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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~:..