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U.S. DEPARTMENT 0!E' HEALTH, EDUCATION, AN'D WELFARE Public Health, Senvrike Heal'th Services and KAentall Healfh Administration

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The Health Consequencess ofS'moking A Report' of the Surgeon ta'enerak 1971 ,TJ U.S. DEPARTMENT OF IIEALTIii, EDUCATION~ AND WELFARE Public Health Service

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Preface Tihi~sreport is acornprehensivereviewof rn~orethan 20! years of research intlo the problemi of smoking and health. This re- search has been carried on under the sponsorship of many groups ini this country andi abroad,, including governments, universities,, private research institutions„ voluntary healtli, agencies, and; the tobacco: imdustry.S'even, years ago, an advisory committee to the Surgeon General concluded that cigarette smoking is a serious hazard tolhealth and is relatedl to illness and deathl from lung cancer, chronic broncho- pulmonary disease, cardiovascular disease and other diseases. In the intervening years, a great deal of new research has been com pleted.. This has resulted, in ai growing understanding, of the bio- mechanisms whereby cigarette smoking adversely affects the hu- rnan organism and, contributes to the~ development of serious illness., It is& encouraging that cigarette consumption in this country is declining. If this decline can be maintained, it will result in better health for our population and in fewer deaths among those of' our citizens who are in their most productive years of life: JESSE L. STEINFELD, M.D., Surgeon General: ®

The H'or.l1,b report. tor for The 11uxslbe and oiti ackilo~ Ati L }:R: o£~ ti.c ANT1i0 uf~ I:. a l; ERB. Oral'. A-MeS Ceni BAkEII of BEiLE I'I O BIaG 110" BOu 1'I BORI BOU: fc Cna ~ S., C OE' En EP' Fn Fi

The \Tati'onal Clearinghouse for Smoking, and Health, Daniel Horn, Ph.D.,, Director, was responsible for the preparation of this report. Daniel P. Asnes, M.D., was consulting editor. Staff ' direc- tor for the report was David G. Coak, M.D. The professional staff has had the assistance and advice of a numberr of experts in the scientific and t'echnical' fields, both in and' outsid'e of the government. Their contributions are gratefuIly ackno«-ledged. Special thanks are dhae the following: A::of:esoN, WiiLiAM H., lP.D'. Chief; Pulmonar~yD'isease Section, University of Louis~-illeSchool, of\Iedicine,, Louisville, Ky. ANT2[oNisEti,, NtCtiaL.aS, R.,, M.D.-Ph. D.-Associate Professor, Department'of' lisherimental .l,Iedicine,McGS:ll University, Montreal, Quebec, Canada. Avf:Re:u'tt, QScait; JI.D..-S'enior 1Vledicall Investigator, VA Hospital, East Orange, N.J. AiRES; SrEPHEN M., itl.D:-Direetor, Saint Vincent's Hospital and M'edicat Center of New York, Cardiopulmonary Laboratory, New Y'ork., NLY. B:chEa, CARL, _II.D,-Director, National Cancer Institute,, National Institutes of Health, Bethesda, AiLd. P'F:«eT;, SAMUEL, ALD:-Director, Division of' Cardiolbgy, Philadellphia~ General .1 I 0 Hospi'ta1, Philadelphia,, Pa. BtxG„RtcHARD Jl,,;tL.D.-Professor of Medicine, California Institute of Tech, nolbgy, Pasadena, Ca17f: BacK, FRED G., Ph, D. Director, Orchard Park Il,aboratories; Roswell Park Memorial Institute, Orchard Park, N.Y. BoRE:v,, HOLLIS, 3T.D,-Professor of Medicine, IYI'arquette School of Medicine, Wood VA Hospital,Milwaukee; Wis. Bo[;TwEU[., ROSWELL K., M.D.-Professor of:Oncology, MoArdle Laboratoryy for Cancer Reseas•chs University of' Wiseonsin, Mad:ison,, wis., C'oaPEx„ THEonoxE;, M.D.-Diu-ector„ National Heart Ihxstitute, National In- stitlutes, of Health, Bethesda, Md., CORNFIELD, JEepntE-Resear& Prof'essorof Biostatistics, University of Pitts- burgh Graduate School of Public Health, Biostatistics Project, Bethesda, Mdl EARL, CHRISTOPHER J., M.D.-National Hospital, London, England. EPSTEIN, FREDERICK H., M.D.-Professor of' Epidemiology, University of Michigan, School of Pubiic Health; Ann Arbor,, Michi FALK, HAxa'L., Ph. D;-Associate Director for Laboratory Research, Nationall Institute of Environmental Health Sciences„ Research Triangle Park, N. C. FERRisy BIIr,rAa2c.N G., Jit., M.D.-Professor, Departmentl of Physiology, Har- vard School of Public Health, Boston, Mass. V

FITZPATRICK, 1VIARx', J., M.D:, M.P.HL-Obstetrician, Perinatal Biology and In " f'ant Mortality, National Institute of Child Health and Human Development, National Institute of Child Health and Human~ Development, National In-` stitutes of Healthy Bet'hesda,, Md. ,~ FR.A;zIeR; TbDDM.-Assistant Director; HarvardCent'erfor Communi'tyhIealthand Medical Care, Harvard School of Public Health, Boston, MAss~ GOLDSMITH, JOHN R.,, M.D.-Head, Environmental Epidemioiogy Unit„ Cali- fornia State Department, ofPublic. HealthyBerkeley,Calif'. HANNA, 1VhCHAEL G., JR., Ph. D.-Biology Division, Oak Ridge National Lab- oratory, Oak Ridge,, Tenn. HIGGiNS, IAN T. T., M.D., Mi.R:.C.P.-Professor, Department of Epidemiology, University, of' Michigan School of Public Health, Ann Arbor, Mich. HOFFMANN, DIETRICH, Ph. D.-Division of'Environmental Toxicology, Ameri- can Health Foundation, New York, N.Y. ISRAEL, ROBERT, A.-Director, Division, of Vital St'atistics, National Center for Health Statistics,, U:S!P'.HIS., U.S. Department of Health, Educationi and Welfare, R'ockville, Mdl KELLER, ANDREW Z., D.M.D., M.P:H.-Chief, Research in Geographic Epide- miology, Veterans Adininistration Central Office, Washington, D;C. KtRSNER, JosEPx, 1VT.D. Prof'essor of Medicine, Universi'ty of Chicago School of Medici'ne, Chicago, Ill'. KNOx,, DAVID L., M.D.-Associate Professor, The Wilmer Ophthalmologicall Institute, The J'ohns Hopkins University School of Medicine, Baltimore, Md. KOLBYE, ALBERT C., JR., M.D.,, JID:-Deput'y Director, Bureau of Food's,, Food and Drug, Adtninistration, U.S.,Depaltment' of'Health, Education and Wel- fare, Washington D.CJ KOTIN, PAUL, M.D.-Directlor, National Institute of' Environmental Health Scienees,, Research Triangle Park, North Carolina.. KRaM'HOi.Z, RICHARD A., MLD-Director, Instit'ute of Respiratory Diseases, Kettering Medical Center, Kettering, Ohio. LrEBOw, AVERILL A., M.D.-Pi•ofessor and Chairman,, Department of Path- ology, University of'California at San Diego, L'a Jolla, Calif. LiLiENFELD, ABRAHAM„ M.D:-Professor and Chairman, Departmentl of' Chronic Diseases; Johns Hopkins School of Hygiene and Public Health, B'altimore,, Md: MACMAHON, BRIAN, M.D,-Proflessor of Epidemiology, Harvard University School of'Public Health, Boston„Mass. McLEAN,, Ross, M.D.-Medical Consultant,, Regional Medical Program of Texas, Austiny Tex.MCMTLLAN, GARDNER C:, M.D.-Chief, Arteriosclerotic Disease Branch, Na- tional Heart and Lung Institute, Nationall Institutes of Health, Bethesda, Md. MITCHELL, RoGER S,, M:D.-Directbr; University of Colorado Medical, Center,Webb-Waring Institute for Medical Research, Denver, Colo: MURPHY, EDMOND A., M.D., Sc. D.-Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Md. PAFFeNBARCER, RALPH S., JR:, M.D. Chief, Bureau of Adult Health and. Chronic Diseases,, California State Department of Public Health, Berkeley, Calif. PETERS,, JoxN M.,, M.D.-Associate Professor of Occupational' Medicine, Har- vard University School of Public Health, Boston, Mass . PETERSON, WiLLiANr, F., M.D'. Chairman, Department of' Obstetrics and Gynecology, Washington Hospital Centler,, Washington, D.C: PETTY,, THohtAs L., 1VI.D. Assoc,iate Professor of' Medicine, University of Colorado Medical Center, Denver, Colo. - vi MC- Q l v 1

1 11 and In- i lpment' ! na1 In-' 'for andd ide- r o01' cal' Id., od el- :h f9 B gaily-t(r•rra. ['>trieKro, M.D.-Associate Scientific Director for Carcinogenesis Eti4ne<<, N:rtional Cancer Institute, National IInstitutesof ' H'ealth,, Beth- ar.aa. \I'd.. StyIU•ra•, I.rtoNARo .1I'., 3I.D.-Professor and! Hiead„Division of'' EpidemioIogy;. 4 r.~ f r<:,t'v of ~Iinnesota School,of. Public Health, Minneapolis, Minn:.. gtrtMkt., )LirtnAEr B., MLD. Coordinator;, Regional Medical Program, Uni- vhrsitv of Ciilifornia at San Diego, La,Joll'a,, Calif.StkMt tR, Jt:ae,MtAx1, 1Vi.D.-Executive Direct'or;, Chicago Board of )&Tealthyflh•alkh I:o~oarchToundationy Chicago, IlL 1'..,i,,FxWoOro. 1'.tUL B., JR., M.D:-Associate Professor, Department of Ob• a~ t andl Gynecology, University of Soutli: Carolina Medical School~ Char!'~aon. ~.~. \'~',ti ! r t t,t:~, Bt:N;tAMttv' L,, 1VT.D.-Professor of' Environmental Medicine, In- r titut,- of' l:rt~•ironmentall Medicine, New York University Medical Center, N, w lf r41, N.Y. Virroe.. \IAt•rtice, M.D.-Professor of Neurology, Department of Neurology, e'a-e AVt-stern Reserve, Cleveland, ©hio.\N'i NiCa.. 1:aNEsT L., M.D:-Presidentl and Medical Director, American Health E',+un~iation. New York, N.Y. 1'ht,- 1'fillnw~ing professional stlaff~ of~ t'he~ hTationall Clearinghouse f„r~ S~~tnok~ing and Health contributed'to~~tlhe~ preparation of th~isxe- port :~ .lridin H. Holbrook, M.D., Richard W. White, R'oliert~S~. Hutch- iirw•. 1•:1'.:ine Bratic, Annabel W. Hecht, Richard! H. Arnacher, I)on<<lii R. Shopland andl Jennie M. Jennings: Shecial thanks are~ due~ Nancy~ S: Johnstom,~ Kathrymi C~arl'y~sl~e,, 1, :. Denrent, and Mlildred HI. R'itchie.~ vii WINY`h..*e AMN :O

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Contents Page iii': ACKNOWLEDGMENTS .............................. v Chapter 1. IlltrodUction .............................. ..1. Chapter 2. Cardiovascular Diseases ...................... 15 Minter3'. ChronicObstructi~v~eBronchopulm,onaryDisease .................................. 135' Chapter -i: Cancer ................................... 231 C'~;ai~tcr 5. Pregnancy ................................ 385 Chamer• Fil Peptic Ulcer .............................. 419. Chaq)rer 7., Tobacco~ Amblyopia ........................ ~ ~ ~ 431 0 a. iz

CHAPTER 1' General Consideratibns; Preparation of' tlhe Present Doowment„ and Summary of the Report

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1 GENERAL CONSIDERATIONS T': nia jor develbpment in the modern historyoftlhee#fectsaf ,rr,oK} ng on health occurred in 1950 with the publication of four rr"r( •,r~~rt.ive studies on smoking, habits among lung cancer pa- twn, -;:,nd among controls (I„ 4, G„7)., At that time,, the question. ":1rt, smokers more likely to get lung cancer thani nonsmok- on; .1;rhough some epidemiologists were satisfied that the an- .,~~ r r•t in the affirmative, others turned for confirmation to inwhaeh t'hesmoking habits of' large popula- t: :. r, - record'ed and the populations followed to identify sub- ~~,, The first report of Hammond and Horn in 1954t_~. si~,•nificantlyelevated overall death rates for smokers, to nonsmokers.. This elevation in death rates, almost ,.c-niined to those,whosmoked!cigarettes, together with~the:c- r-)r a ~;radient according to the amount smoked, changed ~-ion f rornione concerning only liang, cancer to one concern- r;ai (ieath rates and from one concerning smoking, to one. coTacer:nedd with cigarette snaoking:In effect, the question : r:.•. .'L)o cigarette smokers have higher overall death rates ,.,,n:.niokers and'smokers, of pipe& and cigars?;" theimbliicationi of thel:at'er reports ofthe majiorprospec-:r. ;adie in the late 1950's and,early 1960's, it became clear that cIWart•t,e. ;mokers had higher overall death rates than nonsmokers, a-, v:ril as higher death rates from a number of individiZaI causes of deuth..The question then becazne,"Why?,"«'hen the Advisory Committee on Smoking and Health to: the Surgeon General was established in 1962, it undertook the evalua- tion of the scientific evidence up to that time. The:conclusion of the Cc,ngmittee in its 1,9~6'4I Repbrt was that: "`Cigarettesrnoking, is a health hazard of sufficient importance in, the United States to war- rant appr opriateremedial action.'"" Not onlxdid theC~ommitteeconclud'e that the evidence clearly showed that male cigarettee smokers do in fact have higher death rates than nonsmokers butt that the convergence of epidemiological, experimental, and path- olUricad evidence also clearly imdicateda a cause-and-effect relation- ship for several, of the implicated diseases,, particularly cancer of tlhelung and, chronic bronchQtis,,, In several ot'herimportantdis- eases, the evidence oni biornechanisrns to explain epidenlio]ogical 3

associations was felt to: be inadequate at that time to draw firm, conclusions about a cause-and-effect relationship. Three and one-half years later:,, when The Health Consequences of Smoking : A Public Health Service Review, 1967' was publi'shed;, the conclusions of'the 1964 review were taken as a starting, point,, and the nature of the task of interpreting the scientific evidence was& restated as follows : 1. How much mort'ality and excess disability are associated with smoking?' 2. How much of this early mortality andl excess disability wouldl not have occurred if people had not taken up~ cigarette smoking?' 3. How much of this early mortality: and excess disability couldd be averted by the cessation or Vreduction of cigarette smoking,?' 4'. What are the biomechanisrns whereby these effects take place andl what are the critical factors in these mechanisms? That and subsequent reviews in 1968 and 1969 have provided some answers to these questions, particularly in summariziing the evidence for various theories as to how cigarette smoking affects the human~ organism to: produce elevated disease and death rates.. At least five different processes have been suggested whereby: cigaret!te smokers experience higher mortality or morbidity rates than do nonsmokers, 1. Cigarette smoking initiates a disease process by producing progressive irreversible damage. In this case, the total effect would be approximately proportional to: the total accumulated' dosage experienced over the years. Cessation of' smoking leaves impaire& function which does not improve appreciably but does not continue to deteriorate from continued exposure to cigarette smoke. How- ever, such function may deteriorate through aging or through exposure.to other harmfull agents. It appears that such a relation- ship probably exists for chronic obstructive lung disease and posr sibly for the development of atherosclerotic heart d7sease.. 2. Cigarette smoking initiates a disease process with continual repair and' recovery until some critical'! point is reached at which the process is no longer reversible: The totall effect would therefore be affected', to some extent by accumul'atedl exposure but would be affected also by the level of' contemporary smoking. Cessation of smoking, would result in a rapid reduction of risk provided the critical levell ini'tiatimg, an irreversible process has not been . reached. The evidence supports this kind of mechanism accounting both for the high d'ose-response relationshipl in lung cancer and for the reduction in risk frorn lung cancer among ex-smok:ers: 3. Cigarette smoking promotes a disease process either by provi:ding positive support to the development of a pathological condition or by interfering witlh and diminishing the normal capa- . 4

0 bAl.,IN , ,:, rF-„ ~.,-tranism to cope with and defend against adiseasefi.,r ~~ "f i~ i1 maV take place by promoting the development of a ~t;c1i ;~• ~+1 ,ii<e:rsetoaclinficaIlyrecognizable one, by promoting a, ;t:,te to a more severe form, or by increasing fatality rat.* ;,•%-O,•+~ disease states. This type of mechanism could ae- ~s;a„~t~rrr+rle~tl, ~7 increased mortaIi~tyratesfora numberofse- ., r~ :+ + s i or which there is no evidence that cigarette srnoking, r•++IEPin init'iating, the disease.S~ome of the ex~cessmor- W. , :!i n i ectious respiratory disease and from coronary heart take place through thi'& kind ofmechanssmf t r;c smoking produces a set of temporary conditions ,A i~:, rr+=,~ ~c the probability that acrit'ical event wil'loccurwith:o~. 6i.-~abili'ty and possibly fatal consequences. For example,, ~ ir4ence to support the theory that each cigarette cani pro- -t of condi'tionswhichincrease the probability of m~yocar-s., : ~vo through increased demand for oxygen at a time when is ,iiminished. Presumably,,once the supply/demand irmL :..+... :+11(?t,.iated, the probability of myocardial damage would normall level. Cessatian of' smoking should have an. ,~r,~'X+iiate effect of'reduci'ng the risk sharply for morbidity produced through this mechanism. r. cLe smoking, may be artificially related to excess dis- icath b~~ way of a clbse association with some other con- ~' --s;)o,-;ure which is found at a high levell in smokers, but ii:~ ni+ kers„and is itself responsible for the disease. The one ;, ,ieath for which cigarette smokers have elevated deathh generally interpreted in this way is cirrhosis of the :::cti mo;t heavy consumers of alcoholic beverages are smok- +i:+i >iince aleohol consumption is an important part of' the nat produces cirrhosis of the liver, the high rate of cirrho- .,r7if4ias,rcigarettesmokersi~sdiscounted as,resulting, from thisni, ci ()f artificial relationship. Some authors have proposed that there may be genetic factors that link smoking andi certain diseases in this fashion., Obviously, the cessat'iion, of'smokingwoul~dhave no effect on morbidity or mortality from diseases which are artificially related to smoking.. These different ways in which, cigarette smoking can be related t'oie1e%,ated morbidity and mortality rates are important considera- tions in attempting to estimate the potential public health benefits of giving up smoking. Fbr some types of relationship, there would haeno benefsts;for some,, rather small benefit'~s~~;for some,substan- tial' benefits, taking piace over a long period of time; and for others, substantial benefits taking place rather rapidly. During the past few years, a sharp reduction has taken, place in the cigarette smoking habits of the U.S'. population. The hTla- 5'

tional Center for Flealth~ Statistics has recently published a com- parison of smoking habitls in the U.S. in 1955 and! 1966 based on two large scale! household! surveys! (5). These! showed a drop, in, cigarette consumption in men under 55 years of'age but no appre- ciable change among those 55 or over. Among women, every age group showed an increase in the eleven year period. A recent sur- vey conducted for the National Clearinghouse forS'moking and~ Health, based on, a much smaller sample (approximately 5,000 intlerviews), was conduetied' in the Spring of 1970 (3) (itable 1). Eveni with the smaller number of cases„ it is clear that a much larger drop took place in the four years from 1966, to 1970 than in the eleven years fromi 1955 to 196'6. The drop extendedl to the age group 55-64 among men, again with no appreciable d'rop among men over age 6'5'. For the first time, the increase in, smok- ing among women leveled off,, or even dropped slightly among women under 55. The increase among women over 551 was of a lesser magnitude than previously observed. TABLE 1. Percentage of Current Smokers of' Cigarettes (regu- larly or oc~casional'ly)! by sex and age. U.S., Surveys: 1955axtd. 196B (CPS-Current' Polrutation Surueys) and 1970 (1VCSH- Surveyconducted for National Clearinghouse for Smoking & Healtli).' Male Female. A'Se. CPS 1955~~ CPS 196I6~ NCSH 1~970~. CPS 1955~ CPS' ~1966~ NCSH 1970 18-24 ---------- 53.0 48;3 2 47.0 33.3' 34.7 '31,1 25-34 ---------- 63.6 58.91 46.8' 39.2 43.2 40.3 35-44 ---------- 62.1 57.01 48.6' 35.4 41.1 39.01 45-54 ---------- 58.0 53.1 43.1 25171 37.3 36,0 55-64 ---------- 45.8 46.2 37.4 13A 23.0 24'.3 65 - ---------- 25.8 24.6 23!7 4':7 8.11 11.8 '1955' surveyy basedd onn approximately45;000 persons; 1966 survey,basedl onapproximately. 35,0000 persons; 1970 survey basedd onn approximately 5~000 persons. " Fist imated. With the massive changes in smoking behavior which have taken place among adults in the past few years, largely as an expression, of the desire to protect health, changes should be ex- pected in mortality rates among those groups which have experi- enced the greatest reduction bothiln accumulated dosage: and in concurrent dosage. An analysis of U.S: mortality rates for 1970 and the years to follow will provide a, very valuable addition to the knowledge concerning the effects of smoking on death rates. PREPARATION OF THK PRESENT' DOCUMENT Following the publication of Smoking and Health-Report of the Advisory Committee to the Surgeon, General--.iln 1964, the fol- 6

ents were published as reviews of'the medical litera- •,r., r, nin~* the health consequences of'smoking, as called for Lai«-89-9!2: 1. 1T,_allth Consequences of Smoking, A Public Health Serv- 1.e~-iew: 19671. Flealth Consequences of Sinoking; 1968' Supplernent to ;., 1967 PHS R'eview.. ll alth Consequences of Smoking, 1969 Supplement to 11,67 PHS Review. -,, ti-)cumentsr.eviewed themedicallitleraturee which had =,'idished since the original Surgeon General's Report. This ot' publhshing a supplement to a supplement has become irtrticularly ini the light of the lackof availability of the rovie«•.s to the general! public: Therefore, when Public .. ...;-'°2''was signed i'ntolawon Apri~l1, 1970 calling, , for an:, ":(,ilth interval between the last report andl the new re- ; ~ itci'sion was madeto~ review the entirefieldl with em- ; u,e most recent additions to the literature.. ~,.~innad Clearinghouse forSmokin'g and Healthi ha& the 1 , ,i;iit% - forcontinuousrnonitoringandr cornpilati~on of the rarure on the health consequences of' smoking: This is through several mechanisrns: +<t:~ntifac r~eviewcorporation is on contracttoext'ract amti- :nukintr and health frorni the medical, and scientific litera- :a World. This organieationi provides a semi-weekliy acces- ith abstracts and copies of the various articles. Trans- :ffe: oalled for as needed. A;rticles of pertinence are identi- ;%. :t .,~eries of code words and phrases, \iitional Library of Medicine; through the Medlars sys- the Nationali Clearinghouse for Sinokiing and Healthi a r'. r: i;lY li:;ting, of articles in the smoking and health area. These. "re iv\ric«-ed,andpertiinentarticles aa•eord'ered•. Staff members keep, up with the current contents of inedical ;cierltific literatur•eand identify articles of pertinence. Ihi~i'tialdraft's,of'the present reviiewwereprepared by Clearing- house stafff and consultants who reviiewed the previous report's and i'ripntifi'ed those articles which have been important in, the develop- nw>>t of knowledge ini this fie1dL These were abstractedl and' placed. into tabularr form, andl a draft text of the report was prepared. 1•he tirs ', drafts of' the individual chapters were sent to experts for review;, criticism, andl comment with respect to the articles re- viewed,, those articles not included, andl conclusions. The drafts were then revisedi on the basis of these comments and rewritten, until' they met with general approval of the reviewers. The final'. 7 I ~% .

d'rafts were reviewed' as a whole by the Directlor of the Nationall Clearinghouse for Smokingandl Health, the: D!irectoroftheNar tional Cancer Institute, the Director of the National Heart and Lung, Institute, the Director of the National Institute of Environ- mental Health Sciences, and by six additional experts both within and outside of the Public Health Service. SUMMARY OF THE REPORT CARDIOVASCULAR DISEA'SES Coronary Heart Disease 1. Data frorn numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing tlo the development of coronary heart disease, including fatal CHD and its most severe expression, sudden an& unexpectedi death. The risk of CHD incurred by smoking of pipes and cigars is appreciably less tliani that incurred' by cigarette smokers. 2. Analysis of' other factors associated' with CHD1 (highi serum cholesterol, high biood' pressure, and physical inactivity) show that cigarette smoking operates independently of these other fac- tors andl can act jointly with certaini of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the patliophys'iol'ogical changes of pre-existing coronary heart disease and' therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated withi a, significant increase in atherosclerosis of the aorta andl coronary arteries. 5. The cessation of smoking is associated with the decreasedl risk of' d'eathi from CHiD. 6. Experimental' studies in animals and humans suggest that cigarette smoking may contribute to the deveiopment of'CHiD and/ or, its manifestations by one or more of the following rnechaniisms : a~ Cigarette smoking, by contributing: toi the release of catecho- lhmines, causes, increasedi myocardial wall tensilon„contractionvel'ocity; and heart rate, and'thereby increases the work of the heart andl the myocardial demand for oxygen and other nutrients. b:Amongilndividualswith coronary atherosclerosis, cigarette! smoking appears to create an iinbalance between the increased needs of the myocardiumi andl ani insufficient increase in cor- onary blood& flow andl oxy genation. c. Carboxyhemoglobin, formed from the inhaled carbon mon- a.

P linishes the availability of oxygenito the myocardium ;,,l.;o contribute tolthe development of atherosclerosis. ~, •1,ilirmc~~nt of pulmonary function caused by cigarette ma s contribute to arterial hypoxemia, thus reduicing ~-:1,1,nn~t of ox~~y~gen, available t~o~~the~myocardi,um~o r!I- ~~iuoking may cause an increase in platellet adhesive- . .,1rirh might contribute tolacute thrombus formatiom ~';~tratr»ient' of'R~ecent A~ddi.tions~ toKnoivl'edg,e Relati'rzg~ ~,>>(l C'orona7y Heart Disease.-A number~ of~~ epidemi- ti~~;have~ prov~idledl additional evid'enc eence conc~erni~ng~ciga~- r. as a significant risk factor in the development of perimental studies on animals have suggested that ciga- king, particularly the absorbed nicotine and carbon mon= ',ntril,utes to the development of' atherosclerosis. ~rr>:clilar Disease~ : i-r,m numerous prospective studies indicate that ciga- ::i, ,, iy associated with increased mortalit'y, from cere- (6,ease. -iniental evidence concerning~ the relationship of srnok-~ ~; ck,•,1ei,rovascul~ar disease is, at~ present insu~Pficient to: a11bw~ concerning, pathogenesis., However, some of th~e~ ~~ --,gical cons~~it3erations~ discu~ssed' concern2ng, CHiD~ may~ t r.:,in to the relationship of smoking and CVD, particularUy .. inriarctian.~ t'ic Aortic Aneurysm smoking has been observed to increase the risk of ~:n>>onsyphilit'iic aortic aneurysm. , ~lib,,~ rad Vascular Disease. 1'. llnta, from ai number of retrospective studies have indicated tl,at cigarette smoking is a likely risk factor in the development of E eripherall vascular disease. Cigarette smoking also appears to be al factor in the aggravation of peripher.all vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood iiuw and peripheral vascular resistance. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE 1. Cigarette smoking is the most important cause of chronic obstructi~~~e bronchopulmonary disease im the United States. Ciga- rette smoking increases tlhe risk of d~ing fromi pulmonary ernphy- senra and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including coughy sputum pro- 9 .4.~;.-r "'Nv:,.177" 4' WL ,.9s-..:

duction, and' breathlessness, when compared with nonsmokers; Ventilatory function is decreased in smokers when compared withh nonsmokers. 2'. Cigarette smoking does not appear to be related to deathh from bronchial ast'hmas although it may increase the frequency: and severity of asthmatic attacks in patients already suffering from this diisease.. 3. The risk of'developing or dying frorn COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers, while clearly: less than that among cigarette smoker.s.. 4. D+ x-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessat'ion, of' cigarette smoking, is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence:. 5:., Young, relatively asymptomatic, cigarette smokers show measurably alt'ered' ventilatory function wheni cornpared~, with non- smokers of the same age. 6. For the bulk of the population of the United' States, the: im~ portance of cigarette smoking as a cause.of COPD is much greater than that of atmospheric pollution or occupatilonall exposure. How- ever, exposure to excessive atmospheric pollution or dusty occu- pational materials and cigarette smoking may act jointly to pro- duce greater COPD morbidity and mortality. 7. The results of experirnent'sin both animals and hurnans, have demonstrated that the inhalation of cigarette smoke: ils associated with acute andl chronic changes in ventilatory function and': pul- monary histology. Cigarette smoking has been shown to alter the mechanisrn of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that, cigarette, smokers who die of diseases other than COPD have histolbgilc changes charac- teristic of COPD in the bronchiall tree and pulmonary parenchymaa more frequently than d'o nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pul- monary complications more frequently: than nonsmokers., Summary Statement of Recent Additions of' Knozul'ed'ge Relat- ingto Chronic Obstruct'iveB'ronchopulmonarg~ Disease:-Stu~dieshavedemonstlratedthat ci~garet't'esmokers showinereasedl symp- toms and pulmonary dysfunct'ion as well as mortality from COPD when compared to nonsmokers. Investigations of allphal-antitryp- sin deficiency in relationship to pulmonary emphysema have suug- 10

,,,I th,tt ~ cigarette smoking may act~jointly~with: heredita~ry~ fac- t= r~ :r the pathogenesis of pulmonary emphysema. A pathological ~,n anim~als~ has~ shown that long~-ter~m~ inhalation of'ci'garrette~ ,tnu~oke~ procdnces~~ lesions characteristic of~ pul}m~ona.ry~ emphysema., C'A hICEx fu)liJ (.~nI2CE)'• 1. Ii:pidemiologirial' evidence derived from a number off prospecr ti•o, .wd retrospective studies, coupled with experimentlal' and' evidence, confirms the conclusion that cigarette smok- i; the main cause of lung cancer in men. These studies reveal t i1:.c th(P risk of developing, lung cancer increases with the number ,rci~carettes smoked per day, the duration of smoking, and earlier i~:.rtion, and dilminisheswith cessation of smoking. '. C'irarettesmokingisa cause of lung cancer in women~ but ::cV-)nnts for a smaller proportion of the cases than in men. The n(,rt tlity rates for women who smoke; although significantly r:~.,.•her than for female nonsmokers, are lower than for men who <n10ke. This difference may be at least partially attributable to ;if~:rencesin exposures,: the use of fewer cigarette& perday,, the1_1<e otfiltered and low "tar" cigarettes, and lower 1'evelsof inhal'a- ' :(ai~ \ evertheless, even when women are compared with men who. : pnarently have similar levels of exposure to cigarette smoke, the. n)rtaliO, ratios appear to be lower in women.. :~. Ttieriskof developing lung cancer among pipeand/orcigar~naokery is higher than for nonsmokers but significantly Iowerthan for cigarette smokers. -1'. The risk of developing lung cancer appears to be higher among smokers who smoke high "tar" cigarettes, or smoke in such a manner as to produce higher levels of' "tar'"' in the inhaled smoke. 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers. There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have beeni observed' among urban populations when, compared, with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of' lung cancer is presently inconclusive. Fac- tors such as occupational and smoking habit differences may also contribute to the urban-rural difference observe& Detailed epi- demiologic surveys have showni that the urban factor exerts a, small influence compared to the overriding effect of cigarette smok- ing in the development of lung cancer. mI

7. Certain occupational exposures have been found to be asso- cilatled with an increased risk of dying, fron7i lung cancer. Cigarette tobacco smoke. Lung cancer has been found in dogs exposed to t'he inhalation of cigarette smoke over a period of more than 2' years. smoke or its component compounds, have confirmed' the presence of complete carcinogens as we111 as tumor initiators and promoters in~ tracheal instillation or impIantatiion, and inhalation of cigarette cancer so as to produce very much higher lung, cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Ekperimental studies oni animals utili'zing, skin painting, smoking interacts with these exposures in the pathogenesis of lung Cancer, of the Larynx 1I. Epidemiological, experimental, and pathological studies support the conclusion that cigarette smoking is a significant fac- tor in the eausationi of cancer of the larynx. The risk of develop- ing laryngeal cancer, among cigarette smokers as well as pipe and/ or cigar smokers ils significantly higher than, among nonsmokers:. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibiy slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed' to produce premalignant and malignant changes in the larynx of hamsters. Oral Cancer 11. Epidemiological andff experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, iis causally related to cancer of ths lip. 2. Experimental studies suggest that tobacco extracts and to- bacco smoke contain initiators and promoters of cancerous changes in the oral cavitg.. Cancer o f the Esophagus 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of' cancer of the esoph- agus. The risk of developing esophageall cancer among pipe and/ or cigar smokers is greater than for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly Iower.. 2'. Epidemiologicali studies have also indicated an association between esophageal cancer and alcohol consurnption, and that alcoL hol consumption may interact with cigarette smoking. This corn- 12

of exposures is associated with especially: high rates of cancer of the esophagus. eari ro r o f the Urinary Bl'adder and'Kidney 1i., Epidern2olbgical studies have demonstratedi ani association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancer of the kidney is less& clear-cut. `?, f'linicall and pathological studies have suggested that tobacco smoking may be relat'edI to alterations in the metabolism of tryp~ ±cjahan and mayinthi'swaycontribute th~erebytothed'~evelopment ()f urinary tract cancer. ('%tnc•~li• of the Pancreas l:I)idemiological studies have suggested an association between cigarette srnoking and cancer of the pancreas. The significance of the relationship is not clear at t'his tirne.. •uarzniary ,Statement of Recent Additions of Knowledge Relating S,rz ()1; i ng and Ca~n¢er.-Epidemiological studiieshave : confi~rmedlth~atci;;arette smokers incur, an increased risk of dlying from lung, ean- cer and that those smokers who switched to; filter cigarettes incur a'esser risk. Pathologicall studies have showni that cancer of the iuag and cancer of the larynx have.been found in animals exposed to the long-term inhalation of cigarette smoke. SMOKING AND PREGNANCY .l'laternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birthweight and -in increased incidence of prematurity, defined' by weight albne. There is strong evidence to support the view that smoking mothers have a significantlly greater number of' unsuccessful pregnancies due to stillbirth and neonatal death as cornpared! to~ nonsmoking mothers, There is insufficient evidence to support a comparable statement for abortions. The recently published ,Second Report off the.1958' British Perinatal Mortality Survey, a carefully: designedd and controlledl prospective study: involving large: numbers of patients, adds further support to t'he conclusions. PEPTIC ULCER Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater pept'ic~ ulcer mortality ratio. Theses relationships are stronger for gastric ulcer than for duod'enall ulcer. Smoking appears to reduce the effectiweness of' standard peptic ulcertreatrn~ent and to slow the rate of ulcerheaTiing. 13

TOBACCU AMBLYOPIA Toba~ccoarmbl'yo'~pia is presentlxa, raredisordl~ri~n the Uni~ted'i States. The evidence suggests that this disorder is related to nutri- tional or idiopathic dleficiencies in certain, detoxification, rnec'ha} nisms, particularly in handling the cyanide component of tobacco h k smo e. INTRODUCTION REFERENCES' (1) DOLL, R., HILL, A. B., Smoking and carcinoma of the lung. Preliminary report. British Medical Journal 2: 739-74'8, September 23,, 1950. (2) HAMMOND, E. C., HeRNy D. The relationship between human smoking habi'ts' and death rates. Journal of the American Medical Association 155:'1316-1328; August 7, 1954. ) (3) HoRN, D. Address given at National Conference on Smoking and Health„ Sani Diego, Califl, September 9-111, 1970: 13 pp, (4) LEVIN, M. L., GOLDSTEIN~ H., GERHARDT, P. R. Cancer and tobacco smok- ing. A preliminary report. Journal of the American Medical Asso- ciation 143 (4) : 336-338, May 27, 1950. (5) NATIONAL CENTER'FOR HEA'LTHi STATISTICS. Changes iniciga2'ette smoking habits between 1955 and 1966. U.S. Department of' Health, Education,, andl Welfare, April 1970; 33 pp. (6) SCHREK, R.,, BAKER;, L. A.,, BALLARD, G. P., DOLGOFF;, S., Tobacco smokilLg, as' an etiologic factor in disease. I. Cancer. Cancer Research 10'c 49-58, 1950: (7) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic factor in bronchioggnic carcinoma. A study of'six hundred and eighty four proved cases. Journal ofl the American Medical Association. 143!(4) : 329-336, May 27, 1950. 1'4

Contents Page 21 `tudies................................ 38 iu,trt Disease Mortality .................. 38 ~..... ..~..... Ileail Disease Morbidity 39 ...... .•ctive St'udies............................... 401 . .• raction of Cigarette Smoking and Other CHD 40 anrl Sex•um, Lipids ................... ~~ ~ ~ 41 _ ,iu(i Hypert'ension .................... 41 . ,incd Physical Inactivit................. 41 ~~ ~ . .. ...... Taiicl Obesity - 43 ~ ~ ~ .............. .. . - :, •ucicll Electrocardiographic Abnormalities. 47 .~.~. ..~ . anri~ Heart P'ate................ ~~-sation of Cigarette Smoking, on C'oronary 47 47 . )!ral Hy1)oth~esis......................... I~el~iting Smoking, Ather.osclerosis, and 48 52' tZuclies Concerning, the Relationship of' a rt Disease and Smoking ................ 5:6 :<cul~lr Effects of Cigarette Smoke and. 56 ~~ Blhocl Flo«• .............................. 58' ~ ~ i: .,~4ctaiar Effects of Carbon Monoxide ......... 59 ~~~,,~t• Snl~oking on the Formation ofA~t'herosclerot'ic~ 63 f ~ . 1. ,`(,ctof Snlok~ino• oni Serum Li~pidLev~~el'& ........ ~ l:!i~,,ct of Smoking'onThrombosis .............. 65. 66 A1,eas of~ Inhresti~gation.........~...~........~.. 66 ~ <<r ;:: cular Disease ............................... 66' Aortic Aneurysm ........................ 67 Artei•ioscllerosis ........................... 72 1"A;)eninieibtal Evidence............................ . 73' 7::!n,mboan(,-iitis' Obliterans ~ ~ ............... 73' ~ ~ .............. 5un~mai~ and Conclusions ............................. 74! 117 .I

Page Coronary Heart Disease ...........,.......,........ 74 Cerebrovascular D'isease ........................... , , , 7& hTonsyphilitic Aortiic Aneurysm~ ..................... , ,, 7& Peripheral Vascular Disease ........................ 75 References.............................................. 75. I FIGURES ll. National Cooperative Pooling Project, Inter-Society Com- mission for Heart Disease Resources ............... 23 2. Risk of' coronary heart disease (12 years)~ according, to cigarette~ smoking habit and presence of "predisposing factors"' (men 30-59 at entry). Framingham Heart 3. Estimated coronary heart disease death ratios in a 17-511 year foldow-up, and freq;uencies of paired combinations of six high-risk characteristics in college, for all ages 24 at death .......................................... 25. 4!. Relationship between smoking, status and serum choles- terol level at initial' examination, and, incidence of clin- ical coronary: heart disease in men originally age 40-59' free of definite CHD. Peoples Gas Light and Coke Cbmpany Study; 1958'-1i962'........................ 43 5. Average annual incidence of first myocardial infarction among men in relation t'o. overalll' physicalactivity,, class, andi smoking habits (age-adjusted'. rates per 1,000') 44. LIIST' OF TABLES (A indicates tableslbcated in Appendix at end of Chapter) 1. Sudden death and acute mortality with first major coronary episodes .............................. 23' 2. Coronary heart disease mortality ratios related to smoking-prospective studies .................... 26' & Sudden death, from coronary heart disease related to smoking........................................ 30 4. Coronary heart disease morbidity as related to smoking.......................................... 32 5. Coronary hear.t disease morbidity as, related to smok- ing-angina pectoris-prospective studies ....... 37 A 6'. Coronary heart disease morbidity and mortality- retrospective studies .......................... 93 A 7. Differences in serurn lipids between smokers and non- smokers......................................... 98 1a

rQge 74 75. 175'. 7 75. 4 A& 0 LIST OF' TABLES ('CONT.), (A indicates tables lbcated in Appendix at endiof'Chapter): A 8. Blood pressure differences between, smokers and non- Page: srnokers............................................. 1!03 9. Deatli rates fromi coronary heart disease, by systolic blood pressure : ILW-U mortality study, 1951-1961 42 10. Death rates fromi coronary heart disease, by diastolic blood pressure : ILWU mortality study, 1951-19611 42' 11. Death rates f'rom coronary heart disease, among hy- pertensives and nonliypertensi'ves': ILWU mortality studly, 1951-1961 ............................. 4'2' 12. D'eath rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU1 mortality study, 1951L1961....................... 45'. 13. D'eathi rates from coronary heart~ disease, by electro, cardiographic findings in 195111: : ILWU mortality study, 1951-1961................................ 45: 14. 1958 status with respect to heart rate; blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease): Peoples Gas Com- pany Study, 1958!-1968........... ........... .. 45 15. The effect of the cessation of cigarette smoking on the inciidlence of'CHD . . . . . . . . . . . . . . . . . . . . . . . . ... . ., 46 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age,, maximum amount smoked; and: age started smoking, 46' A 17. Incidence of new: coronary heart disease by smoking category and: ~ behavior type for men 39-49 years A 18. Incidence of new coronary heart disease by smoking category and'l behavior type for men 50-59' years 19'. Autopsy studies of atherosclerosis ................. A 20. Experiments concerning the effects of smoking and 105 106 53 nicotine on animal cardiovascular function ...... 107 A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of hurnans.. 113 A 22. Experiments concerning the effect of nicotine or smoking on catecholarnine levels ................ 1119 A 23. Experiments concerning the atherogenic effect of nicotine administration ......................... 120 19.

LIST OF TABLES (CONT.) (A indicates tales located ini Appendix at end of Chapter) Page 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia .......... 64 A 25: Experiments concerning the effect of smoking andd nicotine upon blood lipids (Human Studies) ...... 123 A 25a. Experiments concerning the effect of smoking and nicotine upon blbod lipid§ (Animal Studies)~ ...... 127 A 26: Experiments concerning the effect of carbon mon- oxide exposure upon blbod' lipids. ................. 129 A 27. Smoking and thrombosis ......................... 130 28. Deaths from cerebrovascular disease relatedi t,o smoking ..................................... 68 29'. Deaths from nonsyphilitic aortic aneurysm related to smoking-prospective studies ................... 711 A 30. Experiments concerning, the effect of nicotine and smoking upon the peripheral vascular systemi .... 133 20

r 4 - I1r1TR0DUCTIOhTI Coronary Heart Disease (CHD) cuts short the lives of many men, intheWestern World in their primeprodluctive years. More Americans die from heart disease than, from any other disease. In 1967i, in this country, a total of' 345,1154 men and 227,999 womeni were classified as dying of arteriosclerotic heart disease (ASHD) (196),a category which consi6ts largely of what is commonly: called CHD. During the years from 1950 to 1967,, the age-adjusted death rate from ASHD, increased 15.1 percent (196,197). Besides the many deaths attributed to CHD, much morbidity: results from this disease. The National Health I;xamination Sur- vey of 1960-1962 estimated that 3.1 million American adults,, ages 18 to 79, had definite CHD and. 21.4 million had suspect CHD, together representing about 5 percent of the populationL It vTas further estimated that of Americans under age 65;, almost 1.8 mil- lion had definite CHD and 1.6 million had suspect CHD1 (195).There are severall manifestations of CHD, all related in part to the basic process of severe atherosclerosis, a disease of arteries in which fatty materials (lipids) accumulate in the form of plaques in the walls of medium and largearteries. This process, as it occurs in the coronary arteries, leads to stiffening of the wall and narrow- ing of the lumen which, when severe, result in a diminution in the blood supply to: the cardiac muscle. Angina pectoris, a major mani- festation ofCHD; resultsfromd'im2nution in blood supply relative to the needs of the myocardium. If the blood supply to, a portion ofthe myocardium. is completely obstructed., due for example to the formation of a thrombus at the site of atherosclerotic narrowing, necrosis or deathi of a portion of heart muscle may occur. This occurrence is known as a myocardial infarction. In many cases, a dlisturbance of cardiac rhythm occursat, thetimeofthrombosis;, and the patient may die immediately. It is estimated that approxi- mately 25: percent of patients suff ering coronary artery occlusion die within the first three hoursfoldowing the occlusion: (table1)~ (88). Not infrequently, sudden death occurs in patientswithi severe coronary atherosclerosis but without a demonstrable arterial occhz~ sibn. In these cases, it is thought that the, meager blood flbw to: a portibn ofthemyocardiurn becomes so diminished with respect to cardiac needs as to lead to a fatal arrhythmia, as well as to, per- haps, a myocardial infarction. 21

CIOARETTE SMOKINO(S) AT ENTRY-WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (H)-AND TEN YEAR INCIDENCE AND MORTALITY RATEB. 7,594 WHITE MALES AGE 30w-59-AT ENTRY, POOLIMG PROJECT - 171 RATE FIRST MAJOR + RATE ALL CHD DEATHS ' - PER 1,000 CORONARY RONARY EVENT j-( PER 1,000 150 - 150 - y,, 100- 92 ~tr{~ 85 I76i:`E;~ \\ 1. 100 - 52 \ 50- 45 50- 49 gum 20 \ ~i 22 24 A 22 0- 0 - i..~~ `~'~ #ar,lll 82 RISK NONE S C OR H S+C OR C+H C+H NONE S C OR H S-{-C C+H C+H FACTORS OF 3 ONLY ONLY S-kH -},S OF 3 ONLY ONLY OR S-}-H -}-3 NUMBER 28 8 97 74 167 31 82 17 50 41 90 12 42 OF EVENTS NUMBER 1,249 2,018 1,302 1,794 384 595 1,249 2,018 1,302 1,794 384 595 OF MEN National Cooperative Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal M1, fatal-MI, and sudden death due to CHO) and any coronary death. U.S. white males age30=59 at entry. All rates age-adjusted-by 10-year age groups to the U.S; white mafe po ulation 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cho- - lesterol leuel. or this latter analysis, the following cutting points were_ used: - - (a) Gigarette smoking S -any use at ertry (b) Serum cholesterol C - 250 mg./dl. (c) Diastolic blood pressure H - 90 mm. Hg. - SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). ±wtur.-..~sh+,. 40 1S3(.1Ceo

FIGURE 1-National Cooperative Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHI)) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cholesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking-S-any use at entry (b) Serum cholesterol-C-?250 mg.fdl. (c) Diastolic blood pressure-H-?_90 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). TABLE 1.-Sudden death and acute mortality with first major coronary episodes Author, year,_ Number and Number countrg, type of Data of reference population collection Event events Proportion per 1,000 events (as calculated on the basis of age= Comment a3justed rates) Pooling Project, 7,594 males males 30-59 Medical exam- ination and All first major coronary episodes, nonfatal and fatal. 601_ 1,000.0 American Heart years of age at entry. follow-up. Sudden death (death within 3 hours of onset Association Ten-year of acute illness). 123 246 5 , - - - 1970, - experience. All acute deaths with . U.S.A. first episodes. 165 329.3 (88).... . . .... . Sovace: Inter-Society Commission for Heart Disease Resources (88). Representative references include: (54. 04, 1;8, 177) and others liated as 6a-6k in Inter-Society Commission for Heart Disease Resources report. g0TS94c0 Data from the Pooling Project, Council on Epidemiology. American Heart Association, a national cooperative project for pooling data from the Albany civil servant, Chicago Peoples Gas Co., Chicago Western Electric Co., Framingham Community, Los Angeles civil servant, Minneapolis-St. Paul business men, and other prospective epidemiologie studies of adult cardiovascular disease in the United States. ~~ •

300 2,200 307" CIGARETTE SMOKING: = NONE 77'4Ufj >1 PKG./DAY' 103 •' 87 L- OBS. EXP. 37 19 50:8 30 34'.4 123 NONE ANY ONE ANY' T1MO' PREDISPOSING FACTORS (CHOLESTEROL 3250i HYPERTENSION, DIABETES). *SIGNIFICANTLY DIFFERENT FROM "NONSWIOKER!' P<.05 FiGuRE 2-Risk of'coronary heart disease (12 years) according't'o~eigaretlte smoking, habit andl presence of "predisposing, factors" (men 30-59 at entry).Framingham Heart Study. SouucE: Kannel, W. B., et al. (:94). Numerous epidemiological studies have indicated t'hat cigarette smokers have increased mortality ratios for CHD ;; that is, cigarette smokers show significantly increased deat'h rates compared With nonsmokers (table: 2')~. The risk incurred by cigarette smoking', in- creases With, increasing dosage and,, as measured by rnartality ratias, iis' more marked for men in the younger age groups, under age 60; although the' absolute increment in death rates experieneedl by smokers over that of nonsmokers continues to increase with, increasing,age: Table 2' lists the mortality: ratiosf©und in the major studies. Certain of'these studies, i'nc'luding, those' at Framingham, Massachusetts, the Health Insurance Plan of New York City (HIP)i, and at Tecumseh, M!ichigan, have analyzed morbidity as Welll as mortality from CHD and have indiicatedi that the risk of' developing fatal and nonfatall CHD' is greater among cigarette smokers than among nonsmokers (tables 3 and 4):. Conflicting evidence has been published concerning the relationship of ciga, rette smoking, and the incidence of' angina pectoris:W'hile some 24

Cig.rettes-A, No sport -A' Ht;/SVW;<12:9~ -A' No spprt -B Ht./ 34W-<12.9 -B Height <68' -B L8° 1.9 354. 1!4~ 13 245 114~ 1 3~ 1.41 . 1.0'~ 1.0 1.2 524. 1.0 ~ 668' 33 138!6 . 1.0 142' 190 136'. 483 6'6 ~, 31 1112~ 1 74I 1387 73, ~i , 552~~ 232I 175'. 85 217' 1269 . [:1t it Cigarettes. -A No sport-A~ Ht./~ W.<12~.9~. -A. HG/3rw7t<'~.12:9~ -B: Sys. BP 130+ -g~ Panent~.dMd -B~ 2.0 2.1 96' 1.7: I 321. 1:.7~ L5~ 1 1.3 122~~ 1..41 4,0 '~.491. 1.3'. 1.3~~ . ~ 53 1.0; I279 153I ~ 70~ 1.0 , 5 76. . 1.0 2221 142 6" . 391~~ 146'9. I 289. ~ 64'~ 1242' ~ 591 382'~ 243 97g~. I 201 I I 1 1338 Cigarettes~ -A, . Nosport~ -A~ Sys. BP'130} -A Sys;,BP 130+ ~ -B Height<68 -B~. Height<68 -8 2.41 181 I 1'..9~ 1.4'. 1.4~. 140 I 1.3 1~.6. 1.4. . lll'. ll0i 238 201 L.0 605~~ 0;9'. 3091 1.0~. 2451.2 144 324 442~~.. ~ 373. I 90 1265~. 17, '510 ~, 424~ 417 i 8 44 ' ';239~ 52 ~. I 390 1'A23~ . i Cigarettes~ -A~ No~.sport. -A~ Sys. BP 130+ -A~ Height <681 -B~. Parent d~sadi -B PuenFdead~, -B~ 2.5'. 2.0', 1.8! 73 69 1.5' ~ 1,.3~. 96 124 1-3~~ 1831 1.4'. 1~.0'. 277 1991 1.0~ 735.~ 110, ~1282! ~ 1.0~. 285! 1.1~ . 34'6~ 394 93 1096~ 1S~ 5!09~ ~~ 487' 1.15 I ~. 875 253~ 39: Z37~ 1~~182. Cigarettes-A~ Ht./3,wt:<:12',.9 -A ~ Height<68: -A ParentdAad -B'~. Sys. BP~~130} -B Parent'deadl -B. 1.8~ 1.9~. I ~ 7fi', 1',.3 124 ~I 1.3 1:3 I 1.6. 1.2 1.0'. 30T 102 L0 ' 149~~ I 1',.0 811 99~ 4451 502I ~ 2 .32'. 48I2. 14'3. 412 260: 134' 554I] 470: 227 gg 197 ~ lOni 1 ~ 111911 ~ 291~, 1253~ 11 A- A+ A- A+ A- A+ A- A+ A- A+ A- A+ B- B- B+ 8+- B- B- B+ B+ B- B- B+ B+ PRESENCE (+) OR ABSENCE (-) . OF' CHARACTERISTICS (kor B). Top numbers, in bars, are CHDD dlcedents with paired i combioartions of' characteristics; bottom numbers, control subiects~~.wi~~th combinations, 175 •1.81_~66',~x 524 FIGURE 3-Estimated coronary heart disease death, ratios in a 17-51 year follbw-up, and frequencies of' paired combinations of six high-risk charac- teristics in, college, for all ages at death. SOURCE: Paffenbarger, R. S!, et al. (Z1,6).. 25

TABLE 2.-Cororaary heart disease mortality. (Actual number of deaths [SM = Smokers Aut'lior, year, country, reference Number and i type of' population Data collection Follow- up (years) 1 Hammond' and Horn,, 1958" U.S.A. (77; 78).. 187.783' white males in 0 states 50-69 years of age: Question- naiTe and follow-up of death certificate. 3% Doyle et.al,,, 1964, U.S,A. (54). 2;282'males, Fram- ingham„ 30-6;2 years of age: 1',9i3'males„ Albany, 39-55 years of age. Detailed medical examina- tion,andi fallow'up4 10 8 Doll and Hill, 1964, Gteat Britain (50). Approxi- mately 41,00'0 male British physiaians. Question- naire and follow-up. of death. certificate. 10 Strobel l and Gse]1 1965 Switzer- land 3J49 male Swiss pby- sicians.. Question- naire andi follow-up of 'death certificate. 9 Number of Cigarettes/day deaths. 5,297' NS ......... ..1.00' (709) s(A~0.001)' All smokers .1.70, (3361 ) Q10 ........1'.29 (192). 10-20 ....1,.89 (86!4)'. 20-40',..... 2!.20 (604)', y4'A ......,.2'.41 (118)', 93 NS' ......,...1,.00 (20): A1lsmokers.2.40(73)', <20 ........2,00 (17)', 20 ........1.70 (20). >20 ........3,50 (36,), 1,376 NS ........ 1.00 Pill smokera .1L35 1-14' ....1L29 15-24 .... 1L27' >25'. ........ 1.43. 162 NS ........ 1L00 1-20 ....... 1.48 >20 ........ 1.76 (180). Best, 1966' Canada (2;), Approxi- mately 78,000 male Cana• dian veterans. Question- naire and, follow-up of death certificate. Kahn U'.S. male Questi'on- 83/z, 19666 veteransnaire and U;SiA., 2,265,674' follow-up (.98I).. person, years, of'death h certificate. Hirayama,: 265,118, 'Drained in- 1 1967,.. Japanesee terviewers. Japan (84). adults over age 40; , and'fallbw- up of death certificate. Kannel 5,127 males Medical'ex- 12 etal., 1969„ and.females age 30-59: amination and' U.S'.A. fallow-up.. (94)'. 2,000 10,890 NS ........1.00 (2997) Allamokers .1.74 (4',150) 1-9 ........ 1.39 (439) 10-20 ...... 1L78'. (2102) 21-39 ......1.84 (1292) >39 .......,.2:00 (266) 01 NS ....,..,.,.1'.0;0 (17) 1-241 ........1.13 (69). >25 .......1,.00 (5) 52' NS ......1L00 (27)1i, (p<0.05) SMy20' ....2.20. (~25)~s' NS ........1,00 All smokers .1.60 (13'80 ): <10, ........ .1.55' (337), 10-20 ...... 1.58I (766), >20 ........ 1.78 (277) 1 Unless otherwise specifiedJ disparities between the total number of' deaths and the sum of the individual smoking categories are due to the exclusion of' eitherr occasional, miscellaneous,, mixed, or ex•smokera. . 26 ~i~

ratios related to smoking-prospective studies ahown in parentheses)? NS = Nonsmokers] Cigars„pipes Age.variation ~ Commeata Cigars. NS..li,00 SM. .1.28 Pipes NS,.1,00 SM'..1.03 (420): (31e) 50-54 NS .,........1.00 All smokers .1.93' `10 ........ 1i,38' 10-20 ....... 2.00 >20 ........2.51 (90) (765) (35), (213) (203) 55-59. 1.00 (142), 1.85' (962) 1.38' (50) 2.04 (25'8) 2.47'(199) 60-6465--69' 1.00 (204), 1.00 (273) 1.66' (921) 1.41 (713) 1L17 (49) 1.27 (58). 1.91 (235)' 1.58'(158). 1.92 (I29) 1.56' (73). 35-4k 4,5'-64 65-84.. C!IS .........1L00 1.00 1.00 1-14 ....... ,3.73' 1.40' 1L71 15-24 ....... 4.45 1L73'. ll27 >25 ........ 1L36' 1.92' 1L58' NS..1,00 SM'. .1.45 Cigars~ 30-49 50'-69~~ 70and~ouer NS..1,00 NS ...,.....,.1.00 1.00 1.00 SM'..0.98 (16) <10 ........0:97 (18) : 1.561 (220) 1.71 (99), Pipes 10}20~. ....... ..,.1.45.(115), 1.67 (557:) ~1,29~. (94)1 NS..1,00 >20 ........ 1.851 (65Y 1.761 (184) 1.73 (28): SM..0.96' (95) Ciyars. N'S. ,.1.00 SMi..1,.04 (623) Pipes NS..1.00 7M. . L 08I (386) Data apply . only to maleas aged 4:0-49 and free of CPtD ~at entry. NS inc)ude,pipe, cigar and' ex-smokers. Prelimin-ary reportl 21'p" values speci(iedIonly for those provided by authors..

TABLE 2: Coronary heart disease mortality, ratios ( Actuallnurnber of deaths [SMi- Smokers Authon year, Number and Follbw- Number country, type.of' Data up of referencepopulation collection (years) 1 deaths' Hammond 358,534 Question- 6 14,819 and Garfinkel, males 4q5',875' naire and follow-up 1969, I females of death U:SIA.. age 40-79 certificate. (76). atentry. Paffimbar, 50,000 male Baseline 1'7-51. P146'. ger and Wing 1969 former students. int'erviewand exam- ination and matched with 2,292 U.S.A. (146) follow-up by death controls certificate. Paffenbar- 3;263 male Initial multi+ 1',6' 201 ger et aL„ longshore- phasic 1970, men.35-64screening.. U:S.A, (144). yearsof', age. andlf'ollow- up of death certificate. Taylor 2,571 male Interviews 5 46' etal., 19'~70, railroad employees and regular follow-up UIS.A, (1M... 40-59:years~ oflage.atl exam~~ ination. ent17?. Weir and' 68,153 Call. Question- 5-8 1,718 Dunn, fornia male naire.and 1970, U'.S:A'. (a05). workers 35-64 years ofageat, entry: follow-up of death certificate;, Pooling 7,427 white Medical ex- 10~ 23'9 Project, American Heart Assoc',ia. tion, males 30'-5'9 years of age at entry. aminatSon and. follow-up, 1970, U.S.A. (88). Cigarettes/day M'alea Fi emalea NS ........1,00 1L00 1-9 ........ 1127' 0.84 10-19 ...... 1L60 1.22 20-3I0 ......1:73 1.52 y4o, .,......1.77 041 PVFS~. ........ 1.00~~ 3Mi .........1.50 (385) (p<0:01) NSand<20 1.00 (1',37) (A<0OI) SM >20 ... .2.08' (1,54 ) NS' ........1.00 (4) ' <20 ........ 1.97 (20), >20 ........ 3.60 (22), b1S' ......... 1',.00 AII smokers~. .L60 a-10 ........1.39 !-20 ........ 1.67 >30 ........ 1.74 NS ......... ,1100: (27)i <10 ........1L65 (34) 20 ........1.70 (86) >20 ........ 3I.00 (68) 1'Unles~s otherwise specified, disparities~betweenithetotal number.of'deaths' and~ the sum of'the indiividual smoking categories are due to the exclusion of'.either.occasiona]J misceVlanebus;.i mixed, orex-emokers.. 28

related tosnaoking-prospeative studies (aon't.)shown in parenthesees)" NSI- Nonsmokers] Cigars, pipes Age~~.variation. Comments 40'-49~~ Ns~ ......... 1.00: 1-9~ ........1.60, 10'-19 ~. ....... ,,2:5'9~. 20~-30 ...... .3!7'6~ >40~, ..,......5,51 Ma3es i 50-59. 60~-69I 1.00, 1.00~~. 1.591.48 2.13 ~~. 1.82~. 2:40. 1.91 2:79~ 1.79~ fBased on 70'-79~~ 5-9'~deaths. 1.00: 1.14. 1.41. 1.49~ 1.47 F l NS ..........~.1.00 1-9 ........ .1.3'1, 10+19. ....... ..2:08~ 20+30 .......3'.82 >40 ....... f3131 ema es 1.00~~ 1.00 1.15 1.04 2:37 1.79 2.¢8 2.08 3.73 f2102 1.00 0:76'. 0:9I8~ 1.27 - 90-44 45-54~ 55'-69' NS ......... 1.00, 1.00 1L00 ( PG0:01.). SM ......... 1'_80: (88) 1L60 (163) 1L20 (134)', Data apply only to those free of CHD at entry. 35-44 45-54 55~64 65r6'9' NSIincludea NS ...,.....,.1.00 1.00 1.00 1,00 pipes andl :t10' ..,......4,22 2.05 1.4',1 1'.17 cigars; -t20' ........ ,6.14, 3.17, 1.64, 1.26 SM', includes. -t30i .,.,......8.57 3.33 1.66 1.36 exsmokera. >40~ ..........7.93 3.15'. 1..421.42AIl ......... 61.24 2.95' 1.58 1,24 1.00~. (27)~. 1,20 (24)~. 29' Al~

TABLE 3L Sudden deatk from coronary (Mortality ratios-actual number Author year, Number and' Data Follow-up Numberr country, type of collection, years of' reference: population deaths Pooling 7~427' white Medical 10 145 Project, males 30 59: examination American Heart years of age and. Associationy at entry. follow-up. 1970, U.S.A. (88). TABLE 4L-Coronr;;ry heart disease (Risk ratios-actual number of' CHD [ S1VI = Smokers, NS 1= Nonsmokers PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of eountry:, type of collection up incidents Cigarettes/day reference populatfion years Doyle etal., 2,282'mal@s Detailed 10 Framingham, medical 243'myo- cardial NS .............1.00 (52) All smokers .... .2:36(191) 1964, U.S.A.. 30-62'years examina- of age. tion and, infarc- tions and <20 ...........1',.98 (44) 20. ............. ,,2:05(64') (54). 1,913'males follow-up. Albany, 39-55.years- of age. CHD deaths: >20 .......... 3:04 (i83)~ Stamler 1,329 CHD- Interview 4: 46 CHD NS ..... .. .. ...1,00 (2) etal., freemale andlexamin- <10 cigarettes. 1966„ employeesof' ationwith 3 < 5'5 cigars 2•92' (6D U.S:A., Peoples Gas clinic ....) <' 5: pipes. ... . (177)_ Company follow-up. 10+19 cigarettesL3.67 (8~) 40-59~y,ears >20: cigarettes. of age. > 5~ eigars~ ..,.}:.,3.83I > 5, pipes...:.. (29). Epstein, 6,565 male Initial 4 96 male, M'alea 1967;, and,female medical 92 female 4Q-59 U.S.A. residents examina- CHD in- NS' ............ 1100 (1D. (61)'„ oflTecumseh, tion and' eluding EB .............6'.53 (10) Mich. repeat deaths, Cigarettes .....5.20 (36) follow-upp angina,.and' Femaless examina- myocardial b1S'. .....,.......1.00 (21) tions. infarctfions.EJC............ ..0i89 (3) Cigarettes ..._.1.02 (14) I Unless otherwise specified, disparities, between the total' number of mani- festations and the sum of'the individuall smoking categories are due to the exclusionof' eitheroccasional„ miscellaneous, mixed, or~ ex-smokers: 30, .

ea heart disease relate'd' to smoking ofldpatbs shown in parentheses) Cigarettes/day' Cigars, pipes Comment Never smoked .....,......1.00 ('15) 1.00',(1'b), See table 1 for -_i0 .....................1.90 (23) 1.36' (13) Pooling Pcaiect: 20' .....................1L90 (50) >20 .....................3:3'~~6 (44) m~or6i~di,ty as re~la~t'ed'~ tb~ smok'~ing~ manifestations~shown in~parentheses~:)" EX~~. = Ex-smokers]~. PROSPECTI'V FS STUDIES=Continued! P:ipes,cigars Age.variation~. description of'. Comments Data include CHD deaths; onlp'on males 40-49 years off age .and!f'ree of'. CHD on entry. NS includes pipes, cigars, and ex,smokers. NS includes ex-smakera. Includes all CHD. Ma(esTCdntinued Males 60~and,.ov~er 40~-59: . 1.00 (7) SM ....1.80(2). 1.,27,(I11) 60~~and~oaer 1.96 (23) SM ... .0.86 ( 6 ) Fcma[es-Continued 1.00(47): 1,31 (5) , 0.42 (!2 ): Reexaminatian of',patients was spread over 1 1~j-6-yearperiod,but data are re- ported in , terms of 4-year inci« dpnce rates.. Actual number of: CHD inci- denta derived from d4ta on incidence and total in smok- ing class. 3:1

TABLE 4l-Coronary~ h'eart~ disease~ ( Rlsk~~ ratios-actual number af' CHD [S14L- Smokers~~. NS = Nonsmokers PROSPECTIVE STUDIES Author, year, country,, reference, Number and' type.of' population Data collectionn Follow- up gears. Number of! incidents~. Cigarettes/day Jenkins, 3;182 males Ihitia7 41/-,, 104 myo- NS ............ 1.00 (21) etal., 39-59iyears medical csrdial EX .............2,4T (15) 1968;, of'age.at examina- infarctions. Current, ....... ...2:78. (68). U:S.A. entty: tion and 0-15/day .....,.t1.3'9 (45) (90). follow-up >16 .............3.06 (59): by repeat examina- tions. Kannel, 5',127'males Medical 12 228 myo- Muocardial In/arction et,al., and'females examination cardial Maies~ 1968, , 30-59 years andlfollow- infarc- htS .............1.00 (21) U.S,A. of,age: up. tions. All SM ........1.61(153') (94). 380 CHD! Heavy SM .,...1.85 (59) Risk.of,CHD (av.erall). Males NS............1,00 (61) (-10 ........... 1.34'(25) I 1-20 .......... ,1.80 (90) >20: .............2.41 (76) Shapiro. at: al., 110;0'00male. and female Baseline med- ical inter- 3. Total. Males unspeci+NS ............ ...1.00~ 1969, ULS.A. (1172). enrollees of'Healthh Insurancee Plawof Greater New York (HIP) 35-64'yearss of age. view and! examination andregul9r~ follow-up,. fled. All current ....2'.14: cigarettesi (p<0.0.1): <20 ........... 1.50~ >20~ ............2.33 >4 0 . ........... ,..6':36'. Keys 9,186Imales Interviews 5 65 deaths: NS; EX 1970 in 5 coun- and regu• 80 myocar- (SM <20) ...1.00 (305) Yugo~-~ tries 4A-59 lar follow-~ dial..in.~ A~.lll current~~. alAvia. ~ years~~.af: up.examina-~ farctiana~,. (>20.)', ..........1.3'1(103) Finland age~atent'ry.e tion~by 128langina~ Italy ~~ local'~ pecRoris. Nether- physicians.. 155.other lands - Greece }428 4ota1. 1 Uhles,s otherwisee specified;i dispar.itiess betweenn thetotale numberrof'manir festations andl the sum of theindividiial smoking, categories~ are. due too the excdusion, of either occasional, miscellaneaus, mixedJ or ex-smokers. 32

morbidit)l as related to moking (cont:)) manifestations shown~ inn parentheses p 1~ K,k~~. =~ Ex~mokers] PROSPECTIVE STUDIES-COntinued Pipes,.cigars , ( p<0.001) (Ip<0.001)~. ( comparing~~ 0-15 and 16-4-) ~ Age variati'on Comments tlncludes non- J9-49. 50-59'smokersand I+IS...... 1.00 (4) 1.00 (6) ex-smokers: Current 4.23(35) 226(3'3) );1S'includes former pipee and cigarr smokers. Sf yoea:rdial~ in/arction-Continued! Fi emalta. 1.00~(:31) 1.71! (23) Ii iek o f~CHD ~~ ( averalG)-Continued~ Fcmalhs ~. 1.00~ (59~.) ~ 0:e6(1b) 1.29(1'9), 093 (3) ~ Frmales . Males only 1.00 NSI ...,...1.00 2..00~ SM ........1.82 Ip>0.01) (p<0.01i)~. 3:9'2 Males Females Total myo- 35-44 45-54'55-64 35-44' 45'-54 55-64 cardialin- 1,.00 1.00 1.00 1.00 1'.00! U.00 f'arction in- 2.47 2.47 3.06 1.69 2.25 2.87' 1L80 cludes those 0:52 2:15 1.321 1.25' 2,31 1.65' dead'within 3,043,29 1.81S ' 48 hours. 10;09 7:69 5,30 20:25' 11.79: 4.07 NS' include ex-smokers. Includes all CHD incidence including EKG diagnoses. Covers all countries in- vestigated except.U.S.A.t'DiBerence. betweestotal CHD andithe sum of smoking groups is due to difference in figvrespresented by authors. 33 Y

TABLE 4,.-C'oronary' heart disease'. ( Risk ratios-actual inumber. of'CHD: [SM = Smokers NS = Nonsmokers PROSPECTIVE STUDIES Author, ' year, Numberand, Data Follow- Number of country, type of' collection up incidents Cigarettes/day reference population years Taylor, 2,671 male Interviews 5 46deaths., NS andiEX ....1,.00 (62) et al. railroad and regu- 33 myocar-All current. .... ..1'.77 (i150) 1970 U.S.A. employees. 40-59 lar follow- up examina- - d'ial-in- farctiona' (18J).yeais.af' age at entry,,. Dayton 422'male U.S, et al., veterans par- 1970, ticipatingas U'.S A'. controls in a (;p,,4g)„ clinical trial,of a diet high in unsatu- rated fatL Dunn 13,148 male et al.,, patientss in 1'9700 periodic health U.S.A. examination (55). clinics. tion. 78 angina pectoris. 55 other CHD, 212'total. , Intenviewas up to.8! 27 sudden. <10 ........... 1,.00. (25) and,routine deaths. 10-20 .......... 1.04' (22) follow-up 44 definite >20 ........... 1.17 (13) examina- myocardiall tions',. infarctians'.. Datamnl$up to.1'4 Tatal,un-on new specified: incidents extracted from clinic records. Pooling~. 7;427 white~ Medical 10, 538' Proiect;, males.30~-59~. examination Includes Never, smoked ..1,00'. (53)) American years~~.of~. andfollow- fatal and <10 ...........1L65 (72) Heart~ age~e at entry. up. nonfatal 20 ...........2.08(205) Association myocardiall y20. ........... .3.2B-.(154'.). 1970,. U.S.A. infarction andsuddea (88'.)~... death. Paul et'a1J„ 1, 1963, 989 Western Electric.Co: Screening examination Coronary, U.S.A. (Z48)',.. male workers particip,ating'g and history. ......... caaee.(8T). 23' ina.prospec- 1- 7 2 tive st'udy 8-12 9 for 4?/. years. 13+171 6 18-22 ..,....... 47 23-27 3 9 1 Unless otherwise specified, disparities between the total, number of mani- festations and the sum of the individuall smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or, ex-smokers: 34

mo~rliid~itJ~ccs reltz~ted'to smoking ~ (cont.)~ manifestations shown,in parentheses )1 EX ~.=~E~~x-smokersJ PROSPECTIVE STU'DIES-Continued', Noncarouaryconttols. (U,786) 33 7 11 12 30 0 6. ( p<0:005 ) ~ Pipes, cigars~ Agevariatian~ Commente, 1.00(53) ~1.25(154) ~ tLow SM. $High SM'. sQ-s19 40-49'50:-591.00(25) 1.00(125) 1i.00(T57) 2.17(10) 0.90 (31) 1.41 (53) All CHD including EKG' diagnoses. No.data.onNSasa separate group. t'Inc]udes. N'S, EX, and <20 cigarettes/' day. $ >20 ciga- retteslday. Includes all. CHD b'ut excludes death. No data avail-able comparing smokers, andd nonsmokers. 88 developed clinicall coronary disease„ 47 angina pectoris, 28 myocardiall infarction, 1',3' deaths CH'D. 35 m. ~a41 -.

studies have shown an increased' risk of this manifestation among smokers, others have not (see table 5). . From these longitudinal studies, it has become increasingly clear that cigarette srnoking, is one of several risk factors for CHD~ andd that it exerts both an independent effect and an effect in, conjiunc- tion with the other risk factors. The basic concept may be ex- pressed as follows: The more risk factors a given individual has, the greater the chance of' liis developing CHD. The importance of the constellation of' coronaryriskfact'orswhi~chi includecigarette: smoking, high bloodl pressure, and high serum cholesterol in pre- dicting the risk for CI-1'D' is illkzstrated in figures,1 through 3. Other risk factors are i'ncluded in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developedl concurrently with the knowledge derivedd from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, andd blood pressure, all most probably secondary to the promotion of catecholamine release from the adrenall gland and other chromafl"in tissue. This release of catecholamines is also considered to be the cause of the rise in serum, free fatty acids observed upon, the in~- halation of' cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. 1'n, addition, research efforts have also been directed toward the effects of smoking on, blood clota'tingand thrombosis; since many cases of sudden death and myocardial infarction are associatedd with thrombosis in a diseased coronary artery branch. Cigarettee smoking may be associated withi increasedi platelet aggregation in vitro and thus might play a, role in the develbpment of such throm- bi or platelet plugs in vivo:. Other mechanisms have been investigated. Because cigarette smoking has been shown ini some studies to be related to the prev- alence of angina pectoris as well' as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy andl experimental studies have shown that cigarette smoking plays ai role in athero- genesis. Tlie administration of nicotine has been observed to in- crease the severity of cholesterol'' indluced atherosclerotic lesions in experiQnental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke ini such concentra, tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in, animals, it is reasonable to conclude that the atherosclerotic process may be enliancea„ ini part, by the rel'at'ive arterial hypoxemia in cigarette 36

m m T,un Fl S.-( Irranrrr7/ hearf rlt+.rt." um, rhirfif)( ux rr LtEclf ft) xtnol irtEt _-!trtfltrtrt prt•l-,ris-j,rnnl!s'Eltt'i' ah/i ItF (kink n,li- vtanl numh,•r -4 ( 'tlI! mwnife+tnti,,n+ nL-wo in pwreuthoyrel~ I 55f tin„k,-' . ..tiS - N~msm„k,rx]. Auth,A r. yenr, Numbcr and DaGt F'ollow-up Number cuuntry( type of cullection years - uf- Cignrctt- ~day reference Ponulation - in,idents -- Doyle 2,2t{2 males, Detailed etailed 1_0_ }i1 et a_l., Framingham, medical 1964, 30-f,2 years examination U,S.A. of age. and (54). 1,913 males, fo]low-up. 8 Albany, 39-56 years of age Jenkins 3,182 males Initial medical 4t/y et al., aged 39-59_ examination__ 1968, at entty. and follow- U.S.A. up by repeat (90). examina- tion. tion. I{annel 5,127 males ales Medical 12 et al., and females examination U.S.A. years of age and follow- (94). 30-59 up. Shapiro 110,000 male Baseline et al., and female medical 1969, enrollees of interview U.S.A. New York City and examina. (172). HIP 35-64 tion and years of age. regular follow-up. NS ............... _1.00(30) All ............... 1.09(51) ;'l0 ............... 1.17(15) 20 ...............0.9J(18) >20 ............... 1.15(18) 29 NS ............... 1.00 (9) A11 current cigarettes .......1.44(16) >16 ............... 1.63(14) 107 Males -- NS ...............1.00(16) Heavy SM, >20 cigarettes ........ 2.04(17) Females hTS ...............1.00(58) Cigarette SM ...... 0.66(16) Total Males Females Unspec- NS ......... 1.00 1.00 ified Current cigarettes }191 <40 ... .1.61) >40 ........ -4.8 1)6 t Unless otherwise specified, disparities between the total number of manifestations and the sum of the individual smoking categories are due 1.20 1.20 Cigtu'v and pipes Age variation Comments NS include es- sntokers and pipe and cittar smpkers. NS include former pipe and cigar smokers. Males Males # (p<0.01) NS...1.00 35-44 45-54 55-64 t(p<0.06) S__M_ ..#L71 N5 ............. .. 1.00 1.00 1.00 NS include Current cigarettes ..3,40 1.57 2.06 ex-smokers. <40 ............ .. 2.35 1.40 1.54 >40 ............ .10.16 2.58 6.15 Fem ales NS ............. .. 1.00 1.00 1.00 Current cigarettes ..1.56 1.67 0.97 <40 ............ ..1,67 1.53 1.04 >40 ............ .. - 4.12 - to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

smokers caused by the increase& carboxyhemoglbbin level. With respect to the acute event of myocardiall infarction, atten- t'ion, has been focused on the role of nicotine. Nicotine stimulates the myocard'ium, increasing, it's oxygen demand. Other, eexperiments have demonstrated that in the f'aceof dirn~inishedl coronary flow (due to partiall occlusion, from severe atheroscierosis in man or to partial mechanical obstruction in the animal), nicotine dbes not lead to an increase ini coronary blood flow as seeni in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence off carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and' oxygen supply (which has been decreased) is created by the inhalation of' CO and nico- tine. This imbalance rnay contribute to acute coronary insufficiency and myocardial infarction.. I EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospect'ive. and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD)l. Many of these studies have included' smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. COR0NARY' HEAR'T DISEASE MORTALITY Table 2'lists the vari'ous prospective studies concerning the rela- tion of CHD rnortality and'smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of' devel'oping CHD!. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality rat'ios, from 1.39 for those smoking, 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day. Although the data are not detailed in the accompanying tables,, severall of these stud- ies have also shown that increased rates of CHD' mortality are associated with increasedl cigarette dosage, as measured by thee degree of inhalation and the age at which smokiaZg, began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers' increased risk of dying from CHD appears to be limited mainly to those who~ smoke cigarettes. Some studies that have investigated' other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when comparedl to nonsrnokers. However, the recent study by Shapiro, et all (172) of a large population enrolled in the Healthi Insurance Plan (HIP) of New York City showed a significantly increased 38

i # risk for the development of myocardial infarction and rapidly fatal myocardial infarction for ai group consisting of both pipe and cigar, ssmokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Councilon Epidemiology, isde-scribedl in table 1 (88). Cigarette smokers in the 30 to 59, year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observedl to show a risk slightly greater thani that of' nonsmokers (table 3). The relative risk of CHD mortality is greatest among, cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2', Hammond and! Horn found that for those smoking, more than one pack per day, the risk is 2.51 in the 50 to 54 year age group andl 1.56 in the 65 to 69 year age group. Although the relative risk:for CHD among smokers decreases in the older age groups, the actuall number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- ers continue to rise.. CORONARY ~ HEART' DISEASE ~, 1'UDORRIDLTY' Tables 4 and 5' list the prospective studies carried on in a num- ber of' countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidit'y, includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54), Keys, et al. (111), and Taylor, et al. (183) include a number of CHD1 deatJhs in their data that could not be separatedd out using the information providedl in their respective reports.. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number af cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (172) show that the elevated morbidity ratios declined with increasing age as has beeni shown for mortality ratios. A recent monograph edited by Keys (111) dealt with the 5-year CHD1 incidence in malesa:ge40to 59Erom seven, eountri~es.Assnmmarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (1183). None of the diifferences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population: samples which varied in size from, 505 to 982~ individuals, frorn: the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 39

become available to provide greater statistical stability t&the rates, this intercultural comparison should' prove illuminating.. The results of those studies which have separated out angina pectoris as a manifestation of CHD' are presented in table 5. Doyle,, et al. (54) found no relationship between this manifestation of. CHD andl cigarette smoking. Both Jlenikins, et al. ('90)~ and Kannel, et al. (94)' observed increasedi risk ratios among male cigarette srnokers although these differences were not statistically signifi- cant. More recently, Shapiro, et all (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of'the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by myo- cardial infarction. RETROSPECTIVE STUDIES Table A6' presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased!percentage of smokers among those with clinical CHD, when compared with a selected control popul'atlion, usually without apparent CH'D'. Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE S1WIOB{ING'AND OTHER CHD, RISK FACTORS The preceding, section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. 1WTany of the studies discussed' above have idientifi'ed a number of biochemical~ physio- Iogicaly and envimonmenta'al' factors, other than cigarette smoking, which also increase the risk of developing CHiD'. These risk factors include elevated serumi lipids (particularly serum cholesterol)' andl hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic abnormalities, and a positive family history of premature CHD (88).. A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHiD. Figures 1 through 3 depiot, this, inter= action of risk factors. As may be noted in Figures 1 and 2, the 40 ~

additional factor of smoking greatly increases the risk of develbp- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors., That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of develbping and dying, from CHD'. Smoki'ng and Serum Lipids The interaction~ of smoking and'serurn lipU levels in the deveIop- ment of CHD should be considered in the light of information con, cerning, the relationship of smoking to ~ serum lipid levels. Table A 7 presents studies which deal with the association~ between~ smoking and lipid§, notably cholesterol~ triglycerides, and lipoproteins (con- cerned with lipid' transport)i. While some of the studies have indi cat'edI that smokers show increased serum levels of these lipid con- stituents; others have not. The populations investigated andl the methods of the variousstudies show significant variation. This lack of comparability makes interpretat'ion, of'the findings difficult. It is clear, however, that in the presence of high serum choies- t'erol, cigarette smoking increases the risk of CHD.. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Cbke Com- pany study which show thatl smoking greatly increases the riskof CHD: in each of the cholesterol groups: Smoking and Hypertension Some epidemiolog,icall studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not foundlthis to, be the case (table A8). Reid, et al. (155), ini a study of 1,300 British and. American postal workers, found that the blood pressure difference between the smoking, and nonsmoking groups was eliminated after controiling, for body weight. Tables 9 through 11, derived from the study by Borhani, et a1L (27), demonstrate the follbwing associations: That for both smok- ers and nonsrnokers,, the risk of dying from CHD increases with increasing, diastolic or systolic pressure, and that the risk of xnor= tality from CHD' is higher among, smokers than among nonsmokers in each, blood pressure group. Cigarette smoking, therefore, has been shown tloelevate, CHD~ mortality independently both of' its effect on blood pressure and of the effect of hypertension on CHD: Smoking and Pligsical' Inactivitg The recent study by Shapiro, et al. (172) of more than 110,000' ~~W"

TABLE 9.-Death rates from coronary heart disease, by systolic blood' pressure: ILWU mortality study 1951-61 (Coronary heart disease as classified under ISC' Code 420) Smokers Nonsmokers Systolic blood l Age group pressure in 1951, Pprson-years of observation Death rate' Person-years of'observation Death rate' 45-54, ..................... <130 1,877 27' 2,413' 8 130-149 2;066' 34 2,912' 17 150:-169' 740 95 1,177 26 >170 369 109' 672 45. 55-641 .................... ............... <130 1,067 84 1j650 26 ' 130-149 1,380 94, 2,401 °25 150-169 647 93 1,558 45I >170 5241 210 1,117 126 1 Rate per 10,000 person-years of observation. z p<01025. , p<0! 01. SouacH: Borhani, N.,O:,,et all (27). TABLE 1q: Death rates from coronary'lieart disease, b'y, ddiastolic blood pressure: ILWU mortality study, 1951-61' (Coronary heart disease as classifiediunder ISC'COde 420) Smokers Nonsmokers Diastclic blood' Person-years Death Person«years Death Age group pressure in 1951 of observation rate' of observation ratel' 45,-54' .................. <80 1,427, 26 1,700 6 80- 89 2,115 47 2,947 17 90- 99 96'1 52' 1,507' 33 >100 448I 89 1,020 20 55-64:.................. <80 1,059 1,04' 1,447 221 s0- 89 1~521 59 2;704 15 90- 99 669, 194, 1,521, 346 >100 369 163 954, 147' 'Rate per 10;000:person-yearsof observation. = p<0:05. s p<0.01., Soaaca:, Borhani, N. O:, et al. ('27).. TABLE 11.-Death rates from coronary heart disease, among hypertensives and nonhypertensives:, I'LW'Umortalitystu.dy; 1951 61' (.Coronaryheartl disease as . classified.d under ISC Code 420) . Smokers Nonsmokers Blood pressure Person-years Death Person-years Death Age group status r of'observation rate z of' observation rate x' 45-54 ......... B:ypertensi'ves .......... 883 125 1,871 '32 Nonhypertensives ...... 4,169 29 5,303' 13 55-64,......... Hypertensives .......... 931, 160 2,219 95 Nonhypertensives ...... 2,687 93I 4;407 2116 '. 1According: to: theWHO: recommendation„the, following cutbff' points: are~ recommended forr the definition of hypertension.:: (i1q.N~ormotension-below140/90.mm. Hg.. (2): Hypertension-systolicc bloodpressure. 160 mm. Hg. orover;r orr diastoli@, 95' mm.. Hg~. orover,, or both. (3). Borderline-thee residuali category. In this, analysis;, Normotensives: and. Borderlines wereeombined' and the population was grouped,into 'Nonhypertensives' (1, and 3) and"Hypertensives' (2). ='Rat'e.per.10,000person-yearsof'observation. s' p<0:01. SoUacE: Borhani, Nl O.,.et.al. (27). 42'

80 - 70- 60- 5D - 401- 35 30 22 - 20~~v~~~- 0 5 - ALL NONI NON NON SMOKERS' SMOKERS SMOKERS SMOKERS' SMOKERS SMOKERS <225 225-274 275-{- <225 225-274 275-}- CHD 46" 1 5 2 9 16 12 N 1329" 187' 235 71 336 317' 1'S'1i AGE 49' 49. 50 51 50 49, 50 SYSTDLI C: PRESSURE 134 1331 136 139 131 133 135. WEIGHT RATI U' 1.1,6 1L19 1.21 1.18 1.12 1.15 1.17 FIGURE 4-Relationship between smoking status and serum cholesterol level at initial examination, and incidence of clinical coronary heart disease in men originally age 40-59, free of definite CHD, and followed subsequently without systematic intervention, Peoples Gas Light and': Coke: Company' stludy;, 1958-1962. *For 34 men, no information on smoking status~ was available;, one of these men had a coronary episode. SOURCE: Stamler, di., et al. (177). persons participating in the Health Insurance Plan of New: York City has further identified andl elaborated upon the interaction of the various risk factors. Physical inactivity, both in employment and' during leisure', time, was found to be a potent risk factor for the development of CHD; particularly for rapidly fatal myocardial infarction. Figure 5 depicts the effect which smoking exerts on CHD in combination with physical inactivity. Of' note, also, is the observa- tion that within each activity grouping, smoking greatly increases the risk of' myocardial infaretion, thus exerting an independent effect. Smtokin and Otiesit'y The analysis by Truett, et al. (190) of the risk factor data from the Framingharrl study: revealed that weight, while a significant risk factor, had a consild'erablysrnaller effect on CHD! inci~dlencethan serum cholesterol, cigarette smoking, or elevated blood pres- sure. The results concerning the interaction of smoking and obesity from the San Francisco longshoremen study are.shown! in table 12. ,

11.0 10.0 9.0 8.0 w d m :°. 6.0 3.0. 2:0. 1.0 0.0 Not dead within 48' h rs: Dead within 48 hrs. 10.89 5.72 (57) 5.18 (46) 5:78'. NONCIGARETTE SMO'KERS'. 6.33 3.76 (47) 3.03' I Least, active 4.48 (166) 1.30 (4'1) More active 2.57 (31~) Least' active 2.34 (118) 0.69 (33) More active. Note: Both for c!garette, smokkrs and nonicigarette smokers differences betweeni rates amo,ng, the', fea'st andl more! active men arei s,tatistiially s;ignificant for total Mt and rapidly, fatal Mls at the 0.99 confidence level. For other Mls thei difference is: statistically,significanf only for the nonsmokers (confidence level 0:95). FicuxE 5-Average annual incidence of first myocardial infarction among menn in relation to overall physical activity class and smoking, habits (age-ad- justed rates per 1,000). (A'ctual' number of deaths or myocardial infarctions are represented by figures in parentheses)i SovacE':', Shapirq S'.,, et al. (i172).. Cigarette smoking is thus showni to be a CHD risk factor indepen- dent of' body weight. aTl weight groups, were' observed for the 45 to 54 year age group., smokers~ ini all weight categories. S''imila~r~ findings, although not in This table shows that cigarette smokers in the 55 to' 64' year age'. group: were observed to have higher CHD death rates than non- 44

T:%Kt.s 1L'.-Deatlt'.rates from coronary'heart disease among men urithoutt almor,unlitias, related'to cardiopulmonary diseases by weight classification in 1951: ILT+NU' mortaltity study, 1951-61' (Coronary heart disease as classified under ISC Code, 420) .Agu~Rruup ~, -.t . ...... Smokers Nonsmokers , Weight Person-years Death Person-years Death classification 1 of'obs;ervation rate=' of obsetvation rate 2' Not'overweight ........ Slightly overweight .... Moderately overweight ., Slarkedly overweight .. Not overweight ...,..... Slightly overweight ...., 3'loderatelyoverweightl ., Markedly overweight .., 388: 211 279 7' 962' 28 1,096 0 1~383 28I 1,574 28 1055 22' 1,797 0 222 43I 247, 0' 536' 75' 605 36 855 109. 1,320 °''11 735 88' 1,6'53 °''1'2 ih.•fourclassesare definedl in~ the text. ucr 10,000~person-years~. of observation., nrr.: liorhani, N. O:, et al., ('27). •I'.c1sI E 1:;.-Death~ rates1ro~m: cor'onary heart:disease;, by electrocardiographic findzngs in 1951: ILW U mortality'study,1'951'-61 (Coronary heart.disease.asclassified under I;SC CodL>420) Smokers Nonsmokers Electrocardiographic, Person-yeara. Death Person-years Death. .\;:- wn,unfindings in.1951'of observation rate.r of'.observation.f ratei t', 's ......... Abnormal .............. 5W 1~02 1,020 39 Normal ............... 4.,454'. 38 6,134 15s Abnormal~ ............. 583, 223 1,14'9 96'. Normal ............... 3,031 86 6,479 °31, ~~It:,•.ee pcr10~,000~.person-years~~0 of~observation~,. ~:OOSI Borhani,.N. 0., et~.al. (27)~... T UILE 141-1'958' status with respect' to heart rate, blood pressure, cigarette -mol: i,vg, and 10-year mortality rates, by cause: (1;329 men originally age. 40-59 and free of definite coronary heart disease) Peoples Gas Co.Study; 1'9 &-68, 1t+,59'risk factor status Ten-year,mortality, 1958-68 HearU Cigarette Diastolic Number All causes' CHD, rate smoking pressure', of inen, Number Rate Number Rate NFi NH NH 378' 20 148'.3 5' 112.01 H NH' NH 45 6'. 1'14.9 3 70;3 NH', NH H 107 14, 118.3 6' 61.8 H NH', H 30 8' 221,6 3 62:0 H NH 491 57' 115.8 19 3819 lt H NH 127 22~ 1'71L1 8 62:3 N H', H H 103 22' 190.4 6 65;0 H H H 44 13, 265,4' 6 94'.9 All 21,325 162: 113.2' 55'. 39A "Rate.per.thousand. All rates are age-adjusted by.5-year.age groups to: U.S. male population, 1960:, High (H) : Heart rate ?80; ?10:cigarettes per day; diastolic blood pressure ?90' mm4 Hg. NH is not high, i.e:,, below specifled' cutting points. "No smokingdataavailableg on 4' ofthe14329 men, SovaCO: Berkson, D. M:,,etal. (23).

TABLE 15:-The e$ect: of'tlie cessation of' cigarette smoking on the incidence of CHD (Tncidenceratias-actual' numberr of' cases.or eventss aree shown inn parentheses) Author; year, country, reference Results Comments Jenkins et al., A'a 6HD euenta. N'ever smoked .............. 1.00 (30) Current Ait myocardial iio f arc2ion. 1L00(21). 1968 ' U.S.A. ('90). cigarette smokers ........2.36(84) Former cigarette smokers ........2.16(19) 2178 ( 6'8)', 2.47(15). Death fram GIiD S k d 20' Stinokedl1'-1'9 eigarettea/dag. mo e > ciyarettea/day Hammond and GarfinkelJ Never smoked regularly ...... 1.00 (1I841) 1.00{1,841) Male data only, 1969;, Cur~rentl U.S.A. cigarette smokers....... .1.90(1,063) 2.55 (2,822) (76). Stopped <1 year ......... 1_62 (29) 1.61 (62) 1-4 ...................1L22' (57): 1.51 (1549 5-9 ...,.....,.....,......1.26 (55) 1.16 (135)! 10-19 .......,...........0:96 (52) 1.25 (133) >20 ....................1.08 00) 1.05 (80) All ex-cigarette,.smokers~....1.16~ (263)~ 1.28 (564) Total definite myocardial infarction Shapiroo et ~.al,l, , Never smoked ..................................... ...........1.00: Current.t cigarette smokers .................................1.87i 1969, U.S.A. Stopped''55'.years................................... ........_0j76 (17E!)~... A(1 CI'fD deaths First major coronaryy euent Pooling Proiect, American Heart Never smoked ............. 1.00 (27), >1/2 pack/day .............1.65(34J 1.00 (53) 1.65 (72) Seetable 4 for description Association 1'pack/dky .............. 1i70(86') 2108(205) of Pooling 1970. >1 pack/day ..............3:00(68) 3;28 (154) Project. U.S.A. Ex.smakers ............... ,0.80(19) 1L25 (51) (88). TABLE 16.-Annuat probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started' smoking Age started smoking 15-18 20-24 Discontinued Discontinued! Maximum daily Current, for five:or Current for five or Age number of'ciga_ smokers more years smokers more years rettes smoked (Probability X10 51) 0 10-20 21"39 501 798' 969 - 568 76'6' 601, 811 872 - 551 698' 65-741. ............. 0 1,016' -~~ 1.,015'. - 10-20 1,501 1i169. 1.,4781 1.,213'. 21-39 1,710. 1~334 1,6731 1',098' 1 For age group, 65-74, probabilities forr discontinued smokeras are for 10 or more years ~ of d'ue eontinuance since data for the 5-0 year discontinuance group are not given. Souacet Cornfield, J., Mitchell, S. (45). Based I on , data derived from Kahn+ H. , A. ( 9J )',. 46

Smoking and Electrocardiographic Abnormalitiea Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changesasw~elli as a number of arrhythrrtiiasar'euse- ful indicators of CHiD' and may, therefore, be predictive of the development of clinically overt CHD manifestations~. The results summarized in table 13, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and' Heart Rate Recent analysis by Berkson, et al. (;23), of the data derived from the Chicago Peoples Gas,, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80' or greater were associated with an increase in, the risk of death from CHD. These authors found that t'liis association was independent of the ot'her major coronary risk factors. Table 14 presents the interaction between smoking, blood pres- sure, and elevated heart rate ini increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD1 risk in the presence of elevated heart rate as well as in its absence. THE, EFFECT OF CESSATION OF CIGARETTE' SMOKING ON CORONARY HEART' DISEASE A number of epidemiological studies have been concernedl with the CI+ID, incidence andl mortality among ex-cigarette smokers as compared with current smokers (51, 76, 88, 90;, 93, 1'72)i. These studies are listed in table 15. Table 16 presents the data derived by Cornfield andl Mitchell (45) ' fromi the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction andl deathi from CHD relative to that of continuing ciga- rette smokers. The Pooling, Project (88) and the Western Collab- orative Study Group (192) which adjustedl for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking, is accompanied by a relative decrease in risk of death from CHD' within 1 year after stopping. This decreased risk of CHiD' among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, liowever, that the group of' ex-srnokers is composed of' individtaals who have stopped smoking for a variety of reasons. Those whoo stop because of 'iIl health and the presence of symptoms are gen- erally at high, risk and can bias the group result's in one direction; 47 ~ : :4*,

those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group~ are not fully representative of the entire population of smokers an& may have limited value in predict'ing what would happen if large nurnbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studles, such as the Pooling, Project (88), were initi- ated with only: clinica~ll'yhealthyindividuals: Thedata, from such studies, as well as those from the British physicians study, contain ex-smoker data less imfluencedi by these biases. Fletcher and Horn (63) have recently presented drata derived from the British physicians study of Do1'1i and Hill. Over the past 10-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British popul'at,ion., The! informat'ion, presented' by these~ authorsconeerning al'1card'iovasculardiseasesshowed that for indlividuallss between the ages of 35 and 64, the age~adjlusted death rate for CHD declined by 6 percent among physicians andl rose by 10 percent among the male population of' England andl Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found' to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesteroli (177), increased blood' pressure (27), elevated resting heart rate (23), physical in- activity(172')„ obesity (27),, andi electrocardiographic a:bnormal'i- tiies (27) have been controlled` cigarette smokers stilll show higher rates of CHD than nonsmokers. It has been suggested' by some (39, 170) that the relationship between cigarette smoking and CHD has a constitutional basis.. That is people with certain constiitutibnalmake-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of' the individual and' CHD and between the genetic make-up of'the indi- vidual and his becoming a cigarette smoker. Two sets of'epidemio- logic data bear on this hypothesis:. It lias been maintained' that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 48 1 0 ~ ~

U Type A behavi~orpattern ofRosenmanny et all. (159), whichischaracter.ieed by competitiveness, excessive drive, and an enhanced sense of time urgency. The prospective study organized by the Western Collaborative Group indicates that individuals who ex- hitai't this type of personality are more' likely to have or develop. CHD than those without it (Type B)~, whether or not they smoke. When the incidence rates of CHD1 are analyzedi with respect to smoking, and personality types (tables A 17, A 18) 1, it is noted that in both Type A and Type B individuals the incidence of CHD is greater among cigarette smokers than among nonsmokers. This research indicates that both personality type, as measured ini these studies, and cigarette smoking contribute independently as risk factors to the development of CHD. To what extent such behavior patterns are determined' const'itut~ionallyorrepresent acquired charaeterist,ics'isstill open to questiom The other type of research designed to study the genetic hypoth- esis has made use of data from registries of' twins. Cederlof, et a]. (37, 38, 39, 40) have utilizedl the Twin Registries of Sweden and the Veterans Follow-Up Agency of the U.S: National Academy of Sciences-N'ationall Research Council to investigate the relativee cont'ributions of heredity and smoking to cardiovascular and bron- chopulmonary symptom prevalence. Data obtained by mailed ques- tionnaires were analyzed for the folllbwing characteristics : zy- gosity of the same-sex twin pair, urban-rural residence differences,, smoking concordance, and history of various symptoms. Compari- sons were made between srnoking, discordant monozygotic (iden- tical) pairs and smoking discordant dizygotic (fraternal) pairs, and between unmatched twin pairs and' matched twin pairs. Smok- ing discordance has been defined somewhat differently in variouss reports but, ini general~ describes twin pairs ini which the smoking habits differ between the two members of the same twin pair. Analyzing the data obtained from 9;319 Swedish twin pairs (72.3 percent of the possible respondents), Cederlof;, et al. (39) found that respiratory symptoms were more common arnong' smok- ers in both the unmatched and matched smoking discordant twini pair groups. The authors analyzed the data ini two distinct man- ners. Group A analysis, which did not controt for genetic factors utilized two groups ; the first composed of all the firstborn, and the second of those listed second on the birth certificates. Group B'' analysis utilized MZ and DZ twin pairs which were discordant for smoking, thereby controlling genetic factors. "Angina pectoris,"' as defined by a certain pattern of responses to the questionnaire, was found to be more prevalent among smokers in Group A, but this difference was not present when the data from Group B were an- alyzed. Males ini the first groupexhibited~ a'"hypermorbidity ratio" 49'

of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this d'ifference be- tween the two groups provides better support for the importance of constitutional factors as against the importance of' cigarette smoking in the development of' angina pectoris.. A similar study was done using the responses of'4,3'Z9 U.S! Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and "angina pectoris" among smokers when Group A was analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) reveale.d, no association betweeni smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors conclludledi that this lack of association among the monozygotes and its presence among, the dizygotes and unmatched pairs strengthens the case for a constitlu- tionall hypothesis. A major problem in these studies is the small number of cases available and, therefore, the statistical instability of the results. In the Swedish st'udy, among the 274 monozygotes; only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classifiedi. In neither group was the difference between the prev- al'ence ratios foundi in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of'the data on women shows ai similar lack of significance. Similarcritic,ismsmay be made ofthestudy which utilized theU.S, Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and' high-cigarette-exposure dizygotic groups was not present among the monozygotes. T'he authors ques- tioned whether the excess morbidity associated with, cigarette smoking foundl ini the dizygotic group was causal as it was not pos- sible to reproduce the association when studying, monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are alsoismall solthat the differences in rates db not approach statistical significance. Tibbl'in (188) has questionedlthe value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed' was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) conductedi a study to determine the validity of this questionnaire as a rnailed'i instrument by personally interviewing,and examining 170, of the twin pairs who had replied. Of the eight males who were diagnosed as having, "angina pectoris"' by the qiuestionnaire. four were found to be free of' symptoms on 50

clinilcaT examination, while among 204 responding negatively, two were found' to have anginai by clinical criteria. hTane of the 11 women who were diagnosedl as positive by questionnaire was found to, be clinically affected~ andiof the 136'reporting as negative, three liad' symptoms of anginal pectoris. Other major diffi'culties associated with these studies include the problems of' using prevalence data in the investigation of a disease. (CHD'), from which a significant number of' those affected! diie. shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking populatinn„ andi the low numbers of heavy cigarette smokers ini the Swedish population. In generaly the problems of' using twin, registries to study the etiology of cardiovascular disease with mortality and morbidity ratios ini the neighborhoodl of 2 to I are much more dif0cul't than in studying the etiology of bronchopulmonary disease in, which the relationships are of the order of magnitude, of 4t'o1.1Vlorerecent'ly, Fkiberg,et alL (169), reportedl on, mortalitydatay from the Swedish, Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not' due to, smoking per se but to fac- tors associated with smoking: The very small' numbers of' total deaths presently available (47 deaths among 706 d7zygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving, any conclusions at the present time. Hauge, et al. (81) have recently reported on the influence of smoking on, the morbidity and mortality observed in the Danish Twin Register. Among 762' monozygotic and same-sexed dizygotic twini pairs, angina pectoris was found to, be significantly more fre- quent in those cotwins with a higher consumption of tobacco than in those with a lower or no consumption, A similar tendency was observed' for myocardial infarctions but was not of statistical! significance. Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinicals, and pathological data relating smoking and' CHD; concluded that the evidence from these areas has not "reasonably substantia.ted"' the "hypothesis" of'the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular systemi been shown to be a"elear" and con- sistent one (170). His views are contrary to those of most re- searchers in this field. Although the data from the twin studies are inconclusive withh regard to a role for genetic factors in heart disease, it wouldi be surprisina, if genetic factors did not play su'ch, a role. It is open to 511

question whether findings from twin studies can be used' to distin- guish between the hypothesis that genetic factors govern the levell of' host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking andi the hypothesis that genetic factors "cause" bothi heart disease and' smoking. AUTOPSY STUDIES RELATING SiVlQKIIVG, ATHEROSCLEROSIS, Ah1D' SUDDEN CHD' DEATH A number of researctiers have investigated the cigarette smoking, habits and the cardiovascular, pathology of those individuals dying suddenly from CHD1 and' of large populations of' individuals with andl without histories of overt CHD. Spain and Bradess (175) recently analyzedi the smoking habits of' 189 individuals who died suddenly and unexpectedly, apparentlly from the first acute clinical, episodes of CHD. The authors noted aa close correlation of a history of cigarette smoking with this type of sudden death and' also with shorter survival, times following the acute episode. This association was strongest in those persons under 50 1years of age. The authors also observed that those surviving very short pe- riods of'time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction„ particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of' smoking on myocardial metabolism and oxygen supply and demand rather than on t'hrombus or platelet plug, formation. While the autopsy study of Spain and Bradess (175), concerned sudden death among smokers, other autopsy studies from various countries have been directedi towards the relationship of cigarette smoking to the presence of atherosclerotic disease in the aorta and' coronary arteries. These are concerned with the long-term effects which smoking has on the cardiovascular system and are sum- marized in table 119. The studies of Auerbach, et al. (12),, Avtan- dilov; et al, (13), Sackett, et al. (165), andl Strong, et al. (182)) found that aortic and coronary atherosclerosis were more common andi more severe among sxnokersthan among nonsmokers. Auerbach,, et al. (12) noted that this relationship persist'ed, when the cases were matched for both age and cause of death or when the follow- ing cases were excluded; men with a history of diabetes; men who had! died of any type of' heart disease; and men whose hearts weighed 400 grams or more. Sackett, et al. (1165) found! that the 52

SICA9J(.4C.o ar l Author, -yeax,-Autopsy country, population reference - - Wilens 989 8_9 consecutive and Plair, male autopsies - - 1962, at New York U.S.A. City VA (214). hospitals. Auerbach, 1,372 autopsies - et al., of male 1965, patients in U.S.A. Orange, New (12). 3ersey, VA hospital for whom smoking habit data were available and who did not have overt CHD at death. TABLE 19.-Azstopsy studies of athez-osclerasis (Figures in parentheses are number of individuals in that smoking categoryp lSM - smokers NS = nonsmokers] Data collection Cigarettes per day Routine clinical Severity of aortic sclerosis records of Above average Average S_ e_l_o_ w__ avera_g_ e_ previous_ and NS ........... 9.9 (161) 60.2 29.8 present <20 .......... 19.1(152) 63.2 17.8 admissions. 20-30 ......... 26.4(288) 62.5 11.1 >30 .......... #26.1(199) 61.3 f13.6 Interview with Degree of coronary artery atheroeclerosis_ (o_ve_ra_ ll__ age- next of kin. adjusted results) No athero- aclerosia Slight Moderate Advanced NS ........6.6 (69) 57.3 21.8 15.3 Current cigarette <20 ...... 2.6(139) 30.9 37.3 29.2 20-39 ....0.8(299) 19.7 42.1 37.4 >40 ...... 0.6044) 18.1 36.4 45.9 I Unless otherwise specified, disparities between the total number of in- dividuals - dividuals and the sum of the individual smoking categories are due to the -- - exclusion of either occasional, miscellaneous, mixed, or ex-smokers. Conclusions Comments The authors conclude that in 60 percent of cases, the degree of sclerosis at Smoking data unavailable for 120 cases. Each aorta specimen given autopsy was commen- an "atherosclerotic age" surate with age of patient, by comparison with a regardless of smoking habits. In the remaining 40 percent there is evt- - dence that cigarette smoking may be asso- ciated with an above- ciated average degree of aortic sclerosis. The authors conclude that the percentage of men with an advanced degree of coronary atherosclerosis was higher among ciga- rette smokers than among nonsmokers and that the percentage increased with amount of cigarette smoking. This relation- ship ship persisted even when cases were matched for age and cause of - - death. standard, If "athero- sclerotic age" was found to be 10 years more than real age, the aorta was said to show above- average sclerosis. tpC0.001 comparing 9.9 with 25.1 and 29.8 with 13.6.

TABLE 1_9.-dutopsy studies of atherosclerosis (cont.) (Figures in parentheses are number of individuals in that smoking category)i Avtandilov, 269 male and Not specified, Comparative size of mean area of atherosclerotic lesions 1965, 141 female Russia autopsies. but there were: 180 SM and in inner coat of coronary arteries. Idight coronary artery Left coronary artery (1J). 220 NS._ SM NS SM NS 80-39 ..#16.6(30) 1.3(32) t6.3 2.2 40-49 .. t23.6(3-4) 11.5(27) t16.8 4.4 60-59..t36.3(39) 14.8(39) }27,9 9.9 60-69 ..f31.9(32) 23.8(36) t26.6 22.5 70-79 .. 41.9(18) 31.7(36) 26.1 36.8 [SM = smokers NS = nonsmokers] Author, year, Autopsy Data country, --- re erence population collection Cigarettes per day Conclusions Comments Sackett, 893 total, Patient et al., including 438 interview on 1968, male and 460 admission. U.S.A. female (white) (165). patients autop- sied at Roswell Park Memorial Hospital. Represents all deaths 1956-1964 exclusive of 81 male pipe and cigar smokers and 55 incom- plete files. The author concludes that the worst changes were found in the left and right coronary arteries with less severe changes in circumflex artery and aorta. The results concerning aortic atherosclerosis are given in The authors conclude that form of figure presentation of ridit-analysis. among males, ". . . a large increase in the severity of aortic athero- sclerosis occurred in the groups using either ciga-s rettes only or both ciga- rettes and alcohol as compared with the group using neither cigarettes nor alcohol ... there was only a small and statistically insignificant difference between the group using cigarettes alone and the group using both cigarettes and alcohol, " The severity of aortic atherosclerosis increased with increasing use of cigarettes, when measured both by in- tensity and by duration of smoking. ' Unless otherwise specified, disparities between the total number af in. - dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. Causes of death 96-athero- sclerotic, 102-accidental, 202-various diseases. tT-teat for significance of difference between means is significant at p<0.05 level. - 6IOM;94c0

,e TABLE 19. Autopsy studies of atherosclerosis (cont.) (Figures in parentheses are number of individuals in that smoking category)' t w N UPYS94c0 [SM = smokers NS = nonsmokers] Author, year Autopsy Data , country population collection Cigarettes per day Conclusions Comments , reference - Viel 1,150 males_ Interview with et al., and 290 relatives. ------- 1968 females who Chile died violently (E0_0_),_ in 1961-1964. Smoking infor- mation avail- able only on 566 males. Strong 747 males 20- Interview with et al., 64 years of next of kin 1969 age autopsied within 8 weeks U.S.A. betwen 1963- of death. The results concerning internal fibrous streaks and fatty The authors conclude that: - plaques in the left anterior descending coronary artery "No relationship he- . are reported in graphic form only. An examination of tween atherosclerotic this data indicates that the moderate and heavy smokers lesions and the use of appeared to show consistently higher percentages of tobacco was discernible." diseased areas than the nonsmokers. But the statement of the authors implies that these differences were not .sta_tistically significant when subjected to an analysis of variance. -- - - - Basal Group ( excludinp diseasee related to smoking or The authors conclude that: This report concerns only - - -- - CFID). Mean percentage of coronary artery internal "Atherosclerotic in- ages 25-64. surface involved with raised lesions (number of cases). (188). 1966 at Charity 85-J4 Hospital in NS ................... 2 (5) - - New Orleans. 1-24 cigarettes/day .... 9(14) >25 cigarettes/day ....12 (9) NS ................... 4(14) 1-24 cigarettesfday .... 3(39) >25 cigarettes/day ....17(10) 1 Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. White J5-44 45-54 55-64 19(14) 20 (6) 30(11) 17(10) 26(16) 39 (7) 31(14) 26(25) 39(20) Negro 3 (8) 16(11) 17(14) 11(31) 1-4(30) 28(22) 14(17) 29(12) 16(11) volvement of aorta and coronary arteries is greatest in heavy smokers and least st in nonsmokers." No data on statistical significance provided.

severit'y of aortic atherosclerosis, as measuredi both by intensity and duration, increased with increasing, use of cigarettes and thatt this dose-relationship persisted when the patients were matchedd for the consumption of alcohol. On the other hand, Yiel~ et al. (200)' concluded' from their study of accidental deaths in Chile that "'no relationship between atherosclerotic lesions andl the use of'tobacco was discernible:"' Examination of' the data (provided in graph form only) indicates thatheavy smokers showed consistentlly higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jectedi to~ an analysis of variance. Thus, in addition to the acute effects which smoking exerts onn cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosi's.. EKPER'IMiENTAL STiJDIiES~ CONCERNING THiE~ RELATIONSHIP OF CbRONAEZY HEART DISEASEI AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191., 192, 193, 198) have described in detail and' commented oni the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of'tlie varied research. That concept concerns the.dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS oF' CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been foundi by many researchers to be asso- ciated with a number of specif c acute cardiovascular responses.. These responses have been observed in human as well as animal subjects, including increased heart rate, blood' pressure, cardiac output, stroke volume; velocity of' contraction, myocardial contrac- tile force; myocardiall oxygen consumption, arrhythmia forrna!tion, and electrocardiographic or ballistocardiographic changes (tables AW to A22)~. The effect of these responses on coronary blood flow will'! be discussed in a following section. That the acute effects observ.edfollowing the inhalation of ciga~- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans„ I'rving and Yalnamota (b'9) and Von Ahn (202)~ duplicated the sb

0 effects of cigarette smoking by the administration of'nicotine intra- venously. Similar results in animals were noted by Kien and Sherrod (112). The mechani'smi by which cigarette smoke and henee nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long, been known as a, stimulator of both sympathetic and parasympathetic ganglia~ Research has centereds therefore, on, the function of catecholamines, mainly epinephrine and norepi~- nephrine; as mediators, of these responses. Ueing isolated rabbit atrial myocardium, Burn and Randl (35) noted' that the prior ad- ministration of reserpine to the perfusate blocked the increased' rate and amplitude of contraction seen following the administra- tion of nicotine. West, et a]. (208) showed that the in vivo cardiac stimulating effect of nicotine was blbcked by tetraethylamrnonium chlbride. Leaders and Long (125), Romero and Talesnik ('156 ), and, rnore recently, Ross and~ Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methoniums guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203)' and V4'estfall~ et al. (209,. 210, 211) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of' standard cigarettess caused significant increases in peripheral arterial epinephrixne llev- els, while cornsilk cigarette smoke inhalation evoked no suchh change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion. The source of these nicotine-released catecholam2nes; particu- larly those which mediate the immediate and lbcal cardiac re- sponses to intracoronary injections of' nicotine,, is felt to be thee myocardial chromaffin, tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and' Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of' nicotine into the mesenteric circulation of cats were followed within 1 to 2' seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemicc resistance. Section2ng, of' the mesentleric afferent nerves ledl to a diminished response. The authors concludedi that the cardiovascu- lar response to nicotine may also be neurogenilc in nature. Nadeau andl James (142) injected nilcotinedirectly into thesinus, node artery of dogs and noted ani initial' bradycardia, dhze probably to direct vagal stimulation, followed by tachycardia, due probably to catecholamine release.. 57

That the presence of nicotine may predispose the myocardzum, particularly a, hypoxic or previously damaged rnyocardi,um, to ar- rhythmia formation is suggested by the research of Balazs, et a1L (16),, Bellet, et al. (21), andl Greenspan,, et all., (70. Balazs pro- duced myocardial lesions in dogs either by pretreatment with isa proterenol or ligation of the anterior descend2ng coronary artery. It was found that while norrnal' animals did not develop arrhy- thmias upon challenge with small doses of intravenous nicot'ine;, the animals~wit'hdama~gedi rnyocardiu~rns responded wi'thinereasedl arrhythmial formation shortly after their spontaneous arrhythmias had ceased. More recently, Bellet, et al. (20)~ studied the effect of cigarette smoke inhalation on the ventricul'ar fibrillation threshold in anesthetized dogs. They observed' a statistically significant de- crease in the threshold following smokeinhalatiom Greenspan, ett al. (,74)1, using isolated dog, right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity:. The authors. consider that these two nacotine-indtxced, effects probably predispose the myocardium to the initiation of arrhythmias. CORONARY BLOOD FLAw Studies in animals and' hurrrans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally;, exposure of the normal' subject to these agents results in an in- crease in flow. Kien and Sherrod (1'12),, Leb, et al'. (12&), R;oss and'Blesa, (1,60)~, Tkavell,etaL (189),, and West et al. ('208), working with normali animals,, and Bargeron, et al.(1?')„ working with normal humans, have demonstrated this response.. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most~probably due to the release of catecholamines: Using instantaneous coronary arte- rial flow measurement in dogs, Ross and B'l esa (160) were able to reproduce the effects of intracoronary nicotine vvithi the adininis- tration of epinephrine and were able to block the response to nico- tine by pretreatment with pentolinium. 'I1he direct aetion of catecholamines, on the coronary arteries may not, however, be solely responsikile for the increase in CBF seen with cigarette smoking and intravenous nicotine adkninistra, tion. It appears that the cateeholamine-induced increase in myo- cardial work and tlherefore in, myocardial oxygeni requirement is aa prerequisite for the increase in CBF. Kien and' Sherrod (112), using tracheostomized dogs, found that without blood pressure and' cardiiacoutput changes CBPdi~dl not increase following either the, inhalation of cigarette smoke or the ad',min2stration of nicotine W . Q . n N C12 W .i&

int!ravenousl.,, although CBF did increase following, such changes. Recent work by Leb, et al. ('126)' has utilized Rb11" as a radioactive marker in order to~ distinguish capillary flow from overall total CBF. The authors consider, that this capillary flow represents that portion of CBF which is effectively involved in~ nutrient and oxygen exchange. The researchers observed'that the increase in effective coronary flow was almost proportional to the nicotine. induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardiall shunting was far in excess. Thus,, the imcreased~ workk evoked by the effect of" nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22), working, with normal dogs and dbgs that had under- gone eit'her coronary artery ligation or artificially-indluced coro- nary artery narrowing, n~ted' that the increase in CBF following the intravenous administration of nicotine was signifieantly less among the animals with coronary insufl'iciency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing ini normals. Regan, et al. (154) studied seven, men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patientls and caused no overall rise in CBF. A number of' ot'her, iinvestigators have noted that patients with overt CHD db not respond to the stiQnulus of cigarette smoke as readily as do normals (67, 1w9, 164). Thus, patients with compromised coronary circulation may not be capable of increasing their coronary flow in the face of'the in- creased demands of al myocardium stimulated by nicotine or ciga- rette smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maximal level. Any further in- crease in extraction may produce coronary sinus p!02 values incom- patiblle with proper tissue oxygenation. CARDTOVASICULAR' EFFECTS OF CARBON 1VI0N©xIDE. Carbon monoxide (CO) is a colorless and odorless gas, low levels of which have significant effects on human and animal physi= ology which are j ust now beginning to be understood. According, to Wynder and Hbffrnann (215), it is present in cigarette smoke in concentirations of approximately 2.9 to 5.1 percent. The concen- tration of' CO in smoke is subject to rnany factors, among them 59

the type of' tobacco and the porosity of cigarette paper.Tlie con- centrationi of' CO in smoke has been found to increase significantly toward the last puffs of the cigarett'e.According to: Chevalier, et al. (4Z)1, a concentration of approxi- rnatel'y: 4 percent,Mini cigarette smoke will produce alveolar ~ levels, of' around 0.04 percent which;, equilibrated with hemoglobin, result inicarboxyhernogIobi'n (COIKb)i concentrations of from.3 to 10 per- cent.A, number of 'investigators have compared COI-1blevelsin smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained: from 3,311 longshore- men. Using a regression analysis, they calculated the con:centra. tion of COHb and found that nonsmokers showed levels of 1.2' per- cent while those smoking over 2'1 packs per day had levels of 6.8 percent and that smokers of lesser amounts had intermediate levels. Occupational exposure accounted for the mean nonsmokers' 1'evell being over 1.0 1percent„ anunusuali finding in comparison with otherstudiesF Kjeldsen (113), interviewedi and obtainedi blbod samples from 934! CHD-free smokers and' nonsmokers. The mean COHblevel for196 nonsmoker& was0:4! percent while a1T inhaling, smokers had a mean level of 7:3percent. A114'116cigarette, smokers, regardPessof inhalation orarnaunt smoked', showed a mean level of 4! ,0percent. Carbon monoxide has many variied and significant effects oni human physiology.,An.overalilireviewof these~ effectsmaybefounds in a d'iscus~sion, by Lilienthal (1.27) or more recently in an exten- sive review by the. United States Public Health Service National AirPollu~tionControlAdminist'.ration (1~944. Apart from its' effects, . on respiratory and circulatory function, CO' has been found' to affect certain cent'ral' nervous syst'em functions adversely. These effect's are probably due to interference by CO with the proper oxygenationi and oxidative metabolismm of the tissue in question. CO int'erferes wit'lih oxygen transport in a variety of ways.First, the affinity of hemoglobin for CO is approximately 20U times greater than its affinity for oxygen, and thus CO can easily dis- place oxygen, from hemoglobin. 5econd,, C0, shifts the oxyherno- globin di'ssociationcurve.By increasing theavid'itywithwhich oxygen is bound' by hemoglobin, CO interferes with! 0, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capi]lary blood has been reduced to' approximately 40, percent saturation. Here the shift can sub- stantially decrease the oxygen tension supplying the tissues. Third„ and of more recent note, is t'he possible interference by CO with the homeostatic mechanism by which: 2, 3-diphosphogly- cerate (2, 3-DPG), controls the aHinit'y: of hemoglobin for oxygen. Bunn and Jandl (13.4) have recently reviewed the various experi- 6m,

ments concerning this glycolytic intermediate. The question of' whether the low levels of CO present in the blood of smokers can affecttihis homeostiasi& is! presently underinvestigation(29~, 143)~, and'firm conclusions cannot be drawn at this time. Apart' from its effect on hemoglobin affinity, CO, appears to induce ar.terial hypoxemia, andl this may act as ani additiional cause of tissue hypoxia. Ayres, et al. (14',,1'S), observed unexpectedly that exposure of individuals to CO sufficient to raise their levels of COHb to between 5 and~ 110 percent was associated with ai signifi- cant fall' in arterial p0,. Greater fal'11 in venous p0: was noted, but this was considered secondary to increased tissue extraction. Ini a recent article, Brody andl Coburn (30')' suggested that thils COHb-inducedi arterial hypoxemia was due to, the interaction of a number of factors. These: authors notledl that in the presence of veno-arterial'shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial 0~, gradient and resulted'! in arterial hypoxemia. The presence of shunts as small as 2 percent of cardiac output as well as of' approximately 10 percent COHb: was found'~ to cause ani increase in the gradient. Such ventil'ation~-perfusion (V/Q) abnormalities have recently~ been noted even in asymp- tomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of' COHb found in the blood of' smokers may interact withi these V/Q abnormalities to further decrease available oxygem In normal individuals, coronary flow can increase to meet the increased oxygen demands of' a stressed myocardium (as that und'ernicot'inestimulation), whilein, individuals with severe CHD: coronary: flbw cannot respond as readily. In such cases, myocardial oxygen extraction must be increasedl above the almost maximall extraction foun6 at rest. Any int'erference, with arterial oxygen, levels or hemoglobin affinity couldl very well decrease available oxygen suppl7es below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed below. Chevalier, et al. (41) exposed 10 young nonsmokers to, CO, con- centrations su~fficient to induce COHb levels of approximately 4'1 percent. Taking measurements fromi blood specimens obtainedi at cardiac catheterization under resting, andl exercise conditions,, the authors notedl that the ratio: of oxygen debt to oxygen, uptake in- creased' significantly under conditions of increasedl COHb. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors (121, 122)) had previously not'ed'similar findings anlong smokers and observed 61, I k ~_c I 6

that cessation of smoking, was associated with a significant irn- provement in oxygen debt accumulation,, lhtorerecen.t work byAyres,etal,('15~) hasl focusedl on the~ dif-ference in response to: CO exposure between 7 normals and 4 pa- tients suffering,frorn C'HD' (proven arteriographieal']y). The,induc- tion ofa, COHb concentration of approximately 9 percent ini the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen~ percent: extraction andl no, change in myocardiall oxygeni consumption, coronary sinus oxygen tension;, and lactate and pyruvate extractioni ratios. The induction, of' simi- llar COHb levels in the CHD patients was followed by no change in coronary blood flow; a decrease in the hemoglobin oxygen ex- traction ratio, and no change in myocardial oxygen consumption. However, these patients, didl m~anifesta_ decrease incoronarysinusp.02, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the xnyocardium, was functioning under hypoxic condfitions: Because the coronary flow could not in- crease and' because the myocardium could, not extract GZ f'rorn: Hb02 which was under the influence of CQ, coronary sinus oxygen tension decreased tol a point whichi could inactivate certain oxida- tiveenzyme processe& , Thus,, the myocardial, function ofpers~ons, with C'HD may be unable~ to, compensate for the stressesiniduceds by smoking., Although COiHbl levels resulting from the CO present in the atmosphere during periods of high air pollution are much lower than those d!ue to the inhalat'ionl of cigarette smoke, these concen- trationis of COHb might contribute to the manifestations of CT-ID., Cohen, et al. (44) studied the case fatality rates for patients ad- mittedl to 3~5I:os Angellesarea , hospitals with myocardial infarctioni in relation to atmospheric CO pollution. The authors observed ann increased NIZ case fatality rate in areas of increased pollution~„ and thenonlyd'uringperiodsof'relativelyincreasedi CO l pollution., An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to: Wynder and'. Hoffmann (215),, the amount present ranges from I1'l to 32 micrograms HCN per puff. It is known that al significant amount of thisl material is detoxified to thiocyanate and excreted as such ini the: urine or saliva. However, cyanide is al potent inhibitor of oxidative metabolism. Such inllibition of myo-- cardial oxildlatiive, metabolism~~may~belof importance whenl combinedd with the other factors mentioned above whiclr.tend to decrease the oxygen supply available andincrease the need.r for oxygen on, the part of'the myocardium. 62'

EFFECTS OF SMOKING ON THE FORMATION OF ATHEROSCLEROTIC LESIONS A number of' autopsy studies have demonstrated a significant association between cigarette smoking and the presence of aortic and' coronary artery atherosclerosiis;, even in meni without a hisy tory of' clinical CHD1. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking, are discussed ini this sectionL A rnamber of investigators have studied the effect of nicotine administration, either subcutaneously: or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A23). When administered' alone, nicotine induces certain necrotic changes in the arterial wall. However, in combination withi the administration of increasedi amounts of cholesterol in thee diet, nicotine aggravates either subendbthelial fibrosis (7"5)i or definite atheromatous lesions (i46„ 75, 80, 130, 178), Studies by Choil (42) and by Wenvel, et al. (.207) did not demonstrate tliis synergism, between cholesterol and nicotine. The other rnajor, ccigarette smoke component under discussion in this chapter, carbon monoxide; has a]so been recently implicated in atherogenesis: Table 24 presents the studiies which have relatedd exposure to CG in combinatiioni with increased dietary cholesteroll to both rnacroscopiicand m~icroscopic! aortic and coronary athero-, m~atosis., Astrup, et al. (10) 1 exposed cholesterol-fed rabbits to CO continually over a periodl of up to 10 weeks, The experimental group showed' increased aortic atherornatosis over that shown by the control group,, also cholesterol-fed. Kjeldseni„ et al'., (114:), observed that exposure of rabbits to increased oxygen concentra- tions significantly reduce& the amount of cholesterolLinduced atheromatosis in rabbits. Most recently, Webster, et al. (204) have. extended this research to primates. These investigators found~ thatt cholesterol-fed squirrell monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to, C.O' over a 7-month periodlt'h.an wheni exposed only to room air. )at'ecent discussion has centered on the mechanisms whereby CO1 can induce these changes (9, 212). Astrupi (9), referring to, pre- vious experiments in humans which, had shown increased' vascular permeability for albumin upon chronic exposure to CO (11'), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls: This, he, con- siders, is a primary cause of intimal and medilal~ lipid accumul'atibni and, therefore, of atherosclsrosis. Another point of view has been stressed by Whereat (212), who consi ders the filtration theory to be an inadequate hypothesis for 63'.

TABLE 24. -Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia Author. year, Number and country, type of animal Procedure reference Results Astrup 24 female Regular diet plus 2 percent et aL, albino rabbits. cholesterol: 1967 I. (12) control. Denmark I_I_. (12) continualexposuret_o_ (t0), carbon monoxide: 0.017 percent for 8 weeks. 0.035 percent for 2 weeks. Kjeldsen et al., 1968, Denmark (f17). 24 castrated male albino rabbits, Regular egular diet plus 2 percent_ cholesterol: 1. (12) control. 11. (12) continual exposure. to hypoxia: 10 percent-0Z for 6 weeks. 9 percent 0 2 for 2 weeks. Kjeld_sen 24 castrated male Regular diet plus 2 percent et al.,_ albino rabbit_s. cholesterol: The experimental group exposed to carbon monoxide showed increased macro- and microscopic aortic atheromatosis over that shown by control animals. nimals. Micro- scopic scopic examination revealed inti_mal lipoid deposition limited in penetration by the internal elastic membrane. Coronary vessels were found to show similar changes. Carbnxyhemoglobin (COHb) levels averaged 15-19 percent during the first 8 weeks and 33 percent during the final 2 weeks. The experimental group exposed to hypoxia showed increased macroscopic aortie atheromatosis over that shown by control animals. Microscopic examination re- vealed vealed more intimal and subintimal lipid deposition in the aortas of the exposed rabbits than in those of the nonexposed. The total amount of cholesterol de-. - - posited in the aortas of the experimental group was three times higher than in - those of the control group. Macroscopically, the experimental group showed significantly fewer atheromatous - changes. Microscopically, the experimental group showed significantly less aortic 1969, Denmark (114). I. (12) control. II. (1_2) exposure to 28 percent 02 for 30 weeks, - intimal lipid deposition. Webster 22 female squirrel Diet containing 0.5 percent The experimental group exposed to carbon monoxide showed a greater mean per- et al., m_o_n__keys. cholesterol and 25 percent fat: centage --- -- -- -- - centage of coronary arteries with atherosclerotic lesions and more lumen occlu- - 1970, I . (10) control. There were significantly more CO-treated sion among the affected arteries sion U.S.A. _ II. (12) experimentally exposed to . - monkeys than control monkeys having 35 percent or more apparent athero- (ro4). 200-300 p.p.m.carbon monoxide sclerotic sclerotic stenosis among the affected arteries. Aortic ortic atherosclerosis was appar-_ for 20 hours per week for 7 ently not aggravated by exposure to CO. COHb levels at the end of each exposure months. period averaged 16-26 percent during the final 24 weeks of the experiment.

mural lipid accumulation. The author notes that when the oxid'a- tion of the pyridine nucleotide„ nicotinamideadenine dinucleotide (NAD), is impaired~ the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrial enzymes whose hydrogen donor is NADH. aubstances which slow or impair the reoxidation of this compound tend to increase mito, chondrial fatty acid synthesis (and decrease fatty acid utiTizationi) in the arterial wall. Carbon monoxide prevents thiis' oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process .of' NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem,, particularly in view of' the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial! wa11'i fat metabolism. THE'EFFECT OF'SIWTOKING'ON SER!Um IL+IPID I'.EVELS' In the discussion concerning the epidemiological aspects of CHD, it was noted that increasedl serum cholesterol was a significant risk factor for the develbpment of overt CHD. Serum trilglycerides have als& been rel'atle& to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The: studies concerning this immediate effect are presented in tables A 25 and A 25a. The table is divided into a section concern- ingstudi~eson humans (table A25)! and oneconcerning, studies, utilizing animals or in vitro systems (table A 2'5a) . Although noo consistent response was noted for serum cholesterol, serum free fatty acids were found consistently to rise following smoking. As with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated' by catechol- amine release. This relationship has' been observed in a number of experiments by Kershbaum, et al. (105, 106, 108, 1'09, 110) and Klensch (118). That nicotine is primarily responsible for this rise may be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of' regular cigarettes. While attention has been centered upon nicotine as the agent inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolisrn, These studies are listed in table A26. Among rabbits fed~ increased amounts of ' cholesterol, 65 4> r.

the authors observedi significant increases in c'holesterol and' tri- glyceride concentrations in those exposed' to COi versus thosee maintained in a normal atmosphere. THE' EFFECT oF, SMOKING ON THR'OIWIBOSIS In the study of CHD!, a number of' investigators have turned' their attention to thrombosis because myocardial infarction and sudden coronary death frequently result from thrombotic events. A thrombus may be of either gross or m2eroscopic dimensions, and a minute throm;bus at a strategic site may precipitate a fatal ar- rhythmia. However, thrombotic and prethrombotic states are dif- fiicuilt to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a second'ary role in the consolidation of' an arterial thrombus and little if' any in initiating the process. The prime mechanism in thrombogenesis appears to be the reactilon of the platelet. Several papers have been, written about platelet re- activity in vitro but few about the effect of' smoking, on platelet behavior in vivo. The assay of fibrinolysis, which may also be im- portant, has receivedi scanty treatrnent. The relevant studies are listed in table A27. Many of these are discussed in, the 1968 sup- plement (192) and by Murphy (140). Corroborative data are still inconclusive as to whether smoking shortens platelet survival. O^rBiERI AREAS OF, INVESTIGATION Certain other aspects of cardiovascular pathophysiolbgy may be of importance in the relationship of smoking to CHD1. Glucose me- tabolism andi insulin response, when altered, may alter myocardial response. This topic has been covered in detail ini the 1968 Supple- ment to the Health Consequences of Smoking (192)1. Also, varia, tions in blood hemoglobin and hematocrit may adversely affect coronary'blood fibw., A number of studies showing a possible r~el'a-tionsHip~ of smoking to hemoconcentration havebeeni reviewed pre- viously (191, 192)', and the reader is referred to those discussions. CEREBROVASCULAR' DIS'EASE' The terrn cerebrovascular disease (CVD)i refers to a number of d'ifferent types of vascular lesions affecting the central nervous system : subarachnoid hemorrhage, cerebral hemorrhage, cerebrall embolism, and thrombosis (ICD Codes 330 to 334}. In 1967 in the United States, a, total of 93,071 males and 1109,113 females were listed as dying from CVD' as the underlying cause (196). Epidemiologiieal' studies indicate that cigarette smoking is asso- 66'

0 i ciatedl with increased mortality from cerebrovascular disease; whetlherCVD~is~ listed as the underlyiingorasa,contributorycause of death. Table 28 presents the resul'ts of the seven, major epidemi- olbgical' studies. The smoking, of pipes and cigars does not appearr to increase significantly the risk of dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for rnor- tali'ty from C'UDhasrecentlybeen notedbyfiammond and Gar-finkel (TB) . The datai from their study, as presented in table 28, also indicate that the! mortaliityratilofor cigarett'esmokers is, greater- for persons under, 75 years of age than for older individuals: Many of' the pathophysiological considerations discussed ini the sections concerning CHD may also pertain, to the relationship of smoking and CVD„ particularly cerebral infarction. In a study reported by Kuhn (1'23), 20 habitual smokers re- frained from smoking, for one-half day, and! base line retrograde brachiocerebral angiograms were taken ; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over. 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (132) studied the effect of smoking on the cerebral circulation of '12'moderate/ heavy cigarette smokers as measured indirectly using an~ ultrasonic Doppler technique to record internall carotid artery flbav. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow, and a decrease in cerebral vascular resistance in all subjects. Nlosignificantdiifference inresponse wa& observed between the 4 younger and 8 old'er (over 60 years of'age) subjects. 1Tore research is needed to clarify the role of cigarette smoking in~ the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon~ the cerebral circulatibni (particu- larly its extracranial portion) is likely to be similar to the effect of smoking upon the aortic and coronary atherosclerosis. NION-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death~. In 119!67 in the United States, a totall of 8;448'rnen and 3,173 women were listed as dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to increase the risk of dying frorn, this disease, perhaps by promoting, the atherosclerotic proc- ess which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, andl the risk increases in proportion to the amount smoked. 67

TABLE 28. Deaths from cerebrovassular disease related to_ smoking (Mortality ratios-actual number of deaths shown in parentheses)' [SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Author, Number of Follow- deaths due Pipes year, country, reference Number and type of population Data collection up years - - to CVD as underlying cause - Cigarettes per day and cigars Age variation Comments Hammond 187,783 white Questionnaire - - 33/2 1,050 NS ........1.00_ (164) 1(pK0.01). and Horn, 1958, males in 9 states 50-69 and follow- up of death Cigarettes SM ...... t1.30 (556) U.S.A. years of age, certificate. Other SM ..1.25 (330) (77, 78). Doll and Hill, 1964, Great Britain (50). Kannel et al.__, 1965 U.S.A. (96). - Cigarettes only <10 .. ...3.24 10-20 ...... 1.44 - >20 ........1.46 (41) (140) (83) Approximately ately 41,000 male British physicians. Questionnaire and follow- up of death certificate. 10 605 NS . . ...1.00 All SM ......1.06 All cigaret_t_e_ 1.12 1-14 ...... 1.10 15-24 ...... 1.09 >25 .......1.26 5,127 males and females Medical examination 12 13 NS .........1.00 Heavy SM (6) Data apply only to males 30-59 30-59 ye_ars_ of age. and follow- up. (>20) ,...3.23 (8) years of age at entry. Data apply only to cerebral infaretion. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

Author, year, Number and country, type of reference population Kahn. U.S. .S. male 1966, veterans U.S.A. 2,265,674 (9S). person years. !,7,~i. . TABLE 2$.-Urnthu fruuE ecrchruvu,srarfrue rtiaru.,c r, l'rl'd t-e rmo{;i„ j (runt.) (Mortality or_tality rutius-actual number of dl~iathu .vhu.gn ~ in l~nrrnthry.~..)~~ I SAi -._ smukrrn NS PRt)SI'I:CTIVF: STUDIES Number of deaths due Pipes Data Follow- underlying Cigarettes per day and Age variation Comments collection up-years to CVD as -- - - cigat'y ----- cause Questionnaire 8t/•-. 2,008 NS .... ....1.00 (61_4)Pipes ..1.06 (82) and follow- All SM up of death current ....1.30(1,394) NS ..1.00 (614) certificate. Current Cigars cigarettes .1.52 (692) NS ..1.00(614) 1-9 ....... 1.51 (98) SM ..1.08 (135) 10-20 ...... .42 (325) 21-39 .....1.70 (216) >39 ....... 1.59 (37) Hammond 358,534 males Questionnaire 6 4,099 Current $Based on only and 445,875 and follow- regular Males 5-9 deaths. - - --- --- Garfinkel, females 40-79 up of death cigarette 40-49 50-59 60-69 70-79 1969, years of age certificate. Never U.S.A. atentry, smoked 1.00 1.00 1.00 1.00 (76). 1-9 ...... 2.79 1.95 1.30 0.95 10-19 . . . .1.14 1.48 $1.44 0.92 ' 20-39 .....2.21 2.03 1.62' 1.22 - >40 ...... 1.64 2.40 1,72 t0.68 Females Never smoked 1.00 1.00 1.00 1.00 1-9 ...... 1.50 1.26 1.26 0.83 10-19 .....2.60 2.70 2.15 $0.57 20-39 .....2.90 2.67 1,83 1.28 >40 .....$6.70 $3.52 - -. I Unless otherwise specifled, disparities between the total number of deaths - and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

!I I? TABLE 2$. Deaths from cerebrovascular disease related to smoking (cont.) - (Mortality ratios-actual number ber of deaths shown in parentheses)i ~ - - SM = Smokers. NS = Nonsmokers. Paffen- 3,263 male Initial multi- 16 barger, et al. 1970 longshoremen 36-64 years of age in phasic screening and follow- U.S.A. 1951. up of death (144). certificate. Paffen- >50,000 male Initial college_ barger University entrance and students medical ex- Williams followed up aminations 1967 to 50 years. with follow- U.S.A. up of death (145). certificate. Controls- surviving classmates age-matched. RETROSPECTIVE STUDY Death Rates Cases (158) Controls (615) SM ..................... 45.0 31.3 (P<0.01) Cigarette SM >10 per day . 20.9 11.2 (pG0.01) ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of -- - either occasional, miscellaneous, mixed, or ex-smokers. PROSPECTIVE STUDIES 67 NS and <20 ......... 1.00 (42) >20 ......... -1.15 (25) The 63 deaths from occlusive stroke contributed to the statistical sig-_ nificance. The 95 deaths from hemorrhagic stroke showed no statistical significance as a single group.

fAB[.>; 29.-Deaflts frow rioit,tirfphi(ifir rtt,t'fit' ~r~„1,tI, r I„ :"i "~";(MrV'tality r:4tin.y artu;,l nutnLrl „f drnili h-su iu I--itl, . [SM = tintoktUS Nti _ Nu-m„i.cr: I V Author, year, Number and country, type of reference population ® Data Follow-up Number collection years of Cigarettes per day Pipes Cigar,, Ctrrnrnints deaths Hammond 187,783 whi_te_ Q_ uestionnaire 31/2 68 NS ......... 1.00(25) (expected) and Horn, males in 9 and follow-up SM ......... .2.72(68) (p<0.005) 1958, states 50-69 of death U.S.A. . years of age. certificate. (77, 78). Kahn, U.S. male Questionnaire 1966, veterans and follow-up - U.S.A. 2,265,674 of death (93). person years. certificate. Hammond 3_ 5_ 8,534 males Questionnaire and 445,875 females - and follow-up Garfinkel, 40-79 years of of death 1969, age at entry. certificate. U.S.A. (76). Weir and 68,153 California Questionnaire Dunn, male workers and follow-up 1970, 35-64 years of of death U.S.A. age at entry. certificate. (205). 8491 NS .................. 1.00 (58) NS ..1.00(68) NS ..1.00(58) Current cigarettes .... 5.24(234) SM . .1.13 (8) SM ..2.06(24) 1-9 cigarettes/day ...2.12 (13) 10-20 ................ 5.53(124) 21-39 ................ 5.95 (7G) >39 .................7.26 (17) 337 NS . .. .. .. .. .. .1.00 Data apply only 1-9 ........... 2.62 to males 50-69 10-19 .......... 3.85 years of age. 20-39 .......... 4.64 >40 ............ 8.00 5-8 51 NS ............ 1.00 SM include All ............. 2.64 ex-smokers, ±10 ............ 2.44 NS include pipe ±20 ............2.88 and cigar ?30 ... .. .. .. .. . 2.54 smokers. ' Unless otherwise specified. disparities between the total number of - - deaths and the sum of the individual categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

PERIPHERAL A~RTE'~RI(JSCZER'OSZiS~ Peripheral arteriosclero5is represents the effects on the vascu- lature of the extremities of the pathophysiologic processes which produce coronary and aortie atherosclerosis. A number of studies have been concerned with smoking, as a risk factor in the develop- ment of:thisdisease: Kannel, et al. (95) observed, in the Framing- ham study„ that diabetes mellitus and elevated serum cholesterol; as well as cigarette smoking, were also risk factors in the develop- ment of' peripherali vascular disease. JuergQns, et al. (92) reviewed the records of and contacted 478' male patients with arteriosclerosis obliterans (a severe form off peripheral art'eriosclerosis),, who had' been patients at the PNI'ayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria : the presence of' intermittent claudication„ the marked diminution or absence of' lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of' 350 Mayo Clinic patients of similar age who showed' no clhnical' evidence of' vascular disease. It was found, flor, males under the age of' 60, that 2.5 percent of the cases and' 25 percent of the con- trols were nonsmokers. However, no difference was noted bet'weeni the percentages of heavy smokers in eachi group. The authors also implicated high blood pressure andl elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted'similar findings in a studly of 294 male patients withi intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotlandl. In comparing the smoking his- tories of 100 patients with this complaint withi those of 11fa'healt'hy male controls, the author found that 1I percent of the patients and' 21 percent of the controls had never smoked. A total' of 42 percent of the patients smoked' more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of' peripheral arterial disease, is a significant cofact'or in its d'evelep- ment in almost all' cases. The author also noted obesity, high blood pressure, and elevated serum cholesterol as risk factors. Schwartz, et al. (168), compared the prevalence of risk factors in four groups of'subj'ects : 141 cases withi arteriosclerotic diseasee of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite nurnber of controli individuals who had been hospitalized for injuries. The in- vestigators reported that certain risk factors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- T2'

~:rnt irz hot!h coronary and lower limb arteriosclerosis. The authors that th~einhalati~on ofciigarette smoke appeared to be anInil)nrtant risk factor for coronary arteriosclerosis up to age 55 ;; in arteriosclerosis of thel~owerextremities„ inhalationap- awarecll to increase the risk even in the older age groups. «'idmer, et al. (213) compared 277 male patients with arteriall ecrlu-sioni of the limbs as demonstrated by aortography or oscillog- ral)h' v N~•ith 2;082 men demonstrated by oscillography to be free of ~rteri:rl disease. The authors foundl that cigarette smoking, parti cu!arla- heavy smoking, was significantly more frequent among the ca<es witharteri~a1 occlusion than among, thecontlrols, Increased ~,rta-lipoproteins and systolic hypertension were also found to be ni„re common among the cases. EXPERIMENTAL EVIDENCE i; ® _\ number of' experimenters have investigated the acute effects ,,f -~nloking, or nicotine upon the peripheral circu~latorysystem. 11hc-;e investigators, as listed in table A30, have measured effects n terms of alterations in skin temperature and blood flow as meas- .1:•ed by plethysmography, radioactive i'odinated albumin cliear- ; nce, or radiosodium clearance from the skin. The majority of ire<e studies have shown significant decreases in peripherall blood ,i(nv and skin temperat'ureupon smoking, particularly in persons. «-irhout manifest peripheral vascular disease. The study of Freund and W'atid (68)' demonstrates the dlifferenee: in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of. Str6rnbldd (181) on blockade of this response with automatic sys- tem blockers indieates that the reactivity of these vessels is sec- ondary to the local release of catecholamines. M'ost probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall andl prevent rapid alteration, particularly dilatations inres~ponse tothecatech~olamine& liberated by smoking or nicotine: THROMBOAIrTGIITI& OBLITERANS Thromboangiitis obliterans (Buerger's Di'sease)' (TAO)~ is an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischernic changes. Much discussion has centered uponi the question as to whether this disease is a clin- ical and pathological entity separate from peripheral arterioscle- rosis. McKusick, et al. (128) consider it to be a distinct entity 73

while Eisen (5T), concludes that TAO1 is the acute .infifammatory phase of severe arteriosclerosi's.. Clinically, it has been shown that smoking aggravates this dis- ease andi cessation of smoking frequently aids in complete or par- tial' remission. Razdan, et al. (153) and' Brown, et a1L (32) found very few nonsmokers in groups of patients diagnosed as having t'ypicali TAO. A recent study from Israel (16) involved a case- control comparison of 46' patients with TAO and 32' matched con- trols: Although the controls were found to, smoke less per day than the patients, this difference was not found to, be statistically sig- nificant. However, 100 percent of the smoking patients and only 72'percent of the smoking controls were inhalers, a difference sig- nificant at the 0:02' 1'eve1L CARDIOVASCUI.AR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE li. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the dlevelopnnent of coronary heart disease including fatal' CHD and its most severe expression„ sudden and' unexpected death.~ The risk of~ CHD~~ incurred by~ smokers~ of~ pipes~ and cigars is appreciably less thani that by cigarette smokers. 2'. Analysis of other factors associated with CHD (highi serum cholesterol, high blood pressure, andi physicall inactivit'y) shows that cigarette smoking operates independently of'these other fac- tors and can~ act jointly with certain of'them to increase the risk of CHD1 appreciab]y.. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease andi therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta, and coro- nary arteries. 5. The cessation of smoking is associated witlii a decreased risk of death from CHD:. 6. Experimental studies ini aniimals and humans suggest thatt cigarette smoking may contribute to the development of'CHiD and% or its manifestations by one or more of the following mechanisms : a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wa11i tension, contraction

0 and heart rate, and thereby increases the work of the :io;Ert and themyoeardial demand for oxygen and other'.'`1'1'llE llt5. individhzals with coronary atherosclerosis, cigarette -,,,A;in,gappears to create an imbalance between the increased r.ee(i, of'the rnyocardiumi and an insufficient i~ncreasei~n coro- ,.-,rv blood flow and oxygenation., ~,;rl~0t~-hemoglobin, formed from theinhaled, carbon rnon-%iEle~ diminishes the availability of oxygen to the myoeardiumi i ;di ni<llv also contribute to the development of'atherosclerosis. impairment ofpulnaonaryftanction causedbyci~garet't'enr ~king may contribute to arterial hypoxemia, thus red'uciing, :: anloutrt of oxygen, available to the myocardium. i.rarette smoking may cause ani increase in platelet adhesive- ti«-hich might contribute to acute thrombus formation. CEREBROVASCULAR DISEASE I!;ir E l'rrnm numerous prospective studies indicate that ciga- ~~~~ >~nno~ki ng~~ is~ associated with increased mortality~ from cerebro~~ . -C.1;:CI" [11heaSe: _. H_tij!Grimental evidence concerning the relationship of smClk- ~.,n~Ei~ ce~reb~~rov~as~cul'ar disease~ is at present insufl"icient~ to~~ al]ow~ concerning~~ pathogenesi~s~. However, some of~ th~e~ considerations dfiscussed~~ concerning; CHiD' rnay~ ~ :,rtain to~ the~ rel~ati'onsh~ip~ of' smoking and CVD,, particul'arly~ infarction. NONI-SYPHILITIC AORTIC' ANEURYSM °_*arette smoking has been observed to increase the risk of ~.~ir,,~* tlToni~~ nons~yphilitic~ aortic~~ aneury~sm.~ PERIPHERAL VASCULAR' DISEASE N 1. Datai from a number of retrospective studies have indicated, that cigarette smoking is a likely risk f'actorint~hedeveloprn~ent of peripheral' vascular disease. Cigarette smoking also appears to l,e al factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been, observed'' to alter peripheral' blood flovv and peripheral vascular resistance. CARDIOVASCULAR REFERENCES i 1) ACtlr 50N, P.,. 1111„ JEssor;, W. J. E., Tobacco smoking and serum,lipids,inm old men. British Medical Journal' 2: 1108-1111, October 25;, 119611. (2) ADLER, I., HkNsEL„ 0. Intravenous injections of nicotine and their ef- fects upon the aorta of rabbits. Journal of Medical R:esearch, 15: 229-239„ l9l)6: 75

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CARDIOVASCULAR APPENDIX TABLES i ;. :.. :~.

Author, year, Number and country, --tylieof reference populatCon --- English 1,000 niales with - etal., mani_festCHD, 1940, 40~ye 's of age. U.S.A. Contt~~~Is: 1.000 (60). male non-CHD ~ patients. TABLE Afi_.-CorQzttit'y ltcltrt cfiscasc m«rbicli.fy uu,4 <<u~~'trrliF«~rEt'o~~~cc~iE~t- stE(cliCs (Actual numhrr of cas(,~ shown in _P•urnth-cs)' [SM - Smokers NS = Nonsmukers EX - Ex-smokers] Data collection Cases (percent) --- - Case sclcetion a,rie F'crce7it Smokers from Mayo 40-49 ............79.7(187) Founda- 50~ 59 ............71.7(382) tion files. GO ur over ..... ....... 63.8( Controls: All ages ........ 69.8 same year of admis- sion age- matched. Controls (percent) Percent Smokers 61.9(302) (p<0.001) 73.9 (371) (not significant) - 61.8 (327 ) (not significant ) 66.3 (p<0.05) Mills and Porter, 1957, U.S.A, (131). 474 white male Undefined. coronary deaths. Controls: G06 white males. 40-49 (56) NS ...................7,14 All cigarettes ......... 83.93 Pipes, cigars .......... 8.93 50-59 (135) 6.66 82.23 11.11 60-69 (153) 18.30 49.02 32.68 70_ or over (130) 33.84 18.44 47.70 40-49 (216) 19.91 70.83 9.26 50-59 (188) 24.47 59.94 16.47 60-69 (114) 35.09 43.86 - 21.05 70 or over (88) 54,12 16.47 - 29.41 Buechley Males reporting Question- NS .............. 20.4 (23) NS ........... 42.1(51) et al., CHD to Californi_a_ naire and ~20 ............. 61.1 (69) =20 ........... 4G.3 (56) 1958. Health Survey interview. >20 ............. 18.5 (21) >20 ..........11.6(14) U.S.A. (33). with matched controls from same survey (included those surviving first myocardial infarction). Commenta 84TS94c0

Vf:f1SJ4cO Author, year, country, reference TABLE A6: Coronary heart disease morbidity and mortality-retrospective studies (cont.) (Actual number of cases shown in parentheses)I [SM = Smokers NS = Nonsmokers EX = Ex-smokers] Number and Data type of collection Cases (percent) Controls (percent) Comments population Russek and 97 male and 3 2ohman, female coronary 1958, patients. Controls: U.S.A. 100 healthy controls (163). of similar age, sex, occupation, and ethnic origin. Interviews_ Tobacco usage>&0 cigarettee/day Patients by 70 percent. 35 percent. included 89 authors. with classical myocardial itifarct ion _ and 11 with angina pectoris. Spain and 269 males identified 3,000 males NS .............. 30.0 (81) 29.0 (772) Nathan, as having CHD by in New <40/day ......... 29.0 (78) 33.0 (870) 1961, physicalexamination York City >40/day ......... 13.0 (33) 9.0 (234) (p<0.06) U.S.A. and history. Controls: inter- EX .............. 14.0 (39) 14.0 (361) (176 ) . - - 2,637/3,000 males viewed and - Cigar, pipe ....... 14.0 (38) 15.0 (-400) identified as examined Total ..... 100.0(269) 100.0 (2,637) not having CHD by medical group. Mulcahy and 400 ma'^s less than Hickey, 60 ye:;rs of age with 1967 classical CHD. Data Ireland compared with mal_e_ (135, 1J6). population con- -- sumption figures. Interview. Males Males NS ............. 4.50 (18) 18.2(110) SM ............. 90.75(363) 70.6(427) EX ............. 4.75 (19) 11.2 (68) Total .......... 100.00 (400) 100.0(605) Schwartz 612 male patients Interview, Average amount - 15.5 ( p<0.0001) et al., with angina or laboratory,_ per day as 86.0 1966, myocardial and cigarettes ...... 18.6 France infarction, clinicalex- All SM .......... 86.0 (16P). 612 age-matched controls. aminations, Inhalers .......... 59.0 45.0 ( p<0.00001) Control smoking data obtained from estimated smoking habits of Irish population of same age group. Data apply only to those under 55 years of age.

T_Altl_F: Aft.-C[tt'ul(rGrE! ltrar't tliar<t." r tttarltitl'ttl uu'l eureef,tl~t,t --r, [t~~,.vl„r~Itr ,:;t~r~lt,~ti (c.trtF.) LSM=Smolu•rs Nd=-Nt.os,-6,-r; f;S:_ . Pr 1 ORtS9(:4E0 4 Author, year, Number and Data country, type of collection reference population Villiger and 100 cases with Heyden- recent myocardial Stucky, infarctions, 1966, 72 males, 28 females, Swit- 100 age-matched ~ zer- controls (72 male _. ----- ~ -- land industrial (201). employees and 28 females in hospital for other diagnoses). Dorken, 205 males up to 44 1967, years of age with Germany myocardial infarc- (52). (5.4). tion or sudden death (139 deceased,_ 66 living ). Controls -Hamburg age- matched citizens selected randomly. D'drken, 33 females up to 1967, --- -------- - - -- 1967, 44 years of age Germany with myocardial ( 5d ). infarction or sudden death. Controls-133 females 27-44 years of age from clinic without CVD or lung cancer. Cases (percent) Controls (percent) Hospital history or . _B_fates(7_'2_) NS ............................ 6.94 Females(za) bla(es(12) )rematas(88) - - ~ -- ~ --- -- ~ -- ------. __ . 71.4 f25.0 82.1 interview. Cigarettes ....................... 66.7 1-19 cigarettes/day .............. 18.1 28.6 45.8 14.3 10.7 23.6 10,7 >20 ............................ 48.6 17.9 f22.2 3.6 Cigar, pipe ......................44.4 27.8 EX ............................. 4.2 ,,, }15.3 3.6 Death cer- NS .............. 1.0 (2) 18.4 (76) tificate re- Cigarette Units view. In- 1-5 ............. 1.5 (3) 10.4 (43) terview of 10-16 ............ 32.2 (62) 46.5(192) patient 20-30 ............ --- 43,5 (84) 22.5 (93) or kin. >35 ............. 21.8 (42) 2.2 (9) 100.0 (193 ) (only 28 were mixed or cigar smokers ) 100.0(413) (62 were mixed or cigar smokers) Death cer- ---- - -- tificates, Cigarettes per day ---------- 0 ............... 6.1 (2) 63.2(84) (p<0.001) inter- 1-5 ............. 17.3(23) views. 6-15 ............48.$ (16) 16.5(22) 20-30 ............. 19.4 (13) 3.0 (4) >35 ............. 6.1 (2) Comments These are not pure smoking classes. t(pG0.01) Ex-smokera listed under nonsmokers. Smoking information available only on 193/205. These cigarette categories include mixed or cigar smokers recalculated as to number of ciga- rettes. No patients ----- or controls smoked pipes exclusively.

© TABLE A6.-Coronary heart disease morbidity and mortality-retrospective studies (cont.) ;l k,e k.S 74cQ Author, year, - Number and country, type of reference population Hyams 79 males surviving et a]., myocardial infarc- 1967, tion. 157 age- Japan_ matched controls (8_ 7). hospitalized for non_- CVD but include hypertensive disease. M_ulcahy 100 female patients et al.,_ less than 60 years 1967, of age admitted to Ireland hospital with CHD. (18T). (Actual number of cases shown in parentheses)i [SM = Smokers NS = Nonsmokers EX = Ex-smokers] Data collection Cases (percent) Controls (percent) Interviews NS ..............10.1 (8) 21.0 (33) by trained 1-9 cigarettes - personn_e_l_._ perday ........ 7.0 (5) 10.5 (13) 10-15 ............ 16-20 ............ . 21-34 . ....... >35 ...... ...... 25.4 35.2 . 22.5 9.9 (18) (25) (16) (7) 33.9 (42) 25.8 (32) 17.7 (22) 12.1 (15) AI1 SM .......... 100,0 (71) 100.0(124) Hospital SM ............... 63.0 (63) 45.6(261) interviews. NS .............. 33.0 (33) 45.3(259) EX_ . ..... .. -4.0 (4) 9.1 (52) Total .....100.0(100) 100.0(572) SteJfa, 70 male and Direct Prevalenc_e_ of risk factors 1967, femalepatients interviews. Angina patients_ Poland with recent onset 60.0 (179). exertional angina pectoris. 54 controls of same age. S_chimmler 503 males with et al., healed myocardial 1968, infarctions.714 male Germany controls of same age (167). without detectable heart disease. Hospital N$ .............. 9.0 (44) interviews. EX ..............12,0 (59) Cigar, pipe .... .. 12.0 (62) <19 cigarettes .... 25.0(129) >20 ............. _ 42.0(209) Total ....100.0(503) C-ontrolpronp 48.1 (p>0.1) 26.0(187) (p<0.001) 20.0(142) (p<0.001) 11.0 (77) 14.0(101) (p<0.001) 29.0(207) (p<0_,001) 100.0(714) Comments Smoking on controls obtained from__ statistics of smoking in Irish Republic. Sudden death not included. Authors then followed the 70 patients for 3 years and noted ted that smoking signifi- cantly influenced the incidence of coronary occlusion.

I'AIS>rE A6.-E'urotdrsr}1 keltrl ((id(°utif ittr,rbi(lil,rt aiul ul0rla lilrt--r, trvsprc•tirr stuclu,, (ron t.) (Actual number of caecs shown in parenthexes)I [SM c Smokers NS - Nunsmokers Author, year, Number umbe r and Data country, _ - type of collection Cases (percent) reference population Hood et al., 230 males surviving Interview (230) 1969, early first myocardial oucardial and exam- Never smoked . .1.7_ 5_ Sweden infarction. Controls: ination. EX before . ... ..._.----- (85). 855 randomly selected males 50 years of age. infarction ...... 1.75 EX after infarction .....29.1 <15 cigarettes .28.3 >15 cigarettes ...22.6 All .............. 80.0 Pipe ............ 16.5 Jouv_e 1,229 CHD patients; et al.,_ 802 males, 427---- 1969, females. Controls: France_ 743 individuals of (41). both sexes:age, sex, and social class matched. Kastl, 275 male railway 1969, employees up to 6_5_ Germany years of age sur- (95). viving myocardial infarction. 275 con- trol employees with minor circulatory disturbances. Interview. 43.0 27.4 20.0 47.4 8.8 13.0(p<0.0001) Interview NS ..............$0.0 (55) 29.8 (82) and ex- amina- 2-20 cigarettes or up to6 cigars. . .32.0 (88) 63.3 (82) tion. >20 cigarettes or >6 cigars. ....... 48.0(132) 6.9 (19) EX - Ex smqkers] 24.2 Controls (percent) (855) 19.7 Comments 1 Unless otherwise specified, disparities between the total number of cases and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

T_ASr.E A_7. Differences in serum lipids between smokers and nonsmokers (Actual number of individuals shown in parentheses)' [SM = Smokers NS = Nonsmokers] ) M99f.1(.O Author, year, country, reference Gofman et al., 1955, U.S.A., (72). Thomas, 1958, U.S.A. (185). Dawber et al., 1959, U.S.A. (47). Karvonen et al., 1959 Finland (97). Number and type of population 401 male employees 20-59 years of age. 521 medical students. 2,253 males participating in the Framingham study 29-59 years of age. 525 males in various occupations 20-59 years of age. Results Difference between SM and NS Ages 20-29 Ages $0-89 Ages40-59 Lipid: (NS 55, SM 37) (NS 56, SM 67) (NS 17, SM 44) tSf 0-12 ........ +59.9 p<0.001 -)-19.9 p<0.05 + 3.9 p<0.05 Sf 12-20 ........ + 9.4 p<0.001 + 5.4 p<0.05 - 3.5 p<0.05 Sf 20-100 ....... +20.0 p<0.025 + 9.1 n<0.05 + 8.5 p<0.05 Sf 100-400 ....... +15.8 p<0.025 +12.1 p<0.05 - 4.5 p<0.05 Cholesterol ....... +21.2 p<0.05 + 9.0 p<0.05 - 4.8 p<0.05 Serum cholesterol mg. percent NS (264) SM (257) Qbserred/Expectcd Qbserved/Expected <250 .................................... 170/157 149/161.6 - ---------------------------------- --- --- >250 .................................... 87/99.6 115/102.4 Chi S9uare Value = 5.2 p<0.025 Comments tSf refers to Svedberg flotation units of centrifuged lipoproteins. Serum cholesterol +ng. percent The authors conclude that 29 4 5-59 - 4 4 NS ........................................ 216.1(149) 228.3(131) All cigarettes .............................. 224.8(87-4) 229.5(589) <10 ....................................... 217.4 (75) 229.1 (76) 10-19 ..................................... 221.1(134) 230.1 (95) 20-39 ....... .. .. 225 8(551) 227.8(350) - >40 ..... . ..................... ....................................... . 229.0(114) 238.5 (68) Pipe and cigar ............................. 214.9(128) 2z7.1(16s) Serum cholesterol mg. percent West Finland_ East Finland Helsinki NS ................................. 208.0(64) 226.6 (39) 235.1 (62) SM ................................ 228.7(91) 249.7(103) 257.8(166) there is evidence of a gradient of cholesterol with increasing amount of cigarette smoking in younger men. The _he authors state that no trend was noted associating increasing amount smoked with increasing serum cholesterol, although smokers and nonsmokers did have difl'erent overall --- --- - - ------ ---- - - levels. t;' :`~

PQ~'~r,A.n;kiP M~'" ~,':"s!t".aAeThQd.t449'.`?~ry;mn'±n.+ TABLE A7.-I)iff erences in se>'2411t lipids between smokers and nonsmokers (Actual number of indi_vi_duals shown in parentheses)i [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of reference population Results Comments Acheson and Jessop, 221 randomly chosen pensioners Mean serum cholestcrol Mean 8ota/Alpha mg. percent lipoprotein ratio 1961 65-_85 years of NS .......................................214(38.).. - - _.-2.0(36) Ireland age. 5 cigarettes/day ........................ 20102) 2.1(11) (1) 10 ..................................... 20 ..................................... >30 ................................... 213(34) 201(33) 206 (8) 1.9(33) 1._9(35) 1.8 (8) Bronte- ronte- Approximately Cholesterol mg• percent (3eta/fllpha lipoprotein ratio No data given on numbers in Stewart, 600 healthy 25-89 40-55 25-89 40-55 each group. 1061, males 25-55 tA $E A E A E A E tA-Afrlcan. South years of age. NS ........... 179 197 222 246 2,89 3.34 3.75 4.59 $E-European. Africa "Heavy" SM . . 186 223 204 236 3.82 4.40 4.07 5.40 (81). Konttinen, , 1962, 314 male military recruits 18-25 Serum cholesterol mg. percent Serum erum pkoapho6ipida mg. percent No serum lipid differences found among the various Finland years of age. NS ..................... (145) ............. 203.8 218.0 smoking groups. (119). (Cigarettes per day) 1-10 (53) ............. 206.8 222.3 11-19 .................... (54)............. 213.1 224.7 >20 ..................... (62) ............. 202.3 210.5 Blomstrand 76 monozygotic and Lundman, twin pairs and 1966, 87 dizygotic Sweden twin pairs obtained (26). from Swedish Twin - Registry. I. Monozygotes discordant for smoking: Smokers showed slightly lower levels of cholesterol, triglycerides, and phospholipids than nonsmokers. II. Dizygotes discordant for smoking: Smokers showed significantly higher levels of phospholipids. No differences for cholesterol and triglycerides. cont.) The authors conclude from the differing MZ and DZ results that constitutional factors are probably more important than smoking in determining lipid levels. VOIS9(.acU

r 0 Q TABLE A7. Differences in serum lipids between smokers and nonsmokers (cont.) (Act_ua_1_ number of individuals shown in parentheses)1 [SM = Smokers NS = Nonsmokers] Author, year_, Number and cQuntry, type of Results Comments reference population Fidanza i 11 male prisoners Serum cholesterol mg. percent No statistically significant et al., 34-69 years of Agea_ <39 40-49 50-59 60-69 differences found between 1966, age. NS ............................. .. 195(12) 189(10) 176 (7) SMandNS. Italy <20 cigarettes/day .............. 208(5) 201(16) 202(13) 195(10) (6_3). >20 cigarettes/day .............. 197(5) 176 (7) 171 (7) Serum_ triglyeeridea'mg• percent NS ............................. .. 84.7 71.9 85.0 <20 cigarettes/day .............. 84.5 99.4 101.9 89.8 >20 cigarettes/day .............. 91.0 86.0 65.7 . . Kedra edra and Dmowski, 200 clinically healthy males Serum cholesterol mg. percent Fhoapholipida Total lipida mg. percent mg. percent Serum cholesterol also noted to increase with increasing 1966. Poland (99) 20-50 years of age. NS (100) 170.2 SM 100) 224.9} p<0.01 _ 268.1 1,234.8) 25Z5~ R~0A5 - ~ } 1,362,1 J ta roteins - h o B p<0.01 - - intensity and duration of smoking. . Total fatty acids mg. percent - p p e pcr_cent of total lipoproteins NS(100) ........... 797.8 1 SM 100) ........... 869.9 pCO.01 4~:~~ p<0.01 Harlan et al., 657 former naval aviation cadets Serum cholesterol Serum triglyceride® Lipoproteina Found to be related Found not to be related Sf 0-12 related. p< 0.05 1967, 48 years of age_ to cigarette smoking to cigarette smoking. Sf 20-100 unrelated. U.S .A, (average). p<0.05. Sf 100-400 unrelate d. _ (79). .. .... Heyden- Stucky and Schibler- Reich, 1967, Switzerland (8Y). 500 plant workers 30-60 years of Serum cholesterol Serum triglyceride8 mg. percent mg. percent No statistically significant difference found between age. <10 cigarettes/day ...................... 210.0034) 110.0 SM and NS. >10 cigarettes/day ...................... 260.0(166) 180.0 .1. ..,. ktllS! SE4S94,E0

.., TABLF. A7.-Differences in seruuc liiticls (4lwcren stttulccrs azttl no_ naar~akels (coict.) (Actual number of individu__als shown in parantheses)' [SM = Smokers NS = Nonsmokersl tt Author, year_, eountry,-- reference Number and type of population Results Higgins and Kjelsberg, 5,030 male and female residents bfales NS ..................................... 209.9 (360) Females 210.1(1,439) 1067, - of Tecumseh, Cigarette ............................... 212.5(1,426) 212.4 (910) U.S.A. (83). Michigan, 16-79 years of age. Pincherly and Wright, 2,000 men participating in Serum cholesterol . . Percentage with aeru__m_ _ cholesterol >270 -- 1967, executive health mg, percent m__ g, percent F.ngland examinations NS(677) ............................... 236.2 19.0 (I50). 2R-70 yearsot Ex-smoker(388) ........................ 24G.0 28.0 age. 1-19 cigarettes/day(424) ................ 239.2 24.0 >20 cigarettes/day ( 511) ................ 249.4 30.0 Van Buchem_, 1967, 918 randomly chosen males 40-59 years 0-209 mg. percent Serum choleaterol 2t0-249 mg. percent >250 mg, percent Netherlands _etherlands of age for entry NS ................... 12.4 (32) 14.0 (44) 14.2 (41) (]y!1). into prospective Cigarette SM ......... 71.6(184) 67,$(213) 68.2(197) study. Other ................ 16.0 (41) 18.2 (57) 17.6 (51) 13oy1e et al., 1,_104 male factory 1968, employees 20:-64 U.S.A. years of age. (28). Caganova 49 males living et al., in youth hostel, 1968, 21.6 average age. Czechoslovakia (36). Serum cholesterol l mg. percent NS .......................... 243(519), p<0.005 SM ......................... 251(576)t NS(34) SM(15) Comments The authors noted that smokers showed significantly higher - --- ( p<0.001) serum cholesterol - - levels than nonsmokers. The authors found no correlation between smoking a__ndserumcholesterollevels. Serum Beta-lipoprotein Beta-lipoproteins were found mg. percent to increase with age, but 0.325) smokers had higher levels 1 p<0.001 0.3511 than nonsmokers at all ages. Serum cholesterol Serum Beta-lipoprotein mg. percent tng. percent - ---- ...................... 188.201 359.80 _ ...................... 214.201 p<0.025 498.40} P<0.001 . ----- Beta/alpha lipoprotein ratio NS(34) .......................... ... 1.16 SM (15) - .............................................. 1.55~p<0.025 9C7 15.7{.4cQ

0 N TABLE A7. Differences in serum lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)1 [SM = Smokers NS = Nonsmokers] 1.4SIS9F.rX0 Author, year, Number and country, type of Results Comments reference population Modzelewski 140 males 20-68 Serum-cholesterol Serum Beta-li_poprotcins Serum free fatty acids and Malec, years of age. NS (20) p<0.01 NS p<0.01 NS p<0.01 - - 1969, Heavy smokers Heavy smokers Heavy smokers Poland - --- (188). Kjeldsen_, 934 employees of Serum cholesterol mD_ . percent 1969, various firms NS (196) ............................................. 236 p<0,01 Denmark in Copenhagen. SM (738) ............................................. 247 (113). Pozner 64 male and Serum cholesterol and Billimoria, female healthy mg. percent 1970, volunteers 19-30 NS(20) ............ 176.3 England years of age. Light SM (17) ...... 172.1 (t32). (Over7.3 cigarettes/day ) HeavySM(27) ..... 200.0 p<0.05 (Over 22.5 cigarettes/day) 1 Unless nless otherwise specified, disparities between the total number of cases - and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. Serum triglycerides Total phospholipids Significant figures refer to mg. percent m_ g. percent heavy smokers as compared - - 68.6 193.4 with nonsmokers. 68.4 188.9 87.6 p>0.06 215.0 p<0.001

TABLE A8. Bloocl pressure differences between smokers and nonsmokers (Actual number of individuals shown in parentheses)' . -. ~ ------- [SM = Smokerv NS --= Nonsmokers] ..._------ Author, year, country, Number and type Resu lts reference of population Dawber et al., 1,253 male 1959, U.S.A. .S.A. and female (47). residents of Framingham. Comments Systolic blood pressure No association found Ages F9-44 45-59 between systolic blood NS(149) .................................................... 138.8 Cigarettes(874) ............................................. .....132.5 <10(75) .................................................... 134.7 10-19(134) .................................................. 129.4 20-39(551) .................................................. 132.2 >40(114) ................................................... 136.1 Pipe and cigar(128) ......................................... 135.0 143.0 pressure and smoking. 140.3 144.0 141.6 138.9 141.5 141.9 Edwards et al., 1,737 male hro_ portion of pnales with "liypeztension" (?200/?100 rnm. Hp. ) 1959, England (56). patients of generalprac- NS ........................................ 27.2 percent (151) Cigarettes ................................. 20.5 percent (780) titioners over Pipe ....................................... 25.9 percent (341) 60 years of age. Karvonen et al., 525 males in Systolic blood press_ure_ No data on pipe and 1959, Finland various regions West Finland East Finland Helsinki cigar smokers. No (97). of Finland NS ................................ 139.2(64) 142.6 (39) 132.8 (62) statisticalsignificance 20-69 years of SM ................................ 133.2(91) 135.4(103) 129.8(166) noted. _ t li bl d Di r age. NS ................................ 84.7 ae o oo c pressu e 86.8 89.6 SM ................................ 81.9 84.1 86.8 Clark et al., 1,859 male civil Mean systolic _ Mean diastolic Nonsmoker and smoker 1967, U.S.A. servants. blood-pressure blood-pressure groups were of similar (4s). NS ( 728 ) .............................. 137.0 83.9 average age. SM (407) _ ............. ..... ..... ~ 133.6 (p!5-0.05) )j 1 82.6 (p:-50.06)

, a A TABLE A8.-Blood pressure differences between smokers and nonsmokers (cont.) (Actual number of individuals shown in parenthe_se_s_)1 [SM = Smokers NS = Nonsmokers] Author, year, countiy, reference of population Results Comments Higgins and 5,030 male and Age adjusted Kjelsburg, female residents mean systolic blood pressure 1967. U.S.A. of Tecumseh, Michigan, Males Femalea (88). 16-79yearsofage, NS ........137.9 (360) 84.5(1439) Cigarette ...136.4(1426) 81.4 (910) Reid et al., 676 male British 1967, England and 625 male (155). American posta_l workers 40-59 years of age. Tibblin, 1967, 895 males in Sweden_ Goteborg, Sweden, (187). born in 1913. Age adjusted mean diastolic blood pressure Males Femalea 136.6 (360) 82,1(1439)1 (p<0.001) 131.6(i426) 79.0 (s>:o) J Mean systolic blood pressure (adjusted for difference in weight) UK U.S.A. NS ....... 128.2 (45) 1-_14grams 130.2 (27) 15-24 grams 128.5 (232) >25 grams 127.9 (70) All amounts 129.1(519) 124.8 (89) 133.0 (60) 127.7(169) 128.1(218) 128.6(447) Blood pressure 5110/S70 (89) - NS ...................... 18.0 1-1-4 cigarettes ...........29.2 >15 cigarettes . .. .. .. .. .. 28.1 Pipe and cigar ........... 11.2 ' Unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the -- - exclusion of either occasional, miscellaneous, mixed, or ex-smokers. Number and type The author did note Mean diastolic blood pressure SM-NS blood pressure dif- UK U.S.A, ferences prior to 79.3 81.0 controlling for weight, 79.4 82.1 but not after such control. 78.5 77.3 77.5 77,1 78.7 77.8 115-145/ 150-1T0/ Numbers in parentheses -- 75-95(y68) 100-110(220) >175/]115(75) represe-nttotalin blood 23.0 25.5 34.7 pressure group. 29.2 25.5 18.7 The author noted 20.9 15.5 17.3 a stepwise decrease with 8.6 10.0 4.0 level of blood pressure as smoking increased.

TABLE A17. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years of age (Numbers in parentheses are number of CHD cases in each subgroup) Former Current and Behavior type Never smoked cigarette smokers former pipe and cigar only 1-15 p.......... ................ 25.3(5) 13.8 (7) 1.3(1) 1.6(1) B 1.3(2) 5.1 (3) 2.2(2) 7.3(4) Total ................ 2.9(7) 9.1(10) 1.8(3) 4.9(5) - Source Sum of squares d.f. Within cells ..................................................... 59.471 2.245 Regression on age- ............................................... 0.456 1 Between smoking groups= ....................................... 0.504 5 Between behavior types= ........................................ 0.329 1 Interaction ...................................................... 0.396 5 Smoking group Cigarettes 16-25 26 and over Total 15.8(15) 14.9(16) 9.3(45) 3.1 (3) 4.9 (4) 3.3(18) 9.3(18) 10.4(20) 6.2(63) Analysis of variance table Mean square F P 0,026 .. .. 0.458 17.296 0.001 0.101 3.81 0.002 0.329 12.43 0.001 0.079 2.99 0.011 3 Rates are age-adjusted annual incidence per 1,000 men. effect but ignoring interaction, thus yielding an estimate of each main ef- - - ° Mean squares for "between smoking groups" and "between behavior fect unconfounded by other significant main effects. ------- - -- - types" are each computed eliminating the general mean and the other main Souac.e• . Jenkins, C. D. et al. (90).

TABLE A18. Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age Behavior type A ......................... B......................... ... Total ............... Source (Numbers in parenth eses are number of CHD cases in each subgroup) Smoking group Former Current and i i_g_ arettes Cigarettes Never smoked cigarette smokers pe formerp and cigar only 1-15 16-25 26 and over Total '12.4(6) 18.6(8) 21.8 (8) 16•4(5) 21.5 (9) 30.0(14) 20.4(49) 10.0(4) 5.1(1) 8.4 (3) 4.7(1) 21.1 (7) 19.1 (5) 12.0(21) 11.1(9) 14.2(9) 14.9(11) 11.5(6) 21.3(16) 26.0(19) 16.8(70) Analysis of variance table Sum of squares d.f. Mean square F Within cells ..................................................... 63.527 911 0.070 .. •• Regression on age ............................................... 0.177 1 0.177 2.54 0.111 Between smoking groups? ....................................... 0.522 5 0.104 1.496 0.188 Between behavior types= ........................................ 0.296 1 0.296 4.24 0.040 Interaction ...................................................... 0.129 5 0.026 0.37 0.870 I Rates are age-ad.iusted annual incidence per 1,000 men. effect but ignoring interaction, thus yielding an estimate of each main ef- - =Mean squares for "between smoking groups" and "betiveen behavior fect unconfounded by other significant main effects. types" are each computed eliminating the general mean and the other main SoUaCE: Jenkins, C. D. et al. (90).

O V .:O7,:;a . TABLE A20.-Experit7?ent& concerning tiae< effcc(s of .;molriny tairrl ?licutir2' uu uuirtt(tl cri).tlic.I rr: c' iMr fif ztcfion Author, year, - country, reference Number and type of population Smoking procedure Heart rate Blood Cardiac Coronary pressure output blood flow Bellet 39 experiments Inhalation Definite Definite et al., on dogs which of tobacco increase. increase. 1941,- had undergone smoke in U.S.A. coronary chamber. (21). artery liga- Nicotine Definite efinite Definite tion up to intravenous increase. increase. 45 days before. 0.2-1.2 mg./kg, Burn and 10 rabbits, Experimental Rand, 5 experimental, animals pre- 1958, 5 control, treated with England isolated atria, intraperitoneal (8s). nicotine and the atria of both groups excised and perfused with n icotine. West et al., 33 normal Coronary Definite 1958, adult mongrel intra- increase U.S.A. dogs. arterial (systolic). (208). nicotine: I. 0.2-2.2 µg./kg. II. 0.04-1 µg./kg. Comments Coronary artery ligation increased the frequency of nicotine-induced severe arrhythmias; these became less evident with increasing time since ligation. Isolated atrial specimen showed increased rate and increased amplitude of contractions with admin- istration of nicotine proportional to pretreat- ment. These reactions were blocked by reserpine, - - and the authors consider nicotine effects to be mediated by catecholamine release from chro- _ - - maffin store in myocardium. I. Myocardial contractility increased 40-90 per- cent in 15/15 animals tested accompanied by ST segment depression and T-wave inversion and blocked by tetraethylammonium chloride. II. Coronary blood flow increased 19 percent upon left circumflex artery injection; coronary blood flow showed no change upon left anterior de- scending artery injection, 64 observations on 10 dogs. (Tetraethylammonium chloride blocked CBF in- crease.) The authors found no evidence of coronary vaso- constriction in these healthy animals. constriction 1 Z61S94cQ

Xx i ~. :fi CbtS94.£0 TABLE A20.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont,) Author_, year, Number and Smoking country, type of procedure reference population Heart Blood Cardiac Coronary rate pressure output~ blood - flon: Forte et al., 1960, U.S.A. (c5). 27 observa- tions on S_ dogs. .. . Intravenous nicotine up to 2i.s mg. given as 5-_15 µg•/kg.[ - minute. Definite initial increase then decrease. No_ change. Kien and 21 adult_ dogs Cigarette Definite Definite Increase Sherrod, smoke under increase. incr_ease. following 1960, positive_ increase U.S.A, pressure via in blood (112). tracheostomy. pressure Nicotine 20 and cardiac kg•/kg. intra, output. venously. Epinephrine 6 µg./kg. intra- venously. venously. Travell 14 normal Intravenou_s_ Definite et al., rabbits and nicotine increase 1960, 16 rabbits 0.01-0.1 mg. in normals. U.S.A. with severe (189). cholesterol- induced athe_ro- sclerosis. .>rhwy . • ,' -( Comments No significant change in either left ventricular work or myocacdial oxygen extraction. Effects of cigarette smoke were duplicated by in- travenous nicotine and epinephrine. During cigarette smoke inhalation, it was noted that without blood pressure or output changes, coronary blood flow did not increase and that while adverse EKG changes were noted they cor- related more closely with decreased cardiac oxy- gen utilization than with actual cardiac work. Nicotine-induced coronary blood flow and heart rate increase in the atherosclerotic animals re- quired 10 times and 2 times, respectively, the amounts required in the normal animals.

' V61994C0 TABLE A20. Expcriments concerning the effects of smoking and nicotine on aninial cardiovascular function (cont.) Author, year, - Number and Smoking coutry, reference- type of population procedure Comments Bellet I. 10 normal dogs Intravenous 1. 125 percent The authors noted that: -. et al., - - ~ 11. 9 dogs at --- nicotine, increase 1. The response of coronary blood flow to nico- 1962, varying in- 20 µg./kg./ II. 82.5 percent tine resembled that of anoxemia in the pres- U.S.A, (22). tervals fol- lowing coro- minute for 15-20 minutes. increase IlI' 83.3 percent ence of coronary insufficiency. 2. The greater the induced coronary impairment nary artery --- ---- -------- increase - --- -- --- - - --------- ------- ----- the smaller the increment in coronary blood ligation. . . .... . .. .. . . . .. . . . . . .. . flow. III. 7 dogs with varying grades of artificially- induced coro- . . . . . . nary artery nary narrowing. Leaders 15 adult Left anterior and mongrel descending Long. dogs. intracoronary 1962, injection of U.S.A. nicotine or (125). norepinephrine. Larson et al., 1965, U.S.A. ------ (1Y4)• Nicotine and norepinephrine both increased coro- nary vascular resistance and myocardial contrac- tile force (the former measured by a constant- volume variable-pressure system). The action of nicotine was blocked by pretreatment with hex- amethonium, pentolinium, reserpine, or guane- thidine. -- 13 adult Intravenous_ Definite Definite Systemic vascular resistance and pulmonary artery ------- -- ---- mongrel nicotine, increase. increase. and left atrial pressures showed biphasic re- dogs. 0.02 mgJkg./ sponses of increase followed by decrease. minute for --- --- ---- 10-12 minutes. -1

Author, year, country, reference Folle et al., 1966, U.S.A. TABLE A20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Number and typeof- population Smoking procedure Comments 7 dogs of 30 investigated I. Cigarette smoke inhalation 1. No change in coronary vascular resistance. (Remainder experienced to isolated left lower lobe Ii. 5/6 showed owed increase in coronary vascular resistance due, according to catheterization failures). --- and then blood perfused coronary arteries. the author, to general sympathetic nervous system stimulation. III. 4/5 showed increase in coronary vascular resistance. The authors con- clude that the cardiac effects of tobacco arise almost entirely from the extracardiac actions of smoking instead of the direct response of the heart. (6_ 4). II. Cigarette smoke to rest of lung and then blood passed to general circulation. III. Nicotine perfused directly into left coronary artery. Nadeau and_ James, 1967, U.S.A. (142). 26 dogs Nicotine 0.01-10.0 µg.into sinus node artery. Romero and 16 experiments Nicotine in varying doses in - Talesnik, -- - - -- on isolated perfusate of coronary arteries. --- -- 1967, U.S.A, cat heart. (156). ri 22 mongrel dogs I. (1-4 ) Intravenous nicotine Pu _ _ et al., 1968, U.S.A. . (]52). tc Heart rate showed initial slowing (due probably to vagal stimulation) fol- lowed --- lowed by acceleration (due probably to vagal paralysis and catecholamine - release). No systemic blood pressure changes noted. Over 5 µg. of nicotine was found to produce an initial bradycardia asso- ciated with increased coronary flow, followed by prolonged tachycardia with an initial decrease in coronary blood flow followed by a prolonged increase. Pretreatment with hexamethonium or reserpine prevented both the myocardial stimulation and the increase in coronary blood flow. The - ---------- - ---- authors consider the action of nicotine to be a combination of a direct vasoconstrictive effect and an indirect catecholamine-releasing vasodilating effect. _I. Nicotine produced a definite increase in the force and velocity of left /kg./minute for 3-4 50 µg ventricular contraction. , minutes - -- ------ ----- II. Pretreatment with propranolol produced (relative to results of Group I) : II. (8) Propranolol pretreat- --------- (a) A further increase in left ventricular systolic pressure. ment, then 50 µg./kg./minute nicotine for 3-4 minutes (b) (c) A decrease in velocity of shortening. A significant increase in left ventricular end-diastolic pressure. The authors conclude that propranolol probably impairs the norepinephrine- .__. like effects of nicotine on the myocardium while enhancing its peripheral vasopressor effects. Fo TS,74C.O

TABirE A20.-Experiments concerning the effects of smoking ci>Id vicotilie on animal cardiovasciitar function Author, _ year, Number and Smoking country, type of procedure reference population Balazs Beagle dogs with lesions et al._, induced in myocardium by 1969, either: (1) Isoproterenol U.S.A. pretreatment, or (2) (16). ligation of the anterior descending coronary artery. I. Normals (3-6 per experiment); (a) 4 µg./kg.intravenous nicotine, (b) 40µg•/kg. intravenous nicotine. II. Experimental (3), 4 µg_.lkg• intravenous nicotine Greenspan Cardiac ardiac muscle isolated from et al., the right ventricle of 10 1969, adult dogs. U.S.A. (74). Saphir and 88 mongrel cats . .- --- ~ ------ .. Rapaport, 1969,~~~~ ~~- U. S. A. (166). Nicotine 2-100 kg./cc. in Tyrode's solution per€usate. Comments I. (a) No evidence of arrhythmias; (b) A single or a few ectopic beats in 2/3 normal dogs. 11. Extrasystoles noted in 2/3 animals during the first day after cessation of the_ arrhythmia induced by the lesion alone, but not thereafter. These and nicotine-induced arrhythmias were of a short duration. Nicotine perfusion produced: (1) An inereas: in myocardial contractile force apparently independent of adrenergic innervation. _ - (2) An increased automaticity of the Purkinje fiber system apparently due to release ofcatecholamines from chromaffin tissue stores. (3) A decrease in conduction velocity. The authors conclude that the latter two effects probably predispose to ar- rhythmia formation. rhythmia Nicotine 6-12 µg./kg. injected I. Mesenteric injection of nicotine was followed with 1-2 seconds by: intraarterially to mesenteric circulation. (a) (b) (c) Increased left ventricular systo_1_ic_ pressure Increased systemic resistance. Enhanced myocardial performance. (LVSP). II. Left (a) ventricular injection of nicotine was followed by: Increased LVSP. (b) Bradycardia. (c) Enhanced myocardial performance greater than that seen in mesenteric-injected group. III. Pretreatment with phenoxybenzamine diminished the increase in LVSP while propranolol pretreatment diminished the enhancement of my- ocardial . . .-.._--- ocardial performance while LVSP still showed a significant increase. IV. Mesenteric sympathetic nerve section led to a diminished response. The authors conclude that the cardiovascular responses to nicotine may be neurogenic in nature with receptors distributed in certain abdominal arteries. 9 f~Ig94c0

TABLE A20.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, year, country, Number and type of-~- -~ Smoking procedure Comments reference population Leb et al., 12 mongrel dogs and Nicotine 100 µg./kg. for Effective Coronary Flow (ECF) is that part of the total coronary flow 1970, CBF measured with use of 2 minute intravenously. (TCF) which is "effectively ' involved in nutrient exchange. U.S.A. Rb34 and digital counter. Nicotine injection was followed by: (1) 96.6 percent increase in TCF. (2) 51.1 percent increase in ECF. (3) 73.1 percent increase in myocardial oxygen consumption and analysis revealed that capillary flow increased almost proportionately to my- ocardial oxygen consumption whereas the increase_ i_n__ TCF was far ocardial in excess. (4) Definite increases in cardiac output, heart ra_te,_ left ventricular work, and aortic pressure. Ross and 10 dogs undergoing Nicotine 10-100 µg. intra- Nicotine injection was followed by: - Blesa, instantaneous coronary coronary injection. (1) Increased contractile force. 1970, arterial r_t_er_i_al flow measurement, (2) Decreased myocardial contraction time. U.S.A. . (3) Decreased time necessary to reach peak tension. (160). (4) Decreased total stroke systolic CBF. (5) Increased total stroke diastolic CBF. (6) Increased total stroke CBF. (7) Changes similar to intraarterial epinephrine. (8) Changes blocked by pentolinium pretreatment. (9) No cha_nge in heart rate or blood pressure. The authors conclude that catecholamines released from the ventricular - myocardium mediated these responses to nicotine.

86IS94CU TABLE A21-Experinl,ents concerning the effects of smokingg mut ?Ficotrne oN the cul•diul•usclltnr 5g.:fr/n 0 homnlrs Author, -yea>=, Number and Smoking Heart Blood Electrocardiogram Stroke country, type of pTocedu_r_e_ rate pressu_r_e_ ballistocardiogram volu__m_e_ reference population ----- - Russek I. 28 healthy 1 standard and 1 I. Increase. Increase. EKG: --- - et al., male smokers denicotinized I. 16/28 showed 1955, 21-60 years cigare_tt_e_. significant U.S.A. of age (aver- changes. (164). age 42). II. No sig- II. 37 male patients II. Increase. Increase. nificant with overt changes. clinical CHD BCG: 42-70 years of I• • . • age (average II. 18/37 showed 54), 6 were significant nonsmokers. change. Cardiac Coronary output blood flow Bargeron 14 of 30 healthy 1 cigarette Insignificant Increase. Definite et al., adult male vol- inhaled at ase. increase. increase. 1957, unteer smokers intervals of U.S.A. and nonsmokers 20 seconds. (17). who underwent successful catheterization 18-53 years--- of age. Comments Denicotinized ciga- rettes evoked chang_es of a )esser degree in normals and CHD subjects, but in the latter group there was no significant een difference between these changes. Coronary vascular - resistance fell_ significantly. Myocardial 08 usage underwent no significant change. Pyruvate extraction fell slightly. Authors consider lack of increase in heart rate as due to baseline apprehen_s_ive_ tachycardia.

TABLE A21.-ExpBriments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) sG.'S94EO Author, year, Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate pressure ballistocardiogram volume output blood Comments reference population flow Regan 7 males with 2 standard Definite Definite Increase. No signi- Myocardial 02 consump- et al., history of cigarettes in inerease. increase. ficant tion rose_ slightly in et 1960, EKG-proven 25 minutes change. 3 out of 7. U.S.A. myoca_rdial_ inhaled at The author considers (15_b). infarction minute that the EKG changes undergoing intervals. noted on smoking are cardiac ca- probably due less to theterization. decreased coronary blood flow than to increased workload (oxygen need) where oxygen supply does not increase. Noted no evidence of myocardial ischemia during smoking. Thomas and 113 clinically One standard Definite Definite Definite Definite Pulse pressure showed ----- Murph y, healthy young cigarette increase. increase. increase. increase. a decrease. __ 1969, males. smoked at Smokers responded U.S.A. own pace. slightly but signi- (1gs) y ficantly more - - actively than non- smokers. BCG changes were increasingly common with increasing age, weight, and serum cholesterol. 0 '^M..»"':'tr, J;.

TABLE A21. Experiments concerning the effects of srrzoking and nicotine on the cardiovascular system of humans (cont.) . .... ... ....._.. . _ .-- - -~- --~-- -- Author,_ year, country, referencf Number and type of - population Smoking procedure Heart Blood rate~- pressure - .. . . Electrocardiogram Stroke Cardiac Coronary 6aflistoeardiogram volume output blood - .___..__.--------- ------- ~-- -- flow Comments Von Ahn, The author Cigarette Increase. EKG: Slight ST EKG changes more 1960 reviews a smoking. segment prominent in young, , Sweden series of --- ----- - depression clinically healthy (202). experiments and T-wave subjects than in performed flattening. older, habitual between smokers. Intra- 1944-1954. venous nicotine and smoking showed identical cardio- vascular effects. Smoking elicited angina pectoris in a number of CHD patients. Irving and 5 normal males, i i Y h (a) Sham smoking. (a) No h No change. (a) No change. No change. Cardiac rdiac output measured by dye ents w amamoto, 15 pat t 1963, diseases not de- England fined, 19-66 years (b) Non-inhalation smoking. (b) ange. c No change. No change. (b) No change. No change. dilution technique. (89). of age, all mod- erate-heavy i k (c) 2 standard cigarettes in 10 i (c) Definite increase. Widened pulse, (c) Definite Definite increase. increase. c garette smo ers. (d) m nutes. Nicotine 0.6 mg. intra- venously. (d) Definite - increase. pressure. Definite increase. (d) Definite Definite increase. change. OQn9/,eieo

a 'Pat;Lh A21.-I'xpcrin(ents concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, year, Number and Smoking country, type of pr_o_ce_d_u_re reference population - - Heart Blood Electrocardiogram Stroke Cardiac Coronary rate pressure ballistocardiogram volume output blood - flow Single cigarette Definite Definite I. 10 27 percent smoked at own rate in 6-7 minutes. increase in all groups, increase in all groups. percent increase, increase. Comments ( ) ; ) . II. 5 patients with angina pectoris, all - smokers, ave- rage age 43.4. III. 14 patients with history of definite myo- ___. cardialinfarc- tion, all smok- ers average age 54.1, IL Inter- ter- mediate mediate change. III. 8_ per- cent decrease. Interme- terme- diate change. percent increase. Frankl 5 male and 3 2 standard Definite No signifi- No signifi- The author contrasts et al., female patients cigarettes in increase cant changes cant this response with 19Gfi, with healed 10 minutes at at rest at rest or changes that seen among iJ.S.A. myocardialinfarc- rest and under and at during at rest or healthy young (67). tion 48-69 years graded exercise. exercise. exercise. during individuals. of age 2/8 non- exercise. smokers. Ycntecost I. 14 volunteers anJ with clinical Shilling- CHl), 13/14 ford, smokers, Il'G4, average age IJ.S.A. 39.5. . !I ,Ilt' l u" ,t, u. n (tu i.,r,l,. .~.-..1.,. .r. .. l I,, ,,,. ,,.,. I ,...,r . TU2;S94E0 >.,-- ~,:=. ~w.

A,~ ,,tf.,~rn .,f :,,,,,,t.,n./ u u[ .......r.r~r ..r, ri ~ ~.~r.t .._r....t.... w_K.r.rw J ~ --- . ~' --ns. Author, - y.ear,- Number mber and Smoking He:u1. Illuod 1:1.•:Irnrard.u}n'am Stroke C:.rdinr ~ fh ~unarY ~- country, type of procedure rate pressurc pallistocaniiogram vi.lumc• du4wi blotid reference population flotv Sen Cupta 6 healthy male 1 untipped Increase Increase No change. and Ghosh, nonsmokers. cigarette in in all in all 1967, 8 healthy male 5-7 minutes. group s• groups. 6/8 showed ST India smokers. _ changes. ( 171 ) , 6 patients with All showed ST CHD, nonsmokers. and T-wave patients with 5 changes. _ CIID, smokers. All showed ST 36-64 years of age. and T-wave changes. Aronow male patients 1 0 1 standard high Definite Definite et al., _ _ with classical nicotine ciga- increase. increase. 1968, angina pectoris. rette in 5 U.S.A. 32 59 years of age minutes. (5) Kerrigan 24 male and 1 2 filtered ciga- Definite Definite Cardiac et al. , female healthy rettes in 15 increase increase index. _ 1968, smokers,average minutes with under under rest Definite A S U 45. age measures taken rest and and exercise increase . . . , - - under rest (]02). 8 male and 2 at rest and during exercise conditions. female healthy exercise. conditions. and k exerclse nonsmo ers, average age 33. conditions. Commints Product of systolic blood pressure and heart rate showed a significant increase on smoking while left ventricular ejection time values did not. All patients developed angina more rapidly under a constant exercise load if they had smoked before exercising. The increase in cardiac index, heart rate, and blood pressure during exercise with smoking was the sum of such increases seen with smoking or exercise separately. Neither group showed increases in peri- pheral vascu_l_a_r_ resistance.

TABLE A21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, year, Number and Smoking Heart Blood Electrocardiogram Stroke country, type of procedure rate pressure ballistocardiogram volume reference population Allison 30 healthy male 2 standard ciga- Definite Increase. and Roth, subjects. rettes smoked increase. --------- 1969, U.S.A. (J). --- 19-59 years of age. - ------ - in 12-16 minute period. - Aronow and 10 male patients 1 low nicotine Definite Definite Swanson, with classical cigarette in increase. increase. 1969, angina pectoris. 5 minutes. U.S.A. ...- 32-59 years of . . (7). age. Aronow and 10 male patients 1 non-nicotine No change. No change. Swanson, with classical cigarette in 1969, angina pectoris. 5 minutes. U.S.A. 32-59 years of (6). age. Cardiac_ Coronary output b7ood Comments flow Increase fol- lowed by decrease - - - within 20 minutes. Definite decrease in pulmonary blood volume as indicated by impedance methods of thoracic pulse volume. All patients developed angina sooner if they smoked before exercising. No difference noted in time or onset of exercise-induced angina between smoking and non- smoking procedures. Marshall 42_ normotensive 3/4 of one standard Insignificant Insignificant Blood pressure response et al healthy male cigarette. increase. increase. to cold pressor test ., 1969, prisoners noted to be greater in U.S.A. 18-50 years of heavy smokers. Presyncopal reactions (129). - age. 13 nonsmokers. to 40 degree head-up 16 moderate tilt more frequent smokers. in smokers. 13 heavy smokers. ~a..~_»..,~1....~:~.... +W w

TABLE A22. Experiments concerning the effect of nicotine or smoking on c¢techolamine levels Author, year, Number and country, type of Procedure reference subject Results Watts, 11 dogs 0.02-0.60 mg/kg. Nicotine administration was associated with significant increases in peripheral arterial 1960, nicotine intravenously. epinephrine levels. Ganglionic blocking agents prevented this ef[ect. - U.S.A. (203). Westfall 22 mongrel dogs and Watts, 1963, U.S.A. (210). Cigarette smoking via Regular cigarette smoke evoked a statistically significant increase in adrenal vein, - tracheal cannula; vena cava, and femoral artery levels of epinephrine. Cornsilk cigarette smoke evoked 1 cigarette/8 minutes no change. for 35 minutes. Westfall 21 male volunteers 3 cigarettes smoked in Smoking at rate noted for 21/.2 hours evoked a significant increase in urinary epine- and Watts, approximately 25 30 minutes. 1964, years of age; U.S.A. 11 nonsmokers, (211). 10 smokers. phrine, but not norepinephrine levels. Westfall et al., Mongrrel dogs Standard cigarette smoke Smoke inhalation evoked a rise in cardiac output, stroke volume, blood pressure, and 1966, exposure via endotracheal plasma catecholamine levels. Pretreatment with propranolol diminished the cardiac U.S.A. tube. Smoke inhalation output and stroke volume responses but increased the blood pressure response-the ---- -- (209). every third inspiration for latter effect due to the release of alpha-receptor activity by beta-blockade. - 3 minutes.

TABLE A23: Experiments concerning the atherogenic effect of nicotine administration Author, year, country, _N_u__mber and type Procedure Re_s_ults_ reference ~ of-auimai Adler et al., Rabbits Nicotine 1.5 mg. intravenously in 6 percent The authors noted an arterionecrosis of the aorta, affecting mainly the 1906. solution 6 of 7_ days a_ys per week_ for more than inner muscular layers. Macroscopically, early changes consisted of U.S.A. 4 months. small areas of calcareous ridging and aneurysmal dilatation without (2). notable fatty degeneration or intimal discontinuity. Microscopically, - ------ - - ---- - early changes appeared in the muscle cells of the media, and "chalky" '~ ----. ..-------- -- ..-. . .. . ... __ . . .. . deposits were noted between the elastic fibers. Hueper, 1943, U.S.A. (86). (86). I. 6 mongrel dogs. I. 60 rats. . Nicotine subcutaneously. Increasing dosage up up to 2.5 cc. of 3 percent solution for 1 month. Increasing doses up to 1 cc. of 1 percent solution for 1 month. solution Maslova, R_ abbi_t_s_ I. (10) Nicotine subcutaneously 1 percent 1966, solution 0.2 cc. daily for 116 days. USSR • - 1. 4/6 animals died of infection and showed marked edema and focal hyalinization of the media of the aorta and large elastic arteries. 2/6 animals were sacrificed and showed thickening and hyaliniza- tion of the walls of the coronary arteries and edema of the media as well as endothelial proliferation of other arteries. II. Much less aortic involvement than that found in the dogs; infre- ------- quent arteriolar changes consistin_g_ of fibrosis and thickening of the media. I. Aortic wall--acute swelling of elastic fibers with focal fragmenta- tion and partial disintegration-no intimal fat deposits seen. Coronary vessels-thickening of the vessel wall-no fat deposits. sits. III. (10) Cholesterol only. - - --------- - -- - - - --- -- - - ------ vessels showed swelling of the elastica. III. Aorta-isoiated lipid deposition in the arch and ascending portions - - only. Coronary vessels-no fat deposition. Czochra- Rabbits I, (10) 1.0 g. cholesterol/day for 100 Index of aortic lesion density (cholesterol infiltration): Lysanowicz days. - - - 1. 2 5 et al., . . ... . II. (10) Cholesterol plus 0.0015 g. nicotine/ . . II. 3.A. 1959, day intravenously U.S.A. . -- - - - - III. (4) Nicotine only. III. No aortic lesions noted. (130). II. (14) Nicotine plus 0.2 grams cholesterol II. Aorta-"massive" deposits of "cholesterol" in the intima and vasa per day. vasorum with "loosening" of the aortic wall. Coronary vessels- the larger vessels showed moderate fat deposition and the smaller (46),

TABLE A23.--Fxperinaents concerning the atherogenic effect of nicotine administration (cont.) N 1"- 902:994c0 ~.; AuthoF, year,_ country, reference Number and type ofanimal- Procedure Results Wenzel et al., ~ Rabbits I. ( 12) Control untreated. General findings: Marked aortic pathologic involvement was noted in all 1959, II. (12) Control diet plus 1 percent cholesterol-treated groups; however, no difference was noted between U.S.A. cholesterol and 5 percent cottonseed Group II and Groups IV V and VI (127). - oil added. , ., ., . Cardiac histopathology.- - III. (12) Control diet plus oral nicotine 2.28 mg./kg./day. . IV. (12) Regimen II plus oral nicotine 2.28 mg./kg._/day. V. (12) Regimen II plus oral nicotine . .. . .. .. . 1.42 mg./kg./day. V I. (12) Regimen I I plus oral nicotine 0.57 mg./kg./day. Thienes Newborn rats and Nicotine subcutaneously up to 5 mg./Tcg. 1960, mice. twice daily by the end of I month. U.S.A. Animals autopsied at i year. (lx4). rosgogeat Male rabbits et al., 1965. France (75). .;.r.M.,.: I. (10) Nicotine subcutaneously 0.75 mg./day. (10) Controls-saline injected. Sacrificed at from 20-120 days. II. (27) Same as Group I. (27) Controls-saline injected. Sacrificed at 90 days. III. (66) Nicotine subcutaneously 0.3-1.5 mg./day. --------- Sacrificed at 30 days. IV. (24) Nicotine subcutaneously 0.7_5 mg./day. (24) Controls-saline injected. One-half of each group ate cholesterol- enriched diet (0.5-1.0 percent choles- - teroladded). Sacrificed at 60 days. I No change. II. Advanced atherosclerotic changes in the subendocardial vessels. III. Thickening and fibrosis of coronary artery small branches. ---- -- --- ----IV.-VI. More severe changes with greater fatty metamorphosis and actual early myocardial necrosis, but no dose-dependent_ e_f_- fects observed. No arterial pathology noted. Medial degeneration seen more frequently in controls. Suggests that older animals be used. Significant differences in aortic subendot e~F I'al fib_rosis between control and experimental groups noted only in II and IV. In group IV, the_ nicotine-treated group showed more severe changes.

4 sa a a ® h ..~ _ _. . r. N N TABLE A23.-Experiments concerning the atherogenic effect of nicotine administration Author, year, country, Number and type reference of animal - Procedure Results cont.) Hass et al., Male rabbits Nicotine Diet Vitamin_ D 1966, I. (8) Control Control Control I. Infrequent medial calcific disease without lipid localization. U.S.A. II. (7) Control Cholesterol Control II. No medial calcific disease but frequent intimal atheroma formation. - - - (80). III. (14) Nicotine Control Control III. Rare calcific medial degeneration; no intimal atheromatous disease. IV (15) Nicotine Cholesterol Control The largest number of atheromatous lesions. IV . V. (9) Control Cholesterol Vitamin D , -- -------- - V. No medial calcific disease. VI, (14) Nicotine Cholesterol Vitamin D VI. Consistent medial calcific disease. (Sacrificed at various times) Control-no treatment. Nicotine-subcutaneous injections in oil- increasing amounts 2 times per week. Vitamin itamin D-subcutaneous injections up to 6-8 x 101 IU. Cholesterol-250-500 mg. cholesterol added per 100 g. diet. Choi, Albino--rabita I. Nicotine 1-5 mg./kg-.7day intraperi- 1967, toneally. Korea Cholesterol 1 g•fday (in varying (4;!). combinations with controls). II. Nicotine alone. III. Cholesterol alone. (Sacrificed at 60 days) Stefanovich Female e ino et al., rabbits. 1969, U.S.A. (178). _I. (10) Diet supple- - Percent of aortic mented with 2.0 aurface involved percent choles- with terol. Nicotine in- a_t_he_roecleroais tramuscularly 1. 9.4 2.78 mg./kg,/day, II. 5.7 5/7 days. III. 0.1 II. (10) Cholesterol IV. .. only. III. (10) Nicotine only. IV. (10) Control. E I.Increasing nicotine dosages were associated with decreased atheroma formation (findings not statistically significant). - II. Nicotine alone produced no atheroma formation but was associated with the presence of aortic medial calcification and endothelial hyperplasia. III. Cholesterol alone was associated with a definite increase in atheroma formation. In both stock and-cholesterol-fed animals, nicotine was also not~ot increase aortic triglyceride content and to decrease aortic free cho- lesterol _ lesternl content. ... . .... ..----

.o..a.- «.Aar.. .w. TASI,E A25. Experirrtents concerning the effect of smoking and nicotine upon blood lipids (Human Studies) Author, year, Number and --- Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol triglycerides Other Comments reference population Page 13 male and_ 2_ nonfiltered No change. et al., 7 female cigarettes - 1959, laboratory in 10 minutes U.S.A. workers and blood (147). 17-51 years levels of age. measured over 30- minute period. Ifershbaum 31 male I. 17 subjects Mean rise No change. No change. et al., patients or smoked 2 I, 361 µEq.lL. 1961, staff 16-72 non-filter II. 9.8 µEq./L. U.S.A. years of age, cigarettes IiI. 272-2,304 (104). 7 normals, in 10 µEq./L. 7 CHD, minutes. 17 other II. 9 controls. medical 111. 6 subjects diagnoses. smoked 6 cigarettes in 40 minutes. Serum lipo9roE_eina No change (10 subjects ) . The authors consider the in- crease among controls to be due to fasting. Kershbau_m__ 1. 17 male I„_ IL, III., Mean rise No difference found between re- et al., 1962, patients with healed 2 non-filter cigarettes in I. 858 µEq./L. II. 320 µEq./L. s sults following inhalation or noninhalation. U.S.A. myocardial 10 minutes. --- III. 292 µEq,/L. Statistically significant differ®nce (103). infarctions. IV No smoking. IV. 20 µEq./L. found between increases in II. 16 non-CHD patients. Groups II and III and Group I. fII. 10 normals. IV. 13 normals.

IJ A 2'AB>:.E A25. Exper-inaents concerning the effect of slltotiing and nicotine upon blood lipids (cont.) (Human Studies) - f SM = Smok ers NS - Nonsmokers] Author, -ycar;-Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol triglycerides Other Comments reference population Kershbaum 11 normal 9 standard Definite increase_ et al., patients, cigarettes at start of 1963, in 3 hours. smoking period. U.S.A. Samples at (l0y). 10, 20, and 40 minutes of smoking period. Konttinen 40 healthy Fed at fat meal and moderate and then 20 ----- ----------~ -----._ _.. Bajasalmi, smokers were allowed 1963. 19-20 years to smoke Finland of age, cigarettes of known-nicotine content over fi hour period ~~ proximately (approximately 23 cigarettes ~ consumed ) . NS-definite No change NS-definite increase at --- -------- in either --- increase ---. . _. 6 hours. group. at 2 hours. SM-definite SM-slight increase at increase 6 hours. at 2 hours. Kedra :17 male and 3 cigarettes No change. et al., 5 female smoked in 1965, medical rapid succession Poland students and samples (101). 22-23 years taken at10 of age. and 30 minutes. No change. 3 patients with trime- Both free and total urinary thaphan camphor- catecholamines increased with aulfonate (Arfonad) smoking and the author pretreatment and S considers them as mediators formerly adrenalecto- of the FFA increase. mized patients showed either minimal or no elevation. Beta-lipoproteins defi- nite increase. &O %V 9 9 4,E.U

( tL~';~91~E0 TABI,E A25. Experiments concerning the effect of sllzoking and nicotine upon blood lipids (cont.) (Human Studies) Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure _fattyac7dscholesterol triglycerides O_t_h_e_r_ reference population -- - Murchison 8 male and 4 2 cigarettes I. Definite No change. No change. - - - - - and female mod- in 15 minutes. increase. - - Fyfe, erate smokers I. Lit-ciga- II. No change. No change. No change. 19G6, with various rettes. Scotland diseases 37- IL Unlit-ciga- (1$8). 67 years of -- rettes. - age. Kershbaum 6 normal Various types Regularr cigarettes, et al., heavy of cigarettes filter cigarettes, 1967, cigarette of known charcoal-filter U.S,A. U.S.A. smokers nicotine cigarettes, pipe (105). 28-45 years content. tobacco plus of age. cigarettes all showed similar increase in FFA. Lettuce leaf cigarettes had negligible effect. Comments Both regular and sham smokers showed significant increase_s_ in concentration of serum oleic acid and significant decreases in concentration of serum palmitic acid. Both catecholamine and nicotine excretion rates showed responses to the various ciga- rettes similar to that of the FFA response.

TABLE A25a. -Experiments concerning the eff ect of smoking and nicotine upon blood lipids (Animal Studies) ANIMAL AND IN VITRO STUDIES Author Number , year, - and Smoking Plasma free Serum Serum country, type of proced_ur_e_ fatty acids cholesterol triglycerides Other Comments reference population Wenzel and 48 male 1. Untreated control- -_ ---- Bcckloff, New 12 subjects. 1958, Zealand II. Regular diet plus U.S.A. white 0.1 percent cholesterol- (206). .. _._---- (206). ra_bb_it_s._ 12 subjects. III. Regular diet plus 2.28 mg./kg./day nicotine in water-12 subjects. IV. Diet plus- (a) 0.1 percent cholesterol (b) 2.28 mg•/kg•/day nicotine in water- 12 a_ter- 12 subjects. Kershbaum 5 mongrel Intravenous infusion of 20 et al., dogs. mg_ ./kg. nicotine 1961, in 20 minutes. U.S.A. (104). Ker~:hbaum 20 adult 1. 9_ received IM nicotine et a., mongrel daily for 6 weeks; 12!t5, dogs. up to 1 mg./kg.-U.S.A. II. 5 placebo injection. (107). II I. 6 con trol. Definite increase in 13/15 observations, I. Significant increase . . in 8/9 dogs... IT. No change. III. No change. No change in any group. Group II and IV showed an im- mediate in- crease in plasma_ cho]esteroj and phospholipids with a level- with a leveling of response at 4 weeks. Group IV showed a further in- crease at 8-12_ week period. The authors consider an el- evated cholesterol/ pbos- _- pholipid ratio to be a notable indication of atherogenic susceptibility. The concomitant increase - in phospholipids with the cholesterol may negate the importance of nico- tine-induced hypercho-lesterolemia as an atherogenie stimulus.

t; N am TABLE A25a, Experiments concerning g the effect of smoking and nicotine upon blood lipids (cont.) (Animal Studies) ANIMAL AND IN VITRO STUDIES A_ uthor,_ Number year, and Smoking Serum Plasma free Serum country, type of procedure triglycerides fatty acids cholesterol Other Comments reference population ----- --- Kershbaum 28 adult Intravenous infusion of nicotine. No change. The authors report on the et a]•, mongrel results of the use of ne- 1966, dogs. thalide (a Beta-adrener- U.S.A. gic blocker), phenoxy- (108). . - benzamine,_ and chlor- promazine to block the FFA response to nicotine. Only nethalide was suc- cessful and this consti- tutes .. . . .. .. .. tutes an indication that nicotine stimulates Beta- adt•energic receptors to release catecholamines which, in turn, stimulate the release of FFA. Kershbaum Sprague- Nicotine perfusion. Alth h i i f i et al D l oug cot ne per us n on ., aw ey was not associated with 1967, rat FFA release from fat tis- U.S.A. fat-pad sue, epinephrine did ( 110). - tissue. - - produce a significant in- crease in FFA release. The authors conclude that the sympathetic nervous system mediates the FFA response to nicotine in the intact animal. i~ Ess4co

TABI.r t12G.-I::eperi-U+ellts eci?(ec I•llittg tl;c effec Author, year, Number and country, type of reference population Smoking procedure of ccn•bu>r tttunaa•ide e.rposztre zcponn blood dipids Results Kjeldsen 8 male students 23-27 Five daily one-half hour snn• exposures No significant changes in total fatty acids, phospholipids, or triglycerides. and Damgaard 1968, Denmark years of-agef to 0.5 percent CO for 8-10 days. Overall mean COHb resulting was 12.5 percent. Cholesterol_ showed exposure. a significant increase only during the last 3 days of (115). Kjeldsen,_ 72 female albino rabbits: I. 12 control and 12 exposed I. Serum cholesterol concentrations rose rapidly and then remained slightly 1969, I1. Regular diet, 24 to gradually increasing CO above control values for the 4-week period, Denmark subjects. concentrations (0.015-0.40 II. At 35 days, the seivm cholesterol concentration in the exposed group was II. Regular diet plus perccnt) over a 4-week 2!_ times that in lhe_ control group. 2 percent choles- period. III. Serum cholesterol c.onc entrations among those exposed were significantly II. terol, 24 subject s. 12 control and 12 exposed to higher than those in t he control group for 5 weeks of the 10-week period. _ _ IIL Retculnr diet plus 0.020 percent CO for 35 days. 2 percent choles- III. 12 control and 12 exposed to terol, 24 subjerts. to 0.020 percent CO for N r VUS911E0 7 weeks, then 0.036 percent CO for 3 weeke, Kjeldse n 24 castrated male albino 12 control and 12 maintained at 10 Serum cholesterol and triglyceride concentrations rose to significantly higher _ , 1969, rahbits. Regular diet percent oxygen levels for 0 levels during 3 of the R weeks. No changes noted in serum phospholipids. Denmark plus 2 percent weeks, then 9 percent for 2 (119). cholesterol.-- woeks.

gASLE A27.-,Sntoking and thrombosis Author, Whole Partial Recalcifled _ year, Number and Experi- blood Pro- throrttbo- plasma Platelet Platelet Platelet Platelet country, type of---- mental clotting thrombin plastin clotting adhesive- count survival turnover Other Comments reference population conditions l time time time time ness _ Black- 16 adult 12 fn-dividuals Plasma burn schizo- smoked_ 2_ stypuen et a]., phrenic high- time 1959, patients, 8 nicotine (-) U.S.A. university standard (25). students, all brand smokers. cigarettes. Mustard 7whitemales Compared and with either after Murphy, y_. CVD or periods of 1963. COPD, all abstinence (-) U.S.A. heavy orcontinua- (14_1)r smokers 35- tion of 72 years of smoking. age (+) W decrease increase Platelet clumping time (±) Ambru s 20 healthy nhala- - Deep i Th-romboplpstin 2 students _ and Mink, 1964, U.S.A. (4). male non- smoking medical students <30 years of-age._ _ tion of one nonfiltered (-) (-) (-) cigarette. pencration (+) (-) time increase (-) became ill. Results_ reflect data on 18. Ashby 27 male - 13 controls - Increase of et t al., medical measured at subjects 1965, students a nd 2 separate greater Ireland _ _ hospital times 14 than that (8). staff subjects (}-) of controls members_. measured increase at p<0.01. before and after smoking 2 cigarettes in 20 minutes.

TABLE Aiz7.-.tilno/ciu,rt and Shranthosis (coltt.) .t 4 912:994co --- ------- Author, year, Number and Experi- country, type of mental reference population conditions 1 Sogani 11 observations Smuked 2 cig- and on male arettes or Joshi, ,mq)kers all 2 biri, or 1965, regular chewed I India tobacco betel nut (174). users. quid in 20 minutes Engel- 40 male and 2 cigarettes berg, 20 female in 20 1965, hospital pa- minutes. U.S.A. tients, all (58), smokers 17- 68 years of 68 age. Kedra 39 male and 5 cigarettes and 11 female in 1 hour. Korolko, smokers and 1966, 24 male and Poland 26 female (100). nonsmokers 18-25 years of age. Murchi- 8 males and 2 cigarettes son 4 female in 15 and patients minutes. Fyfe, with lit or unlit 1966, various cigarettes. Scotland diseases, all (139). heavy smokers 3_7_- 67 years of age. Whole Partial Hecalcilied blood Pro- thrombo- plasmaP.latelet Platelet clotting thrombin plastin clotting adhesive- count time - time - t.ime time ness increase decrease decrease increase Platelet Platelet survival turnover Other Comments F_-i6rivolya_is_ Biri- (-}-) tobacco decrease wrappedin tobacco leaf. 6handler- ( in vitro) thrombosis time -f' decrease Thromhin time --- (±) decrease t Smoking both lit and unlit cigarettes caused a rise in platelet adhesiveness which the authors correlated with rise in plasma non- esterified fatty acids.

f TABLE A27.-Smoking and thrombosis (cont.) Author, year, Number and country, type of reference population Glynn 20 male and et al., 17 female 1966, smokers and Canada 9 male and (71). 21 female nonsmokers 17-76 years of age. Whole Partial Recalcified Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet mental clotting thYombin plastin clotting adhesive- count survival turnover Other Comments conditions 1 time time -time time - ness 3 cigarettes Plutelet Smokers foun__d_ in 30 ser_ otinin to have a minutes. greater Platelet tendency for adenosine platelet nucleotide aggregation (-) than non- smokers. smokers. Engelberg and Rutter-_ man, 1967, U.S.A. (59). 94 male and 1 cigarette 53 female in 5 minutes, patients and medical ~ house staff. Thrombus No relation formation found with time increase in (+) free fatty decrease acids. Murphy, Literature Platelet 1968, review with adherenceto U.S.A. summary of (±) (±_) (+) vascular (1_4p)• data and increase increase decrease endothelium conclusions. (-~) increase Fibrinolysis (~) decrease Thrombua formation time (~) decrease Symbols: - - No effect, zt = Questionable effect. + = Definite effect. i Results, unless otherwise stated, concern specific co_agulation test as measured before and after smoking procedure noted.

TASnE A30. Experiments concerning the effect of nicotine and smoking upon the peri.pheraT vascular system Author, year aountry,reference Moyer and Maddock;. 20 subjects~. (including.heavysmokers)g were studied.for thee effeeta of' 1940, UlS'.A.. (18$). thee following, proceduress onn skinn temperature:: thee inhalation off a ]itl cigarette, inhalation~ through an empty paper tube, orr the ad- ministration of 1, mg. nicotline, intravenously. All subjects responded' with~ deereasedl cutaneouss temperature following the smoking and nicotine procedures. No changes were noted following sham smoking. Mulinos and Shulman„ A number of experimental groups, each consisting of 6-17 persons, 19'4',0,. U.S.A. (138). were studied, forther effects~~ of.f deep . breathing and cigarette smoking on skin temperature andd digitt or limbb plethysmography. Theau- thorsconcluded'e thatdeepbreathingt alone could' account.for.t thee changes in temperature andl blood' flow noted' upon smoking andd noted that denicotinized cigarettes evokedl the same or greater vasoconstriotion as that' noted following the smoking ofl a standard' cigarette. Shepherd, 1951, 50 young male smokers were studiedl with plethysmograpby before Ireland(1T8).., andd after the normal and' rapid inhalation ofaf standard cigarette.. The author noted that rapid inhalation was associated with a pro- longedd decrease in extremity.blood flowwhilew aa moree naturall ratee off inhal.ation, wasfollowedbyamomentarydecreases in flow.. The author considered the former reaction to represent'the pharmacolo- gic . effect off the smoke and the latter to represent the physiologic response to deep breathing, as the naturall inhalation of an unlit cigarettee produced thee sametransiente decreasee in, flowasw didd thee natural inhalation of'f thee lit cigarette... Friedell, 1953, 52' male and 48 female young smokers and nonsmokers were studiied' U..S.A. (70). for the effects; of' smokingg on hand' blood volume as measuredd by theusee of'f radioactiveiodinatede albumin. The inhalation of' un-filteredcigarettesd wass associat'edwith an averagedecreaseine handd blood volume.of 199 percent~ inn men and 33'3 percent in women; while filtered cigarettes showed respective decreases of 11, percent and 21 percent. St'rdmblad,.1959;, 11 .. male andd femalesubjects. (smokerss and nonsmokers)) were studied Sweden.(181).. for the.effect.of.the intra-arteriall administration of..nicotine(bra- chialf artery.)) onn bloodl flow to the hand as measuredl by venousocclus~.ion plethysmography. Increasingdoses~ of' nicotineweree asso- ciated with increasing numbers of' individualsmanifestingvaso-constrietion. The vasoconstrcictSve effects of nicotine were abolishedd by the prior administration~of'.either hexamethonium or pentolinium.. Barnett and Boake 99 male patientss with intermittentl claudication (7 ' were heavy smokers) 1960 Australia(18). weree studied fortheeffectr off smoking on bloo& flow to the leg as measuredbyvenousd oc.clusionn plethysmography: Stnokingam un- filtered cigarettee wasfounds notl to prodheee anyy consistentt changes in blood flow to the calf or foot of' the affected leg: Freundlandl`vard,. 15~5 malee pr~ison~ inmates~~. (less~~s tham 35'~ years of~ age) and. 14~ male~. 1960„U.S~,A..(68).. patients~~ with~ peripheral vascular~r disease~~ (approximately 65'5 years~s of'f age): wer.ee studied for the~e effect of'f s;moking, on digitall circ~ulation~ as measured by skin,temp.erature; plethysmogr.aphyy.and radiosodium, clearance from~ the~~e skin. Smoking~.g wass found~ to~~ adverselyy affect the first and thirdl measurea~in.a significantt manner (while plethys- mographic~. valu.es; were variable)~) only~ in the healthy~ prisoners~ andd not~t at alll in the~ patient~ group, Roth and.Schick, 1'000 normall individualss underwent 425 experimentall procedures con. 1960;,U.S.A„ (161')., cerning the effect, of smoking on the peripheral circulation. Smok- ing was found to be associated with a decrease in extremity skin temperature. 1133 y

TABLE A30.-Experiments concerning'the effect of'nicotine an,~.l smoking upon the peripheral vascular system (cont.) Author„ year, oountry; reference Rottenstein etsl., 8 males (18-31 years of' age) were studied for the effect of intra. 1960,U:.S:A. (1:6'2). venous nicotine on extremity temperat'uree and blood flow. Intra-venous nicotinewas.foundto evoke ad0crease.in,skin temperaturee while increasingmusele blood.flow. The former effect began sooner and lasted longer than the latter. Allison and $oth, 30 healthy individuals, (1S-59I years of . age) were studiedl for thee effect. 1969„U:S.A...(9). of' smoking.g two cigarettes om extremity pulse volumes andi skin temperature. Smoking was found to be associatedl with a 2-fi per- cent.decreasein,skin temperature andl a 45-50: percentl decrease.inblood pulsevolumese to segments, . of the finger, calf, andl toe. 1134

CHAPTER 3 Chronic Obstructive Branchopulmanaryl @iisease

tZ%oqsLCo

Contents Introduction............ Epidemiological Studies ............................... COPD Mortality........................ .... ...... COP'D, Morbidity ........................... ..... Ventilatory Function.............................. Genetic Factors..................................... Alpha,-antitrypsin ............................. Air Pollution ..................................... Occupational Hazards ............................... Page 139 141 141 145 146 148 150 152' 153 154 Pathological Studies ................................. 11154 Experimental Studies .......... ........................ 158 AniBnall S'tudies ................................... 158 Studies in Humans ................................ 163 Studies Concerning Pulmonary Clearance ........... 164 Overall Clearance ............................ 164 Ciliary Function ............................. 164 Phagocytosis .................................. 165. Studies Concerning the Surfactant System ......... 1172 Other Respiratory Disorders ........................... 1I72' Infectious Respiratory Diseases .................... 172 Postoperative Complications ...................... 1174! Summary andl Conclusions ........................... 175 References............................................. 176 FIGURES 1. Percent of lung sections vvit'h Grade IV or V fibrosis . .. 161 2. Percent of lung sections with Gradie II or IiII emphysema 162' Lf IST OF TABLES (A indicates tables located in appendix at end of' chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios .................................... 142'

LIST OF TABLES (Continued)! (A indicates tables loeated in appendix at end of chapter) Page A2'. Smoking and' chronic obstructilvepulmonarydasease symptoms-percent prevalence.................. 195: A3'. Smoking and ventilatory function ................ 206 A4. Glossary: of terms used in tables andi text on smoking and, ventilatory function ....................... 215 5. Cessation of smoking and humani pulmonary function 149 A6. Epidemiological studies concerning the relati'onshi'p of air pollution,, social class, and smoking t'o chronic obstructive bronchopul4n onaryn disease (COPD)l.. 216' A7. Epidemi'ological studies concerning the relationship of occupational exposure and smoking to chronic obstructive lironchopulmonary disease ........... 218 8'. Studies concernimg the relation of human pulmonary histology andi smoking ......................... 155 9'. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulinonary parenchyma of animals. .............. 1!59, AI'0: Experiments concerning the effect of the chronic in- halation of'NO, uponithe tracheobronchial tree and pulmonary parenchyrnai of animals... .......... 220' 11. Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . 166' 12. Experiments concern2ng, the effect of cigarette smoke on humani and, animal pulmonary clearance....... 170 A13. Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function .......... 221. Ali4.Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension .... 225 A15. Studies concerning the relationship of smoking to in- fectious respiratory disease in humans .......... 226. A16. Complieatiions developing in the postoperative period in patients undergoing abdominal operations .... 230, A17. Arterial oxygen saturation before and' after operation 230

i INTRODUCTION i Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs: The term COPD refers to three common respiratory ailment's ; narnely„ chronic bronchitis, pulmonary emphysema, andl reversible obstruc- tive lung disease (bronchial asthrna).* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree:It is characterizedl by cough withi the production of sputumi on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically definedl condition of' the i:ung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as welll as the abnormalities in pulhnenary function observed in the presence of the two ailments may be quite sirnil:ar.P'atients with chroni'cbronchitis suffer from productive cough withh or, without dyspnea (breathlessness both at rest or on exertion) while pulmonaryernphysema i~& charaeterizedl mainPybydyspnea.COPD comprises a spectrum of clinical manifestations; thus, it is frequently difficult to determine whether a particular patient is suffering fromi one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885: women were re- corded as dying from chronic bronchitis and emphysema (2;21)1. This figure does not include a sizable number of individuals for whom COPD was a contributory cause of death. During, the past two decades; a major increase has taken place in the mortality from COPD in the Unitied~ States: In 1949, the death rate from COPD was 2.1 per 100;000 resident population, while in 11960 it was 6:0 (222), and in 11967, 12'.9' (221)i. Although •Because.mortality from bronchial asthma does not appear to be related to~ciHarette.smoking,e tHeterm CQPDD will bee usedd henceforth too refer only too chronic bronchitis andl pulmonary emphysema. Exacerbation of pre-existingg bronchial asthma has beenobservedi among, cigaretRee smokers;,Furtherel9borat5on of't'his question may be foundlin.a. previous.Public.Health Service. Review, (223). 139

much of this rise is probably due to changes in certification andi recording methods as wel,ll as to an increased interest on the part of the medical community, an appreciable proportion is also gen~- eralIy accepted as reflecting a reall increase ini disease. Similar in,- creases over the past 20 to 30 years have also beeni observed in Canada (7) andi in Ilsrael (54). The lack of a similar increase in Great Britain, a country withi an extremely high rate of' COPD, may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the dhagnosils of COPD has been made more commonly and ac- curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron- chitis and emphysema have differed in the past' from those used in the United States. The mortality from and prevalence of COPD is probably under- estimated. Ini a study of death certificates, Moriyama, et al. (170)) reported that COPD' is often omitlted, as ai contributing cause of' death. In a study of more thani 35f/' autopsies, Mitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe clinical airway obstruction. Hepper, et a1. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients ini whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of vent'ilatory impairment may be undetectled' by history and physical examination albne. Boushy, et al. (40) 1 evaluated clinicali symptoms, physiologic measurements of'airway obstruction, and morphologic bronchial and parenchymal' changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidenee of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD' as a, contributing cause of mortality is now beginning to be more fully recognizedL Clinicians have long observed that the majority of'their patient's suffering from CCPD were cigarette smokers (1, 150). Epidernib- logical' studies have validlat'ed' this impression by indicating that cigarette smokers are at ai much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke;, reaching ini the smoker of two packs or more aa day a level as high as 18 tiraies that of the nonsmokers (132) . The salutary effectt of giving up smoking has also been borne out by clinical observation and epidemiologicall studies. In a number of studies, smokers were found to suffer, rmore fre- quently than nonsmokers fromi pulmonary symptoms incltzding, T 40'

cough, cougli, with production of phlegm; and! dyspnea. By a variety of pulmonary function tests, smokers were shown, to have dimin- ished function as compared to nonsmokers andl also to have a steeper slope of the expected decline of'funct'ion with age. Tests of ventilation/perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicat'ed' that smokers dying of' causes ot'her, tthan COPD have significantly more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run, a greater risk of developing compTications in the post-operative period than nonsmokers. Abundant experimental evidence of the role of' smoking inn bronchopulmonary disease has been obtained from experiments employing aniinals and tissue ar_d cell cultures. Recent work has demonstrateds ini dogs trained to inhale cigarette smoke through a tracheostoma, that emphysernas pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi developp and that these changes are proportional to the totali dosage of cig- arette: smokeinhaledlIn vivo and in, vitrostudies, have shown that whole cigarette smoke, or certain fractions thereof, inhibit ciliary activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of' inhaled, foreign matter including~ infectious agents from the lungs,, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigirette smoke. The convergence of these lines of evidence, which will be de~ scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important cause of' COPD in man. EPIDEMIOLOGICAL STUDIES' COPD hTORTALI'LY' hlumerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, hav e investi- gated the association between cigarette smoking and COPD. They have shown a~ greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating, smoking and CQPD mortal- ity are presented in table 1. The majority of'the studies separate ;

TABLn 1,-G'hronic obstructive bronch.opulmonary disease mortality ratios (Actual number of deaths shown in parentheses)1 SM = Smokers. NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Number and Data country, type o> collection reference population --- Hammond 187,783 white and males in 9 Horn, states 50-69 1958, years of age. - U.S.A. (105). Follow-up Number Cigarettes/day Chronic years of deaths pipes, cigara bronchitis Emphysema Other Questionnaire 31~. 338 Cigarettes and follow-up SM ......308 NS ....... 1.00 (30) of death NS ...... 30 <10 ......1.67 (10) certificate. 10-20 .....3.00 (57) >20 ...... 3.64 (40) All .......2.85(231) Pipes NS ...... 1.00 (30) SM ...... 1.77 (23) Cigars NS ......1.00 (30) SM ......1.29 (18) D__olland Approximately ately Questionnaire 10 29_2_ Cigarettes Hill 41,000 male and follow-up Chronic NS ...... 1.00 1964 British of death bronchitis 1-14 .....6.80 Great physicians. certificate. 111 15-24 ...12.80 Britain Other >25 .....21.20 (70). 181 All ..... 11.60 Pipes and Cigars SM ...... 3.00 Cigarettes NS ..... 1.00 1-14 ....0.65 15-24 ..1,08 >26 ... .0.63 All ..... 0.81 Pipes and Cigars SM .....0.78

t, . S w ef,"Vzs9LEo TABLE 1._ C1_tr_ o_nic obstructive 6ronchopiclmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)' - SM = Smokers. NS = Nonsmokers Author, year, Number and Data Follow-up Number Cigarettes/day country, - tyPe of--- collection years of deaths pipes,cigars_ reference population PROSPECTIVE STUDIES Best, Approximately Questionnaire 6 124 1966, 78,000 male and follow-up - Canada Canadian of death (30). veterans. certificate. Hammond, 440,558 males Interviews by 1966, 562,671 ACS volun- U.S.A. females teers. (103). 35-84 years of age in 25 states. Kahn, U.S. male Questionnaire 1966, veterans and U.S.A. 2,265,674 follow-up (182). person years. of death certificate. 4 389 SM ...... 369 NS ......20 81/ Bronchitis NS ...... .1.00 (31) SM ....... 64 A11SM ...6.49(348) NS .......13 Current ciga- Emphysema rettes .10.08 ( 229 ) SM ...... 284 Pipes NS ....... 18 SM ......2.36 Cigars SM ...... 0.79 (9) (5) Chronic bronchitis Cigarettes NS ...... 1.00 <10 .....7.02(17) 10-20 ...13.65(-40) >20 ....14.63 (12) All .....11.42(78) Pipes SM ...... 2.11 (6) Cigars SM ......3.57 (1) Current ciga- rettcs only NS ...... 1.00(13) 1-9 ......3,63 (5) 10-20 ....4.51(22) 21-39 ....4.57 (12) >39 ..... 8.31 (4) All ...... 4.49(43) Emphysema Cigarettes NS ....... 1.00 <10 ......4.81 (9) 10-20 .....6.12(21) >20 ...... 6.93 (7) All ......... 5.85(37) Pipes SM ....... 0.75 (2) Cigars SM ....... 3.33 (1) btales NS ....... 1.00 (20) SM (age 45-64) ..6.55 (194) SM. (age . .... .... . . 65-79) .11.41(175) Current cipa_- rcttea only NS ....... _1,00 (18) 1-9 ....... 5.3(10) 10-20 ....14.04 (93) 21-39 ....17.04 (62) >39 .....25.34 (17) All ......14.17(186) Other

Author, year, country, reference Weir and Dunn, 1970, U.S.A. (225). TABLE 1.-Chronic obstructive bronchopulmonary disease mortality ratio_ s(cont.) (Actual number of deaths shown in parentheses)i - SM = Smokers. NS = Nonsmokers Number and typebt - population Data collection Follow-up years - Number Cigarettes/day Chronic of deaths ea_th_s pipes, cigars bronchitis ---------- - -- ~~~~-- ~ ~ ~ - - Emphysema Other - ----- ~ - PROSPECTIVE STUDY 68,153 males Questionnaire 5-8 58 Cigarettes in various and NS ...... 21.00 occupations follow-up +10 ...... 8.18 in California. of death +20 .....11.80 certificate. c>30 .....20.86 All ......12.33 Wicken, 1,18_9_ males. ales. Personal inter- 1966, view with North- relatives of ern individuals Ireland listed on (227). death register. RETROSPECTIVE STUDY 1,188 obtained Cigarettes retrospec- only tively. NS ......1.00(1$4) SM ....1,064 1-10 .....2.95 (245) NS .....124 11-22 ....3.43(300) >23 .....4.44(168) Mixed SM ......1.55 (62) Pipes or cigars SM ......1.94(289) 1 Unless otherwise specified, disparities between the total number of deaths of either occasional, miscellaneous, mixed, or ex-smokers. --- --- --- -- - and the sum of the individual smoking categories are due to the exclusion 2 NS includes pipe and cigar smokers; SM includes ex-smokers. i a.+a,r.<yWiw.-%~+ lqixcc.:. Ws! -~x~~-

the findings for chronic bronchitis andl emphysema. Such specific grouping, of the mortality: data should be viewed' with some reser= vations in the light of the difficulties mentioned above in dis, tinguishing the two diseases clinically.. The dbserelationship of increased mortality ratios with increased consumption of eigarettes is indicated by the results of all the studies whichi present rates for different levels of srnoking.Kahn (132), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.33e while those srnoking over 39 per day incurred one of' 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this., The risk of' dying from CbPD~ among cigar and pipe smokers appears to be much less than that incurre& by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1)~. The effect of stopping smoking on COPD mortality is reflected in thexesults,of Doll and Hill (70, 71)~ intheir st'ud'yof Eritishphysi-cians. They found that during the years immediately follbwing cessation of smoking, mortality ratios remained elevated and' didl not begin~ to decline belbw the level of continuing smokers untit nearly a decade later., This delay in response is probably due to two factors : the presence in the ex-smokers' group of many who quit for reasons of ill health and the long-term effects of cigarette smoke on the respiratory tree„ some of which are irreversible. Kahnl (132) also not'edl that the age-specific mortality ratios for ex-smokers were lower than those: for continuing smokers of cor- responding, amounts of' cigarettes. A better estimate of the potential effect of st'opping smoking on. COPD~ mortality cani be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among, doctors age 35-64 in England and Wales, many of whom, have stopped smoking cigarettes, there was a 24 percent reduction in bronchitis mortality between 1I9'.53-57 and 1961-65; as compared with a reduction of only 41 percent in all'i men of' the same age in England and Wales,, among whom there was no redtiZc- tion of cigarette smoking. (84) . COPD, MORBIDITY Many invest'igators have studiedl the prevalence of bronchopul- monary symptoms (inclluding, those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table A2. Their results indicate that the cigarette

smoker is much more likely to suffer from respiratory symptoms such as cough, sputum production, andl dyspnea than is the non- smoker. Such symptoms; particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also shows that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers: not to the degree found ini cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated' with a decrease in symptom prevalence. Mitchell, et al. (168), studied 60 patients who succeeded in stopping smoking andl 84 continuing smokers, Among the ex-smokers, more than 70 per- cent reported improvement in their cough while lessthan 5 percent of the continuing smokers dU so. Wynder,, et ali, (237)1 followed 224 ex-smokers of cigarettes and noted, that 77 percent reported cessation of persistent eoughi and an additionali 17 percent reportedd definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group: of ex-smokers, VEI+ITII:ATORY FUNCTION Another type of' quantification of the effects of smoking on the bronchopulmonary system has beeni obtained by those groups of investigators who have, studied pulmonary function in various groups. Results are presented ini table A3, and a glossary of the terms usedl in the various t'est's: is presented in tablle A4. The pa, ram.eters investigatledl have included maximal breathing, capacity (maximal voluntary venti]ation), expiratory: flow ratles,, forced expi'rat'oryvolume,and vital capacity. Although eert:ainofthese parameters appear to be more sensitive measures of pulmonary dysfunction than: otliers,the, overwhelming, majority of these stud- ies have shown d'irni¢zished'functioniamong smokers. An increase inn the expectledl age-d2minutioni rate in smokers has been observed in those, studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (11'7)) conducted a nine-year follow-up examination of 385 male residents of a British ind'ustrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average decline in FEV,; ; was smallest in non- smokers, slightly greater in ex-smokers, and greatest in~ smokers. As with COPD mortality and syrnptom prevalence„t'he impairmentt of pulmonary function shows a dose-relationship with increasing amounts of cigarettes smoked. I E 146

The data contained in table A3 provide two different kinds of information. The majority of the studies were conducted on un- selected populations„ which probably inclhdle a number of individ- uals with clinically manifest COPD. Therefore,, these studies re- flect the prevalence of COPD!-related dysfunction (as determinedi by pulmonary function t'ests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz; et al. (140) and Rankin, et al. (189), have shownithat pulmonary diffusing, capacity is impaired' in young asymptomatic smokers when compared with age-matchedi nonsmokers: Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic colllege-age group and by Zwi'„ et a1. (2'4,1), and Krumholz, et al. (140, 142) in groups of y~-oung,asymptom.atic physicians and medical students. Severat investigators have employed tests whiclii measure the relationship of ventilation and perfusion (V/Q relationships)' i'nn the various pulmonary segments. These tests are predicat'ed' on observations, that some segments, oft'helung rnaybe relatively under or overperfused' and that, likewise, segments may be underr or overventilated. Anthon~isen; et a1.(10) investigated pul'monary: function iin10,malesmokerswithclinicallymild chronic bronchi~~tis„ all of whom had smoked cigarettes for at least 20 years. Regionali pulmonary functlioni was studied using radioactive xenon. Desp'ite the fact that overall pulmonary function was nearly normali in sev- eral patients,, all had depressed V/Q1 ratios in some lung regions withi the basal areas, being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways m<i1~~ exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventillatory capacity do not reveal' any impairment. Similar results concerning, peripheral airway ob- struction in bronchitic patients with normal, or only minimally in- creasedl pulmonaryy resistance, have been observed by W'oolcock, et al. (234). These authors also noted that their patients demon- strated' frequency-dependent compliance which was unaffected by the adhninistration of bronchodilator aerosols.. Striedier, et al., (;214)haverecentllyinvestilgatedi the meehanisrm, of postural hypoxemia in 24 asymptomatic smokers and non- srnokers. They found that standard ventilatory tests and lung vol.- umes were normal in both the sirtoking and nonsmoking groups. However, the arteriall pQ- Ineasured' ini the supine position was significantly lower among the smokers and aliveolar-art'erial oxygen gradients, whilebreathi~ngroomair, were larger inismokers thani in 1a7

nonsmokers (more so in, the supine than in the erect position). The increase in alveolar-arterial 0, gradients was greater for heavy than for light smokers. The authors concludedl that maldistributionn of ventilation and perfusion accounted for the observed hypoxemia.. They also felt that this mild diffuse airway disease among asympto- matic smokers is phy siologically significant mainly because of in- volvement of small bronchi, as expressed' by maldistribution unac- companied by gross airway obstruction. A similar ventilatory distribution abnormality among smokers has also been observed' by Ross, et al. (198) with the more severe alterations found in the long-term smokers. Although of' concern in the consideration of COPD, such dis- turbances of the V/Q relationship may also have adverse effects upon cardiac funct'iom depending upon the level of hypoxemia (219). The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygeni transport and alveolar-arterial exchange as well' as oni oxygen debt developedi withh exercise (50). Further research is needed oni the joint effect of thesee pulftionary and carbon monoxide induced hypoxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory funetion.. Table 5 presents those experiments which deali with the effect of cessation of smoking on pulmonary function. Among the param- eters whichi have been noted to improve after stopping srnoking, are : diffusing capacity, compliance, resistance, maximal breathing, eapacity, and forced expiratory volumes. These parameters showedd improvement within 3 to 4 weeks after cessation of srnoking. C'.,ENETI C FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogenesis of COPD. Earlier studies (127; 147) had noted, the existence of kindreds with high incidences of ehronic~ bronchitis, emphysema, or both diseases. Inadd'it'ionto thepresence of genetic susceptibility„Larson, et al. (147) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partiall'y, genetically detemined. More recently; Larson, et al. (148) studied 156'relativesof COPD patients and! 86' control individuals. The subjects underwent pul- rnonary function testing, including forced expiratory volume and residual volume/total lung capacity measurements. The authors observed that' pulmonary function abnormalities were most prew alent among the relatives who smoked and least prevalent among 1'48

TABLE 5. Gessation o f smoking and human pulmonary f unction' Y=i74C.0 Y W, Author, year, Number and country, - type of reference population Results Comments Krumholz 10 physicians Following 8 weeks abstinence Following 6 weeks abstinence (6 subj_ects only)# # All subjects were >5 pack et al., 25-33 years Lung volumes-no significant change. - - - Lung volumes: per year smokers. 1965, of age. Peak expiratory flow rate-increase -------- Inspiratory reserve volume-increase (p<0.06). U.S A. (P<0.01). Functional residual capacity-increase (p<0.05). (141). Maximal breathing capacity-increase (p<0.02). Mean diffusing capacity: Mean diffusing capacity-no change. Resting-increase (p<_ 0_._0_2) Exercise-no change. Compliance-increased in 6/8 tested. Compliance .............. No change Peterson 1 2 smokers After f month cessation After 18 months cessation et al., _ _ studied a_t_ MBC increase (p<0.001). Increase (p<0.01)._ 1968, various FEV1 0 increase (p<0.01). Increase. U.S.A. intervals and Compliance-continued to show increase. Wilhelmsen 16 smokers. cessation Value prior to Value after cessation Significance Mean duration of the non- , 1967, (43.7 mean _ Vital capacity ........4.60 4.57 Not significant. smoking period was 40 U.S.A. age). 0 ..............3.38 FEV1 3.52 p<0.05. days. (230). ~---~~ . /FVC ........76,0 FEV 76.8 Not significant. 1.0 PEFR ... . .............. 6.97 7.45 Not significant. .......... 3.81 MEFR 50~/n 3.93 Not significant. - . . MEFR25ejo .......... 1.31 1.50 p<0.06. Inspiratory resistance .2.07 1.43 p<0.025. Expiratory resistance .2.80 2.04 p<0.02. (184). compared with 12 continuing smokers. ? Abbreviations are explained in the glossary of bronchopulmonary table A4.

the nonsmoking controls. No ~ relationship of this increased preva- lence could be d'emonstrated to alphal-ant'itrypsirr deficiency (see below). In addition, nonsmoking relatives and smoking controls were observed to show approximately the same prevalence of ab- normalities, However, due to the large proportion of females in the nonsmoking relative group and to the clustering of two-thirds of the affected relatives in~ 110 famslies;, firm conclusions cannot at present be drawn from this study concerning the reiatlive contribu- tions of smoking and of'heredity to the pathogenesis of COPD.. In order to determine the relative significance of smoking and heredity in the pathogenesisof COPD; Cederlof, et al. (45, .4:6)~ have used the twin-study methods on registries in both Sweden andl the USA. The specific details of this method are described in the sec- tion on Coronary Heart D'isease:, As may be noted from a summary of their work at the end of table A2, the authors compared' the symptom prevalence among monozygotic and dizygotic twins who were both discordant and concordant for smoking habits. They observed: that the hypermorbidity for COPD symptoms related to smoking persisted even after controlling for zygosity~~ and concluded t'hata causal relationship of smoking and COP'D symptoms was sup- ported. However, genet'ic factors were still flound, to have an appre- ciable influence. Lundmann (159): has applied this method t& the study of pulmonary functiom He studiedl 37 monozygotic and 62 dizygotic twin pairs, measuring forced expiratory volumes and nitrogen washout' gradients, and matched the various pairs for smoking di'scordancy. He observed that both of these parameters were adverselyaffected in twins who smoked andithat these changes were correlated with cigarette consumption. The results are out- lined at the end of table A3. All'pha,ctntztrypsin (E1,r1T)-Ofmore recent note and discus-sion has been the discovery of an association between a hereditary predisposition to: COPD and the relative or absolute absence of adphat-antitrypsin, al serum glycoprotein enzyme. EYiksson (78)' was the first investigator to observe al relationship between the presence of markedly decreased serum trypsin inhibitory capacity andl panlobularr emphysema. Since Eriksson's paper, much ad.d.edl research has been published concerning many facets of this intrigu~- ing area, It appears that A,AT deficiency is inherited as an autosomal recessive: trait (78,, 216) although Kueppers 0 43) considers the transmission to be by an~ autosomad codominant allele. It has been estimated that up to 51 percent of the general population may be heterozygous for this gene (154) although full cross-sectional studies of the population remain to be d'one. Homozygous or severe deficiencyy of this enzyme has been, asso- 150

ciated with a particular type of pulmonary emphysema. While the majority of llungs of emphysematous patients reveal bullous or centrilbbular deformities, particularly of the upper lobes, this hereditary disorder reveals a panacinar change, most severe in the lower lobes (101, 215s~ 226)1. Pat'ientswithemphysemawho, arefound' to have the homozygous deficiency have beeni observed to include a greater percentage of female patients than is usuadly ob. served! in the general, emphysema population. Their disease begins earlier, is more severe, is characterized' by dyspnea rather than cough, and frequently is unassociated with a history of pr.eceding bronchitis (101, 215, 226) . Radiographic studies of A,AT-deficient patients have revealed decreased vascularization of the lower lobes and increased vascularization of the upper lobes (101, 213)1. It is est'imated that between l and 2 percent of patients with COPD have this homozygous deficiency (78, 216)'. In family studies, it has been found that almost all the homozygous individuals are symptomatic by the age of40 and!that those who are not usually show alterations in pulmonary function studies: GiZenter, et al. (98) studied 7 per- sonswi'th, homozygous deficiency. 0fthe five symptomaticindiviid- uals, 4 smoked and all had! abnormal timed vital capacity. Neither of the two asymptomatic individuals smoked or had, this change in vital capacity. All 7, however, were noted' to be hypoxemic at rest and to have decreased'pulhnonary diffusing capacity. It has been suggested (154) that the lack of this proteinase in- hibitor in the serum of homozygous patients predisposes them to emphysema in the following manner: Leukocytes present in the blood containi significant amounts of proteinase enzymes as part of the overall defense mechanism against' infection ; the breakdown of these celds during acute infection releases proteinases into the pul- monary tissues and'these, without the presence of a normal inhib- itor, may contribute to the breakdown of the structural proteins of lung tissue. Heterozygous individuals have beeni defined as those who show levels of A,AT intermediate between those of normals and those. with homozygous deficiency. At the present time, there is much debate about whether or not heterozygotes for. A,AT are at a greater risk of developing COPD than are A,AT normals. A major dYfficultly is the lack of ai precise definition of heterozygosity. At present, the best method' for the determination of the level of A,AT appears to be that of crossed serum immunoelectrophoresis be- cause levels of trypsin inhibitory capacity (TIC) have been shown to rise acutely with infections. Welch, et al. (226) feeli that heterozygotes do not show an in- creased susceptibility to COPD. The heterozygotes which they studied showed symptoms of bronchitis and did not present the

lower lobe perfusion defects frequentl'y noted in homozygotes. They also found no difference in the number of COP'D, patients among the heterozygotic and the general population. Other investigators, no- tably Lieberman, et al. (154, 155), Kueppers, et al. (1k0, and Larson,, et al. (148) found significantly increased percentages of COPD patients among those with heterozygous deficiency as com- pared' with the general population. Lieberman, et al. (1'55), ob- served that the percentage of heterozyg6tes among a groupi of healthy industrial workers was 4.7 percent while that among aa group of patients wit'h emphysema was 18.1 percent. Ini ai recent review, Falk and B'riscoe (79) considered that the available evi- dence points to an increasedi prevalence of COPD among hetero- zygotes. Of more central interest to, this dh'scussions however, is the pos- sible relationship of srnoking to the predisposition of disease among the heterozygote population. Kueppers;, et al. (144), studied three populations:: younger controls, older controls, and a group~ of COPD1 patients. They observed' that of the 25 heterozygotes with COPD, only: 2 were over 70 years of age,, both were female and non- smokers. The remaining 23 were cigarette smolters: Nevertheless; studies which adequately sort out the factors of genetic susceptibil- ity and cigarette smoke exposure have yet to be: reported. An important question is to what extent the relationship bet'weeni smoking and COPD is influencedl by identifiable genetic factors. Att present, it is possible to identify what appears to be only a very sma11 group of suscept'ibies for whom genetic factors may be.para- mount in the pathogenesis of t'heirailrnent. Of greater public healthh import is whether lesser degrees of genetically identifiable: suscep- tibility interact with cigarette smoking to account for a significant proportion of'the problem. AIR' POLLUTION Numerous epid.emiologicali studies have been condu.cted in order to examine the effect of air pollutioni on human nonneoplastic res- piratory disease. Three major types of studies have been utiilized~:: observation of the mortality and morbidity due to an acute episode of increased air pollution, observation of the day-to-day variationn in mortality and its relation to air pollution levels, and geographical comparisons. The majority of'stud2es falli into, the third'., category, and' these are detailed in table A6. A number of'studies did't not show an association among air pol- lution; respiratorysymptoms; and pulmonary dysfunction (81, 20I): More recent studies which evaluated the factors of smoking, sociali class, and air pollution separately noted a greater prevalence of 752

t COPD symptoms, pulhnonary dlysf'unctiony, and COPD mortality in areas of high pollutlioni (12, 122, 146, 233). Lambert and Reid (146) observed that inthe absence of cigarette smoking the corre- lation between COPD symptoms and air pollution was slight and suggested that the two factors may interact to produce higher rates of disease: The evidence which has accumulated ini the past 7 years gives further support to the conclusion of the Surgeon General's Ad- visory Committee on Smoking and Health as stated in its 1964 Re- port that :"For the bulk of the population of' the United States, the relative importance of cigarette smoking as a cause of chronic br.onchopulmonary disease is much greater than, atmospheric pol- lution or occupationall exposures," OCCUPATIONAL HAZARDS Exposure to various dusty occupational environments has been shown in many studies to be associated with the development of various forms of nonneoplastic lung disease. Lowe (158), in a re- view of the relationship of occupationall exposure and chronic bronchitis, noted that among workers exposed to dust significant increases in COPD: mortality were observed. These occupations included coal mining; tinning, galvanizing, riveting, and caulkin:g.Commenting on a previously unreported study of more than 20;000 steel wor ers, he observed that the relati'onshipbetween mean dust exposure levels and COPD prevalence was much stronger among smokers than among, nonsmokers. More recently,, Bouhuys and Peters (37) reviewed those specific industrial exposures related tolung, disease. COPD was found to be associated with exposure to coal dust, asbestos, bagasse dust, iso- cyanates, various irritant gases, and' textile dusts (cotton, flax, or hemp ) . Studies which have investigated the interrelationship between smoking, industrial exposure„and COPD are listed in~t'able A7. Ad- ditional compounds, not listed in the table, but which also appear to be related to CQPD,are chlorine (49)~ andl washing powder dust (97). Cigarette smoking and harmful' dust exposures appear to act in a combined manner in the production of COPD. Although an increased prevalence of COPD is found with cer- tain occupational exposures, in none is the relationship as strong, as that between COPD and cigarette smoking. To demonstrate ann increased occupational risk„ careful analysis of' smoking habits is required. The relative importance of' cigarette smoking appears to be much greater than occupational exposure as an etiologic factor in COPD. 113

Cccdmiumr-Chronic industrial exposure to cadmium in man has been found to induce pulmonary emphysema without significant accompanying chronic~ bronchitis (34, 35, 210). Nandi, et al. (1'2'7) recently investigatedl the contri'bution of the cadmiumi in cigarette smoke to: the pathogenesis of emphysema. AnalyZing whole cigarettes,, ash, and filters, they found that ann average of 69 percent of the cadhnium present in the cigarette (ap- proximately 116' micrograms/20~ cigaret'tes) is inhaled in the smoke. 1ni a related study (153), these: investigators showed that the.level of cadmium in wat'sr-sol'uble liver protein on autopsy was three, times greater in those pati'ents with:a history of chronic bronchitisi emphysema than that found in those without such a history.. LTn- fortunat'eiy; no smoking, histories were available. PATHOLOGICAL STUDIES The relationship between smoking habits andl pathological changes in the bronchial tree and pulmonary parenchyma has been investigatedl by several groups of workers. Nletaplastic changes, although found in nonsmokers,, are much more common in smokers (table 10; Cancer Chapter), and a dose-relationship of increasing metaplasia with increased smoking has been evident in many of the studies. Patholbgical studies whachdeal: prim:arilywith pulmonary parenchymal and non-rnetaplastic bronchial changes are presented ini table 8. Goblet cell distention, alveolar septal rupture, thickened bronchial epitheliums and mucous gland hypertrophy have been found to be more frequent ini smokers than in nonsmokers. Auer- bach,, et al. (17) noted a dose-response relationship betweeni the amount of smoking andl the degree of septal rupture.. Anderson, et al. (4, 5) st'ud,ied the difference in the type of emphysema shown by smok:ers,and nonsmokers. In their study,: listed in table 8, they noted that the group of' patients with panlobu- l'ar emphysema was comprised of equal numbers of' smokers and nonsmokers while of patients with centriilobular emphysema,, 98 percent~ were smokers. More recently,, the same authors studied Iung, macrosections fromi 80 nonsmokers. While rnost were normal~. 24 demonstrat'edi parenchymal dilatationi and disruptioni consistent with panlbbular emphyserna. Thurlbeck„ et al. (217) have alsa ob, served that centrilobular emphysema rarely occurs in, nonsmokers.. Isa

c '1'Altl.E 8.-.SlruliCs cuxr,~,r~rilr!l lhs~ i~, htfi"1l "f ht"tmut (Artual wirnb,•r "C ,,h„-u in p:~r.cntl„ ,~~i . . . . .. SM ~ - Sniukc~s. . . .Nti..- Nu.i,na.. krr, Author, - year, Number mber and country, - tyPe-o€---- Results - afion reference popul Chang, 1957, U.S.A., Korea (47). 62 males and 43 females autopsied within 5 hours of Distention of goblet cells (by pcrccnt of smoking group) -- '.:/!/ i(ft!f Comment. The authors also noted _Bfast of that smokers' lungs surface Whole surface showed shorter cilia 9.1 . . and thicker epithelium 26.5 22.5 (20 percent nonsmokers and 36 percent smokers had respiratory disease.) death (no data NS(22) available on case SM (49) selection ) . I i of None Feiv IX, of surface surface ~~ . 13.6 22.7 31.8 ~ 22.7 . 12.2 10.2 10.2 18.4 Ide et al., 93 males autopsied Mean thickness of tracheal and 1959, within 6 hours of bronchial epithclium (µ) in U.S.A. death. No cases ctgarctte smokrrrs and nonemokers (129). of pneumonia Trachea_ Bronchus or lung disease NS(23) ................. 52.8 47.7 included. Light(31) ............... 62.0 57.5 Heavy(10) .............. 66.2 61.9 Auerbach erbach 654 males over et al., 60 years of ag_ e_ 1963, autopsied at U.S.A. East Orange (17). VA Hospital. Mean ciliary height in trachea No cigar or pipe and bronchus on cigarette smokers were included. smokers and nonsmokers Trachea Bronchus (23) 6.39 5.95 (29) 5.62 5.49 (10) 4.89 4.66 Age-standardized percentage distribution of subjects The authors also noted a according to degree of rupture of the alveolar septums dose-response relation- Degree of rupture 0-0.25 0.5-0.75 1.0-1.25 1.5-1.75 2.0-2.25 2.5-3.00 ship between smoking Never smoked ................. 19.4 50.5 24.9 3.6 1.6 . . and degree of rupture. Current cigarette .............. .. .4 5.1 16.2 39.2 39.1 9_.1 tNone had ever smoked tCurrent cigar ................ .. 24.6 45.4 26.2 3.8 .. cigarettes regularly. tCurrent pipe_ ................. 5.4 23.0 53.5 15.9 2.2 . . Current pipe, cigar ............ 4.8 7.6 46.5 33.6 7.5 ..

Z; a TABLE 8.-Studies concerning the relation of human pulmonary histology and smoking (cont.) -- (Actual number of deaths shown_ in parentheses) SM - Smokers. NS = Nonsmokers Author, year, - Number and country, fype of Results reference population Anderson 39 males and et al., 32 females 1964, (Caucasians) U.S.A. undergoing (5). routine autopsy (40-97 years of age. ) Anderson 107 males and_ et al., 58 females 1966,- autopsied for U.S.A. whom smoking (6). data was available. Megahed 50 male patients et al., with chronic 1967, bronchitis under- Egypt going bronchial (1B8),_ biopsy and lavage. Severity of emphysema (mean degree) Males F_ emalea NS(4) .......................... ............... 1.5 ) . (20) 1.01 SM(35) .... .............. ~ficant) -}(notaign 2. 8 J (12) } 1.9J (pE0.05) _ _ _ - None ................. Mild .................. Moderate ............. Severe ................ Percentage distribution of tobacco usera in 165 necropatiee by degree of emphysema severity Mean severity of emphyscma - - Mean StaCieticaaL Category Severity Signdficanee 36 (12/33) SM(114) ..................... 2.3 (p<0.001) 69 (68/84) NS(51) ...................... 0.9 - 91 (80/33) Male(107) ...... .......... 2.2 (PG0.001) 93 (14/15) Female(68) .................. 1.2 -- - Never smoked ................ 0.9 <20 cigarettes/day ............ 1.9 20-40 cigarettes/day .......... 2.4 >40 cigarettes/day ............ 2.3 Mucous gland hypertrophy Percent NS ...................... 29 (2/7) SM ...................... 77 (33/43) (p<0.02) Comments The authorsaiso noted that: Every person showing se-e vere disease was a smoker. Among those with panlobu- lar emphysema, there was an equal distribution of smokers and nonsmokers while among those with centrilobular emphysema 98 percent were smokers and only 2 percent were nonsmokers.

TAB1,E $.-Staadiea concerning the relation of human pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM = Smokers. NS = Nonsmokers Author,_ year, Number and o_ m_ ments country, - type of Results Comments reference population Auerbach 562 males au- et aL, topsied at East -- 1968, Orange VA U.S.A. Hospital. (14). Degree of .Lraaheat ,and .bronchia.l arteriolar thickening ,(ba Yeree'ntaye of stn9kcra) UA-O.} 0-5-0:9 L0-3.d 1.5-1.9 5,0-(- Never smoked (122) ..................... 46.1 39.3 13.3 1.3 <20 cigarettes/day (120) ................. 11.7 22.0 33.6 28.4 4.4 20-40 cigarettes/day (254) ...... ......... 5.0 8.6 37.4 40.9 8.1 >40 cigarettes/day (66) .................. 1.3 1.4 31.5 46.3 20.6 i Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer chapter.

EXPERIMENTAL STUDIES A'NIM2AL , StUDIE3~~ A number of investigators have studied the effect of the inhala- tion of cigarette smoke on the macroscopic and' microscopic strue- ture of the tracheobronchiall tree and pulmonary parenchyma of animals. Studie& dealing with metaplasi& an:dd cellular atypism of the trachea and bronchi are! lnsted, in tableA16' of'theeancer chapr ter. Studies, moredirectliyconcernedwith the~ pathology of' CO~P'D' are listed in table 9'. They show that cigarette smoke exposure is associated with changes similar to those found in humans with CdPD, i.e., bronchitis, parenchymal disruptions alveolar septa] rupture, alveolar space dYlatation, and'the 1ossof cili& and' eiliated cells in,the bronchial' mucosa. The investigations of'Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and: electron microscopy that dogs who inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyrna with increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus. exposed to cigarette smoke, the following, changes were observed': In 5 dog& sacrificed after on]y 44days, of smoking exposure, there was a proliferation of goblet cells as, well as, a partiallossof'cili'al in the lining cells, and in 5 dogs sacrifieed' after 420 days or more of exposure, the number of cell layers in the bronchial epithelium~ was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present ;~ instead, the s~urfacewas lined with columnar andicuboidal cells with stubbyprojectionsy in~ place of cilia. Mitotic figures were frequent'lyobservedi in the basal cells. These findings may be relevant to carcinogenesis ass weIlas~tothedevelopment of C~OPD,. In, along-term experiment, carried, out by the same group; dogs were exposed to varying doses of cigarette smoke. Details of thee experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separatedi into non- smoker, filter-tip cigarette, nonfilter-light, andi nonfilter-heavy ex- posure groups, The dogs were "smoked"' for 875 days, or approxi- mately 29 months. The animals which died during the experiment andi theanima]s sacrificed' aft`er, day 875 were• examanedfor pul- monary parenchymal changes as well as for bronchial epitahelial' alterations. As seen in figures 1 and 2„ dose-related pathological changes, including fibrosis and' emphysema, were found' in the 1'ung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of'humans with COPD.

TAIStE. ;).-It'X/)rt'-rirEtttts C-rNii'f t'Iiilt,rt tlrr e'/f( ct o[' fhc inhnbrfi-E1 ~,t ri'lat? I~, atirur fG, ti'uchl ~)-l"<oirrhirtl ft'f su1td pttbtlottttetF - pELrt rtrLitirrrtuf Ntu1,irtl.;' fAr'ual niinil,rr nf in I:u,uthr.,~l u .o Author, year. Animal country, andreference strain Leuchten-_ 603 CFl berger, female mice. et al., 1960, U.S.A. (152). Holland et al., 1963, (123). A. Type of exh ps u re 13. Duration C. Material A. Inhalation, B. Up to 8 ciga- rettes/day for up to 2 years. C. Cigarette smoke. Nuniber Months of exposure cigarettes 0 0 1-3 100-200 4-8 250=500 9-23 600-1600 1-23 25-1526 Itesults Number er of vuce showing specified changes Number Of mice 150 No change 146 Mild bronchitis 2 Severe bronchitis with atypiam 2(noatypism) 36 20 9 7 36 19 10 7 34 19 7 8 151 88 33 30 60 rabbits. A. Inhalation. Cytology of trachcobronchial mucosa B. Up to 20 ciga- Generalized rettes/day for - Normal Focal hyperplasis hyperplasia 2-5. Controls .......................... (30)21/30 6/30 3/30 C. "Normal ciga- Exposed .......................... (30) 7/30 10/30 9/30 rette smoke", _ _ Hernandez Adult Grey- A. Inhalation. Mean Mean et al., hound B. Twice daily/ Number of number of parenchymal Groups 1966 dogs. 5 per week. sections months disruption/dog compared U.S.A. C. Cigarette 1. Controls ............. (8)112 .. - 0.7150 I-III (111). smoke. II. All exposed ........... (15)205 10.50 0.9583 II-I IiI. Exposed <1 year . (7) 98 4 60 6421 0 III-IV .... IV. Exposed >1 year ...... (8)107 . 14.74 . 1.2350 - IV-i Generalized emphysema 1/30 11/30 F-yalue insignificant insignificant p <0.05 p<0,02

TABLE 9. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-hronchial tree and pulmonary parenclrynza of animals' (cont.) (Actual number of animals shown in parentheses) 4 Ss'~:59l4~Q Author, A. Type of year, Animal exposure country, - and B. Duration Results reference strain C. Material Auerbach Beagle dogs. A. Active inhalation Controls ...(10)-No evidence of pulmonary fibrosis or septal r_u_pt_u_r_e_._ • et aL, via tracheostomy. Exposed (10)-k'arly (aacrificed) : 1967, B. Up to 12 cigarettes 1. Alveolar space dilatation. U.S A. per day for up 2. Pad-like attachments to alveolar septa. (15, 16). to 423 days. Medium exposure: Septal wall a_1l thickening. C. Cigarette smoke_._ Latest exposure: 1. Focal subpleural pulmonary fibrosis. 2. Ruptured alveolar septa, 3. Granulomata. Frasca Beagle dogs. A. Active inhalation Electron microscopic results: et al., via tracheostomy. After 44 days - Increased number of goblet cells. 1968, $. Up to 12 cigarettes Decreased number of cilia on surface lining cells. U.S.A. per day for up After 420 days- Increased number of epithelial cell layers. (88). to 423 days. Loss of ciliated columnar cells. C. Cigarette smoke. Frequent interruptions in basement membrane. 1 Numerous experiments detailing changes in bronchial epithelium are detailed tabularly in the Cancer Chapter.

91L7 J ~ . ~' J 2 5.7 0.0 12.9 :;ROUP N: GROUP F; GROUP L: GROUP' H: vONSN1OKING FILTER•TIP NO FILTiER' NO FILTER ('/_:as~~s maniyy cigarettes), as Group, H f~;ci~L;r, 1.-Percent of~lung seetions with grade~~IV or~V ~fibrAsi's.. -;]1~amition~d, eti a7.~ (1~0$~)~,. :;t,%-c?n,tl' investigative groupshaveexposedi rodents to variou& an,i;ient concentrations of'nitrogen di'oxide over prolonged periods of time. Thisgas is found in cigarette smoke andl in some indus- tri's11J'y polluted air. The results of these studies are outlined in tatile A1Q. Iit is clear that chronic exposure to low levels of N'O,, is cap;0,le of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking,, andl the devel- oprnent of CO'PD remains to be determined. Rosenkrantz, et al. (Z.96„ 197) have recently undertakeni experi- ments dealing with pulmonary cel2ular metabolism.They exposed Swiss albino mice to cigarette smoke or its vapor phase for varyingg lenkrths of time., On autopsy, animals exposedl to cigarette smoke sho«red, elevations in the levels of lung D'NA, lactate, andl glycogen which the, authors conclude reflect hyperplasia and macrophage infiltration. Similarly, a dbse-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- brohlasticcoldageni synthesis. 161

100t 80 60' Q a 98.8 L 12.9 0.0 24.9'. GROUP N: GROUP F: GROUP L: GROUP' Ht NONSMOKING FILTER-TIP NO FILTER NO FILTER'. Ch as many cigarettes)', as Group H FIGURE 2.-Percent of' lung sections witih~ grade II or III emphysema. SoipRCES I$ammond, et al. (1'04)'. Aviado and coworkers have performed a series of experiments on live aniirsals and in heart-lung, preparations to study the effect of cigarette smoke on pulmonary physiology and structure ('18,,19,, 20; 21, 22, 179, 180, 199; 200, 201, 202). The authors observed'that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulationi of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar to, those observed after cigarette smoke inhalation. The bronchoconstriction was usually foll'owed by bronchodilatationi which' the authors attributed to syrnpathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases;, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviad'o and coworkers as' well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistancee and decreased pulmonary compliance. The authors related' these changes to the bronchoconstriction of terminal ventilatory units., 162

i Similar experiments in dogs showed that the increase in resistance, following either cigarette smoke exposure or intravenous nicotiinee could be blocke& by pretreatment with atropine. As a parasympa- thetic blocker,, atropine would decrease the acute bronchoconstric- tive phase. Most recently, Aviado and', his colleagues (20, 130) have at- tlernptledto induce physiologic and~ anatomic changes similar to: those found in the lungs of patients with: emphysema. They ex- posed male rats to cigarette smoke„ the introduction of the enzyme. papain, as well as to partial tracheall ligation. In 10 rats exposed to cigarette smoketwieed'ailyfor 3'0minutesover a period' of1Q, weeks, no changes in pulmonary compliance or, resistance were! n, ited. Also, no abnorrnal histologicall changes were observed in the: ~~noup exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- c.reaacl numbers of enlarged air spaces and increased pulknonary rt,,istance when, compared withi anirmals: who underwent only tr:icheall ligation. STUDIES IN HUMEY,N6 '1 i:e :uctite effects of cigarette smoke inhalation on bronchopul-, inon:iry function in man have beeni investigated by a number of ,.~-> lit!rs, The results of these studies are presented in tabl's 11. The. of studies, particularly the more recent ones;, found that inlhalation of cigarette smoke ilsassociated with ani acute i~n-cr-::~e in pulmonary resistia:nce and ai decrease in pulmonary com-ri:::nce. ('hapman (48) adsoobserved decreases inpultnonarydi~f-capac.ity and arterial 01 tension. Chiangand Wang (51)~ ~t-ti cnanges in nitrogen washout time and alveolar dilution fac- : r. :tlterations which reflect impaired alveolar ventilation and gas rnixir,g, James (1.11) examined the effect of prior smoking on the mu1- t'iPle br.eath nitrogeni washout test in 41 pneumocon2ot'ic miners and'. 5 normal Young males. Prior smoking of a cigarettle in the subject's normal manner was found to adversely affect the indices of d'is- tribution, in, 20 percent of the miners andl in all of the 5 normals %ti'ho smoked within one hour of testing. The author suggests that timoking beprohibited, priortoi any seri~esof pulmonary functionytudies. A"r10'soniand Williams (9) studied the acute effect of' cigarette ,Mxoke inhalation upon the ventilation-perfusion (:V/Q) measure- m1unt.s in the lung in normals and in, patients withiCOPD, Cigarette smc,king. observed'to cause acute changes in the V/Q measure- na-nts,,.,.nd the COP'D' patientswere found to be particularly Tiable t'othr.se changes'.. 1 B3:

Finally;, Robertson, et al. (194) studiedl the effect of unfiltered and' filtered cigarette smoke and cigar srnoke upon bronchial re- activity in 19' of the most reactive persons in a group of 91, heavy smokers. They observed that bronchial' reactivity was significantly reducedby increasing the retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette srnoke: They concluded that differences in inhalation account for the difference in CO'1?D, prevalence observed between cigarette and'cigar smokers. STUDIES CONCERNING hUL119.'ONA'RY CL'EARAIVCE' Overall Clearance The ability of'the lung to rid itself of inhaled particles that can- not be easily exhaled& is dependent uponi al number of pfiysiol'ogic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of hurnan cigarette smoking and' the exposure of animals to cigarette smoke on, this clearance system are presented in table A13. LaBelle,, et al. (145) and. Bair and Dillley (23): observed! no change in clear-, ance following the exposure of rat's;, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained' prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, etall (3)~ exposed donkeys tocilgarettesmoke via nas~al' catheter and!observed impairment of clearance times. Holma (125) obtained similar result's in rabbits. In a related study, Albert, et al. (2) studied: the bronchiali clear= ance times of 9' nonsmokers and 14' cigarette smokers in a total pop- ulation of 36 subjects. The rates of'bronchial clearance were slower on the average in the cigarette smokers~~ when compared with the nonsmokers, al'thougha: wide variation was, present in each group. In, relation to their study mentionedl above,, they also noted t'hat the: shape of the whole lung clearance curves seen in smokers (with markedly: prolonged 50, percent clearance times) was similar to that developed' in the donkey following acute exposures to sulfur dioxide or cigarette smoke. Ciliary Fianction;. Numerous experiments have shown that cigarette smoke or cer- tain constituent's of cigarette smoke adversely affect and can even bring about al cessation of ciliary activity in respiratory epithelium in~ vivoand in vitro in culturesof' cilh''atedmicroorganisms. The! re- sults of' a number of these experiments are presentedi ini table 12. 164

:{cti~~~itr has beenishown to be affected by particulate matter. .,~ „-i] f,%- the gas phase components of cigarette smoke. The rel- iniportvice of these two large classes of'components of'smoke ir: 1,r-iItcins,r ciliastasis is presently a matter of some discussiionL I)::l"IMnlnand Rylander (63,6~~!~)consider the particulate phase:to i, t4 t•r~:ater importanee: whi~leBattistlaand'Kensler(28, 29)~ con- ;:,; ,~ T iicix pms phase components are more important in the induc- t;,-yu„f c i 1 iit.stasis.. iisvestigatingthe effectofcilgarettesmokeon, then,.,rProlov~7 of the tracheobronchial tree in, aniunals have noted a ~!,crt ;~ E()r absence in the number of cilia in smoke-exposed anz- .......: Lucently,, Kennedy andl Elliot (134) studied the effect of the •ct e:.posure of' cigarette smoke upon the electron microscopic r; Uu•e of protozoan mitochondria. After 42'minutesof exposure r<rream srnoke, they noted destruction of't'h.e internal' mem. ,; _t,:, :t'TiiL'ture of the mitochondria.. .:-. Cis ui•.ette smoke has been shown to be toxic to ciliary func- ;.~ttholopdcal (including electron, microscopic)and'physio- ::I nntl~od~.. 0 0 of cigarette smoke upon pulmonary alveolar phago- tjae I,ur:t of the clearance mechanism, has been studied by ~, i,; i ;~~littroi~sn y~~Iasin and Masini (i6~2) observed increased vari~a~ r~ 1 i:c size of lipid inclttsiians in sputum macrophages obtained -n10l<e.rsascompared tol thoseobt'ain~ed from nonsmokers,. ::.,Fii;itted these differences to a combined effect of' irritation i., ;ti~eo1Lirlining,, increased turnoverofal'veolarcells, and in- :. in' to the macrophages: Green and Carolin (96)' noted ':o cis-arett~esm;okeinhibi~tedl theabilityof'rabbit alveolarmacro- ;>!^.cwt!, to clear cultures of S. aureus. This effect was noticeably rc(iucecl'i b~~- filtration. Similarly, Yeager (239)' exposed rabbit sC(1l;r„m~icrophagQs which had been induced by lGl., bovis to~cigar= ctte smoke and observed a dose-dependent decrease ini protein syn- thesis. '1'his alteration, occurred at smoke solution concentrations :h;rt (liid not affect cell viabilit'y. The alteration was only partlly re+ ver.sihle and Nvas dt.ie mainly to gas phase components. Myrvik and Evans (1175) observedl similar protein synthesis alterations in macrophag,esexposed to 2tiT0=,1t-{ue and Pickren (195) obtained allveolar macrophages at thoracotomy from 17 smokers and' 4 nonsmokers. They found a dvcrease in the activity of oxidoreductases andl hydrolases in, the niacrophat*es of smokers. The reduction in the enzymatic activity directly proportional to the amount of'storedf fluorescent rna, terial present in the macrophages. This material was thought to

TABLE 11.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function (cont.) Author, - year, country, reference Number and type of population A. Method 1 B. Material i C, Duration of smoking Results Comments Simonsson, 1962, I_._ .9_ male and 7 female normals A. Pulmonary function. Mean FE V1.6 (immediatcly after) Mean FEVI o (45'minutes later) No Q significant changes observed in FFiV/FVC. -- Sweden, (most smokers). B. 1-2 cigarettes. I. Significant decrease. No significant decrease. (p07). II. 15 male and 1 _ C. 6-6 minutes II. Significant decrease. Significant decrease. female pulmonary disease patients (most smokers ) . per cigarette. Zamel _amel et al., 1963, England, (240_)._ I. 6 male and 6 female nonsmokers. ------- -- II. 6 male and 6 female smokers (18-32 years of age. ) A. Body plethy- smography. - - -- B. 1 cigarette. C. Undefined. Airway resistance I. Significant increase. II. Significant increase. Chapman, 1965, Ireland (48). I. 1_2_ normal volunteers (all smokeis). II. 6 patients with chronic non- specific lung disease. A. Pulmonary function Arterial blood studies. B. 1 cigarette. C. Undefined. I. All showed a decrease in diffusing capacity. - II. 4/6-significant decrease in arterial 43 tension. No change in vital capacity or FEV. Dermott McDermott r I. 32 normals. A._ Body plethy- Mean airway reaiatance Light smokers showed ..--- _ and II. 28 with chronic smography I, Significant increase. greater changes than - Collin s , bronchitis , B. Cigarette. II. Significant increase. heavy smokers. _ _ 1965, (All ciga- C. Undefined. Wales rette smokers (160)._ 35-60 years of age.) Iazss4co

TABLE 11.-Experiments concerning the acute effect of cigarette smoke iukalrttiun on lasntnn pttdtuotanry function (cont.) Sterling. ~ 1967,~- 11 normal adults - ~ ~ (8 smokers, ~ A. Body plethy- smography. Airway resistance Significantincrease (Return England 3 nonsmokers). B. 16 inhalations. to normal in 30 minutes ). Author, year, country, reference Number and type of population A. Method 1 B. Material' C. Duration of smoking Results Comments Miller and 10 norm al A. Esophageal balloon ))yttamic 1nspiratory and Sproule, 1066, _ cigarette smokers B. technique. I cigarette. FEVQ 5 No significant compliance Significant expiratory resistance Significant U.S.A. (40 years C. Oneinh_ala_tion . . .. . . -- change - decrease. increase (166). of age). every 30-60 seconds. C. 6 minutes. and 7 Chian male normal Pulmonary function A Nitrogen waahout Lung clearance Alveotar dilution All lung volumes, g Wang, nonsmokers . Nitrogen washout. time index factor except for residual 1970, (18-43 years B. 2 cigarettes. Significant Significant Significant volume showed no Formosa of age). C. Undefined. increase. increase. decrease. significant change. _ (51). No significant change in any of the flow rates. Guyatt 710 subjects; et al., 608 smoked 1970, between meas- _ - England ures 202 (100). did not smoke. A. Body plethy- smography. B. 1 cigarette. C. Undefined. -- Bronchoconstriction On the average, non- Significant increase with smoking. smokers and ex-smokere showed bronchodilation and smokers showed bronchoconstriction. The authors uth_ors postulate that the result among nonsmokers is due to the release of adrenal hormones in these sub- jects. 1 All the experiments listed concern studies of pulmonary function be- fore and after smoking the epecified number of cigarettes (unless other- wise specified).

V 0 TABLE 12. Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance - Author, yeea'. country, reference Subjects Method Comments Results Laurenzi Swiss-Webster Mice exposed to Significant increase in S. aureus retention in mice exposed to: et al„ male mice. aerosolofS.aureus (a) hypoxia-retention ratio 2.5 (10 percent 02). 1963, and sacrificed at (b) cigarette smoke-retention ratio 4.6. U.S.A. intervals following (149). exposure to various stimuli. l i LaBelle Albino female Silver iodide or monary n pu 17-30 hours of exposure to cigarette smoke caused no change - - et al., rabbits. colloidal gold clearance as compared with controls breathing room air. 1966, intratracheally._ U.S.A. s t (145). Bair and Dilley, 1.967, Sprague-Dawley female rats, ------ male beagle dogs. o_ gs. Radioactive aerosol. Radioactive aero®ol. U.S.A, (gg), Albert 36 subjects Radioactive tagged et al., undergoing 117 FeOZ particles 1969, experiments. measured with -- - U.S.A. Scintillation (g), counter. ~ e~~tx~±~-rI-s•„• Acute exposure to cigarette smoke had no gross effect on clearance. Chronic exposure to cigarette smoke (up to 18-20 cigarettes/7 hour day/6 day week -- -- - - - for up to 420 days) had no observable effects. The authors noted, however, -- that normal clearance rates were too low to reflect anything but complete cessation. Number of Average su6jccts age 50 percent 90 percent t Approximate values. clearance clearance None of 9 nonsmokers time time had 50 percent times (minutes) (minutes) over 200 minutes or Nonsmokers ................ 9 28 88 357 All smokers ................. 1-4 33 172 t496 --- 20-29 cigarettes/day ......... 7 29 191 $619 30-40 cigarettes/day ......... 7 36 163 $474 Uranium miners ............. 3 62 310 580 Cigar and pipe smokers ...... 4 46 87 376 Emphysema patients ......... 2 66 330 675 M!4AlO/NIANa1~Y 90 percent times over 600 minutes while --- --------- -- - 6/14 smokers exceeded both these limits.

V aT9 9L E0 TAS1.E 12.-Experiments concerning the effect of cigarette smoke on huntan and animal pulmonary clearance (cont.) Author, year, country. reference Subjects Method Results Albert Donkeys exposed Radioactive tagged Average et al., 1969, to cigarette smoke by nasal FeOa particles measured with number cigarettcs in Percent_ clearance Halftime clearance U.S.A. catheter. Scintillation 2-hour period Control Cigarette Control Cigarette (,y) counter. 18-24 58 69 1.2 1.9 , -- 36 58 64 1.0 3.4 Comments Trachaet transit Those donkeys exposed time to the greatest amount of smoke Control_ Cigarette showed residual 0.6 1.2 impairment of 0.4 6.8 clearance for at least 2 months after acute exposure. Holma, Rabbits a_hbits Cr61 monodisperse Exposure to fresh cigarette smoke (1.6 cc. puffs, 40 puffs/8 minutes) caused - -- 1969, (anesthetized). polystyrene a"significant" increase in lung retention 10 minutes following cessation of U.S.A. aerosol. exposure.

originate in tobacco smoke. The authors suggested that the tobacco, ' smoke may have induced abnormalities in the mitochondria of the`~ macrophage. In a study of pultnonary macrophages harvested by{ endobronchial lavage from smokers andi nonsmokers, Pratt, et al. , (187) observed, that the macrophages of smokers contained an ab- normal pigznent. These studies indicate that the function of pulmonary cl'earance carried on by the macrophage and ciliary systems is adversely af- ' fected by cigarette smoke. STUDIES CONCERNING THE SURFA,CTANT SYSTEM The surfactant system of'the lung,consists of various biologically active compounds such as phospholipids and mucopolysaccharidess which are present in the alveolar lining. N'ormaI pulmonary func- tion ils influencedl and partly determinedl by the integrity of this system (203). The purpose of the surfactant system is to main- ! tain the proper amount of surface tension in the alveoli so that the ! expansioni and contraction of the alveoli are facilitated. ~ Studies concerning the effect of cigarette smoke upon the sur- ~ faetant system and the surface tension of the pulmonary alveoli ', are presented in table A14. Exposure of' rat and dog lung extracts ~ to cigarette smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165,, 224). Cook and Webb (57) observed that surfactant activity vv~asdilninished in smokersand in patientswithpulrnonarydisease~ when compared withhealthynonsmkers~ Scarpelli (203) in, a recent review, concludedl that the lowering of maximal surface tension by cigarette smoke has been demon- , st'rated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTHER RESPIRATORY D'ISOR'DERS INFECTIOUS RESPIRATORY DISEASES' !. Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res~-' piratory and bronchopulmonary disease. Tab1e A15 presents a'. summary of these studies. Lowe (1'57) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbelll (43), in a similar study found that the difference vwas not present when the cases and controls were matched for alcohol intake. 1Vforee recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of'investigators (108, 181, 1,83), have reportedi increased 172 I

a i rates of respiratory illnesses among smokers. Finklea, et al. (83) studied a male college population (prospectively) during, the 1968-69 influenza epidemic. They found that smokers of all amounts experienced more clinical illness than did nonsmokers and that thiss relation wasdose-d'ependent, Similaxly,,smokers requiredlmore~bedl rest than nonsmokers. A survey conducted by: the National Center for Health Statistics (220),, involving approximately134,000! persons,, showed that ma1eeigarette smokers reported 54 percent more cases of'acute bron.- ehitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who: had never smokedi, Male cigarette smokers report'ed 22' percent more cases of infl'uenza than did males wholhad never smoked cigar- ettes, while the fernale smokers reported an excess of 9 percent.Experi¢nental evidence in support of this relationship has been noted by Spurgash„ et al. (211). Miee were challenged with Klebsiell'a pneumoriae or Diplococcus pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke exhibited a decrease in resistance to respira- tory infection, as shown~ by: an increase ! in mortality and a decrease in survival time:, Preexposure to cigarette smoke was found to have no significant effect on~ resistance of mie& to inflUenzai infectionn initiated by aerosol exposure. However, exposure of' infected mice to smoke resulted in signifi'cantly higher rnox^tality,, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the ligklt of the experimental evidence: presented above con- cerning the effect of cigarette: smoke on pulmonary clearance, phagocytosis; and' ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function woulldi predispose: a person to: respiratory infections or aggravate already existing ones. Filrther evidence is derived froxn the work of Henry„et al. (109) and Ehrlich, et al. (75),., These investigators exposed squirrel monkeys to atmospheres containing; 10, and 5 p.pm. of nitrogen dioxide. They observed that this& exposure increased the suscepti- bility of the anianals to airborne Klebsiella pneumoniae as demon- strated by increased mortality and reduced llang clearance of viable bacteria~ Infectious challenge with influenza virus 24 hours before exposure to 10 pLp.m., was fatali t& all monkeys vwithin three days. Infected controls showed symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibility to respiratory disease noted in smokers is presently undefined., 173:

POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers runi an increased risk of developing postopera- tive pulmonary complications over nonsmokers undergoing similar operations. 11rIorton (173) reported' on a study of more than 1,100~ patient's undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop bron- chitis, bronchopneumonia,, or atelectasis during the postoperative period than nonsmokers (table A16) . Wiklander and, Norlnn (229) examined the incidence of post- operative complications in 200 patient's undergoing laparotomy in the winter months when it was expected that pulmonary compli- cations would, be, at their maximum. These authors foundi no sig- nificant differences between the frequency of complications in smokers and' nonsmokers. No information about the definition of' a smoker and no data on dosage of tobacco smoke were reported!, P'iper ('188) observed the prevalence of postoperative pulmonary complicationsini 150 patients undergoing laparot'omy. Ofthetota~lf sample, 66.7 percent developed pulmonary complications during the first postoperative week. All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease: Of the cigarette smokers, 73!5' percent' hadl complications as compared to 55.5 percent of the nonsmokers. When the smokers were divided according to dosage, heavy smok- ers being those consuming more tliani 110 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were consideredl to have postoperative cornpli- cations. Piper also, reported that stopping,smoking for up to four days preoperatively had'no apparent effect on the incidence: of compiications. Wightman (228) reported on the ineid'ence of postoperative pul- rnonary complications in 455 patients undergoing abdominal' oper- ations and ini 330 patients undergoing other operations, Of the cigarette smokers, 14.8' percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference betweenithese figures and those of Piper (186) is due to the latter's use of'radiographic criteria alone.. Wightlman utilized only cTinicall criteria. Morton (1'7z')has~recently reporti'edI astudyof' postoperative hypoxemia i'n 10 patients, 5 of whom were cigarette smokers. Four of the smokers had chron2c broncliitis., He found that the smokers had a more.pronounced decrease in arterial oxygen saturation, per- sistingintothe~ second' postoperative~ day (table A17)~.. 174

0 0 In summary, tlie majority of' studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tiVe pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of' developing such cotn- p?ications appears to increase withi increasing dosage of cigarette smoke. SUMMARY AND CONCll:USIONS' 1. Cigarette smoking i's the most important cause of chronic ob- structive bronchopulknonary disease in the United States. Ciga- ret't~e smoking increases the risk of dying from pulmonary emphy- sema andl chronic bronchitis. Cigarette smokers show an increased pre~-alence of respiratory symptoms, including cough, sputum pro- (iuction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. '?: Cigarette smoking doesnot appear to be related to death from bronchial asthma although it may increase the frequency and se- verityof asthmatic attack~:sin patient'& already suffering from this disease; :;. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers ~vhile clearly less than that among cigarette smokers: -1. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and withi a, decrease in pulmonary symptom prevalence.. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non= smokers of the same age. 6. For the bulk of the population of the United States, the im, portance of'cigarette smoking as a cause of COiPD is much, greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce. greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstratedl that the inhalationi of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter thee meehanismi of pulmonary clearance andl adversely affect ciliary function. 8. Pathological studies have showni that cigarette smokers who die of diseases other than COPD have histologic changes charac- 1!75'

teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do: nonsmokers.. 9. Respiratory infections are more prevalent and severe amongg eiga.rette smokers, particularly heavy smokers;, than arnang, nonsmokers. 110. Cigarette smokers appear to devel'op postoperative pulmo- nary: complications rnore frequent'lythani nonsmokers: CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE REFERENCES (1) ABBOTT, 0: A., HOPKINS, W. A., VAN' FLEIT, W. E., ROBIN'SOl;i, JL S. A new approach to pulmonary: emphysema. Thorax 8: 116-132„ 1953. (2) ALBERT, R. E., LIPPMANN, M., BRISCOE, W'. The characteristics of' bronr chial clearance in humans and the effeets' of'' cigarette smoking, Archives of Environmental Healtlhi 18 (5) : 738-755,, May 1969:, (3) ALBERT, R. E., SPIEOELMANS J. R., SHATSKY, S,,, LIPPMANN', M. The effect of acute exposure to cigarette smoke on bronchial' clearance in the miniature donkey. Archives, of Environmental Health 18 (1') : 30-41, January 11969. (k.) ANDERSON, A. E.,, Jk., FuRLANFrro„ J. A.. FORAKER, A. G. Bronchopul- monary derangements in nonsmokers. Americani Review of Respira- tory Diseases 101(4) : 51I8r527, April 1970. (5); ANDERSON, A. E.,, JR:, HERNANDEZ,, JL A., ECKERT,, P., FORAKER, A. G: Emphysema in lung, macrosections correlated with, smoking habits. Science,144 (3621) : 1025'-10261 May 22, 1964. (6) ANDERSON, A. E., JR., HERNANDEZ, J. A.,, HOLMES, W. L., FORAKER, A. G. Pulmonary emphysema. Prevalence, severity, and anatomical patterns in macrosections, with respect to smoking habits. Archives of'Environ- mental Health 12(5) : 569-577, May 1966: (7) ANDERSON,, D. 0., Observations on the classification and distributian of pulmonary emphysema in CanadaL Canadian Medical Association. Journal 89: 709-716, October 5, 1963, (I&) ANDERSON', D. 0., FERRIS, B. G., JR.,, ZICKmANTEL, R: The Chilliwack Respiratory Survey,, 1963. Part IV., The effect of tobacco smoking on the prevalence ofl respiratory disease. Canadian Medical Association Jburnal 92(20) : 1066-1076, May 15,1965'. (9) ANDERSON, W. HL, WILLIAMS, JL B: Effects of cigarette smoke on dis- tribution of pulmonary perfusion., In: Current Research in Chronic. Respiratory Diseases. Proceedings of the 11thi Aspen Einphysema Conference, Aspen, Cbto, U.S. Department of' Health, Education, and Welfare, Public Health Service Publication No. 1879, 1969'. pp. 75-79. (1'Q) ANTHONISEN, N. R., BASS, H., ORIOL, A., PLACE, R. E. G., BiATES,, D. V. Regional lung, function in patients~ with chronic, bronchitis. Clinical Science 35:, 4J5:-511, December 1968.. (11) ASHFORD4 J. R., B$pwN',, S., DUFFIELD, D. P., SMITH, C. S.,, FAY,, J. W. J. The relation between smoking habits', and physique, respiratory symp- toms, ventilatory function, and radiological pneumoconiosis amongst coal workers at three Scot'tish collieries. British Journal of Preventive andl Social Medicine 115: 106-1L7, 1961. 176

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BRONCFIOPULMONARY APPENDIX TABLES

TABLE A2. Smokinq and chronic ottst_ructi~vc pulmolaa~ry cdiscuse sympto~zals'-pe~tec-ltt jarcvxilc>zet, (Numbers in parentheses represent total mimbcr of individuals in particular smoking gruup) SM = Smokers. NS =- Nom ~moku's. EX -_ Ex-smokers. c ;; S9~4~06~.;;S9~4 ~ S9~4~0 0 , Author, year, country, reference Number and type-of - population Breathlessness Cou_gh__ Sputum production or dyspnea - Short - 2.031 male and - NS . .. .. .. - 1.6 (496) et al., female insurance SM_ ....... 6,_4 (1,293) 1939, policy holdera._ U.S.A. (206). Oswald 3,602 male and and 2,242 female Medvei, clerical 1955, workers 40-.65_ England years of age. (178). - Phillips 1,274 male NS ....... 2.0 (451) et al., factory workers S_M_ ....... 61.0 (823) 1956, without overt U.S.A. pulmonary (185). disease or heart failure. Higgins 301 male and Cough and sputum 1957, 280 female Males Males England rural dwellers NS ......... 7.1 (28) NS .......... 7.1 (112). 25-74 years of SM ......... 53.9 (222) SM .......... 19.8 --- - - age. Fexnalas Females NS ......... 4.5 (176) NS .......... 21.6 SM ......... 17.2 (93) SM .......... 9.7 Chest illnesses Other Comments NS ......... 10.9 SM ......... 18.0 Chest illnesses as repre- sented by frequent colds. Chronic Bronchitis Males Chronic bronchitis NS . .. .. ..15.8 (474) defined by SM ~ .......18.4 (1,940) habitual Females cough and NS ...,..32.1 (619) sputum SM .......18.8 (579) - production. Chronic Bronchitis Mates Males NS ......... 3.6 NS ....... 3.6 SM ......... 17.1 SM ....... 9.9 Females Females NS ......... 9.7 NS ....... 3.4 SM ......... 15.1 SM ....... 8.6

TABLE A2.-Smoking and chronic obstructive pulmonarf. disease sytttpto9t+s'-percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) - SM = Smokers. NS = Nonsmokers. EX - Ex-smokers. Author, year,- Number and Breathlessness country, reference type of population Cough Sputum production or dyspnea-- Chest illnesses Other Comments Higgins 94 males and and 92 females Cochran, randomly chosen 1958, (members of an England agricultural - (114). community.) Females Cough and sputum NS ......... (6) SM .........2-4.0 (75) NS ......... 3d (64) SM ......... 3.0 (20) Males Males NS .............33.3 NS ..... 0.0 SM . .. .. ...... .29.3 SM . .. .. 16.0 Females Females NS ............ 45.3 NS . . . . . 10.9 SM ............ 20.0 SM . .. .. 10.0 Chronic bronchitis Males NS ....... 0.0 SM ....... 6.7 Females NS .......0.0_.. SM ....... 5.0 Edwards 1,737 male out- et al., patie_nts_ o_n__ 1969, lists of England general prac- ( 74 ) . titioners >60 years of age. Flick 222 male NS .......10,0 (51) NS .........25.0 (49) and patients not SM .......65.0 (157) SM .........65.0 (156) Paton, _, suffering from - 1959, oxertcardio- U.S.At pulmonary (86). disease, 20-90 years of age. Higgins 776 males in et al., various 1969. occupations England 25-64 years (116). of age. NS ..... 30.0 (47) SM ..... 60.0(138) Cough and sputum SM ......... 7.1 (86) NS ............ 9.4 NS ..... 7.1 NS .........369 (676) SM ............24.9 SM ..... 20.2 Chronic bronchitis NS .......16.6 (151) Cigarettes 29.7 (779) 1- 9 . ...23,4 (235) 10-19 ....,31.2 (369) >20 ..... 33.7 (176) Pipe . .. . 18.5 (340) Chronic bronchitis SM ...... 14.3... ...... NS ...... 3.5

TABLE Bt-E A2. Smoking and chronic obstractive puhitcnarg disease symptoms'-pereent PrTr+tl_elac_ e(con t.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS - Nonsmokers. EX - Ex-smokers. Author, year, Number and country, type of reference population Higgins, 393 males i_n_ 1959, various England_ occupations (119). 66-64 years --- of age. Liebeschuetz,147 male NS ....... 0.0 (62) 1959, soldiers SM 13.0 (83) England 20-30 years (156). of age. 1 Ashford 4,014 male et al.; coal workers. 1961, England (Il). 4R201S9l+EO B_reatblessness Cough Sputum production or dyspnea Chest illnesses Other Comments Cough and sputum Chronic ic bronchitis NS ........ 6.1 (33) NS .......... 18.2 NS .......... 3.0 NS ...... 0.0 1-14 g./day 9.7 (173) 1-14 g./day 30.1 1-14 g./day 23.7 1-14 g./day 13.9 >15 .......42.3 (142) ?15......... 33.8 >15 ......... 23.9 >15 ......17.6 Chronic bronchitis defined as persistent sputum a_n__d_ at least 1 chest illness in past 3 years. Tobacco gram equivalents are: 1 cigarette = 1 gram, 1 cigar = 2-5 grams, 1 pipe = 10-25 grams. Respiratory aymptoms Respiratory NS .......10.3 (677) symptoms- EX ...... 19.5 (123) "bronchitis Cigarettes 21.1 (1,504) and/or Pipe only 35.1 (202) asthma". No Cigarettes dose rela- and pipe 87.1 (90) tionship All SM . ..21.7 (8,214) found. 41:~, _

TABLE A2, Snmoking and chronic obstructive pulmonary disease synaptoms'-pexcent prevalence (cont.) (Numbers in parentheses represen__t_ total number of individuals in particular smoking group) SM- Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness ts country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Bower, 95 male and NS ........ 4.1 (49) NS ........ 20.4 NS ...... 34.7 1961, 77 female SM ........ 27.6 (76) SM ........ 34.2 SM ......38.2 U.S.A. bank employees Pipe, cigar (13) Pipe, cigar 15.4 Pipe,cigar (41). 40-70 yea__rs 63.9 of age. Fletcher and 363 male London NS . ....... . . (30) NS .......... 8.7 NS .......... . . NS ...... 4.3 Tinker, transport 1-14 g./day 15.6 (156) 1-1-4 g./day ..29.9 1-14 g./day .. 8.2 1-14 g./day 1961, employees >15 ......27.3 (116) >16 .........36,9 >16 ......... 8.6 8.2 England 40-50 years >15 ....10.7 (&.5). - of age. Read 170 male and Males and 132 female NS ........ 4.4 Selby, individuals SM ........ 23.1 1961,interviewed EX X ........ 21.2 Australia in an out- Females - - (191). patient NS ........ 4.9 clinic (not SM ........ 186 all patients). Balchum 1,451 male et al., light 1962, industry U.S.A. employees in (24). California. NS ........ 10.2 (263) NS ........ . . 11.0 NS . .. . . . . 9.8 SM ........ 23.3_ (1,_198) SM .......... 30.4 SM .......... 14,5 E_ 1 pack- <1 pack- <1 pack-year .10.0 year . . .. .11.0 (257) Year ......12.0 1- 9 ........ 12.0 1- 9.....17.0 (263) 1- 9 ........ 18.0 10-19 ........ 11.0 -- 10-19 ..... 25.0 (303) 10-19 ........32.0 20-29 ........18.0 - 20-29 .....21.0 (236) 20-29 ....,...34.0 30-39 ........ 21.0 30-39 .....28.0 (144) 30-39 ........40.0 40-49 ........13.0 40-49 ..... 39.0 (92) 40-49 ........37.0 60-59 ........38.0 50-59 .....34,0 (29) 50-59 ........ 45.0 >60 ........ 29.0 - >60 .....50.0 (24) >60 ........ 62.0 Chest illness- chest colds during each of last 2 winters.

T.tlsl E A2.-4»toki>g uit(1 cJrauic ul,struCFirc j,rAfuI „iEw. rf cfi,FnSF"tr„p toqi;~'-to ;-ertlt E,re v t l/cn ec (r•onf.) . (Numbers in parenth_.ses rcPresen4 tolal numl,er of individuals in Itarticular smoking group) SM = Smokers. Nti -= Non~rnokers. EX = Ex-smokers. Author, year, - Number and country, type of reference population Breathlessness Cough Sputum production --or-dyspnca~~ ~ Chest illnesses Other Comments Boucot 6,139 males NS ........ 13.0 (806) et al., 1962, enrolling SM ........ 31,6(6,331) U.S.A. in pulmonary (36). neoplasm project. 11 . Ferris 90 male and et al., 71 female 1962, flax mill- U.S.A. workers. (82). Chronic Nonspecific Respiratory Disease Males Females NS ..16,0(20) 10.0(60) EX . 12.6(16) .. 1-20 .27.3 (22) >20 .63.1(32) 50.0 (4) Ferris and 642 male and 625 female Chronic bronchitis Males Age-specific rates. Anderson, residents of ------ NS .......13.8 (125) 1962, New Hampshire EX .......11.9 (77) U.S.A. town chosen Cigarettes 40.3 (340) (81). by random 1-10 .....29.8 sampling of 11-20 .....34.2 census. 21-30 .....42.3 31-40 .....61.1 >41 ......76.8 Females NS ....... 9,4 (878) EX .......10.8 (37) Cigarettes 19.8 (208) 1-10 .....13.1 11-20 . . . ..22.2 _ _ _ 21-30 ..... .. 81-40 . ...27.3 >41 ...... . Tx (t&u .~79 4 C.Q r

TABLE A2: Sznoking and chronic obstructive pulmonary disease syJttptouts'-pereent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) ~--------- --- -_-------~ ---------- - - --- ----- -- - - - -- . _ .. . . SM = Smokers. NS = Nonsmokers. EX - Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population - - - - Goldsmith 3,381 active et al., or retired 1962, longshoremen. U.S.A. (95). Coates 1,342 male and et al., 242 female NS .....11.2 (747) NS ... 14.7 1965, Detroit post 1-14 ...12.7 (266) (notsig.) 1-14 ,28.2(p<0.001) -- - - - - U.S.A. office 15-24 ...27.5 (402) (p<0.001)15-24 .30.7(p<0.001) (53). employees. >25 ....36.4 (170)(p<0.001)>25 . 34,1(p<0.001) Deane 508 tele- et al., phone 1966, company U.S.A. workers. (67). Huhti, 653 male and Males 1965, 823 female NS ........ 4.1 (122) Finland residents of EX ........ 8.5 (141) (126). a Finnish 1-14 .....31.6 (108) communal 15-24 ...... 40.8 (191) region, >25 ...... 42.4 (85) 40-64 years Females of age. NS ........ 4.5 (709) EX ........13.3 (30) 1-14 ..... 10.4 (77) 15-24 ...... 43.0 (6) >25 ...... -- (1) e_ 9~E0 Males NS .......... 10.7 EX ..........17.7 1-14 ...._._...38.0 16-24 ........ 42.9 - >25 ......... Females NS........... 5.9 EX ..........13.3 1-14 ........ 10.4 15-24} „57.0 >25 Males NS .......... 15.6 EX .......... 24.8 1-14 ........ 25_.0 15-24_ .... ........ ---26.2 >25 ......... 31.8 Females NS .......... 29.2 EX ..........33.3 1-14 ........ 14.3 15-24 ~25}.........14.0 Respiratory conditions NS . .. 31.4 (744) Moderate/hea_vy smokers 43.0 (1,238) Cough and chronic phlegm Current NS ...... 4.0 smoking 1-14 .... 5.3 ( not sig. ) data. 15-24 .... 17.2 ( p<0.001) >25 ... .. 25.3 ( p<0,001) Persistent cough, NS includes phlegm, dyspnea ex-smokers, NS ....... 4.5 (200) pipe, and Current cigarette cigar smokers 16.9 (308) smokers. Chronic bronchitis Ex-smokers Malea represent NS ....... 5.7 those who EX ...... 16.3 have 1-14 . ...38.0 stopped 15-24 . ...41.4 smoking >25 25 ...... 40.0 for more Females than 1 NS ...... 4.5 month. EX ...... 13.3 Dyspnea 1-14 .... 10.4 Grade 11 - 15-26 ...67A only. . . . >25

N O wrr Mf, TABLE A2. -Smoking and chronic obstructive pulmonary disease symptQnis'-pe-rcent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) -- - ---- ----- - SM = Smokers. NS = Nonsmokers. EX - Ex-smokers. A uthor, _ year, Number and Breathlessness country, type of _ Cough h Sputum production or dyspnea Chest illnesses es -- Other Comments reference population -- Wynder 315 male New York City et al., patients in NS ........ 1_4.0 (44) 1965 New York City Pipe, cigar 33.0 (64_ ) U.S.A. and 315 male Cigarettes: (288). patients in - 1-10 ...46,0 (44) - California. 10-20 ...46.0 (88) >20 ....67.0 (85) CaliJornia NS ....... 22.0 (69) Pipe, cigar 30.0 (32) Cigarettes: 1-10 ...46.0 (54) ..74.0 (91) 1U-20 . _ _ >20 . ..74.0 (69) Freour 1,_055 randomly Clinical signs of et al., chosen males in bronchitis and 1966 Bordeaux 30-70 respiratory France _ years of age. insufficiency (a2) NS ......26.4 (45) SM ...... 64.4 (478) Haynes, 179 male Average number of Heavy et al., preparatory severe respiratory smokei: _ 1966 school illnesses per 10 more than U.S.A. students students (adjusted 10 ciga- (108). (108). 14-19 years for age) rettes of age. NS ...... . 0.36 per day. All smokers 2.30 Heavy SM 3.84

N Q N TABLE A2.-Smoking and chronic obstructive pulmonary disease sympto~ms'--percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) ---- ~ SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, yt•ar. country, reference Number and type of population C_o_u_ g_h__ Sputum production Breathlessness or dyspnea Chest illnesses Other Comments Densen 5,313 male Postal Postal Postal Dyapnea et al., and 7,291 NS .. 7. 0 (903) 13.1 19.8 represented 1967, U.S.A. female postal and transit Pipe, cigar 12. Cigarettes 4 (628) 17.4 24.8 by Grade II on ly. (68). workers. only .... 270(2,68_7) 28.9 31.7 Transit Transit Transit NS ....... 6.4(1,012) 9.5 11.7 Pipe, cigar 10.5 (765) 14.1 14.2 Cigarettes only ....23.6(8,746) 23.7 21.9 Higgins 926 white NS .......16.4 (162) NS ........... 31.1 NS ........... 6.0 - - et al., male resi- SM ....... 47.2 (513) SM ........... 46.2 SM ........... 10.7 1968, dents of EX .......19.3 (144) EX ........... 28.5 EX ...........16,8 U.S.A. Marion (118). County, West -Virginia,26-69 years of age. Holland 9,786 male Males Females Males Females and and€emale NS ....... 3 8(1 900) 3.2(3 137) 2.4 2.1 Elliott --- school SM . , .... 6.3(1 098) , 6.3 (664) 6.1 8.3 , 1968, - children. EX ... , ....... 2.9(1,782) 4.3(1,151) - 3.9 4.2 England <1 cigarette/day ...............6.8(876) 6.8 (fs1). 1-2 ............................6.6(417) 8.4 3-4 ............................6.6(124) 8.1 >5 .............................9.9(142) 18.3 czzfj:S94cO

4 'I',11t1.E A2.-Sv:okitrg an cl c•hrrrnir rrir::frurfit c )r,cirr",,,,r1 ;( 1 ir I rr.-, . ,i,;,,,I i„ r, , r i, , ,1, . - , , t,~ t . (Numberv in parenth•s,-.; r,t, n.-ut t u, l qurnl- r ~,f fnS-Jua!. in ;.rn,i.int: t;r,.•t~) I I N 0 m SM -- Snmokers. NS -- Nun,tu okqr:;. l:\ Author, - year, ~~ Number and ISrcnttJc;snc,s country, ~~typeof Cough Sputumproduction ~iir~d;spnea ~ Chest illnesses reference population ..-' -----` --- -- ----- -- Gandevia 762 male and Males 1969 1,304 female NS ....... 10.3 (234) Australia patients SM ....... 51.3 (528) -------- (93). from 13 general Females practices NS .......10.6 (857) in all parts of SM ... .. ..37.4 (447) Australia. ~ Rimington ton 41,7Z9 male 1969 and 22,295 England female persons (193). participating in mass miniature radiography screening. Wilhelmsen 313 males - ------- - et al., 60-54 years 1969, of age randomly Sweden sampled from (8a1). population of GQtehorg. Othvr Cummvnts P-roductive cough upon request. Age-adjusted total Cigarette prevalence of dosage chronic bronchitis gradient Males significant NS ....... 5.1 (9,066) to p<0.001. EX ....... 9.8 (6,510) Pipe .. .. 9.0 (2,921) Cigarettes . (23,243) 1- 9 ..... 9.1 10-19 .....16.0 >20 ......20.6 Females NS ;5.4 (12,361) EX ...... 3.8 (959) Pipe .... 0.0 Cigarettes (8,985) 1- 9 . . 6.1 10-19 ... 10.6 >20 .. ...18.5 _-Chronic bronchitis NS ...... 1.0 (88) EX ...... 3.0 (67) 1-14 grams/ day . . 5.0 (94) >15 . .. 17.0 (64)

TABLE A2._-Smolaing and chronic obstructive pulmonary disease syuaptoms'-pereent prevalence (cont.) - (Numbers in parentheses represent total number of individuals in_ particular smoking group) SM = Smokers. NS = Nonsmokers. EX - Ex-smokers. Author, year, Number and Breathlessness country, type of---- Cough ough Sputum production or dyspnea ~~ Chest illnesses Other Comments re erence popu)-aEion -- - - Lambert ambert 9,975 male Persistent cough and phlegm and and female Males Reid, responders Agc Age Age Age 1970, to a postal 85-45 45-55 55-65 65-69 England survey NS ..... 7(227) 6(200) 11(171) 7 (61) (146)._ (4,688 males EX ..... 7(303) 11(358) 15(335) 18(148) and 6,287 <20 ....15(521) 22(488) 30(490) 37(139) females 20 ...... 23(191) 28(204) 32(149) 38 (37) 35-69 years >20 ....27(146) 28(136) 42(121) 26 (12) of age). Females NS ..... 3(500) 4(637) 5(925) 6 (21) EX ... 3(127) 8(128) 7 (94) 7 (41) <20 .... 9(602) 13(472) 16(306) 11 (65) 20 ...... 16(128) 27(122) 31 (77) 14 (7) >20 ....23 (22) 26 (39) 43 (7) . . (1) Lefcoe and Wonnacott, 310 male physicians in London - Age-standardized rates of chronic respiratory disease 1970, and Ontario, NS ........ .. 1.0 (88) Canada 25-74 years EX ........ .. 5.0 (61) (151). of age. SM ........ .. 34.0 (101) Pipe, cigar ..12,0 (33) i Data collected by either direct interview, questionnaire, review of medical records and/or medical examination. Excluded from ex-smokers are those cigarette smokers who now smoke pipes or cigars. ZE~42:S94C0

i `7C N O ~ SWISsl4leo TABLE A2a.-S>•ttoking and chronic obstructive pullnonard disease sgJniptolns'-percent prevalence (Numbers in parentheses represent total number of individuals in particuar smoking group) . ..... -- ~ -- ------ ------ -- -- ------ - SM = Smokers. NS - Nonsmokers. EX - Ex-smokers. ---- discordant pairs. Cederlof 4,379 twin Prevalence of respiratory symptoms eLal., 1969, pairs (all U.S. veterans) Group A: NS .................. 4.3 4.3 1.6 Group A-as above. U.S.A. in U.S. 1-10 ................ 6.4 6.4 2.7 Group B-as above. (45). National 11-30 ................15,3 16.3 8.0 Academy of >31 ................. 27.7 27.7 16.8 Sciences Twin Pipe, cigar ............. 7.1 7.1 2.7 Registry (of 9,000 avial- Group B: MZ ........................... NS 2.4 SM 5.4 NS 1.8 SM 4.8 able ) . DZ ............................ 2.0 9.8 1.6 9.1 .---- Author, - year,-N_ Number and country, type of _ reference popuation Cough Bronchitis Cederlof et al., 9,319 twin pairs Observedf expected Hypermorbidity Observed expected Nypermorbidity Explanation of analyses for respiratory symptom 1966, registered Group A: cases ratio cases ratio prevalence: Sweden in Sweden Males ........393/151.9 2.6 157/50.8 3.1 Group A analysis-using each (46). of 12,889-- available. Females .... .1361 49.4 Group B SM fNS: 2.8 43/11.2 3.8 firstborn twin as one group in an unmatched relationship _ MZ Males .... 14.6/7.7 1.9 6.6/ 1.1 6.0 (274) to each secondborn twin. Females ... 13.6/7.6 1.8 3.0/ 2.3 1.33(264) Group B analysis-using each DZ Males . .. . 12.3/5.5 2.25 4.5/ 1.8 2.64(733) twin set as matched pair. Females ... 14.5/5.7 2.67 5.5/ 1.8 3.0 (653) All comparisons in Groups A and B are between smoking- i Data collected by either direct interview, questionnaire, review of medical records and/or medical examination. Comments All ex-smokers included - with smokers. gotic MZ-monozygotic pairs DZ-dizygotic pairs Author concludes that since hypermorbidity for smoking persists in smoking-discordant MZ population, a - - - casual relationship of smoking and broncho- pulmonary symptoms is supported. No ex-smokers included in Group B analysis. The authors conclude that the data indicate a strong probability of a causal connection with smoking. Even these symptoms, however, seem to be influenced by genetic factors.

N G TABLE A3.-Smoking and ventilatory function (Numbers in parentheses represent total number of individuals in particular smoking group) - NS = Nonsmokers. SM - Smokers. EX - Ex-smokers. Author, year, Number and country, type of MBC EFR FEV yC M iscellan€wus Comments reference population ~- Chivers, 463 male 1059, employees Cigarettes/day: 64'< England of alkaline 0-5 ....................f97(28) (52). industry 6-20 .................. 89(50) plant. >20 .................. 63 (6) Higg_ ins 773 males E5-34 55-64 et al., in various NS 145 (66) 101 (29) 1959, occupations EX 143 (31) 89 (62) England (25-34 and 1-14 grams (116). 65-64 years .140(193) 87(157) of age). >15 grams .133 (89) 80(136) Height-in-inchea 66•• 68" 70•• 91 (35) 108 (31) 101(21) 88 (75) 101 (112) 109(75) 88.5 (9) 92.6 (9) 113(12) tMean EFR in liters per minute. Regression analysis of data revealed a_ significant re- lationship between smoking and de- creasing function. Wilson 28 male et al., residents_ of 1960 Dallas, U.S.A. Texas, (282)._ former rural dwellers; matched for body surface, age, and height. L. FEV0.75 expressed as mean indirect MBC RV/TLC NS ..... 5.59 (14) NS ....... 21.1 SM..... 84.44 (14) SM .......?27.01 6~)t tI.P:3 7F.1(.0

TABLE A3.-.Suzoking and voatilatorrr f2tuction (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS - Nonsmokers. SM = Smokers. EX - l:x-smokers. Author, year, Number and_ country, type of reference population Fletcher 363 male Mean peak EFR and London NS ........ 670 (30) Tinker, transport 1-14grama 537(166) 1961, employees, >16grams 628(116) England EX ........ 666 (61) MBC EFR FEV Vc Miscellaneous Comments Ashford et al., 4,014 male coal workers FEY1.0 Age: NS SM D_ ata represent results after 1961, at 3 Scottish <21-30 4.09(103) 8.96(280) correction for Scotland collieries. 21-30 .3.86(182) 3.77(666) sitting height. (11). 31-40 . 3.44(138) 3.88(777) SM includes pipe 41-60 .3.04(110) 2.96(766) smoker. 61-60 .2.71(102) 2.56(610) Data on ex-smoker >60 ...2.38 (42) 2.21(237) not included. FE V 1.0 found significant; lower for SM than NS. (85). Franklin 213 male FEV1 0 FEV0 28 FEV0.50 and factory Heavy 2 670 3 011 2 710 ~5Light 8 703 (59) Lowell, workers , Light 12 989 , 72 666 , 32,284 Heavy .. , 1$ 678(104) 1961, 40-60 years , , . , U,S.A. of age. (87). N G ~ O[.)tciS'y7[.!CQ Heavy smoker represents an amount equal to or more_ than 30 pack years. "I

Author, year, Number and country, type of reference population Balchum 1,451 male et al., employees 1962, in U.S.A. California (24). l ight i nd us- t y. Goldsmith 3,311 active et al., or retired 1962, longshore- U.S.A. men. (95). Martt, 1962, U.S,A. (15l). IrS.l".~Jf.4F.O TABLE A3-Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. MBC EFR FEV VC MMEFR NS ....... 15.5 (38) 7.8(19) - Pack/year: <1 ..... 15.0 (257) 8.0 1-9 .... 10.0 (263) 6.0 10-19 . . 10.0 (303) 12.0 20-29 ... 19.0 (236) 24.0 30-39 .., 33.0 (144) 26.0 40-49 ... 38.0 (92) 40.0 50-59 ... 55.0 (29) 45.0 >60 ..... 71.0 (24) 62.0 MEFR FEVi 0 NS ........ 313.63 (260) ._ 2.99 Pipe,cigar 299.26(125) 2.80 EX ....... 295.23 (102) 2.84 Cigarettes/day: --_20 ... .. 309.73 (144) 2.89 20-40 ... 303.44(346) 2.91 ?40 ... . . 307.63 (57) 2.90 Miscellaneous Comments Data for: MMEFR given as percent of individuals with a value of <600 L/M; FEYl.o given as percent of individuals with value of <70 0 percent of expected. Authors concluded that cigarette smoke was found to have a slight effect on pulmonary function. 73 healthy medical per- D~CO Smokers defined NS ..... . . . . 83.10(30) as those smoking sonnel with- SM <5 years .'28.40 (8) >20 cigarettes/ outsignifi- 5-10 years ...,28.20(10) day for varying cant age >10 years ...°24.90(26) periods. difference_ between smokers and nonsmokers. 4W.

C K (.VciSsl4(.o TA111 E , ,. NS ti>t Sm"6, (t',Gl.) r. I•>\ Author, year, country, reference Number and type of MBC EFR population b'RV VC Revotskie 1,130 malc• FEV1.0 et al., and 1,813 Males - Females 1962, temale NS .....0,98 (55) 0.98(25 5 ) U.S.A. residents in Cigarettes/day: _ _ (192). -- Framing- 1-10 .0.97 (90) 0.99 (92) hampar- 10-29 .0.91(163) 0.93(157) ticipating >30 . .0.90 (81) 0.91 (22) in the pro- spective study. - Krumholz et al., 18 physicians MEFR 24-37 years NS ........ 680 (9) 1964, of age. SM . 1590 (9) U.S.A. .. ..... Rest 8wi 20-me ~ical et al„_ students or 1964, graduate U.S.A. physicians. (241). Coatea et al., 1965, U.S.A. (53). MMEFR NS ... 187 (10) 4.34 SM . .'193 (10) 15.09 6.77 15.63 Miscellancrous Mean DL NS SM ......... 36 131 Exercise: 2 minutes ..50 341 4 minutes ..50 148 3 minutes post exercise 39 185 Authors found a significant difference between SM and NS for RV/TLC, compliance, and non-_ elastic resistance. 1,342 male FEV1 p TimedVG~ FEV1.0/VE and 242 Age: NS >25 eip/aay NS >25/day NS - >25/day female post 40-44 12 99(186) 2.85 (69) 3.89 3.85 30.77 0.74 office 45-49 °2.96(170) 2.64 (42) 3.92 3.83 30.74 0.70 employees 60-54 12.76(116) 2.62 (22) 3.71 3,74 10.74 0.70 >40 years 65-59 12.6-4 (64) 2.44 (18) 3.64 3.61 °0.74 0.68 of age. 60-64 12.36 (53) 2.30 (8) 3.30 3.33 10,72 0.70 Comments llata presented in terms of f ratio of observed to predicted values. 3*

TABLE A3. Smokinq and ventilatory function (cont.) (Numbers in parentheses represent total number of individuals als in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV VC refeience population Miscellaneous Comments $uhti, 653 male PEFRt FEV1 0* Forced VC$ Pipe and cigar 1965, and 823 Males Females Malee F emales Males Females smokers not Finland female NS . . . . . .. . . . . .. . . .. . . 569(122) 410009) 3.46 2.42 4.40 3.18 included, (126). residents EX .................... 561(141) 403 (30) 3.39 2.32 4.51 3.19 t Difference of a rural Cigarettes/day: between NS and region in 1-1-4 ............... 618(108) 431 (77) 3.17 2.74 4.40 3.53 >25/day is Finland 15-24 ) 537(191) 3 30))) 51) 4 significant for . ..... .... --- } 493 (7) . } 2 82 . } 8.60 >25 ................. 517 (85) ) 3.081 . 4.261 45-49, 60-64 age groups. # Trend is not statistically significant. Krumholz 20 male et al., medical 1966, students or U.S.A. graduate (142). physicians. Rankin 125 males NS ... 118.1 etal.t withouta SM ...1111.7 1965, past U.S.A. history (189). of respira-y tory disease 2048 years of age. Pulmonary compliance Mean body surface NS SM ... .. .. .. .0.2-41(10) ......... "0.177 (10) CompLtiancc/FRC area for 2 groups was not signifi- cantly different. - - -~ ----------- NS SM - .......... 0.054 ......... 20.042 Smokers are those - with equal to or greater than 5 pack year history. (68) FEV1.0 D~ DL/ NS includes pipe (57) NS ...106.6 NS 31 1 alveolar and cigar smokers SM ........,..1102.7 SM . .... ...'26.9 volume and ex-smokers of 6.22 greater than 1 94.96 pack year. values have D L been corrected for C4Hb.

TAI31i:A;;.r/ t!)L:( 4.-tlt/.tl7;rn'(.ur~ (r'utif.) (Numbers in pzu'.nthi•>cs r p -,cn rt t tal nuiii)" i '4 indi. uli1:' 1., i~ NS - Nunsmokers. S11 9niolts-r... F\ f•a-amul:crc:. Author, year, Number and country, type of MBC reference population 410 male Edelman _ -------- etal., 1966, U.S.A. (73). - community NS ........ 164(162) dwellers Current D0-103 cigarette years of smokers. .°161(118) age. EX ......... 167 (93) Pipe, cigar .. 167 (47) EFA FEV VC hiiscellant us Commenta -- -- Vital cauacity FEV Ex-smokers of 7.89 1 0 2.83 4.93 cigarettes only. 7.36 '2.64 ?4.74 Difference signifi- cant between NS and current 8.09 2.80 4.47 cigarette smokers 8.20 2.91 5.08 at p<0.01. MEFR FEV1.0 FEV1,0fVQ Heavy smoker refers NS ........?10.28 (41) 4.68 =87.6 to greater than Moderate . 10.06 (54) 4.69 85.3 or equal to 1 Heavy .... 9.64 (29) 4.43 83.9 pack years. EX ....... 9.48 (10) 4.74 83.2 Moderate smoker includes pipe and cigar emokers. Difference between NS and heavy smoker is significant. Peters 124 4 male and college age Ferris, students. 1967, U.S.A. (1Bs). Higgins et al., 1968, U.S.A. (118). 926 white ale male residenta NS ........ EX . .. FEV1.0 8.64(160) 8.26(148) of Marion Cigarette SM 3,48 ( 611) 1-14 ....... 3.67 (88) County, West 15-24 ....... 3.67(273) V irginia, >26 ........ . 3.30 (160 ) 20-69 years of age.

TABLE A3.-Slaoking and ven.tilatory function (cont.) -- (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM - Smokers. EX = Ex-smokers. Author, year, country, Number and type of MBC EFR FEV VC Miscellaneous Comments reference population - Sluis- 533 white 85-44 45-54 >55 FEY1 0 1 cigarette - - - Cremer male NS ........ 553(106) 627(101) 444(27) (2_7) 9_5-44 45-54 >65 1 gram. and factory Grams/day: 3.70 3.22 2.76 l ounce tobacco -_ Sichel, workers 1-14 ...... 557 (26) 519 (17) 410 (7) 3.64 3.31 2.24 26 grams. 1968, over 35 15-24 ....... 532 (94) 446 (35) 401(13) 3.66 2.94 2.28 1 cigar = 2 to 5 South years of >25 ........ t528 (66) t494 (31) t380(10) 3.54 3.05 t2.1$ grams. Africa age. t Derived slopes (208). found signifi- cantly different from 0. Stanescu 87 male bus FEY-1 Q Nitrogen gradient et al., drivers; . Younger Ol der Younger Older Younger Older 1968. - - Rumania (212). 27 aged - - - 20-25,60 aged 40-60, all without respiratory symptoms. NS ..... 4,470(14) SM .....'4,500(13) 3,310(40) 13,200(20) 5,125 4,290 15,285 14,290 1,53 11.47 2.49 °3.77 Densen 5,287 male FF:V1 o et al., postal and P-oatal 1969, 7,213 male White Non-white U.S.A, transit NS .................................... 3.29 (685) 3.05 (204) (69). workers in All cigarette ............................ 3.11(2,340) 2.94 (768) New York <25 grams/day ......................... 3.14 (1,292) 2.95 (599) City. ?_25 grams/day ......................... 3.06(1-,038) 2.93 (161) Transit White Non-white FEV expressed as standardized for_ specified postal ------ and transit workers at age 45 and at sitting height of 35 inches. Includes mixed NS .................................... ----- 3.3,9 (620) - - - 3.08 (298) - - smokers. Allcigarette ............................ 3.11(2,941) 2,99(1,041) <25 grams/day ......................... 3.15(1,929) 3.00 (891) ?25 grams/day ........................... 3.02 (1,011) 2.95 (149) ~'E'i2%V:3 9l~~Q

9G~:S91,C0 Author, year, Number and country, type of MBC reference population TAB1.E A3. Siuceking ttxr,cd ventilrttui-y Javctinlz (cotit.) (Numbers in parentheses represent total number of individuals in particular smoking group) - - ~ - - - --------- -- Ex-smokers. NS = Nonsmokers. SM - Smokers. 1•,x-smokers. EFR FEV VC Miscellaneous Comments Rankin et al., 60 male and 10 NS FEY1 0 ..............497,6 (12) FEV expressed as percent of 1969, female SM .............. 78.4 (68) predicted value Australia (190). patients with chronic -- for age, sex, - and height. alcoholism 26-66 years of age. Wilhelmsen et al., 1969, Sweden (231). 313 male residents of Gbteburg 50-54 years of age. PEFR NS ........................... 525(88) EX ........................... 63.9(67) 1-1-4 grams/day ................ 521(94) >15 grams/day ................ 492(64) FEV1 0 VC 3.77 4.83 3.69 4.77 3.62 4.83 3.39 4.56 1963 values only. Lefcoe 310 male MMFR FEV 1 0 MMFR has been and physicians NS ....... 4.09 (88) 3.39 standardized for Wonna- cott, of London, Ontario. Cigarette smokers. 3.64(101) 3.11 age and height. 1970, EX ....... 3.99 (61) 3.38 Canada Pipe, cigar 4.17 (33) 3.17 f

TABLE A3.-Smoking and ventiEatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) Author, year, country, reference Lundman. 37 MZ and 1966, 62 DZ twin Sweden pairs selected (159). from Swedish Twin-Pair Registry. NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. FEY Miscellaneous Comments FEVI,O N2 washout gradient MZ = monozygotic. Significant differences Significant differences DZ = dizygotic. between smoking discordant between smoking dis- The author concludes that the degree of ventilation as measured by P7Z h FEV i i f d f i cordant twin airs e on. T washout was correlated with cigarette consumpt 1.0 n pa rs oun or: tw Group A MZ males 1 p _ found for: was significantly lower for smokers and there was a correlation . and females. Group B DZ males. with cigarette consumption. Explanation of analyses for respiratory symptom prevalence: 2. Group B DZ males. Group A analysis-using each firstborn twin as one group in an 3. Group A DZ males. unmatched relationship to each secondborn twin. Group B analysis-using each twin set as matched pair. All comparisons in Group A and B are between smoking-discor- dant pairs. -- - - - 3 Not significant (difference or trend). - = p<0.05 ° p<0.01 ' p<0.005 6 p<0.001 .+i..'i`'.:' . -

s. g~~.9 9ZIeo . .. __ _-, . .. . .• . TAI3I_l; A4.__._(a( •.. .... •.: . ..•r., ~. . . e)S.Iltt'I/ uf fi~TtEU N>tcd CeE ~r[~i(~ :; < - . .r:. .. . . • . ,.. ~ :... ... ~ .•. ,... ..w - _ 1. _ _ l1~~~ F~ .r . .:~ ':rh~.~~Ufr/ (7r~~( i r<:lilufuf~J ~[(Ilt'ItnlL Symbol - . __ . Term --- -- Volume or rate - - - - _.--- Ilefinition ~ -- -- MBC .... . . . . • Maximal breathing Liters .......................... --- -... __ The maximal vulumc of gas that can be breathed in one minute. capacity. M V V..... .... M a x imal voluntary ventilation. EFR...... ... Expiratory flow rate ......... ... Liters/minute_ .................. _ _ _ __ ~~ Rate of flow for a specified portion of a forced expiration (MMEFR-rate PEFR.... .... Peak expiratory flow rate. of flow measured for middle half of FVC). - MEFR.... .... Maximal expiratory flow rate. - •. ~ MMEFR. . .. ..Maximal midexpiratory flow rate. FE$t..... ... Forcedexpiratory Liters .......................... Volume expired within a specified time interval. (FEVlo- Yolume expir e d volume. _ _ _ _ in first second of expiration. ) - ~-~ ~ - VC....... .... Vitalcapacity............... - ---- ... Liters .......................... -- - Maximal volume of a gas that can be expelled from the lungs by forceful FVC .... .. . .. Forced vital cagacity. . _ ~- . ...... .... .... .. . . .. .. . .. effort following a maximal expiration. FEVt/VC. - ... Forced expiratory Percent ........................ . . . . - - Volume of forced expiration (in time specified) related to vital capacity. ~ ------- -----. _ . . ... .. ~~ volume/vital capacity. - DL. ... •... .. , Pulmonary diffusing ml/min/mmHg The ability of a chosen gas to pass from the alveolus to within the pulmonary ~ capacity. capillary. - - --~---- -- --___ .. . .. .. -. N2 washout... Nitrogen washout - Exponential The stepwise pulmonary alveolar clearance of a gas. (Slope of curve depends gradient. curve. upon the uniformity and adequacy of ventilation of all parts of the lung.) It may be done as a single-or multiple-breath procedure. Compliance .................... Liters/CMH.O ... .. .. .. , , , , , , , , , - - Volume change of the lung produced by a unit pressure change. RV ........... Residual volume ................ Liters .. . . . . . . . . . . , , . , . . . . . . , , . , Volume of gas remaining in the lungs at the end of a maximal expiration. TLC....... .. .Totallung capacity ........... .. Liters ..................,,.,, Volume of gas contained in the lungs at the end of a maximal inspiration. FRC....... ... Functionalresidual Liters .......................... Volume of gas remaining in the lungs at the resting expiratory level. capacity. Aleveolar volume ............. .. Liters .. . . . . . . . . . . . . . , . , . , . , , , , , Volume of gas contained in pulmonary alveoli. ~ SOURCE: Comroe, J. et al. (56) ,

TABLE A6.-Epidemiological studies concerning the relationship of'air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD). Author, year, Number andI type country, of population Results reference. Higgins, 301 males and Male data only (170) : 1957;, 280 females (a) The frequency of' recurrent chest illnesses was high- Englandi living in 2 er in the more polluted region but the prevalence of'. (112). separate other respiratory symptoms and mean valueswere, . districts:. similar., (45-64 years (b) Significant difference observed in COPD mortality of 'age. ) ~ rate. Collegee of 787 males and I (a) Male urban, inhabitants; manifested almost' twice the Generali 782'females prevalence of' chronic bronchitis as rural'; males; this PYacti- 45-6':4years of , differencee could not! be explainedd on thebasise of tioners, age from, smoking.g habits. 1961" medical doctors' (b) No significant urban/rural differences noted for England, case lists. PEFR.1 (55). Schoettlin, 2,6221males (a) No positive correlation found between chronic respira- 1962, 45-75'years tory illnessi and city size. U',S.A. ofage: (b) A positive correlation was found between chronic res- (204). piratory illness and cigarette smoking, (particularly du- ration). (e) No significant'urban/ruralldifferences noted for COPD sympt'oms among females. Ferris.and Anderson, 1,219~males and females living Fo)lowing.g adjustment forr differences in smokingFialiits;.no significant differences in chronic bronchitis were,observed 1962;, U:S1A. (8'1). in 3 different areas of a New Hampshire: town. among.g the 3 pollution areas. 1lfork, 1962;, 339 male trapsport employeesfrom~ Theexcess.p.revalenceof'.serious.respiratorysymptoms.(dy- spnea„ wheezing) and PEFRR dysfunction amongLondon U.S.A. London and Txansportt employees wass only partly eliminated after, 071~.):.~. Norway:~. standardization for smoking, and, the author suggests thatt this is due to d:ifferencesins air pollution levels.. Anderson778residents~.of' et al., Berlin, N.H., and. 1965, 918, residents of' Canada Chilliwack, (8). Canadai Berlin, New Hampshire, has higher S02 and particulate air pollution~levels and'.thed higher respiratorydisease, preva- lence rates among its residents were, not accounted for by age differences;; butt were accountedd forr after stan- dardization f'orsmokinghabits. (exceptt tiiat. PEFR, and. FEV1.0 dysfunction was more prevalent in New Hamp• shire; and the authors suggest that this difference re; flects; air pollutioni differences).. Holland 676 male transport, (a) London employees manifested a greater prevalence of' and Reid1. employees' in Londowand rural COPD' symptoms and PEFR: dy!sfunction than did the rurall employees. 1965, England: (b) Smoking habit differences alone were not suf8cient' to Ehgland explain this difference in COPD manifestatione. (1.24). (c) Both groups manifested pulmonary dysfunction, cor- related withAobacco consumption.. Bates 2161hospitalized' Winnipeg (cleanest, of' all areas in SOz and industrial' et al., veterans~.fromdustfall)m residents manifested decreased' prevalence of 1966, Canada (2Y). variousareasofs Canada. (all standardizedfor, chest' illnesses,, les,s severee gradess of:f dyspnea, and less sputum~ volumee produced wheneompared', toresident'so of' all other areas. age, tobacco consumption, and occupation).. 216

TABLE r1:6. Epidemiolog£aal studies concerning the relationship of air pollution, social, class, an'd' smoki'ngto chronic ob'structivee bronchopulmonary disease (COPD) (c'ont:), Author, year, Number and country; type of' Results reference population Ashley, Standardized Positive correlations: 1569, , mort'ality (ia) Smoke concentration and' bronchitis mortality. England ratios for (b): SO2and2 smokee concentr.ation and, bronchitis~ mor+ (12). males.(4956-63)tality and.sociald class,. for:53'b'oroughs (c) Pollution, and social, class:. with air pollution . indexes. }folla:nd 1:0,971.childrenFactorsaffectingprevalence of: respiratorysymptoms'.::y et, ai.,, over.11years~.of' 1369, age in4 areas: England' ( te2). (a) Smoking-highly significantt association. (b) Area of'residence (pollution) -significant association exceptt for periods of cough and phlegmlasting more. than 3 weeks. (c)', Social elass, age, sex-no association noted. tPinkelstein842females. (a) The.inereasedprevalence.of'respirat'orysymptoms:could and over 25.yearsof' nott bee explainedd by s~ociall class differences. Kant,~r, ageim.various. (b): 1+Fo.overall associationn noted between prod.uctiti7ee cough, lt-d9, regions.of's andl air pollution. I:.S'. A, Buffalo:. C.ooley and 10;887 child}•en Illnesses considered included chronic cough, past bronchitis, Beidl6'-10iyears:of. lilocked nose; 1b7i!, age:from con« (a) Every~ geographicc area: showed w clear gradientoft in-, F'sngland trcastingurbang creasing illness prevalence with~ deereasingsocialg class.. (53). and rural areas. (ib) Social classes 1, Ih andl III showed no urban/rural gradient while IV and V showed a clear excess in fre- quency of chest, illnesses among urban residents overr rural residents: llam 6ert . 9:,9:755 males and (a) The trend of increasing prevalence of' bronchitic' symp- and females toms from rural to urban respondents was not negated Reid., responding by adjustment for smoking differences. 1'.)-0. toques~tionnaireEngland, survey. ('Iti@)., (b). After adjustment for age, andl smokingg habits, malee respondents manifested a clear correlation of' persistentt cough, and phlegm prevalence with increasing air pollu-tion. Correlation.was.nokas strikingin females. (c) Although the proportionate rise in symptom preva- lencee increased, with air pollutionn similarly inn each smok.ing, group, the absolutedifferencese inn morbidity risk in.creased with, increasedcigaretted consumption, suggestingsynergistic influencess of' cigarettee smokingg and airr pollu+ tion. (d) In the absenceof' cigarettee smoking, theeorrelatian~ between the prevalence of' persistent cough and phlegm and air pollution was slight:, I See Glossary of' Terms: Bron chop ul monary table A41 21'x

7,'AB>rEA7~.-Epi'ilemiol'oyicadstuclies~concern'ing'tdter~eZtc~tionship ~of~occuyat~ional'~ exposure and smoking to chronic obstructiue' broncJtopulliaonary disease Author, year, Number and' country, type of: Results reference population Higgins 185 males Miners showed increased' symptom prevalence (breathless- eta1J, (8!4nonminers;ness, cough, sputum). 1956, 101 miners) Miners showed increased prevalence of' chronic bronchitis. England withoutpneumo- Miners showed decreased MBC.1 (i11A). coniasis: Differences in smoking, between, the two groups did not ac t count for.above.differences. Phillips 1,274.males None ofthe-industrial environments wereassociated' with, et al.,, factory employeess an inereased. prevalence of chronicc cough. 1956, . (cokeand e Cigarette smokingandg ageweredirectlycorrelatede with U.S.A. electrolytic', increased prevalence of' chronic, cough. (185). process). Higgins 325~~males.25-34~ Miners~s as~.compared'.to~s workers~.in.non-dusty~occupations:: et al., yearsofiage:and~~ 25-34~4 year.s~of's age-significantly~increased prevalence~.of'~ 1959, 4011 males~:55'-64~~. ehronicc bronchitis and. MBCC abnormalities. England years~~of~.age~.in~ 55-64.years of age-less significantly~increased.prevalpnce. (116). various occupa- of' chronic bronchitis and' M'BC' abnormalities than in tions; 25-34 years~ of'age: group, No smoking information available. Chivers, 463 3 males in No significant differences in PEFR 1 between dusty and 1959;; non-dusty andI non-dusty groups. England dusty oecupations, Cigarette, smoking (iespecially in those >40 years of age) (lime and soda was associated with decreased PEFR values: ash exposure). Higgins and Cochrane, 1961, England 300 male miners andl3~.00.male. nonminers 35-64' years of age. M'iners showed'' increased' prevalence of' symptoms and d1: creased MBC.values whichh remained even after standard- ization for smoking habits. Totall dust exposure was not directly correlated with these findings.. Wit^esofminers.showed similar symptom.and testl changees ass comparedd withwivesh of'f nonminers:, Brinkman and Coates;, 1.,317males40-6;5 years of age withvar~ious Increasedd silica.exposurewas associated with an increasedl prevalence of: chronic bronchitis. Highestt prevalenceof.ehronic bronchitis was.notedin.the. 1962;, silica~exposurenon.exposed group; and', this group was noted to have. U.S:A., histories. the highest number of'smokers and highest: consumption. / (42). Hyatt 267'male miners: I Increased' history of' underground work was associated with etal.,t and ex-minersanincreaseds bronchopuhnonaryy symptom prevalencee and! 1964,. 4'5-55~years decreased pulmonary function valttes.U.S:A,, of age:Theimpairmente of pulmonaryfunction, associated with (1,f8y. underground workwask separatefrom effect of'smoking; but smoking and underground work did show additive effects: Elwood 2;5'28 male and Prepardng, room workers who manifested byssinosis symp• et'.al., femalefiaxe tomsalsosliowed an increased prevalpncee of'f chronic 1965', workers over.35 bronchitis ; independent of age or smoking: whenn compared Ireland years~.ofage:. with non-preparing room workers. (77)... Female wor~kers~s manifested & significant association be- tween byssinosis symptoms andi smoking, while male work- ers didl not. Sluis+Cremer~~ 827,miners and. Those~~e smokers~s exposed~d to~ goldd minee dusti manifested more~e et ai~.,, nonminers over symptoms ~~. of ~. COPD:3 than: did non•dusti exposed'~ smokers, ~. 1967, ~35 years~~ of'agef while~e prevalence ~ of' symptoms, among nonsmokers,, was l . South Africa~ similar~for the.two~ groups. (20.9). 218' I i

0 0 TABLEA,7 . Epidem.iologiaal strudz.'esc'orncerniny, therel'ationshiP of'oc'cupationalexposure and'smokiny, to clironic obstructive bronchopulmonary disease (cont.), Author, year, Number and' gesulte country, type ~of reference population Sluis-Cre,mer 827 mineis~.and et al~., 1967, nonminers~s over~ Snuth Africa 35 ~years~ of age. (i:pa9. ('pont.): The dose relationship of cigarettes and COPD i symptoms was much more noticeable among those expased, to dust. The authorsstresseds the synergisticactionsc of' cigarette' smoking and dbst:exposure. Bouhuy.s~ et:al., 455: male catton Those, . exposedto~ dust manif'ested asignificantly greaterr textile workersprevalence: off byssinosiss symptoms than nonexposed. 1IJ69, UiS:.A. 1,39). (21.4.exposedto dust.inmarding and spinning rooms, 241.not exposed)., Smokers manifestedd asignificantlygreaterprevalencea of byssinosis symptomsthan: nonsmokers: No significant differences in Monday morning FEW values'; weree observed.betweensmokersandd nonsmokers. Prevalence of byssinosis symptoms: did not show any re- lationship tolengthofl employment.. llouhuys et,al., 1rjfi9, U.SIA. (JS).. 216 malee hemp workers and 247 workers in other industries in same region, Hemp workers(especially, thee olderr ones)) were noted too have different,smoking habits from control group-fewer heavy smokers; more lightl smokers, more ex-smokers due to doctor's orders. Aged 20-49 - a., No difference in FEV 1 .l values between 20-f>9 ~y e~ars of: . age.. controls andl hemp workers in any smok- ingcategory,g b. No difference in FEVi,I values between men in different smoking categories.. Aged:5U•-6'9I-a: Hemp workers manifested decreased FEV1 o values in all smoking groups except f'or heaviest smokers: Ex-smok-, ers~s had lowes.t. FEVi0 p. values. b. Thosee smoking most: had lower FEV1'.avalues as.compared with light and non-smokers. The authors ; conclitde that: There appears to be no, synergism between smoking and hemp exposure asss too effect onFEV'1L0 although the selection process whereby those with~ symptoms~ have, aa greater tendency to stop smoking, may obscure such~ a relationship. Chester et al., 1969, U.S,A. (49)'. 139 male chlordne: plant, workers~s (55 ' with,historyy of'.severe ex- posure).., Chlorine-exposed group manifestedl no difference in symp- toms andd aa decreased MBCC value whew compared with~ non-exposed: group. Sinokers, in chlorine-ex posed group had significantl,yy de- creased. MBCC and: FEV values as compared with non- smokers in non-exposedl group. Greenberg 121 workersin Sensitize~d'd groupp manifestedd lower~ FEV1.0/FVCI' values et,al.,, 1ff70 washing powder factory(4&found as compared with nonsensitized,group even' aftersmok+ r ing.habit5, were cont'rolledfor. Englandl tobesensitized (97). to product,. 73 nat). Tokuhata: 801 . male miners~~s et al., 1970, U.S.A. (218). Inereased mine exposure was associat'edI with residual vol- umeand. FEVabnormalitiesV even~ afterr adj,ustments's for age and smoking. A systematic: exposure-impairment relationship was notedd onlyamongy smokers while relatively few nonsmokers showed. COPD impairmentl_. Smoking miners manifested more X-ray alterations and COPD symptoms thann nonsmokers, , regardless~ of'f num- ber of years~of underground.exposure. ' See~Glussany of'. Terms in~ Beonchopulmonary~ table~A4.~ 219' V

TABLE A1IQ!-Experinlent's concerning the efj'ect of'the' chronic'inhalation of NO'Z, upon the tracheobronchial tree and pulmonary Parenchyma of animals Author, year, country„ reference Animall Results Freeman Sprague-Dawley 25 P.p.mr.: and rats. (a) after 37-41 days-moderate hypertrophy, and: hyper-, Haydon, plasia,ofbronchialland' bronchiolar epithelium: 1964 (b Y after 146'-1b7, days-(1i): Advanced hypertrophy and U'.S:A. hyperplasia of bronchial and (9'0). bronchiolar epithelium. (2): Increased lung'volume. (3) Proliferation of connective tissue. Haydon Sprague-Dawley 12.5' p.p.m. to death: et'al., rats. (a): Hypertrophy and' occasional metaplAsia of bronchial 196.5and5 bronchiolar epithelium.. U.S.A. (b): Increase in number of'actively secreting goblet eells: (107,).., Haydon etlal., 196'.7 U.S.A. A'lbino ~rabbits, 8-12 p:.p.m, for 4 months: (a) Abnormal dilatation of' peripheral air spaces. (b)~ Decreasedd densit'yof alveolar walls. (c) Hypertrophy and hyperplasia of bronehiallepishelium. (106), (d) (e) (f) (especially terminal bronchiolar). Increase in.size of alveolar ducts. Increased elastic tissue staining. Increasedl alveolar size. Fteemani Sprague-Dawley 0.8' p:p.m.-2~p:p.m, for entire lifespanc et al., rats. (a) Alveolar distention. 1968, (b) Reduction in number of cilia. UlS'.A, (c) Epitheliall inactivity ("dormancy"). (91). Fi-eeman, et al., 1968" U'.S,A. (89). Sprague-Dawley rat's., 1',8 p.p.m. (a) 5' days-terminal bronchiolar epithelial hypertrophy. (b) 4 weeks-(1) Widespread bronchiolar epithelial hy- pertrophy. (2) Non-nec:rotizing emphysema. Blair Female Swiss 0.5 p.p.m.: et', al., Albino mice. (a) 6' hours/day for 3' months-pneumonitis., 1969, (b ) 24'hours/day for 31 months- (1) Respiratory bronchi, U.S.A. olar obstruction, ($2). (2) Ali eolar expansion and bronchiolar inflammation con- sistent with early focal emphysema.. Kleinerman, Male Syrian Goldew 1970~ hamsters.. U.SlA. (176).. 220 100 R:p:m. for Vy2 hours: (a) thymidine autoradiography-intense burst of' prolif, eration of epithelium returning to normal in 4 days (more persistent distally). (b) elec'tron mic'roscope -(1) Decreased' number of se- cretory cells + seeretory' granules, (2) Increased number of l,ysol somal structures. (3) No change in number of ciliated eells: .. 4ry~-.~ *V'' ~ f

TABLE'A13. Experiments, concerning the effect of cigarette smoke or its constituents upon ciliary function Author, year, country, reference Mendenhall and Shreeve, 19376 U.S.A. (:u.a). System Method l Results Iinv.itro: Cigarette smoke Controls-ciliary activity dEpre ssed approxi-, Calf trachea. by direct appli, mately 4: percentL cation or in Experimental-ciliary activity depressed ap- solution. proximatelY40 , percent. Rakieten In vitro: I. Nicotine iw I. Ciliary activity depressed only upon ex- etal., (a) rabbit Locke-Ringers posure to 100 mg. percent solution. 1942, and;rat solution. II. Ciliary activity depressed after15-20min- U:S:A. trachael I L Cigarette smoke utes exposure depending on concentration (188~). rings. iwsolution: ofsmoke in solution. (b) human, nasal mucous membrane Kordik Iiuvitro: Nicotine in Locke's Nicotine at 10-5 g;/ec had no eEiect on ciliary et al., Rabbit solhtion. activity. 1952. . ttacheal England' Hilding„ 1956, U.S.A. (120). Iie2iitrot Cigarettesmoke Cow trachea (direct' exposure ) . Krueger liuriao! and Rabbit Smith, trachea 1953. U.S.A. ( 194). Dalhamn, 1>eriz•o: 1959, .I. Rat Sweden ti-achea (59). lixvitro: H. Rabbit trachea III. Human ciliated mucosa A7ltracheas showed depressed or absent ciliary activity. Cigarette smoke. Cigarette smoke decreased ciliary activity by approximately 200 beat5/minute: Cigarette smoke. I. 7/10 showed cessation of ciliary activity after one exposure. H. 6/10 showedi cessation of ciliary activity afteroneexposure: HI. 6/7 showed cessation of ciliary activity after one cigarette exposure. Falk Invitro: Cigaret,tesmoke: Decreased ciliary activitynoted on exposureto etalJ, Rat and rabbit cigarette smoke: 1959 traeheal (a) Repetitive exposure wasassociated with U.S.A. epithelium. persistence of response over longer periods (80). of time. (b): "Tar"-rich cigarette wasmoreinhibitory than "tar"=poor: (ic): Filtered smoke was~~. lpss inhibitory than unfiltered. Ballenger, In vitro: Cigarettesmoke Ciliary activitywas fully inhibitedl within 5-28 1960, Human in soltrtion. minutes of exposure depending upon concen- U:S..1. bronchial tration of smoke in solution. (25). andltracheal epithelium obtained during anesthesia. 4-lzsr.c.-„u: 221 1

TABLE A1'3.-Experiments concerning the effect of cxgarette smoke or its constituents upon ciliary' function (cont.) Author, year, country. System Method 1 Results'; reference Wynder In viva: Cigarette smoke; Unfiltered' cigarette smoke-ci]iastasis by 2nd- et al., Fresh water and its fractions 5th puff. 1963', mussel in solution. Acid (phenolic)' fraction solution-immediate UiS'.A, ciliated ciliastasis: (236). epithelium. Whole extract fraction solution-no cillastasis. Neutralf'ractBon: so)ution-nociliastasis; 1 percent phenol' solution.-immediate ciliasta- sisl Dalhamn In,vivo: Cigarette smoke. Unfiltered cigarettes--ciliastasia im 3/6 cats and. Cat trachea: after 55 cigarettes. Rylander; Filtered cigarettes-no ciliastasis after 8 ciga- 1964;, rettes (5 cat's)i. Sweden. Controls:-noo ciliastasis. (5'5 cata)~.(ss). Ballenger Ih,vitro: Nicotine in,aolution. Initial stimulation of activity, f'ollowed' by de- et al., Human cline and complete ciliastasis after' 12-24 1965, ciliated hours' of exposure. U:S.A., tracheal (S6')) epithelium obtained during. anesthesia. Dalhamn In vivo: Cigarette smoke. The longer the time interval between expo- and Cat trachea: sures, the more puffs were required to cause Rylandhr, ciliastasis. 1965, Sweden (62). Wynder In viuo: Various compounds Formie, ac:etic, propionic, benzoic acids all et:al., Fresh water in solution. more ciliatoxic than phenol. 1965, mussel', Oxalic acid less ciliatoxic than, phenol: U.S.A. ciliated Formaldehyde, acrolein: more ciliatoxic than (235). epithelium phenoL Carson In vivo: Cigarettesmoke: Percent decrease in ciliary activity et.al., Catt~rachea~. Control ................................. 0~ 1966, Unfiltered' smoke......................... 53'. U.S.A. Cellulose acetate filter ................... 45 (44). Carbon cellulose acetate filter. ......,..... 30 Dalhamn, In,.vivo:. Cigarette smoke. 1966, Cat trachea. Sweden (iso). Kensler bi.viuo: Cigarette smoke and, Rabbit'~ and components. Battista,, traehea,, in.Tyrode's1966„ cat.trachea,, solution. U.S;A. dog trachea, (18'S'):. monkey ttachea+ rat trachea. 222 Mean number of' puffs required' to produce cfliaat%aia No filter ..........................,....... 911 Charcoal,filter ........................... 170. Cbmmeroiali cellulase acetate filter ........ 194' Charcoal.and.acetate filter .............. ...... 5121 Cambridge filter ........................ 600 Rabbit trachea-Total smoke condensate of 3 cigarettes,, gass phase condensatee of 7 ciga- rettes caused similarr ciliastasis. Other spec'ies-A11 found' sensitive, to ciliastatic components of cigarette smoke: Bulkof'k ac-tivity noted in gas phase (HCH, formalde, hyde, acrolein). Lll

w TABLE A13.-Experiments concerning the effect of' cigaret'te smoke or itss constituent's upon ciliary function (cont.) Author., y-ra rl country, ref'erencr. System ]Vfethod'' Results Dalhamn. In riro: Cellulose:acetate- Increasedlamounts of'tar were associated with and. Catt traciiea. filter.cigarette:s decreasedlnumber of puffs required to inhibitl Ity lander, with varying. ciliary activity. 1'96:.: amounts.of Sweden "tarr' but.simi- ( s,t'). lar gas phases. Ualhamn Inn rivo:. Unfiltered and and Cat trachea. Cambridge-filter Ilylander, cigarettes:. 196®,, Sweden (610. Whole smoke found to be markedly' more toxic to ailiary, activity than volatile (gas) phasee at lower doaages (puff volume)':. This differn. ence diminishes with increasing,p,uff'volume. In vivo: Whole and filteredd ct ai., Cat trachea. cigarette smoke, 1:i6`?, exposed or unex- U..S. a, posed.to."wet. (4.i:t ) . chamber^made" to stimulate ! oral mucoaa and saliva. Wet: chamberr adsorption~ significantl$!' reduced the ciliastatic activity ofl whole smoke, but' did not: affect the ciliastatic activity of smoke previously filteredl by Cambridge or charcoal filters, k,rahl Lm oiv:o:' Cigarette smoke Significant ailiastasis; re:ver:sible. nnd~. Common~ dissolvedlin liulinash, mollusk ~. sea water... 12':69~, ciliat'edl U!S~.a.. epithelium. '. (138). liattlsta, Ln.nitro: Cigarettesmoke.e and: Chicken orHCN'in kensler, trach'ealTyrode's~ I~) G), epithelium. soiution, ti.S.A. The authors observed that:. (1) The more diluted' smoke required more puffs too cause.ciliastasis:. (2) Activatedl charcoal filteredsmokewasd less ciliastatic.thancelluloseacetate filtered smoke and also contained less: HCN' and acralein„ (3) HCN alone was ciliastatic but recovery was more rapid than after cigarette smoke alone. Theyconclude.that the.gase phase.components are more related'tociliastasis (as: particulate matter is not:significantly decreased by char• eoal filtration while HCN andl acrolein are). Battista ln.uiv!o: Cigarette~smokee The authors observed that: andl Hen~traehea. (1) Whole smoke acutely depressedl ciliary Kensler, activityin.y d-6'6 puffs. 19i0;, (2) Gas phase was only slightlyy less dHpres- U'. S. A',. sant than whole smoke. (3) Chronic exposure (1 cigarettelday' for 32' days) to smoke resulted in no apparent permanent': defect, in ciliary activity (al- though mucous productiarn was signifi- cantly increased). 223: . C W ~ ~ ~ ~ . .. ••... i. ~ 4'. ~.

TABLE A13..-1yxperinaen,ts concerning the effect of cigarette smoke or it'a constituents upon ciliary function (cont.) Author,, year, country, System blethod' Results refe~renee, Dalhamn In,vivo: Unfiltered cigarette Average number of puffs required'to arrest and Cattt"acheat and cigar smoke. ciliary actiuity Rylander, Cigarette smoke ....... 73) (p~0:01'). 1970, Cigar smoke .......... 11'41?. Sweden The authors note that cigar smoke is of a (6.S).- different pH~ and that it contains more iso- prene, acetone, toluene, and acetonitrile. Kennedi+Invivo: I4lainstream~ Electron microscopic observations: and Protozoan cigarettesmoke. (1) After 7 minutes exposure-alterationofElliott,. (iciliated).. mitoehondriall structure:19I70, (2) After 42minutav exposure-destructiom U.S.A. of' internal' mit'ochondrial membrane strue- (1By). ture. (8) Cas, phase alone, while ciliatoxic, did cause mitochandrial swelling but no dis- ruption of' membrane st'ructure,. l Unless otherwise stated, method entailed the direct observation of ciliary activity using markers. 224

N N N TABLE A14.-h'xgtcr-inlsTits eolteprttitty tflo• etf,rt of titfrtrefte srnoJ;" (.rr f,xAloi..uarir ."i I I I.irit ~tri, t .sur/ttcf h nr;iou Author, year, countiy. reference System Method }tesults Miller and Rat lung extracts C_igaret.tesmoke: (1) Exposure to cigarette smoke was associuted with decTiascd surf.tce tension in lung extract. Bondurant, ----- (1) Applied to (2) Surface tension of rats (lung extracts) exposed to'cigarette smoke was decrcn9ed 1962, U.S.A. (165) extract. (2) ) Exposure of rats. as cnmpared with those not exposed. Cook and Webb 40 subjects undergoing bronchoscopy: Surface tension values of surfactant 1966, 14 normal 20 100 Stability index (reflects $ Values significantly U.S.A. (57) 7 nonsmokers with pulmonary disease percent percent area area eurfdctant activity) different from values of normals 19 smokers with and - Normal .......... 6.5 60.0 1.61 at pG0.02 level. without pulmonary disease. Pulmonary patients ...... t17.0 #60.0 1.00 Chronic smokers .. 16.7 51.0 1.04 Giammona In vitro: Exposed to Inn vitro: 1967, Surfactant material cigarette Exposure to cigarette smoke was associated with a significant decrease in maximal surface U.S.A. induced from dogs smoke for tension. (94) and rats. 3 hours/day In vivo: In vivo: for up to Dogs and cats (exposed for 1 week)-no significant change. Dogs, cats, and 3 weeks. Guinea pigs (exposed for 3 weeks) -significant decrease in maximal surface tension. guinea pigs. Webb, Bronchial Direct et al. washing, exposure to 1967, from cigarette smoke. U.S.A. dog lungs. (224). Surface tension values of eurfactant 20 percent 100 percent Number area area Stability index Control ........ 11 7.1) 60.7, y (p<11.002 ) (pG0.00$) 1.60 Smoke ......... 10 18.7) 46.8)) 0.84

N N P so,.~s41co TABLE A15.-Studies concerning the relationship of smoking to infectious re_spiratory disease in humans (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country, type of -- collection Results Comments reference populatfon Mills, 118 1_8 male and 1950, female patients U.S.A. with pneumonia_ (167). and 472 healthy individuals from "random" sample. Lowe, 620 male and 1956, 185 female England tuberculosis (157). patients and 419 male and 249 female control outpatients. Dowling, Individuala et al.,- exposed to 1957. "infectious U.S.A. cold agent" (72). and placebo. Hoapital Interview. Caaea Mean age .............................. 49.6 NS ............................. ..... 15.25 Cigarettes only .......................... 63.56 Mixed . ................................ 21.19 ..... Controls 49.6 25.21 62.33 22.46_ Interview by Malea Females trained Cases Controls Cases Controla social NS ..................... 2.6 8.1 37.3 61.4 worker. Cigarettes/day: 1-9 ...... 9.2 12.9 20.5 25.7 10-19 ............... 38.1 35.6 30.8 0.8 2_ 0.6 20-29 ............... 29.4 27.4 30-39 .... 11.3 9.3~ 11.4 _2._4_ >40 ... .... 9.4 6.7 The author stated that there was a significant difference in tobacco usage between the two groups. Cigarette smokers include pipe smokers. The author noted a significant nt deflciency oirnon- and light smokers and an exc.esa of heavy smokers among the cases Interview and Exposed to placebo Exposed to infectious agent No statistically medical Percent Percent significant examination. developin p_ developing differences_ Number "cold" Number cold" noted. NS ................. SM ................. 111 10 78 14 328 34 249 35

(Actual number of cases shown in parentheses) SM - Smokers NS = Nonsmokers Author, year, Number and Data country, type of collection Reaults Comments reference population. OT,,SW4C0 Boake, Parents of Interview Number of No statistically - 1958, 59 families. Pereon- reaPiratory Iltneaeeaf sienificant U.S.A. years illnesses peraon-yeara differences (33). NS ......................... _.(24) 120 624 5.2 noted. Cigarettes/day: 1-10 ......... (19) 99 529 5.3 11-20 ...................(26) 108 486 4.6 >20 ...................... (19) 99 424 4.3 Pipe, cigar .................. (14) 72 304 4.2 Shah Tuberculosis Survey, X-ray, Tuberculous NormaL or t Numbers in et al., institute and by 1-ray nontuberculoue parentheses 1959, employees. interview. NS ........................ t10 (19.7) 178 (168.3) representfigures India SM ........................ 36 (26.3) 215 (224.7) "expected"bYuseof (205). 2 x 2 contingency table. Tuberculous employees were found to have significantly fewer nonsmokers and more smokers. W N V TABL>; A1b.-St2tdiQs concerning the relationship of slllolcrllg to iaicrtimts respiratorlt disecise in F1r11rln>ls (ennt.)

9 ® N ~ a T=~!994eo TABLE A15.--Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM - Smokers NS = Nonsmokers A__ uthor, year, Number and country; type of Data reference population collection Brown 306 male and at al., female 1961, tuberculosis Australia clinic (4). patients, 221 male and female outpatients. Interview Haynes 191 male Interview et al., prep school 1966, students. U.S.A. (108). Parnell 47 smoking- Interview et al., nonsmoker pairs and health 1966 of student nurses service Canada matched for age resords. (181), and parents' occupational class. Results Smoking habits prior to diagnosis Tuberculous patients .( percent ) NS ................................ Cigarettes/day: 1-9 ................. --- 10-19 .............. .............. 20-29 .......................... 30-39 .......................... >40 ............................. Pipes .......................... Controls (percent) 19.9 15.4 19.6 2_6.8 5.4 9.1 4.6 Average number of respiratory illnessesfl0 students (adjusted for age) All severe lower All All aevere or combined - respiratory respiratory_ respiratory episodes episodes episodes NS (99) .................. 11.1 1.6 0.36 SM (92) .................. 20.2 6.7 3.34 Median number of illnesses/student All All respiratory other diecaaest illnesses NS (47) ................... 2.08 2.99 SM (47) ................... 2.54 5.00 Comments Data presented only on Queensland sample. The authors noted that the significant difference between the patients and cuntrols was not present when the groups were matched for alcohol intake. The he authors noted that these e_r_ e differences were statistically significant. t Particularly tracheitis, bronchitis, and pneumonia.

01 HI q N N TAE_t[.E A15.-Studies cencez'nittq the xclratiwusGitl of sRrio),iug to irpfc•ctiuu,, rrspir,ilo rtl rll l,amrtrts (Actual numl er ~j ca- ,vh-n in t!arsrnth •s~•s) S11 -- Smokc•r.5 NS _- N-n,nurk,•rs Author, year, - Number and Data country, type of collection Results reference population Peters 1,496 Harvard Medical history, et al., and chart review, 1967, 370 Radcliffe and U.S.A. students. questionnaire. (188). Finklea et al., 1969 U.S.A. -- - Number of visits to student health unit for respiratory illness/atudent (common colds, pharyngitia, bronchitis, laryngitis, pneumonia-not allergic rhinitis) Harvard Radcliffe NS .................... 1.44 (771) 1.44 (193) SM .................... t2.27 (725) 2.27 (177) <2 years smoked ........ 2.00 3-4 .................... 2.30 >5 .................... 2.50 1,811 male Questionnaire Heavy smokers-21 percent more clinical illnesses than nonsmokers; college prior to 20 percent more requiring bed rest than nonsmokers students. AZIHK/68 Light smokers-10 percent more clinical illnesses than nonsmokers; epidemic and 7 percent more requiring bed rest than nonsmokers. (88). follow-up on morbidity. C-omments ? pG0.001. The authors also noted that: (a) Smokers exhibited serologic evidence of increased subclinical Aaf HK/68 infection. (b) There was no difference in the_ vaccination status between smokers and nonsmokers.

T.tiBLE' A1'6:-Complications developing in the postoperative period in patients und'ergoing abdominal'operations M:enn over 20. Percent Percent' broncho- Percent Group~ Cases' chest Percent, pneumonia total clear bronchitis and atelectasis complication rate Smokers 300 41.7 53.0 6:3 58.3 Light Smokers ............... 180 68:4 27:7' 319 31!6 Nonsmokers ................ 66 92:5 6'.0' 1.5 7:6 Womenn over 20 Smokers ................... 23' 39.1 43.5 17.4 60.9 Light Smokers ............. 62' 77.5 20.9'; 1.6 22.5 Nonsmokers ................ 518' 88.8' 8.1 3.1 1'L2 Souacnt Morton, H.,J. V. (179' TABLE A17:-Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Case Before Group number operation Day 1 Day 2' Day 3 Nonsmokers ...................... Smokers .......................... SaIIace:~. Morton~„ A. (T72).~. 230 1 94 91 94 2 94~ 93 94 3 96' 93 941 4' 95 90 94 5' 9'4 90' 93 6' 95 91 89 91! 7 92 89, 81 89~ 8 91 89 85 89 9 93 91 88' 92 10 90 87 88I 92

i. : 11

Contents Page I'.ntrodizction ........................................... 237 L,ing Cancer .......................................... 23'9! Epidemiological Studies ............................ 240, Prospective Studies ............................. 24'0: Retrospective Studies ........................ . . 240, I:,ung Cancer Trends ini Other Countries.............. 2'44' I'li;tlology of Lung Tumors .......................... 246 Lu21g Cancer Relationships in Womeni .......... . . . . 251 Lung Cancer, the Urban Factor, and Air Pollution .... 252 Lu2ig, Cancer andl Occupationall Hazards .............. 256' Uranium 1VLining ............................... 256 Other Occupat'iens.............................. 256 Nickel........................................ 256 Asbestos ........................................... 257 :3rsenic......................................... 257 Chromium ................................... 257 I'athological Studies ............................... 258' Piilnlonary Carcinogenesis ........................... 258 General Aspects of Carcinogenssis ............... 258' Polynuclear Aromatic Hydrocarbons ....... 264 1Vitrosamine Compound& .................... ~~ ~ 264 Pesticides and' Fungieides .................. 26'6 R'ad'ioactive Isot'opes ....................... 26& Inhi~~bitors~ of Cil~iaryMovement'~ .... I ....... 267 Experimental Studies ............. ........... 267 Skin P'ainting and Subcutaneous Injection, ... 267 Tissue~ and Organ Cult'~ure................. . . . 2'67T1•acheobronchial Implantation and InstilIation. ........................ .2'68' Inhalation ............................. 268' R'eduction in Tumorigenicity ............... 275: Sumrnary~~ and Conclusions .......................... 276 Cancer of the Larynx. ................................ 277 Epiderniiological Stud7es.......................... ....277 P'athological Study ................................. .280 Exper.in7ental, Study ............................... 281 Strmmary and Conclusiions .......................... 281 Oi•al'Cancer .......................................... 284! Epid'em2olbgical Studies ............................ ...28!5. Experimental Studies .............................. .2'88' Summary and Conclusions ............................ 289 3 233'

Cancer of the Esophagus................................ Epidemiological Studies ........... ... ........ .... Pathological Study ................................. Experimental Studies. ............................. . Surnmary an& Conclusions.......................... Cancer of the Urinary Bladder and Kidney .............. Epidemiologilcal Studies (Bladder): ................... Epidemiological Studies (Kid'ney)I .................. Experimental Studies ............................... . . Summary andi Conclusions ......................... Cancer of the Pancreas. ................................. Summary and Conclusions ........................ References ............................................ FIGURES Page 289 289 292' 292' 293 293 293 2966 296. 299, 299 299 299 1. Lung cancer, Finland andl Norvway ................... 245 2; Percent of smoking, dogs with tumors .................. 274 3. Percent of lung lobes with tumors in smoking dbgs ..... 274 4. Effects of chronic cigarette smoke inhalation on the hamsterliarynx ............................. LIST OF TABLES 284 I. Lung cancer mortality ratios ...................... 241 2. Lung cancer mortality ratios for males by duration of A3. cigarette smoking, ............................ 241 Outline of inethods used in retrospective studies of smoking in relation to lung cancer .............. 323 . A4. Group chairacteristic&inretrospeetive~studiesoni lung: cancer, and't'obacco use .......................... 32'9. 5. Annual means of totali lung cancer mortality and sex ratios for selected' periods in Finland and Norway 246 6. Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer ........ 247 A7. Grouping of pulmonary carcinomas .............. 334 8. Tumor prevalence among males andi females 35-69' years of age, by type of tumor and smoking category .................................... 250, 9: Epidemiologic investigations concerning the relation- ship of lung cancer to smoki'ng, air pollution, and urban or rurall residence .. . . . . . . . . . . . . .. . . . . . ... . 253 10. Pathologicand cytologic findings in the tracheo= bronchiali tree of smokers and nonsmokers ...... 259 234 ~'.

LIST OF TABLES (Continued) (A indicates tableslocat'edl in appendix at end of'chapter), 11. A1'2l I I A1 ,'. 1! I I A1-1'. A15. f I a16: 17. 18. 19. 20: Page Identified or suspect'ed' turnorigenetic agents in cigarette smoke ................................ 265 Autopsy studies concerning the presence of radio- activity in the lungs of'smokers .:.............. 335 Experiments concerning the effectls of the skin paintr ing, or subeutaneous' injection of cigarette smoke condensate or itls' constituents upon animals ..... 3'37' Experirnents concerning the effect of cigarette:smoke or its constituents on tissue and organi cultures . . 343' Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents intoithe tracheobronchiad tree of animals .... 346' Experirnent'sconcerningtheeffectof the inhalati~on of cigarette smoke or its constituents upon the respiratory tract of anirnals' ................... 349 Data on pedigreed male beagle dogs of groups F, L,, H, h and N ..................................... 270 Summary of principal cause of death (days Nlo:, 57 through No, 875) in dogs of groups F, L,,H, h and N 271 Datai on dogs with lung tumors indicating, type of turnorr and lobe in which the tumor was found ..... 272' Laryngeal cancer mortality ratios - prospective studies ....................................... 278' A21. Outline of retrospective studies of tobacco use and cancer of theIarynx .......................... 354 A22. Summary of results of retrospective studies of tobacco, use and: cancer of the larynx .................... 358 A23. Number and percent distribution by relative fre- quency: of atypicall nuclei among true vocal cord'd cells, of men classified by smoking category ..... 359 A24. Number and'& percent distribution, by highest num- ber of cell rows in the basall layer of the true vocal eord, of men classified by smoking category .... 36'0, 25., Deposition of 14C-labeled smoke particles in particu- lar regions of the respiratory tract ............ 282 264 Classification of the five registered stages of' epithe- lial changes at the larynx ..................... 2'83' 27. Oral cancer mortality ratios-prospective studies. . 286' A28: Outline of retrospective studies of tobacco use and cancer of the oral' cavity ....................... 361 A28a. Summary of results of retrospective stud7es of smok- ing by type and oral cancer of the detailed, sites. . 368 235 ~. -1 (7) . y. „., 1 > .

LIST OF TABLES (Continued) (A indicates tables located' in appendix atl end of chapter) _. _ _. ~...~: Page A2J. Experimental studies concerning oral carcino- 371 290 A31. Summary of methods used~ in retrospective studies of tobacco use and cancer of the esophagus. ...... 375 A31ia. Summary of results of retrospective studies of ' to- bacco use and cancer of'the esophagus ......... 378' A32'. Atypical nuclei in basal cells of epithelium of esoph- agus of mal'es; by smoking habits and age. ...... 379 A33. Atypical nuclei' in basali cells of' epithelium of esoph- agus of'males, by amount of smoking and age .... 380 34. Kidney and urinary bladder cancer-prospective genesis ......................................... 30: Esophageal cancer mortality ratios-prospective studies ...................................... A35. Summary of methods usedl in retrospective studies of smoking, and cancer of' the bladder ............ A35a. Summary of results of retrospective studies of smok- ing and~ cancer of the bladder ................. 36. Pancreatic cancer mortality ratios-prospective studies ....................................... 294'. 381. 383 298

INTRODUCTION During the early years of this century, a number of pathologist!,s andi clinicians reported a dramatic increase in the incidence of lung cancer. Autopsy studies and studies of' lung cancer death rates re- vealed a significant increase beginning priortoW'orld War I and continuing duri'ng the ensuing years. This epidemic of lung cancer continues to the present day, with nearly 60,000 deaths expected frorn this disease in the Unitled'i States during 1970. Beginning in th:e1920's, a number of reports appeared which suggested' a r.elati:onshap between lung, cancer and tobacco smoking (4, ?113, ?78)1. Since that time, many clinical and epidemiologieal studies have been published which conffrrmi this relationship. The. 1964 Report (2.91)1 contains a thorough reviiewand analysis of the, . data available at that tiine as well as an excellent discussion of the considerations necessary for theireval'uation. 1Iajor epidemiological studies have demonstrated that smokers have greatllk- increased risks of dying from lung cancer, compared. to nonsrnokers. An increased risk of lung, cancer has been found for every type of smoking habit investigated, but two character- istics of the ri'sk are particularly evident : The risk is rnuch greater for cigarette smokers than for smokers of' pipes and cigars, and among cigarette smokers a dose relationship exists. That is;, the more one smokes, as measured by total pack-years of smoking, present level of smoking, degree of' inhalations, or age at start of smoking,, the greater is the risk. It has als& been showni that the risk of' 1~ung cancer among ex-smokers decreases with time almost to the level of nonsmokers; the time requ.ired! is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid formi of'lung cancer is the:most prevalent one in cigarette smoking populations andl that this form accounts for a major portion of the rise in lung cancer deaths (154). Stich studies have also indi- cated a lower prevalence among smokers for oat-cell and adenoi carcinomas of the lung than for the squamous form„ but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. S~moking has been implicated i'n the development of other types of cancer in humans. Among ihese is cancer, of the larynx. A num- 237

ber of epidemiologicali studies have demonstratled' imcreasedl mor- tality rates for laryngeal cancer ini srnokers,, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship, exists between smoking and the development of cellular changes in the larynx, includ'ing carci- noma in situ. Cancers of the mouth and oropharynx have been found to be more commoni among users of all types of tobacco, than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunctioni with other factors such, as poor nutrition and alcohol consumption has not been fully clarified. Similarly; although smokers are more likely to develop carci- noma of the esophagus than nonsmokers, the relative addit'ional contribution of smoking in conjunction with nutritional factors and alcohol' consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that sorne smoking-indnced abnormal meta- bolic product or abnormal concentration of a, metabolic product may be responsible for this increased risk. In additiony cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer.. Epidemiological studies have indicated, an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or "tar." This rnaterial, whenn painted on the skin of animals, leads to the development' of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these carcinogens are severali chemicals which have beeni identified as tumor initiators, that is, compounds which initiate changes ini target cells and also tumor promoters, or compounds whichi promote the neoplastic development of' initi- ated cells. Other,, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equal that of cigarette smoke condensate. Ntamerous experimentis have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the "tar," are administered by varying methods to anitnals or to tissue andi cell cultures in order to investigate the neoplastic- indlucing properties of cigarette smoke. Particular difficulty has been encountered in experiments which have attemptiedi to deliver 238

E ® 0 e 0 whole cigarette smoke to the larynx and into the lungs of' experi- mental animals. This has result'ed, in the use of other methods such as the implanting of pelIets containing suspected carcinogens and! the instilling into the trachea of suspected carcinogens as such, or adsorbed onto fine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second~ the upper respirat'orytract of experi- mental animals, particularly the nose, is muchi different from anall- ogous human structures, resulting in a more efficient filtrationi of smoke in the upper respiratory tract. Nevertheless, ini rodents and& canines, progressive changes apparently indicative of ultimate neo- plkastic transformation have been identified in the respirat'orytract. Recently, two studies in different species and in different target organs have been reported concerning the developrnent of early in vasive cancer followi'ng,t'he prolonged inhalation of cigarette smoke. Auerbach and has coworkers (11) trained dogs to inhale cigarettee smoke through a tracheostorna: After approximately 29, months of' daily exposure, these investigators found a number of cancers of' th~elung. Dontienwill (76), init'h:e second of these two studies, exposed ham- sters tolthe passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed' the development of pre- malignant changes and, ultimately„ invasive squamous ce1P cancer of the larynx. LUNG CANCER' Cancer of the lung ini the United States accounted for 45,383' deaths among males and19,024i deaths among females in 1967 (289)' .. It is presently estimated that approximately 60;000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent' phenonrenon., Death~ rates for lung cancer (1CDCodes 162, 163'), rose from 5.6 (per 100,000 resident population per year), in 1'9;39 to 27.5 in, 1967 (289, 290)1. This rapid increase followed the in- creased use of cigarettes among the United States populatiom The increase has occurred principally among males, although more re- centlk- females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ingi:sthemaj,or cause of lung cancer is derived: from vari~edi types of research including, epidemiological, pathological, andl laboratory investigations. 234. f r. k.

EPIDEIVI'IOLOGICAD. STUDIES'S lung. These studies are outlined' in tables 1, 2; A3, and A4'.. pective, have been carried out in different part's of the worldl to investigate the relationship between smoking and cancer of the Numerous epidemiologiicali studies, both retrospective and pros- those of cigarette smokers (table 1)i. ies to have lung cancer mortaIit'y rates higher than those of' non- smokers, although these are generally substantially lower than Pi'pe and cigar smokers have been shown ini the prospect'ive, stud- (ss). England and Wales during the period from 1953''-57 through 1961- 65, the rates for male doctors of the same ages fell by 38' percent deathi rates from lung cancer rose by 7 percent among all men from 1). During the past 20' years„ half' of' all the physicians in Britainn whol used to, smoke cigarettes have stopped smoking. While thee thancontiinuingsmokers. Imi thei~r study of morethan40~,000~ Briti~:sh physicians, Doll and Hill (174, 75)~ noted a decrease in lung, cancer mortality rates with increasing time since smoking stopped (table Ex-smokers show significantly lower lung cancer death rates duration of smoking (table 2)1, cia.tedi with increased inhalation (table 1) as wellias with increasedi trends. Hammond (118) reported increased mortality ratios asso- inithe mortality from lung cancer with increasing,amounts of cigar- ettes smoked per day. Other measures of exposure show similar Alsoluniforrnlly present in these studies is a dose-related increase 2.20 (118). of female cigarette smokers reveals an overall mortality ratio of show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.611 to 14.20 among male smokers as compared to nonsmoking rnales. The one major prospective study investigations have studied more thani a million persons from a number of different populations for up to 110 years, These studies The major prospective studies concerning the relationship of smoking and lung cancer are presented in table 1. In alll;these Praspective Studies: and controls as well as the relative risk ratios for all smokers. These studies are outlined ini tables A3' and A4. Table A4 presents~ the percent of nonsmokers and of heavy smokers among both cases. ported concerning the relationshsp, of' smoking and lung eancer.. More than 30 retrospective (case-control) studies have been re- Retrospective Studies 240

TABI.E 3.-L)trlr7 valiccvr vurr_ tality ratios (Actual number of deaths shown inparentheses)i SM = Smokers. NS = Nonsmokers. Author, Number year,and type collection Follow- country, of Data up reference population years Hammond 187,783 Question- uestion- 31/. and white naire and Horn, males interview. 1958, in 9 II 6.A. States (120). ages Doll and Hill, 1964, Great Britain (74). Best, 1966, 1966, Canada (21). Prospective studies Inhalation Exsmokers Comments No data Bronchogenic 341/448 (15) _ (Excluding adenocar_ cinoma ) deaths with (18) Never smoked ......... 1.00 microscopic (15) Previously <1 pack/day Continuing ........... 16.94 proof. In-.... cludesthose (7) Durationl <1 year . i6.60 regular 1-10 years .10.44 of ( . cigarette cessationJ ( >10 years . 1.51 Previously sly >1 pack/day smokers who also smoked - Continuing ...........-46.21 pipes and Duration <1 year ..68.23 of 1-10 years .22.82 cigars. t With or cessation >10 years ..17.79 without microscopic proof. Number Regular cigarette Pipe of smoking only cigar deaths (cigarettes/day) 448 Pipe SM . 443 NS ..... 1,00 (15) NS ... 1.00 NS . 15 <10 .... 8.00 (24) SM ... 2.57 10-20 ...10.50 (84) Cigar- >20 ....23.40(117) NS ... 1.00 All ....t10.73(397) SM ... 1.00 50-69. Approxi- Question- 10 212 NS ..... 1.00 (3) mately naire and SM . 209 1-14 .... 8.14 (22) 41,000 followup NS . 8 15-24 ...19.86 (53) male of death >25 ....32.43 (57) British physicians certificate. Approxi- Question_ - 331 NS ..... 1.00 (7) mately naire and tSM . 324 <10 ....10.00 (67) 78.000 followup NS . 7 10-20 ...16.41(204) male of death >20 .,,.17.31 (63) Canadian certificate. All .....14.20(246) veterans. Pipe and d Cigar No data NS .... 1.00 Grams/day 1 14 . 6.00 16 24 . 6.43 >25 .13.71 Pipe NS ....1.00 SM ....4 36 Cigar NS ....1.00 SM ....2.94 Cigarette smokers (3) (12) (6) (3) NS ................... 1.00 (3) Continuing ........... 18.29(124) Duration <5_ years .. 9.67 (6) of ~ 6 9 years . 7.00 (7) cessation 10-20y€ars . 2.57 (3) >20yeare . 2.71 (2) (7) No data # Refers NS ................... 1.00 (7) to cur- (18) Ex-smokers of rent (7) cigarettes only ...... 6.06 (18) cigarette smokers (2) only.

TABLE 1. Lung cancer mortality ratios (cont.) - (Actual number of deaths ahown in parenthesea)1 SM = Smokers. NS = Nonsmokers. Data Follow- Number collection ug-- of years deaths Kahn U.S. .S. male Question- (Dorn), veterans naireand 1966, 2,265,674 followup U.S.A. person of death (139). years. certificate. Prospective studies Regular cigarette Pipe enmoking only cigar Inhalation Examokera Comments (cigarettes/day) 8% 1,256 Pipe SM .1,178 NS ..... 1.00 (78) NS .... 1.00 NS . 78 1-9 . . . . 5.49 (45) SM ....1.84 10-20 ... 9.91(308) Cigar 21-39 ...17.41(316) NS ....1.00 >39 ....23.93 (82) SM_ ....1.59 Hammond,_440,558 Interviews 4 1966, males by ACS U.S.A. 662,671 volunteers. (118). females 35-84 years of age in 25 States. All .....12.14(749) Males Current cigarettes 1,159 only SM .1,110 Malep NS . 49_ NS ..... 1.00 (49) Females 1-9 ..., 4.60 (26) 183 10-19 ... 7.48 (82) SM . 81 20-.39_ ...18.14(381) NS . 102 >40 ....16.61 (82) All ..... 9,20 (719 ) Females NS ..... 1.00(102) 1-19 . 1.06 (20) >20 . .. 4.76 (50) All . .. 2.20 (81) (78) No data (17) (78) (6) Pipe and cigar N3 ....1.00 (78) SM ....1.66 (20) Pipe Males NS ....1.00 (49) NS ........ 1.00 (49) SM ....2.2-4 (21) Slight ...... 8.42(120) Cigar Moderate ...11.45(311) NS ....1.00 (49) Deep ....... 14.31 (141) SM ....1.85 (22) Females Pipe and cigar ar NS ........ 1.00 (102 ) NS ....1,00 (49) Slight ...... 1.78 (25) S_ M._.. 0.90 (11) Moderate) 8.70 (45) Deep )T NS ............ 1.00 (78) Number of cigarettcefday: 1-9 ........... 0.96 (4) 10-20 ......... 8.48 (39) 21-39 ...,..... 9.38 (57) >39 .. . 8.24 (19) ICD code 162 only.

I N A W .~. ....~.».,.. .. . ...,o: Author, Number Follow- year, and type Data up country, of collection years reference population Buell 69,868 Question- etal.,_ American naire and 1967, Legion- followup U.S.A. naires of death (49). 35-76 certificate. years of age and older. Hirayama, 265,118 Trained 1967, male and PIiS Japan female nurse (2k5). adults interview - - 40 years and fol- of age and lowup of older. death certificate. Weir and 68,158 Question- 5-8 Dunn, males in_ naire and 1970, various followup U.S.A. occupa- of death (d0B) _. tions in certificate. te. California. 868 NS . 1.00 NS include -!-10 .. . 3.72 pipe and i20 . . . . 9.06 cigar >30 . . . . 9.56 smokers All . .. .. 7.61 S.f include ex-smokers. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex®mokera. '1'.->,ut.L 1.-LtEng eanccr irtoi-bEalEGy ~t'atioa (cont.) (Actual numbur of dr:,ths shuvn in parcnthcscs)i SM -_ Smukcrs. -- NS --- Nonsmukers. ._-----.-._.--- Prospective studies Number Regular cigarette Pipe of smoking only cigar Inhalation Exsmokers Comments deaths (cigarettes/day) - - 304 NS .... 1.00 <20 .... 2.30 20 ... 3.50 >20 .... 4.90 43 NS ..... 1.00 (3) Rreliminary SM . 40 1-24 ... 2.69 (29) report. >25 .... 6.68 (5)

7]aB1,E 2'. Lung cancer martality ratios for males by duration of cigarette smokitizg (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-54~ 55-69 70-84 25' ar, older ............ 2.77, (5) 3.39 (12) 3.38 (i3) 20: 241 ................. 5.83 (31) 11.11 (72) 12.11, (7) 15-19 ................ 8.71(112) 13,06(176) 19M (27): <15 .................. 12.80 (35) 15:81 (57) 16176' (9)~ Sdu[aCa:,Hammond,E. C. (118). smokers.. although this risk was substantially lower thani that for cigarette noted that pipe snlokers showed an increased risk of ltang cancer, Kreyberg (1'50., in a review of 887 cases of lung cancer in, Norway, large cigars are more commonly smoked but rarely inhaled. small cigars in Switzeriand' as compared to other' countries where be explained by: the greater use and more frequent inhalation of cinogenicity of,Swiss and German cigars. The difference might also might be due to differences in either the amount smoked' or the car- than previously reported. The' authors suggest t'hattheir findings increased' risk of lung cancer was present' among heavy cigar, and' pipe smokers (as well' as cigarette smokers)' to a greater degree and Gsell (1) 1 conducted on a rurali Swiss population note& that an prospective studies, mentioned above. However, a stludy by Abelin Although not presented in tabular form, the data concerning lung, cancer andl pipe or cigar smoking are similar to those found by the'e males and fromi 0.2't'o 5.3 for females. 35'-8!4, 3.211 (20) 9.72(110) 12,81(315). 15.10(101)'. These smoker-nonsrnoker risk ratios range from 112 to 36.0 for LUNG CANCER' TRENDS IN O!THER' COUN'TRIES He observed that the annual perr capita consumption of tobacco did' not reach one pound'' in Iiceland' until 1945, while Great Britain and Finland passed that amount before 1920. In 1957,, Thorarinsson, et. al. (276), noted a sharp rise in the incidence of'hxng cancer in Ice- the relatively late onset of heavy tobacco smoking in the Icelandic popula.tion wheni compared to~ that of Great Britain and Finland. in Iceland'. Dungal (83) noted in, 1950 that lung cancer was a rare disease in Iceland and felt that this rarity could be explainedi by ini some detail. Two such studies have dealt with lung cancer mortality trends smoking and post-smoking periods, long-term trends can be studied spreadl only ini recent years. In; those countries where accurate statistics for lung cancer mortality are available for both the pre- countries in which cigarette smoking has become popular and wide- Severall studies of particular interest are those in which the changing, mortality from lung cancer has been investigatedl in 244

60. 50 40 30--1 20- 10- 4--~ 3-ti Finland = = IIIIIIIIIIIIIIIIIIINorway #0 2- s 193;-36 1939~-4'1 1944-46 1949-51 1954L56 1959-61i 1963-64 Calendar Years FicuRe 1.-Lung, cancer, Finland and I+Torway:. SoUttcE. Kreyherg;,L. (154):. land after 1950 and found a correlatilon between that increase and the increasing sale of cigarettes in that country. Kreyberg (154) analyzed the lung cancer deathi rates of both Norway and Finland in relation tolthe use of tobacco in those two countries over the: past 100 years: Figure 1 shows the substantial difference in lung cancer mortality between the two countries. Kreybelg, observed that cigarettes came into use in Norway in 11886. while the Finni'sh population (more closely allied to Russia, sodo- economically)~ wasconsumiingmore than, 100 million cigarettesper year d'ur.ing the decade of t'he 1880"s: Cigarettes remained scarce in Norwa5- until after World War 1, andl this 30-year lag in consump- aae 245, WIIMIWfWh r 4 AYi

TnsaE'5.-Elnnual'means of total lung cancer mortalityand sex ratios f or selected' periods in Finland and Norway Year FiWand' Narway, Males Femalee 1'936'-3'8' ................... 192' 33 34 30 Sew ratio ................. 6.8 : 1 1'.1, : 1 1963'-65' ................... 1,319 121 355 79' Sex ratio .................. 10.9 : 1 4.6 :V Souaca: Kreyberg, L. (154). tion behindi that of Finland is reRected in, a similar lag in total lung cancer mortality and sex' ratios (tlable 5)1. HISTOLOGY OF LUNG TUIWLORS l, forms. approximatePy equal distribution among males andl females. The author considers the recent rise in lung cancer in, Norway to be a reflection of the increased prevalence of Group I carcinomas. Table 8' presents a summary of Kreyberg's investigation concerning, 793 male and' female cases of lung cancer. Among both males and fe+ males;, the risk ratio among smokers is substantially higher for Group I types than for'those of Group II. However, adenocarcinoma among males shows a, risk ratio of 2.9', signifying a relationship with smoking. Kreyberg attributes the lower' rates noted among females to their significantly lower consumption of tobacco in, alll more frequent, among males while Group II carcinomas show an A number' of investigators' have focused their interest upon the relationship of' cigarette', smoking to, the variedl histology of lung tumors:, The major histological types of lung cancer include squa- mous' ce11' (epidermoid) carcinoma,, small and large cell anaplastic carcinomas, adenocarcinoma (including bronchiolar and alveolar types), and' undifferentiated carcinoma (1153). A review of these studies (table 6) indicates a closer relationship between cigarette smoking and' epidermoid carcinoma than between cigarette smok- ing and adenocarcinioma (42, 113). The work of Kreyberg (153) in Norway, over the past 20 years, provides evidence of' a specific histologic relationship: This inves- tilgator' noted that a clearer association is obtained if'the various' types of pulmonary carcinomas are groupedL Table A7, presentJs' his groupings of the: specific histologic'types: Using, this classification: as a basis for analysis of lung cancer sex-ratios in Norway, Kreyberg has observed, that Group I carcinomas are significantly 24s:

aw '~K .,z N A N -T-A)tl.l; fi.-Is'pitlc>tliolugic rsilc( r~-~ . Author, Number of year, per.S(lnS and country, case selection reference method Wynder 644 autopsies on and males withGraham, confirmed 1950, lung cancer. U.S.A. (316). Doll 916 male and 79 and female cases Hill, with histologically 1952, confirmed England lung cancer. (73). i l",ul'Ly i --- -- . . --~- ----- --- ----- --- Pcrcent castc by h_istologic typ: and s~uo/cing history ' - - - - -' - --- ~ ----- Ai(l lung cancers other tluin adcnocarcinoma (605) Nonsmokers .......................... Light cigarette smokers ................ Moderate ............................. Heavy ................................ Excessive ............................ Chain ................................ 1.3 2.3 10.1 35.2 30.9 20.3 Ctllnnl4ntti The percentage of chain smokers in the general population (7.6) was significantly less than among the patients with adenocarcinoma. The authors refrained from making any definite conclusions due to the insufficient number of cases. I;J!R „j !":1 1; - I r.1 r, Percent patients with lung cancer by average e amount amoked daily over 10 years Males Qat-cell or Epidermoid (475) anaplastic (303) Adenocarcinorna_ (JJ) Nonsmokers ........ 0.2 (1) 0.7 (2) 6.1 (2) Smokers : <5 cigarettes/day .. 2.9 (14) 3.9 (12) 6.1 (2) 5-14 ................ 35.6(169) 36.3(110) 21.2 (7) 16-25 ............. 36.8(175) 34.7(105) 48.5(16) >26 .............. 24.4(116) 24.4 (74) 18.2 (6) Epiderm.oid (18) Nonsmokers ......... 61.1 (11) Smokers: <5 cigarettes/day • 6.6 (1) 5-14 .............. --. 22.2 (4) 15-25 ............. 6.6 (1) >25 .............. 5.6 (1) No statistically significant difference was found between the amounts smoked by the patients in the different histological groups. Number of proven adenocarcinomas too small for conclusions. Femalea Oat-cell or anaplastic (38) Adenocareinoma (10) Males-105 unclassified 31.6(12) 60.0 (5) tumors. Females-l3 unclassified 15.8 (6) 20.0 (2) tumors. 23.7 (9) 10.0 (1) 18.4 (7) ... 10.5 (4) 20.0 (2)

TABr.E 6. Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancerl (cont.) (Actual number of cases shown in parentheses) I teCS9f.6CO Author, Number of year, persons and country, case selection reference method Breslow et al., 1964, U.S.A._ (42). Schwartz - et al.,_-- 1967, France (247). Haenszel et al., 1958, U.S.A. (113). Haenszel and Shimkin,_ 1962,~~ U.S.A. (112). Results Comments 493 male and 25 l Percent of patients with specific lung cMtcers by tobacco usage during the 20 years prior to study Nonsmokers include pipe k nd ci m l fema e cases with histologically A_ rl lung cancers other than gar s o ers on y. a The authors conclude - provenlung_ cancer. 618 age and onsmokers .......................... adenocarcinoma (472) 6.9 Adenoearcinoma (46) 13.0 Controls (518) 24.4 that cigarette smokin_g_ appears to affect the - development of sex-matched controls. Cigarette smokers ..................... 94.1 87.0 76.6 epithelial carcinoma more than that of adenocarcinoma. 430 male and l f Percent of smokers by histologic type amd smoking history e cases ema with histologically confirmed lung Epidermoid Cases .............. 96.0 Anaplastic 97.0 Unknown type 96.0 Gylindrica_ l_ 100.0 t Difference significant cancer. 4 matched Controls ........... 79.Ot 83.0t 79.Ot 96.0 at p!~0.05 level. control groups. 168 female Relative risk for specifded tumors (amokera(nonsmokera) .. . .. . ...... .. 134 cases with final .. ... hi t l ic l cases of lung cancer. _ _ Group I (Kreyberg) Adjusted for age and occupation . ............. 3.Of Adenocar_cinorna 1.19 o og a s determination. t Difference from unity significant at p:~0.01. 2,191 male Standardized mortality ratios Cases obtained from a f l e 10 a m of t cases o lung cancer _ _ _ _s _ _ _p _ percen Epidcrmotid and undifferentiated - -- cancer deaths in _..- . . lung with adequate histologic data. White males total .............................. carcinomas 100 _ Adenocarcinoma - _ U.S.A.during 1968. 100 The authors noted an Never smoked .................................. Ex-smokers ................................... 6 34 18 t absence of important 46 differentials by <1 pack/day ................................... 123 116 histologic type. >1 pack/day ................................... 499 467

TABLE 8.-Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking cate,gory (Smokers constituted 85 percent of populations studied) ~ ~ Smoking category Expected Risk - -- num6ei ratio Sex and typ_e_ of tumor Smoking Non- -among among Total all methods smokers smokers 1 smokers Males Epidermoid carcinoma ............................................ - Small cell anaplastic carcinoma ................................... Adenocarcinoma .................................................. Rronchiulol-alveolar carcinoma . ..................................... Carcinoid ......................................................... _ Bronchial gland tumor ............................................ Total ......................................................... Females Epidermoid carcinoma ............................................ Small cell anaplastic carcinoma ................................... Adenocarcinoma .................................................. Bronchiolol-alveolar carcinoma ..................................... Carcinoid ......................................................... Bronchial gland tumor ............................................ Total ......................................................... 434 431 .3 17.0 25.4 117 116 1 6.7 20.4 88 83 5 28.3 2.9 .... 46 39 7 39.7 1.0 .... 685 669 16 90.7 7.4 12 9 3 .75 12.0 8 5 3 .75 6.6 56 14 42_ 10.5 1.3_ .... .... ... ._,,. ,.,. 32 7 25 6.3 1.1 108 35 73 18.3 1.9 1Number that would be expected if incidence rate among smokers were SOURCE: Kreyberg, L. (154) equal to that of nonsmokers. -

LUNG CANCEIZ RELtkTIONSHQFS IN WQMEN Lung cancer death rates for women are presently muchi lower thani the corresponding rates for men. In addition, it has been ob- served that among certain strains of mice exposed to carcinogenic agents, the male animals show a greater tendency to develop, lung tumors than do the females (200; 307) alt'hough there are strains for which this is apparent'1y 'not so. The extent of the influence of' endocrine factors in the sex variation in the incidence of lung tumors is unknown.. As of 1967 in the United, States, worneni accounted for only about one-sixtli of the t~otal deaths fromi lung cancer (289). However,,tlhe lung cancer death rate in women has, risen by over 400! percent ini the past 40 years. Frorn 1950! to 1967 alone, the rate per 100;000~ population doubled, increasing from 4.5 to 8.9 (2fi'9; 290). A number of retrospective studnes concerning lung cancer and cigarette smokirag among women have found that the difference ilnn the prevalence of lung cancer between males and' females is ac- counted for principally by those tumors classified as Kreyberg's Group 1(1.14; .,11)1. These, as was noted above„are the tumors, par= ticularh= in males, which show the closest relationship withi smok- ing:, Haenszel, et al. (113), in a study of 115$ women withi lung cancer, observedl that the sex differential for hzng cancer death ratesdiminishes, but does not fully disappear when only non- smokers are consi,dered. H'amrnond' (178) found that the death; rate for lung cancer in nonsmoking males was somewhat higher thani for nonsmoking fe- ma]es. However, the difference ini male-female rates was much greater when smokers were compared. It appears that a substantial part of the difference in deat'h rates between xnale smokers and fe- male smokers can be explained mainly by di'fferences in their smok- ing habits. These differences in smoking habits between males and females are of two types. First, overall consumption among females is still significantly lower than that among, maies, In 1966 (281), 30 per- cent of males reported that they had never smoked while for f e- males the corresponding figure was 5'9' percent. This study also noted that nearly: three times as many rnales as females reported~ consurning more than 20 cigarettes per day. Second, it has beenn shown that women smoke differently than men (308) : They begin smoking later thani men (114)' and do not smoke cigarettes as close to the end, where proportionally more nicotine and "tar" are in- haled., Women smoke more filter-tip and "low tar and nicotine"" cigarettes than men. Furthermore, cigarette, smoking still tends to be heavily concentrat'ed' among women under the age at which lung cancer is most likeliy to occur:. 251

Fflnally,, analysis of the ratio of male and female lung cancer death rates (283, 28;4,285, , 286;, 287,288, , 289, 290), reveals that since 1960 this ratio has shown a steady decline, refllecting, the greater relative rise in mortality from lung cancer in the female population. LUNG CANCER, THE URBAN FACTOR, AND piIR POLLUTION A number of studies have been concerned with the relative inft- ences of smoking, urban residence, and air pollution in the etiology of lung cancer.Table 91ists studies performed'in the United States,. G~reat Britain, and Jiapan which have dlealt with this questionL Kotin and Falk (149, 150) andlmore recently the Royal College of Physi~- cians (228) have reviewed the literature concerning the influence of' atmospheric andl environmentall factors in the pathogenesis of' lung cancer. The: studies listed in, table 9 show a number of important trends. Lung cancer death rates are found to be higher, arnong urban popu- lations thani among rural populations. It is not known to what ex- tent this urbani fact'or in the etiology of lung cancer is due to differences in the levels of air pollution. Other factors associated with, urban residence which may influence the etiology of lung cancer are: differences in srnoking habits bettween the two popula- tions; occupational differences;, and possible differences in the re- porting of' lung cancer deaths (228). The studies also uniformly show that within each urban/rural grouping, Iung,cancer death rates increase with increased srnoking. Whether air pollution acts with cigarette smoking to influence lung cancer death rates in, a combined manner is presently unclear (112, 126; 264, 265), andl the evidence concerning a, separate role of air pollution in the etiology of lung cancer is still inconclusive (22$)1. The recent report of the Royal College of Physicians on air pollu-, tion and health (228) concluded that "the study of time trends in the deathi rates of lung, cancer in urbani areas d!emonstrates the. overwhelming effect of cigarette smoking on the distribution of the& disease. Indeed, only the detailed surveys that have taken individuai smoking, histories into, account have succeeded in separating the, relatively very small influence of the `urban factor' on the over- riding effect of cigarette smoking in the development of cancer off the lung." 252'

i TABLE 9.-Fptdettliotogis ittvcsti~yufiours cotrrerning 11ic i'clutiouisfrili of 1ttnJ ttttlrcr tu sntokivg, air pollittiozz, and urban or rural resiclc,nce (Actual number of deaths shown in parentheses) Author, Population year, studied and Country, method of reference data collection Doll, Estimated death rates 1953, from lung cancer England in English (70). population and Age: among nonsmokers 25-44 obtained from 45-64 general register. 65-74 Stocks and Death rates in Campbell. England and 1955, Northern Wales. England Review of patient (Y65). chart or interview with kin or physicians. Hammond 187,783 white males and Horn, in 9 states. 1958, Questionnaire U.S.A. and interview. (1Y0). Results Comments Lung cancer mortality (1950) .per 1,000 Authors noted that Males Females Nonsmokers estimates are based on London Other urban Rural London Other urban Rural All areas very few deaths. 0.126 0.095 0.070 0.028 0.028 0.012 0.020 1.672 1.264 0.851 0.194 0.162 0.120 0.090 3.124 2.006 1.164 0.440 0.326 0.288 1.219 Male lung cancer death rates 1952-64 (per 100.000) ages 54-74 The authors noted the - upward gradient among Rural (68) Mfxed (118) ~ Urban (5S9) nonsmokers, pipe Nonsmokers rs ................................ 14 . . 131 smokers and light Pipe ........................................ 41 25 143 cigarette smokers and the Cigarettes: Light ............................. 87 153 297 lack of a similar Moderate ................................. 183 132 287 gradient among Heavy .................................... 363 303 394 moderate and heavy cigarette smokers. Age standardized death rates due to bronchogenic carcinoma (malea) Data excluded -- _- - adenocarcinoma. when Suburb City of City of standardized for age and Rural or t_ourn 10,000-50.000 >50,000 smoking, rural rate was Nonsmokers ............. ... 4.7 (2) 9.3 (3) 14.7 (4) atillnotedtobe26 Cigarette smokers ........ 65.2(62) 71.7(67) 70.9(59) 85.2(83) percentlesathanurban.

TAB1.E 9. Epidemiologic investigations concerning the relationship of lung cancer to smoking, air pollution, and urban or rural residence (cont.) (Actual number of deaths shown in parentheses) Author_, Population year, studied and Country, method of reference data collection Haenszel 10 percent of all et al.,_ white male lung 1962, cancer deaths in U.S.A. U.S.A. for 1958 (112). for whom next of kin or physicians supplied smoking data. 2,191 cases with adequate information. Doll oll 41,000 male British and Hill, physicians. 1964, Questionnaire and England d follow-up of death (74). certificate. Wicken,_ 1,908 maie and 1966, female lung cancer Northern deaths over 35 Ireland years of age from (.f08). register. Personal interviews with kin or physicians. Results Age- ge- and amokinD-atandardized lung cancer mortality ratios (epidermoid and undifferentiated carcinomaa only) Metropolitan counties Nonmetropolitan counties >50,000 ........-.••.119 2,600-50,000 ...... 90 10,000-50,000 .........161 Rural nonfarm ....74 2,500-10,000 ........... 99 Farm ............67 Standardized death rates for lung cancer Conurbation(49) L_argeTowns (34) Small4'owna (,t$) Nonsmokers .......... 0.03 0.00 0.11 Cigarette smkers: 1-14 ................ 0.48 0.32 0.87 15-24 ............... 1.31 1.88 1.06 >25 ................ 1.90 4.43 2.20 Comments _St_andardized Mortality Ratio = 100 for U.S. white males age 35 and over in 1958. The authors also noted "... joint effects of residence and smoking histories in the schedule of lung-cancer rates far greater than those expected on the assumption of additivity of the separate effects . . ." The authors noted_ that rural mortality data Rural (18) were affected by a 0.12 significant number of city residents 0.52 retiring to the country. 1.15 - 1.17 Lung cancer death rate per 100,000-age- and smoking-standardized Inner Outer Belfast Urban Belfast Belfast Environ.a_ Areaa Males ....... 157(241) 139(157) 135(45) 118(185) Females ..... 22 (38) 17 (24) 12 (6) 23 (35) Small Towns Rural 137(26) 47(149) 22 (5) 12 (43) Total otal number of deaths noted under method of data collection include - 954 controls.

Lt 14 V. N a H 9(. G S9LCO TABLE 9.-Epidetrtiufoqic iztccstigati,iirx cuncerTling the rslatiottslrilR of lung cancer to smoking, air pollution, and atrGan or rural residc>tcc (cont.) - (Artiud numher nf (1.aths shown in parentheses) Author, ---~ Pupulatiun y,~ar, ytudin3 and Country, metht~!I of reference dnta collection Bucll 304 lung cancer et al.,_ deaths among 1967, American U.S.A. Legionnaires (48)• aged 25 and over. Questionnaires to next of kin. Hitosugi, 185 male and 1968, female lung cancer Japan deaths and 4,191 (1Y6), matched controls aged 35-74. Data from questionnaires and interviews. Results --- Age-adjusted lung cancer death rates per 100.000 man years and mortality ratios Los Angeles Rate Ratio Nonsmokers ................ _28_.1_ 25S_ Smokers: <1 pack/day .............. 63.6 5.7 31 ....................... 126.0 11.3 >1 ....................... 241.3 21.6 Comments The authors noted the lack of death-rate difference San Franciaeol All other between Los Angeles and San Diego iego California counties San Francisco regions Rate Ratio Rate Ratio and concluded that 43.9 3.9 11.2 1.0 photochemical smog is not related to 77.1 6.9 61.02 5.4 lung cancer. 134.5 12.0 124.9 11.2 226.0 20.2 137.5 12.3 Lung cancer death rate per 100,000 The authors postulated a slight synergistic effect between smoking and air pollution. Pollution region Males Low Intermediate High igh Nonsmokers ................................... 11.6 8.8 4.9 Smokers: mokers: 1-14 cigarettes/day ........................... 10.6 14.2 28.6 - - >15 ......................................... 21.3 18.6 81.4 Femalee Nonsmokers ................................... 4.6 6.9 3.8 Smokers • 1-14 cigarettes/day ........................... 19.7 16.5 16.8 >16 ......................................... 12.4 20.5 17.1 Ape- and amokiny-adjusted lung cancer death rate per 100,000 Low Intermediate High Malea .......................................... 16.1 22.4 28.4 Females ....................................... 7.5 11.6 8.7

LUNG CANCER AND ~ OCCUPATIONAL HAZARD6. Uraunium Mining The excess risk for the develbpment of lting cancer among uran- ium and fluorspar miners has been known for more than 30 years. In a recent review, Bair (17), noted that radon and radion-diecay products are the only inhaled radionuclides to be epidemiolbgically related to, lhng cancer. Lundin,, et as. (178), in a continuation, of the work in~itiated by Wagoner, et al. (299, 300, 301), have re- cently reported on a 17-year follow-up of 3,414 white underground uraniumi miners:, The authors estimated that smoking uranium, miners experienced ani excess of lung cancer ten times greater than did: nonsmoking, maners, Saccomanno (231), in recent testimony, analyzed the data of't'he United States Public Health Service (USPHS) Stud'y Group asi presented by Lundin, et al. (178) above. He reported' that cigar- ette smoking uranium miners incurred lung cancer rates four times greater than those of other cigarette smokers. Of the62' lung cancer deathsi~n thi~s population, 60 occurred in smokers, He also observed, that among 1001,0001 uranium miners 700 lung cancer deaths per year wouldl be expected; to occur among cigarette smokers compared with only 4 among, nonsmokers. Other Occupatzons Nelson ('199 has, recently reviewed certain environmental, and, occupational hazards as they relate to inhalation carcinogenesis. He observed that cancer of the respiratory tract has been linkedi epidemiologically and~ in some cases, experimentally with occupa- tional exposure to the following materials: chromium, nickel,, arsenic, and asbestos: Doll (72) and! Goldblatt (100), in earlier reviews, also noted, an association with coal, natural gas, andd graphite exposures. Nickel' Morgan (194) noted t'hat much of the: nasal and: lung cancer, at- tributed to nickel exposure may have been due to arsenical' impuri- ties found in processedf nickel' prior to~ 11925. Doll (69), found that the number of' excess deaths among nickel workers under 50 years of age hadi declined following the change in nickel manufacturingg processes. The experiments of Hueper (13'4) and SUnderman„ et al.. ( 267„268;, 269 ) have shown that both guinea, pigs and rats develop lung, cancer following chronic exposure to nickel carbonyl' or nickel, dust. SUnderman and Stiinderman (270)i also reportedl that ciga- rette smoke contains nickel and that this concentration of nickel 256

may be capable of'inhibit'ing the induction of lung aryl hydroxylase, an, enzyme which i'sabl':e todet~oxify aromatic hydrocarbons includ- ing known carcinogens such as benzo[a]pyrene. I Asbestos In 1955, Doll (71) found' that lung cancer was a definite hazard among asbestos workers. In a more recent study, Selikoff, et al, (251, 252) examinedi the relationship of smoking and asbestos ex- posure to lung cancer. These authors followed 370 people who had been asbestos workers during the years 1942-1962; Over a 5-year follow-up period~ 94 deaths occurred~ in this group, of which 24~ were due to bronchogenic carcinoma. The authors noted t'hat according to data obtained from Hammond (118), only 3.1i6'd'eaths from lung cancer would have beeni expected' among smokers; and caiculated a 7:6't'o 1.00 mortality ratio due to asbestos exposure. None of the 87 nonsmokers or pipe and cigar smokers died of lung cancer. When the expected number of'nonsmoker deaths (0:26), is comparedlwith& tlheactua.lnu:mbe~r(1.24) , whi~chi occurr~ed' among, the smoking asbes, tlos workers, ani extremely high mortality ratio of 92'to 1 is obtained,, thus reflecting the possible: interactioni of asbestos exposure andd cigarette smoking. Exposure of mice (179) and rats (106) to asbestos dust or the intratracheal injection of chrysotile asbestos dust has resulted in the production of significant numbers of primary pulmonary car- cinomas, Miller, et al, (184) exposed hamsters to intractracheal injections of benzo[ja]pyrene. These authors observed that the addi- tion of the chrysotile variety of'asbestos to the ilnjections appearedl to promote benzo[a]pyrene carcinogenesis in the respiratory t'ract, as determined by the time of appearance and yielde of papillomas'& and carcinomas, Arsenic A recent epidemiol'ogic study by Lee and Fraumeni (163) has indicated an excess of lung cancer deaths among smelter workers exposed to arsenic for more than one year. Cigarette smoking was not taken into account in their computations'., Experimental work on the induction of cancer in animals using, arsenic has yielded either negatiive or inconclusive results (133, 135)1. , ' Cji.romium Exposure to, industrial bichromate compounds has; been associ~- ated with an excess of lung cancer deaths (22;255). Laskiny et al. (159) have recently reported that intrabronchial pellet implanta- 257

tion of various chromium compounds in rats is associated with the development of squannous ce111 carcinomas and adenocarcinomas. However, Nettesheirn, et al. (200) exposed mice to chrorniumi oxid'e dust and observed that it had no discernible effect on lnng, tumor incidence. PATHOLOGICAL STUDIES Investigators who have conducted! detailed autopsy studies onn patients who died of lung, cancer have reported the increased pres- ence, when compared to noncancer patients, of bronchial epithelial changes which they considered' to be precursors of bronchogenic. carcinoma (7, 8, 23, 51,,.104,, 208, 220, 279, 309). Such changes& include squamous metaplasia, atypical squamous metaplasia (with~ acanthosis, dyskeratosis,, and numerous mitotic figures)y, and car- cinomal in situ. Carnes (54 noted that carcinoma in situ was pres- ent in 119 cases of lung cancer but not in any of the 119' controls who were matchedl for age, sex, and race. Autopsy studies comparing, the frequency of these caneer- related changes in the lungs of smokers and nonsmokers are pre- sented in table 101. , Virtually all the studles noted an, increased prevalence of these epithelial aiterations among smokers as cornr pared with nonsmokers. Definite dbsage-dependent relationships were evident in the: results of many of the reportls:, Also, Auerbach, et al. (14), observed that the number of cells with atypical nuclei' decreases progressively in the bronchial mu~cosa of' ex-cigarette smokers; depending upon the number of years between, cessation of smoking andl death„althougli it usually remains above that found in nonsmokers. The cytologic studfies included in this table (182,, 198, 222) all noted an increased percentage of sputum specimens showing, meta- plasia among smokers as compared~ withi nonsmokers. PULMONARY CARCINOGEI>IESIS General Aspects of Carcinogenesis Agents found in cigarette smoke which have beeni identifLe& as, or are suspected of being carcinogenic, are listed in table 11. The list includes certain compounds which most probably contribute to the pathogenesis of the various cancers discussed ini the other sec= tions of this chapt'er: Nfany other agents have beeni identified in tobacco and tobacco smoke. At the present time, they do : not appear, to bear a dlirect relationship to carcinogenesis. Stedman (262) and. Wynder and Hoffmann (;91'9) provide detailed listings and discus- sionscancerniingthese: materials. 258'~

r. > ,}. t TAStE 10. Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (Actual number of cases shown in parentheses) Author, Number of year, cases and country, method of reference selection C_ h_ ang. 1957, U.S.A. and Korea (55). Hamilton et al., 1957, Results Comments 105 males and Percent of caaaa with bronchial basal cell hyperactivity Smokers included females 40-86 Nonsmokers .................................................. 28.6 (34) pipe and cigar years of age. Smokers ..................................................... 43.7 (71) smokers. Heavy smokers ............................................... f61.3 (31) t D-<0.01 in com- - parison with nonsmokers. Selected Percent of cases with: No lung cancer autopsy Basal cell Squamous 2rqnaitional patients included. material. Number Age range hyperplasia metaplaaia metaplasia U.S.A. Smokers ................ 15 39-77 86.6 20.0 40.0 (117). Nonsmokers ............. 20 28-83 40.0 15.0 36.0 Sanderud, 1958, Norway (f40). Knudtaon, 1960, U.S.A, - (147). ). 100 males autopsied at Nonsmokers Nonsmokera . Percent of cas ................ es with bronc ............. hial squamoue e ................ pithelial metaplasia. - .... 54.0 (39) Gade Institute Pipe ........ ................ ............. ................ .... $0.6 (20) on whom All cigarette ................ ............. ................ .... 79.0 (38) smoking data was available. Cigarettes pe 6-14 ..... r day: ................ ............. ............. . 70.0 (23) 15-25 ..... ................ ............. ................ .... 90.0 (10) >25 ....... ................ ............. . ................ .... 100.0 (6) 100 0 persons 23-85 years No. of Percent o No f cases with: Baeai cell A Squamous pro typ life of age Persona_ change hyperplasia metaplaaia m etap autopsied at Nonsmokers ............. (21) 47.6 28.6 14.3 9.6 Seattle Cigarettes/day: Veterans 1-9 ................. (9) 77.8 11.1 11.1 - Hospitalon 10-15 ................. (11) 18.2 18.2 54.6 9.1 whom 16-20 ................. (44) 20.4 29.6 29.5 29.5 smoking >21 ................... (9) 11.1 83.5 44.4 11.1 data was Pipe or cigar ............ (6) .. 100.0 available. ical rative laaia Nonsmokers in- cludethose smoking less than or eQualto 6 grams per day. Age, occupation, n_, and site of residence were found to have no appreciable effect.

~ TABLE 10. Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) - (Actual number of cases shown in parentheses) Author, year, country, reference Number of cases and- method of selection Results Comments Auerbach et al., 339 persona 22-88 years Number Number o f sections Percent sections with cilia absent Percent sections with some The authors noted a dose-response re- 1961, of age of of bronchial and entirely atypical cells lation of smoking U.S.A. autopsied at persona epithelium atypical cells and cilia absent to: (12). East Orange Nonsmokers: a. loss of cilia. Veterans <40 years of age .... ............. 8 383 0.3 b. increase in Hospital 40-69 ............... ............. 11 560 . . . . number of (excludes 60-69 ............... ............. 28 1,463 . . 0.1 atypical lung >70 ................ ............. 18 918 _ 0.5 cells, cancer). Smokers <1 pack/day: c. carcinoma <40 years of age ..... ............ 14 . 727 0.1 4.7 in situ. 40-59 ............... 24 ............. 1,240 1.0 16.9 Average number of 60-69 ............... ............. 36 1,772 0.5 10.8 sections per case >70 ................ ............. 22 1,101 0.6 9.4 equaled 52.3. Smokers >1 pack[day: <40 years of age .... ............. 17 880 1.6 12.5 40-69 ............... ............. 63 3,027 4.5 17.4 60-69 ............... ............. 84 ....... 4,186 6.9 20.5 >70 ................ ............. 16 756 9.8 23.7 Cross 140 persons Percent aectiona showing et al., autopsied at 1961, Iowa City Normal Hyperplasia U.S.A. Veterans Nonsmokers (31) .......... 61(562) 36(137) (64). Hospital Smokers (109) ............. 44(570) 43(562) on whom smoking data was available. changes in bronchial epithelium (number of sections) t The authors noted Squamous Atypical Carcinoma - that the differ- metaplnaia metaplasia in situ Carcinoma ence between S (33) f15 (58) smokers and non- 16(197) 20(263) 1(12) 2.6(34) smokerswas statistically significant.

T.»i-F: 10.-PrEthologic and cytologic fizUClinqs in the lracheo-bronclsial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) N o. _Author,_ Number of year, cases and country, method of reference selection Auerbach 72 autopsied et al., former ciga- 1962, rette smokers U.S.A. who had been (14). smoking for ?_10 years and had ceased ?5 years ago. Results Number of Percent sections Percent sectiona Per-cent sections aections of with cilia absent with aome atypti- with 50 percent bronchial and entirely cal eelle and atypical eelle Number epithelium atyRical cells cilia absent and cilia present Nonsmokers ........ 72 3,156 0.0 0.1 0.6 Ex-smokers ........ 72 3,436 0.2 0.9 2.6 Current smokers .... 72 3,637 8.0 19.0 80.8 Comments Each ex-smoker matched with a current smoker plus never-smaker for age, occupa- tion, and resi- dence. There was an average of 60.3 sections per subject and none had less than 18 sections.

14 ~ a N TABLE 10.-Pathologic and cytologic fandings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) - (Actual number of cases shown in parentheses) Author, Number of year, cases and country, method of reference -selection Auerbach 456 male and etal.,_302female 1962, smokers and U.S.A. nonsmokers (13). autopsied and matched for age,occu- pation, and residence. Numb er Males : Nonsmokers ........... 47 Cigarette smokers . 75 Females: . . Nonsmokers ........... 47 Cigarette smokers ...... -76 Males: Nonsmokers ........... 36 Cigar smokers ......... 35 Cigarette smokers ...... 35 Results Percent sec- Percent aee- Number of tions with tions with sections of cilia absent some atypi- -- _ bronchial and entirely cal cells and epithelium atypical cells ciliaa absent 2,346 . . 0.1 3,393 6.9 21.2 2,379 . . 0.1 3,507 2.5 13,3 1,706 . . 0.2 1,733 0.3 10.0 1,526 12.8 27.3 Robbins. 103 students Percentixi each_cytolopic class 1966, 17-24 years Slightly Moderately_ typical U.S.A. of age who Normal atypical atypical (8£2). underwent Nonsmokers (46) .................. 86.7 4.4 8.9 aerosol Smokers (58) ...................... 55.2 32.8 10.8 sputum induction. tUa4 Ced44d5I 2 Comments Percent aec- Major findings - - tions with 50 noted: perccnt atypical Urban nonsmokers cells and showed more cilia present_ lesion than rural. Both lesions and 0.7 atypical nuclei 78.6 were much less frequent in non- 0.5 smokers and less 62.6 frequentin pipe and cigar smokers 0.6 than in cigarette 10.7 smokers, 83.1 57.1% of cases had 50-55 sections 31.5% of cases had 40-49 sections 7.3% of cases had 30-39 sections 4.6% of cases had 16-29 sections Smokers defined as Strongly those having con- atypical sumed ?10 ciga- rettes a day for 1.7 ?lyear.

TAIt11: 11/.- /rlllll!!l,1!/1+' ttrrrl Nasiell, 50 nonsmoking 1968, outpatients, Sweden 398 smokers (198). participati_ng_ in general health exam- ination who underwent sputum induction. 157 males and 78 females autopsied fol- lowing sudden or accidental death for whom smok- ing data were available (ex- smokers ex- cluded from female data ) . I(, Nonsmokers ......................................... ... Smokers : 1-10 cigarettes/day ............................... ......... 11-20 ....................................................... 21-30 ........................................................ >30 ......................................................... _ _ '1 Y'~uub~r a14 Parrcntxilo<r-ynLfu):blatn .11 16 1119 47.09 38G 51.43 93 61.29 39 69.23 Sputum cytologic changes Percent with t Regarded by Percent Percent with atypical author as "real Number M_ alc_sMean age metaplasia mc_t_a_ p_la_ sia_t premalignant Nonsmokers 50 42 57.1 18 4change.''Smokers ................ 398 73 45.6 62 27 Number Percent with +netaplaatia The authors found Males: Nonsmokers ................................................. 36 50.0 Ex-smokers ................................................. 21 57.7 <1 pack ..................................................... 32 62.5 >1 pack .................................................... 68 73.5 Females • Nonsmokers ................................................. 34 34.1 <1 pack ..................................................... 18 33.3 >1 pack ................................... .............. 26 46.1 - no evidence of carcinoma in situ or preneoplastic atypical changes.

In ord'er to facilitate understanding of the relationships of' the various compounds to one another, the third column presents the presently understood relative importance of each of the various groups of' compounds:, These compounds have been tested only in, animal's or tissue cultures, and' it should' be stressed that the rela- tive importance of one compound may not be the same in man as it is in animals. Table 11 is davided' into two major sections. The first section detail'sthosecompoundawhich are considered to:be~or are suspectedi of being cancer initiators. These are compounds which induce irreversible changes in responsive cells. In the seconid' section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the malig- nant reproduction, ofcell'sin which neoplastic changeshaves been initiated. A number of these initiators may also act as complete carcinogens in their own right., The evidence concerning the two stage initiation-promotion mechanism is st'ill'rather limited for respiratory tract careinogenesis.. The pol'ynuclear aromatic hydh~ocartions (PAH) listedi are pres- ently considered to play a very significant role in pulmonary car- ciinogenesis due to tobacco smoking: These compounds act as tumor, initiators or complete carcinogens. The particular role of these agents in environmenta]I and occupational carcinogenesis has been reviewedi by Falk, et ai: (93)1. Thatt suchi hydrocarbons are pro- duced from tobacco during human smoking has been shown by Kiryu andi Kuratsune (1.46)1. These authors reported the presence of benz[a]anthracene, chrysene, benzo{a]pyrene, and benzo- [b]fiuoranthene in the "tar"' produced by normal smoking and' measured in either filters or stubs. Two hydrocarbons which have frequently appeared in the Yitera- ture on experimental tobacco carcinogenesis may not actually be present in tobacco smoke. They have been used as representatives of carcinogenicPAl-I, a cla:ss which iincludes many constituents that have beeni identified in cigarette smoke condensate. They are 7,12'-dimethylbenz[a]ant'hracene and 3-methyTcholanthrene andi have been frequently used as tumor initiators or complete carcino- gens, particularly in skin painting and tracheal implantation experiments. The nitrosamine eovnpounds listed: are potent carcinogens affectl- i'ng many organ systems, including the respiratory tract (188, 189). Magee and Barnes (181): have presented a detailed account of experiments in this area.. Nitrosamines have been identified inn trace amounts in tobacco "t'ar"' and'the:condiitions required for their formation (the presence of secondary amines and nitric ox~ide) are 264

TABLE I1L-Identified or suspected'tumorigenic agents in. cigarette smok'e' Estimated' concentra- tion in 100 Preaentlk understood relative Componentscigaretltess importanceine experimental. (35 mm, tobacco carcinogenesis nonfilter) I. Complete carcinogens~, and tumor initiators: Polynuclear.r aromatic hydkocarbons. ........ ~10-30 ug 1..Benzo(a).pyrene .................... 3.9 '~ .:.D'ibenz(a;h)anthraeene .............. 0.4 31 Benza(b)fluor'anthene ............... 0.3' 4..Benzo(j)fluoranthene~ ............... 0:6'. 5,,Dibcnza(a,i) pyrene ................. Trace 6. Benz(a).anthracene ................. 0.3'. 7. Chrysene ........................... 210, S.Indeno.(1,2,3'-cd)pyrene .............. 0.5'. 9. Benzo(c)phenanthrene2 .............. Trace, 10. 3iethylbenzo(a) pyrenes ............. :0.1 11.:ylethylthrysenes .................... 2.0: Tumor initiators. N -heteracyclie hydrocarbons .............. 1-2' Tumor initiators. 1, Dibenz(a,h).acridine ................ 0:01, 2. Dibenz (1a,j) aciridine ................. 1.0~ 3.SH~dibenzo(c,g).carbazole........... .0:0Y ti,nitrosa mines?' .................._.......,,., 1'-10 Suspeeted..carcinogens of possibleimportance:(presence.in fteshsmoke possible). 1. Dimethylnitrosamine~ .:................. 0:4 2. Diethylnitrosamine~ ................. Trace. 3~ Slethyl-n-butylnitrosamine~ ........... Trace. 4l Nitrosopyrralidine.................. ...., 0.4, 5'.blitrosopiperidine. .....................:. Trace. E(aaxides, peroxy campounds, and lactones: 1. Epoxides........................... ........ No data. 2. PeroxidLrs . ..........................,....., Pcesent~ 3. Lactones~ .........................._...., .,... a. 0.-Bevantenalide ................ 20.0 b. R-Bevantenolide ................ 2.0 Certain of these compounds are known . carcinogens; : preseneee i n ~ smoke condensate not established. N-alkyl-heterocyclics: 1. I-methylindole ...................... Present Possible initiator. Pesticides and.fhyngicides:' Naessential.contribution.suspected., 1. TDE1 ............................... 10400 2.o,A-DDD: ........................... 10400 3. DDT' .................................. 10-100 4.iWlaleic,hydrazide .................... 10-100: Beta-naphthylamine ...................... 2-3 Suspected bladder esrcinogenl of doubtful lsignificance at' reported' 1'eve1s,. Polonium~.210 ..~ ...........:............~.......... 1l-50~. Of'~some~importance~,only'in~the~f picocurlies~s case of~relatiNely hilQh~cancen- tration;, but.not important atl reported levels. Nickelcompounds ....................... Present SUspectrdlcareinogens;of some importance. 46'9' V. 1 ,

TASCE 11.-ldent9;fced or suspected tumorigenic agents in cigarette smoke' (cont.) omp,onentss Estimated concentra- tion in 100. cigarettes's (89,mm: nonfilter). Presently understood ~ relative importance in experimental tobacco carcinogenesis II. Tumor promoting agenta : Neutral'promoters (polymers) No data Of pos'sibLeimportance: (unknown structures,) Volatile phenols' ......................... 20-30 mg. Of possible importance. 1. Phenol 2. Ctesol Nonvolatile~.fatty~~acids~ .................... 20-100 mg. Of minor~importance. 1. Stearic acidl 2. Oleic: acid N'-a1ky1 heterocyclics: Of' possible importance. ll 9-metbplcarbazola ................... Present 2 M'odified andd expanded'~ from(319, s'20) with, reference to (S2',. 60, . 89; 171, 129, 202,. 262, 298; 294:.298),.... 2 Has not been tested as an initiator, but is a known complete carcinogen.. s $ee lrieuratb, (202) . "Ske (i111;1P8)I. found in tobacco smoke (38). 1}iowever,, nitrasamines may be arti- facts dependent on the method of smoke collection (201). 'hTeurath (202)~ considers the niitrosamines list'edi in, table 11 as being present in fresh cigarette smake (253, 254). However, con- clusive confirmation of their presence in fresh smoke is not availiable (!38, 138, 155, 319). Certain of the pesticides and fungicides presently in use on, tobacco'have been found to'be carcinogenic (91, 273, 280) . A num- ber of' these, such as DDT, are now being phased out of regular domestic use. The compound's listed have been shown to be present in trace amounts'ini mainstrearll tobacco smoke (111;128) . A recent,, extensive review by Guthri~e (111), provides more detailed informa- tion concerning, these agents.. Radznactive isotopes can be foundi in tobacco and'tobaceo smoke (105). Potassium-40, while present in tobacco leaf,, is not trans- mitted, in any subst''antiai amount to, mainstream smoke (230). Polonaum-2l'0 (P'o~,,,))i, however, is transmitted intothe mainstream smoke (94, 1'23, 142; 145, 215, 217). A number of autopsy studies (table A12) have shown that the bronchial epithelt<um, of smokers contains significantly more P'o~,o than that of nonsmokers. Litt'le,, et al. (172, 173, 1741) have also noted that the concentration of poloni,urn was markedly higher at sites of bronchial', bifurcation. These! aut'hors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic carcinomas are fre- 266

quently located at bifurcations andl that the polonium~ l'evels whichh they found in those regions probably have biologic significance (216). Other investigators (123, 217)' have not observed thiss excess at bifurcations, and in a recent discussion, Wyndor and Hoff- mann (320) concluded that it appears unlikely that P'oz1o in thee amounts present in cigarette srnoke plays a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in cigarette smoke which are potent inhibitors of ciliary movement. Their importance in carcinogenesis derives from the: increased amount of'time which they afford the known carcinogens to be present on the surface of the bronchial epithelium. These inhibitors include volatile aldehydes, hydrogen cyanide„ nitrogen oxides, volatile phenols, and certain, volatile acilds such as formic andl acetic (129). Experimental 'StudiesIn some respects, the animal andi tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in other tissues ini which tobacco smoke, particularly cigarette smoke, is believed to play a role. These general' experi'ments will be presented here, however.,, with the experiments which bear on lung tissue directly. Skin Painting and Subcutaneous Injection Numerous animal studies on rats, mice„ andi rabbits, have been performeduti~lizingknown carcinogens, whole tobacco"tar,"" and' various tobacco condensate subfractions; or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved animall skin. A selected number of these studies is presented in table A113. Numerous other studies, performed prior to and follo`ving T9'53, are reviewed by Wynder and Haffrnann (319). The skin painting method is still considered to be a valid pro, cedure for the identification of agents suspected of participating in pulmonary carcinogenesis, as well'i as for the quantification of' the reduction in tumorgenicity of specific agents. Tissue and Organ Culture The exposure of tissue and organ cultures to cigarette smoke, its condensates, or its constituent compounds has been shown to sig- nificantly alter patterns of eell' growtk and reproduction. Table A14 present~sani outline of t'heseexperirnents. Once againsless severe effects have been noted when filtered smoke was used (165). . 267 .,

Tracheobronchial' Implantation and Instillation More complex experiments concerning, the carcinogenicity of cigarette and tobacco smoke are representedi by those whiieh involve the direct impiantation,, instJillationy, or fixation of suspected ma- terials ihto the tracheobronchial tree of animals. Certain of these experiments are outlined in table A1!5. Recent' reviews by Saffiotti' (233, 231;) Laskin, et al. (159), and 1Vlontesano, et aI. (189) as well' as that by Wynder and Hoffmann (31'9)i provide more detailed' and extensive accounts of these experiments. Of note among the results outlined in thistable are the following : The enhanced carcinogeniieityfound whenibenzo[a]pyrene (B[a]iP)l ilscombined with acarriiersuchashernatite dust(235),, andi the definite increase in bronchial epithelial' preneoplastic and neo- plastic changes among dogs treated' with smoke condensate as com- pared with those undergoing only physical, bronchiali stimulation (224). Inhalat'ion Variousspecies,incl~uding, mice,, rats; h~amsters,and dogs, have been exposed to cigarette smoke or aerosols of its constituents. These inhalation experiments are outlined in table A16. It must be notedl that the majority of' the studies listed involve the passivee inhalation of'the material presented usually in a chamber. Active inhalation experirnents, exemplified by the work of R'ockey and Speer (223) and Auerbach and his colleagues (11, 119)1 invollved' animals which were trained! t'o inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Muhlbock (195) observed that cigarette smoke inhalation en~- hances the already substantial, rate! of spontaneous alveolar' cell carcinoma formation in hybrid mi'ce„ and various investigators in- duced adenomas in experimental animals (108, 168;, 206). Harris andNegroni (121) found that exposuret'o cigarette srnoke achieved some enhancementt of adenocarcinoma formation in mice but did not observe proven sqiuamous cell carcinoma. Some of their mzce had also been exposed to Swine intl~uenza virus aerosol. In ai relatedd study, Boren (32), exposedi hamsters to cigarette srnoke at set inter- vals over a 48-hour period. The author observed alterations in pul- monary cell kinetics (the pattern of DNA synthesis)' as demon strated by H3-thymidine autorad'iography. The pattern of the label- ing' response to cigarette smoke was significantly different fromm that of the response to high oxygen concentrations:. Auerbach, et alL (11) have reported the development of early 269

i 0 rW invasive squamous cell bronchogenic, carcinoma in dogs following a period of direct inhalation of' cigarette sTnoke.These investiga- tors trained beagle dogs to inhale cigarette smoke through aa tracheostoma (.50) and divided the animals into groups according to dosage as detailed in table 17. A number ofl'dogs died during the course of'the experirnent which ran for 875 days, or approxirnately 29 months. The causes of death are listed ini table 18. A1l!, of thee remaining dogs, with the exception of group "h" (high exposure, heavy weight), were sacrificed shortly after day 87,5; ; the survivors among the.heavier dogs are continuing to smoke. Examination of the respiratory tree of the animals revealed aa number of turnors (table 19.). Most of these were similar to the type of tumor w.hichi in man is referred to as bronchiolb-alveolar. This tumorr arises in the bronchi:olar and alveolar epitheliu¢n and tends to be muIticentric. Two striking characteristics of these bronchiolo- alveolar tumors were, tlhe existence of' a histolbgi'c spectrum (fxomm a tumor resembling the: benign condi~tionofadenosisto f'ranklynlalignant tumors with invasioni of the pleura and surrounding p<uenchyma): and the marked tendency to: squamous change. Inva- sive bronchiolo-alveolar tumors were found: in, 12' dogs in the group which had been exposed to the largest dosage of cigarette smoke. Several had turnors of more than one category. Ten of these dogs iradinvasiv.e bronchiolb-alveoiar tumors which did not exten& into the pleura, one dog had an invasive bronchiolo-alveolar tumor %vhich extended to the pleura, and fonr hadi invasive bronehiolo- ;aveolar tumors extending, into the! pleura beyond the pleural- pulmonary junctions. In addition, two bronchogenic sq,uamous cell C,u•.cinonlas ,vere foundl in this group (table 19)1. The dosage de- pendence of tumor, formationi is shown in figures: 2 and 3. Major findings of' the study were twofol'd. First, that smoking rilter-tip cigarettes was less harmful, both, ini terms of pulmonary parenchymal darnageand ]tzng tumors, than smoking identical cigarettes without filters. This supports the generally held view that total particulate matter is a, meaningful indicator of the car- cinogenic potential of a cigarette. Second, lung cancer of two types fc,unci in, man was prodluced, by the inhalationi of cigarette smoke. Tn'o~ of!thedbgsw~er~efound to, have earlyinvasive squam:ouscells carcinoma of the bronchus, and both belonged to the high-dosage s:roup. These carcinomas were indistingui'shablle from early invasive sq,uamous cell carcinomas foundl ini the bronchial tubes of human treings, who smoke cigarettes:The majority of tumors found in tHecl«gswere of a bronchiolo~alveolar type, which althoughi notascornmon as squamous cell cancer in man, is not rare in humans,. This t;vpe i:s~ often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 269 p, ~ p , ` . , . !y M6 1W 4.r

TASLE 17. Data on pedigreed znale beagle dogs of groups F, L, H, h, and N (some of the figures app]y only to dogs surviving876 days or longer) Number of dogs on day No. 571 ......................... Weight at start (day No. 1) mean weight (pounds) ...... Cigarettes per dog in 875 days .......................... Mean number of cigarettes per day ................... Equivalentnumber.ofcigarettesp_erdayfor150poundman --.._ Type of cigarettes:2 - Milligrams of tar per cigarette ........................ Milligrams of nicotine per cigarette ................... . Total dosage in 875 days: Grams of tar per dog ................................ Grams of nicotine per dog ........................... _ Dosage in 875 days relative to starting weight: Grams tar/pounds weight ............................ Grams nicotine/pounds weight ........................ Filter group F No filter group - L No filter group H No filter group h Nonsmokers ---group N 12 12 24 38 8 25.0 25.1 26.0 31.9 30.7 6,143 3,103 6,129 6,129 none 7.02 3.54 7.0 7.0 42.1 21.2 42.0 32.9 _- 17.8 34.8 34.8 34.8 - 137 1.85 5 1.85 1.85 - 109.3 103.6 207.8 207.8 -- 7.19 5.56 11.12 11.12 - 4.37 4.12 8.31 6.61 - 0.29 0.22 0.44 0.35 - 1 The smoking dogs were divided into groups F. L, H, and b on day No. 57. 2 Dogs of groups L. H, and h smoked filter-tip cigarettes during a training period at the start of the experiment, but smoked nonfilter cigarettes thereafter. --- Souace: Adapted from Hammond, E. C. et al. (119).

o ~ Filter No No No tip filter tilter filter Nonsmokers Principal cause of death Group Group Group Group Group Total F L H h - N Pulmonary emphysema and fibrosis ..................... Cor pulmonale (pulmonary emphysema and fibrosis with -----' ---- _- .. right heart enlargement) ............................ Pulmonary infarction .................................. Bronchopneumonia .................................... Aspiration of food ..................................... Uncertain ............................................ Number of deaths ..................................... Number surviving 875 days ............................. Total number of dogs .................................. TABLE 18. Sum?nary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, and N - (Each death classified according to most severe condition-some dogs died of a combinntinn of causes listed) SOURCE: Hammond, E. C. et al. (119). - - 2 - - - 3 5 - 8 1 1 2 5 - 9 -_ -_ 8 1 - 4 1 1 - - - 2 - - 2 1 - 3 2 2 12 12 - 28 10 10 12 26 8 66 12 12 - 24 38 8 94

N N N TABi.E 19. Data on dogs with lung tu?nors indicating type of tumor and lobe in which the tumor was found Number Age at Early squamous Group Day of of death Lobes with bronchio]o-alveolar tumors oell bronchial death cigarettes (years) Non-invasive -Invasive carcinoma - SSC894.CO Group N (nonsmokers) ................. N 904a - 5.1 LA N 904b _. 4.9 RA Group F (filter-tip) ..................... F S78a 6.161" 6.1 LA F 879a 6,170 4.7 LA F 885a 6,224 6.2 LA F 890a 6,269 5.4 LA Group L (no filter) ..................... L 347 1,055 3.8 LA, LC L 812 2,847 5.1 RA L 876a 3,103 5.1 LA, RA L 877a 3,107 5.2 LA, LC L 882a 3,127 5.2 LA, LD L 896a 3,183 6.3 LA, RD L 899a 3,195 5.4 LA Group H (no filter) ..................... H 135 518 2.5 RC - - H 259 1,343 3.3 LA, RA, RD . - H 563 3,404 4.7 LD, RA - - H 716 4,689 5.0 .. I,A - H 753 5,030 3.8 RI LA, RA, RD -- H 760 5,088 4.2 LA - -- H 858 5,970 5.3 LA - - H 876a 6,129 4.9 _ LA, LD, R__A H 877a 6,138 5.4 LA LABB H 878a 6,147 5.3 RA LA H 882a 6,183 5.4 LA H 883a 6,192 4.7 R9, RD , RI LA H 885a 6,210 5.0 _ . . LA, RA LMB H 889a 6,246 5.0 LA H 890a 6,255 4.9 LA H 892a 6,273 5.7 LC,_ RA H 892b 6,273 6.3 . . LA. RA H 897a 6,318 5.2 RA - H 897b 6,318 4.6 LC LA

N V W 95CS94E0 Number Age at Early squamous Group Day of of death Lobes with bronchiolo-alveolar tumors cell bronchial death cigarettes (years) Non-invasive Invasive carcinoma Group h (no filter) ...................... h 606 3,769 h 626 3,928 h 649 4,143 b 704 5,400 4.6 LA - 4.4 LA, RI 5.0 RI LA_, RA 5.1 LA, RA - LA, left apica] lobe; LC, left cardiac; LD left diaphragmatic; RA, right start of smoking. The letter "a" or "b" follows the day of death of dogs apical; RC, right cardiac; RI, right intermediate; RD, right diaphragmatic; sacrificed after day #875. LABB, left apical branch bronchus; LMB, left main bronchus. For smoking dogs, the day of death indicates the number of days since Souacg: Auerbach, O. et al. (11). TABLE 19. Data on dogs with lung tumors indicating type of tlttttor and lobe in which the tumor was found (cont.)

GROUP' N:. NONSMOKING GROUP' F: FILTER-TIP TUMORS' 2 4 DOGS 8 1.2 FIGURE 2.-Percent of smoking dogs with t'umars. SoURCE: Adapted from Auerbach,A., O.,,e('11),. 60 0 GROUP N:: NONSMOKERS TUMORS 2 CO~ES' 76 GROUP F: FILTER-TIP 4 84' FIGURE 3.-Percenti of lung lobes with tumors in smoking dogs. SovxcE'. Adapt'ed!flr'om A~uerbach; 0!, eta al. (11)'. 274 GROUP L: GROUP' H: NO FILTER NO FILTER pJYI as, many cigarettes) asGroup H GROUP' L: 19 24' GROUP' H1 NO FILTER', NO FILTER. (0J=~. as, many ~ cigarettes)~) as Group H 35 168

cigaret'tesmoker& (6, 42, 112), but themagnitudee oft'his relation- ship is not as great as that with squamous cell cancer in man. Rr rlicctinn in Z'untorigenicity The importance of reducing total particulate matter in cigarette Srnoke i's~ reflected in th~edose-dependent results of'the Auerbach- Hammond study. A major objective of experimental tobacco car- cinogenesis must be the reduction in the tumorigenicity of cigarette smoke and other, tobacco products. In a recent article (320), 1I-ynder and Hoffmann have reviewed the various methods applied to achieve this goal. Among these methods are the modification of the tobacco itself, the modification of the conditions of tobacco pYro13-~~sis, the use of additives, and the use of filters. The use of tillters should produce ai reduction of particulate matter as well as of gas phase components. Bross, (-~4)studied974casesof lung cancer at Roswell P'ark: Memorial Institute and concluded' that smokers who switched to filter cigarettes showed a decreased risk of developing lung cancer. I lowever, even after switching, heavy smokers were stilF found too have a mortality risk five times that of nonsmokers. More recently, Wynder, et al. (!324) report'ed' on an interview study.of :»/)patients, withhQstologically confirmedi lung cancer and •>5`?' age and sex-matchedi controls. They found that subjects who Iiaci switched from nonfilter to filter cigarettes teni or more years prior to the study incurred a lower relative risk of lung cancer at alllconsumption levels than that incurred by those who continued to smoke nonfilter cigarettes. The authors suuggest that this difference in relative risk may be due to the lbwer "tar" content in filter cigarette smoke. Prospective studies concerning, the effects of filter cigarette smoking are presently being conducted. Apart from variations in "tar" exposure due to filtration, iltt appears that different patterns of smoking result in the inhalation of varied amounts of "'tar.''' Graham) et al. (103) simulated' dif= ferent inhalation patterns with the use of an analytic smoking ma- chine: He found that smoking a given number of'puffs over a long period of'time results in greater "tar" retrieval than smoking them over a short periodl Also, he observed that taking most of the puffs at the end of the cigarette results in the highest retrieval while taking most at the beginning results in the smallest retrieval. Complementing these observations is the same author's case/con- trol study (1112) of 183 men with lung cancer andl 161 men wit'hh diseases not related' to tobacco smoking. He found that the lung cancer patients had significantly greater high "tar"' yield cigarette smoking patterns than the controls, The risk of liang, cancer was found to increase with the increase in mean number of puffs per 275 : ~;:~'

cigarette, the average length of time taken to smoke a cigarette (except in the highest number of puffs category), and the taking cancer and total cigarette smoke condensate exposure: add further support'to the dose-response relationship between lung of'more puffs at the endlofl the cigarette. TheseJindings, and t'h~os~e~ of the study ~ of~ Auerbach, et~all~ (z1'), SUMMARY AND CONCLLISIoN6 the view that cessation of smoking by large numbers of cigarette smokers would' be followed by lower lung cancer dieat'hh rates. 6. Increased death rates from lung cancer have been observed among, urban populations when compared with populations from rural' environments. The evidence concerning tlie role of air pol'lu. tion in the etiology of lung cancer is presently inconclusive. Factors such as occupational and smoking habit differences may also con- tribute to the urban-rural difference observed. Detailed epidemio- logic surveys have shown that the urban factor exerts a small influence compared! to the overriding effect of cigarette smoking inn the development of ' llzng, cancer: ner as to produce higher levels of "tar" in the inhaled smoke, 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers. There is evidence to support smokers who smoke high "tar" cigarettes or smoke in such a man- mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing lung eancer appears to be higher among parently have similar levels of exposure to~ cigarette smoke, thee tion, and, diminishes with cessation of smoking. 2. Cigarette smoking is a cause of' lung cancer in women but accounts for a smaller proportion of' cases than in men. The mor- tality' rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributed to difference in exposure ; such as, the use of fewer cigarettes per day, the use of filtered and' low "tar"' cigarettes, and lower levels of inhalation. Nevertheless, „eveni wYieni women are compared with men who ap- ettes smoked per day, the duration of smoking, and earlier, initia- risk of' developing lung cancer increases with the number of' cigar- the main. cause of lung cancer in men. These studies reveal that the ologiicall evidence confirm the conclusion that cigarette smoki'ng, is tive and retrospective studies coupled with experimental and path- 1. Ebidemiolbgical evidence derived, from a number of prospec- 276

0 ~. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette. ;moking interacts with these exposures in the pathogenesis of Tung, cancer so as to produce very much higher lung cancer death rates& in,those cigarette smokers who are also exposedlfo such substances. ti. Experimental studies on animals utilizing skin paint'ing,, tracheal imstildatlionorirnplantation, and inhalation ofcigarette,moke or its component compounds, have confirmed the presence off complete carcinogens as well as tumor initiators and promoters in. *.uhacco smoke. Lung cancer has been found in~ dogs exposed to the inhalation of cigarette smoke over a periodiof'more thantwo years.. CANCER OF THE LARYNX C'ancer of the larynx is a disease which predominantly affects. m<rl s~ iili t'he~ 55~~ to 70 year~ age~grou~pe fn, 1967,~ a total of 2'~,4'68~ males .-,ndl ;•}0 females died of laryngeal cancer in the United States. Withi rhe develbpment andl application of more effecti've therapy during . f he~ past :~0~ years~~,, the death rate for~ cancer of~~ the lary~nx~ appears! to, be, dropping~ s~lhghtly~ (282, 289) ;~~ however, the~ incidence eon~- inues to rise: Figures from the Connecticut Cancer Registry (88) s~how ~ that~ t'he~ age-adjiusted inciidenee! per~~ 100;00(l~ popul'~atibn~ of' cancei•~of~ the l'arynx~ for~ males~ rose f'rorn~ 3!.0~~ in 1950 to~ 5~.6~ ih~ 196'1.. EPIDEMIOLOGICAL STUDIES' A number of epidemiological studies have investigated the rela- tion:5hip betlween smoking, habits, and the development of eancer~ of the larynx. The major prospective studies, as outlined in table. 20, show that smokers of cigarettes run an approximately six-to- tenfoldl risk of dying from this form of cancer as compared to non- smokers. S4nokers of pipes and cigars incur a three-to-sevenfold. risk. The retrospective studies listed in table A21I uniformly show fewer nonsmokers and' more smokers among cases with cancer of' the larynx than among matched controls. Table A22' suQnmarizes the relative risk ratios derived from the retrospective studies. The, . widev~ariation i'sdue:to~a number of factors, includingtypeof'popu-latibn and interview technique. But, in general~ the magnitude of' most of these ratios is of the same order as in the prospectiiaee studies:. Wynder, et al. (312) have distinguished between cancer of thee intrinsic and extrinsic larynx. Tumors arising, on the vocal cords are classified as intrinsic and constitute approximately 7,0 percent of'the lesions. The extrinsic larynx:is composed of those sectionsof the larynx excluding the vocali cords and' may also be referred to as 277

a y t N V m Author, year, Number and country, type of reference population t TABLEi 20.-Laryngeal cancer mortality ratios (Actual number of deaths shown in parentheses)1 SM - Smokers. NS = Nonsmokers. Prospective studies Number of Data Follow- laryngeal Cigarettes/day Pipes, cigars Comments collect-ton -up- years cancer deaths -- Hammond 187,783 white Questionnaire and males 50-69 and follow- Horn,_ years of age up of death 1958, in 9 states. certificate. U.S.A. (120). Doll and Approximately Hill, 41,000 male 1964, British Great physicians. Britain (74). Kahn U.S. male (Dorn), veterans, 1066, 2,265,674 U.S.A. person years, (139). Hammond, 440,558 males 1966, 562,671 fe- U.S.A. males 35-84 (118_), years of age in 25 states. 31/•-. 24 Cigarette smokers 17/24. SM . .24 NS .. 0 Cigar Data referring to mortality 3/24 ratio included cancer of Mixcd esophagus and mouth. 4/24 Questionnaire 10 16 All smokers by amount - Pipe and cigart f Includes data on ex- and follow- up of death certificate. SM ..16 NS .. 0 NS 1-1-4 15-24 >25 in grama .............. .. ............ 1.00 ............ 1,00 .............. 7.50 NS ... . 1.00 NS SM . . 5.00 smokers of pipes and cigars. No o NS died of laryngeo- tracheal cancer, therefore 1-14 gram SM set as 1.00 standard. Data combine laryngeal and tracheal carcinoma. Questionnaire and_ follow- 814, 54 SM ..61 NS 1-9 .............. 1.00 ............. 3.27 (8) (1) Pipe NS .... 1.00 (3) Refers to cuixentcigarette smokers only. up of death NS .. 3 10-20 ............ 8.45(10) SM ....10.33 (6) certificate. 21-39 . ............ .13.62(11) Pipe and cigar >39 All ............. 18.85 (3) .............. 9.95(25) NS SM .... 1.00 (3) .... 7.28(11) Interviews 57 NS ............. . 1.00 (3) Pipe and cigar Male data only. by ACS SM ..54 SM (age 45-64) .. 6.09 (32) NS ... . 1.00 (3) Pipe and cigar data refer to volunteers. NS .. 3 SM (age 65-79 ) .. 8.99(18) SM ... . 3.37 (4) males 55-84 years of age.

;k x Prospective studies Number Author, o€ year, Number and Data Follow- laryngeal Cigarettes/day Pipes, cigars Comments country, type of- collection up - cancer - reference population years deaths Weir and 68,153 males Questionnaire 6-8 11 NS .............. - No nonsmokers died of Dunn, in various and follow- SM ..11 ±10 ............. 1.00 laryngeal carcinoma, 1970, occupations up of death NS .. 0_ +S0 ............. 5.09 therefore±l0 smoker s_e_t_ U.S.A. in Cali€ornia__._ certificate. >30 ............. 5.84 as 1.00standard, (306). NS includes_ pipe and cigar smokers. SM includes ex-smokers. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion ---- of either occasional, miscellaneous, mixed, or ex-smokers. TABLE 20.-Laryngeal cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smokers. NS ~ Nonsmokers.

the hypopharynx. These authors noted that the percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls.. However, it is of interest that the excess risk of' laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of laryngeal cancer. Wynder, et al. (312)' reportedl a significantly increased' risk of extrinsic cancer among those with alcohol' intake above 7 ounces of whiskey per day. With less than this amount, no increased risk was evident..Schwartz, et al, (248), not'ed no effect in relation to alcohol intake. Further research into the interaction of'these two variables is necessary. PATHOLOGICAL STUDY Auerbach, etal: (9) studied histological changes in the larynges of942' men, age 21 to 95, who wereautopsiedl at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx «~-ere excluded from the study. Srnoking, histories for al'11 cases were obtained from family members of the deceased by trained inter- viewers. The randomi'zed histological sections were graded by one observer. Tables A23 and A24 summarize the findings in the true vocal cord. Of'the men who never smoked, 7& percent hadl no cells with atypical nuclei, only 4.5 percent had sections with areas con- taini~ng 6'0to69 percentofcellswi~th atypical nuclei'; and none had~ a hQgherpercentlage: The1116 ex-smokershad~ laryngeal histology similar to that of the nonsmokers, as far as atypicat nuclei were concerned. However, disintegrating nuclei were found in 40.5 per- cent of the ex-cigarette smokers and in only 0.4 percent of theg remaining cases. Only one of the 94 cigar and; or pipe smokers had no atypical cells. Three had carcinoma in situ, and one case~ had a section showimg early invasive primary carcinoma. The highest percentage of atypical cells was found among the cigarette smokers. The proportion of' cases with a high degree of cellular ehange~ increased with increased dail.V smoking. Nloneof the pack-or-more-a-day smokers was free of atypical nuclei in the laryngeal epithelium. Of those who smoked two or more packs per day, 85 percent had lesionswi'th60s percent or more atypical cells as compared to 4 percent of the nonsmokers, Between 10 and 18 percent of the cigarette smokersliadl areas of carcinomai,n situ, and 4 of the 644 cases showed earlyy microscopic invasion. The thickness of the basal lievei of the true vocal cordi was also directly relkated to the amount smoked. 280

EXPERIMENTAL STUDY li D~outenwilll (7'6)~ has~ recently ~ reported tihe~~ development of~ an elfective ~ and~ practicable method by which~ small r.odents~~ (ham- sters, ratls; milce~)~ can~ be~~ exposed to long-ter~mi passive inhalationiof' cigarette~ smoke in~~ a manner which circumventls~ the~ fatal effiect'& of~ acute toxicity ~ which~ ruined earlier atltempts~~ but~allows for a dosage~ of smoke great enough to induce the development of chronic patlio. logical changes. The Syrian Golden hamster was found to be the most yuita ble species for such inhalation experiments~ for~ several re,l its~resistanee!to~pulmonary.~infeetibns, its resistance to the effect~, of'niicotine.as compared to that of rats or certain strains of mice, and„ especially,, i~ts~ sus~~ceptibilitiy to~~ devel~op ~ tracheobronchial cancers after treatment with carcinogens; in~ contrast to iits almost total freedom from the~ spontaneous~~ development of these~tum~ors~. Dbiitenwill demonstrated that the concentration of deposited cigailette~ smok~e~ was~ greatest~ in t~he~ harn~ster''s~ larynx~ as~~~ comparedd t~o~ the~ otlher~ portions~ of~ t~he~ exposed respiratory tract~ (tabl'~e~ 25)~, <uic3" that the laryngeal' epitheliumi was~ the~tissue, which~ underwent rnc~ gre ctes~t smoke-induced histolog~icall changes. In s~tucl~,ri~ng the~ chang~es~ ini the~ larynx, the, author~ differentiated ffi-z~ ~4talges of epitlheliad change;, using~, as~ his ref'erence~ the Atlas of "1'un7ol! Pathology of the Armed Fox•ces~Institutle of~P'athology ~~ (5)~~., Table 26, quoted by Dontenwill, describes the five types of change: Th:t-Y range~~ fromi benign, su~~ch~ a& epithelial hyperplasia, to pre- maliignant, exemplified by ~pseu~d~~oepitheliomatous~leukoplakia. The result;:> of the inhalation experiment are presented ini figure I iiir whichia closage~-related' increase inithe~ severity ~~ of~ the epithelial cii~zanges is ~ r.epresen ted! in graphic f©rm. The author ~also~ reported, <<nci depictedl withi photomicrographs, the find~in~g~ of an ~ early ~ in~va- si~~-e sctuanlouy celli carcinoma. This form of cancer is the predomi- nant tYpe involving the human larynx. SL'riTMARY' AND CONCLUSIONS 1. E'pidemiological, experimental, and patholbgical studies sup- port the conclusion that cigarette smoking is a significant factor in; the causation of canceroft'he1'arynx. The risk ofdeveloping laryngeal cancer among cigarette smokers: . as well as pipe and/or cigar sniokers is significantly higher than among nonsmokers. The magniYude off the risk for pipe:and cigar smokers is about the same order as that for cigarette smokers, or possibly s~lightlylbwer.`_'. Experimental exposure to the passive inhalation of cigarette ymokeha~s been observed top>>oduce premali~gnantand malignant changes in~ the larynx of' hamsters.. ,; 0,

Tns1:E' 25.-Deposition of 14C-la6eled smoke particles in particular regions of the respiratory tract' Traced Ti-aced'. Estimate& DepositionProportionali depositionn radio- radio- of area of'the in relation Organ activitpOrgan activity, particlesres~pii•ataryto2he. (nCi) (hCi) (~/c) tractt proportional area Head and palate ... 6'.11, Tongue ........... 0.41 Larynx ........... 0.391I Trachea .......... 0:26 (`I Lungs ............ J 6.95 Total ......,.14,12 Head, palate 5.5' 37.4 Oral cavity 1.6' 10:'J in total. 0,1-0:3 X561-187 7:6'(traeed): 51.7 0.6I X62:3 1000' X1 =14.7 100.0 1 Cigarettes labeledd with "C-1-n}hexadeean:.: data represent mean valuess from. 100 animal9, calhulatedd f'rom, s,u.rface distribution in thehead. =fihe valueof' 1417 ' contains. 0.5Rnanocuriesas estimated firomm quantityof'depo.sitiony in the nontraced' oral cavity regions.(calculated as to proportional area.). SoupcE,: DontenwillJ W. (76)..: 282'

Stage TASLE 26.-Classiftcation of the five registered stages of epithelial changes at the larg/nx', = 1. Pachydermia (epithelial hyperplasia) ................ 2. Leucoplakia ........................................ 3. Yerrucuus leucoplakia ............................... 4. Papillomatous leucoplakia ........................... 6. Pseudoepitheliomatous leucoplakia ................... + + + + + + + t + + 1 Symbols: t= negative; $- minimal; +- weak; +-i- - medium; -•--}--}- = strong. z From Atlas of Tumor Pathology of the Armed Forces Institute of Pathology. 9ouxce: Adapted from Dontenwill, W. (76). Dyskeratosis (pre- mature atypical Acanthosis (thicken- I-lyperkeratosis Parakeratosis (in- cornification ing of stratuminereased complete cornifica- changes in the Mitosis spinosum multi- cornification tion of nuclei in nucleus prolifera- cellular layer) (stratum corneum) thestratum corneum) tion of the basal layer) t t t $ t $ + $ $ t ++ $ + ++. -i-

TOTAL 146 4 0 e i 34 35 8 6' 10 7' 11 4' 5 17 4 5 « ~., ««,«« « «« « ««« ««, . « .. .. « . I «. I I . « . + I .. «««« « «««« . «• «. ««.«« «c. « «r ««. I «. «. i«. « .':••IN • . . «. . • ..« 2 4 6 8 10 112' 141 16 SMOKE EXPOSURE, months 18 20 22-->28 « -ONE' ANIMAL +-ANIM'AL LIVING O-LARYNX' CANNIBALIZED FIGURE 4,-Effects of'chronie cigarette smoke inha]ation on the hamster larynx.R:eview of the results of the inhalatian experiments: number of smoke-ex- posed animals with~ and without changes in the larynx, duration of'smoke exposure, and number of animals still alive. SOUACE: Dontenwild,,w. (76)!., ORA'L CANCE R The cancers included'in this category are those of the lips, tongue, floor of the mouth, hard and soft palate; gingiva, alveolar mucosay buccal mucosa, andl oropharyns. It is estimated that 15;000 of these cancers will be diagnosed in the Un2ted States in 1970,, accounting for about 2.5 percent'' of the estimated 600,000 malignant neo- plasmsreported (289). A variety of histologicaltypes' of malig= nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the: cancers. The incidence of andi mortality from arali cancers ha& remained steady over the past 20 to W years. The Connecticut Cancer Reg- istry (88)', which is a fairly reliable index of incidence, noted thatl the incidence among, rnades remained, between 15.8 and 16.3 per. 100,000 population during the years fromi 1950-1961. Examination of mortality rates over the past 20 to 30, years (282, 289) reveals a similar constancy. The apparent lack of ehange~ ini mortality from oral cancer ini 284

contrast to the sharp increase that took place in lung cancer rates in those years~ is~~ probably~ dhe to several of~~ the ~ following factors. First„pihe and cigar smoking are both significantly related to can~- cer of ~~ the~ or.a1~~ cavity, and the! increase ini cigarette smoking among men, notecli between 192~0~ and 1955, has~ been, tlo~ a large degree, accornihaniedl by ~ corr~espond'ing~, reductions in the use of' pipes, andd cigars. Second, aside from the various changes which the Interna- tionad Classification of~D~iseases~~ (IICD~,) had! ~ undergone during that~t period, the diseases discussed above are recordedl in ICD Codes 1~1~U-1~-18 whi& inclkldle sorne~ neopl'asms~ not found t'o~ be~ relat'edl to~ the use of tobacco: The various sites of' cancer themselves do nott r-ontrilnite equally to the overall rate and are subject to widely dif- ferent cure rates;, so that their contributions to the total incidenee rate~ is~ different fromi their contribution to the overall! mortality~ rate from oral cancer. Although more than 20,000' cancers of the. (>> al c<i~-it,v were estimated as newly diagnosed in 1967,, the totall of individuals recorded as dying from~ ora~ll cancer ddring~ ti?,it~ Year~ was~ only ~ 6,718 (28,41)~. Oral cancer occurs~ pred'ominantl'y~ in people~ of the~ rn~iddle~ and (''.(1er<<,c.fe groups. More than 90 percent of' all oral cancers occur in 1wrsons~ over age 45, with tlhe~~ average~ age at~ time of~ diagnosis apl)rotiinYating~6~0~. Although t'he~maj~ori'ty~of'oral cancers oceur~~in m~t~71. :~here is, recent; evidence that the rati& of~ males, affected to i eniules affected is,deereasing (257). EPIDE MIOLOGICAL STUDIES '1'he~ us~e~of tobacco~~im~ various~ forms~ has~ been associated w~~ith~ the dei-t,lopnlent of~caneer~ of~the oral cavity~and pharynx. The~studies ir, this area of~~ concern a~re~truly international, many~ having~ been carried out in Asian ii~ationsa.9well as~in the~West. The major proshocti've epidemiologiical~~ studie& have~~ found in- creased rates of these~ ct.ncers, for cigarette szMokers~'as~~ w~elll as for pipe~~ andl cigRzr~ smokers~ (see tiab~lle 27). Pipe~ smoking, per~ se, h~as~ 1!mg ~, been recog~nizedl as~a cause~~ of~ lip~ cancer~~ (291). Th~e~rnethod~o1- (1t,°Y ancl re.;ultlsof the numerous retlrospective studies are sum- m~arize(l in tables A2& and A28a. These~ stlu~dies~~ almost uniformly show ~significant rel~ationships,betweenithe~various~forrn~s,of tobacco use~,i~nKll : , ,~ f`h~e~ oral cavity~ and pharynx. .'--i~an r, ~"ir)ns have~ examined t'he~ prevalence or~ i:nei-~ dence~ ot~ i)~'eniaii~,r~nant change,, such as~ oral leukoplakia, as well as, that of cancei of~the~oral eavity..~Inimany~of~these~studi'es„forms~of~ toba~cco; use not prevalent in Western, count'ries: have~~ been investi~-~ gated, iincludiiig~ reverse~ smoking~ (in which: the lighted end of~ the ~ ci,~.,rarette is~ kept, in, the mouth cl~ose~~ to~th~e palate)~ and~ the~ ch~ewing, 285

CO Q TAB1.E 27.-Oral cancer mortality ratios-prospective studies (Actual number of deaths shown in parentheses) SM- Smokers, NS = Nonsmokers. Author yeac, Number and Data Follow- Number country, type of collection up years --of--- Cigarettes P-ipes, cigars Comments reference population deaths Hammond and Horn, 187,783 white males in 9 States 50-69 Questionnaire uestionnaire 31/, and follow-up of death tSM NS 56 ..51 .. 3 20/5_6_ ~ Pipe Mixed 5/56 21/56 Cigar Data referring to mortality ratio do not include cancer of larynx and esophagus. 1958, U.S.A. (120). years of age. certificate. 5/56 t Excludes two occasional only smokers. Doll and Approximately Questionnaire 10 19 A(1 emokera 6y amount Pipe and cigar No NS died of oral cancer, Hill, 41,000 male and follow-up SM ..19 in grams NS ....... 1.00 therefore 1-14 gram 1964, British of death NS .. 0 NS .............. - SM ....... 1.00 smoker set as 1.00 Great physicians. - certificate. 1-4 ............. 1.00 standard. Britain 15-24 ............ 0.25 (74). >25 ............. 5.25 - -- Kahn U.S. male Questionnaire 81/ 61 NS .............. 1.0001) Pipe Data do not_ include pharynx. (Dorn), veterans, and follow-up - SM ..50 ..-- tCigs/day 1-9 .... 0.86 (1) NS ....... 1.00(11) f Refers to current cigarette 1966. 2,265,674 _ of death NS ..11 10-20 ............ 2.93(13) SM ....... 3.12 (4) smokers only. U.S.A. person years. certificate. 21-39 ............ 7.34(20) Cigar (13s). >39 ............. 5.73 (3) NS ....... 1.00(11) All .............. 4.09(37) SM ........ 4.11 (9) Hammond, 440,558 males Interviews by 4 95 NS .............. 1.00 (7) f Pipe and/or t Male data only. Pipe and 1966, 562,671 females ACS volunteers SM ..88 SM (age 45-64) .. . 9.90 (63) cigar. cigar data refer to males U.S.A. ft5-84 years of NS .. 7 SM (age 65-79) .. 2.93(25) NS ....... 1.00 (7) 55-84 years of age. (118). age in 25 States. SM ....... 4.94(15) Weir and 68,153 males Questionnaire 5-8 19 NS .............. 1.00 SM includes ex-smokers. Dunn, in various and follow-up '!-10 ............. 3.69 NS includes pipe and 1970, occupations of death ±20 ............. 1.17 cigar smokers. U.S.A. in California. certificate. >30 ............. 5.52 (306). All .............. 2.76 69ess4co

(Pf "p;ln" or "Nas~s,"' which are mixtures,of t!obaccow~itheither betel nut or lime ash, and other ingredients (241, 255,, 256). Snuff (Iippittt,r. a habit in which snuff is placed in the gum and retained there for prolonged periods, has also been associat'ed' with the deVOloprnent of oral cancer (193, 210), as has the chewing of t'ul).aeco(1,'';, 193, 2411,293').. 'I'he risk of developing a second prim.ary mouth or throat cancer;, ;,ftcr the recognition of the first primary cancer, has been found'' to 1,e greater in continuingsmokers, than in those who quit srnok iiig. A11i of the patients studied by Moore (190) were asymptomatic. i r:it IL;tst three years following the treatment of the first cancer. t> f' t he 117 patients with adequate smoking histories,, only 4 of 43 (:) percent)wYr& quo:tsmoking developed anewprilrnarycancer. ()n the other hand, 27 of 74'(36'percent)i who; continued t'osmoke i~ ~~ Ik,pecli a second primary cancer. E1ov,uver, a study by Castigliano (53) of patients treated for 1•; 11 r;:ncer did not show a greater risk~: of a second primary among iz.-- smokers, In this study, 5 of:26'(19: percent)~ of tlhose;:'.4 nt who dirl not quit smoking develbped a seeondl primary ras compared to 9 of511 (18 percent) of those who did quit. Tl~~(!, )'ate of quittingsmokinginthet'wo studies is markedlyd7f- c~ i t (1:;fS percent in the Moore study andl 62 percent in the Casti~- :. Stucly) . From the data presented in the two papers, it is not to evaluate the other significant ways in which the pop- ;ti;itiiwnh may have differed. 1:~1'ier (140) studied 408 males~withhistologiically confirmed ~(ill;«n()tt~s cell cancer of' the mouth or pharynx.Thi~sauthor d'ealt tiie question of recurrent tumors in a somewhat different mant).ur. 'Ilhe patients were observed for the development of a sec- 6n(d (~i• third primary cancer at an anatomically discrete siite of .ht:~ mo,uthandpharynxwithi'n a medianperi:od of'three years afterr thetirst cancer. He found tlhat'ai second or third cancer(;ter~medi acoexistiilg, cancer')developed in 2'8ofthe:4'08 cases. Among these'_'ti cases with *; coexisting, neoplasrns, 21.7 percent were heavy snlokers, btrtamong, theirmatched''controls; there were no heavy sniukers. Coexisting cancers were most commonly found on the soft 1?it l<<te, an anatomical site! thati& in direct contact withth~ema:in- streani of tobacco smoke. \forerecentl'~y,ti'~ynder, et a1l (3~1'5)studiied 6~male and 23' f,t•niale patients with multiple primary cancers of the mouth and ph,irynx. They observed that heavy smoking prior to the devel''op- rnent of ' the oral cancer, was associated with a greater likelihood ofdevelbping a second primary. Also, continued smoking, after thetir;t primary was found to have a significant association withi the occurrence of a second primary. 287

With or without smoking, use of alcohol appears to contribute to the develbpment of oral cancer (124, 140; 18:, 297, 322)~. In a study of' male veterans, Keller (140) found that heavy smoking and heavy drinking were associated with cancer of the mouth and pharynx. No studies are presently available which determine the relative contributions andl possible interactions of' heavy smoking, heavy drinking, and concurrent nutritional deficiiencies in the etiol- ogy of these cancers. EXPERIMENTAL STUDIES In 1964,, the Advisory Committee to the Surgeon General on SYnoking and Health (291)' reported that cigarette smoke and ciga- rette smoke eondensateshad' failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate' of hamsters and that the oral mucosa appears' to be resistant in general to can- cer induction even when highly act'ive carcinogens such as benza [a]pyrene are applied. Some of the difficulties in experimental de- sign~ were attributed to the fact that mechanical factors, such as secretion of saliva, interfere with ther.et'ention of applied carcino- genic agents' on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained iln the hamster cheek pouch, but it has also been pointed out that the cheek pouch lacks sal.i'varyy glands and that its structure and func- tioni differ from those of the oral mucosa. The majority of'these studies are outlined in table A29: Although cigarette smoke condensate acts as a complete carcino- gen oni mouse skin, the work of several authors (319), supports the concept that cigarette smoke contains cancer promoters that may be of' special importance, particularly in oral carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch, More importantly, regarding the chewing of tobacco, Bock, et a]. (27,30), Van Duuren, et a]. (294), and W'ynder and Hoffmann (321'), have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting, activity of the' smoke. Roth, et al. (226, 227) have shown that the dye-binding capacity of' the~ DNA of' oral epi~theli'~a31 cel~ls~ is~~ significantl~y enhancedl in cigarette smokers in contrast to nonsmokers, probably reflecting an increase ini the DNA content of oral epi'theliali cells in smokers. Smokers hadi values of dye-binding capacity intermediate between nonsmokers and' 21I patients with proveni oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal values. 288

SUMMARY AND COIvCLUSI0Ir1S. 1. Epidemiologiicall and experimental studies contribute to: the conclusioni that smoking is a significant factor in the development of' cancer of the oral cavity and that pipe smoking, alone or, in conjlunction with other for.ms of tobacco use, is causally related to cancer of the lip. 2. Experitnentlal'' studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4„306 deaths among American males in 1967 and 1',321'deaths among females, The deat'h rate from esophageal cancer has remained relatively constant since 19-19'. EPIDEMIOLOGICAL STUDIES The major prospective epidemiolbgi'cal studies (table 30)~ have indicated a significant relationship between smoking and esopha- geall cancer. Overall mortality ratios for male cigarette smokers range from~ 11.7-I' to 6+17: There are insufficient data concerning fensales, for establishing firmconclusions. A number of retrospective stud7es concerning the relatibnship of smoking and esophageal cancer are! outl'inedl in table A31 and A.,1a. Smokers incur risk ratios ranging, from 11.3 to 6.6 when compared with, nonsmokers. As in studies of oral cancer, the effect of alcohol consumptionn must betaken into account in studies of esophagealeancer: Because a relatibnship between alcohol consumption and tobacco use is kno«ai to exist, Wyzid'er and Bross (310) analyzed the association between tobaceo consurnptioni andl esophageal cancer after adjust- ing f©rr alcohoL intake. They found t'hat' in the absence of alcohol consumptibn~ there was no association between the use of tobacco and esophageall cancer but that i'n the presence of aleohol consurnp- ti'on, an increasing relative risk with increasing number of ciga- rettes smoked was apparent, as well as an association between cigar~ and pipe smoking and esophageat caneer., More recently, Takano, et al. (272), in a retrospective study of •?0'0patient,~with esophageal carcinoma, found ani increased risk With smoking which was magnified by increased! alcohol consuQnp~ tionL 'Martinez (183), analyzed the association of' tobacco, usage and esopha;g,eall cancer after controlling for age, sex, and alcohol consumptiioDL Increasing relative risks with increasing tobacco use 289

a' TABLE 30. Esophageal cancer mortality ratios--prospective studies --- - (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, Number of -year,- Number and Data Follow- esophageal country, type of collection up years cancer Cigarettes/day £ipes,cigars Comments reference population deaths Hammond 187,783 white Questionnaire 31/•_, 34 Cigarette smokers Pipe Mixed Data referring to and males in 9 - and follow-up NS ... 1 15/33. 2/33 cigarette mortality ratios Horn, States 50-69 of death SM ... 33 Cigar smokers included cancer 1958, years of age. certificate. 2/33 13/33 of mouth _- .--------- ------------ -~ - -- -- -- U.S.A. and larynx. (120). Doll and Approximately Questionnaire 10 29 All smokers by amount tPipe and cigar tIncludes ex- Hill, 41,000 male and follow-up in grams NS .... 1.00 smokers of pipe 1964, British of death NS ...... 1.00 SM .... 2.00 and cigars. Great physicians. certificate. 1-14 .... 2.00 ----------- ------------- Britain 15-24 .... 3.50 (74). >25 ...... 5.00 .. .. All ...... 3.00 Kahn U.S. male Questionnaire 8? + 111 NS ...... 1.00 (11) (Dorn), veterans and follow-up NS ... 11 fl-9 ..... 1.76 (2) 1966, 2,265,674 of death SM ...100 10-19 .... 4.71(18) U.S.A. person years. certificate. 20-39 ....11.50 (24) (139). >25 ..... 7.65 (3) All ...... 6.17(47) Pipe t Refers to 1.99 (3) cigarette Cigar smoking 5.33(12) only. Hammond, 440,558 males Interviews by 4 46 NS ... .. . 1.00 (6) Pipe attd Cigar 1966, 562•671 females ACS volunteers. NS ... 6 SM (age NS . .. . 1.00 - - - U.S.A. 35-84 years of SM ... 40 45-64) . 4.17(32) SM r•.. 3.97(14) (118). age in 25 States. SM (age 65-79) . 1.74 (8)

._. TABLE 38.-Fsopltugcal crcuiecr iua_1•tatit,+l >~atrus-~t'etst~r~ tiue shtcties (coiat.) (Actual nunibe_r of deaths shtnvn in parenthcsis) SM- Smokers. NS = Nonsmokers. Author year, Number and Data Follow- country, type of collection up years reference population -- H_ irayama, 265,118 male Trained PHS 1?!. SM .. . 21 NS ...... 1,00 (p<0.01) Refers to all 1967, and female nurse inter- SM ...... 2.-47 (21) forms of Japan adults 90 view and smoking. (125). years of age follow-up and older. of death certificate. i j Weir and 68,153 males Questionnaire 5-8 32 NS ....... 1.00 NS includes pipe Dunn, in various and follow-up -t10 ... .. . 1.27 and cigar 1970, occupations of death ±20 ...... 1.69 smokers. - - U.S.A. in California. certificate. >30 ...... 1.82 - - (sOB). All ....... 1.82 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual ividual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

were noted. The consumptioni of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGICAL STUDY Autopsy studies of smokers as compared withi nonsmokers, spe- cifically observing the pathological changes in esopliageall tissue, have been performed by Auerbach, et al: (15). A microscopic study was made of 12;598' sections of esophageal autopsy tissue fromi 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epitheliumL)usophageal epithelial cells with atypical nuclei (having ani irregular distribution of chromatin)' were found far more frequently in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers, An, increase in frequency with amount of cigarette smoking was noted for bothh epithelial cells withi atypical nuclei and basal cell hyperplasia.. Tables A32 and A33 summarize these findings. EXPERIIWIENTAL STUDIES Kuratsune,, et al. (1'56)' investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studiediby fluorescence microscopy. Deeper penetration and a different distribution were found when B'[a]P' was dissolved in aqueous ethanol as compared to B'[la]P in olive oil. It was also found' that benzo [a] anthracene and fluoran- thene dissolvedl in ethanol solution or aqueous caffeine solution could penetrate the epithelium, of the esophagus:. H'orie, et al. (132)' reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink ai solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also develbped in a group, of' 63 mice to which, 4-nitroquinoline 1-oxidle was administered in the same way. None of the 67 control animals given only dfilut'edI ethanol developed neoplasms. Several other authors have reported nitrosamine-ind'uced' esopha- geal cancer in experimental animals (56, 79, 80; 81). As noted above, the presence of nitrosamines in cigarette smoke is stilll a subject of debate. {

SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrat'ed that cigarettee smoking,i's associated with the development of cancer of'the esopha. gus. The risk of developing esophageal cancer among pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studiies have also indicatedi an association be- tween esophageal cancer and alcohol consumption and'tithat alcohol consumptlion may interact with cigarette smoking. This combina- tion of exposures is associated with especi'a1Iyy high rates of cancer of the esophagus. CANCER QE THE URINARY BLADDER AND' KIDNEY EPIDEMIOLOGICAL STUDIES ('BLA'DDE%)' Cancer of the urinary bladder accounted for 6,019 deaths among Arnerican rnades andi 2,743 deaths among American females in 1967 (28>~).Ilncidence rates have increased fromi 1949 to 1962 (88), bu'ttlhe death rates from bladder cancer have remained relatively stable during that period. Improvements in early diagnosis and. therapy may have masked the increasing incidence of'this disease: A number of'epidemiologicaI studies have indicated that smokers have ani increased risk of contracting or of dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney cancer, mortality in the results. The nrnajar, prospective stud- ies, with tiheexception of' that of' Britishi physicians,, have shown, bladder cancer mortality ratios among cigarette smokers ranging, from 1.40 to 2.89. ,S~mokersof more thani 1 pack per day were sh'ownn to incur ratios of 3.42 to 5.41. The study by Doll andl Hill (74, 75)) of Bi•itish physioians, on the other hand, reports death rates for smokers to be lower thani those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers are substantially lower than those among cigarette smokers. Pipe smokers were~shown by both Hammond and Horn (120) and Kahn (13!9)toincur ratios, approxirnating, 1.20. Retrospective studies (table A35a): have also shown an increasedd proportion of smokers among bladder cancer patlients when com- paredi with matched controls: Relative risk ratios for bladder can- cer among, smokers range from 1.0 to 7.3' among all smokers and up to 10.3 among heavy smokers of all types. 293

N ~ A TABLE 34.-Kidney and urinary bladder cancer-prospective studies-Mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, year,-Number and Data country, - type of collection reference population Follow- Number up years of Cigarette/day Pipe, cigar deaths Hammon_d__ 18_9,783 white Questionnaire 31/2_ and males in 9 and Horn, States. interview. 1958, U.S.A. (120). Doll and Approximately Questionnaire 10 Hill, 41,000 male and follow- 1964, British up of death Great physicians. certificate. Britain (74). Best, Approximately Questionnaire 10 1966, 78,000 male and follow- Canada Canadian up of death (21). veterans. certificate. Hammond, 440,658 males Interviews by 4 1966, 562,671 ACS U.S.A. females volunteers. (118). 35-84 years of age in 25 States: 287 NS ._,. 1.00(38) Pipe <10 ...'2.00(14) NS ...1.00(38) SM .249 10-20 .. 2.00(42) SM ...1.17(21) NS .. 38 >20 . . . 3.42(41) Cigar NS ...1.00(38) SM ...1.06(19) 38 NS ...1.00 SM ...0.41 114 NS .... 1.00 Pipe <10 ... 1.33(29) NS ...1.00 10-20 . . 1.44(67) SM ... 0.5600) >20 ... 1.43(15) Cigar All .... 1.40(10) NS ...1.00 SM ...1.16 (3) &laddcr - 138 SM .115 NS .. 23 Kidney 104 SM . 82 NS . . 22 Kidney Bladder Cigarettes NS ............... 1.00(22) SM (age- 45-64) .. .1.42 (64) SM (age 65-79) ...1.57 (28) All SM by amount in grams NS ...1.00 1-14 ..0.59 15-24 . .0.65 >25 ...0.76 All ....0.71 Comments Data include patients dying of prostatic carcinoma. Data refer to pi_c_a__lly microscopically proven carcinomas. Refers to genitourinary cancers as a group. Cigarettes Male data only. 1.00(23) Bladderincludea 2.00(59) other urinary 2.96(56) tractcancerst h,GCS94C0

P eLCs94co l IM ) Ahl.p; 1~I. /iida('1[ O1Frt` r6r'r,Mn yb_lrnli(t.,~ C[llt,', 01 cUf S(d[Cl[C_S--)fOY(((lFtly rEf(SttF± (cUlkt.) IActu:,l nuniha_• nf Jrnth:: :h-cu iu U:Irrnthr;i:1' . 5~1 u Smukor.5. NS Author,_ year, Number and Data Follow- Number country, type of collection up years of reference population - deaths Kahn U.S. male Questionnaire 81/. B{adder (Dorn), veterans and follow- 224 ------ ------ ------- - 1066, 2,265,674 up of death SM .172 U.S.A, person certificate. NS .. 52 (139). years. Kidney 141 SM . .102 NS .. 39 Hirayama, 265,118 male 1967, and female Japan Japan adults 40 (125). years of age and older. Weir and 68,153 males Dunn, in various 1970, occupations U.S.A. in California. (sos). Cigarette/day Pipe, cigar Kidney Trained PHS 1~~. SM NS .... 1.00 nurse inter- SM ....10.00 (6) view and follow-up of death certificate. Questionnaire 5-8 Bladder and follow- 27 up of death Kidney certificate. 27 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. NS ............... 1.00(39) Pipe .............. 1.32_ (6) Cigar ............0.77 (6) Cigarettes/day: 1-9 ............ 0.97 (4) 10-19 ........... 1.34(21) 20-39 ...........1.68(16) >39 ............. 2.75 (5) - All ............... 1.45(46) Bladder Comments 1.00(52) Bladder includes 1.20 (8) other urinary 0.94(10) tract cancers. 1.10 (6) 1.93(37) 8.20(34) 2.52 (5) 2.15(82) Bladder cancer only. Refers to all forms of smoking. NS ...1.00 NS ...1.00 SM include ex- ±10 ..0.86 -±'10 ... 1.52 smokers. +20 ..3.30 ±20 ...2.81 NS include pipe -- - >30 ..2.57 >30 ... 5.41 and cigar All ...2.46 All .... 2.89 smokers.

EPIDEMIOLOGICAL STUDIES (K~dDNEY)~. A total of 5,894 Americans died of cancer of the kidney during 19!6'Z. A relationship between smoking andl this type of cancer has been suggestledl by several epidemiological studies. The three major studies which separately examine the relationship of'kidney cancer to smoking (table 34'),, namely those! of Hammond (118),, Kahni (139), and Weir and Dunn (306), have shown mortality ratios for all cigarette smokers to, range from 1.42' to 2.46. Retrospective studies by Bennington, et aL (18, 19)' have indicatedi a significantl association between all forms of smoking and renal adenornal and ad'enocarcinoma. EXPERIMENTAL STUDIES Numerous experiments have been undertaken by many investi- gators to elucidate the relationship of tobacco smoking t&bladder carei'nogenesis. The two areas of major concern have centered upon the presence of' a known bladder carcinogen, beta naphthylamine, in cigarette smoke andl the presence of abnormal tryptophan me+ tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial' exposure of workers, beta naphthylarnime has long been knowni as & bladder carcinogen. Complernenting such data was the work of Hiueper, et al. (136) who subjected mongrel dogs toidaily subcutaneous injec- tions and oral administration of commercial beta naphtihy lamine.. Thirteen of the 16 animals deveioped bladder papillomas and car- cinomas of the bladder. S'affiotti, etl a11, (236)', fed hamsters a diet containing up to 1.0 percent' beta naphthylamine and observed that 1!8 of 39' anilmals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et a1L (59) ad- ministered beta naphthylam2ne to~ 24 rhesus monkeys for more than 30 montlhs.. Transitional cell carcinomas of the urinary blad- der were indiacedlin 9 of'the! aniinals, and a dose-response relation- ship was apparent. Pailer, et al. (207) and' Miller and St'edinan (185)~ failed' to iindd t'his amine in cigarette smoke., However, more recently, Hoffmanns et al. (127)' identified it in cigarette smoke. The authors, noti'ng the minute quantity present in each cigaret!te (2.2' x 10"g), hesi~ tated' to attach a biological significance to the finding. Of more recent interest have been the metabolites of tryptophan present in certain patients withi bladder cancer. A number of nor- mal and abnormali metabolites of tryptophan have been found, to be carcinogenic when tested, by implantation in the bladd'ersof mice. These include 3-hyda•oxykynurenine (OHIs,y), 3'-hydroxyanthranilic. 29Cr

E 0 acid (OHA), 3'-hydroxy-2'amino~acetophenone (ala orthoaznino- phenols)„the 8-methyl: ether of xanthurenic acidl (CHXa), xanthu- renic acid1 (Xa), Lrkynurenine (Ky), quinaldic acid, and 3-meth- nx, vanthranilic acid (3CHOA) (2, 36, 37, 39~,4r, 48). OHKy and. OHA are frequently present in human urine, as i's kynurenic acid (KyA). Certain investigators have coneentratledl their attention on the presence of abnormal tryptophan metabolites and' increased aniounts of normal tiryptophani metabolites in the urine of patients with bladder cancer ~ as, comparedi withi selectedl controls (1',4~~~, 4~6~,. '1~, 2~41J, 329). These authors have observed the increased f,xcretion of Ky, KyA, OHKy, anthranil'ic acid, OHA, andl acetylky- ,rureiri'ne in such patients, Yoshida, et al. (329), in a recent study concerning the relationship between tryptophan metabolism and l,e',erotopic recurrences of human urinary bladder tumors, reported that those~ patients with recurrences showed abnormal metlabol'ite-ycretion more often than those wit'houtt recurrences.. The relationship ofsrnoking, to: these biochemical findi'ngs, i'si^.re-zentlyuncertain. Kerr, et al. (14,3~), in 3Qexperimentl& on 3. ~n_okers and 3nonsmoker& wrho: were, gi~venlargedoses, oftrypt'o- I>haun, found that smoking increased the urinary excretion of OHKy ,tncl OHA and decreased that of N'methylnicotinamide (an end ,,rfociuct of tryptophan metabolism). Kerr concluded that smoking ittt~-rferes with the normal metabolism of tryptophan. Recently, I~'rown) et al. ( f:~ ) studied 115 ' adult's under smoking and abstinence C'Aadiitions and found that except for the basal excretion of'acetylky- nirretnin~e; tryptophan metabolite excretliondU not ch~angew~ith>Mul<ing or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers underbasal and tryptophan- I6acleri conditions. No differences were observed in the excretion oftiae measured tryptophan metabolites. However„ d:ueto itsinstabil'- it!.%', OHA was not measured. The authors concl'udedl that the rela- tionship of smoking to:urinary bladder cancer waspr~obablynotviaits effect on the kynurenine pathway of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel', et C'~~, M~•5.)~. The aut'horsobserved an elevated concentration of certain ortho-aminoph~enols in the urine of bladder cancer patients and cig~arette, smokers,, when compared with nonsmokers(,244). More recently (2%S), the same group compared the chemiluminesr cence of the urines of smokers, nonsmokers, and bladder tumor patient,.. Theynotledl that nonsmokers showedl thelbwest level of luminescence (which they relate to the presence of aromatic hydro- carbons)and the, bladdert'umor patients the highest leveh The normal' cigarette smokers" leveli was found to be intermediate. 297

N ~ m TABLE 36. Pancreatic cancer mortality rutios--prospective studies (Actual number of deaths shown in parentheses)1 - SM = Smokers. Author, year, Number and Data Follow-up Number country, type of collection years- ofdeuths . reference population S_ e_at, Approximat-ely - Questionnaire 1966, 78,000 male and follow-up Canada Canadian of death (21). veterans. certificate. PI_ammond 440,558 0,558 males - Interviews by 1966 562,671 females ACS U.S.A. 35-84 years volunteers. (118). ofagein25 States. Kahn --U.S. male ;u~~onnaire (Dorn) veterans, and follow-up 1966 2,265,674 of death U.S.A. person years. certificate. (139). 6 SM .,. 35 ) 4 262 SM ...233 NS ... 29 8t/ 344 tSM ...256 NS ... 88 - NS = Nonsmokers. Comments Cigarettes Pipes,cigars Current (cag`arettea only) Pfpea - NS 1.00 NS ..1.00 <10 .... 1.40 (5) SM M ..2.60 (6) 10-20 ... 1.96 (16) Cigars - >20 .... 2.37 (7) NS ..1.00 SM ..2.63 (1) NS ..... 1.00 (29) - Male data o-nTy-. SM (age 45_-64) 2.69(158) SM (age 65-79) 2.17 (75) NS ... .. 1.00 (8S; Pipea t Refers to curre_n_ t smokers 1-9 ... . 0.87 (8) NS ..1.00(88) of all types. 10_20 1.93 (65) SM ..0.74 (8) 21-39 ... 2.18 (43) Cigars - >39 .... 1.87 (7) NS ..1.00(88) All ..... 1.84(125) SM ..1.52(27) Both NS ..1.00(88) SM ..0.93(13) Hirayama, 265,118 male- Trained PHS - 1967, and female ale nurse inter- Japan adults 40 view and (125). years of age follow-up of and older. death certificate. W-eir and 68,153 males - - Questionnairr Dunn, in various and follow-up 1970, occupations of death U.S.A. in California. certificate. p06). 1t/ SM ... 14 - 5-8 SM ... 71 1 UTs otherwise specified; disparities between the total number of deaths and the sum of the individual smoking categories are due to the ex- -- - elusion of either occasional, miscellaneous, mixed, or ex-smokers. N5 ..... 1.00 j(pG0..01) SM ..... 15.56 (14)f NS ..... 1.00 - SM inclades ex•smokers. :Llp .... 2.94 NS includes pipe and cigar ±20 .... 2.45 smokers. >30 .... 1.44 All ..... 2.43

At pre:sent, no definite conclu~sions~ eani be~ drawn~ concerning, the interrelrltio~n_yhi~ps~ of bladder cancer, a~bnormall tryptophan rnetab- oiism, azid t~obacco sm:oking. Further stu~,d~!y is ~~ required in this and tht other z:rea5 of bladder cancer pathophysiology. SUMMARY~'' AND CONCLUSIONS 1. Epidemiological studies h:ave, demonstrated~ an~ association~ of~ cipr~~arette~ smoking w~~ith~ cancer~ of'the~ urinary~ bladder among men. The association of ~ tobacco ~~ usage and'~ cancer~ of the k~idney~ is~ less~ ,~l ear-cu t.. ''. Clinical and pathological studies have suggested that tobacco <Inoking may be related~ to alterations in the metabolism of trypto- ;;ihrin and may in this way contribute to the development of urinary tract cancer. CANCE~R~: 0'~F~ THK PANCREAS e~~eral prospective~ epidemibl':ogic~ studies have suggested a rela- tirm:hip between cigarett:e~ smok:ing~ and! cancer of' t'he~ pancrea~s! : (~table,a£i)~. A retrospective study ~ofl~465~cases~~of~pancreatic~cancer~ iln-~ I:shii', et al. (137), has shown a dbse-related increased riskof' i~ancreatic~ cancer~in~ association with smoking.: Analysis of~ dietary~ data revealed that the relative risk for pancreatic cancer, from ,-;moking was considerably greater than from dietary factors. \ o experimental stud'ies relating to this question have been reported. SUMMARY AND CONCLUSIONS Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The significance of the reldtionship is not clear at this t'ime.. REFEREh1CE'S. (1) ABELIN, T., GSELL, 0. T. Relative risk of'pulmonary cancer in cigar and pipe smokers. Cancer 20(8) : 1288-1296, August 1967. (2) ALIFANO, A., PAPA, S., TANCREDI, F., ELICIO; M. A., QUA ILLARIELI:A, E. Tryptophan-nicotinic acid metabolism in patients with tumours of the bladder and kidney. British Journal of Cancer 18: 386-389;, 1964., (3) ANTHONY, H. M., TxoM~AS, G. M. Bladder tumours and smoking. Interna- tional Journal of Cancer 5(2') : 266-272, March 15, 1970.. (4) ARxIN, .?:.,,WACnrER„D. H. Primary carcinoma of the lung. A diagnostic study of one hundred and thirty-five cases in 4 years. Journal of the American Medicall Association 106(8) : 587-591, February 22, 1936. 299'. « 3 s.. ... ... .. ,.. .,... .. . . .~.,.. .-,. ; . ,x . ~..: s.. . ..:~:-:. , _ . . . ... . .. . . ~ . . .. r

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CANCBR APPENDIX TABLES

'A t JOVS9MUO

TABhE A3.-Outline of methods used in retrospective studies of smoking in relation to lung cancer Author, year, tr u Sex of ca es Number of persons and method of selection l y, co n reference s ' Cases Controls ection of da_ta_ Col Muller 1939, h1 86 lung cancer decedents 86 healthy men of the same age Cases: Questionnaire sent to relatives of de- Germany Germany ceased. (196). . Co,ntrols: Not stated. Schairer and M 93 cancer decedents autopsied 270 men aged 53 and 54 Cases: Questionnaire sent to next of kin Schoniger, (average age 53.9). Controls: Questionnaire sent to 700. 1943, Germany (242). Potter and M 43 male patients over 40 years of 1,847 patients of same group with diagnoses Cases and nd controls interviewed in clinics. Tully, age. other than cancer. 1945. U.S.A. (212). Wassink, M ~ 134 male clinic patients with ~ 100 normal men of same age groups as cases. Cases: Interviewed in clinic. 1948, _ .. ... lung cancer. ~ - - ---- Controls: Not stated. . -. . . . Nether- lands (S0¢). Schrek et al., M 82 male lung cancer cases among 522 miscellaneous tumors other than lung, Smoking habits recorded during routine hos- _ 1950, 5,003 patients recorded, 1941- larynx, pharynx, or lip. pital interview. U.S.A. 48. (246). Mills and M 444 respiratory cancer decedents. 430 sample of residents matched by age in Cases: Relatives queried by mail question- - Porker, Columbus, Ohio, from census tracts strati- naire or personal visit. - - 1950, fied by degree of air pollution. Controls: House-to-house interviews. U.S.A. (186). 9oVss4co

k w N A TABLE A3.-Outlin.e of methods used in retrospective studies of smoking in relation to lung cancer (cont.) Author, year, coU try Sex of ca9E8 Number of persons and method of selection C ll ti f d t , n reference Cases Controls o ec on o a a Levin et al., 1950, U.S.A. (169). M 236 cancer hospital patients with diagnosed lung cancer. ~ ----.. - __.___ .... ... 481 patients in same hospital with nonma- lignant diagnoses. _ Cases ses and Controls: Routine clinical history ~ taken before diagnosis. ._ . .. . . . . ... Wynder and M-F 605 hospital and private lung 780 0 patients of several hospitals with diag- Nearly all data by personal interview; a few Graham, cancer- patients in many cities. noses other than lung cancer. cases by questionnaire; a few from inti- 1950, 1950, mate acquaintances. Some interviews with U.S.A. knowledge or presumption of diagnosis. some with none. 595 diagnosed by tissue examination, nine by sputum, and one by y pleural fluid examinat;on. McConnell et al., 1952, England, (180). M-F 100 lung cancer patients, un. selected, in 3 hospitals in Liv- erpool area. - - 200 inpatients of same hospitals, matched by age and sex, without cancer. Personal interviews by the authors of both - cases and controls. Doll and M-F 1,465 patients with lung cancer 1,465 patients in same hospitals, matched by Personal interviews of cases and controls by Hill, -- in hospitals of several cities. sex and age group; some with cancer of almoners. - - 1952, other sites, some without cancer. Great Britain (xs). Sadowsky adowsky M 477 patients with lung cancer 615 patients in same hospitals with illnesses Personal questioning by trained interviewers. . .. . .. . . et al., 1953, U.S.A. (23$). in hospitals in 4 states. other than cancer. 4OVS94C0

TABLE A3.-Outline of knet/aods used in retrospective studies of smoking in relation to lung cancer (cont.) SOVS94C0 Author,_ year, country Sex of cases Number of persons and method of selection , reference Cases Controls Wynder and M 63 physicians reported in AMA 133 physicians of same group dying of can- Cornfield, Journal as dying of cancer of cer of certain other sites. 1953, the lung. --- U.S.A. (s14)• Collection of data Mail questionnaire to estates of decedents. Cases and controls questioned about smoking habits when taking case histories. $51 di- agnoses confirmed histologically; 494 diag- noses confirmed by clinical, X-ray, and operative data. ------- - Lickint, 1953, Germany (170). M-F $46 lung cancer patients in a number of hospitals and clinics. 2,002 sample of persona without cancer liv- - - - ing in the same area and of the same sex and age range as cases. Personal interviews by staff members of co- operating hospitals and clinics. Breslow M-F 518 lung cancer patients in 11 518 patients admitted to same hospitals about Cases and controls questioned by trained et al., California hospitals. the same time, for conditions other than interviewers, each matched pair by the 1954, cancer or chest disease matched for race same person U.S.A. , , - sex, and age group. . Koulumies, M-F 812 lung cancer patients diag- 300 male outpatients of same hospital over 1958, nosed at one hospital. 40 years of age. Finland - (151) (42). Watson and M-F 301 patients at Memorial Hospi- Conte, Conte, tal with lung cancer. 1954, U.S.A. (105). 468 patients of same clinic during same The 769 consecutive patients of case and - period with diagnoses otheY than lung control groups were questioned by the - - cancer. same trained interviewer. Control group includes patients with oral and esophagea__1_ cancer and bronchitis. Gsell, M 135 men with diagnosis of bron- 135 similar hospital patients with diagnoses Personal interviews, all by the same person. 1954, chial carcinoma. other than lung cancer, and of the same Switzerland age (107).------ - .

w N P TAB1.E A3, Outline of methods t(sed in retrospective studies of smoking in relation to dztng cancer (cont.) Author, year, Sex of Number of persons and method of f selection country, cases _ ~ -__--- - _ Collection of data reference - Cases Controls H_andig, M_ _-F_ 448 lung cancer patients in a 512 patients with other diagnoses, matched Controls were interviewed at about the same -- 1954, Germany Germany (218). number of West Berlin hospi- -- tals. forr age. time as the cases, each case-control pair by the same physician. Wynder_ et al., F 105 patients with lung cancer in 1,304 patients at Memorial Center with tu- Cases: Personal interview or questionnaire 1956, several New York City hospi- mors of sites othe than r respiratory or mailed to close relatives or friends. U.S.A. tals. _ _ upper alimentary Controls: Personal interview. (811). Segi et al., M-F 207 patients with lung cancer in 1957, 33 hospitals in all parts of Japan the country. _ (250). Mills and M-F 578 residents of defined areas Porter, dying of respiratory cancer. 1957, U.&.A._ (187). Stocks, M-F 2,356 patients suffering from or 1957, dying with lung cancer within__ England certain areas. (2s8). Schwartz and M 602 patients with bronchopul- Denoix, Denoix, monary cancer in hospitals. 1957, France (247). 5,636 patients free of cancer in 420 local Cases and controls by personal interview health centers, selected to approximate using long questionnaire on occupational the sex and age distributions of cases. and medical history and living habits. 3,310 population sample approximately pro- portional _ _ portional to ca_ses as regards areas of resi-, dence, and 10 years or more in the area. Cases: From death certificates, hospital rec- ords, and close relatives or friends. Controls: Personal home visits or telephone calls, usually interviewing housewife. 9,362 unselected patients of the same area Cases: Histories taken at the hospital from admitted for conditions other than cancer. relatives by health visitors. Controls: Personal interview in hospital. 1,204 patients (3 groups) in same hospitals Personal interviews in the hospital; cases with other cancer, with nonmalignant ill- and controls at about the same time by ness, and accident cases, matched by age the same interviewer. group.

TABLF, M.-O2[tlbqZe of methods used in retrospective studies of s192ok2Ti(J in relation to lung cancer (cont.) Ai V OTVSJLCO Author, year, Sex of countcy, cases rcference Cases Number of Persons and method of selection Controls Collection of data Haenszel and F 158 lung cancer patients avail- 339 patients in same hospital and service at Personal interviews by resident, medical so- Shimkin, able for interview in 29 hos- same time, next older and next younger cial worker, or clinic secretary. 1958, pitals. than each case. U.S.A. (11S). Lombard and M 500 men dying of lung cancer, 4,238 controls in 7 groups including volun- Personal interviews by trained workers. Snegireff, microscopically confirmed. teers, hospital and clinic patients, random ----------._- 1959, population sample, and housc-to-house sur- U.S.A. vey samples. (176). Pernu, M--F 1,606 respiratory cancer patients 1,773 cancer-free persons recruited by Parish Cases: From case histories or mailed ques- 1960, in 4 hospitals and from cancer Sisters of 2 institutes in all parts of the tionnaires. Finland registry. country. Controls: Questionnaires distributed by Par- (211). ish Sisters. Haenszel M 2,191 sample of 10 percent of 31,516 random sample from Current Popu- et al., white male lung cancer deaths lation Survey. 1962, in the U.S.A. in 1958. U.S.A. (112). Cases: By mail from certifying physicians and family informants. Controls: Personal interview by census enu- merators. Lancaster, M 238 hospital patients with lung 476 in 2 groups, 1 with other cancer, 1 with Personal interviews of both cases and con- 1962. cancer. some other disease, matched by sex and trols in hospitals. Australia age. (158). Haenszel and F 749 sample of 10 percent of 34,339 random sample from Current Popula- Cases: By mail from certifying physicians - - - Taeuber, white female lung cancer deaths tion Survey used to estimate population and family informants. -- ----- - -- - 1964, in the U.S.A. in 1958 and base. Controls: Personal interview by census eau- U.S.A. 1959. merators. (115).

TABI.E A3.-Outline of methods used in retrospective --_....~ studies of smoking in relation to lung cancer (cont.) Author, year,-- Sex of Number of persons and method of selection country, cases reference Cases Controls Collection of data Wicken, M-F 954 patients with primary lung 954 age and sex-matched controls from same Interviews with relatives. 1966, cancer. locale and deceased from nonrespiratory Northern diseases.- --- Ireland (30B). Gelfand et al., M 32 patients with bronchogenic 32 age and sex-matched patients Hospitalization interviews. 1968, cancer. Rhodesia (98). Hitosugi, M-F 185 patients with lung cancer 491 persons sex-matched from similar air- Cases: Hospital interviews. - • 1968, pollution regio_n_s_._ Controls: Interviews by trained_ public health Japan nurses. (126). Bradshaw and M 45 Zulu patients with lung can- 341 Zulu patients without lung cancer. Interviewed by trained African social worker. _ ... _ _ . . ~ . ----_ . __.. . - . __. . . .. . _. Schonland, cer. - ---- 1969, South outh Africa (Natal) (41). Ormos et al., M-F 118 patients with lung cancer, 1969, __ Hungary (204). 3,089 control persons without data on health Cases: ases: Data derived from case histories and his_tory. interviews with relatives. Controls: Interviews with a random sample of train passengers. Wynder, et al., M-F 240 patients with Kreyberg Type 480 age and sex-matched patients - -- - 1970 1 lung cancer. U.S.A. (Jr4). R'TV991.dcO . . f _ -_.. . .. t Hospitalization interview.

TABLE A4.-Group characteristics in retrospective studies on lung cancer and tobacco use SM = Smokers. NS - Nonsmokers. Males Females Author, C_a__se_s_ Controls R l ti Cases Controls ----- -~- ti R l t C year, reference - - _ Number Percent n<in- smokers Percent heavy smokers' _ Number _ P-ercen_t non- - smokers Percent heavy smokersl e a ve risk ratio SM:NS2 umber Percent non- smokers Percent heavy smokeTsl umber Percent non- smokers Percent heavy smokers? ve e a risk ratio SM:NS2 -_- ommen s Muller, 86 3.5 65.1 86 16.3 36.0 95.4 (+) (4) (') (') (') (4) 1939 (196). Schairer and 93 3.2 31.2 270 15.9 9.3 35.7 (4) (4) (C) (4) 16 female Schoniger, - - cases not 1943 (249). analyzed. Potter and 43 7.0 30.2 2,804 26.0 23.0 34.1 (4) (4) (4) (4) (4) (4) Tully, 1945~(2l2). Wassink, 134 4.8 54.8 100 19.2 19.2 4.7 (+) (4) (4) (1) (4) (*) ... ercentages Percentages 1948 (304). estimated from chart. Schrek et al., 82 14.6 18.3 522 23.9 9.2 1.8 (4) (!) (') (4) (4) (4) 1950 (246). Mills and Porter, 444 7.2 ... 430 30.5 ,.. 5.7 (4) (*) (4) (') (4) (4) 1950 (186). (4) (') (') ... Quantity smoked not considered. Wynder and 605 1.3 51.2 780 14.6 19.1 13.0 40 57.5 25.0 552 79.6 1.2 2.9 Graham, ---- 1950 (816). zTVs94co

w TABLE A4. Group characteristics in retrospective stlidies on lung cancer and tobacco use (cont.) - Q SM = Smokers. NS = Nonsmokers. Males ' Females Author, Cases Controls Cases Controls year, Relative Relatixe Comments reference Percent non- Percent heavy Percent non- Percent heavy - risk- ratio Percent nori=- Percent heavy Percent non- Percent heavy risk ratio Number smokers smokers' Number smokers smokers' SM:NS- Number smokers smokers' Number smokers smokers' SM:NS? McConnell cConnell 93 5.4 38.5 186 6.5 23.2 1.2 7 57.1 ... 14 78.6 ... 2.8 et al., - 1952 (180). Do11 and Hill, 1,357 0.5 25.1 1,357 4.5 13.4 9.4 108 37.0 11.1 108 54.6 0.9 2.1 Percentage --... _ ..--- ---- --- ---~ -------__. 19_52_ (73). "heavy" smokers understated. Sadowsky et al., ~1953 (232). 477 3.8 ... Wynder and .. Cornfield. 63 4.1 67.6 1953 (314). Koulumies 812 0.6 58.9 - 1953 (iSI). Lickint 224 1.8 35.8 1953 (170). Breslow et al., 493 3.7 74.1 1954 (42). Watson and Conte, 265 1.9 71.7 1954 (305). Gsell, 135 0.7 68.1 - 1954 (107). 615 13.2 ... 3.9 133 20.6 29.3 96.1 300 18.0 25.0 36.0 - (4) (4) (4) (') (4) (') (4) (') (4) (4) (4) (') (*) Gradient with amount smoked. 1,000 16.0 4.8 310.4 22 64.0 4.5 1,002 90.4 0.1 5.3 518 10.8 42.7 3.2 287 9.7 51.6 ?5.6 135 16.0 14.0 326.8 - 9 36 58.3 2.8 181 82.0

ft - - . ., , - TABLE A4.-Group claaracteristi,cs in retrospective stiarlies on lung cancer and tobacco use (cont.) SM - Sm okers. NS - Nonsmokers. Males - Females -- Author Cases _ _. Controls . . -. -- Cases Controls -_. , , . year, Relative Relative Comments reference Percent Percent Percent Percent rtsk-- Percent Percent Percent Percent risk Num- ~ non- ileavy~~ non- heavy - ratio Num- non- heavy non- heavy ratio hei~- smokers smokers' Number smokers smokecsi SM:NS2 ber smokers smokers? Number smokers smokers' SM:NS2 R and ig, andig, ---~ ---- 415 .. 1.2 34.2 - 381 --- -~ 5.8 ~ 17.9 35•1 33 --- 51.5 ---- - 3.0 131 _._ 70.3 0 -. 2.2 1954 (218). - Wynderetal., (i) (~) . (!) . (4) (4) - (4) . . - ... .. 105 .. 56.2 16.2 1,304 ~ - - 66.0 --- 3.4 1.4 _. 1956 (311).~ - Segi et al., 166 ... •.. 2,124 ... ... ... ... ... -. . .. . ... ... •. • ... Quantities 1957 (250). smoked stated as averages only. Differences _ are statistically significant. Mills and 484 8.4 26.0 1,588 27.6 5.3 4.2 94 83.0 4.3 1,722 73.3 0.6 0.6 Percent "heavy" Porter, smokers under- 1957 stated. Only (187). 50s-e survey - response among_ female cases. Stocks. _ 2,101 1.9 28.2 6,960 8.7 22.3 4.9 255 57.6 17.2 3,402 68.6 10.7 1.6 1957 (469). Schwartz chwartz and 602 1.0 58.2 1,204 9.6 36•2 10.4 (') (') (') (4) (4) (1) Denoix, 1957 (247). Haenszel and (4) (1) (4) ~~- --~ (1) (1) (1) ... 158 51.9 14.6 339 69.6 ~ 8.2 2.5 Shimkin, 1958 (11?). ~ w - - _

TABLE A4`-~`iroup characteristics in retrospective studies on lung cancer and tobacco use (C-ont.) SM = Smokers. NS = Nonsmokers. Males Females Author, Cases Controls Cases Controls _ year. Relativa _ Relative reference Percent Percent P-ercent Percent risk Percent Percent Percent Percent risk Num- non- heavy - non= heavy ratio non- heavy non- heavy ratio her smokers smokers' Number smokers smokers? SM:NS2 Number smokers smokets? Number smokers smokers' SM:NS= Lombard and 500 1.6 4,238 11.0 7.9 (4) (') (') (4) (4) (4) Snegireff, 1959 (176). Pernu, 1960 ((211). Haenszel et al.. 1962 (112). Lancaster, 1962 (1$8). Haenszel and Taeuber, 1964 (115) SIsSJMcI./ Comments ---- Authors' calculations for heavy smoking basedon lifetime number of packs of cigarettes. 1,477 6.6 34.5 713 37.2 20.8 8.4 129 85.3 26.4 1,060 91.6 ~ 0.7 1.9 Quantities given only in grams per day. 2,191 3.4 41.9 (1) 16.2 12.0 5.2 (1) (4) (4) (') Population sample of 31,516 used as base. Not a caee- control study. 23__8 2.5 86.1 476 20.1 71.2 9.8 (4) (1) (!) (4) (4) (') (') (4) (1) (4) (4) (4) 749 60.9 11.5 (!) 67.3 2.5 1.3 Population sample of 34,339 used as base. Not a case-control study.

„ . TAB[.E A4: Group characterist ics in retrospective studies on lung cancer and tobacco use (cont.) - - - - SM = Smokers. NS = Nonsmokers. Males Females - - Author, Cases Controls Cases ontrols Controls year, Relative Relative Comments reference Percent Percent Percent Percent risk Percent Percent Percent Percent risk Num- non- heavy non- - heavy-- ratio non- heavy non- heavy ratio ber smokers smokeYs1 Number smokers smokersl SM i NS2 Number smokers smokersl Number smokers smokersl SM:NS? -- - W+cken, -- 803 - - 4.0 40.0 803 - 14.0 22.0 3.9 151 58.0 29.0 151 80.0 17.0 2.9 Heavy smokers- 1966 (308). - - --- greater than 23 a day. Gelfand et al., 32 6.$ ... 32 63.0 .. °26.3 (f) (4) (') (4) (4) (+) 1968 (98). Hitosugi, 124 6.6 67.8 1,839 13.2 55.0 2.6 61 54.1 6.6 2,352 80.5 2.9 2.3 Air pollution 1968 (125). found to have no effect on • lung cancer rates of non- smokers. Heavy smokers-great- er than 15 a day. Bradshaw and 46 0.0 ... 341 31.7 ... ... (!) (!) (±) (+) (4) (1) Schonland, 1969 (41). Ormos et al., 94 7.6 68.6 1.811 42.9 38.9 9.3 24 95.8 0.0 1,278 81.7 9.7 0.2 Heavy smokers- 1969 (204). grea_ter than 15 a day. Wynder et al., 210 1.4 67.5 420 21.0 40.9 -- 320.8 --- -- 80 16.7 44.0 132 - 57.6 23,3 6.78 Heavy i 1970 (F94_). smokers- greater than 20 a day. 1 For this ta ble, heavy smokers are defined as those smoking 20 or more ' Based upon fewer than 6 case nons m okers. ~ cigarettes per day, unless otherwlse stated. _ _ + Does not apply. W 2 Computed according to method of Cornfield, J. (61).

TABLE A7.-Grouping of pulmonary carcinomas GYoup Ik A, Ebidermoid carcinoma. B. Small cell anaplastic carcinoma ("oat-cell"carcinoma). Group II: A. Adenocarcinoma. B. Bconchiolo-alveolar ce1l,carcinoma. C. Carcinoid tumor. D. Mucous glandd tumor;. Extra (not included in I and II) : A. Large celll undifferentiated carcinoma. B. Combined epidermoid and adenocarcinoma. Unsuitablefor diagnosis. Sduwcs:, Kreyberg, L. (153).. } ;t

, .} Sill, 1965, U.S.A. (229) Little et al., 1965, U.S.A. (174)• TABLE A12, Autopsy studies concerning the presence of radioactivity in the lungs of smokers NS = Nonsmokers. SM = Smokers. Number of cases Results Polf" levels in various tissucs (pc/g tissue) NS ............... 5 SM .............. 12 NS ............... 6 SM .............. 4 ............... NS .. ......... 8 SM ..............26 Peri6r_onchia! Bronchial lymph node8 Lung (average) epithelium 0.011 0.001-2 negligible 0.011 0.008 0.028-1.26 Mean IzaS1P levels in various tissues (pcfkg tissue) - Bronchial tree Alveolac Total lung Liver - ~ --- --- ..- .... . _._....._ .. ... .-.. . . . . Kidney . . _ 3.1 3.4 3.2 14.8 15.0 7.3 9.9 8.6 20.0 20.6 Potto levels in various epithelial tissue regions of f lung (pcfg) t Site: Mainstem bronchus ..................................... <0.2- 1.7 Lobar bronchus ......................................... <0.2- 1.0 Basal segmental bronchus ............................... <0.2- 2.6 Upper segmental bifurcation ........................... <0.5- 7.8 Lower segmental bifurcation ........................... <0.5-13.9 Comments Vertebral bodies, renal cortex, spleen, and urinary bladder showed no differences. The authors found no excessive concentrations_ at bronchial bifurca- tions. The authors noted con- siderable interpersonal variation but did find a trend relationship be- tween increased daily consumption and in- creased Po2io levels in lung parenchyma. No such relationship was noted for age of indi- vidual at death o_r_ for_ total pack-years. 1 Smokers only. i

TABLE A12.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers (cont.) ~~ NS = Nonsmokers. SM = Smokers. ~ ~ Number of cases NS .............. 10 SM ..............14 NS ............... t SM ..............1$ SM ..............26 Pipe ............. 2 Ex-cigarette ...... 1 - Never ............ 8 Results Mean Poa10 levels in various tissues (pc/g wet tissue) Lung Liver - Kidney 0.031 0.103 0.080 0.066 0.125 0.070 Mean Po10 levela in various tieeuea (pe/g) Lung parenchyma Bronchial tree Bronchial bifurcation 0.0025 0.0020 0.0012 0.0078 0.0077 0.0047 Mean Po?10 levels in various epithelia{ tissues (pc/g wet tissue) Bronchial wall and submucosa . ................................. 0.004 Bronchial epithelium: Trachea .................................................... 0.120 Lobar bronchi ................. .... ... . ... ..... ..... 0.190 Segmental bifurcation ....................................... 4.500 Comments f Data not given. Smokers were considered those using more than 1 pack a day. The authors noted that their figures were con- siderably smaller than those of Little et al. (173, 174) and also disagreed with their data on bifurcation.

- -.. - - , ... - . ... - . - -... TABLE A13. Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals Author, A. Method, year, Animal B. Frequency and/ country, and or duration, reference strain C. Material Wynder et al., 1953, U.S.A. (317). CAFt mice A. Painting shaved skin. B. 3/week for 2 years. C. Whole cigarette smoke condensate in acetone. Croton oil once/week. Passey 5 different A. Painting_ unshaven et al., mouse skin. 1955, strains B. 2/week for 9 England (101). months. (209). C. Whole'"tar" or neutral fraction. Orr et al., Mice of 2 A. Painting skin. 1955, strains. B. 1 or 2/week for England 18 months. (.405)._ C. 20 percent cigarette "tar" in acetone. 0.3 percent benzpyrene. Q u V Results P-crcent animals with: - Treatment: Papillomaat "Tar" alone ............................... 59.0(81) "Tar" and croton oil .......... ............ 42.0(31) Acetone alone .............................. (80) Acetone and croton oil ..................... (14) Caneert 44.0(81) 9.7(31) (30) (14) No malignant tumore noted in either group. Papilloma noted on one animal (in whole "tar" group) which later regressed. Number animals with: Treatment: Papillomas Benzpyrene 1/week followed 4/30 at 18 months (separate group received only by "tar" 2/week. benzpyrene and showed no tumors). "Tar" alone ............... 0/50 at 18 months. Comments f Number in paren- thesis represents total in that experimental group. . Skin-painting experiments prior to 1953 are fully detailed in tab- ular form in this ----- - article. ozV994Eo

TABLE AM-Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) - - Author, year, cuuntry, ret"erence - Animal and strain A. Method, B. Frequency and/ or duration,- C. Material esults omments Wynder Mice of 4 A. Painting shaved skin. Strain Papillomas Carcinomas No tumors noted with et al., separate B. 3/week for 80 days. C57BL ................................ 10/89 2/89 acetone alone. 1955, strains. C. Whole condensate Swiss ................................. 22/86 12/86 Stresses U.S.A. --------- in acetone. a differencea in (818). susceptibility of strain. Hamer and Woodhouse, 1956, U.S.A. Outbred albino strain_ mice. A. Painting unshaved skin. B. Varied for 18 months. C. Whole "tar"/acetone, Treatment: : "Tar" 2/week "Tar" and n_d croton oil 1/week. ........ _B (a_) P 3 times then "tar" 2/week ..... Papillomae 1/60 2/30 4/30 (116). benzpyrene [B(a)P-l, croton oil. B(a)P 3 times ...................... 0/30 Sugiura, Rockland A. Painting unshaved e Carcinornaa Papillama 1956, Swiss skin. _ 16/44 12/44 (only 44/60 U.S.A. (26G). albino mice(&0). B. 3/week for 2 years. C. Whole "tar". lived from 365-696 days). Graham et al.. Albino New Zealand A. Painting shaved skin. B. 3/week for 6 years. Treatment: Condensate .......................... Papillomaa Carcinomas 41/41 5/41 - The authore review previous experiments 1957, rabbits. C. Whole condensate. Condensate and croton oil 1/week. 10/10 2/10_ with rabbits in U.S.A. Croton oil and acetone 1/week. - 0/3 0/3 tabular form. (101). Acetone 1/week ..................... 0/7 0/7 Guerin and Mice A. Painting neck skin. Original number Survivo_ r_ s_ Papillomas Sarcomas tControl group. - Cuzin, (Pasteur B. 2/week for>1 year. fC. 112 ...................... 51 0/51 0/51 $ Experimental group. - 1957, strain.) C. Whole condensate. $E.672 ...................... 220 10/220 5/220 U.S.A. (109).

TABLE A13. Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents uhon animals (cont.) I l Bock and Moore, S_ wiss female A. Painting skin. B. 5/week for lifespan. _. Group: Number living at 6 months Percent Skin tumors at 64 weeks 1959, mice C. Whole _ hole condensate Painted ...................... 49 13.0 U.S.A. irradiation. Painted and irradiated ......... 65 44.0 (28). Irradiated .................... 36 Gellhorn,_ 1958, Paris R III mice A. Painting shaved skin. B. Varied for 1-2 years. Trcatment:. Benzpyrene (twice only) ............ Papillornaa 20/529 Carcinomas 6/629 U.S.A. C. "Tar" in acetone, - Croton oil (5/6 week) ............... 4/26 0/26 (99). benzpyrene, "Tar-'(5/6 week) .................. 3/559 2/559 croton oil. Acetone (5/6 week) ................ 0/30 0/30 "Tar" and croton oil (6/6 week) .... 10/175 0/175 Author, year.~- country, reference Animal and-- strain ---- A. Method, B. Frequency and/ ~ or duration,_~ C. Material Results Comments Wynder et al., 1957, U.S.A. (823). Swiss mice A. Painting skin. B. Varied for 12 months. C. Whole condensate in acetone. Treatment: 5/week ...................... 3/week ...................... 2/week ...................... 1/week ...................... Number 50 50 40 40 Percent papillomas 12.0 38.0 10.0 6.0 Percent carcinomas 8.0 16.0 3.0 Wynder and Wright, 1957, CAFl or Swiss mice. A. Painting shaved skin. B. 3/week for lifespan. C. Whole "tar''or nicotine Treatment CAFj: Whole "tar•' ................. Num6er- 30 _. Percent papiUomaa 53.0 Percent carcinomas 27.0 Swiss mice noted to be more sus- ceptible. U.S.A. free "tar" derived Nicotine free "tar" .......... 40 73.0 25.0 Majority of carcino- (828). from pipe and Cigarette "tar" .............. 30 30.0 30.0 gens noted to be cigarette tobacco. Pipe "tar"................... . 30 60.0 20.0 in neutral fraction Treatment Swiss: Whole "tar° ................. 30 53.0 10.0 of condensate. Nicotine free "tar'' ........... 40 43.0 20.0 Cigarette '-'tar'' .............. 30 63.0 33.0 Pipe "tar".................. 30 63.0 60.0

Druckrey, y, Rats 1961, Germany (78). cont.) Author, Animal A. Method, year, and B. Frequency and/ country, strain - or duration, Results Commente reference - C. Material Roe, Albino mice A. Painting shaved skin. Treatment: Survivors Percent skin tumore Author concluded 1962, B. 3/week for 84 weeks. "Tar" and 0.025 mg. B(a)P - - ..... 26 12.0 that cigarette U.S.A. C. Whole smoke "tar'' "'I'ar" and 0.06 mg. B(a)P ...... 15 27.0 smoke contains (225). with added B(a)P "Tar" and 0.25 mg. B ( a ) P ...... 15 13.0 cocarcinogens. in acetone. "Tar" and 1.25 mg. B( a) P- ...... 14 64.0 B(a)P 1.25 mg . ................. 14 TABLE A13. Extlerirrlents concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals A. B. C. Subcutaneous injection. Group: # C .................. ............. ...~ Sarcomas 1/75 } Control group. $ Experimental group. 1/week for 60 weeks. $ E ................................. 16/75 Smoke condensate in tricaprylin and alcohol. a Bock et al., 1962, ICR Swiss mice A. B. Painting shaved skin. 10/week for 1 year. Treatment: Surviving s at 78 mcck Percent Skin cancer Percent Skin neoplasia U.S.A. C. Cigarette "tar". Standard cigarette ............ _ _ 24/30 25.0 54.0 (31). Standard cigarette .... ._....... 21/30 5.0 67.0 Standard cigarette _ ............ 18/30 33.0 44.0 Standard cigarette ............ 13/30 23.0 62.0 Filter cigarette ............... 30/30 7.0 27.0 Filter cigarette ............... 30/30 3.0 23.0 Acetone only ................. 66/66 Control ...................... 65/65 Druckrey and Rats Schildbach, 1963, Germany (82). _A_._ Subcutaneous injection. B. 1/week for 700 days. C. Benzpyrenein tricaprylin. Treatment (BP-mg./merk): 30 .................................. 10 .................................. 3 .................................. - (solvent) ........................ Sarcomas 25/30 14/40 8/50 2/75

TABLE A13. Experiments concerning the effects of the skin painting or - - subcutaneous injection of cigarette smoke condensate or its constituents upon anint2ls cont.) Author, year, - country, reference Animal and-- strain A. Method, B-._Frequency and/ -- or duration, C. Material Results Comments ~ Homburger et al., CAFl mice A. B. Painting shaved skin. 2-3/week for 2 years. Condensate: Complete autopsies Percent Papillomas Percent Carcinomas 1963, U.S.A. (131). C. V arious tobacco condensa_tesin acetone. Pipe tobacco ................. Cigar tobacco ................ Cigarette tobacco ............. 77 84 82 35.0 27.5 27.0 15.0 16.0 16.0 Benzpyrene .................. 54 10.0 20.0 Acetone only ••••••••••••••••• 62 Bock et al._, 1965, Swiss ICR mice A. Painting clipped skin. B. 10/week for 11 weeks. s. Percent concentration of tar Percent surviving Percent Percent cancer and U.S.A. C. Various smoke (type cigarette) : 11 weeks cancer papilloina (29). condensates in 9.2 (standard) ............... 96.0 30.0 67.0 - - acetone. 8.3 (standard) ............... 93.0 27.0 67.0 7.9 (English standard) ........ 90.0 24.0 58.0 8.7 (king) ................... 100.0 28.0 69.0 4.0 (filter) ................... 98.0 9.0 36.0 4.4 (filter) ................... 100.0 10.0 41.0 2.5 (filter) .................... 97.0 4.0 16.0 . A cetone control .............. 94.0 . Untreated control ............ 100.0 Van Duuren Swiss ICR/ A. Painting shaved skin. et al., Ha mice B. Initiating agent once- 1966, Promoter 3/week for U.S.A. 12-14 months. (296). C. DMBAt, tobacco extracts ciga- rette rette "tar". l Initiator Promoter DMBA ...Ethertobacco leaf extract .............. O ........ Ethertobaccoleaf extract .............. DMBA . ..Choloroform tobacco leaf extract ........ O ......,,Choloroform tobacco leaf extract .,...,.. DMBA ...Citrarette "tar" ....................... 0--- .. ..Cigarette "tar" ....................... ... . O .....,..Acetone .............................. Cumulative number of mice with t 7,12-dimethyl- P_ a_pillomas Carcinomas bena(a)anthracene. 4/20 0/20 0/20 0/20 1/20 0/20 0/20 0/20 11/20 4/20 0/20 0/20 0/20 0/20 VzVs9LCo

TABLE A13. Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) 3M,594.CU Author, A. Method year, country, reference Animal and strain B. Frequency and/ or duration, C. Material Results Munoz et al., Swiss ICR/ A. Painting shaved skin. Dark tobacco "tar" At risk Tumors 1968, 4a a mice B. V aried. 4.0 percent ................... 81 50 U.S.A. . C. "Tar" from dark 8.0 percent ................... 71 - 46 and (Colombian) and LiDhttobacco tar: Colombia light (U.S.A.) 4.0 percent ................... 95 26 (197). tobaccos. 8.0 percent ................... 98 54 Acetone ........................ 91 0 Davies and_ Day, 1969, Great Britain (65). Albino mice A. Painting shaved skin. kin. B. Varied regimen. C. Cigarette and cigar condensate. Comments Carcinomas_ The authors noted 17 a shortened latent 1_6_ period for dark ark tobacco. 6 20 0 Percent of carcinoma-bearing animals at 116 week_s Treatment: (actu_a_ l number of animals in yarenthesea) 300 mg. 150 mg. 75 mp. 97._5 mg. Standard cigarette ........ 20.1(29) 13.2(19) 0.7 (1) .. Cigar ..................... 27.1(39) 11.1(16) 2.1(3) Cigar tobacco cigarette ... .. 13.9(10) .. .. The authors concluded that the lack of difference in re- sults_ from the first and third groups under treatment suggests that the increased tumori- genicity of cigar tobacco is due to physical processing factors.

F 4 k+. w A Y TABLE A14. Experiments concerning the effect of cigarette stJtohe or its constituents on tissue and organ cultures Author, year. country, reference Tissue or organ culture ------ Materia]/delivery Results Bouchard Mouse lung. Tobacco smoke condensate Increased number of mitotic abnormalities in the treated cultures: particularly in and May, perfusion for 24 hours the first 5-10 days after grafting. 1960, and subsequent France (85). grafting under renal capsule of mice. Awa et al., Human fetal lung. Direct exposure to Paper smoke induced the most severe changes, consisting of cytoplasmic vacu- 1961, 1961, smoke from: olization and nuclear pyknosis. Also noted were a decrease in the mitotic index Japan (16). a. Wholecigarettese and an increase in abnormal divisions, more so with paper. smoke than with - b. Tobacco alone. the other two. c. Paper alone. Thayer and Kensler, 1964, U.S.A. (275). KB mammalian - tumor cells. Cigarette smoke condensate applica- tion; filtered_ and unfiltered cigarettes. Significant growth inhibition was shown in unfiltered smoke. Cytotoxic compo- nents were noted in both the gas and particulate ulate phases. Berwald and SWR mice and Direct application of Benzo(a) pyrene caused increased cell transformation as manifested by: Sachs, golden hamster benzo(a)pyrene a. Hereditary random growth pattern. 1965, embryos. [B(a)P-l. b. Progressive growth as tumors after subcutaneous injection into adults. Israel (20). c. Ability to grow continuously in culture. Crocker et al., Suckling rat Application of Treated cultures revealed cellular metaplasia, basal cell hyperplasia, increased 1965, trachea in B(a)P in acetone. mitotic rate, and increased H1-thymidine incorporation proportional to the con- U.S.A. U.S.A. (63). organ culture. centration of material and duration of application. Diamond, Various con- Application of Inhibition of cell growth. 1965, tinuous cell B_ (a) P in either U.S.A. (68). strains dimethylsulfoxide (mammalian). (DMSO) or paraffin.

A A TABLE A14.-Experillaents concerning the effect of cigarette svzoke or its constituents on tissue and organ cultures (cont.) Author, year,- Tissue or country organ-culture Material/delivery Results , - refei~ence - - - - --- -- Borenfreund et al Hamster l ng Application of Increased appearance of new small chromosomes and telocentrie chromosomea. a ., ---- 1966, u ----- tissue. B(a)P in either . b. Increased ability to grow in hamster cheek pouch and there become spindle- U.S.A. (y5). DMSOordimethyl- cell sarcomas. formamida ' k,, It,Zi'' 9.7l.4iCe0 Guimard, Chicken embryo Application of Increased mitotic activity and increased incidence of anomalous mitosea. 1966, muscular tobacc_o_ extract. France (110). explants. _ Lssnitzki, Mice neonatal Application of a by- a. Increased basal cell hyperplasia and pleomorphism of newly formed cells. 1968, trachea. drocarbon-enriched b. Increased epithelia] mitosis. Englan_d_ (160). fraction of whole smoke condensate. _ Lasnitzki, Human fetal lung Application of a hy- - a. Cellular enlargement aud promotion of _growth of new bronchi. 1968, in organ culture. drocarbon-enriched b. Increased mitoses, bronchial epithelial hyperplasia, and sQuamous metaplasia. England (161). fraction of whole c. Inhibition__ o_f_ _atromal growth. smoke condensate. Chan et_ al., 1969. U.S.A. (54). Mouse lung bud embryonic cultures. Application of B(a) P in DMSO. Leuchtenberger ~ Mouse lung Exposure to fresh smoke: and and kidney Unfiitered a ---- Leuchtenberger, - ---- tissue and . . --- -... b. Activated 1969, organ rgan cultures. charcoal filter. Switzerland (165). e. Cigaretteor cigar tobacco. a. Cellular disorganization. b. Cellular pyknosis; nuclear shape and size irregularities. c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in those cultures exposed to B(a)P versus those exposed to pyrene or DMSO. a. Decreased RNA production, pyknosis, and death of cells. -- -- ~ ------ - b. Similar results, but changes were of minimal severity. --- c. Similar effects as group a., but less severe.

TA[tt.>: Ai4.-Fxperiutents concerning the effect of cigarette ,1moh-e or its constituents on tissue and organ cultures (cont.) _uthor, Author, year, - Tissue or country, organ culture Material/delivery Results reference ~ Crocker. Various organ Application of Squamous metaplasia; fre9uent pleomorp_hic cells: dedifferentiation of epithelium 1970, cultures: B (a) P in serum. (inhibited by Vitamin A). -- U.S.A. (6°). a. Wholesuck- suck- ling hamster tracheas. b. Whole bron- chial tubes from late fetaldoKs and monkeys. 1• Ii i

TAB1.E A15.-Experinnents concerning the effect of the instillation or implantation of cigarette sntoke or its constituents into the tracleeoUronclaial tree of animals Author, A. Method year, Anima__l_ B. Frequency and/ country, and - or duration Results reference sCrain C. Material-- Blacklock_, CB white 1957, rats. (:reat Britain (24). A. Injection into hmg parenchyma by thoracotomy. 13. Once. C. 3,4-benzpyrene in olive oil, with dead Tb bacilli or in cholesterol, cigarette "~tar". 3,4-benzpyrene: a. 3 mg. in olive oil b. ;t mg. in olive oil with dead Tb bacilli c. 5.75 mg. in cholesterol pellet Number with tumors/number mb_e_r exposed 5/6 sarcoma. 2/4 sarcoma, 4/8 squamous cell carcinoma. 1/8 squamnus cell carcinoma. Cigarette "tar" a. In olive oil b. In olive oil with dead Tb bac_il_li_ 0/10. 1/8 sarcoma, 1/8 squamous cell carcinoma. Controls: a. 0.15 cc. olive oil b. 0.15 cc. olive oil with dead Tb bacilli c. Cholesterol pellets 0/4. 0/4. 0/4. aterial: Wceks Survivors at 20 v+eeks/originad number exposed Number of hamatera with trachtobronchial . carcinomas at death a. DMf3A_ 50µg./week 45 10/20 2 b. "Tar" 200-ug./week 32 11/21 c. DMBA 50 µg./week 12 9/20 then "tar°200. Fig./ week ............ . 30 d. DMBA 100 ug./week .... 17 7/20 4 e. DMBA 100 µg./week j and "tar" 500 } 20 9/20 Della Porta Syrian golden A. Direct tracheal et al., hamsters. instilllati_cm._ 1958, B. Weekly up to U.S.A. 45 weeks. (67). C_._ 1_ percent 7,12-dime- . thylbenz(a)anthra- cene (DMBA), cigarette'+tar" cnncentrate. µg./week .............. J Rigdon, White Pekin A. Intratracheal No neoplastic changes noted in either the experimental or control groups. 1960, ducks. injection. U.S.A. Controls: 99 B. Daily for 721 days. (221). Experimental C. Tobacco condensate group: 52 in liquid petrolatum.

W a V TABLE A1b.-Experinlcnts concerning the effect of the instillation or implantation of cigarette smoke or its coxstitue?Fts into the traclteobronc[lial tree of animals (cottt.) Author, A. Method year, - Animal B. Frequency and/ country, and orduratio__n_ rcfet'ence strain C. Material Blacklock, CB white rats. A. Inuculation at 1961, lhoracotomy. (;reat B_. Once and sacrificed Britain at 1 week-2 years. (25). C. Cig_arettetobacco smoke condensate in eucerin. Ilerrold and Syrian golden A. Intratracheal --- Dunham, hamsteis. inoculation. 1962, 13. 0.5 cc./week for_ U.S.A. 5/6 months. C. Benzo(a)Pyrene in Tween6O or olive oil. Rockey et a1., Dogs. A. Bronchial inoculation -- 1962, or stimulation. U.S.A. B. 3-5 times/week (2.4)• forupto5. . . years. . . . C. Cigarette smoke condensate. Tipton and Mongrel dogs. A._ Bronchial Crocker, Control group and inoculation. --- 1964, experimental l B. Daily for H days. U.S.A. group-1_9_. C. Cigarettesmok__c (277). condensate. Results Controls .................................... - Cigarette condensate ........................ ............... Eucerin alone .............................. Number Percent with of rats malignant tumors 275 1.5 (1 carcinoma, 3 sarcomas) . 72 11.1 (6 carcinomas, 2 sarcomas). 44 2.3 (1 sarcoma). Number of Number with Material: hamsters tumors B(a) inTyeen60 ... 6 3 B(a)P in Twecn60_' 6 3 Tween60 .......... 6 0 B(a) P- in olive oil .. 6 0 Olive oil ........... 6 0 Number Procedure:_ of dogs Controls ........ 'L7 Manipulation of bronchus ..... 25 Smoke condensate 130 Number of tracheo- bronchial tumors 5 (3 papillomas, 2 carcinomas). 9 (4 papillomas. 5 carcinomas). Squamous Pre- metaplaaia Invasive Carcinoma- cancerous with atypical Inflam- carcinoma in situ changes changes mation - 6 24 1 - - 7 25 3 25 98 128 Rapid induction of squamous metaplasia in condensate-exposed osed animals. No tabular data is presented. O4IVS..14cQ

w A m -_-----=-_-_ TABLE A15: Experinaents concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of anitnals (cont.) Author, A. Metho l year, Animal B. Frequency and/ country, _ and urdm•a_tion Results reference strain C. Material Sa(fiotti et al_., Syrian golden 1966, hamsters. U.S.A. (2s7). Kuschner, Hamsters. 1968. U.S.A. (157). Saffiotti et al., Syrian golden 1968, -- ----- hamsters. U.S.A. (235). Borisvuk, Wistar rats. 1969, Russia (34). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a)P (3mg.).) attached to fine_ hematite dust. Percent tum9r- Numbcr of bearing of f Ilumb_er-autopsied: tnznor-bearing survivors at -- } animals_ 15_ weeks Male ............... ~23 15 100.0 Female ............. 17 11 100.0 Total Total number number of respiratory of tumors tract cancers 24 18 17 16 A. Wire mesh pellet implantation into bronchus. B. Lifetime. C. B(a)P, methylcholan- threne (MCA). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a)Pattache_d to a fine hematite dust. A. Intratracheal intubation. B. Monthly up to_ 10 months. C. Cigarette "tar". Number of 9urv1UOrglorigLnat Implant: number in group Wire mesh only .......................... 34/35----- MCA ..................................... 88/91 B(a)P ................................... 89/91 Number autopsicd Inoculate: Control .................................. 176 B ( a ) P in hematite .. . ..................... 55 Hematite only ............................ 41 Number fina_l/ initial Inoculate: Controls .................................. 11/20 Unfractionated "tar'' ..................... 24/200 Denicotinized "tar'-'....................... 9/45 Neutral "tar" fraction ................... 14/100 'This group also received one injection of urethane intraperitoneal)y. Number of ani»taltl'a'Ptlt lung cancer 43 57 Number of han=atc.rs with respiratory tract tumors .... ........ . 35 Duration of inoculation (months) 12 10 8 (1/9 metaplasia) 8 (2/14 carcinomas, 1/14 papillary adenoma).

c TABLF Ai6: F,'xperiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respirtttorif tract of animals (Figures in parentheses represent total number survivors in specific group) Author, year,-- country, reference Animal and strain A. Type of exposure B; Duration C. Material Results ents Comments Lorenz et al., Strain A mice: A. Chamber. E. No increase in tumor formation over that noted in - controls. This strain of mice does 1943, }C. 97. B. Up to 693 hours. have a hereditary U.S.A. (177). $E. 97. C. Cigarette smoke. tendency to tumor formation. fC. Control. $E. Experimental. Essenberg_, 1952, U.S.A. (92). ). Strain A mice: -- C. 32. E. 36. A. Chamber. B. 12 hours per day for 1 year. C. . Cigarette arette smoke. Percent of lany_ tumors C. 50.4 (19) E. 91.3(`-'8) No epidermoid cancer - noted: papillary . adenocareinom_a__ was most common. Percentage difference is significant at p <0.01 level. Muhlbock, Hybrid (020 x A. Chamber. Percent with alveolar carcinomas No other type of 1955, DBA) mice: B. 2 hours per day for C. 31.0 lung tumors were Netherlands C. 32. up to 694 days. E. 79.0 found. (195). E. 29. C. Cigarette smoke. Leuchtenberger_ CF1 albino mice; A. Chamber. 23 of thc ezperimental mice sho_aaed:: et al., C. and E. 275. B. To 8 cigarettes 15 basal cell hyperplasin. 1958, - per day from 14 atypical basal cell hyperplasia. U.S.A. (166). 11-201 days. 7 dysplasia. C. Cigarette smoke. 2 sauamous cell metaplasia. Guerin, 1959, IC and Wistar strain rats. A. B. Chamber. 45 minutes P.^rcentagc of rats teitf pulmonary tumors C. 2.4 percent of 39 survivors. France (108). C. 40. _ per day from E. 5.1 percent of 68 survivors. ~ -~---- ~ --~~ - E. 100. 2-6 months. W A C. Cigarette smoke. ZSI ` S94cQ

TABLE A16.-Isxperiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of anianals (cont.) _ - (Figures in parentheses represent total number survivors in specific group) Author,_ year, country, reference Animal and strain A. B. C. Type of exposure Duration Material Results Comments Leuchtenberger et. al., Female CFl mice: C. 243. A. B. Chamber. V-6 cigarettes Number with severe bronchitia; 1960, E. 360. per day for I Exposure peribronchitis; U.S.A. (167). month to 2 years. Number Number of lengti atypical epithe- C. Cigarette smoke. of mice cigarettea (months) lial proliferation 151 25-1,526 150 0 36 100- 200 36 250- 500 34 600-1,600 51 100- 400 63 100- 400 1-23 30 0 2 1- 3 7 4- 8 7 9-23 8 3- 6 4 3- 6 17 Leuchtenberger et al., Female CFl mice: C. 166. A. Chamber. Number B. ~/-R cigarettes of mice Expos Percent of mice ure with pulmonary Presence of tumors showed an age- - 1960, E. 231. per day for examined (days ) adcnomatoua tumors relationship U.S.A. (168). 81 .................... 17-600 days. . . 56 0 independentof C. Cigarette smoke. 39 .................... 17- 9 0 41 smoking exposure. -- 35 .................... 100-19 9 37 51 .................... 200-60 0 66 Otto, 1963. Albino mice. A. Chamber. Number Exposure Number with Germany C. 60........ B. Approximately of mice None. lung tumors (206). E. 189. 12 cigarettes per examined Varying 3 pulmonary adenomas. day for varying C. 60 up to 24 21 pulmonary adenomas. C. intervals. Cigarette smoke. E. 189 months. 2 epithelial carcinomas. MS94cQ . ' . ja. . ~ '..:

TABLE A16.-Exjzeriments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, yeai; country, reference Animal and strain A_ Type of exposure B. Duration-- C. Material Results Comments Dontenwill and Wiebecke, 1966, Germany Golden hamsters. . C. - _E._ 320 20 A. Chamber. B. Up to 4 cigarettes per day for up p to 2 years. Number of animals' deadai 540 daya Daily average exposure (cigarettes) - Histologic findings in dead animals M ET des = desquama- tive metaplasia. MET bronch = bron- chial papillary - (77). C. Cigarette smoke. 40 .............. 1 8/ 40 MET des metaplasia. 40 .............. 2 8/ 40 MET des PAP trach = tracheal 80 .............. 1 2 44/ 80 MET des (3 MET papillomata or bronch, 2 PAP trach) intense tracheal 143 .............. 1-4 67/143 MET des (13 MET metaplasia. bronch, 8 PAP trach) Leuchtenberger CF mice. A. Chamber. - - - and l B. Up to 1,000 hours. Leuchten- C. Cigarette smoke, berger 1966, exposure to in- Switzerland fluenza virus (164). (PR8). Marked t ra n egreaeion Marked apuamous Marked of lung cell metaplaeia d_yepla8ia parenchyma (percent) (percent) (percent) Controls (M0): Male . tEpithelial tissues of these animals showed an increased frequency of cellular atypism. The authors concluded that PRS influenza virus may act as a cofactor in malig- nant transformation. Female . ... Smoke exposed (59) : ...... 14ale ....... Female ..... Virus exposed (59)t 6.0 3.0 Malc ....... _ 11.0 21.0 13.0 Female . Smoke and virus exposed (68): 5.0 Male ....... 9.0 43.0 t18.0 Female ..... 29.0 54.0 t33.0

A. Type of exposure B. Duration C. Material- Rockey and Speer, 1966, Mongrel dogs: ._e.-i1._..__ E. 19. A. Tracheal fenestra- tion (10). d Nostril inhala- .. . U.S.A. (223). tion tion (9). B. Trachealfenestra- tion-284 treat- ment days.---Nostril inhalation- 180 treatment days. C. Cigarette smoke. Auerbach Beagle dogs: A. Tracheos_tom_a__._ et al., C. 10 (2 with B. Up p to 12 1-967,tracheostoma_ tracheostoma). cigarettes per U.S.A. (10). E. 10. day for up - - - --- to 421 (lays. C. Cigarette smoke. Harris and C57BL mice: A. Chamber. Negroni, C. 200. B. Smoke-12 ciga-_ 19G7, E. 1,437. rettes per 20 Englan_d_ mice for 12 ( Ill ) ,. minutes every other day for lifetime. C. Cigarette smoke, influenza virus aerosol, benz- pyrene aerosol. TABLE A16.-Experinlents concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Results Squamous flYperplaaia metapla- witk aia with Pre- Carci- _ lnJtam- atypical atypical tanceroua noma mation features features changes in situ Controls (11) . 9 1 1 0 0 Tracheal fenestra- tion (10) ... 10 5 6 1 ti Nostril in- halntion (9) . 6 0 0 0 0 Comments tCarcinoma in situ noted in 5 separate sites in this_ animal. Controls, experiment-aF--- No histologic change in bronchial epithelium: a. 1 animal died at 24 days and no histologic change noted. - -- -- -- ------- b. 5 animals sacrificed at 421 days and nuclear atypism noted in all. - --- --- - - ----- c. 2 animals died at 229 and 278 days and nuclear atypism was noted but of lesser severity than in those sacrificed at 421 days. Number of Treatment Number lung care_ i7zomat Controls . ................... 200 0 Influenza aerosol alone ..... 682 15 Be_ nzpyrene aerosol (4 exposures) ........... 200 Smoking .................. 200 Influenza and benzpyrene . 200 Influenza and smoking . .. . . 165 2 8 (all adeno- carcinomas) 3 3 This strain of mice is noted for its lack of spontaneous lung tumor formation. Animals exposed to cigarette smoke showed no hyper- plastic epithelial changes such as those noted by Leuchtenberger.

I rt TABLE A16. Experinierats concerlliz.g the effect of the inlralatioxz of cigaqette srtioke, - or its constituents upon the respiratoril tra,ct of ani?tiitls (cont.) (Figures in parentheses represent total number survivors in specific group) 9CV994c0 Author, - year, - Animal A. Type of exposure countty, and B. Duration reference strain C. Material Wynder et al., Male C57BL6 A. Chamber. 1968, mice: B. Up to R15 U.S.A. (817). C. and E.- cigarettes. more than 40. C. Cigarette smoke, nitrogen dioxide, volatile acids and aldehydes found in ciga- rette smoke, swine influenza virus. Results Comments Conclusions: t tResults not provided No squamous cell respiratory cancer noted. This is attributed in tabular form. to the limitation of inhajation time (CO and nicotine acute effects) and to the anatomicallyy and physiologically intricate . nasal passage defense system. - - Exposure to cigarette smoke, NO2, or volatile acide and d ald_e- hydes leads to reactive hyperplasia and metaplasia, both of which were noted to be reversible. Swine influenza virus exposure produced hyperplastic and metaplastic effects which could not be enhanced by subse- quent exposure to cigarette smoke. i.askin et al., Rats: A. Chamber. Squamous cell 1970, C. 45. B. 1 hour per day Exposure Number carcinomas U.S.A. (159). E. - 3. for up to Atmosphere controls ...... _ 3 0/ 3 690 days. Atmo.;phere plus benzo(a)- C. Benzo(a)pyrene _--_ py''ene exposure . .. .. .. . 21 2/21 aerosol, SOa- _SO2 controls .............. 3 0/ 3 atmosphere- (3.5 p.p.m.). SO2 plus benzo(a)- pyrene exposure ........ 21 5/21 Hammond Reagle dogs. See text . .. . . et al.. 1070, U.S.A. (119). See text.

TABLE A21.-Qutline of retrospective studies of tobacco use and cancer of the larynx M4 jF S94XQ Author, year, country, Cases reference Sex Number Method of selection Schrek et al., M. 73 Referrals from V.A. hospitals in "entire -- --- - 1950, midwest" to V.A. Cancer Center Hines, U.S.A. (2y6). Illinois, during 1942-44; patients with . ..... larynx-pharynx tumors clinically or his- - - ---- ---- -- toloRically diagnosed: Percent Nonsmokers ................ 13.7 Cigarettes .................. 79.5 Cigars ...................... 3.7 Pipes ....................... 6.8 Valko, M-F 226 Clinic patients with cancer of the larynx: - 1952, Czechoslovakia P-ercent (292). Nonsmokers ................ 7.5 Cigarettes .................. 83.2 Cigars . ...................... 4.4 Pipes ....................... 10.6 Sadowsky et al., M_ 273 White male admissions to hospitals in 1953, New York City, Missouri, New Orleans. U.S.A. (232). Chicago; patients with diagnosed laryn- geal tumors, 1938-43: geal - -- Percent Nonsmokers ................ 4.0 Cigarettes only .............. 60.1 Cigars only . ................. 2.2 Pipe only ................... 4.8 Some combination . . . .. . .. .. . 28.9 Controls Number Method of aelection Collection of data 522 From same set of referrals, patients Random sample of 5,003 with tumors other than lip, lung, lar- admissions; question- ynx-pharynx: naires from Hines re- ferrals for 1942-44; records included Percent smoking history. Nonsmokers ................ 23.9 Cigarettes .................. 59.$ Cigars ..................... 10.0 Pipes ...................... 11.5 108 Clinic patients of same age group with Medical history and ques- other diagnoses: tionnaire in clinic. Percent Nonsmokers ................ 22.2 6_ 15_ From rom same set of admissions, patients with illnesses other than cancer: Percent Nonsmokers ................ 13.2 Cigarettes only ............. 53.3 - - Cigars only ................. 3.4 Pipe only ................... 7.0 Some combination .......... 23.1 Sample of 2,605 out of 2,847 interviews (in- cluding smoking his- tory) by trained lay interviewers.

I t~« S a v(IVS9f..i(.O TABi.E A21.-Outline of xet)-ospcetivc stlEdies of toLaceo use and cancer of the lm-ynx (co?,tt.) Author,_ year, Cases country, reference Sex Number Method of selection Controls Collection of data Bliimlein, M_ _._ 241 1 Clinic patients with cancer of larynx: 1955, Percent Germany Nonsmokera ................ 0.8~' (26). Heavy smokers .............. 79.3 Inhalers .................... 95.0 Wynder et al., M. 20_9_ White male inpatients Memorial Cancer 1956, Research Center during 1952 to 1954, U.S.A. (312). with benign or malignant epidermoid tumors of laryn_ x:_ Percent Nonsmokers ................ 0.5 Cigarettes .................. 86.0 Cigars ...................... 7.5 Pipes ....................... 5.0 Cigars/pipes ................ 1.0 Wynder et al., M. 132 Laryngeal cancer patients at Tata Mem- . 1956, orial Hospital, 1952-54: India (312). Percent Nonsmokers ................ 13.6 Bidis ....................... 78.8 Cigarettes .................. 5.3 Hookah ..................... 1.5 -- -- Chilum ..................... 0.8 Schwartz et al., M. 121 Patients hospitalized from 1954_ through 1957, 1956 with laryngeal cancer, in Paris France (248). and other large cities: Pcrcent Smokers .................... 96 Inhalers .................... 58 Roll their own cigarettes . 44 Number Method of selection 200 Patients with no laryngeal disease: Percent Nonsmokers ................ 18.0 - Heavy smokers ............. 4.3 Inhalers .................... 17.0 Personal_ history taken in clinic. Patients and controls over 40 years of age. 209 Patients with other than epidermoid Trained lay interviewers. cancer, individually matched controls in same institutions: Percent Nonsmokers ................ 10.5 - Cigarettes .................. 73.7 Cigars ..................... 10.1 Pipes ...................... 3.8 Cigars/pipes ................ 1.9 132 Controls individually matched as for U.S.A. data above: Percent Nonsmokers ................ 30.3 Bidis ....................... 62.1 Cigarettes .................. 4.5 - - -------------- --- Hookah .................... 0.8 Chilum .................... 2.3 242 Same time and sources; patients hospital- ized for non-cancerous conditions o_r_ trauma: Percent Smokers (p<0.05) .......... 84 - Inhalers (p<0.05) .......... 47 Roll their own cigarettes .... 31 Interviews for smoking and medical histories. Cases and controls indi- vidually matched within vidually institutions; each mem- ber of a set questioned by the same trained lay_ interviewer.

A TABLE A21.-Oxttline of retrospective shidies of tobacco use and cancer of Ehe larynx (cont.) Author, year, Cases country, reference Sex Number Method of selection Wynder et al., M. 60 Patients at Radiumhemmet with squam- 1957, 1957, ous-cell cancer of larynx, from 1952 Sweden (322). through 1955: • Percent Nonsmokers ................ 5 Cigarettes .................. 47 Cigars ...................... 17 Pipes ...................... 15 Mixed ...................... 17 Controls Collection of data - Number Method of selection 271 Patients from same source and time, By trained lay inter- with_ cancer other t_han_ squamous-cell viewers in hospital. of larynx: Percent - Nonsmokers ................ 24 Cigarettes .................. 36 Cigars ...................... 9 Pipes ...................... 16 Mixed ...................... 13 Wynder et al., M. 142 Clinic patients in Havana during 1956-57, 1958, F. . 3_2_ with histologically diagnosed epider- Cuba (325). moid cancer of larynx. Percent Male Female Nonsmokers ......... 1 13 Cigarettes ........... 62 72 Cigars ............... 20 6 Pipes ................ I .. Mixed ............... 16 9 Dutta-Choudhuri M-F 582 Patients in Calcutta cancer hospital dur- et al., ing 1950-54, with laryngeal tumor diag- 1959, nosed and confirmed by biopsy or smear: India (86). Percent Nonusers ................... 14.1 - Cigarettes or bidi ........... 77.8 Chew ....................... --------- 3.1 Both ....................... 5.0 220 Same source and time; apparently pa- Interview of patients 214 tients with cancers other than larynx, i_n__ clinic. Iung, or oral cavity, matched for age: Percent Male Fcmale Nonsmokers ........ 16 66 Cigarettes .......... 45 27 Cigars ............. 22 6 .. Pipes ............... I Mixed .............. 16 288 Not specified Percent Nonusers .................. 41.7 Cigarettes or bidi ........... 52.1 Chew ...................... 3.8 Both ....................... 2.4 Tobacco histories ob- tained during 1951-54, apparently by inter- viewer.

n W V TABLE A21.-Oletline of retrospective studies of tobacco use and cancer of the la.? y?•li (cont.) Author, year,- country, reference Sex Number Staszewski, M. 207 1960, F. 13 Poland (259). Poland Itozenbilds, 1967, Australia (229). Terracol et al.. 1967, France_ (274). Svoboda, 1968, Cases - Method of selection Controls Number Method of selection Patients admitted to_ chronic disease hos- pital during 1957 and 1958 with histo- 912 1,813 1,813 logically confirmed squamous-cell car- _. ----- cinoma of the larynx: Percent Nonsmokers ................ 0.5 Cigarettes only .............. 87.9 Pipes and/or cigars .......... 1.9 "Heavy smokers" . ... .. .. .. . 88.4 Inhalers .................... 96.1 Female smokers ............. 30.8 Collection of data Patients admitted during 1957 and 1958 Author interviewed pa- ........ ... ...... .. to chronic disease center for cancer- tients suspected of lung ous and noncancerous conditions pre- cancer for smoking sumahly not related to tobacco con- history and background. ti sump on: - - Percent Nonsmokers ................ 17.3 Cigarettes only ............. 60.5 Pipes and/or cigars ......... 11.1 "Heavy smokers" 49 0 . .. .. ... .. . ~ -------- . .. . . Inhalers .................... 66.8 Female smokers ............ 8.4 M. 191 Patients admitted to 3 major hospitals No controls. F. 21 with cancer of larynx and hypopharynx: - Percent Nonsmokers ................. 8 Smokers ..................... 92 Heavy smokers .............. 30 M. 961 Private service and clinic patients of ENT No controls. hospital: Percent Nonsmokers ................ 12.1.. Smokers .................... 87.9 M. 205 Patients admitted to a regional hospital 320 Male controls F. 10 over a period o f 6 years all confirmed _ _ Czechoslovakia histologically: - -- (Y77). Nonsmokers ................ Cigarettes ................. Pipes ...................... Percent ... Percent Nonsmoker_s ................ 22.0 2.93 Cigarettes (approximately) . 71.0 94.63 Pipes (approximately) ...... 7.0 2.44 Patient interviews. Patient interviews. Cases: patient interviews. Controls: not stated.

TaBUE A22~.-Sm~mary of' result's~~ of ~ retrospective str(d~ies, of ~ tobacco use and cancer of the larynx (Figu.res~~ in,parentheses representratios~~.based owless~than 5'e case nonsmokers.)~~ Relative risk ratio' all Investigator referencee smokers to.nonsmokers Sahrek et'al.. U S'.A. (246) ............................................. ............... V a1ko,.Czechoslavakia.(292), ......................................... Sadowsky et a11, U.S.A. (2:72) ........................................ ...Blii.mlein. Germany(26.).............................................. ......... Wynder et a]l. U:S:A. (&12)', .......................................... Wynder etal..India.(31Y) .................................................... Schwartzeta].,France (268)~ ........................................... Wynder et al., Sweden (322), ................................................ ,......,... Wynder~et',aa., Cuba (.R25'.)............................................ Dutta-Choudhurietal.,.India..(86). ......................................... Stazewski.,Poland.(269) . ............................~....._....,.....,.....~ ....~..~.~ Svoboda„ Czechos]avakia.(271.)~ ....................................... 3Computediaccording to~method of Cornfield,.d. (61.)... 2.0 3.5 3.7 27.5' 23:6'. 3:1 4.6 6.0 ( 18.9) (males only.). 4.3 (40.0) (malesonly). 8.3 358'

TABLE A2_3. Nuut_ber and percent distribution by relative frequenc_g of atypical nuclei among true vocal cord cells, of men classified by smoking category (100 percent atypical cells defined as carcinoma) Current cigarette smokers - Percent Never smoked Ex-cigarette Cigar/pipe Less than 1 1-2 packs 2 or more atypical nuclei regularly smokers - smokers pack a day a day packs a day Num- Per- Num- Per- Num- Per- Nsm- Per- Num- Per- Num- Per- brr rent ber cent ber cent ber cent ber cent ber cent Total .. ................... 88 100.0 116 100.0 94 100.0 125 100.0 329 100.0 190 100.0 None .............................. 60 75.0 86 74.1 1 1.1 1 .8 0 - 0 Less than 50 ....................... 8 9.1 14 12.1 4 4.3 25 20.0 4 1.2 0 - 50-59 .............................. 10 11.4 13 11.2 50 53.0 54 43.2 87 26.4 29 16.3 60-69 .......................... .... 4 4.5 1 .9 23 24.5 21 16.8 116 35.3 75 39.4 70-79 ,,,,,,,,,,,,,,,,, ,,,,,,,,,, 0 - 2 1.7 9 9.6 9 7.2 44 13.4 38 20.0 80-89 ................. .......... 0 - 0 - 2 2.1 2 1.6 19 5.8 11 6.8 - 90-99 .............................. 0 - 0 - 1 1.1 0 - 5 1.5 0 - 100: Carcinoma in situ .............. 0 - 0 - 3 3.2 13 10.4 52 15.8 35 18.4 Invasive carcinoma .. _ 0 - 0 - 1 1.1 0 - 2 .6 2 1.1 Source: Auerbach, 0. et al. (9).

CVfirS9zIC0 TABLE A24. Number and percent distribution, by highest number of cell rows in the basal layer of the true vocal cord, of men classified by smoking category Current cigarette smokers Number of Never smoked Ex-cigarette Cigar/pipe Less than 1 1-2 packs 2 or more regularlg---- -smokers smokers pack a day a day packs a day ce rows ll Num- Per- Num- Per- Num- Per- Nnm- Per- Num- Per- Num- pere ber cent ber cent Qer cent ber cent 6er cent ber cent Total ........................ 88 100.0 116 100.0 94 100.0 125 100.0 329 100.0 190 100.0 Less than 6 cell rows .............. 30 34.1 7 6.0 4 4.3 3 2.4 1 38 0.3 11 6 0 20 10 6 5 cell rows ........................• 29 33.0 27 23.3 20 21.3 27 21.6 . . 6 cell rows .......................... 8 9.1 15 12.9 15 6.0 25 20.0 51 15.4 24 12.6 7 cell rows .......................... 6 6.8 12 10.3 18 19.1 12 9.6 38 11.6 19 10.0 8 cellrowa .......................... 8 9.1 14 12.1 9 9.6 13 10.4 30 9.1 23 12.1 9 cell rows .......................... 1 1.1 7 6.0 7 7.4 6 4.8 26 7.9 44 1 14 90 7.4 4 47 10 or more cell rows ................. 6 6.8 34 29.4 21 22.3 39 31.2 146 . . Source: Auerbach. 0. et al. (9). ktt

,,*;. .. -W Y'v.Nt. ~ Tast,e A28.-O2cttine of retrospective studies of tobacco ~llse and cancer of the oral cavity (Data obtained from patient interview and other sources) Author, year, Cases country, ... reference Sex Number Method of selection Borders, M. 526 Series of clinic patients with epithelioma -- - - ------- 1920, F. 11 of the lip: U.S.A. (4J). Percent ---- - Tobacco users ............... 80.5 - - - Smokers .................... 76.1 Cigarettes .................. 0.9 Chewers .................... 24.0 Pipes ....................... 59.0 Cigars ...................... 38.5 ............ ...... Ebenius, M. 439 Clinic patients with cancer of the lip: 1943, F. 33 Sweden (87). Percent Male Female Tobacco users ........ 79.7 - - Tobacco users (all pipes) ......... - Pipes ................ .............. 61.8 Chew or use snuff .... 47.4 Cigars and cigarettes . . 12.9 67.6 Levin et al., M. 143 3 Cancer Institute patients with cancer of 1950, the lip: U.S.A. (169). Percent ... ... Smokers .................... 84.5 Cigarettes .................. 45.3 Pipes ....................... 48.1 Cigars ...................... 26.5 .. _ ';:4'. Controls Number Method of selection 500 Series of clinic patients without epithe_- lioma of the lip: Percent Tobacco users .............. 78.6 Smokers ................... 75.2 Cigarettes .................. 44.4 Chewers .................... 13.4 Pipes ...................... 28.6 Cigars ..................... 44.0 300 Not defined. Percent Male Female Tobacco users ........ 68.7 Tobacco users ........ - Pipes ................ 22.9 Chew or use snuff ..... 60.7 Cigars and cigarettes .. 32.6 tl-2 51 Cancer Institute patients with n_ o_n-ca_n_ - cer diseases of same site: Percent Smokers ................... 74.0 - Cigarettes .................. 43.0 Pipes ....................... 30.7 Cigars ..................... 34.9 Comments t Estimate of prevalence of use.

°' Q ~ TAB1.E A28.-Outlinee of retrospective studies of tobacco ase and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, - Cases country, _ _ reference Sex Number - Method of selection Controls Number Method of selection Mills and Porter, M. 124 Deaths from cancer of oral cavity in Cin- ----._. 1950, cinnati and Detroit, 1940-45 and 194n- U.S.A. (186). 46 respectively: ~ Percent Cigarettes only .............. 35.5 Pipes, cigars, or combinations .............. 54.8 Moore et al., M. 112 Patients over 50 years old since 1951 with 1953, cancer of oral cavity: U.S.A. (19s). Percent Chewers .................... b8.0Pipes ....................... 42.0 - - Cigars and cigarettes ........ 38.4 Sadowsky et al., M. 1,136 Hospital patients with lip, oral, and phar- 1953, yngeal canccr. 1938-43: U.S.A. (232). Percent Cigarettes only .............. 42.3 Cigars only ................. 4.0 Pipes only .................. 17.8 Mixed ...................... 28.2 Sanghvi et al., M. 657 Hospital patients with cancer of oral cavi- 1955, 1955, F. 81 ty and pharynx_:_ India (241). Percent Male Female Smoke and chew ..... 38.8 3.7 Smoke only . .. .. .. .. . 46.7 6.2 Chew only ........... 11.7 64.2 - Neither .............. 2.7 25.9 185 Sample of population of Columbus, Ohio, in same proportion of color, sex, and age as in cases: Percent Cigarettes only ............. 32.4 Pipes,cigars,or_ ----- - combinations ............. 29.7 39 Patients of same age groups with be- nign oral lesions or benign surgical_ : conditions: Percent Chewers .................... 31.6---- Pipes ...................... 47.4 Cigars and cigarettes ........ 52.6 615 Patients with illness other than cancer: Pcrccnt Cigarettes only ............. 53.3 Cigars only ................. 3.4 Pipes only .................. 7.0 Mixed ...................... 23.1 299 112 Comments Hospital patients with diseases other Smoking is of bidis among - than n cancer: both cases and controls. Percent Male Female Smoke and chew ...... 24.0 - Smoke only .......... 50.0 6.3 Chew only ............ 8.7 23.2 Neither .............. 17.3 70.5 SVV994E0

w a u TABLE A28. Outlinc of rrtrosguecEive .sttttlias of Fuhnc:c•u i?sc• ttud ranct-r of thc orctf c•urit}1_ (cotiE.) (Data obtained from patic•nt intrrview and rzth(•r sseurces) Author, year,- Cases country, reference Sex Number Method of selection Ledermann, M. 240 Patients with cancer of oral cavity and 1955, pharynx: France (1H2). Pe_rcent_ Nonsmokers ................. 4.6 >20 cigarettes per day ....... 23.4 Number 62 Controls t Method of selection Commen s Patients with cancer of ski muscle: n, bon e, and Differences _ifiere_nces between cases and controls for both Percent high and low alcohol in- Nonsmokers ................ 17.2 take are ihsignificant >20 cigarettes per day ...... 18.6 when smoking is con- trolled. Wynder et al., M. F 1957 543 Patients with cancer of oral cavity: 116 207 232 Patients with cancer of other sites and i - --- --- h i di . , U.S.A. (513). - Percent _s_e_a_ ses: en gn seases: - Percent Male Female Male Female Nonsmokers ......... 3 7 47 Nonsmokers .......... 10 70 Cigars ............... 20 Cigars ............... 13 Pipes ................ 11 Pipes ................ 6 ............... Mixed 8 Mixed ................ 8 . Chew ................ 17 Chew ................ 8 Cigarettes ........... 57 53 Cigarettes ............ 63 30 >35 cigarettes_ >35 cigarettes per day ............ 29 per day ............ 17 >16 cigarettes >16 cigarettes per day ............ - 34 per day ............ .. 11 Schwartz et al., ._.__. 1957, France (248). M. 332 Hospital patients with cancer of oral cav- ity and pharynx: 608 Hospital patients with non-cancer ill- ness and accident cases, matched by . . . . . . . . . . . . age: Percent Percent Nonsmokers ................ 16.4 Nonsmokers ................ 23.4 Cigarettes only .............. 62.7 Cigarettes only ............. 58.2 Pipes only .................. 3.3 Pipes only .................. 3.0 9VVSJf.,CQ

T_AT31..E A28.-Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author,_ year, Cases cauntry, reference Sex Number Method of selection Number Wynder et al.. M. 178 Hospital clinic patients with cancer of 220 1957, F. 34 oral cavity and pharynx: 214 Cuba (S25). Percent Male Female Nonsmokerc ......... 4 24 Cigarettes predominantly ..... 45 62 Cigars predominantly . 33 12 Wynder et al., M. 115 Male patients with cancer_ o_f_ oral cavity 1957, and pharynx: Sweden (322). Percent Cigarettes ................... 36.5 Cigars ...................... 13.0 PiPes ....................... 12.2 Mixed ...................... 16.7 Peacock et al., 1960, U.S.A. (2ro). Percent Chewed or used snuff over 20 years (all patients) ........ 55.6 115 74 72 Staszewski, M. 383 Male patients with oral cancer: 912 -- 1960, Percent Poland (Y58). Nonsmokers ................ 5.7 - "Heavy" smoking index ...... 72.8 Cigarettes only••...•...._.... 72.3 Pipes and/or cigars .......... 12.8 Controls Method of selection Comments Patients in same clinics with non-malig- _.. nant conditions, matched by sex and age: Percent Male Female Nonsmokers .......... _ 16 6_6_ Cigarettes predominantly ...... 45 27 Cigars predominantly . 22 6 Male patients in same hospital with can- cer of sites other than oral, pharynx, larynx, lung, esophagus, breast: Plrcent Cigarettes .................. 36 Cigars ..................... 9 Pipes ...................... 16 Mixed ...................... 13 Alcohol data significant only for bypopharynx. Patients in same hospital without oral cancer and 117 male and 100 female out-patients, randomly selected. - 32.6 percent of first group, and 43.3 per- cent of second group chewed or used snuff over 20 years. Male patients with other cancerous and non-cancerous conditions: Percent Nonsmokers ................ 17.3 "Heavy" smoking index . 49.0 ,... Cigarettes only ............. 60.5 Pipes and/or cigars ......... 11.1

1 Br~S9~,~0 Ia'".^k"_,..:':. TABLE A2$.-Outline of retrospective studies of tobacco nsc• L1ncI era,>ir,er of the oral f•stcit(t (cont.) (Data obtained from patient intervievv nnd other snuires) Author, year, Cases country, reference Sex Number Method of selection Vogler et al., M. 188 Clinic patients with cancer of lip and oral ~~ 1962, F. 92 cavity: U.S.A. (298). Percent Male Female Chewers ............. t32.9 - Excessive chewers .... 22.9 Snuff dippers ........ - Excessive snuff 72.0 dippers ............ -. 41.3 Tobacco users ........ 90.0 90.0 Con trols Number Method of selection 521 Patients of same clinic with other can- 1,064 cer or non-malignant conditions: Percent Ma6e_ Female Snuff dippers ......... ... 16.1 Tobacco users ........ 56.0 56.0 Vincent and Marchetta, M. 66 F. 16 Successive patients with lesions of buccal 100 . . . ...... .. ... .. .. cavity and oropharynx: 50 - Successive patients attending gastroin- testinal clinic, age-matched: 1963, Percent U.S.A. (8@7). Oral Oro- Males: Cavity pharvnx Percent Nonsmokers ......... 3.0 - 27.0 <20 cigarettes per day ............ 18.3 15.1 24.0 >20 cigarettes per day ............ 78.7 84.9 49.0 Females: Nonsmokers ......... 65.5 28.6 82.0 <20 20 cigarettes per day ............ - 8.0 >20 cigarettes per day . .. .. .. .. .. . 44.5 71.4 10.0 Comments # Due to varying tabular treatment of data, per- centages of tobacco users are not all based - - on the same number of cases. Male ale patients used con- siderably more alcohol than male controls. Data refers to all forms of smoking expressed as cigarette equivalents. Cigarette equivalents: I cigar = 5 cigarettes 1 pipe -.2 cigarettes t BN=Betel nut.

F, TABLE A2_8_ .-Outlizle of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year, country, reference Sex Number Shanta and M. 552 Krishnamurthi, F. 20G 1964, India (256). Cases Method of selection Patients with oral and pharyngeal cancer - (unsure of confirmation) : Number Controls Method of selection Comments 300 100 Percent Controls residing in same area matched for age, sex, and -- A_ nterior tongue 7.2 Posterior tongue 2.0 clas_s_:_ Pharynx 5.3 Males 39.1 66.6 75.0 72.8 52.7 (69) (48) (130) (300) 33.3 - 40.0 Females 88.8 5.5 - 8.8 - (18) (4) (26) (100) &_ uccal Males: Lip rnucosa No tobacco habit . .. . - 2.0 Smokers ........... 50.0 45.7 Numberofcases .... (12) (293) Females: No tobacco habit .... 14.3 11.0 Smokers ........... - 4.7 Numberofcases .... (7) (152) Wahi et al., M. 589 Patients with oral and pharyngeal car- 1965, 1965, F. 232 cinoma: India (808)_. --Percent_ Nonsmokers ................ 9.62 Smokers .................... 17.05 Chewers (Betel nut) ......... 35.44 - Both ........................ 37.88 Hirayama, M. 369 Patients with oral and pharyngeal carci- 1966, F. 176 noma: Central and Percent South_ East Male Female Asia (124). Nonusers ............ 1.6 2.6 Smokers ............. 17.1 2.6 Smokers, tBN and tobacco chewers . .. . 46.7 6.6 589 Patients matched for age, sex, religion, 2_3_2_ and social class. Percent 66.6 21.2 5.9 6.4 277 3 Patients with other (unspecifled) dis- Found only a suggestive i b 16 eases: Percent associat on etween alcohol-drinking and Mate Female oral cancer in non- 17.0 33.0 chewers only. 23.8 1.2 t BN-Betel nut. U t

TABLE A28.-Outline of retrospective studies of tot acco use and cancer of the oral cavity (cont.) - --- --- - - (Data obtained from patient interview and other sources) ' OSVS94c0 + Author, year, Cases country, reference Sex Number Method of selection Keller, M. 408 Patients with squamous cell carcinoma of 1967, oral cavity and oropharynx confirmed U.S.A. (140). histologically. Three New York City VA Hospitals 1953-_63: Controls Number Method of selection Comments 408 Next male patient admitted to same hos- Excessive alcohol con- pital -- pital within 5 year age range. sumption noted for Percent Percent Nonusers ................... 5.1 14.2 Cigarettes .................. 68.6 56.4(p<0.0001) Pipe only ................... 4.0 2.9 Cigar only .................. 6.9 6.1 1970 ll i f li d , U.S.A. (141). carc noma o p: ce Percent age an race. Percent Nonsmokers ................ 7.3 16.6 (p<0.001) Cigarettes only .............. 60.2 52.8 - ~ --~----- -------------- Pipe only ................... 6.0 3.4 Pipe,other .................. 6.3 0.4(p<0.01) cases involving floor, mesopharynx, and tongue. Findings indicate the association of heavy drinking with canc_e_r_ independent of the amount of tobacco used. Martinez M Patients with epidermoid carcinoma c 345 115 male and 38 female hospital or clinic Cases found to consume , --------- 1969 . --- F 38 --------- -~---- -------- -- ------------ - oral cavity and pharynx: 114 patients without cancer; 330 male and more alcoholic bever- , Puerto Rico . --~----_ ..------ - ~--- ~-- 76 female residents of aame region, . ._.--.. _ _.... . ages than controls. -- -- - -- ---~- - (183). age and sex matched. Percent Nonsmokers ................ 13.7 Percent 19.2 Heavy tobacco users ......... 24.8 12.2 (p<0.0001) Keller, M. 304 Patients with primary basal or squamous 304 Patients from same hospital matched for

w a m TABLE A28a.-Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites Author Cigarettes Pipes Pipes and Cigars Tobacco Betel nut reference Cigarettes and cigars Bidis only other forms only chewing chewing Miscellaneous Broders (43).......Lip (-) ................................. Lip (+)......... . ........Lip (-).... . Lip (+)..................... Ebenius (87) ....................... Lip (-)................ Lip (-}-)......... ........................... Lip ( -)..................... Levin et al. (169).. Lip (- ) ......... .........................Lip (-}-)..................... Lip (')...................................... Mills and Oral (") .............................................................................. .............................. Pipes and cigars. Porter(186) combined-oral Moore et al. (193) ................... Lip. ....... Lip. ........................... Lip. ............... Snutf-lip, mouth (-). mouth (-) mouth (~-) mouth Sadowsky Lip, tongue, ........................ ...................L_ip.tongue. ............ Tongue. .............. ............... et a]. (232) other oral, ~ other oral (-{-) other pharynx ( -)..... oral (')...... Sanghvi et al. ................................ Oral ............................................. Oral (+) ..... ............... If smokers and (241) chewers-base of tongue, hypopharynx Lederman (162)... Oral (+) .............................................................. .............................. ................ Wynder et al. Floor of ........................ . Each site ............ _ Each site Gingiva. (313) mouth except lip ( )..... Male (*) Female (+) .... tongue (~r.).... .... Schwartz et al. ................. Pharynx (+) ........... Oral (-) .................................... .................... ... (248)

TABLE A2$a-Sumrtdary of resulES of rG't?'os}lectitle att4hlit's of seerol;ik[y (tJl tr}/tc rlpd Qral efnFe6'C of tlct4,ilt•rl sites (coztt.) - -- -- ---- --- - Author Cigarettes Pipes Pipi and Cigars Tobacco Betel nut reference _ Cigarettes and cigars Bidis only other forms only chewing chewing Miscellaneous Wynder etal. O_raland .............. ........................... ............ Oral and ............................. (3JS) pharynx, . .. (-) - phat•ynx, Male Male (+), Female (+) Female (-}-) W T Wynder et al. Pharynx (-}-), ...................................................... .Tongue. ..............................Pipes and cigars (y?y) other site_s_ gingiva, combined- pharynx pharynx tongue (+). P-eacnck et al. ....... 1 - -- -~ ~ ...... (210) ........................... ............................................ Oral (i-) .... ................. Snuff-oral (+)' Stxszewski (259)...Lip.oral ....................... ................. ........................................................ Pipes and cigars cavity (+) ..... combined-lip, oral cavity (*). Vogler et al. ............................... ................................................................. ... . ............... Allforms com- (283) bined (+), Female (+) Snuff-lip and buccal cavity in both cases. Vincent and Marchetta (287) Shanta and Krishnamurthi (25G ................. .................................................................................... ------- Allforms ................ - combined- oral oral (+), pharynx (+). ................. ........... ...................................... ..................Lip. All smoking types ... buccal -pharynx mucosa (+) . . post tongue (-~)- All forms com- bined-lip, oral cavity,_ pharynx (+).

TABLE A28a. Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites (cont.) Author Cigarettes Pipes Pipes and Cigars Tobacco Betel nut reference Cigarettes and cigars Bidis only other forms only_ - chewing chewing Miscellaneous Wahi et al. Anterior (802) tongue and buccal mucosa, Males (-)-) . . .. .. .. . . . . . . . . . . . . . . . .. . . . .. . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . .. . . . . .. Anterior All forms com- -------------- -- - tongue a_ _n_d_ bined_-all buccal sites y mucosa, -- Males (+) Hirayama (124) ..................... ........................ Allsites (-)................. Allsites (-) ... All sites (-)................. Allformscom- com- - bined-base of tongue (+), oropharynx (+). Smoking only combined -buccal mucusa (+). Keller (140) ........ All sites (+) ..... ........................ All sit" (-) ..... ............ All sites (__) .............. ....................... All types smoking combined, heavy -floor of mouth and tongue (+). Martinez (18$) .....Oral cavity, pharynx (+) ........................ ......................................................................... All types of smoking, heavy, combined-oral cavity (+), pharynx (+). Keller (141)....... LiP (-) ................................................... Lip (-{-).... Lip (-)....................................... Alltypesof - - smoking com- bined-lip (+). ~ Only in individuals of low economic status and over 60 years old. Symbols: (+) - significant association. (-) = association absent or not significant. ( ' ) = association of doubtful significance.

TABLE ALJ.--Experiulet)tul staulies eoucct7ri)tg oral carcinogenesis r Author, year, coifntry, reference Animal and strain A. nlethixl. B. Frequency and/ or duration. - C. -M:iterial.-- Results Kreshouer, 1952, U.S.A. (15?). 78 Swiss and C57 mice. A. I'ainting of lower lip mucocutaneous region. B. 10 times in 76 days. C. Cigarette smoke "concentrate". No macroscopic r microscopic changes in controls or experimental animals. Snlley, 36 Syrian A. Painting of cheek Numbrr of Number with Number with 1954, hamsters. pouch. .. . . _ Treatment: sur-vivora be?aign tumora ..... . -_ _ . ca-rcinoma U.S.A. B. 3 per week for 16 1 u Acetone solvent .................. $_ weeks. I3enzenesolvent .................. 4 - - C. . I_3e_ nz ( n) Pyrene in acetone or benzene. Hulsti and Ermala, 60 Albino mice (40 controls). A. Painting of lips and oral cavity. No oral or labial chunges seen in controln orr exPerimental animals. 1955, Finland 13. 140 times in 12 months. (130). C. Tobacco "tar". Moore and Miller, $0 Syrian Golden olden hamsters. A. Material soaked onto wad and secured OrSgival Surviving Inflammation Number and basal cell 1958. in cheek pouch. Treatment: vuumber over 1 year tumors h1[perpingia U.S.A. B. Wads replaced R Controls ........................ 30 23 .. 4 (192). --- ----- ------- - times in 2 years. Smoke condensate ............... -------- -- - 80 55 .. 32 C. Smoke condensate Benz (a) Pyrene. Benz(a)pyrene ................. 20 16 .. 9 Guerin, Strain IC and 1959, strain W rat. A. Chamber inhalation of tobacco smoke. Original ?iumbcr Survivore 11i{ecnt tumora France B. Daily (?). 'controls ............ 40 39 0/39 u V (108). C. Up to 5?;,, months. EzPerimental ....... 100 68 5/68 (3/5 definite eP.ithelioma )

Author, year country, reference Peacock et al., 1960, U.S.A. (210). TABLE A29.-Experirnental studies conccrrting oral carcinogenesis (cont.) Animal and strain A. Method. B. Frequency and/ or duration. C. Material. - 124 Syrian A. Packing of cheek Golden hamsters. pouch. B. C. 1 year. Snuff, Tobacco, Bland material. Dunham and Syrian Golden Herrold, hamsters. 1962, U.S.A. (84). A. Packing of cheek - pouch. B. Normal lifespan or 5-30 months. C. Betel quid ingredients 7-12 dimethylbenz (a)- anthracene (DMBA), Methylcholanthrene (MCA) in beeswax pellets. Results No tumors noted in any of the 42 animals surviving over 1 year. Hyperplasia Malignant Original and/or in- pouch Treatment: num6c^r Survivors flammation tumors . Betel quid 375 90% over 1year 19 - ................. . - DMBA and MCA ............. 71 56/71 over 5-30 months - 23/56 Moore and Christo- pherson, 1962,- U.S.A. (191). Albino hamster exteriorized oralpouch. - A. Painting oral mucosa. B. 3 per week €or 683 days. C. Cigarette smoke condensate. DMBA in 0.5% Treatment: Controls ........................................ Smoke condensate .............................. DMBA ......................................... Animals witlah lcsions (time) 0/18 (at 392 days). -- --- --- -- 0/20 (at 337 days) (10 showed hyper- keratosis). 14/21 microscopic cancers (at 90 days) petrolatum. inating (invasive squamous sancer originating in the skin at the edge of the pouch). Salley, CAFI strain 1963, mice. U.S.A. (SS9). A. Ultraviolet light exposure to and painting of lips. B. 3 per week for 98 weeks. C. B( a) P in acetone Cigarette smoke U V light. Treatment: Number Ultraviolet light and - - cigarette smoke .................... 40 B(a)P and UV light .................. 40 UV light ............................ 40 B(s)P .............................. 40 Duration Tumors weeks 94 48 94 45

TABI.E A29.-Experinlcntat studies concerning oral carcinogcnesis (cont.) Author, year, country, reference Animal and strain A. B. C. Method. Frequency and/ or duration. Material. Results Hamsters A. B. Application to cheek pouch. See results. Treatment: Cigarettes 6 per week ... .... .. Original Number 70 Survivors 55 Duration 64 Leaions - C. See results. DMBA once .................. 13 6 128 2 hyperplasia Croton oil 3 per week . . . . . . . . . 10 10 30 DMBA once and cigarettes 5 per week ................. 30 28 81 12 hyperplasia DMBA once then croton oil ------ ----- --- ~ --------_ .--- 4 dyskeratosis 1 carcinoma 5 per week ................. 29 27 81 7 hyperplasia 6 dyskeratosis 3 carcinoma Bock et al., ICR Swiss A. Painting mouse 1964, mice. skin. U.S.A. B. See results 36 weeks. (so). C. Various extracts of unburned tobacco DMBA. Treatment: DMBA once then: Acetone benzene extract ........................... Concentrated Ba ( OH ) 2 extract . . . . . . . . . . . . . . . . . . . . Diluted Ba(OH) a extract .......................... DMB A only ...:............................... ... Acetone benzene extract ........................... Concentracted Ba ( OH ) 2 extract . . . . . . .. .. . . . . . . . . . Diluted Ba(OH)a extract .......................... None ....................... :.................... Number tumora/ number mice --- -- Tobacco equivalent with tumora (cigarettes/daily) (small papillomaa) 2.5 16/7 0.5 18/8 0.5 6/2 2.5 0.5 0.5

r LSVS94c0 Author_, year, country, reference Animal and strain Protzel et al., Swiss Webster mice 1964, with some having U.S.A. liver damage in-_ ( 21S_ ) . duced either by CC 14 or ethyl alcohol. TABLE A29.-Experiinental studies concerning oral carcinogenesis (cont.) A. Method. B. Frequency and/ or duration. C. Material. 1 Results A. Swabbing of labial Original mucosa. number B. Up to 13 months. Alcohol and CCl4 treated .............. 40 C. B(a)P in acetone. - Alcohol treated ....................... - 40 CC14 treated ......................... 40 No toxin ............................. 40 Reddy and Swiss female A. Intravaginal Original Anguli, _ mice. instillation. number sur-viuore 1967, India (219). B. Daily aily for 324-380 days. C. "Pan"mixture of areca nuts, lime, and chewing tobacco. Elzay, Syrian Golden A. . Application to 1969, hamsters. cheek pouch. U.S.A. B. Daily for 200 days. (90). C. See results. 60 40 Percent at 13 montha with PapiUomae Cancer 74 46 84 b9 90 40 42 16 Original Mortality Number Treatment: number rate animals DMBA Alcohol Smoke 29 41.0 17 DMBA Alcohol ... 29 66.0 10 DMBA . .. .... Smoke 29 42.0 14 DM BA ....... ...... 29 48.0 16 .. Alcohol Smoke 29 42.0 14 Smoke 29 42.0 14 Lesiona 3/40 raised papillomatoua malignant growths 4/40 possible carcinoma- in situ. Percent Percent with with tumors cancer 100.0 60.0 60.0 40.0 100.0 70.0 100.0 88.0

1~r TABLE A31, Summarp of methods used in retrospectvie studies of tobacco use and cancer of the esophagus rr r .±e R~Y~9lSdG o 7 Author, year. couiitry Cases Controls , reference Sex Number Method of selection Number Method of selection Collection of data Sadowsky et al., M. 104 White patients admitted during 1938-43 to 615 White patients with illnesses other than Obtained by 4 specially 1953, selected hospitals in New York City, cancer admitted to same group of hos- trained lay interviewers. U.S.A. (232). Missouri, New Orleans, and Chicago. pitals during same period. 242 records out of a total of 2,847 excluded be- cause of incomplete or questionable smoking histories. ----1960, during 195_7-5_9_._ symptoms probably not etiologically method of data collec- Poland (260). connected either with smoking or with tion. No age adjust- diseases diseases of esophagus, stomach or du- ment or matching. Av- odenum. odenum. erage age of cancer patients, 60.5; controls, 53. Sanghvi et al., 1955, M. 73 Consecutive clinic admissions to Tat_a_ m_ _e- morial Hospital, Bombay. 288 Consecutive clinic admissions of patients without cancer. India (241). 107 Consecutive admissions of patients with cancers other than intraoral or eso- phagus. Wynder et al., M. 39 Patients admitted to Radiumhemmet, 115 Patients admitted to same hospital with 1957, F. 35 Stockholm, during 1952-55. 156 cancer of skin, head and neck region Sweden (322). other than squamous cell cancer, leu- kemia, colon, and other sites. No matching. Staszewski, M. 24 Patients admitted to Oncological Institute 912 Other patients sent to Institute with By means of "detailed questionary." No other details given. No details given ?.n

TABLE A31. -Summary of inetlaods used in retrospective studies of tobacco use and cancer of the esophagus (cont.) vSV~94C0 Author, year, Cases - country. reference _ Sex Number Method of selection Number Schwartz hwartz et al.,_ M. 362 Admissions to hospitals in Paris and a 362 _ 1061, few large provincial cities since 1954. France (24g)• Wynderand _ M. I6o Cancer patients seen in Memorial Iiospi- __ 160 Bross, tal, New York City, and Kingsbridge - 1961, and Brooklyn VA Hospitals during U.S.A. (510). 1950-59 (86% white). F. 37 Same hospitals and same time period as 37 male patients (86% white). Wynder and M. 67 Admitted to Tata Memorial Hospital Bom- _ - _ 134 Bross,_ F. 27 bay. 1961, India (810). Takano et al., M. 167 Patients with esophageal cancer. 167 1968, F. 33 33 Japan (27E). . . Controls Method of selection Collection of data Healthy ealthy individuals admitted to same hos- Interviewed by team of pital because of work or traffic acci- dents-matched by 5 year_ age group and time of admission. Patients_ seen in same hospitals during same time period with other tumors. 64~/-malignant tumor; 36(,-benign con- ditions. Matched by age with cancer patients. Same as with regard to male controls. 43q had malignant and 67% benign_ tumors. Patients with other forms of cancer ex- cept for oral cavity and lungs: as well as various benign diseases. Patients with cancerous and non-can- cerous diseases of non-digestive organs. specially trained inter- viewers who interviewed the largest proportion_ possible of all cancer patients. Cases and matched controls inter- viewed by same person. Data collected by trained interviewers. Interviewed by one per- son. 10% of male and 4%a of female cancer cases histologically confirmed. Interviews at various hospitals. Cases and controls age-matched. I

TABLE A31. Suyn.mary of methods used in retrospective studies of tobacco use and cancer of the esophagus (cont.) W V V osVq94eo (783). --- - community. Author, year, Cases Controls country. . reference Sex Number Method of selection Number Method of selection Bradshaw and M. 98 Patients with esophageal cancer 341 Patient with mali t di --Schonland,- 1969, South Africa . s non- gnan sease. (41). Martinez, M. 120 Patients with confirmed epidermoid eso- 360 120 male, 59 female patients in same hos- 1969, F. 59 phageal cancer diagnosed in 1966. 177 pital with non-cancerous diagnoses. Puerto Rico 240 male, 118 female members from same Collection of data Hospital interviews hy trained African social workers. Interviews by trained personnel.

w w m 19Vs94Co TABLE A31a.-Sumntary of results of xetrospectiroe studies of tobacco use and cancer of the esophagus Relative risk ratio. Author, year, " Percent nonsmokers Percent heavy smokers Percent inhalers among smokers All smokers tononsmakers Country. Cases Controls All --Hea.vy reference Cases Controls Cases Controls smokers smokers Sadowsky dowsky et al., 1953, U.S.A.(282). - 3.8 Sangxhi et al, 1955, India (241). 5.5 Wynder et al., 1957, Sweden ($22). M F 13.0 (about)85.0 Staszew_ski, 1960, Poland (260). - Schwartz et al., 1961, France (249). 3.0 Wynder and Bross, 1961, U.S.A. and India (3t0). American males American femal_e_s_ Indian males Indian females 5.0 41.0 13.0 78.0 Takano et al., 1968, Japan (272). 17.0 Bradshaw radshaw and Schonland, 1969, South Africa (41). 16.3 Martinez, 1969. Puerto Rico (18d). 14.0 :to 13.2 - - - - 4.0 - 17.3 AveraAC number of bidis_ amoked 15.3 14.1 - 3.6 24.0 (about)92.0 2.1 2.0 18.0 95.8 59.0 87.5 80.0 17.0 Total amount amoked 39.0 38.0 6.6 daily (cip_areiles) 16.8 16.0 15.0 48.0 33.0 - - 3.4 4.4 78.0 27.0 16.0 - 5.1 3.2 28.0 - - 2.6 - 94.0 - 4.5 - 23.0 - 1.3 - 31.7 31.6 5.9 - - 2.6 11.1 23.5 17.9 8.6 1.8 3.5

tj zJY-q.7f.aCeO TABLE A32. Atypical nuclei in basal cells of epithelium of esophagus of males, by smoking ha,bits and age Never smoked regularly Current Cigarettes Ex-cigarettes Pipe, cigar Other Atypical nuclei ~ Num- ber Per- cent Num- ber Per- cent Num- ber !'cr- cent Num- 6c+ Per- cent Num- ber Per- cent A. All men: N umber men ...................... 91 - 779 - 181 - 89 - 62 -_ Totalsectionsr .................... 787 100.0 6,752 100.0 1,586 100.0 766 100.0 522 100.0 No atypical nuclei ................. 733 93.1 167 2.5 770 48.5 53 6.9 195 37.4 Some but <60 percent atypical ..... 52 6.6 6,389 79.8 765 48.3 688 89.8 317 60.7 60 percent or more atypical ........ 2 0.3 1,196 17.7 51 3.2 25 3.3 10 1.9 B. Men under age 50: Number men ...................... 26 -. 236 - 28 - 9 - 7 - . Total sections ..................... 223 100.0 2,059 100.0 258 100.0 77 100.0 53 100.0 No atypical nuclei ................. 190 85.2 71 3.4 56 21.7 1 1.3 4 7.5 Some but <60 percent atypical ... .. 33 14.8 1,853 90.0 0.0 195 75.6 74 96.1 46 86.8 60 percent or more atypical ......... - - 135 6.6 7 2.7 2 2.6 3 6.7 C. Men aged 50-69: N umber men ...................... 44 - 445 - 109 - 38 - 31 - Total sections ..................... 379 100.0 3,853 100.0 953 100.0 310 100.0 256 100.0 . No atypical nuclei ................. 373 98.4 83 2.2 461 48.4 37 11.9 74 28.9 Some but <60 percent atypical ...... 4 1.1 2,915 75.6 452 47.4 261 84.2 178 69.6 60 percent or more atypical ........ 2 0.5 855 22.2 40 4.2 12 3.9 4 1.6 D. Men aged 70 or older: Number men ....................... 21 - 98 - 44 - 42 - 24 - Totaisections ..................... 185 100.0 840 100.0 375 100.0 379 100.0 213 100.0 No atypical nuclei ................. 170 91.9 13 1.5 253 67.4 15 4.0 117 64.9 Some but <60 percent atypical 15 8.1 621 74.0 118 31.5 353 93.1 98 43.7 ..... - 60 percent or more atypical ......... - - 206 24.5 4 - 1.1 11 2.9 3 1.4 I Sections with some epithelium present. Source: Auerbach, 0. et al. (15).

TAB[F A33.-Atypicnl nuclei in basal eells of epitFrel2rtnl of esnpfrayw5 of tlrates, by amElrcrtt of sunokixtg and age E9V994C0 Current cigarette smokers Never smoked regularly <1 pack 1-2 packs >2 packs Cells with atypical nuclei Number Percetrt ~IYarmhcr Pecoc-nt Number Perrent Nuneber Perceqtt A. _Allages ........................... 91 179 - 413 - 187 -. Total sections ! ................... 787 100.0 1,5 44 100.0 3,629 100.0 1_,579 100.0 No atypical nuclei ................ 733 93.1 _ 89 5.8 39 1.1 ,39 2.5 Some but C_ 60 percent atypical ..... 52 6.6 1,341 8_6.8 2,957 81.5 1,091 69.1 60 percent or more atypical ........ 2 0.3 114 7.4 633 17.4 449 28.4 B. Men en under age 50: N u mber men ..................... 26 9 - 132 - 55 - Totalsectinns' ................... 223 100.0 433 100.0 1,169 100.0 457 100.0 No atypical nuclei ................ 190 85.2 48 11.1 21 1.8 2 0.4 ... Some but <60 60 percent atypical .. - 60 percent or more atypical ........ 33 .. . 14.8 ... 382 3 88.2 0.7 1,089 69 93.'3 5.0 382 73 83.6 16.0 C. Men aged 50-69: - -Nu m ber men ..................... 44 92 - 240 r - 113 - Totalsectiuns' ..................... 379 100.0 789 100.0 2,116 100.0 948 100.0 No atypical nuclei ................. _ 373 98.4 30 3.8 18 0.9 35 3.7 Some but <60 60 percent atypical ..... 4 1.1 694 87.9 1,607 75.9 614 64.8 60 percent or more atypical ........ 2 0.5 65 8.3 491 23.2 299 31.5 D. . Men aged 70 or older: Number men ..................... ... . .. .. .. ........ .. 21 38 - 41 - 19 - Total sectiunsr................... 185 100.0 322 100.0 344 100.0 174 100.0 No atyhicalnuclei ................ 170 91.9 11 3.4 _ - 2 1.1 Some but <60 percent atypical .... . 15 8.1 265 82.3 261 75.0 95 54.7 60 percent or more atypical ........ ... ... 46 14.3 83 24.1 77 44.2 I Sections with some epithelium present. Source: Auerbach, 0. et al. (15).

i, TABLE A35.-SummaEry of methods used in rat?'espectivc stuulirs of Smokin,cl rewf ccunccr of thce hlucfclcr Author, year, Cases country, reference Sex Number Method of selection Lilienfeld et al., M. 321 Admissions to Roswell Park Memorial Institute. 1956, 1945-55 over 45 years of age. U.S.A. (171). F. 116 Same as males ............................. Schwartz et al.,_ M. 214 Admissions to hospitals in Paris and a few 1961, large provincial cities since 1954. France (.249). Lockwood, M. 282 All bladder tumors reported to Danish Cancer 1961, F. 87 Register during 1942-56 and living at time Denmark (175). of interview in Copenhagen and Fredericks- burg. burg. (Includes bladder papillomas). Wynder, M. 200 First phase: 1963, F. 50 Admission to several hospitals in New U.S.A. (826). York City during January 1957-Decem- her 1960. her Second phase: M. 100 Admission to same hospitals during 1961. F. 20 .. . . . . ... . . ... Cobb and Ansell, M. 136 Patients admitted to V A Hospital in Seattle 1965, 1951-61. U.S.A. (57). Controls Number Method of selection 337 No disease patients. 109 Benign bladder conditions. 317 No disease patients. 214 Healthy individuals admitted to same hospital because of work or traffic accident, matched by 5 year age group.. .. ..... ... ... 282 A. From election rolls matched with cases ac- 87 cording to_ sex, age, marital status, occupa-, tion, and residence. B. Another control group obtained from sam- ple of Danish Morbidity Survey (1952, 1953, and 1954) compared with respect to smok- ing histories. 200 50 100 20 Admission to same hospitals (excluded cancer of respiratory system, upper alimentary tract, myocardial infaretion) matched by sex and age. Same as above. 342 120 patients with cancer of sigmoid colon, 222 patients with non-neoplastic pulmonary dis- ea.S'e.

W ~ N TAB1.E A35. Summary of inethods used in retrospective st:icl?ies of suaoking and cancer of the bladder (cont.) Author, year, Cases Controls country, _ reference Sex Number Method of selection Number Method of selection Staszewski, M. 150 Patients with histologically confirmed bladder 750 Undefined source age-matched. 1966, carrinoma. Poland (261). Deeley and Cohen, M. 127 Patients with histologically confirmed bladder 127 Patients in same hospital with non-cancerous 1966, carcinoma. or pulmonary disease matched for age. England (66). Yoshida et al. M 163 Patients with bladder cancer 163 °'Comparison casesl' , -- 196.4, . - F . __. 29 . _. __ . " 59 ... __... ._ . ~ Japan (880). Kida et al. M 88 Admissions to 15 hospitals in North Fukuaka 89 Selected from patients hospitalized in same re- . _ 1968. . F. 26_ prefecture. 26 -- region for non-urinary ailments and age- Japan (a44)• matched Dunham et a_l., M. 334 Admissions to New Orleans hospitals with his- 350 Admissions dmissions to same hospitals with non-ne oplas- 1968, F. 159 tologic diagnosis of bladder carcinoma. _ 177 _ tic diseases and diseases unrelated to geni- - _ U.S.A,. (85). tourinary tract. Anthony and Thomas, M. 381 Patients with papilloma and cancer of bladder 275 Surgical patients without cancer previously in- _ 1970, at Leeds betweeen 1958-67. terviewed for lung cancer study. England (3). sqV9J{.1[.O

't W m ~ 99PS94c0 TABLE A35a.--Summ,ary of results of r€trospective st-lics of stuo];iug tnul cuoccr of Ebc lehtr(~fc~~ ---- Perei nt ciy;rettes Relative risk ratio: Author, Percent nonsmokers Percent heavy smokers smoked All smokers to nonsmokers year. country, --~- -- All Heavy Cigarette Comments reterence Sex Cases Controls Cases Controls Cases Controls smokers smokers smokers Lilienfeld et al., M. 15.0 29.0 ... ... 61.0 1.0 44.0 4_.0 2.3 ... 2.7 Cigarette and other. 1956, - F. 87.0 83.0 ... ... ... ... 1.4 ... ... U.S.A. (171). Schwartz et al., M. 11.0 20.0 ... .. . 83.0 70.0 2 ... 23 Cigarette only. ..1961,... France (249). Lockwood, M. 9.0 13.4 30.0 15.0 30.0 15.0 1.6 3.0 3.0 Cigarettes main mode of - - -- - 1961, F. 56.0 66.0 4.0 4.0 ... ... 1.5 1.2 ... smoking. Denmark (175). - Wynder et al., M. 7.0 18.0 47.0 23.0 85.0 63.0 2.9 5_2 3.3 Phases A and B com- - - - 1963, F. 61.0 86.0 6.0 ... ... ... 3.9 ... ... bined. U.S.A. (326). - - - ----- - - Cobb and Ansell, M. 4.6 25.8 79.4 43.3 .. . .. . 7.3 10.3 1965, U.S.A. (57). Staszewski, M. 6.7 16.0 85.7 65.7 87.1 72.2 2.7 3.1 2.9 Cigarettes only. 1966, Poland (261). Deeley and Cohen, M. 2.4 7.1 3.1 1966, England (66).

a TABLE A35a.-Summary of results of retrospective studies of smoking and cancer of the bladder (cont.) Author, year Percent nonsmokers Percent heavy smokers Percent cigarettes smoked Ae]ative risk ratio: All smokers to nonsmokers , country, reference Sex Cases Contrlos Cases Controls Cases Controls All Heavy Cigarette smokers smokers "smokers Comments Yoshida et al., M. 8.0 22.7 43.4 33.0 3.4 3.7 - 1968, Japan (330). F. 62.1 86.4 - -- - - - Kida et al., M. 11.0 11.0 32.0 29.0 _ - 1.0 - - 1968, Japan (144). P_'.. 16.0 21.0_ - . 1.4_ - - Dunham nham et al., M. 8.6 14.5 - - 49.4 45.4 1.8 - 1.8 Cigarettes only. 1968, U.S.A. (85). F. 62.2 61.5 _ - 32.0 28.2 1.0 - 1.1 Anthony and Thomas, F. 6.3 6._3_ - - 36_.6_ 29.1 9.1 1.0 - 1.$ Cigarettes only. More than 15 a day. 1970, England (3). L9Y SJl.JcU

03765499

Contents Page Introduct'ioni ....................................... 389 Effect on birthweight ................................. 389 Effect on outcome of' pregnancy ....................... 390 Experimental studies .................................. 4017 Summary ........................................... 415 References .......................................... 415 LIST OF TABLES 1. Summarv of methods used in study of'srnoking and hurnann pregizancv ....................................... 391 '?: Maternal smoking and infantl weight ................ 3~9~73. Maternal smoking andl prematurity .................. 400 4. Comparison of abortion, stillbirth, and neonatali death in smoking and nonsmoking mothers ................... 405: 5. Human experimental datai on smoking, and pregnancy .. 408 6. Animal experimental datai oni the effect of smoking andd nicotine on pregnancy ............................. 411 387 ~as

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INTRODUCTION In recent years, there has beeni increased research on envixon- rnental factors which may: adversely affect the unborn child. The& potential effect of rnaternaU smoking on the fetus has been of par- ticular interest because of' the large number of pregnant womenn who smoke and because smoking is an environmental influence which could be controlded.Based on 1'9'70surveysof' smokinghabitls in representative samples of the U'.S, population, it' is estimated that one-third of Ameri'can women in the child-bearing age group of 15 to 44 years are cigarette smokers:, What propor- tion of these give up smoking or cut down subst'antially on their smoking during pregnancy is not known. F7FFECT ON BIRTHWEIGHT Epidemiological and experimental stud~ies have supported the view that' maternal smoking during pregnancy exerts a retarding influence on fetal growth (tables 2, 6)'. Analysis of over 100;000' births shows that the infants of mothers who smoke during preg- nancy have a mean birthweight of 6.1 ounces less than the infants born to nonsmoking mothers (table 2)~. Several studies have docu- mented that this effect is independent of other factors known to exert a negative influence on infant'birthweight; such as elevatedd maternal blood pressure and small maternal size (1, 36, 39). The reduction in infant birthweight i& greatar among heavy smoking mothers than light smoking mothers (i12, 21, 23, 30,, 41,,50, 58), and has beeni found in pregnancies terminating, in each trimester (12, 16, 23, -4'0; 51, 54). In a study of more than 48,000' women, Under- wood,, et aI. (51) demonstrated that infants born to women who smoked during part of their pregnancy were significantly smaller than infants born to: nonsmokers; and that infants borni to women who smokedl tlhroughout theirpregna,ncyweresignifiieantly smaller than the infants born~ to women who smoked during partt of their pregnancy. Russell, et aiL (39) have presented evidence, that al- though, infantls born to smoking, mothers weighed less than those of nonsrnoking, mothers, they grew more rapidly during the first six months of life. At one year of age, children born to smoking mothers weighed nearly the same as those born to, nonsmoking mothers. They concluded that smoking exerts a retarding influence 389

on, fet'al'growth and that after delivery tlhis is largely compensated for~by~~ a period~ of more~ rapild' ~ growth. As dbcument'ed' in more than 15 prospective and retrospective studies, smoking mothers have significantly more infants who are premature, as defined, by weight albne (<2,500) grams, thani do non- smoking mothers (table 3). Buncher (4) studied' the mean dura= tion of pregnancy in smokers andi nonsmokers in a survey whichl included 49,897 live births, He found that women srnoking, 20 cigarettes a day had a mean length, of gestation which was approxi- mately one day shorter than that of nonsmoking women. He calcu- lated that this shortening of gestation is enough to account for only 10 percent of the known reduction in birthweight that is associated with maternal smokinz. EFFECT ON OUTCOME OF PREGNANCY Some controversy has surrounded, the question of whether ma- ternal smoking, during pregnancy is associated with an increasedd risk of spontaneous abortion, stillbirth, and, neonatal' death., Table 4 summarizes the studies which have dealt with this question. Some of the studies did not demonstrate such an increased risk (7, 34, 50, 51), while others did (12, 23, 33, 58). Many of these reports (7, 23, 33, 34, 41, 49; 58) were based oni retrospective studies and included women delivering their infants in hospitals andl infants whose~ namesappeared on listings ofnewborni children (table 1)., As Russell, et al. (39)' have pointed out, such studies may be sub- ject to selective bias si'nce they tend to underrepresent womeni who have aborted. These retrospective studies also did not systemat- ically control for maternal social cTass, parity, and maternall age„ all of which are related to the out'come of' pregnancy and' also are d related to smoking in some populations. In a prospective study of' more than 2;000 pregnant women, Russell, et all (39) have demon- strated a significantly higher percentage of unsuccessful pregnan- cies (that is, abortion, stillbirth, or neonatal death) among women who smoked~ during their pregnancy than among those who did not. Hie interpreted his findings to mean that 20 percent of ". . . un- successful pregnancies in women who smoke regularly wouldi have been successful if'the mother, hadi not been a regular smoker"' (38)1. The Second Report of the 1958 Britilshi Perihatali Mortality Sur- vey published in 1969' is one of the largest prospective studies to deal with this quest'ioni (5) . It included 98 percent of the total birthss registered diZriiag one week in March 1958' throughout England, Scotland, and Wales. In this study; a large amount of obstetric and sociobiologic information was obtained on 17,000 singleton births. This study reported that "the mortality in babies of smokers was significantly higher than in those of nonsmokers." The increase in

TABLE 1.-Snmmary of methods used in study o Author, year, Retrospective Number country, or of - Data collection reference prospective persons - Simpson, I{, 7,499 Questionnaire was filled out 48 hours 1957, after delivery for all patients at U.S.A. (44). San Bernardino County Hospital for 3 years. Same form used for 2 years at St. Bernardines Hos- pital and Loma Linda Hospital. Lowe, R. 2,042 Questionnaire was filled out for every -- - 1959, - woman delivering at one of six England (23). Birmingham hospitals over a 5- month period. month Frazier et al., P. 2,736 (a) Interview. 1961. (b) Prenatal clinic history. U.S.A. (12). (c) Birth and stillbirth certificates. Herriot et al., 1962, Scotland (7B_ ). B. 2,745 Savel and Roth, R. 1,416 1962, U.S.A. (41). Questionnaire filled out for Aber- deen city residents who were de- livered in Aberdeen City Hospital over a 1-year period. - smoking and Ituman pregnancy Case selection Comments Multiple births excluded. The county hospital population was different, with 50.6 per- cent of the births being "Mexican". Non-Europeans and women with Social workers performed twin births were excluded. interviews. All Negro women seen at Baltimore Nonsmokers include occas Maternity Interviewing Service in smokers. 1959 who were scheduled for de- livery at Baltimore City Hospital and who received prenatal care in clinic of Baltimore City Health Department. 1,500 consecutive patients admitted Included were private and ward pa- Women were considered to Newark Beth Israel Hospital tients, Negro and white patients, smokers even if they smoked ed were interviewed. primigravidas, and multiparas; only 1 cigarette per day. Cesarean n se_ctions, elective induc- tions, tions, nnd multiple pregnancies were excluded. v4VS94c0

TABLE 1.-Summarg of methods used in study of smoking and huz)zan pregnancy (cont.) Author,_ year, Retrospective Number country or -- of Data collection Case selection Comments , reference Prospective persons ---- ~-~- ~ ~ ~ ~ ~ - ~ - Yerushalmy, P. 982 Form questionnaire. 1962, U.S.A. (53). Murdoch, R. 500 Personal interview by author. 1963, _ U.S.A.(SO). O'Lane, R. 1,031 Standard U.S. Naval Obstetrical Code 1963 Sheet was used with supplemental , U.S.A. (33). --- questions. Additional information was obtained from prenatal his- tory. tory. Zabriskie, R. 2,000 History was obtained during the 1963, postPartum period from 2_,000 con- U.S.A. (58). secutive births_ over a 6-month period. -- Yeryshalmy, P. 6,800 Personal interview. 1964, U.S.A. (_$4)._ MacMahon et al., R. 12,192 Mail questionnaire. 1965, U.S.A. (Eb)- Pregnancies terminating in abortion were excluded. All mothers delivering at Nebraska Methodist Hospital from Septem- -- ber 1962 to January 1963. 1,031 Caucasian women who had "Smokers" defined as those - single pregnancies delivered va- smoking regularly_ each day. '--. . .. -- -._ ginally over a 6-month period. Twin deliveries were omitted. All women were members of Kaiser 5,381 whites 1,419 Negroes. Foundation Health Plan. Only Pregnancie_s terminating in single, live births included. All races ex- cept whites and Negroes were ex- ---- cluded.- Mothers of single, white, legitimate Birthweight based on birth live births. Mothers were residents certificate. of Massachusetts and delivered in May or June of 1963. G SMr:7JM(t0

TABLE 1--Summary of methods used in stledy of smoking and human pregnancy (cont.) Author, year, Retrospective Number country, --oi--- of Data collection - Case selection Comments reference prospective persons McDonald and P. 17 7 Interview. White, unmarried p_rimigravidas re- L_anfo_ rd,_ _ _ ceiving obstetric care over a 2- 1965, year year period. U.S.A. (26). Peterson et al., R. 7,740 Cooperative ooperative study involving 17 h os- Includes only those multiparas whose 1965, _ pitals in 13 states, using U.S. Air prior infants weighed >2,500 U.S.A. (34). Force obstetrical code. grams (Caucasians). All preg- nancies with any complication Robinson, P. 1,614 Interview. 1965, Burma (37). Underwood et al., R. 4,440 Interview by obstetrical resident. 1965, Data was obtained on 16,158 preg- U.S.A. (SO). nancies from the 4,440 women. U.S.A. Downing and _R_._ 5,659 Review of clinic records from 1952 Chapman, to 1959. 1966, U.S.A. (7). were excluded. Cesarean sections and induced delivery were ex- cluded. Regular attendees at prenatal clinic. Puerperal women from Roper Hos- pital and Medical College Hospi- tal. Only infants weighing >1.000 grams were included. total of obstetrical patients ~ ~ at clinic. 46.8 percent of women smoked cheroots. Women from Roper Hospital were of above average eco- nomic status. Women from Medical College Hospital ln- cluded Negro and white_ patients. .74Y SJ4[t 0

TABLE 1.--Summarb of naetlrods used in study of smoking and human pregnancy (cont.) Ll.,/tFS9Z.f:U Author, year, Retrospective Number country, - or- of Data collection Case selection Comments rcference prospective persons Ravenholt et al., 1966, U.S.A. (85). H. 2,023 Reinke and Henderson 196G, U.S.A. (8E). It. 3,156 _ Kizer, 19G7, Venezuela (19). 2,095 Underwood et al., 1967, U.S.A. (51). P_ ._ 48,505 Iluffus and MacGillivray, 1968, Scotland, (8). R. 2,543 . __ .. Mulcahy and Knaggs, 3.681 1968, Ireland (88). Epidemiologic questionnaire. Much Study population was identified by 95.4 percent of mothers were data collected over telephone. Ad- the listing of newborn_ infants in white. ditional data obtained from birth a Seattle newspaper during May, certificates. June, and July of 1964. Twins were excluded. Registration data of prenatal clinic. Negro women who delivered single, in__gl_e_, live infants from 1962-64. Interview. Patients receiving care at "-'concep- cion palacias" ' in Caracas. Code sheets submitted from 44 world- Women with single pregnancies de- wide naval installations. Code livered of infants weighing more - ---- - sheets were completed by the at- than 500 grams between July 1, tending physician upon the mo- 1963, and June 30, 1965. ther's admission to the labor room. Antenatalclinic records. All "booked" married city primi- The number of cigarettes . ---. .... . ~ ~ gravidae attending the antenatal smoked was not considered. clinics during 1960, 1964, and 1965. Hospital record review. Mothers admitted to the Coombe Hospital from April 1963 to_ Oc- tober 1964.

w ~ a t7i./V99{.1CQ TABLE 1.-Summary of methods used in study of smoking and human pregnancy (cont.) Author, year. Retrospective Number country, or of Data collection Case selection Comments re etence prospective persons Russell et al., 1968, England (d9). 1'. 2,11_0_ Tokuhata, 1968, U.S.A. (49). R. 2,016 16 Buncher, 1969, U.S.A. (4). R. 49,597 Butler and Alberman, Alberman, 1969, Great Britain (S)._ P. 17,000 Terris and Gold, R. 197 1969, U.S.A. (47). were matched by sex, birth order of infant, age, and marital status of the mother. Data collected by Senior research Women attending the two main ma- Included some threatened abor- _ midwives over a 4- to 5-year ternity units in Sheffield, who ternity tions and some with "bad" period. "comprised a reasonably repre- obstetrical histories. Personal interview or mail question- naire of surviving family members. Data a__ta obtained ed from U.S. Navy ob- stetrical study from 1963 to 1965. Smoking data obtained by physician at the time of mother's adm_is__si_o_n_ to labor room. The British Perinatal Mortality Sur- - - - - vey of 1958 when a large amount of obstetric and sociobiologic in- formation was obtained from birth attendants, records, and_ at inter- view with the mothers. sentative sample." Multiple pre_g- nancies were omitted. Women selected from Memphis and Control group taken from same Shelby County death registry who registry. They died of causea died of cancer of genitalia or other than cancer and were breast since 1950 and who had matched for race, age at been married. death, and year of death. Women with single pregnancies de- Includes cases reported by livered of infants weighing more Underwood et al. (47) in than 500 grams between July 1, 1967. 1963, and June 30, 1965. 98 percent of the total births reg- Another 7,000 perinatal deaths istered during 1week in March were surveyed by identical 1958 throughout England, Scot- methods over a 3-month land, and Wales. period. Public Health Nurse interviewed each Premature Negro ward births mother on first or second post- (<2,500 grams) with no known partum day. cause of prematurity. Controls

TABLE L-Summary of methods used in study of smoking and launtan pregnancy (cont.) - Author, year, Retrospective Number country, oc---- of Data collection r€fcrence- prospective persons Mulcahy et al., -~ P. 100 Interview by physician. - - ---_.. ~ - --- 1070, _ -- ~ - Ireland (29). Case selection Comments 100 mothers of term infants who were free from all significant medi- ical and obstetrical complications. All were between 20 and 30 years of age and were Para III or less. All had normal deliveries. Half were smokers of 10 or more ciga- rettes ---- rettes per day. 64V594C0

TABLE 2.-Maternal smoking and infant weight (Numbers in Parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mean weight of~infant of smoker Comments Author, _ reference Nonsmoker Smoker versus nonsmoker Lowe (23) <10 cigarettes >10 cigarettes Effect on infant weight was independent ~~ per day ~ per day of maternal age, parity, or complica- Male Male ......... 7.43 lbs. (607) 7.18 (187) 7.05 (165) tions of pregnancy. Female ...... 7.23 lbs. (539) 6.74 (163) 6.67 (147) . 7.331bs. Total 146) 6.98 (350) (1 6.87 (312) 170 g. (6 oz.) ....... -------- ---- - , Frazier et al., 3,080 g. (1,717) 2,924 g• (1.019) 156 g. (5.5 oz.) Nonsmokers include occasional smokers. (12). Herriot No data .............. . . (1,473) No data (1,272) 160 g. (6.6 oz.) Effect on infant weight was independ- et al., _ ent of maternal age, parity, height, (16). or social class. S avel and White ........ 3,374 g. (383) 3,141 g. (428) 233 g. (8.2 oz.) Cigarcttea _ Roth Negro ........ 3,1739. (364) 3,031 g. (240) 142 g. (5.0 oz.) per day Infant weight (41). : White smokers: 1-10 ............. 3.210 g. (161) 11-20 ............. 3,1989. (184) >20 ............. 3,0109. (83) Negro smokers: 1-10 ............. 3,042 g. (169) 11-20 ............. 3.012 g. (67) >20 ............. 2,968 g. (14) Murdoch 7 lbs. 7.5 oz. (242) 6]bs. 15 oz. (258) - 8.5 oz. -- Cigarettes - - (9 4 ). per day Infant weight _ _ 1-10 ............ 7 lbs. 2 oz. 11-20 ............ 6 lbs. 11 oz. >20 ............ 6 lbs. 10 oz. > 4 0 ............ 6 lbs. 8 oz. O'Lane 2,978 g. (566) 2,938 g. (465) 40 g. (1.4 oz.) :u.-

TABLE 2.-MaternaL smoking and infant weight (cont.) (Numbers in parentheses indicate absolute number of infants in respective groups) Author, _ reference a_ brisk_ ie Zabriskie (58). 3,320 g. (1,043) 8,0919. (957) 229 g. (8.1 oz.) MacMahon Male ........ .. .... 124.0 oz. (3,053) 116.3 oz. (3,173) 7.7 oz. et al., Female .,.... 119.9 oz. (2,906) 111.9 oz. (3,011) 8.0 oz. (24). _ McDonald - - Light amoaer Heavy am-oker No signfflcant difference be- and and 111.68oz. (87) 110.83oz.(-42) 109.38oz.(48) tween mean birthweighta. Lanford (P6). Underwood Cigarettea - et al.. Group: per day For >20 cigarettes per day (50). I....... 3,522 g. (2,406) <10 ........... 8,349 g. 353 g. (12.5 oz.) (p<0.001) 10-20 ........... 3,236 g.t(1,720) >20 ........... 3,169 g. II ....... 3,304 g. (557) <10 ........... 3,171 g. 212 g. (7.5 oz.) (p<0.001) 10-20 ........... 3.146 g• f(660) - >20 ........... 3,092 g. III ....... 3,126 g. (7,775) <10 ........... 2,938 g. 115 g. (4.1 oz.) (p<0.001) 10-20 ........... 2,965 g.t(3,040) >20 ........... 8,011 g. - $avenholt Male ......... 7.801bs. (171) et a1., Female ...... 7.501be. (150) (J5). Infant weight Difference in mean weight __ of infant of smoker Nonsmoker Smoker versus nonsmoker 7.21 1bs. #(167) .69 lbs. (9.4 oz. ) 7.05 lbs. t (171) .45 lbs. (7.2 oz. ) Comments Cigaret tee per day Infant weight <10 ............. 3,205 g. (260) 10-20 ............. 3,090 g. (395) 20-30 ............. 2,970 g. (264) >30 ............. 3,190 g. (38) Cigarettes InJant weight per day (ounces) Male Female <10 . 121.2 (658) 116.6 (595) 10-20 . 115.2 (1.262) 112.2 (1,259) 20-40 . 114.6 (1_,165) 108.9 (1_,088) >40 . 113.2 (66) 111.7 (49) Patients were divided into 3 groups: I...._P__rivate patients of above av- erage economic status. II....White- patients of average economic, status. III....Negro patients of 1ow eco- nomic status. t Total for all smokers In each group. t Smoked ~4,000 cigarettes during preg- nancY. teVss4co

M wt~ TABLE 2. Maternal smoking and infant weight (cont.) (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Author, reference Nonsmoker Smoker Reinke and 3,135 g. (1,542) 2,987 8. (1,614) 148 g. (5.2 oz.) (p<0.001) Henderson (96)_ K~zer-T18). Data not available Data not available Underwood Cigarettes et al., per day (g1), 3,395g. (24,865) 1-10 ........... 3,286g. (7,609) - - 11-30 ........... 3,196 g. (14,450) >30 ........... 3,182 g. (1,570) Mulcahg 113.3 oz. CiBaiettea and --- --- per day Knaggs 1- 4 ..... ... .. . 111.4 oz. (28).-- 5- 9 ........... 102.3 oz. - 10-14 ........... 102.0 oz. 1_6-19 ........... 102.9 oz. >20 ........... 102.4 oz. Russe1F_ BP et al., <140/ 90 117.2 -!- .7 oz. (984) 107.2 -!- 1.0 oz. (496) (39). 140/ 90 114.2±1.2oz. (340) 108.9±2.4oz. (117) >150/100 99.3±2.6oz. (138) 90.8i-5.8oz. (85) Difference in mean weigh__t_ of infant of smoker Comments versus nonsmoker 97 g. (3.4 oz.) Total number of patients-2,095. 109 g. (3.8 oz.) 199g. (7.0oz.) 213g. (7.5oz.) 1.9 oz. 11.0 oz. 11.3 oz. 10.4 oz. 10.9 oz. The efiect of maternal smoking on fetal 10.0 oz. weight was independent of maternal 5.3 oz. parity, age, height, educational level, - - 8.5 oz. attitude to Fregnancy or work during pregnancy, father's social class, con- sort's social class, and sex of the child or premature delivery. Rutler and Alberman (5). 3,376 g. (11,146) 3_,205 g.- 4,660) 170 g. (6 oz.) Mulcahy 3.83 kg. (50) 3.43 kg. (50) 396 g. (14 oz.) w et al., (29) 10 10 . ZQVS94CO Reduction of mean birthweight of babies born to smokers was independent of unduly high proportion of babies born preterm, and maternal factors includ- ing social class and maternal height. 1

TABLE 3. Maternal smoking and pxematurity (cont.) (Figures in parentheses are the absolute number of premature births) Comments --- Weight gestatiQn-Nonsmokers Smokers Nonsmokers Smokers Premature by Author, Percent of premature infants Mean duration of pregnancy ret"erence Duration of - - Simpson <2,500_ g._ Name of hospital: (44). County .......... 7.77 (144) 11.48 (96) Loma Linda ..... 6.16 (86) 12.13 (49) St. Bernardines .. 5.21 (98) 10.60 (119) Lowe <260 days 6.4 (57) 10.6 (58) _-(23). Frazier <2,500 g. et al., (12). 279.9 days 278.6, days 11.2 (175) 18.6 (179) 38.7 weeks Herriot No data No data Socialclas_s: etal., IandIl ......... 4.0 4.8 (l&). III .............. 3.5 6.8 IV and V ........ 6.3 12.6 S_ a_vel and 36 weeks White ............... 2.6 (10) 4.9 (21) White .39.8 Roth Negro ............... 13.7 (50) 11.3 (27) Negro .38.8 (41). t<2,500 g. White ............... 1.8 (7) 3.7 (16) Negro ............... 3.6 (13) 8.3 (20) Number and percent of premature infants: Nonsmokers . .. . 6.39 (328) Cigarettes per day: 1-5 ....... 7.06 (47) 6-10 ...... 11.18 (89) 11-15 .....11.36 (31) 16-20 ...... 13.6 (77) 21-30 ......25.0 (11) >30 ........ 33.3 (9) At each week of gestation, the mean birthweight was lower in babies of smokers. 38.4 weeks Infants of smokers weighed less ---- than infants of nonsmokers for a wide range_ of preg-nancy duration. 39.4 38.8 2,74_5 patients in the study. At each week of gestation, the mean birthweight was lower in babies of smokers. t Premature by weight but ma_- ture by date (>37 weeks). UeV994E0

<37 weeks TABLE 3.-Mater-nal smoking and prenaa..turitg (Figures in parentheses are the absolute number of premature births) Percent of premature infants Nonsmokers Smokers Comments Nonsmokers Smokers 5.9 (36) 8.1 (30) 3.3 (8) 13.6 (35) 5.1 (29) 11.8 (55) 3.83 (40) 9.93 (95) Cigarettes per day: Prematurity <10 ........ 6.54 (260) 10-20 ...... 9.11 (395) 20-30 ...... 14.39 (264) >30 ........ 10.53 (38) White ............... 3.5 (112) 6.4 (138) (p<0.01) Infants of smoking mothers 0 ro 4 Ne (46) 13 4 (64) - - weighed less than infanta of ............... . g . - nonsmoking mothers in each gestational age. White ............... t5.9 (188) 6.5 (140) f Difterence between smokers and Negro ............... 13.4 (125) 16.7 (80) nonsmokers not significant. Cigarettes per day 4.6 (4) <10 4.8 (2) >10 8.3 (4) Cigarettes per day Overall incidence of prematurity 2.5 (111) 1-10 3.0 (35) in smokers vs. nonsmokers 11-20 4.8 (80) significant at p<0.001. >20 3.4 (16)

A 0 N TABLE 3. Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by Author, Percent of premature infant s Mean duration of pregnancy reference Duration of _ _ - - Comments Weight gestation Nonsmokers Smokers Nonsmokers Smokers Peterson eterson <37 weeks - Cigarettes per day ------ etal., (contd.) (34). 1.3 (58) Robinson (37). <2.500g. 16.5 (152) Underwood et al., (50). <2,500 g. Group: p_ : I II III D_owning_ No data No data and Chapman (7). 2.2 (66) 1--10 1.4 11-20 2.3 >20 2.4 (16) (38) (11) 31.0 (181) Cigarettes arettee per day Percentages and absolute num- remature births are r f b 4.5 (108) <10 4.2 p e o based on 16.158 pregnancies 10-20 5.9 -- - recorded in 4,440 women. <20 7.2 Group I. Smokers vs. non- I 7.5 (42) <10 12.6 smokers p<0.025. 10-20 12.3 Group II., III. Smokers vs. >20 15.9 nonsmokers p<0.001. 9.9 (770) <10 14.1 10-20 14.8 >20 10.2 3.3 (88) 16.7 (270) 37.7 weeks 37.67 weeks p<0.001 22.8 (368) p>0.05 Sa ir 9Jla[.0

TABtE 3. Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by Author, f D ti f Perctnt of premature infants Mean duration of pregnancy C t re erence Weight ura on o gestation Nonsmokers Smokers Nonsmokers Smokers ommen s Underwood <2,500 g. Cigaret tca per day Prematurity by birth weight rose et al., 5.7 (1 417) 1-10 7.5 (671) directly to a significant degree (51). , 11-30 9.4 (1,358) (p<0.01) with each smoking >30 11.2 (176) category. <36 weeks 5.8 (1,442) 1-10 6.9 (525) Data suggested that smoking in 11-30 7.5 (1,084) any trimester decreased birth >30 7.5 (118) weight. Buncher Births t Smokes 20 cigarettes per day. (4). Male 39.65 weeks 1 39.36 weeks _ - Female 39.69 weeks t 39.51 weeks Butler and Alberman <2.500 g. 5.4 (602) 9.3 (433) A significant (pG0.01) difference Terris was found between percent of and mothers who smoked and Gold those who had premature (47). deliveries and the control group.