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The Health Consequences of SMOKING U.S. DEWARTMEhllfi OF H'EALTHI, EDUCATIO1N, AN'D! WELFARE O' Public Health Service ~' ' ~ Hialthi$Krvices and' Mental Heal th, Administration «D

The Health Causequencesaf S mOkiug hiniuary 1973 U.S. DEP'.4RVAIENT OF HEALTH, EDUCATION, AND WELFARE Public Healtli Service

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Preface This report is the: seventh in a series issued by the Public Health Seri-ice~ res-i~etiuing~ and assessing, tlie~~ scientific evidence linking ciga- rette rette smoking to disease anrl premature death. The current report reiterates, strengthens, and estends the fiildings in earlier reports that cigarette smoking is a major health problem~ in the United States, The~ evidence has~ broadened dramaticallly~ in~ recent years: A Ptiblic Health Service assessment of evidence available in 1959 was largely focused on the relationsllip of cigarette smoking and lung cancer. The~ first': formal report~ on thi:s~ subject in 1964~~ found that cigarette smoking was not onlyy a major cause of lung cancer and chronic bronchiti's, but was, associated wit.h~ illness and; death~ froin chronic~ bronchoplllmonary disease, cardiovascular~~ di'sease,~ and other diseases. ~ The 19T3' report confirms~ all these~ relationships and~ adds~ new evidence in other areas as well. The evidence in the ehapter, on preg- nancy~ strongly~~ indi:cates! . a~ causal relationship between ci:garette~ smoking dliring~~ pregnancy and'~lower infant birth~ «~eightand a strong,, probably~~ causal''y association between ci~garette~ smoking: . and higher late~~ fetal and neonatal mortality. Also reported is the convergence of other evidence which suggestls, that cigaretlt~e~ smoki:ng~ d'uring, pregnancy interacts w:ith~ otller~ risk~fact~:ors to~~increase~ the~ risk of~~ an unfavorable outcome of pregnancy for certain women more than others.~ For~ the first time~ in this~ series~ of reports, a separate~ chapter is, d'evotedl to, pipe~ and ci~gar~ smoking and the~ heal~th hazarels involved. Includedl is an, assessment ofi' the health impl~ications, of~ the new small cigars which look like cigarettes. A final chapter„new to~~the~reports, concerns, cig~arette~smoking~and~~e exercise performance. A review of a number of fitness~testls, comparing smokers~~ to nonsmokers indicates~ that cigarette smoking~~ i~mpairs~ exer- cise~ performance for~ many types~ of athletic, events and actin-ities~in-~ volving~~ma~xim:a1 work~capacity~. The~~ interrelationships~ of smoking~ and health are no less~ complex today ~ than they~ «•..ere~ reported~ to be in t1le~ 1~:9641 report:~ But simce~e that~ti;me~ we ha:ve greatly broadencdlour l.nowl~ed'ge~ and Iulderstanding~ of the prolileim : Th:e~cmrrent report s~ymtSolizes~ this progress, e iIfFRLn:i K. IDrV_x'L.,i1~I.Ill'... ~sszstrrr~t Se~rr~ta~~J forllcalth. b P'F.cHJu3ER'~1I.3', 19 y2~.: ll! 9

Table of Contents PREFACE------------------------------------------ TAB!IGE OF CONTENTS_________________ PREPAR'ATION OF THE REPORT AND ACKNOWL- EDMIENTS' ------------------------ Chapter 1. Cardiovascular Diseases_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Page iii v: aii Xi1T Chapter 2. NonneopIastic Bronchopulmonary Diseases------- 33' Chapter 3. Cancer-------------------------------------- 65 Chapter 4: Pregnancy----------------------------------- 99i Chapter 5., Peptic U1cer Disease-------------------------- 153 Chap ter 6. Pipe and Cigar Sinoking----------------------- 167 Chapter 7. Exercise Perforrnance~-------------------------- 239' INDEX------------------------------------------------ 251

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Preparation of the Report and Acknowledgments "Sinoking and Health. Report of the Advisory Committee to the Surgeon General of'the Public Health Service,"' subsequently referred to as the "Surgeon General's Report;"' was published in 119641. The hTlational Clearinghouse for Smoking and Healthy establ'ished in 11965, has the responsibility for the continuous monitoring,, compilation, and review of the world's medical literature which bears upon the health consequences of smoking, As called f'or by Pubiic Law 89'-92, the following three reviews of the medical literature on the health conse- quences of'smoking, which had come to the attention of the Clearing- house since the original "Surgeon General's Report,"' were sent to the Congress : 1. ~"The~ H'ealth~ Consequences of ~ Smoking, A Public Health Service~~ Revie:w:1967" (submittedJuly 1967). 2. "The Health~ Consequences of Smoking; 1968 Supplement to the 1967 PHS Review" (submitted July 1968). 3. "The Health~ Consequences of Smoking, 1969: Supplement to ~ the: 1967 PHS R'eview"' ( submitted July 1969). Public Law 91-222 was signed into law on April 1'1„ 1970; and called for an 18-month interval between the 1969 supplement and the next report. During this period, a comprehensive review of all of the medi'- cal literature available to the Clearinghouse relating to the health, consequences of smoking was undertaken, with an emphasis upon the most recent additions to the literature. The product ofl this review was : "The Health Consequences of Smoking„ A Report of the Surgeon. General : 1971,"' submittedl to the Congress in January of 1971. Sub-sequently, a review of themedh'cal literature in the field, which had cometothe attention of the Clearinghousesincethepublication of'the 1971 report, waspublislied as,"`Il'heHealtl,il ConsequencesofSrnoking;, A Report of the Surgeon Generall: 1972," submitted ini Januaryof' 1972.. VW

Every report published since: the originall "Surgeon G'eneral's Re- port" has contained a review of the medical literature relevant to the association between smoking and cardiovascular disease, nonneoplastic bronchopulmonary disease, and cancer., Severall of' the reports in- cluded reviews of'the rel'ationship between smoking and peptic ulcer disease (1967,1971,1972). an& cigarett'e smoking,and pregnancy (1967, 1969, 1971, 1972') . Other topics relating to the use of' tobacco haved received special emphasis in single reports : 1. Tobacco Amblyopia~ (1971 Report) .. 2. Allergy (1I972' R'eport ) . 3. Public Exposure to Air Pollution From Tobacco Smoke (1972: Report ) ., 4. HarmfullConstituentsof Cigarette Smoke (1972'Report). 5. I\?oncancerousOral Disease ( 11969'Report). The, present document, "The Health Consequences of Smoking: 1i973;'"' includes reviews of the relationships between smoking and! card'iovasculardisea6e, bron,chopulmonarydisease„ cancer, and peptic ulcer disease which are based uponi medical literature which has become a~vailable, to the Clearinghouse since the publication ofthe1972 report.. It also inclhzdes special rev.iews of the health consequences of' pipe and cigar smoking, andi of' the relationship between cigarette smoking and the outcomes of pregnancy. The material in these two latter chapters refllects a comprehensive revieww of' the pertinent world medical literature wliiich has come to the attention of th!eClearing-house since the publication ofthe~ originall "Surgeon General's, Re-port,."' including materiall which has become available since the. 1972 report. The final chapter in this year's report is a review of the: rela- tionship between smoking and exerciseperformance; an area not covered previously in any report. Witht'heexception of'"`Chapter 4,Pregnaney,"each chapter is orga- nized in a, similar fashion. The introduction to each chapter is a sum- mary of the work reviewed in previous. reports. The summary of eachh chapter encompasses only the work which has most recently become a~vailabletothe Clearinghouse. The pregnancy chapter is organized int~o~ separate sections according to several different ontcome&of preg-nancy. Each section includes a~ brief review of previously reportedd work and contains its own separate summ~ary;, in placeof' an overalll summaryy for the entirechapt'er. Viii

The~ preparation of this report~ was! accompiished~ in~ the following~ j' 1/ fashion~: I 1! 1. The continuous monitoring and compilation of the medical liter- 11 ature on t.he health consequences of smoking was accomplished throughseverall mechanisms. (a) An iirformatlion science corporation is on contract to extract articles on smoking, and health from themed'heal literature~~ of the worid.'h'Irisorganization provirlesa semimonthly ae-cessionslist with abstracts~ and copies of t'hevariousartliclles_ Translations are called for as needed. Articles are classified accord7ng, to subject andl filedl by ai series of' code words and phrases., (b): The National Librairyof .l'bedicine; through the hledlhrssyst'em, sends the National Clearinghousefar Srnokingand Health a monthly listing ofl articles in the smoking and health area. These are reviewed, and articles not identified by the information sciencecorporatiion are orderred.(c) Staff members review current medical literature and identify pertinent articles. 2, The first drafts of'the individual chapters were sent to reviewers for criticism~ and'~ comment~ with respect~ to the art!icles~ reviewed,~, articles not included, and conclusions. The drafts were then re- vised until they met, ~ w~i'th~ the general approval ofI the reviewers. The final drafts:w~ere review.edl as,a.vhole by ~ the~ Directlor~of the National C1'earingliouse~~for~S'rnolk~~ing~ and Health, the D'ir:•ector~of the National Cancer Iinst~i'tute,the Director~of~the:National Heart and if.ung~ Iiistitute„ tlhe~ I)irecct~or of~ the~ National Institute of~ Environmental Health~ Sciences, the Surgeon GeneralL, and by~~ additional expert~s botlii within and outside of the Public Health. Service. Acknowledgments The National Clearinghouse for Smoking,andl Health,~ Daniel Horn. Ph. D~., Director, was responsible forr the preparation of this report. Jledical Staff I)irector~ for the, report ~~~as~ E1'vi~n E. _1~dams;~ I~S.D'~.,~ A~ssistant~ _lledical~ Staff I)~ilrector was hl.~ Stephen «'illiams;~ M.D~~.~con- sulting~edi'tors were~Daniel P. Asnes. A'I.I).,~David G. Cook;_:1~S.IJ.,~and1 .Iohn Il. Ilolbrooh~. M.D. The~ professional stat}'~hEis~ hacll t'h~e~~ assistance~ and advice of a number ofl experts iia the scientlifi~c~ancl technical fields.~both iir and outside the~ ix

Government. Their eontributiionsare gratefully ackno«ledged. Speciall tllanksare due the f'ollowing:. AqoeasoN, WiLLtA1r H.,, 31.D:-Chief; Pulmonary Section; School of' Medicine, lCniver,ity of Louisville, Louisville, Ky. :AUESBAcx; OscAta, M.D.-senior Medical Investigator, Veterans!,Administratiion Hr~spital. East Orange, N.J. AYxeN, STEPfIEsSL., 3f:D.--Direetor,, Cardi'opulmonarsLaboratory, S'aintVincent's Hospital and Medical Center of New York, New York,,-N'.Y: Bocx., FRED Gl„ Ph. D-Director, Orchard' Park Laboratories, Roswelli Park Memorial Institute, Orchard I'ark, N.Y. BoxeN, Hor.r[sGL, M:D.-Jfedicai Investigator, Veterans, Ad'niinistrationHos-pital„ Tampa, FlaL BoUT1VELL,. RoSWELI:. K., '.A.D.-Professor of Oncology, McArdle'. Lahorator9' for Cancer Re.,earcha University of'«'isconsin, Madison, Wis. Bxoss,, Ixwt:v4 M.D.-Director of'Biostatistics, Roswell Park Memorial Inst'itute;. Buffalo, N.Y. Cooree,, Ti[F:oooxF;, \I.D:-Director„ National Heart and Lung, Institute, National Institutes of Health, Bethesda, Mdi EPSTE;rv, FREDERICK H., 3I.D.-Director aud Professor of Epidemiology, School'i of Publie Health, University of Michigan, Ann Arbor, Mich. FALK, I1:.~s L., Ph. D.-Associate Director for Program,, NationaU Institute of EirvironuientaiHeaitlh, Stiences„Research Triangle Park, N.C. Faa[t[tts, Be.v,ta:,[i.g G., Jr., '-\I.ID!-Professor of'~ EnvironmentaU Health and Safety,. Schonl,of Public Health, HarvardlUniversity, Boston, Mass. FH.tz[ER, Touu \L-?issistant Director, Harrard, Center for Community Health andl Medical Care, Srhool of Public Health, Harvard University. Boston, Mass. ti RdsTO:c, :lf.Ds-Associate Professor of Medicine; Head~ Division of' Gastroentierolugy, Uni~versitsof U'tah1Tedical School, Salt Lake City,, Utah. Go[aDsMrrH„Jotrs R., 3I.D: Head, Environmental Epidemiology Unit, Bureau of'. (lucupationall Health andl Environmental Epidemiology, Cali£orniaState De-partlmentl of'I't[bli;c Health, Berkeley, Calif. Goas,, GIo BATTA, J1.D.-Assooiat!e Scientific Director f'or Program, Division of Cancer Cause and Prevention, National Cancer Instfitlute,Bethesda, Md. I'droo[sy, IAx T. T., M.D.-Professor of Epidemiology, School of' Public Health, University of J37cliigan,,Ann Arbor, Mich. HoFFMA:r:v,, DzaTS[axy Ph. D.-Chief'y Division of Environmental Carcinogenesis, American Health Foundation,,NewYork:, N.Y. KELLER, :1NuaeW Z., D:JI:Dr-Chief. Research in Geographic Epidemiology, ti'et- eransA,dh[ihistratiouiCAntral Office, Washington, D.C. . IK'ass_1;Ea; JOSEPH B., 1T:D., Pi[. D!-Chief'of Staff and DeputlvDean for 3Tedical ?.ft'ailey„ The I"ritlzker School of'J'fedicine,, University of Chicago Hospitals and. Clinics, (:'hi~cago, Ilh KotBYE„ ALBERT C., Jr.,, M.ID. J.D.-Deputy Director, Bureau of' FoodS, Food and Dr[igA1Luinist'mation„ U.S. Department of Health, Educabion,and Welfare; i6'ashington, D.C. I+izu.c e[oLZ, RIelnh[in A.,, 1T.D.-JIe<lical Director, I7[stituteofl Respiratory ~ Dis-easev, Kettering Medical Center, I€etteri'ng„O'hio: Litcf•NFEUU, ABRAHAM, 3I:D.-Pcofeysor and Cliai'rman, Department of Epidem- iology, School of' Hygieneand' Public Health„ The Johns Hopkins University, Baltimore, Md. Jici:EAN, Ross. AI[D;-ProfesSorofl Medicine, Briwman Gray School of 3ledici'ne;Wal<eForest Uhih•ersit,v;,A4'inst'on-Salem„N.C:

.l'Ic-l1rLLx:v, GARnNEx,C., II.D!-Chief, Arteriosclerotic Disease Branch„i4'ational Heartand'LungInstitute, National Institutes of Health, Bethesda, Md. JI'AcJLkuos, BRrua, JI.D'.-Professor of Epidemiology, School of Public Health{, I[Iarvard University, Boston, Mass. JCEYEa;, \lieRY B., M.S.-Assistant Professor of Epidemiology,, The Johns ~ Hopkins University, Baltimore, Md. \liraHELL, ROGER S., 3T,D.-Chief of' Staff, Veterans Administration Hospital, i')enver. C'olo: lILRrHY, EoscoNn A., \1i.D., Sc: D.-Associate Professor of Medicine and BYO. statistics, The Johns Hopkins Hospital,, Baltimore, bld.. NEZ-resHEra„ PAUL, \I.D.-Group Leader, Respiratory Carcinogenesis;: Biology I)ivision, Oak Ridge National Laboratory, Oak Ridge, Tenn. PhEFEtiD:YRGER;, RA'LPH5., Jr., M.D.-Chief Epidemi..OlOgvSection, Bllreauu ofAd'ult Health and Chronic Diseases, Californiai State Department of! Public. Health, Berkeley, Calif. PeeERSOx, WILLIAM F., \I.D:-Chairman,, Department of Obstetrics and Gyne- cology, Washington Hospital Center, Washington, D.C. PErrY, TEroItas L.. \I.D.-Associate Professor of'3Tedicine and Head, Division; of Ptrlnrona:ry Diseases, University ofl Colorado Medical Center„Denver„Colo. RaLL., DAVau P.. '%'I.D:-Director, National Institute of EnvironmentaP Health Sciences, Research Triangle Park, N:C;. Rn,uscHeR, FRANK J., 1I.D.-Di;rect'or; National Cancer'Institute; National Insti- tutes of'Health, Bethesda, Md. RErvKE, WILLIAM A. Ph. D: Professor, Department of'International Health, The Johns Hopk:insUniversity,Baltimore, 3i'di RFSzenrr, ATTtr.ro D., Jr., '-NT.D.-Professor of Medicine, PulYnonarv Disease DiFision„ Uni'versity o£Utah 3Iedical Center,, Salt LakeCity, Utah. RoRiss, MORTON-Chief of StudS,, Design„ and Analysis Staff, R'egionali bTediicaI Programs Service; Health Services and', 'Mental Health Adtnini'stration, Rock- ville; Md. SAFFioTTI,, UhiRExTO, Di.D:-Associate Scientific Director f'or C'arcinogenesis; Division of' Cancer'Cause and Prevention, National Cancer Institute, National Institutes of'Health, Betliesda, ntid.. ScHUMAx, LEOSARn! 3T., MID:-Prof'essor and Head, Division of Epidemiology, S'choot of Public Health, ti niversity of '.Niinnesota, 3linneapolils, Minn. SHatirxiN, MICHAEL Bl, Jf.D: Professor of Community Medicine and Oncologyy and Coordinator, RegionaU 3Iedical ProgFam; University of Californiai at Sani Diego, La Jollas Calif. STA11LER;, JFRE-MiAH, M.D:-Professor and Chairman, Department of Community Health and Preventive Medicine, Northwestern: Universi'ts,, Chieago,, Ill. Va-Ni DLLRE-,, BErJAariN L., JL.D.-Ptofessor of Environmental :lledicine,, Insti- tute of Environment'al Medicine, New York, University Medicall Center, New York,, N.Y. WYNDER, ERNEST L., 3I.D.-President,, American Health Foundation, New York, N.Y. The following additional staff members of' the National, Clearinghouse for S'moking~ and Health: contributledl to, the preparatfion of'this~ report :~ Richard~ H. Amacher, JTarjorie L. Brigham. E~mi1 C'orwiai; Lillian Davis,,G'srtrude~P. Herrtna Rbbertl S, Hrtit'chi~ngs, Jennie~~ '.%L''. Jennings, Nancy ~ S. Johnston, Dan, Nemzer, Mildred Rit'chie, James A. Robertson, I)onald R. Shopland, and Kathleen H. Smith., xi

i

CHAPTER I Cardiovascular Dise~~ases~~

Contents Intlrodkiction-------------------------------------------- Coronary Heart Disease Epid'emiologicad' St~udies. Smoking,and Certain Risk Factlors---_--__------_- P1ood Lipids~----------------------------------- Electrocardiogram-------------------_----------- Experina;en,tal Studies Cigarette Smoke-------------------------------- Nicotine---------------------------------------- Carbon Monoxide ------------------------------- Smoking and Thrombosis------------------------- Cerebrovascular Disea.se------------------_-_-_----------- Peripheral Vascular D2sease------------------------------- Summary of Recent Cardiovascular Findings------_-------- References--------------------------------------------- List of Figures Ph:ge 3'. 4 11 12 13' 15 17 19 19 19' 23 24' Figure 1. Age-adjiusted incidence rates of CHD' by body weight and cigarette smoking, (white males)--------------- 6: Figure. 2.-Age-adjusted incidence rates of CHD, comparing farmers who smoke cigarettes with nonsmoking farmersL -__ 7 Figure! 3.-Standardized mortality ratios for arteriosclerotic heart di'sease: for males and females by age at ini'tiatfion of cigarette smoking (Prospeetive study 1966-1970)--------- 8' Figure 4.-The effect of' cigarettle smoke inhalation on the ven- tricular fibrillation threshold'. (VFT) of'~ normal dogs and dogss with experimentally produced acute myocardial infarction (A='l2I) ------------------------------------------------ 141 Figure 5.-Effects of smoking five consecutive cigarettes on plasma nicotine concentration--------------------------- 16 Figure 6'. Relative risk of developing, arteriosclerosis oblit- erans (ASO). fbr males by amount of cigarettes smoked_-- 20 F~igpre7.-Relative risk of developing, arteriosclerosisobli't- erans (ASO)! for females by amount of cigarettes smoked--- 2'1. r

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Introduction In the United StatesT eoronaryy heart disease (C1iID) is the leading cause of death and istiie, largest contributor to excess d'eata'hsamong cigarette smokers. The following is a brief summary of the major relationshi'pbetween smokingj and cardiovascul'ardiseases, as outlinedd ini previous reports of the heaTt'h consequences of' smoking. (62, 63,. 64 , 65; 66, 67') .. Many prospective and retrospective epid'emiol'ogical studies have identified cigarettesmoking,elevated serum cholesterol,, andl high blood pressure as major risk factlors forthe development of coronary heart disease: Cigarette smoking acts independently of and synergis- ti~cally.with theother CFiiDrisk factors to greatly increase the risk of developin~gcoronaryheart disease. The risk of develbping CHIDforpipe and cigar smokers is much less than it is for cigarette smokers, but'morethanit.isfornonsmokers. In theLinitedl Stat'es,cigarettesmoking can be considered the maj;or cause of cor pulmonale since it is the most important cause of chronic nonneoplastic bronchopulmonary disease.Autopsystiudies have, d'emonstrated that aorticandl coronary athero-sclerosis are nlorecomm~oni and sev.ere;and myocardial arteriolle wall thickness is greater, in cigarette smokers than in nonsmokers.. Those who stop smoking cigarettes experiencee a decreasedl risk of' death from coronaryy heart disease compared to that of continuing, smokers.. Experimentlal studies in liumans, andl animalssugge5t thatcigarett'esmoking, may contribute to the development of CIiD through the action of~ several inclependent~ or, complementary mechanisms: The formationi of significant levels of carboxyhemoglobin, the releaseof catecholainidies, inadeqpate myocardial oxygenation «-hichmay result from a number of'mechanisms„and an inereaseiniplatelet adhesiveness which may contribute to acut'etlirombusformationi. Thereis,evidence that cigarette smoking may accellerat~e~thepathopliysiological changes of' preexisting coronary heart di'sease~ and thereforeeontributes to sudden deathfrom CHDs. Recently publishedl epid,emiolbgicalI, autopsy,andl experimental in- vestigations have added to the understanding of the associ'ation be- tween smoking ancll cairdiovascular diseases. 495-028 ' 0-73-2 1'

C©rranair,y Heart Disease Epidemiol'ogicaZ Sturi'ies SMrOItI,NG AND CIIRTAIN RISK 1' ACTORS A prospective epidemiological studyof'th~e, factorsasseciatedwitheardiovascular d'iseases: wasconducted among the4,8•I7 white and 2,434black men an~d women of' EvansCounty;, Ga. Tlteinvestigati~oll was initiated with a private census and preliminary examinations beginning in 1960. Followup examinations werecondtlcted after 7 years., C'assell (l3) reported that high blood pressure; elevated serum cholesterol, and cigarette smoking were major ri'sk factors for the d'eveloprnent of coronary heart disease. Increased body weight,, an elevated hematacrit,,and ECG abnormalitlies, were: additional f'actors that were:associated with elevated CI-DDrates.A significant finding of this study was the very low prevalence andl incidence of coronary heart disease (myocardial inf'arction and'anginai peetoris), in black men. The age-adjusted prevalence rates among black men were only half'those of white mem The study showed that blacks were affected' by the various risk factors for CHD'D in a similar fashion to whites but at a lower level of disease. This appeared to be true for anyy level of any risk factor or any combination of risk factors. Greater physical activity of'blacks as compared to .tih~ites appeared to account for part of the observed dif- ference in rates. In this study, subjects were classified on the basis of their smoking histor3~~ at enroldment and both current smokers and exsmokers were considered smokers, Both black andl white : male smokers had ah~igher 4

incidence of'CII'D than: did nonsmokers; but white males had a higher incidhnce than blacks whether they were smokers or not. The age- adjusted~ incidelicerateforwhitenonsmokers was 52:7 per t~housand' conipared to, 9.8 per thousand' for black nonsmokers, White smokerss had' an incidence of 101, whereas the rate in black smokers was only 32.5. The prevalence of CHD increased with the number of cigarettes smoked per day in both groups. The combined effect of', body weight and cigarette smoking on the incideneeof C'HD wa& al'so: . examinedl (26)1. The "Queteletindex'" "was used'' todetern2inerelativeweight: The risk of' developing CIdiI), did not change .vithincreases in relativeweig}itamong nonsmokers,, butt smokers experienced a substantial risk of' cle.velbping CI-II) withh increases in weight (fig. 1). The relationship of smoking to occupat.ion and! CHD was examined! (14). Farmers who performed sustained physical' activityhadi lower rates of' ChID than nonfarmers. Figure 2 shows t.ha,t, while smoking, increased the ri'sk of CI-ID' in both farmers and nonfarmers, farmers' had lower rates thani nonfarmers whether or not they smokedL 1 Quetelet index= aeight X100. height,2

Figure 1.-Age-adjusted incidence rates of CHD by ' body weight and ' cigarette smoking (white males). 160' 150' 140 ' 130 120 1' 10 100 90. " Rate 80 per 1',000 70 males. 60 50 40. 30 20. 1'01 0~l "Distribution by weight Nonsmoker ' Smoker 80 51 Lower third (lean) 90 30' Middle third 150' 64 Upper third (obese) Number 90 183 99 161 127 1119 Cases 5 15 3 14 16 9 ' Smokers excliading ex-smokers. 47 months fbllow-up period! I 'Based on Queteleti index:. SOURCE: Heyden,,S., et al. (26). 6

Figure 2:-Alge-adjusted incidence rates of CHD comparing; farmers who smoke cigarettes wlt!h~nonsmoking farmers. 200. 150 Rate per 1,0000 males 100 50 Farmers 98.3 Cases . . . . (8) (9)' Nonsmokers 0 SOURCE: Cassel, J!. C., et al. (14). Nonfarmers 158! 2 (11) (39) Smokers and Ex-smokers j i Hirayama (27) reported 5-year follbwup: data on smoking in rela- tion to death rates! from: a large prospective epidemiological study of 265;1118' men and women in, Japan. This investigation was the first of its kind to be conducted in an Asian population. During the followup period, 11,858 deaths occurred during 1,269,382 person years of obser= vation. Male and female cigaret'te~ smokers experiencedl higher mor= tality rati,esfrom, arteriosclerotic heart disease thand'i'd nonsmokers.Among cigarette smokers, the mortlality ratios for arteriosclerotic heart di'sease were 1.56' (P<0.6001) for men and, 11.44 (P<0:05') for women. Dose-response relationships were found for both men and women as measured by the number of cigarettes smoked perday and age at initiartion of'smoking ( fig: 3) 1.. 7 M 4

Figure 3.-StandardiPed mortality ratios for arteriosclerotic heart disease for males and females by age at initiation of cigarette smoking, (Prospec- tive study 195G-1i970). 2.09 2.00 -1 11.50 , Mortalityy ratia 1.00 ~ 0:50 -i 0.00 1.00I Plge at start Mon+ ofl smoking, smoker SOURCE: Hirayama, lI. (27). 1.52 >24 20-24 <201 Gordon, et al. (22, 57), in a further analysis of the Framingham data,~considieredbotli by ~univariatle~and mu~ltivariate~analysi~sthe relit-~ tion of certa~inltey-~characteri~sticsto the~devel'~opnient~of coronaru~heartl disease. The~ characteristics were: Iligliiblood~~pressure, e~lel-at~~edlserumm cholesterol,~ eigaret~te~ smoking,,lefti~ventricular hy-.pert~rroph~y~ diagnosed by ~ electroca~rdiograQn,~ andl gliicose~ int'oTerance:~ Cigarette srnoking~ emerged as one of~ the i'rnport'ant risk~ factors for tll~e~ clel-elbpment of corona~ry ~heart~ disease. There was~ a strong association between c?iga, rette smoking an~d~ C'FII)~ other~ than angi'na pectoris, particularly among tiroung~ma~Ue and fema~le~sm~oker.s: The~relatii.Te role~~of~cilgarette~~ smoking as~ a risk~ factor was~ emphasizedi by-~ mliltivar.i'ate analysis. C~igarette~smok~~ing «as~ not~ as~~strongly ~related~ to~~C'UD in women as:.it~t was in menL This may ~ hai-.e~ been in part~ due~ tlo~ tlre~ fact~ that there~ are~ fewer~lt~eavy~ smokens~~among~ «-omen~y and~ wornen tend to~i~nhal~e~sniohe, less than men. Kagan, et aIL (',3~1)~ reportedlprelirninar.y ~findings from~t'he4lonolulu Heart Study. The effect of'migration on dietary patterns and the inci- dence of cardiovascular di6eases~iniaicohort~of ineniof' Japasr~ese~ ances-~ tr•y ~ born between 1900 and 1919. ~who~ were residents of Oa~~h~u in 1965, ~ was ex!am~i~ned in this lsroshective~ stnd~y. I)iiriiig ~~ the 2~ years of~ fol- lowup, lowuh„ 101 men developed~ C'fII)~ in the~ population of~H~,U06 ' men i1ri-

le for apec- k f tially examined~, A significantt relationship to~CI+ID'~ was found for~ the~e following risk factors : Cigarette smoking, elevated systlolic and di,a- stolic blood pressure, increased serunb cholesterol~ triglycerides or uric acid,,and various measures of obesity. Using data from~ the International Cooperative Study on Cardio- vascular Epidlemiol'ogy~~,, Keys, et al., (31~) calculate the~~ probabilities~~ for men aged 40 to 59 to develop coronary heart disease in 5 years. The~ authors notedl " *~ *~~ that tlhe~ relative~ CZTID~~ risk~ of different men within a given population iswell predicted from the results of' the~mu~lltivariate~ analysis of~ t'he~experience~ of'men in~ other far-distant popnlations differing in soeioeconomic, circumstances, language, and ~. ethni~c! back~ground."~ Althoughi the~ CHD~ incidence rate~ of European men was~~ about half that of the~ Americans, the~~ fact sti~111 remained that~ inv~est~igation of the four variables~ (~cigarette~ smoking,, age,~ systolic blood pressure, and cholesterol) was sufficient to identi 'fy men whose~ 1'ikeliliood o~f~ dying of CHD~~ or~ having a~ definite niyo,, cardiail infarctlion within 5years .vas~~greatly ~~ abov~e~the~average. I?'tinsar~~ (51), reported 10-year follativup~ data oni the cohort of~ men in Finland who ~were~~ pa~rt~of the~seven-countrystudy~of coronary~hea2aiy disease, confirming that ~cigarett,e~smoki'ng was~a ma~jor risk factor for ~ CH'D.~ The authors reported a 1.7-fold increase~ in CHD' mortalit'y among cigarette smoker.s: They estimated'. that 1,700 excess CHDD deatihs~~ occur each~ year among ci~garette~ smoking men in~ Finland. Kozareviic,, et al. (38) reported the results of the initial prevalence survey~ and the~ 2-year inciden!ce~ data from the Yugoslavian, study~ of cardiovascular disease. A. total of 11,1211 men between the ages~~ of 35' and 62! were~~ examined in; the~towns of Tuzl'a~ and Remetinec. C~rit~eria~ for the~~ diagnosis of~ CHD were based on obj'ectiv~e electro- cardiographic cnrdiographic findings of myocardial infarctiony left bundle branch block, or sudden death. A very low prevalence of myocardial inflarc~- tion was initially found, and only 36 new case& of CHD: developed over the: 2-year period~L The subjects~ who~ developed CHDD smoked cigarettes~ at~ about the same level' as~ the ~ total study.~ population. T'he~ annual average incidence rate ofl acute coronary heart disease was about 1.6 per 1,000~~ among, both the~ smokei.•s~~ andl, nonsmokers. The ~CIiD ~ incidence~ rates~ found in thisl ugoslav~ian study are appreciably below t~hose~found in tlhe~LTnited States. Comstock (T~6) ~~ examiiied the~ associa,tioit between water hardness~~„ v~airious~ other~ environmental factors i'nchrding cigarette smoking, and death from CHD~. A total of' 189 ~~ deatlrs~ from CII'~D, occurred iiii the~ population of Washington C'orulty~., Afd..~ i~n the~ 3~-y-ear,periiod follotiv- ing aicensus in 19fi.3.~For each case, tw-~o~controls~were randomly sel~ectedd fi•ont the ce>>s~us lists and nbatclded for~race;, sex, and year of birth. T'he~ relati~~e ri'sk~ of'('III)for all smok~~ers~ was 1.;i coiupa~red to~nonsmokers~~ (P'G0:05)~. This rellativee risk among cigarette~ smokers~~ was~ dose~-~

related; persons smoking more than two packs a day 4.ad the highest risk of' CHD. Nla significant association was found between CHD and water hardness. Casciu„etal. (12'),reportedl the prevalence ofcardiovasculardiseaseamong 4,668I miners on Sardinia. Smoking and drinking habits, bloodd pressure, and~ heartratles«ere recorded. Smokers had higher rates of CHR than nonsmokers,, and a dose-response was noted with the number of cigarettes smoked per day. The prevalence of'myocardiaii in- faretion was 0.9 percent for nonsmokers,, 1.62 percent for smokers of'10 or less cigarettes, 2.34 percent forsmokers of'111 to 20 cigarettes, 9.9 percent for smokers of 20 or more cigarettes a day„andl 1.42 percent for cigar or pipe smokers. When cigarette srnokers~ were grouped by alcohol'' consumption, no sign:ificant difference was found in the prev- alence, of myocardial infarction between drinkers and nondrinkers. Kornitzer;, et al. (35, 36, 37) examined the prevalence o~fCHDini 566' male bank employees aged 40 to 59 in Brussels. They determined' an indivi~dual''ssmoking, history, blood lipids, ECG'y peak flow rates,relative weighti, skinfol'd! tlhickness; and blood pressure. The preva- lenceofpossibleCHD, as determined byECG' and C'HDhistorywas'. 7.1 percent! innonsnlokers, 11.6' percentlin cigarettesmokers«-ho~ in-haled, 6.9 percent in, cigarette smokers who did not inhale, 10.6 percent' in smokers of pipes and cigars, and 15.5 percent in the ex-smokers. Among the various risk factors examined, the strongest associationn was foundl for elevations in the serum choIesteroL and the other blood lipids examined, Weaker associations were found for increasedi rela- tive weight, high blood pressure, and tobacco use.. Agnese; etal. (2): examined 265 patients in Italy aged 201to 65 years whohad, myocardial ischemia. P'atientswerematched «-ithi an equal number of control'sbyage: A number of riskfactorsf'or CHD were measured in bothgroups.Cigarettesmoki'ngand elevat'ed serum cholesterol were identified as major risk factors for CpID; particularly for individualsundhrtheageof50. Boudik(10)~ found' the prevalence of myocardial infarction to~ be sign,ificantly (P'<0:001) higher in cigarette smokers than in non- smokersin apopulatioitof 8;292Czechoslovakianimenibetween thea~ges ~: of 52 and 67: Storch, et al. (60)1, Estand7a Cqno, et al. (17)1, and' Jaknszewska (J0)1„instudilesinCermany; l'Ic$ico,,andi Prnlandlof'CHDin indi'vid-uals under the agc of' 40, reported that cigarette smoking was the dominant factorini the development of'CHIDin tliese patients. Golovchiner(21)fiound: cigarette snloking to be a significant f'actorr inthed'evelopment of myocardial infarction in ai study.of 530 patients with C~fID in Leningrad hospitals. no

khest land >ease lood ,ates - the 1 in- kers b'tes, cent l' by pev- ;ers. )' in. tsed ~tesi va- Fas, I}n- bnt ~~-s. i',on iod aa- trs aa,l 9re tm . rly be in- ,,es ka d- ie. Three studies without control' groups from New Zealand (59), epall (I~i'), and India (58) reviewed the prevalence of various risk N factors, including cigaret't'esmoking in populations with documented C1I'D: BLOOD ~ LiruDs In most of the following studies where the effect of cibarette smok ing on blood lipids was examined, there .j-as no control for dietary factors that may indehendently atfectserum lipid levels. Schwartz, et al. (56) examined serum lipids in relation to smoking habits and relative weight in 7,972maleemlpl'oyees of the Parisian Civil Service in the city of Paris. Cigarette smoking, was associated with a slight but significant (P'<0:001~)i increase in serum cholesterol.Theauthois~ found a positive correlation between increased relative weight andd seruin ch~o1'esterol' levels, and a negative correlation between rela- tii'~~veweight and smoking habits.These factors would operatednsuch a way as to reduce the apparent effect of cigarette smoking on the cholhsterol levels. After controlling forrelat'ive weight',however,,theinvestigat'orsfound ai sigpiff'cant(PG0:Q{)1) positiverelat,ionship~ be- tween smoking and serum cholesterol. In a study of various factors in relation to the mean serum choles- terol~ Pincherle (48) examined the followingparameters:blood pres- sure, height, weight, and skinfold thiiekness,X-rayfi'nd'ings ofl the chest andl abdbmen„ the electrocaraiogram„ and smoking, history; 10;000: Britishbusinesse.xecutives~bet'ween the ages of 25 and 65 wereexamiired. A significant association «°asfound betweeni elevated serumcholest~erol, obesity, elevated systioli~cblood pressure, i'nadequatleeYen- cise,radiogr.aphic evidence of art'eriall calcification of theili'ac arteries, and certain other factors; The increase observed inimean serum choles- terol with increasing number of cigaret'tlessmoked was notst~atisticaldys ig i1 ificant. Romslo (53) studied thedistribtltioni of serum lipids in 324Nor- wegian military recruits. Cigarettee smokers had ai small but insignipi- cantiiicrease in serum triglycerides.-No ellevatioir.r.as found fbrserum, cholesterol. TI he subjects were young, and most smokers had onlyy smoked for a few years. Burney and Enslein (111) ~investigftited changes in clinicall laboratory tests as related to agzitg andl smoking in a 5-year study of 5©2' healthy niale veterans. Iit was found that five variablles were needed to predict age-related changes in those over 50. These were: fasting blood glla- iu .. . le,

cose, 2-hour post-glucase blood sugar, total serum protein,,hemoglobin,, and cholesteroI esters., No significant diifferences, in the laboratory data between smoking and nonsmoking subgroups were found. Vlaicu, et al. (70)' examined the interaction of' cigarette smoking with blood pressure anff serum lipids in 100 patients with angina pec- toris who were between the ages of'40~and 59. Half'tHe patients were smokers using more than 25 ~ eigarettes~ a ,day~. The,smokershad lower serum~ lipids and lower blood pressure t'Iian, the 50 nonsmoking pa- tients with angina pectoris. Miturzynska-Stryjecka, et a1'. (43)'~ found that cigarette smoking immediatelyfoldowinga fatty meal did not significantly alter the serum free fatty acid, esterified fatty acid, cholesterol,, or plasma tur- bidity levels over control values. Ciampolini,, et al. (15)examine'd the e#$ectsof cigaret'tesm:oking on blood lipid values in 10 healthy volunteers between the ages of 20 and 40. Cigarette smoking resulted in a prompt rise in free fatty acids and a delayed rise in serum triglycerid'es. The relationship between cigarette smoking and changes ini various serum lipiidl levels has not been clearly determinedlStudies in this areaa continue to present confllictingresults: E L E C'rROCAEtDI OG4RA M IV,y?sokinski (76) examined t'he e#Pect of'smokiaZg on certain param~- eters of cardiovascular function in 100 healthy nonsmokers and 100 healthy smokers who were military recruits 19 to 2.5 years of' age in Poland. Significant prolongation of the QRS interval (P<0.001), flat- tieningof tllie! T' wave,and ST segment depression fo11owingexercisewere seen more frequently in the smokers than in the nonsmokers. Van Buchem, et aI. (69) examined the occurrence and significance of egtrasystoles and' conduction disordlers in 760 healthy Dutch men between the ages of 40 and167 who, were followed far 7 years! The pres- enceofextrasystoleswas~not correlated with cigarettesmokingore]e-vated serum, cholesterol and was not associated with the development of'CHD over the 7-year period. Kattus, et al. (33) tested 314 healthy males 23'to 82'years of age for ischemic ST segment depression on the ECGI d'uringor after submaxiL mal exercise. The abnormal STsegnentdepression identified in301 subjects was correlated signifi'cantlywith elevatedl serumcholesterolym abnornial'' resting ECG,, and a history of! cardiac symptlomsbutnot with smoking,,h:ighbloodh pressure., physieali inacti~vity;or faJnily1iis-tory ofcoronarydhsease. 12

`globin, ry d~ata hoking ia pec- 8 weree lower rg pa- toking, er the ia tur- ~ ~ oking iof20 ~'a,cids irious I' area ram- 100 flat- rcise ~nce Imen ires- ele- tientt for tlgi- 30' roly~ !iot [ `'an Buchem, et al. (68) f'ound no significant association between ci~garette~smok~~ing and i~schemic~ST seg7nent~depression on: ECG~in 120~~ apparently healthy~ men who~ demonstrated this~ abnormality among~ a~~ population of 760 men 510 ~to~~ 70 ~ysars~~ of age~.. Ex pe ri'rrxental ,S'tudies CIGARETTE SMOKE Studies in Man. Summers; et al. (61) examined the effect of cigarette: smoking, onn cardiac lactate metabolism in 15 patients with, severe angina pectoris who, had at least 75 percent obstruction in each of two: or three major coronary vessels. All patients had been long-tlerm cigarette smokers. Cigarette smoking prod''ucedl increases in heart rate,, systolic aortic pressure, tihesystolic ejectioni period per minute,, and thetension-tim~e~e index per minute, but lactate, production was not induced by smoking, ini any patient who did not also have lactate production in the control state. In three patients with lactate abnormalities prior to smoking, inhalation of' cigarette smoke sustained and slightly aggravated this condition. Studies in Animals The effect of' inhalation of cigarette smoke on ventricular fibrillation threshold (VFT) in~ normal dogsand dogs with~ experimentally pro- duced acute m3rocardh'a11 infarctioni was studied by Bellet, et al. (6).. Mongrel dogs weighing 25 to 30 kilograms were anesthetized with sodium pentobarbital, and respiration was maintained using a Harvard ventilator~attached tlo~ an endbtracheal tube. In one~group~~ tli.e~electricale impulses used to, precipitate ventricular fibrillation were delivered through the chest wall, and in another group the impulses were deliv- ered directly to~, tlhe~ heart through electirod'es implanted in the ~ myo- cardium. cardium. The: experimental group of dogs were exposed to the smoke o£' three~ cigarettes over a~ 10-m!iinute~~ period. Each cigarette~~ contained approximately 2' mg, of nicotine. With, acute myocardsa~ll infarctiony, th~e~ VFT was significantly (P<0.001), decreased, but in both the normal and myocardial i~nfarction groups cigaretite~ smoking resulted in a de- crease crease in VFT that averaged 30~ to 40 ~ percent of~ tihe~ control val'ue~ (fig~.~ 4~)~.~ Th.ese~ findings are~ of interest in view~ ofl the increased inci- dence dence of sudden deathi observed among coronary patients who are heavycigarett'e smokers (66). T3

Figurei 4.-The effect of cigarette smoke inhalation on the ventricular fibrillation threshold (VFT) of normal dogs and, dogs with experimentally pro- d'uced acute myocardial infarction (AMI). 0.7 0.6 VFT Watt-sec: 0.5 I I 014 0.3 0 SOURCE: Bellbti s;,,et al. (6). 0.8 . .:~ « Y . ~ Smoking (pormal) , •.,........ ,....... Control (AMI) .~ ., ., ., •~. SmoKinB~( , `•. .. . 15 30 45, 60! 75 90 Time in minutes following cigarette smoking The effects of passively inhaled cigarette smoke on several measures off cardiovascul'ar function ini treadiniIl-exercised d'ogs were exarnined' by Reeceand' Balll (52,), The experimental dogs were trained on t'he treadmblll for approximately 1 year before exposure to, cigarette smoke began. Each dog was passively exposed to the smoke of' 36'6 cigarettes over a 3-hour period 5 day s a week in a 2.2 m.3 chamber ventilated at the rate of'sev.en exchanges per hour., The dogs were exposed to thnss cigarette smoke and were continued on their exercise program for an additienali year. Exposure to cigarette smoke was associated with cadiac enlargement, ST segment depression, and an! increase~ in post!- exercise serumi lactate concentrations, 1'4

NlMion y pro- I ~ ~res ~~ed the ~oke ttes Iat his' ~an rith nst- I NICoTIBJE'. Studies in 1VIan Isaac~and Rand (28) have recently described a method for the assay of plasma nicot'ine. An alkali flame ionization detector was used with a, gas-liquid chromatograph. The test is sensitive to i ng./ml. of nicotine in a 2'.5' ml. sample; 30 minutes elapsed between end of one cigarette and start of next. Blood samples were taken before smoking andl at 5, 10;,and 30 minutesaf'ter the last puff of eachcigarette. P'lasmanicotinelevels increased rapidly during cigarette smoking (fig. 5). The post- smoking decay curve consisted of' two: component&: an initiall rapid phase which may be due to the uptake of nicotine from the blood by various tissues, and a slower phase which may represent metabolism and excretion~ of nicotine. Some accumulation of plasma nicotine oc- curred dnring a day of smoking, but the background level never ap- proached the peaks attained during and immediately following active cigarette smoking. TI he rate of elimination was rapid enough to prevent. any appreciable accumulation of'nicotine from 1 day to the next. The development of' sensitive tests of'~ plasma nicotine levels will allow a greater understanding of various dynamics ofl smoking. Inhala:tion patterns can be object'ively measured, and the role of nicotine in habituation to cigarettes can be evaluated.. rs

Figure 5.-Effects of smoking five consecutive cigarettes on plasma nicotine concentration. 60. 50' Plasma nicotine 40' (ng,/ii 30: 20 10. 01 Smoking period . 0 1 2' 3 4' 5 Time (hours) SOURCE: Isaac, P. F:, Rand; Wl. J. (28). Studies in Animals The effect of nicotine orl regional bloodi flow inn the canine healt was esaminecli by ~ llh,thes and Rival (/~l~). The effects of nicotli'Qle nere~ examined ill norma~llheants'~and after'partial coronaryalrtiery,~occlilsian. Unde~ll~ norlnal~ circzlmstances.~ as~ well as aft'er~ infusion of' nicotine ill ~ normal I1~earts,~ the subendocardiad portion of t'd>,e~ myacardizlvn had a 9~.5~-percer~it~ gx•eaker~ capilla~ryr floer~ than t~he~~ s>;l£)epirardiil~ fraction. Partial Ii,),~ation of the coronarv arteries resulted i~n a22:8,perceiit~ rediiction iili left ventric.ulalr blood flow; llowerer,~ the snbendocairdiall portion reinained S;hz~~ 1>erccnt~ hig-her.~ than in the epicardinnl. After . 16 tv tc I l7 tt tl 11i dWO

coronary~ art'ery~ l'igation„ an infusion of~ nicotine~ resulted in ai signifi- cant ( P<~0~.001)~ reduction ih~ t'he~ capillary flow ~ of l the inner portion, of'~ the my.ocardiunl relative~to theoutEr part. Bhagat; et al. (7) examined the effect of' cigarette smoking on thee cardiovascular system of d'ogs„ various pharmacological agents; e.g., tyra~mine~hydrochloride,, propranololL and chlorisondamine;~ were~used to modify~the evokedl response to tobacco~ smoke~ in order to clarify;~the~ mechanisms,prodncing the observed effects. The~authors~concliudecl that the more important actions of nicotine include a stimulation of sympa- tlietic ganglia and the adrenal~ Inedul'la and the~~ release of catecholk- niines~, £t°ont sympathetic nerve~end'ings and chromaff`iit tissue. Bing, Ilellberg„ and associates (8; 25) studied the microcirculati'on of the Ihft~ atri~um~ of~ anesthetized catl& by~ direct, visualization using iii~gh~-speed cinematography. Nicotine injections~produced a slight but insignificant increase~ in red cell vel'ocity~~~ in the~capildary.~ eircu~lati~onn clnring both~systol'e~and di'ast~ol'e.~ The effectls of nicotine on the biosynthesis of various lipidi fractions in the aorta of dogs were~studiedby~KtYpke~ (.fO). After nicoti~n~eadmin-~ ist~ration. significant reduction occurred in tlie~farmation of free (~1~4C)~-~ sterols, while elevated levels of unesterified fattly, aci~dswere~~ formed in Hie medi~a, and iiitima of~ these~ in vitro~~specimens. 'I`he~ author sug~~gestedd that nicotine may impair oxidative enzyme systems possibly by daunag- ing the rnit-ochondriallstr.uctures, thereby leading to lipid accuQnulationn in the aortla. Schievelbein andl Eberhardt (5:/'), reviewed the card'iov.ascul'ar~ actions~ of~ niicotine~and smoking.~ I I . CARBON MONOYID£ Studles in Man wasVere lion. e in llCll }t ion. "ent lial fiter Numerous~articl'es hav.e~~recently~been published on the~various,effects of carboni monoxide on man and anirnal~s~~and are of part~icu~lar interest because of~ the~ rel~ativ el~y high, leveis~~ ofl carboni monoxide foundi in the main and sidestream smoke~ of' cirarettles~. O'nly~ those~ arti~el~es~ are~ dis~- cussedliere whsch, contain data on the~cardi~o~vascular~effects, of carbon mmnoY lde. Aronow and I?okaw~ (3) ; examined' the effects, ~ of smokiilM-induced carboxy-hemoglobi~n levels~ on angina pect~oris in 101pati~ents~with CHD~~.. The~ time ~ to the onset o£'anginai after.~snioking ~ a~ noniicotine~ e.iga~rette~ was~ measured. Tf ach, patient hadl smok~ed more~ than a pack of ciga-~ rettes a da~y~ for at least 19 years and had a, classical, history of exer- ticonal dssl~~~nea. Smokinr nonnicotine ci~(rarettes failed trn~ resul't'~in an elevation of the~bloodl pressure or.~the heart, rate~~;~ however, there was,a. 0 17

significant (P<0.01) increase in C'OI3b levels to about 8 percent. This resulted in a significant decrease in exercise performance compared to the nonsmoking, state ( P'<0.01i) . This eonf rms that carbon monoxide can compromise oxygen deliveryy independe.ntly of the effect of nicotine. 1liaximal oxygen consumption under conditions of carbon monoxide i~~ntloxication~ were~studied in human volnnteers~ by~ severa~t authors (49, 77, 72). COpIb~~ levels ~ of~ 16 or 20 percent~ resulted in~ a proporti'onate~ reduction in maximal Oz consumption. The volunteers responded to the decrease in oxygen-carrying, capacity of the blood with a tachycardia and relative~ hyperventil'at~ion,du'ring~~ moderate~ exereise~.~ Carbon m~on-~ oxid'e, producesa limitation of' an ihd~ividua~lFs maximal~~ oxygen con~- ~ sumption by~ deereasing~~ tihe~ availability ~ of ~ oxy gen s~uppl ied under c,on-~ ditions of increased oxygen demand. Heistad and Wlleeller (ZIf)~ reported that the~ hy~poxia~ induced by~ carbon monoxide inhalation caused' an inhibition of reflex vasocon- stiri~ctor~ responses despite~ tlie~ presence~ ofl normal arterial oxygen tension. Studies in Animals The effects of carbon monoxide on coronary hemodynamics and left ventricular function in six u~nanesthetized dogs~ were studied by A~dams,~ etal. (1). The~anirnals~ reactedlto a 5'-percent carboxyhermgl~obin level, w~ith~ a 14~-percent~~ increase~ in corona~ry~ b~loodi flow. T«-enty~ percent C'O1Hb~ resulted' in a 57-percent increase in coronary flow and slight increases in heart. rate and stroke volume. Birnstingl', et al. (9)' exposed' y oung adult rabbits to 400 p.p.m. CO, for periods that~~-aried from 6 to 14 hours. The mean COIIb level af.terr a~ series of~ 2s ex!posures~was 17 percent. A qu~~ali~tlative~ iilcrease~ in plate- let stickiness,,as measured by the bead-column method, developed dur- ing~ the 24-hour period following CO exposure. 71'he~aut-laors~observed that, this " * * provides a possible mechanismi for intimal deposition and' a further link in~ t-he, association between habitual smok~~ing, and' peripheral vascular d~isease."'Ast~rup~~ (5)~ foundltlie cholesterol level in the aorta of rabbits e<xposed' to a low level of'ca .bon, nionoxide for 10 weeks to be;~ onit~he ~average,, 2~~.5~ti mes 1igher t~h~an~ in the control rabbi'ts~.. Both the experimental and control groups~were~maintai~ned'orua higli~- cholest!erol~ diet. Oibbons~ and 1litropoulos~ (2r)~ reported that CO~ inhibited cho~~- lesterol~ biosynthesis with accumulation of' lanosteroI and 24.25-diliy-~ drolanosterol in an ivi vitro system of rat liver homo~;enates exposed to a 00-percent CO' atmosphere. It was felt that CO may have in- Huencedl an early step in the oxidative~ elimination~~ of the~ 1~-1«-methy] group~oflanosterol. 118

~4t. This pared' tio pnoxide iicotine. Dnoside brs (.¢9,rtionate id tothe ycardia m mon- en con~- ler con- tced b3~• asocon- DxygEIIi nd left' ldamas„ rl levell lercent i slight m. CO I after plate- d dur- served mit ibn Ig and. ~vel in for 10 ibbits` higli~ t' cho- -dihy-~ posed. :e in- ethyi! SDDO$ITTO, AND THRObiBOSIB Previous reports of the Surgeon General on smoking and health (62, 63y 64, 65., 66) have reviewed the effects of'smoking on thrombosis. Recent reviews and studies have not thus far yielded a unifying con, cept of the effect of smoking,on thrombosis (4;18,1'9,,32, If5):. Cereiirovascwllar Di~sease Paffenbarger and Wing (46)' examined several precursors of- non- fatal stroke in 102' patients with this disease in a population of 10,327 men who hadl attended Idarvardi TJniversity between the years. of'. 1916~ and 1940 and' alsoret~urned' a self-administered questionnaire in 1966. EExamination of university medical records of' these former students revealed four characteristics present in youth that predis- posed those individuals who were more likely to experience a nonfatall st'roke in later life. Theses f'actors were : cigarette smoking,, elevatedd blood pressure, increased weight for height, and short body stat'ure.. The age and' int'erval-adj psted incidence rates per 1,000 were 10.1 for nonsmokers, 15.3 for smokers of one to nine cigarettes, and 17.9 for smokers of' 10 or more cigarettes a day. The relative morbidit'y, ratiosr forthe~ four factors cited above increased from 1.1 for patients with only one risk factort'o1L7 for those with any two risk fact'ors,and to3'.2~f'or patients withiany thre.eor four risk factors. Miyazaki (44) studied' blood flow in the~ internal carotid artery using ultra sound techniques: Internal carotid blood flow, was ex- an7tned under a variety of' experimentall conditions. Inhalation of cigarette smoke in three individuals aged 27, 67; and 69 resulted in an increased blood flow due to decreased vascular resistance. This effect lasted for 10 to 20 minutes follbati=ing smoking. P'eripheral Vascular Disease The association between cigarette smoking and arteriosclerosis obliterans (ASO) ~ was invest'ib ted by Weiss (73). P'atients were con- sidered to have AS0~ if~ both the dorsalis pedis~ and posterior~ tibial Pulses were absent in onelower~e:xtr.emity~and~t~he ~examinang~physiciang made ai diagnosis~ of ASO. Patients~~ were~~ asked the age~ of initiation of~ smoking:: the dEiil~r~ number~~ of~ cig~arettes~ smoked; the amounts~~ smoked .:it~ages 30,150, and 70;~the~age~ at which they stoppecl sm,oking;~ 435-023I 0-73-3'

and, for males, whet'her they srnokedd cigars or a pipe, A total of' 214' male cases, 206' male controls,,390 female cases; and 913' female controTs: were studied. The controll group was composedl of patients wit'hh peripheral vascular problems other than ASO! but who had: dorsalis pedis pulses present on initial examination. In each age and sex group, cigarette smoking, was more prevalent among cases than controls. In both sexes, risks were high for smokers of less than one pack a day, and increased withi the amount smoked (figs. 6 and' 7). It was esti- mated that 70 percent of nondiabetic ASO in the Un2tedi States i's related tothe use of' cigarettes.Diabetes mellitus is a major risk factor for the development of ASO ; liowever; cigarette smoking appeared to act independently of diabetes. Figure 6. Relat'ive risk of developing arteriosclerosis obliterrans (AS% f'or mal'ess by amount of cigarettes smoked. 15.0 10101 5.0' Malas 9.1 Cases 18' 2'1 33 69 Controls 53' 15 26 37' Amount smoked Non- smoker <1 pack day 1 pack day }11 pack day Q. SOURCE: 1Meiss; N. S. (73). w ~'. 20 ~ Q I

~of214 ontrols ~ with ~orsalis group, pIs: Ina a day, js esti- kites is jf'actor. Ired to ' males Figure 7: Relative risk of' developing arteriosclerosis obliterans (ASO) for females by amount of cigarettes smoked. t t I FemaPes. 15.0 _,c 10.0 N ` 5.0 1.0 0:0 15.6 Cases 79 50' 60' 41 Controls 429 83 69' 33 Amount smoked Non- smoker <1 pack day 1 pack day >1 pack day SoURCE: Weiss, w. S. (73). Preuss, et al. (50) examined the relationship between several factorss including cigarette smoking, blood pressurei weight, and history of diabetes and the development of occ.Iusive disease of the peripherall arteries in a population of 300 patients in Germany. Group Ii consisted of' 150 patients with a mean age, of' 59 years who had intermittentt claudication. Most of these patients were ambulatory. The 150 patients in group: II had a mean age of. 60 years and had far advanced periph- eral arteriosclerosis with ischemic pain at rest or evidence of gangrene. I There was no control group~of patients f'meeof'vaseulardisease.Tiherewerefewnonsmokersineithergroup of patients, butt'hegroup~ with zti `~ ~ .i~ W O ~ I

the more severe diseasehadi a higher averagpd~aalyconsumptiion of cigarettesthan did group 1. The inflnence of cigarette smoking on late occlusion of'aortiofemoral bypass grafts was examined by Wray,, et al. (75). A series of 100 patients who had aortic reconstruction for aneurysmal or aortoiliac occlusive disease between 1965' and' 1968 were studiedl Of the patients who had bypass grafts for occlusive disease, 30 patients smoked' ciga- rettes and 16 didi not. Late occlusions f romi thrombosis occurred in nine patients, eachof' whomi was smoking, more than a pack of cigarettes aa day at thetime the throcnbosis occurred (P<0.5 . The authors recom- mend cessation of cigarette smoking to alli patlientl& undergping vascu- lar reconstruction:. Schmauss and! Arlt (55)1„Wilbert (7f,)„and Kradj'ian, et ali. (39) reported a greater than 93' percent prevalence of cigarette smoking, inn three, separate series of' patients with severe peripheral vascular disease. Isacssoni (29) performed venous occlusion plethysmography in 684 meni aged5'5, in Malmo; Sweden. In addition to a detai~led smoking history, a number of'other f'actors were studied', including,blood pres- sure, pul'seT height, weight, FCG,heart volume, and blbod lipids. The plethysmograms were taken on both legs simultaneously with the patient in the recumbent position. Measurements were taken at rest' and during reactive hyperemia prod'uced, by obstructing arterial inflow to: tlh~elegs for,3: milnutleswitha bloodi pressure cuff appliedl to the thilgh.Smokers had a signi'ficantlyl'ower mean flow capacity (nIF'C')thandid nonsmokers. The MFC in the legs was red'uced, in direct proportion to the amount of tobacco consumed per day regardless of the mode of smoking. The MFC was significantly lower with inhalation (P<0.001) and with increasing amount smoked (P'<0'.OiDI).. Matsubara and Sano (4w) studied the effect of cigarette smoking onn human precapillary sphincters of'theleg using a pressure plethysmo- graph applied to the calf.. Precapillary sphincter tone n-as~ estimatedl using the capillaryy filtration~ coefficient, which i's the product of "func-, tional capillary service area'''and the filtration constant of the capillary walil. Four healthyy male subjects were tested. All were regular smokers of cigarettes whohad' not smoked for the previous 24hours; When cigarette smoke was inhaled deeply at 30-secondl intervals over a 12- to. 15-minute period, there was a 19-percent decrease in t.he capillary filtration coefl'iei'ent,, indicat'i'ng closure of' precapillary sphincters. Cigarette smoking also: resulted in a 31-percent decrease in calf'bl'ood flbw; indi¢ating,some degree of constriction of the arterioles in the leg. The:pressurevoliumecurvesofthevenous system were notafi'lectecl byy cigarette smoking. Heistad and Wheeler (?41)~ esamined theefFect of carbonmonoxidie on vascular resistlance and refleY vasoconstriction in the forearms of 12 23 s ( d t u c

ption of remorali ', of' 1100' rtoiliac atients d! ciga- `un nine tttes a ~k~eCOm- vascu- I. (39)' `ing in 'scular [n 684 bking pres- The The ~ the and ~w to ~igh. ~ did bn to node ~tion ~ .g on. 5mo- iated !unc- la'ry kers rhen ~'- to lary 'ers. bod leg: i by ide 12~ healthy men 19 to 23 years old. After control measurements were taken, the subjects were exposed to enough carbon monoxide to produce car- boxyhemoglobin levels of 118 to 20 or 25 percent. Carbon monoxide did not cause a change in alveolar PO2 or PCO2. The arterial oxygen satu- ration was less than 75~ percent, but this decrease did not result in altered resting arterial pressure nor was there much evidence of'f sympathetic stimulatiom Carboni monoxide hypoxia did result in aa significant decrease in vascular resistance in the resting forearm, (P<0:05')', Carboni monoxide exposure also: resulted in a signifi'cantt depression of the vasoconstrictor responses of the forearm following the application ofl negative pressure to the lower body (P< 0:001) and' of ice on theforeheadLI'tappears thatthe~hypoxia induced byearbon monoxide causes an inhibition of reflex of vasconstrictor responses despite the presence of normal arterial oxygen tension. Summary of' Recent Cardiovascular Findings In addition to the summary presented in the introduction to this chapter based' on previous reports of the,heal'th consequencesi of smok- ing; the following statements are made to:empliasizethe recent deveiop- mentlsin t'hefield : 1. Recently conducted epirlemiologicall studies from several coun- tries continue toi confirmi that cigarette smoking is one of the major risk factors contributing to the development of coronary heart disease.. 2. Epid'emiological evidence suggests that black men in the rural South, respond to the same risk factors for coronary heart disease, including cigarette smoking, as white men do but apparently at lower disease rates; which appears to be in part due to differences in physical activi'ty. 3. Data from several' epidemiological and experimental studies sug- gest that cigarette smoking is ai major risk factor in the develop. ment of peripheral vascular disease. This may in part be due to the decreased blood flow in arterioles and capillaries assoeiat!ed with cigarette smoking. Sinoking may complicate the surgicall inter- vention, in this disease by contributing to late occlusion of the treatedl vessel. 4. A laboratory test has been developed which accurately measures nicotine levels in blood. This test will be useful in understanding nicotine metabolism and can be used as an objective measure of cigarette smoke inhalation. 23 0 0

Cardiovascular Re£Erences' (1)', ADAMS, J. D., ERICKSON, H. H., STONE; H. L The effects of carbon monogide on coronary hemodynamics and left' ventrtcular function in the conscious dog. In: Proceedings of the 1st Annual Conference on Environmental' Taaieology, September 9-11„ 1970: Aerospace Medical Research Labora- tory, Wright-Pattersoni Air Force Base; Ohio, AliSRL-TIL-70-102, Decem- ber 1970, pp. 107-110! (2) AGVESE, G;, CANEPA, R., LA RoaCA, ML Eta e valore di alcuni indici per la discriminazione frai sagget'ti normali ed isehemici. (Age and value of several indices for discriminat'ion in normal andl ischemic subjects. ). Giornale di' Igiene e\iedicina Preventiva 11(3) ! : 140-151I July-Septem- ber 1970j (3)' ARONOw, W. S., RaKAw, S. N. Carboxyhemoglobin caused by smoking non- nieotine cigarettes. Effects in angina pectoris. Circulation 44(5) : 782'- 786,, November 1971.. (l), AaTHES,, F. G. An epidemiologic survey of hospitalized cases of'venous, thrombosis and pulmonary embolism: in young women. Milbank Memorial Fund Quarterly 50(1', Part 2)~: 233--243, January 1972.. (5) ASTRUP, P. Rokning orhikoronarsjukdom (11I) :, Karbeskadigende virkning af CO og hypoxi. (Smoking and coronary dise.ase (i11) : Vascular damag- ing effect of'CO and hSpogia. ) Laikartidningen 67(3) : 44'-49, Jam 14„ 1970: (6) BELLET, S, DeGuzmArr, N. T., KOSTis, J. B,, RobsAN, L., Ft.ElscHMArrNw D: The effect of Inhalation of cigarette smoke on ventricular fibrillationn threshold in normal dogs and doga with acute myocardial infaretion. American Heart Journal 83(,L) : 67-7t•i Jgnuary 1972. (7). B:HAOAT, B... RUEHL, A_ R'AO, P:_ RANA, ':WL'., W.,.. HVGHEB, M. J. Effect Of'f cigarette smoke on the cardiovascular system in dogs. Proceedings of the Society for Experimental Biology and' biedicine 137(3) : 969-972; July 1971. (8)BINO, R. J.,.,wAYLAND; H., RICKABT,.,A,, HELLBERI},..K. S•'tudies.on the.corUnarpe micl'ocirculgtion by direct visualization. Giornale Italiano dil Cardiologiai 1: 401-408, September-October 1971. (9) Bas*rsTINaL, Ji. A., BaINSON, K., CtIAKxABARTI, B, K. The effect of short- term exposure to carbon monoxide on platelet stickiness. British Journal of Surgery 58(11) : 837-839, November 1971.. (10) BouDIIi, F. Srdecni infarkt, a koureni. (Myocardiali infarction and smok- ing: ) Casopis Lekaru Ceskych 110'(26) 1: 614-620', July 25,19'71. (11') B!uaNEg; S. Sv., EivsLESN, K. Investigation of changes in clinicali laboratory tests related to aging and smoking. Aging and', Human Development 3(1) r,95-101, February 1972. (12)~ CASCIC; G., :%lARRACCI:PI,, L.,. ZEDDA, S,„ C'ARTA~ G. FULOILEBU,, G. Snllaa flrequenzai delle cardiovaseulopatie tra gli operai dell' industria est'rattiva de11a sardegna. Nota II,: Incidenza, ini rapport'o alll'abitudine al': fumo e all'alcool. (On the incidence of cardiovascular disease among the workers of, the mining industry of' Sardinia. Second communication : Incidence inn relation to habitual smoking, and consumption ofl alcohol. ) Rassegna i 11Tedicai Sarda 71( Supplement 1) : 191-200, 1968. (13) CASSEL, J. C. Summary of' major findings of the Evans County cardio- vascul'ar sttrdies., Archivesaf' InternaU Medicine128(6)~: f397=889; De- cember 1971. W ~ 441 ~ ~ w. MA ~A

bzide Cious ental Ibora• Fcem- er la le of lets.) jtem- non- 782_ rtous prial ning mag- t9"l0. -, D: tion ion. [t of the u1y yary ogia tort- rnall hok- tory nent, mlla tiiva ua e iers : ein goa dio- De- (I4) CAesEL, J. C., HEYDEN, Si, BARTEL, A. G., SAPLAN4 B. H., TYRoLER, H: A., CosNOxr, J. C., HAMES, C. G. Occupation andlphysicali activity and coro- nary heart disease. Archives of Internal Medicine 128(6) : 920-928, De- cember 1971. (15) CIAMPOLINI, E., DRINGOLI, R:, RAYAIOLIi P. Azione del fmmo di sigarette su alcuni, parametri del ricambio lipidico. (Action of cigarette smoking on several parameters of lipid metabolism. ) Atti, dell'Accademial dei Fisiocritici in Siena ;', Sesione bi edico-Fisicai 17 . 474-480,196K (16), COMSTOCx, G. W. Fatal arteriosclerotic heart disease, water hardness at home, and socioeconomic characteristics. American Journal ofIDpidemi- ology 94(11) : 1-10, July 1971. (17)i EBTANDIACANO; A., EsQuIvEL AvnLe4, Jl, 1+TA:LO CAMACA'o, R.~, FEREzSANTANDER„ S., LEON MONTANEZ, E. Infarto juvenil del miocaR'dio. (Myo- cardial inf'arction in the younger age groups:) Archivos del Instituto de Cardiologia de iwSexieo 41 (2) : 137-150, ,riTarch-Apri1 1971. (18) FACCHINI, G., SExERARO, S., DI BiACSE, G., TABARRONI; F., SPAa:voLO, D., AuTORE, A., BorrAt*iTA, E. bTodificaeioni nel soggetto anziano della reattivita al fumo dt sigaretta: Ricerche sullrequilibrio emocoagulativo e fibrinolitico e sui circolo periferico. (Modifications of the reactivity to cigarette smoke in old subj,ects : Research on the hemocoagulative andi fibrinolytic equilibrium and on the peripheral circulstion. ) Giornale dii Gerontologia 119(10) : 779-784„1972; (119), F>vINI:EIB, M. Venous thrombosis in relation, to cigarette smoking, physieall activity, and, seasonal, factors. 3filbank 54emorial, Fund Quarterly 50(1, Part, 2) : 123-141, January 1972. (20) GIBBONS, G. F., :411TROPOULOS, K. A. Inhibition of cholesterol biosynthesis by carbon monoxide: Accumulation of lhnosterol andi Biochemical Journal 127 (1) : 315-317, 1lfarch1972' (21) GbLOVCHINER, I. Y. Nekotoryye sotsial'nyye faktory zabolevayemosti:infark- tom miodarda. (Some social factors in the incidence of myocardial in- farct:) Zdravookhranenie Rossiiskoi Federatsil 15(9) : 12-14, 1971. (22) GoRDoN, T., SoRLIE, P:, KANNEL, W. B. Section 27. Coronary heart disease, atherothrombotic brain infarction, intermittent clkudication-a multi- variate analysis of some factors related to their incidence: The Fram- ingham~Study, 16-year followup. In: Ka,nnel, W. B,,Gordon~T. (Editors). The Fiamingtlam Study. An Epideniiological Investigation, of Cardio- vascular Disease. May 1971~ 42 pp. (23) HAMES. C. G. Int'roducthon. (Evans County Cardiovasculhr and Cerebro+ vascular Epidemiologic Study.) Archives of Internal Medicine 128(6) : 883-886~ December 1971. (24) HEISTAD, D. D., WHEELER, R. C. Effectofcarbonmnnoxide on reflex vaso- constriction in man Journal of Applied Physiology 32(1) : 7-11, January 1972, (25)HEI:LBERO, K., WAYLAND, H., RTCICART, A. L., BING, R; J.Studies on the coronary microcirculation by direct visualization: American Journal of Cardinlogy 29: 593•••r597; \Iay 1972. (26) H1;1:DENy S!, CASSEL, J. C., PiARTEL, A., TYROLER, H. A., HAIIBB, C. G'„ COB- No-NI, J. C. Body, weight and cirgarette smoking as risk factcros. Archives of Internal SSedic.ine128(8) :9115-919, December 1971. (27)HrRAY'AMA„ T.Smokingin relation to thedeath: rates of 265,118 men and women in Japan. A report of five years of follo«-up: Fresente<l at the American Cancer' Society's Fourteenth Science Wri'ters'Seminar, Clear- water Beach, Florida, March 27,1972, 15pp:

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i I nicotine. I men A ISupple+ etion in ;ober 1, i p heart I Heart cember ;Latina ~gment. ~1 cor- NA„ R., pU, V:, heart athies ide la Bocio- 4tion. 0ocio- ~,Pub- p, R. khne'e. t' in a u 26: ation !tres. Qbi,ts yr971. h reQ`- ; The ases ease 0.ary 9rtic rnal the and': try 62. Z ,'he e, effect of acute experiment of cigarette smoking on 1'ipaemia follo-,ving,fat meal.) Polski Tugod:nik Lekarski 25(7) : 251-253, February 16;, 1970. (44) M7YAZA$I, 11. Studies on cerebral circulation by the ultrasonic Doppler technique-with speciali reference to clinical applicatiolu of'the technique. In: Meyer, Jl S., Schade, J. P. (Editors). Progress in Brain Research, Volume 35, Cerebral Blood', Flow, Amsterdam, \etherlands, Elsevier Puh- lishing C'o., 1972,, pp. 1-23'. (45) ORLOVA, N. P'. Some parallels between the blood coagulation activity andithe condition of adrenergic and' cholinergic system of' the organism. Terapev- ticheskii Arkhiv 43: 5"2', February 1971., (.¢0) PAFFENBARSER; R. S., Jr., WYNO;, A. L. Chronic disease in, former college student's. XI. Early precursors of nonfatali stroke. American, Journal of Epidemiology 94 (6'), : 52•4-530, December 1971. (147) PANDEY, Ji. R. 3iy?ocardial infaret!ion iniNepal. Indian Heart Journa122(2) : 73-82, April 1970. (48): PINCHERLE, G. Factors affecting the mean serum cholesterol. Journal of Chronic Diseases 24 (5') : 289-297, August 1971. (19.). PIRNAY,, F., DUJABDIN,. J.,. DEROAl`NE,. R'. PETIT, J.ML 3lusculaT' exercise during intoxication by carbon monoxide. Journal of Applied Plivsiolbgy 31(4) : 573-575, October 1971. (50) PREUSS, E.-G., EDER, H. WELLER,, P: Risikofaktoren bei peripheren arteriel~, len Verschlusskrank,hei',ten, unterschieldliclien Schweregrades. (Risk fae- tors in occlusive diseases of the peripheral arteries, of varying severity.) Zeitschrift fiir die gesamte imiere Medizin und Ihre Gt•enzgebiete 25(10) : 4Fr1-468,, May 15, 1970. (51) PutisAR,, S, Tupakointi ja sepelvaltimotauti. (Cigarett'e smoking and cor- onary heart disease.) Suomeni Laakarilehti 26(il/2) : 27-32, January 9, 1971. (52) REECE, W. 0.,, BALL, R'. A. Inhaled cigarette smoke and treadmill-eYercised, dogs. Archives of Environmental Health 24(4) : 262'-270; April! 1972. (:i3), Ro3I,eLO,, 1. Distribution of'serunl lipids in Norwegian recruits. Acta AIedica. Scandinavica 190(5) : 401-446„November 1971. (54), SCHIEVELBEIN,. H., EEERHARDT,. R., Cardiovascular actions ofnicotineandf smoking. Journal of! the National Cancer Institut,e48!(6) : 1785--1794,June 1972i (~55')1 S'CaacAuas, A. K., ARLT„ E: Morphologische Befunde, post'operativeKompli':- kati~onen; T,etalitiit und Liegedauer nachAmputationwegen, Durehblut-ungsstorungen. (Morphological' findings,, postoperative complications, mortality and duration of bed, rest following amputations occasioned by disorders of' the peripheral circulation. ) Zeitschrift fur Arztliche Fort- bildung 64'(2):: 84'-87, Jannarc15,,1970. (56.)'. S'CHWARTZ, D., RSCHiARD,, J. I.., LELLOUCH, J., CLAUDE,Jl R.. Seruml1pids, smokingandl bodgliuild. Studh-of 7,972' actively employed niales. Revue Europeenne d'Etudes Clininueset Biologiques1'6: 529-536, 1971. (57~)SHURTLESF, D. Section 26. Somecharacteri':stics related'tothe incidenceof'e cardiovascular diseaseand death:Flramingliam Study, 1!6;year followup. In: Kannel, W. B., Gordon, T:, (Editlors). The Framingham Study. An Epidemiological Investigation of Cardiovasculiir Disease. U.S. Depart- ment of'Health, Education, andli''elfare, PublicHealth~ Service, National. InstitutesiofHealth. Washingtlon, D'.C., December,1970; 35 pp. (58) SYNGH, A: P., Si;vaiv, S. P~ Coronaryheart disease-some epidemiological, elihicral„ and electrocardiographic abservatibns,, Journal of' t11eAssocia, tionof'~ Ph3;siciansof India 19(9) : 62i:-G35',, September 1971. 22

(59~), SMYTH; A, J., AnEr, H'.,, LA~xGLEY, R'., B. An epidemiologicali survey of' ischaemic heart disease. New Zealand Medical Journal 71(456) : 284-288, May 1970: (60) STOacH, H., ExGELbsAxx, L., KOHLEa, H. Der Herzinfarkt im jiingeren. Legensalter. (Myocardial infarct in young people.) Deutsche Gesund~ heitswesen 26'('34) : 1593,-1600; August, 1971. (61)~ SUMMERS, D. N.,. RICHMONn, S., WECHSLER, R. 3S!. Cigarettesmoke~:'. Effects on lactate extraction in the presence of'severe coronary atherosclerosis. American Heart' Journal 82(4) : 4'58-467; October 1971. (62). U.S. P'CtBLIC HEALTH. SERVICE. The HealthCdnsequenees. of Smoking. A Public Health Service Review : 1967. U.S: Department of' Health, Educa- tibn„ and Welfare. FPashington,, Public Health, Service Publication No. 1696; R'evised January 1968, 227 pp:. (63) U.S. P'aBLIC HEALTH SEavICE. The Health Consequences of Smoking. 1L968 Supplement to the 1967' Public Health Service Review. U.S. Department of Health, Education, and Welfare. 1'9ashington,, Public HealtL Service Publication 1696; 1968; 1I17 pp.. (64) U.S, PUBLIC HEALTH SEaviCE. The Health Consequences of' Smoking. 1969 Supplement tothe 1967 Public Healthi Service Review. U.S. Department of Health, Education, and Welfare. Washington; Public Health Service Publication 1696-2, 1969; 98 pp. (65). U.S. P'UBLICHEALTH. SEBVICE:, The' Health Consequences of .5"~moking'.AReport of the Surgeon General: 1971. U.S; Department of Health, Educa- tibn,, and! Welfare. Washington, DHEW Publicat'ton 1o: (H'S.II) 71-7513, 1971, 458 pp. (i66) U~S: PuBrIC HEALTH SEavIC& The Health Consequences of Smoking, A Report of the Surgeon GeneraU: 1972. U.S'. Department of'Health, Educa- tion, and Welfare. Washington, DHEBF' Publlcation, No. (HiSA1)! 72-6516, 19'P2', 158 pp: (6Z) U.S, PuBLic HkALTH, SERVICE. Smoking and Health. Report' of'the Advisory Committee to the S1lrgeon General of the Public Health Service. Washing- ton, U:S:Department of Health, Education, and Welf'are;, Public Health Service Publ'ication No. 1103, 1964, 387 pp. (s$). VAIPBtiCHEM,, F... S. P., DaION„ E.!,. WIGBO'QT,. DZ.,. BOBBCHIETEa;, E... Hett vborkomen en de betekenis van een depressie vam het ST=segmentin het elektroeardiogram bijimannen zonder andere verschijnselen. Eeni 7-jarige lbngitudinale studie (I'I'). (The occurrence and the significance Of' a 28 (I

Irvey of' depressi'on of the ST segment in the ECG of men free from other symp- I 284-288, toms. A longitudinal study of 7 years (11).) Nederlands Tijdschrift voor Geneeskunde 114 (8) : 320-332, Feb ruary 21,,1976. Y'ingeren (I6g)~ VAN$UCHE3iy F..S, P.,.DRION,,E., WIGBOUT,.1L, B06SCHIETER, E:,.FBIiM.A, J. R. Gesundl Het v8orkomen en ae betekenis van extrasystolen en geleidingsstoornissen. I Een 7-jarige lbngiltudinale studie (Ii), (The occurrence and significance I IEffects of extrasystoles and conduction disorders. A longitudinal stud'y over 7 urerosis. years (I)',) Nederlands Tijdschrift voor Geneeskunde 114'(7) : 281-286;. ; king., A February 14, 1970: i (70) VLaicII, R., bSACewEi~ E., PATIU~ IL Studiu transversal ("cross-sectional")) Educa, al preslunii arteriale si al lipidelor serice la coronarieni fumatori sii lon No: nefumatorli (Cross-seetibnal study of arterial pressure and serum,lipidfi I in,coronary smokers and nonsmokers.) Medicina Interna 23'(8) : 925-930, Ig: 1968' ~ August 1971. lrtment (71)' VooEL„ JL, A, GLESER, M. A. Effect of'carbon monoxide on oxygen transport Service duringexercise: Journal of AppliedlPhSsiology 32(2) : 234-239; February 1972 .. i Ig. 1969 (72). `'oGEL, J. A., GLESEB; M. A.,,WHEELEB, R. C., WHITTEN6 . B..I{. CRrbonmon- hient of oxide and physical work capacity. Archives of Environmentall Health Service 24 (3') : 198-2(13',, Jiarch 1972. i - (73) WEiss,, N. S. Cigarette smoking and arteriosclerosis obliterans: An epi king. A demiologic approach. American JournaU of Epidemiology 95(1) : 17-25, J@duca• January 1972. u~~-7513',. (74) WILBEBT; L~ Nikotinkonsum und arterielle Verschlusskrankheitl (Nicotinee ~ consumption and arterial occlusive disease:) JTedizinischeKlinik66('36) : ting. A. . 1190-11192, September 3,1971. Educa- (i75) WBAx, R., DEPAL>TA, R. G:,, HUBAr, C. H. Late occlusion of aortofemoral ~-6516; bypass' grafts : Influence of cigarette smoking. Surgery 70(6) : 965-973;. ~ December 1971. Ivisory (76) Wgsoxixsgl, Z. Effects of'tobaeco smoking on certain parameters reflecting Ishing.- i the condi'tionof the circulatory system at rest and during exercise. Polish Elealth Medical Science and &IistoryBul'letin,14(12):: 73'-i 6,, April 1971. '41 Het in,het ijarige 0 of' a 29.

03764317

CHAPTER 2 Nonneoplastiic Bromchopulmonary Diseases ao

~ 03764319 .,~..~. . .~ rt...a.....~...~.~.~~.~~.~~~~. ~~~ _ ~ ., :.....Y..,.....w.~..,_. ..:...,.::. .~_ .. . .....~......~:~._~~.....~..;::,~.~. _ ..~... ~,. . .: : .

I Cantents, Introdtiction-------------------------------------------- Page 35 Epidemiological Studies COPD Mortalzty, dnd:Morbidzty------------------------ 36 Filter Cigarette& --------------------------------- 37 Pulmonary Function----------------------------- 38. OCcupationa,l' Hazards Byssinosis-------------------------------------- 39! Exposure to Asbestos---------------------------- 41. I Exposure to Coal Dust___________________________ Miscellaneous Ekposures------------------------- 4I]i. 4!3' Air Polliction '---------------------------------------- 44', Autopsy Studies----------------------------------------- 45 Experimental and Histopathological Studies: Histopathol'ogical S'tudies------------------------------ 48 Pulmonary F'unetion--------------------------------- 50 Pulmonary Clearance--------------------------------- 51 Phagocytosis---------------------------------------- 5& Bacterial and Mycologi,cal St!udzes'---------------------- 54. The S'urfactdnt System-------------------------------- 55 Summary of Recent Nonneoplastic Bronchopulmonary Find- ings------------------------------------------------- 55 References--------------------------------------------- 56 List of Figures. Figure L-Age-standardized percentage of' chronic: sput= production in males by amount smoked and type of cigarettle---------- -------------------- Figure 2,-Age-stand,ardized percentage distribution of whole lung sections of mal'es with moderate to far-advanced emphy- sema (score 3-9) 1 bysmokingcategory-_--_ _--_--__-_--___ Figure 3'.-Prevalence of emphysemai in adult males at autopsy by smoking categorY'----------------------------------- 38 47 48

List of' Tables PAge. Table 1.-Percente' prevalence ofl byssinosis for men by index of severity andi smoking habits (numbers in parenthesis indicate nunuber of cases in exposure risk group)_________________ 40 Ti able 2.-Degrees of emphysema in current smokers and' inn nonsmolkers according, to age groups ~ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ 46' 34 I Q3 I

Pkge 40 4'6' 1 Introduction The term chronic : obstructive bronchopulmonary disease (COPD), as used within this report',; refers to chronic bronchitis and pulmonary emphysema. The following is a, brief summary of the major relation- ships between smoking and nonneoplastic bronchopulmonary disease «hi'ch have been presented in previous reports of' the health conse- quences of smoking (91; 92; 93„94, 95„96)!. Epidemiological, and clinical studies have established cigarette smoking as the most important cause of CO!P'D in the United States: Cigarette smokers have higher death rates from pulmonaryy em- physema and chronic bronchitis and more f'requently have impaired pulmonary function and symptoms of pulmonary di'sease than non- smokers; Respiratory infections; are more preval'entand'~ more severe among cigarette smokers, particularly heavy smokers„ than among nonsmokers. Cigarette smokers appear to develop postoperative pul- monary complications more frequently than~ nonsmokers. The risk of developing or dying from C.OP'D among pipe or cigar smokers is higher than that of nonsmokers, but it is clearly lower than that among cigarette smokers. Ex-smokers have lower death rates from~ COPD than~ do continuing smokers: Cessation of smoking is associ'at.ed , with improved ventilatoryy function and decreased pulmonary symptom prevalence.. Young cigarette smokers of high school age have impaired ventilatory function compared to, nonsmoking peers. For most of' the United States population, cigarette smoking is a much greater factor in the development of COPD than air pollution or occupational exposure: Cigarette smoking may, however„ act con- jointly with atmospheric pollution or occupational exposure to: pro- duce greater mortality and morbidity from! COPD than would occur from one exposure factor alone. A genetic error, homozygous: allphal-antitrypsin deficiency, present in approximately 1 in 3,600 people in the United States, has been as- sociated with~ the early development of'e severe panacinar emphysema.. Avai'lable evidence does. not permit a firm, conclusion, about the nature of the interaction between, smoking and this condition. Autopsy studies have demonstrated that smokers who die of diseases other than COPD have histologic changes characteristic of COPD more frequently than do nonsmokers., ! ! L 495-028 0-73 4 35

Experiments in both animals and humans have demonstrat,ed, thatt the inhal!ation of cigarette smoke is associated' witli acute and chronic changes in ventilatory function and pulmonary histology. Cigarette smoking exerts an adverse effect on the pulmonary clearance mech- anisms including ciliary andimacrophage function. The effect of cigaret't'e smoking, on~ nonneoplastic bronchopulmonary disease has been examined in detail' in a number of recently published epidemiological, pathological, and experi~rnenta~b stud'ies.. COPD' Mortality and Morbidity Reid (70) reported that age-adjusted mortality rates from chronicc nonspecific lung disease (TCD 502, 5261 527) among British citizens~ varied' with migration patterns.British males living in the United Kingdbmhad~ a death rate of'125~per 100,000, whereas migrants to theI7nited' States experienced a mortality rate of' only 24 per 100,000; which is similar to t'hee mortality rate from, chronic nonspecific lung disease found in the T,T.S:populatien. The possibility that this varia- tion was due to significant differences in diagnostic criteria was in part ruled out by the finding that standardized morbidity surveys of both populations demonstrated differences in morbidity rates that were similar to the observed differences in mortality rates. The prev- alence of respiratory symptoms increased in proportion to the num- ber of cigarettes smoked per day. Cigarette smoking, and air pollu, tion were identified as the major factors contributing to the real!excess in bronchitis morbidity experienced by the British in the United Kingdom. Freour and'Coudray(g3)inv.estigated the prevalenceof respiratory symptoms and chronic bronchitis among a random sample of'4,(>(}0 men and women between the ages of' 30 and 70 who were residents of' Bor- deaux, France. A stand'ard7zed questionnaire was adhministered and, measur.ementsofpulmonai:•yfunction taken. ZPheprevalence~of chronic bronchitis increased wihhi age and cigarette°smok~iilg, In each agecate- gory,, smokers had' more chronic bronchitis than did nonsmokers. Thegreatier t.henumber of cigarettes smoked per dayand th~egreatert'lie: lifetime number of cigaret!tes~smoked, the higher was the prevalence of' chronic bronchitis. C''ondi:•ay., et al. (7.3), in ai study of' 1,357 women in t'he, Bordeaux Study, reported apeevalenceof morning cough of L12pereentamongnonsmokingwomenand18,;11 percent amongwomaen_who smoked~. R.acoveanu.et aL (F6:)studrie,d, thepre.valenceofchronicbronchit!isiit3t?(lresideiitsofa mountaiiLousregii~n and a low-lyi'lr~,~, delta~area in 36

uted that l chronie `,igarette. ;e mech- monary tblished. .hronic : itizens Jnit~ed' to the )0;000, I lung varia- ras in rveys s that prev- num- iollu- xcess aited ttorv imen Bor- and' Onie ;ate- The, the e of rnin [.12 rho itis in I 3'' Romania. Both, areasi were free of' air polllation. The prevalence of chronic bronchitis was higher in the mountains than in, the lowlands, and although a! definite association between chronic bronchitis and smoking was found in both areas, smoking patterns couldl not com- pletely account for the differences observed. Sev eral papers have been recently pubIishedi (24, 25, 26, .37, 55;100) comparing respiratory symptoms, such as cough and sputum produc- tion, among smokers and nonsmokers in different populations. In each study, respiratory symptoms and disease were more common among vigarette smokers than nonsmokers. 'Mostof'these studiies (24, 26;37,, 100) demonstrated a dose-response relationship between smoking andd s}•mptoms for the amount smoked as measured by the number of ciga- rettes smoked per day; the lifetime number of cigarettes,,or the degreee ofinhal~tion.. Ti he spontaneous development of a~ pneumothorax with the resultant rollapseof a hzngis often produced by rupture o~f'ani emphysematou's. ISleb on the pleural surface. Fournier and Zivy (21) rev.iewed 61 cases of spontaneous! . pneumothorax., Thesmoking habits of these patients were compared with those of'matched controls. Spontaneous pneumo- thorax after the age of 25, was strongly associated with cigarette smoking. Zivy (101) further characterized 40 of'these cases.. FIUIPER, CIGARE=B The effect of'smoking plain and filtered cigarettes on the prevalence of sputum production was examined by Rimington (71). A total of' 10,4114 volunteers aged 40 and older were studied by questionnaire and chest X-ray. Oif' this group, 3;045' smoked filter cigarettes, and 2,393 smoked nonfilter cigarettes. The rate of persistent daily sputum pro- dh.iction was 31.9 percent in filter cigarette smokers and' 37.2 per- centin smokers of' nonfilter cigarettes. The difference is significant (P<0:001). Although there was an increase in sputum productiom with the amount smokedl in both groups, the difference between filter and nonfilter smokers was maintained irrespective of the amount smoked (fig. 1'') ~. The author observed, "While there is no doubt ~that smokers of' any type of cigarette are 1'iable to d'evelop chronic bronchi- tic symptoms such as persistent phlegm, itseems likely that those plain cigarette smokers who are unable to stop smoking, cigarettes would suffer less if they smoked filterbrandsofcomparablesize."The effect of smoking modified cigarettes on respiratory symptoms and ventilatory capacity was examined by Freedman, et all (2°2). Six hundred men bet'ween the ages of 25 and 54 who smoked at least 10 cigarettes a: day and hadl symptoms of chronic bronchitis were divided intot~hree equal groups, matched by age, pulmonary function, cigarette consumption, and cough frequency. The individuals were provided 37

Figure 1-Age-st'andardized' percentage of chronic sputum productiom in males by arnount smoked and type!of cigarette: 60 0 40 m 0o .9 d30' i a 20, 10 0, Filter cigarette smokers ~ Non-filter cigarette smokers 37:9 32:5 19.7' 47.2 Number of, volunteers 4,976 382 259 1,095' 878, 1,5681,256 1,256 Mumber witK sputum 83s, 97' 75 304 304I 571 511 " Mbn+ <10'. 10-19 >19 smokers cigarettes/day cigarettes/day cigarettes/day 1'Includes ex-smokers and nomcigarette smokers. SOURCE: Rimington, Jl (71). with test cigarettes "A,"'"I3," or "C " All the test cigarettes contained 1i.f,5mg, of nicotine. "A"dolavered 22mg: of tar,and, "B" and "C" 17' mg. of tar. In addition, "C" had approximat;el'y a 50 percent reduc- tioniin the vapor phase constit'uents: Those providcd with cigarette "C" increased the average number of cigarettes smoked! by about 10 per- cent, where consumption eventually lcveled off: After 4 months, menn smoking cigarette "C"' began to have lower average cough frequency scores than the others. Significant changes didi not occur in sputum production or pulmonary function. The authors observed that, " * * modification of the composition of' cigarettes and their filters can re- duce~smokers' coug)i,, an important and early symptom of bronchitis." PULMONARY FUNCTION Results of studies of'pulmonary function~ and smoking from several countries,, including India (65), Turkey (2) „Germany (7, 34,.38),. and Great Britiani (41) indicate that cigarette: smokersi have diminished average pulmonary function compared& ta nonsmokers. The various measures of pulmonary function used included vital capacity,, expira- tory reserve volume, residual vol'u:me, residua~L functional eapacity,maximum: voluntary ventilation, forced expirat~ory volume in T, second;and peak expiratolry flow rate. 38 V

Other studi~esin which botli pulmonaryfunction, and respia"atorysymptoms are considered (2'1'; 3Q, 36„ 43, 59; 69) have again confirmed that smoking is associated with an increase: in pulmonary symptoms and a decrease in pulmonary function. Ex-smokers experience a decrease in the prevalence of' respiratory sympt'oms and an improvement in pulmonary function compared too vontinuing smokers, These effects have been noted in several' recent ~;tudies (36; 3'1', 43). Ulmer (87) condttcted a survey of'respiratory symptoms in al ran- (Inmlsample of'2;444 individuals between the ages of 10 and 70 years in I)uisburg, Germany. The prevalence of chronic bronchitis as measured I,y cough and!/or sputum production in the, morning or throughout the dayy increased with advancing age and with increasing, cigarette con- sumption (P<0.001). Latimer; etl al. (48) studiedlthe ventilatory patterns and pulknonarycomplications of 46 patients following elective upper abdominal' sur- gerv. Factors that favored the development of postoperative macro- atclectasis included smoking, obesity„andl prolonged anesthesia. Teculescu and Stanescu (84) examined several measures of pulma- nary function in 44 asymptomatic young men between the ages of 18: andl 29 in Romania. h o significant differences were found between the smokers and nonsmokers. This may have been due to, the selection of asyrnptomatic subjects for examination and relatively insensitive meas- ures ofl early airway obstruction. uin~ed . 1 «01 sduc- ~ C6C~f per'- !men ency ttum * * BY3sINOSIs Byssinosis is a respiratory disease found' in cotton, flax, and hemp workers. The earliest manifestations ofl this disease are shortness of breathy coughy and chest tightness. Initially, symptoms occur only upon reexposure to cotton dust at the beginning of' the work week. ln more advanced form, byssinosis is associated wi'th permanent and occasionally severe airway obstruetion„ which may force the worker to change his occupation (~3Z);. Abnormalities in pulmonary functionn tests reflect the severity of the symptoms; however, chest films of' workers with byssinosis reveal no, characteristic findi'ngs: 1WIcKerrow and Sehilling (54) first suggested that byssinosis may occur more freduently among smokers than, nonsmokers. Severall relatively recent studies have clarified the relationship between smoking and byssinosis. Bouhuys,, et al. (8) found 61 cases of' byssinosis in 214 male workers in the carding and' spinning rooms of a cotton milll The prevalence of' . Occupational Hazards 39

byssinosis symptons was' higher arnong, cigarette smokers than in nonsmokers (P'<0.025)'. Szymczykiewicz; et al. (82) foundl a higher prevalence of chronic nonspecific pulmonary symptoms among smokers than nonsmokers in a study of 3,167 cotton mill! «•orkers'in Polandi. An eaaminationi of 500 cotton textile workers by Schrag and Gullett (75) disclbsed 6'3'individuals.with byssinosis; 57 percent (36 workers)' of those with byssinosis smoked more than a pack of cigarettes a day, whereas only 34 percent (152 workers) of' those without byssinosis smoked this amount (P'<0.001),, Merchant, et al, (58) conductex3l a study of byssinosis in a yarn mill i& North~ Carolina;25empl'oyee& «ithbyssinosis wereidentiffed in a,populatibn of' 441 workers: A scale of 0 to 3(based on5weighted questions concerning cough, breathlessness; and chest tightness on Mbnday mornings) was used to indicate the degree ofl severity of' byssinosis among' the working population. The: effect of' cigarette smoking on this byssinosis index is apparent (table 1). Among, the employees with high exposure: to cotton dust,, no nonsmokers had' a byssinosis index rating over 1, but nearly 18 percent of those.currently smoking had ratings of 2 or 3. The effect of' smoking' alone on the hyssinosis index:is significant (P<0:01). Also;,the interaction between current smoking and current exposure-risk on t!he' byssi~nosisindexis highly significant (P<0.005). Women in this study: were exposedl to lower levels of respirablee cotton dust, and among: them no age,, smok- ing, or exposure-risk effects were demonstrated. Smoking among males also had a,significanted'!ect on the bronchitisinclcx (P<0.002). Spirometry results on 131 males and 100 females were categorized by sex, age, and smoking, history. Among men, the greatest impairment TnBLE 1.-Percent prevalence of b'yssinosis for men by index of severity and smoking habits (numbers i& parentheses indicate number of' eases inexposure-ri,sk group) ' Percentage of subject Index rating (see text) Never smokedl Ciirrent,smokers Ex-smokers (23) (85) (21) Severe----------- 3 0 14 5 Nfiod'erate--------- -, 2' 0 4' 5 Mild------------- 1 22 26 29 None------------ 0 78 57 62 Tota1------------------ 100 100 100 Source: I4ferchant„J: A., et al. (68),. 40: b i

jul'lett irkers) a day, sinosis I yarn 4ti fie d Ighted !ss on Ity o f Rrette g, the iad a ently 7 the ween O$: is W to nok- long 102)., d by nent Nvas observed among the smokers who, worked in the high exposure- risk areas. The mean FEV 1 for 66 men in this category was only 76 hercent of' predicted, and their FVC was 900 percent of predicted. Nonsmoking men in both the high- and low-exposure areas had better lpulmonary function than their smoking coworkers. E%POSURE To ASBESTOS Langlands, et al. (45)' surveyed respiratory symptoms, pulmonary function,, and radiological findings among, 252 asbestos insul'ationn workers in Belfast, Ireland. Respiratory symptoms of cough, sputumm l)rochiction„and vvheezing were much more frequent in smokers.. Of the tests for pulmonary function,,the peak flow rate and forc.ed expiratory volume at l second were most impaired in cigarette smokers. Although little difference was reported in the X-ray findings of smokers and' nonsmokers, smokers of more than 25 cigarettes a day had a 20-percent reduction in pulmonary function as measured by these tests. Lungg function and pulmonary symptoms in 1,015 chrysotile asbestos mine and mill workers in Quebec were studied liy Becklake, et al., (6)i and McDonald, et al. (53). An analy.sis of respiratory symptoms indi- cated that shortness of breath was more closely related to dust ex- posure than to; smoking. However, cough, wheezing, and sputum hroduction were much more frequent in smokers than nonsrnokers: Pulmonary function was assessed by measuring, lung volumesi flow rates, andl diffusing capacity. The best pulmonary function was found in nonsmokers with low dust exposure tivhzle smokers with high dust exposure had lower pulmonary function vahxes. In a survey of' 201 asbestas workers, Regan, et a1L (67) investigatedd the relative pomcer of' 16'elinical„radiological;,and pulmonary function variables including smoking for differentiating between asbestosis and chronic obstructive airway disease. Cigarette smoki'ng, was not a char- acteri'sticthat could be used to separate these conditions: FixP03URE 'rO' COAL D'QST The spectrum of pulmonary reactions to coail dust was reviewed in a: volume edited by Key, et al. (40). Hunter (33) noted that,eoal miners, who smokedlexperienced a higher prevalence: of respiratory sympt'oms. (cough,, sputum production, breathlessness,, and wheezing) and de- veloped them earlier than nonsmoking miners. Their pulmonary func- tion tests also tended to sho.v greater impairment than those of nonsmokers. Lainhart and Morgan (44)reported that coal miners had an increase in persi'stent productive cough with increasing, years of exposure to coal dust. This effect was magnified by cigarette smok- i11g independent,ofl agQor year,sof underground .vork. In an aut'opsy 41

study, Naeye (63) observed more right ventricular hypertrophy and! a& higher emphysema index in smoking, , miners than iis~ nonstn.oking, min- ers") Iln commenting on the etiology of pulmonaryreactions incoaI rniit~ersr Lee(4;9)~ felt thatsm~oking in coal minersprobablyfacilitate,d the~~ develbpment of bronchitis and' emphysema, rather than participating in the genesis of the characteristic lesion of' coaL workers' pneumo- coniosis. The prevalenGeof' chronic bronchitis in~ 3,012 ~ ex-coal miners, and 9,361 nonrniners, of similar ageande social class was examined' by Lowe and Khosla (51). AIl were employed at tlie tirne of tlie investigation intwostEel, tivorksin~ South, Wales: The ex-maners, had substantially more chronic bronchitis and more impaired ventilatory capacity than the nonminers irrespective of' age and smoking habits. The prevalencee of' chronic bronchitis .vas 24:9 percent in smoking ex-miners, and 12.0 percent in nonsmoking ex-miners. Tlie prevalence was 18.0' percent and. 7.7 percent in smoking andl nonsmoking nonmiiYers, respectively. In, this study; smoking appeared to be a more important factor for the. development ofchronic.bronchitis than coal mining or age. Haber, eta1~(29): studied cigarette smoking,: dust inhalation, andd sputum production as, factors, in the etiology of chronic bronchitis among, 479 coal miners and 166 farmers in Hungary. In both the miners and the farmers,, there was a significantly higher proportion of chronic bronchit'is cases among smokers than among nonsmokers, and, the, proportion of bronchitics increased with the number of cigarettes smoked: Cigarette smoking was found to be a more im- portant factor in theetivlogyof bronchitis than dust inhalation. Lapp; et al. (ly6) examined changes in several measures of ventila- tory capacity in 93 eoaL miners and 42 nonminers before andi after a work shift. Following the shift, small but significant decreases inn ventilatory capacity occurredl among, the miners (P'<O.q5),, while significant increases in ventilatory capacity~~ occurred among the non- mi~ners(P'<0.05),. D~ecreases.inpulmonary function tests were related to the dust exposure of the miners; however, the greatest decreases in pulmonary function oceurredi among the smokers. Seaton, eta:l~(7f3') examined severa1' measures ofpulinonaryfuuc- tion in 214 coal workers who had radaologic evidence of CI`~'P' tiv ith lung: . opacities that ranged, in sizefrorn less than 1.5 mm. to~ 3 mm. in diameter. They found no_significant difference in pulmonary function between the 102 smokers and 112 nonsmokers with: coal workers' pneumoconiosis.. S~irnilarresultswere reported liy]i.yons, et al: (;52)_.Hyperinflation of tlielungs~ in_eoal miners was studied by l,lorgan, et aI.(,6.7');. Residual volumes, total luurg: capaciti~es„ and_chest X-rays: of 11,455 working_ Pennsylvania coal miners were examined.T.herela-tionshipbetween radibgi aphic~ evidence~ of coaT workers" pneurnoconi- osisand lung volumes«as im eat.igatedi Tilcresidual volume in- :t a I T fl

phy and' a king min- 'coa1' min- itatedi the tlclpating ~ pneumo} ners andi by Lowe stigation Itantially uity than ~evalence. iA nd 12.0 ~ent and. Iwely. In j'i for the ion; and ionchitis oth the 'portion mokers; pber of: pre im- fl, ventila, d after ases inn while ~e non- t,elatedd creases ~ func~- '' with nm:. in nction. Irkers' 52). Wgan, :-ray.s rela- iconi- e in- crctised with radiographic category, obstruction to air flow, andl i:rarette smoking.. Each of these factors had a separate and additive effect that resulted in an increased residual volume. ("lmer (86) examined a random sample of the working populationn in the Ruhr area of West Germany. 1V}Leasurements were made of the tntal lung, capacity, airway resistance, and arterial oxygen satura- tion. All coal' miners had larger total lung capacities tham workers w it liout dust exposure. Smokers had'significantly larger volumes t!han nnnsnwkers (P<0.08). L:upp, et al. (47) examined pul'monaryhemodynamicsin47asymp- trnnatic coal miners. They were divided into two groups depending iil)on the absence or presence of' airway obstruction. Pulinonary hyper- t„nsion was more freq,uent in the group with obstruction. The group „P •?3 rnerr (mean age 51 years) without airway obstruction, had an ;t%vrage cigarette consumption of' 17 pack-years per miner, whereas'e the ;*roup~ of 24 men (mean age56' years), with airway obstruction, ;«-erared 31 pack-years per miner. f^ com the work of several investigators it can be concludedl that vigarette smoking is an important factor in the development of re- sIaratory: disease other than pneumoconiosis, among coal miners (29, ;0, .,61, 47, 51, 61. 86). There is no consensus in recent publications on what role cigarette smoking may play in the development of coal wnrkers' pneumoconiosis (1+0; 61, 76)', N'IISCELLANEOu6 ExP09IIREs The effect of cigarette smoking, oni pu.lmonary, function in jet Eighter' l)ilots and crew members was examined by Browning (9). At high :Lltit.udes,~ 100-percent oxygen i's~~ delivered under~ low pressure to~ the~ ;uir(Irew ~ members~~ in order~ t'~o~~ maintain adequate~~ blood oxygEn~ levels.~ 'fhe vitall capacity was acutely compromised in flight on the 100-per~- vv~nt oxy.gQn, mixtu~~re~.~ This~was~~especially ~ true~ under high G~ (,grauity)~ conditioiis. Smokers had a significant inflight volume loss that was three~~ and one-half times that noted among~, the~ nonsmokers undler~ t hese conditions ( P<U5') . Recovery of' normal vital' capacity foll'ow- itI,•~flight «~as~ also~delayed in the smokers.~ Gregory (?8)~ re~tiiewedi 340 cases of choni'c~bronchitis that occurred a~moa,ig the en2ployees~ofl the~ Sheffield ste:elworks in England. Smoking, was associated with a high prevalence of chronic bronchitis, but of particular interest was the effect of' cigarette smoking on disability. 'I'l~ie~ interval bettiv'~een~ the~ onset of' chronic ~ bronchitis~ and disability from this disease was~sign~iticant~ly less (P<0.02) for~~t'~hose~~smoking~ niore~ than, 30~ cigarettes~ a day~ than for nonsmokers and~~ for~ t'hosso~ 1n1okinr less than this amount (P<0~:02').. I3atawi (5) examined the prevalence~~ of seve~ra~t diee~ases~ including

respiratory illnesses in 4,64'3' employees in Egypt, comprising a 5.3 percent sample of 92,000 employees in 117' major industries: Respira- tory illnesses oecurred' more freqpzently in alis segrnents of the cotlton industry, as well as leather, printing, and glass industries;, 40 percent of all' employees were smokers, and they experiencedl higher rates of' respiratory symptoms and illnesses than nonsmokers. Smokers with occupat'ional, exposure to dhrst werepartiicula rly affected. The effect of' cigarette smokiulg and' occupational exposure to dust on the prevalence of chronic bronchitis was examined by Golli (25) in Romania. There were 2,942'individualsexamined~ of whom 1'42wereempl'oyed in dusty occupations. Chronic bronchit'iswas present in 24.6! percent of the 457 smokers and 4.4 percent of the 2,343' nonsmokers (P<0.001). Increasing age, cigarette smoking, and occupational ex- posure to dust each independently contributed to an increased prev- alence of' chronic bronchitisi . Recent stud'ies~ in metal castiing,plaster, coke„ baking,agricultural,, and chemical industries have documentea a higher incidence of'respir- atory; sympt'om~sand/ordimi~nished pulmonary function among ciga- rette smoking workers than nonsmoking workers (4R; 64, 89, 97, 99). Air Pollution Rei'chel' andi Ulrner (68, 88) examined the effect of air pollution on t!lie prevalence of respiratory diisease among 8,162' men and women in West Germany. The three areas chosen for study had widely d7fferentatmospheric~ levels ~ of sulphur oxides and particulate matter. The fre- quencies of' cough and sputum production were the same within the nonsmokinggroup& in alli three areas. No differences were found in pulmonaryf'unction or arterialbl'ood gases between subjects,of the three districts. Smokers in each area had a higher prevalence of res- piratory symptoms than nonsmokers. The authors concluded, "There is no doubt' that the influence of air pollution is liessimportant than that of age, sex, and smoking habits:"' Tsunetoshi, et al. (85), examined the prevalence of chronic bronr ehitils,in Osaka,Japan: The independent contri'butionsofage, smokinghabitis, and air pollution were examined. In male cigarette smokers using more than a pack a day, chronic bronchitis was three to four times more prevalent than in nonsmokers. In female smokersusing, half a packormore, a day, chronicbronchiti& was! frR-etosixt'imesmore.prevadent thani in nonsmokers. Thestandardh'zedi prevalence of' chroniebronchitis increased with the degree of airpollut,ion,particu- lairly sulphur dioxidepollution,, but notwi~tlh increasing levels of suspended particulatemat'ter., 44 r

® yzng ai 5.3: i Respira~ he cotton 0 percent ~r rates of Gers with e to dust o11i (25) 142 were yt ini 24.6 tisrnokers ,onal ex- edl prev- ,ulturaI, E respir- 1g ciga;- ~ ; 99). t.ion on men in Lfferent 'he fre-Zin the und in of the of res- 'There 't than bron- ioking ioke.rs 1, four using times .ce of rticu-ls of 'If lie Federal Aviation Administration, Department of Transporta- t i„il. and the National Institute for Occupational Safety and! Hea1t'h. oit] v conducted astudy of the lev.elsof certain combustion byprod, u"ts of tobacco on military and civilian aircraft produced bypas- _,.»;,Wt-S• smoking, andl also asked the passengers for their subjective n•artinn to tobacco~smoke (90).I.evels,of carbon monoxide, particu- htv matter, poUycyclic hydrocarbons, ammonia, and ozone.vere meas-, urud on ?0 military and eight domesticflightls. On alll aircraftth~e,,,,•;i5ured level of' each substance was much lower than recommended. ,.-wipaiionai and environmental air quality standards. This was prob- ihlY the result of the efficient ventilation systems required on all air- ,1r1f t( 3Q exch~anges of eabinair each hour).More than 60 percent of the passengers reported that they were bothered by tobacco smoke and suggested that corrective action such ;t; ~~ ~•rcgation of smokers and nonsmokers be taken. More than 70' per- cnt of the nonsmokers who had' a history of respiratory conditions wereannoyed by tobacco smoke.Th:ediscomfortattributed!to tobacco IQniolce in spite of! the ~ efficient ventilation systemrnight haverefl'ected '•ro«-ded seating conditions or drying of the respiratory membranes ,diich results from the very low humidity found on most aircraft. Autopsy Studies _Vuerbach, et al.(4;) studied the relationship between age; smoking habits, and emphysematous changes in whole lung sections obtainedl at airtopsy from~ 1,443 males and 388 females. A tot.alof 7,324: sections I min. thick were graded on a scale o! 0 to 9 according to the severity of' euiph`-sema. No distinction was made between centriIobular and pan- Iobular eniphy.sema~ The men were classifiedl by age, type of smoking (pipe, cigar;,or, cigarette), and amount of cigarettesmoking:, Smoking habits were ascertained by interviewswit'h relatives. Within each of the six smoking categoriies, the mean degree of' emphysemn increased «•ithage. Ad'justingthe data for age revealed that the m~ean degree of' emphysema was lowest among men who never smoked,was higher in pi~pe or cigar smokers,, and hiahestamongregtilar, cigarette smokers. A dbse-response relationship was found for the number of cigarettes smoked per day andl theseverityofempl7ysema. Table2 and flgure2 show these relationships. Fingerland, et al. (19) investigated the prevalence of various patho- logical conditions includingemphysema and chroni'cbr.onchitisin an~ autopsy population comprising all peisons over the age ofl 20 who came toaut.opsy over a 2-year periodl ata',theInstitutaof1P'athol,ogical. _YiiatonYyiir Czechoslovakia; 765 malesandi Ci7:1femalesn ere included 45

in the study. Smoking histories were obtained, frorrli patients before death, medical records" or relatives,The smokers were divided into, three groups based upon the number of cigarettes smoked during their lifetime';, 26 percent of the male nonsmokers showed some evidence of I emphysema, whereas 70 percent of male smokers of more'than 500,000 lifetime ciga'rettes showed these changes (fig. 3). Similar relatiienshi~ps' ~ were demonstrated for chronic bronchitis: I TABLE 2:-De9rees of emphysema in current i smokers and in nonsmokers '. ~ according to age groups e d d f A Subjects wh Current i Packages smoked per day group an egree o g emphysema (see text) o never smoked regularly pe orr p cigar to 1 1 to 2 ?2' <60':. 0 to 0.75---------- 53' 18 12' 3' 2' 0 1 to 1.75'---------- , 2 11 4' 91 24 5 2'to 2.75---------- 0 1 2' 1'7' 130 56' 3 to 3:75---------- 0' 1 5 12' 50 38 4 to 4'.75---------- 0 0! 0 4 8 7' 5 to 6:75---------- 0 0 0 0 4! 5' 7 to 9:00---------- 0 0 0 0! 3' 1 1 ' Totals---------- 55 31 23 45 221 11'2I ~' Mean----------,--- ., 10 . 83 1. 29' 2.,37' 2.56 2: 86 ~ '--------------- .04! 13 .26 . 16 .07 .10 ~ 60 to 69: 0 to: 0:75---------- 35 17 4 0 0~ 01 1 to 1.75---------- 11 8' 1 0 4 1 I 2 to, 2:75---------- 2' 3' 4 5' 37' 23 3 t'o13.75---------- 2' 2' 2 9 42' 24 41 t'o 4.75---------- 0 0: ll 3 11 9 5'to 6.75---------- 0 0: 0 1 8 1 7'to 9.00---------- 0 0 0 1 5 4 Totals----------- 40 30 12 19 107, 62' Mean------------- .39 . 95 1.90 3.59 3! 39' 3.37 SD--------------- . 13. . 16 .34 .35 . 15 . 20~ 70 or older: 0 to 0;75---------- , 68 21 2 0' 0 0. 1 to 1.75---------- , 4 28' 10' 8 2 2 2'to 2!75---------- 5 22 13 23' 40 9 3 t'o 3.75---------- 4 8I 5 10' 38' 18' 4'to 4.75---------- 0 2' 1 7 11 7 5'to 6.75---------- 0' 1 0 2' 9 3' 7 to 9.00---------- 0 0 0 1 12' 5 Tot'a1s ---------- 81 82 31 51 112I 44 Mean------------- .50 1.66' 2. 15 2.98 3.68 3.91'. SD~--------------- .39 .11 .17 .20, .17' .27 I SubJ@cts who smoked regularly up to tima of terminalitllness. Source: Auerbach, 0., et'ali (4). 46

i hts before rided intfl ring their ~idence of n 500,0001 tionships Figure 2:-Age-standardized percentage distribution of whole lung sections of males with moderate to far=advanced emphysema (score 3-9), by smoking catiegory. 60 51.9' 50 ~ 40' . Q m 0 c~ 30 ~. 0 a 20 10, 7.5 36.8 Number 6 14 64 323 of Never Pipe C~igarettesmokers cases smoked regularty or cigars <1 pack/day } 1 pack/day 0 1 23'. 24 9 1 4 62 3.37 . 20 2 9 ~ 1& 7 3. a' 44 3! 91 .27 SOURCE: Auerbach, 0., et aIL (4). Mitchell, et a1. (60)1 conducted a study to determine the accuracy of' the recordedd cause of death on death certificates of' adul'tls; 578 autopsies were performed on patients 40 years of age and older at two large hospitals in C'oiorado. In addition,,409 patients with COPD were enrolled in an, emphysema registry. Autopsies were performed' on the 56 patients who died during the study period,Death certificates were obtainedl from the State Health Department, and the reeorded cause ofl death was compared' with, theautopsyfiimdings.I[n, 211 of'the634 autopsies performed, the cause of' death was found to be CO!PD ;, how- ever, in only 160 of these cases (76' percent) was COPD listed as the cause of death on the dleathi certificate; 3 percent of death certificates incorrectly listed' emphysema, as a cause of death when this was not supported by autopsy evidence. The authors concluded their study by suggesting " **' that nationall statistics, which are based on non- autopsy confirmed diagnoses; might understate deaths fromi chronic bronchitis andi`emphysema"''' 47

Figure 3.-Prevalence of emphysema in adult males at autopsy by smoking category. 80 70. 60' 50, 30' 20 10' 01 Number autopsies 145 Number w/ emphysema, 38 184 66 236 139 60 42' 109 53 Non- Number cigarettes smoked, during life Ex- smokers <a00;000 200.000-500:000 >500;000, smokers SOURCE: Fingariand, A., at aP. (1'9): Experimental and, Histopathalogicali St!udies Flistopathologicol Stzrd'ies StudilesiniM'ani Naeye and Dellinger (63) exarnined the small pulmonary arteries of' 126' male cigarette smokers and 67 nonsmokers for quantitative changes in collagen, elastic tissue, and circularly and; lbngitudinally oriented smooth muscle.Theyfoulida prog7•essive~increaseincollkgen~ 48

48.62 ! I 109 53 Ex- Molters eries Itive ially Igen And longitudinally orientedi smooth muscle fibers and a progressive ,lecres.se in circularly oriented muscle fibers with age. These ehanges tverc more advanced, at each age in smokers than in nonsmokers (P<0:01). Sobonya and Kleinerman (78); quantified the smooth, muscle and nwucous glands in the bronchi of 13'male cigarette smokers and 11 male i,vnsmokers from, Ohio who were 18 to 46' years olld' and had died of' uoilrespiratory causes. The smokers averaged 24 pack-years of ex- posure. Although the smokers had a history of more respiratory syanptoms and colds than the nonsmokers, no difflerence was found in r}iepereentagesof l smoothrnuscleorbronchial gl'andsbetween smokers:Ind nonsmokers. Five of the 13 smokers showed evidence of squamous mctaplasia. 1C~~Zlefsen and Tos (17) determined the goblet cell density in tracheall hiepsiesfrom~ 50 patients with respiratory symptoms or disease. Goblet , v Ll density increased with symptoms of tracheobronchitisandl history: of exposure to dust. A slight increase was also noted in mean gobletrell density with increasing consumption ofl cigarettes from~ 136 in. ,yanptomatic nonsmokers to 154 in smokers ofl more than a pack: a day. Studies in Animals Syzganov, et al. (81) exposed 55 dogs to cigarette smoke inhaledl through tracheostomas for periods of up to a~ year or longer. An addi- tional' 15 dogs served as nonsmoking controle. The smoking animals ,l'eveloped bronchitis, bronchopneumoniay interstit'ial pneumonia„ and hyper.plasia of the bronchial epitheliurn~, Later histologic changes in- vluded squamous metaplasia and papilloma formation not found in controls:The effect of sulphur dioxide (SOJ and cigarette smoke on~ the mucous glands of rats and the bronchial glands of lambs was studied by Mawdesley-Thomas, et a1.(57) . There was a slight increase in the goblet cell count of rats with the inhalationof SOz and cigarette smoke. Exposure of lambs to cigarette smoke inhaled through a tracheostoma resulted' in hypertrophy of t'he~bronchi'al glands..Jones, et al. (-39)' foundl that the addition of phenyTrnethyloxadiazol6 ( PllO ) to tobacco protects rats against some of the adverse effects of exposure to cigarette smoke., Two: groups of" 15 Sprague-Dawley ratis Were exposed to 25' cigarettes a day, 4 days a week for 6 weeks. The group exposed to cigarettes containing P.l'LO' showed less immediate(listtess~after exposure and hadl a lower tracheal goblet cell count,lessthiicl,eningof t.hetrachea~l epitheliumy and fewer cellsin mitosis,than, those exposedl to theregularcigaret'tes., The response of tllierat lung to low levels of nitrogen dioxide (NOz), ,L1 constituent of eigarettesmoke,, was studied by Stephens, Evans; and 49

their associates (l8y 80). Young male rats were continuously exposed to NO2 at concentrations of 2 p:p.mL andi 17 p.p.mL for 1 year. Animals were sacrificed after a short exposure and also at regular intervals over the 12-month period. At the level of 17 p.p.m., destructive changes ' occurred int.he respiratory epit'heliuni within 4 hours. Thesechanges4 inclluded cell hypertrophy, loss of cilia, and increased mitotic activity. After 24 hours of exposure att.his levell some repair began, but cuboidal' ce11sreplaced the normalrespiratory epitheli~um. At 2p.p.m.the,aeute :damage was less severe; and complet'e recovery occurred over ai period' ' of several weeks. Sherwin, et al. (77) studiedl the effectoflowdosesof' NO~,, on ths~al~veolar wall cells of thegiii~nea pig~ TheyfouQadl that'coitinuous `. exposure of 2 p.p.mLNO~ produc:ed!a significant increase (P< 0:05) in , thelactate dehydrogenase (LDF'I)~ index of'tlhelower lobes of the lung, suggesting that the~~ultrat'h~in~ t'ype~11 (;LDH~positit-.e-)~ alveolar w~all cells were being r.eplaced' by rel!ativelyy thick type 2 cells i.•esulting, in a physiologically significant~ blood, gas~ barrier. Pulmonary Function Ingram andi O7Cain (35) studied dynamic compliance in nine smok ers and nine nonsmokers under the age of 30 who were in good' health. Both groups were identical with respect to airway resistances, 14ing, volumes, maximal expiratory flow rates, and static compliance values. Dynamic compliance: felli more rapidly in the smokers than in the non- smokers above a freqtiency of 40 breaths a minute.. The d2fferenceff was statistically significant (P<0A001). Isoproterenol producecll no sig- nificant increase in dynamic, ¢ompliancein eithert'he, smokers, or the nonsmokers. In six of the smokers who stopped smoking, the dynamic compliance curv.es gradually approached the values of the nonsmokers over an 8-weekperiod. Changes over this,relatiwely~ long,period of'ti~meindicate thatl the decrease in dynamic compliance observed in smokers was more likely caused by inflammatory changes or some other mecha- nism rather t'hanmuscular constrict'ion in the bronchioles. The authors conclude& t.hat' peripheral' air«-ayabnormali'ties, are, regularly present in young asymptomatic smokers. T!'he effect of cigarette smoking on pulmonary d7ffnsing,capacity, was studied' by Van Ganse, et' al. (98). Difl'!usingcapacityis depend'entupon upmembrane component, which istheresistance offered' by the lung tissues,, and the volume of blood in the lungcapill'aries. 5tudieswere conductedon14'2 randon7ly selected residentsof. Berlin, N.H., over t'lie~ age.of25.Ii'i1 both meit Zndwomen,,tlsere was a decrease in d'aff!using ca.pacityy for carbon monoxide w°ithani increase in age and 50 3.

Rly expose tx. Animals~ ervals over ~e cha.nges~ se changes~ ic actlVlty it' cuboidil ~ the acute r a peribd OZ on the Dnt!iaiuous < 0:05), in. the lting,, wall cells. >ing in a le smok- ( health. es,, lung i values. he non- nee was no sig- t or the ynarnic 'tnokers of time tnoke rs. mecha- uthors )resent ty was mdent )y the ;ud2es ise in. ~ and n-ith increases in cigarette smoking. Ex-ci'garette smokers tended to lrax-e results siinilar to: those of nonsmokers. The authors found that the mebrane component did not show any consistent change with in- creased current cigarette smoking, whereas the volume of blbod in thelung capillaries decreased markedly with increasecUcigarette consump- tion, and slightly with age. The value ofl this vascular component in n1ale nonsmokers was 75A Thi's decreased1o.49:1 in males who smoked . ~:~, or more cigarettes aday' ( P<0:01I). The figures for women were, 77.2 and 50.7 for nonsmokers and smokers, respectively (P<0.05). Acetaldehyde is found in cigarette smoke and is a known ciliatoxicc at,rent'.., The single-breath retention of acetaldehydevapor by the respi-ra.torv tract of human subjects was,measured by Egle (16')~ who:foundl :l dlirect rel'iationshipbet'weeirthevolume inhaled and'thepercenttakenup. L'p~ to 00 percent of the inhaled acetaldehyde was. removed in a 4inr;le breathL, Stanescu (79)~ studied thesingle-breath oxygen testin: 38 male smokers and 68malenonsmokers who werein excellent,health:A sig- nificant difference (P<0.001) in the, slope of the nitrogen gradient between smokers and nonsmokers was f'aund.Teculescu~ (83) performed single-breath dieterminations of'total lung capaci ty ini 89 males, aged 19 through 6'7who: . had normal chest X-ray& and no history of respiratlorydi'sease. Nosigni'ficant ditl'erenceswerefoundlwithageor smoking habits. Pulmonnry Clearance Studies in Man Tracheobronehial clearance rates werestudied i'nniine pairs of'mono- z~~-gotic and nine~ pairs of~dizygoti~c,t.v~ins by~Camner,, et al. (1~~)~~. A test aerosoll of'r.adibactively ~~ tagged teflon parti~cles~ 6~ tlo~ 7~ microns~ in diarn- eten~ -,vasinhaled and external nieasurements~ of radioactiv~ity~ ii7~ thee huigs~were made. Tlleclearance patterns wit'hin pairs of'monozygotic twins~ were similar,~ more~ so~ than cl~earance~ patterns~ within pairs, of~ diz~i-gotic,tivihs„ indicating ~ that tracheobronch~~i'al clearance rat'es~ may to~some extent be,constit'u~~tiiona111y.~determidied'~. Only~one~individ~ual had been a re~*ular cigarette smoker. Camner and Philipson (10) also~stludied tracheobronchial elearaauce~~ in~ s3uokinr-discordant twins, using~the~sametlecluiiques~ as~in tlhe~pre- vibus studv; 10~ paiirs of~ monozti'gotic twi:ns~~ discordant with regard tlo~~ cigarette smok~ing, w,ere, studied. All the~ smokers~ had usedl M to~ 20 cil,rarettes a day ~ for more than 2~0~ years! Tr~ach:eobronchial clearance was, on tili:e average,~ significaQitly,~ (PCtY.02), slower in the~ smokers~ 495-07.8:0-73~-- a5. g1l

than in the.nonsm:okers: Although the basic rate of mucociliary trans- port may be~ eonsti~t!ut'iienally~ determined, it is~~ evident that cigarette- smoking, decreases the effectiveness of this physiologic rnechanismL The regionall deposition of inhaled aerosols in lnan was studied' by Lippmann, et al. (50)„ who used a monodisperse ferric oxide aerosoll tagged~ with: ai radioisotope. Particles~ were~~ deposited, in~ the ph~arynx~~,, trachea. bronchi, and alveoli. Measurements were made in 65 ' adultls including 14 nonsmokers, 29 current ci~garette~ smokers, six~~ elderly bronchitic~ patients, and' one~~ young asthnaatic. Larger~~ part-icles~~ were deposited in the ~~ upper, a~i'rw~ays~~ by~~ t~urbulent precipitation with only~ the srnall~~ particles~ of ' one to~ five~ micron size reaching, the~ lower air- ways. The cigarette smokers, bronchitics,~ and the asthmatic had a higher proportion of particlps~ deposited' ini the t.raclleobronchial area than nonsmokers. As a result, fewer particles reached the alveoli in t~hese~ patients. These fi~ndings~ may be, the result~ of~ a decrease~ in the~~ diameter of' the~ small bronehioles~ d~u~e~ to~ iutiarnmation,, mucus;~ or~ b ronchoconst riction. Albert, et, al. (3~)~ stud~iied' the~ effects~ of' cigaret~tle~ s~moking~ on the~ ki~netiics~of'bronclYial clearance in a group of volunteers~~most of~whom also ~ part.i+eipatedi in the~ previious study~. A two-phase clearance pattern was described for many subjects. The first, a short, rapid clearance phase, was completed, within a few hours and' probably represented clearance of the upper airways. The second phase varied in durationi from al few hours to 1 day andi represented, clearance of particles deposited in the distal! portions of' the bronchial tree. The aueragee clearance time wasJ2~6~ minutes in ~ 15~~ nonsmokers, 170 minutes~ in 1LRof' the~ smokers,~ and~, 238 minutes,in the~ six patients ~ with bronchitis, most ~ of~whom~h~ad~beenihea~vycigarett~e~smokers formany~years. 1lfucli vari- ation in clearance rates was found among smokers: Ciaarette smoking resulted in diminished pulmonary clearance~~i'n the upper~ai'rway-s~first~.. As a, result, mucus~ cleared from~th~e, lbwe~r a~irw.ays~ accumulated in thQ, larger airways where stasis occurred. Iin severe cases, stasis was more generalized throughout the bronchial tree.. Sanchis, et al. (7~.) also studied lung,clearance mechanisms in nine adult ~ fernales~ who1a~d smokedl rnore~~ than 15~~ ci~~garettesa~, day for more~ thani 5 years andi who had no evidence of bronchitis or respirator3~~ disease. A ~ group~~ of nonsmoking, females~~ matched~ for~~ age~ servedi as~~ controls~. A heterodisperse aerosol of I'"l' taggedi human albumin was i'nhaled by the volunteers, and measurements' of radioactivity were made over three crescentic areas of the right lung, which corresponded to: largeci~liatedlairways; intermediate~bronchi,~and noncili~~ated periph-~ eral~~ airways~ and alveoli. Cigarette ~ smokers exhibited a~~ sl~owing,of'' the~ rapid clearance phase of the large ciliated airways and also a relative aeceleration in~ the second clearazice, hhase: resulting in~ air a~ccunlula-~ tioni of activity at~ the~ li~ilar area. Comparing the~ clearance~ among~ 52

r trans- !arette- M aed by Lerosol krynx, adults Tderly ' were k only ir air- had a !' areaa o1i inn n the is, or n the Phom ~tern ~ance inted ition ,icles rage '9' of' nost rari- ting !tlie lore aine& tore ;or3.• 11 as n-as 'ere ied ah- ,'he: i ve la- ug, smokers andl nonsrnokers; the authors found that the nonsmokers re- tained' twice as much activit'y, in the lung at t'~heend of 24 h:oursasdid the smokers., This finding resulted from the deposition of' much more rnf' the aerosol distal to the ciliated airways in nonsmokers than ih smokers suggesting that seemingly healthy smokers may have.obstruc- tion of the small airways. Chmner, et al. (11) examined'the short-tlerm effects of heavy cigar- ette smoking,on mucocil'arytransport',using the same meth:odsas,in his previous ~ studies (1,0,12').Thesubjects were13men aged 27t'o38'.wholia~d been habituadl smokers for severaly.ears. B'aselineclearancerates%vere measured after refraining from cigarette smoking for 1 hour. 'The subjects then repeated the test but were instructed to "chainismoke"bi•, inhaling thesmoke as deeply. and as freqpently as possible; but %vitllout coughing. Subjects smoked much more intensely than under iaormal circumstances.The speed of mucocilary transport was sig- uiEicantly higheirduring, int'ensiveeigarette smoksng than wheni they \verenot smoking (I'<0.01).Theseresu~lts differ from the results ofot.ber investigators.. The effect of the deep regular inhalation patterns used during the period of heavy smoking on cllearances rates remains uncertain. Studies, in, Animals Rylander (73) studied the effeet of cigarette smoke on the clearance of radioactively tagged particles and viable bacteria in the lungs of 114 experimental and cont.rol g,uinea pigs. The clearance of' parti+eles ineasuresmueustransport whereas the clearance of v.iabl'ebacteriai is a li),tirtiali indicator of phagocytic activity. Inhalation of smoke from 1•igarettes~ .vith varying levelsof"`'tar" resulted in similar decreases in Wt:h the mechanical and bactericida~ll clearance. In each case, the me-clianacal clearance appeared to be affected earlier than thebactericidal clearance. When phenylmethyloxadiazole (PnZlp) .t-as added to the tobacco, neither the mechanical norba~ctericiidall clearance was affected lhy cigarettle smoke. Dalhamn and Rylander (14) alsoreportedthat phenylvinyloxadia- zole (Pti"O), and phenylmethyloxadiazole(RMO)',when ad'dt•d totobacco, were effective in reducing the ciliotoxic effects of cigarette smoke in in vivo cat trachea preparations. Phaqocytosi s, Rylan&r (72~~)~ st-udiedl the effect of aeute~~ and chronic~ exposure to~ «igarette~ smoke~ on the number of alve.ola.r macrophages~in the~ guinea [>ig: Acute exposure to t.he~ smoke~ ofl fiv.e~ or more cigarettes,~ resulted in 53. 0 0 0 0

a significant (P<0.05) reduction in the number, of al'veolar macro. phages. With more prolonged exposure to cigarette smoke, an increase occurred in the number of alkeol'ar macrophages over control values. ~ The effect of nitrogen dioxide (NO2), a, compound found in cigar- ette smoke, on alveolar macrophages ini rabbits was studied by Acton and ltifyrvik (1). Phagocytic activity and virus+induced'resistance to rabbitpox virus were: suppressed byexposuretlo 15:p.p.m.of NO~, overai 3~-hourperiod. Bacterial and Mycological Studie8 The prevalence of'fungi ini the throat was examined by Martin,,et al. (56) in a population of'365 male and 103 female European patients in South Africa whowere hospitalized for a variety of conditions. Throat swabs were taken shortly after adh-rission and plated on appropriatee culture media. The yeasts isolated were Rhodotorula mcilaginosa, Torulopsis gjabrata, and seven species of Candida. A seasonal, varia- tion inn prevalence was noted with a decline in the winter andi with peaks in the spring and summer. Smokers of more than 30 cigarettes a dayy had a higher prevalence of pharyngeal fungi than nonsmokers or tllose smoking less than this amount. No effect of'age or disease category on the prevalence of pharyngeal fnngi was found. The bacterial flora in respiratory tree secretions okitained' at brom choscopy from20'7patients with chronicIungdisease and 48 controls were characterized by Dobisova. et allin a study from Germany (15) 1. No relationship was found betweenismokingo~rseveritlyof respiratory.symptomsand tliecomposition of'thebacterial flora. They also reported, that smokers ~ comprised 84:6percent of those with chronic cough but only 58.3 percent of the controls. The effect's,of nitrogen daox~ide and cigarettesmokee on the, retentionn of inhaled bacteria were investigated by Henry,et al. (32). MalegoIdeni hamsters were exposed to an aerosol of IClebsiolla, pneumoniae follow- ing exposure t!o, NO., and/or cigarette smoke. A control group was ex- posed to the pathogen without pretreatment. Acuteexposnre toeitherNO:or eigarettesmoke resulted in ann increased mortality and de- creased survival tinie f rom Klebsiella infections. Exposure to both NQx arldl cigarette smokere-duced the rate of clearance ofc•.iable bacteria . froni the lungs t!o~ a;leater extent thani exposure to either substance alone. Theinrreaseiln lettiall effects of Kaebsiella exposure, may have resulted~ from inhibition oftliemucociliarytransport system or reduc- tion of' phagocytic capacity of tliealvenlair niacrophages. 54

I macro- erease valizes. ~ cigarl Acton lnce to `~, over ~,et al. nts,in. hroat n iat,e osa,. 'aria- nith tes a rs or, gory~' Iron- ~ro1s 15). tory tted but tion. den p«-- i ex- her° de- fO2 ice we kc- T1ie Sur f actant System Finley and Ladman (20) measured, pulmonary surfactant in ciga- rette smokers and nonsmokers. The surfactant was recovered after en- ~lohronchial lavage.The lipidl content'of surfactant in smokersands nonsmokers was qualitatively similar; however smokers had oni the average only .14.3 percent of thesurfactantlevels found in nonsmokers. "L"heir levels of su.rf~actant ret!urnecl' promptly to levels found in non- smokersfollo.ving cessation of smoking.. Cigarette, smoking m~ayre-duce the quantity of surface active material lining t'healveolarwall's, through either, decreased production,, ani increased removal,, or a ,dilu- nion with mucus1rom the airways. Summary of Recent Nonmeoplastiic, Bronehopulmionary Findings ][n, addition: to the: summary presented in the introdkiction of this chapter, based on previous reports of'the health conseqpences of'smok- ing, the follbwing statements are made to emphasize the recent develop- ments in the field : 1. Epiderniologic.al andi clinicall studies from several countries con- firm that cigaretlte smoking by both men and women: is associated with an increased prevalence of respiratory: symptoms and de- creased pulmonary function compared to nonsmokers. 2:The regular use of filter cigarettes is associated with less cough and sputum production eomparedd with the regular use of' non, filter cigarettes. 3! Cigaretite smoking in combimation with certain occupational ex- posures is associated with: a higher prevalence of respiratory symptoms and CO!PD than is observed with either cigarette smoking or oecupationaI exposure alone. By?ssinosis is found more frequently in cotton mill employees who smoke cigarettes than in nonsmoking workers. 4.Recentautopsyst'u~dies, confirm that pulmonary emphysema, i& much more frequent and severe in cigarette smokers than in nonsmokers. 5. Several recent investigations have confirmed that cigarette smok- ing exerts adverse effects on pulmonary clearance and rnaero~ phage function. 55

Bronehopuilmona'ry References (1) AcroN, JL D:, MYRVIK,, Q. N. Nitleogen dioxide effects on alveolar macro- phages. Archives of' Environmental Health 2.1(lp : 48-52, January 1972. (2) AKatiN, :'1T:, OzauNUL, H. Smoking and lung function measurements. Acta Medica Turcica 8(Y,) : 34-44, 19711. (3) A.r;BERT, R. E., LlPebtaNN, M., PETERSaN, H, T., Jr., The effects of'cigarettef smoking on the kinetics of bronchial clearance in humans and donkeys. In: Walton, W. H. (Editor). Inhaled Particles III. Proceedings of'an International Symposium organized by the British Occupational Hygiene Society, Londbn, Sept. 14-~-23; 1070. Surrey, England, Unwin Brothers, I1td'., The Gresham Press, 1970;,pp: 165--182; (ly,). AUERSA(;H,..O., IIADfSSO-iD, E: Ci.,,riARFINKEL,. L.,. BENANTD, Ci. Relation ofsnroking and' age to emphysema. Whole-lung, section study. New England Journal of Medilcine 286 (16)' : 853-857,, Apr. 20,,1972. (5) Bdxewr, M: A. Ez... Health problemsi of ind'ustrial workers in Egypt'. Inr dustrial' Medicine and Surgery 41(2) : 18-23, February 1972. (6) BEQKI'.AKE,,M. R.,..FQIIRNIER-MASSEy, G., RQssITER, C. E.,.MCDOViALD,.J'., C:.. Lung function~in chrysotile asbestosmineand', mill workers ofQ,uebec. Archives of' Environmental Health 24(6) :, 401-409, June 1972'. (7): BLO.Hy4KE~ M.,. DEPNER, R., GRUNTZI6, A.,., KosCHORRECK,, B., STELZER; OL, Uber Unterschiede in der Herz-Lungenfunktion und Befindlichkeit bei 1Vlannern mit verschiedenen Rauchgewohnheiter. (On differences in the heart-and-lting function and feeli¢ig, healthy, in men with different smok- ing, habi,t's.) Z'eitschrift fur Praventivmedizin, 14(4) : 23a-242, Jully- Augnst 1969:. (S). B'QUHUFs,, A_ WULF80Ny. R:. L.,. HORNER;D. W.,. BRAIN,, J. D., ZIIBKIN,. E. Byssinosis in cotton textile workers. Respiratory survey of a mill' with rapid labor turnaver. Annals of Internal Medicine 71(2) : 257-269„ Au- gust' 1969. (9) BaowxrNa„W. H. Deleterious effect's of cigarette smoking and 10tW percent oxygen on aircrew members in high.performance aircraft. Aerospace Medicine 41(1,) : 39-42, January 1970! (10) CAhrrEx; P., PH,ILIPSON, K. Tracheobronchiall clearance in smoking-discord~ ant twins. Archives of Environmentall Health 25(1) : 60-63;, July 1972. (11) CAaENER, P., PIriLIPSON, K., ARviDssoN, T. Cigarette smoking,in man. Shortr term~ effect on mucociliarg transport'. Archives of' F]nvironmental Health, 23(6) : 421-426, December 1971. (12) CAraNra, P., P2iiLIPSON, K.,, FRIRERa, L. Tracheobronchial' clearance in twins.. Archives of Environmental Hea'1tlh~ 24!(2) : 82-87, Febru'ary1972., (13) CounRAY, P., SERIsE, Mi, FREoua, P'., Recherche epidemiologique sur les' bronchites chroniques et les insufFisanees respiratoires. etude de: pre- valence dans un echantillon de femmes de 30' ai 70 ans,, (Epidemiologic study of' chronic bronchitis and respiratory insufficiene5. Prevalence in a sample of women 30 to 70 years of . age. ) Revue de Tubereulose et de Pneumologie 33'(6) : 769-780; September-October 1969. (14.). DALHAM'N, T., RFLANDER; R. Rednctllon of cigarett'esmok'e ci~liot'ONiCitVby certain tiobacco, additi~ves:, American Reviewof, Respiratory Disease 103(6) : 85a-S57, June 1971. (15) DOBISOVA, M.,,TRwKA;. L., FISER; F:, ToatAnEK,,A. Abhiingigkeit der mikro- biellew Flora im Bronchialbaum von der Branchialsekretion und den liust'ensymptomen bei' chronisehi Lungenkranken. (,Dependence of' tiie bronchial secretion and' couglr sym,ptomsi on the microbiall flora in the 56 a

macro- ry 1972. 'ts. Acta tigarette ~onkess. ~ of an Sgiene iothers, ~tionI of ~nglandi J. C. uebec. ~ aR;, O. Ot bei'. ~ in the I smok- ~ Julq- ~N, E. I with Au-~~ i ercent, jjspaee I' cord- ~1972.. yhort- ~ealth I ~ce in ' 1'972. 'r les I pre- jlogic. ~e inn et' de I w by' ease kro- den thee the bronchial tree of chronic lung disease patients. ) Praxis der Pneumologie 25(5) : 249-254, May 1971., (16) EGLE, J. L. Single-breath retention of' acetaldehyde in man. Archives of' Environmental HeaTth23(6) :,427-433, December 1971. (i17) ELLEFSEN, P., Tos; M. Goblet cells in the human trachea. Quantitative studies of! ai pathological biopsy material. Archives of Otolaryngolbgy 95(6) , : 547-555, June 1972. ( 1S)! EvANS,. M. J.,. STEPHENS, R.. J., CABRAL, L. J., FREEMAN, G'.. Ce11U renewal. in the lungs of rats, exposed to low levels of NO4: Archives of Environ* mental'Health 24(3) : 180-188; .NTarchi 1972: 119) FINGERLAND, A., HvsAx, T., BENDLOVA, J. Contribution to the investiga- tion of the effect of cigarette smoking. Sliornik Vedeckych Praci Le- karske Fakulty Karlovy University v Hradci Kralove 14(2) : 227L-234,. 1971. (20) FINLEY, T: hl., LAnriAx, A. J: Low yield of pulmonary surfactant in ciga* rette smokers, New England Journali of Medicine 286(5) : 223-227, Feb. 3, 1972. (21) FbuRxIER; E., ZTvY,, P. Poumon et tabae. (Lung and tobacco.) Poumon et le Coeur 26(9) : 1109-1125, 1970. (22) FREEDMAN, S.,, FLEmaHeR, 0. M., FYELD, G. B. Effects of smoking modifiedi cigarettes on respiratory symptoms and ventilatory capacity. Journal of the National Cancer Institute 48!(G) : 1805-1810, June 1972. (23): FREOUR, P., CouDRAY, P. Le probleme des bronchites~chramiques a Bordeaux et en Gironde. Etudes epid'emiologiques. (The problem of' chronic bron- chitis at Bordeaux and at Gironde. Epidemiological studies.) Bordeaux Medicali 3( 7/8): 1745-1779', July August 1970: 124) ) GoLLI, V. Ertude epidemiologique des bronchopathies non specifiques. (Epidemiological study af' nonspecific bronchopatbies: ) Bronches 20(5) : 313-330; September-October 1970. (25) GbLLI, V., L'Influence de l'usage du tabac et de 1'emoussi@rage sur la frequence des bronchites ehroniques: (T1Ye effect of the use of tobacco and the inhalation of dust on the frequency of chronic bronchitis.) La. Presse iVfedicale 78: 1542-1543, July 28-Aug. 1~ 1970: (26): GOLLI, V., STEFA.NQN,. Ei, STAN, R'., TtTRPP.ESCU,., B.. Etudee sur la.1lrevalence: actuelle de Ia bronchite chronique dans une population~ urbaine. ( Study of currenti prevalence of chronic bronchitis in an urban population.) Acta Tuberculosea et P'neumologieaBel'gica 60(5) :: 714-725, September- October 19ft , f27): GRAczYx, Jl, BuRALSxA, Z. Przewlekle zapalenie oskrzeli i ocena. wydbinosci oddechoweji u, ozdttowiencow z gruzlicy. (Chronic bronchitis and assessment of respiratory filnct'ion im convalescents after tuber, culosis. ) Gruzlica i Choroby Plue 39(7) : 610~-635; July 1971. (28) GREGORY, J. A study of 340 cases of chronic bronchitis. Archives of En- vironmental Health 22(4) : 428'-439,, Aprill 1971. ( ti 9) HABER, Jl, HORVATH4. R., KIS:HI\ DI 1ZI55;., K., PAL, II., ,5"IMON~. Z., 2iIBO'rI'Csi, H. A dohanyzas es felso leguti hurut koroki szerepe ai Peesi szenbanyaszok kronikus bronchitiseben. (Smoking and upper airway catarrh as factors cau,ing chronic brnnchitis, in coallm,inersfrom the, city?ofPecs.) Orvosi. Hetilap 112(23) : 134-t-1348,, Ju1e 6;,19"T1.. (a0")HAGERup:, L., LARSET,, M. Tobaksrygning og respiratoriskesymptbmer i en Dansk population. Fra 50; ars undersogelsen i Glbstrup: (Tobacco smok- ii7g, andl respiratiorysymptoms ini a IDanish populatiom From, a: 50-year study inGlostrupj Ugeskrift for Laeger 133'('7) : 130'2-130G, Julh9,. 1971. 57 0 0

(31) HARRrs, T.R., MkRCxANT, J., A., KILBUSNti K. H., HAMILTON, J: D. Byssino- sis and respiratory diseases oflcottbn mill workers. Jburnal of' Occupa- tional, Medicine 14'(3) : 199-206, March 1972. (32). HENRY, M. C ., Sps1NaLER, J_ FINDLAY,..J.,,EHRLICH,.Rs.Effects.of.nit'rogeni dioxide and tobacco smoke on retention of inhaledl bacteria: In: Vhal- ton, W. H,, (Editor). Inhaled' Particles 111. Proceedings of an Inter- national Symposium organized' by the British Occupational Hygiene Society, London~ Sept. 14-23, 1970. SSurrey, England, Unwiin Brothers, Ltd., The Gresham Press, 1970, pp. 527-533. (8J) HUNTER, Ml B. Symptomatolbgy. In: Key, M. ML, Kerr, L. E., Bundy, M. (Editors). Pulmonary Reactions to Coal Dust. A Review of U.S. Ekperi- en+ce, New York, Academic Press, 1971, pp. 57--69:. (694) HvrrEaaAN, T:, OSWALD, P., LoDE, H., Hucxkur, HL Veranderungen der Lungenfunktion Jugendlicher, als Folge Iangjahrigen Zigarettenrau- ehens. (Changes in pulmonary function of young, people as a result of cigarette smoking over many years.) Deutsche Medizinische SVochen- sohrlft 96(46) :,1791-1793, Nov., 12, 1971. (35) IxoRAMS R. H., Jr.,, O'CAIN„ C; F. Frequency dependence of compliance in apparentl'y healthy smokers versus nonsmokers. Bulletin de Physio- Pathologie Respiration 7: 195-212, January-February 1971. (36)1 Jwr:clx, E. Pneumopathiesichroniques non speciflques: Enqudtte epidemio- Iagique A Brno: Rapport prelminaire. (Chronic nonspecific lung diseases :. Epidemiological investigation; at Brno. Preliminary report.) B'ronches. 19(2) : 185-199, Jfarch-Aprill 1969. (J7') JANCI$, E. Quelques donnees et correlations provenant d'1iae L+tude epi- demilogique sur ti'incidence des symptomes cairacteristiques des maladies respiratoires chroniques non specifiques. (Some facts and correlations fromi an epidemiologic study oni the incidence of' symptoms character- istic to chronic nonspeeHc lung diseases.) Revue de Tuberculose et de Pneumol'ogie 34(5): 749-752; Julp-August 1970. (38) JANcnic, E., JhNCIx-3IAx, M. Chronische unspezifische Lungenerkrankun- gen. (Chronic, nonspecific lung diseases.) Praxis der Pneumolbgie vere- inigt mit "Der Tuberk:ulosearzt'." 26'(2)1: 69--81y February 1972. ($9)JoNES, R., B'oLDUa, P.,, RErn; L. Protection of' rat bronchiall epithel.ium against tobacco smoke. Biriti'sh liedical' Journal, 2(5806) : 142-144,,Apr. 15, 1972'. (40) KEY,, M. M., KERR, L. E., BuNDY;, M. (Editors). Pulinonary Reactions to Coal Dust. A Review of'. U.S. Experience. Environmental Science Serie& N'ewYork, Academic Press, 1971, 215 pp. (41) KaosLA, T: Indices of' ventilatory measurements; British Journal of Pre- ventive and'Social 1liedicine 25(4) : 203-209, November 19711 (42), KiRCxx,NOpF, bl'., SovAGo, Ji. Az idiilt h8rghurut elofordulasa az~ Ozdi, kohaszati iizemek flhomliengermiii dolgozoi kareben, (The incidence,rat'e of chronic bronchitis among the precision calendering workers at the foundry of Ozd.) Orvosi Hetilap 110'(41'J : 2584-2586, Nov. 2; 1969. (43) KORNITZER, 5f:,, DEnrEESTER, M. La symptomatologie respiratoire en epi- demiologio. Rpsultats de 1'enqtTete effectuee dans une banque Bruxelloise. (Respiratory symptomatolbgy in epidemiology: Results from ai survey effectedl in a bank in Brussels.) Acta Tuberculbsea et Pneumologica Belgica 61(5j6) : 481-506', September-December 1970: (44) LArNKART, W. S., 'MaRaAN, W. K. C. Extent and distribution of'respira- tory effects. In: Key, M. M., Kerr, L. E., Bundy, M. (Editors). Pulmonary Reactions to Coal Dust. A Review of UIS: Experience. New York, Aca- demic Press, 1971, pp.,29-56.. 58 ; _,,:r

4no- 'upa~ ~gen fRal- iter- lene lers,, ~ ' M. leri- !der rau- ~ of Men-. Biil (45)', LAticl:Awos, J. H. JII, WALLACE, W: F. M., SYbiPSON, BT., J. C. Insulatlion workers'in Belfast. 2. Morbidity in men still atl work. British, Journal of' Industriall\Iedicine 28(3) : 217-225, July 1971.. ( iG), LAPP, N. L.,, HArxiNsoN, J. L., B'URGESS, D. B., O'BRIEx,, R. Changes inn vent'ilatbry function in coal miners after a work shift. Archives of En- v ironmential Health 24 (3) :' 24f1-248;, Mit:rch19"72. (~7) L~kPP, N. L.„SEATaN, A., KAPLAN, K. C:, I3u:vsAx1:R, ML R:, MoRGAN, W. K. Cl Pulmonary hemodynamics in symptomatic' coal miners> American Re- view of Respiratory Disease 104(3) :~418-^426', September 1971., (48) LATIMER, Rl G., DICKISIAN, DAY, W. C.,, GuNx, M. L., SeaacIZrr; CJ, ID. Ventilatory patterns and pulmonary complications after upper abdomi- nal surgery determined by preoperative and postoperative computerized spirometry andi blood' gas analysis. American Journal of Surgery 122'(5) : 622-632, November 1971. (49) LEE, D. H. K. Etiolbgy: In: Key,, M. \1l, Kerr, L. E., Bundy, M. ( Editors) . Pulmonary Reactions to Coal Dust. A Review of U:S, Experienee: New York,Academic Press, 197,1, pp. 189-193'. (50) LIPPINrAr:.; M., ALBERT; R.,D,,,PETnRSON', H. T., Jr. The regional deposition of inhaledl aerosalsini man. In; Walton, VG.H:('E~ditor). Inhaled Par- ticles 111. Proceediingsof an Int'ernatilonal' Symposium organized, by the British Occupational'bI;ygi,ene Sbciety, Lond'on, Sept. 14=23',,1970: Surrey, England, Unwin Brothers, Ltd., The Gresham Press, 1970,, pp. 105-122. (15l')! LowE;, C. R., KxosLA, T. Ch,ronic' bronchi'tis ia ex-coal miners working, in ttiesteel industry. Britis~h~Journabof'Industrial 3ledieine29'(1) : 45-49, 1972. (52) LYONs, J. P., RyuER, R'., CAMPBELL, H., Gouax, J. Pulmonary di'sability in coal workers' pneumoconiosis. B'ritish Medical Journall 1(5802) : 713r 716, Mar. 18; 1972. (53'.) MCDONAI:B;, J. C., BECKLAI{E, M~ R6, F"oURNIER, «A6fiEY', G., R'086ITER, C. E. Respiratory symptoms in chrysolite asbestos mine and mill workers ofl Quebec. Archives of Environmental Health 24(5) :~ 358-363, '.Ntay 1972. (54) \1cKEBROav, C. Bi,, ScxILLING, IL S. F. A pilot enquiry into byssinosis in' tw o cotton mills in the Unitled States. Jburnal of the American Medical Association 177(12) : 850-'-853, Sept.,23, 1961., (:59~)1 JS'xrrU;, P., DUmITRIU, M., Gx'ISE,, 0., C'ONIA'ra'ESCU,, C. Cercetaril epid'emio-logice privind bronsit'a cronica la un lat,din populatia generalai a orasului. Bucurestii ( Enidemiological sthldies onichronic bronchitis in a sample of the general popuhition of Bucharest.) 'lledicina Interna 22'(9)1: 1123-- 113'4. September 1970. (S6.). MARTIN. P., KANAREK, D., Zwi. S,, BOYU, A. V., KO0R5HOF, H..J. Thei.nci- d'ence of fungi in the throat. Mycopatholbgia et Mycologia Applicata 45~ (2) : 165-187, Oct.,13; 1971. (57) MAWUESI:EYf-TIIObfAB, L. E., HEALEY, Pl, BiARRY, D'.. H.ESCperi]llenta1' brOn~chi,tis in ani,mals' due to sulphur' dioxide and cigarette smoke,. An auto- mated quant'itati,vest'ud'ye in~:'«'alton„W. H. (Editor). Inhaled ParticlesIII'. Proceedings of' an International' :1y1uposi!uan organized by the British Occupational Hygiene Society;London. Sept. 14-23; 1970! SSurrey, Eng-land. L!'nwin Brothers, Ltdl, The Gresham, Press. 1970.1)1). 509--526. ($S.). MERCICArT. J'.. A., KILBURN, K. II.,, O'FALLO:Y„ AV., Ml, IIAMILTOti.,, .I. D:,.. Lti~MsnFN~. J. C. Byssinositiand cl'ironicbronchit'isanlungcott'ont'extile«°orker,. Anna15uf Int,ernal\Iedicine 76(3) : 423'-433;, _1larch 1972. (59) MILLr:R, G. J., AsllceoFT. 11. T. A community survey ofrespirutory disease tunnngEast Indian and.A'f'ricanadultsim(;uayana. Thorax26(3,) :3.31- 338, .llaly 1951. 59'

(60)! MITCaELL, R.~ S., :1'I.4I6~:EL,~. J.. C.,, D1YRT!, G. A_ SILVERB;. G': W. The'e accuracY~ of'the death certificate in reporting,cause of death in adults, with, special reference to chronic bronchit2s~ and: emphSsemaL American Review of Respiratory Disease 104(6) : 844-850; December 1971. (6I~). DIbR(IA~?Il. «'. K. C., BURGESSL D: B., LA'PP,~. N. L., SEATOY; A., REGER, R.. Bl.. Fiyperinflation of the lungs in: coal miners. Thorax 26(5) : 585-596, September 1971. (62) 1NTAEYE, R. L. Structural features in Appalachian coal workers. In: Key, 1Cf. 1111, Kerr, L. E;,, Bundy, 3T: (Editors)_ Pulmonary Reactions to Coal Dust. A Review of U.S. Experience. :Vew York. Academic Press, 19714 pp: 93-110.. (63) NAE'gt•*, R. I:.,, DELLI:voER; W. S! Pulmonary arterial changes with, age and, smoking. Archives of Pathology 92'M :284-288; October,1971. (i64) OsvsrxsRa4 J:, JA:v'US,, T., 1TxsTIK, 3T. «'y.~stepowanie' przewleklych nies- woistych chorob ukladu oddechowego (p.n.ch.u.o.) wsrod pracowni;kow zakladu przemsslul gipsowego "Dolina Nidr" w Gackach. (Occurrence of chronic unspecific diseases of the respiratory system among wnrkers in the plaster works at "Dolina Nidy" in, Gacki. ) Przeglad', I:ekarski' 24 (7) : 476-480; 1971. (65) PAteDE„ R. S:, 1IARwAHA. R. K., PATEL, IV. Ji Smnking and lung function. Indian Practiitioner 4(17)1: 353-357, July 1971. (66)'RACO3'EANU; C.,: MA:tiSCATI'DE., M.,NIICOLAESCU, V. Cereet'arii epidemiolOglcee asuprai bronsitei cronice in duoa zone fara poluare atmosferica indus- triala. (Epidemi'ological study ofchronicbronchiltis imtwo'regions with- out industrial air pollution.) Studii si Cercetari de JI'edicina Interna 12(4) : 35"67; 1971. (67) REGA:v, G. JIi, TAGa; B.. WALFORD, J., TaoNrsox; M. I., The relative impor- tance of clinicall radiological, and pulmonary function variables in eval- ttating asbestosis and' chronic obstructive airway disease in asbestos workers. Clinical Science 41 : 569-5821 1971. (68)' REICHEL, G. Effect of air pollution on the prevalence of'respi'ratory dis- eases in 1VestG.ermang: 1'n:•,h.nghmd. H. M. Beery, W. T.(iEditors). Proceedings of The Seeond:Internationai Clean Air Congress. Washing- ton, D:C:, Dec. 6-11, 1970: Academic Press, New York, 1971, pp. 186'-191. (69). REICH:EL,. G., UL3IER. W. T., IHONOM',IDES:. ~'.. Z. Elnfilisse der. R'aIICherge- wohnheiten auf~ die Fiaufigkeit unspezifischer Atemtivegserkrankungen, III. 3fitteilung; (Inflaence of' smoking, habits on the incidence of' non- specific respiratory diseases. II'Il (Communication.) Internationales Archiw fur Arbei:tsmed'izin27(1/2) : 4i~42, Oct. 30, 19'70. (7Q)' REID, D. D: Bronchitis among the British. Israel Journal of' :lfedical Sciences7'(12) : 1'569-1'5'72, December1971i. (YY)1 RitulrwaTox, J. Phlegmi and filters. British Medical Journal 2(5808)': 262-264, Apr. 29,1972: (72) RYaArrDER;, R. Free lung, cell, studies in eigarettesmokeinhalationex'- periinents. Scandinavian Jourmill of Respiratory Diseases 52'(2)': 121- 128, 1971. (7'd)' RvLAIN'oER, R', Lung,clearanceof particles and bacteria. Effects of cigarette smoke exposure. Archives of' Environmental Health 23(5) : 321~-326, riTovemher 1971. (74:)' S'Arrclnls, Jl, DaLOVZaIi, J1., CirAL.ME'RS,, R., NEwao[;sE, J'1. T. Regional' di,trihutiom andl lung, cle;ir<<aice mechanismsii1 smokers and nr7n- smokers,iii.• Wa'It'on; W. H. (Editor). Inhal~e& Particles III. Procec+dingsof' an International Symposium organized by the British, Occupat'sonal.

~curacy Hygiene Society, London, Sept. 14-23, 1970. Surrey, England, Unwin special Brothers;,Ltd., The Gresham Press, 1970. pp. 183--191. ~'iew ofl SCHBAG, P'., E., GuLLETr,A. D. B~yssinosisinicotton textile mills. American Review of Respiratory Disease 101'(4) : 497-503, April 1970.. ~; R. B'. (r16) SEATON, A., LArP, N. L., 14ToBGAN, 1V. K. C. Relationship of' pulnlonary ~590, impairment in simple coal workers" pneumoeoniosis to type of' radio- I graphic opacity. B!riti'sh Journal of industrlali Mealclne 2a(l) : av-oo, : ' Key, 1972. ~p Coa'1 (77) SHEBwII3, R. P:,, DIBBLE,, J., WEINER, J. Alveolar wall cells of the guinea I,I 19714 pig. Increase in response to: 2' p.p:m., nitrogen dioxide. Archives of En- vironmental Health 24I(1) :: 43-4'7,, January1972. Ce and' i75), SOBONYA, R. E., KLEINERMAN, J. 3torphometric studies of' bronchi in. I young smokers. American Review of! Respiratory Disease 105(15) : ' nies- 76&-775; 1Tay 1972. ~ifcow (7Jy Si'.ANeseu:, D. C. Age and smoking dependency of the single-breat'h oacygenn brence test in healthy subjects. Pneumonologie 147(1) : 46-51,1972. prkers (60) STEPHExs, R', J., FBEEyIAN, G!, EVANS, M. J~ Early response of' lungs to' ~ki 28 11 low levels of nitrogen dioxide. Archives of'~ Environmental Health 24 (3) : 160L 179, March 1972: iction, to (81) SYZGAxov, A. N., GoLOViv, Y: A., TROITSKAYA, Y. G. 0 vliyanii tabachnogo: dyina pri kureniii na organy dykhaniya v eksperimente. (Experiments ~ogice on the influence of tobacco smoke on,tbe'respirat'ory organs during hdus- smoking.) Eksperimental'naia Khirurgiia i Anestezioiogiia 16(6) : I',th- 23^26; 1971. erna (82) SzYVfczYKlEwlcz, K. E., KuxsKIS H., GIELEc, L: Clinical evaluation of! the j respiratory system in cotton workers. Bulletin ofPolish Medical Science ~por- and History 13'(3);: 110-114, July 1970. ~val- (83) TECULESCU, D. B, Validity,, variability, and reproducibility of si'ngie- ~stos 11 breath, total 1ting capacity determination, in normal subject's. Bulletinn de Ph3.sio-Pathologie Respiratoire 7(3) : 64a-65&, 3lay-June 19711. i dis- (84~)TECULESCU) D:,, STA'rrESCU, D. Ventilatia si mixica pulmonara la barbati. )ra). ~' tineri~ sanatosi, fumatori si nefumatori. (Pulmonary ventilation andd iing- ~, distribution ini young healthy males, smokers andl nonsmokers. ) Studdi 191. si Cercetari de bTedicinai Interna 5(11)', : 419-423, 1970. j1'ge-. (8'.7)i T$UNETOSHI, Y., SHIIifIZU,.T.,,TAKAHASHI,,HL, ICHI'NOSA\kA, A.,.UEDA„M., gen~. NAKAYAMA, :V.,YAM'AGATA„ Y.,. OHSHItio, A. Epidemiiologicall study ofpon- chronic bronchitis with special reference to effect of' air' pollution. aIes Internationales Archiv fur Arbeitsmedizin 29(1!) : 1-27,,19711, ; (86) tiLifKR, W. T. Emphysema of the lung: Clinical and experimental investi- ~cal gations of its pathogenesis. Geriaterics:: 25(5) :~ 164-165; 168-169, May 1070. g),: (87) ULMER, W. T. Lung function studies in epidemiologic investigations of respiratory diseases. Bulletin de Physio-Pathologie Respiratoire. ',ex- 6:: 605--616, 1970. ZL'_ ~ (88) ULSfEB, W. T.,, REICHEI„, G. Zur Epidemiclogie der chronisehen Bronchitis ;' und deren Zusam:menhang mit der Luftversehmutizung; (A contributioni Itte to the epidemology of' chronic bronchitis and to its', relhtion to air 26, ~ poilution. ) Deutsche lied'izinsche Wochenschrift 95(151) :: 2549-2554, Dec. 18, 1970: ial (89): Ut.xlcH, L., :11'ALIK, E. Chronic bronchitis in agricultural and chemical ITI- workers: Arhiv za' Higijenu Rada, i Toksikologiju 21(il),: 35-47, 1970: gs (19Q)', U.S. DEPART\fENT. OETR'.1.1\SPORTATION,, FEUERAT'. :1:ITATiIOV. AD\TISISTRATION„ all U.S. I)EPARTAib2tiT OE.' IlEALTII,, EI)CCATiION~ ANDIVnGPARE,. NATIONAI: INSTI'rUTE FOR OCCUPATIONAL SAFETIIiAND HF7ALTH.. H'ealtihi cY.slleCt.Sof. 61

Smoking in Transport Aircraft. U:S; Department of' Health, Edtrcation~ and Welfare, Public'HealtihiService, Health Services and! ~Iental HeaTth. , Administration National Institute for Occupational Safety and Health, Rockville;, Md., AD-736'097, December, 1971', 85 pp. i (91) U.S., PuBLra HeA'LTH SERVICE. Stnoking and Health. Report of the Advisory Committee to the Surgeon General' of the PublicHealth, Scrvice: Wash- ington, U:S'. Department of' Health, Education, and Welfare„ Public Health Service Publication No. 11f13;,1fl64; 387 pp. (92Y U.S, PUBLIC FIEALTHSkRVaoe. TheHeal:th Consequences of Stnoking. A Public Health Service Review: 1967. U:S. Department of Health, Eflu, catlion, and , Welfare. Washington, Public Health ServicePublicationNio: 1696, Revisedl January 1968, 227 pp. (93)U.S. PUBLIC HEALTH SERVICE. The Healthi Consequences of Smoking, 1968 Supplement to the 1967 Public Health Service Review. U.S. Depart.mentt of' Health, Education, and Welfare. Washington, Publ,icHealth Service Publication 1696, 1968, 117 pp. (g$)' U.S; PUBLIC HEALTH Sr;BVICE. The Health Consequences of Smoking. 1969' Supplement to the 1967 PPublic Health: Service Review. U.S. Department ofHealth„ Education, and' Welfare. Washiingtnn„ Public HealthService, Publication 169G'-2; 1969, 98 'pp:. (95). U.S. PUBLICHEALTIL SERSICE.. 'hhe Health. ConSP.fluences of :+mDking'., A Report of the Surgeon Generali: 1971. , U:S!D'epartment of Health, Edu- cation, and Welfare. Washington, IDHEXV Publication No. (iH'S3I) 71- 751'3', 1971, 458 pp. (9B) U.S; PUBLIC HEALTH SERVICE. The Health Consequences of Simoking. A Report of the Surgeon GpneraL: 1972. U.S. Department of Heal;th, Edu, cation, and Welfare. Washington, DI$EW I'ubli,cationi K'o: ('HS.1L) 72- 651G 1972; 1fi8'pp: (97) VALIC„ F., SrAHUr..rAH„ D. B'. Kronicnil bronhitis u pekara. (Chronic bron- chitis in bakers.) ILi'jecnicki Vjesnik'9&(7)!: 739-748, 197T.(98) VAN GANSE, W. F:,,FeBBIs;, B. G, .Jr:, CoTES, J. E.. Cigarettesmoki'ng andd pulmonary dilffusing'capacitF (transfer flactor). American Reviewof! Respiratory Disease 105 (1) :'30--41, January 1972. (99), WA'LitiEB; D~ D., ARCHIBr.ILn,~ R. 21I'.,, ATT~FIELn,Jf. D. Bronchitis in men employed in, the crnkeindustrg% British Journal of Industrial, l'Iedici~ne28(4')': 35f3-363, October 1971. (la0.)YOK;6Y'A1C1A,, K.,. S~EBA; Y., Kbn18HIQIDE,. T., MAT8UJfOTO„ T:, NAGOSHr, S, AsAHr, T., SAKAtj M., HIWADA, K. Jlansei kikanshien no ekigakutekii kenkyu. (Elridpmiological survey of chronic bronchitis.)Dry,o24(2) :~ 10-5-114; FebruarS 1970:. (f01) ZrvY, P. Le pneumothorax spontan~ des fumeurs. Le poumon tabagique. Tiabagisme al'veolaire et troubles mctaboliq,ues. (Spontaneous pneumo- thorax of smokers: tobacco lung: alk•eolar nicotilnismi and metabolic disorders.) Revue de TOberculose et de Pneumologie 34 (1) : 125-158, 1970: 62 , I

i ~ Iducation, ~( Health~ ~ fIea:lth, Advisorg p: Wash- Public Public Ilking. A ~ti, Ed'u- 11'ioati'on ~ bg: 1.968 kirttnent ,5hrvioe ~g. 1989 ~rtnient 5ervi~ce~ Iing. A 4, Eflu- [ ) Zi- ~ng: A Edn. ) 72'- j men ioine 1teki :. (2) i l4ue: rimo- >olic 458,. I

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Co~mtemts Page Introductiom-------------------------------------------- 67 ILiing Cancer-------------------------------------------- 68. Egidemiologieal St2idies-__-____________________-____-_ 68' E'x-Smokers----------------------------------------- 71 Lirdnium, Mining and Exposure to RadioactivztV _ _ _ _ _ _ _ _ - _ 72' Air Pollution---------------------------------------- 72 A'sbestos-------------------------------------------- 73 au,topsyand Cytol'ogical SGudies-__--_-_____-__-___-____ 73 nral Cancer -------------------------------------------- 74 Cancer of't.he Esophagus_________________________________ 76 Cancer of t'he Larynx ------------------------------------ 76 Cancer of'the Pancreas___________________________________ 77 C aneer of the Kidney andl Urinary Bladder_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 77 E_.perimentall Carcinogenesis-__________________________-__ 78' R'espzratory Tract Carcinogenesis'_ _-- _ _- _ _ _ _ _ _- _ _ _ _ _ _ _- _ 78' Experiments in Mice_________________________________ 80 Aryl Hydrocarbon Hydroarylase (AHH), _ _ _ _ _ _ _ _- _ _ _- _ _ _ _ 82 Cell an.d Tissue Culture Studies_____-__________________ 84! B~inding of ~Polycy,cli;aH'ydrocarb'onst~~o~~DNA~ dnd~RNA_ __- 86 AT-lVittosdmines in Toba.cco Smoke_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 87 Summary of Recent Cancer Findings_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _. 88 Referenees--------------------------------------------- 88 List of Figures Figure 1.-Standardized lung cancer mortality ratios of' Japanese by number of' cigarettes smoked (1966-70) ------- 69. Figure 2'.-Lung cancer mortality ratios of Ja.panese by age, at initiation of' cigarette smoking (1966-70) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 69 Figure 3.-The survivall of'~ ex-srnokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx,orlarynx------------------------------------ 75. 65

List of Tables Page Table 1.-Age-standardized lung cancer death rates of' British physicians and the population of' England and `?Pales at various time geriods----------------------------------- 70 Table 2.-N-dimethylnitrosamine (DMNA) content of'~ con- densates obtained from several tobaccos grownn in both! . "high"' and "low" ni~~trogen soils------------------------- 87 ' 66

Introduction Tiiis introduction is a brief summary of' the major relationships brt weensmoking, and cancer which have been established in, previous nvl)orts on the healahi consequences of smoking', (;9~L,92,93,,94, 95, 961)~. ('i'(;arette smoking has been clearly identified as the major cause of 14u1- cancer in the TJ.nited S'tates:This conclusion is based on detailed vhi'kllniiological, clinical,autopsy„ and experimental data, which have :uccutnulated over a period of more than 20 years, For both men, and woxmeii,, the~ risk ofdevelopinglung; cancer is directly related to total klxpostu•e to cigarette smoke as measured by the number of cigarettes smoked per day,, the total lifetime number of cigarettes smokedl, the duration of' smoking in, years; the age at initiation of smokingy the depth of inhalation of tobacco smoke; and the "tar" and nscotine levels in the cigarettes smoked. Lung cancer death rates, however,,are lower for Nc•,omen than they are for men, ai finding due, in part;, tloa differencein exposure. `Vomen, smokers use fewer cigarettes a day, choose filtered cigarettes with lower"tar'''' and nicatine~ val!ues,, and also tend to inhale less. E-Iowever; even when women experience comparable levels of' ex- posure to cigarette smoke as men, their mortality rates for lung cancer stiill remain somewhat lower. Those who stop smoking experience a decline in the risk of'develop- ing lung cancer relative to continuing, smokers. The air, pollution! commonly found inan urban setting, appearsto result in elevatedllung cancerdleathi rates; however, thiseffect is relatively small comparedl to the overriding effect of cigarette smoking:. Certain occupational exposures have been found tio be associated with ani increased risk of dying from, lung cancer. Cigarette smoking interacts with many of theseexposures!.toproduce much higher death rates from lung cancer than would result from one e.xposure alone. Inte racting exposure factors may be : experiencedl simul'taneously or at~ different times. The uranium mining and asbestosind'ustries,are exam- ples of occupations in which this interaction occurs. The bronchial epithelium of smokers often shows premalignant changesincludingsquanlous,m!etahlasiay atypical squamous metaplasia,, and carcinoma in situ. Pipe and/or cigar sinokers experience a risk of developing lung cancer that is higher than t'herisk of nonsrn~o~kers;howe,ver, it,remains 495-028 Q'--73 M ,. , d

significantly lbwer than the risk of'cigarette smokers. A more complete discussion of the risks from pipe and cigar smoking, is found inn another chapter of this report. Epidemaolbgical, experimental, and autopsy data have demonstrated that cigarette smoking is, a, significant factor in the development of cancer of the larynx, oral cavity, esophagus, and urinary bladder. B-naphthylamine, a carcinogen known to cause cancer of the urinary bladder in humans, has beenidentiified in cigarettesmoke. Thereisalsoe an association between cigarette smoking, and cancer of the pancreas. Experimental studies with animals in which cigarette smoke or one of it's const!ituent' compounds is administered in & variety of assays have confirmed the presence of'complete careinogens„ cocarcinogens such as tumor initiators and tumor promoters, and tumor accelerators in cigarette smoke. Reeent'1y, additional epademiological, autopsy,, and experirnental' studies have added to our understanding of these rel'ationships., Lung, Cancer Epidem,ialogical Sta.t,dies An ongoing prospective epidemiological study condtzcted in Japan provides a unique opportunity to examine the relationship of cigarette smoking ta death~ rates in a population: withgenetic, dietary, and other cultural' differences from previously examined Western popula- tions., Hirayama (37) has now reporte6 5-year foll'otivup data on 265,118 men and women aged40 y ears and older.. This represented 91' to 99 percent of the total' populatiotr in the area of' the 29 health districts where the study was conducted. A totali of' 11,858 deaths occurred dur- ing, the 5-year periodl which incUaded a total of 1,269,382 person-years of observation: Both men and' women wh.o sm.oked cigarettes experi- enced higher death rates from lung cancer than nonsmokers. Among smokers,the lung, cancer mort<alityratio«-as3'.85 ~ fbr men and 2:44 for women as,compared to nonsm~okers~ . (P < 0.001). Dose-response, relation- ships were demonstrated for the number of' eigarettes smoked per dayy andl the age at initiation of smoking (figs. 1 and 2). These mortality ratios,areconside-rablylower than those reported, forthehnited States, Canada,, and Great Bri~taQn, and may reflect ai lowerar-eragenumber of cigarettes smoked a da,y;an olcder.age at imitiation of smoking, or re- duced inhalntion ofe cigaret~tle smoke among the Japanese. In spite of these differences, thee overall results,of'thisstudy, includingthe dbse- responserelationships, are similar.toAhe resnlt&ofal'l the other major., 68

.1 s, l

TABLE 1I.-Age-stand'ardized lungcan.cerdeath rates of Briti:'sh, physicians and the population of England and Wales at vdrinus time periods Lung cancer standardiied!deiath rate per 1,6C10 men per year in- Dootors. England and Wales Years------.--,-------------------------------------- 1953;-57 185741 196i-65 19M-57 19,58-611 1962-65 Death rate per 1,000~----------------- 1. 10 0. 85 0. 83 1l 49 1. 71 1. 88' Source: Doll, R., Fllee;D3.,C. (tt). Kennedy (~.45); studied primary lung cancer in 29 men and 11 `eomeni diagnosed before the age of 40 land found a strong association betweeni cigarette smoking and'the development of this disease. Boucot, et al. (11) further characterized the 121 cases of lung eancerdetected in the population of tiliePhiladelpllia pul'monaryneoplasm research project. Ti he risk of developing lung cancer in- creased with age, was higher ini nonn-hites than in whites, and increasedd sharply with, increased cigarette consumption. The relationship~ between cigarette smoking and lung cancer was investigated in a retrospective study by: Ferr.ara (25) in La Plata, Argentina. The: smoking,habits of 144' lung cancer patients were con- trasted with those of 386' controls. A dose-response relat'ionship, was found between cigarette usage measured by the number of cigaret.tess smoked per day and the durat'i'on of smoking,and the risk of'develbping lung cancer. A high incidence of' lung, cancer is reported from the island of Jersey in the Channel Isles compared to England and wales.. The island has no heavy industry and only minimal levels of air pollution. Cragg (16) ~ studied 144 patients who developed lung cancer on Jersey during a 4-year study period. Only three nonsmokers were found among the 113'patients for whom histories were available: Fingerland; et al. (26) determsned' the prev.alence of! 1'ung cancer and certain other diseases in an~ autopsy series of 1,338 adults in Czechoslovakia. Some 198 cases of primary lung cancer were identifiedl. In the autopsyy population, 1.4 percent of the nonsmokers, 14'.1 percent of'thosesmoking Tesst11~an200,,O0b'lifetime eigarettes,, and 33.3' percent of those smoking more than 500,000 lifetime cigarettes had lung, cancer. Rickard and Sampson~ (71)~ studied 94 Negro patients with lung, cancer in Washington, D.C.,, and found, that 57 (92 percent) of 63 patient's whose smoking history was available were: regular smokers. Epidemiological studie& conducted in Italy (10)i,, Swe,deni (48), Poland (46), Russia, (42), Cuba (73), 11Tiexico (13), and the Nether- lands (98) demonstrate an association between cigarette smoking and, lung eancer. 70 I # i

omen fween lung mary LC In- ~ased was lAta,, iCon- I was Oes ?ing ~ of T'he. :ion, hsey und icer li in led. ent ;ent tng [ng 63 irs. id Berg, et al. (5) examined the incidence of recurrent primary cancers following initiall prirnary~ cancers~ of~ the~ respiratory and upper di- 'restiti-e systems in New York. During 23,802 man-years of observation in .1,11i5 patients with an initial squamous cell cancer,, 518 second cancers developed at other sites. Patients whose first primary cancer ;nas in the lung had an observedl to~ expected relative risk rat'io~ of' 5'.:7~ ( P< 0.05 ) forr subsequent cancers of' the respiratory or upper GI ~,V:;tem~. Patlient'is, with the~~ first cancer in the~ oral cavity or~ laryna frea(luently developed a second cancer in the lung.. AIiedical records _ ontirnaed long sTnoking, histories among almost all of' these patients Nti IioAeveloped second cancers. C'uncer~~of the~ lung~, oral cavity, larynx, and esophagus were~~ reported !~v Schmidt and De~ Lint, (79)~ to be~comrnon~ causes, ~of~death~ amongg f,WN ' men and women who hadl received treatment~ for~ alcoholism~ in~ Toronto. The authors attributed this finding to the strong, associa- t irn.t that exists between alcohol and tobacco~ u~se~andnot bo~~ the~effect of zi Lcoholl alone. Carcinoma of the trachea is~ a relativeiy~ rare~ condition with, only ahout-1D0 cases~ha:ving~bee~n reported in the literature~.,lii a study~ of~41' l)atients~ w~ith, carcinomai of~ the trachea, I}Iaj'du,: et~al. (.31) found an, ~-,Pparent association between cigarette smoking and the development =4 'epidermoid cancers,of this st'ructure:~ An association between ci:garette~ smok~ing, and the development of~ broncliu:olo-alveolar~ carcinoma in~ 74 patients-~was, described~ by ~ Delarue;~ et al. (18). . Ex-sm;okers Those who stop smoking experience a decline in the ri'sk of dev.elop- ing lung, cancer relative to continuing smokers: Doll and Pike (2N) <<onducted a~~ st~udy~of~ the~ smoking habits and causes~~of death of 40,000~ Briti,sli physicians. Smoking ha.bi~tis, were~ surveyed in~~ 19~511, 1957',~ and . l:)6G., Durii,2;, the~ study ~ perio<l,, more~ than 3,500 physiicians~ becan:ze~ ex-~ .~niokers~., The age-standardized percentage of ex-sni,okers~~ among 1?hy~-~ sicians 65 to 64 years of age rose from 1I8',1 percent in 1951 to 26,5 per- cent in 195 1 and ~?~J~:5 hercent, in~ 1966. Concurrently, t~h,e~percentage~of hhy:sicians~ s~nioking, ci~,rnrettes~~ fell fi-om, 44.1 percent to 22.0 percent, while over ~ the~ same period estimates of' the~~ per capita ci'garet;te~ con- sttmption for the adiilt male population in the~ Linited! Kingdom su~g- (*este<1 ,t slir.ht increase in ciga~ret-te~~ consumption. Over this 15-year~ heriotl, the~ niorttility from hu2g,cancer arnor:7g,physicirans~~dlrophed con- sidera1hly: While~~ lung cancer death rates among,the nnale population in 1!ar,aand and Wales increased to~ some~ extent (tla~ble~ 1)~.: :llthougll cer~- 71

tain limitations apply to the interpretat,ions derived from secular data, analysis~ of the~ study ~ design and the~ magnitude of the results~ ihdi-~ cate that~this study constitutes important evidence~of~some~of'the~bene~-~ fits~~ tliat'~ result fi•onii the cessation of~ cigarette snsoking. Uranium Mining and Fxposure to Padioaetivity Epidemiological evidence supported by autopsy studies has estab- lished that'~airborne~radiationy~ particularly~ in synergi~stie~comb~imation «itlrcigarette smoking,,is the major cause of the excess of respiratoryy cancers among uranium miners. Lundin;, et al. ('53), considered quantitative~ and~~ temporal aspects! of radon.idaughter~exposure and respi'ratory~cancer ini a report'~~fromthe: Epi~d!emiologica1 Study ~ of~ United States~ Uranium Miners. They~ ob-~ served a stati~stiicalZy~ significant excess~~ of~ respilratory~ cancer among «hi~te~u~raniom mii7ers~~at each cu~mulative~~ radiation exposure category dow~n to~~ and' including~ 120-3W WL'M (w~ork~~ing~~ llevel montlLs)~_ The authors~ noted that although cigarette~ smokiirg~ alane~ entailed a risk of the~ dl;~veloprnent, of' eancer~ of~ the respiratory.~ tract in, miners just as it~ does in nonm~iners; cigarette~~ smoking, in combination wi'th; radion~ daughter exposure appeared to result in an even greater risk.~ Several authorsi (30, 44,~63„8/~~, 104) continuelo~ report the presence~~ of' polbni~um-~210 or~one~of the~th:oriurn isotopes in tobacco l~eaf;~ tlobacco~o smoke, or the l ungs of smokers. Air Pollution Data standard'ized, for~cigarette sm:oki~ng~~ind'icate~the existence:of an~ u~~rban factor~in the~develapm~ent of~lung carlc;er; it is~likelythat ai'r~po1- lution,,frequent,ly~ part~ofi the city.~ environment, is~ai component of~ the~ urban factor. Th~e~ National Academy of~ S'ci~ences,published a review (6r')~ of the~ biolbgicall effects of atmospheric polluti~on~ by~ particulate pol!ycyclic~c organic matter.~ Detailed epidemiological,,experimental, physicaI,,and chemical data were revie«-edi., It was concluded that air pollution„ as commonly ~ found in urban settings, was found to~be associated with: in- creased creased lung cancer~ mortality in cities, An examination of the data presented,~however, indicates that eigarette~ srnok~ing is,,i¢l, most~ cases, the~ overridia'ig factor~ in tihe~ development of lurrg, cancer. IPolycyclic hv~d~rocarbons~an~d relatedlcompourrds which~aire~known~to~cause,cancer of the~lhng and other organs in experimental animals were~ found t'~o~ 72 I

ftr data, ~indi- le hene- I estab- ~ation ratory i 'spects Im tlie. Ey ob- ~nong egory. ; The jsk of ist as ~adon ~ence laceo: be p resent in relatively high~ concentrations in cigarette smoke; inlarge ,1u,1ntities in: the~ air of industries in which workers have high-Tung, ,•~mcer rates,, and also in the air of urban communities. Sterling and Pollack(~86)~ reviewed theeffect!sof' air poldutionon, ,leath rates! from lung cancer. They suggested that partielesresulting, f rom the combustion of' organic fuels may be more strongly related to thc incidence of lung cancer in the populkation than cigarette smoking. 'Irhe eumulat'ed epiderniological dat'aregardiiircigarette smokangand ltnu; cancer were not considered by the authors in this report. Asbestas. Ogarettesmoking asbestos workershave, ma~rked2'yelev~ated Iung(I:uicer dleath rates compared to: nonsmoking asbestos workers. Berryi6) examniedt.he combined etfcct~of asbestos exposure~ and smoking on mortality from huig cancer among 1,300 male and 480 female asbestos f„lotory workers over a 10-year period. There was no significant i'n- cr.ease in llung cancer mortality amon~g smoking or nonsmokingn orkersn-ith a law-to-moderate exposure to asbestos. Ho«•ever; among smokers «-ho had heavy exposure to asbestlos,, 32'. lung cancer deaths occurred among 663 men (9.9 expected), and there were 1& deaths among 292 n-ouien (1'.4 expected). This confirms the greatly increased risk of de- veloping lung cancer among asbestos «~orkers who smoke cigarettes. Autops y and'Cy,tolog,icad Studies f'an pol'- 'the the 'clic and y as in- ata ?es„ sl'ic ser to! The respiratoryy tract of cigarette smokers examined at autopsy flre- qttentIy demonstrates epithelial changes consiidered to be precttrsors of bronchogenir; carcinoma. Such changes include squamous metaplasia, atypical squamous metaplasia, and carcinoma in situ. Herrold (35) studied histolog~ie~ types of prirnary~ lung cancer~in, U~.SL~ vete,rau& who .vere~ subj~ects~~ of~ the Horn study. Q!f~ a total of, 2,241 wh~ite~~ male~ vetr~ eraais who died of lung cancer over an 8-year period~ histologic mate- rial «-~as~ a-v~a~ilable~ fbr.~revie« in 1,477 7~ patients. Histologic types were~ rroul~~ed according to the~ Kreyberg classification of Gsoups~ I anld H tniil,ors. Group I tuaimors~, epidermoid and oat-cell carcinomas, were~ prePs{>>it in 2~7::3'~ percent o£~ the~ 55~ nonsmol.ers~ and were~ present in 57~.8~ hercei~it~of tlie~~4l72 "cnrrent~smoke,rs~~of cigarettes~only.?'Thedi'tfere.nce \v~as statli'stically~ sipnaifi~cant (P<0.01?1~):, confi~rming,tlic~strong, associa-~ tion behveen cigarette~ snioking~~ and Kreyberg'Group~ I tumors. 71 ;Q tj O

- ~i Auerbach et al. (2) examined epithelial changes in the bronchial tree ~ of 456 men, and 302' vr omen who had died of' a cancer other than lung ; cancer. There were 72 ex-smokers among the men, all of whom had '' smoked for 10 year&or more buti had'quit smoking for at least 5 years prior to death. Atypical ceils were present in 93'.2 percent of the current ~ The prevalence of atypical cells (hyperplastrc and metaplastic) in the sputum of 1221ma1e and 128 female «-orkers was examined by Rob- bins (72). These smokers, all under the age of' 10; were mat'ched' with a control group d~rawnfrom a population ofcollegestludents. Atypical cells were found in 14 percent of the smokers andl 5' percent of the non, smokers: smokers; 6.0 percent of the ex-smokers, and 1.2 percent of' the non- I smokers. Areas of epithelium composed entirely of'~ atypical cells devoid It of' cilia were found in the bronchial tree of'. 8 percent of'the current a smoke:rs, 0.2 percent of the ex-smokers, and none of the nonsmokers: ~ TJnusual cells withi di'sintegratiing or fading nuclei were found exclu- ~ sively in 15 percent of the ex-smokers. Oral Cancer Data from the large ,Tapanese prospective study by Hirayama (37), indicate that mortality rates from cancer of the: oral cavity among males are higher in smokers than nonsmokers; A dose-response rela- tionship: was demonstrated for, tiheageat initiation of'smoking. Thestlandardized mortality ratio among cigarette smokers was 10.0 for men (P<D.001) and 1.22I for women compared to nonsmokers. These ratiosare not stable due to the few deaths that occurred from oral can- cer in thss study. Certain relationships between cigarette smoking and' cancer of the oral cavity, pharynx, and larynx were investigated by Moore (59). Over a 15-year period', 1,000 patients with invasive squamous carci'- nomaat these, sites were, treated ini Kentucky. Of thesepatient~s; 203: . had a history of cigarette smoking and had had no recurrence of cancer for a period of 3 years or more. This group was further dividedi on the basis of' current' smoking habits. Of the 122 who continued to smoke,48 (40 percent) eventuallyy developed ai second cancer at these sites,, whereas onlyfive(6 percent) of'the81 who stopped smoking de- veloped a second malignancy.. This sixfold' difference is~ statistically significant (P<0:001).. The survival curves for t!hese two groups are presented in figure 3. 74

ii ial tree ~ n lung pm had ~5 years lurrent' le non- devoid urrent iokerss exelu- Lic) in F R'ob- wit'h ~pical! ~ non- I I I . (37) long rela- I The Ifor 2ese pan- t'he F9),. Fci- 1~03 Ii,o,f, L'ed t.o ese ~e- ~y ,re Figure 3.-The survival ofl ex-smokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx, or larynx: 100 90 80, 70 60' 30 20 10 0 4' SOURCEt NAoore„ C. (59). 5 6 7 8' 9 Follow-Up (yr) 10 L 1i 12 13 Martinez (57), studied the~relationship~between smoking in various f orms and cancer of the oral cavity in a retrospective study of 153' p,rtientlswit!h this disease. Dose-response relationships were demon- strated for the amount smoked,,the amount of' alcohol consumed~ and tiliadevelopment of cancer of the oral cavity. TyIdesley(90) examined the prevalence o£' leukoplakiai among, 402 English coal miners of whom 280 smoked and chewed tobacco. Tobacco chewing was commonly found to be a substitute for smoking in under- ground' conditions where smoking was impossible. Leukoplakia wasf found in 3.6 percent of the chew.ers,,-whereas no leukoplakia was found among the nonchewers.. Nelison and Ship (62) determined the relative influence of eight vari'ablefactorson the development of oral cancer in relation toagEat t!heonset of disease ina population, of 191 patients.rithacanfirmed diagnosis of a primary squamous cell carcinoma of the oral cavity. The factors considered inclhzded age,sex;race~,, consumption ofalco- holandl tobacco„ certain systemic diseases,and oral trauma., Thelprevalence of'heavy tobacco use was more common among the younger patients. «'hsle 91 percent of the cancer patients under the age of 45 smoked more than 20! cigarettes a day; only 59 percent of t~hepatient!s, over 65 smoked this heavily. 75' ~ K.'w

Reverse smokihgis a~ common practice in some parts of India, whereby thelh ;htedl end of a homemade cigar isheld inside the mouth. Pindborg, et al. (64) conducted an epidenriological survey of 10,169 villagers, in the Srikakulam district of south India and~ found that. 43.8 percent of those interviewed practiced reverse smoking. TLeuko•, plakia was~ found' in 818 percent of reverse smokers compared to 0:1 percent in nonsmokers. The 10 patients found to have oral cancer were all reverse smokers. Reddy, et al. (68) found that rev.erse smoking rvaspracticed by73. of 100 patients with orali cancer. Reddy,, et al. (66, 67) reported characteristic histologic findings of' the oral' cavity in biopsies obtained from reverse smokers. In two other studies from India, changes in the ultrastructure of the oral' mucosa of chewers (5h), and smokers (G5) are described'. Cancer~ ofl' the~ Esophagus In the Japanese prospective study, Hirayama (3'7) reported that ~ ~ male smokers had' a mortality ratio for cancer of the esophagus of 2.24 compared to nonsmokers (P<0:001)'.. NTartinez (57) studied the relationshipbetween smoking in various, forms~ and the development of cancer of' the esophagus in a retrospective study of 179 patients. ~ Dose-response relationships were demonstrated for the amount smoked and alcohol consumption and! t3i~edeWel'opment of cancer of the esophagus. Cancer Qf' the Larynx The mortality ratios for cancer of the larynx in the large,Japanese prospective study were reported by Hirayama (37) to be 11.0 for male cigarette smokers and 9.0' for femalie cigarette smokers compared to nonsmokers (P'<Q.001).Stell (85)1 concluct~ed'' aretrospectii've study of 11W patients tiv~itlii carcinoma of' the larynx. Only 13 percent of the patients were non- smokers or ex-smokers compared with 4!1 percentof'the: controls. The relativerisk ratio for heavy cigarette smokers was 3.48 compared to nonsmokers. The relative risk was 1.34 for smokers of pipes and cigars. b'Toore (59) reportedi the occurrence of second primary cancers in 203'sol:okers whoAiad been surgically treated forcancer r oftheoralf cavi~ty;pharynx,orlarynx,,witkout recnrrencefor.a period~of'3 years. 76

yf Iindia, e mouth. bf' 10,169 tnd, that Leuko- ~d to. 0.1 cancer moking ~~ i; et ad: l cavity iEs f'rom. ~ Ihewers i I ' that, ~u~s' of 0 the ~ment xentsi ioked f the i nese, nale 1~ to. ¢ith~ ion- rhe red, nd «'i'tttin an aiverage~followup; period of'7~ years, 40~ pereent'~of t'he~ 122'. l,atieirts who continued to smoke developed second primary cancers „f t i,E.~ uhper~ respi~ratory or digestive~~ tract, but only~ 6~ percent, of the l,utirtits who stopped smoking developed second cancers. A total of :,oi l,utients «•ith cancer of'the larynx underwent lar3~•ngectomy. Of tl~t, ~ 16 «1'lo~ contli'ntied t~o~~ smoke,~ t'~ltree~ developed a second' cancer,~ wiu,reas, ~ none of the~ 34: ' ex-smokers~ without a larynx : developed a. -,,cor id primary malignancy.. Cancer, of Uhe Pancreas I I'iray.ama (37) reported a~ significant association between cigarette =m0king~andlthe~~develbpment~of'cancer of the~pancreas~, The~~mortality n,itios were 2.05 (PC0,001) for men and 1.91 (P<0.05) for women.. Krain (~,47')~ reviewed a number~ of~ environmental factors~that may~ lbr associated with the~~ 15~~ percenti~ annua~t increase~~ in~ the death rate f roni cancer of' the pancreas~ found in the Uhit~ed States. The strongest , n~<I~ociations~ appeared to~ be~ with cigarette smoking and certain „(Tupationali exposures.. Cancer of the Kidney andl Urinary Bladder Hlirayama (37) reported a mortality ratio of 2:71 f'or cancer off thekidneyand bIdder in women whosmokecigaretties(P<0:001,)~.The mortaIity ratio of 1.07 for men who smoked; compared' to non- smokers was not significant';,however; the fe.v deaths from this cancer atnongmen in theJapanese! study did not allow conclusions to: be dra~wn. Hoover and Cole (39) examined the strength of the associ'ation between cigarette smoking and': the development of bladder cancer in successive birth. cohorts of' men and «omen, in the United States, Denmark, F.ngland'y and Wales. Increasingrates, of bladder cancer wer.e observed in populations characterized by an increase in cigarette smoking among successive birth, cohorts.. The association was con, sistent in both men andl women, andl wasalsoconsistentf'or diffierent national'ities and urban and rural groups. These findings suggest aa causal role for cigarette smoking, in the desxelopment of bladder cancer: Iln a retrospective study from Germany, Fischer (27)examined thesni:okinghabi'tsof1,02 men with bladder cancer and a controLgroup of 198' men who had benign prostatichypertrophy.Ti'herelative risk 77

, ratio was 6.4 for smokers of fewer than 15' cigarettes a day, andl 27.5 for smokers using more than this amount. Only 3 percent of' the men~ ~ with bladder cancer were nonsmokers.. ~ Xipell~ (1Q3~~)studied renal nodules~ in 2~5Q~patients~ in AustralM who came to autopsy. Benign adenomas were the: niost common 1'esions f' and were found in 22 percent of the patients: The remaining nodules ~ were cysts, thrombosed veins, abscesses,, granulomas; and metastatic ~' lesions. A, statistically significant difllerence~ between the smoking habits'of those with adenomas and those with the miscellaneous lesions z ~! was~~ reported (P<0:012)1. All the adenomas were~ found in smokers. C~ole,~ et~ al. MY conducted a retrospective~~ study of~ 461 persons~ ~ with transitional or squamous cell carcinoma of the lower urinary ; tract., After the~~ data were~ controllled~: for cigaret'~te~ smoking, occupa~-~ tional exposure appeared to contribute to M percent of' the lower ~. urina~ry~ tract cancer among men aged 20 to 89~ compared to the~ 39 percent attlributedl to cigarette smoki~~ng~ in n7err~ in a~ previ'ous~~~ report (15). T Werf~-Mfessing~ and K~atnl~en, (100) examined the association of' occupational exposure~~ and smoking~~ ini t~he~ development of bladd'er cancer in 346 males in the Netherlands who had' this disease. The { sm~oking~ habi~tls, of cancer~~ and cont.rol' patients in each group~ «ere~ ~ nearly ident'ical ; however, patients with, bladder cancer had a longer ` exposure to hazard'ous~~ woi•king, conditi~ons~ th:an~ di'd~ controls. Experimental Carcinogenesis Experimental~ studies, ma~inlyy in animals; have, added t~o~ an under-~ stand4ng~of! m<Rny~ of'the processes~~ia7wolved, in ~tobacco~ carcinogenesi's~~. Possible~~ mechanisms~ of~ chemical carcinogenesis were~ reviewed by Miller and Miller~ (58)~, Ryser (76)~, and Leone~ (5l). Electroni spin resonance studies of carcinogenesis were reviewedl by Swartiz (87). Franke (28) discussed the posible rolle of hydrophobic interactions of~ polycyclic aromatie~~ hydrocarbons~ with, protein in~ chemical car- cinogenesis. Chemical carcinogenesis in Sy~~rianihamsters~wa~s,~revietiv.edl by Shubik (82) and'$omburger (38).. Re:spiratory Tract Carcinageneais E~pidemiological~~ cli~nical, and au~~tlopsy~ data from studnes~ of~~huma~~ns have established cigarette smoking as the major cause of lung cancer in the j'nited States. One: ofl the~ reasons~ it~ has~ not~ been possible~~ to 78

lia who lesions aodules ,astatic noking lesions iokers. ersons rinary ~cupa- !lower lie 39 . ioious ler- sis. by y'in. 7). ins lr -d rliaracterize fully the mechanisms responsible for this causal relation- ~k, iE> is the lack of an ideal anian.al model in,%vhi:ch to study respiratory t~ract~~carcinogenesis~in the laboratory. Exposing~~ animalsAo cigarette~ anokc~ in a closed chamber d'oes not~ repTica~te~ the~ kinds of~~ ex~~posure~~ .ru0l-ing ~ humans~ recei.-e,, although sorne~ recently dieveloped smoking , dr:mibers provide conditions similar to the exposure experienced by Iiuiiran smokers. 1Tany animals are obligatory nose breathers and,. irr tlrem. a large~ horti~on of tlli~e~ partienla~te~ phase~ of cigarette~ smoke ~ nri' V he removed by~ turbulent precipitation ioi~~ tiLe~ na~~sa~~U passages~ or l,I rN-nt: before reaching the sites~ in the lung, most c.ommonly~~ exposed irI liumans. ~V~uerbachy, et a1L (3~)~ first demonstrated that~ malignant~ liing tuai~lors~could be produce& in smokinh, d~ogs~w~ho «-ere~~ taught to~ ~runke through a, traeheostomEi. Severa~l investigators have~~ recently ,~xuuriiiried respiratory tract ca~rcinogenesis~ in aniinals~~ using~ intra- tr;i(•l'ie;rllinstilhiti~ons~of~chemiial carcinogens found in cigarette~smoke, irucludtinb benzo~~(a)pyrene~ and! 7H-di~benz~(dl,g)carbazole~. Tumors~ re,rilting from this type: of treatment are~ freduently ~ simila~r~~ to~ lun:g nuriors found in humans (wl~ 32. 33. 36, 77. 8l1).. H~arris,, et all, (33~)~ examined the~~ acute ultrastructural effects of herrio(a)~py,rene~ carripd~ oni ferric oxide particles, ~ on the~ tracheo~- !')r()uclniall epithelium~ of t~he~ Syrian Go~lden hamster. Test su~~bstances, . were adaninistered by intratracheal instillation. Fe.rri~c, ox~~idie~ alone rt"sultedl in some~ focal replacement of' columnar~ epitheliilm~ with laol,'.-gonal basal cells. This~ effect w~as~ reversed by t,erm~iinati~on of th:e~~ treatment: Aftler treatment with benzo(a)pyrene and ferric oxide, t:ncal replacement of the columnar cells with pleomorphic cells oc- 1,rrrredi These pleomorphic cell's~~ lcadl the~ ultrastructui:al f'eatures~ of' rtY~pica~l sq~uansous cells~,ancfi. were siiYlilar~ to~ t,he~ hy~~perplasti~c~epitlreli'al '-cl~ls~ described' in the~ bronchi of smoking , dogs and the~ neoplastic~ ,~lliuaanous eells~ found in human bronchogenic ca-rcinoma.. In an extension of this study, Harris,~ et al. (~32)~ reported that vita- nrin A deficiencY or~ the~ application of lienzo~~(a)pyrene~-f'erric ox~~i'de~ tiirourh ilitratraclieal! inctillation resulted in-squ~annous met~aplasia of tlie~ trachea. I3oth lesions~ appeared to~~ be~ morpliologicaldy~ similar~ by liglit naicroscol>tir,~ but~ at~ the ultrastructura~ll level si~,*nihcant d'iffer- 4~nces Ive~re~ observed. Squamous nnet<aplasia induced~ by benzo(a),py- rene-fcrric oside~ was~ characterized by~ defects~~ in tlhe~ basement me.ml5rane; enlarged nuclei with cy~t~~oplasmic invaginations, and pleomo~rphi'c~nuclcoli not~ seen followii<zg~vitamin A deficiency~.. Sellak~u~ma~r~ and S'hubik~ (~80)' treated' Golden Syriani hamsters w~ith~ %1:~eekly intr,ltracheall instiillationsof~ 7H-dibenz~(c,g)~carbaz~ole~~ (7iH1- UI3(')~~ suspend'ed with equal amounts~~ of~ ferric oxide~in~ a saline~ solu-~ ti~on. Une group ofl 35 hamsters was treated with 45 mr~. of' the~ Carcino~r;en and a second group was~ treated w~ith~ 15~~ mg: llore~ than ~s~'-) percent of~ the a~~ainra.Is~ in each group developed respiratlory~ tract. 79

tumors. Most of the tumors occurred in the major airways andi were;' single~ and' rnnltiple~ applications. A single administration of~~ 37.5 mg., ous concentrations of benzo(a)pyrene and ferric oxidW were used in~ , Saffintti,,et al. (7'7')~ eramined, the careinogeni'c~ effects of benzo (a) I pyrene prepared as~ a~ suspensioni of fi'ne~ crystal2ine: particles at- ~`,i tached t'o~ ferric~ oxide in a physiologic saline~~ solution and admimQs~ tered kiy~~ intratracheal applications to~ Syrian Golden hamsters, Vari were found less frequently. squa:mous cell carcinomas. Adenocarcinomas and anaplastic c.arcino~nas ofbenzo(a)py.rene, witli12.5 mg. of ferricoxideresulled in five broncTiogenic carcinomas and five histologically benign respiratory tumors in a total of 61 hamsters. Following multiple adn-vinistrations,, bronchogenic carcinomas inchtd'ing anaplasticandisquamouscell types were induced i ~ all dosage ~ groups and' a~ positive dose~-re~sponse~ rela- tionslii'p~~ was~ demonstrated. Feron (24)~ studied respiratory tract tumors~~ in S'yrian~~ Golden hamsters folloiving, tracheal instillati~ons~ of fizrfurall and/or benzo,(a), hy'rene. Of the 62' hamsters. 41 developed respiratory tract tumors of which squamous cell car.ci'noma, of the trachea wast~hemost freq,u~entt type observed: Fiarfurall it, combination with benzo ( a) pyrene resulted in a hinheryieldr of tumors than was seen with benzo (a)pyrenealbne. Furfural albne possessedd no carcinogenic activity. Shabad (8Z): andl oneof'his, _ col2aborators,. Y''anysheva,, produced benign and malignant epidermoid lung tumors inratsfollotivi~ngsinglea11d muiltip1Je administrationsof' benzo(a)pyrene byintra- t'racheal instillation. Dose-response relationshipswere demonstrated: E~'xperiments in Mice Cigarette smoke~~ condensate (CSC~)~,, various fractions of CSC, and, many chemical compoun& identified in CSC~ have been tested f4r~ tumorigenic activity~ in mice by~ aa variety of' methods,~ includi~ng~ skinn pa~inting~~ and snpcutaneoir:- inj~ectioirs. Complete~ carci~nogens~~ and in- complete~ carcinogens,, which i~~ncl'ude~ tumor initiators, tumor~ pro~-~ uioters, and tumor accelerators have been described. Several' recent.t studies~ h<nre~ been conducted using mice~ as~ tlhe~ eaperimental' animal which examine~ furt~her~ the~ mechanisms involved' in tobacco carcino-~ genesis.. T.ee~ and O'NeiIl (50)~ nleasurecl the, effect of duration~~ andi dosage of~ benzo (a) pyrene applicationson~ the rate~ of~ dev.e:lopnient~ of~ benign and malignant skin ttmiors~ in m~ire: 'Z'he~ incidence rate for tumor formation Nvas' d~itectlyy p~roportGonal~ to~ lioth, time~ and~ dose. q'hese~ data conf'ormedl quite~ closcly~~ to postulated mithematic<<I models of the rate of tumor dev elopment.. 80 ~. t ~ ' I c.

t n d were hcino~nas ~ enzo (a) tles at- dininis- s'. Vari- used in 7.5 mg; in 6r,eiratory ations, , 1 types e rela- t l'olden ,zo ( a) ors of' quent tulted' ilone. iluced' wi ng ntra, 6ited. land for >kin in- )ro- ;e.nt na1' no- tge gil ,or se of' I)ii~~-ies aiid «"hitehea.d (17) studiedi the effect of altering the "tar" ;iudi nicotine ratio of cigarettes on experimental carcinogenesis. No. ~i_nuiticaut difference in tumor yield was found between condensates 4)k,i;cined fronr the smoke of cigarettes containing 16.6 mg, "tar" and nig.~ nicotline and other cigarettes~ cvntaining~~ 10:0~~ ing:, "tar"~ andl 1~.a I~n1(r. nicotine.. '-~everal studies by Bock,,et al. (7, 8, 9) have examined the tumor prowoting- activity ofl a number of flractions~ of~ cigarette sm~oke~con-~ :iens,ite (CSC)~.~ A number of~ subfractinns~~ of the: neutral fraction ,if~ ('S(" were~tested for~tu~~rmor~ promoting~acti'vity in mice~~ pretreated %O~tli 1-1,1•3~-dimethyIbenz(n)antihracene~ as~ a tumor initiator~ (8).~ The, . niost, poTa~~r~~ subfract~ioiis~~ and the fraction: containing~~ benzo(a)Ipyrene~ «ere the most active tumor promoting fractions. In another stndy (,)). the weak acid fraction of CSC'' was found to be a very weak ('0uihl~ete~ carcinogen which probably ~ acts primarily as~ a tumor pro- inutiug~~ agent. The promoting activity depended primarily: on the nuriVolatile constituents of this fraction. ilTore recently,, B'ock, et al. reviewed the tumor~ promoting~ effects~ of CSC and extracts~ of' t~"b,u,co leaves. _V combi'nation of t~wo~ subfraetions~ of the~ tobacco~ ex-~ t ra(•ts. ~is wel2 as five majpr fractions of CSC, were foundi to have tininor promoting~ activity. Tlie~ fraction containing, the polynuclear~ ;re~otmitic~ hydrocarbons~ was~ found to~ be.~ a complete carcinogen. Tw~a. >+ii>fraetions~were~ found to~be~ strongly synergisti'c~in their~tumor~pro- u,ot~i~irg~ activity w~hen applied simultaneously to~ mouse~ skim Lazar, et al. (49) found that hy,droquinone applied to mouse skin in conj,iinction with the active fractions~ of CSC accelerated the early last.ologic changes that result from the application of "'tar" or its fractions., Van Duuren,~ et al. (97')~ have~ suggested that "'cocarcinogenesis"' be differentiated fromi "tumor~~ promotion"' defining~ "cocarcinogenesis'''~ ,ts~ tlhe~ production of ~malignant tumors by ~ t~~o~ on~ more~ agents a~pplied. simultaneously or~ alternately ~ in~ single~or~ repeated doses ta mouse~ skin and -''tumor~pr.omotion"~ as a single~ treatment with one agent foll'owed by single or~~ repeated treatment with a second agent.~ Using, these~~ defiiiiti~ons, the~ a-trthors, found severall tumor~ prom~oting, agents~ to: possesscoca~~rcinogeni'c actiivit~y..~ Roe, et al. (i:/) studied' mechanisi.ns of mouse skin carcinogenesis~ using benzo(a)~pytene~ and a~ neutral fraction of OSC applied singly or in various combinations with each, other: Skin tu¢nor~incidence~rates~ ialcreasedwitih the dose~ of applied niaterial for both~ the~ neutrall frac- tion and benzo(a)~hyrenef l~I1i'xtures~of the neut~zal~ fraction with benzo-~ ( a)~pyrene ~ (lid not act ind'ependently~ ini the production of~~ ma]lignant sk~izi~ ttuuors~ l'nut syncr-~istically;~ su(,gestiidh that some. of~ the~~ compo- nents~of the neutrail fraction act as~~cocancinorrtins~~ rather thEUi as conrl- plrt~e~carcinogens~. ar

Schmahl (78) found a direct relationship between the dosage aq duration, of subcutaneous injections of tobacco smoke condensates and! the development of sarcomas in rats. ~ Maenza, et al. (56) studied the efl'ects of a combination of nickel. subsulfide (~ i3Sz) and benzo (al) pyrene on sarcoma induction in rats. `' The interval between administration of the carcinogen andl the de-~ velopment of sarcomas was significantly shorter (IP'<0.001) ini male~ Fischer rats given injections of a combina,tion of 10 mg. of M;S'z and'T 5 mg. of' benzo (a) pyrene than in rats given either ingredient alone. ;. There appeared to be a synergistic interaction between nickell com- ~' pounds and the polycyclic aromatic hydrocarbons. ~ Healey;, et al. (34), added further refinements to a technique for v measuring, the nonspecific esterase activity of mouse ski¢xi following appli~cationsof various chemical compound's:~~°~~itlr few exceptions,, , changes in esterase activity reflected the known tumor prodbcing activity of a number, of polycyclic hydrocarbons and tobacco condensates.. ~ Sydnor, et alL (89) exaxni'ned' the effect of' an aqueous extract of' ,- cigarette smoke eondensate,on benzo(a~.)pyrene-induced sarcoma in, female Spra:gue-Dawley rats. Benzo(a)pyrene was~ injected subcu- „ taneously in various concentrations of' 12.5 µg: to 400 µg: per dose dis- ; solved in sesame oil. Injections were given on alternate days for 30 doses. The mean tumor induction time was accelerated in five of' `: seven groups given the aqueous extract of CSC' in their dirinking water. A:nimals given any benzo(a)pyre-ne eventually developed sar- ~ comas at the site of'injection. Dose-response rela:tionships were demon- strated for the concentration of benzo(a)pyrene administered. It appeared that aqueous extracts of CSC contained one or more com- ponents which functionedias cocarcinogens. Aryl Hydrocarbon Hytlroxylase (AHH) Certain of the~~ch~ernical componnds~ found in the ga~s,and particulate~ phase of cigarette smoke are absorbed through the lung or oral cavity into the general circulation. Possiblv through such absorption some chemical~: carcinogens are~ carried to~target~organs~~ not directly ~exposedl to cigarette smoke.~ S~ame~ of these chemical compound~~s~ are~ probably.~ excre~tedi unchanged while others are~ metabolized t'o~ v~ariousdegrees~ by~ enzyme~syst~ems present~in the~ liver andl many~ other tissues. Tlie~ ~ microsomal mised-function oxidases are~ key~ enzyme, systems~ for the metabolism~ of' a«id~e~ variety of chemical compound~s~~ ineluding~ the 82

of nick hinra ~ the de in ma1e~ rI3Sz an ' nt alone. Kel com~ ~ilue for' 111owing eptions, ; aducing' tobacco' ract of )ma in subcu- 'se dis. ys for ?ve of _ nki~ng d sar- ~mon- !d. It com- '•hensical carcinogens found in cigaret't'e smoke. Aryl hydroearbon. hnduoxylase(', AHH) is~ a part of the cytochrome P'-450~ containi'nguniccosomal enzyme system that is present in several tissues of humans ;1udl m~anyanimal species. The activity of this enzyme system is in-dured following exposure to the appropriate chemical stimulus. The ii N,dcoxylation ofpolycycliic liy,drocarbons~results in the detoxification id ~:oine and the, activation of others to reactive carcinogEnic forms. An understanding,ofthe role of AHH in the metabolism of chemical ir, 'i.nogens in man may help clarify some of'the mechanisms involved iut«baccocarcinogenesis. 1$ecentl'y„ several studiesexaminedl AHH :t,•c Wity in animals and man. Studies in Animals. .Sydnor; et al. (88) found that an aqueous extract of CSC adminis- tc+red in the. drinking water of rats potentiated benzo:(a)pyrene- iiicliaceA AHH actiuityinthe liver. TheliiverAHH activity was~I i;,rhtlyincreasedlbytheaqueousextract ofl OSC alone.Rondia and Gielen (75) reported that rats exposed to various levels of carbon monoxide developed a decrease in AHH activity in li'ver iirmiogenates, The reduction in AHH activity developed after 120 i1oiirs exposure to levels of carbon monoxide which prod'ucedl carboxy- heinog lobin levels belb«-. 15 percent. Welch, et al. (99) reported thatthe administ'ratli'on of benzo(a)- pvrenetopregna,nt rat& resulted in, an increase of the invitro, AHH', activity of maternal liver, placenta, and fetal liver.A twentyfold ]ii-her dose of'benzo(a)pyrene was necessary for stimulation of AHH nctivityin fetal li'verthan in the plaeentaor maternal liver. Studies in Man ulate Ivity some osed rees TI]ie the t~he. Levin, et al. (52) studied the induction ofAHH activity in human skin. Human foreskin obtained from circumcised childrenwas main- tained in~ tissue~ culture mediu~m: Exposure to~~101µ/D~T: of'benzo(a):py- rene, for 16~~hours led toi a twofold to fivefold increase in~ the activity~ of'~ AHH in the exposed skin over controll values. Whitlock, et all (101) reported the presence of AHH ini humann lymphocytes. The~~ AHH activity of lymphocytescompared torat liver~ or hanster ernbryo~ ce11's~ is relatively~ low. Treatmenti~ with~ pokeweed mitol;c,n albne, increased AHH activity about twofold. Holvever,~ aa threefold to eightfold rreater~ AHI+I~activity was~found inicells,treatedi witli the mitogen~ and benz~(a) <antlrracene~ than in resting cells. 495-028 P 0-737 83

Cell anttl'Tzssu,e Culture Studies In studies of tobacco carcinogenesis„ cigarette smoke condensate (CSC),~ subfra~ctions~~ of CSC, and individual chemical eompounds~ ~~ found in CSC~ haa-e, been adni~i~nistered to~ a variety of ~ animals~ using ~~ sereral'routes of administration. Tests on living animals are frequently "~ complicated~~ and t~~im~e~consuming. Cell and~tissuecul!t~ure~systems, offer ~~ an, alternate~ tool for the~ shid~~y of~ carcino;enesi~s~ -wliich,, in some~ in- stanees~,, is~~ relatively more ~ rapi~d' thani animal ~ test'ing~. Specific ~ enzyme ~~ systems~ and other cel!lular~ f'unctions~ can~ often be~~ st'tidiied'. in greater~ ~~ detai~l, using these~ systems. ~ Cells ~ obt~ained from a variety of ~ti~ssuesand n.~ animals can be~grown or~maintainedl in c'~ultu~re~~bottles~«-lien nourishedd with an appropriate nutritive medium in a supportive atmosphere. When these cullures are exposed to various chemical compounds; changes can occur which may range f'rom minor morphologic varia- tions to malignant transformation or cell death. Toxic effects on cell cultures must be differentiated from malignant transformation. Sev- eral stu'dies~~ liave~~ recently~ examined, the effect of' cigarette~ smoke conclensate or individual polycyclic hydrocarbons found in CSC on various cell andt'issue cult'ure~systems~.~ Benedict,, et', al. (4) studied polycyclic hydrocarbon produced cyto- toxicity, malignant transformation, and chi+omosome deformity in aa variety of~~ cell, lines~ derived from rats, hamstersY and~ human tumor, cells. The cytotoxic effect of benz~o~(a)~pyrene~ was found to~ lae~ related'' to the aryl hyelrocarboci, liydroxylase activity (AHH)~ of the given ceIl' culture. Benzo(a)pyrene was cytotoxic to fetal rat hepatocytes, but this effect was probably relftted'to the action o£ the hydroxylated' metabolite, 3'-hydroxy?benzo~(a)~pyrene,~ since th~e, cytotoxicity was~ blocked 'when t'he~ AHH~ systemi n-as~ overloaded with phenobarbital. Cell strains not possessing AHH activity showedi no cytotoxic effects from benzo(a)pyrene~ alone~;, ho«-eti=.er„ in the presence of~ fetal~ rat liepatocy~~tes possessing ~AHH ~acti<<ity; enough benzo (~a~) pyrene~ metabo-~ litles~ were! secreted into the~~ medium to~~ indkrce cytot'oxie effects~ in the normally r~esistlent, cell l~ines,~ In~ hamster~ seconda~ry~ cultures, at~ t'h~e~e chromosome leuel~~ cytot~oxicit~y~ «-as, associated «•~itlii cliromat,iidl breaks,, whereas malignant~ transformation was more~ closely~ rel~ated to aneuplbidy. Diamond ('19), studied't'h~e~metaboli~sm, of benzo~~(a)~ p'yrene~ and 7,12~- dimet'hy~lbenz(a~)~anthracene (~D-MII3'y1) iirmouse,~harnster,rat,monliey,~ and human cell cult~ures~ Metaboli~siu, of hy.drocarbonslo~ "alkali solu~~ ble''~ and"~`water solta~ble"~ dhrivatives, ~. ivas~~ measured'. Th~e~ results sug- gested gested that the~ pareut~ compounds ii-ere~ first metabolized~~ to~ "alkali extractalile~"~d'e~~rii,ati~ves~and t~lreii~to "Iwater~soluhl~e"~deriiN-ati~~%,es.~All tl.re~ cell cultures tested which were, sens~itive~ to, the g~ro%vth~-inliihi'tory~ effect's of benzo(',a~)~1>yr.euo- or Dl'fB~A were able~ to~ metabolize these~ 84

,•arcinogenic hydrocarbons~~ to~ "water soluble'"' derivatives.~ The~~ data~ MV Co~nsistent with the hypothesis that metabolism of the carci'nogen, nlq uired for (yrowth-inhibitory~or~cytatoxic effect& , -~evera1 authors~ have examined malignant transformation ini celd. 1,nltures. Inui' and! Takayama (41~)~ cultured hamster lun:g~ fibroblasts ;, nrL tlien esposedl themito~ crud'e~ cigarette~ "tar"' for a period of' 3~ hours. Between 3~~ to~~ 4K hours folliowi~ng~ this~ exposure, toxic effects of the rar''~, including cell necrosis,~ swelling;, vacuolization, and' disintegra- 6ut ofl cytoplasm were observed. The death of' 40 to 70 percent of rlw c•ells Nr~ithini 72 liou~rs~ was~ followed by~ the appearance~ of~ t~rans+~ i,)rined cell~s~AN-ltich grew ~ at rapid rates:~These~ transformed cells pro• ~ ii icedl nialignant tumors~ when inoculated in the~ cheek~ pouch of ham- -ters~. Controli cell lines produced no changes when inoculated in a~, <irnilhr fashion. In~ a similar study ~ by~ Di P~aolo,~ et al. (21), trans~formation~, of pri~- ru,try hamster cell cultures~wasindiuced by~benzo~(a)pyrene„3~-rnethyl~- 1'iu~l;uttlllrene„ or i;12~-dim:ethylbenz~(~a~)anthracene.~ Transformed cell 1 Mes were established and subsequently inoculatedl in hamsters pro- ~lncin,fr malignant tum~ors~at various sites. Characteristic cli~romosom~al~ rhaniges in~the transformed cellls~«-ers~alsod,escribedL. _1~n increase~ in proliferati~on~~ and tumor prodhxctiion rate~ of L-Strain ~ ellls ~ produ~cedl by treatment w~ith~ cigarette~ "`tar"~ was studied by~ liiai and Takayama~ (40). L-Straan~celd cultures not esposedl to~"'tar"' did not produce~ ttunors, wwn~ inoculated in~ C3H~ mice~. 'A:fter an rxposure t!olow concentrations,of' cigarette~ "tar" significant ch~anges~s occurred in the~ cultures characterized by~~ enlarged ce11s w~i'th~ vacuolated cytoplasm:, giant cell formation, and accelerated growth rates. These transformed cells, producedl tumors~~ in 70~ percent of injected C3HI Mice. -Nagata (60) treated cell culltures~ obtained from kidneys~~ of' new- ~ born mice Avith 20-methylcholanthrene in variou~s, concentrations. Con, trol! cullturesleould not be~ maintained for Iong~;~however; the~ treated cells formed two~ permanent~ cell lines which had a transformed'~ mor- phology~ and altered kasyotypes. F~pitTtelial carcinomas~~ .1 ere~ produ~cedl after~ the subcutaneou~s~ injection of these~ transformed cells i'nto~ un- conditioned newborn mice. Freeman, et~ a1L (29) isolated hamster-specifi~c~ C-ty-~pe~ RNA ~ v~i'ru~ses~ from tumors inducedl by~ cell cultures~ transforniedl by~ chemical car-~ cinogens. Cell~ cultures~ were~ prepared from~ earlti.~~~ passage hamster~ enibry.o cells~ anKl treated for 7~ days with 3!-metih~ylcholanthrene~or cer-~ tai~n~ fr.actions~ of~ cigarette~ srnoke~ condensate. Fo11owing~ treatment, niorphological~ly~ transformedl celll l~i'nes AN-ere~ isolated ai:tdl imtiirt~ainecl. Subsequent inoculation in newborn hamsters~~ produced malignant tumors~ at tlie~ sitle~ of inocuhttion. -N~eAl-~ cell liues~ were establi~shedl fromm sonie~of~the resulltine; tumons: N-o infectli'ous~~viruses~«-~ere isolated from celI lines~prior~to:iuocttlation; however.~C~-type R~~NA N-i~ruses~were iso-~ s S' WE

lated from~ tumors and from cell lines derived from tumors. The au- thors concLuded that the,chemiical treatment and activation of viruses appeared to be related events., Sivak and Van Duuren' (8-3) developed a cell' culture system thatt responded witli~ characteristic changes in cell morphology to the appli- cation of various fractions of tobacco leaf extract's. Certain dose- response characteristics were demonstrated, suggesting ai mechanism whereby various tobacco, fractions might be rapidily screened for tumor-promoting activity. Dietz and Fl!axmair (2Q)' studiedthe, toxicity of aromatic hydro carbonson normalhumani epidermal cells ini vi'tro.Pieces of adult human abdomi'nal skin were maintained' in tlissue culture medium andd exposed to3'-methylcholantihrene and' benzo (a)pyreneat, a concentra- tion of 1 µg./m1l for a periodd of' 4 days. The cultures were then kept for an additional3'monthsfollowing. exposure. No malignant transforma- tion~ oceurredl; h:owever, giant cells~ and a more disorderly pattern of'f growth .ti:ereobservedi i'mthe treated cultures «eeksearlier than silnilar changes in control cultures. Binding of PolycycZic Aydrocarbons to DNA and PNA There is evidence that some chemical carcinogens including certainn of the polycyclic hydrocarbons found' in: cigaretltle smoke condensate are~ active because: of the reaction of~ the carcinogen orr a~ reactive me~- tabolit_e~~ withi cellular m~acromolecules. Dun~can,~ et al: (23)! studied a series~ of' radioactive polycyclic~ hydrocarbons with respect to their~ metabolism and tendency~~ to bind with cel~luliir DNA and RNA in monolayer culltures, ~ of~ primary~ mouse~ embryo, cells. All the tested' hydrocar•bons~ were~ metabolized t'o~ "water soluble"~ metabolh'tes~ at approximately equal' rates. A "binding index" was caloulated' to db- tiermine the~~ binding of~ various~~ hy.drocarbons~ to~~ cellular DNA ~ and! RNA. group of hydrocarbons with a high "binding index"' con- sisted' of potent carcinogens, while another group «°ithi much lower values for the "binding index" were with but one exception non- carcinogens. Carlassare, et a~l~~, ~ (12) ~ studied the in v:ivo,bind~ing~ of ~benzo ~(~a) pyrene to~ D~,~~ A. Bonzo(a)~pyrene-3'H ~ «•as~ fed tomale~ and' female~ hTCT.i mice which were~ sacrificed after 15~~ hours. The DNA was~ extracted and purified'from tlie skin, spleen, and li'n-er: The binding of benzo(a)py` rene was greatest in tihe~ liver and somewhat less~ in the spleen and skin~., It was calculated that' the~~ average, molecular weight of DNA was.6 million and that 1 molecule of benzo(a)pyrene was bound to e~very~46~.8~~ molecules of~DNA ini the liver, suggesting~covalentl bindi~ng, of ~benzo~(ia ) ~pyre.ne t~~o~~ DNA.~ I I d ~. ~ I 86

he au- riruses p' that &'ppli- I dose- ~nism d for. ~ ydiro- adult ~ and ntra~. ~ ft for pq'rna- FP of 11i1ar tain. Pate kne- al a tieir Ited I at d'e- Ind. pn- ver un- ine jce hd! Y` Ld A ;o 9 .11Lsandrov andl Vendreliy (11) found that cigarette smoke conden, -ucc, the hexane-extracted fraction of' CSC, and benzo(a):pyrene all . uddbited,RNA synthesis inmouseskin. R?-Ni.trosamines in Tobacco, uSmoke `I'he~ largest'~number of chemica~li earciui!ogans~~ which~ have been iden- nrtiezli in cigarette smoke condensatle~ are pol~cyclic hydrocarbons. \'-nitirosanii2ie compounds known for many years to be potent car- ino_rens have produced malignant tumors in ai number of'organ sys- t~~i,.ms~ of~ a wide variet'y of~ animals. These~ compound~s~ were~ recently~ i~lhtttifiecll in~ cigarette smoke,~ O'~nl'.~~ recentl~y liias~ an association been frnnld between exposure tio~~ hTI-nitrosamines~ and malignant tumors~ i'nn hnuians (55).~ -N~-nitrosamines are~ formed chemi~cally~ by a~ reaction of \O! and NOs or nitrites with secondary amines: The chemical pre- 4•ua•sors of'the N-nitrosami'nes have been i'd'ent'ified in ci'garette smoke ('0ndensate~ (C~SC)~ by a~~ number of investigat'ors. These, studies .vere~ reviewed by Wynder and )8-Ioffmann (102) .~ AZlore recently, Rhoades andl lishnson (;69)~ developed a method for the~ determinat'ion of hr~-nitrosa- luiales i'Zr tobacco: smoke~ condensat'e~ using, gas chromotography. Two \-nitrosamihes~ were~ found in CS'C~: one «as~ identified as N-dimethyl-~ ioitrosamine~ (D.11~~NA)~ and the~ other~ was~ believed to~, be~ N-~methyl- (+th~ylilitrosamine~ (M~~EN..~)~ (43', 70). The concentration of~ DMINA 11er cigarette~in nanograms, was~determineds in condensates~ from ex- nerimr~ntal~ cigarettes made -from single tobacco~ varieties rath~er~ than a tobacco blend. Each tobacco tested was grown in both, a lon-- :uul high-~ni'trogen soil. High-nitrogen soil'~~ conditions~ resulted in a~ ~~onsid~erable~ inerease~ in nitrosamines~., A popul~r brand of nonfilter cigarettes~ was a1so tested. These~ resul~t's~ are~ presentedl in tabl~e~~ B. TABLE 2: .,V-dimetliylnitrosamine (DMNA) content' of' condensates obt~ained~ from several t~obaccos,gr~own, in~ botk "high" and~ "low"~~ nitro- gen~ soils Tobacco type Soil nlttogen DR4N,A (nano- grams per cigarette) R6bineon-____, --------- Low nitrogen----------------- 0 Cattertlon_____. -------------- db----------------------- 5 Bhrlev----- --do----------------------- 3 Robinson_-___-____-_ 1"•Iigh nitrogen----------------- 27 Cattiertom____________ ------------ do----------------------- 60! Bitrley -------------- ------------ do----------------------- 140 II.S'1 nonfilter--___,___ 8'. Source:,Jbhnson, ID. E., Rhoades, J. W. (4$), 0' 87 ~ ~ W f~

Summary of Recent Cancer Findings In addation to the summary presentedl in the introduction of'th2s' chapter, based on previous~reports of the health consequences'of smok- ing, the following statements are made to emphasize the recent devel- opments in the field :. 1. Recent epidemiological, andl autopsystudies from several coun-triesconffrmth<2t cigarette snioking"isthemagor cause of lung' cancer. 2. Continued cigarettesmoki'ng by patients fol9owi'ng successfull surgi~cali removal of' a~ cancer of the oral cavity, pharynx, or larynx wi'thout'tailor recurrence for a period of3yearsisasso- ciated'n°ithasignificant increase (P< 0:Q01)inith&riskof'devel~oping a~ second primary cancer of the u'pperrespiratoryor diges-tive tract compared!to similar patients who, discontinue smoking at the time of their surgery. 3.Theintratrachealadmini'stration ofcertiain polycyclic liydrocar- bons' found in cigarette smoke condensate result's in the forma- tion of' an<aplasticand sqqamons',cellcancers of theNngand re- spiratory tract in hamsters and rats.1'fany of' these tumors are histologically siinilarto the lung cancersfoundi most frequently in cigarette smokers. 4. The application of cigarette smoke condensate or polycyclic hy- drocarbons tovarious cell cu.ltures often results in transformation to cells with a more rapid and disorderly growt'h pattern. Trans- formed cell" linesfrequent'ly producebe.nign or malignant tumolrswheirtr.ansplantedtoetperimental aniina~ls.. 5. -N-nitrosamines havebeeli, identifedin cigarett'esmoke: These compounds are known to bee potent cancer causing chemicals for avarietyof'anima~ls. Theya~ppear to be formedirr higller concen- trationsfi•om tobaccos raised itndenhigJi-nitrogen soil conditions. Cancer Refierences. (1) ALExANDROV, K., VErroERLx, C. Action de condensats de fumee du tabac sur la synt'hese de R_\A dans Ia peau des souris. (Action of tobacco smoke condensate oni the synthesis of RNA in mouse skin.) Chemieo- Biological Interactions -1(3 ) : 1.55;-161, February 1972. (2.). AUERBACH, 0., IIAJSIIOND,. E. C., GABFINKEL, Ii, El)ltheliAll changes'S lnn e%~-cigarette smokers; Cancer Cytology 11i(1) :5-12;,1n71. (3Y AUESeaCfr, O:, HAuUMoso, E. ('., IiiaMAV, D:, GAxFINKEL, L. Effects of cigarette smoking on dogs. II. Pulmonary neok1asms: Archives of' En- vironmental, Health 21 (;6) :754--7CkR;,December 1970i. 88

I ( BE:rEDIOT, W'. F:, GIEr.EN, J~ E., NEBERT, D. W. Polcyclic hydrocarbon- I f' this produced toxicits, transformation, andi chromosomal aberrations as a function ofl aryl hydrocarbon hydroxylase activity in: cell cultures. InternationalJournalof'~Cancer9(2) : 435-451, Mar.5,1972. omok- level- I (5) BERC; Jl W:,, SCxarrIENF-ErD, D:,, RITrER,F. Inci'denceof' multiple primaryy cancers. III. Cancers of the respiratory and upper digestive system as multiple primary cancers. Journal of the National, Cancer Instit'ute. , 44(2) : 263-274, February 1970. 'oun- (6) BERRY, G.,, Nr".w$ousE, M. L., TuROK, M. Combined effect of asbestoss ;lung exposure and smokiing on mortality from lung cancer in factory workers. Lancet 2'(7775) ' : 476-47 9, Sept. 2, 1972. SsfLi1 (7) Bocx,,F: G. Tumor promoters in tobacco and cigarette-smoke condensate. 1, or Journal of the National Cancer Iinstitute 48(6) : 184'9-1553;, June 1972. 1 (1b) BoaK, F:,G.,,SsvAIN; A. P:,,STEDNCAN, R. L. Composition studies on tobacco. 4SSor we1- NLI: Carcinogenesis assay of subfractions of the neutraU fraction of cigarette smoke condensate: Journal of' the National Cancer Institute (geS, 44(6) : 1305-1310',, June 1970. (9): Bocx, F. XLIV. G.,, SWAIN, A. P., STEDacAN, R. L. Compositionistudies on tobacco. Tumor promoting activity of subfractions of the weak acid II fraction of cigarette, smoke condensate. Journal of the Nationall Cancer car- a- re- are. ~tily i ClY- ion k15- brs Institute 47('2) :4'29-436„Augnst,1971.(10.), BO'rr¢cEIELI.I„ R., DEI:NERr,. E., MosANaHINI, 0. Rapporti tra carcinoma, broncopolYnonare primitivo e fumo di tabacco. (Relationship between primary bronchopulmonary, carcinoma and tobacco smoking. ) 14IGnerva IlTedica Giuliana 90) : 289-291, November-December 1969. (II'), BOUCOT,, K. R.,, WEISS, W.,, SEIDMAN, H., CiARNAHAN,. W., J., C00PER, D:, A. The Philadelphia pulmonary neoplasm research project : Basic risk factors of lung cancer in older men. American Journal of Epidemiology 95 (1i) : 4-16. Januars 1972: (12) CARLASSARE, F., ANTONELDO;, C.,BACCICH,errl,. F.,, :4iAIFER, P. Onthe binding of benz(a)pyrene to DNA "in vivo". Zeitschrift fur Natur- forschung 27 (2) : 200-202, February 1972. (13) CARRADA BRAvo, T., NUNEZ JARQuIN, E. El diagnostico roentgenologico de las neoplasias bronchopulmonares primarias. (Reoentgenological diagnosis of primary bronchoplumonary neoplasms. ) Revista Mexicana de Radiologia 25 (5) : 1$5--196, September-October 1971. (11y) CoLE, P., HoovER;, Rl, FRIEDELi„ G, H. Occupation andl cancer of'the lower urinary tract. Cancer 291(5) : 1250-1260,, May 1972. (15)' Cor.E,, P., MoNSON, R. R., HANINO, HL, FRIEDEa.r, G. Hs Smoking, and cancer of the lower urinary tractl New England, Journal of Medicine 284(3') : 129-134,,Jan. 21,1971. (16) CRAOC, J. Lung cancer in Jersey: Its incidence and associated biochem- istrr. British Journal of' Clinical Practice 25'($) : 3G4}-3!6:i, August 1971. (17) DAVIES, R'. F., W'HITEIiEAD, J. K. A study of' the effects of' altering, the tar/nicotine ratio in experimental tobacco carcinogenesis. British. Journal ofCancer24(1) : 191-194, Mareh1 1970. (l8) DELARIIE, N. C., AIIDERSONy. W.,. SANDERS, D., STARR,. Jl BroDchlolbalR'.eolar' carcinomaL , A reappraisal after 24 years. Cancer 29(1) : 90-97, Janu- ars1972. (19:), D7AMotiD, L. JTetnbolism, of' polycsclfi.ch;vdrocarbons in mammalian cel'll cultures. International Journal' of Cancer 8(3'),: 451-462, 11iov.,15, 1971. (20)DiETZ, M~ II., Ft,AxaiAN,, B! A. Toxicit'y of' aromatic hydrocarbons on normali human epidermal cellb in vitro:, ('nace,rResearch 31(9) : 1206-120&, September 1971. 89

(21) DrPAoI:o, J. A., NELSON4 R. L., DONOVAN, P: JL Morphological; oncogenic, and karsolbgical characteristics of Syrian hamster embrfo cells trans- formed in vitro by carcinogenic polScyclic hydrocarbons,, Cancer Re- search 31(8) : 1118-11'27, August 1971. (22) DOLL,, R., PrKE, !L C. Trends in mortality among British doctors in re- lation to their smoking habits. Journall of the Royal College of' P'hysicians'.6'(2) 1: 216-222', January 1972. (23) DUNCAN, M., BeoaKES, P., DiPPnE, A. 3ietabolism and bind!ing to cellular macromolecules of a series of hydrocarbons by mouse embyro cells in. culture. International Journal of! Cancer 4(6),: 813-819, Nov. 15;, 1969: (24) FEROw, V. J. Respiratory tract t'umors: in hamsters after intratracheal instillations of'benzo (a) pSrene alone and witihifurfhlral. Caneer Research 32(1) : 28-36, January 1972'. (25) FERSARa„F: A. Ecolbgical analysis of'lung cancer in the city of La' Plata. In': Englund, H. 1T.,, Berry, W. T. ( Editors. ) Proceedings of! the Second International Cliean, Air Congress, Washington, D.C., Dec. 6i-11, 19701 Nevv'York„Academic Press,197'1, pp. 244-247. (26) FIrraERLAND, A., HuseK, T., BENDLOVA, J: Contributionito the investigation of the effect of cigarette smoking. S6ornik, Vedeckych, Praci' Lekarske. Fakulty Karlovy University v Hradcil Kralove 14(2) : 221-234, 19711 (27) FrsaxER, G. Rauchgewahnheiten und Blasentumoren. Eine klinische U'n- tersuehung. (Stnoking' habits and bladder tumors. A clinical study.) Zeitschrif't fur Urologie' und Nephrologie 64 (4), : 271'~-274,, April 1971. (28) FRANR•E, R. The' possible role of' hydrophobic interactions of' polycyclic aromat.ir'h5drocarbous with protein in:chemical careinogenesis. 1Talecu+ lar Pharmacology 5(6) : 640-6:i7, \'ovember 1969. (29) FREE]fAN, A.h7.,KELLOFF, G. JI,.GILDEN, R. V., LA'PTE,W. T....SM1KAIN, A. P.,. HuEBNER, R. J. Activation and isolation of hamster-specific'C-tSpe RNA viruses from tumors inducedl by cell cultures transformed' by chemical carcinogens. Proceedings of'the National Acadenly of Sciences (USA) 6'8('10):: 2386-2390; October 1971. (30) FuRNICA, G., TOADER, M. Continutul de z1OPo in diferite sorturi de tigari. (PoaOcontentl in different cigaretteblends.)Ilgiena 18!(8): 469-474, August 1969. (31) HA.IDU, S. I., Huvos, A. G'., GooDNER, J. T., FooTE,, F. W., Jr.,, BEAME, E. J., Jr., Carcinoma of the trachea. Clinicopatholog'ie study of 41 cases. Cancer 25(6) :~1448-1456; June 1970. (3`L) HARRI9,,C. C., .ry, PORWI,,:1'T. B:,. KAUFMAN, D. G., SMITH, J. M., JACKSON, F. E:,. SAFFIOTTI, l.J..I1.istiogeneSls.Of. sflllamousmetaplaSiainthe hamster'tra- cheal epithelium ~ caused by vitamin A deficiency or benzo (ia ) p;Frene-ferric oxide. Journalloft'lleNat9onal Cancer Inst9t'ute4'8~('3)~: 743-747, March. 1972. (:T3). HARRI6y C. C:,, SPORN, 2%IL. B'.,. KAUFMAN, D.. G!, S1'fITIr,. J. 'M.,. BAKER,. 111. , S.,SAFFroTTI, U. Acute ultrastructural effects of benzo(a)pyrene and'ferriic oxide on the hamster tracheobronehial epithelium. Cancer Researeh, 31(12) : 1977-1981, Decetnher 1971. (34)~ HEALEY, P:,. MAWDESLEY-THOMAS, L. E.,., BAHRY,D'.. H.. The' effectl of sOmee polycyclic hydrocarbons and, tobacco condensates omnonspeciflc esterasee activity in sebaceou5glanrdsof mouse'skin. Journal, ofPathol~ogp105(2) :147-152; October 1971. (35) FI>:RROLD, K. McD. Survey of histologic types of' primary lung' cancer in, ULS. veterans. Pathology Annual 7: 45-79; 1972. 90

Fenic; tansr I Re- ~ re- ~ of lalar ~S in ;9fi9. heali rrch i ata• ond! 9Z0: ion. ~`ske B., ~a- 'ic ch le ie n Iln;Ao, F., FuJISawa; T.,, Tsusuas, E., YansaMunA, Y. Experimentnll cancer of' the lung in rabbits induced by chemical carcinogens. Cancer Research 32(6) : 1209-1213;,June 1972. 1.t7) HiaAYaNrA, T. Smoking in relation to the death rates of'~ 265;118 men and! women in Japan, A report of' 5 years of' followupj , Presented at the American Cancer Society's Fourteenth Science Writers' Seminar, Clear- w,ater'Beach, Fla., Mar. 27, 1972, 15'pp. ;8) I3oasuxGES„ F. Chemical carcinogenesis in, Syrian hamsters. Ins I3om- burger, F: (Editor). Progress in Experimental Tumor Research. Path- ology oftheSyrian, Idamster: Vol. 16,, Basel, S. Karger, 1972, pp. 152-175. „U I, HOOVER, R.,, CoLF., P'. Population trends in cigarette smoking and bladder cancer. American~ Journal of Epidemiology 94(5) : 409-418, November 1971!, ioJ INui, N.,, TAnAYawcg, S! Acceleration of proliferatibn and, tumor produc- tion of rate of L-strain cells by treatment with ciga:rette tar. G'ann 62(4'.) : 315-320,August 1971. ~ fl) Ivua,, N., TaKArAnse, S. Effect of'~ cigarette tar upon~ ti'ssue, cul'taurecells, Neoplastic transformationi of'liannster lung cells by tobacco tar in tissue culture: British Journal' of Cancer 25(3)': 574-583, September 1971. u.1,?) IvaKmNo; G. I. 0 rolilkureniya v zabolevayemosti rakom legkogo. (Role of smoking, in, the incidence of lnng, eancer. )Vrachebnoe Delb 9: ~ 99-101;. 1971. (.+3) Jbnnso.N, D. E., B:HOAnES, J. W. N-nitrosamines in smoke condensate from several varieties of' tobacco,, Journal of the National Cancer Institute 481(6) : 1845-1847;, June:1972: JoYErr, G. The thorium-series in cigarettes and in,lungs of' smokers. Experi- entia 27 (1)~ : 85-89,,Jan. 15;,1971., i5) KeNvEnY,, A. Lung, cancer in young adults. British Journali of'~ Diseases oftheChest66'(2')~:147r154, April 1972. ( ~fi) KoszasowsKZ, T. 0 raku pluca-po 25 latach. (Lung; cancer in, the course of 25' years.) Pollikil Tygodhik Lekarskil 26(47) : 1805-1807, Nov. 22, 1971. i!F7) Kxaiv, L. S. Crossing of the mortality curves for stomach and pancreatic carcinoma. International Strrgery 57(4) : 307-310;,Apri11972. (~8) LAassoN, S. A;Idersspeciflk incidens av prinrar lungcancer i sverige. Trenden under periodeu 1959-66. (Age specific incidence of lung cancer in Sweden. The trend during the period 1959-66.) Lakartidningen 68(38) :, 4229- 4236; Sept. 15,1971'. (.~9) LAZAR, P., IzARn, C., _1TossiE-TESTA, J., CriouaounrNaov, I. Interaction entlre 1'liydroquinone et le condesat,de fumee de cigarette dans les tests eutanes a court terme du pouvoi'r carcinogene. (Interaction betweenn hydroquinone and cigarette smoke condensate in short-term skin tlests of! carCinogenicactivity.) Coniptes Rendus Hebdomadaires des Seances de l':>;•cademie des Sciences ; D: Sciences N aturelles 274 :-19('i-49:), Jan. 17,, 1972. (,50)! LEE, P. N., O'tiEiLL, J. A. The effect both of time and dose applied on tu- inour incidence rate in benzopyrene skin painting experiments. British Jlournal of'~ Cancer25'(~4) : 759:-77.0, December1197.1. (51)LeoNE, G. linportanza del ftittorii ambientalinella patogenesi dei t'~umori, dell' uomo. Ruolo dell fumo di sigaretta, (lmportanceof environmental . Eactorsin thepathogenesis of tumors i~n, man. The role of cigarette smoking.) 'Minerva Jlediiea. 62(49) : 2461-?.480,, June 20, 1971. 91'

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Contents A Page Iiltroduction-------------------------------------------- 103 Smoking and Birth Weight Epidemiological Studies Cigarette Smoking and the Low-Birth-Weight Infant- 105 Evidence for a Causal Association~ Between Cigarette Smoking and Small-for-Dates Infants------------ 106 EVidencei for~ an Indirect Association Between Cigar rette Smoking; and Small-for-Dates Infants------- 110! Experimental Studies Studies in Animals Tobacco Smoke----------------------------- 114. Nficotine----------------------------------- 115, Carbon Monoxide--------------------------- 116'. Polycyclic Hydrocarbons--------------------- 1'17 Studies in Humans Carbon Monoxide--------------------------- 118 Polycyclic Hyd'rocarbons--------------------- 119 Vitamin B12, and Cyanid'e; D'eto:xification-------- 119 Vitamin C---------------------------------- 1'19. Possible?1lechanisms--------------------------------- 114 Timing of t~heTnfluerr,ce ofC'igaret~te Smoking~ on: BirtJi~ Weight------------------------------------------- 120 r.S'ite of' Action at the Tissue and Cellular Level------------ 121 Signific¢n,ce of the: A'ssociation------------------------- 121 Birth IVei'ght Summary------------------------------- 1'2'2 Cigaret't'e Smoking and Fetal and Infant Mortality Introduction---------------------------------------- 123 Spontaneous; A.bortion'-------------------------------- 123 Spontaneous Abortion Summary------------------ 124 Stillbirth------------------------------------------- 124 St'illbirth Summary------------------------------ 125' 495-02S 0-73-8 99,

Page Cigarette Smoking and Infant Mortality-Con. Late Fetal and Neonatal Deaths------------------------ 126 Epiderniloiogical S'tudies-------------------------- 128' C~omparisons~ of t'he! Mortality Risks~ of' Losv-~ Birtli-W~eight Infants Born to Smokers and Nonsmokers------------------------------ 126 Recent Studies------------------------------ 128 Anal}-sis of'Previously Reported Studties-------- 130 Factors Which I'nfluenee~ Perinatal MortalityOt•her Than Smoking---------------------- 13'1 Experimental Studies Studies in Animals-------------------------- 132 S'tudfies in Humans-------------------------- 133 Significance:of' the Association-------------------- 133 LateFet'al and'~, Neonatal Death Summary---------- 134 Sex Ratio'---------------------------------------------- 135' Summary------------------------------------------- 135'. Congenital 1VI!alformations-------------------------------- 136' Congenital Malfor7reation Summary--------------------- 137' Lactation I'ntroduction---------------------------------------- 138 Epidemiological Studies------------------------------- 138 Experimentad' Studies--------------------------------- ' 138 Stud ies, in AnimalsNicot'ine----------------------------------- 13'8' Influence on the Lactation Process------------- 138' Presence of Nicotine in, the 1Vlilk-------------- 139 Evidence for an Effect Upon thei Nursing Off- spring ------------------------------------ 139 Nitrosamines------------------------------- 139 Studies in Hurnans Nicotine: and,ior Tobacco Smoke--------------- 139' Influence on the Lactation Proeess------------- 1'39. Presence of' Nicotine in the MiIk-------------- 140 Evidence for a Cliniical Effect Upon the Off - spring------------------------------------ 140~ Vitamin C---------------------------------- 14'1' Lactatibn; Summary'---------------------------------- ----------------- - - - - - - Preeclarnpsi'a-------------------------------------------- 142' Summary_------------------------------------------_ 142' R'eferences---------------------------------------------- 142

Page 126 126, 126 128 130, I 131 132 133 13'3 i 134 135 135'. 1' 3 6 137 l3'8 :38' 38 38' 38 39, 39 19 191 9 0 List of ~ Fngures Page Figure 1.-\Iean birth, weight for week of' gestation according to maternal smoking habit: control week singletons--------- 104~ Pi,ure 2.-Percentage distribution by birth, weight of' infants off mothers who did not smoke during pregnancy and of those Ncho smoked 1 pack of cigarettes or more per day---------- 105 Figtire 3.-Percentage of: pregnancies with infant weighing less than 2;5000 grams, by cigarette smoking category----------- 108~ Fi;ure 4.-Average birth weight by maternal smoking, habit (a) before current pregnancy and (b) during, current preg- nancy------------------------------------------------ 110 Figure 5.-Percent of'low birth «-eight white infants by smok- ing: status of'~ their motlhers------------------------------ 113' F'inure 6.-Neonatall mortal,'itu rates among, single white births in hospitals (by detailed birth weight and specified gestation groups: United States)'--------------------------------- 1128 Figure 7.-Perinatall mortality rate per 1,000, total births by cigarett~e smoking category----------------------------- 129' List of Tables Table 1.-fnfant birth weight by maternal andl paternal smok- ing habits-------------------------------------------- L11 'Table 2.-Effiect of carbon monoxide& exposure of pregnant rabbits on birth «-eigh't--------------------------------- 1117 T.able 3.-Compariaon of' the perinatal mortality for infants n-eighing less, than 2,500 grams, of smokers and nonsmokers- 127 Table 4:-Effect of carbon monoxide exposure of pregnant rab- bits on birth weight and neonatal' mortality---------------- 133' Table 5'.-Proportiion of: male infants delivered to smoking and' nonsmoking mothers----------------------------------- 136 Table 6.-Relative risk of congenital malformation for infants of' cigarette, smokers and nonsmokers, comparing available s~tudies with regard to study design, study populatibn,,sample size; number of infants «-irt,h~ malf'ormations, and definition of mal~formation----------------------------------------- 137 1011

Imtradiwction ('igarettesmoking isa commonhabitamong women: of'chil'd-bearin~g;i~,re in the United S'tates: Iln 1970, approximatielyone-third of Amer-ic,ul women of child-bearing age were cigarette smokers: The percent- ,z _-e of F.S. women who smoked throughout preYnancy is not definitely ;:alown, but is presumably,~ lo«-er„ probably in the neighborhood of 20, rr, •?5 percent. Witliia large fetal population at potential, but prevent- al~le, risk; t'lie relationship between cigarette smoking, and' the out- ('Olueof premlancyhas been the focus,ofconsiderableand continuing: research. Lver~.~ investigat'or who has examsnedithe relationship has confirmedl that the infants of women who smoke during pregnancy have a lower avenage birth weight than the infants of' women who do not smoke uluringpregnancy.: INIuclii evidence indi'catlesthat cigarettesmokin'g duringpregnancy causes this reductian, in infantf birth weight. Sw?v'eral investigators haved'emonstrated that tihefetal' and neonatal mortalitiy, rrate is significantly higher for the infants of' smokers than for the infants of nonsmokers; other investigators have not foundd higher mor- talityf'orsmokers' infants-Stu'dies~of the associntionbetween maternal cigarette smoking and congenital malformations have produced con-f[icting resullts,Thefollowing is a revieww of' «orkpreviiously reported and recent studies which -bear on therelat'ionshspsbet'ween ci~garettesmokingand, dilfferent outcomes~ of pregnancy. I'nadditi'on„ the chapter includes a review of the rellationship between cigarette smoking and lactatli'on. Smoking and Birth Weight Epri'demiologieal Studies LIGA'RETTE SMOKING t1ND THE LOw'-I3IRTH-WEIGHT INFANT In~ 1957, ~ Simpson (90');, using a retrospect~ive~ study~ designy, deter- mined that among 7,499 women in~ S'an Berna;rdiim County, Calif., the deliverv of infants weighing~less~than ~ 2~,5(l0 grams was~nearly t~«-ice~ as~~ 103

frequent among cigarette smokers as among,nonsmokers. Snlisequently, ~ Lowe (46) studied 2,042 women ini Birmingham, England, and, d'em- :~ onst'rated in his retrospective study that the i'nfants of smoking ~ mothers were del7vered only slightly earlier (1.4 days on the average) ~ than those of nonsmokers. He further noted that for gestations of 260! days and over, the infants of smokers «ere' consistently lighter in ~ «eiglatdnring, each«-eek of gestation~ than those of the nonsmokers. This finding' has been confirmed siilce; and figure 1 fromi the B'ritish ~ Perinatal Mortalit'y Study (13), provides illustration of this relat'ionship: Given thenearly constant disparity present betl«-eenthebirth . weights of the infants of'smokers and nonsmokers for gestations of' 260 days and over, but, absent prior to that time, and' giveni the similar birtliweight's ofi~nfant's,of' nonsn2okersands of wolnenwhogaveup smokingearly.in pregnancy and didi not begintosrnoke ag ain; ILoweinferred tliat, theidifluen:ce of' smoking upon birth weight miglitlie mainly in the later months of pregnancy. F'leemph~asized the tentative nature of this conclusion, sincetaie number ofinfants.ti-itlh a gestation of less than 260 days and the number of women whogan-e tip smoking early in the pregnancy' and' did not begin to smoke again were both small. Figure 1'.-Mean birth weight for week of gestation according to maternal smok- ing habit: control week singletons.' 125'. 2 85 75. 1 3650' 3400 2900' » (D 2650 ~ ~ 2400 12150 36 37 38 39 40' 41 42' 43+ Gestation in completed weeks ~ This term refers to singleton births In Engiand; Scotland, and wales occurring during the week of March 3-9; 1958, whichi are included in the Perinatall Mortality Survey. These comprise 97' percent of all births notified in England and Wales or registered in Scotland during this week. SOWRCEc Butler, N. R., Alberman, E. Dl (13). 704

ntly, lem- liing ige) 260 r in ters; tish this Irth ;260 ~ 1 lar lup ?we lie ion i ng ~th bk- I Lowe found that the infants whose mothers smoked throughout 1>regnancy «eibhed, on the average, 170 g~ranl~slessthan thoaewhosemothers did not smoke. In addition, he notedl thata'the ent'iredistiribu- rion of' weights of infant'sf ofl smokerswas shifted to the left (t~oward lower weights) relative to that for the infants of nonsmokers. This i6)xling, too, has been confirmed by other investigators, Figure 2 offers na)~illustration froml\TacATahon; etal. (49). Given that the infants of smokers andl nonsmokers differedi only .<li-(rhtly with respect to the duration of gestation, Lowe concluded that tiie lower birth «eight of smokers' infants must be attributed tol a iiirect retardation of fetal growth. In other words; on the basis of his ~l'ata,, the infants of smokers were sma11-for-dates rather than truly preznature. NDanyinvestigatorshavesubse,duentlly confiQ-rnedl this point (12, l4,,, 6a., 78,,83,123). Buncher (12), in a study of 40;89/ births among I-.S'. naval n ives, in the same popul6tioni studied byIlndemroodl, et al. (100), found that the imfants of smokers were,, on the average, de• llivered only 1' day earlier than those of nonsmokers. This finding accounted' for only 10: percent of the discrepancy in birth weight, be-t`veen the two groups of infants. The remainder of the studies resulted in t1xedetection of' either similar vari'ationsingestationall length or no ar.eragedsfference. In a recent study; Aiulcahyand A~furphyl Figure 2.-Percentage distribution by biith weight of infants of' mothers who did not smoke during pregnancy and of, those who smoked: 1 pack of cigarettes or more perday. I~NFANT1MEIGHT' AND: PARENTAL SMOKING, HABITS t 10 2 ~ ¢ 100, 6 il m o. 4 ~ P T ~ T r i 11 Nonsmokers ----- Smokers r". 4 5. 6 7 8~~ 9' 10 1i1 BIRTH WEIGHT (SCALE IN POUMDS; INTERVALS OF 4, OZ.). SOURCE: MacMahan, et al. (49). T 11 i 105

in a sample of 5,099 Irish mothers; concluded that although the babies born to cigarette smokers were delivered sliglitlyr earlier than those of nonsmokers, independent of age and parity, the direct effect of smoking in retardingfetal growth was more significant. The following points, based upon the results from manyy differentt studies, can be made about' the relationshi'p between cigarette smoking during pregnancy and lower infant birth weight: 1!. Women who smoke cigarettes during pregnancy have a higher proportion of low birth-weight infants than do nonsmokers. This excess of low-birth-weight infants among cigarette smokers pre- dominantly consists of infants who are smalI-for-gestational age rather than gestationally premature. 2. The ent!iredistributlion of birth, weights of' the infants of ci~ga~- rette srnoker& is~ shifted toward lower weiglits compared to the birth tivei;ghts of the infants of nonsmokers. 31 The birthi weights of' the infants of cigarette smokers are con- sistently lighter, than those of the infantis. of nonsmokers when the liirth weights of the two se.ts of infants are compared' R-i'thsnn groups of similar gestational age beyond the 36th week of gestation. The results of the studies which have beenconsidered so far identify a relationship between cigaret•te smoking, and loR-er infant birthh weight and' illustrate some aspects of' that relationship, but do not indicate whether the association is causal or indirect:The succeeding two sections ofl thi's chapter contain evaluations of the available evi- dence whi'ch bears upon tihe nature of' the association between cigar- ette smoking during pregnancy and the incidence of small4or-dates infants.. EvIDENCE FOR: A CAUSAL ASSOCIATION BETWEEN OGARETTE SDIOgING AND SMAII:L-FOR-DA'ITES INFANTS Evidence previouslyy reviewed in the 19711 and 1972 reports on the heaTthi conseqpences of smoking (101, 102) ) suggests that cigarette smoking, is causally associated withi the delivery of' slnalMor-dates infants. The following is a summaryy of this evidence : 1. The results from all 3b1studies in which the relationship between srnokingandl birth weight was examined havedemonstratedl a strong association between maternaT ci9arette smoking anddeli~-eryoflo~~-birth-weight infant~s. On t'heaverage; t'hesmoker has~nearh~-~ twice the risk of delivering a Iowbirth-«-eight infant as thatt of a nonsmoker 106

1:3, 17, 20, 25, 29, 35, 42, A 46, 47, 49, 57, 58,, 59, 65, 70, 72, 73,. ;7 . ,8: 80, 83,85, 90; 95, ,99y,1G10,113,1 18). , •?: The strong association between cigarette smoking and the de- li.\ ery of small for-dates infants first demonstrated with results from >ndtlies of retrospective design (3,13, 17, 35, 46; 47, 49, 57,68, 59, 65, ;6: 72, 73, 77, 80,85, 90„95, 99,100,118)~ has!been repeatedly confirmed >ul,,equentlybyd'atafram studies ofprospect'i!ve design (20,,25,,29, 42, ;'8. 83,113) . :;. A strong dose-response relationship has been established between c i_,r,urette smoking and the incidence of' low-birth-weight infants (25, ;.>. _~f:, 59;100,1'13). t. When a variety of known or suspected factors,ivhich, also exert an iiifluence upon birth weight have been controlled for, cigarette smok- ini-, has always been shown to be independently related to low birth ght (1,13,25,43,A13;78,83).:. The association has been demonstrated in many different coun- tries; among, different races and cultures,andl in different geographicall sott ings ('13„1~7,25, 29, 36,1f2,,13, 59; 73, 78~ 80„1 ~13) 1. G. Previous smoking, does not appear to inflluence birth weight if tliemother givesupthehabi't prior to the start of herpregnancy (25, i%y..f:9;113). ,. The infants of smokers experience an accelerat'ed, growth ratelurin,; the first 6 months after delivery, compared to infants of nciismokers. This finding is compatible with~ viewing birth as there- movaI of the smoker's infant from a toxi~cinfluence(',83). 5% Data from experimentsin animals hav~e: documented that ex- l,osuneto tobacco smoke, or someof' itsingredients results in the (lelivervof' low-birth-«eight off'spring(7, 8, 9, 23, 40, 87,117)'. Several recently published studies have provided' additional sup- porting evidence for a causal relationship between cigarette smoking, and smnll-flor-dates infants. The~ Ontario~ Perinatal' nl~ortality Study(66) was conducted among 10 teaching hospitals during 1960 andl 1961. 'The authors of this retrospective study of 50,267 births demon- strated ai significant excess of infants weighing less than 2,500 grams among cigarette smokers as compared with nonsmokers (P<0.001). Smoking was significantly dose-relatedl to the percentage of preg- nancies terminating in the delivery of a low-birth-weight infant(fig. 3). ti iswander andl Gordon (63) have recently reported data from the Collaborative Perinatal Study of the National Institute of Neuro- logical Diseases and Stroke., In this prospectiv~estudpof'3J,200~ preg- loancies„ which «°ere nearly equally divided among black and shite«-oinen, the authors found a significant dose-related exeessof low-birth-weight infants among smokers of both groups, compared to nonsmokers of'the same race. 107

Figure 3.-Percentage of pregnancies with infant weighing less than 2',500 grams, by cigarette smoking category. 12'.0 11.0 10.0 9:0 8.0 5.0 4!0 3.0 2:0 0.0 4.7 7:7 12.0 Nonsmoker <1 pack ?1 pack per day per dax. Number of infants weighing. <2,500 grams: 1,322 1,186 793 Total births: 28',358' 15,328: 6,581 (P <0.001). SOURCE: Ontario Department of Health (66). 108 '

Rantakallio (76)~ carried out a prospect'ive study of 11,005 single hirths in Finl'and. Gigarette smoking mothers hadsignifieantly moreirifants weighing less than 2;500 grams than did nonsmokers (1' <0.001).IP,uslt and Kass (82),, in a prospective study of 1,040 pregnancies in E3o;~ton4Massachusetts; Domagala, et al. (19), in ai retrospective study of 1.832 pregnanciesini Poland; and 'Mukherjee and :1lukherjee(51~), in a retrospective study of 2,886 pregnancies in India, each found a igiaificantly higher incidence of low-birth-weight infants among r i.*;irette smokers. Ilutler,et~ al. (15) have furtheranal'yzed the British Perinatal nlor- t;ulity Study data. Analysis of the 16y094 questionnaires revealed that i? ):5 percent of the women were cigarette smokers before pregnancy. _1'fiter the fourtli, nzonth,thaspercentage had decreased to~ 27.4 per- ceiit. Given the large number of women in the study, andl the sig- iidficant changes in smokiiigbehavior«hich occurred~ Butler,, et al. f'cmnd it possibl'e to consider the effect of a change in smoking be- havior on birth weight; bet~s~een the beginning ofl thepregnancyand the fourth month (after which smoking behavior was reportedly ~table),. The authors stated, "If smoking itself (rather than the type of woman «ho~ smokes) has a deleterious effect on~ the fet'us, it would be reasonable to expect the mothers who gave up smoking (11aring pregna.ncy to show differencesin: tlhebirthweight and peri- iiatal mortality of theiroffspring compared with thosewho~contii2ued to smoke." Their results are presented in figure 4. The birth~ weights hysniokirng categorieswereestimated byusingamain: effect model Withoutmediating ~~-ariables. However, the authors reported that when the mediating variables (soeial' class, maternal age;, parity,, maternal lieight;, sex of infant, gestatiionalage, and perinatall mortality): were~ alloNvedl for,, theresultis: of theanalysis were very.similar. The effect of cigarette sinoking,before pregnancy was insignificant compared to that of smoking regularlyafter the fourth~ month of gestationL Ti heauthors concluded, "The~ finding that a change~ in maternali smoking liabit~schlring, pregnancy had the effect of putting the baby intoabiu•th weight and perinatal mortality categoryassocia,ted withthe newsnlokiiig: habits points toward some kind of cause-effect,relationship. *~*'ll'hisfindingis further strengthened by the birth weigl,itanaly.sis which shows that the diminution in birth weight of the offspring of sm:okingnaotherspersists and is indeed li'ttlechanged wlienallowance, has been made for a number of other social and obstetric mediating factors."' 109

Figure 4-Average birth weight by maternal smoking habit, (a) before current' pregnancy and (b) dluing, current pregnancy. Number of cigarettesJda 3,400 9" E ~ 3;300. 3,100- 0 I~ . ,k,._. I I I I --L----- --., 0 20-30 1!Q-19 5-9 0 1-45-9, 10r-11920-30, tVumberof cigarettes/day before current pregnancy SOURCEc Adapted f'rom Butler;,et aii (15):. lbtal births: 21,671 . EVIDENCE FOR'AX YrTDIRECT ASSOCIA1Zo1'BETZ4'IIEN LIG.IR;E=S3IOIiI\G AND SMALL-FOR-DATES INFANTS Yerushalmy(113,114, ;110.)~ has suggested, that smoking isan indexto a particular type of rehroductive outcome and thus does not pl'ay a causal role in the productian of small~f'or-da,tes infants. He has de- veloped several, lines of support for this~ hypothesis, from an analy,sis, . of data from t!1ie prospective investigation of 13,083 mothers in the Oakland Child H'ealth and Development Study. H'e has emphasizedl that ineffecti've randomization and the phenomenon o' self-select!ion complicatetlied'eveloprnent of' appropriate inferenceswith~ regard to, causality-.Such difficulties d'o~ notpreve,ntthe identification of causal associations, but t1leydemand careful and criticall anal'ysis~ of the data. Yerushalmyhasquesti~aned the causal nature of the relaftian- shipbetween cig2rettestnokingand small-for-datesinfa,nts because of: (a)~ Therelationship~ betweenthesrnoking h.zbitof the father and low birth weight oftlie infant,, (b), behavioral d~iffererucesbetween smokersand' nonsmokers; and (c) comparison of' theNrth weihhts 110 in current' pregnancy; after the fourth month of gestation I

i current tes/da la ncyr; lanth i ~ I 'ptal jths: 67T ~ of a«oman's infants born during the periods when she smoked ciga- rettesand when she, did not. 1 eruslialiiny (114) has stated that the smoking habit of the father (,ou lil! not reasonably be related to the birth weight of the infant. From~ prel'iminarydata derivedl from t'hestudy, however,, hedetermined' t!iat there wasaiL increase& incidence: of' lo«-birt~h-weightinfants wlien thefathers~ smoked and, moreover, thereR-asan apparent,dbse- rnsponse relationship as found for maternall smoking. However, he noted that'onlywhen, both the husband and the~ wife smoked wa& the inridence: of low-birth-weigl'it babies increased. He felt that theselindings supported the conclusion that smoking was a marker of t~~pes of individuals and not a causal factor for low birth weight. t~)therinvestigatars have since examineds thisrelationship: (',49,, 100), hilt none hasconfi,rmed an independent association forpaternal;nloking. Theassociatiion between paternal srnokingand birth«eight :il)pears to be an indirect one. Paternal and maternal' smoking, be- li:ivior are higlilycorrelated and maternal smoking is strongly related to infant birth weig)1t: Underwood, et al. (100)~ studied 48,505: worn.en,t heir h2zsband's'smokingbehavior;and the relation with birth «.eight. (table 1). If the mother was a nonsmoker,, then the father's smoking liadl no influence on the birth weight of'the infant. 'I':L~B uF L.-I'nfant birth ~ weight ~~ by ~ maternal, and paternal~ smoking habits ~ Mothers: Fathers (nonsmoking mothers) Cigarettes per day Birthweight (grams) Birthweight, (grams) Number - Irlumber, Mean IDiHerenceI Mean DiSerenceI . lex ~ aa de- rsis t}le ;ed on ,rd of of h- se er !n tls \o ne------------------ , 24„86+i' 3, 395 0 9, 547 3, 396 0 1 to 10----,-,------------ 7,,609' 3, 2W 109 3,493 ' 3,389 7; 11 to~30---------------- 14„450 3, 19& 199 10,403 ' 3; 3911 5 >30---__-,---,-_-------- 1,570 3,182 ' 213' 1,330 3,393 3 I Nansmoker mihus smoker. Sdurce: Underwood, et al. (t0ll)1 Yerushalmy (115); pointed out that other investigators had found marked d~ifferencesbet'weensmokersand nonsmokers. In his own Audhr; hefound that nonsmokers used contraceptives sie ifiicantl'ymorefrcquently, than did smokers.BZloreover,ai significantlyhigherprrnhor.tion of smokers drank coffee; beer, and .Fhiskey.I3o«-ever,~ herlid not adj2ist for these variables in his, analysis of theassociation, between cigrtiret'tesmokingand lower infant birth weight. O'tlheri'n- vestigators have also found di'fferences between sanokers and non- smokers. Forexarnple; Frazier„et.al. (w5)found significant d~ifferenees in the distribution of parity, work history;, education, and psy¢ho= 11n

somatic complaint score between smokers and nonsmokers. However, «'hen smokers were compared with nonsmokers of' the same parity;, education,workhistory., and psy.chosomatic coniplaintscore, cigarette smokers still had ai significantly high~erproportioni of small infants than did nonsmokers. Asprevi~ouslymentioned, whenever otherflaetors known or suspected to influence birth weight havebeeai controlled, cigarette smoking, has always been dernonstratedl to have an inde- pendent and significant elfect: Ounsted (69)~ offered evidence that tlre~best~predictor~of'the~ birth, weight of a mother's. future offspring, was the birth weight of her previous children. Herriott, et al. (,35~)~ found~, prematurity rates for previous pre;nancies~ among smokers t'o~~ be~ markedly higher thann among: nonsmokers, independent of~ parity, height, and social elass:~ Ev~i'dentlx~ awomam whose~ previous! . infant!s~ have been small tends~ to continue~ to ha~ve~relativel''y~ smaller than a~verage~ infants in subsequent pregnancies: The question is, wil'1~ tliose~infants~~ be enen~ smaller than, expected if she smokes? Goklstein,~ et ~a~11 (2S) ~, in a~ comprehensive review, proposed a~~ research design i'n whichi a woman would serve as her own control to compare outcomes of pregnancies during which she smoked with those diiring, which she did not with consi~deration of~the~ eff'ect~ of' parit'y~~ on the~~ outcome. Yerushalirsy (1'12)' has~ recently tested this type of research design, usi'ng~d'ata fcom h~is~O~akland Gro~wth~Study: ~Pith~information on the~ age at which! awom~an began to~ smoke cigarettes„ her sm:oking~~ status~ d~u~ring, th~e~ pregnancy actually studied,, her~ prior~ reproductive experience, andi the outcome of' her present pregnancy, the author compared the outcomes of' pre,-nnncy during periods of smoking and nonsmoking using the woman as her own control'. As the author noted, "If smoking causes the increase in low-birth-weight infants, then the incidence of low birth we.ight for infant's born to smoking, mothers dizring the period before they acqu2red the smoking habit, should be relatively low. If, on the other hand, the high, incidence of' low birthh weight is due to the smoker; then it should!be high for infants of fut.uree smokers also when they were born before their, mothers started to smoke." Yerushalmy theni proceeded to compare the reproductive experiences of' four groups~ of women:(a)l Those who smoked in none of their preb ancies,, (ib), those who smoked in alli of their pregnancies~,, (c) thosewh:oweresmoking now but prez:iously bad not smoked dilring, some pregnancies (future smokers),and(id)thosewhowereex-smokers now but had previously smoked during some pregnancies.. These outcomes are shown in figure 5'. The incidence of low-bi'rtfi- weight infants, in the pregnancies of thefuture smokers, before theystartecl to smoke,, wassimilar tolha.tfor women~ who smoked in everypregnanc-y, which was~ significantly- higlierthan that ofinfantlsfrom. 1112

iwever, ~arity, rarette hfants actors ;o11ed;inrle- birth. 4 her ds for tbann class. ds to luent than arch pare ;ring 1 the. ~rch 6on King, tive thor and tedye the lers i be Irthb ure I to ces eir Fc), ng ~s'.. 11- 'y ~p. rn luothers «-ho had never smoked. He also noted that ex-smokers, during tfw period before they quit, gave birth to relatively few low-birth- v,~, . larl a iirfants ; the incidence~ was si~gnificantly~ lbwer than for mothers' Wim s~inoked during~ all of their p~regnancies. He~ concluded that the~ tinriin~rs cannot be~easily~ reconciled .vith~ a cause-effect basi~s~fbr~smok- ~a ~1,: ~,irid birth weight. ItIe~ said, "Rather the ev~i'dlence~ a'ppears,to ~ support ti iee hypothesis that the higher incidence ofl lotiv~-birt~hrweight~ infants is &w to~t~he snaok~er;~ nott the s~ntokin.g~"~~ -1'liere are several considerations' which limit the interpretations v.loiclr can be drawn from this study. The information on smoking LwIS,Ivi~or~ of' the women during, past pregnanci~es~ was~ apparently ~ dle- ri % cd from the woman's age when she began to smoke, her smoking, ',It-?tavior~~early~ in the~ studw~ pregnancy„and the~age~at which she had prior pregnanci'es. Thus, if~ the woman reported that she, began _1n0king at a certain age, an&that she was still smoking at the time of ; iw stud}-, it « as apparently inferred that she had smoked during all of h(,rprebziancies. Since~noquestibns~were~~spe~cifiically~asked~abou~tactua~l >+nokiug behavior d~urin,g~~ each previ~ous~ pregnancy, it is possible that t:w woman indeed had not smoked during~every~ pregnancy~ or that tl eamoudit or way she smoked had differed from current smoking Figure 51-Percent of low birth weight white infants by smoking status of' their mothers. Gravidas' smoking habits Percent low birthiweight infants in previous pregnancies Nonsmoker (during all pregnancies) Nonsmoker (future smoker)' Smoker (during all pregnancies) Smoker (future ex-smoker) 5.3' 1 2,529 9.5 I'- 210 8.9 *$ 2;(176~~ 6.0' 1 ~ 651 4 6 8 10 Percent. 'Difference is statistically significant (P <0.01). °°Difference is statistically significant (P <0'.02)'. SOURCE: Adapted from YerushalMy, J. (112). 113

habits. This would be important t'oknow given thest'rongdose- response relationship which has been established between cigarette sm:okingandlowbirtTr weight, and would tend tomakethereproduc- tive outcomes for ea-smokers similar to those of' nonsmokers; and different from those of' women who smoked in all' pregnancies.. For ex-smokers, the age at which, smoking began was not elicited. Hence, some of the infants of' es -smokers may have been born before theirmothersacquiredr t'he~ smoking habit. Thi's.vould alsot'end to make the reproductive experiences of es-smokers~ more like those of nonsmokers and dif£erent from those of women who smoked in all pregnancies. No direct adjustm:ent for age, parit!y.,, and other variables was reported~ although Yerushalmy stated that the stud'y population was limited to the births that occurred to women at age 25' years or less: He notedi that, "In order to adjust for parity, the same comparisons were performed for firstborn infants only. The numbers were reduced considerably, but the same tendencies as foundi above were noted."' However, no data were presented. Primiparous births and births in teenagers are stronglyy associated with: the delivery of low-birth, weight infants.. If the pregnancies which occurred among future smokers included a: predominance of very: young women and priini'parousbirths, the reproductive experiences of future smokers wouldl tend to be similar to those of women who smoked during all pregnancies, andl different from those of nonsmokers.. In the absence of more precise i'nformationi on actual smoking behavior during pregnancy and more rigorous adjustment for maternal age, this study does not provide acriticall test of'thehypothesis that it is the sm:oking, d'uring pregnancy which is responsible for the higli, proportion of small-for-dtLtes in- fants born to women who smoke. Expeximental Stucliea .,~TL7DIES I.x A~NI3PALS Tobacco Smoke Several investigators 1avediemonstlrat'ed that eaposure, of' pregnant. rats or rabbits to tobacco smoke lead5 to: a reduction of birth «-eig ht in the offspring, as comparedto controls (23,,8i, 117):. Younoszai, et al. (117) reported data fronm studies in, rats which indicated that some agent present in cigarette smoke other than nicotine was responsible for thereductiion in birth.veight observed. The aut~hors,suggest~ed that carbon monoxide might also not be responsible for the retardation of

I d'ose- kre.tte bduc- and i ~ited. efore id to. Be of' ti~ all liwas was less. sons ~ aced ;ed." ~ is inil ight ~ kers ~ous ~ d to ~. and' ; 6se ~, tore ~ ~ide. ~. ncy a nt' ;ht al. me ble: iat of fetall growth; however, the evidence~ presented was inadequate to support a firm, conclusion. Haworth and Ford (33) recently extended the experiments of Younoszai. A group of pregnant rats was exposed t'~o, cigarette tobaccosmoke for 6 to 8 miirutes; five times, a day, from, days 3 to 20' of ges- tation. These rats were compared with another group whose food intake was, restricted to the~ amount actually consumed bythe~tobacco~exposedrats, andl both, were compared to a welMed control group. The animals in both experiments were killed on the 21st day of' restation,, and weights of the entire body~„ theliver;and the kidney of each fetus were recorded' The total average fetal weightof the ;rroup exposed tJo, tobaccosmok~ewassi'gnifiicantlylowertlian that of both the food-restricted aud' control groups. Thef'etall weigTitsof the latter hwo~groups werequitesimil'ar: Protein and DNA analyseswere performed separately on the entire forebrains and hindbrains of the fetuses and on the entire carcass. I3othDNA and protein were sig- nificantly and proportionatelyy reduced in, the carcass and hi2idbrains of the animals exposed to tobacco smoke. This implies that cell number was reduced and cell size was normal, and suggestst'hat the exposure~ to tobaceo: smoke either inhibi'ted cellular proliferation or acceleratedl celluhar destruction. Nicotine Several workers have: demonstrated that chronic injections of large closesofnicotineinto pregnant rats resulted' in a reduction of' birth Wei!ght of the offspring(7;8,,9, 23, 40). Otherinvest'i:gatorshave, de- termined that trit'ium-labeIled nicotine injected into pregnant rabbits and' C1{-l'abelled nicotine injected into pregnant mice crossed the placenta~ tlo; thed'eveloping; embryo and fetus (89, 98)1. Kirschbaum; et al. (44 found no significant acute effects of small doses of nicotine, injectedl intravenously into near-term sheep, on blood gas composition, pH, blood pressure, or heart rate in either the: ewes or their fetuses. The authors concluded that the influence of' maternal smoking upon the fetus must result from chronic effects or through the effects of other variables which they did not study. Recently,, Suzuki, et al. (94) ~ evaluated the short-term effects of' in- jected nicotine on thecardiovascular performance, acid~basestatus, and oxygenation of pregnant female Rhesus monkey-s and their infants during, the second half of gestation using the mothers as thei'r own controls. Nicot'inew.as administered either asasingleintrav.enous: dose of 0.5 to 1.0 n1g. or as a continuous infusion of 100 µg./kg. over -105-028 0-73-0 1is

a 20-minute period. The' injection of nicot.ine in the larger, single dose into the mother produced a ri'se in maternal bIood'. pressure and aa falll in maternal heart rate, and an immediate fall in both fetal blbod pressure and fetal heart rate followed by persistent hypotension and tachycardi~al in the fetlus.Subsequent to theinj'ection of1!.0 mg./k~g. ofl nicotine into pregnant monkeys,, in~ a single dose, significant changes in the arterial blood of the older fetuses incllud'ed a fall in pH, a rise in base deficit, and afal'1 in oxygen tension. Carbon dfiox~idetensione remaanedunchanged.Nicotine inj ected directlyy int'othe fetus prompted an immediate rise ini fetal blood pressure and a faIl in fetal heart rate. These responses were similar to those previously seen in the motliers following a direct injection of' nicotine.. The changes were more prominent in older rather than in, younger fetu~ses.'TPhe authors sum- marized their findings by stating that: (a) fetuses in different ges- tational stages are~ differentially responsive to a given dbse of nico- tine, probably because of the different sta'gesof devel'opment of' the autonomic nervous system; (b) diminished intervillous space per- fusion resulting from vasoconstriction intlheuteri~necirculation ap-pears to be mainly responsible for the fetal asphyxia following the injection into the mother, because: fetal hypotension and bradycardia were not preceded by thet''ransient hypertension seen f'o1lowingthe direct administration of' nicotineto:thef'etus~;, (ie)the differences be-tween the results obtained' by Kirschbaumi and by Suzuki~ et A may reflect either the! considerabledosaged'ifferenees or species, differences; and (d) the doses which the authors employed were much larger than those which a human mother would absorb from usual cigarette smok- ing, but that differences ini tolerance t'o nicotine between the~ Rhesus monkey and'i humans would imply that the dosages were, in fact,, com- parable and that, "Hence, it cani be envisaged that the concentrationn of' nicotine which could be reached in the organism of a smoking mother would reduce oxygen availability: to the fetus." Carbon Monoxide Longo ('Jy5) has reviewed the work of several investigators which has demonstrated the transplacental' passage of' carbon, monoxide from mother to fetus in animals. A recent study which related CO, to birtlh weight was published by Astrup(2),. He found that continuous ex-posure throughout gestation of' pregpant rabbits' to different levels of'ambient , carbon monoxide resulted ini a stlatistically sirnificant dose-related' redkiction in bi~rth-weight (table 2). Theactua1 significance level was not reportedL 1116

TaBiE2'.-Effect of' carbon monoxide exposure of pregnant rabbits onb~irthu.eigTit f3roup 1, CkrouR2, Group 3, 0 percent 8 to 10 percent 16Ra 1B'percent COEItl CDnUCOlitx~ Number of' pregnant,rabbits---------- _- 17 14 17 T6tal, number of babies--------------- 116 81 123 Average weight ofi babies in grams----- 53. 7 51. 0 44. 7 JOti.ucE: Astrup, P: (E). Polycyclic' Hydrocarbona' Polycyclic aromatic hydrocarbons (P:,-~H) suchiasbenzo(a)pyrene(B'_1P)'~ are constituents of' cigarette smoke whicii, have been impli- cated in thegeneration of cancers in many animal species (111). N''o, st'udies! presently available relate benzo(a)pyrene to a reduction inn birth weight of exposed offspring. Evidence suggests, however, that BAP does reach and cross the placenta. Aryl hydrocarbon hy&oxy.lase (AHH)~ is a part of thecytlochrorneP`-45'Q:-contains'ng, microsomal enzyme system,, present in many t'issues of different species: This enzyme sy stem isindueed to hydroxylate polycyclic aromatic hydro- carbons after exposure of' cells to PAH. Several' investi'gators~ have utilized the inducibility of the enzyme system to demonstrate indirectly that benzo(a)pyreneand oth~erpolycyclic hydrocarbons reachths~ placenta and fetus. Welch, et al. (108) extended this work by administering the polly- cy-.clic liydh•ocarbon,3-metliy]chola'ntlirene(3-MC), to rats during late gestation. The metabolism of'benzo(a)pyrene'«as studied in vivo' (us- ing' trit,iumrlabelled benzo (a) pyrene) and in v itro,AHHI activity was increased in fetal livers to adult leveli; by pretreatment with 3-MC Since a relatiivelyhigh dose of poly cy.clic! hydrocarbon was: requiredd to stimulate enzyme activity in the fletus; compared to the dose which stimulated placental enzyme activity, theauthors, suggested that theplacentlai may protect the fat'us, from exposure to polycyclic hydro- carbons. However, immaturity of the fetal enzymesystlem might also account: for its apparent relat'iveinsensitivi'tyto polycyclic~ hydro- carbons. Therefore, an exposure of' the fetus to 1evels of pol'y- cycliehydrocarbon similar to those experienced by themot''her cannot be ruled out by the available data. 117 O ~'. ~ ,Dr O

Schlede and Merker (86), have studied the effect of benzo (a ) pyrene administration on aryl hydrocarbon hyd~roxylase activity in the mater- nal liv.er;, placentlay andl fetus oft1lerat during the latter half of gestation. The pregnant animals were treated with large oral doses of benzo (a) pyrene 24 hours prior to saerifice. Control rats had no detectable levels~ of' aryl hydrocarbon hydroxylase in their placentas. Treatment `vith benzo(a)pyrene resulted in barely detectable placentall lovelson gestation day 13, but steadily rising values~untlil d~ay1i5; andl then constant levels thereaf tier. N'oactivity was detectedlinthef'etusesof untireated controls. In the treated animals, the fetal enzyme activity rosest'eadilyfromthe 13thtotlhe18t17 day ofgestiation.Theauthorsf concluded that the stiinulaatory effect of benzo(a)pyrene treatment on aryl hydrocarbon hydroxylase activity in the fetus demonstrates thatt benzo(a)pyrene readily crosses the rat placenta. ST'L; DIEB' Ii1 HII3I:4\ S Carbon Monoxide Smokers~ andl their ~~new~born~ infants~ have~ siignificantly ~elevatedl llevels of' carbon, monoxide as compared with nonsmokers and' theiir infants (31, 84, 88;116). Recently,,I3aribaud',,et al. (5) studied 50 nonsmokers and' 27 c.igarette smokers and their neav.borns. Alli smokers inhaled. The authors foundlthat the~mean level of'C4 contentt in the~blood of non- smokers was 0'.2i1 volumes percent compared with 0.672 volumes per- cent in th:e~ blood of smokers~.. The vadues~ for, bl'ood sampl~es~ from the~ umbilacal cords~~ of~ their newborns~~ were 0!352 ' and 0.949 volumes~per- cent; respectively. AToreov.er, a definite: dose relationship was foundi betw~eeni CQ~~ levels~~ and number of ciga;rettes 'snioked. ~.'ounoszai,~ et al. (116) found,~ in ad~d~~i'tion to~elev.ated carboxyhemo- globin levels~ among~ the infant's, of smoking mothe~rs; significant elevation of' mean capillary hemotocrit's, and significant reduction of~ stan d4rdl bicarbonate levels,, as~ compare'to the~ infant's ~ of nonsmoking mothers.. Since no evidence for nicotine effects upon blood' glucose, seru,m~ FFA levels, or urinary catecholamines, or for hypoxia was~~ present„they concluded that the higher hematocrit levels in the infants of~ smoking mothers may~ have~ represented~~ al compensatory response~ to the decreased oxygen-carrying capacityy of' tlie blood due to the presence of'carlaoxyhemoglobin. Longo (45) pointed out that a level'ofl 9 percent carboxy~hemo„ l~obin in thefetus~ i~:s1he eqpivalent of~ a 41 percent~ decrease in fetal blood flow ~~ or~ fetal hemoglobin concentration. In revie.ving, tl)e~ studies of~ CQ~~ l'evels,in human mothers and theia•~new~borns, lse~ made~ the follow~-~ lie!

Frrene iiig comments: "These~ samples were obtained at the~ time of'vaginal. %tier- delS~-ery~or Cesarean, section and may~not~accuratel'y reflect the~norrnall ~f~ of ~~ <<<il!ues of (~CrOHb)F~ for~ several reasons. The~~ number~ of cigarette& loses~ ~roioked by~ the~ mothers dnring labor~ may~ be~~ lEss~ than their normal ~' no coidsumption an& was not~ specified in, these~ studies. The~ blbod san7, ~Ltias. p1cs: were collected at varying time periods following~ the ~ cessation ntal of'sinok~ing. In addition, many~ ofl the~~ samples were probably~ taken~ and c;irly.~in the~~ dav before CO1Hb levels had built up to the~~l~evels~~reached 'uses .ifter~prolbnged~ periods ofl smok~ing~. Thus actual level~s~~of' (CQ'Hb),:;,~ v~ity and (~COItb~)~F~ may be~h~ig)1er than the reported~ values."~~ hors i t on AT, . P' 1 1' H d" b onat o vci c ic v ocar ons I t j The~ results of several studies~ concur~~ thatl~ cigarette~ smok~ing, is~~ Arongly, associated with the induct'i'on of aryl' hydrocarbon hydrox- vlase~in the~hnma~~n placenta (18;,38; 61'~,~99,~1~09)i. This~ findingiQnplies that'~ benzo(a)ipyrene or other pollyrcyclic hydrocarbons, reac,h the placenta. To date, evidt nce to support the passage ofl polycyclic hydro- ca~rbons~ through the~ placentai to the~~ human fetus has not'~ been published. r kels i lnts kers rhe ;on- >e r- the 5er- 4nd i ~T1o- ant , ~ of i'ng bse, Lvas, ,nts Inse the `'itamin B. and Cyani'de Detoxiification. -.NTcG'arry and Andi?ews (.l:8) determined serum vitamin Blp levels in 836women at their first,prenatal clinic visit. They found that the serumle1-e1s for smokers were signific<antly lower than for nonsmokers. After adjustment for gest'ationad age, parity, social class, hemoglobin llevel, hypertension; and maternal «~-eight,sm~okers, still had signifi- cantly lower levels of Bl,. They also foundl a direct, statistically sig- nifa'cant dose-response relationship between cigarettes smoked and serum vit:arni'n B12, level. They again confirmed the relationship be- tween smoking and low birth weight!. The authors suggested that the lowered vitamin~ B12 levels reflect a disorder of cyanidedetoxificati~on.. Cyanide is a~ demonstrable ingredient in cigarette smoke (39, 60, 62,, 6'~.'; 68. 74, 94. Vitamin G Venulet (1Q5;1~06yZ07)has~ demonstrated that the vitamin C' level is significantly lbwer in the serum ofl women who smoke cigarettes during pregnancy, comparedl to values for their nonsmoking counter- parts. Possible Mechan:isms. The following mechanisms, have been proposed for the production of' lo«• birth weight and other unfav.oralilie outcomes of pregnancy following exposure toci~g~:rettesmoke:

11. Adirecttoxi~cinfiuenceof'constituentis,ofcigarettesmokeupon, the fetus (2; 45, 50; 51, 117). 2. Decreased placental'perfusion (94)... 3'. Decreased maternal appetite and diminished maternal weight gain, with secondary effects upon the fetus (B, 33,, 36,, 65, 75, 99- 117). 4. A direct effect upon the placenta (36, 57, 65, 110). 5. An osytocic effect on uterine activity (44). 6. A disturbance of vit'amin B'lp metabolism (48). 7. A disturbance of'vitamin C metabolism (105,106,107)~. Of the potential mechanisms, available evidence suggestls~ that neither decreased maternal appetiteand, decreased maternall weight gain nor a, direct effect upon the placenta are responsible for a sig- nificant reditction in, birth weight. Dxisting, evidence does not permit firm conclusions ~ concerning the relative significance of the remaining mechanisms. Timing of 'th-e Influenee of'Cig°arette Smoking on Birth Weiglzt Several investigators have published resullts which bear on the time. period during which exposure to cigarette smoke: most affects fetal growth. Low,e! (/'6)~ and Zabriskie(;118) have offered evidence whiehsuggests that cigarette smoking intiuences fetal growth most during thesecond!halfofpregnancy.Butl'er, et'al.(15)~ found thatthebirtlht weights. of infants of women who did not smoke after the fourth month of pregnancy were essentially the same as those of'the infants of' nonsmokers: Ti his implies that the influence is most probably exerted after the fourth montifl: of' pregnancy. Hlerriott, et al. (35), however,, found that women in lower socioeconomic classes who gave up smoking early in pregnancyt'~endedto have intermediate weight babies as com~-pared with nonsmokers and persistent smokers, but his numbers of' women were smallandtheresul't'swerenotst'atistica~llysi;gnQficant: Underwood, et al. ('100)found thatcigaret-tesrnokingin anysi'ngle trimester was associated with: a lower birth weight of the infant, although tliedifferencebetween th~ebirth~ wei~ghts, of infantsofs women who smoked only during a single: trirnester and infants of non- smokers was not statistically significant because of small numbers. Several investigatorshaved'etecteds a nearly constantdi'6ferencebe-tween the birth weights of the infants of smokers and nonsmkers; delivered dilring, the last month of pregnancy, following gestations ofl comparable length [fig. 1, (1~1)].Although this observation: is 17a.

eight y, 1 99= i compatible with the suggestion that the influence of cigarette smoking uponithe, fetus occurs prior to the last montli, of pregnancy, it is based upon data derived from cross-sectional rather than longitudinall studies. 'IL'heresult'sofm:anyhuman epidemiological studies~ suggest that maternal smoking prior to pregnancy does not influence fetal weight gain (15, 25,46,49;113). Site: of' Action at the Z'issue and' Celliud~ar Level rhat ight ~sig- tmit ling I I I I ; ;.~~. a W ch 6g th th. of ~d r, ~g n- bf r Tlie use of labelled nicotine (98) and the preparations of autoradio- grams have permitted the localization of nicot'inewitihinthe~ tissues of the fetus and mother. Tjalve,,et al. (98) found' high lievels of nico- tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18'- aiiy miee fetluses. The use of other labelled constituents during various parts of gestation might further the und'erstanding of how certain ingredients in cigarette smoke produce an impact upon birth weight. Ilatirorthand: Ford (33) havereported data which su~ggest that the reduction: of birth weight of rat fetuses caused by the action of the ingredient(s) of tobacco smoke results from~a reduction ini cell number, but not in cell size: Signiicance o ftlie Association Among all women, in the L nited States„ cigarette smokers are nearly twice as likely to deliver low-birth-weight infants as are non- smokers. Assuming that 20 percent of pregnant women in the United S'tates smoked cigarettes through the entire pregnancy (extrapolated from data on changes in smoking behavior during pregnancy collectiedd for the British Perinatal Mortality Study), taking, into account the apparently different risks of' delivering: ai small ~ for-dates inf'ant for Caucasian and non-Caucasian women: who smoke during, pregnancy; and considering the number of infants with a birth weight less than 2,500 grams born to Caucasian and non-CRucasian, «•omen,, an excess of '~ nearly 43,000 occurred in the 286,000, low-birth-wei'ght'infants among the3i500;000inflants born in the United Sta.tesin 1968, becausee of the increased risk among women who smoke of having small-for- dates infant's.Since neonatal mortality i~s~~ higherforlo-w-birth-weigth infants, n-ithgestationaI age held constant, the excess of small-for-dates infantsanaong, smoking mothers would imply a significant excess morta~lityy risk as we11. 121

Birth Weight Sunmm,a ry A causal association between cigarette smoking and fetal growth retardation is supportedl by the following evidence: 1. The results of all 42' studies in which the relationship between smoking and birth weight was exazn.ined have demonstrated a strong association: between cigarette smoking, and delivery of small4or-dia;tes infants. On the average, the smoker has nearlyy twice the risk of'delivering a low-birth-weight infant as that of' a nonsmoker. 2. This association has beeni confi'rmed~ by both retrospective andd prospective study designs. 3. A strong dose-response relationship has been established betw een cigarette smoking and, the incidence of' low-birth-weight infants. Available evidence suggests that the effect of smoking upon fetal growth reflects'. the number of cigarettes smoked daily during a pregnancy, and~ not the cumulative effect of' cigarette smoking whichi occurred before the pregnancy~~ began. 4.When a, . variety of known or suspected factors which also exert'an, influence upon birth weight have been controlded for, cigarette smoking has consistently been shown to be independently relatedl to low birth weight. 5. The association has been found in many different countries, among different populations, and in a variety of' geographicall settings. 6. New evidence suggests that if a woman gives up smoking by theh fourth month of pregnancy, her risk of delivering a low-birth- weight infant is similar to that of'a nonsmoker., 7. The infants of smokers experience a transient acceleration of growth~ rate d'uring the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the removal of the smoker's infant from a toxic infl'uenee. 8. The results of experiments in animals have shown that exposure to tobacco smoke or some of its ingredients results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of'rabbits.to carbon monoxide during gestation results in a dose-relatled reduction in the birth weight of their offspring. 9. Data from studies in, humans have demonst'rat'ed that smokers' fetuses are exposed directly to agents within tobacco smoke; such as carbon, monoxide, at levels comparable to those which have been shown to produce low-birth, weight offspring in animals: 122

Cigarette: Snnokiarg, and Fetal and Infant Mortality In,troduction Several previous studies of' the relationship between eig,arette smok- i71g and higher fetall and infant mortality among the.infantls of smokers have been reviewed in the 19711 and 1972 reports on, the health con- sequences of'smoking, (10 ; 102). In many of these studies; the authors combi'ned two or more cat:egoriesoffetal andl infant mortality., Differ- ent mortality outcomes,, such as spontaneous abortion, stillbirth, andd ileonatal death,, areinfl.uenced bydiffErent: sets of factors. Among other factors,, the frequency of' abortion is influenced by congenital infectipns,hormonal deficiencies,,and cervicall incompetency. In addi-tion to other factors, the frequency of stillbirth is infl'uenced by pre- matureseparation~ of~ t'heplacenta,, ut'erineinerti'a,,and dystocia. Along with other factors, the frequency of neonatal death is influenced by ,-estational maturity, birth injuries,, and delivery room and nursery care. Separate an:alysis ofl the relationship of cigarette smoking to each different mortality outcome; with control of the unique set of factors which influences~ it, mayfacilitatle~ understanding, of the rel'ationship.. Sp:ontaneous Aborti,an;. Previous epidemiologicall and experimental studies of the relation- ship between spontaneous abortion and cigarette smoking reviewedl in the 1971 and 1972 reports on the health: consequences of'smoking (101,. 102) fornrithe basis of the following;statements: The results of several studiesY both: retrospective and prospective, have demonstrated ai statistically significant association between ma- temlal' cigarette smokin; and spontaneous abortion (43, 65, 70, 99, 118). Data from some of these studies have documented a strong, dose- response relationship between the: number of cigarettes smoked and the incidence of spontaneous abortions (70, 99, 118).. In general, vari- ables other than cigarette smoking (!e.g., maternal age, parity,; health„ desire for the pregnancy,, and use of'medicat'ion), which may influence the incidenee of spontaneous abortions, have not been controlled. Tihe results of the one study, in which adjustment for the woman'ss desiree for the pregnancy was performed, indicated that after such adjjust- irnent cigarette smoking during the pregnancy retained an associ'ation with spontaneous abortion ofborderli~nesignificance (43). The time period during whsch~ cigarett',esmok~ing might'exertan influence on the incidence of spontaneous abortions has not been determined. Abor= 1 23'

tions have~ been prod!u~cedl in animals only witlilarge d~oses~ of nicoti'ne~ (w3; 96;,104); tlie, releva~nce~ of~ these ~~ stu~dies ! for huQnans~~ is uncertain. SPO\iTASEOOL•S ABORTIO1i'i SLM3L!:1RY Although several investigators have found a significantlyhigher, dose-related incidence of' spontaneous abortion~ amongcigarett'esnokers as compared to nonsmokers,, the Iack of control of'significant variables other than cigarette smoking does not permit a firm con- clusion to be drawn about the nature of the relationship. AStiZlb'irtJi Epidemiological: , studies of the~ association~ between czgarette smok- ing and stillbirth previouslW reviewed in the 1971 and! 1972 reports,on~ the lieal'th~ consequences of smoking (101, 102) form~ the basis for thee following stat'ements:. In one group of' retrospective and' prospective studies, a higher still~ birth rate was fonndl for the infants of smokers as compared to thosee of nansxiokers (14; 25, 43)'., In another group: of retrospective and prospective studies, no significant difference was detected in the still birth rate among the infants of'smokers and nonsmokers (16, ,20; 85,,99, 100) . Differences in study size, numbers of cigarettes smoked, or the presence or absence of' controli of variabl'es,suchas age and parity, which may influence stillbirth rates, were probably not sufficient to explain the differences in results olitained'. Several recent epid'emiological studies have added t'o our under- stand'ingof the: relationship between cigarette smoking, and stillbirthL Niswander and Gordon(63) have reported data from 39;2115 ' preg- nanciesfolllowed prospectively and collectedl between 196Jandl 196'Bat 12 university hospitals, in theUnitedl S'ta.tes.A random sample of women who presented to hospital prenatal clinics were:enrolled in the study. The authors reported no increase in stillbirths among whi~te smokers as compared with white nonsmokers.11: higher incidence of' sti'llbirths! was, foundl among, black women who smoked than among nonsmoking black women, and a dose-response relationship with eigarettessmoked was suggested, although thefind'ings did not attain statistical significance: Tkeresults~were~e not adjusted for other vari- ables. FR'ush and Kass, (82) flound, in a prospective study of 3,296 pregnancies at Boston CityHospital,, anonsignificantincreasein 1ziS

~-.ti1lbirthsamong white women who smoked, but a: statistically sig,-txifi- rant increase in stillbirths among,black women who smoked (P<0:02). 'f 1'iese findings are consistent wit1l, those previously outlined by Ir'r~irier,etl al. (25) and Underwood, et al., (99),., R.umeau-RRoquette (81), in a prospective study of 4,824 pregnancies n Paris, demonstratedd that the risk of stillbirth, was significantly Isi'grher for cigarette smokers than for nonsmokers (P<0.001). The :u,rthors, also presented evidencet'hat a woman with either a previous: . :,tiiillbirthi or at least one prior infant weighing less than 2,500': grams, at liirth was significantly more likely to have a future stillborn infant riian a woman witlioutsuch an, obstetrical history. After previous 0i,.,xetricalhistorywas controlled,smokerostill retained ai statistically: ~i(rsifiicant increased risk of subsequent stillbirth as compared to non- ~nu0ltiers (P<0.01). Of further interest was the, finding that among Nvomen who previously had delivered only living infants, weighing over 2,500 grams; cigarette smoking had no influence on the stillbirth~ ratie: Previous experimentall studies were reviewed in the 1971 and 1972 n-ports on the health consequences of smokin:g(101,,102),, Theauth:ors (lFinonstrated that exposure of' pregnant rabbits to, tobacco, srnokeand pregnant rats tc large doses of injpcted nicotine resulted in, a signiff- cant increase in stillbirths(7;8;,23; 87)., STILLBIRTH SVJibLARY 1. The results of recent studies suggest that cigarette smoking is most strongly associateell tiv ith a higher stillbirth rate among women who possess less favorable socioeconomic surroundings or an unfavorable previous obstetrical history. In the United States, black women have higher stillbirtli, rates than «hitewomen:. The finding that cigarette smoking is associated with an even greater difference between the stillbirth rates of the two groups merits speciall attention. These findings may provide at least a partial explanation for the lack of ai significant difference in stillbirth rates between smokers and nonsrnokers, which some investigators have found. 2. The results of'experiments in animals demonstrate that exposure to tobacco smoke and some of its ingredients, such as nicotine, can result in a significant increase in stillbirth rate. nzs

Late Fetal'anel Neonatal Death8 ConsidErable variation has~~ occurred~ in~ the definition of'the~ study~ population among the~ studies in which the relationship~ of~ cigarette~ smoki~ng~ to~~ fetaL mortality~ (other~ tHan~~ abortion) and~ early infant~ mortality was examinedL The most commonly identified study popula- ti'ens, ~ have been perima,ta~ll deaths, neonatal~~ dea~t'hs,, and late fetal plus neonatal deat~hs:~Perinatal deathsare a~combination of'late~fetal deat~hs~ (,i.e~.,,stillborn i'nfa.nts~)~~ and deat!h~s,occurrinb within the~fi'rst week of' life.~ Neonatal deaths include~ all~ deaths~~of~ liceborn infalYts~ within the first 28 days of life:. FJPIDEMIpI o('ICAL SrLTDIF,S tifost~of~the earlier~epi'demiological studies of the association between cigarette~ s:noking and late fetal plus ~~neonatali mortality w~ere~ reviewed in~ the: 1971 and' 1972'~ reports on t!h~e° health consequences~~ of smoking ('1n'1, 102). A revietiv~ of previously unreported' stud'~ies~ (67, 76), as~ weTli as~ reexamination of preu~~iou~~sly~ cited' studies,, forms~ tlre~ basis of' the~ following statements : The results~ of several prospective and' retrospective~ studies~ indicate~ a statlistically~~ s~ignificant~ higher 1at~e~ fetall and/~or~neonatal mortality~ for the infants of' smokers compared to those of' nonsmokers (~1:/; 17;. N:3~.¢3)~.~T'he results~of other~prospective~and'retrospective ~stud'nes iden- tified no significant difference~ in the~ mortality~~ rates~~ between: the in- fants fants of smokers and nonsmokers (20,~F~<5, 7'3;, 85, 100~~, 115~)~. If mortality rates.; ere compared' for those infants of smokers and' nonsmokers weighing less than 2.500 grams, the infants of nonsmokers apparently had a~ considerably ~ hi bher ~ risk ~ tli~an ! did those of ~ smokers.. Th~e~~ resu~ltsof recent st~udiesi~ coupled' with a critical revie«~ of~ the design and analysis~ of~ previous~ studies, and a reexamination of~ exist- ing data, m~ay~~ provide at~ least a partiali esplanation~ of~ discrepanciles~ between the results of previous studies.. Comparisonsaf' the lfortalit' v ~ kisks~ of Low-B'i'rth-Weiriht Infants Born toStnokersun~d Nonsmokers Theperinatal' perinatatmortaliinfantsn•eighing, less than 2,500 grams appears to be Iower for those infantsborn to women who smoke ditri~ng pregnancy than for those horiv t'o nonsmokers (table 1126

Iudy ~tte ~ant ilus hs I o f' klhe III I 3)., fIIoR-ever, available evidence shows that cigarette smokers'' i'nfants tend tohe, small4or-gest<ational age rather than gestationallypre- matlure. Hence, within a given birth .zeight group,, the infants of .fnokers are, on the average, gestationally more mature tlian those of' nonsYnokers. Data collected bytlie National Centerfor H'ealthSta- tisties (703)~ d'emonstirat'e that wit'hina given birth weight group, theluore gest~ationalIy mature an infant, the lower is its mortality risk (fig. 6). Thus; the difference in perinatal mortality ri'sks experienced 1,v theinfantsof cigarette smokers and nonsmokers, within~comparablelnrtli weight classes, reflect~s thefacts that the: two setsofl infants are not of the same average: gestational age, andi that gestat~ionall age is a major factlor infliiencing late fetali and neonatal mortality. An accu- rate est'iinate of' comparative mortality risks for the: infants of cig- arette smokers and nonsmokers~ requires adjustment for gestational af-T:e_. For infants of comparable gestational age, lower birth weight i's asr sociatedi with higher mortality (fig. 6). Since infants of cigarette ~mokers llave;, on the: average, lower birth weights than the infants of nonsmokers, within groups of comparabl'egestationall age, cigarettesutokers'' infants should experience higher mortality rates than nan- <nroke rs"Inf'antsof'simidar gestational ages-f n: a~~ recent review,A!Teyer.md Comstock (51) provided a more extensive discussion of these hoints. I 'I'ABLE 3.-Comporison of the: perinatal' mortality, for infants weighing less than 2,500 grams,, of smokers and: nonsmokers Perinatal mortality rate (deaths per.1,000 live births) Author, reference Smokers I+7dnsmoWers L'nderwood, et al. (100)---------------------- , 187 269 Ontario Department of' Health (67):------------ , 232' 300 Kullknder and Kallen (43)-------------------- 129, 139, IRantakallio (76)--------------------------,--- 288' 344 Yerushalmy1(112)~:Black women--------,---,---,------------- 114 202' White! women--------------,------------- 114 218. Butler and Alberman, (14)-------------------- 269 284 I' Reported neonatal mortality rates only. 127

Figure 6,-Neonatal mortality rates among single white' births in hospitals (by detailed birth weight and specified gestation groups: United States). ~. JANUARY 11 TO' MARCH 31,,1950' 1 ~~28'-3'1 weeks ` `. _ 32-35'~ weeks ~ ~ « . `~ 37 weeks and ouer : w • .M M « .~ ._ ..~~ 4, 11 u c c . . 1 ..i0~ .y~0, 0~. .~:0, -4O' a~.0'~ .yi O~~ ~p Ou'3~. ~ O O~tCJ: tCf~~.O~ O S ~[7h n0 ON NU) Ldh f~O' OiA .-i ,.;Ni NNi N N C11itlV~ N M~ fl7 c+'i BIRTH WEIGHT (ini grams)'. 400' 200 100 80' 60'. 10 8 SOURCE: U.S. PublicNealth Service„Wistional CenterfarHeatthiStatistics(103): Recent Studies The Ont'ario PerinataI bfortality Study (66;, 67) was conducted' among~ 10! teaching hospitals during~ 1960, and 1061.~ In this~ retrospec- tive~~ sthtdy~ of 51,490~~ pregnancies,, a statistieally~ significant increase in the perinatal mortality rate~ was, demonstrated for~ smokers" in- fants as compared with those of nonsmokers; the infants of smokers experienced an overallrel~atii-.e~ risk of 1.2'7~ (P<0~.001)~. 117foreover,,tli~e~ investigators found a,stati~stical2y~significant d~ose-response~ re'lat'ionship~~ between, the amount of~ ciga'rettes~smoked and the perinatall mortality ~ rate (P<0.001) (fig. 7). 128

Figure 7.-f?erinatal' mortality rate per 1,000' total births by cigarette smoking category. L" L 27.7 (0 t! O. r 23.2 Nonsmoker Number of periratall deaths: 659 <1i pack of cigarettess per day 425 33.4 ~_- 1 pack of cigarettes per daN 220. Total births:: 28;358! 15,328 6,581 (P C0:00T) , SOURCE: Ontario Department of Health (66). Recently ~ Butler„ et aL (15) further analtyzed the British Pdrinatali Mortality Study. They found' a highly significant association between maternal smoking after the fourth month, of pregnartcy and both late fetal and neonatal deaths. Infants of smokers had an increase in the late fetal~ mortality~ rate of' 30 percent',, and an increase~ in the~ neo~-- natall mortality rate of~ 26~~ percent„ compared to: the i:nfant,s, of' non- smokers.. The overall mortality ratio of late fetal plus neonatall deaths was 11.28 I (P<0.001I). Given the large number of women in the study; a~nd the, significant changes~ in smoking~ behavior which occurredyv they fonnd~ it~ possible t'oconsider~~ the~~ effect of a change in smoking 129

behavior between the beginning of' pregnancy and the fourth month on~ late fetal and neonatal' mortality. A statistically,~ significant and' dose-related increase in mortality occurredl among the infants, of inothers who~continued to~snioke~after~the fourt~hi month of pregnancy, as compared with the infants of nonsmokers and those of women who smoked prior to the: pregnancy but gave up smoking by the fourtlu month of gestation. Niswander and Gordon (63) reported dat'a, from the prospective Collaborative Perinatal S'tudy~ of the National Institut~e~ of Neurologi- cal cal Disease and Stroke. The 39;215 pregnancies registered at 12 uni- versity hospitials in~ the Unitedi States~~ .were~ almost equally ~ dividedl between black and white w.omen~,, Ti hey~ found a nonsignificant increase~~ in perinatall mortality among tiie inf ants of white smokers as compared t~~o~ those~ of w.hi~te: nonsmokers;~ the~ overall mortality ratio was: . 1.13 ~ ( P>Q:1)'.. The infants of' blacl: smokers, however, had a significantly highe~r~ mortality~~ risk than: did~ those~ of black~ nonsmokers'~;~~ the mor- tali'ty~ ratio~ was~~ 1,1'8 (P<~©.02)~. 'Moreov~~er,~ a defi'nQte~ dose-response re~-~ lationship~ between cigarettes smoked by pregnant mothers~ and mortality~risk was~shown for black infants. Bdack~ Nvomen were~not~ed ta smoke~ s~i;taificantly~ fewer cigarettes, on the~ a~v~erage~,~ than white~ women. Rush andi I%ass~~ (;82)~ found, iiYa prospective~~ study ~ of 3,276 ' preg- nancies folliowed, at Boston City IlIospital,~ a nonsignificant increase~ iiu late fetal plus neonatal mrtal~i'ty~ rate~ among~ the infants! ~ of wMilte~ women who~ sTnoked' as~ compared to~~ tlsose~ of u-hite~ nonsmokers, How-~ ever, the infants of'black women who smoked hadia statistically sig- ni~fica~nt, increase in mortality rate compared to~ the infants~ of' black~~k nons~mokers~ (P<~0.01)~. The overall mortali'ty~ ratio~ for bl~ack~ womeni w~~li~o~~ smoked was 1.86: Ti he difference in frequency~ of'stillbi'rt!h among~, the infants~~oY smokers~and!nonsmokers~~was~the prirnary~factor which contributed& to~~ the~ signi'fieance~ of the~ diffQrence, in~ mortali'ty~ rates. Analysis of Previously Reportedi S'tudies Prev~iously~report'~edstudoescanbe,div~~idedi~nt'o~~two~groups~: _t group in which the~ late~ fetal plus~ neonatal mortality~ rates~~ for~ iirfints born, to~~ cigarettle~ smokers, were significantly higher than those~ for, the infants born to nonsmokers, and, a group in which no significant ditferences~ we~re! detectedl in the~ mortaluty~ rates for the infants bornn to smoker.s, ~and, nonsmokers. The ~results°of~several stadies~~ (14. 17, 25, 55;,84; 92) yieldedi m~ortalitv~ ratios rangin(r ffarni L3'8~ to: 1.78. The result's of other~ studies (20. G-5.~ 7'6. 87, l00~;~ 115) yiel~ded'y mortali'ty~ ratiosrangisig~~ from 1.01 to 1.0i~: Both groups contained' retrospeetive~ and proshect~ive~studies:of~ comparable, size. The two groups did differ i'30

th W bf' e ~il<ruii3cantlyr; hotiti-ever,~ti•ith regardl to control of variablesother than (-i-;a•ettesniokinb whichintluenceperinatal mortality. 1'actors~ «'hich~ Influence~ P'erinatal \Iortality~ Other Than Smoking liutller and Alberman (13),: on da~ta from tlie~ British Porinatal' ylortttility~ Study, emhloyed a 1bgi~t transform~ation analysis of'variance;. ;ui~d dernonstrated that mate~rnall hei9lit, age„ parity, soeiall class, andl ~-cvere~ preeclampsi'a all had a significant independent effect on~ late fx>tal and neonatal mortality. Rumeau-Roquette (81~)~ provided evi- (lencetllatai previous~st~illb~i'rth or~l'o.v~-birtli, «•eightinfa,ntsign2ficantly~ increased the~~ risk of~ a future stillbirth. 'Mey,er and Comstock (51~~)' i)rov~ided exam~plles,of~ho.r the diffe~rentiall distribution of smoking and. ,>tlier~flactors«-hi~ch, are~related to:perinatal mortality, in a population L)f Nroznen, can bias data (e:g., black women have higher perinatal iu„~rtality rates tlhan~ do~~ white: women,~ but black~ women smoke, less t4ati white women do. 1-Ience„ nonsmokers will tend' to include more N)lack~ .v~oiuen,~ and slmke~rs, more~~ «-h~ite~~ women. Thu's~ will tend to~ reduce: any differences between the groups in mortality rates.) Meyer and C:omstock~ concluded,~ "Comparisons,of~ mortality~ rates of smokers'~~ and nonsmokers' babies should be made within subgroups according to parity, socioeconomic st!atus, and other appropriate risk factors, aud not separated by~ birth~ .veight."~ I'n three of~~ tlhe~ studies in which a~, sign~ificantly~ higher~ mortality risk ~ was demonstrated for the infants of smokers; adjustment for other variables~ was~ performed. The~ results~ indicated that, after such ad.-~ jitstment„ a significant independent association between cigarette sinoking and infant mortality persisted (l3' andl 15, 17,, 81). Of the studies Which revealed no significant increase~~ in mortality risks forr smokers'~ infants,~ one (115)~ controlded! for race~ alone. Hence, at least~~ part of'the: discrepancy~ in results~ between tihe~ two~~ gl•oups~ of~ studies may be etplai'ned by a: of'control of variables other than smoking. Another possible, at least partial, explanation of the discrepancy in results obtained by the two sets of studies is that cigarette smoke may be: more harmful to the fetusesof certain women than, others. Several de~velbping~lines~of evidence suggest that this!may~belhe case;~ 1~.~ Ciga~rettesmoking~andsociioeconomic~background.. Butler, et al. (15) noted that when data from the British Perinatal. lliortality~~'StudV ~ are~ groupedl by social class~~ of~ the~~ mother's~ husband, the late fetall plusneonatal mortality ratio for infants of smokers and nonsmol:ers in the upper social classes I and II i's 1.110; the mortality ratio for the: entire sample: was 1.28. Rus1i and Kass (82): reviewed the British Perinata~ll liortali'ty~ S~~tud3-,~ along, , R ith several ot~h~er~ studies, and noted that all have shown the strongest association between excess infant mortality and ci'garette smoking among the infants of those 495-028 0-73-10 1i31i

mothers with lower socioeconomic status. Comstock andi Lundin (16) found excess mortality among, smokers'' infants almost entirely con, fined to those whose fathers had a, grammar school education or less. Several of'the studies wliicli revealed no, significant difference in mor- tality among the, infants of smokers and nonsmokers were conducted in predominately middle class populations (20;100;115). 2. Cigarette smoking and previous obstetrical'egperience. Peterson, etal.(72) had rigidi criteria for entry into, his study population of 7,740 women. He included only those women who pre- viously had healthy infants with a birth weight greater than 2;500 grams. He found a significant decrease in birth weight among smokers' infants, but no significant increase in mortality rates. Rumeau- Foquette (81) found that among women who previously had delivered only healthy infants weighing more than 2,5C)0' grams, cigarette smok- ing was not associated with an increasedl risk of stililbirth ;~ among those, women with a previous stillbirth, smoking was significantly associated with increased risk of a f'uture stillbirthL 3. Cigarette, smoking and genetic diff'erences. T1ie eonsistentfind2ng that the mort'alit'y risk for tlie.infants of blackk smokers is higher than the risk for the inf'ants of' whi'te smokers, even when the socioeconomic background for both: is~ ostensibly similar, suggests that genetic factors also may interact: with smoking to pro- duce enhanced risk (82, 99, 115). A:vaiiable evidence suggests, that if' those women,, who are already likely to have small infants for reasons other than smoking, smoke during pregnancy, their infants willi be most unfavorably affected. This means that the women in the United States whose infants will be most aff'ected by cigarette smoking are:those who have an unfavor- able socioeconomic situation, ha:ve a history of previously unsuccessfull pregnancies, and are black. E%PPRIbfE _r'TAL ..~'rI'D3ES' Studies in AnimalS Studies previously reviewed in the 1971 and 1972 reports oni the health consequences of smoking (101, 102) demonstrate that exposure of'rabbits: and rats to tobacco smoke and& to~ injections of large doses. of nicotine resulted in significantlly increased late fetal' and neonatal mortality. Astrup (2) has recently studied the effect of continuous exposure of pregnant rabbits to carbon monoxide on stillbirth rates. He found a significantly higlier,, dose-related incidence of stillbirths and deaths within thefirst 24' hours of life among the offspring of the experimental rabbits('table 4'). T32

T:~I3t-E 4.-E-ffe~et~ of' carbon monoxide exposure~ of ~ pregnant rabb'i~ts~ on b'i,rth ~ we ight and ~ neonatal mortality Group 1, Group 2;, Group 3, 0percenG 8 to 10 percent 16to18pereentCOHb COHb COHb tudy , pre. 3,500' kers, leau, ered inok- hose ited *k wen ilar, )'ro- idy ake !ed. -Vi1'1. or- ful. ;he ire. 5es al us !s; iss le Number of' pregnant,rabbits------------ 17' 14 : 17~ 11,,ta1 number of'babiesL ---------------,- 1116' 81 1!23' rtillhorn and' ~ babies, ~ died with~infirst 24 huurs------------------------------ t 1 z' 8' a 44 (E<q:001) ~ 1. peree~,nt: :.10~ perc~~ent. - 36 peroent. 5uurce:: Astrup.:P• (I)i~ Studies in H'umTns Some investigatiors~ have~ examined' the~ causes o~f' death among the infants of'smokers as comlaared with those of nonsmokers. Comstock, ct al. (17) found that infants of smokers died more frequentlyy of' as- phyxia, atelectasis,,and immaturity. Kullander and Ka12en (43) ~ f'Gundd abruptlio placentae~~ signifi~cantly~ increased as a cause of~ death~ am~ong~ smokers' infants. Bntler~and Alberman~ (14)1 found' little~ difference~ in~ the~ death rat'es~ for the inflants~ of~ smoke~rsand nonsmokers from iso- immunization and malformations, but higher rates were found for srnokers'~ in~fants~~ in the~~ groups~ in~ which~ death occurred before~ or ~ d,ur- ing labor, or in which death resulted from massive pulmonary hemor- rhage, or pulmonary infection. As the authors noted, "The latter three: are conditions known to be associated with small-for-dates babies:''" They pointed out that distribution of causes, of'~ dea,th~ in the~~ sm~oking, group could be accounted for almost entirelyrby the exc.ess of low-birth- weight ba'bi'es., Th~is~support'sthe~ conclusion that the~ mechanism whieh~ a ffects birth weight al'so~influences mortality. SIG15i IFICANCE' OF. THE' ASSOCI ATION The fallowi~ng~calculation is offered to~gil•.esom,e~idea of t'he~order of magrn~itude~ of increased late fetal and neonata~l~~, mortal'ity~ associated w~it1l ci'garette smoking during~~pre~;ixancy. If Nvomelr who smoked dur-

ing'pregrlancy in the United, States had an elev ation in risk of 28 per- cent for late: fetal and' neonatal mortality, as~ dcrrionst'rated by Butler,, et a1. (l5)~ for Britain, Scot~land,, and' Wales, and if~ ?0~~ percent~ of pregnant women smoked throughout the pregiiancyyl the higher risk of'stil'lbirth and neonatal death for the infa'ntis of m'others who smoke cigarettes during pregnancy would account for approximately 4,600 of' the 87,263 stillbirth~ and neonatal~ deaths~ in the United Sta'~tes~ in 1'968~. LATE hETAL AND rVTFO'ZV'ATAL DEATH SU3T3SA$Y A strong, probably causal association between cigarette smoking, and' higher lat'e fetal and'i infant mortality among smokers' infants is, supported by the following evidence :. 1!. Twelve retrospective and prospective studies have revealed a sta- tistically significant relationship between cigarette smoking andd an elevated mortalityri~sk among the infantlsof smokers. In threeofl these studies, of sufficient size to permit adjustment for other risk factors, a highly significant independent association between smokng and'mortality was ~established. Part of the discrepancy in results between these' studies and those in which ai significant' association between smoking and infant mortality was not dem- onstrated may be explained by a lack of' adjustment for risk fac- tors other than smoking. 2. Bvidence is converging,to suggest that cigarette smoking may be more harmful to the infants of some women than others; this may also, in part,,explain the discrepancies between the results of tlhe'. studies in which a significantly higher mortality risk was shownn for the infants of smokers compared to those of' nonsmokers and the results of' those studies in wh'ich' significant dh' fferences in mortality risk were not found. 3. Within groups of similar birth weight, tlie infants ofl nonsmokers appear to have a higher mortality risk than do the infants of' ciga- rette smokers. This results from the fact that the infants of non~- smokers within such similar birth weight groups are' on the average gestationally less mature than the infants of' cigarette smokers. Available evidence indicates that within groups of sim- ilar gestational age; infants of lower birth weight experience a higher mortalityy risk. Since the infants of cigarette smokers are I Based an extrapolatiom of' data on smoking behavior change during pregnancy fromm the British Ferihatal Mortality study; which probably yields a conservative estimate. 134

er- ler,, of' isk ke of' 68. !g is smalMor-gestational age, one should expect that if theinfantsof' cigarette smokers and nonsmokers are compared within, similar gestational age~ classes, the~ infantsof' cigarette~ smokers would have the higher mortality rate. 1. The results of'recent studies have documented a statistically sig- nificant dose-response~relationship between the number or amount of cigarettes smoked and late fetal and neonatal mortality. 5. New data suggest that if a woman gives up smoking,by the fourth inonth of pregnancy, she will have: the same riskof~ incurring a fetal or neonatal loss as a nonsmoker. f,; Avai1'ableevidencestrongdysupports cigarette smoking as one cause of fetal growth retardation. The causes of' excess dea.t'hss anonb the infants of' smokers~ are those associated with small- for-dates babies. ;. Data fronl experiments in animals have demonstrated that expo- sure to tobacco~ smokeorsome~of its, ingredients, such as nicotine or carbon monoxide, results in a significantincreaseinl'atefetal and or neonatal' deaths. S. The results of studies in humans have shown that the fetus of a smoking mother may be directly exposed to agents such as carbon monoxide within tobacco smok~e;, at levels comparabletothosewhichIhavebeen shown to~prodh.tcestilllbirth inexperionental' animals. Sex Ratib, 9 0 _Ylthough a number of small studies have found a, slight, usuallystatisticallynonsigpificant,increasein the proportion of female infants born to snlokers„the three~largest studfiesof'Underwood,et al., (418;505F: pregnancies)~,Butller(15',791 pregnaneies),and Mac'M'~ahon (']i2,1155, pregnancies) have found similar infant sex ratios among, both smok- inm and nonsmokiilg: mothers, withtheetpected slight excess, of malesalnOn(r each (tlble5). Suonm-ary Arail'ahle~~ evidence strong~ly~ i'nd~icates that maternal cigarette smok~- iRig do:,s~ not inftnence the sexrat'ib~of newborn infants. 35 135 9 9 0

71`ASLE 5.-P'roportian of' made infants d'elivered' ta smokznq dnd' non, smoking rrcotfCers Author reference Pre na cie Proportion of male lntants Stat'istical i ifi , g n s Smokers rihon- smokers c gn cance Underwood, et al. (100)_--..-------_---- 48,505 .518 .519 None. Butler and,Alberv:nan (1'4)-------------- , 15,791 . 518 .516 Do. IG'1ac1VDahon,, et aii (49)-----,------------ 12, 155 .513 .512 Do. Kullander and Kallen (13) ------------- 6,363 ' .515 .501 Do. Reinke and I'lenderson, t(78)------------ 3,,156 .,49B .517 ' Do. Frazier, et al.t (2'~6)--------,---,-,--------- 2,915 . 472' . 505 Do., (P >-0.05) Kizer (4$)---------------------------- 2, 095 .502 A93 ' None. Herriott,,etlal. (36)-------------------- 2,745 .492 .517 Do. Ravenholt, et a1 (77)------------------- 2,052 .501 .533 P<0.05 Lowe (46)'---------------------------- 2,042 . 532 .529 None. Ritssell} et a1. (83)--------------------- 2, 002 .513 .512 Do. I Black women. Congenital Malformations Previous epidemiological stud7es which examinedi the relationship. Betw,een cigarette smokiiig and congenital malformations were re- viewed in the 1971 andi 19'72 reports on the health consequences of' srnoking (101,,102). Recently, the authors of the Ontario Perinatal Mortality Study (66, 67), a retrospective study of' 51,490 births, re- ported no, difference in malformation rate for the infants of' smokers and' nonsmokErs. The various studies of the association between ciga- rettesmokingand congenital malformation have differed'signifieantly with regard tostudydesign, the type of ' population sampled, sample size and number of infants with malformations, the deffnition of` mal forrnati~on, and results~ (;tabTe6')~. Previous experimental workk wasreviewed' in the 1971 and~ 1'972' reports on the health consequences of smoking (101, 102). The chsck embryo has been empioyed in recent studies, Thedi'reet application of' nicotine to tlhee embryo results in cephalic hematomas (26), , malforma- tions of the cervical vertebrae (93), and anomalies of the heart (27), depending, upon dose of' nicotine and period of incubation in which eaposureoecurs: Anomalies of't1ielimbs of chicken embryoscan~ alsobeinduce& byexposureofithe egg to high levels of carbon monox- ide U). 136

~al ce D5)' x 'fnBLE' 6'.-llelati.ue risk of congenital malforr>zati.on for infants of e~'rtarette~ smok'ers~ and nonsmokers, comparing available studies~ with rr~garrl to study , design, st~udy~ popula:tion,, sample~ size, numb~er~~ of ~ infants' with malfae•matinns,~ a'nd~~ defi,nitibn of malformati~on Author, Study~design~~ Study~ population~ re ference . Sample size Infants with malfor= mations Relative risk Definition,af' SSijNS malformations Lo,ve -------- Retros;pective. Stillborn plus 24-hour h dp 2,042 23 1:36, Major. at s. ('crostock, et al. ----- do--------- Neonatal deaths-----,.-, 230 37 .31 bfaJpr, cause of death 1'erushalmy(11E): Prospective.-- Infants,Iess than. 695 59 . .57, Illajon. 2,500 g. 0=1.tario D'epait- Retrospective-, Stillborn plus 1st« 51,,490 1,744 .97 c:ent of,Ilealth week deaths plus 7). survivdng infants;. P•,ulerand kl- do--------- Stillborn plus neo- 7;123 1,382 1.19 bia)or„cause of1 t;€•iman (14). natalldeaths. death.. liullsnder and Prospectit e---, (a) Stillborn pluss neo- natal deaths plus remainder 137 43I 1125' taJor' and minor Sslnn (.yJ). ofldeaths, to age malformations: 1. (b) Surviving infants to age 1. 4; 903 700 1.06 edrick, et al. etrospectlve_ (a) t!Stillborn plus neonatal deaths r and deaths to age l,t'sur- vlvors 3 to age T. 1'7,418 88' 1.55 (1). (b) i Neonatal deaths r (3-month study). 7,822 ' 204, 1107 (o). t kntopsyproven congenital cardiac malformationi %Clinically determined congenital heart disease. Congenital 3lal f'brmation Summary. Given the considerable variation in study desib y study population, sample size, number of' affected infants; definition of malformation, and results, no conclusions can be drawn about any relationship betcveen, maternal cigarette smokin;, and congenitaL malformation at thepresenttime: 137'

Lactation Introduotion The following, section is a review of available evidence which bears upon any interaction between cigarette smoki;ng and'] actation. Empha- sis is placed upon the relationship of cigarette smoking to the quantity, of milkproduced, tothe~ presenceof' constit'u~entsofcigaret'te,smokewithin the milk, and to effects upon the nursing infant medRatledd throughi changes, in either the quantity of milk available or the sub- stances within the milk. Epidemiological Studies: Underwood, et al., (99), in a study of 2,000 women from various sociall and economic strata, observed a d'effnite but statisticaldyy insig- nificant trend toward more frequent inadequacy of breast milk pro- duction among, those smoking mothers who attempted tla nurse compared to nonsmokers.Mi12s (52)1„ini a study of 520 women, found that among womenwho irid'hcatedi either a desire to nurse or no desire to nurse yet continuedl to nurse beyond 10 days, and who had delhuered their first 1i've-born infant, t'he! average period of nursing for mothers who smoked was significaiitly shorter than for nonsmokers,, 1i'oreover, among the 244 mothers w hohadgiven up smokingduring, at least the fina13! mont'hs of' their pregnancies,, the average length of' nursimg wasid'ent'iical to that of tlhe nonsmokers: There was no~ significant difference between smokers and nonsmokers with regardi to complete inability to nurse thei'roffspring. This study isdifl'icult to, interpret because the author did not determine the reason(s) for the discontinuation of nursing, among the women. Experimental Studies STiJDIEs! . I-N ~ A~riPI1MTAP,s~ Nicotine Infl'uence on the Lactation, Process Blake and'i S'awyer~ (12)~ studied the~ influence of subcutaneously i'njected& nicotine~ (4 mg~. total over a 5~~-minute~~ period) upon lactation in the rat.~ They found that nicotine inhibited the suckl2ng-ind'uced! 138

iears pha, itityaokey ated sub- ious sig- >ro- irse. ~ vho iied brni ,vas 24 ths l' to een ;rse hor ing Jy :)n ~d rise in prolactin, Noeffect of injected nicotine wasd'ernonstrat;ed for osytocin secretion since milk release was not blocked. Wilson (110) examined the effectis of nicotine supplied through ,lriillkingwater (0.5, 1.0, and 2.0 mg. daily) on the weight gain of nu2-sing rats. Apparently, the nicotine had been available throughout (restation as «-.ei'1„because tlie~authorcommented on a redluction in litter size among the experi2n.ental' groups; more or lpss proportionate to the (lose of nicotine; hence, a prenatal effect could not have been dis- tiiig-uished from a postnatal one. Average birth weight was similar for i-xperimentall and1control groups. No difference in weight gain was seen f„r any of' the groups. The lack of impact on birth weight suggests that dbse was lower than that used in other studies.. Presence of' Nicotine in the Milk Hatcher and Crosby~~ (32)~, using~a frog bioassay, reported traces~of'~ nicotine~ in cohv's~ milk ~~ 24~ hours~ after, the~ intramuscular~ injection of :0 mg:/kg. and 5~ hours after~the injection of'0.5~mg,/kg, Etridence for an Effect Upon the Nursing Offspring. Hatcher and Crosby (32). found that 0.5 mg./kg. nicotine injected into nursiing catls had no apparent harmful effect upon the kittens. _1;pparently4.0, mg:/kg: suppressed lactation. Kittens fed the milk fromf the cow which had been injected «ith~ 5J mg,/kgnicoti'ne were also apparently una ffectled. Nitrosamines Mohr (,53)found that , diethylnitrosamineand dibutylnitrosamine, when administered to lactating hamsters, were associated with the cllevelbpment'of' typical tracheal papillary tumors in the young; sug- gesting passage of' these compounds in -the milk. Although diethyl nitrosamine and dibutylnitrosamine have not been identified in ciga- rette smoke, many N-nitrosamines are potentcarcinogens, and some of them are present , in cigarette smoke (37, 79)':. Srun>Es i_N~ I+IIImAws Nicotine and/or Tobacco Smoke Influence on the Lactation Process Emanuel (22) noted no reduction in, milk production among 10 wett nurses who were encouraged to smoke seven to 15 cigarettes daily; 139

~ some were observed to inhale the smoke. Hatcher and Crosby (32) ; noted that after a mother smoked seven cigarettes within 2' hours, it "' was difficudt to obtain a specimen of breast milk. Ferlman, et al. (71) ` found that of' 55 women smokers with an adequate milk supply at the ~ beginning of his study;,11 (20 percent) of the women had an inade+ ~ qpate supply at the time of discharge from the hospital. No relatibn- ° ship: was reported between the nusnber of' cigarettes smoked andd the ` likelihood of developing an inadequate milk suppliy:. The authors' im- ~ pression was that there was no greater proportion with an inadequate milk supply amongsmokerstlian among nonsmokers, but no, cor- roborating datai were supplied. Presence of N'icotine in the Milk. Hatcher and' Crosby (32): found', using a frog bioassay, that the milk of' a woman collected after she had smoked seven cigarettes ini 2' hours contained approximately 0.6 mgr jliter nicotine: Emanuel (22), using a leech bioassay; studied excretion of'nicotine in the milk of' wet nurses who were encouraged to smoke for the experi'ment: After the subject's had smoked six to 15 cigarettes over a 1- to 2-hour period,,the author found nicotine in their milk 4 to 5 hours after smoking,,withia maximum concentration of 0.03 mg./liter. Bisdomi (70)i demonstrated' nicotine in the milk of a mother who smoked 20' cigarettes & day. Thompson (97) found approximately 0.1' mg./liter of nicotine in the milk of a mother, who smoked nine cigarettes a day (plus three pipe- ful's),. Ferltnany et al. (71), using, a Daphnia bioassay, demonstrated nicotine in the milk of all!women who smokediin their study. Moreover, they found a direct dose-relationship between concentration of nicotine and the number, of' cigarettes smoked. No comment is made by the authors on the possible inaccuracy introduced by egamining, only the residuall milk following nursing, but it is well known that the composi, tion of the fore milk and hind' milk is di~fferentand perhaps, t'heconcentration of nicotine also differs.. Evidence for a Clinical' Effect Upon the Offspring Emanuel (22) ' noted' that among the infants in his study, loose stool's were observed only in the one whose wet nurse had smoked 20 ciga- rettes in the previous 4 hours. Bisdom (10) observed a case of "nico- tine poisoning" in a 6-week-old infant whose mother smoked 20 ciga- rettes a, day. The symptoms ineludedi: restlessness, vomatin,g;,diarrhea, and tacliycardia. Nicotine was d'emonstrated in the milk„ and the symptoms abated when smoking was stopped! Greiner (30) also de- scribed a case of' possiblenicotinepoisoning in a 3-week-old nursling, 140

~ (32) ,. )urs, it ~. (71) at the nade+ a.tion- d the y'' iin- q;uate ~ cor- t the ~' lin 2 22), ~ ~ the ~ the ~ th~ ~ted ~ ~ay. t'he. ipe- lted ver, tine the ~Ghe tisi- :tlie ols ,>a I 10- .a- 'a, ze e- ig whose mother~smoked3~5~to~40ciga.rettes~a day. The~sy.rn~ptom,s,incl'uded A,..onliting~~ and l'oose~ stools~. Fallowing~ the~ curtailment of ~ slnoking, the~ s~-.inhtoms gradually abated over a 3 day period. Perlrrlan, et all (71) noted no effect of~ smoking, on the weight gain of the infants, of'the~ ~1nokers in their study., P'urtherrnore„ no untoward symptoms were ubserved. They therefore doubted an effect of smoking on lactation., 1'hcv~ noted' that the dose: recei'ved by the infantls~ was beneath the toxic I«vel as computed~ from adult experience; and this~~ accordedl with~ their clinical observatli'ons. The: fact that they admitted to the study only wonsen with an apparently~ ad'equate~ milk supply~ m~~ay~ have~ affected tiieir~ results. The~~authors~~ suggested that perhaps,the~laek of~effect of s~uioking ~ upon lactation might represent'~ the development of tolerance~e to ~ nicotine,, as botih the mother and the offspring hadl been egposedd thr.oughout'the pregnancy.. VITAIILIN C Venulet (105, 106, 107):, in a series of studies, demonstrated that flie level of v.itlaanin~ G was~~ reducedl in the m~ilk~ of smok~ing, mothers as conipa~red with nonsmokers. The~ clinical significance of this observaltion has not been evaluated., Lactation Swmmary~ 1. The two pertinent epidemiological studies suggest ai possible: in- fl'u~eneeofsmokingupontheadequacyof'milksupplyI+I'owever,, with onIylimit;ed numbersof'women and without control ofotherpotent'ially significant variables,, no conclusions can be drawn. 2: Studies iQi, rats have demonstrated that nicotine can interfere with suckling-induced rise in prolactin. The relevance for humans is uncertain. 3: Evidence exists that nicotine passes~ into breast milk. No: . clear evidence f©r ani acute effect upon the nursing infant i's available: Potential chronic effects havenot been studied. 4. ivenvevidencefrorra experiments with m ~ice suggests that nitros- ainines., known carcinogens, pass through themilkt'~osucklin,gyoun~:

Pneedampsia Previous epidemi'nlogical studies of the relationship betR-.een cig- arette smoking, and preeclampsia were reviewed in the 1971 and 1972 reports on the health consequences of'smoking (1tJ1;102) and form the, basis of thefollo«ing, statements':'The results, of several large prospective and retrospective studiess indicate a statistically significant lower incidence of' preeclampsiaamong smoking women (14, 43;.1fJ0). The results of one large retro- spective study d~emonstratedl a significant inverse relationship between the incidencee of preeclampsia and the number of' cigarettes smoked (10(J)~.When other risk factors,silchaspari'ty, social class, maternal weight before the pregnaney, and maternal weight gaiili during the pregnancy were controlled, smoking women retained a significantly decreased risk of preeclampsia (21),. The lower riskofpreeclampsiak for cigarette smoking women, has been demonstrated'' in Britain and Scotland' (14,, 21, /8, 83), The United States (100, 118),,Venezueia ('42)'.,andl Sweden (43);.1[f a maternal smoker doesdevelop preeclamp- sia, ho«ev.er, av.aiIable data suggest that her infant has a~ higher mor- tality risk thani does' the infant of' a nonsmoker with preeclampsia (21;,83). Sum,mary 1. Available evidence indicates that maternal, cigarette smokers have a significantly lower risk of developing preeclampsia as compared to nonsmokers.. 2. If'awoman w_hosmokes cigarettes, during,pregnancydoes developpreeclam:psia, her infant has a higher mortality risk than the infant of a nonsmoker with preeclampsia. Pregnancy B;eferences. (1~). ABERLPATHY,, J... R„ GBEENBERG„ B. G:,, WELLS, H... B..,FRAZTER;, T. K slnolCingg asans independentt variable in a multijllee regression anal.ysisupon birth weigfit, and gestation. American Journal of Public Health and the Nation's Health 56'(4) : 626'-633,' Apri1 1966.. (2) Asxatur; P. PathoIogische Wirkungen massiger Kohlenmonoxid-T{on¢en- trationen., (Pathological effects of'moderate carbon monoxide concentra- tions. ) staub-Reinhaltung der Luft 32(4) : 146~-150, 1972: (3Y BAtLEY, R. R. Theeffeetof maternal smoking on theinfanti birth weight_ i9ew Zealand Medical JournaD 71(456) : 293-294, May 1970. 142

n ¢'ig- I 1972 mi thee udies ~~' ~ rlpsia :, ~ etro- ~ tireen k . okedd ernal ~ ~ r the tntly lpsia and uela mp- uur- J rSm IS '"r. (4')i BeKER;, F. D:, TUMASONIS, C. E: Carbon monoxide and avian embryo- genesis. Archives of Environmental Health 24(1) : 53-61, January 1972. (5) BARisALD, L., YACOUB, M., FAURE, J., ~IALIYAS, Y., CAU, G. L'oxyacar- bonemi'e de Lenf'ant n@ de mere fumeuse. (Presence of' carbon monoxide in the blood of'a child born of' a smoking mother.): :ifedecine Legale et. Dommage Corporel 3(3) : 272-274',, Ju15-augusti-September 1970. (6)', Br;AL, V. A. Nutritionall studies during pregnancy. Journal of the Ameri- can Dietetic Association 58(4) : 321-326, April 1971. (7): BECKER, R. F., Kz:va, J. E. Studies on nicotine absorption during preg- nancy. II. The effects of' acute heavy doses on mother and neonates. . American Journal of Obstetrics andl Gynecology 95(3) : 515~-522;, June, 15,1966. (3) BECKER; R. F:, Liz-rLE„ C. R: D., KixG, J. E. Experimental studies on nicotine absorption in rats d'uring,pregnancy!: III. Effect of subcutaneous, injection of small ehronic doses uponimother,,fetus, and neonate. Ameri- can, JournalofObstetrics~and Gynecol'ogy,1100(7) : 957r968, Apr. ii, 19681(J) BECKER, R. F., riTARTIx, J. C. Vital effects of chronic nicotine absorption, andl chronic hypoxic stress during pregnancy and the nursing, period. American Journal of Obstetries andi Gynecology 110(4) : 522-533, June 15,19711 (10) BisDom4 C. J. W., Alcohol and, nicotine poisoning in infants (sucklings), ~Iaand§ehrift voor Kindergeneeskunde 6: 332-341, 1937L (11) BLAKE, C. A., SAWYER, C. H: Nicotine blocks the suckling-induced rise in, ci'rculating prolactin in lactat!ing, rats. Science 177(4049) : 619-621,, kug.18, 1972. (12) BUNCHERS, C. R. Cigarette smoking, and duration of! pregnancy. American. JOurnaUof Obstetrics and Gynecology 103(7) : 942-946;, Apr: 1, 1069„ (13) BUTLER, N. R.,,ALBERxAN, E: D. (Editors), Perinatal Problems: The Sec- ond Reportl of' the 1958' British Perinatal Mortality Survey. London, E. and S. Livingstone, Ltd1,1969, 395 pp~ (14) BUTLER; N. R.,, ALBERMAN, E. D. (Editors). The effects of smoking in ;'ers i as lop (ii5) (16) the M. 9is nd n-, t. pregnancy. Chapter 5:, In: Perinatal Problems. Edinburgh, E. and S. Livingstone,, Ltd., 1969,,pp. 72-84., BtTLEx, N. R., GoLDSrErv, H., Ross,, E. M. Cigarett'e smoking in preg- nancy: Its influence on birth weight and perinatal mortality. British Medical Journal 2'.,127=130; Apr. 15, 1972., Co.csrocK, G. W.,, LusDiw, F. E., Jr. Parental smoking, and perinatal mortality. American Journalof' Obstletricsandl Gyncology 9'8(5)~:708-r 718, July 1„19G7. (17) CoMsTocK, G. W., SaAH, F: K., MEYER, M. B., ABBEY, H. Low-birth weight and neonatal mortiality?rate related tomaternaI smoking, and socio- economic status. American Jburnal, of' Obstetrics and GSnecology 11i1( li) : 53--59, Septl 1, 1971. (18) CoxrEV; A. H., WEr,cH,, R., KuNTZStANS R., CHAqG, R., JACaasor, M., _lTUtiROFAURII,. A. D., PECK,, A. W.,, BYE, rL.,, POLAND, A..,, POPPER6, P'. J.,. FiNSrER, Woc.FF, J. A. Effects of environmental chemicals on the metabolism of drugs, carci'nogens;, and normal body constituents in man: AnnalS of the New York Academy of Sciences 179;~ 155-172, July 6, 1971. (19) DoMACALA„ J., DaacAaALA, L. Zachowanie sie wagil urodzeniowej oraz czestosc wystepowania wczesniactwa I wadl «•rodConych u noivorodkoxvkobietpadacychl tyton. (Birth weight and incideneeof' prematuritsand congenital anomalies in newborns of mothers smoking tobacco. ) Pedi- at'riaPolska, T.47(6) :735' 7'38;,1972.. 1'43

(20) DowN¢rPa, G. C., CHAPMAN, w., E. Smoking and pregnancy. A statistical studyy of 5,65Wpat'2ents. California Medicine 104(3) : 187, March 1966. (21)1 DuFSUa;, G., 3i., 3lacGu,LiVRAY„T.,The incidence.of preeclamptic toxaemia in smokers and nonsmokers. Lancet 1(7550) : 994-995, 3iay 11, 1968: (22) EMerruer., W. Uber das Vorkommen von Nicotin in, der Frauenmilch nach Zigarettengenuss. (On the presence of nicotine in breast milk fol- lowing the use: of cigarettes.) Zeitschrift fiir Kinderheilkunde 52':, 41~- 46,1931. (23) EssENnESG,, J. 14T., SCHWIND, J. V., PgTRAs, A. R'. The effects of nicotine andicigarette smoke oni pregnant'female albino rats andl their offsprings; Journal of' Laboratory and ClinicaP .1Tedicine 25 : 708-717, 1940. (24) FeniucK, J,, Ar.aEastart, E. D., GOLDSTEIN, H. Possible teratogenic effect of' cigarette smoking. Nature 231 : 529-530;, June 25,, 1971'. (25) FsAzax, T. M., DAVIS, G. H:, GbznsTEiN,, H., Goc,DHEan; 1: D: Cigarette smoking, and prematurity :, A prospective study. American Journal of'~ Obstetrics and G'y!necologg81(5) : 988-996, BTa91961. (26) GATSirra, R. R. Effeet of nicotine on chick embryo. Archives of'~ Pathology 78 :, 652-657, December 1964. (27) Gir.Amr, S! H. Nicotine andl cardiogenesis. An experimental study. Pathol- ogia et Microbiolbgia 37(5) : 383'-39io;1971. (28)~ Gbr.nsTm:r, H., GOLDBERG, 1. D., FhAZtEu, T. M., DAVIS, G. E. Cigarette smoking, andl prematurity. Journal of' the Ameriiran OBteopathic Asso- ciatibn 64 : 541i-549; January 1965. (29)~ GouJASn„ J., ETIENNE, C., EVRARD, F. Caracteristiques maternelles et poids de naissance. (Ji'aternal characteristics and bi',rt'h weight.) Revue dui Praticien19'(29,,Suppl'ement) : 54„59--62, 65;N'ov. 1, 1969. (30) GeeirrER,, I. Nikotinvergiftung, beobacbtet bei einem Saugling. (Nicotinee poisoning observed in a breast feeding infant.)' Jahrbuch f'ur Kinder- heilkunde 146: 131-132, 1936. (31) HADDON, W., Jr., NESBIT, R. E. L.,, GARCIA, R. Smoking and pregnancy : Carbon monoxide in blood during gestation and at term. Obstetrics and Gynecologyl8(3):: 262-267, September 1961. (32) HnTCaEB, R. A., Chosav, H. The elimination of' nicotin in the milk. Journal of' Pharmaceutical and Experimental Therapy 32(1) : 1-6, 1927. (33) HawoxTfr, J. C,,, FORD, J. D: Comparison of the effects of maternal under- nutrition and exposure to cigarette smoke on the cellulhr growth of the rat' fetus. American Journal of Obstetrics and Gynecology 112(5) : 653'- 656, riTar. 1, 1972. (34) HE$orr, H. J., The effects of smoking during pregnancy : A review withi a preview. New Zealand 1ledical JournaP 611: 545--548,, November 1962. (35) HesxzoTm, A., Bn.LUwiCZ, W. Z., HYTTEN, F. K Cigarette smoking in preg- nancy. Lancet 1: 771-773;,Apr. 14, 1962: (36)~ JAavrNEN, P: A., OsTExLUNn; K. Effect' of'smoking during pregnancy on the fetus, placenta and delivery. Annales Paediatriae Fenniae 9: 18-26, 19M (37I) JoHNsox; D. E., RHOADES, J. W N-nitrosamines in smoke condensate from several varieties of tobacco, Journal of the National Cancer In- stitlute 48(6) ~: 1845-1847, June 1972'. (38) JucxAu, bi: Rl Human placental hydroxylation of' 3,4-benzpyrene during, early gestation andi at term. Toxicology and Applied Pharmacology L8(3) :, 665•'-675, March 1971. (39)K£irrTr, C: H., TusHS P. G. Measurement of thetotal' smokeissu~ing, from a burning cigarette. Tobacco 160(15) : 26-29, Apr. %196r;. 744

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eristfics; 'he Col' cal Dis- :'-80. for the. ~Ce' 12: 6tetrics iI Dior- anada, ~ Com« i ,of the, 'poron- ,tality ase of. ! 1956. tental', pros, abor- rrtid- -otine rican i pre- dans. ~ by- king. !insk B of qber ion: Ina- !nd rth; ica (',i7). RAVENHOLT, R. T., LEFIN81f1; 1K'_J., NELLI6T,, D. J.,. TAKENAGA, M.. EffeCts'f of smoking, upon reproductioni American Journal: of Obstetrics and Gynecology 96(2) :, 267 ?&1, Sept. 15, 1966i, REi` xE, «'; A., HENDERSON, ai. Smoking and prematurity in the presence of' other variables Archives of Ehvironmental Health 121(5) : 600-606, May 1966. 179) RxoaDES, J: W., JoHNsoN, D.,E. ;tletbod for the determination of ti-nitro< samines in tobacco-smol:e condensate. Journal of the National Cancer Instlitute48 (6) : 1ti4'1'-184I3;,June1972. ii'~O) RanIxsaN;, P. 'Yshwn nshymi B'wrmmywtvzmn hhrswn wh~shp'tw '1 h,m, h'n br .vhyl«-d1 ( SinokdngbyBurm~ese women during pregnancy and its influence on the mot!her, the fetus and the newborn.) Harefuah. 69(2) :!37-39; 1965. (q'1)~ Rvv4e:au-RouQUETTE, C., Gotrs'ARO, J_ KA'MINsxr, M., SeaWAaxz;, D! Mortalite perinatale en relation avee les antecedents obstetricaux et l'usage dtr tabac. (Perinatal mortality in relation to obstetric antecedents and tobacco: usage.), I'aper' presented atl the Third European Congress of'Perinatal Medicine, Lausanne, Apr. 19-22,' 19~72',8'pp. (6') Rusii, D:,,IiAss, E. H. \iaternal smoking: A reassessment of the associa~ tion witihiperinatai mortality. AmericanJournallof Epidemiology 96(3) :183'-196,, September 1972'. (83) RUSSELL, C. S,, TAYI:oR;, R., LAW, CJ, E. Smoking in pregnancy, maternall blood pressure, pregnancyy outcome, baby weight and growth, and other related factors. A prospective study. British Journal' of Preventive and S'ocialA'ICdicine 221(.3) : 119;-1'26„July 1968:01'-~) RUSSELL, C. S., TAYLOR, R'., 31,AnnISO~, R: N. Some effects of' smoking im pregnancy. Journal of Obstetrics and Gynecology of the British Common- wealth 73 : 742-746, October 1966. (,85) SAVEL, L. E., Roxa„ E; Effects of smoking in pregnancy! : A continuing retrospective study. OO bstetriesand Gynecology 20(3) : 313-316, Septem- ber 1962. (SH)~ SCxcEnE; E., IEEeKEe, H.-J. Effect of benzo(a)py,renetreat!ment on the benzo(a)pyrene hydrox;T•lhse activity;' in maternal liver, placenta, andd fetus of' the rat during day 13 to day 18 of' gestation. tiaunSn-Schmiede- berg's ArchivesofP'harmacology272'(.1):R9-100, Dec. 21„1p71. (S7) CCIroE-NECK, F. I. Cigarette smoking in pregnancy. New York State Journal of V'IedLcine 41: 104:5r1948; Oct. 1, 1M1. (88) SCOPPETTA, V. Sul contennto di assido di~ carbonio nel sangue circolante digestantilf'umatrici;. (C'arbonimonoxidecontentin tbeblood ci'rculatingin pregnant smnker~s~.) Archi'M1•iodi Ostetricia e Ginecologia 73(3) : 369-375, Slac-June 1968'.. (8'9)SiEnQe; S. 35., E:aseo, S. Identification of dru'g9in thepreimplantation, blastocyst and inithepl'asmas uterine secretion andurilneof'the pregnant, rabbit. Journal of Pharmacology and, Ekperimental'Therapeutics 176(1):: 63-75; 1b71.(9/X)SY'xePso:v, W . J:, A preliminary report on cigarette smokingand' the incidence of prematuritg., American Journal of Obstetrics and Gyne- cology 73(4): 808-815. April1©57. (91) SPEARS. #'.W:.RouTii:, W. E. A, combined approach to thequantitativeanalrsis of tlieviolatilecomhonents,ofl cigarette smoke. Paper presented! at the1'8th TobaccoChemist's Research Conference, Raleiglt, N.C., 19641 495-028 0-73-11

~ (92) STEELEy Et., ILANGWORTH,, J. T. The relationship~ of! antenatal and post- natal factors to sudden unexpected death in infancy. Canadian Medical Association Journa194: 1165-1171, May 28; 1J66! (93) STRUDEL, G. Action teratogene du sulfatedenicotnne sur1'embrson d'ee poulet. (iTeratogenic aetion, of' nicotine sulphate on, chick embryo.). Comptes Rendus Hebdomadaires des~Seances de 1'Acadamie des Sciences;: D: Sciences Naturelles 272 (4) : 673-676, Jan. 25; 1971. (94,). SUZUKI,,K., HORSGUCIII,,T:, C.oNIAS-tiRRUTIA, A. C.,, IrUELLER+FIEUBACII, E.,. JiaRISaISIA, H. O'., ADA.IsoNS, K., Pharmacologic effects of nicotine upon the fet'us and mother in the Rhesus monkey. American Journai', of Obstet'rics and Gynecology 111(8) : 1092-1101i, Dec. 15; 1971. (95) TERRIS, M., GOLD, E. M. An epidemiologic stiudy of prematu:rity. I.,Relati;on t'o smoking, heart volume,, emplbyment; and! physinue. American Journal of'Obst!etricsand'GSnecolbgy 103(3) : 358'-370; Feb. 1, 1969! (196i)'TtiIENEB;, C. H., IAM:BARD, C. F:,, FIELDING, F:, J.,, LESSER;. A'., J.,ELLEN- HoRN, M. J. Alterations in reproductive functions of white rats asso- ciated with daily exposure to nicotine. Journal of'~ Pharmacology and'. Experimental Therapeutics 87: 1-10, 1946~ (97) THOMPSON, W. B. Nicotine in breast milk, American Journal of Obstetrics and Gynecology 26: 662-667', 1933. (98)~ T.YaLVE, H., bIANSSON, E., ScHaIITERLOw, C. G. Passage of "C-nicotine and its metabolites into mice foetnses and placentae: ActaBharmacolbgica et. Toxicologica 26(6) : 539-555; 1968. (i99)~ UiNDERWOOD;,P. B., HES'TER,P,,I..,.LAFITTE, T.,.Jr:,, GREGG, K.. V..The.relation, ship of' smoking to the outcome of pregnaney., American Journal of'~ Obstetrics and Gynecology 91(2) : 270-276, Jan. 15; 1965.. (a'00)i UNDERWOOD, P: Bl,, KF.SLER,. K. F., O'LANE, J...M., CALLAGAN, Dl. A.. Parentall smoking empirically related to pregnancy outcome. Obstetrics and' Gynecology 29(1) : 1-8, January 1967.. (101) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of' Smoking. A Report of'the Surgeon, Gleneral : 1971. Washington, U.S, Department of, Health, Education„ and'Welfare,, DHEW Publication No. (HSMQ71-751% 1971, 458pp, (102) U'.S. PUBLIC HEALTH SExvrCE. The Health Consequencesi of' Smoking. A Report of' the Strrgeon General : 1972. Washington, U.S. Department of Health, Education, and Welfare, DHEW Publirationi No. (HSM) 72-7516, 1972, 158 pp. (IO8) U..S,. PUBLICHEALTH'. SERVICE. NATJONA'L, CENTER FOR. HEALTH, STATISTIC6. Weight at birth and survival of the newborn-United States;,early 1950. `Vashingt'on;, U.S: Departtnent af'HeaIth„Education, and!1Velf'are, Public Health Service Publication No: 1000, Series 21,, No. 3, July 1965,, 33 pp. (104) VABA, P., KiNNUNEN, O. The effect of nicotine on the female rabbit and develbping, foetus: An experimental study. Annal§ Medicinae Experi- mentalis et Biologica Fenniae 29 : 202-231, 1951. (105) VENULEm, F. Nastepstwa niedoboru witaminy c u palaczy. (Consequences of' vitamin C'de8ciency in smokers.) Poisltie Archiwum Medycyny Wewnetrznej' 26 : 393--402, 1956; (106) VE:vUI:ET, F., LAUSZ, H. Ubytek witaminy c w narzadachi zab podd'anychh dzialaniu dymu tytoniowego. (Influence of tobacco smoke on ascorbic acid' content in moth,ers' milk.) Acta Physibl'ogica, Pblonica 4(4) :351- 356, 19541 (107) VEVULET, F', DAxysz, A. Wplyw palenia tytoniu na poziom; witaminy c w mleku KobiecTln. (The influence of tobacco smoking on the level of vitamin C in human milk.) Pediatriai Polska 30(9) : 811-817, 1955! i4:8

I post- edi~call bn de' iryo. ) nees',, ~ btihee ial oL' lation tirnal k.LEN+ !asso- i and Ftrlhs IE and' ica et tion- IL of' fnthl and I g. A 't of 6,lIi) ~, AA it of' ~ ~res. f 950. 01ic f' pp.' ~nd p'erl- pces Oy lpch kbic' I I51- ew I of (108), li'Er.cH„ R: M., Go,&mir, B, ALVaRES, A. P'., CoNNEr, A. H: Effect'~ of enzyme induction on the metabolism of benzo ( a) pv!rene and 3-methgl-4- monomethy-lgminoazobeneene in the pregnant and fetal rat. Cancer Re- search 32(i5) : 973-978; May 1972. f, 109.), WELCH, R. =IT.,, HARRr60N,., Y.,E:., GoAY3['S,. B..W.,, POPPERSy P. J., FtN6TER,. M., CONNEY, A. H. Stimulatory effectaf' cigarette smoking on the hydroxyla- tion of 3;4-benzpyrene and the N-diemethviation of' 3-methyi-4-mono- methylaminoazotienzene by enzymes in~ human placenta. Clinical Phar- macology and Therapeutics 10(l)1:100-109, January-February 1969. (110) «'rLSaN, EJ W. The effect of'smoking in pregnancy on the: plaeental' coeffl- cient„New Zealand13iedical Journal 74I(475) : 384-385, 1972. (111) «'Y:vnFR,, E. L., HOFFMANN, D. Tobacco and Tobacco Smoke: Studies in Experimental Carcinogenesis. New York, Academic Press, 1967,, 730 pp. (112), YERUsHALarY,, J. Infants with low-bi'rth, weight born beforethei'r mothers started to smoke cigarettes. American Journal, of Obstetrics and Gyne- cology 112 (2) : 277-284, Jan. ].I5, 1972'.. (113 ): YEfaLSHALatY, J. Mother's cigarette smoking and surrivaU of infant. Ameri- can Journal of Obstetrics and Gynecology S8;(4) : 50;r518; Feb, 15,,1964,. YeRUsH Ar:My, J!: Statistical considerations and eralhiatiom of'epidemiolbgf~ eal evidence. In: James, G., Rosenthal, T. (Editors). Tobacco and Health. Springfield, Charles C. Thomas, 1962, pp. 208-230. (115) YERUsHALarr, J. The relationship of parents' cigarette smoking to outcome of'pre,gnancy-implications as to the problem,of inferring causation,fromn observed associations. American Journal ofl Epidemiology 93(6) : 443- 456;, June 1971. (116) YbuNaszAi,, M. K., KACLC, A., HAwoRTHSJ: C. Cigarette smoking~ during pregnancy: The effect upon the hematocritt and acid-base balance of the newborn infant: Canadian 3ledical Association Journal 99(5) : 197-200,~ Aug. 3, 196& (117 ) YocNOSZAi, JT. K., PELOSO, J~, HAWORTH, J. C. FetaU growth retardation in rats exposed to cigarette smoke during pregnancy. Americani Journal of' Obstetrics and GS necology 104(8) : 1207-1r?13, Aug, 15,,1969. (118) ZARRrsxrE, J. R. Effect of' cigarette smoking during, pregnancy. Study of 2;000 cases. Obstetrics and GynecolbgS 21(14)1:405-411, April 1963. 149'

Pe.ptic, Ulcer, Disease

Page Introduction-------------------------------------------- 155 Epid'emiological and Clinical Studies---------_---_--------- 155 Experimental Studies Grrstrie Seeretion _------------------------------------ 157 Pancreatic Secretiw ---------------------------------- 1159 Summary of Recent Peptic Ulcer Disease Findings-_-------- 162 References--------------------------------------------- 1163 List of Figures Figure 1.-Ga.strie ulcer mortality ratios of Japanese (men and Nromen combined) by age at initiation of cigarette smoking (1966-70) -------------------------------------------- 156' Figure 2'.-Effect of' cigarette smoking, on volume of secretin- stimulatedd pancreatic secretion in humans_--------------- 160 Figure 3.-Effect of cigarette smoking on seeretin-stimulated, pancreatic bicarbonate output in humans----------------- 161 ' 151

Introductim Previous epidemiological and experimental studies of'the relation- ship between cigarette smoking and peptic:ulcer disease were reviewed: in the 1971 and 19?2 reports on the health consequences of smoking ('Ii;.Z8)andlform! thebasisofthefolloaeingsummary: Tlieresults of epidcmiol'ogical studies indicate that cigaretit'esmok- i ng males have an increased prevalence of peptic ulcer disease , andl a -reater mortality from pept'icul'cer ascomlpared tononsrnoking males. Among males; the association betvveen cigarette smoking and peptic~~ ulcer disease is stronger for gastric than for duodenal ulcer, but sig- nificantfor bot'h.For males, cigarettestaoki'ngappears toreducetheeil'ectiveness of standard peptic ulcer treatment and to slow the rate of pepticulcerhealin~g. The: relationship: between cigarette smoking and t'.he prevalence of and mortality from peptic ulcer disease is less clear for females than for males.Experiment.al studies of'the effect of cigaret.te smoking ini man, and of'the effect of injection and infusion of nicotine in animals, on gastric eecnetion and motility have produced confti'ctin~g resul'ts: In dogs, an infusion of nicotine has been found to inhibit pancreatic and hepat'ic bicarbonate secretion, thus demonstrating a possible link betweenn cigarette sniokingand dhodenal ulcer:, R'ecently,, additional epideYniological,, clinical, autopsy,,and experi- mental studies have confirmed then association between: cigarette smok- in- and gastric ulcer mort.ality and have clarified a mechanism through which cigarette smoking might be linked to duodenal ulcer: EJpid'demiological an& Clinical Studies Previous studies of'the relationship between peptic uleer disease and cigarette smoking have been conducted in, predominantly white, West- ern populations. A large prospective epidemiological study is currently being conducted in Japan. From, thisstudy, Hirayama(6)' reported .5-year folloti<<up data on 263,118 menn and women, aged 40 years and old'er,,representing 91 to 99 percent of the totall popnlation in the area of the 29healthi districts in .vhieh the study was conducted. Both male A I 0 a I 0 I 0 a a 9 I

an& female cigarette smokers experienced higher d'Ieath rates from gastric ulcer as compared wi6.h~ nonsmokers: The mortality ratio for cigarettesmokers was 1.81 for males, (F'<O.QOl)and 2:15' for females(R'<O:fJ5).The morta:l'ityratioforsmokers(rnales' and femalescom- bined) was dose-dependent as measured by age at initiation of'smoking (fig. 1)., Theresultsofl this study, i'nthecontextof'the genetic and cul- tural differences between Japanese and lVestern populations, provide a significant confi rmation of the association~ between cigarette smoking and gastric ulcer mortality. Figure T.--Gastric~ulcer mortai'ity ratios of'Japanese (men and womenicombined)n bx age at' initiation oficigarette smoki'ng,(196Cr197t1), 5.00 4.00 1.00 0 Nonsmoker SOURCE: Hirayama, T. (6). 1156 >25 <24 <19 Age at initiation of'cigarette smoking (yrears).

i I from~ ;io for 4 Oales t com= oking 7' al cu1- ~' lovide '£ oking Alp, et al.(1) conducted a retrospective survey of 638 patients, admitted to two Australian teaching hospitals between 1954 andl 1963, with: chronic gastric ulcer confirmed by roentgenographic, endoscopic, or surgical examination. The findings in the patients were compared with information available about the South~ Australian populationn obtained at census in 119'51 and 1961, and with a~ control group of 233, subjects matched for age and sex with the ulcer patients. Cigaret'te, tise, a family history of peptic ulcer, domestic stress, and aspirin and alcohoL intake occurred significantly more freqpzently among ulcer patients. Alp, et al. (2)1 found that after surgical treatment, recurrence of the ulcer was significantly more likely to recur among those patients wllo continued to smoke, drink, and use aspirin (P'E0.001).Fingerland, et al. (5) compared the autopsy findings from, 76'5'males with their smoking history. The autopsies were performed without selectibn during 1965 and 1966' at the University of Hradec Kralove, (: zechoslovakia. P'ept'ic ulcer was significantly more frequent among male ex-smokers andi male lifelong smokers than among male non- smokers (P<0.02)~. Among males, a dose-response relationship was~ found between estimated total cigarette consumption and the presence of peptic ulcer at autopsy. Cooper andi Tolins (h) reported results from a retrospective study ofl the relationship betR een cigarette smoking andl postoperative eom- pliications arnong 2,988 :males, admitted to 19 V'eteransAdministration hospitals, for the su~rgicall treatmentof' duodenal ulcer. S4noking, his- tory was obtainedi for 1,4411 of the men,, and of' these 273 were non- smokers, 1,018 smoked cigarettes only, and 93 smoked' cigarettes plus a pipe and/or cigars. The authors found no evidence:of an association between either the number of cigarettes smoked per day;,or the number of years ofl cigarette smoking, and postoperative complicati'ons, opera- tive mortality, or length ofl hospital stay. They emphasized that their results, must be viewed with considerable caution and listed several potential sources of' bias. Iin addition, they noted, `'`* **' that these results apply only to the immediate postoperativefi'ndings and do not apply to the lbng-range effects of' smoking upon the patient after surgeryy f'or duodenal ulcer disease." Experimental Studies Gastric Secretion STL7DIES I.N HIID'iANS Morales,, et al. (10, 11) studied the effect of cigarette smoking on gastric secret'i'on in a group of 312 patients. The patients included 13~8'. O ~ 1i57 ~ ~ ~ ~ ~

with duodenal ulcer, 93 with gastric : ulcer, andl 81 with other gastro- intestinali disorders, who served as control§.. Cigarette smoking, was significantly more freq,uent among the patients with peptic uIcer than among the controls. The chronic effect of smoking on gastric secretion was quite variable. Male smokers among the controls and in the group with duodenal ulcers had ai significantly increased baseline acid output as compared with nonsmokers in the same groups ( P<0.05)., 'tlfter a subcutaneous injection of' histamine; only the group of maie smokers withi gastric ulcers had a significant increase in acid output over the values obtained' for nonsmokers in the same group (P<0:05'). 4mong the.smokers in the control group, the relationship between gastric acid output andithe: number of cigarettes smoked daily was dose dependlent. No such rela- tionship was obtained for either of the twolgroups with peptic ulcers.IIn. these experiments, the acute effect of'smoking on gastric secre- tion was slight. In one set of experiments, a group of eight smokers served as its own control. The smoking of two cigarettes prior to collection of gastric jiuice had no significant effect on acid output as compared to baseline values. After smoking twocigarettes, and~ alsoreceiving, a subcutaneous injection of histarnine,, the patients experi- enced no~ significant change in gastric acid output as compared to baseline values; 21 male patients, including members from t!he groups with ul'cers, and controls, smoked onecigaret'tel hour after an intra- venous infusion of histamine. A transient depression of' gastric acid, output was noted as, compared withi t'heval'uesobtained from ni'nepatient's who did not smoke. STAIDIFES IN ANI4IA7yS Konturek, et al'. (8), studied the effect of intravenous infusion of' nicotine on the formation of acute, experimental dkiodenal ulcers in cats. The authors infused nicotine intravenously in doses comparable to the smoking of four, eight„ and 16 cigarettes per hour into cats in whom near maximal gastric acid output had been stimulated~ with intravenous pentagastrin. The investigators found that nicotine in the~ two lower doses hadl no effect upon the gastric acid output stimulated by pentagastrin, but that the highest dose produced a significant de- crease in response, due to,a fall in botlhvolhime and acid concentration. Nicotine alone failed to alter a negligible basal gastric secretion. In control' animals (pentagastrin alone), duodenali udcer& were found in, eight of' 10 animals. Nicotine at the two lower dbses, in combination with pentagastrin, produced ulcers in alll 26~ animals. At theinter-mediatedose~ of nicotine, the mean ulcer area, was, twice that found in 158

I ~ast'ro- g, was n than i. ~iable.. denal pared, neous astric! n.ined ~rs in jcl the irela- lcers. lecre* ~kers ~ )r to, ut as I lal'so peri- d to )aps ltra- ! Rcid hine kof 6 in tble sin ~ith the ted de- on, i Inn inn on er- in the control group. At the: highest dose of nicotine, peptic ulcers ap- peared in only two of six animals and the areai of ulcer was reduced compared to controls. Shaikh, et al. (14) studied the acute and chronic effects of sub- cutaneously injected no:cotine on gastric secretion in rats.. Under basal conditions, the volume of gastric secretion was initially depressed, then stimulated, and depressed' again as the dose of' nicotine was increased. Acid output was decreased over the entire range of nicotine d''osage. Pepsin output reflected a similar triphasic response to in- cre.asiing nicotine doses as did gastric secretory volume. In the absence of nicotine, pentagastrin stimulated gastric volume, acid, and pepsin output. The inject'ion of nicotine„ in increasing doses, administered simultaneously with pentagast'rin, resulted in a gradual decrease in response for alli parameters.. `'olume of gastric juice, acid output, andid pepsin output werea1l increased significantly by chronic exposure to nicotine alone. Based on an average smoking dose of nicotine, the dose of nicotine employed in: the chronic experiments corresponded to the smoking of three to five cigarettes per day. Thompson, et al. (16) extended the study of rats described above by studying the effects of chronic nicotine injections in vagotomizedd rats and rats with discrete lesions in the hypothalamus. In sham- operated animals, chronic nicotine injections significantly increased baseline volume of gastric juice, acid output, and pepsin output. Fol- lowing vagotomy, the nicotine response was completely: suppressed. Caudall hypothalamic lesions did not influence the response to nicotine in the presence of intact vagus nerves. Anterior hypothalamic lesions,, ranging from the anterior hypothalamic area to the ventromedial hypothalamus, blocked the nicotine-induced gastric secretory stimula- tion in: the presenceof'intact vagi. The authors concluded that chronic nicotine-induced gastricseeretory stimulation is mediated via anterior hypothalamic, activation and intact vagus nerves. The importance of local effects remained uncertain. Pancreatic Secretion STIIDIES IN HUMANS Bynum; et al. (3)' studied the effect of cigarette smoking upon pan- creatic secretion in 23'healthyyoung,malesand females. Fi'vecontroli male nonsmokers: were compared with: seven malle and two female light smokers, (less t'~han one pack of cigarettes per day for less than 3years) and eight male and one: female heavy smokers (more than one pack of 1~s9 0 ® ® e 11 0 0 0

cigarettes per day for more than 3' years). Pancreatic secretion was measured by the double secretin test, using Boots secretim The experiL ment was divided into two parts for the smokers: A basal collectionn period and an experimentall period during which the subjects smoked seven nonfiltered cigarettes at the rate of four per hour. Light', srnokerss had basal v.alues for pancreatiic secretory volume and bicarbonate out- put in response to secretin whi& were not significantly different from, contpols. After the subjects had smoked, significant depression of'both pancreatic volume and bicarbonate output was noted (P<.001). Heavy srnokers had basal values that were significantlyy l'ess than in the control subjiects (P<0.01). Stnmoking, however, did not further depress the response to secretin (figs. 2 and 3). Solomon, and Jacobsen (15) reviewed some possible rnechanisms whereby the increased prevalence and mortality from, duodenal ulcer among cigarette smokers might be produced'. They concluded that eviidencefromstud'ies in animals,,coupled with thefind'irrgs of' Bynum, et al. (3), supported the hypothesis that the mechanism active in humans involves impaired neutralization of acid secondary to the inhibition of pancreatic bicarbonate secretiom Figure 2.-Eff'ect of cigarette smoking,on volume of secretinrstimulMed pancre+ atic secretion in humans: N11ean volume of pancreatic fluid ini milliliters per Ikilbgram body weight 3,0 2~.5'. 2.0 11.5 11.0 0.5 0. ^ 2:9 1.51 00 1 2 bo ~.. E r" p Y E ~.. ~ E . c, 0 Z E co E W O~~ V~' lYaV)~. Z ae oa J .-1I 11 Significantly different ~ from i nonsmoking test, within group 1 of light: smokers (P <0.001). 2 Significantiy different from nonsmoking controls (P <0:01). SOURCE: Bynum~ et al. (3). 160 1.9'' 2,0'

~ was ?eri- Ition >ked. Iters& but- lnom both 01!). l! the iress I I Isms lcer tllat 6, b' in t'he I ~ (cre- i Fligure 3'. Effect of cigarette smking on secretin-stimulated pancreatic bicar= bonate output in humans. Mean hourly output of' bicarbonate in milliequiva- lents per hour 11.5' 84 551 8.1 7.12 r-1 m N ~C y~ pp Y: t16' J9 O'o c o' c o e a c 0 M ~•~ O U; Z~~~. ~~. O. VJ~ ~ Z 0~~. ~~. OI ~ E .•; N,m ~,~ u, ~ ~ z cc J J = _ i'Significantly different from nonsmoking test within group of' light smokers (P C0.001). "Significantly different, from nonsmoking controls (P <0.01). SQURCE Bynum, et, all (3). STUnrs ix ArrsMALs Konturek,, et al. (7) extended his research on the mechanism of nicotine-induced inhibition of pancreatic secretion in the dog, using the design previously emplbyedi (9)'. Infused secretin alone led to al sustained increase in pancreatic bicarbonate output. Intravenous nico- tine, at all four doses of infused secretin, produced a significant in- hibition of pancreatic volume and bicarbonate output (PG0.05). Infused nicotine appeared to inhibit competitively the effect of secre- tin on pancreatic secretion of fluid and bicarbonate. Topical (intraduo- denal) nicotine failedl to affect significantly the response to infused secretin. Stimulation of endogenous secretin by an acid infusion into the duodenum produced the expected pancreatic secretory response. Nicotine either applied to the duodenal mucosa or injjected intra- venously significantly inhibited the pancreatic secretory response to endogenous secretin. ~Ticotine had no significant effect on total pancrea- tic protein output. n?icotine did not alter the cholecystokinin-induced stimulation of pancreatic secretion. The authors concludedl that nico- tine may inhibit pancreatic secretion ofI flu'ud and' bicarbonate both 12 10 8' 6 2' 0 0 @ III 0 G

by a direct effect on pancreatic secretory mechanisms, acting as a com- petitive inhihitor of secretin,,and by a secondary effect on the duoden.al mucosa, depressing the endogenous release of secretini by acid. Robert (,12) studied' the potentiation of' active duodenal' ulcers by nic.otine adininistration in the rat. Subcutaneous infusion of pentagas- trin and carbachol resulted in the dose-dependent formation of duo- denal ulcers within 24 hours. Nicotine alone produced no, ulcers. Increasing doses ofl subcutaneously infused nicotine, in combination~ with the other two agents, resuIted' in a steadily: increasing dose-related incidence and' severity of the duodenal ulcers. Robert notedl that Konturek, et, al. (9) found, that nicotine inhibitedi pancreatic and biliary bicarbonate secretion ini dogs, and that Thompson, et al. (1Fi )~ foundl that acute dbses of nicotine in rats either depressedl or did not alter gastric secretion: He concluded that the most probable mechanism by which nicotine potentiated acute duodenal ulcer formation in the rat was via a suppression ofc pancreatic secretion. Robert, et al. (13)! further tested this hypothesis by infusing acid via the esophagus of rats in doses f'ound' to cause duodenal ulcers inn one-third of'the experimental animals. One group ~ofrats also received a, subcutaneou& infusion of nicotine. Another received nieotine;but only water was infused via the esophagus;, 31 percent of the animalb receiving acid but no nicotine had duodenal ulCers; 93 percent of the nicotine-acid group had duodenal ulcers,, whi1enoneof'~ the nicotine- water group had ulcers. The ulcers in the nicotine-acid group were more numerous,,extensive, andl deeper than those in the animals which received acid alone., Summary of Recent Peptic Ulcer Disease Findings. In addition to the findings relating cigarette smoking to peptic ulcer disease, summarized in previous reports on the health consequences of smoliing (17, 18) and cited in the introduction to this chapter, recent studies have! contributed further to our understandiitg of the association:, 1. The finding of' a significant dose-related excess mortality from gastric ulcers among both male and female Japanese cigarette smokers, in a large prospective study; andl in the context of the genetic and cultural differences between the Japanese and pre- viously investigated `Vestern populations, confirms and extends the association between cigarette smoking, and gastric ulcer mortaIity.

i I ~ Iom- ~na;i Ilby. wo. ~rs. ion ted 4at ~ndl r6), IIot sm the ;id iinn ledd fiut L'1a he le- J`e ~}1 i ~ i ar )f' a.t lie 2. Data from experiments in several different animal species sug- gest that nicotine potentiates acute duodenai ulcer formation by means of inhibition of pancreatic bicarbonate output.. 3. Cigarette smoking, has been demonstrated to inhibit pancreatic bicarbonate secretion in healthy young men and women. Peptic Ulcer Disease Refierences, (1) ALr, M. H., HisLor, L. G., GRANT, A. K., Gastric ulcer in South Australia, 1954-G3. 1. Epidemiological factors, Medical Journal of Australia 2'(24) : 1128-1132, Dec. 12, 1970. (2) ALP, M. HL, HIIBLOP, I. G., G$erT, A. K. Gastric ulcer in South, Australia, 195?i-63. 2l Symptomatology andi response to treatment. Medical Journal of'Australia 1(7) : 372-374, Feb. 13, 1971. (3) BrxuM, T. E.,, SaLOMorr,, T., E.,, JoHNsON, L R., JaCOSSON„ E. D. Inhibition of pancreatic secretion in man by eigarette smoking. Gut 13(15) : 361465, May 1972. (4) COaPES, P., TbLiNs,,S: H. Relationship betweeni smoking history and compli+ cations immediatelq following surgery for duodenal ulcer. Mount Sinai Journali of'.Medicine 39:(3) : 287,29'l; May-June 1972. (5) Fr'xaERLAND,, A., HusxK, T., BenDLOVA, J. Contribution to the investigation of the effect of cigarette smoking. Sbornik Vedeckych Pract Lekarske Fakulty Karlovy University v Hradci Kralove 14 ('l ): 221-234, 1971., (6) HtaAYAniA, T. Smoking in relation to the death rates of 265;118 men and women in Japan. A report af'5 years'of; followup. Presented at the Amer- ican Cancer Societ+VS 14th Science Writers' aeminar,' Clearwater Beach, Fla., Mar. 27;,1972, 15' pp. (7) Ko.rTUSEa, S. J., DALE, J., Jl&consaN, E. D:, JoHNsoN,,L~ R. biechanisms of' nicotine-induced inhibition of pancreatic secretion, of bicarbonate in thee dbg. Gastroenterology 62'(3) : 425-429, 1972. (8) KoxTUBEx,, S. J., ReDECSr, T., THOR, P., DEmBLNss:r; A., JACOBSOx, E. D: Effects of' nicotine on gastric secretion andi ulcer formation in, cats. Pro• ceedings of the Society for Experimental Biology and Medicine 138(2') : 6~.74-67i, November 1971. (9) Ko:vTUBEK, S. J., SbLOmo.rs T. E., bTCCaEiuH•r, W. G., JoHNsox, L. R., JXCOSSOx, E: D. Effects of nicotine on, gastrointestinal secretions: Gastro- enterology 60(6) : 1098-11Q5; June 1971. (10) ,lio$Ar.Es, A., SILVA, S:, ALCALDE, J., 1V AassBLUTH„ J., Rayos, Jl, BEY, H., SANz;, R, Cigarrillo y secrecion gastrica. I. Analisis de la secreeibnn gastrica en pacientes digestivos fumadores y no fumadores. (Cigarettes and!gastric secretion.,I. Analysis of'gastric secretion in smoking and non- smoking ulcer patients.) Revista Medica de Chile 99(4) : 271-274, April 1971L (11..). MORAI:ES, A., StI:VA'., .S!, OsOEIo, G.,,ALC,I.DF:, J.,WAI6BBLUTH, J..ClgarrllllDysecrecion gastrica., II. Efecto del' cigarrillo sobre Iai secreciSn, g§strdea. (Cigarettes and gastric secretion, II.. Effect of cigarettes on gastric secre- tioni) Rievi'stai Medica de Chil+e99~(4) : 275-279,,April 1971. . 495-0-8' 0-73 ~-12. MC z 8 Q ~ ~'. 1163' t ~ ~ ~ Ul . 0

(12), RosFaT„ A. Potentiation, by nicotine, of duodenal ulcers i'n the rat. Pro- ceedings of the Society for Experimental Biology and Medicine 139(1) : 318--322, January 1972. (13) RoBexT, A., STOZVE; D. E., NezAMis„ J. E1 Possible relationship between smoking and peptic ulcer. Nature 233(5320) : 497-498, Oct. 15, 1971. (14) SxAixH; 1Vi. 1.,, THompsoN, J. M, Ausss, D; Acute and chronic effects of nicotine on rat gastrie secretion. Proceedings of the Western Pharma- cology SocietF' 13: : 178-184„ 1970. (15) SoLobtoN, T. E., JACOSSON, E: D. Cigarette smoking and duodenal-uicer dis-, ease. New England Journal of' Medi:cine 28Fi(2'2) : 1212-1213; June 1„1972!. (16) THomrsoN, J. H., GEoaoE, R., AxauLO; M. Some effects of'nieotine o&gastrie secretion in rats. Proceedings of' the Western Pharmacology Society 14: 173-177, 1971. (1'7) U.S..Pusric HEAnTH SBSSZCE. The Health Consequences of Smoking. A Re- port of the Surgeon General: 1971. U.S. Department of Health, Etlucation, and' Welfare. Washington, DHEW Publication, No.. (HSM) 71.-7513;. 1971, 458 pp. (18)~ ITtS: Pusr,ic~ HEALTH SksvicE. The Health Consequences of Smoking, A Report of the Surgeon Generall: 1972. U.S. Department of Health~ Educa- tion, and Welfare., Washington, DF3EW Publication No, (HSM) 72-6516; 1972; 158 ' pp. 164'.

ii Contents Page Introduction--------------------------------------------- 1711 Tl1ePtevalence of Pipe, C'igar„ and C'igaretteZTsage---------- 173~ The Definition and Processing of Cigars, Cigarettes,, and Pipe Tobaccos--------------------------------------------- 175 C'hemicai Analysis of'Cigar Sinoke------------------------- 177 \Iortality Oreralt Morta,lity=------------------------------------ 179 Mortality and Dose-Response Relationships. Amount Smoked-------------------------------- 180' Dn.lialation-------------------------------------- 183 Specific Causes of Mortalily--------------------------- 189 Cancer----------------------------------------- 189 Cancer of the Lip------------------------------- 190, Oral Cancer------------------------------------ 191. Cancer of' the Larvnx---------------------------- 193' Cancer of' the Esophagus------------------------- 1'97 Lung Cancer------------------------------------ 203 Tumorigeniic Act'ivity---------------------------- 210 Experimentlal Studiies---------------------------- 210 Cardiovascular Disease& -------------------------- 215 Chronic Obstructive Pulmonary D'iisease~~ (COPD) - - - - 216, Gastrointestinal D!isorders------------------------ 2M Little Cigars-------------------------------------------- 2'22' Conclusions--------------------------------------------- 229. References---------------------------------------------- 230. List ofFiguires, Figure L-1'nhal~tion among pipe smokers by age----------- 184 Figure 2.-Inhalatt'ion among cigar smokers by agE-Ham- mond------------------------------------------------ 1'85 Figure 3.-Depth of inhalation among, cigarette smokers by age-Hammond--------------------------------------- 185 Figure 4.-Percent distribution ofl 130 brands of cigarettes and. 25' brands of littlle cigars by tar content------------------ 22'5 167 O ~ Ca~ ~ CJl'

Page Figure~ 5'.-Percent~ distribution of' 130~ brands~~ of' cigarettes and 25brands of little cigars by nicotine content______________ 226'. LI isU of Tables Tab1ei.-Percent distribut'ion ofU.S'., males~aged 21 and older by type of tobacco usedl for the years 1964, 1966, and 197'0-_ 173 Table 2.-Percent distribution of U.S. males by type,of'tobacco used and agefor 1970---------------------------------- 174' Table 3.. Percent distribution~ of' British~ males aged 25 and older by type of tobacco used for the years 1965, 1968, and 1977i'------------------------------------------------- 174 Table 4.-Amounts of' several components of' 1 gram of' par- ticulate material frorn~ mainstream smoke of tobacco prod- ucts ------------------------------------------------- 177 Table 5.-A comparison of sev.eral chemical compounds found in the mainstream smoke of cigars, pipes, and ci'garettes-_-_ 178 Table 6'. Mortality ratlios for totall deaths by type of'smoking, (males only)------------------------------------------ 180 Table 7.-Mortalit'yratiosf'or tlotaldeathsofcigar andl pipe smokers byy amount smoked-Hammond and Horn-------- 181 Table 8.-Mortality ratios for total deaths of cigar and pipe smokers by amount smoked'-Best----------------------- 181 Table 9. M'ortality ratios for totall deaths: of ci$ar, and pipe smokers by age and amounti smoked-li:ahn-------------- 1182 Table 1Q.-Mlortality ratios f'or total deaths of cigar and pipe: smokers by amount smoked-Harnmond!----------------- 182' Table11.-The: extent ofinhalingpipes,c'igars; and' cigarettesby British males aged 16' and over in~ 1968 andi 1971 ------- 186 Table 12.-Inhalation among cigar, pipe, and cigarette smokers by age-D'olll and Hill---------------------------------- 1W Table 13.-Mortality ratios for total deaths of cigar and pipe smokers~by age and inhalation-Hammond--------------- 187 Table 114.-Percentage of British male cigar smokers who re- ported inhaling a lot or a fair amount by type of product smoked---------------------------------------------- 187 Ti able 15.-P'ercentage of individuals reporting, inhalation of "almost every pufF" of tobacco smoke by current and pre- vioustobaccolusage and type of'tlobacco usedi------------- 188' Table 16.-Percentage of British males who reported inhaling a lot or fair amount of cigar smoke: by current andi previous tobacco usage and type of tobacco previously smoked (1968)----------------------------------------------- 188 168

~age !'26 73'. 74 f7 Page Table 17.-Extent of' reported inhalation of' cigar smoke by British male cigar smokers who were ex-cigarette smokers in, 11968, analyzed by extent,of reported inhalation of cigarettiee smoke.ehenpreviouslysmokingcigarettes----------------- 189 Table 18'.-Niortality ratios for total cancer deaths in cigar and' pipe smokers. A summary of prospective epidemiologicall studies----------------------------------------------- 189 Table 19. Relative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospectYvestudies----------------------------------- 192 Table 20.-Mortality ratios for oral cancer in cigar and pipe smokers. A suQnmaryof'prospective:epidemiol,ogical'studies-- T9~3Table 2I1.-Ro1'ativerisk of' oral cancer formen„ comparing cigar, pipe, and cigarette smokers wath~ nonsmokers. A sum- mary of retrospective studies--------------------------- 194 Table 22.-Mortality ratios for cancer of' the larynx in cigar and pipe smokers. A summary of'prospective epidemiological studies----------------------------------------------- 196 Table 23.-Relative risk of cancer of the larynx for men, com- paring cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies---------------------- 198 Table 24.-Mortality ratios for cancer of the esophagus in cigar and pipe smokers: A summary of prospective epidemio- logicall studies----------------------------------------- 200 Table 25.-Relative risk of cancer of' the esophagus for mens comparing cigar, pipe, and cigarette smokers with non- smokers. A summary of'retrospectlive studies--------------- 201 Table 26.-Mortality ratios for lung, cancer deaths in male cigar and pipe smokers. A summary of prospective studiies---- 204 Table 27:-Lung cancer death rates for cigar and pipe smokers by amount smoked-IDoll and Hill---------------------- 204' Table 28.-Lung, cancer mortality rat'ios for cigar and pipe smokers by amount smoked-Rahn---------------------- 205 Table 29.-Relative risk of lung, cancer for men, comparing cigar, pipe, andl cigarette smokers with nonsmokers. A summary of retrospective studiies------------------------ 206 Table 30.-Changes in bronchial epi'theliumi of male cigar, pipe,, and cigarette smokers as compared to nonsmokers---_ 209 Table 31_-Tumorigenic activity of' cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals-_ 213 Table 32.-Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of prospective epi- demiological studies----------------------------------- 2116 169 I 0 ® ® 0 0 I t

Page Table 33.-Mortality ratios for chronic obsttlruetive pulmonary deathsin m~a1ecigar and pilpesmokers. Asu.mmary of pros- pective epidemiolbgical stludies-------------------------- 219 Table 34.-Prevalence of respiratory symptoms andi illness by type of smoking--------------------------------------- 220 Table 35. Pulmonary function val'ues for cigar and pipe smokers as compared to nonsmokers--------------------- 221 Table 36'. Mbrtalirt,y ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies--- 222 Table 37.-Shipment of small andl large cigars destined for domestic consumption (1970; 1971, 1972)----------------- 227' Table 38,-Selected compounds in mainstream smoke-------- 228 Table 39.-The pH of the mainstream smoke of selected tobacco productas-------------------------------------- 228, 170

Intiroductiiorr r22 i'2!7 ~28. I28 This~ eha.pter, is a review of' the epidemiological, pathological, and esperimental data: on the health conseqpences of smoking cigars! and'~ I)ipes, alone, together, and in various combinations with cigarettes. Previous reviews on the health consequences of'~ smoking have dealt primarilyy with cigarette smoking. Although some of the material on pipes:and cigars presented in this chapter has been, presented in previ- ous reports of'the Surgeon General, this is the first attempt to summa- rize what isInown about the health effects,ofpipe and, cigarsmoking:, Since the use of pipes and cigars is limited almost exclusively to men in the: United States; only data on, men are included in this review.. The influence of pipe and cig~r smoking on health~ is determined byexaminiRrgtheoverall and specific, mortalityandi morbidiityeg-perienced by users of these forms of tobacco compared to: nonsmokers. Epidemilogical evidence suggests that individuals who limit their smoking to only pipes or cigars have overall mortality rates that are slightly higher than nonsmokers. For certain specific causes of deathyhowever„ pipe andl cigar smokers experience mortality rates that are as great as or, exceed those e$perienced! by cigarette smokers. Thiss analysis becomes more complea when combinations of smoking forms ar~e, examinedL Theoveral2 rnortalityrates ofl thosew1v) smoke pipes, cigars,, or both in combination with cigarettes appear to be inter- mediate between the high mortality rates of' cigarette smokers and' the lower rates of those who smoke only pipes or cigars. This might seem to suggest that smoking pipes or cigars in combination with ciga- rettes diminishes the harmful eff'ects of cigarette smoking. However, an analyTsis of mortality associated vr ith smoking combinations of ciga- rettes, pipes, and cigars should be standardi'zedl for the level of con, sumption of each of' the prodhzcts smoked in terms' of the amount smoked, duration of smoking, and the depth and degree of inhalation. f' or example„cigar smokers who also smoke a pack of cigarettes a day might be egpectedito have mortality rates somewhat higher than those who smoke only cigaret'tiesat the level of apack a d'ay„assumingthat, both groups smoke their cigarettes in the same way. Mixed smokers', who inhale pipe or cigar smoke in ai manner similar to the way they smoke cigarettes might bee expected to have: higher mortality rates than mixed smokers who do1 not inhale their cigars and pipes and also 1z1 1

resist inhaling their cigarettes. ~,~nf!ortunately, little of the published material on~ mixed cigarette, pipe, and cigar smoking contains, these types of'analyses or controls:A paradox seems to: exist between the mortality rates of ex-smokers of pipes~and cigars and ex-smokers of cigarett'es. Ex-cigarette smokers experience a relative decline in overall and certain specific causes of mortality following cessation. This decline is important but indirect evidence that cigarette smoking is a ma jor cause of the elevat'ed mor- tality rates experienced by current cigarette : smokers. In contrast to this finding„ several prospective epidem.iological investigationsy Hammond and'H'orn (I0), Best (9)~„Kahn ('50), and H'ammond! (38), have; reported higher death rates for ex-pipe and ex-cigar smokers than for current pipe and cigar smokers.. This phenomenon was ana- lyzedl by Hammond and Garfinkel (3J). The development of ill healthh often results in a cigarette smoker giving up the habit, reducing his daily: tobacco consumption, switching, to pipes or cigars; or choosing a cigarette lbw in tar and nicotline. In many instances, a~ smoking- related disease is the cause of ill health. Thus, the group of ex-smokers includes some people who.are illl from smoking-related diseases, and d'eath; rates anehigh among personsin:ill health.As' a result„ ex-cigarette smokers initially have higher overalll and specific mortality rates than! continuing cigarette smokers, but be- cause of the relative d'ecrease in mortality that occurs in those who quit smoking for reasons other than ill health, andl because of the dwindling number of i11i ex-smokers, a relative: decrease in mortality is observed (within a few years) following cessation of' cigarette smoking. The beneficial effects of cessation «ouldi be obvious sooner were it not for the high mortality rates of those who quit smoking for reasons of illness. A similar principle operates for es-pipe and ex- cigar smokers, but because of't!he lower initial risk of smoking these forms! and thereforethe:smaller margin, of benefi't' following cessationythe effect producedl by the ill ex-smokers creates a larger and more persistent impact on the mortality rates than is seen in cigarette smoking. For the above reasons a bias is introduced into the mortality rates of current smokers and!es-smokers of pipes and cigars,,so that a more accurate pi'cture of' mortality might be obtained' by combining the ex-smokers with tlie current smokers and looking, at the: resultant mortality experience. Because of' a lack of data that would allow a precise analysis of mortality among ex-pipe and' ex-cigar smokers, a detailed analysis of'these groups could not be undertaken in this review. For each specific cause of' death, tables have been prepared which summarize the mortality and relative risk ratios reported in the major t7z

ters Cers ;of ~ect lor- ,' to Ins, ~eIS ha- Lth his Xlg tg- nd kdd le- ho ke. by te Br 19 K- tI, re ~e, Ss ,e le lt f'. prospecti~--e and retrospective studies which contained' informationn about pipe and cigar smokers. The smoking categories used include: cigar only, pipe only, total pipe and cigar, cigarette only, and mixed. The total pipe and cigar category includes: those who smoke pipes only, cigars only;, and~ pipes and cigars. The mixed category includes : those who smoke cigarettes and cigars; cigarettes and pipes; and cigarettes; pipes, and cigars. 'Mortality and relative risk ratios were calculated relative to nonsmokers. The Prevalence of Pipe,, Cigar, and Cigarette Usage: The prevalence of pipe„ cigar, and cigarette smoking in the United States was estimated by the National Clearinghouse for Smoking and Health from~ population surveys conducted in 19641, 1966;,and 1970 (98; 99; 100). In each survey, about 2,500 intervieavs were conducted on a national probabilitysamp16 stratified bytyype of populationandl beographic area. The use of'these products among adult's aged' 21 and older is summarized in tables 1 and 2: The prevalence of pipe, cigar, and cigarette smoking in Great Britain for the years 1965, 1968i and 1971 is presented in tablu :;: TABLE L.-F~ercen;t distr~~ib'ution of ~TT.S::7>za,le smoke~rs~~ aged~ 21 andolder~ by type of tobacco used' for the years 1964, 1966„ and 1970 Forms used 1964 1968 1970 (percent), (percent) (percent) 1. Cigar only----------------------------- 2: Pipe only ------------------------------ 3'. Pipe and cigar-------------------------- 4. Cigarette only -------------------------- 5.~ Cigarette and cigar---------------------- 6: 8 1.7 3,9 28 6 11.3 ' 5.5 3.0 4. 9' 31.,2 9.9 5: 6 3: 6. 4.4 25. 9 6,6 6. 7. 8. Cigarette: and pipe:.--------------------- Cgarette; pipe, and cigar---------------- Nonsmoker-----------------------,------ 5j 3 7: 7 3417 4: 9: 61 3! 34. 3 5. 3 4 6 4410 Total------------------------------ 100.0 10010 100'.,0 Total pipe users; (2+ 3+6-}-7)--------------- Total cigar users (1+3'-{-5+7)-------------- Total' cigarette users (4-}-5+6-F7)----------- 18: 7 29. 9 52: T 1'9:, 2' 26. 7 52.41 17. 9 21. 2' 42: 3' Source: U.S. Department ot Healthi Education, and Welfare (98, 99,10n);. 173:

TABLE 2.-P'ercent dzstribution of U.S. male smokers by type of tobac= co used and' age for 1•970' Forms used' 1. Cigar only----------------- 2. Pipe only------------------ 3. Pipe and cigar-------------- 4. Cigarette,only-------------- 5. Cigarette:and'cigar---------- 6. Cigarette and pipe---------- 7. Cigarette;, pipe,, and' cigar---- E', Nonsmoker----------------- Tota1------------------ Number of persons in sample--- TataP pipe users--------------- Total cigar users-------------- Total cigarette users---------- Age groups 21to34 38to:44 45'to54, 55to64 65to75' + 3,7 6' 5 4.7 6.7 9.3 4 3' 3. 5 3.0 ' 3. 2 3.6 '. 3. 8 3.3 5. 2' 414 6'. 9: 28.8 29:0 27. 1 24:3' 13:61 6.8 : 10.4 5.5 5: 2' 41 2' 6.6 4.4 5.6 4! 0~ 3.8 . 5: 8 4.8 5.0 4. 0 1.4 40:2 38. 1 43:9 48:,2 57.2 100.0 100.0 100L 0 1M 0 100.10 1i, 0w 528 523 405 388 20. 5' 16. 01 18.8 15. 6' 15. 7 20. 1 25.01 20.4 20. 3' 21!. 8' 48. 1 48.6 43.3 37.5 ' 210 Source: M S. Department of'Health, Education, and Welfare (1A0). 11'AS1,E. 3,-Percent' distribution of British male smokers aged 25 and older by type of tobacco used for the years 1965, 1968, and 1971. Formsused: 1. Cigars only'----------------------------- 2. Pipe only------------------------------ 3. Cigarettes on1y----,--------------------- 4. Cigarettes and pipe~--------------------- 5. MixedIsmokers------------------------- 6. Nonsmokers'---------------------------- Total'---------------------------- Number of' persons in sample--------------- Total pipe users--------------------------- Total cigar------------------------------- Total cigarette~-------------------------,--- Source: Todd, G. F: (B!,). 1' 74 1965 1968 1971, 1.9 21 8 3.3 ' 5. 1 5.6 ' 5. 9'. 46.8 ' 45. 7' 40.8 '. 8: 0 7T 0 6: 1. 7. & 9. 1 8.4 30. 7' 29. 9' 35.4 100:0 100.0 100.0 3)576 3, 566' 3,594 13.9 14.3 13, 3 9.0 11.7 ' 11. 3 67,6 67.6 61. 6

The Definition and Processing of Cigars,, Cigarettes, and Pipe Tobaccos CigaretGes A. 3' B. 6 3. 6' L 2 3. 8 1.4 7. 2 10; ~ 388 The U.S+ Government has defined tobacco products for tax pur- poses. Cigarettes are definedl as "(1) Any roll of' tobacco wrapped in paper or in any substance not containing tobaccot and (12) any roll of tobacco wrapped in any substance containing tobacco which, because of its appearance, the type of tobacco used in the filler„or, its packaging and labeling, is likely to be offered to„ or purchased by, consumers as a cigarette described in subparagraph Cigarettes are further classified by size, but virtually all cigarettes sold in the United States are "`small ci'garettes"' whichl by definition weigh "not more~ than 3' pounds per thousand"' which is not more thani 1.361 grams per cigarette (',96). American brands of cigarettes contain blends of different grades of' Virginia, Burley, Maryland, and' oriental tobaccos. Several varieties of cigarette tobaccos are flue-cured. Ifn this process, tobacco leaves. are curedl in closed barns where the temperature is progressively raised over a period of several days. This results in "'color setting," fixing, and dry~-ing, of the leaf. The most conspicuous change is the conversionn of starch; into simpler sugars and suppression of oxidative reactions. Flue-cured tobaccos produce an acidic smoke of light aroma: (35,,112);. Cigars r Cigars have been defined' for tax purposes as:: "Any roll of tobacco ,vrapped in leaf tobacco or in any substance containing tobacco, (other than any roll of tobacco which: is a cigarette w ithin the meaning of subparagraph (2) of the definition for cigarette)"' (112). In order to clarify t!he meaning of' "substance containing tobacco" the Treasury d'epartment has stated that, "The wrapper must (1) contain a signi& cant proportion of natural tobacco;, (2) be within the range of colors normally found in natural leaf'tobacco; (3)': have some of the other characteristics, of the tobaccos from which produced;e.g:,nicotine content, pI-I,, taste,, and' aroma;, and (4)1 notbesochangedl in the reconstitution process that it loses a11 the tobaeco: characteristics" (102). Further, "To be: a cigar,thefilder, must besubstantial,'ly of' tobaccos unlike those in ordinary cigarettes and must not have any added flav.ori'ng which would cause the product to have the taste or aroma generallyattributed to cigarettes. The fact that a product dioes 1i75

not resemble a cigarette (suchas~ many large cigars do1 not~)and'has adistinetiv.e cigar taste and aroma is of considerable significance in making this determination" (102)1. Cigars are also classified bysiae, "Smalll cigars"' weigh notl more thani 3 pounds per thousandi and, "large cigars"' weigh more than 3 pounds per thousand. "Large cigars" are further divided intolseven classes for tax purposes based on the retail price intended by the manufacturer for such cigars (96). Cigarsaremad'eof'fi1d'er,, binder, andwrappert'obaccos. 'Mosti' cigar tobaccos are air-cured and then fermentedL Nfore recently; reconsti- tutedl cigar tobaccos have been used as wrapper, binder, or both. Cigars are either hand4ol'led or machine made. Some brands of'smalli cigars aremanufactured' on regular cigarettemakingmac;hines. 'Il'heaging, and fermentation processes used in cigar tobacco production producee chemical catalytic, enzymatic, or bacterial tiransformations as evi- denced by increased temperature, oxygen utlilizationy and carbon dioxide generation within fermenting ciYar tobaccos. ]fni this complex process, up to 20~ percent of'tlied~yweight of'theleaf is lost through decreases in theconcentlrat'ion ofthemostl readil'yfermentablema- terial's such as carbohydrates, proteins, and alkaloids. The flavor and aromaofeigartobaccosare iazi largemeasuretheresul~t'sof 'preciselycontrolled treatment d~uringtheferment'ation process(35; 36, 112). Pipe Tobaccos The definition of pipe tobacco used by the LT.S. Government was repealed in 11966 ' and there is no Federali tax on pipe tobaccos. The mostpopular pipetokiaccos~ are made of Burley; however, many pipe tobaccos are blends of different types of tobacco. A few contain a significant proportion of midrib parts that' are crushed between rollers. "Saucing" material, or casings containing licorice, sweetening agents, sugars, and other flavoring materials are added to improve the flavor, aroma, and smoke taste. These additives modify the characterist!ics of smoke components (112)'.. CancLu sian. B'ecauseof t!heuniquecuringand processing methods used in the production of cigar andl pipe~tobaccos; significant phy.si~cali and chemi- cal differences exist betweeni pipe and cigar tobaccos and thoseusedl i'n »b.

has a ce in, nore an 3 even the igar lsti- ~ars rars r 01ng *e evi- bon ilexx igh ha- ,ndi ~lY~ 'as he pee a tSy Cs cigarettes. The extent to whichi these changes may alter the health consequences of smoking pipes and cigars can best be estimated by an analysis of the potentially harmful chemical constitutents found in the smoke of'these tobaccos; the tumorigenic activity of smoke conden- sates in experimental animals, andi a review ofl the epidem.iological data which has accumulated on the health effects of pipe and cigar smoking.. Cliemi'cal Analysis of C:gar Smoke Only a few studies have i been conducted that compare the chemical constituents of cigar smoke with those found in cigarette smoke. Hoffmann, et al. (43) compared the yields of several chemical com- ronentls, in the, smokefrom ai pl'a7n 85 mm: cigarette,, two types of cigars; and a pipe. The particulate matter, nicotine, benzo(a)pyrene, and phenols were determined quantitatively in the smoke of' these tobacco products: One: cigar tested was a 135'-mmi long„ 7.8-g.,, U.S''.- madie cigar. The other was a handmade Havanai cigar 147 mm. long weighing 8.6 g. The relative content of nicotine in the particulate matter produced by the cigars was similar to that of the cigarette tars. The benzo(a)pyrene and phenol concentrations in the cigar condensate was two to three times greater than in cigarette "tar''" (itable 4). f£uhn, (58) compared the alkaloid and phenol content in conden- sat!esfroman 80-mrn. Bright-blend cigarette sold comrnerciallyinAustria with, that obtained' from 103-mm. cigars. These were tested TABLE 4.-Amounts of se77erall components of Z' g: o f particulate material from mainstt eam smoke : of tobacco products Tobacco product I Standard' 8.5 mm. 8.5' mm. Compound U.S. Havana pipe Cigarette plain U.S. plain UiS. cigar A cigar B tobacco tobacco cigarette cigarette (b) (b) in pipe, in pipe, (a) (b) (b) IrTicotine: (mg.)---------- 46.2' 63'.6' Benzo(a)pyrene (µg.) ____ 3.9 3. 6' Phenol (mg.)_----------- 8.2 6.7 a-Ctesoll (mg.)---------- 1.6 1. 7 m+p-Ciesol (mg.)------- 4.8 3: 8 m-}°p-Ethylphenoli (mg.)-_ 1. 1 1.5 56:1 61.0 65:9! 77:4 6. 0 3.6 L 2 1.3 15.0 7.3 ' 2.9 4. 1 1.9 1.4 .6 .8 '' 5.6 3. 4 1.4 1.9 1L 1 1.3' .7, .7 177 I Smoking conditions: (a) 1 puff' per minute, duration 2'scc., puff volume 35' ml. L (b) 2 puffs~ per: minute, duration12 sec:,.puff volume 35 ml. Source: HoHmann, et al. (.r,.4).

with and -without the use of a~ celhzl'oseacetatefilter. Tli~econcentra-tions of'totall alkaloids andi phenol in the cigar smoke condensate were essentially the same as in the cigarette condlensate, but pyridine values were about 21/2 ti~meshicher in the cigar condensate., Campbell and, Lindsey (T7) measured' the polycyclic hydrocarbons levelsin thesmoke of'asmal'1lpopular-type cigar 8.8'cm8 long, weighing, 1.9 ~ g.Significant quantities of anthracene; pyrene, ft'uoranthene, and benzo(a)pyrene were detected in the unsmoked cigar tobacco, in con~- centrations much greater than: thosee found in Virginia cigarettes butt of the same order as those found in some pipe tobaccos: The smoking process contributed consi:derably: to the hydrocarbon content of the smoke. Table 5 compares the concentrations in the mainstream smoke of'cigarettes; ci'gars;and pipes of fourhyd!rocarbons frequently found in condensates. The authors reported! that the mainstream smoke from a popular brand of small cigar contained the polycyclic aromatic hydrocarbons; acenaplithylene, phenanthrene, anthracene, pyrene, flnoranthene, andl benzo(a) pyrene. Theconcentrationse ofthese hyd~o-carbons in the mainstream smoke were greater than those found in Virginia, cigarette smoke. Osman, et al. (69) analyzed the volatile phenol' content of cigar smoke collected from a 7-g. American-made cigar wit.h: domestic filler.. Afterquantitativeanalysisof'ph:enol', cresols, xylenols,and'meta and para ethyl phenol,, the aurt•horsconcluded that the levelsofthesecom- pound'sweregeneral'1y siiniilar to those reported for ciga:rettesmoke. O'sma:n and Barson (68) also analyzed cigar smoke for benzene, toluene, ethyl benzene, m-, p-;, and o-xylene„ m- and p-ethyltohiene, 1',2,4' triin.ethylbenzene; andi dipentlene, and generally found levels within the.range of't:liose previously reported for cigarette condensates.. In summary, available evidence suggests that cigar smoke contains mani- of the same chemicali constituents, including nicotine and; other alkaloids, phenols, and polycyclic aromatic hydrocarbons as are found TABLE 5.-A comparison of several' cliemical''compounds faund' in the mainstream smoke of cigars, pipes, and cigarettes Compound 1Vlicrograms per 100 g: o('tohiacco consumed Cigars Pipes I ' Ci@arettps Acenaphthylene--------------------------- 1.6 29. 1 5: o: Anthracene------------------------------- 11.9 110. 0 10.9 Pyrene----------------------------------- 17.6 75!5: 12;5 3;4-benzp_vrene---------------------------- 3.4 8. 5 . 9 I This is a light; pipe tobacco. Source: Campbell, 7: M., Lindsey, A. J: (17). 178

lra- ere. ues ion 119 qid ~ Dn* but ~ ~ng :~ the ~ ~ke : nd ' ~ >rn ~ tiie ne, ~o- ; inn iar ~r. nd n* ke. sls . M ns ier id' !he in~ cigarette smoke: Most of these compounds are found in concentra- tions whicli equal or exceed levels found in cigarette "tar.'"' A more compl'ete picture: of the carcinogenic potential of cigar "tars"' is ob- tainedi from experimental data in animals., Mortality Overall MortalitySev.eral large prospective studies have examined the health conse- quences of' various forms of smoking. The results of' these investiga- tions have been reviewed in previous reports of the Surgeon General in~ which the major emphasis has been on cigarette smoking and its effect on overall and specific mortality and morbidity., The following pages present a current review of the health consequences of smoking pipes and cigars. Data~ from the prospective investigations of Dunny et al. (31), Buell,, et a1.(16)1,Hirayama(42),, and W"eir and Dunn (~105), are not cited, because in these studies a separate category for pipe and cigar smokers was not established.. The smoking habits and mortality experience of 187,783 white men between the ages of 50 and 69, who were followed for 44' months were reported by Hammond and Horn (~41) . The overall mortality rates of men who smoked pipes or cigars were slightly higher than the rates of men who never smoked. The overalll mortality rate of cigar smokers was slightly higher than that of pipe smokers. In a study of' 41,00(Y British physicians,, Doll and Hill (28, 27) re- ported the overall mortality of pipe and eigar smokers as being; only 1 percent greater than that among nonsmokers. Best (9),, in a study of 78;000 Canadian veterans, reported overall mortality rates of pipe andd cigar smokers slightly above those of nonsmokers. Kahn (50) exam- ined the death rates and smoking habits, of' more than 293,000: U.S.. veterans~ and Hammond (38) examined the smoking habits of and mortality rates experienced by 440;559 men. In these studies„ pipe smokers experienced mortality rates similar to t.hose of men who never smoked regularly;, whereas cigar smokers had death rates somewhat higher than men who never smokedi regularly. Table 6 summarizes the results of'these five studies., Thus, data from the major prospective epidemiological studies demonstrate that the use of'pipes and cigars results in a small but dlefi,- nite increase in overall mortality. Cigar smokers have somewhat higher death rates than pipe smokers, and mixed smokers who use cigarettes in addition to pipes and cigars appear to experience an inter- mediate levell of mortality that approaches the mortality experience of' cigarette smokers. 495-028,oL--73'-- 13 179

TnBLE 6.-M'orta:l'ity ratios for total deatJis by type of' smoking (males only) Smoking type A uthor„reference Non- smoker Cigar only Pipe only Cigar and pipe Cigarette and cigar Cigarette and pipe Mixed (cigarette and other) Cigarette only Hammond and Horn 1 (4o)---, 1. 00 1. 22' ll 12' 1. 10 1.36 ' 1. 50 1., 43' 1. 68 IDoTl and Hill (2s)--------- 1.001 ---- ---- 1.01 ------ ------- 1. llli 1.28 Best (9)'----_--- 1. 00 1.06 1.05 .98' 1.22' ll 26 1.13 1.54 Kahn (dQ)------ 1. 00 1. li0 1. 07 1. 081 ------ ------- 1.51 1.84 Hammond 2 (3&)--------- 1.00 1.25 1. 19 1.01 ------ ------- 1. 57 1.86 "Only mortality ratios for ages 50 to 69 are presented! = Only mortality ratios for ages 8.5 to 64, are presentedl Mortality and Dbse-Response R'elat'ionsliiPs A consistent association existls between overall mortality and the total dose of smoke a cigarette smoker receives. The methods most frequently used'o to measure dosage of tobacco products are : Amount smoked, degree of inhalat'ion, duration of smoking experience, age at initiation,, and the amount of tar in a given tobacco product. Forr cigarette smokers, the higher the dose as measured by any of tihese parameters, the greater the mortali'ty.The significance of the small'i increase in overall mortality that occurs for the entire group of pipe and cigar smokers can be analyzed by examining the mortality of subgroups defined by si¢niIar measures ~ of dosage as used in the study of cigarette smokers, A3TOUIr fr SMOKED H!ammond and' Horn (40) reported' an increase in the overall mor- tality of pipe and cigar smokers with an increase in, the amount smoked. lndiv iduals who smoked more than four cigars a day or more. than 10 pipefuis a day had deathi rates significantly higher than men who never smoked (P<0.05 for cigar smokers and P'<0.05 for pipe smokers) (t~able 7):. Cigar and pipe users who smoked less than thiss amount experienced an overall mortality similiar to men who never 160'

qales rette iy .. 68 .28 54 84 186 srnokedl Thestludyof Canadian veterans (9)also~conta.ined evidenceof' a dose-response in mortality by amount smokedl for cigar smoker5. No dose-response relationship was observedl among pipe smokers (table 8). Kahn (50) reported a consistent increase in overall mortality with an increase in the amount smoked for both pipe and cigar smokers (table 9). Hammond (38) found' no consistent relationship bet«een overall mortality and the number, of cigars or pipefuls smokedl (table 10). TABLE 7.-1Vlortalityratiosfor totat deaths ofcig,ar andpipc smokers by, am:aunt smoked-Hammond and Horn Amount smoked Nonsmoker ----------------------------- Cigar only: Total ------------------------------ 1 to 4 cigars------------------------ }4 cigars-------------------------- Pipe only: Total------------------------------ 1 to 10'pipefuls---------------------- >10 pipefuls------------------------ Number of d@aths Observed Expected 14lortalityratio 1,664 1, 664 1. 00! 653 598! 1.09! 410 400 1.03! 229 185 ll 24 609 560 ll 09 391 374' 1105 204 172' 1'.19 Source: Hammond, E. G., Horn, D. (40). TABLE 8.-Mortality ratios for tatal' deaths of cigar and pipe' smokers by amount smoked-Best Amount smoked 10 to 20pipefuls---------------- 141 140. 84 1.00, >20 pipefuls------------------- 36 35. 90 1. 00i Number of deaths Observed Expected Modality ratio Nonsmolter------------------------- ---------- ---------- 1. U0 Cigar only: Total-------------------------- 90 82• 07 1'., 10 1 to 2 cigars-------------------- 64 564 05 ll 14 3 to 10 c'-gars. ------------------ 231 19: 40 1.19 > 1101 cigars--------------------- 1 1. 59 . 63 Pipe only: Tota1-------------------------- 570 566.99 1.00 1 to 101pipefuls------------------ 374 370.09 1.01 Source: Best„E. W. R. (9). 1,81

The above e'vidence'suggests that a dose-response relia.tionship may exist between the number of cigars and pipefuls smoked and overall mortality. FIowe'ver,becauseof'thehigh-mortalit'y rate ofex-sm~oke'rs: . of cigars and pipes, it is difficul't to interpret the data presented with- out out including this group with the continuing smokers. Without data which examines patterns of both daily rate of smoking and inhal'ationn at various age'leve]iS, no firm conclusions can be drawn as to the'nature of this dosage relat'ionship, 'Tl'Anr.E' 9.-Mortality ratios for t'o~tdl~, death,s~ of cigar and pipe smokers by age and' amount smoked=Kahn' Mortality ratio„age. Amountsmoked 58 Qo 84 6S'to 74' Pilbnsmoker-----------'-------------------------- 1.00 1.00 Cigar only: Total-------------------------------------- 1.01 1.08 11 to 4 cigars per day------------------------- .89 ll 00' 5 to 8'cigars per day------------------------- -, 1. 14 1L 23'. >8' cigars per day-----'---------------------- 1.65 ' 1L, 28 Pipe only: Total!-------------------------------------- - 1.08 ' v. 06, 1 to 4 pipefuls per day----------------------- 1. 16 .91 5 to 19 pipefuls per day'---------------------- 1.04 1. 10, }19 pipefuls per day'------------------------ ---------- 1. 18 Source: Kahn, H. A. (5q). TABLE 10.-Mortality ratios for total deaths of' cigdr and pipe smokers by amount smoked`Hammond' Amount smoked Mortality ratlu lwTonsmoker----------------- 1L, 00 Current cigar smokers:. Total-------------------- 1L 09, li to 4 cigars per day------- ll 03 >4 cigars per day--------- ll 18 Source: Hammond,,El. C. (18)'. 1' 82 Amount smoked M'ortalitip, ratio Current pipe smokers: Total-------------------- 1. 04! 1 to 9 pipefuls per day----- 1.08 > 9' pipefuls per'dax------- . 92'

Inhalation ofl tobacco smoke directly exposes the bronchi and the lungs to smoke and results in the absorption of'the soluble constituents of the gas and particulate phases. Without inhalation tobacco smoke only reaches the oral cavity and the upper digestive and respiratory tracts and does not reach the lungs where further direct effects and systemic absorption of various chemical compounds can occur.. Although the smoker has some voluntary control over the inhalation of smoke, the physical and chemical properties of' tobacco smoke to a degree determine its acceptability and "'inhaTability.7D' The ~ condensate of pipe andi cigar smoke is generally found to be alkaline when the pH is measured by suspending a Cambridge filter in COz-free water. Cigarette condensate is slightly acidic as measured by this method. Since alkaline smoke is more irritating to the respira- tory tract, it has been assumed that the more alkaline smoke of pipes and cigars was in part responsible for the lower levels of inhalation reported by pipe and cigar smokers. Brunnemann and Hoffmann (15) have analyzed the pH of whole, mainstream smoke of cigarettes and cigars on a puff-by-puff'basis using a pH electrode suspended in main- stream smoke: Smoke from several U.S. brands of'cigarettes was found to be acidic throughout the entire length of the cigarette. Of' interest was the findang, that cigar smoke also had an acidic pH for the first two-thirds ofl the cigar and became alkaline only ini the last 20, to 40 percent of the puffs f rom the cigar. Available epideniiol'ogical evidence indicates that most cigar smokers do not inhale the smoke and mostt cigarette smokers db. The fact that smoke from the first half' or more of a cigar is acidic, near the range of pH values commonly found in cigarette smoke, and becomes alkaline only toward the end of the cigar might suggest that the pH of the smoke of a tobacco product may not be the only factor thatinfluences inhalation patterns. Per- haps"`tar"' and nicotine levels as well as the concentration of' ok,her"irritating" chemicals also affect the degree to which a tobacco smokee will be inhaled. Nicotine is rapidly absorbed into the blbod stream from the lungss when tobacca smoke is inhaledl The amount of nicotine absorbed frorni the lungs is primarily a function of the nicotine concentration in the smoke and the depth of inhalation. Some nicotine may also be ab- sorbed through the, mucous membranes of' the mouth. This is moree likely to occur under alkaline conditions .chen nicotine is unprotonated (3, 15, 79). This suggests that cigar smokers mayy be able to absorbb some nicotine through the oralcauity without having to inhale, par- ticulkarly during the time that the smoke from the cigar is alkaline. 1ea ,

With the development of' sensitive measures of' serum nicotine levels (48) the extent to which nicotine is absorbed through the membranes of' the mouth in pipe and cigar smokers can be more accurately determinedl, Inhalation patterns of' smokers were determined in severaI of thee large prospective and some of the retrospective epidemiological studies. Inhalation was usually determined' by the administration of a ques- tionnaire that required a subjective evalhiationi of one''s own patterns ofinhalati~on. A1'thoughi the accuracy of t!heseqpestionnaiereshas not been confirmed by an objective measure of inhalationS such as carboxy- hemoglobin or serum nicotine levels, their reliability is supported by mortality data whichdemonstlratehigber, overall andl specific death rat'eswith self-reported increases~ in the depth of inhalation. Doll and Hill (26) andI'-Iammond (3&')presented information on inhalation patterns of pipe; cigar, and cigarette smokers (figs. 1, 2, 3i and table 12). Some 80: to 90 percent of' cigarette smokers reported inhaling, with the majority of' individ'uals inhaling moderately or deeply, whereas most pipe and cigar smokers denied inhaling at all.. Pipe smokers reported slightly more inhalation than cigar smokers., For each type: of' smoking,, less inhalation: was reported' by older smokers: This change may represent less awareness of inhalation, differences in smoking habit's of' successive cohorts of smokers, or it may reflect the: operation of'selectivefactorswhichfavor survival' of noninhalers. The Tobacco Research Council' of the United Kingdom hast since 1957i„periodi'eally reported the use of tobacco products by the British, Figure I.-Inhalation among pipe smokers by age. M'o inhalation Some inhalation Age 40 SOURCE: Hammond„ E: C. (38): 50 60' 70' 80 184

4els lnes !ely the ies. ies- rns not Ky- by ~th on !ed or ull. M ler bn, it ~ !o,f, tce >h. Figure 2.-lhhalation among cigar smokers by age-Hammond. SOURCE: Hammond, E. C. (38). Figure 3.-Depth of inhalation among cigarette smokers by age: HammondL None Slight inhalation Moderate inhalation Deep inhalation AVge 40 SOURCE: Hammond'y E. C. (38)., Recent reports edited by Todd have contained data on the inhalation pattern of cigar, pipe, andi cigarette smokers (92, 93, 94). Table 11'i shows that most cigarette smokers inhale a "lot" of "fair amount" whereas most pipe and cigar smokers donot'inhaTeatalll or "just alittle."' Little change is observed in the inhalatiion patterns of a given product since 1968. Best(9): reported inhalation data among, malie cigarette smoker&by smoking intensity and age group, but did not report the inhalation~ 60' 70 80' 185

pat'tlernsof' pipe andd cigarsmokers, The overall mortality ratesofs current pipe smokers who inhaled at least slightly were reported by Hammond'! (38) as being somewhat higher t'han for men who never smoked regularly. The overalll mortlalityy rates of current cigar smokers who reported inhaling at least slightly were appreciably higher than for men who never smoked regularly (table 13). Available: evidence indicates that cigarette smokers inhale smoke to agreaterdogree than smokers~of cigarsorpipes:Once a smokerhasllearned to inhale eigarettes,,hmRever, there appears to be a tendency to also inhale the smoke of' other tobacco products. For cigars,, this is evidently true whether one smokes both cigarettes and cigars or switches from cigarettes tlocigars (tables 1!4, 15;16). Bi-ossand Tidings (14): examined th:einhal'at'ion patt'ernsofs smokers of' large cigars, cigarettes, and those «•.ho switched from one tobacco product to another (table 15). Nearly 75 percent of those who: were currently smoking only cigarettes reported inhaling "almost every puff" and only 7 percent never inhaled. The opposite was true for per- sons who had always smoked' only cigars among whomi 4 percent re- TA$LE' 11~.-Th,e~ extent of' inhaling pipes;, cigars, d~~nd~~ cigarettes~ 8y, British; males aged 16' and over in 196'8' and 1971 V Tobacco product Amount of inhalation ~ Cigars Pipes Cigarettes ~ 1968 1971 1968 1971 1958 1971 Iilhale a lot------------------------ 23 19 8 8 47 47 C Inhale a f'air amount---------------- 16 19 1'0I 8 31 W Inhale just a lit'tle------------------ 27 27' 24 ' 26' 13' 15 Do not inhale at a11L---------------- 34 35 59 58 9 8 P; Total------------------------ 100~ 100~ 100 100~ 1001 100 Sourae: Todd, Ci. F. (91; 94). TABLE 12.-lniial'ation among cigar, pipe, and' cigdrette smokers by .lr age-Doll and Hill Percentage of [nhalers, age Smoking type. 26'.to.34~. 35to~44 4b~to64 b8~to164~~. &5~.to74: >74~, Cigar and pipe---------------- 12.00 10.00 ' 7. 00, 5:-00 4.00 4.00 Mixed (cigarette and other)----- 74. 00 60. 00 47. 00 36! 00 30. 00 26.00 Cigarette onlx---------------- 90. 00 85: 00' 75. 00 66: 00 58. 00 41.00 Source: Doll, R'., Hill, A. B: (P6)i 186'

ported inhaling almost every puff and 89' percent said they never inhaleclL Cigar smokers who also smoked cigarettes reported inter- niedi'ate levels of inhalation between the cigar only and' cigarette only categories. Inhalation patterns~ weresimilar whet.her~ theindivi'dua1 continued to smoke both products, stopped smoking cigarettes but continued smoking cigars, or stopped smoking cigarettes and switched to cigars. In alll three groups, about 20 percent reportedd inhaling "almost every puff." This suggests that once an indi'vidualP's inhalation patt~ernsare established on cigarettes, hemaybemorelikel:y to inhale cigar smoke if he switches to cigars, or uses both cigars and cigarettes, than the cigar smoker who has not smoked cigarettes. Tad'd! (93) reported similar data for a sample of' smokers in the United Kingdom (table 16). The preti-.allence of! inhaling a"lot"' or "fair amount" of smoke was highest among cigarette smokers who -were currently smoking cigarettes (77percent)and lowest among, current cigar smokers who had previously smoked only cigars or pipes (188 percent). Individuals nho, switched from, cigarettes to cigars maiat- TABLE' 13,-Afortality ratios for total' dedtJts of cigar ¢nd' pipe smokers by age cund intuclat£on-Hdmmond Irlhalation hEortality ratio, age 45' to 84 , 65 ta 84 Nbnsmoker----------------------------------------- 1.00 1.00 Cigar only: Total------------------------------------------ ll 09 .98 No inhalationL -_---------,-----__ ---------------- 1.02 .91 Some inhalatlion--------------------------------- 1.28 1. 37 Pipe only: Total------------------------------------------ 1.04 .95 No inhalation-----,------------------------------ . 98 .87 Some inhalation--------------------------------- 1.21 1. 11 Source: Hammond, E. C:,(d8)., TnBLR 14.-Percentage of' British male cigar smokers who reported'g inhaling a lot or a fair amount by type of' product'smoked Type of product 1968 1971 Number of Percent Number oi Percent'. indiwidua]s individuais Cigars only------------------------- 706 23.0 111 27.0 Cigars and cigarettes----------------- 1, 193 42'. 0 277 44.0 Cigars and pipes--------------------- 596 35.0 109 32.0 Cigars;,cigarettes; and pipes---------- 26 52'.0 15 32.0 Source: Todd, G. F. (99. 9,1). 167

tainedl somewhat higher levels of cigar smoke inhalation than those cigar smokers who had never smoked cigarettes (30' percent). Toddl (93) examined further tlhe relationship between the inlialationn of' cigarette andd cigar smoke. In generaly cigarette smokers who switched to cigars were much less likely to report iiihaling, cigar smoke: than cigarette smoke:;, however, those who in the past reportedd inhaling cigarette smoke a"lot" or "fair amount"'' were much moree likely to report inhaling cigar smoke to the same degree tlian those ex- cigarette smokers who in the past did not inhale the smoke of their cigarettes, (ta}51e 17)~.. TABLE 15.-Percentage of' individuals reporting inlialdtion of "almost every puff" of tobdcco smoke by current and previous tobacco usage and' type of tobacco used' Type,of tobaeco smoked Number Percen- f T inh l d t Confidence limits - Current usage Previous urage ype a e age o patients inhaled: Lower Upper Cigarettes only---- Cigarettes only____ 2; 359 Cigarette__- 74.8 73: 1 76.6 Cigarsionly_______ CiRars onl'y_______ 649, Cigars----- 4. 5 3. 0 6. 0 Cigarettes and cigars. Cigarettes and cigars. 520 _____do__,___ 20: 4 10: 5 28.0 Cigars Cigarettes and cigars. 93I ----- do_____ 118.3 ' 9.0 30.0 None------------ Cigarettes and'. 186 ----- do_-___ 21.5 ' 17.8 24.2 ' cigars. Cigars----------- Cigarettes only---- 64 ----- do----- 117.2 16.0 281 0 Source: Bross, I:,D. J:,,Tidings;,L (14). TA;BLE 16.-Percentage of B'ritish males who reported' inhaling a lot or fdir, amount of cigar smoke : by current' dnd' previous tobacco usage and' type of tobacco previously smoked (1968) Type of'tobacco smolred, Number of individuals Type inhaled Percentage inhaled Current usage Previous usage Cigarett'esonly_-______ Cigarettesonly------ 2,586 Cigarette'-____ 77:7 Cigars only----------- Nonsmoker--------- 306 Cigars_______ 18.0 Cigars only--,---------- Cigarettes only------- 321 -----do------- 30:0 Source: Todd, O. F. (9k). 1186!

i kose li~on vho gar ted ore ~eg- keTr tost and' Fe' iper TABLE 17.-Extent of reported inhalation of' cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1968; analyzed by extent of' reported' inhalation of' cigarette smoke when previously smoking cigarettes Extent of inhaling cigars Extent of inhaling cigarettes Inhale a lot Inhale a littln oriair amount or not at all' Percerel' Percent Inhale a lot or fair amount-----------------,------ 44.0 5.0 Inhale a little or not at all------------------------ 56: 0 95.0 Tota1------------------------------------ 100:0~ 100.0 Sample size------------------------------------- Source: Todd, (]I. F. (9S). 244 56 Speciflc Causes of Mortali'tty Cancer Several prospective epidemiological studies have'n shov'n a signifi- cantly higher overall cancer mortality among pipe and cigar smokers, compared to;the cancer mortality ofl nonsmokers (table 18)'. Pipe and cigar smokers have mu& higher rates of cancer at certain sites than at others. The upper airway and upper dfigestive tracts appear to be the most, likely target organs. The relationship of'pipe and cigar smoking to the develbpment ofl specific cancers i's detailed in the follbwing sections, TABLE 118.-Mortdli.ty ratios for total ' cancer deaths in cigar, and pipee smokers. A sumnzdry of prospective epidemiological'studies Type of smoking, Author~ reference Nonsmoker Cigaronly Eipe only Total pipe and cigar Cigarette only. Hammond'and Horn (!0)-,--- ll 00 1: 34 1. 44! -,--,----- 1.97 Bestl (9) ------------------- 1.00 L 13 1.38 -------- 2.06 Hammond (38) ------------- 1.00 ------- ------- 1! 21 1.76 Kahn (60)----,------,------- 1.00 1.22 ll 25' ll 25' 121 1'89

Cancer of the Lip. Approximately 11,500~ new cases of' cancer of the lip are reported each year. Because of the possibility of early detection and surgical accessibility of'cancers in this area, there aree less than 200~doaths from cancer of't'h:elip each year in the United States. Sotne,ofthe earliest seientific investigations exploring the association betweeni tobacco, use andd disease examinedi the smoking patterns of individuals with cancer of'the lip. Broders (13) in 1920 examined'' the smoking habits ofl patients in a retrospective study of' 526' cases of epithelioma of the lip andi 500 controls.. Of the cancer cases, 59 percent smoked pipes, whereas this was true for only 28 percent of'the control's. No association: was found betR.een cigar or cigarette smoking and cancer of the lip. In a restrospective study of 439' clinic, pat'ient's with cancer of' the lip andl 300, controls conducted in Sweden, Ebenius (32') reported a significant association between pipe smoking and cancer of tlie lip, A total of' 61.8 percent of the lip cancer cases smoked pipes, while only 22.9' percent of' the controls smoked pipes. No association was found between the use of cigarettes, cigars, or chewing tobacco and cancer of the lip. ][ni other retrospective studies, Levin, et al. (60) reviewed a series of' 143' cases of cancer of the: lip, and Sadowsky, et a1: (77)' reviewed 571 cases of cancer of'the lip. lfn both studies, a strong association was floundl between pipe smoking and cancer of the lip. No significant association was found between the use of tobacco in other forms and cancer at this sit'e: l[n, a study of environmental factors in cancer of the upper alimen, tary tract, Wyndier, et al. (113)', found an association between pipe smoking, cigarette smoking, and cancer of'thelip: There were only 15 cases of cancer of the lip in this study:S~taszewski (87)examinedi the smoking habits of 394 men with carcinoma or precancerous lesions of the lips. An associationi wasfoundl between tlh:e, smoking of pipes and cigars and cancer of the lip; but this was only of doubtful significance. A significant associationn was found between the use of'cigaret't'es and cancer of the lip. Keller (51) conducted a study of lip cancers in which he considered a number of factorsincluding, histologic types, survival,, race,occupa-tions„ habits, and associated diseases. A total of 304 patients with primary basal cell or squamous cell carcinoma of the lip and'i 304 controls from the same hospital matched for age and race «-ere con- sidered in this series. A significant association was floundl between smoking in a11 forms~ and'' combiziationsand carcinoma of thelip., Iitl was a1'so found that inereasing: age andi outdbor occupat'i'ons with exposure to~ thesuni wereequadly significant factors in the etiology ofl lip cancer. 190

In summary, it appears that there are several factors involved in the etiology of cancer of the lip. Among the various forms of'tobacco use, pipe smoking either alone or in combination with other forms of' smoking seems to be a cause of cancer of'the: lip. Table 19 summarizes the results of'these retrospective studies. Oral! Cancer The lips, oral cavity, and pharynx are the first tissues exposed to tobacco smoke drawn in through the: mouth. Variations in inhalation during,the smoking,of various.tobacco products result in different pat- terns of distribution of smoke throughout the respiratory tree. How- ever, the oral cavity and adjacent tissues are the sites most consistently exposed to tobacco smoke. For this reason, differences in inhalation should result in less variation, in exposure to tobacco smoke for these sites than for the lower trachea and t.he lung. The inherent carcinogen- icity of pipe, cigar, and cigarette smoke is most reliably compared at those tissue sites where dosage and exposure to, tobacco smoke are most nearly equal. Data from, the epidemiblogical studies suggest that little difference:exists between the smoking of'cigarettes„pipes„or cigars and the risk of developing orallcancer. Hammond and Horn (40) examined the association between smok- ing in, various forms and cancer of'the combinedi sites of lip, mouth,, pharynx, lary.nx,, and esophagus. The mortality ratios were 5.00 for cigar smokers,, 3.50 for pipe smokers; and 5.06 for cigarette smokers comparedto:nonsmokers. All the deaths from cancer of the lip, oral cav- ity, and pharynx reportedl by Doll and Hi1D (26) occurred in smokers.. The death rates from cancer at these sites were 0.04 per 1,000 for pipe and cigar smokers, 0:10 per 1,000 for mixed smokers, and 0.05: per 1,000 for cigarette smokers. A fairly detailed analysis of oral cancer was pre- sented by Kahn (50) who differentiated between cancer of the oral cavity and cancer of the pharynx. The mortality ratios for oral cancers were 1.00 for those who never smoked, 3.89 for all pipe and cigar smokers; and 4.09 for cigarette smokers. A further breakdown of the pipe and cigar smokers demonstrated a mortality ratio of'. 4.11 for cigar smokers, 3.12 for pipe smokers,,and 4!.20 for smokers of pipes and cigars. For cancer of the pharynx, the mortality ratios were 1.00 for those who never smoked,, 3.06' flor all pipe and cigar smokers; andl 12.5 for cigarette smokers. No deatihs oceurredl among those who smoked only cigars: The mortality ratio was 1.98 for pipe smokers and 7.76' for smokers of pipes and cigars. Hammondl (3b')' combined cancers of the lip, oral cavity, and pharynx. The pipe and cigar smokers had a mortality ratio~ of 4.94 and the cigarette smokers a mortality ratio of 9:90 compared to nonsmokers. 1I9'1

64VV941E0 TABLE 19.-Relat,ive risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Author, reference Broders (13) : Cases----------------------- Controls_____________________ Ebenius (32) : Cases----------------------- Controls____________________ Levin, et al. (60) : Cases----------------------- Controls____________________ Sadowsky, et al, (77) : Cases----------------------- ---- Controls____________________ Wynder, ' et al. (11 3) : Cases----------------------- Controls-------------------- Staszewski (87) : Ca,ses----------------------- Controls_____________________ Keller: (51): Cases----------------------- Controls--------------------- Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette only Miaed Relative risk____________ 1.0 0 0.8 4.3 --------- 0 --------- 537 Percent cases___________ 7 19 41 --------- 1 - 500 Percent controls_________ 4 16 6 --------- 26 --------- IZelative 1.0 .7 4.1 0.5 _______ _________ 439 Percent cases___________ 49 6 41 4 ------- --------- 300 Percent controls_________ 65 12 13 10 Itelative risk____________ 1.0 1.9 2.9 - 1 4 143 Percent cases___________ 15 27 48 -------- - --------- -- _ . - - 45 _________ - --------- 554 Percent controls_________ 22 20 24 --------- 46 --------- Itelative risk_ _ _ _ _ _ _ _ _ _ _ _ 1. 0 1. 1 4. 3 2.6 1.4 0.4 571 - Percent cases___________ 8 2 18 6 44 22 615 Percent controls_________ 13 3 7 4 53 19 Relative risk------------ 0 . 8 1.8 --------- 1.0 2.2 14 Percent eases___________ - 0 7 29 --------- 36 29 115 Percent controls_________ 24 9 16 --------- 36 13 Itelativerisk------------ 1.0 _________ 2.1 2.4 ________- 394 Percentcases------------ 7 _________ 12 73 _________ 912 Percentcontrols_-_______ 13 _______-_ 11 61 __-______ Relativerisk____________ 1.0 1.4 4.0 2.6 301 Percentcases------------ 7 2 6 1 60 6 265 Percentcontrols--------- 17 4 3 0 53 0 I Percentage based on less than 20 patients. Ratios: relative to cigarette smokers. ;.

These studies are summarized in table 20: They demonstrate that <wokers experience a large:andsignifieant risk of developing, cancer uf the oral cavity compared tononsmokeils: This risk seems~tobeabout rhe same for all smokers whether an individual uses a pipe, cigar, or i ~ aret.te.. 1 number of retrospective studies have examined the relationship between smoking in various foims and cancer of'tlte orat cavity. Thee results of these studies are presented in table 21L Some of the variations i n relative risk of'developing, oral cancer observed in the retrospective ~ -tliclies is probablyy dhie to the lack of a uniform definition of oral cancer r 1)v anat'omie,al sit''eand the variaus, means used in sel'ecting, and deff!n-{ in r cases and controls. It appears, however, that a significant risk of t developing oral cancer exists for smokers compared to nonsmokers and this ri'sk is similar for smokers of pipes, cigars, and cigarettes. j Several epidemiological investigations liave demonstrated an asso- ? <<iation between the combined use of alcoholi and tobacco and the ~ de~~elopment of oral ll cancer.X few of these studies (i52, 6°~y6~3, 109)~~ i contain data on pipe and cigar smokers. Heavy smoking andi heavy ~ drinking are associated withi higher rates of oral cancer than are seen { with either habit alone. 1 TAsnE 20.-11'lort¢lity ratios for oral can+cer in cigar and pipe smokers. A summary of prospective epidemiological studies e 0 ® Author;, reference. m ~ ~ Hammond'and Hornl'(40)- Doll and Hii11,2 ' (26,,2'7)--- Hammond ('38)---------- Kahn (b0)',: Oral 4'----------,---,- Pliarynx'------------ Smoking type Non- smoker Cgar only Pipe only Total pipe and cigar Cigarette only Miaed' 1.00 5: 00 3. 50 -------- 5. 06 -_------ 0. 00: -------- ------ 0: 80, 1.00 2: 00 1.00 -------- ------ 4.94 3'9. 90' -------- 1L 00 4.11 3. 12 3,89 4.09 -------- 1.00 -------- 1'.98' 3.06 12. 54 -------- I Combines dataSor oral;,laryna; and esophagas:, 2 Ratios: re]ative to cigarette smokers. 3 Mortality ratios for ages 45 to 64 only are presented. 4'Eacludes pharynx. c 0 Cancer of the Larynx The larynx is situated at the upper endl of the trachea. Because of! its' proximity to the oral cavity, the larynx probably has a similar' exposure to smoke d~ra.vn through the mouth as the buccal cavity and phaaynx. Tobacco smoke that is not inhaled! may stilll reach as far as the larynx and upper trachea. Pipe, and cigar smokers develop cancer of thelitrynx at rates comparable to those of cigarette smokers. These a. 1'93

3?AALt: 21.-Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers uilh nonsmokers. A summary of retrospective studies Author reference Relative risk ratio and percentage of cases and controls by type of smoking Number ------ , Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette Mixed only n7ills and Porter (65): Relative risk_____________ 1.0 -________ -------- 7.0 4. 1_________ Cases----------------------- -- 124 Percent cases------------ 10 --------- -------- 55 36 --------- Controls-----------. -------- 185 Percent controls---------- 38 --------- -------- 30 32 --------- Sadowsky, et al. (77): Relative risk_____________ 1.0 2.0 4.4 --------- 1.4 2. 1 Cases----------------------- 1, 136 Percent cases____________ 8 4 i8 --------- 42 28 Controls_____________________ 615 Percent controls---------- 13 3 7 --------- 53 23 Schwartz, et al. 1. (&3) : Relative risk------------- 1.0 _ _ _ _ _ _ _ _ _ ---- 1.6 --------- 1.5 --------- Cases----------------------- 332 Percent cases------------ 16 3 --------- 63 --------- Contr-ols-- - - - - - - - - - - - -------- 608 Percentcontrols---------- 23 77 3 --------- 58 -- ------ Wynder, et al. (109): --- - - - Relative risk_____________ 1.0 3.6 6. 1_ --------- 3.0 3 3.3 Cases----------------------- 543 Percent cases------------ 3 20 - 11 --------- 57 8 Controls_____________________ 207 Percentcontrols---------- 10 13 6 --------- 63 8 Wynder, et al. (113): Relative risk_____________ 1.0 1. 7 .9 _________ 1.2 1.4 Cases----------------------- 115 Percentcases------------ 23 13 12 --------- 37 16 Controls_____________________ 115 Percentcontrols---------- 26 9 16 --------- 36 13 I8VV944c0

::,~ , ... Wynder, et al. (116) : Relative risk_____________ - - 1.0 6.0 -------- -------- .P. Case9----------------------- 178 Percent cases---__-_--__- 4 33 -------- -------- ~ Controls--------------------- 220 Percent controls__--_-_-__ 16 22 0 N x Pernu (73): Relative risk_____________ - - 1.0 - -__-_-__ 3.6 -------- I Cases----------------------- 1,400 Percentcases___-___-____ -- 21 ________ -- 10 ________ w Controls_____________________ 713 PercentcontroLs__-____-_- 39 -------- 5 ________ I ~ Staszewski (87): Relative risk_____________ 1.0 -_______ 3.5 Cases----------------------- 383 Percent cases____________ 6 -------- 13 Controls_____________________ 912 Percent controls---------- 17 it Keller (52) : R.elative risk_____________ 1.0 3.1 3.8 2.2 Cases----------------------- --- 408 Percent cases____________ -- 5 7 4 10 Controls_____________________ 408 Percent controls__________ 14 6 3 13 Martinez (62): Relative risk_____________ 1.0 1.7 1.3 ________ Cases----------------------- ---- 170 Percentcases____________ 8 10 1 ________ Controis--------------------- 510 Percent controls__________ 14 10 2 Martinez 1 (63) : Relative risk_____________ 1.0 2.0 2.8 ________ Cases----------------------- 346 Percent cases___-________ 12 10 15 _____ Controls--------------------- 346 Percent controls__________ 22 9 1 F This study comhtnes data for oral cancer and cancer of the esophagus. zeVV94,C0 2.2 59 50 2.9 11 7 3.6 --------- 72 --------- 61 _________ 3.4 ________- 69 --------- 56 __-_---_- 1.5 2.3 39 34 44 25 1.7 2.5 34 34 36 25

rates are several times the rates of nonsmok:ers. The siQnilarity of the mortality ratios of cancer of the larynx f'or smoking in various fonns suggests that the carcinogenic potentials of the smoke from cigars,, pipes, and cigarettlesare quite alike at thissi'te. Several of tlhe~ prospective epidemiological studies include d'at~aan deaths from cancer of the larynx for pipe and cigar smokers as «eldl as forcigaretlt'esmokers.Havnmond and I-1orn (40), combined data for cancer ofl the larynx with cancer of the esophagus and oral cavity. The mortality ratios comparredi to nonsmokers were 5'.00~ for cigar smokers, 3.50~ for pipe smokers, and 5:06' for cigarette smokers, Tlrere were no deaths from carcinoma of' larynx among nonsmokers in tlhe' study of I>1'ri'tish physicians by Doll and Hill! (26:)~ ; however, thedcath rate for cancer of the lary.nx among pipe and'cigar smokers:was 0.10 per1I,000 wh:ilethe deathi rate.f'or cigarette smokers was 0.05' per 1,000. Kahn ('50)reportedmortallityrat'~i'osforcancer of'thelarynx of10:33' for cigar smokers; 9!441 for pipe and cigar smokers, 7.28 for all pipe and cigar categories'combined~ and 9.95 for cigaret!te smokers: No deaths from cancer of the larynx occurred in pipe smokers: 1-I<ammond (38) reported a mortality ratio of 3.37' for all pipe and cigar smokers and a mortality ratio of 6.09 for cigarette smokers in the age category 45 to 64. These studies are summarized in table 22. Several': retrospective studies have examined the smoking habits of patients with cancer of the larynx and appropriately matched controls. The small number of'e pipe and'r cigar smokers ihi each study results in relative ri'sk ratiost that are quite unstable; however, it appears tliatt pipe and cigar smokers experience a risk of' developing, cancer of'thee larynx that is similar ta the risk observed among cigarette smokers (table 18). TABLE 22.-Mbrtality rdtios for cancer of th,e larynx in cigar and pipe smokers. A summary of prospective epidemiological st'ud'2es Author, reference Smoking,type Mixed Non- Cigar only Pipe only Total pipe Cigarette smoker and cigar only. Hammond and Horn 1 (40) ------------------ 1.00 5.00 3.50 -------- 5.06 -------- Doll and'Hill z(26; 27)--_ 0: 00, -------- ------ 2.00 L 00 0.60 Hammond (38)'---------- 1. 00 -------- ------ 3. 37 3 6. 09......... Kahn (50) -_ -,-_ -,------_ _ 1.00 10.33 ' ------ 7.28 9.95 -------- I Combines data for oral, larynx, and esophagus. I Ratios: relative to cigarette smokers. 3: onlymortality ratios, for ages 45 to fr4'are presented. 1'96

the 'ns rs,, oni elll or ty. ;ar ~re in be ,as ler ~of a.ll Jo' 4d its ry ~ df. Is.. in at. lie rs. Wynder, et al. (108, 113) distinguished' between intrinsic and ex- trinsic larynx caneers: For smokers the relative risk of' developing cancer of the intrinsic larynx was similar to the relative risk of lung, cancer whereas the relative risk of dev.eloping extrinsic larynx cancer was more like the relative risk of cancer of theiupper digestive tract. Histologic changes of the larynx in relation to smoking ini various forms were described by Auerbachy et al. (5):. Mi.croscopic sections of'~ the larynx from~ 942 ' subjects were examined flor the presence of atypicali nuclei andi proliferation of' cell rows. Sectionsi were taken from four separate areas of the larynx in eachicase: Among those who smoked cigars and pipes but'nat cigarettes;only I percent had no~ atypical cells and niore than i5i percent of the subjects had lesions with 50 to 69 percent atypical cells. Four of'the cigar and pipe smokers had carcinoma in situ and in one of these four cases earlyy invasion was seen in three of the sections. Of those who never smoked regu- Iarly.,i5 percent had no atypical cells. Tlieci'garand pipesm~okers,had ai similar percentage of cells n it.h atypical! nuclei as cigarette smokers who smoked one to two packs per day,. With respect to the proli£era, tion of cell rows in the basali la}•.er of the true vocal cord; the least proportion of cases with eight or more cell rows was found in men ,,ii never sm~oked,, and the greatest proportion was found in heavy cigarette smokers. Pipe and cigar smokers had a distribution of celll rows that was comparable to that of cigarette smokers who consumed about a pack a day. Several retrospective studies have reported an association between t'.he combined' use of tobacco and alcohol and cancer of the larynx. A study by `Vynder, et al. (108) included some information on pipe and cigar smoking in relation to drinking habits and the develop:nent of cancer of the larynx,, but because of the limitied number of' pipe and cigar smoking subjects this relationship could! not be adequately determined. Cancer of the Esophagus The esophagus is not dfirectly, exposed to tobacco smoke drawn into the niouthi; however, the esophagus does have contact with that portion of tobacco smoke that is condensed on the mucous membranes of the mouth and pharynx and then swallowed. The esophagus i's also ex- posed to a portion of tobaccosmoke, tllatis~deposit,edl in the mucus cleared from tlle lung by the ciliary mechanismior by coughing. Varia- tions in inhalation of~ atobacco, product maynot appreciably alter the~ exposure the esophagus receives from smoke dissolved in mucus and saliva. This suggest.ion receives support from the prospective and retrospective epideneiolopcal studies which demonstrate simillar mor- tality rates for cancer of the esophagus in smokers of'cigars, pipes, andl cigarettes. 197

TABLE 23.-Relative risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Author, reference Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only Pipe only Total pipe and cigar Cigarette only Mixed Schrek, et al. (s1) : Relative risk------------ 1.0 0 1. 1 --------- 2.3 --------- Cases----------------------- 73 Percent cases----------- 14 0 7 --------- 80 --------- Controls--------------------- 522 Percent controls--------- 24 10 11 --------- 59 --------- Sadowsky, et al. (77) : Relative risk------------ 1.0 2.2 2.3 --------- 3.7 4. 1 Cases----------------------- 273 Percent cases----------- 4 2 5 --------- 60 29 Controls--------------------- 615 Percent controls--------- 13 3 7 --------- 53 23 Wynder, et al. (108) : Relative risk------------ 1.0 15.5 27.7 11. 1 24.6 --------- Cases----------------------- 209 Percent cases----------- .5 8 5 1 86 --------- Controls--------------------- 209 Percent controls--------- 11 10 4 2 74 --------- Wynder, et al. (118) : Relative risk------------ 1.0 9.7 4.5 --------- 6.3 6.3 Cases----------------------- 60 Percent cases----------- 5 17 15 --------- 47 17 Controls--------------------- 271 Percent controls --------- 24 9 16 --------- 36 13 Wynder, et al. (116) : Relative risk----------- 1.0 14.5 16.0 --------- 22.0 16.0 Cases----------------------- 142 Percent cases----------- 1 20 1 --------- 62 16 Controls--------------------- 220 Percent controis--------- 16 22 1 --------- 45 16 A f. 9.7 i SSVV94EO

9gVV944C0 _ __ia---- Pernu (73): Relative risk------------ 1.0 ___-___-_ 4.5 --------- 8.7 3.2 Cases----------------------- 546 Percentcases-__--______ 7 __--___-_ 4 ____ ----- 78 4 -- Controls--------------------- 713 Percent controls--------- 39 --------- 5 - ---------. 50 7 Staszewski (87): Relative risk------------ _ 1.0 -_____--_ --- 5.9 50.2_ __-____-- Cases----------------------- --- - 207 Percent casee----------- - -- . 5 _-_______ -- 2 88 --------- _-- Controls--------------------- 912 Percent controls--------- 17 --------- 11 61 _______-_ Svoboda (90): Relative risk------------ 1.0 --------- 2. 6 --------- 10.0 --------- Cases----------------------- 205 Percent cases----------- 3 _ 3 --------- 95 --------- Controls--------------------- 320 Percent controls--------- 22 --------- 7 --------- 71 --------- Stell (&&) : Relative risk------------ 1.0 _____-__- 1. 3 2.4 --______- Cases----------------------- _ -- - 190 Percent cases----------- - --- 11 -_____-__ 8 79 --------- Controls_____________________ 190 Percentcontrols--------- 17 ___--_-__ 10 50 ---------

In the prospective epidemiological studies, cigar,, pipe, and cigarette smokers alll had similar mortality ratios f'rom cancer of the esophagus. Hammond and Horn (4D)' combined the categories of carcinoma of the esophagus, lEarynx, pharynx, oral cavity, and lip and described mortality ratios of 5.00 for cigar srnokers, 3.50' for pipe smokers, andl 5.06 for cigarette smokers. Dolll and Hill (26) reported an esophageal' aancer mortality ratio of 2:0'for pipe and cigar smokers„4.8 for mixedl Smokers, and 1.5' for cigarette smokers. Kahn (50) reported the fol- lowing mortality i atias for smoking in various forms cornpared to non- smokers: cigar only, 5,33; pipe only, 1.99;, pipe and cigar, 4.57; all pipes and cigars combined, 4.05; and cigarettes only, 6.17. The results of these prospect.ive studies are summarized in table 24. Several retrospective investigations have also examined the assoeia, tion~ between smoking in various forms and cancer of the esophagus. These studies have been summarized in table 25. The evidence sug- gests that cigar, pipe, and cigarette smokers develop cancer of the esophagus atrates substantially higher than those seen in nonsmokers, and that little dift'erence exists between these rates observed in smokers of'pipes and cigars and cigarettes. Histologic changes in the esophagus in relation~ to smoking in vari- ous forms were investigated by Auerbach, et all (7), who looked for atypical nuclei, disintegrating nuclei, hyperplasia, and hyperactive esophageal glands. A total ofl 12,598 sections were made from tissues obtained fromi 1,268 subjects. For each of t.he parameters investigated, pipe and cigar smokers demonstrated sigmificantl more abnormal histologic changes than nonsmokers; however, these changes were not as severe or as frequent as those seen in cigarette smokers. Several retrospective studies conducted in the I7nitedl States and other countries have examined the synergistic roles of tAbacco use and heavy alcohol intake on the development of cancer of the esophagus. Four ofl these investigations contain data on pipe and cigar smoking (12, 62, 63: 107). It appears that smoking in any form in combination with heavy drinking results in especially high rates of cancer of the esophagus.. TnsLE~ 24.-Morttclity, ratios for cancer of the esophagus in cigar and pipe smokers: A summary of prospective epidemiological studies Smoking type Author, reference Non- smoker Cigar only Pipe only Tbtal pipe and cigar Cigarette only Mixed HammondlandHbrnJ'(40)_ 1.00 5.00 3! 50 -------- 5.06 --_-_--- IDo11 and Hill (.°C6; ,°L7),__,-_ 1.00, -------- ------ 2.00 1.50 4180 Hammondl (3S)---------- --, 1.00 --------, ------ 3: 97 "4. 17 -,------- Kahn (60)'-------------- 1. 00 5.33 1.99 4.05 6. 17 -------- I Combines data for oral, Jarynx,,and esophagus. 2 Mortality ratio for ages 45'to &Sl 200

o; 1 fI-- y ~• 11 m TABLE 25.-Relative risk of cancer of the esoph,dgus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sumrriary of retrospective studies N Q 8gI.I'V9I'f:0 Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number - -------- Nonsmoker ------- - Cigar only Pipe only Total pipe and cigar -- Cigarette only Mixed - Sadowsky, et al. (77): Relative risk------------ 1.0 4.8 3.8 5. 1 3.8 3.3 Cases 104 Percentcases - - -- 4 5 8 6 60 18 ----------------------- _-- -- - --- - Controls--------------------- 615 Pereent controls--------- 13 3 7 4 53 19 Wynder, et al. (118): Relative risk------------ 1.0 3. 1 2. 1 --------- 2.6 . 4 Cases 39 Percent cases - -------- 13 15 18 --------- 51 3 ----------------------- --- - - Controls--------------------- 115 Percent controls --------- 24 9 16 --------- 36 13 Pernu (73) : a Relative risk------------ 1.0 --------- 3.0 --------- 2.7 5.9 Cases 202 Percent cases----------- 17 --------- 7 --------- 59 18 ----------------------- ---- Controls--------------------- 713 Percent controls --------- 39 --------- 5 --------- 50 7 Schwartz, et al. (84): Relative risk------------ 1.0 --------- 2.6 --------- 11.7 8.6 Cases----------------------- 249 Percent cases----------- 2 --------- 2 --------- 88 7 Controls--------------------- 249 Percentcontrois--------- 18 --------- 7 --------- 67 7 Wynder and Bross (107): Relative risk------------ 1.0 3.6 9.0 6.0 2.8 3.7 Cases----------------------- 150 Percent cases----------- - 5 19 9 4 51 11 Controls--------------------- 150 Percent controls--------- 15 16 3 2 55 9 ,.

N 0 N TABLE 25-Relative risk of cancer of the esoph,agus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies.-.-Continued Author reference Number Bradshaw and Schonland (12): Cases----------------------- 117 Controls--------------------- 366 Martinez ( 62) ; Cases----------------------- 120 Controls--------------------- 360 Martinez ! (63): Cases----------------------- 346 Controls-------------------- 346 Relative risk ratio and percentage of eases and controls by type of smoking Nonsmoker Relative risk------------ 1.0 Percenteases 15 ----------- - Percent controls--------- 32 Relative risk------------ 1.0 Percentcases----------- 8 Percent controls--------- 14 Relative risk------------ 1.0 Percentcases----------- 21 Percent controls--------- 22 Cigar only --------- --------- --------- 2.0 9 8 2.0 10 9 Pipe only - Total pipe -and-cigai Cigarette only Mixed 4._ 8_ -------- 2. 3--------- 41 -------- 63 --------- 18 -------- 58 --------- -------- 1.5 2.2 -------- 31 43 -------- 34 34 2.8 -------- 1. 7 2.5 15 -------- 34 34 1 -------- 36 25 I This study combines data for oral cancer and cancer of the esophagus. ~ r ~ ~ ~ + CT n . F ~ m ~ u Z F' ~ .~ ~ O © .., - g urc - Gr ~ y 4; "'7 Q rp ~ ry U v~ n c~ ~D !Y ~ ^'3 n ~ cfl ,..r r 9 m f8~~9~~:0

Lung Gancer. Abund'ant evidence has accumulated from epidemiological~ experi- »iental, and autopsy studies establishing, that cigarette snn.oking is the major cause of lung cancer. Several prospective epidemiological! studies have demonstrated higher lung cancer mortality ratios for pipe and cigar smokers than for nonsmokers, but the risk of d'eveloping,lung cancer for pipe and cigar smokers is less than for cigarette smokers. Table 26 presents a summary of' these prospective studies.Dose- i esponse relationships such as t'hose that helped demonstrate the nature of'the association between cigarette use and lung cancer could not be as thoroughlystudied for pipe and' cigar smokers because of the rela- tiv ely few smokers in these categories. Although the number of deaths were few,,Doll and Hill (26) reported increased death, rates from lung, cancer for pipe and cigar smokers with increasing tobacco consump- tion (tablE27)..Kahn (50) also demonstrated a dose-response relation- ship for lung cancer by the amount smoked (table 28). A few of the retrospective studies contained enough smokers to allow an examination of dose-response relationships for pi'pe an:d cigar smok- ing and lung cancer (1, 61, 74; 77). An increasedi risk of developing lung cancer was demonstrated with the increased use of pipes and cigars as measured' by amount smoked and inhalation. The retrospec- tive i'nv estigation of Abelin, and Gsell (1) is of particular interest, The smoking habits of 118 male patients with cancer of the hing from a rural' area of Switzerland were compared with those reported in a sur- vey of' all male inhabitants ofl a~ tawn ini the same ree on. About 20~ percent of the population of this: area were regular cigar smokers, the nlost'popular cigar being the Stumpen, asmald S~viss-made machine- manufactured cigar cut at both, ends with an average weight of 4.5 g. Iln this investigation, cigar smokers experienced a risk of developing lung cancer that was similar to the risk of cigarette smokers. A dose- response relationship was demonstrated for inhalation and amount smoked. These data suggest that the heavy smoking of certain cigars may result in a risk of lung cancer that is similar to that experienced by cigarette smokers. Several pathologists have reported histologic changes in the bronchiall epithelium in relation to~smoking in various forms:Knudt- son (57)~ examined the bronchial mucosa ofl 150 lungs removed at au- topsyy and correlated the histologic changes note.dl with the history of smoking, age, occupation, and residence. Specimens obtained from the six cigar, and pipe smokers demonstrated basal cell hyperplasia;; however, there was no squanious or atypicali proliferative metiaplasiaa as is frequently seen in the heavy cigarette smokers. Sanderud (78) examined histologic sections from the bronchiali tree of' 100 male autopsy cases for the presence of' squamous epithelial. 203 1

metaplasia. In this study, 39 percent of the populittioni were non- smokers, 20 percent were pipe smokers,, and 38 percent smoked cig- arettes: A total of 80 percent of the pipe smokers and cigarette smokers diemonstrated squamous metaplasia of'the bronchial.t'ree, whereas only 54 percent of'the nonsmokersl2ad this abnormality. Auerbachy, et al.(6), examined 3~6;340histologiic sect'iionsobtainedfrom 1,522! white adul'tsfbr variousepithelial lesions including: presence or absence of'cil'iated cell§, thicknes&or number of'cell rows, atypical nuclei, and the proportiom of cel2s of' various types. The pathologic findings in the bronchial epit.helium, of pipe and cigar smokers are compared to those found in nonsmokers and cigarette smokers (table 25)!. Pipe and cigar smokers had abnormalities that were'intermediat,e'between thoseof'nonsmokersand cigaret't~esmokers;although cigar smokers had pathologic changes that in some categories approached the changes seen~ in cigarette smokers. TnBLn~ 26~.-Mortality, ratios~~ for' lu~n.g, cancer deatlts ' in male, ~ cigar and'~ pipe smokers: A summary of ' prospective studies Auth fe Type of smoking or, ,re renoe Non- smoker Cigar only Pip' a only Totl;l'pipe and cigar Cigarette Di~iaed' only. Hammond and'Horn (40)- 1. 00, 3,35 ' 8.50 -------- 23, 12 19.71 Doll and Hill (26, 27)--,-- 1. 00' -------- -----,- 6. 14 13.29 7: 43' Best (8)' --------------- 1.00 2.94 4.35 -------- 14.91 -------- Hammond (38) ---------- 1.00 1.85 I 2.24 1.97 9: M 7.39 Kahn (6.q)-------------- 1.00 1. 59! 1.84 1.67 12. 14 -------- TAByE 27.-Lung cancer death rdtes for cigar and pipe smokers by dmount smoked -Doll dnd' Kzll 8inoking type Death rate per 100 Number of deaths 1wTonsmoker-----------------------,---------- 0. 07 3 Cigar, and pipe: I to 14 g. per day----------------------- .42 42 12 15't&24 g. per day---------------------- .45 6 >24 g;,per day------------------------- . 96 3 Cigarette only------------------------------ .96 14'3' 8ource: Doll, R., Hill, A. B: (t6). . 'I?:~, I L'ip( 204

Tns>:;E2'8:-Lung, cancer mortality ratios for cigar and pipe smokers by am ount' sm oked-KaJtn ined ing: o`ss, The igar rette that kers, )riess ted i 9: 71 7.43' 7. 39 xunt 3' 12 6 3 143 Smoking ,type Mortality ratio Number of deaths ti onsmoker--------------------------------- 1. 00, 78' Cigaar smokers: <5: cigars per day'----------------------- ll 14 12' 5 to 8' cigars per day--------------------,- 2.64 11' >8 cigars per day----------------------- 2.07 2 Pipe smokers: <5 pipeful§ per day--------------------- .17' 2~~. 5 to 19 pipefuls per day------------------ 2.20 12 > 1'9' pipefuls per day-------------------- 2.47 3 Cigar and pipe: 8 or less cigars, 19 or less pipefuls-------_- 1.62 ' 18 >8 cigars, >19 pipefuls------------------ 2'. 19 2' Source: Kahn, H.,A. (50).

TABLE 29.-Relative risk of lung cancer for men, comparing cigar, pipe, and_ cigarette smokers ?/I2th nonsmokers. .okers. A sum- mary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number - __- Nonsmoker Cigar only - Pipe_ only Total pipe and cigar Cigarette Mized only Levin, et al. (60) : Relative risk-- - -- - ---------- 1.0 0.7 0.8 --------- 2. 1-__--_-__ --------- Cases----------------------- --- 236 Percent cases- ---------- 15 11 14 --------- 66 --------- Controls_____________________ 481 Percent contro ls--------- 22 23 25 --------- 44 ________- Schrek, et al. (81): Relative risk-- ---------- 1.0 . 6 .7 --------- 1. 7_________ --------- Cases 82 Percent cases 15 4 5 61 ----------------------- - ---------- - --------- __-__-___ --- Controls____________________ 522 Percent contro ls--------- 22 23 11 --------- 59 __-__-_-- Wynder and Graham (111): Relative risk 1.0 5. 1 3 6 - 15.7 -- -- ---------- - - . ______-__ __---__- Cases----------------------- 605 Percent cases- ---------- 1 4 4 --------- 91 --------- Controls-------------------- 780 Percent contro ls--------- 15 8 12 --------- 65 --------- Doll and Hill (25): Relative risk-- ---------- 1.0 -----_ --------- 5. 1--------- 9.6 -______-- --------- Cases----------------------- --- 1,357 Percent cases- - ---------- .5 --------- 4 - --------- 74 --------- Controls--------------------- 1,357 Percent contro ls--------- 5 --------- 7 --------- 69 --------- Koulumies (56) : Relative risk-- ---------- 1.0 - - --------- 9.6 --------- --------- 29.3 --------- Cases----------------------- --- 812 Percent cases- ---------- •6 -- --------- 2 --------- 77 --------- Controls-------------------- 300 Percent eontro ls--------- 18 --------- 6 --------- 76 --------- Sadowsky, et al. (77) : Relative risk-- ---------- 1._ 0 2.4 1._ 4_-_____-_ 3._ 7 5.6 Cases----------------------- 477 Percent cases- ---------- 4 --- 2 3 --------- ------ 57 31 - Controls_____________________ 615 Percent control s--------- 13 3 7 --------- 53 19 A !l..1.•livr r%~k 1.0 4.0 - M7V94C0

0 V ---- --- --- - - - 477 Percent cases Controls 4 615 Percent controls____ 2 -- 13 .1 Wynder and Cornfield (110): Cases ----------------------- Controls _- Controls--------------------- Randig (74): Cases----------------------- Controls_____________________ fi3 133 415 381 Mills and Porter (65): Cases----------------------- 444 Controls_____________________ 430 Mills and Porter (66): Cases----------------------- 484 Controls_____________________ 1,588 Schwartz and Denoix (82); Cases----------------------- 430 Controls --------------------- 430 Stocks (89): Cases----------------------- 2,101 _ _--- Controls--------------------- 5,960 Lombard and Snegireff (61): Cases----------------------- 500 Controls_____________________ 1,839 Pernu (7g): Cases----------------------- 1,477 -- Controls--------------------- 713 Relative risk____________ -- Percentcases___________ Percent controls_________ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ _---- Percentcases___________ Percent controls_________ Relative risk____________ - Percent cases___________ Percent controls_________ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ - Percent cases___________ Percent controls_________ Relative risk____________ Percent cases___________ Percent controls_________ Relative risk____________ Percent eases___________ Percent controls_ _ _ _ _ _ _ _ _ Relative risk_ _ _ _ _ _ _ _ _ _ _ _ Percent cases___________ Percent controls_ - _ _ _ _ _ _ _ Reiative risk_ _ _ _ _ _ _ _ _ _ _ _ - - Perc-ent cases___________ Percent controls_________ 3 ------- 57 31 7 --------- 53 19 1.0 2.5 4.0 _________ 4 13 6 ___-_-__- 21 27 8 _________ 1.0 5.3 5.0 -_-__-_-- 1 21 11 __________ 6 19 11 ___ __ 1.0 --------- -------- 7 --------- -------- -- 31 --------- -------- 1.0 --------- -------- 8 --------- -------- --- 28 --------- -------- 1. 0 --------- 1 11 1.0 --------- 2 --------- 9 --------- 8.5 --------- 77 ___- 45 --------- 5. 0 --------- 67 --------- 64 --------- 6.0 5.4 _________ 37 55 --------- 26 43 2. 8 4. _5 _________ 13 78 --------- 16 57 _________ 4. 7 --------- 13.5 --------- --- 6 --------- 96 --------- 14 --------- 78 --------- 3. 1 --------- 5.0 --------- ---- - - - Q --------- 89 --------- 13 --------- 78 --------- 1.0 --------- -------- 2 --------- -------- --- 10 --------- -------- 1.7 8.1 _________ 4 95 _____ 15 75 _________ 1.0 --------- 4.2 --------- 9.2 11. 1 7 4 --------- 77 13 -- - 39 --------- 5 --------- 50 7 '-~..~-.....~..-..«: '3 : MME0

S6VV9LCQ TABLE 29.-Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies-Continued Author, reference Number Relative risk ratio and percentage of cases and controls by type of smoking Nonsmoker Cigar only ~ --- -- - Pipe only ~ Total pipe and ctgar Cigarette only Mixed Wieken (106): Relative risk------------ 1.0 --------- - -------- 2.2 4.3 4.2 Cases 803 Percent cases 4 10 78 7 ------------------------- ------- ----------- --------- -------- Controls----------------------- 803 Percent controls--------- 14 --------- -------- 16 64 6 Abelin and Gsell (1) : Relative risk------------ 1.0 30.7 21.8 39.9 31.0 24.7 Cases 118 __ Percent cases 2 28 7 58 25 24 ------------------------- ---- -- ----------- Controls----------------------- 524 Percent eontrols--------- 35 19 6 31 17 10 Wynder, et al. (115) : Relative risk------------ - - 1.0 --------- -------- 2.0 12.4 --------- --- Cases------------------------- 210 -- Percent cases ----------- 3 --------- -------- 5 92 ---- Controls----------------------- 420 Percent controis--------- 21 --------- -------- 15 47 ,.

TABLE 30.-Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to no71smoker$ N O Group Number of subjects Percent sections Sections with with epltheliai epitheliuum- lesions Percent 3 plus cell rows with cilia Percent atypical cells present Total sections Percent hyperplasfe and goblet cells in glands ~ 1st set (none vs. pipe vs. cigarette-_matched on 1:1 basis) : i+Tonsmoker---------------------------- - - - 20 985 21.7 11.2 2.6 1,031 10.3 Pipe only ------------------------------ 20 924 65.5 38. 1 37.0 979 35.9 Cigarette only------------------------- 20 914 96.8 88.6 95.2 982 72.1 2d set (none vs. pipe vs. cigarette-matched on frequency basis) : Nonsmoker---------------------------- 25 1,246 22.9 13.4 . 7 1,277 11.5 Pipe only---------.---------.------------ - 25 1,164 68.7 38.7 38.2 1,247 37.9 Cigarette only------------------------- 25 1,126 96.3 88.7 99.5 1,237 75.5 3d set (none vs. cigar vs. cigarette) : Nonsmoker---------------------------- _ _ - 35 1,706 27.4 12.7 . 8 1,748 15.3 Cigar only-------.---------.------------- 35 1,733 90.8 40.0 73.6 1,828 52.5 Cigarette only------------------------- 35 1,526 99.0 92.7 97.8 1,693 80.2 Source: Auerbach et al. (6). - ~=~:;',t ^ .- __ . __~---_ 96VV94c0

Tiimorigenic Activity The tumorigenic activity of tobacco smoke can be modi,fi'ed ia1~ both a quant'itat.iveand' qualitati'vesense. Physical or chemical changesimtobacco that result in a reduction of' total particulate matter upon combusion of a given quantity of tobacco may result in a reductionn of carcinogenic potential. Suchi factors as tobacco selection, treatment, blendi~ng;cut, and' addit.ivesmay quantit'ativelyaltertar~ production.. Wrapper porosity and filtration, may also affect tar production. Quantitative changEs in the tumorigenic activity of tobacco tar on a gram-for-gram basis can be producedl by the selection and treatmentt of'tobacco,,the use of additives or tobacco sfieets; or adjustments in the cut and packing,density.C'ombustion temperature can also produce quantlitative changes in the particulate matter of tobacco smoke. Although high-temperature burning producesIess particulate matter in the smoke, i't appearsthat tumorigenic components occur in higher concentration when tobacco is pyrolizedi at'tlemperat'uresliigher than 70p° centigrad'e(;34). Cigars, pipes, and cigarettes are similar in that they are smoked orallyy and have a common site of introduction to the body. The tissues of the mouth,, larynx, pharynx, andl esophagus appear to receive ap- proximately equal exposure to the smoke of these products: Inlialationn causes smoke to be dlrawn deeply into the lungs and also allows for systemiic absorption of' certain constlituent:sof tobacco: smoke which then can be carried further to other organs. Pipe tobacco and cigars vary from cigarettes in a number of charac- teristics that can produce both quantitative and qualitative changes i'n the total particulate matter produced by their combustion. Experi- mental evidence suggests that althoughthere is some difference in the amount and quality of tar prodiucedl by cigars, this cannot account for the reduced mortality observed'' i'n cigar smokers compared to cigarettee smokers.. Experimental Studies Several experimental, investigations have been conducted to examine the relative tumorigenic activity of tobacco smok- condensates obtained from cigarettes, cigars, and pipes.llTost of these studies were standard- ized in aniattempt to make tlie results of the cigar andlpilpe experiments more directly comparable with the cigarette data and most used the shaved skin of mice for the applieation of tar. Tars from cigars, pipes,and cigarettes were usually applied on an equal weight basis so that qualitative differences in the tars could: be determined. In sev.eral ex- periments„the nicotine «-asextracted from the pipe and cigar conden- sates inani attempt to reduce the acute toxic effects that resulted inn animals, from the high concentrations of' nicotine frequently fonnd in these.prodnct'se zio.

Aha %s inn ipon ;tion aent, tion.. x on nent ithe hs in. ;ture that co is )ked 6ues ap_ t:iion i for hich irac - % in ,)eri- tkle for rette nine i'nedl ard- ents rithe lpesi that eg- len- i in I in Wynder and' Wright (117) examined the differences in tumorigenic activity ~ of~~ pipe and cigarette condiensates. Tars~ were~ obtained by ~ the~ smoking of a popular brand of king-size cigarettes and the same ciga- rette tobacco smoked in 12 standard-grade briar bowl pipes. Both the cigar.ettes~ and pipes~were~ puffed three~ times a minute~ with a,2'-secondd puff! and a35-ml. volmne. Both the~ cigarettes~~ andl pi'pes~attained similar masilnum combustion zone temperatures; however, the use of cigarette tobacco in the pipe resulted in a combustion chamber temperature that averaged~ about 150~°'centigrade~ higller~than temperatures, achieved when pipe tobacco was uscdL Chemical fractionation was accomplished and equal concentrations of the neutral fraction were applied i'n threee weekly applications to~ the~ shaved skin of~ CW1F, and Swiss mice. The~ results~indicate,that neutral tar obtainedif'rom, cigarette~tobacco~ smoked, in piipes, is more activ~e~tl7an that obtained in the~usual manner from~ cigarettes. About twice as many-. cancers.vere obtained in both the CAFl and the~ Swiss~mice,~ and t'he~ latent period was~~ about~2 months shorter.. Extending these data, Croninger, et~a]. (20)~ examined the~ biologic: activity~ ofl tars obtained from, cigars,~ pipes, and cigarettes., Each form . of tobacco was~~slnoked as~it was~rmnu~factured in a manner tolsimulateI 11nm~ani smoking or to~ maintain tobacco combustion. The whole~ta.r was~ applied in, dilutions of one-to-one~ andl one~-to-two~ with acetone~ to~ th~e~ shav ed backs of female CAF;, andl female Swiss mice using three .~l~hlications~each~ ~~ eek~for the life-span span of'the~ animal. The ni eotine~~ ~ti ~as~ extracted from~ the~~ pipe and cigar~ condensates~~ to~ reduceI the acute toxicity of~the solutions. The Swiss mice,,pipe~„cigar, andci~garette~tars produced both benign and m~alignant tuinors: The incidence irates~~ of' maligfil~Uat tumors given as:percent''~s z~ ere~: 44„411, and 37; respectively~. These resnlts suggested a somewhat higher degree of carcinogenic activity ~ for cigar and pipe ~ t~a rs thani for cigarette tlair: Similar~ results were~ reported by Kensler (53): who~applied conden- sates obtained from cigars ancL cigare:ttes, tl the shaved skin of~ mice: The incidence of papillomas produced by cigar smokee concentrate was no~~ different from~ that of~ theI cigarette~ smoke~ condensate. Similarliy;~ there~ «-as~~no~ difference between cigar and cigarette~smoke~condensates when caT•ci~noma~ inci~dences~were connpared.. Homburger„et a~~lL (.1.:.~)~, prepared tars~from cigar,,pipe,,and cigarette toiaecos~ that were smoked in the fQrm of cigarettes. ]fni this~ way„ all tobaccos were smoked~~ in an identicall manner~and uniform combustion temperatures~ «ere~ achieved.~ Recause~~ of this stlanelardivation,~ diff~er-~ ences~ in tumor~ yield could be attributed to~ tobacco blend~ and not the~ manner in which the~ tars~ were, prepared. The~ whole tars were diluted one-to-one «ith, acetone and applied! to the shavecl, skin of~ CAF, mice three~ tiines a.i•eek for the lifespan of~ the test animal. Skin, cancers~ were~~ produced more quiekly.~ with pipe: andl cigar smol:e condensates than~ with cigarette smake~ condellsat'es. This~suggests~that~the~ smoking~ 495-028 0-73-15' 2' 1 1' t' I a, i ; r I

of' pipe andi cigar tobaccos in the form of' cigarettes does not alter the condensates to any significantdlegree. Davies and Day (22) prepared tars from small cigars especially manuf'actured from a composite blend of cigar tobacco representing, small cigar brands smoked in the United Kingdom,, cigarettes espe- cially manufactured from the same tobacco used for the cigars de- scribed above, and plaini cigarettes especially manufactured from a cpmpositle~ blend of ' flue-cured tobacco representing the major plain cigarette brands smoked in, the United Kingdom. The whole tar was diluted to four concentration levels and applied to the shaved backs of' female albino mice for their lifespan using four dosing, regimens. A statistically significant increase in mouse skin carcinogenicity was shown with the cigar smoke condensate compared with the tars obtained from eitherflue-cured~ or cigar tobaccociga:rettes. Theseresults are consistent with those of'' the: previously reportedd investigations. The effect of curing on carcinogenicity was examinedl by R'oe„ et al. (76)~. Bright tobacco grown in Mexico was either flue-cured or air- cured and bulk fermented. Both flue-curedand air-cured tobaccos were made into cigarettes standardized for draw resistance and were smokedd u~nder similar, condi'tions. Condensates from thesecigarettes, werea:p- plied to mouse skin three times each week in an, acetone solut'.ion. The development of'skin, tumors«-as, higher in mice treated with! the flue- cured condensate than in mice treated with the air-cured condensate (P'<O:Q1'1). The dilff.erence may have been due to the use of equal weights of condensate rather than the use of extracts from an equall number of cigarettes. Theaiir-cured cigarettes~ produced a, greater weight of' condensa;tethani didi t!he~ flue-cured cigarettes. A chemical analysi'sof the two tobaccos and two condensates revealed only sma111 differences in composition. Evidently air curing of Bright tobacco in the methodl usedl is nott associated' with a loss of reducing sugars. A more detailed analysis of these experimental studies is~ presentedl initable 31. These experimental data suggest that cigRr and pipe tobacco con- densates,havea carcinogenic potential that is comparabletocigarettecondensates.Thisissiihport~ed byhuman, epidt;miologiical data for thosesitesexposedequallyt'o tli:esmoke of cigars, pi~pes, and cigarettes.The partially alkaline smoke derivedl fromi pipes and cigars is gen- erally nott inhaled,, and as a result there appears to~ be a lower level ofexposureof the lungs and other systems totlie harmful properties of pipe and cigar smoke tha,n, occurs u•ithcigarette smok~iiig.ftis~ antic~-ipatled that 1nodificationsin pipetobaccolor cigarswhich would result in al product that was more readily inhalablewould eventually result in elevated mortality fromicaneeraf the liuig,, bronchitis,an:d emphy- sema, arterioscleroticcardi,ovascu~lar diseases, and the other condi~tions which have been clearly associated with cigarette smoking. 212'

[II -- - ~-~ ~ ~"'~_ .. n ~ .~ .,~ ... ..... _ _~. .-__--- '1- iC 0 -~ R' [~n ~ U~1 ~ ~ ~ ~ ~ ~ ~ ~ @ s TASLE 3 1.- Tumorigenic acti7lity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals (Key: A=Method. B=Frequency. C=Duration. D=Material.) Percent Author, reference Animal Activity Treatment Number Papillomas Carcinomas Wynder and Wright CAFI and Swiss mice. A. Painting shaved skin. B. 3 times a week. CAF1: Pipe (cigarette tobacco)___-_- 30 60 20 (117). -- - C. Lifespan_ (24 months). --- Cigarette------------------- 30 30 3 D. Neutral fractiop tar from cigarettes and cigarette Swiss: Pipe (cigarette tobacco)___-__ 30 63 50 tobacco smoked in pipes. Cigarette------------------- 30 63 33 Croninger, et Female Swiss A. Painting shaved skin. Cigar, nicotine free (1:1) ------- 46 65 41 al. (20). mice. B. 3 times a week. Pipe, nicotine free (1:1)-------- 45 71 44 C. Lifespan. Cigar (1:2)___________________ 78 33 18 D. Whole tar diluted in Pipe, nicotine free (1:2)-------- 89 30 16 acetone. Cigarette (1:1)---------------- 86 47 37 Acetone controls______________ 23 0 0 Kensler (6$)__-_ Swiss mice______ A. Painting shaved skin. Cigar tar (J) 100 mg. per week__ 100 42 41 B. 3 times a week. Cigarette tar (G) 100 mg. per 100 40 28 C. Lifespan. week. D. Whole tar diluted in Cigarette tar (E) 100 mg. per - 100 34 34 acetone. week. OOSV9,GCp N Y t .

N A I03 V 9& f;0 TABLE 31.-Tu7no7"igenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals-Continued (Key: A=Method. B=_h'requency. C=lluration. L)=Material.] Author, reference Animal Activity Homburger, et CAF, mice------ A. Painting shaved skin. - al. (45). B. 2 to 3 times a week. C. Lifespan (2 years). 1?. Whole tar diluted 50 per- cent in acetone. Davies and Female albino A. Painting shaved skin. Day (22). mice. B. Varied. C. 116 weeks. D. Whole tar in 150 mg. - acetone. Roe, et al. Female Swiss A. Painting shaved skin. (76). mice. B. 3 times a week. C. Lifespan. D. Whole tar diluted in acetone. Treatment Number Percent Papillomas Carcinomas Cigar tobacco cigarettes t 65 mg. 100 37.5 19 per week. Pipe tobacco cigarettes t 64_ ing. 100 23 20 per week. Cigarettes' 62 nig. per week---- 100 15 23 Acetone controls-------------- 100 0 0 Cigars, small 83 mm. long 150 144 44 27 per week. Cigar tobacco cigarettes 150 72 32 14 per week. Cigarettes 150 per week-------- 144 28 13 Flue-cured Bright tobacco 180 400 52 30 - mg. per week, Air-cured Bright tobacco 180 400 68 23 mg. per week. Acetone controls 0.75 cc. per 400 1. 3 0.5 week. I Cigar, pipe, and cigarette tobacco smoked as cigarettes ut similar combustion temperatures. 1. 1

(.riAl¢DIovAscUL-1R DT6FZASE,4'. . r* The majority of deaths in the United St'ates each year are due to cardiovascular diseases. Cigarette smoking has been identified as aa major risk factor for the development of coronary heart disease (~CHD). However, pipe and cigar smokers experience only a small increase in mortality from, coronary heart disease above the rates of nonsmokers. Cigarette smokers have higher death rates from cerebro- vascular disease thannonsmokers, .vhereas pipe and cigar smokers have cerebrovascular death rates that are only sligkrtly above the rates of nonsmokers.. Table 32 summarizes the major prospectiv e epidemiologi- cal inv estigations that eramined the association of smoking in various forms and total cardiovascular diseases, coronary heart disease, and cerebrovasculardi'sease: Doll and, Hill. (w8), Best (9), and Kahn (50)~, examined dose-responserelat'ionshspsfor pipe and cigar smokers andG reported a slight increase in mortality from~ coronary: heart disease with an increase i:n the number of'ci'garss or pipefuls smoked. Other prospective epidemiological studies have also examined the relationship of smoking in various forms to coronary heart disease and related riskfactors: Jenkins, et al.(19)in the Western Collaborative OroupStudy of coronary heart disease, reportedl an incidence of' coro- nary heart disease in men aged 50 to 59 whowere pipe and cigar smok- ers that `vas intermediate between the rates seen in cigarette smokers and nonsmokers. No ~increase in incidence of coronary heart disease was seen arnong; the pipe andr cigar smokers in the younger age groups.. Shapiro, et al. (8a.), in a study of' the: health insurance plan (HIP') population, reported incid'ence rates for myocardsal infarction, angina pectoris, and possibleMI, in pipe and cigar smokers that were similar tio the incidence rates seen in cigarette smokers. These rates were con- siderably higher than those of nonsmokers. Data from the pooling project (47) suggested that the incidence of CHD deaths, sudden death, and the first major coronary event in pipe and cigar smokers was intermediate between the incidence experienced by cigarette smok- ers and nonsmokers. In contrast to these stud'ies; Doyle,, et al. (30) reported no increase in CHD deaths; myocardial infarction„or angina~ pectoris in pipe and cigar smokers over the rates of nonsmokers in the Framingham study. The retrospective studies of Mills and Porter (64), Villiger and Heyden-Stucky (104), Schimmler, et al. (80):, and Hkood,, et al. (!I;6:)i contained' data suggesting that pipe and cigar smokers experience mortality rates from coronary heart disease that are essentially similar to those esper.ienced by cigarette smokers. The retrospective study of' Spain and Nathan (86) reported lower ratesof' coronaryheart dis- ease in all smok~ing, categories than were: found in nonsrnokers,Van Buchem (103), and Dawber, et al. (23): examined serumcholes-terollevels, in groups of individuals classified accord'hng to, sm,oking 215 I i E

habits., In theset'wostudies; pipe and cigar smokershad serumclioles, terol let-els that were nearlly irlentiical with the levels found in nonsmokers. Tibblin (91) and Dawber,,et al. (23)1 investigated tllie~effect'of'smok- ing on blood pressure. The proportion of smokers d'ecreased in groups with higher blood pressures, although this was not as dramatic for pipe and cigar smokers as it .vas'for cigarette smokers: IIn an experimental study using anesthetized dogs, Kershbaum and Bellet (54, 55): examined the effect's of inhaledl and noninhaled ciga- rette; cigar, and& pipe smoke on serum free fattyy acid levels and urinary catecholamine and nicotine eieretiom In this study, inhalation of to- bacco smoke from all these sources resulted in similar increases in serum free fatty acids and in catecholamine and nicotine excretion. TABLE 32. 1l2ortad2ty, ratios for cardiavascular d'edths in: male cigar and ' pipe smokers, A summary, of prospective epidemiological st'udies Author, reference Category Type of'smoking Non- Cigar smoker only Pipe only Total Clga- pipe,and rette only 14fYaed cigar Hammond and Cardiovascular 1. W 1.26 1.07 ' ------ 1.57 _____- Horn, (40). total. Coronary----------- 1.00 1.28 ' 1.03 ' ------ 1.,70' _-__-_. Cerebrovascular-_ _ _ _ 1.00 1.31 1.23 ' _ - _- - _ 1.30 _ _ _ _ _ _ Dol'Landi Hill' Cardiovascular 1.00 ----- ------ 0.99 1.26 1.13' (26, 27). total. Coronary----------- L 00 ----- ------ .941 1.23 ' 1. 18 Cerebrovascular-_--_ 1.00 ----- ------ .95 1. 13 .97 Best (9) -------- Cardiovascular 1.00 1. 14' .95 ------ 1. 52 __-_-_ total. Coronary----------- 1'.00 .99 1.00 ------ 1.60 -_--__ Hammond ~ Cerebrovascular_-_-_ Cardiovascular 1.00 11 ' 28 1. 00 ----- .85 ------ ------ .88 U. 06 ll 90 _--___ (38). total; Coronary.----------- 1. 00 1.35 11. 19 ------ 1'.84 1.58 Cerebrovascular__--_ 1.00 ----- ------ 1.09 1'.41 1.40' Kahn (50)------ Cardiovascular 1.00 1. 05 1'. 06 1! 05' ll 75 ____-- tot!al. Coronary----------- 1. 00, 1.04 11. 08 IL 05 ll 74 -___-_ Cerebrovascular~___-- 1. 00 1.08 11. 09 1L 06 L 52' __---_, I Mf ortality. rat i.os ~{or ages~ 5'b to 64~4 only, are,. presented . CHRONIC OFBS"rRi;('TIi\'E PUL3fON:1RY DISE.aSE ((iO!PD)'. Chronic bronehiti~s~and pulmonary emphysema account for most of the, morbidity: and~, mortality from chronic respiratory disease in~ the~ L7nit~~ed titates. Ciga~rette snookers~ have~ higher deat1l, rates fi•om~ thesc~ ;i 216. O ~ ~ ~ ~ ~ 0 ~

diseases and have more pulmonary symptloms and impaired pul- monary function than nonsmokers. Cigarette smokers also have more frequent and more severe respiratory infections than nonsmokers. The relationship between smoking, pipes andi cigars and these diseases is summarized in tliis chapter. The major prospective epidlemio3ogical studies are summarized in table 33, In a retrospective studly of' 1,189! males, andl matched controls in Northern Ineland,Wicken (106.)~ investigated smoking in various forms~and mortality from bronchitis. Th~erelativerisk ratios com- pared to nonsmokers for mortality f'rom, chronic bronchitis were 1.98for all smokers. 1.55 for pipe and eigar smokers, 2.25 for cigarette smokers, and 1.49 for mixed smokers. Nroma review of these prospective and retrospective studies, it from appears~~ that pipe andl cigar~ srnokers ex'perience~ mortalit~y~ rates~~ , a - 11 1,.. ,.1,;4: 111 ll. tih,,+T, ,~h fli. ML.,. .,E., r.Fl I 11 .< .......... .... „LLZ.,,~~~...,u ..,..u .. ,.,~,.~~ .,. .., ...~ ....~., .,~ ...,.. I . I smok,ers~., Although, these mo~ra~lrity.~ rates~ approach those of' ci'gare,tte~~ smokers, in most iiist~ances~ they are~ intermediate between the rat'es~ of cigarette smokers and nonsmokers. i d Pipe and cigar smokers have significantly more respiratorysymp- r toms andl illnesses! than nonsmokers. Those, studieswh,ich contain data on pipe and cigar smoking as relatedl torespir•atorysymptomsaresummarized in table :34. Only a few studies have examined pulmonary function in pipe and cigar smokers. There appearsta be little ditFerence in pubuonary func- tion~ values for pipe and cigar smokers as compared to nonsmokers 0 t bll 5 e a ). ( s ~ ~7 + Naeye (67) conducted an autopsy study on 322 Appalachian coal' ~ workers who were classified according to the type of coal mined and tobaccousage: Eznphysemawas slightly greaterin cigarettesmokers, as were anatomic evidences of chronic bronchitis and bronchiolitis. '1L' hose chan es found in l e and cr ar smokers were intermediate g p p g I ~ between those of cigarette smoking, miners and nonsmoking msners. 5gChanges in~ pulmonary histology in relatiorr to smoking habitsandl i b ib l d b A h l i l age wereexani uer ros s; a arrupturer ne y ac et a (8) veo ~,.i. r thickening of the wallsofslmlll arteries, and thic.keningof the walls of the pulmonarti-aiteriol'es were found tobehighly relatedl to thee smoking habits of'the 1,340 male subjects examined. The 91 pipe and cigar smokers over the age of 60 were found to have somewhat more alveolar rupture thani the men of the same age distribution who ~ never smoked regularly. However, pipe and cigar.srnokersas a, groulihael far less rupture than cigarette smokers. The same relations as described above were found for fibrosis, thickening of the walls of the arterioles if and small arteries,~ and pa,dl~ik~e attachments to the alveolar septums. ~e Tobacco~ snioke, has~ beeii shown experimentally ~ to Ilave~ a ci'liostatic e~ffect on t'he~ respirat'oryy epithelium. Tlle~ interval between pulls, the~ 2117

amount of volatile and particulate compounds in the smoke, andi the exposure volume have been shown to infl'uence the toxic effect of' tobacco smoke. Dalhamn andl Rylander (2Z ) exposed the upper trachea of anesthetized cats to the smoke of' cigarettes and cigars, observing the effect on ciliary activity through an incident-light microscope. A chemicall analysis of the gas and particulate phases revealedl that the cigar smoke was more alkaline and,, in general, contained higher concentrations of isoprene, aeetone, acetonitrile, toluene, and totall partiiculatematter comparedl tocigarettiesmoke. Tiheaverage number of's puffs required to arrest ciliary activity was found to be 73' for the cigarette smoke and 1114 for the cig ar smoke. The difference is statisti cally. significant (P C0.01). Of the two smokes,,the smoke 'with the highest concentration ofI volztilecompounds was found to be! t ~eleast ciliostatic. This suggests that the degree of ciliotoxicity ofi a, smoke is not necessarily correlated to the level of'one or several of the substances found in the smoke. Passey, et al. (70,71;, 7'M') studied the effect of smoke from flue-cured cigarette tobacco cigarettes and air-cured cigar tobacco cigarettes on the respiratory system of rats: In two separate but similar experi-ments, a total of 48 animals were expo d to. E:nglish cigarette tobacco smoke, IBwereexposed to air-cured cigar tobacco~ smoke, and 12~ were exposed toan air-cured B'unley.tobacco smoke. The rats in groups were exposed to the specific smoke in a snmoke-fillled cabi'net,, Animals ex- posed tolhe smokefromair-cured tlobaccosremained liealthythrough- out the experiments, even at high levels of smoke exposure. The three deathsthat, occurred within, this group were from nonrespiratory causes.Isr kiothiex.periments;the rats exposed t~ocigarettetobacco smoke began todie.rithin 1 or 2 months, and ineach.experiinentmostoftheani'mals died within a,week or two of the first deaths. At autopsythey rats exposed to, flkte-cured tobacco smoke on, gross examination were found tohav.egreatly enlarged lhingsy t'hetrachea wasoft~en full of mucus,and there was evidence of pneumonia. On microscopic examina, tion it, was found thatt the trachea and bronchi contained' purulent celltdarexudiites, evidence of metapl'astic changes;an absence of cilia,, and goblet cell hpyerplasia. Typically; the causeof' death wasalobaror bronchopneumonia. The author concl!uded that, "the smokes of'flue- cured t;obaccosaremore: dangerous to man and to animals than those of'air-cured tobaccosi"' 218

I Unfortunately.; few details were published concerning the method used to expose the animals to the different types of smoke. The fre- quency and duration of exposure were not speciffedy and the extent of actual inhalation of smoke by the different groups of rats was either not determined or not reported. It is also difficultto determine the effect of smoke exposure on the frequency andl severity of respiratory infections when animals are expo5edlto smoke in groups where common exposure occurs. The rat strain used was not identified, but it was noted that animals appeared to suffer from an endemic rat bron- chiectasis. It is not known to what extent epidemics of respiratory infections occurred among these animals. Because of'these difficulties, no firm eoncTusion can be drawn concerning the effect of' smoking flkle- cured or air-cured tobaccos on the incidence of respiratory infections in~ rat's. TABLE 33:-Mortdlity ratios for chronic ob'structive pul'mondry dcatli.s in male cigar dnd pipe smokers. A' summary o`f prospective epidemia logical studies c Type of smoking', Author, reference Categnrry Non- Cigar Pipo Total Cigg- f smoker only only pipe and'rette only Mixed cigar Hammond and COPD total-------- 1.00 1.29 1.77 ----- 2.85 ------ Hbrn (40). Emphysema-------- ---- ----- ----- ----- ------------ Bronchitis---------- ---- ----- ----- ----- ------------ Doll' and Hill, COPD total,-------- ---- ---,-- ----- ----- ------------. (2E, 2'7). Emphysema-------- ---- ----- ----- ----- ------------ Bronchitis---------- 1'.,00 ----- -----, 4.00 7.00 , 6.67 Best (9) -------- COPD totall-------- ---- ----- ----- ----- ------------ Etnphysema. ------- 1L 00 3. 33 . 75 ----- 5.85 ' ------ Btonchit'is---------- 1L 00 3. 57, 2. 11 ----- U 42 Hammond (3b')-- COPD' total-------- ---- ----- ----- ----- ------------ Emphysema,-------- 1.00 ----- -,---,- 1L 37 1 6: 55 -----_ Bronchitis---------- ---- ----- ----- ----- 1 ------------ Kahn (60)------ COPD' total-------- L 00 . 79 2'. 36 .99 99 10.08 08 -----_ Emphysema---_---- 1. 00 11. 24 2. 13 1. 311 14 17 ------. Bronchitis. --------- 1.00 1,.,17 1.28 1.17 4.49 ---,-_-, I Only mortality ratios for ages 55 to 64 are presented. 495'-628 0-73-16 149 ~ ~ ~ ~ ~. ~ ~

TnBL>r 3!4.-P~revalenae of respiratory symptoms ¢ndillness by type of smoking Percent prevalence Author, reference Number and' type oi' Illnesss population 1+1an. Total Ciga• smoker pipe and, rette 1Wfiied cigar only Boake (10)___ Parents of 59 Cough____________ 32' 32' 48: ______. families. Sputum 24 15 20' ______ production. Chest il'lness______ 5 4 5______ Edwards, et 1,737 male Chronic bronchiti& , 17 119' 31 14 al. (38). outpatients. Ashford, et 4,014 male Bronchitis________ 10 1 35 211 37 al. (4). workers in 3 Pneumoconiosis____ 11 t 34 14 2' Scottish collieries., Bower (11')__- 95 male bank Cough------------ 0'' 0: 29' ______ employees: Sputum 8 15 33 ______ production. Wheeze----------- 8' 31 33 ______ Chesti illness------ 15 54 40, ---__- (California). Chest illness 7 6 11 ______ (New York). Chest illness 91 10 12' (California). lInfllienza 28' 24 31 __ _ _ _ _ California. York). patients in Influenza (New 11 21 24 - andl 315 male (C'alifornia).. Wynder, etal. 315 male paL Cough (New 14 33 56 51 (114)L tients in York). New York Cough 22 30 67 66I Densen, et al. 5,287 male Persistent cough_ _ 7 111 25 -_____ (24). postal and Persistent 1'1 16 26, ______, 7;213'male sputumm transit production. workers in Dyspnea.--------- 16' 19, 26' ______ Nlew York Wheeze----------- 14' 21 32'------ City. Chest illness______ 13' 16 18 -_____ Cederlof, et 4,379twinpairs; Cough----------- 4 : 7 17 al ('18). all i.ilS! Ptolonged cough_-_ 2: 4 11 -__,-__ veterans. Bronchitis____-___ 2 3 10 ______ Rimington 411,729 male Chronic bronchitis_ 5. (76), volunteers: 220 1 9 17 __

! TABLE 34.-Preralence of respiratory symptoms and il'lness by type of' smoking-Continued A th f nd t f' b N IDn Percent prevalence r or, re erence u tun er, a ype o population ess Non- Total smoker pipe and cigar Ctgs- rette Mized'd onlp. Comstock, et 670 male tele- Persistent cough_ _ 10 16 41 ______ aii (1'9). phone Persistent 13 20 42' ______ emplbyees~. sputum. Dyspnea_________ 33 39 44'-_____ Chest illness in 14! 18 20 ______ Lef coe and! 310 ma.1e phy- past 3 years. Chronic respirar 9 18 44 ______ Wonnacott (69). sicians in London,, tory disease. Chronickironchitis- 1 12 34 -_____ Ontario: Obstructive hung 1 3 4______ disease. Asthma---------- 7' 3 6 ------ Rhonchi'---------- 0 3' 9'--_-_,_ I 'Figures for pipe only!:. TnBLE 35:-Pulrnondry function a,ulues for cigar and pipe smokers ass comparedto nonsmokers Type of'smoking, Author, reference Number and type of'population Function Pdon. smoker Total pipe and cigar Cigarette only Mixed Ashford, et 4,014 male FEVi.ol _,--___, 3. 39 1 2. 59 3.14 2.62 - I all (J+), ol'demith, workers in~ 3 Scottish collieries., 3,311 active uffmeter---- 13.63 99.26 26 03.44 _-_ __ etall (37). or retired FEVI.o------- 2:99 2.80 2:91 ____,__ longshore- TVC--------- 3. 87 3.68 3.88 ! _--_,__ Comstoek,, men. 670 male FEVi„o------- 3. 12' 3.26 ', 2.82 ____, et al. (19). Lefcoe and! telephone employees. 310 male FEVI,o------- 3.39 3'. 17 3.11 _-__-_ i; Wonnacott physicians MM'F~R liters 4.09 4! 17 3.64 -__-__ ~; F- (69). in London, per second. Ontario. /' I Figures for pipe only, v t 221'

GASDROI'NTESTIN A:L DISORDERS Cigarette smokers have an increasedl prevalence ofpept'ic ulcer d'iseaseandl agreater' peptic ulcer mortality rat'iothan is: . found! in~ nonsmokers. These relationships are: stronger for gastric ulcer than. for duodenal ulcer.Cigarett.e smoking appears to reducee the effective- ness of standardl peptic ulcer treatment regimens and slows therate of' ulicer healing. Cigar and pipe smokers experience higher deathh rates from peptic ulcer disease than nonsmokers. These rates are higher for gastric ulcers than for dluodlenal ulcers butl are some«-hat, less than those: rates experienced by cigarette' smokers. Table 31 presents the mortality ratios f'or'ulcer disease'in.cigar and pipe smokers as reported inthe~prospectiue epidemiol'og ic'al studies.Retrospectiveorcross-sectionall studies by T>rowell (95), Allibonea'nd Flint (2),, Doll, et al. (29), and Ed.rards, et al. (33) containn data on ulcer di'seasein pipesmokersaswelD as:cigarette smokers: hToassociation was found between pipe smoking and ulcer disease in these investi~gations., TABLE 36. 1Y2artality ratios for peptic ulcer disease in male cigar and' pipe smohers: Summary, of prospectiue studies Type~e of'smoking. Aluthor~ reference Illness Non- Cigar smoker only' Pipe only Total pipe and cigar C1ga- rette only Miaedl Hammond and Duodenal ulcer------ 1. 00 0. 25 H' ( 0 1.67 ------ 2:16 _-____ orn 4 ). Doll and Hill Gastric ulcer-------- 1.00 ' ------ ----- 4.00 T. 00 5. 30 ('26; 27). Hammond (38)-- Gastriculcer-------- 1.00 ----- ----- 2.04 2.95 ___,--- Duodenal ulcer------ 1.00 ' ------ ----- .92 2.86 -_-,-_- Kahn (60)------ Gastriculcer-------- - 1.,00: 2,' 90: 2. 84 2. 48, 4.13 _-___- Duodcnal ulcer------ 1. 00' 1. 58 1. 59' 1. 39 2.98 -_-,-__. lLittle Cilgars In the, past year, several new brands of' littlle cigars(weighing, 3 pounds or less per 1,000) have appeared on the nationall market. These eigarette-siaed products, are manufactured, packaged, advert'i'sed, and sold in a manner similar to cigarettes. Little cigars enjoy several legal advantages ouercigarettes ~: ~ They have aceess : to ~ tellevision ad'vertising'; they are taxed by the Federal Government andby most States„at much lower ratesthancigarettes„resulting in a significant price advantage; 222'

5e ;d 11 and they do not carry the warning label required on cigarette pack- ages and in cigarette advertising. A market appears to be developing for these products, as there has recent'ly been a sharp increase in the shipment ofl little cigars destined' fordomestic consumption (table 37). It is important to estimate the potential public health impact of' these little cigars. An adequate epidemiological evalaation~ of the ef- fect of little cigar smoking on health could take 10 or 15~ years and is probably an impractical consideration; however, a review of the epide- miological; autopsy, and experimental data concerning the health~ con- seqtzences of cigarette; pipe, and cigar smoking summarizedl in this and previous reports is helpful' in considering the potential impact onn health of smoking little cigars. An amalysisof' the chemical constit-uents suggests that both cigarettes and cigars contain similar com- pounds in similar concentrations. Two exceptions are redhicing sugars; which are not found in quantity in the fermented tobaccos commonly usedl in cigars, and the pH1 of'the inhalpd~ smoke. The pH of the smoke from U.S. commercial' cigarettes is below 6.2 from the first to the last puff; whereas the smoke f'rom, thelastRaif of'a cigar may reach as high as pH 8 to 9. With increasing pH, nicotine is increasingly present in the smoke as the free base. Skin painting experiments in mice indicate that tumor yields with cigar or pipe "tars" are nearly identical with those obtained witheigarettes "tars~''. In addition,, the epidemiologilcall data suggest that depth of' inhalation probably accounts for the fact that cig<lrettesaresomuch more:harmfnl than cigars and pipesi'n con- tributing to the development of lung cancer, coronary heart disease„ and nonneoplastic respiratory disease. For, such, diseases as cancer of the orallcavity, larynx, andlesophagus, «here smoke from cigars, pipes, and cigarettes is available to the target organ at comparable levels, the mortality ratios are very similar for all three forms of tobacco use. Severali factors, including "tar,"nscotine; andl the pH of the smoke,, probably operateto influence inhalation patterns of' smokers. The relative contribution of individual factors to the inhalability of a tobacco product has not been determined. Smoking those brands of little cigars which can be inhaled by a significant portion of the population in a manner similar to the pres- ent use of cigarettes would probably result in an increased risk of de- veloping, those pulmonary and cardiovascuIar diseases which havee been associated with cigarette smoking. On the other handi,, smoking those little cigars which are used like most large cigars whereby the smoke is rarely inhaled «ouldl probably result in lower rates of' those pulm.onary andl cardiovascular diseases than would be found among cigarette smokers. Only a limited analysis is available comparing the chemical' com- pounds found in little cigars, cigarettes, and large cigars. The FTC ana~lyzed thetair and nicotine content of all the little cigars (34) and . cigarettes (97) currently available on the market. Little cigars have 229 9 a

generally a hig)ier~~ "'tar"' and nicotine levell than~ cigarettes, although~ considerable overlap resul'tls in some little cigar brands having, "tlar"' and nicotine llevels comparable to those of some brands of cigarettes (figs:~ 4 and 5)~. Hoffinann andi Wynder (I4) ' recently~ compared th~~ree~~ brands of little cigars with an unfiltered cigaret.te, a filteredl ci'garette, and a, large cigar. They measured' a number of'smoke constituents, in- cluding: "tar,'7 nicotine, carbon monoxide, carbon dioxide, reducing sugars, hydrogen cyanide, acetaldehyde, acrolein; pyridines, phenols,, benz(a)anthracene~,-and benzo(a)'pyrene (table 32). Cigarette A was the Kentucky reference cigarette, cigarette Bwas a popular brand of' filter cigarette. Cigar A was an 85' mm. little cigar, cigar B was an. 85 mm. little cigar, cigar C was a 95 mm~ small cigar, and cigar D was~ a 112 mm. popular brand of' medium sized cigar. The~ srnoke~ pH~ was analyzed pu~~fE~ by puff~ (tabl!e~ 39). Cigaret'tle~~ smoke was found to be acidiie (',pI-I less than 7) for the entire cigarette. The~ smoke from little~ cigarsbecam~e~ alkaline~ only ~ in~ the last~ puff or two, whereas about the, last 40 percent of'thepuffs from the larger cigan~were alkaline. Although the~pHl~of the~tlot~all condensate obtai~ned' from~ cigarettes~ is usually' ~ acidic and the totall cond'ensate~ obtained from cigars is usually alkaline, the above data indicate that smoke pH of tobacco prodkzcts changes during the combustion process. Sinoke from large cigars may be acidic dh'zring the first portion of the smoke and not become~a~lkaline untillthe lastha~lf~of'tili~e~cigar~is: smokedBrunnemann and Hoffmann (15), using the same techniques de- scribed above, examined the effect of'~ 60 leaf' constituents on smoke pH.. For~severallvarieties~of cigarette~tobacco„they~~ found a high correlationn between~ the,total aklaloid and n~~itrogen content a~nd smoke ~ pH. Stalk~~k position~~ also~ affected smoke ~ pH. 'Il'obaceo~ leaves, near tlte~ top~ of' tlie~ plant, which contalin high levels of tar and nicotine, y~ielded a sm~oke~ with a muchihigher~pHf than leav.es~ lo..-err on the~ plant. At pr:esent~ it is~~ not~ known to what extent t~hese~ factors~~ i'nfluence~ the~ p1-lf of the~ smoke of~tobaccos~com~monl'y~used in cigars~or how these kinds of pH~ch~anges intiuence~the~ inhalability of tobacco smoke:. The~ inhalation of'sm~oke, however„appears to be tlte~~ most i~mportantlt factor~ d~etermining~ the, impact a cigar will have on overalll health. Those~ physi~call and chemical charact'~eristics~~ of a tobacco~ product which most influence~ inhalatlion, of tobacco smoke have~ not been accurately~ determined. Nevertheless, it appears likely that the smoke~ of'sorne brands of'cigars mayy be.compatible with inhalation by a sig- nificant: portion of the smoking~ population,~ since~:~~ (a~)~ Little~ cigars~~ have tar and nicotine levels which. in some brands, are similar to the l~evels!~ found in cigaretlt:es,~ and (b' ) the ~ p~H'i . of the~ smoke~~ of~ some~ little~~ cigar brands is acidic for the major portion of the little cigar and becomes alkaline only in tlhe last puff or tv-o:~ 2za!

It is reasonable to conclude that smoking little cigars may result in health effects similar to those associated with smoking cigarettes if little cigars are smoked in amounts and with patterns of inhalationn similar t.o those used, by cigarette smokers, fmr the reasons cited above, and''theseadditiionallreasons~: (a)~Int'hoselit•tleciga.rs for«-hich pre-liminary data are available,, the concentrations of carbon monoxide, hydrogen, cyanide, acetaldeltyde; acrolein,,pyridine, phenol„and poly- cyclic hydrocarbon levels are comparable to those found in cigarettes; (b) cigarette smokers wH.o switch to cigars appear to be more likely to inhale cigar smoke than cigar smokers who have always smoked cigars (14'); and (c) cigarette smokers who switch to little cigars mayy be inclined to use them as they did cigarettes because: of the physical similarities between the: Tittle ciga:rsand' cigarettes,, includsng, their size and shape;, the number in a package, the burning rate, and the tio'ne it takes to smoke them. Figure 4!-Pereent distribution of, 130 brands of oigarettes andl25 brand5 of little cigars by "tar" content. 50 45 1 arettes Little Ci ar 40 35E 30 115 10' 0 , L11L~R Mg „tar" 0 0 0 16.0 8.01 32.0 32:A 0 1 810. 4.0 Cigarettes 0-4! 5-9 10-14 15-19 20-24 25-29 30~34 35-39 40+44! 45-49 Little Cigars 3.1 3'.1' 10.0 46.2 23:1 10.0 319 0.8' 0 01 SOURCE: U.S;.Department,of, Health, Educaition, and'.Welfare (97)and.Federal Trade.Commission (34). 225'.

Figure 5.-Percent distribution of 130'brands of:cigarettes and 25 brands of little cigars by nicotine content. 50 YI VI Cigarettes~ Little cigans F a iw i v ry ~ d ~ ~ ~ ~ p~ 0 N 1[l h O N Ia7' n O' N ~1 O~ ©~ Cjl .+ ~ '. .-r a N~ N~i lei ~i c+7, CT, 0 Ct Q!' QD M te~e Cm ai st cri M v N Ln m p o 0 O: N~. Q0~~. N ~ CG` ~~. Wv SOURCE: U.S. Departmenti of' Health, Education, and Welfare (97) and Federall T.ade Com- mission i(34). 226

TAB1,E 37.-Shipment of' small and large cigars destined' for domestic consumption (1970, 1'971, 1972). Year 1970 1971 1972 Small cigars January---------------- 58; 328; 5'20 85, 753, 780' 123, 477, 550 February--------------- 63, 431, 580 72, 092; 205 179i 817,, 839. March----------------- 85; 881, 860 46, 542, 800' 198; 165, 593. April' ------------------- 101, 613, 500 59,,059, 920, 125; 335, 740 May------------------- 81, 093, 180 93,,237, 473 159;,334, 56.5 June------------------- 82, 471„120' 94, 560, 140, 180; 582; 243. Subtbtal---------- 472, 819; 760 451, 246, 318 966;,713, 530 Ju1l-------------------- 62, 143, 140' 70, 332,' 500 127; 713, 320 August----------------- --, 68, 220, 365 127, 709; 310 670, 936, 869 September-------------- 79, 101,045 95; 027, 340 422, 534, 705 October---------------- 90; 752,880 109, 567, 900 708, 116; 830, November-------------- 64; 290, 600 106, 666, 107 5514 326, 888 December-------------- 63,806,010 123, 809, 553' 485, 587, 014! Subtotal'---------- 4'28, 314, 040 633, 112,,710 2, 966, 215,, 626 Yearly total------- 90!1, 133, 800 1, 084, 359, 028 3, 932, 929;,1i56 Large cigars January ,------ ------- February ------------- ll^larch'- ---------------- April'------------------- h'Iay------------------- June------------------- 581, 742;,001 57,3; 039, 120 534, 565, 488 595, 249;,522 586,810,844 562; 414, 577 629, 977, 375 665,, 998, 099 654, 827, 796 652, 800, 2001 655, 850, 213 554, 242, 048 748, 040„796 670, 064, 933 719;,489; 529 644, 539,,03'i 692,436,529 578, 501, 068 Subtotal---------- 3, 852, 348,,925' 3, 844,,199, 738 3, 604, 040,,506 July------------------- 647, 397, 547 619, 838, 386 520, 873, 339 Augusti----------------- 673,,082, 971' 662,970,148 ,' 682, 333', 630 September-------------- 721,561,449 680, 476, 4'18' 594, 843, 957 October---------------- 797, 601, 253 679, 420;,968' 693, 150, 668' November-------------- 696,526,464 742, 948,,802' 650,746,540 December-------------- 596, 244', 159 516, 879, 415 437, 429„996' Subtotal,---------- 4, 132, 413, 843 3;,902, 534, 137 3;,579, 356„130 Yearlytotal------ _ 8,,084, 762, 7687, 746, 733,,875711183, 396„636 Sdurce: II.S. Department of the Treasury, (101). 227

TABLE 38. -Selected' compounds in' mainstream smoke Smoke eompound "Tar"; milligram per cigarette_ __ Nicotine, milligram per cigarette_ Carhon: monoxide, volume per- CarMon dioxide, volume percentL_ Reducing sugars, percent ofl tobacco weight______________ Hiydrogen, cyanide;, microgram per cigarette_ _ _-----_-__-__ _ Acetaldehydo, microgram per cigarette-------------------- Acrolein, microgram, per cigar- etlte------------------------ Tot'al' pyridines, micrograms per, cigarette-------------------- Phenolj microgram per cigarette__ Benz(a) anthracene, nanogramn per: cigarette_ _-_-______-____ Benzo(a)pyrene, nanogram per cigarette-------------------- Cigarette A Cigarette B Little Little Small (nonfilter) (fllter) clgar A cigar B cigar C 36. 1 20! 3 17'., 4 31. 8 40. & 2.7 L 4 . 6 118 ' 3. 1 4. 6 4. 5 5. 3' 11. 1 7.7 9.4 9~ 6 8. 5 1112 ' 12.7 9:3 7:9 1l5 2.9 17, 536.0 ' 361.0 381.0 697.0 1!, 029: 0 770.01 774.0 630. 0 1, 238! 0 1,150.0 1105.0 71. 0 4!1L 0 54.0 66. 0: 82'.8 27:3 58.0 85:3 80:3' 124.2' 33.0 35:1 63:4 9411 74. 0 31.0 34. 0 25.0 39.0. 47.0 20.0 18: 0 22.0 30., 0 Source: HutImann,, D., Wynder„E. L. (44). TABLE 39.-The:pZd of'the mainstream smoke of setected'tobacco products (Numbers in parentheses indicate number of', last puSa' Average pHi Cigarette A (nonfilter)' Cigarette B (filter) Little cigar A: Little cigar B Small cigar C. Cigar D 3d puff_,____ 6. 19 6. 15 6.44 6.55 6:53' 6:4'7 5th puff---- 6. 14' 6. 12' 6.34 6: 46 6.49 7th puff'---- 6~: 09 6.01 7.03 6, 51 6.56 '. 9th, puff---- 6~: 02 5.83 ' -------- 6' 98' 6.59 . 6.27 13th puff'--- -------- -------- -------- 6.39 18th puff--- -------- -------- -------- 6. 41 23dlpuff---- -------- -------- -------- 6.81 28th puff--- -------- -------- -------- 7:22 33d puff_--_ 7 53 323th puff--- -------- -------- -------- -------- -------- 7.78: Lagtpuff_,__ 5.96(11!) 5:76(1'0) 7.73 (8) 7:25'(1'0'), 7. 11(11) 7:96(43) Source: Hoffmann, D., Wynder„E. L. (44)', 228

Conclusions Pipe and' cigar smokers in the United States as a group: experience overall mortality rates thatare slightly higher than those of'nonsmok- ers, but these rat'es are substantially lower than those of cigarette smokers: This: appears to be due to the fact that the total exposure to smoke that a pipe or cigar smoker receives f'rom! these prodncts is relatively low. The typical cigar smoker smokes fewer than five cigars a day and the typicall pipe smoker smokes less than 20~pipefuls, a day. Most pipe and cigar smokers report that they do not inhale thesmoke. Those~ who do inhale, inhale infrequently and only slightly. As aa result, the harmful effects of' cigar and pipe smoking appear to be largel'ylimited to increased death rates from cancer at those si'teswhi& are exposed to the smoke of these products. Mortality rates from cancer of t!heora~l cavity, intrinsic~andc extrinsic larynx, pharynh,and esophag us are approximately equal in users of cigars, pipes, and ciga- rettes. Inhalation~ is evidently not necessary to expose tliese sites to tobacco smoke. Althougli these are serious forms of cancer, they account for only about 5 percent of the cancer mortality atnongmen.Coronaryg heart disease,, lung cancer,,emphysema, chronic: bronehitis,, cancer of the pancreas, and cancer of the urinary bladder are diseases which are clearly~~associa.ted! with cigarettesmoking,but'fior cigar and pipe smokers death rates from these diseases are not greatly elevatedd above the rates of'nonsmokers. These diseases seem to ~ depend on mod- erate to deep inhalation to bring the smoke into direct contact with the issue at risk or to allow certain constituents, such as carbon mon- oxide; to be systematically absorbed through the lungs ortoaffsct theternporal patterns of absorption of other constituents such asnicotinethat can be absorbed eitherr through the oral mueosa or through the luna . Evidence from countries where smokers t'end to consume more cigars and inhale them to a greater degree than in the L; nited States indicates thatt rates of lung cancer become elevatedl to lev,els approach- ing those of'cigarette smokers. AvailWe data on the chemical constituents of cigar, pipe, and'' cigarette smoke suggest that there are marked similarities in the com, position of these products. Pipe andl cigar smoke, however, tends to be more alkaline than cigarette smoke, and fermented tobaccos com- monly used in pipes and cigars contain lpss reducing sugars than the rapidlyy dried varieties commonly used in cigarettes. Experimental evidence suggests that little difference exists between~ the tumorigenic activities of' tars obtained from cigar or cigarette 229 0

tobaccos. Malignant ski6 tumol:s appear somewhat more rapidly andd in larger numbers in animals whose skin has been painted with cigar tars than in those'animals painted with cigarette tars: One must conclude that some risk exists from smoking cigars and pipes as they are currently used iii the' United States, but for most d'iseasesthis is small' compared to the risk of smoking cigarettes as they are commonly used. Nevertheless, changes in patterns of''usage that wouldbring, about increased exposure either through~ inerease& indi- vidual use of cigars and pipes or increased inhal4ation of pipe andcigar smoke have' the potential of producing risks not unlike those now incurred byeigarette smokers. iV'Iecllanical or, chemicalmodificationsl of pipe tobacco and cigars that «oul'd' result in a smoke more eompat- ible' with inhalation couldl llav.ethi'seffeet. Fiipe an~dl Cigar References (L) 2,.BEnIN, T., GSELL, O, T. Relative risk of' pulmonary cancer in cigar and pipe smokers, Cancer 20(8) : 1288-1296, August:1967: (2) AI.I:ISoN¢, A.,, FLINT, F., J. Bronchitis, aspirin, smoking,, and other factors in the aetiology of peptic ulcer. Lancet 2': 179-182,, July 26, 1958. (~3)AR3fITAGE,. A. K., TURNER;. D. M. AbsOrptil7nn off niCotine'e in cig"arettee and cigar smoke through~ the oral mucosa: Nature 226(5252) : 1231-1232; June 27, 1970. (k.). As'H'.FORD, J..Rs, BRo'wIi, S., DUFFIEZ.D, D. P:,. SM,rDH',, Q.. ~.g,.,, F'AY',. J.. w'. Jl The' relation betweeni smoking habits and physique, respiratory symp- toms, ventilatory function, and radiological pneumoconiosis amongst'~ coall workers at three Seotti'sh collieries, E3ritiqhJoiunal of Preventive and Social, Jiedicine 15: 106-1i17, 1961. (,9), AUERBACII4 O., HASIMaND,, E. C., GARFINKEL, L. Histologic' changes in the larynx in relation to snial:ing7ialiits. Cancer 25(1) :'J2-104,,January 1970: ( 6:). AUERBACH„ Q:,, .caTOUT., A. P., HAJfIMOND,, E. C., GARFINKEL,: L. Changes~ in, bronchial epithelium in relation to sex, age,, residence„ smoking and pneumonia. New Eilgland Journal of' Medicine 267 (3),: 1I11-11J, July 19', 1962. (7) A:UERBACH,. 0., STOUT, A. P., HA4I3iOND;, E. C:,.!irARFINKEL, L. HlstolOgic' changes in esophagus in relation to smok'ing,habits.,A:rchives of Environ- mentlalHealth11(1) : 4-15, July 1965~ (8): AUERaAOH, 0.,. STOUT,. E>L., h.. HAMMOND, I''~u. C':, GARFINKEL, L.. S.mokinghabitsand age in relation to pulmonary changes. Rupture of al'veolarr septums, fibrosis and thickening of'walls of small arteries and arterioles. New England Journal of 3ledici,ne 269:(20) : 1045-1054, Nov. 14, 1963: (9) BEST, E. W. R'. A Canadian Study of Smoking and Health. Ottawa. Depart- ment of'~ Nationali Health and Welfare, 1966; 137 pp. (10) BoAx:E, W. C. A study of illness in a group of Cllevehuid families. XVIII. Tobacco smoking andi respiratlory infections. New Ehgland Journal of Medicine 259(26) :1245-12-19; Dec. 25,1958;(11)~ BotivER, G. RespiratorFsymhtomsandy ventilatory , function in 172adultsemliloyed in a bank. Ameri¢an: Review of Respiratory Di:seases83i: 684-689, 19611. 23q,

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CHAPTER 7 Exercise! Performance I~

Contents Introd!uction-------------------------------------------- Page 241 IVII Studies of Smokers-------------------------------------- 24!1. Studies Comparing Smokers to Nonsmokers: Ath,letic P'erformance--------------------------------- 243 Bicycle Ergometer Performanee------------------------- 244 ,. Tread'mill Performance -------------------------------- 245 Performance in Other Tests of Fitness------------------- Discussion---------------------------------------------- Biomechanisms----------------------------------------- 24'5246'1 246 Summary---------------------------------------------- 247 References--------------------------------------------- 248 .

C'. 4: ~ Q: ~ ~~' N~ ~

Introduction II Although it has long been held by athletes andl coaches that cigarette smoking, is associated with "shortness of wind"' and impaired perform- ance, until recently there has been lit't1E scientific evidence W support this view. In the past few years, a variety of studies have appeared dealing with~ the effect of cigarette smoking on the response of' man to exercise. TI he following is a review of these studies.t1ge; sex, training,, health, weight, and other factors are known to infiuence exercise performance. Because rnostof the investigations were carried, out in healthy,, young male volunteers, the groups were quite comparable with regard to age, sex, andl health; however, weight,, training,, and other factors were often inadequately controlled. Furthermore, problems in study: design and statistical analysis limit the value of several of'these studies.1Vlany forrns of exercise were performed' in t'hese experiments, in- cluding : pedaling ai bicycle ergometer, running on a treadmill, running on a track,, swimming, step climbing, gripping a hand dynamometer, and doing several different exercise activities as part of a battery of tests; Small to maximum amounts of' work were carriedl out in the various studies revewed. Studies of Smokers I Most of the studies of habitual! cigarette smokers followed a similar format with respect to smoking: (a) The subject's refrained f'rom, smoking, for a few hours prior to testing, and (b) two test runs were performed', one without smoking, and one in which smoking imme- diately preceded; the exercise or was incorporated with, the exercise protocol. Several investigators (1,,15, 28) studied the effect of smoking on, maximum grip strength. W,ilTgoose (28) reported a greater mean per- cent recovery of grip strength after the nonsmoking trial than after the smoking trial. Kay and Karpovich (15) and'i Anderson and Brown (1) all followed a protocol similar to that of Willgooseexcept thatt theyrandomiaed the smoking, and nonsmoking trials, andsubstitutied 241'

ai "placebo" cigarette for the nonsmoking triaL In neither of these studies were statistically significant diff'erences observed between the grip scores for the smoking and nonsmoking trials. Reeves and Morehouse (24) administered ai battery of tests to 15 collegesstudents.Thetest~swere:! A tapping t.est~, a strength, testl, a jumping test,and t'~heshortforrnof theHa~rvard steptest., Npstatis~- ticall'ysigni'ficant differences in perfoiniancewerenoted under con- ditions of smoking or nonsmoking. A total of 32 college studentls. from intermediate swimming classess abstained from smoking for 15 minutes„2liours, and 12 hours in a study conducted by Pleasants, et al. (23). Following the abstinence, they swain distances of 100 and 200 yards. Althouglx act~ual' swim,mingtiimeswere not published, the authors reported no statistically significant differences betaz-een the mean swimming times after the different periods of' abstinence for either distance. In 1946, Juurup: and '-NIuido (13) carried out several experiments in whi'ch three young cigarette smokers exercised on a Krogh's bi'- cycle ergometer. Smoking was found to increase the pulse rate at rest as well as during exercise. Although the effect was less con- sistent than on the heart rateT smoking was also associated with elevatedd blood pressure. Smoking had no effect on oxygen consump- tion. Henry and! Fitzhenry (12), in 1949, using the bicycle ergometer, also found that smoking exerted no effect on, oxygen consumption. In the same year,K~arpoviclii and Hale (14) studied bicy.cleergometerperformance in eight young men. In all subjects, the average riding time was better in, nonsmoking tests than, in smoking testei, how- ever, the results were statistically significant for only three of' thee eight subjects. Kerrigan, et al. (16), more recently measured direct arterial blood pressure, heart rat'e; and cardiac output in 25 habitual smokers at rest and after exercise. Smoking two cigarettes produced statistically significant (P<0.01) increases in cardiac index, heart rate; and arter- ial mean pressure compared to the immediately preceding controll period. Exercise after smoking resulted in~ an increase in cardiac in~ dex over either t'heresting, period, or the exercise peri'od, which fol- lbwed abstinence; the resultant cardiac index appeared to be approxi'- mat'ely the sum of the exercise and smoking, effects.. Exercise tests preceded by smoking, were also associated wtih sigi7ificantly higher (P<0:01) and more prolonged elevations of'bloodpressurethanthosenot preceded by smoking:. In the study by Goldbarg; et al. (,1'1)of nine habitual smokersper,formingsubmaximal exercise on a bicycle ergometer;car.diovas- cularresponses were measured via pulmonary and subclavian artery catheters. At rest, after smoking, the mean cardiac indlex and mean heart rate increased.D'urialg successively increa6ing levels of exercise, thehcart rate was ;reater and stroke indexl,o~~-er than values for 242 i

e t ~~ yl U h cotnpalrabl'ework before smoking : The, net effect of smoking was to decrease theeffi;icency of the heart duringexercise in the upright position by causing ai smaller stroke volume and a higher heart rat'e. Rode and Shephard (wS)' investigatedi near maximal treadmill exer-cise performance in six habitual smokers. A 1-dity abstinence froml cigarette smoking was associatedl with a, 13- to 70-percent dpcrease in the oxygen cost of breathing. Abstinence was also followed by a slmv- ing of the heart rate and a decrease in expiratory minute volume after exercise. The study of KrtunhoTz;Iet al. (18) is different from those cited pre- viouslyy in that bicycle ergometer exercise performance was measured in habitual smoliers, both before andl after 3' to ~ G weeks~of I abstinence. Among the 10 subaects who abstained from smoking for 3i «eeks,Ithere was alstatisticallysignificant (P< 0.05) decrease in heartrate; oxygen debt, and ratio of oxygen debt t'o: total increase in oxygen uptake pro- duced by the 5i minutes of exercise.. Using a "double 9-inch progressive step test" Rode and Shephard (25~) studiedi several hund'redparoticipants of a smoking withdrawall clinic at the time of entry andl at a 1-year foll'owup. Among, those R ho returned for the followup andl `sho gave up smoking, absolute aerobic power increased insigniticalntly, ; however, the relative aerobic power diminished in both sexes among those who q,uit smoking because of the veight gain experienced. Studies Comparing Smokers to Nonsmokers t V Ath;letic Per f'orm-ance In 1968 Cooper,,et al. (6) evaluated 419 airmen during their initial 6.reeks on active duty in the USAF. A 12-minute rnaximuml running test .vas performed at least 1 hour after cigarette smoking. The meann distance covered in 12 minutes by the nonsmokers was sigiiificantly greater (PG0:05) than that covered by the smokers at the beginning, tliemiddle, and the end of training. All cat'legoriesofsmokers and non-smokers improved their performance at the end of training; however,l the maximum change in performance oflthose smoking 10 to1:30 cig- arettes per day was significantly(P<a:001) less than that ofnon-smokers.. David (y )~ administered a battery of t'leststo88 milritary.personliel~ aged 19 to 39 y.ears. A 1I-mille run ,%vasinchided in theAesting. and cig.-arette smok~ing«-as associated .vithasignificant decrease in perform, ance in this event. 243

Some 45~ special forces soldiers were investigated' at sea level and 13,000: feet above sea level by Fine (8). The subjects were randomly: assigned to a placebo group or an acetazolamide treated group. Cig- arett'e smoking was positively correlated to decrements in 600-yardd running performance from sea level to: altitude in both groups. Pleasants (22)1 studied 106 students from intermediate university swimming classes.Swimmingtimeswere: measured for 100-and 200- y"urd distanees, before and after tlrainingand for 800-yard distancesaf'ter training. The: mean swimming times of nonsmokers were less than thoseof' srnokers, insix of' seven listed categories,, bu~tt these dif- ferences were not statistically signiificant.. Bzcycle Ergometer Performancz Chevalier, et al. (5) investigated'r cardiovascular parameters in 32 young physicians after a stiandard 5-minute ergometer test.Oxy,gen debt accumulation among smokers was significantly (P'G0.01) greater than among nonsmokers. The heart rate at rest and 3 minutes after exercise was significantly (P<0:02') faster in smokers than in non- smokers. Using a 5-minute ergometer test, 18' housestaff physici'ans„ half' of whom smoked, were investigated by Krumholz, et al. (17). They noted the foldowi'ng:, Oxygen debt accumulation after exercise was signifi- cantly (P'G'0.02) greater insmokers thannon-smokersT t'he ratio~of thee oxygen debt' to totall increased oxygen uptake during exercise was sig- nificantly (P<0:001) greater in smokers than in nonsmokers" andd the diffusing capacity at rest and with exercise was significantly (;P < 0.05 )! decreasedi ini smokers compared to nonsmokers.. Kerrigan, et al. (16) studied cardiovascular parameters in smokers and nonsmokers at rest, during, and after a 5-minute bicycle ergometer ride. Cardiac index andd blood pressure values obtained during exercise performed' immediately after smoking were greater than those found in nonsmokers performing the same exercise. Similarly„heart rate and bloodd pressure remained elevated forlbnger periods in thosewlio: exercised immediately after smoking t~han in nonsmokers performing the same task. Aerobic capacity scores were. examined in 60 university stud'ent vol~ unteers~by Peterson and Kelley. (20)1. Subjects worked at submaximal levels on ai bi~cycleergometer before;during; andl afteratra2ning program. At all of these interti-.alis, nonsmokers had significantly (Ia<0.05)i higher mean aerobic capacitiy scores thani smokers. Both groups increased their aerobic capacity during training but non- smokers consistently performed better t;hroughout training, 244

T readmall Per f orma rure H In 11960 Blackburn,, et all. (4) carriedl out, severall measurements of' II cardiovasculiir function after different amounts of treadmill exercise were performed by 2?33' professional men, 15'J~ university students„and 414 railroad workers. The differences between the smokers and non- smokerswereof' smalll magnitude. Basal otygen consumption was ' slightly higher in smokers than in nansnolcers., Also, re sting, pulse rates were higher in smokers of most groups. Coope«,et al. (6)~ studied 47outof' 410' airmen with, treadmill test-ing. Cardiopulmonaryindileesmeasured on the treadmill, including maximum indices, w.ere comparable in smnkers and nonsmokers ex- cept for a significant (1''<0:01) reduction itn the maximum minute vollume auiong, t he sniokers. I A total of 377 proslaectiveC~aanidfian firemen performed the: I3'alke- Ware test of «rork capacityy in treaKhuill' studies carried out by Glass- ford and FIowell (10). The meatt perforniaiice scores of nonsmokers were significantly (P< 0.01)greatertlian those of smokers. The effect of vitamin C suphlhnientation ou t'readmill exercise: per- formance~ was investigated in 40 ~ mal,e volunteers by Bailey, et all (13). Significant differences in orygen utiliaation andventilatoryf'unction between sm~okeisandl nonsmokers were noted in only two, ofthe2I separate ana~lj:ses of variance perforined.. Masinial oxygen intake during treadmill exercise was esamined by McDbnough, et al., (l9)' in 86heallhy, middls-aged male~ volunteers.Cigarette smoking was one of six variables which together provided al mult'i2~le correla~tioni coefficient of 0: i:3'.. Perf'armanee zn Other Test's of Fi,t'n,ess When physical fitness tests were administered tlo 88 military per- sonnel by David (7), cigarette smokingwas~ floundl to be associated with, a significant (P'<0:001)dtcreasein performance:in the dodge and jump test, andl a significant, (P<0.02) decrease in performance in the crawling test: L; singa st'~eptest, a breathholdfing test,and an, ergometer test,, Franks(',9)examiiied 58' middle-agedi men. Nonsmokeiswere able t.ohokl their breath longer and had greater vital capacityrresidual after t he stelr te st than the smolters. In 19711. «''ysokinski (,2,9)~ studied 200! young Polish soldiers usingLetunnv'stest which inclnderll301knee-bendincexercises,,a fast run for :.>0 seconds, and a run for3 minutes. C~igai.•ette,snloking Nvas a:ssociatedd withi a significant (IP'<0.01)i reduction iiu thevi'talcahacity andl a ~ 245,

marked rise in the pulse rate at rest and after exercise. Intense exer- cise also caused a greater rise in the systolic blood pressure.in~smokers than in nonsmokers. Dliscussvon. Most of'the studies in habitual cigarette smokers compared exercise performance in "smoking"' and "nonsmoking" runs after onIyy a f'ew hours of abstinence. In some studies, smoking ad'versel'y~, affected per- fbrmance (11, 13,,14,, 16; 18, 06, 28) ,, while in others it did not (1, 12„ 15„23,,2/).Some of these apparently discrepant results are due to dif- ferences in methodolbgy and in amounts and types of work performed.. l[n, al1 ofl the more recent studies of habitual smokers in which, moderate to near maximal amounts of work were performed and sophisticatedl measurements of oxygen transport and cardiopulmonary function were made, impairment of function during smoking trials was found. (11;16;18, 26')i. Thedataof'Krumholz, et al.(18): alsoraisethe question of whether residual effects ofe cigarette smoking infllaence "nonsmoking"'trials per= formed after a, fe.vhours ofl abstinence; they found statistiicall'y sig- nificant decreases in heart rate and oxygen debt produced by exercise after 3 weeks of cessation. The work ofl Rode and Shephard (25)' suggests that physical fitness improves with cessation, but t'1iisimprovement maybenegatedl if the subject gains a substantial amount of~ weight after~giving up smoking; Several investigators compared exercise performance or postexer- cise cardiopulmonary function of smokers to nonsmokers. Although only minor differences between smokers andl nonsmokers were found in a few of these studies (3; 4', 22),, in most of them (5, 6; 7, 8,,10, 16;. 17,,20, 29): the performance or function of the nonsmokers was better than that of the smokers: Both nonsmokers and smokers improved their performance wi'th~ tiraining, but nonsmokers maintained their ad- vantage throughouttraining (6, 20). Biomechanisms The citedlstudies indicate that cigarette smoking exerts it'sadverse eff'ect on exercise performance through several mechanisns.. Cigarette smoking appears to impair cardiac l~erformance during exercise by increasing, the heart rate and exerting a variable effect on cardiac 246

output (.5,11;,13, 1'6;18„26, 29). Cigarette smoking is associ'ated' with. an increased osygen, debt after exercise (5, 18). Also, one study indi- cated that the oxygen cost of hyperventilation was greater among smokers than among nonsmokers (26). Some of these adverse effects of' smoking, on oxidative metabolism are mediated by the elevated carboxyhemogTobini leuels found in smokers. COexerts these effectsthroughone~or moreofl the following, mechanisms: (a) Reduction of the amount of hemoglobin avaiIablie for oxygen transport, (b): shift of the oxygen-hemoglobin dissociation, curve to the left~ with, consequentiRlterference~ in oxygen release at the~ tissue level~ (c)~ induction of arterial hypoxemia4 and (d) possible interference with tliehomeost'a~tic mechanism by which 2,3,DPG controlsthe affinity of hemoglobin for oxygen (2T);. Because carboxy- hemoglobin has a half'Iife in the body of'~ at least 3 to:4 hours„its infi!uL ence may: still be measurable several hours after abstinence from smoking (27). AX recent investigation of' maximal muscular exercise d'uring CO in- toxication in five male volunteers demonstrated reduced maximal Oz consumption in spite of a much higher heart rate and a relative hyper- ventilation (21). Astrand and Rodahl'' (2) commented recently on the adverse effect of' cigarette smoking on oxygen transport :"Al1 other factors being, equal~ a reduction in the oxygen-transporting capacity is associated, with a corresponding reduction in physicali performance capacity dur- ing, heavyormaximall work ***. Because a regwl'arphysical train- ing program only increases the maximal oxygen uptake by some 10 to 20 percent, a 5- to 10~percent reduction in maximal aerobic power duee to smoking may play a si'gnificantrole in many types of'athletic events and in very heavy work." Other studies cited in this review document the adverse effect of smoking on pulmonary diffusing capacity (18) and on pulmonary function with exercise (6,29). Summary il Clinical st'udies in hea~~lthy,~ young men ha~~~~e~ shown that~ cigarette~ smoking~ i'mpa~iR•s~ exercise~ performa~nce,~ especi'all,y~ for~~ mnny' types, of at~hletic events~and activi'ties inv.ol~ving~ma~xi7m~l work capacity:~ .S'ome~ of'these~ et£ects~~ are mediEitedi by~ redu~cedl oxygen transport and re~ducedi cardiac and pulmonary function. 247

U Exercise Pirformlanee References ( (1) ANDERSON, J. M., Bxowx4 C: W. A. study of the effects of smoking upon grip ~ strength and recuperation from local muscular fatigue. Research Quar- ' terly 22 (1) : 102-108, March 1951. ~ (2) As^rRANn,, P'.-0:,, ROnAHL, K. Factors affecting performance. In: Textbook of Work Physiology. New York, 3dcG'raw-Hill: Book Co., 1970, 669 pp. ' (3) BAU.EY; D. A., CARROxs A. V.,, TEEeE,, R. G.,, WEHSER, H. J. Vitamin C' 1 supplementation related to physiological response to exercise in smoking, ` \ iti ki A i l f li i l t 23 7 I i ca r ion and nonsmo mer cani Journa , o n l u ( J : , ng, subjects: C 90,5r912; July 1970. (¢) BzACgBUR,x, H., BsoZER:, J_ TAYLOR,, H. L. Common circulatory measure- ments in smokers and nonsmokers. Circulation, 22':, 1112-1124, December 1960. (5) CHEVALIER, R: B'., BowERS, J. A.,, BONDURANT, S., Ross, J. C1 Circulatory and ventilat'org effects of exercise in smokers and nonsmokers. Journal of' Applied Physiology 18(2) : 357-360, March 1963: (6) COOPER, K. H., GEY, G. 0.,. BOTTENBER4., R... A. EffectsOfcigarette. smoking on endurance performance. Journal of' the Ameriiean Medical Association 203!(3) : 189-192,,Jan. 15; 1968. (7): DAVm,, K. H. Age, cigarette smoking, and tests of physical fitness. Journail of Applied Psychology 52'(4) : 296-29E3, August 196& (8) FtxEy B. J. Personality traits as related to symptomatology and running, performance at altitude under normali and drug (acetazoleamide) condi- tions. Perceptual and Motor Skills 27:: 97:,-990, 1968: (9) FRANKS, B; D. Smoking and selected cardiovascular-respiratory measures. Research Quart'erly 41(2) : 14'0-144:, riLay,1970: (10), GLASSFORD, R. G.,, HOWELL, 11. L. Smoking, and physical fitness : A prelim- inary report. Canadian Family Physician 15(10:)~: 60-&2, October 1969: U ~ (11) GOIinBARa, A. N., KROSE, R. J., RES:cEKOV, L. Effects af' cigarette smoking ~ on hemodynamics atl rest and during exercise. I. Normal subjects. Chest ~ 1 60(6) : 531-536, December 1971. (12) HE:vRY, F. M., FrrzHEVaY, J. R. OO xSgen metabolism of' moderate exercise, ' with some observations on the effects of tobacco smoking. Journall of' ~ Applied Physiology 2: 464-468,,February 1950: (13) JuuRI;P, A., MLxno, L. On acute effects of'~ cigarette smoking, on oxygen ` consumption, pulse rate; breathing rate and bloodl pressure ini «•orking, organisms. Acta Physiologica Scandinavica 11: 48-60, 1946. (14), KARPovica, P. V., HALE, C. J. Tobacco smoking andl physical performance. Journal of Applied Physiology 3: 616-621, April' 1951. (1'5) KAY,, H. W., KARrovlcH„ P. V. Effect of smoking upon recuperation from 1or {I cal muscular fatigue. Research Quarterly 20: 250-256',, 1949. (16). KIIRRI6A\, R:, JAIS„ A. C~, DOYLE,. J., T. Thee circulatorfreSponse: too eigarI rette smoking, at rest and after exercise. American Journal of the 1Sedi: cal Sciences 255: : 113-119;, February 196& (17) KsuMHOLZ, R. A., CaEVAZ,IFR,, R. B,. Ross,, J. C: Cardiopulmonary function in young smokers. A comparison of pulmonary function measurements ~ and some cardiopulmonary responses to exercise between ai group of, y!oung i smokers and a comparable group of nonsmokers:,Annals of'Internal Medi- cine 60(4) : 603'-610;, Apri11964. ~ (l8)KRIP\LHOLZ, R:. A., ('HEVALIER, R. B., Ross, J. C:(Vhangess ini cardiopuI- I monary functions related to abstinence from smoking. St'udies in, young ~ cigarette smokers at rest and exercise at 3' and 6 weeks of abstinence. Annals of Internal Medicine 6`?(`?)~: 197-207, F.ebruarS 19654 248

I (19) rilaDoNoucn4 J. R:, Kusuun; F., BeuCE, R. A. Variations in maxiniali oxygen intake with physical activity in middle-aged men. Circulation 41(5 ) : 743-751, May 1970. (20) PETassox, F. J., KELLEY, D: T.. The effect of cigarette smoking upon the acquisition of physical fitness during: training, as measured by aerobic capacity. Journali of the American College Health, Association 17(3) : 250-254, February 1969. (21) Pia:vAr, F., DUJARDIN, J., DeaoANTxE; R., PErtrr, JL M. Muscular exercise during intoxication by carbon: monoxide. Journal of Applied: Physiology . 31(4) : 573-575, October 1971., (22) PieASASTS, F~_ Jr. Pretraioling, and post-training, swimming endurance of'f smokers and nonsmokers. Research Quarterly 40'(4)i: 779-782, 1969. (23)~ PT:EASArrTS; F:,,Jr., GttucAN„J., R'sTLiFF, J- W:,,Jr. Effects of short periodss of abstinence from cigarette smoking on swimming, endurance of ehronic, smokers. Research Quarterly 38 (3'); :•174-479, 1966. (2h), RkEVBS, AV: E., 1loxeliarsE, L. E: The acute effect of smokinguponi the physi- call performance of' habitual smokers. Research Quarterly 211: 245-248, 1950! (2:5) RonE, A., SAEraARn, R. Js Smoking withdrawal and changes of cardiores- piratory fithess: American Review: of' Respiratory Disease 104(6) : 933- 935, December 1971. (26) RonE, A., SaE.raAto, R. Jl. The influence of cigarette smoking upon the oxy- gen cost of breathing in near-maximal exercise. Medicine and Science in Sports 3'(2),: 51-55, summer 1971.. (27) U.S, PusLIc HizanTa, SERvicE: The Health Cbnsequences of Smoking:, A Re- portl of'the Surgeon General : 1972. U.S. Department of'~ Health, Education, and Welfare. washington~ DHEW Publication No. (HSM) 72-7516, 1972, 158 pp. (28) Wira,aoosE; C. E. Tobacco smoking, st'rength, and muscular endurance. Re- search Quarterly 18':,219--225, 1947. (i29) WYSOffrNsxi„Z. Effects of'tobacco smoking on, certain parameters reflecting, the condition of t'he circulatory system at rest and during exercise. Polish Jiedicali Science and, History 14(2)~: 73-76, April 1971. b- I I U.S. GOWERNMENT.PRINTING OFFICH : 1973-CH495-028 249'

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The Health Consequences of Smoking, JJanuary 1973 INDEX Pages 2'511-261 U.S'. DEPARTN~IENTOF HEALTI1„ E:DL;OATI~.ONI, AND WELFARE. Public Health Service

DHEW'Publication No: (HSM) 73.8704

INDEX ' Abortion, spontaneous effect of maternal smoking, 123,1124 Acenaphthylene in cigary pipe, and cigarette smoke;,1'78' Acetaldehyde as ciliatoxic agent in cigarette smoke, 51 Aerobic capacityy effect of cessation of,smoking, 243 effect of exercise and smoking, 243,244 Air pollution and' bronchitis; in smokers vs. nonsmokers, 36,37 effecU on mortality rates from lung cancer, 73 as factor in lung cancer development, 72,73' imOsakat Japan, 44 prevalence of respiratory diseases:and„441 andl smoking in military and civilian air- craft, 45, Alcohol consumption interaction with smoking, andl other, risk factors in CHD,,10 and smoking, in cancer developments 71 and smoking; _in esophageal, cancer deveL opments 76,200 and smoking, in laryngeal cancer etiology,, 197 and smoking„in,oral cancer etiology, 193 Alveolar macrophages effect of cigarette smoke, 5'2;53 effect of nitrogen dioxide, 54 Alveolar rupture in pipe/cigar smokers vs, cigarette smokers and nonsmokers, 217 Angina pectoris carbonimonoxide inhalation and„17,18 incidence ini pipe and cigar smokers„21',5 Anthracene in cigar, pipe„and cigarette smoke, 178 Arterioles effect of smoking, 22,23 Arteriosclerosis obfiterans smoking as cause; 1'9;20 Aryl hydrocarbon hydroxylase effect of'benzo(a)pyrene in pregnant rats, 119 role in metabolism of chemical carcino- gens, 82,83 Asbestos effect on pulmonary, function in smokers vs. nonsmokers, 411 eff.ect! on radiological findings in smokerss vs. nonsmokers, 411 effecYon respiratory symptoms in smokers vs. nonsmokers, 41 andl smoking, effect on mortality rates from lung cancer, 73' Athletic performance running, effectof smoking;,243;24'4 smokers vs. nonsmokers;,24'3',244 swimming, effect of smoking, 244 Autopsy studies COPD and smoking, 45-48 lung cancer in U.SI veterans, 73,74 Bacterial flora in smokers vs. nonsmokers with COPD, 54 Benzo(a)pyrene carcinogenic effect in laboratory animals, 78-80 in cigar, pipe, and cigarette smoke„ 177;178' effect on DNA and': RNA, 86 s87, effects: during pregnancy in laboratory animals, 117,118' Bicarbonate inipancreatic secretions, effect of smoking, 159,1601 Bicycle Ergometer performancee cardiovascular parameters in smokers vs: nonsmokers, 242-244 Birth weight effect of' maternal smoking, 103-114; 119-122 effect' of maternal, smoking before andl during current pregnancy by cigarette consumption, 1107-109 effect of maternal smoking during pre- vious pregnancies,112'-114' effect of maternal, smoking, mechanism of action, 119,120: effect of paternal smoking,,110,1111 effect~ of tobacco smoke, nicotine, or carbon monoxide in laboratory animals, 11I4'-118' gesta4ioni duration in smokers vs. non- smokers, 103-106 and maternal smoking, epidemiologicall studies, 103-114 timing of influence of smoking, 1120,121 Bladder, cancer see also Renal,cancer incidence in smokers vs, nonsmokers, 77',78' smoking in etiology of, 77,78' Blood flow effect of smoking, 19,22;23 Blood lipids effect of smoking; 11,12. 251

effect of smoking and relative weight; in male Parisian,civil servants; lil effect ofl smoking in middle-aged patientsi with anginai pectoris„ 12 effect of smoking in young hlorwegian, military recruits, 11 elevated, as risk, factor in CHD, 11 Blood pressure effect of exercise and smoking,,. 242;244L246' effect of pipe and cigar smoking, 216 effect of smoking in middle-aged patients: with angina pectoris„ 12 Body height interaction with smoking as factor in cerebrovaseuiar disease, 19. Body weightt interaction with, smoking, as factor in cerebrovasoular disease„19 and smoking, as factors in CHD' incidence„ 4-6 and smoking, eff'ect:on blood lipids, 11 Bronchial, epitheliumm histological changes at autopsy and smok- ing habit, 74 histological changes in cigar, pipe,,cigar- ette smokers ~s: nonsmokers, 203, 204„ 209 premalignant changes in smokers, 67 Bronchiolo-alveolar cancer smoking and„71 Bronchitis and disability„in smokers vs. nonsmokers, 43 dust exposure as a factor; 44 mortality ratios in male pipe and cigar smokers, 2117;219' prevalence in Duisburg, Germany, by age and cigarette consumption, 39' prevalence in ex-coal miners andi non- miners by smoking habit, 42 prevalence ini miners and farmers in Hlun- gary, by smoking,habit, 42 prevalence in pipe and cigar smokers, 220,22'11 prevalence in smokers vs: nonsmokers in Bordeaux;, France; 36 prevalence in smokers vs. nonsmokers in, mountainous or low-lying areas, 36,37 prevalence in smokers vs. nonsmokers in Osaka, Japan, 44: prevalence: in smoking vs: nonsmoking yarn miB!workers, 40 in, smokers vs. nonsmokers, autops,y stu- dies„4'5 „46 smoking vs:,coallmining inietiology of, 42 smoking vs., dustl inhalation in etiology of',, 42 Bronchitis, chronic see Bronchopulmonary diseases, chronicc obstructive 252 Bronchopulmonary diseases; chronic ob- structive see also Emphysema and bronchitis autopsy studies,,45-18 as cause listed on death certificates vs. at autopsy, 47' epidemiologicalI studies„36'-45 mortality and morbidity studies„36-39 mortality rates in British, citizens by rttigra- tion patterns,, 36 mortality ratios in, male pipe and cigar smokers, 21'6,217,219 summary ofl previous findings, 35,36 summary of! recent findings,,55 Byssinosis, prevalence in, cotton mill employees,, smokers vs. nonsmokers, 55 prevalence in men by index of severity and smoking,habits, 440,411 prevalence in smoking va nonsmoking, cotton milllworkers,,39 smoking,and„39-41 Cancer see also Specific site, e.g;, Lung cancer mortality rates in alcoholics, 7L recurrent, primary„ incidence in smokerss vs. nonsmokers, 71!,74 summary of previous findings,b7,68 summary of recent findings„88 Capillaries eff.eata of smoking„ 22. Carbon monoxide cardiovascular effect6„ experimental stu- dies;,17-19 effecYt on birthweight and neonatal mortal- ity in aninsals, 133 effect on cholesterol biosynthesis,,imvitro„ 18 effect on cholesterol level in aorta in, rabbits, 18 effect on coronary hemodynamics and, ventricular, function imdogs, 18 effect, on exercise performance in:smokerss vs. nonsmokers„246,24'7 effect, on maximal, oxygeni eonsumption,. 18 effect, on, platelet stickiness in rabbits„ 1'8 effect, on reflex vasoconstrictOr responses;. 18,23 effect on vascular resistance and reflex vasoconstriction„22,23 effects during pregnancy in laboratory animalk,,116411,7 Carboxyhemoglobin levels : effect on exercise pr,rformance inismokers vs. nonsmokers„246,24T ~ following smoking of non-nicotine ciga- rettes, 17,18. ~ 4~. ~. ~

in, neonates of smoicing, mothers, 118;,1!1'S' Carcinogenesis cell and tissue culture studies, 84'-86' effect of:tobacco curing methods; 212 experimental, 78-87' initiating, and promoting agents in, cigar- ette smoke,,68 mechanism of action, 78, 80-87 of respiratory tract in laboratory animals:,, 78-80 role of cigarette smoke condensate, W84 Carcinogens effect on cell transformations, 84-86 effect, on respiratory tract in laboratory animals„78-80 Cardiac index effect of exercise and' smoking, 24'2-2441 Cardiovascular diseases see also Coronary heart disease mortality ratios in male pipe and cigarr smokers, 215,216 smoking and, 3•23 summary of previous findings, 3 summary of prospective epidemiological studies for cigar and pipe smokers, 216' summary of recent findings, 23 Catecholamine levels effect of' cigar, pipe, and cigarette smoke in dogs, 216 Cell and tissue:culture studies tobacco carcinogenesis and~ 84•86 Cell cultures, malignant transformations induced': by to• bacco tars oncarcino&ens,,84-86 Cells„atypical, in ex-smokers, smokers,, and nonsmokers at autopsy, 74 Cerebrovascular disease interaction of smoking and, other risk factors, 19 mortality ratios in pipe:and cigar smokers, 215,216 Cessation of smoking compared benefits in cigarette vs: pipe/ cigar smokers, 172,173 effect on absolute aerobic power„243 effect on infant birth weight, 107-109 1124114: effect on pultnonary surfactant level§, 55' as preventive measure in ocelusive disease: 21,22 CHDD Cholesterol levels effect of carbon, monoxide in rabbits, 18' effect of smoking and!body weight, 111 effect of smoking aed clinical parameters iniBritish,business executives, 1,1 inipipe:and cigar smokers„215,2'16 Chronic obstructive bronchopultnonary di- sease see Bronchopultnonary disease, chronic obstructive Cigarettes definition and processing, 175'' filtered, effecL on respiratory symptoms, 55 modified, effect on respiratory symptoms and ventilat'ory capacity, 37,38'8 plainivs: filtered, effect on sputumiproduc- tion„37,38 similarities with little eigars, 224,22'5' Cigarette smoke condensate, effect on RNA, 86 N-nitrosamines:in, 87,88 role in experimentallcareinogenesis, 80-84 Cigarettes, non-nicotine effect on carboxyhemoglobin levels; 17,18 Cigars definition and processing, 175,1'76 Cigars, Gttle chemical composition of, 224',2'25,2'28 evaluation of potential public health im- pact, 22'2=228' shipment for domestic consumption. 1970-1972,222~224,227. similarity to cigarettes, 224,225 sugar and pH differences withi large cigars and cigarettes, 222'-224' tar and nicotzne :content,, 224•226',228 Cigar smokers relative risk in lung, cancer development; 67,68 Cigar, smoking, effect, on mortality and morbidity com• pared to cigarette smoking, 171-173 in esophageal cancer development4, 197,200-202' gastrointestinal disorders and, 222, health consequences of,,179 histoIogical effects on bronchial, epithe- lium„203',204I 209 histological effects on esophagus; 200 histological effects on larynx, 197 inhalation,patterns and„184-L89 see Coronary heart'disease Chest illness in laryngeal cancer development, 197-199' prevalence in pipe and' cigar smoker:s,. 220,221 in lung cancer development, by amount smoked, 203-206' Cholesterol, effect of carbon monoxide biosynthesis mortality ratios from cardiovascular~ di- seases and, 215,216 0 , in vitro 1'8' mortality ratios from COPD: and, 217,219 ~ , ~ ~ 253' ~ f .i~ N

mortality ratios from esophageal cancer and, 197,2W mortality ratios from laryngeal cancer and, 193,196,1197 mortality ratios from lung, cancer and 203-205 mortality ratios from oral cancer, and 191,193 oral cancer development and, 193-195 overall mortality rates by amount smoked., 180-182 overall mortality rates fromi cancer and; 189 prevalence in Great Britain, 173,174 prevalence in United States, 173,174 pulmonary histological changes and, 217 Ciliary activity effect of pipe/cigar smoke vs. cigarette smoke in cats, 217,218'. Clinical laboratory tests effect of aging and smoking,, in, healthy, male veterans„ 11 Coal dust effect on pulmonary function in smokers vs: nonsmokers, 41-43 effect on respiratory symptoms in smokers vs. nonsmokers, 41-43 Combustion temperature effect on tumorigenic activity of pipe and cigarette tobacco; 210,211 Congenital' malformations mate,rnal,srnoking and, 136,137 Coronary heart disease epidemiological studies, 4-11I experimental studies, 13-19 incidence in European vs. American men, 9 incidence in farmers vs. nonfarmers by smoking habit,, 7 incidence in Hawaiian men of Japanes, ancestry, 10 incidence in male bank employees ir Brussels, Belgium, 10 incidence in men in Yugoslavia, 99 incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers„ 215,216' incidence in white males by body weight and smoking habit, 5 incidence in whites vs. blacks in Evans County, Georgia, 4,5 in India, 11 interaction ofi smoking with other risk~ factors, 4'-11 mortality rates in Japanese men and wo- men by cigarette consumption and age av initiation of habit, 7,8 mortality rates in smoking men in Finland, 99 mortality ratios in pipe and cigar smokers, 215,216 in Nepal„ 11 in New Zealand;,11 ' smoking;, in individuals under 40 y%~ars, 10 and' smoking, in myocardial' ischemic pa- tients in Iltaly,,10 COPD see Btonchopulmonary diseases, chronic obstructive Cough effect of asbestos exposure im smokers vs. nonsmokers, 41' effect' of coal dust exposure in smokers vs., nonsmokers, 41,42 efl'ect, of filtered cigarettes, 55 effect of modifiedi cigarettes„38 prevalence in pipe and cigar smokers,. 220',221i prevalence in, smoking vs: nonsmoking women in Bordeaux, France,, 36 Cresols in cigar,,pipe; andlcigarette smoke, 177' Curing methods incidence of respiratory infections in rats and„218;219 Cyanide detoxification in pregnant smokers vs: nonsmokers, 119 7 H-Dibenz (c,g)carbazole carcinogenic effect' in laboratory animals; 791 Diet, and smoking, effecton.blood lipids,,12 DNA binding of polycyclic hydrocarbons to, 86,87 Dust exposure bronchitis and, 44 as occupational i hazard, 43,44 smoking and, 44 Dynamic compliance in smokers vs. nonsmokers under 30, 50: Dyspneaa prevalence in cigar and pipe smokers,. 220,221 Electrocardiogram abnormalities, effect of smoking and other factors, 13 effect of smoking, im middle-aged Dutchi men; 112' effect of smoking„ in young military re- cruits in Poland, 112. Einphysema see also Bronchopulmonary disease, chronic obstructive f 2'54

incidence in cigar/pipe smoking coal mi'- ners vs: cigarette: smokers and non- smokers, 217 mortality ratios in male pipe and' cigar smokers, 217,219 prevalence: in males by smoking category, at, au topsy, 48' prevalenee in, pipe/cigar and cigarette smo- kers vs. nonsmakers, autopsy studies, 45,46' prevalence in smokers vs. nonsmokers, 55 in smokers vs. nonsmokers, autopsy stu- dies, 454'7 Epidemiological studies bronchopulmonary diseases and smoking,, 36-455 coronary heart disease and smoking, 4-13,23 lung cancer and smoking, 68-72 peptic ulcer and smoking, 155-157' Esophageal ~ cancer alcohol consumption and, smoking in de- velopment of 200 inhalationpatterns and4,197 mortality ratios for cigar, pipe,, and ciga- rette smokers vs: nonsmokers, 197,2000 mortality ratios in Japanese male smokers vs. nonsmokers, 76 relative risk in cigarrs pipe„ and cigarette smokers vs. nonsmokers, 197,200-202' smoking and alcohol consumption in de- velopment of, 76 summary of retrospective studies,, 201,202 Esophagus histological changes in cigar, pipe,, ciga- rette smokers vs, nonsmokers, 200 Exercise performance on bicycle ergometer, effect of' smoking, 24'2,243' cardiac index, effect of smoking, 242,243 effect of smoking and smoking,abstinenee; 241,242,246,247' influencing factors, 2411',246,247' summary of findings and mechanism of action, 246,247 on treadmill, effect of smoking, 243,245 Experimental! studies COPD and,smoking, 48-55 coronary heart disease and smoking, 13-19 effect, of carbon monoxide on pregnantt animals, 132;13:3'. pregnancy in laboratory animals„eff'ect,of tobacco smoke, nicotine,, carbon mono- xide, and polycyelic hydrocarbons; 1i14L118 Ex-smokers compared mortality rates:for cigarette vs. pipe/cigar: smokers, 172,173 histologjcal' changes in bronchial epithe- lium at autopsy, 74 low birth1weig3it, infants of, 112-1I14 mortality rates from lung cancen, 71-72' prevalence of respiratory, symptoms,,39 pulmonary function, 39 relative risk in lung cancer development, 71-72 survival after treatment for pharyngeal, laryngeal, or oral cancers, 75 Fatty acid!levels effect; of eigar,, pipe, and cigarette smoke in dogs„21fi: effect, of smoking, 12 Fetal mortality effect of'maternal smoking, 123-135 epidemiological studies in smokers vs„non- smokers, 126-132 Fibrosi's in pipe/eigar smokers vs. cigarette smokers and nonsmokers, 217. Fitness tests various, smokers vs. nonsmokers„245 Framingham study interaction ofl smoking and other risk factors in CHD;,8 Gastric secretion effect of nicotine in laboratory animals,, 158,159~ effect of smoking in ulber patients; 157,158 isastrointestinal disorders prevalence in cigarette and pipe/cigar smo- kers, 222 Gestatiom and low birth weighY infants, effect of maternal smoking, 103-106: Gestatlonal age effect on perinatal mortality rates in smo+ king, vs, nonsmoking m,others;, 126-132' Glucose intolerance as a risk factor in CHD, 8 Grip sttength, effect of:smoking, 241,242: H'eart rate effect of exercise and smoking, 242-246 Histological studies hrrlg cancer in U.S'~ veterans, 73 Histopathological studies in laboratory animals„49,50 in smokers vs. nonsmokers„48,99. Honolulu Heart Study interaction of smoking and other risk factors:in CHD; 8,9 ' 255

q relative risk in pipe/cigar smokers, 67;68: smoking as cause, 67' summary of retrospective studies,,206-208' Maternal-fetaLexchange polycyclic hydrocarbons and; 119 Maternal smoking see Smoking, maternal. 3-Methylcholanthrenes effects during pregnancy in laboratory animals, 117 Morbidity from chronic:bronchopulmonary diseases, 36-39 IVlortalityy compared rates for cigarette vs, pipe/cigar ex-smokers;,172,173 from chronic bronchopulmonary diseases, 36-39 from, COPD, in cigar/pipe smokers vs. cigarette smokers and nonsmokers„ 216,217 overall rates for cigar smokers, vs„ pipee smokers, 179,180 overall rates: for pipe/cigar smokers and' dbse-response relationships„180-189 overall rates for pipe/cigar smokers vs.. nonsmokers„179;180 overall rates from eancer in pipe and cigar smokers, 189 ratio in pipe and cigar smokers by age and inhalation, 184',187' Mortality rates CHD in Japanese: men and women by cigarette consumption and age at initia- tion,of habit, 7,8 Myocardial infarct incidence in European vs. American men, 99 incidence in men in I'ugpslavia„9' incidence in miners in Sardinia, 10 incidence in pipe and cigar smokers, 2'15' prevalence in smoking, vs. nonsmoking, men in Czechoslovakia, 10 and smoking,, in patients in. Leningrad hospitals, 10 Nicotine in cigar, pipe, and'cigaretrce smoke„17,7 clinical effects on offspring of smoking motfiers; 14'0,1i41 in duodenal ulcer induction in, cats„ 158,159 effect on cardiovascular, systemiin dogs, 1'7' effect on gastric secretion incats, 15$,1591 effect on gastric secretion in rats, 159 effect on heart, blood,flow in dogs, 17 effect on lactation in laboratory animals, 138,139 effect on lactation in smokers vs. non- smokers;,1'39;140 effect on lipid biosynthesis in aorta in! dogs„ 17 effect on microcirculation in atrium in cats„17 effecti on pancreatic secretions in animals, 161,162 effect on pipe/cigar smoke inhalation, L83;184 effect on rat and mouse fetus, site of action, 1211 effects during, pregnancy in laboratory animals, 115,11& experimentall studies, 16,17 in little cigars compared to:cigarettes andd cigars, 223-226,228' in milk:of laboratory anim,als,, 138,139 in milk of'smoking mothers, 139 as potentiator of duodenal, ulcers in ani- mal's„ 161-L63 Nicotine levels iniblood, new assay method, 15,23' Nicotine secretionn effect of cigar, pipe,, and cigarette smoke in dbgs; 216 Nitrogen dioxide effect on, alveolar wall cells iwguinea pigs, 50 effect on bacterial retention in, hamsters, 541 effect on rat; lung, 49,50 Nitrosamines, effect, on lactating hamsters, 139 N-Nitrosamines determination in cigarette and tobacco smoke condensate, 87,88 Obesity as a risk factor for CEID, 9 Occlusive disease smoking and, 21 Occupationn andl smoking, as factor in, CHD incidence,. 5,7 Occupational diseases asbestosis, 41 byssinosis; 394'1 coal workers pneumoconiosis, 42 Occupational exposure pancreatic cancer and„77. andi smoking, bladder cancer andt, 78 Occupational hazards asbestos exposure, 41,73 coal dust exposure„4!1 43 cotton; tlax, and'' hemp, dUst exposure, 39-41 257

dust exposure, 43',44 1007o pure oxygen exposure, 43' radiation exposure in uranium miners, 72 smoking and~ 39-44 smoking as:additive risk for COPD, 55 Otal,cancer alcohol, consumption and smoking in etio- logy of, 193 inhalation patterns and, 19 11 mortality rates in Japanese male smokers vs: nonsmokers, 74 mortality ratios for pipe, cigar, and cigar- ette smokers vs. nonsmokers, 191!-193 recurrent, incidence in smokers vs. ex- smokers, 71,74;75 relative risk ofi development in pipe, cigar,, and' cigarette smokers vs~ nonsmokers,. 191i,194,195 reverse smoking and, 7,6, smoking in etiology of', 74L76 summary of retrospective studies, 1194,195 Oxygen debtt effect of smoking, 246,247' exercise performance and, 246,247 Pancreatic cancerr occupational exposure and, 77 smoking,and, 77 Pancreatic secretions, bicarbonate content, effect of: smoking, 15'9;160 effect of nicotine in animals, 1'61,162effect of smoking,,159,160 Passive smoking, effect on cardiovascular function inidogs; 14 Peptic ulcer see Ulcer, peptic Per?natall mortality effect of maternal smoking, summary of findings, 1,34,1135 Peripheral arteriosclerosis smoking and, 21 Peripheral vascular disease smoking and,,19!-23' pH pipe/cigar smoke inhalation and, 182 of smoke in cigarettes, cigars, and little cigars; 223',2241,228 Phagocytosis effect' of cigarette smoke in laboratory animals, 53,54! Pharyngealcancer recurrent,, incidence in smokers vs. ex- smokers, 74,75 Pharyngeal fungi smokers vs. nonsmokers in South Africa, 54 Phenols inicigar„pipe; and cigarette smoke, 177 Phenylmethyloxadiazole (PNIO) protection against adverse effects of cigar, ette smoke in animals;,49;53 Physical activity as a factor in coronary heart disease, 4,5 Pipe smokers relative risk in lung cancer development,, 67.68 Pipe smoking effect on mortality and morbidity com- paredlto cigarette smoking; 171-173 in esophageal cancer d0velopment, 197,200-202 gastrointestinalidisorders and, 222 health consequences of, 179' histological effects on bronchial epithe- lium, 203',204',209 histological effects on esophagus, 200 histological effects on larynx, 1977 inhalatlonpatternsand, 184F189in laryngeal cancer development,, 197-199 in lung, cancer; development by amount smokedi, 203-206 mortality ra.ios from cardiovascular di+ seases.and,,21!5,2'16 moitality, ratios from COPD' and„21'7;219 mortality ratios from laryngeal cancer and~. 193,196,197,2000 mortality ratios from lung cancer and,. 203-205' mortality ratios from oral cancer and, 1911,193 oral cancer development and, 1i93'-195 overall mortality rates by'amount'smoked, 180+182' overall mortality rates from cancer and„ 189, prevalence in Great Britain„173,174 prevalenee:in United States, 173,174 pulmonary histological changes and, 217 Pipe tobacco definition and processing, 176, Plethysmogram abnormalities;, ini smokers vs. nonsmokers,, 22' Pneumoconiosiss in coal miners, smokers vs. nonsmokers,. 42 Pneumothorax, spontaneous smoking,and„37. Polycyclic hydrocarbons binding to DNA and RNA, 86,87' effects during pregnancy in laboratory animals„ 117:118' nraternal-fetalexchange and~ 119 Post-operative complications in duodenal! ulcer removal, smokers vs. nonsmokers, 1'57 258'

smoking„obe:sity, anesthesia and„ 39 Preeclampsia maternal smoking and, 114'2 in, smoking,vs. nonsmoking women, 142 P>:egnancy effect of maternal smoking, 103'-1422 effect of maternal smoking„mechanism ofl action, 119,120 effect of tobacco smoke, nicotine,, and carbon: monoxide in laboratory animals, 114'-118' and previous smoking habits,, effect onn infan ti bir th: weight, 112-114 timing of intluence of smoking on birth weight, 120321 Ptematurity effect of smoking„ 112. Pulmonary arterioles histological effects of pipe/cigar smoking, vs, cigarette smoking, 217 Pulmonary clearance effect,of heavy smoking; 52;53 effect of smoking, 55'5 mechanical vs. bactericidal clearance: in gpinea pigs,,53 mechanismy, in smokers vs. nonsmokers, 52,53 in monozygotic vs. dizygotic twins, 51 particle: deposition in smokers vs. non« smokers, 53' Pulmonary diffusing capacity in smokers vs. nonsmokers in Berlin, New Hampshire, 50,51. Pulmonary emphysema see Emphysema Pulmonary function in asymptomatic young men in Romania, 39 in, coal miners, smokers vs. nonsmokers,. 42,4'3' in, coal miners vs. nonminers, 42 effecti of asbestos, exposure and smoking, 41, effect, of coal dust exposure and smoking„ 41-43 effect of lung, hyperinflfttion in coal mi- ners„412,43effect on exercise,penformance in smokers vs. nonsmokers, 246',247 iniex-smokers, 39 in jet fighter pilots, smokers vs: non- smokers„43 in pipe/cigar smokers vs: nonsmokers, 217,221 pulmonary hypertension and, 43' in smokers vs. nonsmokers, 55 in smokers vs: nonsmokers in Berlin, New Hampshire, 50,511 in smokers,vss nonsmokers, under 30 years of age„50 smoking and, 38;39' ` Pulmonary histology of' pipe/cigar smokers vs. cigarette smokers and nonsmokers, 217 Pubnonary macrophagess effea of, smoking„55 Pulmonary surfactanti levels effect of smoking; 55 Pulmonary tissue histopathological differences in smokers vs. nonsmokers, 48',49 Pyrene in cigar, pipe, and' cigaret:te smoke„ 17 8' Race as a factor in coronary heart disease, 4,5,23' as a fact'or in perinatal,mortality in smok- ing vs. nonsmoking mothers, 129-132' as a factor in stillbirth rates, 124,125 Radiation exposure and smoking; as cause of respiratory can- cers„72' Radioactive particles in tobacco leaf.,, tobacco smoke, and smo- kers' lungs; 72'. Renal cancer, mortality ratio in Japanese men and wo- men,, smokers vs. nonsmokers, 77' smoking in etiology of77,7,8. Respiratory symptoms see alsoCoughy,Sputum product'~ioneffecY of asbestos exposure ini smokers vs. nonsmokers, 41 prevalence in, Duisburg, Germany by age and cigarette consumption, 399 prevalence in ex-smokers, 399 prevalence in pipe and cigar smokers, 217,220,221 prevalence in smokers vs. nonsmokers, 55 prevalence in smokers: vs. nonsmokers in Bordeaux, France, 36 in smokers vs: nonsmokers by amountt smoked, 37' Reverse smoking leukoplakia and; 76 oral,cancars and,,76 RNA binding ofl polycyclic hydrocarbons to, 86,87 Running effect of smoking; 243, 244 Sex ratio effect of maternal smoking, 135,136 Single-breath tests smokers vs. nonsmokers, 51 259'

a Smoke, cigar chemical constituents in, 177=1179 ciliotoxicity,, 218 effect of curing methods,,218',219 effect of pft on inhalation of, 183 tumorigenic activity in laboratory animals,, 210-214 Smoke„cigarette chemical constituents in, comparedl to pipejcigar, smoke, 177,178 effect of curing methods,, 218,219 effect on bacteriall retention in, hamsters, 541 effect' on bronchial' epithelium inidogs, 49 effzct on phagocytosis in laboratory ani- mais, 53,54 effectonpulmonary clearance, 51-53 effect, on rat and mouse fetus, site of action, 121 effect, on ventricular fibrillation threshold in dbgs, 13;14 experimental studies, in dogs, 13,141 reduction of adverse effects in animals by phenylmethyloxadiazole (P:1fO), 49,53 and sulphur dioxide, effect on glands in, laboratory animals, 49' Smoke„little cigar pH of; compared to cigarette and cigar smoke, 224,228 Smoke; pipe chemical constitlrents in„177,178' ciliotoxicity of, 218 effect ofI pH on inhalation of', 183' tumorigenic activity, in laboratory animals, 210-214 Sinoke, tobacco. eflfect,onair pollutioniin aircraft, 45 effect on nonsmokers, in aircraft, 45 effect on stillbirth rate in1aboratory ani- mals, 125 effects during pregnancy in laboratory animals, 1114,115 pH', of„ef fect of leafl constituents„224 tumorigenic activity, 210-214 Smoking effect on blood lipids,,11,112 effect on cardiac lactate metabolismy 13effect on leg,blood mean-flow capacity, 22'1 effect on plasma nicotine levels,,15-17' effect on precapillary sphineters„22 health hazards:of, s,imilarities, of cigarettes with little cigars„224,225 interaction withiother risk factors in CHD,. 4-111 as most important cause of COPD, 35,36' prevalence in U.S., andl Great Britain, 173,174 Smoking abstinence effect on exercise performance, 241,242;246,247 260 Smoking, maternal, as cause of birth of'small-for-dates infants, 1106-111 congenital malformations and, 136,137' effect on birth~ weight, 103'-114,119-L22 effect on birth weight, summary of find- ings, 122 effect on gestation durationt,103'-106 effect on lactation, 1!38-1411 effect on neonatal carboxyhemoglobin levels,,118,119 effect on sex ratio„13'5,136. effects: during pregnancy, 1'03-142'1 effects during pregnancy, mechanism of action~ 1:19,120 indirect association with~ small-for-dates int'ants, 110-114 preeclampsialand, 142 selective action on, fetus of certain, womenn vs. others, 131 spontaneous abortions :and,,123;124 stillbirths and„ 124,1125 timing of influence on birth weight, 120,121 Smoking,,paternal effect an infant, birth weight,,111A',1 T li Sputum prodtrction effect of asbestos exposure in smokers vs, nonsmokers, 41 effect of filtered cigarettes,,55 effect of modified cigarettes„37,38effect of plain vs. fiiteredlcigarettes, 37,38 in males by amount smoked and'type : of~ cigarette;, 37;38 prevalence in pipe and cigar, smokers,, 220,22~1' Stillbirths effect of maternal smoking, 124,125 rates in blacks vs, whites„ 124,1125 in,smokers vs. nonsmokers, 124',1125. Sudden death incidence in pipe and cigar smokers„ 215 Sulphur dioxide and! cigarette smoke, effect on glands in laboratory animals„49Swimming effect of' smoking„242,24'4 Tar contenti effect, on respiratory symptoms and venti- latory capacity, 38 Tars in little cigars, compared! to cigarettes and ci2ars, 223-226,228'. Thrombosis smoking andi, 19 Tobacco flue-cured vs: air-cured, effect on respira- tory system in animals, 217,2118 OW

Tobacco chewing leukoplakia and„75 Tobacco leaf'extQacts effect on cell cultures, 85,86 Tiacheal cancer smoking and, 71 Tteadmill performance: cardiovascular parameters in smokers vs. nonsmokers, 242-24!5' effect of vitammC; 24'5'5 oxygem intake in smokers vs. nonsmokers, 245 Triglyceride levels CHDiand, 8' Tumarigenic :activitq of cigpr„pipe, and cigarette smoke conden- sate in skin painting experiments in animals, 210-214 of tobacco;smoke, 210-2141 Ulber, duodenal mortality ratios in male cigar and pipe smokers, 222 nicotine'induced', in cats,,158,159 post-operative complications in smokers vs: nonsmokers, 157 potentiating action of nicotine, in animals,. 161I-163 prevalence in smokers, mechanism of~ acY- ion, 160! Ulcer, peptic clinical studies, 155-157 epidemiological studies, 155-157 gastric secretion, in smokers vs. nonsmok- ers, 157,; 58 increased mortality in' Japanese smokers vs. nonsrnokers,,155',15fi. mortality ratios in Japanese adults by age at initiation of smoking habit,, 155,156 mortality ratios in male cigar and pipe smokers, 222 predisposing factors, 157' recurrence in smokers vs& nonsmokers, 157 andl smoking, summary of previous find ings, 155' Urinary bladder cancer see Bladder cancer; Vascular disease, peripheral smoking and„19-23 Vascular reconstructionn effect of smoking, 22,23 Ventilatory function effect of exercise and'smoking„244';245 Ventricular fibrillation effect of cigarette s,moke in dogs, 13,14 Ventricular hypertrophy as a risk factor in CHD,, 8 Vitamin B, Z, in pregnant smokers vs. nonsmokers, 119 Vitamin C effect on treadmill performance in smo- kers vs. nonsmokers,, 245 in milk of smoking mothers;,141 in, pregnant smokers vs. nonsmokers; 119 Water hardness: and smoking as risk factors in CHD; 9;10 9U.5. GOVERNMENT PRINTING GFFICE::197:3' 727-647:/2181-d261.

. UHEN PublicaticmiNu. ( HSN1) 7-',-8704

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