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03764963

The Health Consequences af SMaKING 1969 SUPPLEMENT TO THE 1967 IPbbllic Health Service Review: IIT.S! DEPARTMENT OF~ HEALTH, EDUCATION, ANDI WELFARE Public Health Service

1''969 ' Supplement to Nblic ~~ Health~ Service Fahii'catiOn No. 1696-B' Library of Congress Catalog No. 68-60025 For sale by the Superlntendentof'Doeumenta, iT 8., (lovernment Printing Offiee Weshington, D.C. 2M02- Brice 50 cents

I Foreword This is the third report required by Section 5(d) (1), of'the Federal Cigarette Labeling and Advertising Act, whi& directs: the Secretary ofI-feaTt~H, Education,, and Wellfaret'osubmit annual reports~to, the Cmngress on the health consequences of' smoking. The preced'ing two reports were The Health Consequences of b'7naking, A Publ'ie Health Service Review: 1967 and The Health C'ov-sequenceso f S7noking,1968 Supplement to the 1967 Publi.c Health Service Review. The present Supplement was submitted ta the Congress on July 29;. 1969. iii

Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn,, f'h. D:, Director, was responsible for the preparation of this report; Albert C. Kolbye, Jn., M.D., M.P'.H., LL.B'., was consulting editor. Stafiff director for the report was Daniel P. Asnes, M.D: The professional staff has had the assistance and advice of a number of experts in the scientific and technical fields, both in: and outside of' the Gouernment. Their contributions are gratefully acknowl'edgedSpecial thanks are due the 1ollowing : ANDERSON, WILLIAM H.,, M.D.-Associate professor of medicine, University of Louisville, School of'Med'icine, Louisville, Ky. AUEasaeH,, OSCAR, M.D: Seni,or medical investigator, Veterans Admini'strationi Hospital, Eastl Orange,, N.J. AviAno, Do:arrrco M., MLD:-Professor of pharmacology, Department of Pharma- cology, School of' Medicine,,University of Pennsylvania, Phiiadelphia, Pa. ArnEs, STEPHEN M., M.D: Director, Cardiopulmonary Laboratory, Saint Vin- cent's Hospital and Medical Center of' New York, New York, N.Y. BATES, DAVID V:, MLD:-Chairman, Department of'Physiology, McGill University, Montreal„Quebec, Canada. BErsEr, SAMUEL, M.D.-Director,, Division of Cardiology, Philadelphia General Hospital„Philadelphia, Pa. BiNG, RICHARD J., M.D:-Professor and chairman, Department of Medicine,, Wayne State University, Detroit, Mich. BLOnsqursT, EowARn T., MID.-Chief, Chronic Respiratory Disease Control Pro- gram,, Health Services and Mental Health Administration, US1P.H.S,, Arling- t'on, Va. BocK, FaEn G., Ph. D;.-Director, Orchard' Park Laboratories, Roswell Park Memorial Institnte, Orchard Park, N,Y. BoaErrs Hor,Lis, M.D:-Chief of pulmonary disease, Professor of medicine, Mar- quette School of'Medicine, Wood VA Center, Milwaukee, Wis. BOUTWELL, RoswEr.L K., 113 D.-Professor of oncology, McArdle Laboratory for Cancer Research, University of Wisconsin„Madison, Wis. CooPEa, THEODORE, M.D.-Director, National Heart Instithrte; Nationall Institutes of Health~ Bethesda, Md. CORNFIELD, JaxomF_-Biostatistics Project, Bethesda, Md. DE LA PUENTE, JosErH-Chief,,Program Studies Section, Kidney'Disease Control Program,, Health Services and, Mental Health Adminilstration, U.SJP.H.S.,, Arlington, VaL EASTMAN, NiCHOrsox J'.,,113'.D. Professor emeritus of obstetrics, Johns Hopkins Hospit'al, Ba1t'imore,,Md. ELIOT, ROBERT S., M.D.-Associate professor of medicine, Diwisioni of'Cgrdiology, College of Mediicine, University of Florida, Gaanesville,, Fla. i~l

EiwnrcoTT,, KENNETH M., M.D.-Director, Nationall Cancer Institute, National In- stitutes of Health; Bethesda,,Md. EPSTErN, FREDERICH H., M.D. Professor of epidemiology, Department of' Eppi- demiology, University of Michigan, Schooli of Public Health„Ann Arbor, Mich. FArK,, HA:vs L., Ph. D:-Associate director f'or laboratory Tesearch; Nat'ional. I'nstitute of Environmental Healt& Sciences, Research Triangle Park, N.C. FERRZS, BENJAMrN G., Jr.,, .1f.D.-Professor, Department of Physiology. Harvard Schoollof Public Heaith+ Harvard University, Bost'on, Mass. Fox, SaaiLEr: M:, HI,, ltl'.Ds-Chief,, Heart Disease and Stroke Control Program„ Health Services andi MentaI Health Administration, U.S.P:H.S!., Arlington,,Va. FRAZiER, ToDD M.-Assistant director, Hlarvard Center for Community Health and Medical Care, Harvard School ofPiiblicHPalth, Bocton; Mass. H'ASS, GEORCE M., 3i.D:.-Chairman, Di',vision of' Pathology, Presbyterian-St. Luke's Hospital. Chicago, 111. , HIGaINS, IAN T. T., MLD;, M.R:C.P.-Professor,, Department of' Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. HoFTbtANN, DrETRrCH, Phi D.-Associate member, Environmental Carcinogenesis, S'lban-Kettering Institut'efor Cancer Research, New York, N.Y. KELLER, ANDREW Z., D:3i.D., M:P'.H.-Chief', Research in Geographic Epidemi- ology Research Service,, Veterans :i,dtninistration Central Office, Department of:Medicine and Surgery. Washington, D.C. •KEBSasnuac, Ar.r-R.ED, M.D.-Assistant Chief, Division of' Cardiology, Philadel- phia Gcneral', Hospital,, Philadelphia, Pa. (Dr. Kershbaum, who contributedl to this,and previous reports,,died suddenly ini:llarch 1369:) KoTrN,, P'AUL. MID;-Director, National Institute of Environmental Health Sciences, Research Triangle Park, N:C1. KRUatHOLZ, RtcrrARD A., M.D. Director, Institute of' Respiratory Diseases, Kettering, Medical Center,, Kettering,, Ohio. LEUCHTENBEROER, CECrLE, Ph. D.-Head. Department of Cytochemistry,, Ssciss', Institute for Experimental Cancer Research; Lausanne, Switzerlandi LEUGHTErBERGER,. RLOOLS;, Ef.D.-Professor,, SwiSsInstitutefor Experimental Cancer Research,, Lausanne, S~vitzerland. LIEBOw,, AvERrDL A,, M.D.-Professor andl chairman, Department of Pathology, L'nii-ersitiy of Califbrnia, San, Diego; La Jolla, Calif. LrniENFELD,ABRAHAM; M:D: Professor and chairman, Department of Chronic Diseases; Johns Hbpkins School,ofl Hygiene and, Public Health, Baltimore,, Md. LYoN„ HARVEY W., D.D;S:,, Ph. D: Secretary, Council on Dental Research, American Dental Association; Chicago, Ill. MAC114AHON, BkzAN4 M:D.-Professor of epidemiology, Harvard University School of' Public Health, Boston, Mass. MCLEAN, Ross, M:D.-Professor of medicine (pulmonary disease), Emory Uni- versity, School of Medicine, Atlanta, Ga. MITCHELL, RoGERS., M.D:-Director, W:ebb-Wa:ring, Institute for Medicali Re-search; University of' Colorado Medical Center, Denver, Colo.. MuRPHY, EDMOND A.,, MiD:, Se. D.-Associate professor of' medicine,, The Johns Hopkins Hospi:tals Baltimore, Md. PaiFffENBARGEa, RALPH, S.,,Jr.,.M.D: Chief, Bureau of:Adult.Health.. and.Chronic Diseases, Department of' Public Health, Berkeley, Cai'if. PETERSCN; WrLLrAar. F...,. M.D:-Chief,. Obstetricsand. Gynecology Service, USAFHospital, Andrews, MSHCB„ Andrews Air Force Base,, Washington, D.C. •Decea®ed. Wt 0

PErrg; THOarAs L., M.D.-Assistant professor of medicine, Unlversity of' Colb- rado Medical Center, Denver, Colo. Rocassss, PAUL G., riT.D.-Heart Disease andl Stroke Control Program, Health Services and Mental Health Administration, U.S!P'.Ii:S:, Arlington,, Va. Ross„ WILLIAM L., M.D.-Chief, Cancer Control Program, Health Services and. Mental Health Administration, U.S.P.H.S., Arlington, Va. SAFFIQ'rrI,. U1VfsEETa,. ril:Ds-Associatee scientific director for~ carcinogenesis,, etiology,, National Cancer Institute,, N'ational Institutes of Health, Bethesda4. nrd. ScHACaTax, JosEPa-Statistician, Adult Heartl Activities; Heart Disease and Stroke Control Program, Health Services and Mental Health Administration, U.S.P'.HIS., Arlingt'on~ Va: SCauMAr, LEONARD M., :iI':D'.-Professor of' epidemiology, University of' nTin- nesota.,, School of Public Health, Minneapolis, Minn. SHiMxiN, MICHAEL B., 3LD. Director; Regional b3edicali Programs, University of California at San Diego,, La: Jollay Ca1iY'. Sn:vESMAN, SoLS, Jr., D.D.S'-Professor af oral biology, School of Dentistry, University of California, San Francisco, Calif. SMrrn. LOWELL C., D.D.S.-Chief,, Preventive Services Section, Community Pro- grams Branch, Division of Dental Health, U.S.P.H.S., Betnesda„ Md. STAMLER, JEREMIAH, INLD.-Eaecutive direct'or; Chicago Health Research Foun- dation, Chicago, Ill.STEOMArr4 RussEr,a. L., D. Sc.-Head, Smoke Investigations, Tobacco Laboratory, U.S. Department of A'gricuiture;, Philadelphia, Pa. TfECxB, RicFiASU W.,, D.D:S:-Director, Research Institute, American Dental Association, Chicago, Ill. ToatN, CHARLES E., Ph. D.-Professor of human biology, University of' Colorado Sohool of D'entistry,, Denver, Colo. TYLER, WALTER S., D.V.1Wf., Ph. D.-Professor and chairman, Department of Anat- omy, Schooli of Veterinary n1'edicine,, Universi'tp of California, Davis, Calif. UNDERWOOD, PAUL, M.D-Assistant professor ofs obstetrics and gynecology, De- partment of Obstetrics and Gynecology, University of South Carolina Medical' School,, Charleston, S.C. VAN DUUnErr, BENJAmi w L., riti:D~-Associate professor,, New York University Medical Center,, Institute of Environmental Health~ New York, N.Y. WEIR, JOHN M.-Director, Bureau of' Dental Health Education, American Dental Association, Chicago; Ill. WYY®Ea;, ERNEST L., M'.D:-Associate member, Sl+oan-Kettering I'nsbitute for Cancer Researchi , New York,, N:Y'. The foTl'owing, professional sta-ff' of the National! Clearinghouse for Smoking, and' Health contributed ta the preparation of' this report : Louis Nemser, 1VT.D:, David V. ,Sharpe;M.D:,,DorothyE. G~reeny,Rh. D., Richard Eisinger, Robert S' hIutchings, Erni1 Corwin,, and Richard W. White. Special thanks are due Jennie IVZ. Jennings, Mildred H. Ritich iie; and Donald R. Shopland.. vii

] J ]

Table of Contents Page Foreword----------------------------------------------- ha Acknowledgments--------------------------------------- v Rart 1. Current Information on the Health Consequences of Smaoking: Summary of the R'eport--------------- 11 Part 2. Technical Reports on the Relationship of Smokin.g, to Specific D7seasei Categories---------------------- 7 Chapter 1. Sffioking, and Cardiovascular Dis- eases~--------------------------- 9 Chapter 2. Smoking and Chronic Obstructive Bronchopulmonary Disease------- 35 Chapter 3. Smoking and Cancer--------------- 53 Chapter 4. Effects of'~ Smoking on Pregnancy---- 75 Chapter 5. Smking, and! Noneancerous Oral Dis- ease--------------------------- 83 , ix W. C3 ® .,, I r: rt S ~~",r

03764973

PART I Current Information on the Health Canseqaences of' Smoicing. l'! AL

03164975

Summaryof tha Report This ~ reportt is a review of the pertinent medical li terature on the health, eonsequences of smoking which has appeared since the publiea- tionof the 11968 Supplement to the 1967 Public Health Service Review: The 1964 Report of the Advisory Committee on Smoking and Health, the 1967 Public Health Service Review; and the 1968' Supplement have presented the broad base of converging epidemiiological,, physio- logical,,pathological,, and clinical evidence on which knowledge of the health hazards of smoking is based. ][nclhzded in this evidence are data which show the magnitude of the excess mortality and morbidity among smokers.. The following conclusions regarding the heallth, consequences of smoking were summarized in the 1968 SuppllemenL General Mortality Infornaation Previous findings reported in 1967 indicate that cigarette smok- ingisa.ssociated with an increase i~n overall mortality and mor-bidityandi leads to a substantial excess of deaths in those peoplenho smoke. In addition,, evidence herein presented shows thatt life expectancy among young men is reduced by an average of'~ 8 years in "heavy"' cignrette smokers,, thosew1iosmoke over two packs a day, and an averageofl 4years in "'light" cigarettesmokers,e those who smoke less:than one-half pack per day. Smaking and Cardiovascular Diseases Current physiological evidence; in combination with adtlitionall epidemiological evidence, confirms previousftindings and suggests, additional biomechanisms whereby cigarette smoking can, con- tribute to coronary heart disease. Cigarette smoking adversely affects tihe interaction between the demand of the heart f'or oxygen andi other nutrients ~andi their supply. S'omeof'the:harmfuT cardi- ovascular effeets appear to be reversible after cessation of'cigarette smoking., Because of'' the increasing convergence of epidemiological and physiological findings relating, cigarette smoking to coronary heart disease, it is conchided that cigarette smoking can con- tribute totliedevel'opment of cardiovascular disease and partiic- ularl3~~ to de:ath, from, coronary heart disease. ,S'r,zokzng and Clironic Obstructi,ve Bronch,opulmonarry Diseases. Additional physiologicail and epid'emiological evidence confirms the previous findings that cigarette smoking: is the most important cause of chronic non-neoplastic bronchopulmonary disease : in the United States: 3.

Cigarette smoking can adversely affect pulmonary function and disturb cardiopulmonary physiology. It is suggested that this can lead to cardiopulmonary disease, notably pulmonary hypertension~ and cor pulimonale in those individuals who have severe chronicc obstructive bronchitis. Smoking and Cancer Additional evidence substantiates the previous findings that eigarette smoking is the main, cause of' liung cancer in men. Ciga- rette smoking is causally related t'o lung cancer in women but ac- counts for a smaller proportion of cases#han in men. Smoking is a significant factor in the causation of cancer of' the larynx and in, the development of cancer of the oral cavity. Further epidemi- ological data strengthenthe association of cigarette smoking withh cancer of t.he bladder and cancer of the pancreas. The most recent Ptiblic Health Service review of the effects of smoking on pregnancy was presented in the 1967 Report. The con- clusions of thatreview were as follows: Clearly, more research is needed to elucidate the significance of the relationship of'smoking i'npregnancyand low birth .veight.Additional Iong=range morbidit'y studies are neededy as well as studies on~ t'he effect of smoking on uterine activities and! placental bloodd flow. Smoking,does have an~effect on the outcome of pregnancy. How- ever, it is not known whether this effect is deleterious or not. Until such evidence is presented' so as to clearly define the role of smokingiln pregnancy, itismore, prudent atthlstiinetoadvisepregnant women to stop or decrease their cigarette-smoking practices. No substantial negat~ive evidence has appeared whicli refutes these judgments. On the cont.rary,,stud'ies~made available since the publica- tion~ of the 1968~ Supplement andi reviewed by panels of experts in the relevant medical areas confirm previous findings and add new evidence that smoking, is a health hazard'. Highlights of the 1969 Supplement are as follows: I. Smoking and'Card'iovaxcular Disease8 Further data from prospective studies confirm the judgment that cigarette smoking is a significant risk factor that contributes to the de- velopment of coronary heart disease, apparently by promoting myo- cardial' infarct and cardiac arrhythmias. Analyses by severaI investii- gators of other associated fact'ors (high serum cholesterol, high bloodd pressure and body weight) show clearly that the effect of cigarette smoki'ng persists and is appreciiable, even when these other factors are careflullyevalua.ted., Autopsy stu~dies, suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and, the coronary arteries. Experi'rnentall studies in animals have pro- 4 ,A-

ndl an _on aic !iat ,a tic- sa nd' ni- ith of' ;n- of' ht. as 'al. VV- >t. )le see ag' %se a- he ce mt t- >d ~ re Eaa vided new information on the pathologicall effects of cigarette smoking on the arteries., This further supports the view that cigarette smoking promotes atherosclerosis. II. Smak'iny and CAron.ic Obstructive BronchopuZmonm-y Diseases Recent studies have demonstrated that cigarette smokers may have significant disease of the small airways in the absence of bronchopul~ monary symptoms. This~disease is demonstrated by the finding of ab- normalities in the ventilation/perfusion relationships in the lungs of cigarette smokers., Animal e.r-periments have demonstrated the path- ological effects caused in the lung by exposure to cigarette smoke : or t!ospecified concentrations of'products, found~ in cigarette smoke. Con- ditions si¢nilar to pulmonary emphysema in man have been producedl in: some of these experiInents, Other studies have investigated the path- ological effects of'smoking on pulmonary clearance mechanisms and d'emonstrated' t'hat pulmonary clearance may be signi$'cantly impaired by the; effects of' cigarette, smoking. Epidemiological and laboratory evidlence supports the view that, cigarettesmoki'ng can contribute to the development of'pulmonary emphysema in man. III. Smok'inyg and Caneer A maj'or pathological study of histological changes in the larynx has demonstrated a dose-relationship between smoking, and premalig- nant changes in the larnyx. New animal models for the!experivnentaI study of' respiratory cancer, which may be helpful in~ elucidating the mechanisms of respiratory tract carcinogenesis, have: been de- veloped and refined. More studies have been d'one to, identify those substances in tobacc.o ~ smoke which take parti in carcinogenesis. Thesestudies may help, to dlefine the exact biomechanisms involved iin the cause and effect relationship between cigarette smoking and lung cancer. IV:Effect of Smoking onP'regnancy New data are presented which confirm, the finding that maternal smoking during pregnancy is associated with low birth weight in infants and also indicate that maternall smoking, is associatedi with an increased incidence of prematurity defined by weight alone:In addi'~- tiony it appears th& maternal smoking during, pregnancy may be as- sociated with an increased incidence of'spont'aneous abortion, stillbirth, and nerrnatall death and that t.his relationship may be most marked in the presence of other risk faetors. V. Smolcing. and'. Noncancerou e ~ O raU Disease The chapter on noncancerous oral disease is the first Public Health Service review of this subject.The data available lead tothe conclusion that ulceromembranous gingivitis; alveolar bone loss;, and stomatitis. 5'

nicotina are more commonly found among smokers than among nonr smokers., The influence of smoking on periodontal disease andi gingi- vitis probably operates in conjunction with, poor oral hya ene. In addition, there is evidence that smoking may be associated with edentulism and delayed socket healing: Tobacco ~ smoke ~ contailn~s, a large,number and a wid'evarilety of com- pounds which may result in complex and multiple pathophysiolbgicall effects on the various tissues and organ systems. While further researcls is need'edd to investigate the exact biomechanisms involved' in~the patho- logical effects of smoking, the evidence clearly shows that cigarette smoking constitutes a major health hamard in the United States., >~ 6 O 4r.~. ~ ~ ~. 40

non- I ungii- j In avith 'iOID- LPCh, tho- ~ette 0 PART 2 Technicat, Reports on the Relationship of Smoking to Specific Disease Categories

TSSV94co

CHAPTER 1 Smoking and Cardiovascular Diseases Contents Pa8e SummarY---------------------------------------------- 1l1 Epidemiolbaical St'udi+es---------------------------------- 1!2 Atherosclerosis------------------------------------------ 25' Thrombus Formationi and Blood I+Flbw--------------------- 27 Carbon Monoxid'e--------------------------------------- 2'8' Cited References---------------------------------------- 29 Cardibvascular S'uppl'smental Bibliogaraphy ----------------- 31 , 9

03764983

SMOKING AND CARDIQVASCULAR DISEASLS' SUMDiARY 0 Coronary heart disease (CI'ID) among,men in the Western world is an epidemic which cuts short the lives of many in their prime produc- tive years.. The evidence linking smoking and CHD has been reported not only from studies in the United States, but also from such diverse areas as West Germany, the IT.S.S.R., France,, Israel4 Italy, and the British Isl'es. The 1968 Supplement (27) st'ated : Because of the increasing convergence of' epidemiological and' physiological findings relating cigarette smoking to coronary heart disease, it is concluded that cigarette smoking can contribute to the develbpment of cardiovascular disease andi particularly too deathi from coronary heart disease. Tlia, convergence of autopsy data andi experimental data presented in this and previous reports suggests that cigarette smoking promotes atherosclerosis, including that of the coronary arteries. The results of physiolbgical' research andi the findings of diminished' risk of CHD in. those who have stopped smoking, indicate that there is also a more immediate mechanism operative:, The mechanisms which might be re- sponsible for the promotion of'myocardial infarction and fatali cardiac arrhythmias by cigarette, smoking were extensively: reviewedd in the 1968 Supplement (27) . Briefly stated, nutrient supply to the myocar- diurn in general and,, perhaps more importantly,, to focal ischemic areas of the myocardium may be seriously compromised by a combina- tion of'effects caused by smoking, and the deprived myocardium may become infarcted or, ddevelop an arrhytliminL These effects include diminution of blood flbwthrough, atherosclerotic coronary vessels and diminution of'available oxygen for tissue use resulting from the bind- ing of carbon monoxide to hemoglobini in the place of' oxygen amd' 11 0

possibly, although presently speculat'iue,, the: poisoning of respiratory enzymes by hydrogen cyanide. C'igaret'te ; smoking has been shown ta be ~ an important risk factor inI the development of' CHD. It is important both by itself and in the presence of' other sign2fieant risk factors, In combination with certain other risk factors; the joint effects appear to be even greater tlhan those accounted for by those risk factors independently. EPiDEMIOLOCrICAL STL7DIES'. Hammond~, et, ah (11), have presented newda.tla~ on mortali'tyf'rom CHD, stroke,, and nonsyphilitic aortic aneurysm among more than 800,000 men and women who were between the ages of'40 and 79 ini 1959. The authors were attempting, to evaluate tlhe significance of' multiple factors (sex, age, diabetes,, high blood pressure, body weight, change in~ weight„ exercise, ciga.retit'e! smoking,, sleep, andl nervous tension) in the variations in death rates from these three diseases. It shouldi be noted that this information consisted of self-reports obtained by ques- tionnaire and were not obtained from medical examinat'ion. Causes of' death were based, on deatlii certifieate reports. As illustrated in table 1, coronary: heart disease death rates and mortality ratios increased with increasedl cigarette smoking, for men in: all a~ge, groups and for women under the age, of' 70. Although the mortality ratios were higher in~ thei younger age groups, the differ- ences in death rates between nonsmokers and heavy smokers became progressively higher with ilncreasing, age. Although CHD1 rates weree higher for those who were 10 percent or more above the average weight for their height-age-sex group, and for those who reported having high blood pressure,,the trendlis clear that the effect of smoking persistss andl is appreciable, even when these other factors are held constant. (table 2):. 12 O ~ ~ ~ Cd. lb. I

a.tory ° TABLE ~ 1.-Ueath; rates and' mortality ratios for eoronary, hheart disease and stroke, by amount of ctigarette smoking, sex,, and age actor . Coronary heart diaease, Stroke: ad in Regularly smaked cigarettes Regularly smoked cigarettes ! with Never Never te'r Sex and age smoked i tte Numbersmoked'd'aily amoked ci tt Number'smokeddally lea c gare s regularly 1r9~ 10-1'9 20+39 40 or gare es regularly 1-9 10-19 20-39 40 or mone more DEATH RATES from Males: 40-49 years'-_-- 69 109 176' 2516' 375 I4I 39 216 31 23' than 5o-59 years--_- 60-89 years-._., 257 650 409 961, 648 1, 184' 616' 718 L 241 1,166 40 168 78 219 59 242 81 272' 96 289, 1969. 70-79 years..-. 1y 730 1,970, 2, 43'1 2,573 2,548 650 617 698' 792 r'445 Itiple Females: 40-49years---_ 13 17 27' 47, ='43 10 15 2& 29 2'57 1 ange 50-59 years.--,-, 59 68 140 158 220 27 34 73 72 295 60 69 years-.-- 268' 279: 479 558' 1S42 110 139 236 201 -_ rL) in 70-79 years---- 979 740 963 1', 243', ._'. 4'87 404 1276 622 ._ Id be'e qll'eS- MORTALITY RATIOS t les of' Males: 40-49 years-_-,- 1.00 1'. 60 2 59 , 3: 76 5 51 L 0D 2,79 "1114 221, 1'. 64I 50-59 years_,-.,- 1.0!9' 1.59 213 2 40 2'79 1:00 1.95 1.48 2 03 2'4'0 and 60-69 years.... 1.00 1.48 1482 1 1.91 1.79 L 00 L 30 1. 44' 1.62 ' 1.72 70-79 years 1 00 1 14 1 41 1 49 1 4'7 L 90 95 92 1 22 2' 6'8 men 1~ the .... Females: 4tk-49 years---- . 1.00 . 1.31, . 108 . , 3. 62' . 3' 3: 3I L 0D . L 50 . 2.60 60 . 2 90 . z'b. 70 50-59 ea s 1 00 1' 15' 2 37 168, 3 73 1100 1 26 2 70 2 67 3 3: 52 iff er- r ---- y 60-69years.... . 1.00 . 1.01 L79' 208 . 3102 1.00, . L26 2'1'5 1.83 __.. Yame' 70-79 years----, 1.00 .76 .98 1.27' ...,_ 1100' .83 2.57 L 28' ---- were ff ght ving 5]St8 I The' mortality ratio ts the observed rate divided by the e:pected'rate. 1' Rates based upon only 5 to 9 deaths. Souacr : Hammond, E'. C., etaL (11). itiaQlt 13 O W .3 lA W' OD (7)

TABLE 2. Coronary heart disease death ra,tes for men and wmrtenn classified'by'smoking habits, dge', blood pressure; and relative weight. E:tentl ot' tte kin i No high blood pressure, by relative weight High blood pressure;. by relative weight gare smo g, e and age T'otal' Less than 90 90-109 110-119 120 and Totali over Less than 90 90-109 110-119 120 and over ~ MEN None or sllgpt'c 40-49 years__-__,__-____. 52 127 46' 64 128 20S' --- 195' 11210 226 140 216 263 390 620 1686' 611 643 699 60-69 years-______-.-__ 603 542 573 701 763 1,503 1; 777 1, 295 1,860 1,855 70-79years-_-____,__,__- Intermediate: 1,611 1J 167 1, 555 1', 840 1; S68 2,738 3,342 342 2,588 2,! 651 3,100 40-19'years------------ 116I 108 104 141 245 249 ' 1354 266 i' 286' 50-59 years------------ 373' 352 363: 405 538 876' 1,424 686 1,182 995 60-69 years------------ 888' 814 890 984 973 1,876 1,913 lj 999 1,447 ' 1,710, 70-79 years------------ 1,9731 '. 2,237 11778 1,953 ' 2,901 3,220 3, 700 3,172 2, 213: 5, 451 2aormore: 0 40-49 years------------ 222I 123 235 309' 276 647 687 550 765' 888 50-59 years'------------ 530' 422 536 666 641 1,137 1,148 1;153' 933' 1,41 60-i9 years'------------ 1,047 ' 978~ 1,019 1; 249 1,307 1,986 2,160 1,993 I 1; 744, 2, 075' 70-79 years'------------ 2,296 2,'346' 2,205 2,151 2; 846 4;1P3 5',141 4, 20'5 13,692 WqhiEY!P, None or slight: 40-L9 years------------ 8 I5 ~ 7 _,__ 22 63 ___ 53 ----- 75 50-59 years------------ 4U 39 32 64 68 161 100 142 157 229 60-69 years------------ 201! 153 191, 265 323 469 400 495' 462 469 70-79 years------------ lntermediate: 776 832 7791 667 754', 1.338 11313 1,217 1,449 1,626 . 40-49'years------------ ,- 15 17 12' --- --- 86 ---, 176 50-59 years._,-__------_ 76' 69 70 153 173 281 3611 281 1233 1 198 6'0-69years------------ - 2254 337 244', 422 -__, 730 732 743 848 1 484 70-79 years------------ 20 or more: 607 736 551 _,-_ ___, 1,161 I1}854 1,014 40-49'years------------ - 36' 25 38 1421 173 144, __- 198' ----- _____, 50-59 years------------ 120 118' 128 - 1135' 358I 1263 291 1'584I 1706 60-89'years------------ _- 467' 34U 539 1637' __,_ 811 1 798 1,100 _,____ _-,-__ 70-79 years------------ 644 1 866', 1585 _--, __,_ 2,463 --_ 13,743 I Rates based!upon only'5 to 9 deaths. Sovacs;: Hammond, E.,CI, et aL (1'1). Haminond'S et aI. also' studied CHD mortality among men who were eg-smoker& of' cigarettes. The death rates from CHD were lower among the ex-smokers thani among,those still smoking, at the beginning of' the study, thei size of' the difference being larger the longer they: had been off'', smoki'ng (table 3). Some people stop smoking because': of illness or sympt'omaand: these! peoplewoald be expected to have'higher'death, rates than those who stop for other reasons, Ear;lyy deaths a;•nong' those with preexisting disease mayy account, at least in part, for the high dleath, rates from CHD among ex-smokers in the early years ofl abstention. 14

lfortnlity ratios for stroke were higher among' cigarette smokers with the exception of those ov.er, 70 years of age. Male ex-cigarette smokers had mortality ratios for stroke approximately equal to those of nonsmokers. A clear increase in mortality from nonsyphilfitic' aort'ic aneurysms with increasing cigaretlte; smokinga~mong' men aged 50--69~ ils, seen in table 4. The mortality ratio for heavy smokers was 8.00. IFIammond; et al. found' that death rates from the three diseases var- ied considerably with relat'ive weight, alnount of exercise,, amount of cigarette smoking, and hours of sleep per niight. Subjects who were obese, took little or no exerc'ise, smoked many cigarettes a day, or slept 9, or more hours per night had highi death rates.. Those with a combi'- nat.ion of'these factors have especially high death rates from the three, diseasesi rere wer ,ing hey' .use ave ~ths art, wly for ex-cigarette srrtokers wit1i d history of smoking only cigarettes, by number of' yedrs since la,st' cigarette smoking and for current cigarette smokers, coronary, lheart disease and stroke,: compare.d' to persons who never smoked regularly„ in men a.g:ed' 4Q-79 TnBLE 3.-Observed and' expected number of deaths and mort¢Z'ity, ratios -I Type oCsmoker Ei,dgarette smokers (former smokers o11-19 cigarettes a day): Stopped: Lesathan 1 year-------------- 1-4 ,years'---------------------- 5r9 years---------------------- 10-19 y,ears----°-----_--------- 20 or more years-------------- Total----------------------- - Currentcigarettesmokers------------ Never smoked regularly _, _,.----------- E z-cigarette smokers (former smokers . o120 or more cigarettes a day) : 9topped': I.ess than 1, year-------------- 1-4 , years---------------------- 5-9 years---------------------- 10-19 yesrs-------------------- --, 20 or more years-------------- TotaL---------------------- Carr,ent cigarette smokers_ _,-.-,-_-__ _-, Never smoked regularly--_ _-_ _,_ _ _ _ _-_, Coronary heart disease Stroke Observed Expected Ratio: Observed Expected Ratlo 29 17.9 1.62 57 4&8' 1122' 55'~ 43. 7 1.Z8 52' 54.1! .96 70, 81J7 1'.08 2168 228: 9 1'.18' 57 58. 9 L 00 1,063 559.I5 1.910 207' 1g4.5 1.54 1,841 14 84L 0 L 00' 501, 501.0 1.00 62 38.8' L 81 154 101.9 1.51 1'35' 11'8.5 1.1d 1'33' 106.11 1.25 80 76.4 1.05 584 439.7 1.28 94 101:1 0.98i 2, 822 1',104. 7' 2.' S5 4N0 284. 7 1.87 1,841 4841.0 1. 010 501' 50110 1.00 8ovaca: Hammond; E'. C., et al. (11).. is GD,

TABLE 4. Aortic aneurysm deathh rates and mortality ratios for men aged 50-69y classilZed' by cigarette smoking habits [Rates per 1~p00 population] I Never C1nrent smokers, by daily Measure smoked cigarette consumption regularly DeatH rate---------------------- 13' 34 50 59 104 Mortality ratio------------------ 1.00 2.62 '' 3.85 ' 4.54 8. 00: SouxcE: Hammond! E. C:, et al. (11).. They also found that death rates from CHD~ and stroke were lower in ex-cigarette smokers than in men who were currently smoking ciga- ret't'es at the time they enrolled in the stud'y. The death rates of', male ex- cigarette smokers wiio had not smoked for 10 to 2G years were no higherr or only slightly higher than the death rates of' men who had never smoked regularly. Death rates from the three diseases were lowest among subjects without a history of diabetes or high blood' pressure. who were not obese, took at least moderate exercise, never smoked reg- ularly and slept 6' to 8 hours per night. Nevertheless, even these sub- ject,s hadl substantial death: rates from CHD, stroke and nonsyphiilitilcc aortic aneurysm. Stamler (24) has anaylzed 10-year mortality data on ai total cohort of inen, aged 40-59 ini 1i958;,wlio were employees of'' the Chicago Peo- ples Gas Light and' Coke Co. Of 1',465' men eaamiined,1,325were found initially to be free of definite CHD, and' have been followed without systematic intervention: Higher overall d'eath rates were found among the smokers in, the study. Table 5 shows the death, rates from CHD and from all causes for men with various risk factors., Recent papers~ by Thorne, et al~ (25) and by Raffenbarger,, et a1. (19) report further results of studies of' CHD among f'ormer college students. College health records and other college records were re- viewed to ascertain the presence or absence of factors under considera- tion. Cases were identified from death certificates in the study of fatal' CHD'(,1'9)~ and' from questionn~aaresands physical exam,ina:tionsin thestiudy of nonfatal CHD (25). Matched controls were obtained for each case. In both nonfatall and fatal CIID; signi'fi'cantly more smokers were found among the cases than among the controi's. Combinations of risk factors resulted in greater CHD morbidity and mortality ratios than, did single factors. Eigure 1 shows.the.morbidity ratios for com- binations of pairs of risk factors in nonfatal CHD andd table, 6 shows mortality ratios for combinations of risk factors in fatal CHD. 16 .,~,,,

OGGV94c0 TAHLE 5.-f0-year mortality rates for sudden death, coronary heart disease, stroke, cardiovascular-renal, and all causes combined among men aged 40-59, classified according to cigarette smoking, cholesterol, and blood pressure [Peoples Gas Light Co. Study, 1958-68. Men originally free of coronary heart sisease and followed without systematic intervention.] 10-year mortality 1958 risk factor status-ctgarette smoking (10 or more a day), Sudden death All CIID Stroke All CV R All causes hypercholesterolemfa, hypertension I Number Number Death Number Death Number Death Number Death Number Death of-meaiti --- of rate 2 of - -rate of rate of-- rate of rate in cohort deaths deaths deaths deaths deaths -- --- - --- -- - - No risk faetor 284 0 0 1 0 3 2 9 5 4 11 9 13 42 6 ------ ------------- -- -------- -- --- ---- -- - Hypercholesterolemfa or hypertension only-l factor-------------- 216 4 19.6 13 . 53.1 6 . 19.5 19 . 72. 6 27 , 101.5 Cigarette smoking only (10 or more a day)-1 factor--------------- 405 4 10.0 15 37.1 5 11.8 20 48.9 44 107.7 Hypercholesterolemia and hypertension only-2 factop------------ 60 1 9.9 3 29.6 1 40.7 4 70.3 8 121 9 - Cigarette smoking (10 or more a day) and hypercholesterolemfa or cigarette smoking and hypertension-2 factors------------------- 293 11 37.2 17 - 57 1 6 19.9 26 86.4 53 . 169 9 - Cigarette smoking (10 or more a day), hypercbolesterolemla, -- - . . hypertension-all3---------------------------------------------- 67 2 25.1 6 76.0 2 25.4 8 101.5 17 2 25.8 Total------------------------------------------------------- 31,325 22 16.2 55 39.2 22 14.9 81 56.6 162 113.1 I Risk factors include: Serum cholesterol 250 or more mg./dl.; diastolic blood pres- 2 Smoking data were not obtained for 4 of_ the 1,329 men. sure 90 or more mm. Hg; 10 or more cigarettes/day. SOURCE: r All rates are age-adjusted by 5-year age groups to the U.S. male population, 1960. : Stamler, J. (tf). All rates per thousand. _T.01k. At17.40 Y

TABLE 6'_-Estlmated coronary lieart! disease death ratios in a 17-51, yeai follourup among forrrter college students; classified according to combiti7,e presence (+)' or absence (,-)' of each of three speci,fied' risk factora; and by age Risk factor Age (years) at: death from coronary heart'disease. Cigarettes;, Systolie BP;, Ponderal 10 or 130 or more index, moreJday mm. Hg less than 12.9 Total 30-69 years 30-44 years 4:5-54, years 65-69 years + + + 4.3 1(1. 9) 1 5.7 1(4.8) + - -fs 1.8 2. 3 1. 6: '. 1(2.0) + + - 4:2' 2.9 4:5 5'.6 - + + 1.91 2.9 1. 6' 1L 8' -}: - - 1. 7 2.2 1.9~ 1'.3 - + - 1.3 1.2 1.2' ll4 - - + 1L1 1.4 1.4 .8' - - - 1.0 1.0 1.0 1.0 I Numbers in parentheses indicate eapeeted number coronary heart disease decedents less than 5. 3ooacE: Paffenbarger, R. S.,,et al. (19)'. In ai study of participants in the Health Insurance Plan of New York, Weinblatt, et al'.,(29) reported that cigarette smoking males who developed angina pectoris were more likely to develop infarction than were nonsmoking anginall patients, but there were not enough cases to draw definite conclusions. Weinblatt, et al. (3fJ) also reported that the prognosis after the de- velopment of a myocardial infarction appears to be independent of smoking status prior to the infar ct: In the absence of' d'ata indicating which patients stop smoking, and how stopping smoking is relo,ted' to the severityy of myocardiali damage, one cannot evaluate the effect of smoking on prognosis. If the persons who stop smoking tend to in- clude the most debilitated~ the effect of continued smoking on prog- nosis would be underestimated. In a~ prospective study of over 3,000 men, Jenkins~, et aL (1ly;)1 re- ported that the incidence of' CHD' in men aged 39=49 was three times higher among the cigarette smokers: among the nonsmokers (ta- ble 7). 'The incidence of CIiD increased with increased da;ily cigarette consumption. For men aged 50-59,,the relationship between cigarette smoking and CHD was found' to be; significant only for the heavy 18

~ d'e- it of .tiIIg'. %l1 to ;t of ) 'in- rog- ' ne- imes (t'a, rette rette wy 0 4 li 2 Gg.nttas'.10+1/tlay.-A~ S),s. BP'130+mm~. NB;-A~. Sys, BP~ 130+mm. Mg,-B! "am < aa~.in:-B 3:9, 3.41 I ~ 2.a. 23~ F 0+/diY~-A~ ~6garaEtp 1 Sys. BP'130+mm. MB._A. H.ight/.V-_-j~h-t ~ < 12:9_B~ Spmrts~~.<. yV./dk'.-B. 4.a 3~.4 ~~ 3.7. ~2'•q CigareMn 10+/day: A~ H.fght/ g~12:9~-A' Haight< tia in.-B H.igM. <~~ 6B~In.:-B 5.2 I 5.7. 4.9 0garettet Iq+/day-A~ Halght/ r.~ 12.9-A Sports~. < 5 hn./wk _ B Sports~ <~. S.hr./Wt:-B 4.8 2.7 3 2 1. 171 lb Syi, 81 130+mm...H,-A~ ~ M.iSht <~.g6t in~.-A~ I Meight/. w-< 12.9-B'~ I Spiorti. < 5'.hc;/wti-9~. d.9. 4.5 ' M - - 3ai : 1.9 ' M A- A'+~ A- A+~ A- A+,'~ A- A+ B-~ B- B+ B+ a=. 8-~ B+ B+~ MIESElKE~.. (+) ~.OR AsaENCL ~(-) iOi FAQrORS~ (A x~. B)', Numtro~ in tNnans .ge. .~andd inbrwl~adiqi.taA~ aRtack~ rMS~M~ nonfattl~ Ct1d~~frum cdlagei a..-taking :to 1962. 4 2 0 4 2 1 0 FrausE l.-Morbidity ratios of' coronary heart disease for paired combinations of factors ini college. 5ouscE : Thorne;,bfi.C., et ali (25),. 19, i

smokers (table 8). Former cigarette smokers also had significantly ' higher CHD incidence rates, but no data are given on length~ of time sinMstopping, smoking, or reasons for stopping. Pipe and cigar smok- ' ersdiid not have higher CHD incidence rates. After controlling f'or ~ other risk factors such as lipid levels, diastolic blood pressure, and ! body build, the authors found that the association between~ cigarette smoking andCHiD! remained (tables 9, 10). The relationship between ~ smoking and CHD was stronger among those men who exhibited be- havior type A than those exhibiting behavior type B(t'ables 11, 12). ! Behavior type A is characterized by enhanced competitiveness, drive„ ; aggressiveness, hostility.; and an excessive sense of time urgency. Be- ~ havior type B' indicates an absence of these characteristics. Analysis of the data on behavior and cigarette smoking showed; that both, fac- { tors have effects on the CHD' rate. Again; these associations weree stronger in the younger age group. j

~- .,. ..---- - " ~»-_--- , qa ~ ~ 9 . ~ 9 - r~ N c` ~o M TABLE 7. Annual incidence rates of coronary heart disease for men 39-49 years of age, classified by smoking history - and by current practices as to cigarette smoking [Age as of the beginning of the 4M year period of obscrvation] Smoking bistory Current cigarette smoking by number per day Total - subjects Never Pipe and Former Current None 1-15 16-25 26 or more Morbidity status smoked cigar only cigarette cigarette .., I Num- Rate I Num- Rate Num- Rate Num-_ ber bar ber bar Total number at rlst-------.---- 2,258 ..... 540 ----- 405 ..... 239 - - Total number CHD mm ------- 63 6.2 7 219 3 1.6 10 All myocardial infarction........ 52 6.1 4 1.7 3 1.6 10 $ymptomatlc ............... 38 3.7 1 .4 2 1.1 8 - Unrecognlsed--------------- 14 1.4 3 1.2 1 .6 2 Fatal ........................ 9 .9 0 0 0 0 1 Angina pectoris only............ 11 1.1 3 1.2 0 0 0 Rate Num- bar Rate Num- ber Rate Num- bar Rate Num- bar Rate Num- bar Rate ----- 1,074 ..... 1,191 ----- 211 ----- 434 °... 442 ---.- 39.3 43 38.9 20 23.7 5 6_ 3 18 d 9.2 20 4 10.6 9.3 35 7.2 17 3.1. 4 4.2 13 8, 7 18 9.5 7.4 27 6.6 11 20 4 4.2 11 b.8 12 0.3 1.9 8 1.7 8 1.1 0 0 2 1.0 8 3.1 .9_ 8 1.7 1 .2 0 0 5 2.6 3 1.6 0 8 1.7 3 .6 1 1.0 5 2.6 2 1.1 I Annual rate per 1,000 men at risk. for continuity. -- -- =These distributions of cases for various smoking categories are significantly dif- r Difference in CHD frequency between this group and current nonoigarette ferent from chance at P-0.001. smokers is significant at Pa0.01. 3 Difference in CHD frequency between this group and those who never smoked cigarettes (ool. 1 and 2combined) is significant at P-0.01 by chi square test corrected 8ovaca: Jenkin, C. D., at al. (14). VssVsLCo .1

Y y N sssV94co TABLE 8. Annual incidence rates of coronary heart disease for men 50-59 years of age, classified by smoking history and by current practices as to cigarette smoking [Age as of the beginning of the 4% year period of observationJ Total Smoking history Current cigarette smoking by number per day Morbidity status su_b_ Jects Never smoked Pipe and cigar only Former cigarette Current cigaretto None 1-15 16-25 26 or more Num- ber Rate I Num- Rate her Num- Rate ber - Num- Rate ber Num- Rate her" - Num- Rate ber Num- -ber Rate Num- her Rate Num- Rate ber Total number at risk------------ 924 ----- 182 ----- 161 ----- 137 ----- 444 ----- 483 ----- 109 --- - 167 ----- 165 ----- -- Total number CUD ca9es - - 70 10.8 9 311 0 11 15 2 - 9 14 6 41 20 5 29 213 3 6 - 12 2 - 16 21 3 319 25 6 -- --.- - All myocardialinfarctlon 52 12 5 . -- 0 7 3 . 8 11 0 . 5 8 1 . 33 16 6 . 19 8 7 5 . - 10 2 15 . 20.0 . 13 17 5 -------- - 9ymptomatic-------- --- - 35 . R4 . 4 4.9 . 4 5.5 . 4 6.5 . 23 11.5 . 12 5.8 4 . 8 2 11 14 0 . 8 10.8 -- - - - Unresxagnized 17 - 4.1 2 2.4 4 5.5 1 1.6 10 5.0 7 3.2 1 . 2.0 4 . -- 5 3 5 6 7 ---------- ---- - Fata1------------------------ - 14 3.4 0 0 3 4.1 3 4.9 8 4.0 - 6 2. 8 2 4.1 4 . G 3 . 2 2.7 Angina pectoris only------------ 18 4.3 8 3. 7 3 -4.1 4 6.5 8 4.0 10 4.6 1 2.0 1 1.3 6 8.1 I Annual rate per 1,000 men at risk. - i These distributions of cases for various smoking categories could occur 0.10 of the time by chance, hence are not signiflcant at Pm0.06. 3 Difference in CUD frequency between this group and current noncigarette smokers is significant at P=0.01. BoURc$: Jenkins, C. D., et al. (14).

TABLE 9. Annual incidence' rates' of new coronary heart d'isease, by smoking habits, adjustedfor age: and seriatim, for specified other risk factors [Rates are annual incidence per1,000 men, aged 39'to 49 years at, entry into studyJ i Specified'other risk factors Never' Former smoked cigarette smokers C fiolesrterol-----------------.-. --------- 33 931 Beta~alph aratio-------------,-----------, 31 91 Lipalbumin----------------------------- 31 95' Systolic BP ----------------------------- 31, 91 Diastolic BP------------------------,---. 29 89 Ponderalindex`-----,------------------.-- 29 91 Ptiysical activity------------------------. 29 93 AmounG o[iexercise----_--------------_- 29 91 Ihc.ome level ---------------------------- 29 91 All of'4he above-------------------, 36 93: T ri gl ycer'id es,---° ----------------------- 31, 88' I Level of significance of F-ratio for' analysis of covariance:, SOURCE: Jenkins, C. D:,,et al. (14). Plpe and cigar only Daily cigarette consumptionn t 1-15' 16-25 26 or more 22 49 89 100 0.005 18 49 91 102' .001 181 51 89 102 .002'. 18 49 95' 100 .001 16 49 95' 104, .001 16 49 95' 107 .001 18 47 93 104 .0011 18 49 93' 104 .001. 18I 49, 93 104, .001 20 51 89, 98 .007 20 40 80 104 .002 TABLE 10 Annual incidence rates of' new coronary heart d2sease; by srnoking habits, adjusted'for age and seri,'atim•', for specified other risk. .factors [Rates are annual incidence per 1,000 men, aged 50 to 59 years at entry into study] Specified other risk factors Never smoked Former ciga ette Pipe and l ci Daily cigarette, consumption - ) r smokers y gar on 1-15I 16-25 26 or p more Choiesterol-------,------------------,---- 115 142 153 115 211 264 0:154. Betalalpha ratio-,---,-------,------------- 107' 142 144 120 213 262 .127 Lipalbumin----------------------------- 1091 140 151, 122 218 262 .135 Systolic BP ----------------------------- 118 127 144 129, 211 266 .136', 109 127 135 127' 220 273 .066 P6nderal index-----,-------------------- 107' 131 140 122 222 269 .084', Physical activity -.-.,----------------,--. 113 142I 149 115 213' 249 .21I6 Amount of exercise--------------------,-. 113 141' 151 118' 211' 255 .203 Income,level---------------------------- 113 138I 147 120, 220 258 I .15'6 All of the above------- --------,---- 113 1161 138 140 213I 258 .158 Triglycerides'--------------------------- 1'13' 1471 144 80 195 260 .121 ' Level of significance of' F=ratio for analysis ot'covaruanee. SovaCE: Jenkins, C. D., et al. (1a)+ 360-328 0-69~-Ci 23 ,•7 ~ ,~a_ _

TABLE ABLE 11.-Incidence of new coronary heart disease, by smoking category and behavior type, for men aged 39-49 (Rates are age-adjusted annual incidence per 1,000 men] Current and former i l d i Daily cigarette consumption l T t Behavior type Never smoked Former cigarette smokers gar on y pe an p c - 1-15 16-25 26 or more a o Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases A----------------------------------- 5.3 5 13.8 7 1.3 1 1.8 1 15.8 15 14.9 16 9.3 45 B ----------------------------------- 1.3 2 5.1 3 2.2 2 7.3 4 3.1 3 4.9 4 3.3 18 Total------------------------- 2.9 7 9.1 10 1.8 3 4.9 5 9.3 18 10.4 20 8.2 9ouacs: Jenkins, C. D., et al. (14). TABLE 12. Incidence of new coronary heart disease, by smoking category and behauior type, for men aged 50-59 [Rates are age-adjusted annual incidence per 1,000 men] Current and former Daily cigarette consumption Total Behavior type Never smoked Former cigarette smokers pipe and cigar only 1-15 16-25 26 or more Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases Rates Cases A----------------------------------- 12.4 5 18.6 8 21.8 8 1_0.4 5 21.5 9 30.0 14 20.4 49 B----------------------------------- 10.0 4 5.1 1 8.4 3 4.7 1 21.1 7 19.1 5 12.0 21 Total------------------------- 11.1 9 14.2 9 14.9 11 11.5 0 21.3 16 28.0 19 16.8 70 Booacs: Jenkins, C. D., et al. (14). (.1VV V9F.d4O

l:pidemiological studies l'inking, smoking and CHD have been car- riecl outl in; various countries.~ In, a. retrospective studyy in Dublin, of 400 patients under the age of'~ 65 who experienced' myocardial infarc- ti~ori,~ 1'Tulcahy,, et~ al. (l8)' observedl a~ definite.~ association~ between smoking and the dievelopment; of the disease:. .L proshective epidemiologicall study of risk factors of CHD, in an. Israeli population,,indi~cat~es that sm:oking~isassociated~ wit~h~ a~higher~ risk of'CHD: (17). Tn a retrospective study of 503 male patients with myocardial in- Nrrtibn and 714 age-matched controls~ in 1'Uiunich,, Schimmler; et' a1'.~ ('2)1 report that cigaret'tle~ smoking~ plays~ a significant role~ as a, riskk factor. ~ _V recent~ paper~ by~ Cederlof, et a1. (5) employs the~ twin-stud~ method on a popu~lati~on~ of~ American twins, using ai similar~~approaclli t~u~ tl)att previously employed inia Swedish~ twin population. The~ pur~-~ pose is~ tlo~ compare~t:he,cont~ri~bution of~ genet~i~~c~ and environmental~ in-~ fl'unnces~ to ~tlie development of angina~ pectoris~. The authors imply~ thatt tlheir studv ~ indicates-~ a more~~ i¢nportant roTe~ for genetic factors~~ thann for smoking. H!owever;~this~~study can, be~critiieiized on several~ grounds.~ The authors based their detection of angin.a pectioris on t'he results of' a self'-adn-rinistered questionnaire designed to elicit a historyy of chest pain of'presumable cardiac origin; previous studies in Swedish tiwins have shown a ~ low.~ rate~ of cl'inical' confirmation o' heart di~sease~ in~ those classified positive by questionnaire: No data are available on the health and smoking habits~~of ~58 pereent~of'the~orig~~inal group~ or~ tlte~41percent of the "eligible twin pairs'"who were nonrespondentis. The authors' definition of a present smoker includes persons who havee stopped, smoking cigarettes for up to 3 years and thus includes per~- sons~~ who~ in other studies~ have been classified as~ ex-smokers~.. This~ definition of a~, cigaretit'~e~ smoker, might'~ contribute to~~ an underestima- tion tion of~ the~ immediate~ effect of~ current cigarette smoking, since~ au: unstiated number~ of recent~ ex-smokers a~re, included in the~ same~ cate- gory as current cigarette smokers: The relkit~ionship between cigarette smoking and the development of angina pectoris has not been clarified. However,~ Aronow, et al. (7)~ lrave~ shown that smoki~ng~one cigarette: before exercising, reduces~ the energy expenditure required for patients with: classical angina pectori~s~to~ develop, chest~pa,in while exercisi~ng~on a bicy'cle~ergometer:~ ATHEROSCLEROSIS A review of' autopsy studies by Strong and Auerbach, suggesting that cigarette smoking,has a chronic effect leading,to advanced!degrees of atherogenesis, was presentedl in tlie Health Consequences of' Smok- ing, 1967 (~2'61). Further studies have recentl'ybeen~ published in this area. 25

Sackett, et al'. (21) have demonstrated a clear dose-relatiionship be- tween cigarettie smoking, and the severity of aortic atherosclerosis at autopsy. Their study of 11,019 consecutive autopsies, on patients who had been interviewed about their smoking habits prior to deathy showed asignificant increasei~n tlheseveritiy of aortieatherosclerosis with increasing use of cigarettes, measuredl both by intensity and by duration of smoking. An autopsyy study from Russia by Avtand&lov; et al. (3) dlemon strated a significantly greater degree of atherosclerosis in the coronar3.~ arteries of'smokers than in those of nonsmokers. Viel, et al. (28)' have reported on the severity of coronary athero- sclerosis at autopsy of 1,150 men and 290 women who died violent deaths in Chile, Information on smoking habits was available on 566 men. The authors report no relationship between atherosclerotic le- sions and the use of tobacco. The degree of atherosclerosis was ex- pressed as the percentage of the surf'ace of the intima of the left anterior descending coronary artery covered by fatty streaks andl fibrous plaques: An exnmination of the data presented in graphic form~ indicates that't~hemod'erate and'i lYeavysmokersappearto show consistently higherpercentages:of diseased areastlhanthe nonsmokers. But the statement of the authors implies that these differences were not statistically significant when subjected to an analysis of' variance: A study by Astrup was`revie.r.ed in the 196'8' Report (27)~. This sttidy showed that in rabbits on a high cholesterol diet, chronic carbonw monoxide exposure lias a marked atherogenic effect. Kjeldsen, et al. (1b) compared thevascular pathology in rabbits fedl a high cholesterol diet and maintained in ani hypoxic atmosphere (10 percent oxyb n), with that in rabbits exposed only to the high, cholesterol diet, The authors demonstrated that hypoxia leads to an increase in the degree of plaque formation in the coronary arteries and' in the amount'of visibleaartic atheromatosis, as well as toan increase in the aortic content of' cholesterol andl trigl,'ycerides. In addition, the hearts of the hypoxic animals showed marked perivascular xantho- inatasis, often infiltrating the surrounding myocard&um. In sum- marizing this experiment and their previous findings ofl increased' atheromatosis in hypercholesterolemic rabbits subjected to high carboxyhemoglobin (COHb) levels, the authors (i2) state that tissue hypoxia seems to be an important factor in initiating these lesions, regardless of the manner in which the hypoxia is produced. Although tlh~e! COHb levelsiln th~e, rabbits and the degree of hypoxia were much hi-dier thali that experienced byhuman; smokers, tlh~eseresults suggest a mechanism by which smoking might contribute to atherosclerosis. Hass, et al. (12), extending studies reviewed in the 1968' Report (27), have demonstrated that the administration of'injections of nico- 26

e'- at h, ,is ,y a- . :T it i 6' e- k- ft id icc tine to hypercholesterolemic rabbits who are also giveni vitamin D enhances the peripheral atheromatous calcific arteriall disease which is produced by the combination of hypereholesterolemia and vitamin Radministration. The addition of nicotineto the regimen alsoxesulted in the frequent occurrence of'thromboarteritisi in the distal calcified arteries of' cardiac and skeletal musclle, and of'the smooth muscle of the gastrointestinal tract. The nicotine effect was reproduced by sub- stitluting, appropriate dosages of' adrenalin for nicotine and abolished by adrenalectomy. Lellouch, et al. (16)1 have reported that the administration of a mono-amine oxidase (NTAOi) inhibitor to rabbits on a regimen of daily nicotine injections significantly reducedi the number of animals who developed fibrotic lesions of the aorta inresponse to nicotine. Further work is in progress to elucidate the mechanism of the MAO effect'.. Evidence presentedi in this and previous reports suggests that ciga- rettie smoking promotes atherosclerosis. Tt3ROMBUS FORIISATTON AND BLOOD FI.oN' Hess, et al. (13) discovered aggregations of platelets, erytlirocyties,, fibrin,, detached epithelial cells, and some as yet unidentified' cells on theaort.ic and carotid walls of rabbits subjected toeiganettesmoke: The discovery of .a plasma~ factor which increases the in vitro syn- thesis of' fibrinogen by human liver biopsies has been reported by Pilgeram, et al. (20)1 in older patients -who have recovered from myo- cardial infarctionL Thi'sfact'or has been tentatively identified as free fatty acid (FFA). The authorsstatletlhat the association between FFA and' fibrinogen synthesis may provide the link between hyper- lipemia and elotlt,ing.Oigarettesrnokingcause& an inereasein FFA through its stimulation of catecholamine release.. Several recent studies have begun to elucidate the role which ehangesini blood vise-osityand certain features of the microcirculation might play in the development of atherosclerosis and coronary heart disease. Dintlenfass (7) has suggested that myocardial infarction andl coro- nary thrombosis may be the result of ai number of factors, separate, or interrelated, all' leading to a high viscosity of' the blood: These factors may affect the migrationi and adhesion of platelets, the voliimel of plasma,, and the rigidity of the red blood celL Phenomena leading to high bloodi viscosity m ayoccur in focal areas 'leading to occlusion of small' vessels, resultant ischemia,, and an inf'ractiionofeit!liersubclini~cal or catastrophic proportions, depending on the location and number of v.essels involved. Dintenfass a1s0 believes that an increase in blood 27

viscosity precedes the clinical manifestations of the high blood vis- cosity syndrorne, and that the increased blood viscosity seen in post myoeardial infarct patients is a reflection of'the etioliogy rather than the effect:of the disease. Lf ocal hypoxia leading,to an increase in the rigidity ofthe blbod celll might be produced by cigarette smoking through the increase in COHb. Platelet a:dhesiveness~~ is~ increasedl by~ smoking, probabl'y~ sec- ondiiry to the release of'catecholamines (0T)1., In a study of 50 white males with rnyocardiaT infarcts and 40 con- trols, S~tables,, et a1. (23~)~~ found that t'he~ patients~ with~ myocardfi'a11 infarct had a mean hematocrit level significantly higher than that of the controlsi Studies ofl blood v.olume indicated that a reduction in plasma volume rather than an increase in redl cell mass among the myocardial infarct patients accounted for the elevated hematocrit.. CARBON MONOXIDE Several revievs of the pathophysiology of exposure to carbon mon- oxide (CO) have appearedi recently. These are pertinent to the discus, sion of'the relationship of smoking to health, since cigarette smoke contains amounts of CO1 sufficient to cause a COHrb: level of 5' to 10 percent in the smoker, depending on the amount smoked and degree of inhalation (9„10). . BBartlett (4) has pointed out that becausethe absorption of CO1 from the ambient environment is dependent upon the concentration of' CO in t'heenvironment as contrasted to that in theblood, smokers, wi'thaCOHb~levellof6 percent will not absorb C'Ofrominspired airunless, the concent'ratiion of CO in the air exceeds 30 parts per million. I-Iow- ever, he also states that because the excretion of CO'1 between cigarettes will be~~ lower in CO~~ polluted air;~ the~ smoker will have a ~ higher~ long- term, average CO~pI4 level in a polluted environment. Patient& with heart disease may be particularly susceptible to the hypoxic burden caused by the presence of COH'b. Goldsmith, etal. (10)~ havestatedl that for the U.S. urban popula- tiion, cigarette smoking is probably the most important cause of increased! COHb above the end'ogenous level producedl by herne catabo~ lism, followedbyautomobileexhaust',occupat'ional sources, and home heatiingand cooking, devices, in that order. Although Dinman (6) minimizes the importance of the effect of' C.O levels of 5 to 10 percent on the myocardfi'um; he states that al short- coming in, his approach is that f'ocal areas of myocardial ischemia are noti reflected in the determination ofl oxygen saturatilon~ mad'e~~ from, samples~of~ blood taken from t'~he~~cor,onary~sinus., Such~ areas~~of ischemia might be~ important in, initiating~ fatal~ arrhythmias: Levels~ of COHb 28

vis- post than I II celli :e inl sec- con.- °dial Aof n in • the non- cus- loke ) 10 ;z~ee rom Co 1h a less UvG'- ttes ng- -ith ieni .la- of bo- nne Cd l )rt- are: om nia Rb which decrease further the oxygen supply to the iscliemic myocardium might be read7ly provided by cigarette, smoking. Eliot, et al'I.., (8) halve~ reported effects~ of cigarette smoki'ng~ on: the: oxygen a ~ffinity of hemaglobin independ'ent of the presence of' CO.. Their resulits~ suggest that~ cigarette smoking may have~ both~ acute~~ andl chronic effects on oxygen aftinit'y which differ in direction. The authors caution, however" that~the in~ viv0~ oxygen affinity of~ hemoglobin may be different from that~ implied by the~ static! equ°ilibriizm dat'laL Further~ researcli.is in progress. CITED REFERENCES (1) AROVOW,, W. S., KAPLAN, bT.,A., JACOB, D. Tobacco: A precipitating factor in angina pectoris. Annals of Internal Medicine 69(3)) : 529-:536', Sep- tember 1968. (2): AsTRUP;, P'., KJELDSEN, K., WANSTRUP, J. Enhancing influence of' carbon monoxide on the develbpmenti of' atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis R'esearch 7l: 343-354, 1967. (3) AvTANDH.ov; GL G., KoLE:rovA, V. I., ParroMARE:vxo, O. V. KureniFe tabaka i s'tepen''aterosklerotscheskogo porazheniya koronarnykh arteriy serdtsal ii aorty. (Tobacco smoking and the degree of atherosclerotic lesions of' coronary arteries of the heart and aorta.) Kardiologiya 5(T),:'30-34; January-February 1965. i:4) BARTLETT, D., Jr. Pathophysiolagy, of exposure to low concentrations: of carbon monoside: Archives of' Environmental Health 16 (Z) : 713:-727, May 1968. (:; ) CEDERLOF, R., FBtBERG;,L., HRUBEC, Z. Cardiovascular, and respiratory spmp, toms in relation to tobacco smoking. A s'tudy on American, twins. Archives of Environmental Health 18(6) : 934-940; June 1969. (6) DYNsfAN,, BL D. Pathophysiologic determinants of community air qualit'y standards for carbon monoxide. Journab of Occupational Medicine 10('9) : 448!-463; September 1968.. (7) DixTEVFnss, L. Bloodi rheology in; pathogenesis of the coronary heart diseases. American Hea,rtl Journal 77(1) : 139+-147, January 1969. (8) ELtoT; R:. S., STREIFF, R., SA'LHAxY, J. i1il, MtZUxAMi,, H. Personal Com- munica'tion': April 1969. (9) GOLDSMITH, J. R. Carbon monoxide. Science 157: 842-844, August 18; 1967. (10) GoLDaMiTH, J. R:, LAxDAw, S: A. Carbon monoxide and human health. Science 162(3860) : 1352=1359, December 20, 1968. (111)l HAMMOND, EI,C., GARFINKLE, L. Coronary heart disease,, stroke, and aortic aneurssm, Factors in the etiology. Archives of EhvironmentaI Health 19(2) : 1I67-182, August 1969. (112)l HASS, G:,. HENSO1V', D., LANDERH'.oLM, W.,, HEMME.Ns;: A. Preventionn ofnico- tinel induction of at'herocalcific thromboarteritis in rabbits., Circulation, 38 (4, Supplement, 6) : 8, October 1968: (13) HESS, HL, RaosT, H. Raucheni und arterielle VerschlUsskrankheiten. Fortschritte der bl`ediizinl .861(19) :', 84Y! 843, October 10, 1968. (14) JENKINS, C. D:, ROSENMAN, R. H., ZxzANsxr, S. J., Cigarette smoking; Its! rela'tionsbipl to coronary heart disease andl related risk faetors in, the. Western CollaboratiFeGroupStiudy. Circulation 38(6'):1140-11615i, December 1968. 29 _V r

(15) KJELnsES, $:,, WANSTRUP, J., AsTRUP, P. Enhancing Influence of art'eriail hyposial on the development of atheromatosis in cholesterol-fed rabbits. JGurnal of Atherosclerosis Research, 8(5) : 835-845, 1968: (1's)LELLOUCII, J.,JA~CIYroT, B~, ANGUERA,, G.,. GttGSGOGEAT,, J., BEAUMONT, JL-L., Action chronique de la nicotine sur 1'intima aortique du' lapin. Influence d'un inhibiteur de la, mono-amine oxydase (I.M.A.O.) Journal of Athero- sclerosis Research 8(1) : 137-142', January/February 1968. (17) MEDALIE,. J.H.. KAHN, HL, A'.,, GRQENy, J. J. NEUFIILD,. HL N.,, RISS, E;. The prevalence of ischemic heart disease in relation~ to selected variables. Israel Journal of Medicall Sciences 4(4) : 789-800„ July-Augustl 1968. (18) lIuLCAHY,, R:, HICKEY, N., MAURER, B. Coronary heart disease, ai study of risk factors in 400 patients! under 60 years. Geriatrics' 24(1)::,1C)6-114, January 1969: (19). PAFFENBARGER, R..S., J!r.,.WI:'PG,,A., L..CharaCteri$ticsiI1 college.youth!pre-drsposing to fatal coronary heart d'isease~ in later life: (In press:), America n i Journal of' Epidemiology: 1969: (20) PtLGERASr4 L. O'., PICgART, L. R. Control of' fibrinogen biosynthesis:, The role of! free f'at'ty acidl Journal of Atherosclerosis Research 8: 1:r r166; 1968. (21) SACxrTT, D L., GIBSaN, R'. W'., BxosS,, IL D. J.,, PicsREN, J. W. R'elation between aortic atherosclerosis -and the use of cigarettes and': alcohol. An autopsy study. New Ehglandl Journal of Medicine 279(26) : 1413-1420,. December 26, 1968. (22) ScIIr)IMLER; W., NeFF, C;, SCHIMERT, G. Risikofaktoren~ und Herzinfarkt. Eine retrospektive St'udies,, Munchener Medizinisehe Wochenschrift 1110 (27) :~ 1585-1594, Ju'ly 5; 1968. ('23), Sz~ABLES,,D.P., RUBENsTmN, A. H:,'_11E:rz,,J:, LEViN, N: W'. Thepossibie~rolee of hemoconcentration in: the etiology of myocardial'.infarction.,Ameriean Heart Journal'73(2') :155-159, February1967: (24) STAULER;, J: Personal Communication. 1969. (25): TEIORNE, M. C., W'ING; A. L., PAFFENBARGER, R. S., Jr. Chronic disease inn former college studtrnts. VII. Early precursors of nonfatall coronary heart disease. American Journal of Epidemiologg 87,(3) : 520-529; May 1968. (26) U.:S. PuBLIC HEALTH, SERVICE. The Health Consequences of'Smokiing. A Pub- lic,Health, Service iteview : 19674 W'ashington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1967. 199 pp. (27) U.S. PURLic Ho;ALTH SeRVICE. The Health Consequences of Smoking; 196& Supplement to the 1967 Public Health Service Review. Washington, U.S. Department of'. Health, Education, and Welfare,, Public Healthi Service Publication No,1696,1968. 117 pp.. (28) VIEL, B'., Do-,aso, S., SaLCEno, D. Coronary atherosclerosis in persons dying violently. Archives of Int'ernal Medicine 122'(2)1:97-103, August 1968.. ( 23 ). WEINBLATT, . E.,. FRAN K„ C. W., SHAPIRO, . S.,. SAGEB; ,R. . `'. _Pr~ogllOStic . factors in anginal pectoris-a prospective studS. Journal of Chronic Diseases. 21(4)1:231-245, July 1968: (80 ) W.izIVaLATr;, K, Sn:ArIRO, S., FRANK, C. W., SAGER, R: V. Prognosis of inen after fi'rst myocard'ial inf'arctlion : Mortality and first recurrence in rela- tion, to selected parameters. American Journal of Public Health and the Nation's Health 58(8)1: 1329-1347; August 1968. 30. i I I I

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552. SrAMLEB, J., BEaxsoN, D: M., LINnBExa, H. A., SoYVaENC; R., MzI:LES, W. A.. Risk of mortality : Low risk and very high risk strata of middle agedl male population-9 year mortmlityy experience in the Peoples Gas Co. Study. Circulation 38 (4, Supplement 6) : 188; October 1968. 553:, STAMLER, J., MoaoxNIEx; L.,.HALL, Y:,,B'ERxsovy,D~ Ni.,LINnBEEa,.H.,.Co.IIEN,. D'. B.,, EPsTEIN, M., riSrnl,ES, W: A., SoxucEN-C, R:, BAax„ G. Prevention of atheroaclerotic coronary heart disease. Medicine Today 2(8, 9, 10) :, Au- gust, September,,Ortober 1968. 40 pp. S54., TURPEIIV'EN,, 0:,, MIETTINEN,.. Itl.,, KARVONEN,, MI J.,, ROI:VE;, P.,. PEH:KABINEN,. 1ti2.,, LEHTasuo; E. J., ALIVIexA, P: Dietary prevention, of coronary heart disease :~ Long:-terml eaperimentL I. Observations on, male subjects. Ameri- can Journal of Clinical Nutrition 21(4) : 255-276; Apri1196$. SaS. VExEss,, L. Blutbiltlunt'ersuchungen beil nikotinvergifteten Ratten. Deutsche Zeitschrift fiir Gerichtliche '.NSedizin 56(2) 1: 62-6;51,1965: S56. VINTxB, I. B., MANTILLA, G. D'., BESaET, C. V'., OLLETA, S. M., SXnA„R, C.,, Ronxfcunz, R. O:, BELTTtAN, J. S! Algunos aspeetos de las dislipemias en lai cardiopatia coronaria. Medicine CPinica 51(1) : 26-30; Juiy 1968. S57. VooEL, J. H. K., JACOSOwrrz„ D., CaiosEY, C. A. Distribution of! nor- eqinephrine in the failing, bovine heart. Correlation of chemical analysis and fluorescence microscopy. Circulation Research 24l(1) :, 71-84„JanuarS 19ft S58. ZLSS.IA:v, B. M. Atopic symptoms caused by tobacco hypersensitivity. South- ern~ 3ledicall Journal 61(11) : 1i17:r1179, :ti ovember 1968. 34,

tsohe t'. C., Ls en nor- lysis uary CHAPTER 2 Smoking, and! Chronic Obstructive Bronchopulmonary Disease ,,,th_ I/ Contents Page Summary---------------------------------------------- 37 Chronic Bronchitis -------------------------------------- 37' Prevalence of Chronic Obstructiive Bronchopulknonary Disease_ 38 F'ulmonary Emphysema ---------------------------------- 38 Experimental Studies in Man__-__________________________ 39 Studies in Animals'-------------------------------------- 40. Other Studie& ------------------------------------------- 42' Cited References ---------------------------------------- 43' Chronic Obstructive BronehoPulmonaryDisease Supplemental Bibliobraphy----------------------------------------- 46' 35 a

a -.. .<r42&-_..,- r

SMOKING AND! CHRONIC OBSTRUCTiIVE' BROIVCHOPULIWIONARY DISEASE SIInca1ARY Additional evidence which supports .the previous judgment of a cause and effect relationship between cigarette smoking and chronic obstructive bronchopulmonary diseases, especially chronic obstructive l,ronchitis,, continues to accumulate f'rom both the United' States and abroadL New work has been published in the past year which provides additional information on the possible mechanisms by `vhichi cigarette smoking can lead to the production of pultn.onaryemphysema~ Thesemechani'sms include collapse of sma11 airways, changes in pulmonary surfactant, impairment of' pulmonary clearance, disruption of' the normal architecture oft1lebronchial epithelium, and obstruction off capillaries of the bronchi and alveoliL At present, there is no unified hjIpothesisfor,tlie~ patihogenesis of pulmonary emphysenYa;, however,, the pathogenetic mechanisms may involve more thani one component of liing t'issue. Epidemiolog)call and laboratory evid+encesupports the view thatci~gar~ettie smoking can~ contlri~but'etothedbvelopment of pulmonaryemphysema, in m~am CIIRONIO BRON-CHITIs Cigarette smoking is t'he xnost important cause of chronic bronchitis. In the past year, studies from various countries have appeared ini the literature reconfirming this association. In studies of populations of 1•;orking men in Italy (15), the Netherlands (6), England (16,35) ', an& tlie United States (9)1, smokers were found to have a significant iii- crease in either incidence or prevalence of chronic bronchitis as com, hared to the nonsmokers. Studies of'populations f'rom rural and urban S«'eden (31)~ an& ruralAustiralia (295)1 produced siinilarfindings.A South African study(I'5)demonstr.ated decreased forced expiratory %'olumes (FEV,,) andl peak expirat~ory flow rates (PEFR) with in- creased tobacco consumption, even in those who did not have chronic bronchitis. 37

PRI'EVA,LANiCE~ OF' CHRONIC OBS'TRUCTIVE BRObFCHOPIIL3iONARY' DISEASE The prevalence of' chronic obstruct'ive bronchopulmonary disease is probably underestimated. In a study of death certificates, Mbriyama, et al. (39)~ have reported: that chronic obstructive bronchopulrnonary disease is often omitted as~ a contributing cause of d'eath. Mitchell, et al'. (38) also found that the disease often goes unreported. Barach,, et al. (5) maintain that much of the reported increase in the preva, lence of chronic obstructive bronchopulmonary disease can be ac- counted for by better diagnosis. However, Barachy et al. base their statement on the supposition that the rising, death rates from chronic obstructive~bronehopulmonary disease are inc.ompatible with t.he fact that many people are giving up smoking. Hosvever;, it should be pointed out that chronic obstructive: bronchopulmonary disease asso, ciated with cigarette smoking may be the result of' many years of ex- posure to cigarette smoke and the mortality rates from bronehitis and emphysema would not reflect large-scale smoking cessation for some time to~come. Burrows (10): has pointed out that the effects of cessa- tion of smoking on the course of already existing chronic obstructive bronchopulrn:onary disease may be difficult to assess, since it may bee that those who are disabled by sev.ere~ disease tend to stop smoking, more often than those who have mild'er forms.of the disease. The bene- fciall effects of cessation of smoking'coul'd thus be maskedl PtTr,aoti ARY EMPHYSEMA M any agents appear tocontribute to the development of emphysema, but epidemiological and experimental evidence indicates that cigarette: smoking is the most important agent in the development of pulmonary emphysema in man. Mention of the theories of pathogenesis of pul- monary emphysema,, long the subject of debate among medical scien- tists (l, 34, 46, 17, 48), may help to serve as background for the presentation of recent research on the role of cigarette smoking in the development of emphysema. Two major theories of the pathogenesis of chronic obstructiv,epul'-monaryemphysema have been proposed.Onetheorystat'esthat the primary: lesion of' emphysema is vascular and involves obstruction either by thrombosis or by endarteritis of the pulmonary or bronchial arterial branches: The resultant loss of nutrient supply is thought to~result in ischemic necrosis of the alveolRr wall and septa. The other major theory statlesthat chronic obstructive pulmonary emphysema, results from the direct effect of toxic!i'nhaliintson thepulmonaryti'ssue, in the areas of the terminal broncliiioles and alveoli. According to this theory, changes seen in the pulmonary and bronchial vessels are 38

3e. is ma, tary hell,, ach, eva- ac- heir onic fact l be Lsso- ` exand. ome ;ssa- ;tive y be iing ene- :ma;, -ette iany. Pul- ien- tliee the pul~ the tion 1Iia11 ight ther ema. ~.Sue, this are secondary to the destruction of nonvascular tissue. It may well be that the, pathogenesis of pulmonary emphysema can involve several mecha- nismsand that both of these theories may be applicable but not mutu- aldyexclusive (44). EXPERIMENTAL STLIDIES' IN MAN Anderson, et al. (2) have reported preliminary results which indi- cate that cigarettle smoking, causes acute changes in the ventilation/ lmrfitsibn rel'ationshi~ps: of the~~ lung and that~ patients~ with chronic olhstructive~ bronchopulmonary~~ disease~appear~to~be~~ parti~cularly~ liablc~ to these changes. In some patients the changes are predominantly in perfiision, ai finding which lends support to the vascular theory of' ll,iliilonarv emphysema. In other patients, the changes are predorni- n:intly in ventilation, a finding which lends support to the theory of'f the~ dire~ctt effect of~ inhalantls~ in the pathogenesis~~ of~ pulmonary~ c~nilphysema., Anthonisen,,et al. (3)~ investigated pulmonary function in 10~ male~ ~-ndOkers with clinical0;y mild chronic: bronchitis,, all of whom hadl s~i'o«hedi cigarettes for at least 20~ years: Besiides,the~~usual~ pulmonary~ ! ionctiion tests, these investigators emplbyed a technique for the assess- iiwnt of regional pulmonary function:using~radiioactive xenon.~D'espite~ r,lie fact th,nt oti•-eralI_pulinonary~~ function .vasmearly~normal in several p,iti~ent~s,~ all had dlecreased ventilation and depressed; ventiilation/per- fn~ion ratios in some lung, regions, with: the basal' areas being those most commonly~ affected:~ The~ author suggested that significant dis- easfl~ in the peripheral airw~~ays~ may exist~ in patients~~ whose chronic I,ronch~itis is~ clini~cally~ mild and who~ show no~ present impairment'~ofl 1,oistilatory capacity. The radibactive xenon test may reveal severe (1<»npromise of~ the~ overall gas~ exchange~ w~hen~ usual studies of~ ventila- tet'y~ capacity~ do~ not reveal impairment. These changes~ in the~ d~istal airways may become more: signi$a'cant clinically as the patient ages, tiince~ aging h~as~ been showiv to be~ associated with a diminution in the 41ompliance of the~~ l'ung~ (29~~)~. Peters, et al'~.~(4Q) have~reported that the~ lowerr flow ~ rates found among colllege~ st'udent.s~ who smoke, especially A lower lung volumes, mayy reflect disease in the small airways. The diminution in fl'ow~ i~~n these~ swbjects~ was approximately proportionate~ to the total lifetlime number of cigarettes smoked.. Fullnser, et al. (2029, ~~w3, °.1~'~)~ have found a high prevalenee,of C'ursch= niann's type spirals i'n~ the~~ sputumi of cigarette~~ smokers.~ The easi~ly~ reoo,--nized spirals consist of inspissatedl mucus and are casts of the liimens~ of small bronchiiol~es: Tlsese~ spi~rals~~ were foundl in the~ sputum of ?3' of' 24 ~ ci~garette-smoking~ women and in 97~ of 100~~ cigarette~- smolcing men. The total number of spi~rals on four slides prepared for 360-928' 0-69-4 39

microscopic examination varied from 0~ to 500. Six of 10 ex-smokers had' spirals in their sputum, but the number of'spia"als was red'ucedl to a totall of 10 or less on f'our slides. A nonsmoking control group ex- posed to ~ cigarette smoke at work showe& alowpreval'ence of'spirals, while a control group of'' nonsmokers not exposed to cigarette smoke at work showed no spirals in their sputum. Fullmer has suggested that Curschmann's spirals may play ai role in the developrnent of em physema by producing obstruction at the bronehiolar level. The spirals rnaya1soaIl'ow prolonged contact between admixed inhalantls, includ- ing cigarette smoke and the bronchiolar walls. A study ofl the presence of spirals. in the sputum of a group of nonsmoking asthmatic bron c.hitics would be usefullin an attempt to determine whether the presence of'spirals is a direct result ofl exposure to cigarette smoke, or is a charac- teristic of the sputum of' bronchitics, whatever the cause of their bronchitis. STUDIES IN ANIMAIS y p cketts„ et a1L (',1I')~ R~ic ketts„ in sheep by occlusio in the distri ferences 40 Frasca„et a1'.('1~'~,18) have reported on electron microscopic observa- tions of the bronchial epithelium of' dogs exposed' to cigarette smoke by active inhalation through a tracheostorna., The epithelium of a dog exposed to44' daysof' smoking bymethod'spreviouslydeseribedi by: C~~han,et al. (11~)~~ showed a,proliferation of'goblet cellsanda~~ partial 1'oss of'cilia in the surface lining cells. After 420 days of exposure to cigarette! smoke,thenum~ber of cell l~;yersin the epitheliumwas found to be twice that of the nonsmoking dogs.G~obletceTls and ciliated columnar ce115 were no longer present; instead~ the surface was lined with columnar and cu~~~boida~ll cells with stu'bbyprojections in placeofciTia.l'Zitoticfigu~reswere~frequentlyobserv~ed~ inithebasal cells. Thesefind'angs mayberelev~~nt to: carcinogenesi'saswell as, to thedev~elop-ment of chronic obstructive bronchopulmonary disease.. Tyler (;tk9)1 and ~1~TcLaughlin, et a1L (,~')havestudied the physiology and morphology of' pulmonary emphysema in the horse. The lung of' the horse has been reported to be similar in subgross anatomy to that of'man (36). They have studied, both the spontaneous disease; one of the several causes of the syndrome known as "heaves," and~ a similar but not i~d~enticali pulmonary diseasei~nduced 'ry the : inaection, of' chl'or- promaaineorofstyrenebeads into~ thebronchiall arterial circul~,tian. . Their findings of obstructive lesions in the bronchial circulation and of' accompanying emphysematous changes i'ni the pulmonary paren- m a rovide indirect support of a~ vascular theory of emphysema. ch were unable to prodnceemphysematouslesions n of'the bronchial artery;, however, species dif- bntion of this vessel may be an important factor

mokers. uced to iup ex- spirals„ ;' smoke ed thatt of em- spiralsi includ- resence ,bron- resence ,harac- f their bserva, smoke F a dog 5ed by partial ;ure to found 5Iiated , lined `.ace of These velop- iology ing, of o that :)ne of imilar chlor- I ation. n and ,?aren- ~ sema~. esions s dif- factor. in both experimental and spontaneous disease. The bronchial artery in the horse is reported to supply the alveolar septa, whereas in the sheep it is reported to reach only as far as the terminal' bronchioles (:36). A pulmonary: disease~ similar~~ histologiaally: to pulinonary~ emphy-~ ;eina in man appears spontaneously in certain populations of rabbits (1: ). Boatman, et al. (8) have studied this disease by means of the electron microscope. Three of their findings which tend to support the theory-y that the disease is primarily vascular in origin are as follows : lhss of'capillary en~dotheliumy, partial or~ complete~filling~of~the~capiT-~ laii, lumens with collagen, and frequent recanalization of the damaged C,ipi19~aries.~ Freemany et al'. (Z9,, 2D; ~?1) have investigated the effect of' chronic exposure of rats to vary.ing concentrations of nitrogen dioxide (NOz), a--as which is found in cigarette smoke and in industrially polluted air. 'I'hese illvestiaators showed that the exposure of'rats over their lifetime of 2 to :313•,ears to concentrations of 2(-t1), parts per million of'NOz iesul~ted in~ reduction in cilia of' the bronchial epi~t'helium, a reduction ini norniall exfoli~ation,~ and~ the~ a,ppearanee~ of~ unidentipied crystalloid inclusions: Exposure for only 16 weeks to a higher concentration of 4 (-1) parts per million led to liypertrophy of the epithelium of the tcnminal bronchioles: Ratis exposed to~ concentrations varying, from 10 (-`7 )~ to1 25~~ (~-t 2')~ parts~~ per~ mild'ion o' N02 dleveloped large, heavy, 1uotied~ematous lungs~~ accompanied by~ d'orsal kyphosis: The increase: in~ we~~i--lit of'the~lt~tng~ a~as~ shown to be~caused by widespread hypertrophy~ of the~ re~spiratory~ epitlhelium,~ especiallly~ in the bronehsolles~ closely asso~~- I•i;ited Nvith a~h-eola~r~ dnct!s, and ini the~ terminal bronchioles. Hyper- trophy ~ of' t1i~e! bronchial epithelium and accumulation of~~ anrorphous~ proteinaceus mat!erialy fibrin strands, and macrophages resulted in nar- rowing of the lumens of' tlh~e~ termina11 bronch:iol~es~ at th~eir~ junct'~ions~ %%'~ithl the alveolar ducts. Focal hypertrophy of alveolar epi'thei'iumm appeared~~ to be: associated with~compression~of~~ alveolar~eapillhries. The ;ii Q'spices~ of the lung~~ were~~ increased in volume. Other investigators have also reported an increase in alveolar size, in rocd'ents exposed to NO2. Blair, et al. (7) exposed' mice to 0.5 part's 1>el' million of \ O;, for 6, 18; or 24 hours each day. The animals were 'Ap~osed to --NO~_ for periods varying from 3'~ to 12mont'1is ~; ~ the~ degree ~ cf chanbe~ in the pulmonary~ li~istol'ogy~ appeared to~~ i~ncrease~ with in*~ creased' total lpngth of exposuxe.~ Besides producing, enlarged alveoli, (':+~~Posure~ to~ N02 ~ al'so~ prodkiced e-arly~ bronchi~olar~ i'nfl~ammatiion with a concomitant~reduction in the~size~of the~ distal airways:~ 41 i

0 OTHER STl7DIE.S In a recent extensive review of the nature andi role of' pulmonary surfactant, Scarpelli (/*3) states that the lowering of surface tension produced by the action of cigarette smoke on surfactant may pre- dispose to the development ofemphysema.. Cigarette smoke contains powerful ciliostatic agents (50, 51, 52) which can interfere with pulmonary clearance. Components of both the particulat'eandtlhe, gaseous phases ~ adverselyaffect ciliary activi'ty.Dalhamn,,etal. (14) hav.e pointed out that ini assessing the; effect ofl one or another of the components of cigarette smoke oni ciiliary activit'y in various animal systems particular attention must be paid to the level of'exposure, since at different dosages the particulate and gaseous ph:aseshave different relative effectis~ on ciliaryactivi'ty: Other recent work by Dalhamn, et al. (13) has further clarified the extent to which certain components of cigarette smoke are retained iiii the human lung and includes the observation that retention ofl gaseous components depends inn part on adsorption of'the gases on particulate matter:. Ballenger;, et al. (4) have indicated that the in vitro ciliostatic effectls of oxidizedd nieotine are: enhanced' by prior infection of' the tissue explants with Influenzal B' Virus. Holma (30) has reported that cigarette smoke has acutie depressant effects on pulmonary clearance in: living rabbits.. Recently, observations have been published on the metabolism and function of tlie pulmonary alveolar macrophage which, together with mucus transport', performs the function of riddsng, the lung of both inanimate particles and bacteria. Green (27) points out the im- portance of the alveolar macrophage in pulmonary clearance of infectious agents. He has also observed a deleterious dose-response effect of' cigarette smoke. on the phagocytic activity: of the macro- phage and' suggests that this effect may be related to the development of chronic bronchopulmonary disease. In another paper, Green (26) found that the cytotoxic activity of' cigarette smoke on pulmonary macrophages may be inhibited by ghitathione and cysteine. Izard (32) observed that the gaseous phase of cigarette smoke or one of' its components,, acrolein, inhibited the ~ mu:ltipl'icatiion of cultures of Dunaliella bioculnta and also: observed that the addition of cysteine to the medium protectedi against these effects of acrolein. Heise, et al. (28)~ have reported that rabbit pulmonary alveolarr macrophages secrete lysozyme into a culture medium. Lysozyme may beactive in the clearanceof bacteria fromthelluing:. Roque, et al. (42)~ found a decrease in the activity of oxiodoreduc- tases andl hydrolases in the alveolar macrophages of smokers. They ;. 42

7, 52) f' both tivity. °ect of 3t'1vTty to the aseous recent't which Y1lung ments i and lether rg of e im- :e of'. )onse acro- ment ,y of I by 1ase I the rved :hese also found that the reduction in, these enzymes was directly propor- tional to the amount of' stored fluorescent material present in the macrophages. This material is thought to, originate in tobacco smoke. Roque, et al. suggested that the tobacco smoke may have induced abnormalities in the mitoehondria of the macrophage. Kilburn (33) theorizes that the pathogenesis of chronic obstructive. bronchopnllnonary disease is related to the failure of' macrophagess to be cleared from the alveolil andl bronchioles because of impaction of iitucus. He suggests that dissoliltion of the cells exposes the alveoli. :1nd bronchioles to damaging enzymes and to the phagocytosed par- t iWles contained in the macrophage. CITED RE,FEREn CES I'i -IDELaiAN,, J. U. A reviewand reappraisal of emphysema. Diseases of' the Chest 51(2) : 15Qr161,,February! 1867. ;'7 :1NDeFSOti, W. H., WILLIAMS, J~ B. Effect's of cigarette smoke on distribu- tion of pulmonary perfusion. In: Current Research in Chronic Respira- tory Diseases: Proceedings of the 11th Aspen Emphysemai Conference, Aspen, Colo. U:S: Department ofl Health, Education, and Welfare, Public Health Service Publication No. 1879, 1969. Pp. 7p--791 i,;!) ANrHoNISE^e, N. R., BASS, H., ORIOL, A., PLACa„ R. E. Gl, BATEs; D. V. Regional lung functioni in patients with, ehronic bronchitis: Clinical Sci- ence 35: 49a--511, December 1968:. ~ i I) BaLLEYGER;. J. . J.,.MCFASLAND~ , C:R6, HARDIIQO, H:. B:, KOLL, Rf.,, I'IASifiTEAD, D. The effect of air pollutants on pulmonary clearanee: Laryngoscope 78 (8) : 1387-1397, August 1968. 3') BAxACay A. IL., SEGAL, M. S. The increased recognition and, incidence of' chronic bronchitis and pulmonary emphysema. Annals of Allergy 26(7), : 333-357, July 1968. 1r;) BIERSTEKER, K. Bronchitisklachten bij' Ratterdhms gemeente-personeel. Nederlands Tijdschrift voor Geneeskunde 112(26) : 1208-1211,, June 29',, 1968. (3) BL.^.rR, W. H:,, HENRY, M. C., EHRLraH, R. Chronic toxicity of nitrogen dioxide. II. Effect on~ histopathology of lung tissue. Archives of Environt mentai Health 18(2) : 186-L92', February 1969., (8) BOATMAN, E; S., 1inRTIN,, H. B, Electron microscopy in pulmonary emphy- sema of rabbits. American Review of Respiratory Diseases 91(2) : 197-205, February 1965, . (9), BRivxMA:v, G. L., Btocs;, D. L~ The prognosis in chronic bronchitis. In: Current Research in Chronic Airways Obstruction, 9th Aspen Emphysema Conf'erence, Aspen, Coio. U.S. Department of Health, Education~ and Welfare, Public Health Service Publicationi No. 1717, May 1968. Pp. 317-326'., (10), BtTRaow.s; B. The course of patients with chronic obstructive lung disease. In: Current' Research in Chronic Respiratory Diseases. Proceedings of' the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1879, 1969: Pp. 253-258. i11) CAHAN, W. G., KtauAN„D: An effective system and procedure for cigarette smoking by dogs. Journal of' Surgical, Research 8(1L) : 567-575: Decem- ber 1968. 43 A.

(12) CALDWELL, E. J., FaY, D. L. Pulmonarymechanics i'n the rabbit. In:, Current Research in~ Chronic Respiratory Diseases. Proceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of'~ Healths Education„ and Welfare;, Public Health Service Publication No.. 1879, 1969: Pp:,307-320. (13): DALHAMN, T., EnFoas, 3f-L.,, RYLANDER, R. Retention of cigarette smoke components in human 1tings. Archives of Environmental Health 17(5) : 74'6'-748, November 1968. . (ii4) DALHAsix4 T., RYLANnER; R. Ciliotoxicity of cigarette smoke and its vola- : tile components. American Review of Respiratory Diseases 98(3) 509~-511, September 1968! (15) DEPoslrErs„C., MARCONE, G, Indagine statistica sulia morbilita bronchitica nelle fornaci dl laterizi e suoi rifiessi in medicina sociale. Nota II:. Bfedicina Sbciale 18(7)~: 290-293, Ju1y 1968: (16 ) FiETOHER C. M., TINKER, C. M., HILL, I. D:, SPaizER, F. E. A 5-year pro- spective field study of early obstructive airway, disease. In: Current Research in, Chronic Respiratory Diseases. Proceedings of'the 11th Aspen Emphysema Conference,, Aspen, Colo. U.S. Department of'~ Health, Edu- cation, and WeIfare,, Public, Healt'h, Service, Publication No. 1879, 1969: Pp. 249-252. (17) Ff3ASCA, J:. M.,, AUERSACCH; 0., PARKS,. V. R., JAbfIESaN,, J. D. Elec+t.ronn microscopic observations of'~ the bronchial epithelium of'dogs: 11. Smoking dogs. Experimental and Molecular Pathology 9(3) : 380-399. December 1968. (18) FRASCA, J. M., AUEReaCII,, 0., PaaKS, V. R., JAMresoN, J. D. Electronn mi'croscopirobservations of'the bronchial epi'thelium~of dogs. I. Control dogs. Experimentall and Molecular Pathology 9(3) : 363-379; December. 1968. (19): FIE.EatA.N, G., CRANE, S. C.,, STEPHENS, R. J., Fuarosr„ N. JL Environmental factors in emphgsema and a model sTstem, with NOs. Yale Journal ofl Biology andl :lfedicine 40 (5/6) : 566-575, April/June 1968. (2Q): FREEMAN, G.,, CRAN.E,, 5.L,;, STEPHENB;. R. J., FL'RI09r, NL J. Pat'hogenesisof the nitrogen dioxide-induced lesion in the rat lung: A review andd presentation of' new observations. American Review of Respiratory Dis- eases 98 (3) : ~429-443', September 19i'i8. (21) FREEMAN, G!, STEPHENS, R. JL, CRANE, S. C.,, Fuarosr, N'. J. Lesion of' the lung in rats continuously exposed to two parts per million of' nitrogen dioxide. Archives of' Environmental Health:17(2):: 181-192, August 1968. (22) FuLIMER, C. D; Microscopic observations of sputumi of chronic cigarette smokers. A preliminary reportL R'ocky Mountain Medical Journal 65(8) : 13, August 1968. (2.3.). FULL'SiER, C. D., StIORT,. J. G., ALLEN„ A., WALKER, K.. Microscopic Ubserva;- tions of sputum of chronic cigarette smokers: Incidence of bronchial and bronchiolar spirals, fibrils, casts. A preliminary report. Presentled' atl the Annual Scientific Meeting of the Utah State Medicall Association; September 12, 1968. 7 pp. (24) FuLLMER, C* ! D., SHORT, J. G:,, ALLEN, A., WALKER, K. Sputum of' chronic cigarette smokers-microscopic observations and incidence of bronchial and broncbiolar spirals, fibril§; and casts. Rocky Mountain Medical Journal 66(1) : 42-46, January 1969, (25) GA:vns.rzA, B. A productive cough, upon requestl as an index of chronic - bronchitis: The effects of'age, sex, smoking habit, and environment upon: 44 O 4.~ .~ CJ't' O M~+ Y. ~

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~Ylit'ss 1968. et of' In: ` the it of 1879, Smoking and Cancer Contents Pa¢e SummarY---------------------------------- 55 Epidemiological Studies---------------------------------- 55' Lung Cancer--------------------------------------- 55'. Ora1 C'ancer-------------------------------------- 58'. Laryngeal'Cancer----------------------------------- 58'. Cancer of the Uri:nary: Bladder and Kidlney_ _ _ _ _ _ _ _ _ _ _ _ _ 60 Cancer of the Pancreas--_----_---_--_____________-__ 60' General'.Aspects of Carcinogenicity________________________ 61 Tobacco: Alkaloids____-__-________________________-_- 61 N'ickel--------------------------------------------- 62' Experimental Aspects. of Carcinogenesiis _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 62 Retention of Smoke Constituents _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ 62 Changes in Celll Cizlt'ures Inducedl by Cigarette Smoke_ __ 62' Experimental Studies of Bronchogenic Carcinoma in Animals------------------------------------------ 63 E.Yperimental Aspects of Cancer of the Bladder and KidneY------------------------------------------ 64I Cited References ----------------------------------------- 65 Cancer Supplementall Bibliography_ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 69 53 N

t

SMOKING ANID CANCER' Suai3z~~y Previous reports (59, 60, 61) have presented the evidence that ciga- rettesmok~ing, is! . a majoreau'seof' lung, cancer and that cessation of cigarette smoking, sharply reduces the risk of dy ing from lung cancer as compared to the risk taken by those who cont.inue toi smoke. Ciga- rette smoking was also shown to be a significant factor, in the causa- tion,of cancer oftliel6urynx. A strong associa;tion, betR-een variousf'orms , of'smoking and cancers of the buccal cavity„pharynx, andi esophagus was a1soshown.Data were presented which indicated that cigarette smoking was associated with cancer of the urinary bladdler. Data were a-i so , presented which, suggested tih at cancer of t he kidney and pancreas maybe rel'ated!to: cigarette smoking. During the past year, both population studies and lh,boratory studies from various countries have added to the weight of the evidence linking smoking and cancer. A major study of histological changes in the larynx has demonstrated' the higher risk of' premalignant c.hanges among smokers:Mare: studies have been done to identify those substances in tobacco smoke which take part in carcinogenesis. New ,inimal IIlod0i; for the experimental study of respiratory cancer, whiehh may be helpful ini elucidating t~hemech<nnnsms of respiratory tract oarcinog~enesis; have been developed and refined. EPTDE3IIOLOGIL:aL STL`DIES It is interesting to, not'ethat epidemiological information on cilga-r~et'teismoking and 1ung cancer, similar tlothat .rhiich~ has been collectledd in theIlnsted Stat~es'and Western Europeancount'riesy is now beingre- ported from Eastern Europe and Afnica as well., Lung Cancer InNorwa.y; a study of histologically proven cases of lung cancer by Kreyberg demonstrated the low frequency of' lung cancer among nonsmokers. The cases were collected between 1950 and 1064 from two hospitals and a, diagnostic laboratory which service all parts of Nor- way. The author states, that the popula;tion, represented in this study is most probably: geographically representative of the whole country. In comparing his results i,n Nlorway withi t'hose in other European I, I,II 380-82&0-691-5' 55 .i

countries, Kreyberg stated that a nonsmoking, Norwegian populationn today shouldl present lung cancer cases in the same number, with the same sex ratio, and with the same representation of histological types as prevailed in l'1Torway 40 years ago, and in Europe in general at the beginning ofl this century (24, 25). The risks of developing various histological types of lung cancers among smokers„ as contrasted to nonsmokers, are presented in table 1. Two facts are strikingly apparent from the table. First, the preponderance of the higher risk of lung, cancer in smokers lies in the categories of epidermoid carcinomai and anaplastic small cell carcinoma. Second, while female smokers have a higher risk ofl developing lung cancer than female nonsmokers, the relative risks are smaller than those for males. At least part of this difference may be accounted for by differences in smoking habits be- tween men and women. Women tend to smoke fewer cigarettes, to smoke brands lower in tar and nicotine, inhale less and smoke less of each cigarette thani do men;, therefore, women have lower exposure to cigarette smoke. TABLE I.-T'umor prevalence amor;g males ¢nd' fem¢les 35-69 years a age, by type of' tumor and snzokzng, category [Smokers aonstitnted' 85 percent ot populations studied] i, Sex anditype of tumor Smoking category Expected Risk number ratio Total 8moking, Non- among among all methods smokers smokeraL smokers. Males: Epidermoid carcinoma-__------ 434 431 3~ 17.0 ' 25A ~. Smalll cell anaplastic carcinoma-- 117 116 1 5.7 20.4 ~ Adenocarcinoma--_ -- _ ---- -- Bronchiolb-alveolar carcinoma_-- Carcinoid--------------------- 88 46 83 39 5 7 28-3 39.7 2-9 S 1.0 Bronchial gland tumor_-_----_-. Tbta1---------------------- 685 669 16' 90: 7 7.4 . Females: Epidermoid carcinoma--------- 12 91 3' .75 ' 110 Small cell anaplastic earcinoma__ 8 51 3 .75 6.6 ' Adenocareinoma--------------- 56 14 42' 10.5 1.3' Bronahiol'o•alweolarcarcinoma-_- ____ ---- -_-- ----__ - Carcinoid---,-------------,---,-- 32 7' 25 6.3 L 1 Bronchial gland tumor--------- ---- ---- ---- ------ ---- i Number that' would be ezpected' it ineidence rate among smokers', was eqpal to thatiof nonsmokers',. Sooace: greyberg;,L. (t4).. 56

ati t rio ,d no luu~ and~, Pe a; thi~s ml of e. I 0 2. 0 '6. 6 ![. 3' L1 a. 9 Brett, et al. (8)': found that the mortality rate for llung cancer in smokers in T'+.~tigland was especially high for the smokers who, "tlroopedP'Ahe cigarettes off the lip while they smoked~ a habit whichh runs•,result~ in t'hedeTiveryof' al greater dose of smoke fromi eachh cigarette. Gelfand,et'al. (19)inai st'ud'yof'lungcancerinfthodesianAfi-icansT reported a preponderance of smokers among the lung cancer patients ah compared to a controll group. The authors express the opinion that r1>o112ition does, not play a role in respiratory cancer in R'hodesia.. In the 1967 Hleallthi Consequences Report (59), it was pointed out tliat t1ie.lung cancer risk of ex-smokers declined, relative to those who 4•omtinued to smoke. I[t equalled that of' nonsmokers about 10' years after stloppimg, smoking„amdltilierateofdec.linedepended on the num- l)cr of cigarettes previously smoked' and the duratiom of' smoking.. ll;rossi et al. (10)reportled that the risk of' developing lhmg cancer, is lotiver among filter cigarette smokers tlhan nonfil'ter cigarette srnokers.. Since filter cigarettes are generally lower in tar content than nonfilter ei.(Taretltes, this study supports t.he inference that the tar cantent of ci,vQ•etltes is ai meaningful measure of egposure to risk. In view oft'he fact thatpra~cticaldy all lung cancer patients started to smoke nonfilter cigarettes and have smoked filter cigarettes only inn recent years and for a variable length of'time, a more exact comparison of'therisksrun by smokers of f-t'lterand nonfilter cigarettesrnustawait fiurtherstudi~es (67).The rela.tionship of smoking to lung cancer in women is an area of contiiniingconcern,,since wernayexpect a continued increase of lung cancer in women with the increase in cigarette smoking among them since World War II. Lombard" et a11(32)show~ a relationship of cig<u•ette smoking to epidermoid lung cancer in women but not to arienocarcinoma.. It is generally agreed that the contribution of eiga rette smoking to the development of epidermoi,d and oat-cell lung cancer (Kreyberg, Gioup I) in males is significantly greater than to the development of Rdenocarcinoma (Kreyberg G'roup 1fI)i. An association of other diseases to cancer of the lung is~ found in a report by Salker, et aL, (48). Salzer and his colleagues have reportedd in ani autopsystudythat'lungcancer amd': scars, from st'om~achulcersame stiatistically associated andl suggested that cigarette smoking may haRxecontributed tloboth conditions. A study byStaml'er, et al. (bv)indicatedl that male cigarette smokers with elevated cholesterol levels had higher rates of lung cancer than those with lower cliolesterolJ levels. Additional studies are needed to confirm and elucidate these observat ions.. Erograms have beeni recently established to~ perform cytologicall examinations on the sputum of smokers, since they representt a population at a high risk for the development of carcinoma of 57

the lung. These programs have detected individuals with atypical or frankly malignant cells in their sputum before a shadow has appeared in, the lung fields of' x-ray (18, 62). Valaitis, et all (62), reported that some degree of cytological abnormality was found in the sputum of percentage. Auerbach, et al. (1) studied the histology of the larynx of 942 men, agedl 21 to 95, who were: autopsied at a single hospitall between 1964 and 1967. Casesof' primary cancer, of the ; larynx were excluded from~ the study. Smoking, histories for all cases were obtained from family members of the dleceased by trained interviewers. The numerous ran- domized histological sections were gradedl by one observer. Table 2' shows the percentage of cells with atypical nuclei found in the truee vocal cord. Of'the men who never smoked, 75' percent had'' no cells withh atypical nuclei; only 4.5 percent had sections with~ areas containing, 60 to 69 percent of' cells with atypical' nucl'ei, and none had a higher hygi:ene. LaryngeaZ Cancer muc,osay hard palate, and lip, to 94 percentt or more for cancers of the floor of the mouth, soft palate, tonsil, or oropharyng. Unfortunately, comparable percentages of smokers in: a~ control population are not presented!hTo newstudieshaveappearedw whichi clarify the relative contributions of other env ironmentali risk factors for oral cancer, such as alcohol consumption, nutritional problems, and poor orall 83 percent for cancers of' the gingival and alveolar mucosa, buccal epithelium more susceptiblls to the : carcinogenic substances ini tobacco. In a study of' oral malignancies indexed in alarge tumor registry in California, Chierici;, et al. (13) found that 88' percent of the cancerr patients were smokers. The proportion of' smokers ranged' from 81 to (3b') may be associated with tobacco use and may result in an oral to oral and oropharyngeal cancer in a district in India. Pindborg also presents evidence from India indicating that oral submucous fibrosis study by Wahi (641:) reports on~ the relationship of' tobacco chewing which previously was considered the obviously associated habit. A associated' with these conditions than is the chewing of betel nutt and New G'tiineans. They report that smoking may be more closely and histology of oral leukoplakia and leukoedlsma among Papuans the world include one by Pindborg, et al. (39) on the epidemioiogy the use of "nas" (a mixture of tobacco and ashes) andlthe developm,ent. of 'cancer~of the oral cavilty: (37)!. Other~studiiesof 'interest~from around cigarette smoking and lung, cancer, as well as an association~ between In the Soviet Uinion, Orlovskiy has shown an association between 4.8' percent of the smokers and 0.9 percent of the nonsmokers.Oral Cancer 58

TABr E 2.-Number and percent distributinn by' relative frequency of atypical nuclei am'ong true vocal cord cells, of men cl'assifted'by smoking category. [10p per cent atypical' cells'defined' as carcinoma]' I4weeil I f jween lIlt ~ound. !r~logy. auans losel~ 4 nut , iIt.„ 11 xving i also 'TOSls I orali ~lccC1 ' Tn _~ ~ncer' : ~ cealI a the ' ely,, ' not itive t'cer,, oral <. sen, .964 rom nily 'an- le 2 ;rue rath ang' her t P Never smoked regularly Ea•cigarette smokers Cigar/pipe smokers, Current'cigarette,smokers ercen atypical nuclei N um- ber, Per- cent Num- ber Per- cent Num, ber Per- cent Less than 1 p~k a day 1-2 packs a day 2lor more packs a day Num- ber Per- cent Nam- ber Per~ cent Num- ben Per= cent Tota1----- 88 100.0 116 100: 0 94' 100. 0 , 125' 100.01 329 10(101 190 100.0 Sor;e ----------- 66 75.0 86 74.1 1 1.1 1, .8 0 0 Less than 5'0---- 8 9.1 14 12.1 4 4.3 25 20.0 4 1.2' 0 ----- 50-59 .,-__-_____- 10 1',114 13 11.2 50 53.0 54! 43.2': 87 26.4: 29 15:3' 60;CFe----------- 4': 4.5 1 .9 23 24.5' 21 16.8 116 35.3' 75 39.44 fo-79----------- 0 ----- 2 1.7 9 9.6 9 7.2 44 13.4 38 20.0 ---------- 0 0 ----- 2 2.1 2I 1.6 19 5.8 r1i 5.8 t499----------- 0 ----- 0 ----- 1 1.1, 0 ----- 5 1.5' 0 ----- 1D0: C arcinoma in sdtc ----- 0 ----- 0 ----- 3' 3.2 13' 10.4' 52I 15'.8 35 18.4 Itivasive car- crnoma___,__ 0 ----- 0 _____ 1 1.1, 0' _____ 2 .6' 2 IL1 SOURCE: Auerbach„O., et al. (t). The 116' ex-smokers had laryngeal histology similar to that of the' nonsmokers; as far as atypical nucllei were concerned. I+Iowever, dis- integrating nuclei were found in 40.5 percent of the eg-eigarette smokers and in only 0.4 percent of the' remaining cases. Only' one of the 94 cigar and'/or pipe smokers had no atypicall cells. Three had ear- cinoma in situ and one case had a section showing early invasive pri- mtiry carcinoma. The highest percentage of atypical cells was found' among the cigarette smokers. The proportion of cases with a high d'e- gree of cellular change increased with increased daily' smoking. None of' the pack-or-more-a-day smokers' was free of atypical nuclei. Of those who smoked two or more' packs per day, 85' percent had lesions with 60 percent or more atypical cells as compared to 4 percent of the nonsmokers. Between 10 and! 1I8percent of the, cigarettiesmokers hadl areas of carcinoma in situ, and four of the 644 cases showed early microscopic invasion. The thickness of'the basal level of the true vocalt cord'i was' also directly related to the amount smoked (table 3).. 59 :W ,~ r,. . . ., .. . _

TABLE 3.-Number dnd' percent d'istribution, by,' highest number of' celd rows in the basal'' layer of' the true' roca!' cord; of men classified by smoking cdtegory k i tte N di )i Ci / i Current cigarette, smokers eversmo e i-c gare Number of cell regularly smokers rows gar p pe smokers Less than 1 pack a day 1-2 packs a day 2 or more packs a day. Num+ ber Per- cent Num- her Per- cent Num* her Per- cent Num, her Per- cent Num- ber Per- cent Num- her Per- cent Total----- _, 88 100.0 116 100.0 94 100.0 125' 100.0 329 100: 0 190 ~ 1'00: 0 Less than 5 cell rows ---------- 30 34! 1 7 6.0 4' 4.3 3 24' 1 0.3 0 ---- ~ 5 cell lrows __ __ _ 29 33.0 27 23.3 20 21.3 27 21.6 38 11.6 20 10. 5' 6 cel l, rows------ 8' 9.1, 15 12,9 15 6.0 25' 20.0 51, 15.4 , 24 . 12.6 '-~ 7cellroars------ 6 6.8 12' 10.3 18' 19,1 12 9.6 38 11.6 19. 10.0 ,x 8cell'rows------ , 8 9.1 14 1'21 9 9.6 13 10.4 30, 9.1, 23'. 12.1 ° 9cellirovrs------ 1 1111 7 6.0 7 7:4 6 4:8 26' 7.9 14, 7, 4 '~ 10 or more cell raws.,-------- 6 6L8 34 29,4 21 723 39 31.2 145 44.1, 90 47.4. SOURCE: Auerbach, O;, et al. (I). Cancer o f the Urinary Bladder and' Kidnney Several studies have dealt with t1i~e, relationship ~ of smoking to can- cer of the blad'dt,r and kidney. James,,et al. (23)' demonstrated that an association existed for' cancer of'tllie' blad''der. The study by Fraumeni (17) also showed epidemiological evidence for such a relationship for bladder and kidney cancers. Bennington, et al. (3, 4Y indicated an as- sociation between all kinds of tobacco usage an& adlenocarcinoma of the kidney asweIl a&adenoma of thekidney.Ho.vev'er, on the basis of this The previouslyy suggested association between cigarette smoking and cancer of the pancreas was again noted in a Japanese study by Iishii; et cers of the urinary tract is needed. Cawer o f the Pancreas strength andi mechanisms of the association between smoking and can- wasfoundl between cigarette smoki~ngand epidermoid cancer of thek~idney, a relatively u'ncommon, type~of cancer. Further research on the tory factor. Tlii'sstudyfound norelationsh~ip topipe smoking„and only a very weak relationship to cigar smoking. A significant association smokers, they consi'dered excessive cigarette smoking to be a contribu- strong, association between excessive cigarette smoking, and adenocar- cinoma of the kidney, and although the disease is not uncommon in non- demiology of ~ cancer of ~ the ~ k~~idney'~,, Wynder;~ et~ all (68) hav'e, shown a number of cases involved. In ai preliminary report ofl a study on the epi stu'dy alone, the~ relationship between "all ki~~nd'!s,of~ tobacco?" and cancer of the kidney;~ cannot be~ considered as~ established! in view ~ of'~the~small 60 al. cr rc ,

. q Y a a1l (22), in whichi the authors reported a higher relative.risk for pan- creatic cancer among,smokers than among nonsmokers. GENERAL AsPE()Ts OF (ry=AR!CINOGENICITY The majority of' the tumorigenic agents in tobaceo: smoke are found in the particulate matter "tar." The well established carcinogenicity of'tobacco "t'ar"' in avariet'y of' animal species and tissues (66) was reconfirmed recently (11, 35,10, 52, 56). A small portion of' the smoke partieulates (0.03 percent) is made up: of' polynuclear aromatic hydro- carbons (PAH) with two or more rings. A concentrate containing polynuclear aromatic Iiydrocarbonsandl amounting to 0.6' percent of' the whole "`tar"' wa& found tobet!h~emost carcinogenic fraction of to- bacco smoke (66). Another preparation of a P'AHi concentrate inducedd significant cytologic changEsin m:ousetrachea and human fetal lung«-1ien grown ini organ culture (28, 29). Ot'her applications of concen- trat.ions of selected polynuclear aromatic hydrocarbons have produced similarresults(27'). O!f'tlie identified PAM, at least 112 are known tumor initiators. These particular cotnpounds have been shown to: be carcinogenic, even when applied in doses of a f'e«micrograans (63,66)~. Tumor initiat'orsinducecllangesin the target cells,, espeeiallyin DNA (9~y14'). Tumor pro- moters are agents which promote the neoplastic transformation of ini'~ t'iatedi cells. Although tlie: structures of mostofthesetumor prornoters are still unkilosvn, there appear to be several' different types in tobacco smoke (5. !I, 5.9„ 66). Recently,, Bock,, et al. (6) published data which confirmed earlier findings that whole cigarette tar, the neutral frac- tion, two neutral subfractions and the weak acidic (phenolic) f'ractiom contain tumor promoters. Onerecentstudyindicat'ed that, "tar"' ob-NainedI fi-omI . tobaccost'emsonlyhad essentially no tumorpromotingactivit.y (65). D'uring, the last year, several studies have reconfirmed' the finding that selection of'tobacco and the use of tobacco sheets andi filters cann lead to a significant reduction of "tar"' and PAH in cigarette smoke, as, weld ast'oa, redu~cti~oni of'the tumorigenicity of tobacco "tars:"' Simi- lar results have also:been reported for commercial cigarettes (21, 34). Etiperimental studies demonstrated that with tobacco additives one can reduce "tar," nicot'ine„PAH and tumorigenicity of cigarette smoke ~ (12, w7).In termsof selective reduction oftobac'cosmoke components, theseiinvestigationsmay be of practical value, as well asofaeademie interest (57). . Tobacco Alkaloids Present evidence, does not indicate that tobacco alkaloids are car- cinogenic. A possible exception rnaybe cotinine,whichi .vasreport'ed to induce malignant tumors in rats [principally leukemias (58) ]' and 61 M T!~ +N

adenomas of'the bladder in mice (7). Boyland recently suggested that one or more of the three possible nicotine-N-oxides may be present in tobacco smoke and may be carcinogenic (7). Tobacco alkalbids could theoretically contribute to the overall car- cinogenicit'y of tobacco smoke, based on the possibility that in tobacco, smoke nornicotine and other secondary amines may react vrith, nitro- gen oxides to fQrmi the N-nitrosamines, of which several are known carcinogens, especially N-nitrosonornicotine and N-nitrosoanabasine (36). So far„ however, N-nitrosamines of nornicotine and other alka- loid N-nitrosamines have not been detected in tobacco smoke (36). N~icke~lT1Ie relationship of nickel compounds to the development of cancer has been discussed in a recent review by Sunderman (55), who sug= gests that there is a possibility that nickel carbonyl may be present in cigarette smoke and may act as a cocarcinogen by inhibiting the induction of' pulmonary benzopyrene hydroxylase„ an enzyme which converts 3,4-benzpyrene to noncarcinogenic hydroxylated derivatives. EXPERIMENTAL ASPECTS OF ('~i.aRCUNOGENSI5 Retention o f Sm,oke Constituents. Studies on human smokers by Dalhamn, et aI. (15) demonstrated' that about 60 percent of thev.o1atile, , water soluble compounds of cigarette smoke, 20 percent of' the volatile, nonwater soluble com- pounds, and 1'6 percent of the partliculate matter of cigarette smoke can be retained in the mouth when the smoke is held in the mouth f'orr up to 2 seconds. Under conditions in which the smoke is immediately deeply inhaled, between 91 and 99' percent of'the components of' ciga- rett,esmokeinvestigatled (particuTate: matter, toIuene,,acetonitrile, ace- tone, isoprene, acetaldehyde) were retained, NTith the exception of'' carbon monoxide, ofw,hich Z to 60 percent was retained (16). Changes i'n Cell Cultures Induced by Cigarette Smoke Leuchtenberger, et al. (30) have reported that passing cigarettiee srnoke through a charcoal filter prevented the diimage caused by either tivhole smoke, or the isolated gas phase of' cigarette smoke, to culturesf of mouse kidney cells. In the same paper, they reported that the single. exposure of'tissue cultures to puffs of charcoal-filtered smoke produced a signifieant' increase in the mitotic index of the kidney cells. In an- other study, Leuchtenberger„ et al. (31) reported that single exposure to nine puffs of the gas phase from charcoal-filtered cigarette smoke quickly stimulated the synthesis of' DNrY: and RNA byy cultures of mouse fibroblasts. Repeated exposure of the cultures to the filtered gas phase resulted in morphological and' cytochemical changes indicative 62.

11 car- obaccoo nitro- i mown basine alka- (36). ancer I sug- •esent' Ir the hich. `.iives, ated s of om- ~oke for tely , iga- lce- of' of abnormal proliferation. Since the same alterations were found to be present, to a much lesser extent, in some control cultures,, the authors considered that the filtered gas phase enhanced characteristics already possessed by the cells. They concludled that'the gas phase of'unfiltered cigarette smoke contains not only substances which inhibit cellular metabolism, but also factors which stimulate cellular metabolism. These latter factors may be unmasked by passing the gas phase throug4 a cha.rcoalfil't!er. Theident'itiesof'thespecific gases!removed by the char-coal filter and the extent'towhi& each was removed were not reported bv the authors. Investigationn of the relationship between the changes observed ini the t'issue cultures andi in vivo metaboli'sm~ is necessary for the interpretation of'the results of'these experiments; Exper°imentd, St'udies of Brmuh;ogeni.c Carcinama in Animals Because of the, technical problems involved in inhalation experi-mentsin small animals, (59, 61),, various animal models have been de-i-elbped which do not employ the inhalation of smoke. These models have been used to study the role played by carcinogenic substances found in tobacco smoke in the induction of bronchogeniccarcinoma~ Safflotti ('43)1 in a, recentireview of! experiinentalrespiratorytract carcinogenesis described the development of experi'mental' models for the induction of pulmonaryy tumors andl discussed a method of' in- ducing broncliogenic carcinomas in Syrian golden hamsters by intlra- tracheal instillation of a finely particulated crystalline carcinogen (e.g., benzo(a)py.rene) attached to a suspension of' fine particles of a carrier dust (e.g., ferric oxide). Ti his method reproduces some of the conditionsofhum~an exposure to~inhalpd carcinogens and'has resulted& in incidences of up to 100' percent of respiratory tumors, mostly squa- mous cell and anaplastic carcinomas of the larger bronchi. These tumors have been found tio be invasive, metastasizing, and'transplant- able. Saffiotti reported t.hat the carrier dust particles play an essential role in transporting the carcinogens through the bronchiolar and aibeo- lar wall into thelung tissues where they are phagocytized. The carcino- gens are then eluted by the plasmai and diffused into the lung tissue, reaching up to the mucosa of the larger bronchi (42,,ly4, 4,5, 46). Varia- tions in particle size and distribution in the suspended particulate matteraff'ect.the retention rates of benzpyrene in the1ungs(47')_ Thedevelopmentiof this experimental model has led to the undertaking of newresearcli, in many1aboratoriesattemptingtodefi'nethe, factors responsible for carcinogenesis in the respiratory t'ract.. Two other techniques: used to produce squamous cell carcinoma, in small laboratory animals are the passage of threads impregnated with carcinogenic hydrocarbons into the lung and the implantation of wire 61 .g,

mesh pellets in the bronchus. The latter tlechn2que gives a dose-response relationship between~ carcinogenic hydrocarbons and sqiaamou& cell carcinoma of 'the lung in rats (27) . In order to overcome the traumatic effects of the surgery involved! in these procedures,,two additional tech- niques have been utilized. In one method, the carcinogen is suspended in Freund's adjkivant andl upon tracheal instillation can lead to bron- chial cancer (69)., In this experiment, even more cancers were found when the rats were pretreated with tubercle bacilli. Pretreatment of the animals with tubercle bacilli produced inf'arcts; as well as scarring of the lung. This finding is of interest because earlier stiudies sliowed tliatscarring of rat lung by the halogenated' hydrocarbon hexachIoro- tetrafriuorobutane increases their susceptibility to the development of squamous carcinoma when exposed to, carcinogenic hydroearbons. (54). That scarring of the lung may increase the susceptibility of the lung to carcinogens ~ is ini line with some recent' observations on humans by Bennett',, et al. (2) who showed the: frequent occurrence of pulinonarx scars in males with adenocarcinoma of the liung.Experian;ental Aspects of Cancer o f the Bladder and KizdTzey Tobacco smoke appears to contain traces of'several aromatic amines which are established' bladder carcinogens. Of' these,, however, only Betanaphthylamine has thus far been identified in tobacco smoke with 2.2 x 10,8 g. per cigarette (2d). At concentrations such as this,, it ap- pears unlikely that such arornaticamines can account for the increased risk among cigarette smokers of developing kidney and bladder cancer. A more likely correlation may exist between these types of cancers ini smokers and! their el'evatedd urinary excretion rate of carcinogenic metabolites of tryptophany and their oxidation products (49; 60).. Recently, the tobaccar alkaloid cotinine was reported to induce ade- nomas in the bladder of mice [16 percent (7),]. This observation needs further testing. Cotinine is one ~ metabolic product of' nicotine and is found in to'bacco, cigarette smoke (Q6)~ and the urine of smokers (33). A study by Schlegel, et a1! (61)' indicates an el6vated concentration of certain o-aminophenols plus their phenogazon-oaidation prodhzcts in the urine of certain types of'' bladder cancer patients and cigarette smokers, when compared to the urine ofi' nonsmokers. Further studies are needed on this problem. 64 0

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CHAP1'ER 4 Effects of Smoking on Pregnancy Contents. Ptee. SUITIP[18,ry --------------------------------- ?7,, Epidemiological Studiies---------------------------------- 77 ExpeTimental'Studies------------------------------------ 80 Cited R'eferences---------------------------------------- 81

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EFFECTS OF SMOKING ON PREGNANCY with mothers who' did'" not smoke. neonatal death has been investigated in several studies. As detailed below, some of the studies reported a statistically significant increase in unsuccessful pregnancies in mothers who smoked when compared between maternal sm'oking and spontaneous abortion, stillbirtliy and smoking and low birth, weight and prematurity. The relationsh2p 1967 Report(11) . In the 1967 review, the literature cited' supportedi a ' relationship between maternal smoking and low birthweight and pre- maturi'ty in infants. However, the evidence relating the maternall smoking to fetal', or neonatal death was not definitive. The addition of new studies has reconfirmed the relationship between maternal pregnancy have been published since the: review of this topic in~ the New studies on the effect of maternal smoking on the outcome of of pregnancy remains to be~ determined. smoking, but the meahanism of the effect of smoking, on the outcome Maternal smoking, during pregnancy' is associated with decreasedd infant' birth' weight and iiicreased' incidence of prematurity, as de£Inedd by weight alone, and may be associated with an increased incidence of spontaneous abortion, stillbirth, and neonatal death. Changes in the metabolism of the placenta and in various hematological factors in the newborn infant have been found to ~ be' associated with maternal SU3IDZ'AR'H. EPIDEmIOLODICA'L S`rC7DIES In a prospective study of more than 2;000' pregnant women, Russell, et al. (8)' eaamsnedl the effect o'f' the mother's smoking habits andd blood pressure on the outcome' of the pregnancy and on the birth weight of the -in'fant. A smoker was defined as one who~ regularly smoked five ~ or more ~ cigarettes a d'ay. In each blood pressure categoryy, the percentage of unsuccessful' pregnancies (~abortion, stillbilrth, neo- natal d'eath) was higher for smokers. Although fewer smokers were foundd in the higher bl'ood pressure categories,, women who: smokedd and had bloodl pressure levels equal' to, or greater than, 150/100 had a rate of unsuccessful pregnancy of 31.4 percent as compared to a rate of 14.5 percent among nonsmokers with the same blood pressure . 77 .i . .v4

levels. Although the number of women in the two groups was small (35 and 138, respectiwely), the difference observed was statistically signifiicant.F'or tliosewith blood' pressure levels of less than 140/90, the percentage of unsuccessful birth was 6.5 among smokers and 2.7 among nonsmokers; for those with blood pressure levels in the range of 140/90; the percentage was 6.8 among smokers and 4.1 among A study of increases in the infants" weight and in their head circum- ference during the early weeks of life revealed that the babies of smok- ing mothers grew faster than those of 'nonsmokers through the sixth month after birth. However, the mean weight per week of conception age (duration of pregnancy, plus age after birth) was greater in babies of'nonsmokers through the sixth week after birth,,the effect not being visible at the sixth month examination. These last two findings support the theory that smoking during pregnancy acts as a retarding infl'uence on fetal gro.v th and tliata catching-up phenomenon begins among, thee babies of'smoking mothers at birth w henthe toxic influence is removed. In a controlled study of 197 premature births among Z1?egroes„Terris, et al. (9)1 found a significantly higher prevalence of smoking among the mothers of premature infants. P'nematurity was defined as a birth weight of 2,500 grams or less. maternal age, parity, maternall height, social class of' woman's father, educational level,, age of consort, maternal attitudle towardl the preg- nancy, work during pregnancy, andl sex of'offspring. For each variable, the smoking effect w as clearly distinguished as a separate effect even when the individual factor was itself associated with smoking (con- sort's social class, father's social class, and maternal ed!ucationall level). tion of spurious associations. These includ'ed : social class of consort, ing variables for their possible effect on~ birtl'u weight and the produc- blood pressure category. Various factors were examined as eonfound- Inkeeping,with previous'pindings; Rnssell'yet al1„found that t~hem!eane birth weight of'the inf<a.nt was lower for the smoking mothers in each come of pregnancy as women who db not smoke, been unsuccessful if these women had the same risk of'unsuccessful out- among,wornen who smoke regularly during pregnancy would not have findings of Russell, et al., one out of every five unsuccessful pregnancies effect relationship, the least that can be said is that on the basis of the abortion and perinatall death. In the -absence of proof of a cause-and- tionship between maternal cigarette smoking during pregnancy and during the pregnancy. This statement implies a cause-andLeffect rela, every five unsuccessful pregnancies in women who smoked regularly would have been successful if the mother hadl not smoked regularly' Extrapolating from his series, Russell (7) estimated that one out of' nonsmokers. 78 :

Mulcahy, et al. (6) studied the relationship between smoking habits and the outcome of pregnancy in 3y681 women admitted to~the Coombe Lying-in Hospitali in Dubllin, Ireland. Besides finding significantlly lower birth weight for infants born to mothers who smoked, they dis- covered al significant increase in the incidence of neonatal death, still- birth, and spontaneous abortion. These effects were independent of age orparity., No significant difference in therat'eofcongeniitlal abnor- malit'ies was found betweeni the offspring of'the smokers and those of the nonsmokers. Kizer (4) studied the effect of maternal smoking on the outcome of pregnancy in 2,095 patients in Venezuela. He found a signi'ficant dim- inution in the birthi weight of infants of' smoking mothers and a higher incidence of' premature rupture of'the membranes, but did not find a difference in the incidence of' abortion or perinatal mortality:. Luff'us,etat, (2)~ studied the reIat'ionsliipbetween smoking, during pregnancy and the incidence of album:inuric preeclamptlic toxemia in 2,543 married, urban primigravidae attending antenatal clinics in Aberdeen,in 1960. Albuminuric preeclampsiai is defined as albuminuria in pregnancy in .vhichi the urine contains at least 0.25' grams of al- bumin per liter accompanied by a rise in, diastolic blood pressure to 90 mm Hg: or, more, on 2 or more days after the 26th week of' gestation. or progressively during labor. The incidence of' albuminuric pre- eclampsia was lower -in smokers than in nonsmokers. Among the preeclamptics, however, smokers lost more babies in the perinatal period than the nonsmokers. The babies of smokers, both normal and preeclamptic, had a lower mean weight than the babies of nonsmokers.. In the preeclamptie group, a greater percentage of' the babies of smokers weighed less than 5 pounds. These differences are~in keeping with: tliose~found in otherstludiesbut do: not'reachi statistical signifi- cance. The implication is that smoking mothers are less likely to be preeclamptic; possibly by way of blood pressure effects,, but are more likely to have their pregnancies result in perinatall death in the event they are preeclamptic. In ai study of' 5,843 deliveries in Hungary; hul6p (3)' f'ound' a sta- tiEtically significant increase in premature births among women who smoked during their pregnancies, whether the women were married or unmarried, held a job, or were unemployed. Lacuska, et al. (5)' found a higher frequency of' premature births and abortions among women who smoked during pregnancy than among nonsmokers, although the differences fell' short' of statistical significance:. Tokuhata (l0), analyzed theferti~lstyh~i'storyin relationto smokiugin groups of married women who die+di of' breast cancer, genital can-cer, and! various noncancerous diseases. Statistically significant in- creases in both the rate of infertility (as judgedl by absence of preg- a4.

nancy) and in fetal loss (defined as abortions and stillbirths) were f'ound' in smokers who dfiedl of noncancerous diseases. These differences withstood analysis for a number of possible confounding factors. However, since the sample was made up of women who died in a certain geographical area in a given amount of time;, biases may have been introduced. Retrospective findiings in a~ group of' dead people are not necessarily the same as findings dorived in a prospective stludy of a living,population. Although by this time the evidence for reduction in birth weight of' babies born to smoking mothers is overwhelming;, a problem that remains to be solved is why some studies db and others do not appear to show fetal wastage as measuredi by a,bortion, stillbirth, and neonatal' death. It may be that the method of selection of the population under study, especially the degree to which entire obstetrical! histories are included, accounts for this variation. T &PERIbTEIrT71AL STC DIES I Younoszai, et al. (13)' compared varibus hematological factors in the blbod of' 16 smoking mothers and newborn infants with those of 16 nonsmoking mothers and their offspring. Both groups of' infants were delivered at term and' appearedl clinically well. The smoking mothers had' a mean carboxyhemoglobin saturation of venous blood of 8:3' percent as compared to 1.2 percent in the nonsmoking mothers. Corresponding figures for the ~ umbilical vein cord blood were 7.3' per- eent and 0.7 percent. A mild metabolic acidosis was seen in the infants ofl smokers. These infants also had a higher mean capillary hematocrit thani those of the nonsmoking mothers. The authors point out that the differences, although real, probably are not of' clinical signif~icance in the newborn. However, the effect of chronic exposure of the embryo and fetus to carboxyhemoglbbin levels and other hematological abnor- malities has not been elucidated. Welch, et a.l. (12), reported that the placentas from women who smoked during pregnancy show a much greater ability to hydlroxyl'ate benzo(a)pyrene than the placentas fromi women who did not smoke dnring pregnancy. The placentas from women reporting similar cigarette consumption varied greatly in the degree of BP hydi•osyllase activity. However, no information isavaii'able oni the brand of ciga-rettes smoked or the degree of inhalation, differences.vhiclt may result ini different dosages of BP. It is possible, but not likely, that car- cinogens in tobacco smoke reach the fetus in significant amounts. The ultimate effect of' the exposure of the human fetus to carcinogenic substances is unknown. Becker, et al. (1) studied the effect of subcutaneous injections of' increasing doses of' nicotine on groups of pregnant rats and their off- 8m i i ~:: sl, su tL g? loi ol' h,: h

spring. They found that the rats receiving nicotine injections con- sumed less food and gained less weight than control' animals and that the magnitude of this effect increased when the dose of' nicotine was greater. Whereas no other differences were found in the rats receiving, lower dosages, those receiving 3.0 mg./kg. or 5'.0' mg. f kg. daily had! offspring which differed from those of the controls in being lighter,, having a longer gestation, a higher mortality rate during t'he first 4'$'8 hours of'life, and a fetal appearance: CITED REFERENCES (1) BEcKER, R. F., LrrrLE, C. R: D.,, Kixo; J: E. Experimental studies on nico- tine absorption in rats during, pregnancy. III. Effect of subcutaneous injection of small chronic doses upon mother, fetus, andi neonate. Amer- icanJournal of'Obstetrtcs and Gynecology 100(7) : 957-968;,April 1, 1i968. (2) DUFF-us„G. M., bfACGtLLIVRAY, I:,The incidence of preeclamptic.toxaemia inn smokers andlnon-smokers. Lancet 1(7550) : 991-99~5, May 11, 1968J (3'): FuLOr,,T. Uber Fruhgeburten alleinstehender beruf'statiger Frauen. Sante Publique 8(4) : 381-394, 1967. (k) KizER, S! Influencia del habito de fumar, sobre eli emharazo,, parto y recien nacido: Revista de Obstetricia y Ginecologia de Venezuela 27(4) : 595r 643, 1967. (5) LACUSxA, A., BoHUxrcxY, F., FkLO, S. Fajcenie a gestacia. (Stnoking andi pregnancy.) CeskoslovenskaiGynekol'ogie33(3) :,197-2Qp, 1968: (6) J3ULeAIIY, R., KNAOCS; J.F. Effect of age;,pari'ty,,and cigarette smoking onn outcome of' pregnancy. American Journal, of Obstetrics and Gynecol'ogy, 101I(6)~: 844-849, July 15'~ 1968: (7) R'LSSELL, C. S; Another hazard of'smokingf New Scientist 41(631) :64-65, January 9, 1969. (8) RussErn, C. S.,, TAYLOR,, R,, LAw, C. K , Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weightl and growth{ and other related factors. A, prospective study. British, Journal of' Preventive and! Social Medicine 22(3) : 119-126,,July!1965:. (S) TERRZS; Bi.,,GoLn, E. M. Anepid'emiologicstludly of prematnrity. I. Relation: to smoking, heart volume, employment, and physique., American Journal of' Obstetrics and Gynecology 103 (3) : 358-370, February 1, 19691 (10)ToxuHATA, G: K. Smoking in reli3tion t'o infertilitg and fetal loss. Archives of'Envilronmenta~l!Health 17(il 3a3-3.59, September 19fi8:(11) U.S: PURLIC HEALTH SaRVacE. The Health Consequences of Smoking. A Public Health Service Review : 1967. Washington, U.S• Department of Health, Education, andl Welfare, Public Health Service Publication No. 1696; 1967. 199 pp. (12:): `v ELCII4. R. :1T,,. HARRiSO.N*, Y.. E.,, GoZHi.liI,. B'.w., POPPERS, P. J_ FI\ STiER,,,M., CovreEx, k,. Hl Stimulatory effect of' cigarette smoking, on the hy-droxyn1a~ tion of 3,4-benzpyrene and the N.dimetbylation ofl3=methyL4-monomethy1- amiinoazobenzene by enzymes In human placenta. Clinical Pharmacolog5' and' Therapeutics 1Q (1) : 11X1'`109, January-February 1'969: (13) YovxoszAl,, M. K., KACic, A., HAWORTH, J. C. Cigarette smoking during preguancy: The effect uponl the hematocrit and aci&base balance of the newborn infant. Canadian Medical' Association Journal 99(5) : 197-2U0; August 3, 1968. 81i n rs

17

Smoking and Contents Noncancerous Oral Disease PaQe suIISTTLary '---------------------------------------------- 85 Epidemiologicall and Clinical Studies--_-------------------- 85 Cited References---------------------------------------- 88. 83 O W ~ ~. ~ O ~ 09. . A ., I v .f

SMOKING AND! IrTONCANiCEROiIS O!ItAL DISI+]ASE SUMMARY The previous reports have not presented findings oni noncancerous oral disease. Several recent studies have made a review appropriate at this time:Thhis review of the avaiila'ble literature leads to the conciusioni that ulceromembranous gingivitis, alveolar bone: loss„ and stomatitis nicotina are more commonly found among smokers than among, non- smokers.'The influence of'srnoking on periodontal disease and gingivitis probably operates ini conj unction with poor orall hygiene. In addition, there is evidence that smoking may be associated with ed'entulism and' delayed socket healing. While further experimental and clinical studies are indicated, it wouldl appear t'hat•nonsmokers have an advantage over smokers interms of their orallhealth. EPIDEMIOLOQIGAL AND CLINICAL S'fl'IIDIE$ Beriodontal disease.is a chronic destructive process affect'ing the sup- porting structures of the teeth (gingiva, periodontal fibers, and alveo- lar bone). It is generallly considered inflammatory in nature. SoTomon„ et all (21) studf edl data on 3,552 nonsmokers and 3,639' smokers, all white and between the ages of 20 and 79. He found that periodontal disease occurred without significant statistical difference in male and female nonsmokers.of the same age, but that smokers of both sexes had d a higher prevalence of'the disease. The prevalence in female smokers. paralleled that in male smokers in the younger, age groups but re- sembled that of the nonsmokers in the older age groups. The authors believe that this difference is related to increased smoking in younger women., B'randtzaeg, et al'L(3) examined 206 Norwegian Army recruits be- tween the ages of 19 and 25' and found a trend toward increased perio- dontal d'i'seasewith~ increased smoking.However,, when an analysis of covariance w as performed, most of the changes in periodontal disease severity were accounted' f''or by changes in~ oral hygiene. This finding suggests that tobacco consumption may influence the periodontal tis- sues but only withh accompanying, changes in oral hygiene. A seemingly contradictory paper reporting on periodbntat diseases in 8;206' Ceylonese was published by Waerhaug, (25). He found to- bacco smokers to have less periodiontal disease than nonsmokers. He 85'. .,t

pointed out, however,, that for many individuals the alternative to smoking tobacco is chewing betel nuts, which is associated with even more periodontitis than cigarettes, Thus,,t'obacco users are relatively better off. Therelationship~ofsmokirng to gingiviti~si tlheinitial stage ofperio- dontal disease, has -also been studied. Arno, et al. (2) examinedl 11,3!46' employees of a manufacturing, company in Oislo and f'oundl that to- bacco~ smoking was associated with an increase in the prevalence of' gingiQitis. However, its importance as compared with that of oral hy- giene was not a dominating one. Ludwick, et a1L (15) studied 2,577 naval enliistees at the Great Lakes Naval Training Center andi found no relationship betw een smoking and simple marginal gingivitis, but a significant one between smoking and ulceromembranous gingivitis (necrotizing ulcerative gingivitis, Vincent's gingivitis, trenchmouth). This is an acute form of periodontal disease of apparent sudden onset, characterized byulceratlion of the tips of the interdental papillae, gin- gival bleeding,,pain, and fmul!odor. In the Il7nited States and Europe, it occurs primarily in -adol'escent's and' young adults. P'acteria,, local fac- tors, systemic factors, and psychogenic factors have been suggested as contributing,to its etiology (10). Pindborg's study (17) of 1,433 Danish Royal Marines between the ages of 16 and 28 revealedl that the prevalence of chronic marginal gin, gi!vitis, was not affectedlby smoking, but tliata'theprevalenceof ulcero-membranous gingivitis was much greater in, smokers thannonsmokers: A second study by Pindborg (16) of 3,505 Danish military personnel confi'rmedl these findings : nonsmokers had a prevalence of'uleeromem- branousging, ivitis of 2.2percent,, while for those who smoked 10g, or less of'tobacco daily, the prev.alence was 7.0 percent, and for more than 10 g. a day it was 9.5 percent. Smitt (20)~ foundl a prevalence of ulceromembranousgingivi'tis of' 2.5 percent in~ Dutch Navy recruits. In those who smoke 50 g. of to• bacco, for a week or more, the prevalence was 1i0:5 percent. Frandsen, et al. (9) investigated' the correlation between the form of tobacco used and occurrence of gingivitis ini Danish~ 14fiarines.He found that 1,848 cigarette smokers and 273 pi'pe smokers had essentially the same rates, of simple marginal and ulceromerrrbranousgingivitis.Arno, et al. (1) and Hierulf (11) have investigated alveolar bone, changes in smokers. Arno studied 728 men between the ages of 21 and 415; and found that alveolar bone loss, measured as the percentage off maximum height adjacent to the mesial and distal surfaces of each tooth present, was higher among those with, high tobacco consumption.. The author suggested that tobacco consumption is a complicating fac- tor in periodontal disease and when accompanied by poor orall hygiene i :x

and unfavorable systemic background may help speed'up~the destruc- tion~ of thesupportingtissues of the teeth., I-IErulf measured intlerdental boney septa in 389 men and 215 women at the Ilnst'ituteofDentistry iln, Stockholm. I-Ie,too, found asignificant relationship betweenismoking,and bone loss. The relationship between cigarette smoking and edenti'ulismi has been studied by Summers, et al. (!~), in a sample of residents of Tecumseh, Bliicli. Information on 324 dentulous and 841 edentulous people revealed that amongmales~iln both groupsthose, withthe~ greatest evid'enceofperiodontal disease smokedl significantly more cigarettes than those «-ithi medium or little evidence of' the disease. Solbmon, et al. (21) foundl significantly more edentulism and& advanced periodontal disease in both men and women who smoked cigarettes than in nonsmokers of the same age. Jackson (12) has cited heavy smoking as a f'actorindelayed heal~ingof tooth sockets after extraction. Stomatitis nicotina is a form of palatal leukoplakia (4). It is charac- terized by raised urnbilieated papules with small centlrali red depres-s~ions~located primarily on tllie, softpalatieand the posterior regi:on, of the hard palate. The papules represent blocked palatal mucusgl'ands~ and't'lie, red!depressionsaretheirinflamedl ductorifices; Sau~nders ('18)) notes that the lesions begin as tiny red! dots and may progress veryy rarely toulceration.Althougll it somet~imesoceurs'i'n cigar and cigal- retlte smokers, stomatlitis nicotina is found most freqiuentlyy in pipe smokers (;./f, 5, 19). According to Chapman, etal, (41,~ pipe smoking points a stream of smokedirectlyontlothepalate;, thereby allowing longer,contact between it and t'h~esmoke than in other forms of tobacco use. The condition disappears with the cessation of smoking (6, 7. 8, 1If,,18,19, ,2~.), though Kerr (13) warns that healing may be slow, someL t'i'Qn:es requiring months before no lesions are present. Thoma (23)observedl a patient who~ woredentures, for over 40 years and showed lesions of stomatitis nicotina ondyon the part of'the palate that was not coveredi by the prosthesis. He concluded that the ehangeswere due to localsurf'ace rather than to syst~emicintiuences., Lewis (14), Saunders (18), and Thoma,, et al. (24)1 advise biopsy to rule out malignancy in advanced cases. Forsey, et al. (8)' feel that no association between stomatitis nicotina and cancerloasbeen d'emonst rated. 360-928 0-89--7 87r'

CITED REFERENCES (1) ARxo, A,, SCHEI, O:,,LDVDAL, A., W'AERxAUO, J. AUveolgr bone loss as a func- tion of' tobacco consumption. Acta Odontologicai Strandinavica 17 : 3-10, 1959. (Q) ARVO, A., F6'AERHAUC, J, LauDAr,, A., ScHEr, 0. Incidence of' gingivitis as related to sex, occupation,, tobacco consumption„ toothbrushing, and age. Oral Surgery,, Oral Medicine,, and Oral Pathology 11(16):: 587-5954 June 195& (3) BRANDTZAEa, P:,, JAmiso:v, H. C. A study of' periodontall healt!h, and oral hygiene ini Norwegian army recruits. Journall of' Periodontology 35 : 302- 307, July-August 1364. (4) CHAPacAY, I., 3iALxrx, Rf. Palata.l leukoplakia in a female cigarette smoker. Contribution to study of tobacco-induced epithelial h5perplasiai in human beings. New York State Journal of J3edicine 61(12):: 2044-2045, June 15, 1961. (5)! CHAPMA:r-, L, REDISH, C. H Tobacca-induced epitheliial proliferation in human subject. Long-term effects of pipe smoking on epithelium of hard palate. Archives of Pathology 70(2) : 133-140, August 1960. (~S)~ DECHAUSiE,, al., G~RELLET;, M:.., PAYEN, J!., Lellcoplasie: papnlellsee chezles~ fumeurs ou stomatite nicotinique. Presse ytedicale 69(56) : 2583=2585', December 25, 1961. (7) Eli tabaco y la mucosa oral. Odontoiatria 12'(10) : 619-F,21, October 1955. (8)! FoasEY, R. PL,SuLrIVAV, T. J. Stomatitis nicotina Archives of Dermatol- ogy 83 (6) : 945-950, June 1961. (9)1 FBA:rDSE:v, A., PtN DBORa,, J. J. Tobacco and gingivitis. Ill., Difference in the action of ci'garette and pipe smoking, Journal of Dentall Research 28(5) :, 464-465, 1949! (10)~ GRA:wT„ D. A., STERN,, I. B., EVERETT, F. G. Necrotizing ulcerative gingivitis. Chapter 18. In: Orban's Periodontics. A Concept-Theory and Practice. 3diedition. St. Louis, C. V: 3Tosbs Co., 1968. Pp. 285-298. (i11:) HERULE; G: On the marginall aleolar ridge in students~:, A roentgenographiec study. Acta Genetica et Statistica Medica 2(3) , :~ 256-288; 1951. (1'Q) JACxsov, J. A. Heavy smoking-a factor in delayed socket healing. Na- tional DentallAssociation Quart'er1y: 15-116, October 1960., (13) KEF:a D. A. Nicotine stomatitis. Journal of'' the Michigan State Dental. Society 30: 90-911 May 1948: (14) LESVrs, A. B. Effects of smoking on oral mucosa. Oral Surgery, Oral 14iedi- cine; and' Oral Pathology 8(10) : 1026--1!033,,October 1955. (15) LuDwicx„ 1'F'., MASSLER, M. Relation of' dental caries experience and gin- givitis to cigarette smoking in males 17 t'o 21,years old (at the Great Lakes Naval Training, Center). Journal of' Dental Research 31(3): 319-322, June 1952:. (18), PINDBORG, J. J:, Gingivitis in mil;itarx personnel with special! reference: to ulceromembranous~ gingivitis. Odontiologisk, Tidskrift 59(6) : 403-499,, 19511, (17) PI:rDRORC, J. J. Tobacco and gingivitis. I. Stat!istical examination of the significance of' tobacco in the development of' ulceromembranous gingi- vitis and in the formation~ of calculus. Journall of' Dental Research 26: 261-264, 1947. a8 )

(18) SnuNnERS, W. H; Nicotine stomatitis of the palate. Annals of Otology, Rhinology and Laryngology 67,: 618-627, 1958.. (1'9) ScxwARTZ, D'. L, Stomatitis nicotina of the palate. Report of two cases. Oral, Surgery, Oral 3iedicine, andi Oral Pathology 20(3) : 30Cr315,, September 1965. (20) SMITT, P. A. E. S; Some clinical and' epidemiological aspects of' Vincent's gingivitis. Dental Practitioner andl Dental Record 15'('8) : 281-286; April 1965: (21) SoLauo:v4 H. A., PRIORE, R. L., BROSS, L D. J. Cigarett'e smokiog, and, peri- odontal'disease. Journal of the American Dental Association 77(5) : 1081- 1084, November 1968. (22) SUMMERS, C. I, OBERMAN, A. Association of oral disease with 12 selected variables: II. Edentulism. Journal of Dental Research 47(4) : 594-598; August 1968. (23) THO.rA, K. H Stomatitis nicotina and its effect on the palate. American Journali of' Orthodontics and Oral' Surgery 27(1) : 38-47;, January 1941. (24) Txo2MA, K. H.,, GoLnaiAN„H: \I. Orall Pathology, 5th edl, 1960. St. Louis, C. V. Mosby Cb. P'p: 955--958.. (25), «'AnRxAVC; J. Prevalence of periodontal disease in Ceylon. Association with age, sex, oral hygiene, socioeconomic factlors, vitamin deficiencies, mai nutrition, betel and tobacco consumption, and ethnic groupi Final report. Acta Odontologica Scandinavica 25 (2) : 205••-231, 1966. 89' P

w~'.

0 ndex Acrolei n effect on Danaliella Dioculata, 42 Adenocarcinoma risk ratio of smokers, 56' smoking and, for men, 57' Ad enoca rci'n oma, , ki d ney smoking and, 60 Age coronary disease incidence rates and smoking, history by, 21-24 coronary disease mortality rates by, 13T14, 17 coronary disease mortality ratios by,,13; 18 stroke mortality rates by,13, 177 stroke mortality ratios by,,13' Albuminuric preeclampsia see Pregnancy tozemias ATkaloids, tobacco see Tobacco allkaloids Alveolar bone loss smoking and„85•-87 Alveoli,, pulmonary changes in rates after exposure to nitrogen dioxide„41 o-Aminophenolsconcentration, in urine of' cancer patients andd ' smokers, 64 Angina pectoris incidence rates and smoking,history, 21-22' smoking and, 18 in twins, genetic and environmental factors,25 aee also Coronary disease Aortic aneurysm mortality, for men by amountt smoked, 16 see alao Cardiovascular diseases. Aromatic hydrocarbons carcinogenicits„61 Arrhythmi& smoking, and~ 4 Arteriosclerosis aortic, 26 coronary,26 experimental studies, 2(r277 hypoxia and, hypercholesterolemia in, 26' severity of, and smoking, 26 smoking and, 4-5, 26-27 see also Cardiovascular diseases; Coronary disease Atherosclerosis see Arteriosclerosis Behavior and coronary disease,2fl, 24 Benzo(a)pyrene hydroxylation by the,placentay W hydroxylation by pulmonary benzo- pyrene hydtoxyl'ase, 62! Benzopyrene hydroxylase inhibition of by nickel carbonyl in cigarette smoke, 62' Betanaphthyiamine content in cigarettes, 64Betel nut chewing, smoking and oral leukoplakia, 58 Birth weight effect of maternal smoking on, 5, 77-78, 8q. effect of' maternal smoking on; andl other factors, 78 Bladd'er neoplasms cotinine andl, 64' . experimental aspects of, 64 smoking and, 60, 64 Blood chemicad~analysis comparison for smoking and non- smoking mothers and their in- fants, 80 Blood cholesterol levels and! lnng neoplasms in male smok- ers, 57i andl coronary disease mortality. 17 Blood circulation effect of'smoking on, 11„27-28 Blood flow effect of'smoking on, 27-28 91 I

I Blood platelets effect of' smoking on, 27-28 Blood pressure coronary disease mortality and, 14,, 17 coronary disease and smoking;,14 smoking and, effects on~ pregnancy outcome; 77-78 Blood viscosity and arteri~osclerosis;,2T Bodv weight relationship to coronary disease mortality rates and smoking, 14! Bronchial epithelium effect of nitrogen dioxide on, in rats, 4'11 effect of smoke on, in dogs, 40 Bronchial neopliisms risk ratio of'smokers, 56'. Bronchitis incidence of among,smokers, 37 smoking and, 4 smoking as cause, 37 sec also Emphysema Bronchogenic carcinoma sec:Carci'noma, bronchogenic Bronchopulmonar3 disease, chronic prevalence of;, 38 Buccal neoplasms see Oral neoplasms Canceraee \eoplasms and specific listings; e.g., Lung neoplasms Carbon monoxide and carboxShemoglbbin levels, 28-29 effects on myocardium; 28 CarboYyhemoglobin levels, 26,28 ' leveis i in ; smokers, 28-29; 80 Carcinogenesis experimental; 62-641 possible role of'tobacco alkaloids in,. 611 Carcinogens aromatic hydrocarbons, unspecified, 61 bladder, in tobacco smoke, 644 implantation of, 64 use in esperimental' brouchogenic carcinoma, 63-64I Carcinoid risk ratio of smokers, 56 Carcinoma, alveolar cell risk ratio of smokers; 56 92' Carcinoma, bronchogenicc animal models'for, 63r64! experimental induction of; 63-641 risksatio of smokers, 56. Carcinoma, epidermoid experimental induction of, 63-64 risk rat'io of sunokers„56' Carcinoma, larynx sceLa ryngeal: neoplasms Carcinoma, smallicelli risk ratio of'smokers, 56'. Carcinoma,,sqvamous celi' aeeCarci'noma, epideTmoi& Cardiovascular diseases and mortality rates;17i smoking and, 3-5'5 see also Aortic aneurysm ; Arterio- sclerosis ; Coronary disease ; Thrombosis Cessation,of smoking effect on risk, of lung neoplasms,,55a. 57 stomatitis nicotina resolution, 87 Cholesterol see Blood cholesterol. Chronic bronchitis see Bronchitis Cigarettes filter, and risk ofl lnng neoplasms, 57 filter vs. nonfilter, comparison of'~ safety, 57 Cigarettes, daily consumption aortic aneurysm mortality by, 16M and atypical nucletin larynx, 599 coronary disease incidence rates by, 15, 21-24 coronary disease mortality by, 13' Cigarette smoke see Smoke, cigarette Cigarette smoking, see Smoking Cilia effect of cigarette:smoke on, 42 Cocarcinogens nickel carbonyl as, 62' in tobacco smoke„61 Coronary disease epidemiological, studies, 25' incidence rates by age, 21-22, 24 incidence rates by behavior type, 20, 2-1'incidence rates by smoking and other risk factors, 23 1

Coronary disease-Continued incidence rates by smoking history, 2i 24 incidence rates in men, 21-22' incidence rates;, smokers vs: non- smokers, 18, 20-22' morbidity ratios, 19 mortality among former college students, 16,,18'. mort'alilty rates tisage,13-141 mortality rates by amount smokedw 13 mortality rates by blood pressure, 14 mortality rates by relative weight,, 14 mortality rat'es by sex,13'r14 mort'ality rates by smoking classifi- cation, 14 mort'ality ratios tiy age, 13' mortality ratios by amount smoked, 13' mortality ratios by sex, 13-14 smoking and, 3'-5;,1!1, 20~ smoking,as etiologie agent in, 11 see adso Angina pectoris ; Arterio- sclerosis; Cardiovascular dis- eases; Myocardial infarction Coronary heart't disease see Coronary disease Cotinine effect on rats and!mice,,61-62' in experimental induction of'biadder adenomas, 64 seeal'so Tobacco alkaloids CurschmannIsspirals~s in sputum of smokers, 39-40 Cysteine inhibi;tion of smoke cytotoxic action oni macrophages„42'. Death,sudden~ rate by smoking, cholesterol, andi blood pressure;17 DNA effect of' aromatic hydlrocarbons on,, 61 effect, of cigarette smoke on synthe- sis, 62-63 Edentiuism relationship tosmoking,,87 Emphysema in horses,, 40 pathogenesis of, 38'-40 smoking as cause,,37-3& see also Bronchitis Epidemiological studies coronary disease and'smoking,12-25 laryngeal neoplasms and smoking, 58'-60 lung neoplasms and! smoking„ 55-56 maternal smoking and outcome of pregnancy, 77-80 oral neoplasms and smoking,,58 pancreatic neoplasms and smoking, 60-611 urinary tract neoplasms and smok- ing, 60 Epithelium hypertrophy caused by nitrogen dioxide; 41 Es-smokerss coronary disease mortality for men,, by amount smoked, 15 coronary disease mortality for men, by years stopped smoking, 15~ coronary disease mortality for men; compared to nonsmokers, 15 decrease of lung neoplasm risk, 57, stroke mortality for men, comparedd to nonsmokers,,15 thickness of vocal cords, 60. Fertility and smoking, 79-W . Fetal'death and!maternal smoking, 77-78 Filters, charcoal and effect of cigarette smoke on cell' cult'ures, 62 Free fatlty acid plasma factor, smoking effect on, 27 Gingivitis Incidence among Danish Royal Marines, 866 incidence among Dutch N'avs, re- cruits, 86 incidence among U:S; Naval, train- ees; 86 and smoking, 85-86 Gingivitis, ulceromembranous relationship to smoking,, 86 Glutiathilone inhibition of'smoke cytotoxic action on~macrophages, 42l Hemoglobin effect of smoking on oxygen affinity, 291 93 o-+

Hydrolases reduction of in smokers" alveolar macrophages,, 42-43 Hypercholesterolemia and hypoxia, in arteriosclerosis, 26 Hypoxia and arteriosclerosis, 26 Infant mortality and maternal smoking, 77-7 S Inf'antss growth rate, effect of maternal smoking on, 78 Influenza B' virus enhancing effect in vitro on oxidized nicotine, 42 Inhalation depth and retention of' particulate matter of smoke, 62 Kidney neoplasms epidermoid, associated with ciga- retlte smoking, 60 and smoking,,60, 64 Kreyberg study lung neoplasms and smoking, 55--56 L'aboratorytechniques for inductioni of experimental neo- plasms, 63-64 Laryngeal neoplasms smokers vs. nonsmokers; 58-5i1. Larynx atypical nuclei in cells of smokers, 58-59 effect of'cessation of smoking;on, 59 premalignant changes in, andl smok- ing, 5, 55 see also Vocal cords Leukoplakia smoking and betel nnt,chewing. 58' stomatitisni'cotana, 87 Lung cancer see Lung neoplasms Lung function effectl of smoking on, 5, 42 effect of smoking on ventilation/ perfusionrel'ationships; 39~ Lung neoplasms and~ blood cholesterol levels in male smokers„57 decrease in risk of for ex-smokers„ 57 detection of' by sputum; analysis of smokers, 58'' epidemiological studies, 55r58 epidermoild; in male smokers; 57 incidence rates in female smokers, 4,57 incidence rates in male smokers, 4 incidence rates in~.Norway, 55-56 Kregbergstudy, 55-56 mortality rate, 57 oat-cel3„i'n male smokers; 577 of smokers, in Rhodesiay 57 andismoking, 4-5 and ulcers, relation to smoking, 57 see also Respiratory'Cract neopl:asms, Lungs effect of'nitrogen dioxide on rats', 41 pathological effects of smoking on, 5scars and susceptibilitq to carcino- gens, 64 LSsozymee secretion by rabbit pulmonary alve- olar macropliages, 42 Macrophages, alveolar effect of cigarette smoke on, 42 lysozyme secretion by rabbits', 42' and pathogenesis of chronic bron, chopul'monars disease, 43 reduction of enzymes in smoker.s'; 4'2 -43 Maternal smoking see Smoking, maternal Men incidence of lung neoplasms and, smoking ini,57 DIbnoamine oxidase inhibitors. effect on rabbits receiving nicotine, 27 Morbidity ratioscoronarP heart disease, 19 \Iortality and smoking, 3' study of Chicago PeoplesGas Li'gptand Coke Co. employees, 16-17 Mortality rates aortic aneurysm; for, membs amount' smokedl 16 cardiovascular diseases, 17 coronary heartl disease;, by age,. 13-14 coronary heart disease, byamount suioked,12-13;,17 coronary heart disease, by bloodi cholesterol, 17 coronary heart disease, by blood pressure, 14, 17

Mortality raties-Cbntinued coronary hearti disease;, by relative n eight, 14 coronary heart disease, by sex, 13-14 coronary heart disease, by smoking classification; 14 coronary heart disease, smokers vs. ex-smokers, 15 coronary heart disease, smokers vs. nonsmokers, 12-13, 15-17 Iung neoplasms, 57 stroke, 17 stroke, by age,,12'-13' stroke, by amount smoked;,12-13. stroke, by sex, 12-13 stroke, smokers vs. ex-smokers, 155 stroke, smokers vs. nonsmokers, 12=13, 15 Mortalits ratios aortic aneurysm, for men by amount smoked; 16 coronary heart di'sease, by age,. 12-1'3; 18! coronary heart' disease; by amount smoked,, 12'-13; 18 coronary heart disease, by sex, 12-13' coronary heart disease, smokers vs: ex-smokers, 15 coronary heart disease, smokers vs, nonsmokers, 12-13, 1., stroke, by age, 12-131 stroke, by amount smoked, 12-13 stroke, by sex:, 12-13 stroke, smokers vs, ex-smokers, ];i5 stroke, smokers vs. nonsmokers, 12r13, 15 Mucous membrane smoking au& neoplasius of, 58 Myocardiallinfarction etiology of, 2T-28' incidence rates and smoking history, 21-22 and smoking, 4, 16 atsocardium: effectl of cigarette smoking on,:11 :V as (tobacco and ashes ) and oral neoplasms in the USSR, 58 Negroes maternal smoking and prematurity in, 78 Neoplasms by sex, 56' prevalence of,,smokers vs. nonsmok- ers, 56 by type of tumor and'g smoking his- tory, 56' see also Specific type of neoplasms, e.g., Lung neoplasms; Neoplasms, experimental Neoplasms, experimental . broncbogenic carcinoma„63-64! epidermoid carcinoma, 64 Nickel carbonyl, as a cocarcinogen, 62I Nicotine effect on hypereholesterolemic rab- bits, 27 effect onipregnant rats, 80': see also Nicotine metabolites; Nicoo- tine, oxidized;, Tobacco alkaloids Nicotine metabolit'es; 61-62 Nicotine-N-oxides presence initobacco smoke, 62' Nicotine, oxidizedd in vitro ciliostatic effects, 42' \ itrogen~dioxide: effect on rats"lungs; 41 \-nitrosamines, 62 \-nitrosoanaba sine,,62 n'-nitlrosonornicotine, 62' Noncancerous oral diseasee acc Oral disease, noncancerous \ornicotine, 62' Norway incidence rates of' lung neoplasms, 55-56 Oral d'isease; , noncancerous and smok- ing;, 5-6, 8:i-87 see also Gingivitis ; I:eukoplakia ; Periodontal diseases;, Stbmatitis nicotina Oral hygienerelationshiP, to: smoking and noncan- cerous oral disease, 85-86 Oral neoplasms incidence of and smoking,,5S' andi smoking, 58, andItobacco chewi'ng„58 Oxidoreductases reduction of'~ in smokers' alveolarr macrophages; 42-43 Palatee smoking ~~ and! stoma~titis, ni'c~otina,, 87~ Pancreatic neoplasms and smoking, 6"1. 95

Periodontal diseases and smoking, 85-86 andl smoking, in Ceylon, 85-86 and smoking, in Norwegian Army recruits, 85 Plasma and thrombus formation~ 27-28 Polynuciear aromatic hydrocarbons see Aromatic hydrocarbons Population studies bronchitis and!smoking, 371 Preeclampsiaa sce Pregnancy toxemias Pregnancy effect of' blood pressure andi smoking habits on, 77-78 carboxyhemoglobin lesels~ of smok- ers,,80 effect of'nicotiise on, in rats, 80, effect of' smoking during; 4-5, 77-81 effect of smoking dllring, in II'un- gary; 79. effect of'smoking during, in Ireland; stroke mortality ratios by, 13' tumor prevalence among, smokers by, 56 Smoke, cigarettee effect on alveolar macrophage, 42 effect on bronchial epithelium of' dogs, 40 effect on i ciliary activity, 42 effect on DNA and RNA synthesis, 62 -63 effect on D°unalliclla biociclata, 42' effect on,pulmonary surfactant; 42' effect on tissue cultures, 62' gas phase, 63 inhadationmethods, 62 nickel carbonyl in; 62 reduction of tar content,,61 retention of tars in mouth, 62! Smokers arteriosclerosis in, 26 reduction of life expectancy, 3' sputum analysis of, 39-40, 57-58 Smokers, cigar/pipe 79 incidence of atypical nuclei in effect of smoking during, in Strot- land„79 effect of' smoking during, in Vene- larynY, 5:1incidence of coronary heart, d'isease; 21-24 zuela, 79 Pregnancyt'oxemias preeclampsia, and smoking, 79 Prematurity and maternal smoking, 77, 79 andl maternal smoking, among Ne- groes,, 78 ~ Pulmonary disease in rabbits, similar to emphysema, 41 Pulmonary emphysema see Emphysema Respiratory function tests of'smokers, with mild bronchitis, 39 usingrad'ioactive xenon, 39 Respiratory t'ract neoplasms experimental induction of, 63'-64 RNA synthesis effect of cigarette smoke on, 62'-63' Sex coronaryy disease incidence rates andd smoking history by, 21-22, 24 coronary disease mortality rates by,, incidence of gingivit6s;,86' incid'ence of stomatitis nicotina, 87' thickness of vocal cords, 60 Sinokers vs, ex-smokers atypical nuclei' in larynx,,59 coronary disease mortality for men,, by amount smoked, 15' coronary disease mortality for men, by years stopped' smoking, 15' coronary disease mortality for men, compared to nonsmokers, 15'5 stroke mortality for men, compared! to nonsmokers,,15 thickness of vocal cords, 60, Suiokers es. nonsmokers aortic aneurysm mort'ality, 16 atypicali nuclei in larynx, 59 comparison of'blood factors :of motfr- ers and infants;80 concentrations of o-aminophenols inn urine, 64 coronary drseaseincidence,18,20-22' coronary disease incidence and be- 13,17 7 haTior type, 24 coronary disease mortality ratios by,, coronary disease mortality, by age;, 13 stroke nrortality rates by, 13, 17. 13' t

Smokers vs. nonsmokers-Cbntinued coronary disease mortality, by amount smoked, 13 coronary disease mortality, by sex, 13 coronary disease mortality ratios, by age, 13' coronary disease mortality ratios, by amount smoked, 13' coronary disease nmrtality ratios, by sex, 13' Curschmann's, spirals in sputum of',. 39-40 incidence of! edentulism, 87 incidence of gingivitis, 86 incidence of periodontal disease, 85-86' incidence of preeclampsia among pregnant women, 79 prevalence of' neoplasms, by type of tumor, sex and age,, 56 stroke mort~ality,byage,13 stroke mortality, by aniount smoked, 13' stroke mortality, compared to ex- smokers, 15 stroke mortality, by sex, 13 stroke mortality ratios, by age, 13 stroke mortality ratios, by amount smokedy 13'3 stroke mortality ratios, Dyy sex, 13 thickness of'vocal cords, 60 urinary excretion of tryptophann met'aboiites, 64 Smoke, tobacco aromatic hydtocarbons in1 61 bladder carcinogens in, 64 carcinogenicity of, 62 cocareinogensinj 61 nicotine-N-oxides in; 62 Smoking and alveolar bone loss, 8.i,-87i and angina pectoris,,18' and arrliythniia, 4 and arteriosclerosis, 4;,5' and' behavior type, 20; 24 and bladder neoplasms, 60 and bronchitis,+ and cardiovascular disease. 3':-5 as cause ofl bronchitis, 37-40 as cause of emphysema, 37-38 as cause of' laryngeal neoplasms, 55 and coronary disease, 3-5, 20 effect on blood circulation, 11 effecti on blood platelets, 27=28'' effect' on free fatty acidj 27 effect on hemoglobin oxygen affinity, 29 effect on larynx and true Pocall cords; 59-60 effect on lung function, 5 effect on pregnancy, 4-5, 77-81 1 effect on thrombus formation, 27-28' effect' on ventilation/perfusion rela- tionships of'lung, 39 andfertilits history, 79-80 and gingivitis, 85-86 andkidney neoplasms, 60, andlllungneoplasms,,4, 55-58 andlllung neoplasms in men, 57 and lung,neoplasms in women, 57 and umrtality„3' and niyocardial infarction,, 4, 18'8 and noncancerous oral diseases, 5-6, 85-87 and oral neoplasms, 58 and pancreatic neoplasms, 60-6111 and'pregnancy tiogemias„791 and premalignant changes in larynx, 5 relation to bloodi choiesteroll and lung neoplasms, 57 relation to lung neoplasms and stomach ulcers,,57 acac ¢14o Smoking, niaternali Smoking characteristics andl incidence rates of lung neo- plasms for men, 56' and incidence rates of lung neo- plasms for women, 56 and lung neoplasm mortality rates,. 57 Smoking historyy aortic: aneurysm mortality rates by, 16'6 aortlic,aneurysm mortality ratios by, 16' and coronary disease incidence rates,21-24 coronary disease mortality rates by, 13-14, 17 coronary disease mortality ratios by, 13, 15, 18 incidence of atypical nuclei in. larynx by, 59 stroke mortality rates by„ 13, 17, stroke mortality ratios by, 13, 15 97

Smoking, maternal andi ability of placenta to hydroty- late benzo (a ) pyrene; 80 and abortion; 77-79carbotyhemoglobin levels; 80 effect on birth weight, 5, 77-78, 80 effect on infants' growth rate,, 78 effect on pregnancy, in Ireland, 79 effect on pregnancy, in Scotland, 79eff'ect onipregnancy;,in t'enezuelh, 79epidemiologicall studies of effects,, 77-80 and fet'al death, 77r78 ' incidence of preeclhmpsia, 79 and infant mortality, 77-7~8: and preuraturit'y, 77, 79 andprematuni'ty, amongN'egroes, 78~ Squammiscell carcinoma see Carcinoma, epirlermoid, Stomatitis nicotinaa and pipesmok~ing; 87 Stroke mortalit3'rates, by age, 13'3 mortality rates, byamount smoked, 13 mortality rates, byses„1l3 mortality ratios, by age,,13 mortali,tyratibs, by amount smoked,. 13 mortality ratios, by sex,13' Su rf'actiants effect of cigarette smoking,on, 42 Tar content of cigarettesmoke,, reduction of, 61 of' cigarette smoke, and tumorige- nicity, 61 Tars, cigarette retention inmouth,,G2 Tars, tobacco, ca,rcinogenicity, 61 Thrombosis effectof'smokiiig,in; 27-28 plasma and, 27-28 Thrombus formationn and smoking, 27-28 Tissue cultures effect of cigarette smoke on, 62-63 98 Tobacco f'ormused and, relation togingivitis,. 86 and oral submucous fibrosis, :i8 see also Tobacco alkaloidy, Tobacco al,kaloids and experimental bladder neo- plhsms, 64 possible role in carcinogenesis, 6°_' acc'col4o:Cotinine;1V'ornicotine. Tobacco chewing and oral neoplhsms, 58, Tooth extraction effect of' smoking on healing of' socket! , 87Tiyptophan met'abolitesurinary excretion of by smoker ;,6#' Twin studies: genetic and environmental factorsin~ anginaipectoris, 25 L'lceromembranousgingivitissee Gingik•itis;,uleeroinembranous. Ulcers and lung neoplasms, relation t'osmoking, 57, tirinarstract neoplasans and smoking, 60; 64! Urine o-aminophenol~s concentration in, of smokers and cancerpatients, (i-1, excretion of tryptophan metabolit'es by smokers, 61 Vincent's gingivitis relationship to smoking, 86' Vitamin D and nicotine, effect on hypercho- lesterolemic rabbits, 27 Vocal cords effect of smoking on thickness, :;9-G0 secat'so Larynx 11'omen, blood pressure andl smoking habits during pregnancy,, 77-78 incidence of' lung neopl'asms and smoking, 4, 57 U.SGOYERNMENTiPRINTING.OFFlCEi1916H. o--96P-928

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