 2.88 48.2 ± 2.50 52.1 ± 3.24 p(.03 P<•01 Nicotine to smoker mg/cig 1.07 t 0.024 0.89 ;0.023 0.88 ~ 0.032 p(.001 pE.001 Nicoline cumpensation ratio 0.88 ± 0.018 1.08 ± 0.029 1.07 ± 0.039 p<.001 pf •001 --- - Tobacco butt length min 8.4 ± 0.79 8.8 + 0.65 9.8 t 0.96 Cigarette consumption daily 23.8 ± 1.86 27.0 + 1.60 25.4 * 1.00 Mean level ± standard error 7d Boo~SO~~ot

INHAdiATIIONA~ND.#BSORPTIO'~NOFTO$ACCIO~S:WOKE~~ 191 _ ~ . . I In Table 1'4:5 are shown the results of subjects in Group B who electedltoiremain period'of the study: No changes in, butt length or cigarette consumptii'onwere noited e se on n s n o n u r c t mo g p rt s c J p -~>.y . e on the low tar roduta ~` t' d a d wh ~ b'ects we d'th'rd ki e' s th on lbw tar prodiucts. There are no significant differences for any parameter between As in Group A thenicotiine compensation ratio is significantly higher after switching to the low tar, product, suggesting some attempt to compensate but again, as shown y , p p p _,1,_ : b the nicotine diose this com ensatiorr is not com letr As before uff volume This study would confirm other reports in that changes in smoking,parametrn changes in butt Ifngt'h or cigarette consumption. would appcar to be an important fhctiorunicompensation ande there are no significant are 11 demonstrable when subjects swftch to products in a different tar group - there is some attempt to maintain the `dbse"of smoke at a constant level. Inhalation In addition to the above study we have had the opportunity of'louking at the inhalation, pattern inione subject smoking products fromi different tar groups. The subject is a habitual middle tar smoker and measurements of carbon monoxidla - increment and smoke exposure index were made on two consecutive days whilst he smoked his normal brand of cigarette. The results are shown in Fig. 14.13 where it can be seen that there is good agreement between the two sets of observations. 0.007 0. 005 01001. x Middle tarp,roduct' A High tar product • Low tar product f~ ~I I t I tl 1I 20 30 40 70. 50 60 EXPOSURE INDEX (litre sec) Fig. 14.13 The relationship betwcen the increment in alveolar carbon munoxidk partial,pressurrand the smoke exposure index for a habitual middle tar smoker smoking his normal pnoduet (x), and' low tarpraduct (0) and a high tar product' (,~,~. For comparison the linear regression lines of middle and low tar smokers are shown.

1'9'2 SMOKING BEHAV'IIDt1tt' On a third occasion the subject was given a low tar producttoismoke and; aa indicated, there was an increase in exposure index with a marginal fall in carbon monoxide increment. This result parallels the resulrcs obtained from the measurements of smoking parameters outlined above and might suggest' an attempted compensation. The results are also in!agreementwith the previously defined relationships of carbon monoxide increment and exposure index for the different product groups. On another occasion the subject was given, a high tar product to smoke. Inthia situation the results, as shown, are not as one might have expected; the!exposure index decreased as one might have predicted but the carboni monoxide increment unexpectedly showed a dramatic fall. Furthermore, considering the carbon monoxide yield of the product, t'he rise in alveolar carbon monoxide was well below that whirhl one~would have predicted from the carbon monoxide incremertt - exposu!re index relationships as previousl,v discussed. Observation of the chest, pneumogram tracing offere& an explanation for this discrepancy in that the patrcern observed was that' demonstrated, in example 2 of'Fig. 1'4'.7 with an apparent activeexhalation prior to the first inhalation fpllowing,the puff. The only other time: that this pattern has beenobservedl was inone habit~ual high tar smoker who: has been studied and he consist'entlyshowed this feature inhis smoking. The reason for this unusual patternlof smoking must be in terms of aniorganoleptic response, a topic which, has been little discussed in relation to smoking behaviour, The middle tar habitual smoker switching to the high tar product comrnented spon- taneously on the taste and strength of the cigarette such that, he found it difficult to inhale. Such organoleptic factors may however not only be relevant when con• sidering the changes in smoking,pattern, on switching to or: smoking a prodlsct in a higher tar category but'may also be important, ini cont~ributing to the changing parampters.observed, when switching to a lower tar product. If middle tar smokers are asked to comment when given a low tar product they frequent'ly indicate the I products to be unsatisfactory in terms of their strengthiand taste. Conciusionm In this paper„we have attempted to outline some~of the available techniques forthe: analysis of smoking parameters and cigarette smoke absorption, and described their application in alwideranging series of stud'ies. We may attempc to:summarise the act of smoking in terms of the parameters discussed as follows: I. There is 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 aiveolar carbon monoxide levels). 2. There is a significant correlation between the amount of'smoke absorbed by the smoker and t'he smoke exposure indkx derived from the volume and time periods of inhalations.following the puffing of a cigarette. It will thus be realised that the 'dose' of tobacco smoke absorbed by the subject is not simply the product of the 'dose' of smoke presenrtedlto the smoker and the smoke exposure. Rather it is cquallto the product of the 'dose of smoke inhaled and the smoke exposure wherc the'dose' inhaled, tends to:be a constant and represents the 'dose' of smoke presentcd to the smoker modified by factors which are not clearly defined. 1005053010

t • INHALATION AND ABSORPI'lION OF'POBACCt) S4IIOKE' 1'93'. With,regard to differences in the act of'smoking between smokers of different product types we have seen thatfor habitual smokers of middle and'1ow tar products .- there are no demonstrableo differences and the dose of cigarette smoke presenied.to a smoker is:dependent upon the cigarette specification. Diffierencas in, absorption of smoke inhaled are dependent upon the pattern of inhalation but for any given inhalation pattern differencerin, smoke absoprtion are again dependent, upon the cigarette specification. . In switching,studies there is some evidence that subjects adjust their smoking,to maintain a constant `dose"of cigarette smoke but, whila this rnay be true, the possibility of changes due to organoleptic factors has noCbeen ruled out. Whatever the cause of the observed!modifcations tolthe smoking,profile it wou!ld'be important ton ascertain whether, these persist or are relatixely short lived. The broad'approach,to the analysis of smoking taken in this paper has perhaps challeng¢d some widely held concepts and certainly raised aJarge number of questions which will require further study. One mverrdd'ing question, however, which must be posed is whether this type of study can be justified at all? The answer must be `yes' forthe current yardsticks.available for measuring success in providing,a [ow risk product are smoke chemistry screening and the results of bio-testutg in animals, based on standard smoking,parameters: As we have seen the smoker cani may modify these parameters and hence modify the quality andi/on the quantity of smoke when smoking a particular, product. We need to know the extent of such modifcations in order to attempt, in the short term, tolpredict lbng termimorbidity response rather than await the results of loing term epidemiologicaI studies. In any. event, in the final analysis; the yardstlick for judging the relative.risk fact'or of different srnoking,products must be the human response. r Acknowledgement We thank Professor A. Guz, Department of Medicine. Charing Cross Hospital Medical School fbr providing,facilities for technique development. We are grat~eful to the Edit or of Clinical Science and Molecular Medicine for his permission to publish Fig. 14.8 and Fig: 14.9.. References Adams, P.1. (1966), Measurements onpuffs taken by humanismokers. 20th Tobacco Chemists Research Conference. Winston-Salem„N.C: Armitagg, A.K. (1!973) Some recent observations relating tolthe absorption of nicotine fromi tobacco: smoke. [nSrnokingBellaviour: Nlutivesand lncentives;. ed. Dunn, W.LL pp. 8'3-9'L. Washington: V.H. Winston,& Sons. Ashton, H. & Watson, D.W. (1970) Pi,ffing frequency and nicotine intake in cigarette smokers. British Nledical'lournal; 3, 679•68.11. Comer; A.K.,& Creighton„D.E: (1978) The effect of experunental conditions oni smoking behaviour. Thls vnlurne 10054'5~!011

194 SMOKING BEHAYIOtJ[L' Guillerm; R. & Radziszewski, ff. (1975)' A new method of analysing thract off smoking. A,'nnalsduTabnc, 1:3,1,014!10, Rawbone, R.G., Coppin, C.A. & Guz, A. (1'976) Carbon monoxide in alveolar air as an index of exposure:to cigarette smoke. Clinical'Sciersce and Molecular Medicine, 51, 495-501.

SECTION 6

Schachter, Si. Pharmacological and Psychological Determinants of Smoking,. In: -Thornton, R'.EI. (Editor). Smoking Behaviour. Physiological and, PSychological Ihfluences. Edinburgh, Churchill Livingstone, 1978, pp.20S-228'. The low nicotine and tar campaign is based on the notion that ci'garette smoking stems from a variety of psychological, sensory and manipulative needs which,can probably be as well satisfied with a low as with a high nicotine cigarette. If a smoker is smoking to keep nicotine or its meta- bolites at some optimal level, if he switches to low nicotine brands, he may smoke more cigarettes and take more puffs of each. In this case the concerned smoker should smoke high, not low, nicotine cigarettes. The recommendations for smoking low or high nicbtine cigarettes depends onn the relative importance of the pharmacological versus phychological needs satisfied by smoking. Studies on the effects of nicotine on shock tolerance, irritability, and stress and those that support aipharmacplooical basis for smoking behavior are reviewediwith the conclusions that: (1) The psychological and probably the sensory and manipulative gratifications of smoking are illusory. Serious smokers smoke to prevent withdrawal. (2) Smokers regulate nicotine intake. (3) Variations in smoking,rate which customarily have been interpreted inipsychological terms seem betterr understood'as an attempt ot regulate nicotine. (4) Apparent exceptions to a regulatory model of smoking seem understandable in terms of withdrawal. The smoker who fails to regulatp suffers withdrawal. Therefore, a serious case can be made for a pharmacological, addictive view of cigarette smoking, unless there is a long.-term effect of switching brands soithat smokers~ eventually return to their former level of consumption. Two such studies on long.-term effects of switching brands are reviewed. Overall conclusions are that switching to:low nicotine cigarettes results in an increase in amounts smoked so:that the campaign for low nicotine cigarettes is not ustified.

17. Pharmacological and! psychological determinants of srmoking The gist of the anti+smoking campaign is simply ''Quit and! if you can't or won t quit, switch to~a low-nicotine, lotiv-tar cigarette'. With the backing of the American Cancer Society, the Royal College of Physicians and the Public Health Service, this message pervades the mass media and appears responsible for the tedious competition among,tobacco companies for the safest cigarette, thesearch for an acceptable tobacco -free cigarette stimulated by the British government and taxation policies such as that of New York' City which taxes cigarettes by nicotine and tar content in an apparent effort to use economic muscle in order to help the smoker help himself.' Though no one has bothered'to make explicit the premises on whichsucli policy is based, it appears reasonable to guess that, in part, the lovv nicotine and'tar corrtpaign is based on the notion that cigarette smoking stems from a variety of psychological, sensory and manipulative needs whirh~can probably be as well satisfied with~a low as with a high nicotine cigarette. The possibility that this campaign may perversely bc increasing the health~hazards of smoking has been raised by Dbmino (1973);, Russell (1974a) and others who point out that there is evidence, after all, that nicotine is addicting. To the extent that the smoker is an addict, he is probably smoking to keep nicotine or one of its actiWemetabolites at some optimal level. If„then, the heavy smoker does switch to low nicotine brands, he may very, well'end up smoking more cigarettes and taking more puffs of each. HewsTl in the process of regulating,nicotine probably gFt the same amounts of nicotine and'tar and unquestionably get more of the combustion products, such as carb=monoxide which appears to be at least as much of a medical villain as tar or nicotine:for it is implicated in the incieased risk to smokers of arterio, sclerosis, ischaemic heart disease,,fetal darnage and so oni(I;arson, Haag and!Silvette,. 1961; US Surgeon General's Report, 1'9°72). If'this shift in level of smoking is permanent, theinet effect of switching to low nicotine cigarettes shouldl beto inerease the dangers of smoking. From this point of view, the concerned smoker should smoke higli, not low, nicotine cigarettes. Since almost everyone would agree that cigarette: smoking involves both pharRna- cologicai and psychological determinants there does seem to be some support for either position. Whether rationality dictates the recommendation of a low or a, high nicotine cigarette depends, of course, on the relative importance of the pharmacological vetsus the psychological needs satisfied by smoking. I F 1005053015

PEdARa'{ACOLOGICAL AND PSYCHOLOGICAL DETERMINANTS OF SbfOICIM6 209 On the gratificatio ns ofi smoking Altnost any smoker can convince you and himself that there are major psychologqcal' components to smoking. They will convince yoathat smoking calms them; that it' helps them work; that they smoke more at a party and so on. In short, smoking serves some psychological function; it, does something positive fon the smoker and *T this is the reason he smokes. This emphasis on the functional properties of smoking is at the heart of virtually every serious psychological attempt to understand, smoking. :' Presumably nicotine~or tar or some component of the act of smokingis so gratifying r.Vi4 that despite the well-publicised dangers the smoker is unwilling to give up the habit. :.:~~; Undoubted1v the ultimate eulogy of the act is hiarcovitz's suggestion (Marcovitz, 1969V that 'as a psyehologicall phenomenon, smoking is comparable to the ritual of the Eucharist. There the communicant incorporates bread and wine and iniso doing symbolically introjects the Lord Jesus Christ. This is a conscious process, with the hope of identification, of attaining some of the attributes of Jesus. Similarly, the l ;.;X, 'pcting in an unconscious fantasy some object smoker incor orates the smoke intro J P which wt11l confer on him its magic powers."(p. 11082). Among,these magic powers, smoking,serves to'detimit the body image in the quest torthe sense ot seu; to `relieve the unconscious fear of suffocation' and as 'proof of'iinmortality'. Though ;, ~% ?y no one has matched 14iarcovitz's panegyric, almost all'attempts to account for the habit have assumed that it does something positive for the smoker - an assumption that is shared by the smoker himself for n'umerous studies indicate that heavy smokers report that cigarettes relax them or stimulate them„put them at ease, give them some thirtg to do with their hands, and so on. In short, for both the psychologist and, the smoker, the act of smoking is functionalt it does something fprthe smoker' and this is the rea€onihe smokes. In this paper, I shall concentrate on one of the presumed!motivations for smoking. Smokers widely report that they smoke more _,fV when they are tense or anxious and'they also report that smoking calms them. Smoking, then serves a respectable psychological function and this presumably is one of the motivations for and explanations of smoking under stress. Before worrying through interpretiations of these facts, let us make sure that they are facts. Firstly„does smoking increase with stress?' The avat7able evidence indicates that indeed it does, if the stress is fairly intense: In, two almost'identical experiments (Schachter eral, 1977b;'Schachter, Silverstein and Perlick, 1'977), my associates and'I manipulatedistress within the context'of experiments presumably designed to measure tactile sensitimity: In high stress conditions, such sensitivity was measured by the administratio'n, sporadically over an experimental hour, of a series of intense, quite painful shocks. In!lohv stress conditions, the shocks were a barely percepttbbe'tingle. Between the!testing intervals, the subjects, all smokers; were free to smoke!or not as they pleased. In bothistudies, the subjects smoked'considerably more in higtnh than inilow stress conditions. Turning to the effects of smoking on stress, we ask next does smoking reduce stress? The answer appears to be that it depends upon how you look at it. Silverstein (1976) attempted to answer thequestiiomby measuring how much electric shock a subject was willing to take within the context of a study of tactile perception, The procedure required that electrodes be attachedi to a subject's fittgers, thar he be exposed to a series of shocks of gradually increasing voltag; and that he report when 1o05os301!s

210, SMOKING BEI3AVIIDt1'It' - he could fust feei t'he shock, next when the shock first becarne.painful and finally when the shock became soipainful that he could no longer bear it. Silverstein assumed ` that,the more anxious the:subject, the less pain he would be willing to tolerate. There! were four experimental groups - smokers who smoked either high or low nicotine cigarettes during the experiment or who did not smoke at all during this time andia group of non-smokers who did not smoke. The results of this experiment are presented in, Figure 17.11. The ordinate plots the number of shocks the subjects endured before calling it quits. It is:clear that =3` smokers take more shocks when they are smoking high nicotine than when smoking low nicotine cigarettes than when not smoking. Given this pattern one has a choice ;., of interpretations: either nicotine decreases anxiety or lack of nicotine increases' anxiety. The choice of depends, of course, on the position of the group of non- smokers who, as can be seen in Figure.17.1 take virtually the same number of shocks. as smokers on high nicotine. It would appear then that, smoking is not anxiety reducing but, rather, that no smoking or insufficientnicotine.is for the heavy smoker, anxiety increasing. Precisely the same pattern of results emergerin~a study of irritability conducted1by Perlick ('1'977'). Within the context of a study of'aucraft noise, subjects„wat'chirtg a,television drama, rated how annoying they found'a series of sim'ulatedlover-flights. Daring,the experunent, heavy smding subjects were permitted ad,lib smoking of high nicotine cigarettes in one cond'ition; of low nicotine cigarettes in anotherr condition and were prevented from smoking in a, thit& condition. Finally, there was a, control group of'non-smokers. The results are presented irn Figure 17.2 where it can be seen that smokers onhigh, nicotine! cigarettes are markedly less irritated. • by this series of obnoxious noises'than are smokers restricted to low nicotine cigarettes or prevent'edl from smoking. However,,t'Iiese high nicotine smokers are neither less nor more irritated! than the group of non+smokers. Again, it would' appear that smoking I doesn't make the smoker less irritable or vulnerable tp annoyance„ not smoking or insufficient nicotine makes him more irritable. This same pattern~is characteristic of psychomotor as well as emotio'nal behaviour. Heimstra, Bancroft and DeKock ('1'967) exarnirted! the hypothesis that smoking facilitates driving performance by comparing ad la3 smokers, depriwed'smokers and non-smokers in a si;%-hour simulated driving test. On a variety of m'easures of'trarking and vigilance, ad lib smokers do neither better rlor worse than non-smokers but do markedly better than deprived smokers. Again and again, then, one finds the same pattern - smokiitr3,doesn't improve the mood or calm thesmoker or improve his performance when compared wsth!the non- smoker.' However not smoking or insufficient nicotine makerhirrticonsidkrably 'There is of course, an alternative interpretation of this consistent pattern. Rather than indicating withdrawal„it is conceivable that people who become smokers ue by nature more frig}itenedlof;shocltf more irritated by noise and worse drivers thanpeople:who never becomesmmkus, and that for sueh, people smoking is indeed calming and does improve psychomotor performance. Though nothing short of a longitudinal study could' unequivo+cally settle the matter, it shouldibe noted,that there have been a formid9ble number of studies that compared smokers and non-smokers onivirtually every personality dimension imaginable. Smith (1'97l)) in hisaeview of thisiliterature concludes'thatthe only variables which, with reasonable consistency, disctdrrtinate : between smokers and non-smokers are extravers'ion and anti-social tendencies: And evenion these variables the differences are quite small. 1005053017

PHARtitA'Ct)LOGICAL A14D PSYCHGLOG1CAdi DE71SR.Ni[NANTS OT SM©K1NG 2111 THE EFFECTS OF NICOTINE ON TOLERANCE OF SHOCK NUN1B'ER OF SHOCKS 20 t c~.._ NON-SM0KERS 15 10 0-3 rrrg 1 I nrng LOW HIQ,H NICOTINE CONTENT Fig. 17.1 1005053018

212 SMOKING BEHAVIIDUR' THE EFFEGT& OF NICOTIINE' ON' 1RRITABILl~TY~ A b' HEAVY SMOKERS NiOW S'M©KEP5 ANNOYANCE ftATIING (MAGNITUDE ESTIMATION). 300 t 250 t 200 } 100 ~ 50 f 0 LOW HIQH 0 NO (0-3n)(I-3'mg), NO SMOKING NIC NIC SMOKING Fig. 17.2 NICOTINE N'1ANIP'l1LAT10N, worse on all dimensions. Given this persistent fact, how then, to account L the fact that the smoker smokes more when he is stressed? One can, obsious:.; i*,.ounr fimr the generally debilitating,effecxs of no or low nicotine by assumir,g th_: ;he deprived smoked is in withdrawalibut this assumption alone cannot accou_ fo; the effects of sUress on smoking rate unless one assumes tharstress, in so-ie f~on; depletes the available supply of nicotiine. And this hypothesis, of coursr _: ic,Ount, for this pattern of data only if it is the case that the smoker, an addiz„is S=:rking to keep nicotine at a constant level. 1005053019

PHARMACOLOGICAL AND PSV!CHO'LpGICAL D'ETERS6iI'NANTS OF SMOKING 213 Anotherway of phrasing this same conclusion is that the heavy smoker gets nothing out of smoking. He smokes only to prevent withdrawal. I' freely admit that this is a perverse conclusion to reach about a habit that is quite as costly and universally' pervasive as smoking but the existing data for humans don't encourage any other conclusion. Though my colleaguerand I have found occasional hirtts that smoking may do something,for the smoker when compared to the non-smoker (Silverstein, as subjects. It may be that in the early stages of the smoking habit, there are indeed ... .,: rnajorgrati'frcations and effects, that the smoker gradually adapts to these effects andi 1976) in general these differences ~ have been quite small. In addit6on; Heimstra (1973'). has presented tentative evidence that'smokers may have somewhat less mood fluctuation than non-smokers and there have been numerous studies (Larson er al, 1961) suggesting that smoking may affect one or another psychomotor or mental ability but inigeneral these have allibeenismall effects and inconsistent from study to study. It should be noted, however, that altnost all studies of the matter have used long-time, heavy smokers by the time smoking no longer does anything,for hirrt he is t'horoughiy addicted. or some nicotine metabolite as the active:agent, is addicting, the evidence in support of this assumption is puzzlingly inconsistent. On the assumption that one manifesti ation of addictionlis the regulationlof nicotine intake, studies of the matter have either pre.loaded subjjects with varying amounts of nicotine or have manipulated the nicotine content of t'he available cigarettes and measured the effects on smoking. There have been at leasc ten such studies on human subjects with results varying fromino indication of regulation to one study which appears to indicate exquisitely precise eontrol'of nicotine intake. At one extreme, Finnegan, Iarsoniand Haag (1945) and Goldfarb, Jarvik and Glick (1970) supplned subjects with severallweeks' worth of cigarettes of varying nicotine content, and checked daily cigarette consumption. 'I?hough bothh studies did find some subjects who regulated - i_e:, smoked substantially more low than high nicotine eigaret'tes - the groups of subjects as a whole failed to demonstrate regulation; In sharp contrast, Ashton and Watson (1970), observed subjects smoke high and low nicotine cigarettes under controllediconditions and' found evidence of . precise regulation in that theu subjects puflfed'considerably more at Iuw than athigh nicotine cigarettes and, via this mechanism, extracted almost the same amount of nicotine fromithe two kinds of cigarettes. Betweemthese extremes Frith (1971) and Russell et al (1973) find! reasonably gpod evidence of nicotine regulation and' at least five studies (Herman,1974; Jarvik, Glick and N,lkamura, 1970; Johnston, 1942;, Kozlowski, Jarvik'and Gritz, P975; Lucchesi; Schuster and Ernley, 1967),have found a tendency for smokers to regulate nicotine intake but, at best, crudely and impreciselly. Though there is probably no single, simple reconciliation of this spectrum of diverse results one suggestion may partially account for the general failure to find concltzsive evidence for the precise regulation that might be expected from the addictionhypothesis.. There are smokers who don't inhale; there are smokers who simply toy with the habit smoking an oceasional cigarette at parties and meetings and', most importantly„there are undoubtedly many smokers, sensitive to the health hazards, who deliberately itahibit: smoking by such devices as imposing an upper linut' on daily consumption, scheduling Nicotine as addiction Though almost everyone would probably agree that cigarette sntoking, with nicotine 1005053020

T 214 SMOKING BEHAVIOUR smoking, restricitng,smoking to particular occasions and!so on- all deyiccs intcnd'ed .-= _: P to lower consumption and which would tend to mask such behavioural'mani'festations : ; of addiction as tracking nicotine content. To the extent that such pcople are subjects in studies of regulation, one should expect that the manipulationn of levc[of nicotine ~' would have weak effects on smoking behaviour. ~ In aniattemptto eliminate such, subjects, Schachter(i1977) deliberately selected!a : group of subjects who satisfied the:following criteria: a. By self-report, the subject currently smoked1 at least a pack a day and had'smoked • at this level for many years. b. By sellf-report, the subject was trying neither to cut down or limit his smoking. c. If the subject had every attempted to quit, he reported great difficulty and suffering. - d. By self-report, the subject exhibited 'regular' smoking behaviour, i.e. smoked about the same amount each day, began smoking in the rnorning,and continued' regularly throughout the day, etc. . The salient characteristics of each of these subjects are presented on the left side of Table 17.1 where it can be seen that they al1 had smoked a, pack or more a day for at least twenty years. Bor the course of the experiment these subjects agreeditp smoke onlythe:experimenter's cig4retrcies and on aiternating,weeks each subjectwas presentied with cartons of specially prepared and packaged cigarettes which delivered! either 1.3 mg of nicotine per cigarette or 0.3 mg of nicotine per cigarette. Art bedtime, the subjects noted the number of cigarettes smoked. Obviously, there was an inherent and deliberate circularity in the design of this study. I'was simply asking,do smokers who appear to be addicted by one set of criteria (behavioural selfdescription)„behave inianiaddictad fashion on a totally independent criterion (nicotine regulation)? The effects of'the nicotine manipulation are presentedion the right side of Table 17.1. Obviously, the manipulation had a strong Tabte 17.1 The effects of nicotine content on smoking Subject Characteristic_s Smoking Behaviour. Cgs/day on: Subject Age Sex No. yrs. a serious smoker No. cigs/day self-report Low (0.3 mg) Nic High (1.3 mg) Nic qo Increase High Nic to Low Nic J.A. 52 F 30, 30 31.25 21.S0 +45.3 S.S. 37 F 22 40 S5:0D, 40S0, +35.8' R.R. 38 F 19 40 42:50' 30.75 +38.2' R.S. 41 F 27 20 22.75 20.00 +113.8 QR 47. F 29 40-45: 70.75! 58.75i +20:4' R.a. 50 M 40 30 ' 30:25I 26.25 +15i2 1.E S2 M 33 33 48.00 44.25 + 8:5 Mean 45.6 28.6 33.6 42.93 34.57 +25:3

PHARtitACOLOGICAL AND PSYCHOLOGICAL DETEMUINiAMmS'OF'SMOKING 2'1'S and consistent effect on these long-t2ine heavy smokers for each of them smoked more low than high nicotine cigarettes. One the average, there was a 2S% increase (pG.01) ~, of smoking accompanying the manipulations of nicotine content. that the manipulation involved a fiour-fold d'ifference in nicotine content wh9e smoking .... increased, only 25%„it would appear to be at best crude and imprecise regulation. There . ..~„ It does appear, then, that heavy, long-time : smokers do regulate nicotine. Given ; is,, however, reason to believe that nicotine regulation is considerably more precise than ; , these data suggest, First, several studies(Ashton and Watson, 1'970; Herman, 1974; cigarettes would have:to smoke almost nine packs a day of our low nicotine cigarettes to get his customary dose of nicotine. Under these circumstances, virtually any theory Schachter, et al, 1977b) report that smokers puff more at low than at high nicotine cigarettes - clearly a mechanism for increasing,nicotine intake. Second, given the range of nicotine content inithisstudy precise reaulation was virtually impossible. For example, a subject' who normally smoked two packs a day of 1.3 mg nicotine of addiction would, predict withdrawal for the subjects on low nicotine cigarettes. It does appear, then, that heavy smokers do adjust smoking rate so as to keep nicotine at a roughly constant level. To account for this fact, one may suppose that there is an internal machine of sorts -one which d'etects the level of nicotine and regulates smoking,accordingly. To beginconsideration of the nature of svch a regulator let us review some of the basic facts about the metabolic fate and excretion of nicotine. As summarisedby Goodman!and Giltnan (1958): 'Nicotine is chemically altered in the body, mainly in the liver buG also in the kidney and lung. The fraction of nicotine which escapes detioxicartion is completely eliminated as such in the urine along with the chemically altered forms. The rate of excretion of'the alkaloid is rapid, and increases linearly with the dose. Whentheurineisalk~aline, only one fourth as much nicotine is excreted as when the urine is acid; this is explainedd by the fact that nicotine base is reabsorbed from an alkaline urine: (page 622). The effects of the acidity of the urine on the rate of excretion of unchanged! nicotine suggests, given the fact that smokersregulate nicotine intake, that the pH', of the urine may affect the rate of'smoking. Whether an effKct' of any consequence is to be anticipated„however, depends on the proportion of unchanged nicotine which is excreted. One can make reasonably accurate estimates from the work of Beckett and hisassociatesi Beckett„Rowdand and Triggs (1965) have shown that subjects who smoke twenty cigarettes a day excrete anaverage of 1'.0pg nicotine per minuteunder normal cond'itions„ 5:0 1y g nicotine per minute when the urine was made acidic by the oral administration of ammonium chloride!and 0.1 p g/minafter oral administration of the alkaliser sodium bicarbonate. In another study, Beckett and Triggs (1!967) have dbmonstra!ted'that smokers whose urine has been maintained acidic excrete in unchanged form about 35%of known quantitics of nicotine that have been adm!in- Though unfortunately no systematic provision was made in this study to measure withdrawal, there is dramatic anecdotal evidence that the subjects who were the worstt regulators in this study were in states of marked irritability andl explosive emotimnality while on the low nicotirte cigarettes. Supporting this observation, Perlick (1977)iand Silverstein (1976) have both demonstrated experimentally that heavy smokers on low nicotine cigarettes are marked2y, more anxious and irritable than such smokers on high nicotine cigarettes. H• 10U5053022.

216 SMOKINC BEHAVIOUR istered either by intravenous injiection, inhalat2onof nicotine vapour or smoking. Ptrtting,these facts tiogether, it appears reasonable to estimate that the proportion of nicotine which will be excreted in unchanged form will vary with the rnanipulated'. acidity of the urine as follows: urine is: ` % nicotine excreted acid 35 normal 7 alkaline <1 Obviously the exact proportions will vary with the precise pH of the urine. Howevery, one thing,seems clear: given the quite low proportion of unchanged nicotine which is excreted under normal or placebo conditions, increasing the alkalinity of'the urinee can at best have trivial effects on plasma level nicotine while increasing the acidity of' urine can potentially have substantial effects. If then, one assumerfirst, first,,that in urinary pH are reflected in circulating nicotine and second, that the amounts smoked vary with changes in plasma level nicotine, it should be expected that experimentally increasing the acidity of the unine will increase the amounts smoked. To test this guess, Schachter, Kozlowski and' Silverstein (1'977) manipulated urinary pH by, in alternate weeks, administering to a group of 131 smokers substantial daily doses of placebo or of the acidifying agents vitamin C'(ascorbic acid) and Aciditlin (glutamic acid hydrochloride). The subjects were given cartons of their favourite cigarettes and kept count of the amount they hadIsmoked each day of't'he study. The effects of these manipulations on smoking,are presented in Table 17.2'where it' can be seen that aeidiiicationis accompanied by increased smoking. During the period they were taking,either of two different acidifying agents, subjects smoked 700/'o more cigarettes than during,the time they were taking a corn starch placebo. - It should be specifically noted'that inkeeping with the magnitude of the phannacol- ogical effects this 20% increase is not a large experimental effect. On the basis of our estimation of nicotine excretionione would expect, at best, roughly a,30r1'o increase Table 17.2 Ttireffecta of vitaminC, Acidulin and'placebo on cigarette smoking, Condition Cigarettes smoked Mean % change per day Vitamin C 26.7' Placebo 2311 Acidulin Comparison Vitamin C vs Placebo Acidulin vs Placebo from placebo +19.8 +20.9 <.os !'nsI

PHAIL1tACOi.O6ICAIL A'NDPSYCHIDLfJCICAL: DETERMINANTS OF SMOKING 217 in smoking with even a strongly effective acidifying manipulation which~ours was not. It seems dear t'harof the body's two chief mechanisms for disposing of nicotine, enzymatic breakdbwn and, urinary excretion, of unchanged nicwtine,,tlte urinary excretion route plays by far the lesser role in the confirmed smoker. Nevertheless acidification does affect smoking,behaviour and this finding raises the possibility that it may be usefiallto invoke this bit of pharmacological machinery in order to understand some of the presumed psychological and situational determinants of srnoking rate. Conceivably, events that stimulate smoking may do so:via their action on urinary pH. To learn~ if this guess had' any merit as a possible explanation of the stress-smoking relationship, Schachter et: al (115'Z7b) examined the effects of a variety of academic stressors on pH. In one study, subjects urinated immediately before an obviously stressfui event suehl as d'el'ivering a Coilbquiumlecture or taking Ph.D, examinatimns. And, for control purposes, these same subjects urinated ac precisely the same time on routine, non-stressful'days. The results are presented in Table 17:3 where it cann be seen t'hat for nine of ten subjects, the urine,is considerably more acid'ac on stress than: on control days. Precisely the same pattern is manifest in another study of the effects of stress (Schachter, er a1, 1977b). Nine of the twenty members of an undergraduate seminar Table 117.1 The effects of academic stresuon urinary pH Subject pH' on: Stress Day Control Day Stress-Control E.G. A. CollioquiumiTalk 5.50 6.35: -0.8'5 H:T. 5.70 5.93 -0.2'5 M.C. 6.70 6.90 -0.2b H.K- 5.50 6.20 -0.70 ~ S.S. 5.40 6.4I5 -1.05 Q. E.D. B. Ph.D. Oral Defense 5.40 7.10, -1.7 0 CA 0 A.L. 6.00: 6.2®, -0:20 CA' W C: Ph.D. Comprehensive Examination 0 B.S. 5.85 5:80 +0.05 IV . I /~~ ~1 LS 5.2D 5.70 -0.50. D:P. 5.40 5.70 -0_3.0 All subjpcts(mean) S'.67 6.24! - .57 were assigned to read highly technical material and prepare 1045 minute oral reports for class. The remaining students were simply expected'to listen to the reports. Alll' of the students urinated shortly before class. For the reporters pH'.averaged 6.01 and for the listeners 6.67 (p .OS): Before a control class, pH was identica1for the two

2'1'8' SMOK1NG B'EF+fi#VIOUR groups of students. It does appear that stress, at least of the sort'endernic to~academiC 't<-' .., J however, considerably calmerthangroups of smokers who are prevented from ~ smoking, or: permitted to smoke only low nicotine cigarettes: This fact'can be interpreted as h=,' ' life, acidifies the urine,- a f nding which at least encourages the exploratlom of a pharmacological interpretation: of smoking behaviour, 'fo review the line of argument so far: it has been widely reported that'smoking increases with stress and that smoking is zalming. These observations appear to go hand in hand and to supporr the assert2on that nicotine or tar or some component of the act of smoking is anxiety reducing. The experimental facts are peculiarly at'variance with this interpretation. Smoking dbes.inerease wi th~stressbut smokingg smokers are no more or less calm than a control!group of non-srnokers. They are, indicating that smoking isn't anxiety reducing but'that' not smoking or insuflicient nicotine is anxiety, increasing: In effect, the smoker smokes more during stress because ~-~ of budding withdrawal symptoms andl not because of any psychological property of nicotine or of the act of smoking. Such an interpretation is plausible.if one assumes f>w::., that the smoker smokes in order to keep nicotine atsome constantlevel and that there is something about the state of'stress that depletes the body's supply of nicotine. A variety of studies have been described which, via the:effects of urinary pH' on the rate!of'nicotine excretion, suggest'a biochemical mechanism that couldiaccountfior this set of facts. Though this elegant juxtaposition of facts makes altnost irresistable the conclusior~ that the smoker's tnind is in the bladder, obviously we are hardly yet in a, position to rule out psychological explanations of'smoking. Though'anxiety reduction'' seems, by now, a particularly unsatisfactory explanation of the stress-smoking, relationship, innumerable other purely psychological explana'tions are still conceivable. Ferster ('1970), for example, has attempted to explain the relationship in theseterttas: 'With the increase in emotional syrnptoms there is frequentlya major cessation in rnost of theongo•rng,repertoire the person might engage in. With such a temporary decrease in the frequency in most of the items in al person's repertoue; the relative importance of even the minor reinforcers increases enormously. Thus the relative posit6on of smoking in the entire repertoire is increased considerably whenother, major it'etns of the repertoire are depressed: Sm,oking,becomes something to do when no other behaviour is'appropriate': (page 99). In short, though the effect of pH oni nicotine elimination is a well established pharma- cological fact, it may have little, if anything, to do with the effects of stress on smoking, for it is certainly conceivable that, stress, with or without acrompanyirlg,pH changes, wilI~ affect smoking rate. In order: to learn if pH changes are a necessary and suflficient' explanation of the stress-smoking,relationship, it is clear that we must experimentally pit the:mind against the bladder and this Schachter,,Silverstein and Perlick (1977) - attempted!to do in an experiment, which independent'liy manipulated stress and the pH of the urine. If it is correct that pH changprare a necessary parn of the machinery, we should expect rnore smoking in high, than in low stress conditions when pH is uncontrolled and no difference between the two conditions when pH is experimentally stabilised. If, on the other hand, pH changes are irrelevant to the smoking-stress relationship, therrshoulti be more smoking in high than in low stress conditions no matter what the state of the urine.

PHARMACOLOGICAL AND PSYCHOLOGICAL IDETERMiINANTS OF SMOKING 219 9 In this study, too,, stress was manipulated by use of electric shock. The experimentt alteady describ ed on the effects of stress on smoking,('Schachter et a4 1'977b) was replicated with one majpr modification - in one pair of conditions the high or low stress manipulation began ffity minutes after the subjects took alplacebo; in the other condition, it'began fifty minutes after subjects had taken 3g. of bicarbonate of soda - azr agpnt virtually guaranteed to quickly elevate urinary pH' and for a time to stab- t7ise it at highI}r alkaline levels. In Table 17.4, we note fust the effects of the man- ipulation on uriirary pH. Examining first the two placebo conditions, it will be noted1that pH decreases inithe High Stress condition (p =.02),and tends to increase. Table 17.4 The effects of themanipulartions oin~urinary pH Nfean piH: No. of'subjects whose pH: Condition N Pre- stress Post- stress Pre- post Decreased Stayed same Increased High Stress- Placebo 12 6.00, 5.83: -0.17' 8 3' 1 Low Stress- Placebo 12 5.99 &13 +0:114 4 1 7 High Stress- Bicarbonate 1'2' 6.08' 7.44, +i.36' 0 0 12 Low Stress- Bicarbonate 12' 6.20, 7.01 +0.81 2 1 9 in.the Low Stress condition. In the two bicarbonate conditions, in sharp contrast, pH inereases markedly from the beginning to the end of the experiment and the, stress manipulation has had absolutely no effect on pH. Next we note that on alvariety of seDf•report measures, the manipulation of stress was highly successful in both the placebo and bicarbonate conditions. Obviously, then, the conditions necessary tolpit the psychological against the pharmacological explanatibnof the effects of stress on smoking have been established. Subjects in, High Stress conditions are considerably more tiense than are subjects in Low Stress conditions, whether they have taken a placebo or bicarbonate. In the placebo conditions, however, where pH is uncontrolled„stress aeidi'fies whereas in the bicarbonate conditions, it does not. The effeets of these manipulations on smoking are presenrted in Figure 17.3 which plots the mean number of'puffs taken by subjects once the stress manipulation had begNn. It, is clear that with placebo, there is considerably more smoking in high than in low stress conditions while with bicarbunate, stress has absolutely no:effect on smoking,(interaction p<.01)i It does appear, then, that smoking under stress has nothing to do with psychological, sensory or manipulative needs that are presumably actiivated by the state of stress but is explained! by the effects of stress on the nane of excretion of nicotine. The smoker under stress smokes to replenish nicotine supply. not to relieve anxiety. Obviously, the research presented is an openly reductionist attempt to explain uenu

220' SMOKING BEH,PIVIOUR THE EFFEGTS OF SODIUM BIIIGARBONAT'E AND PLACEBO ON, SMOKING UNDER STRESS NUiMB'ER OF PUFFS 30t . 20 10' T LOM/ DEGR'EE OIF STRESS' HIGH! Fig. 1'7:3

PHARMACOLOGICAL AND PSYCHOLOGICAL DETERMINANTS OF SMOKING 221 of the effects of psychological variables without making,use of the conceptual equipment of psychology. I believe that in the case of stress; the attempt has been successful'for given the facts outlined, attempts to formulate the : stress•smoking relationship in psychological terms (Ferster, 1970;,Hunt, 1970; Marcovitz, 1969; Nesbitt, 1973; Schachter, 1973) seen unnecessary ad hoc constructions. In addition to stress, there is evidence suggesting that this may also~be the case forr the widely reported effects of party-going on smoking. In two studies„Silverstein, Kozlowski and Schachter (1977) have found that party-going does increase smoking and have also toun(V that parties markedly increase unnary acidity. This is true tor non+smokers' s as well as smokers-a finding,which indicates that'it is not'smoking which is the cause -! " of acidity and which rnakes'somewhat more plausible the guess that the urinary pH -• mechanismimay also be responsibie:for the party smoking relationship. I suspect that many of the presumed'psychological and situational determinants of'smoking behaviour may prove reducible tio, these elementary biochemical terms. It must be admitted, however, that satisfactory though this mechanistic view of smoking may be for understanding the behaviour of many, perhaps mosty smokers, the apparent exceptions to this model are maddeningly various. There are smokers (Schachter, 1973) who do: not track nicotine content. Though it is known (Isaacc and Rand, 1972) that plasma nicotine level is zero on awakening, there are smokers who4ind cigarettes distasteful in the morning and do not light up their first cigarette before lunchtime. Though withdrawal is a necessary component of virtuaily any model of addiction, some orthodox Jewish smokers, forbidden to smoke on the Sabbath, report that they can do so without a qualm. And so on. Just how to cope with such blatant exceptions is problematic. Perhaps it is necessary to invent psychologicai'typologies (McKennell, 1'973; Russell, 1974b; Tomkins, 1968) toaccommodate the distressing,apparent variety of smokers, but I find'this'an unsatis• f~ing scientlfc stratagem. As a working hypot'hesis, I propose instead'that virtually " all'Iong-titnesmokers areaddicted and, suggest that, many, perhaps all; exceptions to, an addiction model can b'e understood'in terms of such notions as self-control, cioncera with health, restraints etc. Certainly alI smokers are aware of the dangers andI expense of'smoking: To the extent that such concerns are prominent, the smoker probably inhibits his smoking by such devices as imposing an u!pper, limit on his daily consumption, scheduling his smoking, and so on -devices intended to lower consumption and' which would tend to masksuch behavioural''manifestations of addiction as~tracking nicotine content. If thi's is correct, we should' expect to find other, less obwious indications'of addictionn and, of these, I would'suB8est that withdrawaliis the key. Obviously anyone can give up smoking, limit his daily intake or restrict smoking,to particular times or occasions if he is willing and ablrto put up with the withdrasval syndrome. If it is correct , tharvirtually alliIong,titne smokers are addicted, it should be anticipated'that smokers who don't smoke in the morning wi11, be more irritable at that time of day than in, the afternoon; that smokers who restrain their sm'oking will be more volatile people than heavy smokers, and so on. To: test such expectations, Perlick ('1'977) in the experimentdescribed'e'arlier, compared a group of'heavy, unrestrained'i smokers~ to a, matched group ofhighly restrained smokers, mostly former heavy smokers who on a variety of indices indicated that'they were deliberately and'successfully attempting to cut down, though not eliminate, smoking by a combination of devices . 1DOS0a~~~~8

222' SI+iOKITlG BEEdAV!IbUR' such as smoking cigarettes only halfway, smoking,very low nicotine cigarett~es, counting daily intake and the h7te. On the average these~restrained, srrtokers reported smoking,at a rate less t;han, half of their former level. As described earlier, all subjects rated how annoying they found the noise of each of a series of simulnted aircraft over-flights while, depending on condition, they were either prevented from smoking, or permitted ad lt7iismoking,of'high or of'low nicotine cigarettes. It should be noted first that inithe conditions where they were permitted to smmke, restrained former heavy smokers smoked'oniy half as muclvas did current hearryy smokers. They behaved in the laboratory, then, as they report they do in life. The effects of these manipulations on the two groups of smokers are presented in, Figure 17.4. As noted earlier, the extent to whichiheavy, unrestrained smokers were annoyed depends on the nicotine manipulation. When they did not smoke or smoked very low nicotine cigarettes they THE EFFECTS OF N1COTiNE DEPRIVATION ON THE IRRITABILITY OF' HEAVY S'11OKERS~:NO'N-5M0KER5, AND RESTRAINED SMOKERS ANNOYANCE RATING :-~, :. (MA'GNITUDE ESTIMATION) 3001 A HEAVY 'SM0KER5 5 C NON I SMt)KE'RS' 61f.5TftAIPJED' SMtDKfiRS. 250 200 ~ 150 so 0: lDW NIGM 0 0 LOW MIG ._ NO (0.3 m9) (('3 nn9)' NO N0: (Oa3 i^9)(1'3 ng)' SMit)KJNG NI4 NIG 51MOKUiIG' ' 5A'10KIMG, fiUC NIG NICDTINE W1AN1PULATION Fig. 1 7.41 were markedly more annoyed than when they smoked high nicotine cigarettes. The restrained, former heavy smokers stand' in fascinating contrast for they were: chronically annoyed - as they should be evenlin the high nicotine condition where they were still getting,considerabl.y less nicotine than in former days was their want. In other tests of't'he same hy,pothesis, Perliek (1977) dernonstrates that such, restraiited smokers eat more than do heavy smokers whenigiven free access teicandyand alsu do worse at a proofreading task requiring concentration. Restrained sniokcrs appear to be chronir:a'lly more irascible, to nibble more and to have poprerctonccntratiim than 1005053029

0 PfiAR'hfACOLOGICAL AT;tD!PSYCHOt.OG1CAL DETER%f INANTS 0'(i S~'lID1:IMG' 223' unrestrained smokers. It is possible to control and restrict smoking;bu2 at ai price - and the price appeamto be a chronic state ofwithdrawal.' It does appear that one of the exceptions to a purely addictive view of'smoking is no exception. I suspect that this shalPbe the case with most of these exceptionst and that by'taking,account of withdtanwal we can understand those studies (Finnegan erQl,' 1'945) (Goldfarbb et A 1'970) which fail to demonsurate nicotine regulation. I:et us review our conclusions so far. For the confirmed smoker: 1!. The psychological andi probably the sensory and manipulative gratifcations of smok'ing,are illusory. Serious'smokers smoke to prevent'withdrawal. 2. Smokers regulate nicotine intake. 3, Variations in smoking rate which customarily have:been interpreted in psychological terms seem better understood as an attempt to regulate nicotine. 4. Apparent exceptions to a regulatory model of'smroking,seem understan'dable in terms of'withdrawal.'Ihe smoker who fails to regulate suffers withdrawal. Given this array of factra formidable case can be made:for a predominantly pharmacolbgical„addictive view of cigarettie smoking and it wouldy certain9y seemm that the campaign for low nicotine cigarettes is misguided and rests onia set of fallacious premises. It must be noted: however„that with the exception of the Perlick (1977) study these conclusions are all based on stud'aes in which the state of nicotine deprivation or'lowered nicotine intake is maintained from an hour or so to, at most, a few days as inithe Schachter (1977) study. Can we expect that, in real l'ife„shiffing to a low nicotine cigarette will, lead to a permanent increase in amounts smoked or is there some sort of adaptation process so that eventually the smoker returns to former levels of consumption? ' The question is crucial and particularly so in light of ('a) Hammond et aCs (1976) demonstration th'at heavy smokers of low nicotine cigarettes are in: considerably more danger than light smokers of highh nicotine cigarettes even when tar'and nicotine intake, by'my ealculation from their data, are probab'Iy, roughly equivalent and (b) Ross's ('1'976a, I'9'7'6b) evidence that carbon monoxide, hy,drogen cyanide and nitrogen oxide delivery is:considerably greater inimost of the popul'ar, brands of low nicotine„Filter cigarettes than in high nicotine,, non- filter ;cigzrettes. The!only evidence I know of on the long-time effects of switching brands derivess from a major study conducted by the American Cancer Society (Hammond and Garfinkel, 1964) and a considerably smaller scale version of the same study sponsored by the Public Health Service (Waingrow and Horn, 1968). In both studies subjects were interviewed about their smoking habits'twice over a two-year period. Since • One alternative interpretation of these data must be considered. It is conceivable that naturally irascible:people are most 1Diely to restrain their smoking. If so, thesrresults could bcattributable to self=seleetion ratherthan,withdtawaL Acutely aware of this possibiliry; Perlick (1977)lcompared these groups on numbers of personality and dtmographic variables and found~no diffcrences betwcen, the two groupL t With one exception- therrare a small number of long-time, light smokers who give no cvidence of nicotine reeulation Schachter (I1977) and no indication ofwithdrawal when dcprivedof nicotine; Perlick (1977). What to make of such cases is, at this time, equivocal but by any of the standard criteria of 3ddictionthey appear to be genuinely non•addictedsmokers. 1005053030 _ .,,

224 SMmKPNG BEHAVIOUR over this period many subjects switched brands of cigarettes, it is possiblt to evaluate the effects of changing,brands ow the number of cigarettes smoked. On the basis of such analysis, these investigators conclude that switching to a cigarette with lower nicotine content does not increase the amount'smoked'and on this basis Hammond `" er a4 (1976) justsfy the campaign for low nicotine cigarettes. 11 It shall be my contention that'the particular mode of'analysis employed inithese studies unfortunately obscures the relationship of shift in nicotine level to amount smoked and in fact what, trends exist in these data suggest, for many smokers aa conclusion that is opposite to that drawn by these authors: Though both studies are similar, I shall restrict my discussion to theRammond and' Garfinkel'(1964)) paper for inthe:Wautgrow and Horn (196g) study the number of subjects who switch to lower nicotine brands is so small (I+J = 161) and the data are presented in such a way that it'is impossible from the published material! to make the kindlof analysis requiredl Hammond and Garfinkeli(1'954) divide their group of 98,632 male smokerss into fiour categories - those who in 1959-6b'smoked'less than tien cigarettes a day, 1i0.19 cigarettes a day; 20-39 cigarettes a day; and forty or more cigarettes a day. An interviewee is categorised as changing,the amount smoked only if in 1961-62 his answer to the qtrestion'how many cigarettes do you usually smoke a day?' moves him from one category to another. Thus if a 195'9 pack-a-day smoker were in1'961to report that he smoked 35 cigarettes a, day, he would not be classified as inereasing,ift smoking; only if in 1961' he reported smoking forty or more cigarettes a:day would be be so classified. To understand'the problems created by this particular mode of'categorisat2oniit is necessary to examine a frequency distribution of smoking behaviour. Since Hammond & Garffutkel present only grouped data, I have plotted in Figure 17.5 the distributionn of answers to a question about' daily cigarette smoking included in some of'my own surveys. It is immediately evident first, that most smokers answer such a question in round nurnbers, that is, they say they srnoke twenty, thirty or forty cigarettes a day and second, that in each of the Hammmond'>Garfinkel categories by far the . heaviest concentration of smokers fall at thclower end of the category. Thus in the 20139 cigarettes a day category, 669'o of the subjects report that they smoke twenty ©garettes and 77% report that they smoke fewer than thirty cigarettes a day. Givew this distribution it can be simply calculated that i'f every subject in the 20-39 cigarette category were to increase smoking by 25`h, the liiarnmond-Garfnkel criteria would permit us to classify only 3.5%of t'hese subjects as increasing. Similarly, if every subjeet inthis category were to increase~his smoking by 50% only 24% of all of the subjects wouldibe classif~ied as increasers. Though not as extreme thesame unfortunate dreulmstance!obtainsinitachofthese categories except the 4~0+cigarettes category where, by definition, no one cart: increase smoking, for 40+ is the maximum category. It can scarcelybe considered surprising,that these investigators find relatively few people who increase smoking with time and fand'that changing brands has no effect on t'he amount smoked. Even more perversely a breakdown of the Hammon-Garfnkel data indicates in Table 17.5 a significant tendency for a shift to a lower nicotine cigarette to result in.an increase in amount smokedlin those categories (1-9') and (10-1'9) where, as indicated in Figure t'7.5; because a larger proportion of subjects are at the upper end of the category, the distributions are swchlas to make it more likely that changes will

® PHARMACOLOGICAL AND PSYC1t0LOIGICAL DETERSfINnNTS'OF SMOKING 225 FREQUENCY 01STRIBUIfION OF NUMBER OF GiC,ARETTES_ SMOKED PER DAY' NUMB'E?. OF GhSES 140 T n 120t ' II00t 80t 60} 410 t n wf 1-4 6-9 10 I I-!4 15' I6i9 120 2t24 25 26*?9'30 35 40 45 50 5D l NUN1OEFl OF ClGARJ:TTES 5190KED P[R' DAY 5 Fig. 17.5 be detected. Though these differences are small, they are highly significant and do at' least suggest that an analysis based on a less stringent criterion of change might very well reveal that switching to low nicotine cigarettes has a marked effect on amounts smoked. Ihough~ the results of my own work obviously bias me to this expectation, it is clear that this point is hardly yet proven within the context of a large scale, long time flield study. It is also clear, however, that the majpr body of data that has been used to justify the campaign for low nicotine cigarettes dioesnothung, of the sort. Table 17.5 Changes in number of cigarettes smokedper day in relation to decrease in in nicotine content per cigarette (Adipted from Hammond and Garfinkel, 1964, Table 8) 1961-62 cigarette smoking,of men who smoked: 1- 9 cigarettes a 10-19 cigarettes a 20-39 cigarettes a dny in 1959•60 day in 195I9L60 day in 1959-6i01 Changss ut nicotine content of cigarettes smoked in 1961- 62 vs: 1959-60 Total N % who increase to 10+ Tot'al % who increase to 20+ Total °S who . increase to 40+ 5136 3'9.9' 14047 42.4 51456I 9.3 5132 47.4 13'33 47.3' 4648 9.1. 11.17 12.12 0.2 .001 .001 na. ;:,

226 SMOKING BEHAVIOUR Acknowledgements . . I antindeb'ted'.tt7lDr. Jeremiah Barondess and Dr. Danrid' Rush for their critical reading of this paper. The permission of the editor of Annals of Internal liiedicine to reproduce this article is gratefully acknowledged. References Ashton, H. & Watsonl(1970) Puffing frequency and nicotine intake in cigarette smokers. Brdti.rh hledlcallournal, 3; 679-6811. ~Beckett!, A.H., Rowland, M; & Tiiggs, E.G. (1965), Significance of smoking in investigations of urinary excretion rates of amines in man. Narure. London, 207, 200-201. Beckett, A.H. & Triggs; E.G. (1967) Enzyme induction in man caused by smoking. Nature. London, 216, 587. Domino, E.F. (1973) Neur~opsychopharrnacology of nicotine and'tobacco smoking. In Smoking Behaviour: Motives and Lncemtives, ed. Dunn, W.L. pp.S-3'1, Washington: V.Hi Winston4 Sons. Ferster, C:B. (1970) Cornments on paper by Hunt and'Matarazzo. In Learning Mechanisms in Smoking, ed: Hunt, W.A. Chicagp: Aldine. Finrtegan, J'.K., Larson, P.S. & Haag, H.B: (1'945) The role of'nicotine in the cigarette habit: Science, N. Y., 102, 94-96. Fri 'Uli, C:D: (1!97'i') The!effeet of varying the nicotine content of cigarettes on human smoking behaviour. Psychopharrnacologia; 19, 18'8'-192: Goldfarb4 T.L., Jarvak, M.F. & Glick, S.D.(1970) Cigarette nicotine content asa determinant of'human smoking behaviour. Plychopharmacologi4 17, 39-93: Goodman, L.S. & Gil'rnan, A. (1!9'58) The Pharrrtacological Basis of Tlcerapeutics, New York: MacMillan. . Hammond~ E.C. & Garfinkel, L. (1964) Changes in cigarette smoking: Journal of the Narional Cancer Institute, 27, 419-4!42. ' Hammond~ E.C., Garfinkel, L., Szidm'an, H. & Lew, E.A. (1976) Some recent fitnd.ings aoncerning cigarette smoking. Paper presented at a meeting on, "The Origins of HumaniCancer."'at ColdiSprings Harbor Laboratory on September, 14; 1976. Heimstra4 N. (1973) The effects of smoking,on mood change. ln Smoking Behaviour: Motives and Incentives ed. Dunn, W:L., pp. 197-207. Washington, V.H. Winston & Sons. Heimstra, Ni W., Bancroft, N.P. & DeKock, A.R. (1967) Effects of smoking upon sustained performance in alsimulated driving task. Aiurals of theNew York Academy of Sciences, 142, 295.307. Herman, C.P. (1974) Externat!and internal cues as determinants of thesmoking behavior of lighr and heavy smokers. Jounral'of Personality and'Social Ps,vchulogy.. 30;664-672.Hunt, W.A. (1970) (ed) Learning hrechanisms in Smoking Chicagu: Aldine. Isaac, P.F. & Rand, MJ. (1972) Cigarette smoking and plasrrta levcls of nicotine. Nature, London, 236, 3081 Jarvik, M.E., Glick„SM. & Nakamura, R.K. (1970) lnhibitioniofcigarctte smoking, by'orally administered nicotine. Clinical Plrarniacolnsy and Tlrrra,herrtics„ 11, 574-576. . 1005053033

PHARMACOLOGICAL A'ND'PSYCHOLAGSCAL D'ET&RMTNANTS O'F SMOKING 227' Kozlowski, L.T.,,Jarvik,lr1.E: & Gritz, E.R. (1975) Nicotine regulation and cigarette smoking. ETutical Pharmacology and'Therapeutics; 17, 93-97. Larson, P.S.,,Haag; HLB.,& Silvette, Hi (1961) ; Tobacco. Experimental and Clunical. S•tudies. Baltimore: Williams & Wilkins. Lucchesi, B.R., Schuster, C.R. & Emley, G.S. (1i967) The role of'nicotine as a determinant of cigarette smoking in man with observations of'certain cardiovascular effects associated with the tobacco alkaloid. CTfnical Pharmacology and Therapeutics, 8, 789-796. . Marcovitz, E. (1969) On the nature of addiction to cigarettes. Jour>,ral'of the Aimerrcan Psychoanalytic Association, 17, 1074-1096 McKennell, A.C. (1'973) A Comparison of Two Smokbag Typologies Research Paper, 112. London: Tobacco Research Council. Nesbitt, P.D. (1973) Smoking, physiological arousal, and emotional response. Journal of Persortality arrd Social Ps3 cholngy, 25, 137 -145. Perlick„D: (1'977) The wit!hdrawal syndrome: Nicotine addiction and the effects of stopping,.smoking in heavy andilight smokers., (Unpublished doctoral d'issertation). Columbia University. Ros:s, W.S: (1'976a) Poison gases:in your cigarettes, Part 1: Carbon Monoxide. Reader's Digest, November, 1976. Ross„W.S: ('1976b) Poison gases in your cigarettes, Part II, Hydrogen Cyanide and Nitrogen Oxides. !*'eader'sDfgest, December, 1976. Russell, M.A.H. (1974a) Realistic goals for smoking,and health. Lancet, I; 254-258. Russell, M:A.H. (1974b) The smoking,habit and its classitiication.Practitiovrer, 212, 79'1.800: RusselI, MIA.H., Wilsoni C., Pate1, U.A.,,Cole, P.V. & Feyerabend, C: (1973) Comparison, of'effect on tobacco consumption and carbon:monoxide absorption of changing to high and lrow, nicotine, cigarettes. Bdtish Al edical Journal, 4, 5 112-5~16. Schachter, S. (1973)', Nesbitt's paradox. In Smoking, Behayiorur.• Nlotives and lncentives ed. Dunn; W.L. pp. 147-155. Washington: V.H. Winston & Sons. Schachter, S. (1977) Nicotine regulation in heavy and light smokers. Journal of Experimental'Psychology: General,' 1106, 5.12. Schachter, S., Kmzlbwski, L.T. & Silverstein, B. (1977a) Effecmof urinary pH on cigarette smoking. Journal of ExperimrntalPsychology: General. 106, 13-19. Schachter„S., Siiverstein, B:, Kozlowski: L, Herman, C.P. & Iiiebling; B. (1977b)i Effects of stress on cigarette smoking,and oniuritoary pH. JournaLof Experunental. PsyeAology: General, I06,,2430: Schachter, S., Silverstein, B'. & Perlick, D. (1977c) Psycholpgical and pharmacological! explanations of smoking under stress. Journal of ExperimentaLPsychology: General, 106, 31-4I01 SiH+erstein, B. (1976)i An addiction explanation of'ci¢arette«induced relaxation. ('Unpublished!doctoral dissertation). Columbia University. Siliverstein, B.,, Kozlowski, I..T. & Schacluer, S, (U977) Social life, cigarette smoking, andl urinary pH. Journai'of Experimental Psychology: Grnrra4' 106, 20123. Smith; G.M. (1970) Personality and smioking; A review oFl the empiricallitcrature. In Learning,rlfechanisms in Smoking, ed. Hunt, W:A., Chicago: Aldine. Surgeon General's Report (1972) The HcaltJi Cvnseqttenccs of Smoking, U.S. Departmenrof Health, Educationiand Welfare. 100S0S3034

2281 SMOKING BEHAVIOUR Tomkins, S. (1968) A modified model of smoking beHaviour: In Smoking, Health and'Behavion ed, Borgatta, E.F. & Evans, P.R. Chicago: Aldine. ~= Waingrow; S. & Horn, D. (1968) Relationship of number of cigarettes smwkcd'to "tai' rating. National 'Cancer Institute Nlono,graph, 28, 29-33'. N ~. Q ~. 0 ~ W. 0 -, W U1 ~

Changes in the Cigarette Consumption of Smokers. in Relation To Changes in Tar/'Nicotine. Content of Cigarettes Smoked LAWRENCE' GA RFI'1`l xEL '.-'•:Abstract: Over a 13-year period, 59 per cent of 28,36,11 =.`'~ smokers decreased the tar and nicotine (T/h1) level in the cigarettes they smoked without changing the number of cigarettes smoked to any important extent. On, the other hand; more than 54 per cent of the : "less than one pack a day" smokers as compared tolonly 25 per cent of the "one: pack or more a day" smokers increased the number of cigarettes smoked. l+diicotine dependency plays a minor role: in determining,the smoking habits of those who continue to smoke on a long-term basis. (Am J Public Health 69i 1274- 1'276, 1979.) Several investigators have suggested that lowering tar and nicotine (TLN) content of cigarettes may result in in- Address reprint requests to Lawrence Garfinkel„Assistant Vice Presidtnt„ Epidemiology and Statistics. Department of Research, Am-^ican Cancer Society, Jne., 777"1}tind Avenue, New York„NY 4 This paper, submitted to the Journal March 2'Z„ 11979;,was n,_/ and acceptedlfor publieation May 24, 1979. 1274 . . creasing,the cigarette.hazard because smokers will increase the number of cigarettes they smokea" 2 An increase in nico- tine dependence or "regulation?"' occurs over short, periods of tinte,' suggesting to some thao lowering TIT'f' content may doi more harm than good. However, TIN yields have de- clined'by about' one-half 'o ver th e past' 15-20 years without a doubling of cigarette consumption,' Evidence from the American Cancer Society (ACS) study indicates that low TIN smokers had small but'measur- able reductions in mortality from all' causes, heart disease, and lung cancer compared to those who smoked relatively high, T/N cigarettes,s yet those who smoked' one or more packs a day of low TilAl'cigaretter.had higher mortality rates than those who smoked;, less than one pack a day; high TCNi cigarettes. Thus the number of cigarettes smoked:could be a more important factor in morbidity than the TIN'level of the cigarettes smoked. Findings of the ACS study, suggesting that most smokers who reduced the T/N content of the brartdl of cigarettes smoked the same number of cigarettes two years later' have been challeng€d as statistical' aatifacts." For this reason, the ACS study data~ were reworked and re- analyzed. A,1PH December 1979. Vol. 69. No. 12 2

~ TABLE' 1i-Outcome of' 1972 Follow-up, of Subjects Who ~, Smoked Brand-Specified Cigarettes in 1959'. Number Per Cent Smoked cigarettes only in 1959 132,381 No attempt to trace in 1972` - 9,600 Total subjects to be traced in 1972 DDied between 1959 and 11972' Not traced in 1972 122,781 100:0 - 31',203 25.4 - 7.169 5.8 ; Total traced alive in 1972 84,409 68.8 Traced! ati ve, no questionnaire receivedT' - 22,050 (26.1)1 Questlonnaire received in 1972 62.359 100.0 Ex-cigarette smoker 23.727 38.1 Qgar or pipe smoker, no cigarettes 4,372 7,0. Incomplete replies to smoking i 5,699 9.1 Cigarette smoker 28,561 45:8 time to be used for the doUow-up. alMough tne subiecta were traced. 'For administrative reasonsf ttuee of the29 ACS divisfons did not paniei- pate in the 1972 falow-up. A few additional subiects requested tflatthey be removed trom itne study. "In some oounty, units: questionnaires were not distributed occotleeted in Materials artd Methods In 1959, more than 1,000,000 men and women in 1.1211, counties in 25 states enrolled in the American Cancer So- ciety`s prospective study. They completed a, four-page ques- tionnaire including questions on their smoking habits. In 1961, 1963L 1965, and 1972, the survivors completed a ques- tionnaire in which they reported their current smoking hab- its. The subjects were traced, over the 13-year period of the study, and death certificates we're obtained for those report- ed dead. Mortality rates in relation to smoking and other fac- tors have been reported' elsewhere:'-'o' The data base is not a representative sample of the pop- ulation of the counties in the study. Migrant workers, biacks, and' institutionalized' populations are underrepresented. Hoa+ever, it has been a valuable source for cohort studies of morbidity and mortality. This analysis is concerned with the changes in number of cigarettes smoked in 1'959 and, 1972 by the men enrolled in the study, in relationto the changes intheTl'N content, of'the cigarettes they smoked. (Changes in smoking in women will be reported! later.) For this purpose, the exact number of cigarettes smoked in 1959 was recoded and the data reana- lyzed. On both tha 1!959 and 1972 questionnaires. the men reported the brand of cigarettes smoked. The T/N content of the cigarettes smoked in 1959 was classified according to in- formation from an analysis by Foster D. Snell, Inc., and pub- lished in the November 1959 issue of Rearlprs Digrsr:' TM content of'brands of'cigarettes reported in 1972 was classi- 8ed' by the Federal Trade Commission report of May 1972. ' 'Tfiis is the only published'sourte for the T!N contencof'ciga- rettes in 1959. A,JPH December 1979. Vol. 69. No. 12 TABLE 2-Changes In Cigarette Consumption of' Smokers ln Relation to Changes inTarand Nicotine ContenEof Cigarettes Smoked, 1959-1972' Change in Number of Cigarettes Smoked NT N* Totat ' Level of Cigarette Increased No. % (Row %) Same (Row %) Decreased (Row %) All Cigarette Smokers Increased 3,380 11•8 29.1 32.2 38.7 Same 8.190 28.7' 31.7' 33.6 34.7 Decreased 1f3i991 59,5 31.5 34.1 34.4 TOTAL 28,561 100.0 31.2 33.8' 35:0 Smoked less than I Pack a Day in 1959 Increased • 709 12.3 53.6 12.8 33.6 Same 1,680 29:2 54.5 13.7 31.8 Decreased' 3.374 58:5 54.7' 13.0 32.3 TOTAL 5,763 100.0 5~4.5 13.2 32.3 Smoked 1+ Packs a Day in 195 9. Increased 2;67:1 11.7 ' 22.5 37.4 40:1. Same 6,510 28.6 25,8 38.7' 3&5 Decreased 13,617 59.7' 25.7 39.4 34.9 TOTAL 22;798 100.0 i 25:3 39.0 35:7 Ii'esuf<ts There is attrition in ttacing; a cohort of people over a period of 13 years for a number of'reasons. Some attempt Nr~y was made to trace 93 per cent of the 132;38IL men who were ~yx7 current smokers of cigarettes only in 1959 (Table 1). Twenty- five per cent had died and 6 per cent could not be traced; of the 84.409 remaining, we did not receive a 1972 question- naire from 22.050 (26 per cent) for administrative reasons (Table 1). The distributipns by smoking habit in 1959 of these. 22,050 men and of'the 7,169 men not'traced were similar to the distributions in 1959 of those who returned question- naires in 19T2 . Among those whoreturned questionnaires, 38 per cent of the cigarette smokers in 1'959 were no longer smoking in 19T, another 7' per cent had switched to cigars or pipes, 9' per cent~ did not answer the question on smoking or omitted number or brand of'cigaretrtes smoked'; 28L561 (46 per cent) reported'they were still smoking cigarettes in 1972' and re- corded the brand that they smoked. Fifty-nine per cent of the subjects who were still, smok- ing cigarettes in 1'972 were smoking cigarettes with a de. . creased amount of tar and nicotina(Tabie 2), Of those who irrcreased the TIN level' of their cigarettes, 29 per cent in+ creased the number of cigarettes smoked per day. 32 per cent smoked the same number, and 39 per cent decreasedd the number. Of those who decreased the TIN level of'the cigarettes they, smoked the respective percentages were 32'7&, 3a9'o, and 349'0. This is very slight and unimpressive 10050~~037 11275, I

PW®UC HEA'LTIi BRIEFS C evidence that nicotine-dependence may lead td an increase in the number of cigarettes smokedi if'their TLN levell is lower. . The mean increase in number of cigarettes smoked by those who increased their consumption was 10.2; the mean decrease ini number by those whol decreased' consumption was 10.6. The:distribution oE the increases and decreases in term; of numbers of cigaiettes smoked' were similar. Table:2 also shows the changes in consumption by TlN'levelforthose.who smoked less than one pack, and one pack or more a day at the time th+e study began iA 1959. The less thati one pack a day smokers were more likely to inci'ease their consumption of cigarettes in 1972' (54.5 per cent) than the one' pack or more a day smokers (25.3I per cent). This difference clearnly was not related to change in T/N level off the cigarettes they' smoked in the two pei•iods, (Tabie 2). A separate analysis l also was made of men who reported that they were~not sick or had no history of canet:r, heart disease,, or stroke in both 1'959 and 1972; the proportion.of men who increased" decreased or maintainedltheir consumption at the same level between 1959 and 1972 was virtually the same as that for the total group. Hence a disproportionate number of ill persons among the heavier smokers1° cannot explain the difference. Discussion The effect of nicotine : dependenci on smoking habits may' be more evident in the short tun than in the long run. The nuinber of cigarettes smoked per day is apparently a more important variable than T1N level in predicting,change of cigarette consumption over a long pericd' of time. Those . who smoked less than one pack of cigarettes a day may have. . beeni able to quit smoking,moreeasily than ihose who smoke'. :. onre or more packs a day1z due to their lower level'iof nicotine ``" dependence: However, if the less than mne pack al day stttokers continue to smoke, the data in, this study indicate that twice as thany' increase their consumptidnl of cigaretrtes when compared to the heavier smokers. This finding is not related to selection for illness. One possible explanation is the phenomenonknown as "regression to the mean."'Light smokers who continue to l smoke have more leeway to in- crease tllando decrease the number of cigarettes they smoke, and ht:avy'smokers have more opportunity to decrease than: to increase the number they smoke. 13EFEREMICES 1. Ashton H, Watson DA; Puffing frequendy andinicotine intake in cigarette smokers. B' Med Jour 3i679-681, 1970. 2. Russell MAH: Realistic goals for smioking and health. I:ancet 1:254-257, 1974. • - 3. Schacter S: Pharmacological and psychological determinants.of smoking. Ann Int: Med 88:104-114, 1978. 4. Editorial: Do people : smoke for nicotine?' B Med Jour 2: I04'1- 1042. 1977. 5. Hammond EC. Garfinkel L. Seidtean H: et'a1: Tarand'nicotine contentl of'cigarette smoke in relation to death rates. Envir Res 12:263L274, 1976. 6. Hammond EC. Garfinkel L: Changes in cigarette smoking. J Nat Cancer I nst' 32;49-&3. 1964. 77. Hammond EC: Smoking in Relation to the Death Rates of t9tte Million Men and Women. National Cancer Institute Monograph #1'9:, 1966, pp 127-204. 8. Hammond EC. Garfinkel L: Coronary heart disease; stroke and aortic aneurysm. Factors in the etiology. Arch Env Health. 19:167-182. 1969. 9. Hammond EC: Smoking in relation to mortality'and morbidity. Findings ini the first thirty-four months of' follow-up in 1 a pro- spective study. J' Natl Cancer Inst 32:J'161-I 188, 1964. 10. Lee D'Hh:' (ed)i Smoking habits and I air pollution in relation io 1ung,cancer. In EnvironmentallFactors in Respiratory Disease, New York. Academic Press. 1972: 11., Hammond EC. Garftnkei L: The Influence of Health ion Smok- ing Habits. National Cancer Institute Monograph *19, 1966, pp 269-285: 12., Hammond EC. GarfinkelIL: Changes in cigarette smoking 1959- 1965. Am I Public Health 58:30-45, 1968. Fiftieeilt'1n Annual San Francisco CancerSymnposium "The Pharmaceutical Aspects of Cancer Care'" is the titVe of the 1'Sth1 Annual i Cancer Symposium, to be held Vlarch 15-16, 1980, at the Hotel Hyatt on Union Square. San Francis'co. The symposium is sponsored by the West Coast Cancer Foundation in! associationi with The American Cancer Society. Continuing Education credit has been applied for: For, further information, contact: West Coast Cancer Foundation. 50' Francisco Street. Suite 200, San Francisco, CA 94133. (415) 981-4590. 1276 IUPH December 1979, Vol. 69, tilo: 12

exington, Kentucky Conference Repart 2 { 0 ALTH CONFERENCE „ F February 24th and! 25th, 197.0 0° E UNIVERSITY OF KENTUCKY . :. W 4 •t ~. C~D ; ~ . , ~i06ACC0.AMD HEALTH RESEARCH U'!STITUTE

I ..! Published'by. TOBACCO AND HEAI.TH' R'ESEARCH! INISTITUTE Office of the Director University of Kentucky Lexington, Ky. 40506, R. B. Giriff'ith~, Ph.D., Director Susan S. O'Neill (Mrs.), M.L.S., Information Research Specialist Lawrence Hinds,, Administrative Assistant Virginia Sypulski (Mrs. ) ,,Secretary (The prompt and efficient editing of the Discussion Highlights by the Area Chairmen, Dr. Claus Grunwald, Dr. Harold'Burton,. Dr. Walter Siaith, Dr. Grace Donnelly, Dr. Ernest Chick, and, Dr. James Flesher, and by Dr. John Benner is:worthy of special thanks and acknowledg:aent'. ) . . . \ , 1

INTRODUCTORY REMARKS H. R. Burton, Ph.D.,,Department of Agronomy In the first session of the conference we learned how the chemical' and physical prop- erties ofltobacco can be widely varied either by the use of different varieties or'the way tobacco is grown and cured. This tobacco is purchased by the tobacco companies and is manufactured'into products that are sold to the consumer. Since the procedures and pro- cesses used by the manufacturer are proprietary, there is little public information avail- able about them. We know, however, that special processes sometimes are used in the manu- facture of cigarettes, such as the utilization of reconstituted, tobacco and fi'lters. These two processes can significantly modify the smoke. To focus your attentionion this important area of the program, threa papers will be presented. In the first, "The Pertinence of Tobacco Modifications to Chemical Composition' and'Biological Activity," I will present some data obtained in some of our work concerning the effect of additives on smoke composition. Following,that, I will then present infor- mation from the literature which relates chemical composition and'biologi'cal acttvity' to product modifications. The other two papers will describe the production and characteris- ti'cs of the University of Kentucky sample cigarettes. •-_ ,. •. THE'PERTIWE:ICE OF TOBACCO PRODUCT MODIFICATI'ONi TO CHEMICAL COMPOSITION AND BIOLOGICAL ACTIVITY Hi. R. Burton, Ph.D., Department of' Agronomy : ABSTRACT On the basl's of' research at the University and'results reported in the literature, data are presented'which show significant alterations in smoke composition as a result of add- ing compounds such as sodium nitrate, sodium molybdate, sodium sitannate, ammonium vanadate, and'potassium chlorate to tobacco before cigarette manufacture. Smoke yields and composi- tion are also affected by product changes involvi'ng,the type of cigarette paper used, filters, and inclusion of reconstituted tobacco. Moisture content of'the cigarette affects smoke yields and composition. Biological activity of smoke condensate as measured by tumor 'product." than one kind of bi'oassay before concluding,that a given modification, results in a "safer tivity may be reduced but acute toxicity increased, indicating the need to conduct more affected by some or all of these product modifications. In some instances mouse skin ac- production on mouse backs is affected by chemicall additives to tobacco, the inclusion off reconstituted tobacco, moisture content of'cigarettes, and extraction, of'tobacco with or- 7;."ganic solvents. Acute toxicity of smoke as measured by inhalation techniques is also. INTRODUCTION Interest in tobaccoland tobacco product modification is of'special pertinence to the tobacco and'healfih question since many of the industrial processes to which tobacco is subjected before and during the manufacture of'saleable products have an influence on the chemical composition and biological activity of the smoke, It therefore is important to determine the effects ofl these variables. Since the processing of tobacco and the manufac- ture of tobacco products are industry-oriented, very little well-defined'data have been published in regard to their effects. The purpose of this paper is to present a briefl review of studies with regard to certain tobacco and product modifications that have some influence on the chemical composition and biological activity of smoke. It is assumed, that the data which is presented will' stimulate thinking and raise questions with regard to this important area of tobacco and health research. 21 1005053p41

DISCUSSION There are many areas of study concerning tobacco and'product modification, but since this is a brief review of the progress of research in this area, only the following topi,c's' will be covered: chemical additives; reconstituted'tobacco; and physieal modifi'cations, suchlas weight of'cigaret'tes, porosity of paper, and the moisture content of cigarettes. Smoke filtration, one of the more pertinent areas of product modification, will not be covered in this paper since it encompasses a large number of public'ation's, and has been adequately reviewed'by Kiefer and Touey (1!). One area of interest, especially at this University, i's the modif'icationlof'smoke con- densate by the use of chemical additives. Additi'on of chemicals to tobacco has long been recognized as a potential means for modifying both the chemical composition and biological' activity of the smoke. The reports by Bentley and Biurgen (2) and'Hoffmann and Wynder (3,4,5) have shown that this is'a means for altering the chemical composition. The studies of modification of smoke by utilizing chemical modifiers was initiated at the University of Xentucky in 1966 as part of a cooperative agreement between the Universi'ty'and the U.S.D.A. by Drs. D. TAecEI TPH A.YD 9RCOTINE vALUES'FUR CIGA'iLSTIS tlADE If01[ Burdick, J. F. Benner, and H. R. Burton. The means TaEArED roms,ccos for evaluating the effect of additives on smoke composition were to determine the total particulate matter, and the levels of nicotine, phenol, o-,m-, p-cresols' and benzo[a]'pyrene ('BaP)' in the smoke condensate of cigarettes madie from each treatment of tobacco. These determinations were used as indicators for the ro osed biolo ical activi't of P P g y the smoke condensate. Some of the results ob- tadned for total particulate matter and nicotine from the latest treated tobaccos are shown in, Table I. The wide variation in bothit'he yield of particulate matter and nicotine shows the effec- tiveness of the additives on the yield of smoke condensate. These data show that additives will selectivel'y reduce or increase the levels of particular smoke components. For example, the values for phenol for these add'itives ranged , from 70'Z for 2,3Lepithi'opropyl methyl e'ther' to :2b62 for sodium molvbdate as cemnared ta cioaretrea .'191X for sodium pyrovanadate. The same wide range of variati'on betweenitreated'samples was allso shown in the earlier studies (6). sodium molybdate. BaP values ranged'from 48x'for sodium stannate and'sodium thiocyanate to Tno~mene TPM Ncrort~,e Ferric acerylac.tonote 30.86 0.99' HCONHNH 58' 33 1 61 Na,v~oad } . 26'.9s . 1.30 Fe (NO3)3, 27.46 1.66 NaCNS 21.89 1.40 No25 29:61i 2:m~ ~s No,S 25 156 1.61 BHf 41.26 ' 1.57 NaYy207 23.67 1''u Na3vOK 22.49 0.49 A'luminun lactate 33.97' 11.99' Fel(c,o4)3, 27.03 1.86 NcSb(T; 11.83 1.40 Nar.rno4 21.12 1.76 Nasno3 23.42 1.94 Oithiobis (benmrh7azol.) 30.97 1.55 p(c20a)3 29:42 1.60 s-, CH"GHOC>t 24.63 1.47 NM ~' 29 33 2 07 cH ~~pC2H5)3 34.73 2.16 Na~ io 26.32 2.37 ~ NH.'H o3 0 80 3. 1 9S' Azoben:.n. 39.51 2.16 '"~ . .• '* made from untreated tobacco. o-Cresol varied'from 59% for sodium thiocyanate'to 270X for. There also is interest in the effect of'physicaS parameters of'cigarettes on the total. yiel'd'and composition'of the resulting smoke condensate. It shouldibe noted that most of the work in this area has been contributed by tobacco and related industries. H. Muller, G. Neurath and H. Horstmann (7) have studied the effect of'paper po'rosity on the yield of total particulate matter, nicotine and BaP. They reported that on a per cigarette basis there was a decrease of both total particulate matter (TPPd) and nicotine wit'h increased paper porosity (Figure 1). However, if'these data are calcul'atedion the basis of percent tobacco burned in the mainstream smoke during puffing, there is no change in the TPNf'or ; nicotine (Figure 2)i. This indicates that paper porosi'ty:onl'y aids in diluting the mainstream smoke which results in the apparent decreases of TP"1 and nicotine. Also, it was found that paper'porosity had no influence on BaP'recovery when calcu:2ated on the basis of ppm in the smoICa condens'ate. _ In another study G. Neurath and H. Harstmann (8) and H. Ehmko and G. Neurath (9) re- ported the effect of moisture of the cigarette on the yield and!chemical composition of the smoke condensate. They found that on a per cigarette basis TP"i increased withh increasing moisture content of the cigarette. However, if'the TPM values are reported on the basis 22 1005iU53+042'

11 1 1 1 1 1 I I I, 1O 20 3G 40 5G PAPEXPOR©SITY (m3~ cm-2min-1). Fi9ur. li. Paper porosity v, TPM and MicotGne,. 10 20 30 40 50 PAPER POROSITY (ml cm 2mia'1) fi9yn 2. Paper poraity a;TPM and Micotin.. Od C z ` 0 of amount of tobacco burned, there is no:influence of mositure.on the yield of'smoke condensate (Figure 3)!. Increased moisture content, however, does sel'ectively'reduce the levels of nicotine and phenol in the smoke condensate (Figure 4). Seehofer, et al (10) have reported that the decrease in phenol'is &: result of the greater filtration, efficiency of'tobacco when the moisture levelis increased. FY'g- ure:5'shows the per puff eontribu- tian of phenol in the!smoke con- densate for cigarettes which con- tain 8.5, 12.0 and 18.5% moisture.. Withian increase otmoisture con- tent in the cigarette, the percent contribution of phenol is quite low during the fi~rst puffs of the cig- arette in comparison to theilow moisture cigarettes. This shows that with increased moisture the tobacco is selectively retaining phenol which is volatized or de- composed during the ensuing puffs. In a relatedistudy Neurath (8) reported' that as the moisture level increases there is a s1i'ght in- crease in BaP and a marked increase of BeP. These dataishow that mois- ture content in cigarettes alters smoke composition by increasing, the level of some smoke constit- uents while decreasing the levels (Mull.r, 1964) of' others. ~'In recent years the increased utilization of reconstituted tobacco in the manufacture baceo on smoke composition. In 1964 it was estimated that reconstituted tobacco sheet made upi15Z of the weight'of the average cigarette. It should be noted'.that the:use of recon- stituted tobacco by the industry is economical since it enables them to use tobacco prodkicts~ that were ordinari'ly'consi~dered waste materials. The question arises as to what effectt this tobacco modification has on the chemical composition of smoke. of tobacco products by industry has generated interest in!the effect of reconstituted to- W Q . (A Z W' 0 z 10 8 O 6 e 1•75 0,. ~ ,. Cn .~~ Wet' . . . .,. `Dry il l 5 10 15' 20 MOISTURE Fi9ar3'. Montve vs % TPM/arams.of tobucco bum.d: A stud'y 'reported by R. F. Moshy and Howard ?1'. Holter ('11)) partly answers thi's question. Two samples:of'tobacco were obtained from flue-cured crops that were grown iin 1962 and 1964 in South Carolina. Reference cigaret te controls~were made from the orig- inal tobaccos and'stems:('70:30). The remaining tobaccos were pro- cessed'iinto reconstituted!sheet tobacco and manufacturediinto cigarettes. InialL there were two, reference cigarette controls and eight reconstituted cigarette samples, fbur from eachicrop. 23

. J ~ %., : influence on smoke composition. ~ V) . uct modifications which hawe an Some of the data that were ob- ~ taiaed from this study are not di- •-4, rectly related!to reconstituted --- ~ tobacco, but to other various prod- C)` 350 ~ ~0 5 0 W In Figure 6 the influence of weight WJ 3~ `~ Z of the cigarette on the dry total ~~ •4 - particulate matter i's shown. The ~ data were o'btained1from the control J cigarettes and not from the recon- Q stituted tobacco. It is seen that. ~ 250 .3 Z the optimum yield of total particur Latc matter per gram of tobacco .:burned is dependent on cne czgsreii a200 t , r r arette increases the yield of tar ~ ~' I I 'weight. As the weight of'the csg- J 2U increases to a maximum and then de- I Q' 1 M015TURE creases. Otte perhaps would naively fiqve 4. Nbistur* vs Phenol and MMCorine levels. (Neurath, 1963) have assumed that there woald be a direct relationship between,TPM and cigarette weight. Moshy ex- 'plained the observed maximum by the hypothesis that as cigarett'e wei'ght is increased'poor burning is the dominant factor until a weight is obtained where filtration becomes the dominant factor. In regard to this study it was found that nicoti'ne reduction paralled TPM reductioniwhich showed there was no selective reduction of nicotine in the condensate. This indicates that the percent nico- tiae in the smoke condensate is independent of cigarette weight. In Figure 7 the tar content obtained from the cigarettes of the four reconstituted to- bacco sheets and the control tobacco are shown. They clearly substan- tiate that the tar deliveries ean be increased or decreased depending on the type of processed tobacco ' sheet utilized,. The analytical data that were ~ reportediare shownlin Tab1e II'. It should be noted that nicotine PUFF fiyur. 5. Perc.nt pi+.nol/poff A puff nunber. (S.e}wf.r, 11965). 24 . Ys reported as percent of the con- densate. For samples H and! J theree is a marked decrease in nicotine, but these two reconstitutedis!heets contained'a 20% level of addi'tive. Fzom this table it also is seen that the level of BaP and phenoil decrease;both on a per gram of'f tobacco burned basis and percent of tar basis as compared to the control cigarettes, E and K. The ef'fect of reconstituted tobacco on two gas phase constituents analyzed! are also reported. The reconsti- tuted tobaccos give a higher yield of acrolein than t'hrdt of the con- trol cigarette. However, there can be no interpretation of this observati'on since there is no knowl!ed'ge of the influence oflthe

weight ` A . the gas phase. This 1~0 1•1i • CIGARETTE WEIGHT . Figure 6. Cigorette weight va TPM/9,tobocco contwned'. (M03hy, 1968) and pressure drop'of'the ci'garettes on acrolein delivery in is also true of the carbon monoxide delivery in the gas pha'se. From the discussion oflfactors that influence the chemical composition of smoke, it has beenishown that physical and chemical modifications of manufactureditobacco products have an effect on smoke delivery and smoke composition. For any study it is therefore im- porfi ant to define'the physical characteristics of the!cigarette in order to obtain mean- ingful data from the smoke condensate. A poor control of the characteristics could lead to erroneous conclusions as to chemical composition and'biol'ogical activity. 1.2 1,.3 1.4 1.5' CIGARETTE VWEIGHT' Figure 7. CgorelM~~.wtight vs~~.TPM~~,~ (lMbshy; 1968) 25 1•G

5.7 6.2 4.3 5,.9 6.2 4.8 4.1 2.6 2.3 4.8 which iwthen manufactured into iA'aLt 11 :e;3a r~.'. NOw tnat iC nas meen e5i;ao- lished that toibacco prodwct modifi- cation influences the chemical com- cHE?LItAL ANALYSIS' Oi' S19oKE' i80Ft uco.vsrIauzm TOBACCO positi'on of smoke, the question is ~ .~.~ Phenoli B.ntoCo]Pyr.nez' Aacrotein co asked, "Dmes p'rodulCt moG2r'ica'tlon nK9/gtb Ma9/9tb ff4o(9rb aty/9rb have a significant influence on the I 82(oL 15) ----- - 13 (12)' have reportedithat the addition 134(0140) 0,.029(0.9) 113 17 218(0L52) 0.ox7(l.0) T! Ip tumorgenicity of smoke condensate 150(0:41) 0.o3r(i.o) - 11 is probably'one of' the more widely 99(O:a0) 0.019(l.n ~ 6 known studies. Wynder and Hoffmann 10(Oi05) •~---, ~ q tOti(0:40) 0.o33(t.2) 1117 tl modi'ficati'on of tobacco on the 4'`.t t c0 o ltzfo~.~oJ o.o~(0:n 1117 )r, smoke?" The effect of chemical •-~i ~,~j Ir4 Ip biological activi'ty'of the resulting of' certain chemicals to tobacco 1' Valbes in porenthaea are percent of eondenwre 2 Vallus in porentheses are ppm oF'candensare nitrate cigarettes and smokediunder stan- x:~ dazd conditions yields a condensate reported (5) that the addition of activity. In particular they have which has a decreasedi tumorigenic -f ~~, to tobacco markedly reduced tumorigRnic activi'ty'of the smoke condensate that was : , . generated from those manufactured cigarettes. In the ensuing studies of chemical modiiisrs they have reported that the level of BaP'in the smoke condensate is a good!"indicator" for the observed mouse back tumorigenic activity (i2). Figure 8 gives some i'nformation for the tumorigenic activity and the level of'BaP from cigarette smoke condensate of.several chemi- cal treatments and tobacco types. altaration of smoke condensate by utilizing chemically treated tobaccos. ;;'ehecks to indicate it there is a vaiid' relationship between tumorigenic activity and the As was mentioned earlier, the work in our laboratory has been concerned with the al- teration of'the composition of smoke condensate. During the course of the investigation, we found several additives that markedly altered'the composition of the resulting smoke con- .densate. Two samples were submi'ttediand are currently being bibassayedifor their tumori- genic activity by the bioassay facilities. The sampLes are potassium chlorate which de- creases the level of nicotine, phenol and'BaP,-and ammonium vanadate which inereases the level of phenol and BaP'. Phenol (promotor)i and'benzo(aJ;pyrene (initiator) have long been, recognized as promoting or initiating.tumor8enicity and therefore have been used as indi- eators for the proposed tumorigenic activity of the smoke condensate. Since the samples .have such a wide range of phenol and BaP content in the smoke condensate, they are good reduced phenol and BaP content that were obtained from reconstituted tobacco sheet.. reconstituted sheet tobacco results in a smoke condiensate which is less tumorigenic than smoke condensate from a reference tobacco. This reducedltumorgendcity parallels the :`Hoffmann and Wynder (12) have also studied' the effect of physi'aa1' modifications of to - .:bacco products on the tumorigenic activity of'the smoke condensate. They have shown that One of the shortcomings of a bioassay is the inabili'ty to correlate the biological activity of one study to another because there is no reference to which the data can be comparedl. It hasibeen shown that chemical modifiers reduce the biological response using the mouse back bioassay, as does the use of reconstituted tobacco,, but since no reference tobacco was used, there is no way to relate their relative tumorigenic activities. In order to obtain more meaningful data,, it is important tolhave a well-defined reference tobacco that can be used for all*product modifications. Since some tobacco product modifi'cations result in smoke condensate having decreased tumori'genic activity, does this mean that the smoke has less biological activity? Studies by Dontenwill et al. using,smoke inhalation techniques (X3) and mouse back bioassay (1) have given information which partially answers this question. In using the mouse back bio- assay Dontenwill found the smoke condensate from the reconstituted tobacco sheet had less 26

whenimeasured in inhalation studies. tumorigenir acti'vi'ty'than the reference cigarette which supports Wynder and Hoffmann's results. However, these dat&showed no:correlation between BaP content of the condensate and tumorigenic activity. Using smoke inhalation techniques, the~acute toxicity of'the . smoke was tested against hamsters, rats, and mice. Table!III gives the data obtained fromithese modified tobaccos. Values for the c'ontent of carbon monoxide and nicotine weree also determined. In general the smoke from modified cigarettes was more toxic than th'at of the reference cigarette..It is interesting to note that the smoke from both modified to- bac'cos' whictllextlibita' decreased tumorigenic activity in the mouse back biioassay is the most ~toxie in Ehis smoke inhalation study. This most certainly is due in part to the increased carbon monoxide content of the smoke. It may be concluded, therefore, that smoke from r ; given cigarette may'be les~s carcinogenic'as measured by mouse skin painting, but mare toxic i4'. ._ _~~... . . .i . .. .. . . Fiyune 8. Tunar resporne an mouse skin and Ba P in smoke cond6nws.: (Nbffmann, 1968) TIAECL III ACUO;L'TOYICITY 0? S!lOKE PRUM MODIlIED TODACCO P&ODUCiS USING AN INNruA2IDN TEMSqIIE Type of Cfyonttt. Val. % Niwtin, Cont.nt rim, of'Exposw. To Srnoke Uaeil O.ath VYlinutn , C/J, Of Smok., (mg/Ciq.) Pu6f No. liFNanut.r Raf hbusr(IC1) I(¢AL6/eJAX) EI (Standard - Cig.) 4.6 2:b3 10 18+t1 16 76 13I ET (Munidity <',6%) 4.3 2:60 10 117 12 13 16 Ex (Extrocf.d!With 70% Ethanol) 3.1' 0.68 1l0 176' 36 ' 64 38'. E6I (E-R.constitut.di 8 8 12 Tobacco) EGZ (EG + NaNO3) 7.7 7.01 0i82 0.47 8 7 25 21 8 6 14 (E-Tobacco Stsnn) E 3:3 • 0iJ6 9 71 241 43 39 ~ E6 (R.consritut:d Tobacco fran E 11'.ll 0.64 . 10 26' 11 111' 13 K (E + Charcoal Fit.r) 5.1, 1.68 10 114! 17 23 19. A (E + Ac.rote Filter) 4.2 1.31 10 160 27 30 40 E' +Cambnidyq Filt.r) 4.6' • 0i 10 147 I1581 - 37 - - E +O~ E¢' +0 0.64 2.60 10 10 49 - 22 20 - » 2 , (G. Reckz.h, 1969), The information pre- sented above shows that tobacco and'.tobacco product modific'ation,dio have aa marked effect on the chem- ical compois:ition and bi'o- logical activity of smoke. This is by no means a'com- plete review of' this area, but is only meant to show ~ that smoke composition is ~ altered by product modifi- O cation. This review also points out the need for CA using well-defined samples O in order to obtain valid CA data f©r studying both, the w chemical composition and Q. biolo~gfical activity o'f' ~i smoke. 27

REFER!ENCES Keifer, J'. E. and Touey, G. P. Filtration of' tobacco smoke particles. In: Wyndier, '~ . der, akuten und-chronischen Toxizitat von Cigarettenrauch bei passiver Berauchung von Versuchstieren. Arzneimittel-Forsch. 19:237-41, 1969. Dontenwil!1, W.; E1'menhorst„ H.; Harke, H.-P.;, Reckzeh, G.; Weber„ K. H.; Misfeld, J'.; and Timm, J'. Experimentelle Untersuchungen uber die tumorzeugend Wirkung,von Zigaret- ~., ;0 tenrauch-Kondensaten an der Mausehaut. II. Einzelvergleiche zwischen den kondiensaiten -.modifi'zieter zigaretten. Z. Krebsforsch. 73:285-304, 1970. PRODUCTION' OF SA.MPI:E CIGARETTES FOR TOBACCO AND HEALTH RESEARCH id~ 0 Atkinson M S ID rt t of A o a men nom e gr p y • _• , . ., E. L. and' Hoffmann, D. , Ed.'s, Tobacco aud Tobacco Smoke, New York, Academic Pr:545-75, '~rM' t.- • •Al.twiZ . k: . Bpntlev. Hi. R. and Burman. J'. G. Polvnuclear hydrocarbons in tobacco and tobacco "' Burdick, D.; Benner, J. F.; and Burton, H. R. Thermal decomposition of tobacco. IV. condensate by addition of'sodium nitrate to tobacco. Cancer Res. 27:172-4, 1967. . Hoffmann„ D6 and''i Wynder, E. L. The reduction of the tumorgeni'cilty of cigarette smoke i~ 1 Deut. Med. Wachschr. 88:623-8, 1963. • -;'; 4. Wynder, E. L. and Hoffmann, D. Ein experimenteller Bertrag zur Tabakrauchkanzerogenese -t t~ ogonesis. •A'cta Pathol. Microbiol. Scand. 52:119-32, 1961. 3. Wynder, E. L. and Hoffmann, D. Present status of laboratory studies on tobacco carcin '•++ Analyst 8'5:7'27-30,1 1960. "~' smoke. III. The inhibition of the formation of'3,4-benzopyrene in cigarette smoke. Apparent correlations between thermogravimetric data and' certain constituents in smoke si~`~e,:-, from ehemically-treated tobaccos. Tobacco Sci. XIII:138-41, 1969. . Muller, H.; Neurath, G. ; and Horstmann, H. Einfluss der Luftdurchlassi'gkeit von Cig- arettenpapier auf'die Ausbeute und Zusammensetzung des Rauches. Beiltr. Tabakforsch. 0,4rrd ;'2:271-81, 1964. Neurath, G. and Horstmann, HI• Einfluss des Feuchtigkeitsgjahaltes von Ci'garetten auf ;~: die Zusammensetzung des Rauches und die Glutzonen temperatur, Beitr. Tabakforsch. 2:93-1001, 1963. . Ehmke, H, and Neurath, G. Einfluss des Feuchtigkeitsgehaltes von Ci'garetten auf die ;,Zusammensetzung des Rauches II. Bei'tr. Tabakforsch. 2:205*-8, 1964. Seehofer, F.;' Hanssen, D.; and Schroder, R. Uber zugweises Abrauchen und Pro-Zug- 13. Reckzeh, G.; Rucker, K.; Harke, P.; and Dontenwill, W. Untersuchungen zur Bestimmung experimental approach. J. Am. Med. Assoc. 192:88-94, 1965- bacco smoke modification. In: National Cancer Institute MonogFaph No. 28:133r481, 1968. Wynder, E. L. and'Hoffmann, DL Reduction of tumorgenicity of cigarette smoke. An 11. Moshy, R'. J. and Halter, H'. M~ Reconstituted tobacco leaf technology: A tool for to- •, Analysen. Beitr. Tabakforsch» 3:135-50, 1967. PIP The Reference Cigarette 1"'V.JV53'1J48 %y ~. The ~~el oplnent q~biological testing techniques in the area of smoking and health re- J' search has rived much attention in recent years. Relatively less attention, however, has been devote~~Jloe substrates (cigarettes) burned to yield smoke components. Re- searchers in the University of Kentucky Tobacco and Health Program in 1968 recognized the need for a "reference standard" to serve as a basis for inter- and intra-1!aboratory comparisons. Scientists in various research laboratories were using commercial cigarette brands as'a source of'tobacco'smoke products. The use of different commercial' brands, or even the same commercial brand acquired at different times over a, period of'time, as a source of tobacco smoke products makes results from different laboratori'es difficult to, inter- pret or correlate. It was known that the composition of both gas phase and parti'culatee phase of cigarette smoke depend, upon many factors, of which the composition of the tobacco blend'in the cigarette is among the nost important. Domestic cigarettes i'ncLudie varying amounts oflflue-cured„ air-cured, and'oriental or Turkish tobacco types as well as dif- ferent amounts of non-tobacco additives, such as sugar and glycerine..

Editor Norman A. Krasnegior, Ph.D MIIDA Research M1bnlograph 23 ;~:- r- Jarnuary 197S _ - Alcohol; Drug,Abuse, andlMenusl HealthAdministratiori, _ :T--~=- _ Public Health Service E: DEPARTMENT OF HEALTH, EDUCATION, AND WELFy4R 5600 Fishers Lane ' • Rockville, Maryland' 20857 Division of Research ~ National Institute on Dhug Abuse i- ,.._,-.1 r r. ~ r.

Tobacco Deplendenc'e: Is Nicotine . Rewarding or Ay_ersive? : M. A. H. Riusselli, M.B., MRCP, MRCPs}rch To understand tobacco~smoking:is:like doing a large and'very diffi- aiLt jigsaw puzzle. P shall;focus on the role of~nicotine in tobacr co use, partly because it may be a kind of straight edge tolthe puz- zle which we can usefully begin to piece together without getting Lost among allithe pieces that go in the middle. But the role of nicotine interests me for another very practical reason. If,it iss aa important factor„ amd if most.people do smoke chiefly to dose themselves withinicotine, the present low-tar, lo-.+-niootine approach, to safer cigarettes is obviously.wrong, and, it wousd, be more logicall to develop low-tar, medium-nicotine (or even high-nicotine)Iciga- rettes (Rissel!1 1976a). lile know that tobacco smoking,is:highly dependence-producing. We know that nicotine has numerous pharmacological effects, peripherally and in the brain, which are potentially reinforcing. We know that it has effects on behavior and performance which are potentially rein- forcing, We know that it induces tolerance iaianimals and that they become dependent on nicotine.i;njeetion_s to maintain performance.. We know that most smokers absorb nicotiaie in amounts sufficient to produce these rewardhng effects:, that they acquire tolerance to some of its actions, and that they suffer from physical as.welli as psycho- Iogical, withdrawal effects when.they stop smoking. We also know that the rapid absorptionlof nicotine.through the Lungs prodinces intra- venous-like high-nicotine boli in the blood which reach the brain: within alfew seconds after each inhaled puff. The possibility that this produces a rapid puff-by-puff pharnacoLogical reinforcement in the reward centers in the.brain some 70,0'00 times a year would go, a Long way toward explaining the, tigh dependence-producing potency .of cigazette smoking, ('Risssell -1976b). If we could prove that nicotine is what smokers seek, we.,could be confident that the puzzle was_virtually comoleted. Wortumately thbs is~not the case and we cannot escape the nagging fact that powerfuQ addictive syndromes occur where pha!nnacoiogical factors~ clearly play no part. (he does not have to look far for examples such as gambling, nail-biting. and the desire for sweet tastes 100

or high4at and'high*cholestero,t'foods. With tobacco smoking there are numerous nonpharmacological components which could make it equally dependence-producing. Nicotine titrati=studies have attempted!to prove that people smoke for nicotine. But, as I shall go~an to show, these data do not disprove (indeed they can be better fitted to support)i the hypothesis that people smoke and innale for nonpharmacol'ogic effects such as taste, aroma,,sensorimotor ritual, and the local irritation by nicotine and other components of tobacco to sensory receptors in the lungs and' respiratory tracts„ and that the pharmacological effects of nbcotine are aversive and tend to imhibit inhalation rather than reinforce it. Definition of "Iaependence"' and "Addiction+' . If we agree that tobacco, smoking i's~for many a form of dependence, what does this mean? There are some who restrict the term "addictiont' to compulsive syndromes which are maintained largely by the need to relieve or avoid physicali withdrawal effects. The issue of.'phys- ical" versus '~sychological" dependence is a somewhat false da'chotomy,, as the two are so intenroven. I use the terms "dependence" and; "ad- dictionl"isltercliangtably to refer to a state in which the urge or need for something is so strong that the individual suffers or has great difficulty in going without~ it, and' iat extreme cases cannot stop doing it, or using it, when it is' available. Fiow high a degree of dependence is required before the conditionlis labelled a"d6'- pendence disorder" or "addiction" is somewhat arbitrary. I wmusd''like to emphasize one point. It is the strength of the urgee or need' which is important, not whether it is predominantly pharma- cologically or nonpharmacolog~cally determined. Strong social or psychological rewards can produce a higher degree of dependence • than weak pharmacological ones. .To what extent, then, does tobacco smoking depend on pharmacological as ogposed-msocial or other nonp harmacologicat'reinforcement?' Ahdito what extent do smokers smoke for positive rewards (pharma- eological, nonpharmacological or acquired by conditioning) as op- posed to seeking relief from, or avoidance of, unpleasant,withdraw•al effects (pharmacological, nonpharmacological or conditioned)? In other wosds,,how mucti is smoking maintained by positive versus: negative reinforcement? Erpressed Motives of Smokers'. Many smokers find it difficult to explain why they smoke. Some will say they smoke because they find it pleasurable, that,it'helps them to relax, or simply that they are addicted. There are obvious patfall's to accepting such statements at face value. APhen people find themselves doing something frequently and to some exten: against their better judgment, they may tend to attribute this to pleasure, addiction, or some such "rational" explanation6 They are, • however, unable to tell us what makes the behavior pleasurable, re- laxing, or addictive..•Nevertheiess, the statements of smokers them- 101 101

selves are an essential starting point in dete:mining the motives underlying the dependence. A number of'peops'e, such as Fforn in the U.S.A. (IIkard, Green and iiorn 1969) and: DkKennel'1 (1i973) in Britain, have used factor analysis to make systematic studies of the responses of smokers to questionss on moti'ves for smoking:. We have done a similar study (Russell, Peto, and Patel 1974)lusing a 34-item questionnaire combining various as- pects of the earlier work of'Horn and McKennell. We obtained six factors represen2ing various~motives for smoking: psychosocilal!, in- dulgent, sensorimotor, stimulation, addictive, and' automatic. Ult- like previous studies, we did not obtain a sedative smoking factor,. . Items designed to form a sedative factor loaded instead on the addic- tive! and stimulation factors. It is not intended here to discuss the factor structure,,but it may be that the negative affect and agitation which smoking apparently sedates are generated'by cigarette withdrawal, and that in such cases "sedative" smoking is withdrawal relief smoking,rather than smoking for sedation of'negative affect due tolother causes. 'Ihe most striking finding of our study was the clear-cut separationn of the factors and their items intoltwo distinct clusters~, which we interpreted'as representing pharr.iacol'ogical and nonpharmacological mo- tives. Ifsis is shown in figure 1 where the items have been plotted according,to their loadings on the first two unrotated factors, which respectively accounted for 18 percent and 8 percent of the variance. 'I}be~'pharmacological'"'cluster was coamrised of'the addictive, auto* matic, stimulation, and sedative smoking,iteaLs. The psychosocial, sensoridnotor, and indulgent factor items w+ere all in, the 'honpharma- eologicali" cluster. Some validation is provided by the correlation of the ""pharmacotogical°' group of factors with cigarette consump- tion; it was these factors that also differentiated a criterion group ofaddi'cted heavy smokers attending a withdrawal clinac from the maia, sample of normal smokers (figure 2). The questionnaire has since been modified and further validation will be soug(it by . examining the relation of factor scores to blood nicotine and COFb levels and to clinical outcome. Pharmacologi'cal studies have shown that in smoking doses nicotine •is predominantly a stimulant drug but that it also has some sedative acti'ons (Russell 1976b). The self-report data of'smokers suggested similar effects, and this led us to label the two main item clusters as "pharmacological" and "nonpharmacoLogical," T4ie addictive fac- -tor items were concerned with craving and! the relief of withdrdwal' -symptoms, or, in other wurds~, with negative reinforcement smoking.. The high correlation between the positive:effects of'stiimulation and the negative addictive factor items suggests that once st{fficientt nicotine is taken in to provide stimLlation, withdrawal effects are likely to occur. Tfias daes not appear to happen to the same extent 'with indulgent smoking (smoking for pleasi Hrnw mueh the pl~eas- urable aspects depend on, nicotine is obviously an important question:. As a final caution, it should be emp}iasized'that stimulation, seda- tion, and withdrawal relief'smoking do not necessarily indicate ` 1 D2'

FIGURE 1 Loadings of 34 it'enns on the first two unrotated factors 26 P. .21'I .8P .2Sm .25 .41 ..34'P .15I' 3Sm. •'24A''d.1~4 ~ 2~ P~ 3 .27Sm .13Sm .18 P .29'Sd 1 .2 .3 .4, -5 .6 .1 20St. •17Ad• 9Ad - 23 S t'. .6 Sd 19A. .37Ad .12St .16'St .1IOA .3I2A . 7St .33'St' St : S'tidnulation„ I- Ihdulgsnt, P: Psychosocial, Sm=Sensorimotor, Ad :Add•uctive„AlAutomatic; Sd :Sedative. I Loadings of 34 questionnaire items on the first' tiro uunrotested f;ac- tors. The upper Zeft'cluster is comprised of "honphazmccoloaical^ motives for smoking from the psy,ciu~socn:.al, sensortitmotor, andy induZ- gemt'smokinsq faetors. The "pharmaeoZogical" i'tems representing stim- uZation; sedative, addictive, and automatic smokirry are all in the lower right cluster. (Reprinted with permission from RusseZZ, M:r1.R.; Peto, J.; anci Patel, O.A. 1!hs classification of'smoking by factorial structure of motives. JourraaZ o< the Roval Statist'ical' Soc iety; Series A, 13'7: 313-333„ 1974. Q 19'7~4„ RoyaT Statzst~r.cr~ Sociecy:1 ~ 103'.

z 4 LU 3•0 0'5 `-r -. - ' / (sample Mean factor scores by sex for'Mairi'&'Smoking Clinic'samples . . FEMALES Smokinq ~ ~ clinic A% MALES sample . . . `, . • , . , % ~ . , ' % IF J. . / .. CCBIAI Cl^. •-- - _ Jt\\ % a I ..', - / I Main I FICUnL 2 1 1 1 1 1 FACTOR I FACTOR 2 FACTOR 3 FACTOR 4 FACTOR 5 FACTOR 6 Stimulation Indulgent Psychosocial Sensorimotor Addictive Automatic MALES ) _J "Sedative Mean faotor ecores by ses for "Main" sample of normal emokere (N=175) and "Smoking Clinic" aample (N-103). There ie no difference between the eamples in ecoree on the induZgent, peychosoeial and senaorimotor factors, but the differerwee on the othen factore are highly eignifioant (p E.001). (Reprinted with permiseion from Russell, Peto, and Patel, 1974. Q 1974, Royal Statietieal Society. See citation, figure 1.) ~ / ~ . .__...- - ` I ` , , ~. .~ MoMosooi -

pharmacological mediation. It is possible that a similar factor structure with the same ts.v! main clusters of items could, have been obtained by applying a similar qtiestionnaire to regular gamblers. ttievez2heless, the evidence so faa• available from this kind of'ap- 'proach suggests that smoking depends on a mixture of pharmacological and nonpharmacological motives amd'that pharnaeologicall motives dominate in the case of addicted heavy smokers. Onset and Mai,ntenance of Smoking inhalation coincides with or determ2nes the development of a regu- lar smoking pattern6 Many smokers then, progress to a further stage of smokimg,for a predominantlymegative reason: avoidance or relief of the effects of, withdrawal. What proportion of smokers reach, this stage, how long it takes,, and to what extent the withdrawal effects are mediated by pharmacological as opposed to nonpharmacological factors are iaa}adown6 quantities to exert numerous potentially rewarding pharmacological effects. It is not known, however, whether the establishment of gradually in most smokers until nicotine is absorbed in sufficient Daniel Horn (this volume) has discussed, the factors involved •in the estabsishment and maintenance of the smoking hab,it-two quite dis- tinct processes. He has perhaps paid insufficient attention to, one outstanding British study by Bynner (1969, 1970) which greatly clari- fies the process of recnaitment to smoking in schoolboys. It is also worth emphasizing the, finding ofDScKennell and Thomas (19'67')that of those teenagers who smoke more than a single cigarette, only 1S percent avoid going on to become regular dependent smokers. Why this escalation should'be alinost inevitable may be explained in the following way: The first feW cigarettes are u,sually, unpleasant,, but skill is quickly acquired to limit the intake of smoke to a: com- fortable level'. Tolerance to the unpleasant side effects of nico* tine soon develops, thus lowering the threshold for further attempts. If'the psychosocial rewards: are sufficiently strong to cause the act to be repeated in the face of the side effects and physical' dis- eomfort, there is little chance that it will not continue, as the side effects rapidly disappear. The factors controlling the onset of'smo'king are summarized in figure 3, and those•determining its maintenance are shown in figure 4. In the early stages, smoking,is intermittent and is usually confined' to~social situations. A'ferr remain occasional social smokers for many'years. But, in the majority, eonsumption gradually rises and ceases to be confined to social situations. After a few years smoking occurs with great regularity. Intialation also increases DbninhaLed Smmking, Sone.cigarette smokers do not inhale and consequently absorb l~ittie nicotine. Systematic comparison of noninhaliers and, inhalers couldd throw much light on the irscportance of pharmacological vs. nonpharma- col'ogical factors, but to~myknowle+d'ge this has not been done. 1#part from novices and occasional social smokers, some heavy (two-pack-a- day) smokers do not inhale; this is confirmedi:by low plasma nicotine 105

F1GiURE 3 Parental attitude School attitude Health risks Sensory discomfort Nicotine effects Availability of cigarettes Curiosity - Rebelliousness To appear tough Anticipation of adulthood Social confidence Parental example Ofdprsibssmokirag, Frienda smoking ~, . Smoker Ths main psyc3tosociaZ' factors dgtesmininp the onset of srr.oking. On the right are the positive reinforcere or incentives to smoke: An- ticipation of adulthood inc2udea~ an impatiance to be grown up ar=d' . a tandency to participate in the activities of otdar teenagers, such aa drinking,, taking an i,nteree t in the opposite ses, going to damces aaid'coffee bars, and staying out late. On the left are the factors that discourage smokiieg; tuao of tkese-the sensory di:aeomfort:of the first fem cigarettes and the wspZeasant aide affectg of nico- tine-eoon diaagpear as the aet' is repeated, thereby l.owering the threshold' for flcrther attempts. . (Reprinted with permd.ssion froe Russell, M.A.B. The smoking habit and its cLasaification. The Pr<sctiti.oniar„ 212:792'-8n0, 1'974. Q 19I7i1, The Practitioner. 106.

J FII;UAtE' 4 Health~ Expense Social pressure Mastery 'Aesthetic Example Stop smoking lIContinued smoking Factors contraZZirsg the maintenance and dR.scontimrance of smoking. For most' peopZ'e~ betaro middZe age, the factore motivmLing contirmed smokirag are stronger than the motives to stop. The: "tftstery" motive is the wish to show rri.ZZ power and gain control' ouer the habit. "Aesthetic" refers to the feeling that smoking is dirty aad'messy, whi'Ze "$'sampZe" concerns those who wish to stop to set a good e==+ ple to cini Zdren or other irrmressionetb Zd g;rouns. (Reprinted' roi th permission from Russel'Z, M.A.H. The smoking habit ;c.d' its classi- fication. The ~Frac~ti~tio~ner2I2r79'1-800, 1974. C 1974, The Practita©ner.) ' 107 PSychosocial rewards Sensorimotor, rewards Pleasure Sedation Stimulation Withdrawal reiied/awoidance : I

and Q"F9b 1eve1's (figure 5). Such: smokers may,, however, be highly dependent in terms of'craving and'diffi'culty in giving up smoking. We do not 1now how many cigarette smokers are noninhalers, nor do wee laiow whether they have: lower ratings of' dependence (with or without control for dai'ly, consumption). To study this would reqtaire measures of QHb or expired air CD, for smokeri themselves do not reliably know the extent to which they inhale. FIGURE S' 100 120 . Time (min) • PQaama nicotixe corscentzmti.ona in an irehaiing smoker and a noninhal- ar during, and after smoking one cigarette. The in3raler smoked onLy one pack a day, and had iittla dtifficulty gi.ving up smokisrg. Thae noninhaler smoked more than three packs a day and' suffered iistener, craving when he tri.ed' unaucaeaatklZy to quit. LReprtintad' fixmr Fey,ensbend, C.; Levitt,, T.; and Rueaell, M.A.S. A rapid estimation ' of nicotine in bY:.oZogical' fluuds. Jov.rhall of Plsarnracy and Pharnra- ~eoZo 27: 433-435„ 1975, with per.miaaion. Q 1975, Journal pf ~.az+macv and Pharrxscoloqy.l I • 108

Though less rapad't'han absorption through the lungs, it is generally }seld that with snuffing, tobacco-chewing, and noninhaledipipe and cigar smoking,absorption of'nicotine throughithe nose or mouth is sufficient to provide a pharmacologically rewarding effect. The role of pH! in determining the rate of absorption, is macial (Russell 1976b). Nicotine-containing chewing gtmn with a buffer to keep the pH in the mouth at about 8.5 produces plasma nicotine levels com* parabi~e to inhaled cigarette smoking, but absorption is nuch slower (Russeil, Feyerabend, Cal'e 1976; Russell et al. 1977). The few , snuff users we have tested'have had high plasma nicotine levels. But what about noninhaled pipe and' cigar smoking? Although the pH of air-cured!tobacco smoke is alkaline (about pH 8.S), is the buffering capacity of'the smoke sufficient to bring the pH of saliva inthe mouth up to this level? I am not aware of any studies which show, this. There is, however, one recent Fnglish study which suggests that nicotine absorption from nonintialed cigar smoking may be mini''rnal ('Iluzier, Sillett, Mc*lbcol 1977). TABLE 1' Blood Nicotine and CQ-1b Levels from Cigar Sinoking, i¢i priunary and Secondary Pipe and Cigar Smokers R Before 20 min 40 min 60 min 120 mvn Ng =hTE'(ng/nl') lp (Iv- 5) 3.3 4.0 4'.3 S.l 4LS 20 (W5) 12.8 30.7 4I5'.6 36.2 24.7 M (ii) 10 (N~-5) 0.8 1.0 1.0 0.9 1.0 2(N=5) 2'.9 6.6' 8.4 9,& 8.1 The cigar was discarded at 60 miinutes.. Abstracted' from Tia7eer,, J.ri_M:; SiZZett, R.W.; and MrlVichoZ, M.W. Effect of carbosj,haemog,Zobin and'pZasma nicotine concentrations in primary pipe and c-.gar smokers and es-cicarette smokers. Bri'tish. MedicaZJournal, 2:1387-1389, 2977. 01,977,; Brti:tish Medi.ca~-naZ'. Repro by permission. *Primary, pipe and'ei,gar smokers are those who have never been regu- Zctr ctigarette smokers. Secondary pipe and cigar smokers are er-csg- arette smokers who have switchedto a pipe or cigars, which they ~ then tend to inhale (CastZeden and Cole, 1973; Cowie, Si'ZZett and' BaZi, 19'73). 109 ,

, 'Ilurner and' his colleagues measured, plasma nicotine and, M levels of smokers before, during, and'lafter the smoking, of allarge cigar (12.4 an, 6.2 g) .'!he results in table 1 show clearly that the noninhaling primary pipe and cigar smokers absorbed virtually noinicotine. 'Ihe authors claim that these smokers were nevertheless addicted in terms of craxing, and suffering, when they could not. smoke. ihe authors believed'that their study seriously challenges the role of nicotine in tobacco dependence. They did not, however, - make systematic ratings of dependence. True primary pipe and cigar smokers are an atypical'mi'nority of the smoking population,. The fact that ex-cigarette smokers who skritchito a pipe or cigars often continue inhaling is an indication tha2„ once experienced, the in- • halation of tobacco smoke is difficult to:forgo6 Though further study is obviously necessary, it would seem.that strong dependence may occur in cigarette smokers, pipe smokers, and'cigar smokers who do not inhale and who consequently absorb, little nicotine. This suggests that tobacco dependence canibe mediated by nonpharmacological factors sucln as~taste, smel'l, sen- sorimotor ritual, and the like. Indeed, nicotine itself may con- tribute to the flavor, sharpness, irritancy, etc., and ma bey rewarding for these effects apart from its pharmacological actions. Nicotine Intake from Cigarette Smoking It comes as no surprise~to find wide individual variation among smokers in blood nicotine levels just after a cigarette. Values range from below 10 ng/dnl to more than 50 ng/ml, withian average for heavy smokers of around 35 ng/ml. Neither is it unexpected that the individual smoker tends to obtain a fairly consistent peak nicotine level after each cigarette, whether it is smoked ia; the morning or afternoon, from one day or week to! the next. Of the majiority of smokers, who do inhale, we are nowhere near the stage of knowing whether they smoke for some positive effect of the blood nicotine peaks, whether they smoke to av+oid the pharmacological effects of falling below a certain blood nicotine trough, or indeed ,,&ether the nicotine intake~ and' its pharmacological effects are merely incidental'to iaihal'ation which is deteratiined by nonpharmaco- logical factors. It would seem from preliminary pharmacokinetic findings (Russell and Feyerabend, 1978)lthat the predominant bt'ood' profile for inhalers who smmke one cigarette per hour or less is one of repeated'high nicotine peaks (figure 6), whereas the accu;aalation of nicotine in the body of those who smoke at least d'ne cigarette every 30 minutes:wmald tendito show smaller peaks.relative to!the overall Level (figure 7). They might more likely, therefore, be motivated by the need for "trough maintenance." Very tentatively I: suggest that'if nicotine has a pharmacologically reinforcing role, trough maintenance may be the main motive for the addicted smoker, whil'e~ optinal peak effects may be more important to indulgent smokers, who smoke less heavily. 'Ihe peak blood nicotine levels of the two ' types, however, do not appear to differ greatly, and peak b1'ood' nicoti,ne does not correlate with cigarette consumption, r- OZ ('Russe11 et al. 19'75 and 1977). 110' I

FIGURE 6 SO Y C ~ W C O E d' 30 201 0 Ciqcrette smoked 09 10 Ili Time ( hours) t 12 13 ~ t, t t IS 16 . t t PEasma nicotine concentrations in an inhaling smoker while smoking at a rate of one cigarette per hour for sewen hours. AZthoughthere is some accurmaZation of'ni.cotine, the predomrnant' profile is one of prormi.nent bZood nicot'ine peaks fvZ'Zowi.'ng each cig,aret'te. This iZ- Iustrates'the characteristic pattern of the "peak seeker"'type of smoker meretioned' in the tert. (Figure rep;roduced vith aerrrission f}!om RusselZ, M.A_B:; Feyeraberrd, C.;, and Cole, P. V: Plasma nico- tine ZeveZs after ctigsrett'e smoking and'cheoinc nticotine gum. British M'edicaZ Journal,, 1:1b4.-1~046,, 1976. Q 1976, Rrtitish medi- caa d'ourna Z . J 11R los

FIGURE 7 60 -1 50 1 I  . :   :  •!  .',  1.   :   : d  4 1 • • oiganetle smokeOl •Time Ihi' 'PZasma nicotine concentrations in an inhaling smoker rJhiZa smoking at a rats of three cigarettes per hour for s+even hours: alood savn- ples ivere taken just before and two ms.nutes after each~ cigarette. The bZood nicotine buildg up to a°steady state^'urith peaks which are smaZ!Z relative to the overa2'Z Z'euel. Tkis tiZZustmtes the chamcterist'ic pattern of the "troug3s'.rnaintainer" type of smoker suggested in the text. (Reprinted from RusseZZ, M.A.B:,and Feyerabend, C. Cigarette smoking: a dependence on high nicotiite. boZi. Druc MetaboZ'ism Resniews, 8:29-57, 1978, by courtesy of HarceZ Dekker, Inc., c 19'78'. ) , 112' ,

It is temptiing,to postulate a three-stage process, with smokers be- ginning to: smoke forpsychosocial reasons, the majority then,l'earn- ing to inhale and progressing to smoking for the effects of thee sharp blood nicotine peaks that.fol'low each cigarette (peak-seekers), and some finally going on to a third stage of negative reinforcement smoking to.avoid the withdrawal effects of dropping below a certaistn blood nicotine level (trough-maintainers). As mentioned, however, the issue is far more complex: Noninhalers may also progress to asecond stage of regular indulgent smoking for positive nonpharmacological rewards, as well as to a thirdd stage of negative withdrawal relief'smoking medilated'by nonpharma- • cological'factors,. Further complexities arise froa interactions between pharmacological andinonpharmacological components,'due to conditioning and!other processes. Plausible, as all this may seem,, with many resemblances to other diug addictions, it has yet to be established that smokers do indeed smoke for the phar:nacological' effects of nicotine rather thanifor nonpharmacological reasons. Use:of Iow-.Tar, Low-Nicotine Cigarettes What can be learned from studies of the use of lowr-nacotiine ci'ga- rettes ? Among Ernglish cigarette smokers, only 10 percent of men and'18 percent of'women regularly smoke law-nicotine brands. Most low-nicotine brands smoked in Britain have standard deliveries of', 0.6 to 0.8'mg nicotine; yet it is still possib,le.to maintain high b,iood'nicotine levels, of 40 ng/ml or more, by smoking these brands. It is only when the nicotine yield.is reduced to 0.4 mg or less that this becomes di!ffieult„ and relatively very few peopl'e smoke ciga* rettes of'this type. The lack of'popul'arity of low-nicotine cigarettes may seem too provide evidence of a need,for nicotine. Similarly, the tendency 'when smoking them to smoke more cigarettes,or take larger andimore frequent puffs and inhaLe more deeply has been interpreted as~ reflecting a;need to titrate nicotine. There is a serious objection to this imterpretation,, however. Z''aw-nicotine •cigarettes al!so have low yields of other consituents, suchas tar, which contribute to the taste andisatisfaction of the smoke. Indeed, they aree often alsodi'fficult , to light and'tosmoke., Regulation:of Nicotine Intake Seif-regi.alation of nicotine.in2ake, or nicotine titration, is: probao,ty the most useful approach for studying,the role of nico- tine in smoking. It has been comprehensively discussed by Schachter (this volume). As he points out, theze are numerous studies showing that smokers modify their smoking patterns to: compensate for a reduction of"the.tar and nicotine yields of their cigarettes.But,,as mentioned above,, owing to the high, correlati'on, (> 0.9): of' tar and nicotine yields, we cannot knrn+

J C fifraa such studies~ whether the smokers are regulating, their intake of nicotine rather than tar or some other factor. Qily one study, by Gol~dfarb~ et a1i. (1976), has used cigarettes isnn which tar and nicotine yields were independently varied'. 'Ihe num- ber of'cigarettes smoked was unaffected'by tar yield but varied inversely with nicotine yield, although~insufficiently to madntain~ urinary nicotine excretion constant. While most studies have shown that compensation on l'ow nicotine cigarettes is often only partial (Russell 1976b, Sutton et al. 1978), we have found that smokers 1ower, their intake very accurately when switched to high nikotine cigarettes. Blood nicotine levels on cigarettes yielding 3.2 mg, nicotine averaged 29 ng/ml, compared to 30-ng/ml on cigarettes yield- ing 1.3 mg, nicotine (Russell et a1. 1'97S). It seems, therefore, that that self-regulation dowm.ards to avoid an excessive intake may be more sensitive and complete than compensation upwards to, avoid a reduction in nicotine and/or tar intake. There have been very few direct studies of'nicotine titratilon, i.e., those which avoid confoundment with tar intake and other factors. •They have, however, with one exceQti~on, been most convincing in their support for nicotine titration. For example, Stolerman et al'. (1973)'showed that central chol'inergic blockade.with arecamylamine caused snokers~to increase the nunber of cigarettes smoked!by 26.5 percent and'the number of puffs by 25.3 percent compared to pl'acebo. Inithe study by Iucchesi, et al. (1967), intravenous nico- tine infusion reduced the number of cigarettes smoked by an average of 29.8 percent comparedi to saline. Furthermore, 22' mg of' IV nico- tine bitartrate (about 7'.3'mg base) caused a mean decrease of about 2: 5 eigarettesduriaig the 6-hour infus i'on period. The nicotine de- livered by 2.5 cigarettes in the mid,1960''s, though not stated by the authors,, would have been about 7 mg. Titration of similar accuracy was demonstrated! during Sohachter's manipu,iation: of urinary nicotine excretion via its pHi (Schactiter, Iuozl'owsld and' Silverstein 1977). It would take too long to go fully into our own faalure to rep Iicate Lucchesi's findings' (Ki=r et al. 11977). 1has could have ha& something, to do with the extreme artificiality of our ex- peri,mentai conditions. Although our subjects continued to puff at baseline levels during and just after the IV nicotine, it is possible that they titrated by inhaling less. We did not measure blood nico* tine levels, so we do not know whether or not this was so. 'Ihe sensitivity of the nicotine titration demonstrated in these more direct studies is in keeping with the view that self-regul'ation of nicotine intake dowiiwards is more sensitive and complete than caa- pensation upwards. ()ne other direct approach has been to study the effect on smoking behavior of nicotine-•containing, chewing, gum. 11wo studies have shown a modest inhibitory effect (Kozlowski, Jarvik and Gritz 1975; Rvssell et al. 1976). In our study (table 2), a dose of 20 mg nicotine per day taken in the gum reduced cigarette consump- tion by 17' percent (p <. 05) and C'CHb by 41 percent (p <. 01) compared to placebo, gum, About 90 percent of the nicotine in the gum is re- leased', but much of this: is no doubt swallowed„ absorbed ih, the gut,, 114

TABLE 2 Effect of'Nacotine Qiewing Om on Plasma Nicotine Levels Auriiig ad Zibitzon Smoking (means of 41 subj ects)' No guaa Placebo gun Nicotine gum Cigarettes per day . 33:3 23:0 20.9 M M 8:S 7.2 6.3 Plasma nicotiae (ng/nl') 30.11 24.7 27.4 Note: One piece of gum containing'2 mg nicotine was chewed hourly for 30 min to a, total of ten pieces per day. The specific effect of nicotine (as opposed to the effect of placebo guzn) accounted for 171 of the reduction in daily cigarette consur,iption (23.0-20.9) -:- (33. 3-2D.9) x 10'0, - 1'7'. By similar calcul!ation, it accounted for 413,of the reduction in OCHb and hence degree of inhalation. Adzpted from RusseZZ, f1iZsnn,, Feye^abend, and CoZe. Effect ' of nicotine cneving-gucn smoking behaviour and as an aid to eiga- retts! wi.thdrawgl'. British ldedical Joucrna'Z, 2:39'1-39'3, 2976. cQ 1976, British Me tcourraci Yeprtinted by permission.) and metabolized in the liver before reaching the systemic circulation. It is not known hosr much of the 20 mg daily dose wvuld have been absorbed'through the mmuth. Nevertheless, despite the extra nico- tine from the g}ma, the average plasma level ofl 27.4 ng/mg (table 2), was raot significantly different from the base-line 1'evel'of 30.1 ng/ml when smoking normally without g=,,showing once again fairly accurate downsrard titration. Qn the placebo osn, the small decrease in p1as- ma riicoRine (pG05) suggests that a drop in plasma nicotine may be better tolerated than an, excess. Adaptation and' Coapensation Theoretically, a smoker may adjust to a dilution of nicotine (and tar) content of smoke either by adapting to a lower dose or by com- pensating to maintain intake„ smoking more cigarettes.or increasing, the intensity of puffing and inhalation. The degree of compensation may range froml nil', to partial, to complete. The reduction, of ni,co- tine (and tar) intake to which adaptation is required will'obvicusly vary accordingly: Adaptation to a lower dose will only be complete when any negative affect or discomfort has subsidedL The time courses of adaptation and of compensatory ehanges~in smoking pattern: 115'

_.J may differ, and they may also interact. For example„ the degree of' corpensation may be reduced a.s adaptation to a lower intake reduces the urge for a higher intake. Increase in the intensity of puffing may generate discomfort of a different kind (from that generated by the reduced intake), to which adaptation of a different kind may or may not occur. For, examplle, to increase: puff'volume from 40, m1 to 60 ml to maintain smoke intake per puff may involve little effort, but an increase from 60 ml to 80 ml may make the smoker aware of' I only partial and, that'some smokers compensate while others do not. Tl contrasts strikingly with the very accurate downward titration some awkwardtaess or discomfort. There are further complexities. For example, a!smoker may be able to take a larger puff of diluted smoke, sufficient to maintain nicotine (and tar)i dosage per puff, but the dilution may reduce impact and flavor below an acceptable level. Response to such interactions will vary, dependi''ng,on the degree to which the smoker requires to maintain nicotine (and tar) intake on a per puff basis or on a per cigarette or per unit of tiane basis. Furthermore, the unit of time may refer to the time taken to smoke one cigarette or tollonger periods in which several ciga- rettes are smoked. Hbst studies of smokers' responses to changing to low-nicotine ciga- rettes have been focused on demonstrating a significant compensatory change in a group of smokers. They have beeniless concerned withh individual differences and have not attergptedito measure.the degree of compensation. We have recently examined'the extent to which smokers compensate for the di'Iution of smoke produced by ventilated cigarette holders (Sutton et a1!. 1978')., There were no changes in the number of czgarettes smoked. However, measures of'plasma nico- tine and 0CHb showed, on average, partial compensation of about 40 percent on Hoider 2 (60 percent dilution), but on Holder 1 (20 per- cent dilution) there was~ no significant compensation (see figure 8). Individual differences were marked, ranging from full compensation to none at al'1. About half the~subj'ects were clear-cut noncompensa- tors. A similar 50;/50 differentiation of ind-avidual smokers into compensators and' noncompensators has: been observed by others~ (Cherry and Forbes 1972; Freedman and Fletcher 1976; Forbes et al. 1976'). A further finding,, shown in figure 80 was that the degree of compen- sation on Nolder 2 did not change between 2 days and 7 days,,_but adaptation to the lower nicotine intake did improve over this time. Withdrawal symptoms subsided and subjective satisfaction on~Fbidar 2 increased. How muchl this difference in the short term trends of thesee two processes would be reflected in the long term is obviously an important question. The adaptation acquired over this short periodd was.trans'ient. Plasma nicotine and CCHb had returned to former levels five days after the holders~were abandoned.,,The only long term study, by Freedman and Fletcher (1976), suggested that adapta- tion acquired over several months could be maintainzed, an& that smokers who ha& adapted to a lower, tar and'nicotine.intalee at mouth level (based on butt analysis) did not increase it again when they reverted tolsmoking stronger cigarettes. , These findings highlight the fact that'compensation is, on average, 116'

__... _... . QsNo fioldlm i R Holder 1 FIGURE 8 2!= Holder 2 Amount of compensation when using ventilcted cigarette holders,, based on the means of 18 subjects. The observed and'"e_^tected!"' blood nicotine and C08b levels on the fiolders are e_-vressed'as percentages of the mean no-holder levels. The "expected" levels are based'on the dilution factors of the two holders, about .2f0 percent for Holder 1 and 60 percent for Holder 2. The shaded areas represent the difference between the observed'and'"e.~-pected" levels, which is a measure of the amoumt of compensation. The Lined'area (for COflb on RoZder I at 2 days) indicates a negative O-E difference, i.e., observed levels were lower than "expected° levels. Thus, though there was significant compensation on Holder 2 on all measures, there was eZearZy,none on Holder 1., Siqnsficancee of lJ!i E'difreTences'.• ''p<.02, *''p<.'01, ••''`p<.001. (From Sutton, S.R.; Feyerabend, C:; Cole, P.V.;, and RusselZ,, K.A.R. Ad7ustrrent of smokers~ by , ventilated cigarette holders. Clinical PAc.--nacoloa:r and The t_~i_cs, 24: 39'5-9~015, 1978. ~ 1978, T e C. V. Mos~- y, o: ~ Reprcnzec aMtn pession. J 117'

of nicotine in the experiments cited previously and may be partly explained by the fact that it requires some effort by the,smoker to1 increase smoke iintake but no effort to, reduce it. Although satisfaction is reduced uhen the smoke is diluted, this is not necesr s'arily due entirely to failure to maintain nicotine intake. Other factors~such as the effort of compensation, loss of taste and iartpact' of the smoke in the mouth, throat, and lungs may contribute. It would appear on balance that smokers tolerate a decrease in nicotinee intake better than an iaicrease. The Role of Nicotine pur uncertainty about the rose of aicotine in tobacco dependence is reflected'in the title of'this conference where tobacco andinicotine are linked, ambiguously, as "tobacco/nicotine."' As I see it, the stroke between them procl'aias loudly what we don't 3alow, and itt is~on this issue that I have tried to focus. In terms of unequivocal evidence that people smoke for nicotine, even the few direct studies which purport to show that people smoke to obtain a pharmacological effect frominicoti:ne and that titration indicates a need for nicotine, could be interpreted as showing nico- tine to be pharsaco,logically aversive. Thus, when Lucchesi adminis- tered nicotine intravenously, smoking was inhibited (iucchesi. Schuster, and!Pmley 1976); but when Stolerman blocked the pharmaco- logical effects of nictotine, his subjects could smoke more (Sto1'er- man et al. 1973)'. S'Lr.ui;larly, Schachter'"s~subjects could smoke more when nicotine:excretion was increased (Schachter, Ko¢Zowski, and Silverstein,1977). In other words,, these: studies could be seen ass showing that excessive nicotine is aversive; they do:not show that smaller amounts are pharmacologically rewarding. On we be sure that people are not dependent on inhalation for nonpharmacological . reasons such as taste, smell, ritual', sensory stimulation to the lungs and respiratory tract - to which nicotine might contribute? Are peonle perhaps addicted to inhalation for nonpharmacological rewards~ but'imhibbted:from indulging more because they find excessive nico- tine pharmacologically aversive? Simply because nicotine! has so many phazmacologicaleffects in smoking doses, it does not necessarily follow that these effects are reinforcing,rather than aversive. Is there, indeed,,any evidence that nicotine is rewarding? Esridence that nicotine can be pharmacologically rewarding,is scanty. Firstly, throughout history people have never shown a strnng incli- nation to inhale smoke, however aromatic or flavorful, which dtces not contain a psychoactive drug. 1his historical evidence is com- pelling but only circunstantial. On the other hand, there is a surprising lack of evidence beyond the anecdotal level that animals will learn toi self-inject nicotine as avidly as they'do other ad'- dictive drugs. Untillattendfing this conference I was aware of only two incomplete reports (Clark 1969; Ltieneau and! Inoki '1967)i. The careful studies of, Hanson and his col'leagues~ (this volumel are a major contribution to this area. A prelirLinary reservation is thit they may not have shown conclusively that their rats were indeed' T18 N 0 0 CA 0 Cal w 0 ~ !

, seeking nicotine as opposed to~increasing,the rate of lever-pressing diie to its stimulant action. The study design did not include & free choice situation, whieh could have gone a long way to settle this question. •' Apart from the historical evidence and animal self-adm3nistratian, studies, there is the well-known pioneer study by Johnston (1942). He reported that when smokers were given hypodermiic injections of' nicotine they "almost invariably thought the sensatiion pleasant." He also reported that the craving following withdrawal of cigarettes was relieved'by injecti= of nicotine. Has Johnston„ all thosee years ago, done what all! of us have failed to doy namely shown that nicotine is both a positive:and negative reinforcer for human smokers? I3nfortunately, he has not. His studies were uncontros'1ed and nonblind. Iiowever,, his approach to the question has been more direct and relevant than any of our efforts. We still lack a direct study in hurnans to! show that nicotine is pharmacologically rein- forcing. Whether or not it is rewarding in optimal' doses, it cer- tainly seems to becoome aversive.when these are exceeded, and!the inrolications for safer cigarettes remain the same. Less tar and Q) will be taken in by smokers if their cigarettes combine a low tar and low CO delivery with a mediun to high, rather than low, nicotine delivery. Sumnary and Conclusions The role of nicotine in tobacco dependence is discussed. Review of the data available in the literature raises many questions but provides few answers beyond the following conclusions. (,1) pharmacoiiogical reinforcement is not an essenii'al feature of addictive behavior. ( 2)i'Ihere are ,,-.Lny nonpharmacological: factors involve& in tobacco: smokiaig, and these appear to be sufficient to generate strong;depea- dence in smokers who do not inhale. _ ( 3)' The low acceptability of 1'aw-nicoti¢ie cigarettes is nat neces- sarily due to the low, nicotine. NonphaRmacological factors are also involved. ( 4)', Smokers who: inhale seem to tolerate a decrease in id.icotine in- take better than:an increase. ( 5) Sbrtply because nicotine has many pharmacological effects~in smoking doses, it does not follow that these effects are reinforcing rather than aversive. ( 6) Evidence iis,: scanty that animals:~+sll self-inject nicotine as avidly as they do other addictive drugs. ( 7) Apart from circtanstantial historical evidence that people have never shown a strong, inclination to inhale smoke that does not con- 119 I i

tain a psychoactive drug, there is no direct experimental study which shows that nicotine is pharmacologically rewarding,or re- g inforcing in hirnans. C ( 8) Whether or not nicotine is pharmacologically rewarding in op- timal doses, it seems to become aversive when, these doses are ex- eeeded. ( 9) The hypothesis that people smoke and'inhale for nonpharmaro- logical rewards, including the taste and irritancy of nicotine it- self, but are inhibited from, smoking,more because they find exces- sive nicotine pharmacblogically aversive, has not yet been dis- proved. (10) The implications for safer cigarettes remain the same no mat- ter whether nicotine is rewarding or aversive: The safer cigarette should have a low tar, low (0, but med'iaun to high rather than low nicotine yield. A CKNOW'LED 0,11 LYTS I thank the Medical Research Council' and Department of Health and Social Security for financial support'. I am also grateful for helpful comments from my co1'leagues, J. Richard Eiser, ?ftrtin Raw, and Stephen Sutton6 REFERENCES • Bynner, J.3x: The Y~ Smoker. Government Soci'al Survey. London: I~SO, 1!969'• . Cowie, J.; Sil'lett, R.W.; and Ball, X.P. Carbon monoxide absorption by cigarette smokers who change to smoking cigars. Lancet, 1: 11033'-1035, 1973. implications for anti-smoking strategy. Royal Society of Health Journal!, 90:159, 1970. Castleden, C.M., and Cole, P.V. Inhalation of tpbacco smoke by ~ pipe and'cigar smokers. Lancet, 2:21-22, 1973. Qierry, W.H., and' Forbes, j~.f. Canadian studies aianed' tos.~ard' a 1ess, harnaful cigarette. J Nat.-r Cancer Inst , 48:1765'-1773y 1972. Qark, M.S':G. Self-administered nicotine solutions preferred to placebo by the rat. Brit J Pharmacol, 35:367P, 1'96'9. , Bynner, J.M. Behavioural research into children's smoking: Some Deneau, C.A., and Inoki, R. Nicotine self-admi'nistration in mon- . keys. Ann N'_Y: Acad' Sei• 142!:2!77-279, 1967. 12')

, Feyerabend, C.; Levitt, T:;, and Russell, D1.A.H: A rapid gas-liquid chromatographic estimation of nicotine in biologicai fiuids. J. Pharm Pharmacol, 27:434-436, 1975. - Forbes, W.F.; Robinson, J.C.; HanLey, J.A.; and Colburn,, H.N. .Studies on the nicotine exposure of individual smokers. 1. Changes ii¢ mouth-level exposure to nicotine on: switchi.,ng, to lower nicotine cigarettes. •Int J Addict, 11:9'33-9'S0, 1976. Freedman, S'. , and Fletcher, C:M. Changes of smoking; habits and cough in men smoki;ng;cigarettes with 301 h&M tobacco substitute. Bri~t ?1e+d J, 1:1427-1430, 1976,. Goldfarb, T.L.; Gritz, E.R.; Jarvik, M.E.;; and Stolernsan, L.P. Reactions to cigarettes as a fuaaction of nicotine and tar. Clin P;larmacol Ther, 19:76'7=77Z„ 1976. Ikard',, F.F.; Green, D:E.;, and Horn, D. A scale to differentiate between types of smoking as related to the management of affect. Int J A~, 4:649, 1969. Johnston, L.M~ Tobacco! smoking and nicotine., Lancet, 2:742, 1942. Kozlowski, L.T.; Jarvik, M.E.; and Gritz, E.R. Nicotine regulation and cigarette smoking. CI'in Pharmacol Ther, 1Z:93-97, 1975. Kunar, R.; Cooke, E:C.; Lader, M.H.;, and Russell, M.A.H. Is nico- tine i=ortant in tobacco smoking? Clin Pharmacol Ther, 21:520- 529, 1977. iancc.hesi, B.R.; Schuster, C.R.; and FJvley, G.S. The role of nico- tine as a determinant of cigarette smoking freqtnency in man with observations of certain cardiovascular effects associated with the tobacco alkaloid. Clin Phar.nacol Ther, 8:789-796, 1967. McKennell, A.C. A conroarison of two smoking typologies. Rbsearch Paper No 12. London: Tobacco Research Council, 1973. McKennell, A.C., andiThomas, R.K. Ad{alts'' and Adolescents' ~Smo~kin~ Habi'ts and Attitudes. Government SociTSuwey. naon: ~t 0, 1~67. Russel'1, M.A.H. The smoking habit and its classification. The Pract _, 21'2;:791-80I0„ 1974. • ~ Russell, M:A.H.; Peto, J.;, and Patel, U.A. The classification of smoking by'factorial structure of ;notives. J Say Statist Soc A,. 137:313-333, 1974. - - • Rtassell, M.A.H.; Wilson, C.; Patel, U.A.; Cole, P.V.; and Feyerabend, C. Plasma nicotine levels after smoking,cigarettes with high, medlcaa and low, nicotine~yields. Brit Med J, 2:414-4'16, 1975.. • Ftussell, M.A.H. Low-tar meditsn-nicotine cigarettes: A new approach to safer smoking. Brit Med J4 1:1430-1433, 19716a. 121

Rmssell, M.A.H. Tobacco smoking,and nicotine dependence. In: Gibbins, R.J., et al., eds. Research Advances in Alcohol and D~~~ug Problerns. Vol. III. New York~i~ ~,-T9~7~ p.T47._ Russell, M:A.H.; Feyerabend, C.;,and Cole, P.V. Plasma nicotine levels after cigarette smoking and chewing nicotine gtaa. Brit Med J, 1:1043-104b, 1'976. 'Rms,e11, M.A,H6;Wilson, C.; Feyerabend; C.;, and Cole, P.V. Effect of' nicotine chewing-gtaai on smoking, behaviour and as an aid to ciga- rette withdrawal., Brit Med J, 2.391-393, 197'61 Rwssel'1, M.A.H.; -Sutton, S.R.; Feyerabend, C.; Cole, P.V.; and Salooj;ee, Y. Nicotine chewing-gum as a substitu[e for smoking. Brit Med J, 1:1060-1063, 1977. RRussell, M.A.H., and Feyerabend, C. Cigarette smoking: a depen- dence oni high nicotine boli. Druz Metabolism Rbviews, 8:2h-57, 1978. Schachter, S.; Kozlowski, L.T.,; and Silverstein, B. Effects of urinary pH on cigarette smoking. J Ex` Psvcltoli Cen)', 106:13-19, 1977. Stolerman, I.P:; Goldfarb, T.; Fisilc, R.; and Jarvik, r!:E. Influen- cing cigarette smoking with nicotine antagonists. Psychopharmaco- logia, 28:247-2!59, 1973. Sutton, S.R.;; Feyerabend, C.; Co1e, P.V.; and Russell, M.A.H. Ad- justment of'smokers to dilution of tobacco smoke by ventilated cigarette holders. Clin PharTsacol 'Iher, 24:395-40'S, 1978. Turner, J.A.?{.; Sillett, R.W.; and r'r-Nicol, t'..W. Effect of'cigarf smoking on carboxyhaemoglobin and plasma nicotine concentrations in prinary pipe and cigar smokers and ex-cigarette smokers. . Brit t•ted J,. Zi:1357-1389, 1977. - - aLZ'HpFt' Micfiaei' A.H. lhassell,,.M.,B., MtCP, MRCPsych A'r33icti'on Research Unit T}:e Institute of Psyc'tiiatry ' W .~ ifi.: biaudsley Hospital~ De.-:nark Hill Lc.*don, S;E:S ~ Fszlandi . ~ 1 W 0 122

Schachter, S. Pharmacological and Psychological Determinants of Smoking.. In: Thornton, R.E'. ('Editor)~. Smoking Behaviour. Physiological and Psychological Influences. Edinburgh, Churchill Livingstone, 197'8,,pp.2'©8-22$. The low nicotine and tar campaign is based on the notion that cigarette smoking stems from a variety of psychological, sensory and manipulative needs which can probably be as well satisfied with a low as with a high -nicotine cigarette. If a smoker is smoking to keep nicotine or its meta- s bolites at some optimal level, if he switches to low nicotine brands, he may smoke more cigarettes and take more puffs of each. In this case the concerned smoker should smoke high, not low, nicotine cigarettes. The recommendations for smoking low or high nicotine cigarettes depends on the relative importance of,the pharmacological versus phychological needs satisfied by smoking. Studies on the effects of' nicotine on shock tolerance, irritability, and stress and those that support a pharmacolog,ical basis for smoking behavior are reviewediwith the conclusions that: (1) The psychological and probably thee sensory and manipulative gra~tifications of smoking are illusory. Serious smokers smoke to prevent withdrawal. (2),Smokers regulate nicotine intake. (3) Variations in smoking rate which customarily have been interpreted in psychological terms seem better understood as an attempt ot regulate nicotine. (4) Apparent exceptions to a regulatory model of smoking seem understandable in terms of withdrawal. The smoker who fails to regulatPp suffers withdrawal. Therefore, a serious case can be made for a, pharmacological, addictive view of'cigarette smoking, unless there is a long-term effect of switching brands so that smokers eventually return to their former level of'consumptioni. Two such studies on long-term effects of'switehing brands are reviewed. Overall conclusions are that switching to low nicotine cigarettes results in an increase in amounts smoked'lso that the campaign for low nicotine cigarettes is not ustified.

17. Pharmacological and psychological determinants of srnokingi 5 SCHACHTER The gist of the anti+smoking campaign is simply 'Quft andl if you can't or won't quit, switch to a low-nicotine„lotiv-tar cigarette'. With the backing of the American Cancer Society; the Royal College of Physicians and the Public Headth~Service, this message pervades the mass media and appears responsible for the tediouscompetitnons among tobacco1 companies for the safest cigarette, the search1 for an acceptable tobacco •fcee cigarette: stimuiated by the British government and taxation policies such as that of New York City which taxes cigarettes by nicotine and tar, content in an apparent effort to use economic muscle in order to help the smoker help himself. Though no one has bothered to make explicit the premises on which such policy is based, it appears reasonable to guess that, in part, thelow nicotine and tar compaign is based onithextotion that cigarette smoking,stems from a variety of psychological, sensory and manipulative! needs which can probably beas well satisfied with a low as wsth a high nicotine cigarette. The possibility that this earnpaign, may perversely be increasing the health hazards of smoking has been raised byDbmino ('1973), Russell (1'974a) and'others who, point~ out that there is evidence, after all~ that nicotine is addicting. To the extent that the smoker is aniaddict, he is probably smoking tn~keep~nicotine or one of its active metabolites at some optimal level. If, then, t'heheavy smoker does switch, to iow nicotine brands, he may very well end up smoking more:cigarettes and takiitg, more puffs of each. He will in the proeess of regulating nicotine probably get the same amounts of nicotine and tar and unquestionably get more of the combustion products, such as carbon monoxide which appears to,be at least as much of'a medical villain as tar: or nicotine for it is implicated in the increased risk to smokers of arterio- sclerosis, ischaemic heart disease, fetal damage and so on (Larson, Haag,and Silvette, 19611; US Surgeon General's Report, 1972). If this shift in level of smoking,ia permanent, the net effect of switching to low nicotine eigarettes should be: to increase the dangers of smoking. From this point of view, the concerned smoker should' smoke high, not low, nicotine cigarettes. Since almost everyone would agree that cigarette smoking,involves both pharma- eological and psychological determinants there does seem to be some support for either positionl Whether rationality dictates the recornmendation of a low or a highh nicotine cigarette depends, of course, on the relative importance of'the pharmacalogicaI, versus the psychological needs satisfied by smoking. ~M 10'05053074 -

PH,AIRMACOL©CICAI: A,1tD'P'SYCHOLfJCICAL DET'ERVt1NANTS OF SMOKING 209 On the gratifucationa of smoking, Almost any smoker camconvince you and himself that there are majwr psychologicall components to smoking: Theywill convince you that smoking,calms them; that'it helps them work; that they smokemore at a party'and so on. In short, smoking serves some psychological function; it does something positiive fort'he smoker and Presumably nicotine or tar or some component of theact, of'smoking is so gratifying thaU despite the welllpublicised dangers the smoker is unnvilling to give up the habit. =~ -,. .:.: this is the reason he smokes. This emphasis on the functional properties of smokuog, .,, „ is a the heart of virtually every serious psychologicaI'attempt to understand smoking. i', ,.> I Undoubtedly the ultimate eulogy of the act is Marcovitz's suggestion (Marcovitz, 1969) that 'as a, psychological phenomenon, smoking is comparable to the ritual of the Eucharist. There the communicant incorporates bread and wine and in so doing symbolically introjects the Lord Jesus Christ. This is a conscious process, with the hope of identification, of attaining some of the attributes of Jesus. Similarly, the smoker, incorporates the smoke introjecting in an unconscious fantasy some object which will eonfer on him its magic powers.' (p. 1'0$2). Among,thesemagic powers,, smoking serves to'delirnit the body image in the quest for the sense of self,'-to 'teyeve the unconscious fear of'suffocation''and as `proof o'f'inunortality'. Thoughh no one has matched Marcovitz's panegyric, almost all!attempts to account for the habit have assumedi that it does something positive for the smoker - an assumption that is shared by thesmokerr himself for'numerous studies indicate that heavy smokers report that cigarettes relax them or stirnulate them„put them at ease, give them something to do with their hands, and so on. In short, for both the psychologist and the smoker, the act' of smoking is functional; it does something for the smoker and this is the rm-on he smokes. In this paper, I shall concentrate on one of the presumed motivations fpr smoking. Smokers widely report that they smoke more when they are tense or anxious an& they also report that'smoking calms them. Smoking, themserves a respectable psychological function and this presumably is one of the motivations for and explanations of smoking under stress. Before worrying through interpretatnons ot these fact!s, let us make sure that they are facts. Firstly, does smoking increase with stress? The available evidence indicates that indeed it does, ifthe stressis fairly intense. In, two almost identical experiments (Schachter etcrl, 1977b; Sckach'ter, Silverstein and Perlick, 1'977), my associates and I manipulated, stress within the context of experiments presumably'designed to measure. tactile sensitivity: In high stress conditions, such sensitiirity was measured by the admiiustration, sporadically over an experimental hour, of a series of intense, quite, painful shocks. Inilow stress conditions, the shocks were a barely perceptiblie tingle. Between thelesting intervals, the subjectis, all smokers, were free to smoke or not as they pleased. Inbothistudies, the subjects'smoked considerably more in high than inlotiv stress conditions. Turning to the effects of smoking on stress, we ask next does smoking reduce stress? The answer appears to be that irdepends upon how you look at'it. Silverstein (11976) attempted to answer the questioniby measuring how much electric shock a subject was willing to take within the context of a study of tactile perception,. The procedlnre required that electrodes be attachedl to a subjeet's fingers, that he be exposed to a series of'shocks of gradually increasing voltage and that he report when

210 s`tpKlN6IIEHavtOUR he eould' first feel the shock, next when the shock fust became painful and! flnally when the shock became so painfuLthat he could'no Imnger bear it. SIIverstein assumed that the more anxious the subject, the less pain he would be willing to tplerate: Tltere were fo;ur experimental groups - smokers who smoked either, high or low nicotine cigarettes durirng,the experiment or who did not srnoke at all during;this time and a gnoup of non+smokers who did not srnoke. The results of'this experiment are presented'in Figure 17:1. Tlhe ordinate plots the nurnber of shocks the subjects endured before calling;it quits. It is clear that srnokers take rnoreshocks when they are sznoking,high nicotine than when smoking low nicotine cigare,ttes thani when not smoking. Gixen'this pattern one has a choice of interpretatimns: either nicotine decreases anxiety or lack of nicotine increases anxiety. T7ie choice of dppenda; of course, on the position of the group of non- srnokers who, as can beseen in Figure 17.1' take virtualljrthe same number of shocks. as smokers on high nicocine. It would appear then that smoking is not anxiety reducing but, rather, that no snioking,mr insufffcieno nicotine is forthe heavy smoker, anxiety increasing. Preeisely the sarne patterniof results emerges in a studyof irritabillty aond'uctedby Perlick (1977). Wthin the context of a studyof aircraft noise, subjects; watching a television drarna4 rated'how annoying they found a series of sirnulated over-fhgtits: During the experirrtent, heawy smok'ing subjects were permitted ad k7r smoking of high nicotute cigarettes in one condition, of low nicotine cigarettes in another condition and were prevented from smoking in a third condition. Finally, there was a control group of non-smokers. The nesults are presented in Figure 1'7.2 where it can be seen that smokers on high n•tcotinecigaretites are markedly less irritated. bythis senies of'obnoxious noises than are srnokers restricted to low nicptnne cigarettes or prevented from smoking. However, these high n6cotine smokers areneither less nor more irritated than the group of non-srnmkers. Agaia it would appear that smoking dmesn't make the smoker less irritable or vulnerable tp annoyance, not smoking orr insuffcient nicotine makerhim more irritable. This same pattern is charactezsstic of psychotnotor as well as emotional behavimur. Heimstra{ Bancroft and DelCock (19b7) examiuaed the hypothesis that smoking facilitates drivirtg performance by cotnparirtg ad k'b smokers, deprived smokers andd non-smokers in a six-hour simulated driving; test. On a variety of ineasures of trarking and vigilance, ad libsrnokers do neither better nor worse than non-smokers but do markedly better than deprived smokers. Aigairr and again, tlien, one finds the sarne pattern - smoking doesn't improve the mond or caltrt the smoker or improve his'perforffnance when epmpared with the norr smoker:' Hiowever not smoking,or insufffcient nicotine makes him cortsiderably 'T}iere is of course.,analternative interpretation of this consistent pattern. Rtither than indicating withdrawal, it is coneeivabte that peaple who become smokers:are by nature more frightened of shock. more irritated by noise and worse drivers than people who never become smokers; and that for such peoplrsmoking,is indeed calming and does improve psychomotor performance. Though nothing short of a longitudinal study could unequivocally settle the matter~ it should be notedlthar there have been a formidable nuntber of studies that compared smokers artd non-smokers on virtually every personality dimension imaginable. Smith (1970) in his review of thisliterature coneludes that the oruty vzriables which+ with reasonabie consistensy, discriminate between smokers and non~smokcrs are artraversion attd'anti-social tendencies. Md even on these variables the differences are quite small. 1005053!076

7 SECTION

Selective R:eduction of Tumorigenici'ty of~ Toba~cco~ Smoke., 11. Experi mental Ap- proacMes142 Dixtricft Hoffmann, Ph.D., and Ernest L. 1Wyndpr, M.D., American HeoJfrsi Foundation, New York, New York IC?021' FOUR YEARS ago at the Fint 4Norld Conference on Smolting and Healthi we reviewed'experinaental approaches toward seiectively reducing the tutnori- genicity of tobacco smoke (1'). Since then,, signifi- cant progress has been made on the identification of tumorigenie agenrts in tobacco smoke and also on the reduction of the carcinogenicity of' the partictulate : matter of tlie : stnoLe, (2 5). Emphasis has been placed on the removal of the precursors for tumorigenic agents in tobacco smoke. For this purpose, changes were explored in the farm practices of' growing, and harvesting tobacco, in the curing, processes, in the selection of leaf and plant eomponents, 'and in the blending of the various tobacco varieties. New procedures have been: investigated for the prodinction of reconstituted tobacco sheets: `4!any publications and patents have also dealt with the modification of the burning characteristics of tobacco! and the inhibition of pyrosynthesis of tumorigenic agents: In addition, a number of. tobacco, substitutes are currently being tried.. iDEI*ITIFICA?lON OF TUMORNGENIC: AGENTS Three basic types of tumorigenic agents have been identified in tobacco smoke: tumor initiators,, tumor accelerators, and tumor promoters. In addition, tobacco smoke also contains tumor in- hibicors and resorption retarders. Tumor Initiators Fractionation experiments have shown that no single major fraction is responsible for the total carcinogenic and sarcogenic activity of tobacco- smoke condensate and that only the neutral por- tion induces al significant number of tumors in thee experimental animal (6-14). In sevcral! laboratories, concentrates of tobacco "tar" containing, the polyr nuclear aromatic hydrocarbons (PAH) were shown to be complete carcinogens (6-9, 11-13). In our own stud'ies, we concentrated the PAH into, the neutral' fraction B and subfraction BI, which amounrced'to only 2% and 0;69, of the "tar", respec- tively (text-fig. 1). Excluding B: frotn a recombina tion of all fractions.Ied to a>50, reduction in thee tntrttorigenicity, whereas recombining all, fractions (including B) only slightly rediuced' the activity relative! to the original tar (13). Dontenwill et' al. (H) confirmed these results. These findings suggest our working hypotheses: The carcinogenic hydrocarbons contribute signifi- eantly to the turnor=initiating activity and' to the overall earcinogenicity of tobacco tar (J5). Further fractionation, experiments led to the isolation and identification of several known as well as severali new tumor initiators in tobacco smoke [text- fig. 2;, (13, 16)J. - The carcinogenic polycyclic hydrocarbons are formed during the burning of'tobacco (1, 15). Twoo distinct mechanisms have been suggested and substantiated for the pyrosynthcsa of PAH. The first (17) involves the pyrolytic fortnation of hydro- earbon-free radicals and their combination to givee compounds with a condensed aromatic ring spstem. (text-fig. 3). The second mechanism involves the. Diels-?.Idcr add!ition of dienes to dienophiies to~ form new ring systems, which subsequently are dehydrogenated to polycyclic aromatic systems (text-fig. 4). I Presented at a workshup of the Second, World Con- ference on Smoking and Health, sponsored by the Unired Kingdom Health Education Council, held in London, September 20--24; 1'971. s Supported hy Public Hrrlttf Service research gFante NIH-11CI-70-2oS7' and CA 0'12376 from the National Cancer Institute. , 1853

f' = 1856 Tsxr-stotrrtm l .-Fractionatioa of eigarette-smol•e eond'eaeate and sesuhs of'bioassays: H©FFMAYtV AND WYNDER . 4latter mechanism is at least partially re- spionsible for the relatively high concentration of alkylated PAH in tobacco smoke compared to ~ that in other environmental combustion products, such as gasoline engine exhaust and other urban air pollutants (13, 18). The major diene in tobacco smoke is isoprene (U.3-0.7 mg/cigarette) (ZD),. Iso- prene and other volatile 1,3=d"aenes can' form Die1s. Alder adducts «ith dienophiIes,,such as indene and acenaphthylkne, and thus~ form alls}-Iated! poly- cyclic hydrocarbons. The volatile dienes and dicno- philcs are formed by pyrolysis of'tobacco terpenes,, which amount to 0.5-2.0% of the dry leaf weight: Tobacco, therefore, is unique : in containing pre- cursors w.hich produce an inhadant with relatively high concenrcrations of carcinogenic alkylated PAH. G- Tumor Acceleralors CI•^ RNNire ~~.CrcinO"niCA[tn+ly ~ t'• RNM~.auma'K~+^9!=lnily Tutnor acceleraton, are inactive as whole car- cinogens, tumor initiators, and tumor promoters. However, they accelerate the activity of carcinogens and tumor initiators when applied! together to the target organ. We showed tha;t tobacco tar contains such, neutral 'accelerators as tranr-4,4'-dichloro. stilbene, JY a1ky1 indoles, and JY=alkyl carbazoles. These substances are concentrated from the par- ticulatt matter together with the carcinogenic PAH' because of their sirmilar polarity (text-fig. 5; (13)], Tumor Promoters The first experiments with fractions of tobacco tar showed that the noncarcinogenic acidic por- z 1 c

_...._ .r...._._ sELECThVE REDITCITOM 2N TOBACCO CJARQNOCENTM O0Mi1; hI t7idM DIOuR/ & j/ cfi4lnf n 1«,n+donen,nm.m. .n4 M.uhn-xen Pjmtl; A1 irdhncaM IMM+oJ 1.2.3-cm pyr.ne Tsxr-statraz 2: Tumor initiators in the parriculate matter of tobacco smnleu tion significantly increases the tumorigeniciry of the neutral portion (6). Subsequently, Gellhorn (19)' reponed a tuzmor-promoting activity for the total condensate, a result since confirmed many times (13-15, 21-23). ,.At present, information is only lisnited on the chemical nature of the tumor promoters. As early as 1957, promoter activity was shown to reside in the weakly acidic portion of tobacco tar (6, 24--215). We idtn ti'ficd" certain volatile phenois and fatty acids as tumor promoters (15, 25). But these agents cannot by themselves account for the tutnor= I promotimg activity of the entire weakly acidic I fraction. Recent studies by Dr. G. Siager of our laboratory suggested tumor-pronnoting activity for certain X-alkyl atninophenol3. Bock et'al. (21) found that 2 neuaal subfractions had some activity on mouse skin~ which had been initiated .6th 7,1'2-dimrthylbenzQa]antltracene (DNIBA); One of'these subfractions was enriched in the PAH. - . In our own studies, the apparent turnor-pro- anoting activity of' the PAH concentrate Pcaction (BI) on mouse skin initiated with DMBA could be VOL. 48, NO. 6, JUPtE 1972 Benzalalpy,rene TExz-taeoxa 3.-Pathways for the pyroaynthesis of beazo- Cn]pb'rene. d swsc ka+ee tt Ttams 4; 4'-Oiehl6tos1ilGane, 1-Methylindolt 9-Methylnrbstols l2DCyg/1D0 ciqJ {42{uj/1D0cigJ' Il0µg/100 cigJ Tsxa-racuxE S.-Tutaor, acceleratocs in t.mbaeeo aar• einogenesis.

' 1858 HORFM,ANN' AND WYNDER n :.. & explained by the complete carcinogenicity of B!I (table 1:; ('13)]. Fraction BII, containing about 0.5% of the total' tar, and in which esters of' cottl, parable polarity as tlie : PAH' had been enriched, did not show any earcinogenicity or tumor-pro- moting activity. The same appiied' to the most polar fractiiDns of the neutral' portion. The appar- ent discrepancy between our work and that of Bock could' be due to the possibility that we did not eltlte the very polar fraction from the chroma- tography column and/or that the polar compounds wered onridized or otherwise altered on the column. Additional studies are needed' to cl'arify this difference. BGadder Carcinogens Cancer of the bladder occurs more freqtnently in cigarette smokers than in nonsmokers (2,, 27, 29). The biological data on the induction of bladder cancer in the eacpericnental anirnal! are rather in- conclusive (2, 13, 27, 29). Only traces of the po- tential bladder carcinogens, aminofluorene and 0-naphthylamine, have been found in cigarette smoke (28; 30),. "A'e believe it unlikely that these minute amounts of carcinogenic amimes can by themselves cause the increased risk of the cigarette smoker to develop cancer of the urinary tract. There are 3 hitherto uninvestigated possibil- ities as to causes of bladder cancer in smokem: 1) the presence in tobacco smoke of other known bladder carcinogens, such as certain N nitros- a¢nines or aminophenols; 2) the: nicotine metab- olites e.wtcreted in the urine, e.g., nicotine N-oxides and, cotinine, which may be bladder carcinogens,, as was suggestedi by Boyland'. (31);, and 3)! a disorder in, the metabolism of' tryptophan which increases urinary excretion of 3-hydroxyanthranilic acid and 3-hyd'roxykynurenine (32, 33): (These metabolites of tryptophan are carcinogenic when itnplanted into mouse bladders. The urine of heavy eigazette smokers contains up to 51D~', more of these metabolites than the urine of nonsmokers.): It could be that increased ercretion of certain o-aminophenols is of importance in bladder car- cinogenesis of smokers. Carcinogens in Gas,Pltese Several types, of' camcinogena have been dus- cussed as possibly being present.in the gas phase.of' tobacco smoke: arsine, nickel carbonyl, and nitro olefins (34). Unfortunately, chetnical' analytical data are insufficient for determining the importance of these: compounds. Tobacco scientists have been interested, for years in N tlitrosamines as possible volatile carcinogens in tobacco smke. Since Druckrey and' Preussmann advanced the idea of theformation of nitrosamines in tobacco smoke (35); a number of analytical studies have identified several volatile A=nitros- amines in tobacco smoke (15, 3tr-38): However, as discussed by Neurath (39); these studies did'not exclude the: possibility that the identified nitros- anunes were formedi as artifacts: Cigarette smoke contains nitrogen oxide and volatile secondary amines, but is practically free of nitrogen dioxide: (1\O3) (15; 40, 41:), the reagent responsible for the formation of nitrosatalines. Since the smoke leaving the burning cone is free of 10zafortnation of'N01 ean only occur in the short time (a second or less) during which the smoke travels through the re- tnaining, tobacco colunm and is diluted witli thee air which di$luses, through the ~ paper. The moment the mainstream smoke leaves the mourthpiece, which is connected, to the smoking machine;, it is diluted with air. This leads to artificial formation of NOs and, consequently, N-nitrosamines (15, 39). In analyzing nitrosarnines, we excluded this artificial' formarcion of niitrosamines by leading the smoke through a sodium hydroxide solution and' by blowing nitrogen through the collectioa vessell immediately after the puff was taken (fig. 1). This, was done by using the Biorgwaldt 20 cigarette smoker with rotating head4 by srnoking, cigarettes on every other channei; and, by connecting the remaining 10 smoking chatulelss zo a nitrogen source. This arrangement eliminated "aging" of the smoke. After the smoke of 300 cigarettes was collected, the volatile N-nitrosannines were enrichedl by dis- tilladon and extractions and were reduced with diboran (text-fig. 6). The resulting unsymmetrical! hydrazines were condensed with 3,5-dinitrobenzal- dehydie, and'the resulting hydrazoncs.+•ere analyzed! by gas chromatography %xith either an clectron- capture detcctor or a flame+ioniza2ion detector. • JOUA'?tAL OF THE NaTIIC)NA'L CANcER LlSTITUTE ` ....,'

~.r TAm.ls 1.-Tumorigentcity uf frnction Ill Initiul Tirst Tumor hicide ~ Totid ~ Tcet Inntoriuls No. hunur Aftur 12 (nonthH After 15 months No. m t mico (inunths) _ Mico % surviving 1'* % Cl - D1ico surviving °/ 1 ~ °Io G u ors M ~ 1. C4111i+letu ciu•cinuqen: 10- a 0 0 30 0 0 0 0 ~ G 7 ~ 5 / 10 10 8 40 0 7 50 10 0 , 0 2.5I% 10 15 7 11 0 7 10 0 2 .~ r II Initiator: 1'rumoter (°Ju sulutfun) ~ Id IT 11125 wg 2.5% croton oil 30 - 4 14 07 13 0 73 13 0 87 0 0 111 25 ukg 50% tobacco lnr :111 7 20 23 0 18 '27 0 15 Ill 25 mg - :{ll - 28 0 0 20 0 0 11 ~ - 5% croton oil 2 lifi - 57 0 0 53 0 - 0 0 - . tobacco tnr 50°J 50 7 35 S 0 29 12 0 0- n a ~ 0° III. Pro(noter: tn u ~ n11IIIA, 150 MR 10% 111 10 a 3 40 20 2 40 20 12 ~ -P ~ puplllomn•bcurlnL adcu. /(: ~ au'ch~wuu-bcSU1nL mIco.

1860 HOFF9LANN &ND Wl'\DER' Cir,arette Smoke Cotilcted Ss N90H • NaCi. DisL red. pressure Distillate I' . HCi. + NaCI Dist. red: oressure Distillate Q • NwCt 16 hrs. extraction Ether Extract Red. 82H6 R~ N-NH2. ,W •oCH- i~') 2 'NOt V-N R,--- Tsarr-nctrne 6.-Analysis of, volatile 14''nicosaaoines in tigarette smoko. B=H. ~ diboran., Using mass spectrometry, we identified dimethyl- nirtrosamine and methylLethylnitrosamine. We used sjC-labeled dimethyinitrosanzine as an internal standard for the quanrcirca'tive analysis. The details and results of this study will be presented soon. Rcdioelements Like most plants, tobacco contains traces of' radioactive isotopes (15, 41)'. Some investigators,, notably Radford, Hunt, andiLittle (42), considered, the radioeletrnents, especially nOPo and' 2!°Pb, in tobacco as a critical factor in the associatnon be- tween cigarette smoking and lung cancer. We do not agree, since thehighest concentration of u°Po reported in cigarette smoke is by far too low even to act as a tumor initiator (4, 43). Theree are studies in the literature concerned~ with the reduction of the radioelements in tobacco. As shown by Tso et al. (44, 45)' and' as discussedi in this workshop, the most prouusing route for achieving this goal is the elimination, of fertilIzers rich in 12'Ra, 2S0Pb, and nOPo. Using special filters that retain =1DPm, though repeatedly recom- mended, seems less practical (3, 46). REDUCTION' OF' TUIMiORIGENNGTY The reduction of radloelements in, tobacco atnose leads to a discussion of the selective ie- duction, of the tumorigenicity of' tobacco, smoke and the progress made during, the last 4 years in' this researcli area. Selection ofTbbacco and Tobacco Leaves Ir4 a, current collaborative study on 4' Bright tobacco varietics' with Dr. T. C. Tso (48), we found that cigarettes fabricated of tobacco, leaves from higher stalk positions delivered' more' total particulate rnatter, (TENI) and nicotine in the mainstream smoke, a result which coafirms earlier findings by Sugawara ct al. from the Japanese Tobacco Monopoly (47). We also found that increasing stalk position meant higher concentra- tions of hydrogen cyanide (HCN), volatile phenoli, and PAH in the mainstream smoke. We seieeted the weak carciinogen, bi:nz(a]anthracene (BaA), and the strong carcinogen,, benzo[a]pyrene (BaP), for the analysis. As shown in text-figure 7, for the mainstream smoke of the Bright varieties S.C. 38' and \.C. 95, the percent increase' of the TPM and phenols correlated with increasing stalk pcsition. A similar trend was observed for other volatile phenols and HiC1, whereas BaA and BaP were increased signifcantliy less. This finding suggests to us t;hat, in addition to the different mechanisms for the pyrosynthesis of ~ the smoke constituents, the precursors in tobacco Q for TP1T„ phenols, and HChII differ quantitativel'y . Q with increasing stalk posttian from the precursors CA for the PAH. 0 The former group of precursors includes long- CA chaitt alkanes, protein, and' the carbohydrates Cj ' extractable with alcohol. However, we can aiready Q conclude that, with increasing stalk position, the ~ wax layer of the leaves increases and, with it, the ~ yield of TP'Vd, HC.\, and, the carcinogenic prrtentiall of the resulting' particulate matter. Another approach for reducing the carcinogenic pooentfial of tobacco smoke is to decrease the latnina. fOURN:4L OF TBIE \aTiOXAL C.a.XCER IIXSTrrVTfi .. . . '. ~ i . -. -- .

SELEt:Tri'E' REDUd'rIO"fi' IN TOBACCO CARCL\OCENE5t5 v © © 0 0 © ® 0 0 © 0 1 r c S IIN.Cfr)p ~ ~MM WK Np1 portion of the tobacco blend in favor of the stem portion. For exa2nple, we compared' the main- stream smoke of'a popular American blend with the mainstream smoke of a cigarette made esclu- sivelyy from the stem portion of the same blend. Not only did the stem cigarettes produce less tar,, PAH, and' phenols than the lamina cigarettes, but,, in addition, the tar from the stems was significantly less active as a complete carcinogen and as'a tumor promoter{table 2; (49; S!0)]i This reduced activity must have been due to a selective reduction of thee concentration of' tumor promoters, since the con- centration of' PAF3 was actually higher in the stem ' ~ tar. The removal of the tumor promoters would ` have been at' least partially responsible for the larger decrease in the percentage of TPM in the stem smoke: The absence of waxes in the stem portion of the tobacco plant resulted in a signifi- cantly lower tar yield; the absence of phytosterols t M' l Tgx-r-rtaU/ez 7.-R'esults of chemical ' analysis of the mainstrcata smoke 301 , from cigarettes made from, Bright, tobaccns S.C. 58 and M:C. 95. Values are given for 1.0' g of ,N tobacco smoked. and terpenes resulted in a lower absolute yieldi of PAH, and thus, according to our working hypoth- esis, also loweredi tumor-promoting activity of'the resulting tar. . . . The increased incorporation of tobaccb stemss into a, cigarette blend is one way to selectively reduce the tumor-promoting activity of tobaccoo smol:e. This reduction of the promoting agen'ts' could' be achieved by not utilizing the upper 1'eavess of'the tobacco, by selective extraction, and more practically, by tobacco selection (cidr infra). It was demonstrated' im 1963 that the particulate matter from Burley and \L`Iaryland tobaccos was, less tumorig.nic than' that of Bright and Turkish tobaccos (51). We explained this finding in terms of a selective reduction of'turnor-ini'tiatiag activity in the tars. Roe at c1 - (52), using, Mexican Bright tobacco, flue <cured and' redried' one batch of it and air-cured and bull:'-fermented' the other batch. TABt;E 2.-Tum!origenicity of condensat'es fromllamina and stem cigarettes Ci arette T1iP BaP' Phenol Ti/morigenicity f g 85 mm'# mg/ ci arette ng/' cigarette Kg/ cigarette Complete carcino enicit Tumor promotion§I g g y SO F'o tar: 30 c/-v t:ar 1 8D','a tar Il 33! % tar A. Lamina cigarette 27.6 29 96 14/50 26/60 431,190 1'1/30. B. Stem cigarette 12.4 16 58 8150 110/60 16/00 6/30 -Cig,trettes A and Bwert preparedlrom tUr same tuu"w Wnl tFLst ttttmber tndicaies tumor-beatina miee: srxondn=ber indieates miee at tiecinain= of ezporiment. tComplete carctnoFenicitc:1b monttu' npplirsrton plus S montW' obsercation. {4lumor pevmotionrlcitiatur iJO,4 DiItDA; L moratlis' appbieation p6u,2 montlu' obsrseatlon: VOL. 48, NO. 6, JxT1PE 1992'

compared tar on a weight and, not on a cigarette Cigarettes were made from these 2 di'fferentiy processed tobaccos. Whereas the air-cured tobacco delivered more tar than theflue-eured tobacco on a weight basis, the carcinogenicity to mouse skin was significantly higher for the tar from the flue-cured tobacco. The authors hesitated, howevery, to ascribe the reduced' tumorigenicity of the tar from, the air- cured tobacco to the difl'crent curing, l2ecause they basis. It appears to us that the different curing processes are developed for specific types of tobacco and that the chemical composition and physical characteristics of the uncured tobacco leaf are more itnportant causative factors for the organo- leptic characteristic and biological activity of smoke than the curing process. In generali air- cured tobaccos deliver less particulate matter than 9ue-eured' tobaccos. • we orionally considered the increased yield of TP'_1-I, volatile phenols, andl PAH for the smoke of Btnrley leaves from higher stalk positions to be -:. prinzarily a function of the decreased nitrate con- The nitrate concentration of Bright tobacco i's much lower than that of Burley tobacco. In fact, z tent of these leaves (1),. Based on our current studies, however, we realize that, in addition to the decreased nitrate content, the upper Burley leaves also contain a higher concentration of wax con- stituents. i?'''`The difference i,a n2trate content of Bright and ' Biurley, tobacco and lower tutnorigenicity of Burley tobacco tar compared to that of Bright tobacco tar led us to model' studies involvin, alkali nitrate as an additive in tobacco (1,, 53). On a gram- potassiiam nitrate or sodium nitrate had' a signifi- cantly lower overall' tumorigenicity than the control tar,, but an unclianged tumor-promoting, activity. In a subsequent inx atigation, we could dennonstsate that only the concentration of TPM, PAH, volatile phenols, and nicotine was reduced, a result confirffied by Benner ct a1. (.i4), whereas the concentration of naphthalenes, indoles, and others remained unchanged (55). Terrell and Schrneltz (56)' reported that, as expected, the smoke of these cigarettes was significantly enriched . to-gram basis, the tars from cigarettes with, add'ed' in nitrogen oxides, acetaldehyde, and' acrolein. These data as well as the increased concentration of nitroalkanes and nitrobenzenes support our hypothesis that PAH, are partially pyresynthesizedd from C,H-radicals (text-fig. 8; (»)J. During recenr years, model studies, primarily from the Eastern Regional Research Laboratory of the U.S. Department of Agriculture, from the University of Kentucky, and from, the Tobacco Industry in England,, have shown that additives can change the burning characteristics of tobacco and reduce the yield of certain smoke constituents,, especially PAH (S4y .57-59)L Certain metal oxides can also catalyze the oxidation of hydrocarbons in the burning cone andy with it, inhibit the pyro- synthesis of carcinogenic hydrocarbons. The re+ duction of the concentration of'these carcinogens by metal oxides can signi,flcantly reduce the tumor- igenicity of the resulting tars, as we could' demon- strate for nickei(II)acetate, which, forms nickell oxides in the burning cone (51). .-. Schmeltz and his group and studies from the University of I+'.entucky, and from the Japan I'vLionopoly Corporation demonstrated that addi- tives can also change the pH' value and the redox characteristics of the smoke and, with it, possibly, the tumorigenicity of the resulting tar (54, 60=6. ): Hopefully, these analyticali data as welll as those with modified cigarette paper will, soon be sup- ported by tumorigenicicy bioassaysi This then would enable us to evaluate these rather impor- tant areas of tobacco research. ~ Reconstituted Tobacco Leaf Several other approaches have been investigatedd for the selective reduction of''the tumorigenicity of tobacco smoke, induding selective filtration„ to- bacco fermentation, use of tobacco, substitutes, and use of reconstituted tobacco leaves. The alloted time fbr this discussion as well as the scarcityy of published data permit us only to d'iscuss the importance of'tobacco sheets in respect'to selectiti-e reduction of the tumorigenicity of tobacco smoke. As already sho.vn, in 1965 and at the Conference 4 years ago, the use of reconstituted tobacco sheets can significantly reduce the tumorigenicity of the resulting smol:e. Two years agoi Dontenaviill rt al. (11) reported a large-scale study with one type of JOtIR\Ad: OF TPIE aa1TIO1eAL CANCER L\iTITL'TE 1005053085 ~asT"TC N' ' Q ~, ,wiai~4la.wT"'"~.+~n ~ ..1~~.. I r i ~ . :,i„ -,q. ~... . ...

I SELECTIVE REDUCTION IN TOBACCO CARCINOCE`lESIS 1863 : tl 101 Ttacr-raaunE 8:-Selecmve cigarecte-smoke components depending on the nitrate content of tobacco (values for 100 g of tobacco smoked). reconstituted tobacco sheet: The smoke of' the cigarettes delivered significantly lower amounts of' TP-N1 than that from cigarettes of genuine to- bacco andi was selkctiveiy reduced in nicotine, phenol, and -BaP: The tumorigenicity of the resulting tar was reduced to about 4'0%' of the controi' tar's activity: During the last 6 years, we studied, in eoopera- tion with R. Moshy and H, Halter (1, 63),, the effect of the tobacco-sheet preparation tech- niques on the chemical composition of the resulting smoke and the tumorigenicity of the smoke partic• ulate matter. In the first experimental series, Bright tobacco was powdered and made into a sheet from awatcr slurry or toluene slurry, at temperatures below 6'S°C and at temperatures above 9a'C. For all 4 sheets,,we observed a signifi- cant reduction for TPNI, nicotine,, phenol, and. BaP as well as other PAH. The particulate matter for the sheets was tested in 33 ;' acetone suspen- sion and, after 1S ' mor.ths of testing, was found to have a significantly reduced, complete carcino- genicity compared on a weight basis with the tar from cigarettes made from the original tobacco. Ia the second series, we tested cigarettes made from tobacco sheets with different physical forms and with 59,, F~\'O, as additive. Again on a gram- to-gram basis; the tars from the reconststuted, tobacco had <5CD% tumorigenicity than the: control tar. The condensate from the cigarettes with the foamed sheets and the foamed sheets with K:YO3 exhibited insi;nificant reduction of tunnor-promoting, activity when tested on mouse slcln, initiated with 150 ' Ecg D' NSBA. The latter results encouraged us to repeat these promising' experiments on a large scale. Whereas Honvard! Halter u^ill discuss the physicochemicall aspects and analytical data of these reconstituted tobacco sheets (64), we present text-figures 9 and, 110 to summarize the bioassay of the tar from these cigarettes. The data demonstrate clearly that tobacco sheet preparation offers a practical reduction of the tumoriSenicity of tobacco. With foarnedi sheets, the yields of TP.%I could be re- ducedi by 66-70. a; Furthermore, nicotine, volatile phenols, and, polycyclic hydrocarbons could be vot.. 48, %'o. 6, Jt'NE 1972

TixT.sacuu 9. Survi+val rate and twmor response o[' Swvias ICR' female mice to cigarette condensaw. 1O.-Tumor-promnting . cigarette-smoke comdennaces. TL+cr.Facuxs r+lr+n* In I01AK4 1 Y.l ' ~ ' ll.llW p 1 t.S.W ! I. 11 tr. :• ~ wn "'/a.a.wsti SK 1-1 wI M..w~ l.M ~ G.{ l41 1.7~ 0.SI~W ' LA ( O.OL I 0~/{~ 0.1n4y ~La 0.01. O.~~r /.w tnAlsla= 154p ~t1A. u~np~ ouKatmn IYn1R PNTOIM 70S St~OC~ CD~K`n1pM! WKI .«us Cromfoolf .4W'llAtonten hy+p.rApp{Kyyn UKr Psouan.' rar 1 [wsnen~ yr~nq ` nur*e.r ~ M.ruqI I Suev*wrs0 nKo I .aubmn.,~ ncr I ~ ~ f0 7~ p U I, a ~ c n n .~ t t JptlRN.AL ©F THE \a.TIONAL C.A\'CER L\3TTIUTE'

3ELEC3TVE' RSDVCTIO\ LN 'r081#'CCO CA1tCSNOICE\'ESLS signihcantly and selecticely reducedl These data are sutpported by the significant selective'rediuetion of tumorigenncityy of the tars from foamed re* eonstituted tobacco' sheets. as in the past, we have cotnpareti in the bioassay, the ttunorigenicity of' the tars on a gram-to-gram basis. Therefore, by using these reconstituted sheets, we hava selectiveiy reduced the potential of tobacco to form carcinogens in the smoke. I+ioweti•er, agaiu compared on a geattt-to-grarn basis, the tars from these foatned' tobacco sheets showed only a mimor reduction of tumor-proatoting actii+ity. Tobaccco Substitutes . Several years ago, we showed that the tars of eigarettes made exclusively of hay had minimal carcinogenic activity and littie tumor-promoting activit} (.i0). Tar from cigarettes mad'e of spinach had a significantl}• lower tumor-promotirog activity than the particulate matrcer of the tar of the stand- ard' tobacco eigarettes. Since hay contains practi- caIIy no ..•aaees and spinaeh has a relatively low concentratian of' waxes, compared to tobacco leaves, thrse studies suggested that the precursors for tlne tumor-promoting activity of tobacco smoke'e reside maunly in the waa layer of the leaf; a resuitt in accord with our tobacco-stem stvdies. We tested the parciculate mamter of cigarettes ;~aaade e.ecllusivel~~ from oxid'ized cellulose for their. ; tumorigenicity and tumor-promoting activity. As -' sla9wn in text-6gure 11, tlze particulate tnatter of these ciga'rettes produced tumors in only 2 of 100 mi.ce afier 1'4 ffionths of testirag and, therefore„ showed no signilzcant tumorigenic activity. The same tar, however, showed sigpificaat tumor- promotirag actirity, although much lower: thann that of the tobacco tar. Presently we are analyzing the smoke obtained fromz other tobacco subsutues and are repeatirng the miologFcal tests. Althoughh the studies are not compleced, they appear encouraging. SUMlMIrAFtY Tobaccp smol•e contaiits tumor initiators, tumor acceleratwrs, tumor promnters, vol'atile earcinogens, and bladder carcinogens. A4ost tumor initdators were identified' as PAH and nitrogen-containing, VOL:. 48, SO. 6, JO'XE 1972 /. 1865 •rra ~Tm-IhxnCe.uloj. CJer+,v ..r. 'tar'frorn Bi.na.a U S: ciqOr.tt. CanpiHf Coronoq.nc+ly ~. tlii ~qo9r.. i~ 24 3E a0_ 48 6 WeDs Ttxr-slovu,1i1. Tumorfgeniciiy ot a"tzr"'derivedi firom eigarettes made froia a eellulose derivacve (50%% econcentratioa): heteroaromatics. Tuaaor aeceltrators have compar- able polarity with the P.4H' and are inactive as tumor initi'aton and tumor promoters. They ia- crease, however, the activicy of carci.mogens and tumor imitiators. So far, tusnor accelerators have been identified' as Nalkyl imdoles, N-allCyd car- bazoles, and 4',4"-dichlorostilbene. Volatale phenols and some satura'ted and unsamarated fatty acids con- tribute to the tumor-promoting activity Of the pareiculate matter of tobacco smoke: However, most tumor-promoting agents in tobaeco smoke resnain to be id'enti6ed. It is suspeeted thar the voiatLle phase of tobaccoo smoke contain:t trace amounrs of several types of carcinogens: Untili now, only some voliatile M' niurosamines have been identined. The only bladder carcinogens so far found in tobacco smoL•e are traees of ~-naphthylamime and of an amino- fluorene. Ar present,, however, enzytnatic changes induced by iahaled' cigarette smoke are mote likely correlarted' with the himher risL- of the' ciga- rette smoke to induce bladder cancer than the presence of traces of bladder earcinogens in tobacco smnl-e: Since the F'irst World Conference on Smokimg and Health, a considerable number of studies reported on the reduction of the ttuaorigesucity

t866 HOFF\tA\Ji' AND WYNDER of tobacco smoke. These : include reduction by changes in the agrir:ubtural' practices of growing and harvesting tobacco, changes in the selection of' tobacco types and tobacco leax•es according to stalk posiRions- and' nitrate content, the modifica- tion of the curing and fermentation prouessses; an& the preparation of reconstituted tobacco sheizts: Vlodkl stud!ies' with additives' contributed to our tmdentanding' of the mechanisms of' the pyro- formation of the tumorigenic agents in the smoke. Chemical analytical data and bioassay re- sults were presented' for the smoke from ciga- rettes made from tobacco stcrns' and from different types of reconsdrtuted tobacco sheets. The par- ticulate matter from tobacco stems was significantly less tumorigenic and had a significantly lower. turnor-promoting activity than that from; the latttina portion. From the various types of', re- constituted tobacco tested, the foamed sheetss gave the most encouraging results with respect to, selective reduction of' total tumorigenicity and,. with it, selective reduction of tumor-initiating activity. Discussed aLso was the possible importance: in tobacco carcinogenesis of the various types of components in the wax layer of' tobacco leaves. REFERENCES (1) Horrsu.etx D{ WvNor.tt EL: Selective reducdonof the tumorigenicity of tobacco smoke. Eicperimentai approaches. Nat Cancer Inst %4onogr 28r1'5,1-172, 1968 ' ((2) The Health Consequences of Smoking, A report of the . Surgeon General, 197 1. U.S, Deparaaentof'Healtli, Education, and Welfare. (3) h'UiuLEx R, AiouaENx..vzs: W, Scxtsswerst P:~ ()ber die Cerminderung gesundheitsschadigendtr In- halt¢stoffe des Tabakrauehes. Ber Iast Tatiakforsch (DresdLKt ) 15:,1 w6 ~~-190, 1968 (4')' WrhrnaR EL, HorrxANN D: Experimental tobacco earcinogenesis. Science I62:862-871, 1968 (5) Sexizuatrat P: Uber die Vermindcrung gesundheits- scb3digender Inhaitsstoffe des Tabalrauches. Birr Inst Tabakforsclt (Dresden) 1i6i11i6-i25, 1969; 17:66-93, 11970 (6): WYNOCn EL, WietaxtT G': A study of tobaeeo careino- genesis. 16 The primary' fractions. Cancer, 10,:255- 271, 1957 (7). SL6LKOPr C, RicxzN W, DHou G: Untersuchungen 8ber die krebserzeugenden Eigenschaften des Zigarettenteeres: Z Krebsforsch 63:241-749, 1963 (8) HorrstrtcN D, Wn.•Dett EL: The tumor initiators in tohacco,smoioe. Proc Amer Assoc Cancer Res 7:32, 1966' (9) BoxtNSrvtc YP: Blastomogenic activity of' smoking products. Vop Eksp Onkol 3:47-33{ 1968 (10) Ror, FJ, KEwxxs F, BtsHor D: Examinatioa of! the: neutral, (raction of tobacco smoke condensate for tumor promoting activity. Iot Alkylierend wirkende Verbindungen. 2. Konferenz Ober aktuelle Problerne der Tabalcforschung (Weber KFhI; ed.). Hamburg, Wissenschafii.icbe Forsehuagxstelle im Verband' der Cigarettenindustrie, 1968, pp 112-1 l3 (11) Donru+wtu. W, EtaaxxoasT H; Hwxrc HP, et al: Expctimentdle Untersuchungen tlber die tumorer- •. zeugende Wirhung von Zigarettettraueh-Konden• sa'ten an der Mausehaut: I: Gesamtversuch. II.. Einzelvergleiche zwischen den Kondesaten tnudi- fiaierter Zigaretten. III. Untersuehungen zur Identi5¢ierung' und Aareicherung, tumorausl8'. sender F'rahdonen, Z Krebsforsch 73:263'-2'84; . - 285-304; 305-314;1970 (12) WxtrxxzAo JI:, RomtwuL K: The mouse s1'in carcinogenicity of cigarette smoke condensate: Fractionated' by solvent partition methods. Brit J Cancer 231: 840-857, 1969 (73), HorrM.vN D, Wtrecnca EL: A itudy of'tobacco car- cinogenesis. XI. Tumor iaitiators,, tumor aecelcra- tors, and tutttor promoting activity of condensate fiactions. Cancer 27:848-864, 1971 (1;4')' Ros FJ, Pato R, K=wstrts F, et' al: The mechanism (LS) of careinogenesis by the neutral'fraction of cigarette smoke condeawte. BritJ Caater 24: 788-806;,1970 WtrNnete EL, HoFrwANN D: Tobacco and Tobacco Smoke. Studies im Experimentai Carciaogeaesis. New York, Acadernic, Press Inc., 1967,130 pp (Ib) HorritwNN'D,,RArFtsWwrG, NzsNowS, et a1:Chetnical studies on tobacco smoke. XVI.,A1kydAuoranthenes: -Quantitative determination in cigarette smoke formation by pyrolysis and tumor initiating actnvioy: In preparation (J7) BAocf:x G.M, DonxELLSt JK, S'roTSCVooo T\'i: The formation of aromatic hydrocarbons at high tem. peratures: Aust'J, Chem, 18:1249-1266; 1965 '. (18) HorrNANN D, Wmout EL: Chemical anadysis and carcinogenic bioassays of organic particulate pol- liuants. In Air Polludon ('Siern AC, ed.), vol, II, chapt 20. New York, Acadoatic, Press Inc., 1968,, , pp 187-247 (19) GtLLNOw+t A: Cocancino4enie aetia-ity of cigarette tobacco tarw Caneer Res 18: 51o-5;U7,, 1958 (20) Hor~r>u.arN D, RATHCASCr G: Chesaical studies on tobacco smoke. XIV. Quantitative deterrainationn of fluorenes in cigarette smoke and their formation by pyrosynthesis. Anal Chem 44:899-905{ 1972', (I?T) Boax FG, SwwtN AP,,SrEnuarr R11,: Bioassay of'major fraction of cigarette smoke condensate by an accel- erated technic. Cancer Res 29!:384-387„ 1969 (2?)' WvNoa3t EL, HorrstANY D: A study of tobacco car- cinogenesis. Jfi. Tumor promoting activity. Cancer 24I:289-301, 1969 JOt1R.1.ai: O'F' THE NATIONAL CAXCER IASTITUT&

s£LECTIVE REDUCTION IN TOBACCO C.11RCiNOGENES15 : j ~ 7 f (23), VM'Dt7VREN IBL,SNMG.A'„KATZ C,.et a1:.Cigarette, smoke carcinogenesis: Importance of tumor pro- moters. J Nat Cancer Inst 47:235-240, 1971 (21) Roa FJ, Si.2AUA.Y, MH, Coxs:r J: Incomplete car- tinogem in cigarette staoke condensate: Tumor- promotion by a phenolic fraction. Bsdt J' Cancer 13:623-633, 1959 (25) WtrntDaR EL, Horrst"x D: A study' of tobacco car- einogenesis. VIII. The role of the acidic fractions as promoters. Cancer, 14:1'306-131'51 1961 (26) Bocs: FG, SwAr.r AP, STEDxwrt RL: Composition studies on tobacco. XLIV. Tumor-promoting' activity of subfractions of the weak acid' fraction of cigarette smoke condensate. J Nat Cancer Ittsc 47t429-436, 1971 (27) Royal! College of Physicians: Smoking and Health Now. London, Pittman 'Medical & Scientific Publ: Co.,,1971, 14'S pp (28) PAttaR M,, Ht7sscx WJ, Kvmm H: Untersuchungenn der aliphaoischen und' arontatischen primaren und, sekund5ren Ataine des Zigaretcenrauches mit Hilfe, der Gas ChrDmatogcaphie und Massenspktro- tcmtrie. Fachi \1ittl,Oescerr Tabakregie 7:1'09~-118, 1967 (29) U.S. Public Health Se:vice: The Health Consequcnees of Srnoking.,A Repoct of the Surgeon General: 1'96+}. Washington, U.S. Public Health Serv. PubL,11i03, 1964, 3'87' pp (30) ;tlwsuaA Y, Horrst"rt D: Chemical studies on tobacco smoke. VII. Quantitative determination of l-naphthylamine and,2-naphthylamine in cigarette smoke. Anal Chem 4!1':63D•-632, 1969 (,71) Bbus.w.~sa E:'The possible carcinogenic,action of alka- loids' of tobacco and betel nut. Planta Medica SuPPI 11:1'3-23. 1968 (32) Kzaa~. Wh, Bwasu; '1i, LEvars' PE, et al. The effect of cigarette smoking on bladder carcinogens in man. Canad Med Assoc J 93:1-7, 1965 (33) BRowx RR, Pnccz JIv1, SATraR EJ, ec'a1: The metatr- olisns of cigarette smoking of tryptophan in patientss with bladder cancer. Amer Indust Hyg Assoc J 30:27-34, 1969 (3i/) Horraeuxrt D, WYtrDLR EL: Chemical studies on tobacco smroke: XV. Cheatical' composition and tumorigenicicy of tobacco smmke. In Symposium on the Composition of,Tobacco and Tobacco Smoke (Schmeltrr 1, ed.). Plenutn Publ Co. In press (35) DrtucxaEY H,,; PREUSsstArtr R'Zur Entstehung car- einogener Nutrosamine am Berspiel des Taba- ltrauches: Naturwissensehaften 49:49&-1'99; 1962 ' (36), NttuuATx G, PRistwx B; WtcxaRx H: Zur Frage der ,Y:litrosoverbindungert im Tabakrauch. Beitr Tabakforsch 2:311-3II9, 1964 (37) Joxxsox DE, \.1sLt.AR JD, RxoADES JW:' Nieros- atnines in tobacco smoke. Nat' Cancer Inst Monogr 28':1811-189, 1968 (3i9) Pwusx M, Kius H: Die Bestimmung von 11"-';\ittos- aminen in Zigarettenrauchkondensat: Fachl! aiittl; pesterr Tabakregie 12:203-211, 1971 VOL. 48, NO. 8, Jt7\'£' 197.'' (39) NEtta^TSC' G: Stickscoffverbindungen des Tabakrau- . ehes. Arzneimittelfotschtmg' 19:1093-1106, 1'969 00) NoRSUx V, Kttrs CH: Nitrogen ostides in tobacco . sceoke. Nature (London)1203:9'1i5-916, 1'965' (41) SitsDrtwx RL: The chemical composition of tobacco andi tobaccosmoke. Chem Rev68!:133-207,1968 (42) RwDroRa EP, HeNT ' VR, LrrrtE JB, et al': Carcino- ; aeniciry of tobaccoetDoke consuituentts Science 163:312-313,,1969' 03), WymDait EL, Horrx,wtt D: Experimental tobacco carcinogenesis. Science L6S :312-3113, 1969 (4f) Tso TC, STSrrEKs GL, Fzuwt ES, ec al: :AgFonomie factors affecting polonium.210 and,lead-210 levPls in tobacco. I: Soiliand fertilizer. Agrm J 60:647-fi49, 1968 (43), Tso TC: Manipulation of leaf cliaraeteristies through production-role of agriculture in health-related tobacco research. J tiat Cancer Inst4'8:1'811-181'9, 1972 (M) R.afoaD EP JR, Ht:aT VR:'Ggarettes andipolonium- • , 210. Science 144:366-367, 1964 . (47) SuoAryvAtA S,, Koswaxt U, IactntA H, et a1: Chemical' components in Bright yellow smoke. Sci Papers Centrali Res Inst, Japan \lonopoly Corp 111:249- 234, 1969' (48) RATracasrs G, Tso TC, Horrnaw D: On the corre- lation between various leaf constituents and'seieeted smoke compounds. Pcesented at the 25th Tobacco Chemists' Research Ccnference, Ilouiiville, Ky., Oct. 6-8, 197,1 (49) Wrnosa EL, HorrwAsrN D: Reduction of tumordgeni- eityof'cigarette smoke: An experimenrcal approach. J:a.%fa 192:88-94, 1965' . . (J0), : A study of tobacco earcinogenesis.,X. Tumor promoting, activity. Cancer 2!1':28rJ•-301,, 1'969. (;f1), t Ein experttneateller Beitrag zur Tabakrauch- kanxeroBenese. Deutsch Med Wschr 88:623*•628, 1963 (52) RoE Ff, Ct.Aat JC, Btsxor D, et al: Comparative carcinogenicity of mouseskin of smoke condensates prepared from cigarettes made from the same to- baceo cured' by'two processes. Brit JI Cancer 24:107- 121', 1970 (33)' HonntwnN D, W%aiDEx EL: 'I'he reduction of the txumarigenicity of cigarette stnoke, condensate by' addition of sodium, nitrate to tobacco. Cancer Res 27:172-174, 1967 (.f4) Ptuceedings of'the Tobacco and Health Conference. Report 2, Tobacco and Health Research Institute, Leungton, Eiy., 1970, 136 pp' (55) R+zxs:wxr G, H+oFrnuNrr D: Chemical studies on tobacco srnoke. AIII: The inhibition of the pyro- synthesis of several selected smoke constituents. Beitr Tabakforsch 3':30?-306,,1970 (56) TaRRZ.zz JH, SCxsaELrz I: Chemical effects of sodium, nitrate content. Science 160t1456. 1968

studies on tobacco. XIL. Changes in,smoke composi- tion and,Sltration by artificial alteration'of'smofce I 1868 HOFFMAYY AYD WYNDBR (S7)' Baxntcst D, Bc.vrmit JF, BtrnToK HR: Thermal' de- composidon of'tobacco. IV. Apparent correlations between thetsnograviameeic daca and certain con- stitttents in,smoke from chemieally, teeated tobaccos. Tobacco Sci 13:138-141, 1!969'. (3d)', Trataa'ts: JH, Siexstxt:rz I: Alteration of eigaaettee smoke composition. I'. Influence of certain additives. Tobacco Sei 14':18-81, 1970' (S9) Cxrwtasoary BB; Ktt:xon.V KD, Tttart.tiToK R: Re- duction duccon in the eoncentration of aromatic polycyclic hydrocarbons in cigarette smoke. Chem, Ind (Lon- don) 1,971, 672 pp (60)' Lwzarrz L, Szaamwv RL, SrxAxcE ED:,Composition 7 f h . r .- Fiomtt 1'.-Smo:ing'machine with collection device for analysis of.Y-niirarosanninea in eiguette smoke. pH: Fotnie acid and' acetic acids and volatile pbenolb. Beitr Tabakforsch S:d44-li08, 1968 ('6d) Bz:xzacar RC, L,uattsz L, STxA.vcs ED, et al; Redox characteristics of cigarette smoke. Chem Ind' (London) 1'9D0, pp 800-802 ('¢2) Central Research Institute, Japan Nionopoly Corpo- ration: Evaluation of tobacco quality from pyrolytic aipects. Scientific Papers 110, 111, 112, 1'968, 1969, 1970 (63) Niostnr RJ, Hss.rasa HW: Reconstiiuted-tobaeco.kaf- tachnology: A tool' for tobacco-smoke modification. Nat Cancer Itsst Monogr 28:133-1'48, 1968 (64) Hwssza HM, I7o 'TI: Reconstituted tobacco--stnok- ing and health possnbilities. J Nat Cancer Inst 48t 1869-1883, 1972' :_.., srSt~.-~~'' '~y~ y- ~y ~S}fIF Ti~~~. . _ ~ t .7 :~.

. SECTION 8

The following materials are page proofs of'the Banbury .Report #3, "A Safe Ci'garette?", furnished by courtesy of the: Cold Spring Harbor Laboratory"s Banbury Center. The reports-are presentations delivered in 1979 at a Cbld Spring Harbor Laboratory conference; the final publication will be available in mid ,May, 1980..

The Limiting Facwrs , . in Understanding the iViatura[ History J" of Tobacco SrnoiCe Effects - in the Lung MARIO C: BAT77IGELL! Division of'Pufmonary! Medicine University of North.iCarolirlta Chapel Hill, North Carolina 27514' The function of' the respiratory apparatus ultimately consists of matching a certain ventiltttory flow to, a corTeaponding flow of blood at t.he alveolar membrane. The deceptive sim-piicity of these elements of respiratory physiol- ogy hardly betrays the vast array of the pathological factors toward which the respiratory apparatus is vulnerable and that eventually lead to respiratory im- pairrttent and failure in an aimost infinite complexity of steps and phases. Ventilatory disordetx, for instance, are the direct or mediated consequence of mechanical deranaements, such as obstructive lesions (tunctional or structural) or power failure of either a muscular or neuroloeical nature-either one the possible consequence of pharrnacoio¢ical, infectiouss toxic, oral'terttative etiol, ogy. Perfusion chan2es, similarly may derive from a constellation of factors, such as embolic phenomena, infectious processes. or cardiac pump failure or its inadequacy. Each of these, in,turn, tnay, be the possible consequence of untoward exposure to noxious factors, cigarette smoke included. Although it' is convenient to enter a discussion of potential and actual causes in this context, it is considerably more difficult to analyze the realistic events in detait in any given and real instance. Often the blz: k box of the natural history of respiratory diseases is very much tightly seaied and inscruta- ble. This is particularly true in the intermediate and early phases ot' the d'ase:se process. Our knowledge of pathology, although consiidectbl'!. is discontinuouss and incomplete, a series of snapshots when! the facts call for a high-gradd movie sequence. The actual chain of e+sents; going from health, to disease, remainss largely an unresolved mystery, The transition between health and diseases. as eloquently commented in a recent paper by Thurlbeck (1979), urgently needs clarification through structure-function correlative studies. In the particular case of cigarette-smoke injury of the respiratory function; the end points are well identifned, but the intermediate steps are not4 Cellular', tissue, and organ damage are known mostlv in their conclusive and' adv;utced stages, when the reversibility of the injury is limited or, as for the case of neoplutic changes„ largely not~ expectctll For pre+•~entive intervention, this 1005053094 r

limitation in the knowledge retains a major importance. In term5 of prospective ~: projections. for instance: the definition of a safe cigarette. the as ailable data are painfully inadequate. Missing are the quantitative parameters. the sequence in chronology of each aberrancy, and the intetaelation between different' and dkcrete processes making up the whole natural history of the injury. To establish a dose-effect relationship, a much needed step in modeling tox- icolo¢icall vrocesses, these dimensions must be secured for each exposure ' modalitv. and for each chemical or combinationi ofi'chemicals and suspected agcnts, or. in other words, for each dose characteristic. If correctioni must be ai attempted~ the very process causing injury needs to be better identitied in details of natural history. with adequate rneasurements obtained along, a time ~ sequence. Otherwise the only option available for prevention would' be un- wj-' selected and total, abolition of tobacco use, a solution ideally jusritied but ;:~ realistically impractical. The appropriate questions. then, are: Do we know the morphological details of cigarette smoke inhalation to a degree adequate to formulate .apro- priate standards of' use or safety?' Do we know the relationships linking the ,; :~ ; charrcteristics of exposure (i.e., dose) i to the relevant morphological' and funa tional aspects of effect in relation to their specific features of reversible and irreversible outcome? Do we know this, with accuracy sufficient to extrapolate elements of guidance usefull in engineering a, safe product''' We speak of emphysema, of chronic bronchitis, of obstructive respiratory Iesions, of neo- ,.; plastic effects, often neglecting that these are the far advanced results of a process that has progressed usually for years and, often for decades. These advanced results have destroyed details of cytological physiology and their f ne .• morphological cotrelates, which at earlier times must have characterized the progress of in)ury. The search tor early aspects of this history has traditionally concluded in the identification of the following five separate phases (Bates 1979) in the natural history of chronic airways disorders: 1. hypertrophy of mucous glands in large ainvays: 2. alteration of physical' properties of the lung; 3, morphological changes of small airways; 4. early loss of alveoli: • 5. regional nonuniformity of these changes leading to altered ventilation-' perfusion relationship. Some of the difficulties inherent to these studies are: 1. longitudinal morphological studies of human tissue; 2. tetli,tic animal modcls for chronic disease: 3, correlative studies of structure and function. Recenr views have been voiced against this sequence, questioning, for instance the hypcrsccretoty phase as an obligatory step in this pathological .L 0'IJ5QP if-~!V~S

U Clmitiny Factors of Tobaew Smok*J166 sequence, even deeper doubts are shadowing an elementary understanding; of the problem of neoplssia. lndeed; to be speciffc. the question of independent carcinogenicity of the major individual constituents of tobacco smoke, in the J*~--~ actual context of'human exposure. remains larcely conjecturat. 71 Not the least of the concern in this context of complexity is offered by the wide constellation of putati*.e or real (and proven) respiratory effects in re Psponse to tobacco smoke, which are listed here without any attempt to rank them in importance or chronological order a°; {r ,~1„ ~ { ~ ~,I I 1. reflexes. { T: ,. 2. secnetions, 3. smooth muscle activation, 4. surface chantes. 5. permeability effects. 6: chemotaxis, 7: immune mechanism. 8'. hyperrtrophy, 9. metapiasia. 10. proliferation. . Having reco¢nized the varietyy of consequences resulting from exposure and having identifed the main agents participating in this exposure, we are left still with disturbiit, ;aps in knowledge. The main variables that are recognized .; .; ;.. .-! to influence andicontrol toxicolbgical effects are: . l. nature:of agent. 2. effectiive~quantity (intensity and!dttration).. ' 3. nature of actions, 4. host factors (susceptibilicy, etc:). , ~ The details of information on this matter can be oni.• sunnised. perhaps on aa qualitative base. without much data for their respective quantitative values. 1'n summary, it is prudent to conclude that the problem waits to be better defined in its constituent detailk betore its solution can oeaccomplished. Unless the details are known in their temporal' and dosimetric characteristics (which chemical, which process, which locus„which tiine, etc.): the black bux will not i offer wide avenues of remedy and correction.~A vigorous programof research. : coordinated in scope and pursued with, the support of funding commensurate ~ with the magnitude of the task in quesoion, still awaits conception and' im• plementatimn. It is consoling to realize that the solution ot`the cigarette smoking toxicolbgy will represent a milestone in pulmonary medicine, well beyond the immediate saving of lives and health. For the moment, the question posed by the definition of a safer tobacco product may be rcasonably answered with the~st:ucmznt advocating combustion that generates less g,ueous products and less particulates. In plain words, the dose must be sltL,hed. 1005053096

681 M.C. Batdgali . REFERENCES Bates. D.W:. 1979. Chronic brunehitis. and emphysema: The search for their natural history, In~ The Lrne in the tranritirn benaeen IJealthi and disease (eds. P.T. Macklem and'S_ Permutt). voi, 12. Marcel DcU:er Inc.. New York. Fletcher. C.M: and R. Peto. 1'976. The natural history of chronic airtlow obstruction. Brdl. Lrtt. Union Tuberc. S3:78! Thuribeck. W.:W. 1979. Changes in lung structure. In The Lung in the transition benruen hea/th und'disru.re teds: P.T. \4acklem and S. Permuttu h+tarcel' Dektcer Inc.. New York. : , _ CIOMMEMTS. s w'YNDER: The end& point in chronic obstructive pulmonary, diseass (COPDI. in terms of a less: harmful cigarette„ is far more difficult to measure a'tan~ the end, point of 1un; cancer and' myor.irdial infarction. I wonder whether you~ ebuld! comment' on this from an epidemiologic standpoint: that is, wharwould be~the first endpoint that you would be lookins for in a study of COPD? ~ BATTtGEL1:1: Probably a singlie indicator of incipient effect does not exist. It is more likely a choire of several indicators that would be used: simulta, neously andl changed as new data become available. 'Ihe tests eurrentlv accepted for small airways, such as the tlow rates at lower luns volumes and the middle -maximal expiratory rates, are currently considered the most sensitive indicators. Of coursz, clinical subjective evidence of ab- norm'al'. airways (cough. sputum, etc.) and the mea.surement of diffusion function may be additional irldices, encompassing,emphysematous change in addition ttD bronchitis. _ However, these are coarse indicators, limited to the effects of cigarette smoke on the airways quite independently of'any effect caused on other systems (i.e. cardiovascular system). and in fact witnout much~ direct correlation with the neopiastic effects on respiratory, ttissues

0 Carbon Nionoaide' as a Contributor to the Heaitb Hazards of C'icarette Smoking _ POUL A'STRUP _ Department of'Clinical Chemistry CL Rigshospitalet DK-2100 Copenhagen. Denmark There is clear evidence that moderately elevated carboxyhemoglobin, (CGHb) levels are associated with various chan_es of the cardiovascular systzm: Those changes occur at COHIb levels of 5-20%, which are not uncommon in, inhaling smokers. A very significant chan.e is the increased vascular permeability. Carbon monoxide (CO) exposure (20-25% COHbI of men for 3 hours leads to a50(k' increase in disappearance rate from the blood of injected serum ""I-labeied albumin, (Parving 1972) and to an i increase in, capillary filtration rate measured plethysmo¢rsphically on the calf (Siicgaard~Andersen et al. 1967). Increased pcrmeabiiity where the lymph flow and the protein flux in the thoracic duct increased considerably during exposure to CO was also demon- strateti' in 11 do-s. It was of interest that the increase in protein tlux wa,s moree pronounced for the high-molt:culnr-weighr proteins than for the luw- molecufar weight proteins (Parving et al. 1972). CO1 exposure also leads to hypierlipemia as shown first by Astrup et al: ('I!967) and Kjeldsen (l'969). This was demonstrated in r.ibbits fed usual fodder with or without the addition of cholesterol snd, exposed to COHb level., betl+reen, 15' and, 25%. We have seen this effect of CO in al our experiments. 'I7fe CO-induced elevatinn of serum cholesterol has usually led to IS-2017'c higher lexels for the first 2-31 weeks in comparison to the groups not expo.rd to CO; after this period, the serum cholesterol levels were approximately the same in both groups. Many investigators have found somewhat hi~her serurn cholesterol levels ini smokers in comparison to nonsmokers (Schievelbein I!968), usually about 10-1IS'me%„which maybt:explainedlbyrai,ed COHb l'evels. AT}1EAtOGEM1C AND ARTERIAL WALL-INJURING EFFECTS OF CO The above mentioned effects of' CO on vascular permeability and cun serum cholesterol are clhtrly atherogenic and are related to our earty findings (see. for

I 0 . l 76/ P. Astnup example, Astrup et al. 1967)demonstrating that the moderately elevated COHb levels for 8-1'0 weeks were associated with an incrcased accumultition of' cholesterol in the arterial walls of cholesterol-fed rabbits. Since the aortic cholesterol accumulation was about 150% greater in the exposed animals in eomparison to the nonexposed~ we neglectatd' a possible effect of the slight hypercholesterolpmia during the first weeks of the exposure period. We were therefore surprised to learn when we repeated our experiments a couple of years ago (Stettder et al. 1977). this time keeping serum cholesterol concentrations on the same level in the two groups of'anirnals by individual cholesterol feedin:, that no enhancement of the cholest~-.ol accumulatiom in the arterial •wcills occurred under these circumstances. Furthermore. the cholesterol uptake rate in the arterial' intima of' CO-exposed' animals, measured by using a sophisticated double isotope technique, was not increased, either, except. in the aottic arch where a slight increase was dernonstrated. Perhaps the more important coronary arteries were not investigated here. Hoa'ever, others nSarma et al. 1I975) have found that human, coronary arteries petfused' with blood huvin_ W'c COHb increased their cholesterol uptake in compsrison, to coronary arteries perfused with normial blood: The lipids sy,nthesis inithie arterial wall did not change. Because the hypercholesterolemic effect of CO exposure is observed only in the frst' weeks of' exposure: the enhant:ement' of' arterial' accumulation of cholesterol has beenidifficult to observe in long-lastine experiments of 40-60 weeks or rnore, with serum cholesterol' levels hi;hly increased in both the exposed!and the nonexposed groups of animals (Armita_e et al. 1'976).. The pathologists in our group observed mit;roscmpically morphologicali changes in the arterial intima of noncholesterol-fed'rabbits exposed to f80'_200' ppm CO ('1-t-16no COHb) for a few weeks (Kjeldsen et, al'. 1'972). These injuries were characterized first of all by an increased subendothelial edema and& esti_ators. also by other lesions indistinguishable from what experienced' ins have described as early atherosclet rotiie intimal changes. A couple of years agoo we tried to repeat our findings of intirnal damage caused' by CO exposure. (Hugod et al. 1978). c. blind technique was applied, and the pathologists were unable to document injuring effects of CO on the intima of arteries. The experiments were repeated using CO cpncentrations of 200-4000 ppm, with the same lack of'c-•idence of a direct histotoxic effect of CO on the intima or subintima of coronary arteries and aortas. Therefore, our conclusions today are that moderate CO1 exposure does not lead to morphological chunges of the vascular wall. The atherogenic effects of experimental CO exposure must therefore be related' primarily to tiy,percholesterobcmic effects and not to arterial w.allg injuring effects. Tlie role of increased vascular permeability in certain vascular regions is unclear. The well-documentedihigher prevalence of'ztherosclerosis in smokers in comparison to nonsmokers is clearly correlated to their COHb levels„since it can be calculated thatsmokers with COHb levels o~f S% or more have a 21 tirncs higher prevalencc of atheroscierosis than smokers with a 1o0sas~099 ~>

0 4 taust' be explained primarily by the effect of CO on the lipid metaboli'sm: secondarily by a possible increase in endothelial petmeability in ccrrtain regions. and further by myocardial effects of CO. _: -_. . ' CO EXPOSURE AND tWYOCARDIAL EFFECTS ~ It has been reported by v_;uious: authors that prolonged miidi CO exposure inn experimental animaS leads to dt__enerstive myocardial chances (Campbell 1929-1'930; Christ 1'9:z5: Ehrich et al'. 1'9-1-t.: Lewey and' Drabkin 1944). The.e anatomical, changes clo:zl?v resembled those produced by hypoiiaand consisted of'edema. degeneration of the muscle fibers. multiple small perivascular ne- croses. and: hemorrhages. Microscopic scarification of the heart muscle was also reported. . Wltrastructural studies by the pathologists in our team (Thomsen. 1'974; Thomsen and Kjeldsen! 197-1), have demonstrated local areas off partial cnr, total necrosis of' myofibrils and de_enerati.ve changes ot' mitochondria in the myoeardiis of rabbits and Mtacaca iris monkeys exposedl to about 200 ppm CO for not more than 2 weeks. Those studies. however. were not pertormzd' by using a blind technique. and we are at present n:ptating the experiments. The results are now under e+alu•rtion. The reported effect of CO on, myocardial tissue is, similar to the effects caused' by hypoxia: therefore. the CO effects are probably explained by an impairment of the oxygen transport and oxygcn unloading functions. not only of hemo-lbbim (Hb) but also of myo=lobin tMbo. which has a still hieher affinity for CO than Hib. This impairment leads to decreased venous and tissue oxygen tensions in eontrast, to the quite normal oxygen tensions observed in moderate hypoxia. where compensating cardlorespinitory adjustment exists. To counteract de- creased myocardiaF ox;•_cn, tensions of elevated COiHb levels. a•:onsidzr.cble increase in coronary blood flow occurs: in man there is about a.25c increase at 9-10%COHb (Ayres et al. 1970) with oxygen tensions in the.coronary sinus about ?1~7c below normal. This is in accordance with the oliservation! of'a greater myocardial stress in individuals havine COHb levels of 5-9( in comparison: to non•CO'expos.:d individuals at compar.ible work lnvd. ('Knclson 1972). One-fourth ot the ex- posed individuals aged 411-60 years developcd abnormal elcctrocardiograrn,, with arrhythmia in some. Similarly, angina pectoris and intermittent clLud!icatim develop carfier att comparable workloads in patient+ with very moderatcly increased CO'Hb: levels (2%) than without CO (Aronow and I,bell 1'973'; Aronow et aJ. 1974). CO EXPOSURE AND FETAL DE1lELOPMENT' Fetal developtncnt in rabbits is grestly influcnced by 9-1dD~'r and 16'-1I3% .... . .. . . 1.1005053100

The tindinss ane a reduction in birth wei_ht and a hi;hly increased neonatali mortality. The same effects are found by exposure of pregnant 'rabbits to hypoxia ('l0`7c oxygen) (Astrup et al. 1975). Also. exposure to nicotine in11uL ences the fetal development in a similtu way probably caused by a neduced' oxygen supply due to vessei,contractions in the fiettus. CON6LUSIONS' The conclusions of studies reported in the literature and of our own studies of about 10 years on the physiological a:..l pathological effects of moderately elevated CO'Hb levels in man and animals are that they lead to: 1. increased vascular permeability; 2. ittcreased' serum cholesterol levels with subsequent enhancement of arterial cholesterol accumulation: 3. decreased work-load threshold for developing claudicatio. angina pectoris, etc: 4. changes in myocardial function and probably also in myocardial structure in CO-exposed men and animals; 5. effects on fetal development andneonatal motrtality. Therefore, a reduction in CIQ levels in tobacco smoke would undoubtedly lead to a~less hazardous cigarette. REFERENCES ArmitagF. A.K.. R:F. Davies, and D:W4. Turner. 1976. Threffects of carbon monoxide on the develbprnent of atherosclerosis in the white carneau pigeon. Arlrerosclcrosvs 23:333, Aronow, W.S. and M.W. Isbell. 1973. Carbon monoxide effect on exerciee•induced angina pectoris. Ann. Intrrn. ;Nrd: 79:392. ~ Aronow. W:S.. E.A. Sto-mmer: and M.W. Isbell. 1974. Effect of carbon monoxide exposure on intermittent claudi.:ation: Cerculutii,n 49:445: Astrup; P.,,K: Kjeldsen. and J. Wanstrup. 1'967. Enhancing influence of carbon monoxide on thedevelopment of atherornxtosis in cholesterol-ted rabbits. J. Atlirrosclar. Res. 7:343'. Astrup. P:, K. Kjcldsan. H:M. Olsen. and! D. Trolle. 1972. Effect of moderate carbon tnonoxide exposure on fetal development. L"nvcu I1:1?''0. Aserup, P.. D: Trolle, H1 M. Olsen. and K. Kjeldi;en. 1975L Etlfect of modcrate hypoxia expsoure on fetal dtvclopmcnt, Arch. Etmiron. HK•ulr/r 30: t5~ Ayres. S,M.. S. Gi:utelli~ and H. Mueller. 1'970: Myocardial and systemic responses to carboxyhemoglobin. Ann. Ns Y. Auud: 5ri: 174:268. Campbell. R'.F. 1929-30: Tis+ue oxygen tension and carbon monoxide poisoning. J. Pli~sitrl. ti8af.. Christ. C. 1935. Expezimcntelle Kuhlenoxydvergiftung. Hbrzmu+kclnekroaen und Elr:lc- troiwrdiogramm: Qritr: PurNul. rtrau. .tll,t:: Puthul: 9+3:I1!I. El+rich; W: E.. S. B;ctlct. and F. H: Lewey. P9". C:udicu changes t'rom CO puiwning. 10050101 ~~3

Carbon Mbno:idr 179 Hugod. C.. L.H. Hawkins. K. Kjcidi;en, H.K. Thomren: and P. Astrup. 197R. Effectof carbon monozidecxr-.1sure on aortic and coronary intimal morphology in the rzbbit. arhrrusclrrrnis 33:3. Kjeldsen. K. 1969'. "Smoking and. A'therosclerosis,° p. 143. Thesis. Uni.•ersity of' Copenhaeen. Munksgaard. Copenhagen. K/`Idsea. K.. P. A:ytrup: and J. Wan,uup. 1972. Uitraattvctural intimal changes in the rabbit aorta after a mWcrate carbon monoxide e.-posurt:.Adrrr,+xclcrrsis. 1i6:67: Knelsqn, J.H. 1972. UUnited States air quality criteria and ambienrst:rndards for carbon monoxide. l'Dl B~rrirhte. Nr. 180:99. Lewey. F.H. and D:L'. Dr.rbkin, 1944. Experimentalichronictarbonmonoxide poisoning of'db__s. .-Iwtrr.,J. Mrd: St•i: 2b8t50.. Parn•ing; H.-H. 1972. The effect of hypoxia andicarbon nonoRide on pla.ma volume and eapillary, permeability to albumin. Saand. J. Clin. Lab. lmrest. 30:49. Parving. H.-H!. K. Ghlsson. H.J: Buchvrdt-Hansen. and I4ti Rorth. 1'97'_. Effect of carbon monoxide exposure on capillary permeability to albumin and a;-macrogiob- ulin. Scand. J: Cliir: Lsrh. lvmcsr. 29:3S I. Sarma. J S':.M.. H. Tillmanns. S. Ideka. and R.J. Bing. 1975. The ef•fect of carbon monoxide on lipid metabolismot humancoronaty arteries. ArJtnrrrxclernsis 221:d93L Schievelbein. HL. ed: 1966. NNikorin. Phurmak-alogrt and' To:ciltologir des Tabuk- sraarhrs: Georg Thieme Verlag. Stuttgart. Sig;aard-AndersenJ:. K. Kjzldscm F. Bonde Petersen. and P. Astrup. 1967. A possible connectibn between carbon monoxide exposure. capiltary tiltration irate. aad athero• - sclerosis..tcta Mcd: Sourid: !ti_:397. Stender. S:. P: A'strup: and' K. Kjeldsen. 1977. The effect of carbon monoxide on eholesterol in the aortic wall of'rabbits. Adrrrusrl'rrosis 28.3'57'. Thomsem H.K. 1974. Carbon mconoxidt-induced aeheroscletosis in primates. An electron microscopic study on the coronary arteries of' macaca itis.monkes s. arlterusvlrrosis aD:_°33. Thomsen. H.K. and K. Kjcldsen. 1974. Threshold limit for carbon monoxude-induced! myocardial damaee..arrh. Envirnn. H~eultJi. 29:73. Wald. N.. S. Howard. P.G. Smith. and K. Kjeldsen. 1973. Association between atherosclerotic dise:,se-. and carboxyhaemoelbbin levels in tobacco smokers. Br: Mrd. J. 1:761. COMMENTS SiCHwAttTZ Dr. AstruF. I was very impressed with your lovely set of data. I would like to ask you a question about the pregnunv rabbits: Were they exposed during the e:uly part of the pregnancy? ASTRIUP: Diuring~the whole pregnancy: SCMWARTZ: Were there any fetal anomalies, were there any congenital anomalies? ASTttUP: There wetie about four or Piwe congenital anomalies.. SCHWAttTL•' It's particularly interesting becaune there have been an increasing number of reports suggesting that smokinu durinr nrr+onancv maw result 10050531102 S

« 0 Smo~Ci'~ng and Ca~d'~iovascolar Disaases. COUhY'J. SCHWARTZ AND HENRY C. McG1LL. JR.. Departrnent of Pathology The University of Texas Health Science Center and Departrrtentiof'Cardiopulrnonary Disease Southwest Foundatiomfor Research and Educationi San Antonio, Texas 78284 WALTER R. ROGERS Department of 8'ioengimeenng Southwest Research Institute San Antonio, Texas 78284 __ The mid-l!958i+ saw a growingconviction that lunz cancer and cigarette smok- ing are causally related. This concern cultninuted in ii landmark reports. one from the British Royal College of Physicians (J96'2 )2) and the other from an~ Advisory Committet. to the Surgeon, General! ( public Health Service 1964). In the former, it was concluded that ci:_arette smoking is indeed a cause of lung cancer: and in all likelihood' contributes to the devzlupmeno of coronary artery disease. The report of'the Advisory Cmmmicee to the Surgeon General, was conclusive. It, noted a, greatly incrzastd' mortality in male smokers,, together with a signi'Gcantlw• enhanced mortality from coronary ;utery di.ease. While a causal~ relationship between cigarette smoking and lung cancer was defunitive, the causal nature of the relationship between coronary disease and cigarette smoking was adjudged to be mar__inal and therefore scientifically inconclusive. T'he early failures to detect any clear causuil relutiunmhip betWeen~cigarette smoking and heart disease may retlert both the greater preoccupation at that time with lung cancer and the heterogeneous nature of the cordnary arteryy disease syndrome. Ut is interesting to note thnt, even in the Framincham Study (Kannel et al. 1'968'), the: early data showed only a relationship between vital capacity and ci_arette srncnkine. This shortcoming lias clearly been remedied in subsequent reports. tJndtrtitundine the nature of basic mechanisms that might link cigarette smokim_, to the development of various cardibvascul5r diseases wilL we believe., gixe us the ability to develop in s logical manner multiple levels of intervention needed to dii;suade al population to desist from cigarette smoking or to accept less palatable cigurettes: In this discussion we will de,cribe the various categories of'cardiovarseular di'se:ue, emphasizing those pon.,ihly influenced by ciiz:,+rette smoking. Addi- tionally. we shall attempt to cnutlinc the nature of' the relevnru' lesions utd! the basic meehani.rtts through which ,ntukin__ might intDitrnce pathogenesis and then discuss a cig•rrcttr-,muking mudcl' in the nunhumun primate. kuPiv cynr,tcrphultrs t i i ( 1005053103

0 s ,. . E21 C.J.' Sehwairtz, Ht:C. f4teGilt, J.., and VV.R: Atogers CJl1TEGaRf ES OF'CARDf 0VA5CULAfI'DISEASE The four principal categories of'cardiovascular disease upon which ci¢arette gtttoking might have somc acceleratin= or adverse influence are cardiac. disor- den of the peripheral' circuJation; strokr, and venous thrombosis: Within the cardiac category there are four subr:ategories, narnely, angina pectoris.. myocardial infarction. sudden cardiac death. and' cor pulmonale. The latter is listed simply bet:ausc of the undisputed role which cizarette smoking has in thee development of chronic bronchitis and'emphysema. Myocardial infarctimn, on the other hand. is associated' not only with, severe coronary atherosclerosis, but also with a vsriable degree of cardiome~_- aly, and, in parrticu'lar, with a high frequency of occlusive coronary artery thrombi, Coronary artery thrombosis accounts for in excess of 90% of cases of recent transmural infarction (Chandler et al. 1974'). Itt transmurai infarction, it is the presence of occlusive thrombosis that distinguishes this condition from both, angina pectoris and subendocardial in- farction. Factors, such as sm,,kin_, that might modify the origin or develop- ment of transmural infarction, may do so either by irtlitencing mural diseasee that is, atherogenesis, or, alternatively the prrocess of'thrombogenesis. Sudden unexpected cardiac death (SCD) has been the subject of a number of recent reviews ( Prineas. and Bll:uieburn 1975). Of particulnr importance is the growing realization that only approximately one*third! ot• SCD~ cases are associ- ated with traditi'onal myocardial infarction (Schwartz and Walsh 1i971). Of patients dying suddenly who were subsequently successfully resuscitated, only approximately 40% exhibited enzymic or electrocardioArzphic evidence of in- farction (Cobb et al. 1975). AJthou_h patients with SCDlfrequendy exhibit the traditiional! formula for ischemia~ namely large hearts and severe coronary atherosclerosis, they show a not unexpectedly l'ow frequency oi occlusive coronary thrombi' (Schwartz et al: 1975),. A variety of' other mechanisms potentially leading to SCD nted careful evaluatiion, including the roles of platelet' microembollsm, disturbances of the cond'ucting systera or its 'L. lood supply, intramyocardial small vessel disease, and other nonischemic causes of myocardial injury. Other categories of cardiovascular disease of particular relevance to this discussion include disorders of the peripheral circulation, cerebral infarction and transient ischemic attacks, and the important disorder of venous thrombosis with its serious thromboembolic scquelae: Disorders of the peripheral circula- tion~ include the clinical syndrome of intermittent claudication (c.f., angina pectoris)iand peripheral gangrene. Buerger's disea_se (also known as thromboangi'itis obliterans) was tint described in 19016 and has been the subject of much dtbate: Clinically the syndrome is contoned to the lower limbs, with thrombosis involving bothh arteries and the neighboring veins. This interesting though uncommon di,csse occurs predomin;uotly in young males and almost inkariubiy inih+r.tvy cigarette smokers. .1•• ~KCnrrierinn whirh n.r..nrnfn.A L"......... 'Fte.tn. ... ..... .V_. •.1 Aft '~l+4' 100Sll~W31~ 11

0 Smoking and IGardiovascular Dis.ases 168 Stroke, like disorders of the heart: is indeed a heterogeneous complex including intracerebrul' hemorrhage, infarction. subarachnoid hemorrhage. attd' ttansient ischemic attacks. lntracerebral hemormaLe, in most cases. is directlyy attributable to rupture of the lentuculoytriute arteries, occurring on the basis of bo6 hypertension and smsll miliary aneurysms. resembling ;trinus of heads. first described by Chsrcot and Bouchard (12365). The pathology of cercbral' infarction in many rcbprcts is similar to, that of myocardial infurction. ylb~t cases of infarction result from thromboatheroselerotic occlusion. but embolic obstructimn and hemodynsmic or low output crises are also of' pathogenic significance. Transient ischemic attacks may uncommonly be due to the combination of arterial stenosis und!recurrent but transicnt reductions in cardiac output or blood pressure (Enstcott et al: 1954). More commonly, however, they result trom atheromatous or thrombotic emboli arisirr_ either in the aortic arch or ccr••ical arteries as the result of plaque ulceration or the fragmentation of murul thrombi. Venous thrombosi,, occurring most frequently within thc deep leg % cins. is a major source of pulmonary thromboembolism. Venous thrombi' ori._inav: within the valve pockets and extend both proximally and distali.v, the fragile extensions being predmminantHy a coagulum of blood or clot rather thun al thrombus. It is these proximal extensions that fragment and cmbolize to the pulmonary arteries with a significant morbidity and mortality. CAUSA!'. RELATIO'1`']SHIPS'AMbMG,SELECTED CARDIOVASCULAR i9ISEASE'EIND POIIUTS AND CIGARETTE SMOKING In Table I our interpretations of'the relationships amom= cigarette smoking and selected disease end points are summarized. These relationships are reviewed in detail in a recent report of the Surgeon Gzneral!(Public Health Service 197y). It is, apparent that cigarette smokinL, is si_~niticmttly related& to the three major components of cardiac di,ense. namely antiina pectoris. myocardial inturction. and sudden cardiac death. In the former two cateaories. the as1ociation, are significant for both rnules and itmales, while for SCD the di,ta do not permit discrirninatipn between thr: sexes. Athero-cliero.is veverity and cigarette .mcnk- ing are sienifiicantly correl'uted in male.,. but in: femal;:snrt adequate data are available. Stroke is n~ hetcrm_cneous di.e;Lse complex that encmmp;Llses a number, of' disease end points including intru:crebr.,l hemorrhaLe: sub;u-achnoid hemor- rhase, cerebral int'arction. and tr.ut.icnt i,chernic ;tttucka. It is theref'bre not surprising that the relationship between cuprette +moking and stroke is incun- cltuive. This relation.,hip may be cl:uitiwd by refining the clinical dixusc end points in future rewsreK ctliirt.. For one ot' the stroke c:,tcg0rie+, namely transient' ischemic uttuk.,,, the data are regrettabl;v inadequate. There appe:uN to be little doubt about the correl•rtion, hetwcen ,mokiinL snd uhirum- boathero.clerotiic periphersl.•a+cular di.eu.+e. and b;:tHUcn, smoking and. : '

Table 1 Causal Relationships Among Selected Cardiovascular Disease End Points and Cigarette Smoking Consensus on relationship to cigarotte smoking positive negative - - Inconclusive. Nature of disease end point Sex with adequate data with adequate data confiicting, or Inadequate borderline . data Angina Ixaxturis M 0 Myocardial inf•rrction F M ~ Suddcn cardiac dcath F O 0 Athcrosclcrwis M ! Stroke F M 0 Trrnsicnt ischemic attacks F a • IlucrEcr's diseasc Periphcral vascular discasc Athw-rosclerotic aorti_c ancury.m Venuus thromtxx:.mlxwlic di.cst.c M ' M F r 'Puaaibk• infcrwtiun bctweca .muking and hinh 4.4nNrol piftz. - 9O14SUSUQT . . t ! I

Stnoking and Cardiovsseulir Disensesd 8S exclusively to males, also shows a stronc correlation with c't=arette smokinL. Data linkin, venous thrpmboernbolic disease and cigarette smokin_ remain. inconclusive (Table 1). This area cleculy requires intensiticatiom off aesearch efforts. It is also of interest that orall contraceptives and cigarette smoking may inter,tct'in tnhancinc both arterial and'venous thrombosis. ,~.. " MECHANISMS U111KIMIG SMOKING AND CARDIOVASCULAR DISEASE We are convinced of the need to explore and understand basic mechanisms of disease. Bwg outlining selected'disea_se end points and their principal components of -watho_enesis. we should be able to determine the potential basic mechanisms through which cigarette smoking might influence pathogenesis. The tive prin- cipal components ot pattiogznesis that have been identitied are atherosclerotic narrowing. arterial and venous thrombosis, cardiac anrhythmias, arteritis. and microembolism. Basic mechanisms throuph which cigarette smoking might influence thee process of' atheroeenesis include effects on lipoprotein4 cholesterol, and lipid metabolism: endotlieliai str~,tcture and function: arterial smooth muscle cell proliferation and connective tissue synthesis: the platelet release reaction: monocyte-macrophage function: and cellular and humoral immune systems. Aspects of this complex problem hah,ebeen recently reviewed by McGill e! al. (1978); In the pathogenesis of either arterial or venous thrombosis. ci_•aretrtz smoking is most likely to exert its influence via prostacyelin-thromboxarte generation, platelet-vascular wall interactions; endothelial injury. altered coa,-,u- lation and hemostatic mechanismse or disturbances in the immune system. In SCD ventricular fibrillation is an important intermediary mechanis= It appears that a number of basic mechanisms possibly influenced by cigarette smoking may be involved in the development of the lethai arrythmia5. These include ischemic rnyocardial in;ury, coronary artery spasm. damage to or functional! disturbances in conducting tissue, and' an altered ebectrica4- physiolocical! role of agents released by platelet microemboli in the microcircu- lation, either in, the genesis of focal areas of vasospasm. or in modifying myocardial excitability. Peripheral vascular disease has as its basis tlirombo-atheroselcrotic dis- ease: Basic mechanisms in%oived in its evolution ~nd upon which smoking might exert some influence :ue essentially similar to those for atherosclerosis or thrombosis in other parts of the circulation. Additionally microemboli of either an atheromstous or thrombotic origin may play an important role in .smme cases. Such~emboli :tre most likely to arise from ulceration or mural thrombo.is in the aorta or ilio-temorall artcrics: One special category of pcripher.tli vascular disease. Buerger's dises,e, iti clearly a nonatheroaclerotic di,order. but rather a vasculitis involvint both arrteries and veins associated witlt a migratory thrum- bophlcbitis: The two esatntiall component, in p•rthueenesi, are artcriti, and thrombosis. Basic mechani,rns, po,,ibly linking , +mukin__ and this dii.<order' include an abnormtal hypersensitivity in, some indiividuul. to tubaccu __lyticupro- s.

M - 861 C.J. Schwant3, H.C. McGill, Jr:, and'W:R. Rogers ' tein together with disturbances in the immune systetn+ abnormal platelet func- tion in association with elevated carbuxyhemoelabin ('COHa) levels (Binvtin~_1! et al. 1971), and eadothelial and vascular injury. Why this disorder is almost exclusively the domain of the young male also needs critical appraisal- The patho,renesas of transient ischemic attacks in most cases is n:eurrent microembolism. Basic mechanisms of relevance; therefore. are not only those associated with atheroCkenesis and thrombocenesis. but also with the processes of plaque ulceration and the fragmentation of thrombi. Thrombus~ instability includin~_ the contribuoion of fibrinolysis might therefore be important in the origin of platelet mictotmboii. since ti~brin! t..rmally, hhelps wstabiliize thrombi!. It is difficult to identify mechanisms where! sr^okin_ might evem remotely facilitate plaque ulceration. The role of smoking in the modif catiian of both hemostatic and coagulation mechanisms is much Iess remote. SOME ASP'ECTS'OF CURRENT SMOKING RESEARCH With ciparette smoke cmntainin8 im excess of several thousand pqtentially noxious components (Publir Health Service 1979). aad with the habitof smoke inhalation, being a uniquely human practice. experimental studies: on the rela- tionship between ~ cigarette smoking; and cardiovascular disease pose numerous design and conceptual problems. We have undertaken studies of this relation- ship by developing a model to simulate the human exposure. Emplioyin¢g operant conditioning techniques. baboons (Papid eynoeephulus) have been trained to smoke cigarettes in a manner not dissimilar to their human courttzr- parts (McGill et al. 1'978; McGill and Rbgers 1980). With, this approach, we are currently studying the influence of prolongFd periods of cigarette smoking on selected' cardiovascular and respiratory disesue end points. together with a number of relevant intervenin8; variables. In terms of disease end points, atherosclerosis is a: maj:ir emphasis. Variables. selected because of their rrele- vance to basic pathogenic mechanisrtts, that are being examined include lipo- protein„ cholesterol, and Iipid levels: plutelet. leukocyte; and lymphocyte dy- namics; plasma factiorrVlIl levels; myocardial and endbthelial ultrastrnecture: grewth and'behavior of'arterial, smooth muscle cells in culture; and the response of smokin¢ and contro'4 animals to a purified tobaccp gly,coprotein. ) Additiional studies are iniprogrets to evaluate thc~intluence of acute (2-hr) rigarette smoke inhalation on endothelial' strveture and function as stuciied' by both transmission and scanning electrom microscopy, lipid and lipcnprottin ehanges, and selected indices of the endocrine response. Tabie 2 summarizes selectedi mc:ut, dosimetric indicators of smoke rxpo+ sttre for two periiods, nameiy weeks 94-1IS and. 176-179. of a 3-year experiment (W. R. Rogers et ai.. in prep. ). The animals smoked more than two packs of cigarettes per day, resultin8 in signitnc•,utt thouFh modest zlevatiuns of blood ruboni monoxide (CO), pl;t.,ma thiocyanate, and urinary cotinine le%els. The blood CO levels presented' in, Tablc 3, correspond to a percentage COHb

. Table 2 s Selected Physical and Chemical Dosimetry Measures ofCigarette Smoking and Control'Baboons Duration of smoking i Cigarettes per day Put3` %olume tml) CQ 1(mIYd1) Pjasqna thiocy,anate (µg/ml) l:riiiatytotinine lµJm1D 42.9 .3513 0.24 4.80 i 3.49 42:7' 46.0 -16,7 39.0 47.0 50.0 0.08 0.22 0.08 1.66' 4'.s0 2.24 0.62 2:,S 0.23' As indicated in Table 3. the mean serum total cholesterol. triglyceride. and very low-density lipoproteins plus low-density lipoprotein cholesterol le:elis of smokers were less ;than those of'shams, but the differences are not stati5ti- callysignifbcant. The hi_h-density IGpoproteincholesterol' levelsofsrnokers s were reditced (P < 10) compared to ihose of'shams. Fasting blood slucose leveis of smokers werr si=ttil'icantiy grcater (P < .05) than those of sh:uns. Several selected hematologic characteristics of smokers and sh3ms~ are given in Table 4. Cigarette smoking baboons exhibiteti, a sdgnificant (P < .05) leucocytosis and differential cell counts ittdiicatedl that this response was largely atttibutable to a, tyrnphocytosis. The platelct counts, hemoglobin levels; and hetnatocrits of'smokers and shams did!not differ signifcantly: Table 3 Serum Cholesterol, Triglyceride. Lipoprotein, and Fasting Blood Glucose Concentrations in Cigarette-Srtnoking and Control Baboons Mean selected Experimentai category response variables (weeks 1i63-179) smokers shamismakero Total cholesterol (mg/dll 1'53' 165 Triglyceride (nd/dl) 51.8 56.3 VLD'L.' + LDL" cholesterol (mg/dl) 53.6 58.7 HD'L''chulesterol (in8/dl) 90:7 99.8' Fs+tins blood eluco%c lmvldlD 95.0 89.8 •V ery 1uw-deasicy lipopnxein: 'Low+density lipupnuhin. 'Hi}k-dtmity tipopraein.

«. !8TCJ. Schwartz. H.C. IWeG7c, Jr., and W.R. Rog.rs Tabla 4 Selected!Hernatohogic Characieristics of Cigarette Smoking and Control Baboons ~ Mean hematologic response variables L. ukocytes (11IU'/mm') Lymphocytes (10'7mm') Platelets (11b'Imm') Hrmoglobin (tidl) Hrmauocrit ( K ) smoker . 7.59 5.56 289 12.9. 38.8' sham i smoker sham 6'.42 8.28 7.92 4.02 - - 278: 298 279 12.8 13.5 13'.3 38.6 40.2 39.8 Factor-VIQ1 levels were signif cantly reduced! (P <' .05) in cigarette smok - ing, baboons (Table 5). These preliminary findines may ind'irettly indicate an influenceof ci;arettesmokins on vascular endothelium. Further studies will hopefully clarify this interesting point. In sumrnary, we haxc used operant conditioning techniques with the baboon to provide a model sxstem in which the effects of cigarette smoking on cardiovascular diseases, can be studied' ezperimentally. Our, initial' results con- firrm that the b•rboon, is a human-like model for such study. Future studics should provide valuable information on basic mechanisms lunking, ~,moking and eardiovascular diseuses.. ACKNOWI.EDCl1REPITS This research was supported. by grant HL-19362 from the National Heart. Lung, and SloodJnstitute. Table 5 Factor-Vlll Leveis After 3 Ye1.rs of, Cigarette Smoking Experimental category R Mean factor VII M of, human level) Smoker Sham smoker 1a 16 238 307 Facur-VI11 a+rva imclcn+l en hv D.T.S': Timmermrm. Seripps Clinic. San, DieYt+: uxine

Stooklny andiCkrdiovascular Diseasesd 89 REFERENCES Birn•ctiir;l. M.A.. K. Brinson. and B.K. ChaJcrabarti. 1971. The etTect of short-term exposure to.carbon monoxide on platciet stickiness. Br. J: Sur;t: 58:d'37'. Chand/er. A.B.. 1. Chapman. L.R. Erhardt. W.C. Roberts. C.1: Schsvartz. D. Sinapius. D.M. Spain. S. Sheny. P.M. Ness, and T.L. Simon. 1974. Coronary thrombosis in myocardial infarction. Report of a workshop on thr role of'crsro- nary ttirom'bosis in the pathogenesis of acute tnM1ocardial infarction. Am. J. Cardiol. 33:823. Charcot., 1:M. and C. Bouchard. 1868. N?ouveiles recherches sur la pathorenie de' ('hemorrhagie cerebrale. rlrch: Ph.•sinl. Nr,rm. Pathol. 1:643. Cobb. L.A.. R:S: Baum. H. Aliarez. ill; and W.A. S.natfer. 1'975. Resuscitatiom from out-0f-hospital!centreculnr ttbrillation. 4 years follow-up. Cirrr,lcuian (suppl,. 111)'S2:223'. Davies, M.J.. N, Woolf, and: W.B. Robertson; 1976. PPathology of acute mn•ocardial, iafarctiom with particular reference to occlusive coronary thrombi. Br. Meurr J. 38:659. Eastcott. H.H.G. 1969. Arterial sargerr. Pitman Publishing Co.. Ltd.. London. Ed,tcott. H.H.Ci.. G:W. Pickering. and C.G: Rob. 1954. Reconstrniction of interttal carotid artery in a patient with intermittent attacks of hemiplegia. Lancer 2:994. Heberden. W. 18'118: Cornmenturies on dtr Iristury and cure of diseuses. «'ells and' Lilly. Boston. Kannel.,W.B.. W.P. Castelli'„and P:1it. McNamara. 1968. Ggarette smoking andlrisk of'.coronary, heart disease: Epidemiobogic clues to pathogenesis: The Framingham Study. Norl. Cancer Inst. .blanogr. 2'5:9. McGill. H.C.. Jr. and W.R. Rogers. 1980. The baboon as a model for cigarette smoking. In SYmposirrm on, the use of nonh'uman primates in cardiuvwscular diseases. San Antonio. Texas. /ln pressl McGill. H.C.. 1t.. W.:R. Rogers. R.L. Wilbur: and' D.E. Johnson. 1978'. Cigarette smoking baboon modei:' Demonstration of Yeasibility: Proc. Soc. F-rp. Binl: .l!'ed: 1157c672: ~ Miller, R.D:., H:B. Burchell. and I.E. Edwards. 1!95'l. Myocardial infarction with andd withoutiacute coronary occlusion. ArcG. Intern. Med. 88:597. Prineas. R'.1. and H. Blnckbum. ed. "975. Suddert~ coronary death outside hospital. Symposium on Sudden Coronary De:rth Ouuide Hospitals., Minneapolis. 1974. Circulation (suppl. lUi ) 52:1. Public Health1 Service. 1'9l`rl. Smoking and healrh. A report nf the adiasnry committee to the Surgeon General of the :'ublic lJbulrlr Sen•ice. DIHEJM publication number (PHS) 1103. Government Printing Otdice. Wushington., D.C: 1979. S/naking andhealth: A rryNmr uf rhe Surgeon General: DH$W publica- tion number (P'HSo 19-5(D066'. Govemment' Printing Otiice. Washinrtton. D C. Royal College of Physici:uts; of London. 1962. Smnking, and heaJik; twnmure' and' report an smukinK' in rrlution ru cancer of the lunR and, other diseases. Pitman Medical Puhli+hinL Co.. Ltd:, London. Russell. R.W.R. 1961. O'bservations on the retinal blood vessels in monocular blind- nexu. Lncet 2:'14'?: Schwaru. C.J. and W.J. Walsh. 1971. The pathmlogic ba..ies uf sudden death. Pru.4: Curdir,rYar. Dia. 1'.Z':165:

. . 904 C.J. Sehwarts: H.C. MeGill, Ji•., and'W:A1 Ftog.rs Schwartz. C.):, A.B. Chandler. R.G: Crerrity,. and H.K: Maito. 1978, Clinical utd, pathological, zspet:ts of arterial thrombosis, and. thromtioetnbolismi Adr: Fxp. Med. Biol. W:111. . . ~• :CQMMEPJTS . WYDtDHR: 1have been concerned for many years at how little attention we have paid to the effects of smoking on cardiovascular disease. Here see some very, pertinent data, relative to ! al major cause of death., I have two questions: 1. 1 take it you: have measured the catecholamines in your monkeys: could you tells us about this? and 2.. If you were asked what would be the less,hartttful cigarette, in respect to cardiovascttlar disease and you had to make a, recommendation to this group~. would you like to see a reduction in nicotine and' CO. and what else? What would you recommend, to us with your current state of'knowledge? SCHWARTZ I don't think I can make a recommendation. 1 don't have enough data to, make a decision as. to which would, be the leastharmfui or the least hazardous ciearette. I think, we reall jr need. to manipulate the future ! studies onhigh-nicotinen low-tar cigarettes and various combinations, and, perform permutation studies in the baboon model specifically, to try, to get at that. We did, not measure catecholamines in the chronic study that has just bet:ncompltted. We are.,in fact. measuring,cortisols and catechols,in the acute'studies that are being undertaken at the moment.We were trying to look, at the equivalent effect of'ten cigarettes in baboons over a, 2-hour period, that is, in, animals that have never been subjected to any cigarette smoke eaposure at all. We attempted this to see just, what the~ acute effects might be., The assumption was that there could be a continuous additive injury-type phenomet:on going on over many years. We want to see if we~ can identify any acute basic changes that take place in the tissues at an ultrastructural and a basic biiochemicali level. . r wY•NDERc This is a crucial' point. If you measure cotinine-niicotine levels in the bioodstneatteof cigar andipipe smokers, you tind that they areashigh as those among cigarette smokers. Since we know there i's•no increased risk for coronary disease among cigar or pipe smokers, e'ven with their elevated cotinine-nicuune levels. I wonder if you are going to study catecholamines? SCHWARTZ:, We are: indeed. I' can just comment that the plasma cortisol levels go up dramatically with the ten-cigarette: exposure. It'r a dramatic effect. Of course, plasma cortisolitself has been: shown to correlate dramatically with the severity ofi atherosclerosis. :r:

Gt7R1: I would just like to reconcile some apparent' differences between your ;Yy~# presentation and! Dr. Astrup's presentation. Is it true that' what you were referring tu before was speciticallv obtained with CO exposurr°only,. not withlci arette smokine) Would' ou care to comment on whether there is '' ~ y an implication that other smoke components may counteract the effects of _ CO7' • ;'SCHWaRT2: The data, has not yet been totally analyzed. It may be possible. with more varied' anadysis, to look at independent effects of CO levels versus other factors. I can't answer that question. Our study basically gives the results of chronic smoking exposure in nonhuman, primates on lipids- ant. various other things. whereas •Dr. Astrup's data is qµice clearly the effect of CO. I don't think these are necessarily in eontl6ct, but we obviously have a more complicated sys- tem. ~ GORt: Dr. Astrup presented!some similar data at a meeting in Berlin almost a 1' year ago. I' remember that even at that time he showed some different results at different times during the experiment and could not confirm previous experience concernin,... ASTRUP: ...direct toxicity of CO on the endotheliall lining?' GORI: Right. At that'time, we werralsospeaking of the necessity of carrying on studies with CO in different anitnals, particularly in primates. Do you - think that the results that Dr. Schwartz has reported are more pertinent'to the human, situation than what one could have obtained with rabbits or with guinea pigs? A:STRtuP: I' think they are, because he uses tobacco smoke. I think it is J' important, to distinguish between the various components in tobacco smoke for identifying the real'toxic ones. , • . . ~ SCHWARTZ: I agree with Dr. Astrup that one really needs to be able to do. _ these things, both i^ terms of the total smoking situation and tr.e manipu- lation of different types of cigarettes gi'ving,differenrtypes of response. lnn addition, in the acute studies example. ti think we should be looking, at some of the smoking components, spet:iticallyas independent %ariables:

rcinogens, Cocarcinogiens, and Tumor linhibitors in Ciigiarette Smoke Condensafe' : _• BENJAMIN L VAN'DUUREh! Laboratory of Organic Chemistry andlCarr°nogenesis Institute of Environmental Medicine New York Uttiversity Medical Center New York; New York 101016 -- 'I1te frst report on the csucinogenicity of cigarette smoke condensate (CSC) on mouse skin fWyndec et a1. 1953) prompted chemical studies on thrc:ucino;,_ens responsible for the observed results: In several' reports (Van Duuren 1!958a. 1958b;, Van Duuren et al. 1960). the isolation. characterizauon. and' quamtdta- tion of a series of aromatic hydrocarbons and heterocyclics were described. tituny subsequent reports confirmed' and extended these findings (Wynder and' Hoffmann 1967). Some of these compounds and their coneentnuons in CSC. ane listed in Table L since they are relevant to the discussion to follow. Thee concentrations listed are from a compilation, by Wynder and Hbffmann ( 1'967). From our own studies on the carcinogrniciiy of CSC tOt,ris et al. 1i958x, we concluded at that time that other factors (i.e.. promoters an&or cocarcinogensp must aiso be present in CSC to account for the observed mouse skin1 carcino- genicity: These biologically active cofactors are the subject of this discussion dealing lurgely, with work from our laboratory. INi'f7Y1TORS AND PRC'VfOTEFfS IN TOBACCO CARCINOGIENESIS' An early report by Boutw• Il and Bbsch (1959) ddiscussed the tumor•promoting ability of a series of phenols, In these two-stage carcinogenesis experiments, a single dorsal mouse skin application of a subcsrcinogenic dose of a carcinogen such as 7,12-dimethwibenz(ulanthracene (D11BA) is followed' by repe•rtedd applications of the promoter at the same site. This defimibiom is :iven here to distinguish tumor promoters from cocarcinogens, which will be discussed later. From the work of Boutwell and Bosch. cited above, it was clear that very few phenols were tumor promoters. Phenol itself was a weuk tumor promoter in their work, and we cont0rmed this in subsequent work (Van Duureni et al.. 1968). However., in the same study, we found' that a whole senes of tobacco phenols and related compounds were devoid of tumor-promoting activity. Yevenheiess. CSC whcn tested ss a promoter in the two-stage prutocol de- scribed abovt did show notable activity. lm a group of 60 I1CRJHa Swiss mice 105 a

106 /'B.L Vnn Duuren Tabre1 Concentration~of'Some Carcinogenic Aromatic: Hydrocarbons and Heterocycfias iniCSC . jug in CSC from Compound I 100 cigarettes ~ Carcinogens Betuo(a lpyrene 2:S DibenY[u.1i lattthr.acene 0.4 Benzo(jlfluornnthene 0.61 Dibenzo(a:i IPyrene Dibenz(u,h laeridine ttaces 0.01 Diben2[ur.jhcridine 0.27 7-1$'.Dibenzo(r;X,l0srbazole 0.07 NoncarcinoQens Pyrene ~ 7.S-10.3 Fluoranthene: 7:5-10.3 Benzo(q:h.f lperylenc 0,6 treated once only with 50 gg DMBaA followed by repeated application of CSC. (40 i mg in 0:1 ml acetone rave tiines weekly). 14 animals developed. squamous carcinoma of the skin. The expenment was terminated after 573 ' days. In the same series of expenments: CSC alone, at the same dou, resulted in onlv four animals with skin cancer. The dosage of 50 /xg D'h181A alone did not result in any skin cancers (Van, Duuren et al. 1971). It must then be concluded that the mixture of many chemirals lutown: as CSC is, indt;ed', not: only a carcinotenbut also, a tumor promoter. We next examined the tumor-initiating activity of some noncarcinogenic or weakly carcinogenic aromatic hydrocarbons. which are CSC components. This experiment showed that dibenz(a,c lanthraccne, chrysene, benz(rr lanthracene. etc., are tumor initiators in two•stage carcinogGnesis using a mixture of phorbol' esters prepared from croton oill as the promoter (Van Duuren and Orris t'9b5: Van Duuremt et al l I970). With all these undines and those of other resesrchers in, hand4 we were still not satisfied that we could account for the observed animal cat~cinogenicitv of CSC. In addition. numerous early epidemiologic studies (Public Health Service 1964) llinking cigarette smoking, an& human Iung, c•.utcer sugoested that further animal studies were needed to pinpoint other cotactors.. COCARCINOGENIC AGENTS Alniobvious approach was to test' CSC Components for cocarcinogenesis in the clnssical Bcrcnblum protocol, (13i:rcnbiurn 1941). In Bcrenbllam's experiments erotnn nil -+ ti•-t;• I••••rrne i fqGr IIP1. when annlier,i .,~„...+.•.....~...•i.. .„, _. .. .

0 either agent'applied alone: Thus. this type of test is operationally different from the two-stace carcino-enesis experiments described above and, moreover. it is the way in; whi& humans are exposed to cigarette smoke. We. therefore. undertook a series of experiments on cocarcinogenesis of' CSC components with quite remarkable results. Five major compound types were tested for cocarcino¢enicity on mouse skin. They were phenols. noncarcinoYCnic aromatic hydrocarbons. lonefihain aliphatic hydrocarbons., long-chainm fatty acids. andl alcohols. A summury, of some of these findings are given in Table 3' (Van Duuren et af. l'973: Van Duuren and Goldschmidt 1976). In these experiments. ? I pure chemicai com- ponents of'CSC and related compounds wta tested for cocarcinogenicity. The compounds were applied to: mouse skin. 50 fe-rtala ICR/Ha Swiss mice per group, thrice weekly. together with! 5Ag per application of BI(u )IP. The duration of' these tests was 4-i0 dhys. The compounds listed in Table 2 all enhanced'f sionificandy the carcinogenicity of B(a,]IP but did not notably reduce the days to first tumors. except in the case of fluoranthene. A recent report of the Public Health Service (1979) lists: all the known phenols: in CSC. Of these compounds, catechol is by far the most abundant phenol! in CSC. Its concentration in nontilter cigarettes ranges from 0. 16 to 0.5 mg per cigarette and 0.0I6 to 0.2 mg per filter cigarette. None of the compounds listed in Table 2 are tumor promoters or carcinoaens on mouse skin. We are. therefore, dealin_ with a series of comvounds that appe:us, innocuous but is harmful in the presence of minute amounts of'a carcinogen. In the course of our work on cocarcinogens cited above, we compared the cocarcinogenic activities of a series of compounds with their tumor-promoting activities. Phenol, for example. is a weak promoter (Van Duuren et al. 1968) wwhereas im our cocarcino__enesis experiments referred to above, it' is a~ tumor inhibitor. Only the two most powerful known tumor promoters. phorbol myris• tate acetate and anthralin (1.8-dihydroxy-9-anthrone) ihowed': both types of' activities (Van Duurerr et al. I'958): Neither of these two compoundy are components of'CSC. STRU CTURE-ACTIVITY RELATIONS'HIPS ~ OF COCARCINOGENS It is noteworthy that 1lthough catechol is a potent cocarcinogen. its position isomers, resorcinol and hydroquimmne. are not only inactive, but partially inhibit the tumorieenicity of' B[u]IP. The cocarcinoeenicitii:s of these various phenols are compared in Figure 1. In the aliphatic hydrocarbon series decane undecane (C„H.,,) and tctradecane (C;,H_,,) are potent corarcino- gens. Their lonSer-chain analoes.,hexadccane (C,,,H_„), cicosane (C,,,H,_),, and' octacosane (C.„H:.,,) are inactive as cocsrcinogenx and some of theae longer- .chain hydrocarbons also partially inhibit B(aJP carcinocenicity. We have ob- served in other recent studies ,imilar ,truetucil speciticitirs for tumor pro- moters, both in the anthralin series (Vam Duuren et al'. 1978i) and in the phorbol ester scriex ('Van Duureniet alL 1'979).

1t)S14I.L. Van Duunn 0 Figure I EY E) ® Cocarcinogenicity ofphenoisf (+) Aetive (-)iinutive:. Since the compound types that were cocarcinogenic in our tests vary so Widely, in their chemical structures, it, is unlikely that they aff have the same mode of action. Several possible mechanisms come to mind to account for the cocarcinoaenicity or turnor-inhibitory activity of these: compounds. They in- chtde: I. induction of carcinogen-activating enzymes; 2. other alterations of metabolic pathways, e.g., activation, or deactivatdon: of dctoxifying enzymes: 3. physical'.effect. i.e.. increased'or decreased rate of carcinogen1 absorption: 4. effects on DNA repair mechanisms. These possible modes of' action are in need of further studies. It will also be very important to examine these cocarcinogens using, such: mouse skin carcino- gens as /3-propiolactone, which, is a direct-acting carcinogen and' nitrosamine carcinogens. Inhalation studies in mice and/or rats are also clcsuly indicated. SUMMARY AND CONCLUSIONS In tobacco carcinogenesis, we are dealing with a complex interplay of a variety of biolbgicalJy actiwe agents. These agents are classi