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THE HEALTH CUNSEQUENCESaF S1iOICING 1975 U. S'. DEPARTTtENT' QF HEALTH, EDUCATION, ANDi WELFARE' Public Healtth Service : ,

T'q "~i~~~s 5,. .. . . . . .. J 41 PREFt#C E t Each year the Public Health Service reviews the scientific data related to the health consequences of smoking and submits its review to the Congress. This report, the ninth in the series,, summarizes : recent research in four major areas: cardiovascullar disease, cancer, respiratory disease, and the effects of smoking on the nonsmoker who . ;i shares the environment of those who smoke. t. 11s has been the case with each of the previous reports in the series, the research summarizedi herein further confirms the relation- .ships between, cigarette smoking and disease and premature death andl a , ~, refines our understanding of the mechanisms underlying these relationships. . . . . .. „' .. M . ~ .. . . . Cigarette smoking remains the largest single unnecessary and ~ preventable cause of illness and early death. In the eleven years since the report of the Advisory Committee to the Surgeon General in 1964, there has been progress toward reducing this toll. Fillions ~~ of Americans have stopped smoking cigarettes, and millions more have' °= not taken up smoking. Even for those who continue to smoke, there . t has been a striking,red'uction in the "'tar" and' nicotine content of' " cigarettes used by the vast maj,ority. At the same time „ however„ ' counter-balancing these gains,, there has been an increase in cigarette G 1y To~ eliminate the needles& deaCh, andd disabilityattributa~bleto . ;~'. cigarette smoking, the Public Health Service remains committed today, as in the past, to increasing,the knowledge about the health conse- . quences of smoking and to ed'ucating,the American people as to the nature and extent of the hazards of smoking. This is a task, not for rti government alone, but for the great institutions of soci'ety as a wtiole-- ~ the family, the schools, thie healith, care system. Through concerted effort, 'a climate of respect for our own heal!th, and that of othiers can be created. Such a climate must certainly be conducive to reducing and art ,4 eventually eliminating, the needless tiurden of disease and premature death imposed' by cigarette smo~king,., a Theodore Cooper„ PT.bi. Assistant Secretary for Heal th June 1975' ~' Q.J ~ CTa ~ i-~ ~ iii ~~_-- ',.~C`.ti, ` . n C. ~'f y smoking by' womeni and' young people, especially teen-age g'irls.: . , vrj: .- ~.5. ~. . ` Y 'V1 a

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C TABLE OF CONTENTS Page PREFACEI . . . . . . . . . . . I . . . . . . . .1 . . . . . . iii TABLE' OE''' CONTE;JTS . . . . . . .i . . . . . . . . . . . . . . v' PREPARATION OF THE REP©RT AMACKNOWLEDGPiENTS' .....,, vii INTRODUCTION: Overview--The Hea1th Consequences of Smoking, . . . . . . . . . . . . . . « . . 3 CHAPTER 1. Cardiovascular Diseases . ., . . . . ., . „ . 13 CHAPTER 2. Cancer . . . . . . . . . . . . . . . . . . . 45' CHAPTER 3. Nbn-Neoplastic Bronchopulmonary. Diseases . . . . . . .. . . .~ . . . . . . . 63' CHAPTER,4. Involuntary Smoking . . . . . . . . ., . . . 93'. INDEX . . . . . . . . . . . . . . ... . . . . . . . . . . . . 117 v

PREPARATION~OF THE' REPORT AND' ACHINOT,Ti,EDGMEP3TS Previous Reports Revi'ews~of the scientifi'c evidence linking smoking, to health effects began in 1964 with, "'Smoking, and' Health. Report of the Advisory Coanaittee to the Surgeon General of the: Public Health Service,'' or as subsequently referredito, "'the Surgeon General's Report." After this report,, Public Law 89-92 was passed requiring supplemental reports to Congress on this subject. In compSiance,, three reports were submitted: 1. "The: Health, Consequences of Smoking,, A Public Health Service R'eview : 19'6 7'. " 2. "1'he Health Consequences of Smoking,, 1968 Supplement to the. 196 7PHS I R'ev'iew. " I. "'The~ Health~~ Consequences~~ of~ Smok~i'ng~~,, 19'69~, Supplement to~ the~ 1967'PHS Review." In April 19'70, Public Law! 91-222' amended'the previous law and called' for an upd'ated& report on the health effects of smoking no later than January 1, 19'71, with annuaL report& thereafter. "The Health Consequences of Smoking,, A Report of the: Surgeon General: 1971„" a comprehensive review, of all the scientific literature available to the Clea~ringhouseforSmok3n~g and Health, and with emphasis on the most recent. additions to the literature was that updated report. Since then, the following annual reports on the health consequences of'smoking have been submitted: 1., "The Health Consequences of Smoking,, A Report* of the Surgeon General, 1972. '111 2'. "'The Health Consequences of Smoki'ng,, 19'73'." 3'.. The Health Consequences of Smoking, 1974." Each: report since -the original "Surgeon General"s Report" as reviewed'the scientific literature relevant to the assoc3ation between smoking, and cardiovascular diseases, non-neoplastic bxonchopulmonary diseases, and cancer. Smoking as related to~the following, diseases and conditions has been reviewed periodically in the reports: Q Pregnancyr (1967, ,11969, 1!9'71, 1972, 1973) Peptic IJlcer Disease (1967, 1971, Noncancerous Oral Disease (1969) 19'72, 19'73) vii

Tobacco Amblyopia (1971). Allergy (1972) Public Exposure to Air Pollution From Tobacco Smoke (1972) Harmful Const3:tuent&of' Ci'garetteSmoke (1972) Pipe and Cigar Smoking (1973)' Exercise Tolerance (1:9731 The 1975 Report The present document, "'fihe Health Con"sequences of Smoking, 1975'," begins with an overview of the health consequences of smoking and'contains the current data on relationships between smoking and cardiovascular diseases,, non-neoplastic bronchopulmonary diseases, and, cancer. A fourth chapter, "Involuntary Smoki'ng,,," reviews, the effects to nonsmokers of exposure.to smoke-filled environments. Although emphasis is on the latest additions to the literature, where necessary to, provide the background or framework, research from earlier years is included. This report was prepared'by the staff of the National Clearinghouse for Smoking and Health in thef'ollowingway: 1!. The Technical Information Center of the Clearinghouse continually monitors and collects the scientific literature on the health consequences of smoking through several establishedd mechanisms: a., An information science corporation is~on contract to: extract articles on smoking and health from the scientific literature of the world. b. The National Library of Medicine,, through the MEDLARS':system, provi!d'esa: month~lylistiing ofarticlesl on smoking and health., Articles not provided by the information science corporation are ordered. c. Staff members review current medical literature and identify perti'nent articles. 03%4d3g 2. The literature was reviewed by the Medical Staff Director who wrote, f irst draf ts for this report. These draf ts were sent to: reviewers for criticism andi comment regarding the format,, the appropriateness of the articles selected'for discussion, and the Vi:ii

conclusions. The final drafts of the total report were reviewed by the Director of' the National Clearinghouse for Smoking and Health, the Director of the National Cancer Institute, the Director of the National Institute of Environmental Health Services,, the Director of the National Heart and Lung Institute, and by additional experts both inside and outside the Public H'ealth Service„ ACKNOWLEDGr1ENTS'. The National Clearinghouse for Sznoking and Health, Daniel Horn,, Phl.D'.,, Director, and Charles A. Al'thafer,, Acting, Director, is responsible for the preparation of this report. Medical Staff Director for the report was David' M. Burns, MI.D. Consulting editors were Elvin E., Adams,, M.D., Daniel P. Asnes, M.D., John H. Holbrook, M'.D. „ Paull Schneiderman, M.D'.., and H. Stephen Williams,, M.D. Technical Editor was Priscilla B:. Holman, and Technical Information Officer responsible for the literature collection was Donald!R. Shopland. The professional staff has had the assistance and advice of the followi'ng experts in the scientific and technical fields whose contributions are gratefully acknowl!edged. Reviewers ANDERSON, William H,., M'.D.,--Chief, Section of Respiratory and Environmental Medicine, University of Louisville„ Louisville, Ky. AL1ER'BACH,Qscar,M.D.--Senior~ MedicalInvestigator,, VeteransAdtninistration Hospital, East Orange,,N.J. BOCK,, Fred G., Ph.Dl.--Director, Orchard'P'ark Laboratories, Roswell Park Memorial Institute,, Orchard Park„ N.Y. BOREN, Hollis G., M.,D'.--Assistant Director of the Medical Center and Associate Dean of the College of Medicine, University of South Florida, Tampa, Fla. FALK, Hans L., Ph.Dl., Associate Director for Programl„ National'Institute o Environmental Health Sciences, Research Triangle Park, N.C. FERRIS, Benjamin G., Jr.,, M.D.--Prof essor of' Environmental Health and Safety„ School of Public Health, Harvardl Umiversity, Boston, Mass. GOLDSMITH,: John R., M.Dl.--Medical Epid'emiologist,, Epidemiological a Studies Laboratory, California State Department of Health, GJ Berkeley, Calif., ~ HIGGINS, I'an T. T., M'.D.--Professor of Epidemiology, School of Public 11 'Health, University of' Michigan, Ann Arbor, Mich. ~ ix

r HOFFM'ANNi, Di'etrich, Ph. D'.--Member,, and' Chief, Division of Environmental Carcinogenesis, Naylor Dana Institute for Dfisease Preventioni, American HealthFoundation, Valhalla!,;. N.Y'. KELLER, Andrew Z., D.M.D.--Chief, Research in Geographic Epidemiology Medical Research Service, Veterans Administration Central 0!ffice,, Washington, D.C. CP Diseases, Kettering Medical Center, Kettering, Ohio. OLZ, Richard A. ,, M.D.--Medical Director, Institute of Respiratory LENFANT,~ Claude Ji., M~-,, M!.D~~., --Associate Director for~ Lun& Programs, National Heart and' Lung~, Institu~~te,, National Insti~tutes~~ of~Health~, Bethesda, Md. MacMAHON„ Brian, M.D.--Professor, Department of Epidemiology,, School of Public Health,, Harvard University, Boston,,, Mass.. McMILLAN, Gardner,, C., M!.D.--Associate Director, Associate Director for Etiology of Artheriosclerosis and Hypertension, National Heart and Lung Institute„ National Institutes of Health,, Bethesda, Md. NETTESHETM, Paul, M.D.--Gtoup Leader, Respiratory Carcinogenesis Group,. Biology Division, Oak Ridge National Laboratory, Oak Ridge!, Tenn. PAFFENBARGER, Ralph S'.,, Jr., Mi.D.--Epid'emi'ologist,, Resource for Cancer Epidemiology, California State Department of Health, Berkeley, Calif. PETTY, Thomas L.,, M.D.-Professor of Medicine,, and Head, Division of' Pulmonary Diseases,, University of Colorado Medical Center, Denver, Colo. RALL, David P., M.D.--Di'rector,, NationaT Institute of Environmental Health Sciences,, National Institutes of Health, Research Triangle Park, N.C. RAUSCHER, Frank Ji., M.D.--Director, National Cancer Institute, National Institutes of Health, B'ethesda, Md,. RENZETTI, Attili'o D.„ Jr., M.D.--Professor of Medicine, and Head, Pulmonary Disease Division, University of Utah Medical Center, Salt Lake City, Utah RINGLER, Robert L., Ph.D'.„ Acting Director, National Heart and Lung Institute, National Institutes of Hlealt'h„ Bethesda, Md. SAFFIpTTI„ Umberto,,rL.D.--Associate Director for Carcinogenesis,, National ~ Cancer Institute, Nationall Institutes of health,, Bethesda,, Md. ~ SCHMELT7.„ In-7in„ Ph.I?.--Associate Member and Head', Section of Bio- `~ ~ organic Chemistry,, Division of Environmental Carcinogenesis, Naylor &J Dana, Institute for Disease Prevention, American Health Foundati'on, u'alhalla,, N.Y, Q'' x

SCflUK#.N, Leonard M'.,, M.D.--Professor andi Director, Division of Epidemiology School of Public Health, University of Minnesota, Minneapolis, Minn. SN']hfKZN, Michael B'. „ M.D.--Professor of' Community Medicine and Oncology, School of Medicine, University of Cali'fornia, La J'olla, Ca1if.. NYNDER', Ernst L., MI.D'..--President and Medical Director,, Americani Health. Foundation,, New York,, N.Y'. Special assistance for the Card'iovascul!ar Chapter was provided by JENNZNGS, Michael, M'.D., Medical Epidemiologi'st, OMio Department of Health, Columlius, 0'hhio:, and MAN'NING, Kathleen, Mi.,, R.N., Department of Staff Development,, Boston City! Hospital, Bostoni,, Mass. The ffollowizLg staff inembers of the Center for Disease Control a1so, contributed to the preparation of this report: Bureau of Training,- Jmlia M. Fuller, Winthrop N'. Davey, M.D. ,, and Seth N., Leibler„ Ed.D. ;National Clearinghouse for Smoking and Health - Nancy M'. Johnston and Sanda Lager. ® xi

C" INTRQDiJ'CDION : Overview--The Health Consequences of Shiokin;g,

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CVER'VI'EW- HF.ALTH' CONSEOUENCES OF' SMOKING Tihe statement, "Warning: The Surgeon General Has Determined That C'igarette Smoking, Is Dangerous to Your Healthi,"" has been required by law on cigarette packaging since 1970 as a part of the Public Health Cig- arette Smoking Act of 1969. This Act was a response by the U'.S. Congress to the scientific information on the health consequences of cigarette smoking,suammar3!zed in reports then available (the Surgeon General's Report of 1964 and' thie subsequent' 1967, 1968, and 1969' PFS' Health Consequences of Smoking). This Act was plassedibecause a series of important questions,concernd'.ngcigarette smoking, andihealthhad beeni answered. The following discussion summarizes the basic questions, the methodology used to determine the answers, and the answers themselves. The initial question tobeanswe~red' concernin&the health consequences~ of smoking was "Are there any harmful health effects of smoking cigarettes?"' The answer to this question was provided in two ways. First,, it was demonstrated that some diseases occurred more frequently in smokers than in nonsmokers. Second, a causal relationship was established between smoking and' these diseases. A reasonable place to begj:n to look at the health consequences of' cigarette smoking was in thie area of overall death rates. If cigarette smoking,contributed substantially to the development of any major disease, th~is, would be reflected in a higher overall death,ratefor smokers:. Several large prospective studies have clearly shown that cigarette smokers have higher overall deathiratesth:aninonsmokers ofthe~ same ageandisex., Demonstrating,this association, however, was not enough to establish, the causal nature of'the relationship between smoking ancT excess deathh rates. The decision whether or not an association is causal is not merely a statement of statistical probability. Determining that the association between smoking and excess death rates is causal was ajudigement made by DHEW after a number of' criteria had' been met, no one of which by itself was sufficient to make this judgement. These criteria include: a. The consistency of the association.. b. The strength of the association. c. The specifici'ty of the association. d'. The temporal relationship of the association. e. The coherence of the association. 3

The association between cigarette smoking,and excess death rates has consistently been demonstrated in &large number of studies performed during the last 3©'years. The few studies not showing this relationship: had serious defect&in their design or analysis which limite&the interpre- tation of' their results. The strength of the association has~been firmly established by repeatedly showing that cigarette smoker&have one and a half to two and a half times the overall death,rates of nonsmokers. The specificity of the association was d!emonstrated by establishing that substantial excess overall death rate&occurred in:populations of smokers grouped by age, sex, race, socioeconomic class,; occupation, place of residence, and' many other variables. The temporal reLationshdipof the association between,cigarette smoking and overall death rates wasclearliy shown by the marked decrease in excess death rates that occurs after stopping; smoking. The coherence ofthe:ass,ociation wasestabl'ished'byshowing that aa dose-response relationship persisted' when dosage was.measured'by number of cigarettes smoked per day, duration of smoking, age at initiationlof smoking,,, depthof' inhalati'oni, or pack years ofsmoking., This relationship was alsed'emonstrated in prospective as: well as retrospective studie&. Thus, the extensive evidence concerning the health consequences of' smoking gathered by many researchers and analyzed'for consistency, - strength,, specifici't.,,temporal relationship,andcoherencehasclearl'yestablished cfigarette smoking, as the cause of'the excess mortality among, cigarette smokers. The establishment of, smoking as the cause of excess mortality broughtt up the additional question: "'How are the health consequences of smoking,, expressed'as individual disease processes?" The most important specific health consequence of cigarette smoking in; terms of the number of people:affected'is the development of premature coronaryh~eart d!isease(CHIa). Retrospecti've!studiiesestablished that cigarette~smokers, have agreaterrisk, of death due to:. CFIDand havs,ahigher prevalence of CHD~ thaninpnsmokers. Prospective studie&confirmedd that cigarette smokers have higher death rates from CEIDd and established that they have ah3gher incidence of'CEID than nonsmokers. Long-term folliowup of healthy populations~has confirmed that a cigarette:smoker is more likely to have a myocardial infarction and to die from CEID than a nonsmoker. Cigarette smoking has been shown to be one of the:maj',or independent CHDirisk factors and to act synergistically with the other majlor alterabl'e CHD risk factors (high blood pressure and'elevated!serum cholesteLol). Autopsy studies have shown that persons whiolsmoked.cigarettes have more severe coronary: atherosclerosd!sthan persnnw who, did'not smoke. 4

C A second major health cons quence.of smoking is the development of cancer in smokers. Cigarette smoking was firmly established' as the major cause of lung cancer by several large retrospective and prospective studies. The risk of developing lung cancer was found' to be 10 times greater for cigarette smokers than for nonsmokers. The risk of developing,lung,cancer increases with the number of cigarettes smoked per day: and is greater in cigarette:smokers who report inhaling, who started smoking,at an early age,, or who have smoked for a~greater number of years. Smokers of filter cigarettes have been shown to have a]:ower risk of developing lung cancer than smokers of nonfilter cigarettes,, but the risk remaines well above that for nonsmokers. The risk of developing cancer of the larynx, pharynx, oral cavity, esophagus, and urinary bladder was also~found!to be significantly higher in cigarette smokers than in nonsmokers. Pipe and cigar smokers were found to have elevated risks for the development of cancer of the oral cavity, pharynx, larynx, and esophagus when compared to nonsmokers. Pipe and cigar smokers report that they inhale muchiless frequently than cigarette smokers. As a result their lungs receive much less smoke exposure than cigarette smokers''. This is felt to be the reason for the lower incidence of cancer of' the lung for pipe and cigar smokers compared to cigarer,te smokers. FTomen have had'far lower rates of lung cancer than men. This has been attributed to women's tendency to smoke fewer cigarette per day, the fact that fewer women than menismoke, and the fact that women smokers generally select filter and low tar and nicotine cigarettes. However, the percentage of women smokers in the Hnited States has increased dramatically in the last 30 years, and since 1'9'S5 the death rates from lung cancer in women have.increased proportionately more rapidlyttian the rates~for men, reflecting this increased proportion of women smokers. The tar from cigarette smoke has been found'to ind'uce malignant changes in the skin and respiratory tract of'experimental animals,; and a number of specific chemical compound's contained in cigarette smoke were established as potent carcinogens or co-carcinogens. Malignant changes including carcinoma in situ were found in the larynx and in the sputum exfo!liative cytology of experimental animals exposed to ci'garette smoke. Nonmalignant respiratory: disease is a third area of smoking-fnd'uced morbidity and mortality. Cigarette smokers have.been shown to have more frequent minor respiratory infections, miss more dayrs from work due to respiratory illness,, and report symptoms of cough and sputum production more frequently than nonsmokers. Retrospective an&prospective studies with long-term fo]:lowup have found that cigarette!smoking is the primary cause of chronic bronchitis and emphysema in the United States. Cigarette smokers have also been found to be more likely to~ have abnormalities of their pulmonary function tests and1have higtier death rates• from respiratory 5

diseases than nonsmokers. Data from autopsy studies have shown that cigarette smokers were more likely to have the macroscopic ctianges of'. emphysema, and that these changes are closely related to the number of. cigarettes smoked'per day. Mucous cell hyperplasia has been found more often in cigarette smokers. Cigarette smoke also inhibits the ciliary motion responsible for cleansing, the respiratory tract. An add'itional area of hea];th concern has been the effect of cigarette smoking during pregnancy. Mothers who smoke cigarettes during, the last two trimesters of their pregnancy have been found to have bablies& with a lower average birth weight thaninonsmoking mothers. In addition cigarette smoking mothersh~ad alhigh~errisk of having astililborn child, and their infants had higher late fetal and neonatal death rates. There are some deta to show that these risks due to cigarette smoking,are evenn greater in women who have a high risk pregnancy for other reasons. These effects may occur because carbon monoxide passes freely across the placenta and'is readily bound by fetal hemoglobin, thereby decreasing thee oxygenicarrying capacity of fetal blood'. Having established' the health consequences of smoking, two additionall questions became important. They are, "'Canithe health consequences to the individual be averted by stopping smoking or by changing the cigarette?"and'"What are the overall public health consequences of cessation?"' The first question is the simpler of the two to answer. In the individ'ua1„ cessation of cigarette smoking resullts~iiv a:rapi&declineof the carb on monoxide level in the blood over the f i'rs t 12' hours. gymptoms of cough, sputum prod'uction, and shortness of breathiusually improve over the next few weeks. A woman who stops smoking by the fourth month of her pregnancy has no increased risk of stil~:lbirth or perinatal death in her infant rel~;ated!to smoking. The d'eterioration in pulmonary function tests that occurs inisome smokers becomes less rapid than that of'continuing,smokers. The death rates from ischemic heart d'isease, chronic bronchitis, and'emphysema also quickly become less thanithose of the continuing smoker. The risk of d'eveloping, cancer of' the lung, larynx, and oral cavity declines substantially in ttiefirst fewyears, after cessati'on and 10 to 15 years after stopping smoking approximates that of nonsmokers. A smoker who switches to filter cigarettes and' has smoked'ithem for 10 years or longer has a lower risk of developing,lung cancer than aismoker who continues to smoke nonfilter cigarettes. The risk to a filtered cigarette smoker, however, still remains well above that of a nonsmoker. The public heal'th benefits of'cessation are more difficult too determine than the effects of' cessation on the individual. Just as

C cause-specific death rates have reflected the effect of cigarette smo&ingg on certain diseases, they shouldialisoreflect any substantial beneEitsto be gained by cessation or reduction in cigarette smoking. Several factors combined to produce a reduction in per capita dosage of tobacco, exposure in the Unitedi States for the years 19661-19'70. FYrst, per capitaa consumption of cigarettes declined'from 4„287 cigarettes per person in 1966 to 3,985 in 19'70. Second, during this period there was a slow but significant decrease in the average tar and'ni'cotine content of' cigarettes as well as a decrease in the amount of tobacco contained in, the average cigarette. The decline in p r capita consumption d'uring those years occurred'in the'face of a substantial increase in the proportion of'women smokers and so reflected predominately a decrease iin cigarette consumption by men. Since 19,701, althoughithe per capita consumption of cigarettes has increased„ the average levels of tar and' nicotine have continued' to decline, making it more difficult to predict what has happened to per capita dosage.. Examination of cause-specifilc death rates for the period of this dieclining, per capita consumption (Tab1e 1)i reveals that there was a downturn in the male deathirate from: ischemic heart disease beginning,in 1966 which reversed the upward trend that had occurred over the previous two decades. This decline in the death rate from ischem2c heart disease has not occurred in women. The male deathirate from chronic bronchitis has also been declining since 1967, and'the male death rate for emphysema has declined since 1968 when it was first recorded as a separate category. Female death rates for these two diseases have not shown these trends. Despite the impressive coincidences of the decline in deathi rates among,maTes occurring, at the same time that there was a decline in per capitalcigarette consumpti'on,, it is impossible to be certain of the exact cause of the decline in th~e'deathrates- These d'iseases,areinfluenced by a variety of factors, in addition toicigarettesmok.ing, such as blood pressure and air pollution. Some of these factors have also been.subject to major control efforts which may have contributed to the decline in the death rates. In addition, there have been therapeutic advances in the treatment of these problems which may also tiave helped lower the death rates. A decline in male d'eath rates from lung cancer should also follow the decline in p~ercapi'taconsumption. This rate would not be,influenced asmuchs by chanlaes in other etiologic factors or changes in therapy because cigarette smoking causes from 85 to 90 percent of all lung cancer and there have been no major improvements in survival due to changes in, therapy. GJith lung cancer, 7

, ~ZlrY,.!" :,:,.. . •:~'.-.h t:, ..t~ ., ,... r .... Ischernic Heart Utsease ,: puronirBronchit9s P (410-413)2e«3 T r s (490,491)2 ; ~.'i,V ..P.-1 ~' i r1.ir ({,r.nAd TABLE 1 beatkrQtas for selected cauges, b}+ scx 146 3-1'9731'' Year 1963 1964 1965. 1966 1967 1968 1969 1970 1971 1972 1973' Y W;<=~ .« 4 S r, : Emphysema (492)2,4: 361.6 2209 i;.~.S.f4.3 1.6 Y' 354'.2 ~ 218.5 L§ } y' ltC ~;4•2 , 1 5 ;; E i xis cr 6 2221 . . -.1., 43 16 361.6 226.5 4.7 1.6 3'57.0 225 4 4.8 1 6 `. ` G ". t t 40017 , : 277.5 p) -0 4.7 - 16 ~392:0~j,273.6 0 .-f .~ ,34:4 1.4 zi.~ 272'0 , 387:2 , ; ~..• # fs` 4.3 14 . :; Y '`381.0 273.8 tl t'~. ~~._:..4'.0 1.4 .. 382.4 277.6 ' ` 4:2' 1.5 '378.5 276.01 . • 3:8' 1i.5' .{; 18.2 3:9 60.3 14.8 17:6' 61.3 _ 15 4 '.' . . r 43.0 -7~:5, 44.4 7:7ii 46.0 8.3 48.0 8.9 r: 20:9 3.7' 53.5 111, 1~ F119'•5' 16,' c` 54.7 , 111.8 r..\ U9L11 "3,7 S7A ., 126 s . . 18.3 3.8 ,. .. 57.8' 133 ~`"`'. 4 t Campil'edl frem Vitat Statistics of the United States, volumes Service, U.S, Department of Hlealth. Educatipn, for L963 iiA73 National Center for Health Staais6ics Public Health and Welfare IVUmbens after causes of death are category numbers from the Eighth, Revision of the internationall Classification of Diseases, used' in :J , Vital Statistics of the United States beginning iri 1968; prior to 1968 S h e t eventll udL Revision wasse 3The rates for 1963-11967 are for the category Arteriosclerotic Heart Disease inclluding,Coronary Disease (4'z0) and for 1968•1973, thee category Isahemic Heart Disease (410-413) to reflect a c1Ymificati h on c ange from the Seeth Eihh Ft ,vn togtevision. - 4Emphysema was recorded as: a separate category beginning,in 1968 with the Eighth Revision. ~ tt , r~rt^:,'.`( ~ ~....,~ . . :~.{. .. .- . . .4 Ij1 o)S.?~~•~1:..".i et4ibv, ~t1, Y.Ki. „ ? . .. "'+'.. ,. f j:...~/:..T F.. ('160:rll63) Z _ p E Yt' IuialSgnan t Neopllasms of ' iRt;spiratory System '' i ?r « . 33 8 s

C however, two, additional considerations must bekeot in mind. A d'eclinein death rates.Irom lung cancer would be expected to lag several years behind adecl!ine,.in peT capitaconsumption.In~ addition, thed'eclinein consumption and swi'tc'tu to;low tar and nicotine cigarettes occurred predominately in the Younger age %roups where death rates from lung cancer are low partly b'eca''.se of~ the long latent period, (about 2'0 years)' between onset of ex, posure to cigarette smoke and the development of lung cancer. For thesee reasons, it is necessary to look at lung cancer death rates by age group rather than total lung cancer death rates. The lung cancer rates by age groups for 1971 show that there may be aidecline inithe lung cancer rates for the younger males (under 4S), but the confidence limits on these trends at present remain wide enough to make it impossible toisay whether it is a real decline or merely a leveling, off. The national health statisticss broken down by age group are currently available only through 1971. The data by age group from a few more years will be necessary to determine accurately whether the lung cancer death rates are going down or leveling,off. The total death rates for all respiratory tract cancer are available through 1973; they showacontinuedlincrease, in boththemale and femaIedeatli rates reflecting,the fact that older age groups have both a higher incidence of respiratoryy tract cancers and have not had as large a change in smoking-behavior. A demonstration of a decline in male, age-specific death ratess for lung,cancer would add one more important piece of data to the already substantial evidence on the health consequences of smoking. 9

CHAPTER 1 CARDIOVASCULAR'DISEASES

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CONTENT5 Page Coronary Heart Disease (CHD) . . . . . . . . . . . .I . . . . . 15 Iutroduction. . . . . . . . . . . . . . . . . . . . . . 15 Cigarette Smoking as a Major Risk Factor for Coronary Heart Disease. . . . . . . . . . . ... . . . 15: Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease. . . . . . . . . • 16'. Hypertension . . . . . . . . . . . . . . . . . . . 17 Cof f ee Drinking . . . . . . . . .I . . . . . . . . . . 20 Ventricular Premature B'eats . . . . . . . . . . . . . 21 C'arbon:tK'onoxide . . . . . . . . . . . . . . . . . . . . . 21 Introd'uction . . . . . . . . . . . . . . . . . . . . 2'1 Sources of Carbon MonoxideExposure andHuman Absorption . . . . . . . . . . . . . . . . . 2'2 Effects on Healthy Individuals. . . . . . . . . . . 2'2 Effects on Persons With Atherosclerotic Card'iovascular Disease. ., . . . . . . . . . . . . 2'7' Studi'es on the Pathogenesis of Cardiovascular Disease.. . . . .. . . . .. . . . . . . . . . . . . 2'8 NYcotine . . . . . . . . . . . . . . . . . . . . . . . . 2'9' Acro.Iein . . . . . . . . . . . . . . . . . . . . . . 29 Cerebrovascu]lar Disease. . . . . . . . . . . . . . . . . . . 29 Effects of Smoking on the Coagulation Syrstem. .. ... .. 30, Stunmary of Recent Card'i'ovascular Find'ings. . . . . *. . . . . 32 Bibliography. . . . . ., . . . . . . . . . . . . . . . . . . . 33' M+ Crt, 13, N

C List of Tables Page Table1.--Age-standardiaed blood pressure changes,QmmiRgY at followup for continuing,cig;arette smokers and quitters according,to wei'ght changes ................... ....... 18' Table 2'.--Niuimber of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters .....................................................191 Table 3'.--Mean percent of carboxyhemoglobin saturationliu smokers and nonsmokers by sex and race .................... ....... 23'. Table 4.--Mean percent of carboxyhemoglobin saturationlin smokers and nonsmokers by employment status ....... ............ 2'4 Table S.--Median percent carboxyhemoglobin (C©Flb)i saturation and 90, percent range for smokers and nonsmokers by location.., .............. ............ i ...... ..«...e ........i ......25 Table 6.--Mean percent carboxyhemoglobin (COHb) saturation in cigarette smokers 1 hour after last cigarett8..............26. Table 7.-Age-standardized death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking, (lifetime history)i and age at start of ........3]~ study .................... .......... .....................

CORONARY HEART DI'SEASR' (CHID)'. Introduction Coronary Heart Disease (CHID) is the ma3'.or cause of death in the Uriited'. States and is!the most important single cause of excess'mortaiity among cigarette smokers. The evidence relating smoking to CHID has been reviewed in previous reports on the health~consequences of smoking (HCS 1, 2', 3', 4,. 5, 6, 7', 81. The following, is a brief sinnmary of the relationships + between smoking and CHID presented'in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocard'ial i'nfarction andIdeath from CHD~.. Cigarette smoking,acts both independently as a risk factor and synergistically with the other CFID'k risk factors. The magnitude of the risk increases directly with the:amount smoked'. The excess risk of CHD among smokers has been demonstrated in some Asian, Black, and Caucasian, populations and is proportion- ately greater for younger men., especially those below age 50. Cessation of cigarette.smoking results in a reduced mortality rate fromiCHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly! higher risk of death from CHID than nonsmokers,,but they incur a much lower risk than cigarette smokers. This has been attributed!to the lower levels of inhalation that characterize most pipe and cigar smoking,. Data from autopsy studies have shownicoronary: atherosclerosis to be more frequent and more extensive inicigarette:smokers,than in nonsmokers, anid'experimental work in humans and animals has suggested several mechanisms by which smoking,may influence the development of atherosclerosis and CEID. The formation of' carbox,yhemog]!obini, release of catecholamines, creation of an imbal'ance between myocardial oxygen supply and demand', and increased'platelet adhesiveness leading to thrombus formation have all been demonstratedlin smokers and proposed as exp' anations' for the excess CHIDimortality and, morbidity among smokers. Cigarette Smoking as a Major Risk Factor for C'oronary Heart Disease The evidence tstablishing,smoking, as a major risk factor in CHD has been reviewed in previous reports (FICS 1, 2, 3, 4, 51, 6', 7, 8). During, the last year new epide:miolooic datalhave been published on the relationship between coronary artery disease:and smoking. Bengtsson (CV72, 2~40)studied thesmoking,habitso,f women!withmyocardiaS infarction (MI) in Goteborg,, Sweden. He found that smoking was significantly more common in a group of 46 women (80 percent smokers), ages 50-54, who had amyocardial infarction than in alcontro.l group~ of' 5:78hea];thynonhospitaliaed women (37.2 percent smokers). 15

c '0ther investigators examined the effect of cig;arette smoking on survival of people with acute myocardial infarction. In a study of 400'patients with documented myocardial infarction who survived to be admitted to a coronary care unit, Helmers (CV 242', 243,, 244) found no significant difference between the percentages of smokers and nonsmokers among survivors s tudied af ter the first 24 hours, from 2' days until discharge, and from discharge to 3 years. Reynertson and Txagourni'.s(CV41)~, in a 5-year prospective study of137' patients with~documented CHD~at age 50 or less, were also unable to find'any relationship between CHD mortality rates andd smoking habits. Smoking habits after entrance into the study were also considered and again no difference in mortality rates was found. The Coronary Drug Projlect (Ref. 10) was able to find an effect of cigarette smoking on mortality after myoca:dial infarction. This groupp studied 2,,789' men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3'months aftera myocardial infarction and m:ortality(t-value of2.94)'. None of these studies were able to examine the smoking habits of the grouplof people wholdie suddenly as a first manifestation of CHI), and therefore may have excluded that group in which.there is the highest excess mortality due to cigarette smoking, (Ref . 11)1. Additional data from the Swedish twin-study'of'Fri!berg, et al. (CV 38) have been reportedi. They found an excess CNID mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers were to small tolbe significant, the authors suggest that this tends to support the theory that bothismoking and CHD are constitutionally determined. These data!must be viewediwi'th caution, however, since the difference was demonstrable only in the old'er age group (born 1901 -]1910). When the younger age group (born 1911 - 1925) wasconsidered, noexcess,CfID~.mortalitywas,seen in the dizygotic group but a small excess was noted in thie monozygotic group (,three CHD deaths in the high smoking, group andione in the low smoking group). Also the difference in cigarette consumption between the high and low smoking,groups was relatively small (seven cigarettes per day). Consequently, datalfrom thiis study are not sufficient to warrant the conclusion that both smoking and' excess. CHD mortality are constitutionally determined rather than smoking being a cause of the excess CPID.imortality. Cigarette Smoking in ReSation to Other Risk Factors for Coronary Heart Disease Cigarette smoking, elevated serum cholesterol, and elevated blood' pressure are generally accepted as the three majior modifiable risk factors for CHD. However, there is less agreement concerning other CHD' risk factors-- obesity, physical inactivity, diabetes mellitus, elevatediresting heart rate, psychologic type A behavior, etc. Thefollowing,studies,present recent© evidence on the relationships betwe n smoking and hypertensiom, coffee ~ drinking, and ventricular premature beats. .~ . 0! ~ 16 ~ C11'

Hypertension Results from several studies have shown that smokers on the average have slightly lower blood pressure than~nonsmokers.. Some investigators have attributedl this finding, to~ the fact that smokers on the average weigh, slightly less than nonsmokers. Three current studies (CV 231, 104, 193)' discusa~ thj!srelationship. Gyntelberg and ',Meyer(~CV 231)~„ based on their evaluation of 5,249 men ages 40-59,, were of the opinion that lower blood pressurein smokers could not be,accounted for bydiffer~encesin weight, age,, or physical fitness. Kesteloot and Van,Houte (CV 104),, in a study of' 42',804 men, performed a multiple regression analysis on age,, weight, and height and1found that cigarette smokers had lower blood pressure than non- smokers; however,,wheuthey included serumicholesterol values in the analysis,, thed'ifferencein blood pressurewasreducedito~ approximately 1 mm Hg. Although this difference was statistically significant basedlon the large population, the actual difference in blood pressure was too small to be of clinical importance,. Seltzer (CV 193) ) studied 794men selected for their initial good health and normal bloodpressure (below 1400 systolic and 90 diastolic)' and'followedi them for changes in cigarette smoking habits,, weight, and t'_ood pressure. During the 5-year period of the study 104 men gave up smoking. For every age group~except those over 55, there was a significantly greater weight gain (8' Ib) among the "quitters"than among the continuing,smokers (3.5' lb)i. Blood pressure increased'4mnn:H&systolic and 2'.,5mmHg diastolic in the quitters with nachange inisystolic and a slight reductionin diastolic (-1.1 mm~ Hg) in~ persons whocontinuedi to~ smoke., In ord'erto exami'neblood pressure changes in relation to weight change,, both continuing smokers and quitters were grouped accordi'ng,to their weight changes duri'ng the period of study (Table 1). The most significant finding was an~increase in the systolic blood pressure (+1.77'mg Hg) among, the quitters even:in that group with significant weight loss. In contrast,,the continuing smokers with significant weight loss had a decline in systolic blood pressure (-3'.2& mm Hg). Diastolic blood pressure in qu3tters showed anincrease with weight gain and no change with weight loss, while continuing smokers showed a e decreasein diastolic pressure with weight loss andino change with weight ga:fn. The data on subjects whose blood pressure had increased to hyperten- sive levels (systolic ;~ 150 and diastolic ? 95) were evaluated, and it was found that quitters had a much higher frequency of becoming hyperten- sive chancontinuing,, smokers (Table 2') . Seltzer, in interpreting these data, suggested that cigarette smoking, tends to inhibit blood pressure increases, with only minimal pressure rises occurring, even in instances of substantial weight gain. When this inhibiting effect of cigarette,sTnoking, is,removed a~sin the case of thequitters~„ sharpp rises: in blood pressure become evident. He cautioned', however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight andthat his data do not allow anievaluation of the degree of blood pressure changes according to how recentTy, cigarettes were given up. 17

TABLE~I F. -Age~st'andQrd'ized~bfoood'pressure~~cfianges'(irrrn hfg)l'~~ al~foll'o~wup~for~ continuirtg~, cigarette smokers and 'qpid'ters accordih'g~ ta ~ iweig/ir cJtanges~ Weight Change (LB)' Smoieiag,Class Signific Wt ao ant' $ Nm Sign Wt Ch ificant ange Moderate Wt GaSt S igniFicant Wt Ga3u No.. L. -2 LB 5 to-S No,, LB' -4~ w +4 No~ LB +5 to +12 N LB' +13 to +30 Nfean systolic BP changes: Cbntinuing,smokers 32' -4.00 84I -1.52' 71 2:85 24 1.50 Quitters 13 11.77' • 27' 2.22 27 4.04 32' 3669' Mean d'iascoGc BP charr$es:,' Continuing,smokers 32 -3.28 84~ -2.04 71 0'.73'. I i 2+4 -0:04 Quitters 113' -0! 31 ~, 2'~7~ -L9ti~, 27 4;30. 32 3.94 fStandardized' on basis of age disOrdbution!of' current'cigaret'te smoker& Source: Seltzer, C.C. (CV 193)i.

;V C Ti A8LE ~~ 2:. - Number ~o f~sabjects ~~ who ~ had'~ d'evelwped `hyperrension~ at . followup, for conxinuimg,cigarette srno,kersand'q,ui,tt'ers Blood pressure levels Continuing cigarette smokere `. Quitters Number Percent Number Percent Systolic blood pressure 1150+ 6' 2'.8' 9 ~~ 8:7 Systolic blood pressure 160+ 2' 03 5 4.8. Diastolic blood pressure 95+ 3' 1.4 5 4.81' Source: Seltzer, C.C.,(CY 19.1j. ~

C The results of t:ae, ischemic heart disease study by Kahn, et al. (Et'ef. . 1) raise additional questions about Seatzer's~ data. Kahn followed 10,00'0' Israel3i male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertensio: He presented no data concerning, persons who stopped smoking, b,.~._ he d'.i6 show ciLaL the incidence of hypertension increased'with age and that the age-adjusted incidence of hypertension inismokers was over twice that of nonsmokers (76.9/'1000 for smokers uersus~ 35'.4/1000 for nonsmokers) . Seltzer reported no data on the incidence of hypertension in nonsmokers, and'the age distribution for his group of smokers (',the ori'ginal source of the q,uitters) is heavily weighted to%ardi younger age groups (with only 33 of 2'14 men age 50 years or over). According to Kahn"s d'ata.,, this age group would be expected'to have a lower incider.ce~ of hypertensioni„ and,, in fact, Sel!tzer: found' only small numbers of men who developed'hypertension (',eight with diastol.ic hypertension) (Table 2). Making interpretations based on such small numbers is, hazardous ;, for example, the difference between current smokers and quitters~i'n the incidience of diastolic hypertension could have been produced by only three men quitting smoking because they d'eveloped' hypertension.. " Cof fee Drinking The Boston Collaborative Drug, Study (Ref. 2) recently reported a correl'ation between coffee drinking, (,7 6 cups per dau)' and myocardial infarction that persisted after controlling for the, ef.fect of cigarette smoking. This was a retrospective studyof 276 patients with a h,ospi'ta1 discharge diagnosis of myocardial infarction and 1,104,age,, sex, and hospital- matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteri'stics that make izterpretati=di'fficult. In controlling for the effect of' cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked'more than one pack per day. Because c'igarette consumption is highly correlatediwith coffee consumption (CV 166,, CV 54), it can be expected that within such broad smoki'ng, categories those •aho were heavy coffee drinkers~tended to be heavier smokers .than those who consumed smaller amounts of coffee. It is.also possible that the hospitalized controls represented persons who drank less coffee than the general population because of'serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning,the extent to which tF-erelationship between coffee d'rinking, and myocardiall infarction is independent of the relationship:of both variables to cigarette smoking,. The question of the i~ndependent nature of'this relationship~is also:dealt with in a prospective study by Klatsky, et al. (CV 166) of 464 patients with myocardial infarction who previously had had multiiphasic health checkups. Both ordinary controls and' CHD risk faWtor-matched controls were drawn from 250,00&people who had u-ndergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee dfinking, andl myocardial infarctiomwhen risk-matched controls were usedl.. 20,

The Framingham Study (CV 258)~ recently published data on coffee drinking based on a 12-year followup of 5',209' men and women ages 30-62. An increased risk of death from all causes was demonstrated in coffee drinkers„ but this relationship was accounted for by the association between coffee consumption. and cigarette smoking. No association betweencoffee d'rinking, and myocardiial infarction or between coffee drinking andithie development of CFID,, stroke, or intermittent claudication was demonstrated. Heyden, et al. (CV 54) also found no relationship~between excessive coffee consumption (~ 5 cups per day) and atherosclerotic vascular d'isease. . Ventricular Premature Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD'. Vedin, et al. (CV 87)~, in a study of 79'3 men in Goteborg;,Sweden, examined~the~frequencyofrhythm and conductiondisturbances; at rest and during exerc3se. They found no statistically significant correla- tion between cigarette smoking habits and the presence of supraventricular, and ventricular premature beats at rest or during exercise. . - Carbon Monoxide Introd'uction Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemoglobIn levels below 15 to 20 percent were thought to have little effect on humans. Currently there is considerab]le interest in determining the effect of chronic exposure to low levels of carbon monoxide HCS 5, 6', 7, 8)i. Carbon monoxide is present in concentrations of 1 to 5 percent of the gaseous phase of cigarette smoke (Ref. 3, Ref. 4). The concentration varies with temperature of combustion as well as with factors which control the oxygen supplysuch,as the porosity of thepaperan~d' packing; of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemog,iobin levels in smokers vary, from 2 to 15 percent depending on the amount smoked, degree of inhalation,, and the time elapsed since smoking the last cigarette.. Carbon monoxide, which has 2'301times the affinity of oxygen for hemo- globin, impairs oxygen transportation in at least two ways: First,, by competing with oxygen for hemoglobin binding sites, and second, by increasing the affinity of the remaining hemoglobin for oxygen, so that a lower tissue Pa2 is required co deliver a given amount of'oxygen to the tissues. Carbonimonoxide also binds to other heme-containing pigmeftts, most notably myoglobin,, for whichlit has even a g;reaterr a£finity thart for hemo- globin. The significance of this binding,is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements p and larga amounts of myoglobin. ~ ~ M ~ 21.

Sources of Carbon Monoxide Exposure and Human Sorption. Several researchers (CO 61, 6, 134, 135, 125, 133) have estimated the relative contribution of cigarette smoking and air pollution tothe humann carbon monoxide burden as measured by carboxyhemogiobin levels (COHb). Kahn, et al. (CO 134), in a study of 16,649 blood donors, determined that smoking was the.most important contributing, factor,, followed by industrial work exposure. Nonsmoking, industrial workers had COH'a levels of 1.3'8 percent, and, nonsmokers wi'thout industrial exposure had'levels of .78'percent. Cigarette smokers,, on the other hand„ hadivery hi'gh levels. Smokers withlindustrial exposure had levels of 5.0l percent, while smokers without industrial exposure had levels of 4.44 percent (Tables 3' and4). Stewart, et al. (CO 135) found similar results in a nationwide survey of blood donors and'noted marked d variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However, in all areas,, smokers still had COHb levels two to three times higher than nonsmokers and had d inareasing, COHb levels with increasing level of cigarette consumption (',Table 6)1. Similar findi.ngs were reported by Torbati, et al. (CO 12'5)' in alstudy of 500' male Israeli blood donors. Nonsmoking workers exposed to automobile exhaust--London taxi drivers (',C016) and garage and service station operators (CO 61)--have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these highlexposure occupations smokers have markedly higher COHbi levels ($.1 and 10.8 percent) than nonsmokers (6.31and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed too an average of63 ppm CO withipeak exposure levels as high a&2117' ppmCO!; cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (CV 184). Studies on the C0'burden of each cigarette have determined the body burden of CO' per cigarette to be 7.10-8.66 ml (CO 46),, and the increase in CJ'Hb level produee&by smoking one cigarette to be .94 to 1.6 percent after 12 hours of abstinence (CO' 121„ CO 46). The 1'iallf-life for the washout of CO' in healthy college smokers (CO 46)' was calculated to be from 3' to 51 hours. Effects onlHealthyIndsvidluals Several studies have beeniputilished on the effects of carbon monoxide on healthy ind'ivi:d'uals. Small doses of CO (COHb levels 2'.4-5 .4 percent) were found to have no effect on heart rate (CV 160). Raven,, et al. (CV 197), in a stud'yof young, men,exposed during exercise on a treadmill to 50 ppm C0,(',COIIblevels 2.,51 percent in nonsmokers~and4.1 jin smokers), ,foun~d no d'ecreasein maximum aexobic capacity when the subfects were tested at 25°i C. In a similar experiment conducted at 350 C by the same researchers (CV 9'6)„ there was al decrease in maximum aerobic capacity in nonsmokers exposed to 501ppm C0, but not in smokers despite an increase in the carboxyhemoglobin levels of 1.5 percent in both groups. They postulated a possible physiologic ad'aptation of smokers to carbon monoxid'e. Ekblom and Huot (CO 47) studied five young, men 2'2.

. C ~ TAB'LE' 3. - Mean percent of carbox,~hemogl'obin saturation in smd/cers and nonsmokers by sex and race Tat:Ll!Satnple Nonsmokers Smokersl No. X'tS~ No. X~Si ,, No. X±SX TotallSample 16,649 2.30:t 0:021 10,157 085 ± 0'.01 6,492 4,58+ 0.03 Male 10,54'2' 2.66 ± 0:03' 5'„888 1.00 ± 0.01 4,654 4.76 ± 0.04. Female' 6,107' 1,.68 + 0:03' 4,269 0641± 0.01 1,838 4.1'0 + 0.06'. White 15,167 2:28±0.02' 9,474 085It0.01 5,693 4.66't0.04 Male 9,669 2:65 t 0:03' 5,508 1'.00 t 0.01 4,161 4 4.83 0.04 Female 5,498' 1.63 t 0:03' 3;966' 0641 t 0',01 L532 4.19 ~ 0.06 Black 1,429 2.59 + 0:06 : 64!1 0186 t 0.03 788' 4.00 ± 0.'08 M ai'e 829 2.911 t' 0:10 347 1.07 ± 0.05' 482 4:24 ±' 0A0 Female 600, 2:15 t 0:09 294 0'.62 ± 0.04 306 3.63 t 0:12 1'Smokers are: defined as those who smoked on the day of giwing,b[ood., NOTE. - 7C = mean, percent';!Sx = st'andard error of'mean percentl Source: Kahny A.,, et all (Co' 1'34)~ 23

Ta~~BLE' 4. ~- Mean percent of 'carboxyliemoglobin saturarion inrn smokers~ and'nonsmokers by employment status Nonsmokers Smoketsl IVo: X t Sx No. 7C' *- SX Persons employed 8,478 0.89't 0.01 5,962 4.6'1 t 0.03 Classed'as ind'ust'rial workerst 1',523' 1.38' ± 0:04 1,738 5.01 ± 0.06 Classed'as workers other than industrial 6.955 0.78 * 0:0'1 " 4,224 4.44 t 0.04 Ptrsons not employed' 1i,678' 0.63' ± 0:02. 531 4.24 ± 0:1i1 tlndustrial workers are empl'oyed in either durable or nondurable goods manufacturing (craftsmen„operatiives, on Iaborers),, Smokers are defined as those:who smoked on the day, of'giving blood. 1+T©TH: - XI ='mean percent; SX, = standarderror of mean percenr., Source:: Kahn, A.,,et all (CO 1'34). 24

l ., C TABLE 5~1. - Median percent ~ earb~ozyhemoglobim (COHh'~) , saturation and ~Q~0'~ pe'reen~~r ~ nnnge for smokers arrd nonsmokers by location r Cigarette Smokers Nonsmokers 1 Location Median Range Median Range Anchorage 4.7 0:9 - 9.5 1.5 0.6' - 3.2 ' Chicago 5.8' 2:0' - 9'.9' 1.7 .0~- 3.2. 1 Denver 5.5 , 2'.0 - 9_8 2:0 0'.9-17 Detroit. 5.6 1.6 - 10:4 1'.6 0.7 - 2:7 Honolulu 4.9 1.6 - 9.0' 1.4 0.7 - 2:S Houston 3.2 1.0 - 7.8. 1.2 0.6 - I5 Los Angeles 6.2 2.0 - 10.3 1.8 PL0 - 3:0 Miami 5.0' 1.2 - 9.7 1'.2 0.4'- 3ff Milwaukee 4.2 1'.0 - 8.9 1.2 0.5 - 2.5 New Orleans 5.5 2:0 - 9.6. 1.6 1.0 - 3!0. Pl'ew York 4.8'. 1.2 - 9.1 1.2 0.6 - 2.5 Fhoenix. 4.1 0'.9 - 8:7 l.2 U -2•S St. Louis 5'.1 13 - 9:2' 1A 0:9' - 2.1 ' Salt Lake City 5.1' 1'.5 - 9.5 1.2 0:6 - 2'.5 San Francisco 5.4 1.6 - 9:8 1.5 0'.8 - 2.7 Seattle 5.7 1.7'- 9.6 1.5 0.8 - 2.7 Yermonti New Ha mpshire 4!8 1.4'- 9.0 1.2 0:8 - 2.11 Washington, DC 4'.9 1.2 - 8.4 1.2 0.6 - 2.5 Source: Stewart'„1R.D.,,et all (CO 135). 25. (

TABLE 6, -1u4`ean percent~cruboxyhemoglnbin' (COHb) saturotibmin cigarettee smokers 1' hour af ter last cigarette Packs ofCigazet'tes Smoked' Per day Location Nonsmoker < YS ys-1 1 1% 2! M'iiwaukee 3. 1.3 3.0 4.2' 53 6,2' 4.7 New H'ampshire,. Vermont 1.4 3.3 4.4' 5:7 6.7 5.3' New York City 1.4 3.1 4,3' 4!7 5.8I 6.3'. Washington, D~.C 1.4 3:8 4.6 5.2 5.8' 6.6 Los Angeles 2:0. 4:0 5.2 6:0 7.4' 7.5 Chicago 2:0 4.8 5.4I 6'.3 7.1 7.7 Source:~ Skewarti, R.D.,,eti al. ({C013S)., 266 i

who inhaled' CO to reach given COHb levels. They reported that as COI3B° l'evels increased',, there was a decrease in maximal oxygen~uptake and'lower heart rates at maximal treadmill exercise. Sagone, et al. (CO 63), in a study of 9 cigarette smokers and 18 non- smokers ages 20-32, showed significantly higher values for COHb, red'cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2',3 DPG were unaltered while oxyhemoglobin affinity P'50' and ATP levels were significantly lower in the smokers. The three smokers with~highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smoking. The authors interprett these data as evidence of tissue hypoxia. Millar and Gregory (CV' 128), in al study of both fresh heparinized' blood and ACD-stored blood from a blood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokers; this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (CO 22), ', in al study of pregnant women, found' COHb levels itx the fetus to be 1.8 times as great as those in the simultaneously measured blood of the mother. Fetal blood was exposed to carbon monoxide in vitro, and fetal'hemoglobin was found'to have a shift of the oxyhemoglobinn disassociation curve to the left as occurs with adult hemoglobin. The higher fetal COHb levels were attributed to the lower fetal Pp and a resultant decrease in the ability of oxygen to compete for the feia]l hemoglobin. It was felt by the authors that the high COHb levels may be responsible for the lower birth weight of infants born to mothers who smoke.. Effects on Persona with~ Atherosclerotic Cardiovascular Disease Aronow and Isbell (CV 179) and And'erson, et al. (CO 24) have shown a decrease in the r:can duration of exercise before the onset of pain in patients with angina pectori's exposed to low levels of carbon monoxide (50 and 100'. ppm),. Carboxyhemoglobin levels were significantly elevated (2'.9percentafter 50, ppm; 4.5percent after100'ppm~) and the systolic bloodl pressure, heart rate, and product of systolic blood pressure times heart rate (a1measure of cardiac work) were all significantly lower at onset of anginal pectoris. In a continuation of this work, Aronow, et al. (ICV 194, CV 263) studied eight patients during two separate cardiac catheterizations,,one during whichh each patient smoked'three cigarettes and one during,which each patient inhaled' carbon monoxide until the maximal coronary sinus COHb level equalled'that produced by smoking during the first catheterization. All eight had'angf:o- graphica]~:ly demonstrated' CHID (> 75 percent obstruction of at least one 27 0

coronary artery). Smoking,increased the systolic and diastolic blood'pressure,, heart rate,, left ventricular end-diastolic pressure (LVFDP)',, an&coronary sinus, arterial, and venous C0 levels. No~changes were noted in left ventricular contractility (dp/dt)',, aortic systc>lic ej,ection period, or cardiac index, and decreases were f©und in stroke index and coronary sinus,, arterial, and venous 1MV-Z, When carbon monoxide was inhaled, increased LVEDP and coronary sinus, arteriaT, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in~left ventricular dp/dit„ stroke index,, cardiac index and coronary sinus, arterial, and venous Pb2 were found. These data suggest that carbon monoxi~de has a negative inotropic effect on myocardial tissue resulting in the decrease in contractility (dp/dt) and stroke index. When the positive effect of nicotine on contractility and heart rate is added by cigarette smoking, the net effect is increased cardiac work far the same cardiac output. In the heart with~coronary artery disease there is a greatly resLLricted'capacity to increase blood flow in response tos this increase in cardiac work. The result is earl'ycard'iac decompensation manifested by elevation in LTJEDP' and angina pectoris. Aronow, etal.haarealso~ shown decreased exercise time prior to onset of angina pectoris in persons exercised after ridi'ng for 901minutes on the Lo&AngelesFreeway (C0121).7[n a related study„ they demonstrated a decrease in exercise tj.me before claudication in a group of patients with intermittent claudication who were exposed to,50 ppm CO (CV 118)I. Studies on the Pathogenesis of Cardiovascular Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (CV 106) noted that inicholesterdl-ffed rabbits exposed to 170 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to,340 ppm for 2 weeks the cholesterol content of the aorta was 2.5 times higher than that of' cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits: intermittently exposed to carbon monoxide for 12'or 4 hours per day produced' three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at 10 and 16 percent oxygen fiad' 3'to 3.5 times the aortic cholesterol content, while those exposed to 26, and 28'percent oxygen had a considerable decrease in cholesterol accumulation. Further work by these authors (C0 12'2) revealed'that in rabbits fed normal diets but exposed to 180 ppm carbon monoxide for 2'weeks, there were local areas irr their hearts of partial or total necrosis of myofibrils; in the arteries there was endothelial swell!ing, formation of subendbthelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (CO'19), the luminal coats showed pronounced changes characterized by severe edematous reaction with extensive swelling and formation of' subendothelial blisters and plaques. Th~eauthors:postulate that carbon monoxide increases endothelial permeability to albumin which results in forma- tion of edema leading,to changes indistinguishable from early atherosclerosis. ~ za ~ ~

This postulate is made even more significant by the findings of Parving, (CV 129) who showed an increased' transcapillary escape rate for 131 i- labeled albumin in humans exposed to .43 percent C0 (COHb 20 percent) for 3 to 5'hours, but not inithose made hypoxic to an altitude of 4300 meters (hemoglobin 75 percent saturated). By exposing rabbits to different concentrations of carbon, monoxide (,501„ 100, and' 1'80 ppm) for varying periods (.5,, 2', 4, 8, 24,, and 48' hours)',, Thomsen and Kjeldsen (CO 129) were able to show a threshold of 10'0 ppm of' C0 for myocardial damage. The demonstration of damage at this level of C0. (COHb 8-1G percent) is possibly explained'by the affinity ratio of carboxy- myoglobinitoicarboxyhemoglobin which is about 3 to 1. Thus, a COHb level of 10 percent would'be accompanied by a carboxymyoglobin, level of 30'percent. This ratio can gradually increase with decreasing Pp2 to a ratio of 7 to l att a Pp2 of 40 mm Hg,, a level reached'in many tissues including the myocardium. Nicotine In a, study of the effects of smoking cigarettes with low and high nicotine content, Hill and Wynder (CV 144)' notedlincreasing serum epinephrine levels with increasing nicotine content of the smoke, but serum norepinephrine level's were unchanged. Serum corticoids were also markedly elevated on smoking high nicotine cigarettes. No free fatty acid changes related to nicotine were detecte&. Also note& were increasing,serum epinephrine Ievels with increasing number of low nicotine content cigarettes smoked. Acrolein Egel and Hudgins (',CV 2!49)' did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significant increase in~blood'pressure and heart rate in rats. CEREBROVASCULAR DISEASE' There has been conflicting evidence on whether there is an increased risl~ of cerebrovascular disease due to.smoking (HCS 1, 2, 3, 4, 5, 6, 7, 8'). A~prospective study by Paffenbarger (Ref. 5) of" 3,991 longshoremen followed for'i8 years showed no correlation between fatal strokes and smoking. H~owever,,boththe~ D'or~n study of U. S. veterans (Ref. 6)~ andHammond!"s,study of one million men and women (Ref. 7) showed a small but significant increase in the death rates from cerebrovasccular disease among cigarette smokers. The Framingham 18r-year followup of men ages 45 to 54 (Ref . 12) and Paffenbarger "s study of'men who entered Harvard between 19'16 and 194Q (Ref 4) also showed an excess risk of cerebrovascular disease associated with cigarette smoking. :"~Two recent studies provided more data on this topic. Ostfeld, et al. (CV::100; 196),; in a study of'2,748 people ages 65-74 receiving old age assistance in Cook County,, Illinois,, were unable to find any relation ~ habits at the start of the study and incidence of 'tietween ci kin arette sm 0 g g o new',strokes or prevalence of transient i'schemic attacks. Nomura, et al.. (',CV:246),, in a study of the population of Washington County, Maryland, ages W' ~ ~ 4T9. QD' 29

c 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. rlomura noted that "in athero- sclerotic strokes the Framingham study and P'affenbarger''s investigation of former college studentsincluded!a great percentage of strokecases under the age of 55. Because these two stud!ies found an association between cigarette smokingand atheroscleroti'c strokes and the present study did not, it may be that the association is age-dependent." Hammond (Ref. 7) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates inicigarette smokers andinonsmokers increases as persons get older except in males ages 75-84 (Table 7')'„ indicating that the excess death rates associated!with cigarette smoking increases with ad'vancingage. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with age, reflecting the fact that cerebrovascular disease death rates attributable to other causes increase withiage much more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk_ factor for stroke at all ages, but other causes of strokes become proportion- ally so important in older age groups that in studies not based on very large populations the risk due to cigarette smoking is masked by the large total number of strokes due to other causes. EFFECTSOFSMOKINOWTHE0OAGUhATION SYBTF..MSeveral studieshavecontributeditoan understandling of the, role, ofsmoking in thrombogenesis. Levine (CV 13), in a controlled double blindl study, showed that smoking a single cigarette increased the platelet's response to~a standard aggregating stimulus (ADP). This phenomenon did not occur when lettuce leaf cigarettes were smoked and was independent of a rise in freefa.ttyacid's,in the plasma. The author postul'atesthat this maybedne toincreas3ng epinephrine levels. These data may have relevance for two other studies. In the clinical trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, England, (CV 158)i it was found that cigarette smokers were at increased risk of sudden death,. This increased risk was not present in smokers treated' wi'th clof ibrate. However, the researchers were unable to relate this reduction in risk to any effect of cllofibrate oniserum lipids. RecentlyCarvalho,,et al.(CV 259)! evaluated 29' patientsw!ithifamilial hyperbetalipoproteinemia and noted that their platelets had an increased sensitivity toaggregating stimuli (ADP). Treatment with cliofibrate returnedi the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction initheexcessrisk,ofsud'den death could be due to a clofitrrate induced reversal of increased sensitivity to aggregatingstimuli produced'by smoking. 30

c TABLE ~ 7. ~- Age«standardized'~ d'eatJ} rates and mortalit;r~ ra~tios~ for cerebral'uascular lesions for men and'n women by type of smoking (1'ifetime history) and'age at start of study Type of 3molOing Age Groups 45-5455-64 65-74 75-84 CVL Death Rates per 1004000 Person-5liears Men Never smoked regulerly Pipe, cigar Cigarette and other. Cigarette only Total W omen Never smoked regularty Cigarette Total' 28 92 34'9' 1,358 25 100 369 1,3711 28 12936 ` 990 42 130 477 1,1'68' 35 116 391 1,272 18 57 228 1,082' 38 88 3'15 1,277 25 64 238 1,091. CVL Mortality Ratios Men Never smoked regularly 1.00 1.00 1'.00 1.00, Pipe, c igar 0 j89 1.09 1.06 1.01 Cigarette and other 1.00 1.40 L03' 0! 73 Cigarette onl'y 1.50 1.41 1.37 0.86 Women, hiever smoked regularly 1.00, 1.00 ILOO 11.00 Cigarette 2.11 1.54 U8 1.1$' NOTE. - C V L= Cerebral vascular lesions:, Source: Hammondl E.C. (Ref, 7). 31

SITNlM1AF2Y' OF' RECENT CARDIOVASCULAR FINDINGS 1. Data fromone recent study suggest that cigarette smokers are:more likely to develop hypertension than are nonsmokers. There is some evidence that suggests that stopping,smoking,may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major source of elevated carboxyhemoglobin levels,,with occupational! exposure and air pollution being far less~important in most circumstances. Carboxyhemoglobd:n levels in cigarette smokers are two to three times the levels in nonsmokers and incresse with the amounts smoked. 3. Elevated carboxyhemoglobin levels have been shown to.decrease maximal oxygen uptake in healthy people as well as to decrease the exercise tolerance of persons with angina nectoris andlintermittent claudication. The carboxyhemoglobin levels at which these effects take place are well within the range prod'uced by cigarette smoking. 4. Carbon monoxide at levels.of exposure commonly reached' by cigarette smokers has been shown to decrease cardiac contractility in persons withi coronary heart dYsease. 5.. Carbon monoxide has beenishown to produce changes Iike those of early atherosclerosis in the aortas of rabbits. • 32.

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(Ref'. 11)I INTERSOCIETY ' COMMISSION FOR HEART DISEASE RESOURCES. Athero- scl!erosis Study Group and Epidemiology Study Group. Primary prevention of the:atherosclerotic diseasea.Circulation 4'2(6)~: A-54-A-95, December 19'70. (CO 6) .IOIv'ES, R. D. ,, COMhtINS, B'. T. , CERNIK, A. A. Blood lead and carboxyhemoglobin level's, in Lond6n taxi drivers. Lancet 2(7772): 302-303, August 12, 1972'. (Ref. 6) KAHN, H. A. The Dorn study of smoking and mortality among,U.S. veterans: Report on 8-1/2 years of observation. In: Haenszel, W. (E'd'itor). Epidemiological Approaches to the Study of Cancer and' a'ther Chronic Diseases. Bethesda,, Md., U'.S'. Publi'c Health Service, National Cancer Institute Monograph No. 19, January 1966, pp. 1-125. (R'ef. 1')KAHN, H. A., MEDALIE', J.H'. ,NEUFELD, H. N., RISS, E., GOLDBOURT, U. The incidence of hypertension andiassociatedifactors: The Israel ischemic heart disease study. American Heart Journal 84(2) : 171-182, August 19!72'. (CO 134) KAHN, A., RUTLEDGE, R. B., DAVIS, C. L., ALTES, J. A.,, GANTNER,, G. E., THORNTON, C. A., WALLACE, N. D. Carboxyhemoglobin sources in the Metropolitan St. Louis population. Archives of Environmental Health 29'(3): 127-135, September 1974. (CV' ]i04) KESTELOOT, H., VAN' HOUTE„ 0'., An epidemiolog;ic survey of arteriall blood pressure in~ a large male population group~. American Journal of Epidemiology 99(I): 14-29, January 1974. (CO' 19) KJELDSEN, K., ASTRUP, P., WANSTRUP, J'. Ultrastructural intimal changes in therabbi't aorta aftera:moderate,carbon monoxide exposure. Atherosclerosis 16(1) : 6'7-82, Ju1:y-August 19'72'. (C0 122) KJELDSEN, K., THOMSEN, H. K., ASTRUP, P'. Effects of carbon monoxide on myocardium. Ultrastructural changes in rabbits after moderate, chronic exposure. Circulation Research 34(3): 339-3'48', Ifarch 1974. (CV 166) KLATSKY, A. L., FRIEDMAN,, G'. D., SIEGELAUB, A. B. Coffee drinking prior to acute myocard'ial infarction. The Journal of the American Medical Association 22'6(5):~ 540-543, October 29:,, 1973. (CO 46) LANDAW~,, S. A. The effects of cigarette smoking, on total body burden and excretion rate~s, of carbon monoxide. Journal of Occupati'onaS Medicine 15(3)~: 231-235, March 1973'. :36

c (CV13) LEVINE, P'. H~~., An~ acute effect ~~ of cig,arette~~ smok~~i'ng~, on platelet (Ref. 12) function. A~ po~s~~s~~ible~~ link,betwee~n smoking~ and arterial thrombosis. Circulationi 48(3): 619'-623, September 1971. McGEE, D. Section 28. The probability of'developing certain, cardiovascular diseases in eight years at specified val'uesof some characteristics. In: Kannel,, W. B., Gordon, T. (Editors),. TheF'ramingham Study: An epidemiological investig~ation of cardiovascular disease. U.S. Department of Health, Education,,, (CV' 128) and Welfare,, Public HealthiService, National Institutes of Health,, Publication ?I'o. (NIH) 74-618, i-iay 1973, 152' pp. MILLAR, R. A., GREGORY, I'. C. Reduced oxygen content in equil!ibrated! fresh heparinized and' ACD-storediblood from cigarette smokers.. British Journal of Anaesthesia 44(10): 1015-1019, October 1972.. (CV 246) NOMURA, A., C~.OINfSTOCK, G. W., KULLER,, L.. , TONASCIA,, J. A. Cigarette smoking and strokes. Stroke 5(4): 483-486, July-August 1974. (Ref . 4 ) OSBORNE, J!'. S.„ ADAMEK, S., HOBBS, M'. E. S'ome components of gas phase of' cigarette smoke. February 19'56. Analytical Chemistry 2'8(2): 211-215, (CV 100) OSTFELD, A. M.,, SHEKELLE', R. B'.,, KLAWANS, H. L. Transient ischemic attacks and risk of stroke in an elderly poor population. Stroke 4(6): 980-986, 2Tovember-December 1973. CV 196) OSTFELD,, A. M. , SHEKELLE', R. B'. , ICLAWANS', H:. ,, T U'FO,, H. M'. Epidemiology of' stroke in an elderly welfa re population. American Journal of Public Health 64 (5) : 450-458, May 1974. (Ref. 5) PAFFENBARGER',, R. S., Jr. Factors predisposing to fatal stroke in longshoremen. Preventive Medicine 1(4): 5'2'2-528„ December 1972. 'ef. 9) PAFFEIyIBARGER',; R'. SI. , J!r.,, WING, A. L. Chronic disease in former .colllege students, XI. Early precursors of nonfatal stroke AmericanlJournal of Epidemiology 94(6)1: 52'4-5301, December 19'71. (,CV 129) PARV'ING„ H. -H. The effect of'hypoxia and carbon monoxide exposure on plasmaivolume and capillary permeability to albumin. Scandinavian Journal of Clinical and Laboratory Investigation. 30'(1) : 49-56y; September 1972. (CV 19~~7~~)~ RAVEN, P. B;.~„ DRIIIKWATER'~, _B. L., RUHLING,,R. 0'.~,~ BOLDUAN',,N1., TAGU'CHI,, S., GLIIIER',, J.,, HORVATH, S. Mi. Ef f ec t o f carb on. monoxide and peroxyacetyl nitrate on man's maximal aerobic capacity. Journal of AppliediPhysiology 36(3) : 288-293, March 1974. b 37 M

(CV ' 41) REYNERTSON, R. H., TZAGOURNIS, M. Clinical and metabolic characteristics. Effects on mortality in coronary disease. Archives of Internal Medicine 132 (5) :' 649-653, Nbvember 1973. (C0 121) ' RUSSELL, M. A. H'. Bl,oodi carboxyhaemoglobin changes during tobacco smoking. Postgraduate Medical Journal 49(576): 684-687, October 1973. (CO'~ 6~~3)i SAGONE, A-L~.~, Jr~~.~,, LAWREN'CE~, T.~,,BALCERZAK~~, S.~ P'. Effect ~ of smoking, on tissue oxygen supply. B1'ood' 41(6) : 845-851, June 1973. I' (CV 193) SELTZER, C. C., Effect of smoking on blood pressure. American Heart Journal 87(5): 558-564, May 1974. (CV ' 160~)~~ SHEPHARD,~ R.~ J.~ The influe~nce~~ of small dos~es,of carbon monoxide upon heart rate. Respiration 29 (5/6) r 516-521, 1972. (C0' 1') STEWART',, R. D., BARETTA,, E. D., PLATTE, L. R., STEWART, E. B.,, KALBFLEISCH, J., H. ,VAN YSERLOO, B. ,RWf„ A., A., Carboxyhemo- globin levels in American blood donors. Journal of the American Medical Association 229(9): 1187-1195, August 26, 19'74. (CO, 129) THOMSEN, H. K., KJEI:DSEN,K.Threshold! limit for carbon monoxide- induced myocardial damage. An electron microscopic study in rabbits. Archives of Environmental Health 29(2): 73-78, August 1974. CO 125) TORBATI, I. Di., HAR-KEDAR, I., BEN-DAVID, A. Carboxyhemoglobin levels in~ b1oodidonors~~ in reTa~ti'on~ to~,cigaret~te~ smokingand to~~o occupational exposure to carbon monoxide. Israel Journa]l of Medical Seiences~ 10(3): ~ 241-244, March, 1974. (tHCS 1) ' U'. S. PUBLIC' HEALTH SERU'I'CE'. Smoking, and: Health. Report of the Advi~so ry Committee to the SurgeonGeneraJ1 of the Public HealthService. Washington, U.S. Department of Health, Education, ` and Welfare, Public Health Service Publication No. 11013, , 1964, 3'87' pp • (HCS 2) U.S. PUBLIC HEALTH SERVICE. The Health Conseq,uences of Smoking. A Public Health Service Review: 1967'. U. S. Department of H'ealth,,Ed'ucation, and: Welfare. Washington, Public Health Service Publication I3o. 1696, RevisedIJanuary 1968, 227 pp. . ,r i . 3,t5

C (HC'S 3) U.S. PUBLIC HEALTH'SERVICE. The Health Conseq,uences of Smoking.. HCS'4!X 1968. Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education,, and Welfare. Washington, Public Health SertricePublication 1696:„ 1968,,117' pp. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1969'. Supplement to~ the 1967' Public Health Service Review.. U.S. Department of Health,, Education, and Welfare. Washington, Public Health Service Publicati=169'6-2, 1969, . g8pP!• (HCS 5) U.S'.PUBLZC'HE'A'LTHSERVICE.The Health Consequences of Smoking. A Report of the Surg,eon General:: 1971. U.S. Department of Health, Education,, and Welfare. Washington,,DHEW Publication No~. (HSM) 71-7513, 1971, 45'8 pp. Q1 ~S 6)' U~.S~.PUBLIC HEALTHSER'VICE. The Hea1!thConsequences of Smoking,., A Report of the Surgeon General: Health, Education, and Welfare. No. (HSM)' 72'-6516, 1972', ]i58' pp. 1972. U.S. Department of' Washingtoni, DHEW'Publication 'HCS~7) U.S. PUBLIC~HEALTH SERV'ICE., The~ Health Consequencesof~ Smoking: 1973. U'.S'. Department of Health, Education, and Welfare. Wa:shington,„ DHEW' Publication No,. (HSM) 73-8704, 1973, 249 pp. HCS 8)' U.S, PUBLIC HEALTH SERVICE'. The HealthiConsequences of Smoking: 19'74. U.S. Department of Health,, Education, and Welfare. Washing,ton,, DHEW Publication No. (CDC) 74-8704. (CV8'7)VEDIN, ,J. A., WILHELM'SSON',, C. E.,W'ILHELMSEN„ L.BJURE'„ J. ,EiCSTROM+-JODAL, B. Relation of resting and exercise-induced ectopic beats to' other ischemic manifestations and to coronary risk factors. Men born in 19'13I., American .Journal of Cardiology 30 (].)~: 25-31, July 11, 1972'. (CO' 133)', WALLACE, N. D. ,, DAVIS', G. L., RUTLEDGE, R. B'., Eml„ A. Smoking, and' carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and empirical considerations. Archives of' Environmental Health 29'(,3): 136-142', September 1974. GD

CHAPTER' 2' CANCER

c

b C 1~,, Contents Pa e Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 45 Lung Cancer . . . . . . . . . . . . . . . . . . . . .. . ., . . 46 Epidemiologic Studies . . . . . . . . . . . . . . . . . .46 Smolting, and Air Pbl.lution. . . « .. . . . . . . . « . . .46 Exfoliative Cytologyr. . . . . . . . . . . . . . . . . . 49' Experimental Carcinogenici'ty. . . . . .. . . . . . . . . . . .4'9 Carcinogens in Cigarette Smoke . . . . . . . . . . . . . 49. Asbestos. . . . . . . . . . . . . . . . . . . . . . . . 50' Infecti=and Carcinogenicity. . . . . .. . . . . . . . .50 Other Cancers . .. .. . . . . . . . . . . . . . . . . . . . . . 51 Oral and Laryngeal Cancer. . .. . . .. . . . . . . . . . .51 Genitourinary Cancer. . . . . . . . . . . . . . . . . . 51 Nasoph,aryngeal Cancer. . . . . . . . . . . . . . . . .5.1 Aryl Hydrocarbon Hydroxylase (AHH) . . . . . . . . . . . . . .52 Suurmary of Recent Cancer E'indings. . . . . . . . . . « . . . 56 Bib liography . . . . . . . . . . . . . . . . . : . . .. . . . . .57 43 r,

c List of' Figures Page Figure 1.--Productioz of'aryl hydrocarbon hyd'roxylase (AHH) in macrophages from one person in response to cigaret te smohing. . . . . . . . . . . . . . . . . . 53 List of Tables. Tablle_1.--Distribution by type of lung cancers in a composite series of'nonsmokers and a representative hospital series. . . . . . . . . . . . . . . . . . . . Pa e . 47 Table 2.--D'istribution by type of lung cancer in populations wi,th:specific occupational exposures. . . . . . .. . . . . . . . . . . .. . . . . . 48' Table3.--Aryl hydrocarbon~ hydroxylase:(AHH)ind'ucibiliityin patients with ]iung, cancer„ with other tumors, an& in healthy controlls. . . . . . . . . .. . . . . . . . . 54 44

d , INTRODUCTION The major relationships between smoking and various cancers' have been documented' in previous reports on the health consequences of smoking (HCS 1,, 2, 3, 4, 5, 6, 7, 8). Based on evaluations of detailed epidemiologic, - clinical, autopsy, and experimental data accumulated over the last 30' years, cigarette smoking has been clearly identified as a causative factor for lung, cancer. The risk of devel!oping, lung cancer increases directly with increasing cigarette smoke exposure as measured'by number of cigarettes smoked per day, total lifetime number of cigarettes smoked, number of years of smoking, age at initiation of'smoking, and depth of inhalation. Lung,cancer death rates for women are lower than for men but have increased dramatically over the last 15 years coincident with the increasing number of women smokers. This increase has occurred imspi'te of the fact that women smokers use fewer cigarettes per day, more frequently choose cigarettes with filter tips and low tar and nicotine delivery, and!tend to~ inhale less than men. A person who stops smoking,has a decreased risk of developing,lung cancer compared to the continuing,smoker„ but the risk remains greater than the nonsmoker"s for as long as 10 to: 15 years after the person stops smoking. Cigarette smoking is a significant etiologic factor in the development of cancer of the larynx, oral cavity, pharynx, esophagus, and'urinary bladder and is associated with cancer of the pancreas. Certain occupational exposures have been foundito be associated with an increased' risk of dying from lung cancer. Cigarette smoking interacts with these exposures to produce a greater risk of developing lung cancer than from occupational exposure alone. Uranium mining, and'the asbestos industries are occupations which have only sliightly increased lung cancer rates for nonsmokers but dramatically elevated rates for cigarette smokers. Pipe and cigar smokers experience mortality rates from cancer of'the oral cavity, larynx~„ phazyrnx,and esophagusapproximatelyequalJtothose of cigarette smokers. Their risk of'developing cancer of the lung is lower than the risk of cigarette smokers,,but it is significantly above that of d nonsmokers. This is probably due to the fact that pipe,, cigar, and cigarette smokers experience similar smoke exposure of the upper respiratory tract, while cigarette smokers (due to their greater'tend'ency to inhale),have a greater exposure of their lungs to smoke than pipe or cigar smokers. The bronchial epithelium of smokers often shows premalignant changes suuch as squamous metaplasia, atypical squamous metaplasia,, and carcinoma in situ. The pathogenesis of these changes is related to the various carcinogenic and co-carcinogenic substances in cigarette smoke, the exact mechanism of these carcinogens remains under investigation.

LUNG CANCER . Epidemiiologic Studies Harris (CA 36) has reviewed the reports of lung, cancer in nonsmokers and compared them to a representative.hospitaL series and' has shown marked differences in the pathological types between the two: groups (Table 1). When only! nonsmokers are examined!„ the excess of squamous andl oat cell carcinoma in men compared to:women is not observed'. Adlenocarcinoma is by far the most common type of lung cancer in nonsmokers while squamous cell is by far the most common when smokers are included. The strength of the! relationship between smoking and the development of lung,cancer differs markedly withithe type.of lung tumor. Squamous and oat cell carcinoma are very closely: related to:smoking, behavior whi'le,, according, to this study, bronchiolar carcinoma shows no excess risk attributable to smoking. Harris also presented the percentages of different histologic types of cancer found in several industrial exposures (Table2'.);these~percent d'istribution patterns resembled those found imsmokers far more closely than those foundi in nonsmokers. Wynder, et al. (CA 519'),, in a retrospective study of 350 lung cancerr patients and hospitalizzecontrols,, noted that the relative risk, of developing lung cancer was far less in those smokers wholhad smoked filter cigarettes for more than. 10 years than in smokers of plain cigarettes (,261.8' and 46.2',, respectively). Even with smokers of filter cigarettes, the risk increased with increasing number of cigarettes smoked' and was signiificantlygreater than the risk of nonsmokers.: Smoking and Air Pollution, B'ecause of the magnitude of the association between smoking and the d'evelopment of epidermoid lung cancer, it is difficult toievaTuate th&effects of other possible causes of lung,cancer such as air poliluti'on. Higgins (CA 110): recently analyzed respiratory cancer mortality in Great Britain and the United States. In the United States, altlioughthe age-specific death rates for males continued to.increase:, the rate of increase was not as great as in the past. Female lung cancer mortality rates, bycontrast, have increasedisteadily since about 1955. If these increases continue,,the American Cancer Society estimates that lung, cancer among women will move from fourth to third place in 1975 as the site responsible for the greatest number of deaths due tor cancer among women (Ref. 1)'. In Eng,landiand'Wales, Higgins noted that between 1940 and 1969 lung cancer rates for men declined inithe age group under 555 and increased only in men over 65. After adjusting for cigarette smoking, an:independent effect of'air poLlution was sought. It.was found that the lung, cancer death rates for men ages 25-64 in greater London decreasedimore than the rates in the rest of the country; he attributed this decrease tol the greater decline in smoke pollution in London than elsewhere.

C a TABLE 1. - Distribution by type of lung cancers in a composite series of nonsmokers and a representatiue hospital series Distribution (Pencent) Type of cancer Nonsmolkers All' Patients IWlan 1N'omen lifen Women Squamous cell carcinoma 14! 12' 47 22' Oat cell' carcinoma 4 4 17, 11 Bronchiolar carcinoma S 8 23 Adenocarcinoma 57 'S4 110 20 Large cell anaplastic carcinoma 8 8 I7 14'. Carcinoid'. 14 16 0'.6' 4. Other specific types < 1 1 2 U'ndifferen tiated 1 4. 2 Total'number of cases 51 2741 1,903 315 Ilncl'udes oat celi earcinoma and' large cell anaplastic carcinoma4 Source: H'arris„C.C. (CA! 36): 47.

TABLE 2. - Drstribwtion by type of lung cancer in populations with specic occupational exposures. Distributipn (qe) ~in, populations with exposure to- Type of cancer Arsenic N'ickel' Chromium Nematite! Asbestos: Squamous cell carcinoma' 40, 57 48 33 44 Oat! cell carcinoma 13' 43 16 6' 60 6 Adenocarcinoma~ 7' - 24 - 25 Oa[cell or anaplastic 40' - - _ 24 carcinoma Anaplastic 12' 7' 1 SourcerH'arris, C.C.,(CA 36). 4b

Exfoliative Cytology Microscopic examination of respiratory epithelial cells shed into the sputum1has become a useful aid in the diagnosis of lung,cancer and has been employedlin many lung cancer screening,programs for selected high risk gXoups. Saccomanno,, et al. (CA 151)' have conducted periodic cytologic examinations of the sputum of uraniumiminers and a group of nonmining controls. Many of thes,e indi'vidualsdevelo~pedlabnormal squamous cell metaplasiath~at progressed in several cases to become invasive carcinoma. Both cigarette smoking and' radiation exposure from uraniimi mining,were associ'ated' with an increased'' prevalence of these cytologic changes. Of the two factors, cigarette smoking,was noted to be the more important (in both miners and nonminers) for .the development of atypia and carcinoma in situ. Neither cigarette smoking nor uranium mining could be correlated with the length of'time it took for these changes to progress from one pathologic stage to the next. Schreiber, et al. (CA 113)' studied'exfo,liative cytology of the lungs of hamsters treated with.intratracheal injection of the carcinogan benzo(a)pyrene. They noted progression from mild atypia to squamous metaplasial, to moderate and marked atypia, to changes indicative of cancer. These cytologic changes in~animals exposed to carcinogens are comparable to those found in humans who smoke cigarettes. EXPERIMENTAL CARC IE'OGENiIC ITY Carcinogens in Cigarette Smoke A great deal of effort has be n expendedito identify those substances in cigarette smoke that cause malignant changes. The hope is that, if these carcinogenic substances can be identified and removed from cigarette smoke, the risk of developing lung cancer as a result of smoki'ng,can be reduced. Carcinogenic substances which act as tumor initiators, accelerators, andipromoters in experimental animal.systems have beenlidentified in cigarette smoke. Hoffmann and Wynder (CA 152) conductedi an extensive analysis of the tumorigenicity of tobacco smoke. Using the gas phase of cigarette smoke, they identified' certain known carcinogens but were unable to induce carcinoma in the respiratory tract of experimental ani~.maLs. They interpreted these resul'ts as indicating that the levels of carcinog,ens present in; the gas phase alone are below the concentrations necessary for tumor activity. In the same study, Hoffmann~and Wynder examined the particulate phase oft~ob~accoand identified several carcinogens. Thema,j'orityof tumor initiators in the particulate phase were polynuclear aromatic hydrocarbons and alkylated polynuclear aromatic hydrocarbons. They found that a

(. significant inhibitioniof pyrosynthests,of: these substancesleads,toa significant reduction of the tumorig;enici:ty of tobacco smoke. They also identified several tumor accelerators--substances which accelerate the carcinogenicity and'tumor i'nitiating,activity of'the polycyclic aromatic hydrocarbons. The tumor accelerators found were trans-4, 4"-dichlorostilbene, N-alkyl indoles, and' PT-a1ky1 carbazoles. They also reported' that the tumor promoters in cigarette smoke occur in the acidic portion of the particulate matter but did not further characterize them. Hoffmann,, et al. (Ref. 2)1 reported' id'entifying,,the nitrosamine, W-nitrosonornicotine,, in concentrations of 1.9 to 88.6 ppm ini unburned tobacco. This is one of the highest concentrations of an environmental nitrosamine (a family of compounds containing, several organic carcinogens) yet identified,concentrationsinfood and'drink rarelyexceed' 01.1 ppm. This substance is readily extractable from tobacco by water and so would be present in highs concentrati:ons in the saliva of persons wtio chew tobacco. As yet, h''-nitrosonornicotine hasinot be n established as carcinogenic, and even the known carcinogenic nitrosami'nes are not felt to act topically., A:sbestos . The combination of cigarette smoking and asbestos exposure has been shown to result inia particularly high risk of developing lung cancer. S'elikoff,, et al. (CA 298) have shown that asbestos workers who smoke have 90 times greater risk of developing lung,cancer than nonsmoking, nonexposedd people. Shabad, et al. (CA 217) recently studied' the possible causes of the synergistic effect of cigarette smoke and asbestos. They studied'the carcinogenic activity of different types of asbestos in the U.S.S.R'. and noted that all samples of chrysotile asbestos had traces of benzo(a)pyrene. (a po1'ycyclic aromatic hydrocarbon carcinogen found in cigarette smoke). In addition, they noted that chrysotile asbestos had'a high adsorption activity for benzo(a)pyrene. This was not found in the other types of asbestos tested (,anthophyllite and magnesiaarfvedsonite).. In these animal studies, 2!0'percent of the rats exposed to chrysotile asbestos developed precancerous lesions; inhalation of chrysotile plus benao(a)'pyrene or of chrysotile plus cigarette smoke increased' the frequency of the lesions toi 57 and 38 percent, respectively. The synergism between asbestos and smoking may be the result of potentiating,the carcinogenic exposure by adsorptionlof carcinogens onto the asbestos and therefore prolonging its retention iin the lungs. Infecti'on and Carcinogenicity There has been some discussion concerning the association between lung, cancer and' chronic bronchitis. Both diseases can be caused by cigarette smoking; however, chronic bronchitis may also influence the development of 1'ung,

C cancer by some independent mechanism. Schreiber, et al. (CA 54 )l administered N-nitrosoheptamethyleneimine to germfree rats, specific-pathogen-free rats, and rats with chronic murinepneumonia., Theincidance~of lung,neoplasmsw~as 17 percent in germfreemales,, 37 percent in specific-pathogen-free maIes~,, and 83 percent in ininfected males. They concluded that chronic respiratoryinfection may enhance the neoplastic response of the lungs to a systemic carcinogen. OTHER CANCERS Oral and' Laryngeal Cancer Schottenfeld, et al. (CA 231)' have studied the role of smoking on the development of multiple primary cancers of the upper digestive system, larynx, and ]iung. They followed 733'patients surviving, a first primary epidermoid cancer of the oral cavity, pharynx, or larynx for 5 years. The average annual incidence for a second primary was higher in men (18.2/1000) than in women (15.4/1000). Both men and women who developedi a second primary tumor had heavier tobacco exposure prior to their first cancer than those who did not develop a second'malignancy. The authors were unable to show a significant relationship between smoking habits after removal of the first primary and development of a second primary. They postulate that this fad!lure to show an association is due to the long induction period between presence of a carcinogen and occurrence of the cancer, and they expect that a rel.ationship, if present, may become apparent after 7'or 8 years of f©llowup. Genitourinary Cancer Schmauz and Cole pelvis or levels of cancer of the rapid'd levels of urine for (CA 250) studied 43 persons with cancer of the renal ureter and noted that smoking,was only a risk factor at very high consumption (over 2'-1/'2 packs per day), despite its being related too the bladder at all levels of smoking,. They postulate that, due to transit of urine through the renal pelvis and ureter, very high exposure are required to have any effect whereas the bladder stores some time and even small amounts of carcinogens in the urine may be sufficient to:irfluence~ the bladder~ epithe~lium. N'asopharyngeal Cancer Lin, et al. (CA 162'), in a retrospective study of nasopharyngeal cancer in~Taiwan using,neighborhood controls, found smoking, to be significantly associated with the development of'nasopharyngeal carcinoma. A person smoking,over 20 cigarettes per day had twice the risk of a nonsmoker of developing nasopharyngeal cancer. 51

ARYL HYDROCARBON HYDROXYLASE (AHH) Due to the great variation in the amount of smoking,exposure before the development of lung, cancer, attempts have been made to idientify groups~of people who may have a greater sensitivity to the carcinogenic effect of cigarette!smoke. Interest has developed in the possibility that aryl hydro- carbon, hydroxylase(AHH)': . may! be a geneticallyd'etermined'enzymethatmed'iat,as such increased susceptibility to certain environmental carcinogens. AHH is an enzyme system which metabolizes polycyclic aromatic hydrocarbons;; some of the resulting,metabo]!ites are carcinogenic. It has been postulatedd that persons with high level&of this enzyme may: be at greater risk of developing cancer fr=exposure to the polycyclic hydrocarbons in cigarettee smoke than those with low levels., The amount of AHLi produced in response to anlinducing stimulus can be usedito separate a population inMthree groups (those capable of being, induced to produce hi'gh,, medium, andilow levels of' AHH'. K'ellermann,,et al. (CA 82') studied, the induction of AM activity in, 353 healthy subjects (67 families with 165' children)'. They felt that the enzyme was controlled by a single gene locus wiith two alleles (one able tolbe ind'uced to produce high AHH!levels with a gene frequency of .283 and one, to prod'uce low levels with a gene frequency of .717). All six~possible crossmatings were found in the families studied„ and no devi'ations from the expected phenotypes were found'in the children. Can~trell,et al., (CA 2'23),, studied 19' healthy voluntee~rsand found that cigarette smokers had higher levels of AHH'in their pulmonary aIlveolar macrophages than nonsmokers. In one subject they showed an increase in AHH activity starting I week after he began to smoke 10 to 15 cigarettes per day (CA 2231? Fig. 1). Holt and Keast (CA 26)' also showed increased' levels of AHH activity in homogenates of lung tissue from mice exposed' to cigarette smoke. Kel~lermann (CA 4)' also studied the inducibili'ty of AHH i'n~ the lympho- cytes~ of 50 patients with bronchogenic carcinoma and compared them to a healthy white populati'oniand to a group of patients with nonrespiratory malignancies (Table 3)1. They found'ithat lung cancer patients hadi a statistically significant, higher percentage of persons homozygous for the high allele, i.e., able to be inducedi to high AHH levels, thanleither the healthy or tumor controls. They postulated that the reason for the greater freq~uency, of persoZshonozygousfor thehighAHH:i'nducibilitya1.leleiinthe lung cancer group was that this group was more susceptible to lung cancer due to their increased ability to convert polycyclic aromatic hydrocarbons into carcinogeni'c metabolites. The incidience of luno, cancer, however, does 5.2

FIGURE L-Plrod'uctibn of aryl hydrocarlion~hyd'roxylase ('AHIH) in macrophages f'romt one person in response to, cigarette smaking, ~ _x ' a t a° 0:04 . u. a E' 0 j03' ~ 11 ~ Os02' ~ ~ x 2 a' 0:01 ~ F""'':"" •":.7.•' -115' 0 10 20' 30' 40 50 60 70, 80 90 DAYS' PAOTE.-Shaded'bar indicates durat'ion of'smoking;,t'he vertical lines indicate the range of' duplfcate determinations at' each time period: Source: Cantrell, E:T.,, et aIL (CA' 223)'

TABLE'~ 3: -~~Ar,ytli}+diacarbon ltyd'rozylase (.AHH)l in~ducib'ilily~ in~~ patients~. wiih~' lung canaer,~ wri!}~ ot!'rer~~tumors, and irr~~ hea,6tJty~~aon~trola~ ~ NUMBER INi DiSTRIBU'DION OF' GENE FREQUENCIES GR!OUP' GROUP GENOTYPES('PER'CEN'i')~ OF A AND $ ALLELES AA AB BB A B Healthy control 85' 44.7 4'5'.9 9.4 0.6'76' 0.324 Tumor control 46 4I3:5 4'5':6 10.9 0.663 0:337 Lung cancer 50, 4.0 66.0' , 30.0' 0:370' 0.630 l AA = low inducibility; A8 = intermediate inducibility; B!B = high inducibility Source: Kellerman; G., et al. (w;A' 4). 54

not show a markedly familial occurrence pattern,, therefore, a single genetic locus can, not be~themajor factor determining susceptibility. Persons with, increased ability to metabolixe polycyclic aromatic hydrocarbans,may well be a gzoupatincrease&riskofdeveloping, lungcancer: iiftheysmoke; however, prospective studies of random populations controlled for smoking and environmental factors will be necessary before this genetic susceptibility can be confirmed.

SLINg1ARY OF RECENT' CAi':CER FI.NDI'NGS. 1. Filter cigarette smokers have a lower risk of developing,lung cancer than nonfilter cigarette smokers,, but that risk is still greater than the risk to nonsmokers and increases with increasing number of filtered cigarettes smoked. 2'. Ci'g,arette smoking and exposure to radioactivity by urani'um mining, have been related to cytologic changes in the respiratory tract epi'thel'ium including carcinoma in situ. Cigarette smoking has been more strongly related tothesechangesthan m3.ningexposure. 3. Chrys,otiSeasb~estoshas~beenishown tocontai'n traces of thecarci'rnogen benzo (a)'pyrene, and the combination of the two, has been shown, to be a more potent carcinogen in rats than either alone. 4. Heavy smoking prior to a first primary oral or respiratory cancer has been shown to be related to the development of a second primary in the respiratory tract or oral cavity. 5. Results from one study have shown a greater proportion of Iung, cancer patients having high levels of aryl hydrocarbon hydroxylase activity than among either healthy persons or persons withother cancers., Persons with high levels of AHH may be a group which has a genetically determined increased risk of liung,cancer if they smoke, but no excess risk if they do not smoke. 56

BIBLIOGRAPHY' (Ref~~., 1) AMERICAN C,ANC~~ER~ SOCIETY.~ 175 ~~ C'ancer~ Facts~~ and~ F~igures~~.~. New Y©rk, N. Y'., 1974, 31 pp. CA 223) CANTRELL, E. T., MARTIN, R. R., WARR, G. A., BUSBEE, D. L., KELLERMAI+iN, G., SHAW,, C. ]Ind'ucti'on of aryl hydrocarbon hydroxylase in human pulmonary alveolar macrophages by cigarette smoking. Transactions of the Association of. American Physicians, 86th Session„ Atlantic City, New Jersey, May 1-2',, 1973. Vol. 86. pp. 12'1-130. HARRIS, C. C. The epidemiology of'different histo]:ogic types of bronchogenic carcinoma. Cancer Chemotherapy Reports 4(2'„ Part 3) : 59-61,, March 1973. HIGGINS~„ I. T. T. Trendsin respiratory cancer mortality: In the United States andlin England and Wales. Archives of Environmental Health 28(3): 121-129, March 1974. HOFFMANN, D.,, HECHT, S. S~. , ORNAF, R. M. „ WYNDER, E. L. N''-nitrosonornicotine in tobacco. Science 186(4160): 265-267, October 18, 1974. HqFFMANN',, D.,, WYNDER, E. L,. Chemical composition and tumori- genicity of tobacco smoke. In: Schmeltz, I. (Editor). The chemistry of tobacco and tobaccoismoke. Proceedings of the symposium on the chemical composition of tobacco and tobacco smoke held during, the 162nd National Meeting of the American Chemical Society in Washington, DX.,. September 12-17, 1971. Plenum Press, tJew York, 1972'r pp • 123-1!47. (CA 26) HOLT, P. G., KEAST,, D. Induction of aryl hydrocarbon hydroxylase in the lungs of mice in response to cigarette smoke. Experientia 29: 1004, August 15, 1973. (SA 82) ' RELLERMANN,, G., LUYTEN-KELLERMANN, M., SHAW',, C. R. Genetic variation of aryl hydrocarbon hydroxylase in human lymphocytes. American Journal of Human Genetics 25: 327-331, 1973. (CA 4)', KELLERMANN, G'. , SHAW, C. R., LUYTEN-TCELLERMANN, M. Aryl hydrocarbon1hydroxylase inducibility and bronchogenic carcinoma. The New England'Journal of Medicine 289(18): 934-937, November 1, 1973.

(CA 16'2') LIN, T. M.,, CHEN, K. P'., LIN, C. C., HSU', M. M.,, TU, S. M.,. CHIANG,, T. C., JUNG, P. F., HIRAYAMA, T. Retrospective study on nasopharyngeal carcinoma. Journal of the National Cancer Institute 51(5) : 1'403-1408I, November 1973. (CA 151) SACCOMANNO, G., ARCHER,, V. E. „ AUERBACH, 0. , SAUNDERS, R. P. ,, BRENNAN, L. M. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 33(].): 256-270, January 1974. (CA~ 2'50)', SCHMAU2'~, R., COLE, P~~.~ E'pidem~iology~ of cancer~~ of the renal pe]ivis and ureter. Institute~~52(S)~~:~~ Journal of the National Cancer 1431-1434, May~1'9~74.. (CA231) SCHOTTENFELD~, D., GANTT, R. C., WYNDER,, E. L. The role ofalcoh~ol and' tobacco in multiple prtmary cancers of'the upper digestive system,, larynx, and lung,: a prospective study. Preventive Medicine 3(Z): 277'-293', June 1974. (CA 54)~ SCHREIBER„ H., NETTESHEfiM, P. ,, LIJINSKY, W., RICHTER, C. B., WALBURG, H. EI. ,, Jr. Induction of lung cancer in germ- free, specific-pathogen-free, and infected rats by N-ni'trosoheptamethyleneimine: enhancement by respiratory infection. Journal of the National Cancer Institute 49(4): 1107-1114, October 1972. CA 113)' SCHREIBER, H., SACCOMANt30i,, G. ,, MARTTiN, D. H'. „ BRENNAN, L. Sequential cytological changes during,development of respiratory tract tumors induced in hamsters by benaol(a)pyrene-ferric oxide., Cancer Research 34: 689-698, April 1974. (;CA29'8)i SELIKOFF, I. J.„ HAMMOND1, E'.C.,CHURG',„ J. Mortality experiences of asbestos insulation workers 19'43-119'68'. Pneumoconiosis. Proceedings of the International Conference on Pneumoconiosis, 3d, Johannesburg, 1969'. Oxford University Press, New Ylor&,. 1970. Pp. 180-186. (CA 217) SHABAD, L. M., PYLEV!, L. N., KRIVOSHEEVA, L. V., KU'LAGINA, T. F~., NEMENKO, & A. Experimental stud'i'eson asbestos carcino- genicity. Journal of the National Cancer Institute 52'(4): 1175-1187, April 1974. `

U.S. PUBLIC HEALTH,SERVICE'. Smoking and'Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Department of Health, Education,, and Welfare, PublicH'ealth, ServicePubIication IQo,.110i3, 19,6'4,387'pp. (HCS~ 2)~ U.,&. PUBLIC'HE'ALTHSERVICE.The Health ConsequencesofSmoking,.A Public Health Service Review: 1967- U. S. Department of Health.,Educati;on,, and Welfare. Washington~, Public Health Service Publication No. 1696, Revised January 1968', 227 pp. 'HCS 3) U.S. PUBLIC HEALTH SERVICE. The Health Consequences, of Stnokiing. 1968., Supplement to the 1967 Public Health Service Review. U.&. Department of Health,Education,and Welfar&. Washing,ton,PuublicHealthService Publication 1696, 1968, 117pp~. HC'S 4~), U!. S. PUBLIC HEALTHSERV.ICE. The Healthh Consequences of Sinoking., tiC5' 5) L969. Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Education, andlWelfare. Washington, Public Health Service Pubiication 1696-2', 1969, 98' pp. U. S'. PUBT:IC' HEALTH SERUTCE. The Health Consequences of Smoking. A Report of the Surgeon General: Health, Educatiom, and'Welfare. W 1971. U.S. Department of ashington,, DHEW Publication (HCS~ 6)~~ No. ('HSM)'71-7511,, 19'71,, 4518 pp. U'..S,. PUBLIC~ HEALTH SERVICE. The~ Health Con~~s~equences~ of Smoking. A Report of~ the Surgeon General: 19'7Z., U.S. Department of~. Health, Education, and' Ws~lfare.~ Wash~ing~ton,, DHEWP'ub~lic~ation. No. (HSM) 72-6516, 1972,, 158 pp. (HCS~~,7)~~ U. S', ~ PUBLIC HEALTH SERVICE. The~ Health Consequences of Smoking; 1973. U'.S. Department of Health, Education, and Welfare.. Wash~ington,~ DHEW~ Publication No. (ESM)~ 73-8704, 19'73,~ 249~~ pp. (,HCS~~ 0 ]U.~S', ~ PUBLIC' HEALTH SERV'ICE'~., The Health Consequences~~ of Smoking: 1974. UU.S. Department of Health, Education, and Welfare. Washington, DHEWPubliication 1V,o.(CCDC)7'4-8704. (CA 59~)~~ / ~ WYN'DER, E. L., MABUCHI, K~~.~ ,, BEATTIE, E~,~ .7~. , Jr., The epd:d~emio~- logyof' lung cancer.Journal of the,American Medical Association 2T3'(13')~:', 2221-2228, September 28, 19701. 5'9

C

CHAPTER 3: NON-NEOPLASTIC BRONCHOPW'LM0I3ARY D'ISEASES'

\.

Contents Page Introduction.. . . . . . . .. . . . . . . .1 . . .1 . . . . . . .65. Smoking and Respiratory Morbidity! . . . . . . . . . . . . . . 66 Smoking, and Air Pollution. . . . . .1 . . . . . . ., . . . . . • 66. Smoking,and'0'ccupational Disease., . . . . . . . . . . . . . .71 Mill Workers - Byssinosis.. . . . . . . . « . . . . . .71 Firemen. . . . . . . . . . .. . . . . . i . . . . . . . . . 7'1 Smoking, and!Pulmonary Function,Tests. . . . . . . . . . . . .71. .? 1-Antitrypsin. . . . . . . .i . . . . . . . . . . . . . . 74 Autopsy and Pathophysiologic Studies . . . . . . . . . . . . .7'6 Autopsy Studies. . . .i . . « . .. . . . . . . . . . . . .76 Pathophysiologic Studies: ih:Humans. . . . . .i . . . . . 80 Pathophysiologic Studies in Animals .. . . . . . . . . .80, Summary of Recent Bronchopulmonary FindingS. . . . . . . . . 83 Bibliogzaphy . . . . . . . . . . . . . .i . . . . . . . ., . . . 84

List of Figures Fi'gure. 1.--Respi'ratory bronchioli'tis in smok,ers and control g'roups. . . . . . . . . . .1 ., . . . . . . . List of Tables Tab~~Ie~ 1.~--Leve~l's~ of sulfur~ dioxi'~de~ (~S~~02)~~ and total suspended particulates (TS~P)~ in four Utah~ communities, 1971, and in five Rocky Mountain communities, 19'70. . . . . . . . . . . . . .I . . . . . Table 2'.--Mean annuall levels of sulfur dioxide (802,) and' totah suspended particulates (TBP):in four areas. . . . . . . . . . . . . . . . . . . . . . . . Table 3'.--Age-adjusted~percentage~of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to.chemi'cals, fumes, sprays, and' dusts. . . . . . . ., . . . .. .. . . ., . . . . . . Tabile 4. -The T '1.-anti'trypsin levels.and'frequency of pr~otea~s~e~~ inhibitor~ (Pi)~ phenotypes in~ h~ealthy, populations. . ., . . . . ... . . . . . . . . . . . . Table 5--Means of the numerical values.g,iven lung sections at autopsy of male current smokers and non- smokers, standardized for age.. . . . . . . . . . . . . Table 61.--Means of the: numerical values gi'ven, lung sections at autopsy of female current smokers and nonsmokers,, standardized' for age . . . . . . . . . . . . . . . . . Table 7.--Nieans of the numerical values given lung, sections at autopsy of male former cigarette smokers, standardiaed1for age . . . . . . . . . . . . . Page' . 81 . 681 . . 69' . 72 . .75 . 7'7 78' . 79 64

C INTRQDUCT ION' Chronic non-neoplastic lung diseases are major causes of permanent and temporary disability in the United States. Chronic obstructive pulmonary disease (COPD) is the largest subgroup of these diseases and in this report refers to chronic bronchitis and/'or emphysema. Relationships between smoking, and non-neoplastic lung diseases have been reviewed in previous reports on the health consequences of smoking (HCS 1, 2, 3, A, 5, 6,, Z, 8). Cigarette smoking, is the most important cause of COPD. Cigarette smokers have higher death rates from chronic bronchitis and emphysema, more frequentlyreport symptoms of pulmonary disease, and have poorer performance on pulmonary functionitests thanido nonsmokers. These differences become even more marked as the number of cigarettes smoked increases. The relationship between cigarette smoking and COPD has been demonstrated in many different national and ethnic groups, and is more stri.king,in men than in women. Pipe and cigar smokers have higher morbidity and mortality rates from COPDD than do nonsmokers but are at lower risk than cigarette smokers. Cessation of cigarette smoking results~in improvedipu'lmonary function tests, decreased pulmonary symptoms, and'reduced COPD mortali'ty rates., In additionto an increased risk of CC1PD~„ cigarette smokers are more frequently subject to and require longer convalescence from other respiratory infections than nonsmokers. Also,, if they require surgery, they are:more likely to develop postoperative respiratory complications. The relative importance of air pollution in the development of COPD remains controversial,, but is clearly less significant under most circumstances than cigarette smoking. The combination of cigarette smoking and polluted air, however,,may prod'uce higher rates of COPD' than either factor alone. Several occupational exposure groxips incur an increased risk of COPD, and cigarette smoking adds~significantly to this risk. In particu2ar, exposure to cotton fiber and coal dust appears to act in concert with. cigarette smoking to promote the development of pulmonary disease. Autopsy studies have demonstrated a dose-related effect of cigarette smokinQon the severity. of macroscopic emphysemal.Increased goblet cell density, alveolar septal rupture, thickened bronchial epithelium,, and mucous gland hypertrophy are more commonly!found in the lungs of smokers than in those of nonsmokers. Many pathophys3'.ologilc mech~anismsbywhichismoking, may cause COPD,hav!e been proposed'.. Decreased overall pulmonary clearance, reduced'1ciliary motion,, and impaired alveolar macrophage functions have all been related'to cigaret~tesmoking and probably play a role in the development of COPD. The exact mechanisms whereby cigarette smoking contributes to the development o£ COPD, O howevzr,. remain only parti'a1Tyunderstood-. ~. ~ O Ilk 65

SMOKING AND RESPIRATORY MORBIDITY An increased prevalence of respiratory symptoms in smokers from early teens to those past the age of 801has been well established. Bewleyr„ et al. (BP' 33), in a study in Derbyshire County, EngTand, extended these findings to include younger children. In alquestionnaire study of 7,115' school- children ages 10 to 11-1/2 years,, he foundd that 6.9 percent of the boys and 2.61percent of the girls smoked more than one cigarette per day. The boys who smoked reported more morning, cough (21.5% to 6,.,1%) „ cough during, the ) day or night (48.0% to 20%), and cough of 3-months duration (18'.0Z to 4.1%) than their nonsmoki!ng,schoolmates. The percentages for the girls were similar although based on smaller numbers of smokers., As in manystud'ies of'this type, it was impossible to control for air pollution, social class, or smoking,habits of the parents; nevertheless, the results suggest that cigarette smoking,even in this young age group produces respiratory symptoms. Fridy, et al. (BP 171), in alsomewhat older population (average age 25 years), examined' the effect of'smoking on airway function during,mild' viral illness. They measured' closing volumes for 22 subjects (9' cigarette smokers - average age 29.1, and 13 nonsmokers - average age 251.7) before onset andlat weekly intervals from the beginning,of a mild respiratory illness until all symptoms had subsided. The closing vollumes for smokers prior to illness were higher than those for nonsmokers, but the difference was not statistically significant. In the tests done during, the illness, the smokers had a statistically significant increase in the closing volumes (from 37.0 to! 45.8 percent of their total lung capacity, while nonsmokers hadino change 32.7 and 31.7 percent). Smokers remained symptomatic more thanitwice as long as nonsmokers (35.7'and 16.5' days, respectively), and the mean d'urationn d of pulmonary function abnormalities in smokers was 29.7 days. Nonsmokers had no change in pulmonary function tests during,ilTness.. SMOKING AND' AIR P'OLLUTION The relationships among air'po1!lution, smoking, and'COPD remain .controversial. Reasons for this controversy include difficulties in controlling such variables as socioeconomi'c class, degree of crowding, ethnic differences,, and age distribution as well as determining the exact type and amount~of individual pollution exposure. Measuri'ngind'ivi'.d'ual pollution exposure even withina small area is d'ifficult since both amount and type camvary dramatically from street to street (e.g., proximity of a street to a heavily traveled expressway). In an effort to control as many of these variables as possible, two basicap~proachesin~ studyd'esign have been,tried., Thefi'rst approach is to find areas where pollution levels have been well measured and then to select study populations that are as similar as possible in areas with different pollution levels. Thus, effects on a population in a.low pollution area can be compared to those on a similar population in a high pollution area. The secon&approach is to select a population that is as uniform as possible, for example, twins„ and then measure individual responses to different pollution exposure. Both approaches have drawbacks as will be evident from the following studies. 66

C Using, the first approach, the Community Eealth and' Environmental Surveillance System of the Environmental Protection~Agency (BP 29, BP' 14)) has conducted surveys in areas with different types and levels oTpMution in four different parts of the United States (Chicago,, New York City, the Salt Lake Basin, and1the Rocky Mountain area). Within each part of' the country, the researchers i'dentified commun3!ties of similar socioeconomic status but different pollution levels. They then administeredia questionnaire through the school systems to determine the frequency of lower respiratory tract infecti'onlin thechildren and their famil'ies:.Theyreported an increased incidence of lower respiratory tract illness in childrenlin high pollution communities compared to children in low pollution communities. This d'iffereince was demonstrable only in chil'dren1whosefamilies hadi lived in~ the high pollution communities for more than 3 years. They also reported an i'ncreased'prevalence of chronic bronchitis in parents who lived in highipollution communi!tiess compared tolparents from low pollution communities. They calculatedithe excess risk of chronicbr~onchitis prod'ucedbyairpo9!lution, to be one-thirdlof that produced by smoking but to be additive with smoking. Several major problems in these surveys make it difficult to evaluate the results. The authors describe the areas as having different kinds of polluti'on. The Salt Lake Basin and Rocky Mountain areas were felt to be high in sulfur dioxide (S©2) and'low in total suspended particles (TiSP), while New York and Chicago were high in both these pollutants. As a result,, in the Salt LakeB~asiniand Rocky Mountain areas, communiti'.eswere separated iinto lowand high pollution communities only on the basis of their SO2 levels.M'any communities classified as low pollution communities on the basis of their S02 levels had higher levels of total suspended particles than the communities classifiedias hi.gh pollution communities by SO level (Table 1). In fact, the average total suspended particles level for tie low pollution communities in the Salt Lake Basin was higher than that for the hligh pollution communities (Table 2) in the Salt Lake Basin. These differences exemplify the difficulties of using,only one pollutant as a marker of, total pollution exposure. Additional problems with these studies were the differences in socioeconomic class measurements between low and!high pollution communities in some of'the regions. In the Rocky Mountain area, the percentage of fathers who completed high school varied from 91 percent in one of the low communities to 58 percent in one of the high~pollution communities. There were also major differences between high and low pollution communities in the percentage of families with more than one person per.room in the Salt Lake Basin(59'.6% to,51.2Y)'~ , Rocky: Mountain area(',87'.,0% ' to68.0%') , and. New York (85.0%' to 72.0%). Residential stability (percentage of' families li'ving, in the community for more than 3 years) was different in the high and low pollution communities in New York (58.0T' to 36.Q%)', and Chicago (56.(1y' to. 46.0%). The percentage of parents who currently smoke also differed'for high and low pollution communities, iniNewY'ork (53% to45%'forthe fathers and 47% to 37% for the mothers). These differences rai'se questions as to whether b7

TABll.E~ 1'i. -~ bevels~of sulfur~ dioxide~(S(12) , and~to~tal suspended particulates~(T'91')~ in four i'l'tah communities, 19 71', and' iir five Rocky Mountain communities, 1970, ~ Atea Community' Pollu tion Pollution levels imu8/im3 Classdfi cation S02 TSP Utah (Salt Lake Basin). Low 8' 78 Intermediate 1 15' 81 Intermediate 2' 22 45 High, 62 66 Rocky Mountain Area Low 1. 1'0' S0 Low 2 26' 6'8' Low 3 46' 110. E$igh, ll 109 43 '. High 2 186' 102 SourcerChapman. R.S,, et al. (BP2A).' 68

TABLE 2. - Mean annual' leuels of sulfur dioxide (SO2)'and total suspended pareiculates (T'SP) in four areas Pollution lev els i n µg/m~' Area SOZ2 TSP ' During Study Low High~ Decade Preceding Study Low High During Study Low High Decade Preceding$tudy. Low High Five Rocky Mountain ~Areas~ 10 275 110' 263 45 110 50 1'01l Salt Lake Basin 9 65 < 20' 144 78 66 82 62 New York. 2'3 63' <'30' 431 34104 4'0, 2'01 Chicago 57 106 109 2S0 111 1'5'1 121 1i65 N'OTE., - Area includes, highest- and lowest-pollurtedlcommurrities. , Sourca: French, I1G., et ali (EP I4) ,

the high and low poll'ution communities were really similar enough populations to justify the claim that differences in incidence of respiratory tract illness could be attributable to differences in air pollution. Increased prevalence of'COPD has also been d'emonstrated in areas off high pollution in the Netherlands (BP 119), yokkaichi,, Japan (BP 78), , and' Cracow, Poland (;BP'112). Again, however,,these studies were poorly controlled for socioeconomic status. Several recently published studies have used the second major method of investigating the relationship between smoki'ng,, air pollution, and'COPD', i.e., to select a uniform:population and then to measure individual differences to poll'ution exposure. Comstock, et al. (BP' 13), in an attemptt to control for occupational exposure and socioeconomic class,,studied threeseparate,unsform populationsoftel!ephone workers and used as a measureoft pollution the location of'the place of work and residence. The populations studied were telephone installers and repairmen in~B'altimore~,, Newl'ork City, Washington, D.C.,, and rural fTTestchester County in 1962 (survey 1')' and in 19'67' (survey 2)'„ and telephone installers and'repairmen in Tokyo in 19'67 (survey 3). They were unable to find any relation between pulmonary symptoms andidegree of urbanization of place of work or place of residence (ei:ther current or past). They were:, however, able to establish alstrong correlation between smoking habits and' pulmonary symptoms. Given the crude estimation of pollution exposure used in this study (all workers in each city were treated, as th:oughthey:received the same:exposure),, a small d:Ifference, inisymptomss due to air pollution could have been missed,, whereas the difference due to smoking could be detected both because it was larger and'because it was possible to determine individual exposure more exactl:y. Hrubec, et al. (BP' 12), in a study of twins from the U.S. Veterans Registry, were unable to show a difference in respiratory symptoms either between individuals with different exposure to air pollution or between members of twin pairs with different air pollutiomexposures. However,, they too used a.crude measure of air pollution exposure (by each aip code area), and so . could have missed a small difference due to air pollution despite being, able to relate respiratory symptoms to smoking,,, socioeconoanicstaflus,,; and alcohol intake. Colley, et al. (BP 2321), in a study of 3,899 persons (',20-year-olds born during the last week of March 1946 in the United Kingdom)', were also unablee to show a relation between COPD and air pollution. They used as their esti'mates of air pollution exposure the domestic'coal consumption inithe towns where the subjects lived. This method' of estimating air pollution exposure is subject to the same limitation cited'for the previous two studies-limited sensitivitytoismall risks d'ueto,air pollu~tion. W

In summary, if an increased risk of CnPD' due to air pollution exists, it is small compared'to that due to cigarette smoking under conditions of air pollution to which the average person is exposed'. The possibility remains that the two different kind'sofexposure may in~teract toincrease, the total effect beyond that contributed by each exposure. SMOKING AND OCCUPATIONAL DISEASE' Fri'edtnan„ et al. (BP 31)i,, in a study of 70,289 men and women who had. had Kaiser-Permanente multiphasi'c health checkups,,noted that smokers were more likely to report occupational exposure on alquestionnaire (Table 3) than nonsmokers. The differences are small but statistically significant and need to be considered'when investigating the relationship'of smoking to occupational diseases. They were not able to determine whether smokers' responses reflect•actual differences in exposure or an increased awareness of andisensitivity to occupational exposure. Severa7l recent studies have confirmed' previous findings that exposure to coal and' granite dust and cotton fiber carries an increased' risk of COPD. This risk is further increased by cigarette smoking. Other new data have been published which clarifyy the risk in certain occupational groups. Mill Workers - Byssinosis Berry, et al. (BP 41),, in a study of 595' workers in the Lancashire cotton mills over a 3'-year period, found that the decline in foxced~ expiratory volume in one second' (FEV'1) was 19 ml/'year greater in smokers thamin nonsmokers(59m1/year compared! to4'0ml/year) ,, but they could not demonstrate a dose-response relationship. Firemen Sidbr and P'eters (,BP' 94, BP 9'5)1, in al cross-sectiional study of 1,,768 Boston firemen, were unable to show a significant relationship between severity of fire exposure and impairment of pulmonary function tests or prevalence of COPD; there was a clear harmful effect of' cigarette smoking, on both. They postulate that they were unable to show an increased prevalence of COPD in this cross-sectional study because firemen who develope&COPD were. no longer capable of ineeting the physical demands of the job and had retired,. thus removi'ng,them from the study population. They were able, however, to show a higher incidence of COPD'i'n men under the age of 35 years who had been on the force more than 6 months when compared to persons of the same age who had just beenihired. SMOKING AND' PULXONARY FUNCTION TESTS It is recognized that smokers as a group have poorer pulmonary functi!on tests than nonsmokers. The standard pulmonary function tests generally on"Ly ~ . W ~ . ~ 7 1 N ~ O~

TABLE 3. - Ageadjusted p8, _ntage of cigarette sinokers and norisrxrokers i( ch race-sex group responding positively to exposure ro' chemicals, fumes, sprays, and' d'usrs Whites Dlacks Yellows Ezpasure Time periodl Smoking,srthtus . % .. %. '~ %'% i % . % Men Wnrrten, Men Women Men Women Chemicals, cleaning Before 1 year ago Smokers 24.0' 6.4 26.01 11.8 I 16.7 4.1 fluid's or sollvents (or Nonsmokers 18.9 5.1 19.2 6.7 12.9 5.11 chemical sprays)2 Inithe past year Smokers 12.1' 3.0 14.2 5'.1 13.1' 3.5' Nonsmokers 9:7 2.6 111.6 4.5' 9.4 3'.8' Insect or plant sprays Before 1 y,ear, ago Smokers 4.0' 1.0 6,6' 2'.1' 3.8 0.3'. Nonsmokers' I 3.5 0:9 5.1' 1!.9' 2.5 1'.0. . In the past year Smokers 2.9 2.1 I 4.8 2.9 3.0' 1.3' Nonsmokers 2.9 1.8 4!8 3.01 3.6 1.8 Ammonia, chlorine, Before 1i year ago Smokers 7.9 2:3' 103 4':8' 6.2 0199 ozone or nitrous gases Nonsmokers 6.2 1.9' 7.01 3:2 4.5 1.7 (nitrous oxides or other irritating gases)2' In the past year' Smokers 5.4 11.9' 7.6 3,9 8.0 0:5. Nonsmokers 3,7 1.5 5.8 3:1 3.5' 1.7, Engine or exhaust fumes Before L year ago~ Smokers 11.8 1.0 17.6 1.9 I 4 0' 0:0' (more than 2'hours a Nonsmokers 6.9 U 13.1 0.6 I 3.6 0.1 d'ay)2 ln the past' year Smokers 8.7 03 17.6 1.0 ' 4.3' 0.5 Nonsmokers 5.2 0.5 ' ' ' L 2 13.3 3.9 0.2 Plastic or resin fumes Before 1' year'ago Smokers 5.1 1.1 3.3 1.2 3.1 0.1 Nonsmokers 3.5' 0.8' 3.0 0.6 2.2 0'.3' In the past year Smokers 3.3 0.8' 3:9' 0.9 3.0' 0.1 Nonsmokers 2.5' 0.6' 4:3 0.6 Lead fumes or metal Before: 1 year ago Smokers 8.2' 0:9 9! 1' 1L5 4'.1' 0.1 fumes (leaded sprays: Nonsmokers 4:3 0:5 5:8 0.6 2.6 0.1 or paint sprays)2 In the past year Smokers 5:5 0.7 7.7 1.3' 3:3 0.5 N'onsmokers 3.1 0.5 6,8 0;8 . 2.4 0.4 Asbestos, cement or Before 1' year, ago . . Smokers 7.1 0.6 11.5' 11.2' 2.7 0.0 grain (or flbur) dusts2 Nonsmokers 4L4 0.3 8.8' 0.8 1 1.6 0.1 In the pascyear Smokers 2.8 0.4 7.5 1.0 2.7' 0:1 Nonsmnkers 1.8 0l3 6.2' 0'.8 0.3' 0.8 Silica„ sandblasting„ Before l year aga Smokers . 6.9' 0'.6 10.5' 1.3 3!.5 0.3 grinding or rock drill1 Nonsmokers 4.0 0l5' 6.8' 0L7 2.9 0.0 irtgdust (sandor coal)2 Iln the past year Smokers 3.9' 0.5 8.0' 1l0 3.3' 0.4 Nonsmokers 2'.3' 0'.4' 6.6 0.9 3.5 0_4, Total number of subjects Smokers 14,485 16.059, 2,609 2.869 65''4 446 Nonsmokers 8,282 18,526 1'„11'6' 3,218 712 1,313' tWith a few slight'variations, the questions were worded as follows: Before 1' yearago• "Before t year ago have you ever worked'in a place,where you were often ordaity araund_ ln the past year: "tn, the past', year have you worked inia place where you were,ofben or, daily around 24faterial in pa;entheses appears in "past year"'questionbut not in "before 11 year ago^'question:, Source: Friedman, G.D., tt' all (BP' 31'):

become abnormal late in the patholog~c process of COPD and usually only after irreversible ch~anges~ inth~e lungs have occurred.: As aresult„ tests areneed'ed that will id'entifypersonsat risk of d!eveloping,CaPDbeforethey have irreversible loss of lung function. Standard tests of pulmonary resistancee are inadequate for this purpose because they measure predominately resistance in the large airways while the first changes of'COPD occur in bronchioles that are 2'mm and smaller. Small airway resistence may be measured through evaluating f requency dependent compliance „ but this is of ten cumbersome to perform. Closing volume and maximum expiratory flow rates at 25 and 50' percent of Vital capacity have the advantage of being relatively easy to perform, yet are still able to measure changes in the small airways. Closing volume is the lung,volume at which~ the alveoli in the dependent portions of the lung begin to close, and it is usually expressed' as a percent of vital capacity. Bl:evated closing volume is cons3:deredlevid~ence of small airway disfunction.. Maximum expiratory flow rates at 25 and 50 percent of vital capacity measure air flow at low lung volumes where the resistance of the small airways makes up a much larger proportion of the measured resistanc . Several recently published studies contain data on small airway disfunction in smokers. Lim (BP 19) studied 50 smoking and 50 nonsmoking;high school students and found in smokersa stati'sticallysigp~ificant reductionin the forced exp3ratory volume in one second when the test was started at normal end expiration low lung volumes). . S'tanescu„ et al.(BP 58)' noted elevated closing,volumes in 16 healthy asymptomatic smokers whenicomparedito 16 nonsmokers,; but was unable to show any difference in maximum expiratory flow ratesat 25 and 5:0 percent vital capacity. Ruff, et a1.(BP~ 73) stud'ied~ 50 subjects ages 18 to 82' and showe&increasing, closing volumes wi'th age and smoking. Martin, et al. (BP 285), in a study of 50 subjects ages 12 to 68, found.that 25 percent of'the smokers had abnormal closing volumes, and Oxhoj, et al. (BP 307) noted el'evated' closing volumes for 50'-year-old' smokers compared to nonsmokers. Dirksen,, et al. ('BP'306)' reported higher closing volumes in smokers and notedino change with cessation of smoking. Hoeppner, et al. (B'P 244) also showedi elevated closing volumes in healthy smokers ages 16 to 61, but found these to be closely related to diecreases in the static transpulmonary pressure. They postulate that the elevated closing volumes may be xelated to decreased elastic recoil rather than changes in small airway resistance. The data have established'the fact that a greater percentage of smokers than nonsmokers have elevated closing,volumes, but the number of smokers with elevated closing,volumes who will develop COPD remains to be determined. Stebbings (BP49)',, i'n a further analysis of Densen's data (BP 86) on the ch:anges,in pulmonary function test values in malepostal'workErs,and:tr:ansit workers in New York City, noted significantly less decline in FEV1 among,Black smokers when compared to White smokers. This difference persisted even when corrections were made for differences in amount smoked, 73'

age at which smoking began, inhalation,patterns, and smaller initial lung volumes in Blacks. Black and White nonsmokers did'not differ in the rate of decline in FEV . By age 60 years, Blacks who smoked one pack per day hadia- .34 liter smaTler cumulative decrease in FEU'1 than Whites who smoked the same amount. Cf 1-ArPTTTRYPSIN It would' be useful tolid'entifythepopulationsatexcessive~ risk of developing COPDI £rom smoking,. They then might be made aware of the hazard before they develop symptomatic lung,disease. Persons with Of'1-antitrypsin deficiency may be such a population. Of -antitrypsin deficiency is a rare homozygous recessive genetic defect wAich occurs in approximately one out of every 3,600 people and results in an increased susceptibility to and premature development of' COPD. There is some evidence that smoking hastens the development of COPD,in these people. The heterozygous state (producing intermediate levels of the q''1-antitrypsfin in serum) is far more common than the homozygous state and is found in approximately ]i0' percent of the popul!ation. It is uncertain whether the heterozygous defi'ciency state predisposes to COPD. C/11-antitrypsin inheritance patterns suggest multiple codominant alleles at one gene locus, some of which (most notablY the S and Z'alleles)'Z produce lower serum protease levels than the normal M-allele (Table 4). The pathophysi~ologicmechanism,of the deficiency stateisfelt to~be theinabilityto inhibit tlie~ proteasEs found in thegranulocytes,and pulmonarymacrophages which go on to damag;e essential constituents of lung tissue. Several recent reviews of the enzyme and the clinical syndrome produced'by its deficiency have been published ($P 318'r BP 227, BP 16'5). In most studies of patients with COP'D,, investigators have found' an increased prevalence of the partially deficient heterozygote phenotypes when compared' to healthy control populations. In the few studies not finding this relationship,, only (yl-antitrypsin levels were measuredi. Because 1 antitrypsin is an acute phase protein and increases withlinfection, it i'~difficuTt to separate out the partially deficient heterozygote phenotypesy by measuring only ,A'1-antitrypsin levels. It is necessary to identify the products of eac~ allele electrophoretically iin order to identify the deficient phenotypes. Two recent studies using this technique showed anli'ncrea ediprevalence of deficient phenotypes in patients with COPD but not among control populations. Mittman, et al. (BP 93) studied 240 patients'with COPD' admitted to LaVina Hospital in Altadena, California, and'found that 19.1 percent had deficient phenotypes compared to only 7.1 percent of alcontrol 74

TABLE' 4L - The a t-antitrypsiir I'evels andfrequency of protease inhibitor (Pi) phenotypes in healthy populations HlealtByr populat'ions Protease inhibitor. (!Pi)' type n 1-antitrypsin ooncentration (9a normal) Expected frequency of Pi'types (per 1,000 people)'. MM 1i00 898 (FM„FF,I':N,Iu1V~,MX) 1100 28 MW 80 _a MP 80 1' M8 80 41: ' (FS;IS) 80 1 MZ 60 29 (FZ) 60 1 SS 55 1 SZ' 40, 1 ZZ. 1 S' <I a Seert rarely in Spanish populations. Source: Mittman, C.,, Lieberman, J!.,(8P 2'64)~ 75

Scandanavian po~pulation~., Keuppers and Donhardt('BP 170) found, prevalencerates fQr deficient phenotypes of 3'.5 percent in healthy controls,, 12'.9 percenr in persons retired from work because of COPD,,, and 15.7'percent in patients hospitalized for COPD. Additional population studies have been done to determine the effect oftheheterozygpusstate on theAesvelopmentof COPD'., Webb,, et a1., (BP18)i studied,5100 persons visfi.ti'ng, a multiphasic screening clinic in Monroe County, New York, and'found that 11.6 percent had deficient phenotypes. He was unable to show differences in symptoms or in pulmonary function test values between persons withinormal and deficient phenotypes. In a study of 45]1 randomly selected adults from the same county (BP 128), pulmonary function studies were done on 40 deficient heterozygote phenotypes (20MS':and 2GNIZ), andi on normal phenotype (WE),i control,smatched for age, sex, and smoking habits. When total pulmonary resistance was measured!by a forcedloscillometric technique, the nonsmoking MZ subjects had significant impairment compared to thei'r normal phenotype controls. All cigarette smokers, regardless of phenotype, had abnormal values. Although the data are still inconclusive, it may well be that heterozygousd'eficient persons are agr~oup~at excessive risk of developing COPD especially if they smoke. AUTOPSY AND PATHOPHYSIOLOGIC STUDIES A'utopsy Studies. Auerbach, et al. (Ref. 1): have previously shown dose-related macro- scopic emphysematous changes in the lungs of smokers. Now in an autopsy study (BP' 105)',of1„582' men and,38~8~ women,, theyhave~ examined'microscopiclung,parenchymal changes in relation to cigarette smoking. They were able toishow that rupture of alveolar septa (emphysema), and fibrosis and'' thickening of the small arteries and arterioles are far greater in smokers thamno:nsmokers,ande increase wfith, increasing amount smoked (Tables5and~ 6). When these researchers examined'former cigarette smokers, they found' that those who hadistopped more than ]i0'years prior to death had fewer pathologic changes than those who had stopped less than 10 years before: death. But even in those who had stopped for more than,10 years, there was a greater degree of pathologic change in those wholhad been smoking more than one pack per day than in those who had been smoking less than one pack per day (Table 7). Niewoehner, et al. (BP' 322), in anlautopsy study of 39 men who died, suddenly from various causes and who were below 40 years of age (201non- smokers and 19 smokers), observed a respiratory bronchiolitis associated 76

ti TABLE 5. - Means of the numerical values given lung sections at autopsy of male current.smokers and'nonsrnokers, standardized for age. Subjects Who Neve Stnoked Current Pipe Cig o r Current Cigarette Smokers r Regularly r a Smokers <,5 .5-1 1-2 > 2' Pk. Pk. Pk. Pk. lvumber of' Subjects 175 141 66 115 440 216 Emphysema 0.09 0.90 1.43 1.92' 2:17' 2~:27' Fibrosis 0.4'0, 1'.88' 2.78 3.73' 4':06, 4!28' Thickening,of arterioles 0'.110 1'.1T 1'.35' 1.66' 1.82' 1.89, Thickening of arteries 0.02 0.23' 0.42' ' 0:68 0:83' 0.90 NOTE. - IYumerical values were determined by raring' each,lung section, on scales of 0-4 for em,physemaiand't'hickening,of arterioles; 0-7 for fibrosis„and 0-3 for thickening of the arteries. Source: A;uerbachi„O., et at., (BP 103):, 77

TABLE ' 6: - Means of the numai'caat mlhees given lung sections at autopsy of ferrraLt cNurrertt smokers and'nonsmo,kers, stand'ardized for age Subjecta /Vlio Never Smoked! Crtrent! Cigarettis Smokers R'e gtdarly <1' Pk. a1 Pk Number of Subjects 252' 33 64 Emphysema 0.05 1.37 1.70 Fibrosis 0'.37 2.89' 3.46 Thickening of arterioles 0'.06 1.26 1.57 Thickening of arteries 0.01 0.40! 0'.64'. NQTE. - Numerical values were determined by, rating each lung~ section on scalea of 0-4 for emphysema and thickenitfg of the arteriioles, 0-7 for fibrosis, and 0-3 tor thickening of the arteries: Soureer. Auerbach+ 0., et al. (B!' 1'Q5). 78 ,

t c TABLE 7. - Means of rhe nwrneaieal'ualues gi>'en lung sections at autopsy of nrate former cigarette smokers, standardized for age. Stopped Z 10 xr. Stopped <10yr. Formerly Smoked <1 Pk. Pk.. <i. Pk. Pk. Number of 9ubjects 35 66, 51 13! Emphysema~ 0.24 0.70 1'.08', 1!.69. Fibrosis 1.14 1.74' 2:4'4 3.30 Z'hickening, or arteriales 0.57 M93 1.25~ 1'.59 Thickening of arteries 0.04 0'.1I6 0!36 0.611 NOTE. - Numercial!valuex fior each finding, were determined' by rating,each lung section on scales of 0-4 for emphysema and' thickening of the arterioies; 0-7 for fibrosis, and 0-3 for thickening of'the arteries. Source: Auerbech„0., et aL (BFI'Q5). . 7 9I

with clusters of pigmented alveolar macrophages in the lungs of smokers. They foundithese changes only rarely in the lungs of nonsmokers (Fig. 1)i. The smokers were young (average age 251.7'years), were a heavy smoking _ popuLationi(average 20.1 pack years)', but did not differ significantly fromm the nonsmokers in age, sociia'class, or pollution exposure. However, 12' of' the 19 smokers had had productive cough or frequent cold'compared to only 3' of the 20 nonsmokers. These authors postulated that bronchiolitis may bee responsible for the abnormalities in the tests of small airway function of smokers. Pathophysiologic Studies in Humans Yeager, et al. (BP 3013) ) showed decreased pinocytosis in human alveolar macrophages obtained from asymptomatic cigarette smoking volunteers when compared to those obtained from nonsmoking controls. - Warr and'Martin (BP' 217) studied alveolar macrophages lavaged'from four healthy smokers and'four healthy nonsmokers. Only two members of each group^ were reactive to delayed hypersensitivity skin tests for Cand'ida alblicans. Macrophages from nonsmokers responded' to Migration I'nhibitory Factor (MIF) by a depression in migration of at least 30 percent,,whereas macrophages from smokers did not respond to MIF'. The cells from smokers were notede to migrate three times faster than those from nonsmokers. When Candida antigen was added to the medium, cells from the nonreactive subj,ects (both smokers andinonsmokers) were not inhibited, the cells fromithe reactive nonsmokers were inhibited,, but the cells from reactive smokers were not inhibited. 'fhus, macrophages from smokers did not respond normally to either MIF or antigenic challenge. Pathophysiologic Studies in Animals Roszman and Rogers (BP 47)' noted that either the nicotine or the water soluble fraction of whole cigarettes smoked' suppressed the immunoglobuhin response of lymphoid cell cultures. When concerftrations of over 200 microgarams per milliliter of nicotine of the water soluble fraction were added, they were able to completely suppress the response and to observe this suppression even imcells,exposed' for2hoursprior to the antigenic challeng~e. Guinea piga (BP 48) exposedito the smoke of five cigarettes andithen lavaged 2 hours later had fewer pulmonary macrophages and leukocytes in the lavagefluid than di'd'controls not~exposed to smoke., The d'ecreasei~n the number of macrophages was highly correlated with, acetaldehyde, tar,, nicotine, hydrogen cyanide, andiacrolein concentrations in the cigare te smoke. The decrease in ttie number of leukocytes was more closely correlated' with pH of the particulate phase and concentrations of acetaldehydie and' tar. 80

• .P C IFtGURE' 1i. (R'esptratory broncWi'otitia iin, srnokett and control group 5, 0 •. - NONSM'OKERS' r (N•.r..M. .aMi.1. 1 i i SMOKERS NOTE.-The position of, each symbol represents the number of sections per case in which ibronchiolitis was identified. Source: Nievwoehner„ D.E., et al. (8P 322). 81

l. Tracheal mucous velocityr has been shown to be decreased in purebred beagle dog,s~ (BP' 56)~ exposed to 100 ciga~reztes, per week forT3 , 5 ffionths,. In donkeys (BP 297) low level exposure to whole cigarette smoke accelerated' tracheobronchial clearance, whereas at intermediate and'high levelis of exposure, clearance was decreased'. At high exposure levels whole cigarette szaokehad' twicetheeffe~ct of' filtered smoke in,decreas,ingcl'earance., 8'2

1 SU,%MRY OF RECENT' BRONCHOFIJ~~LMON;ARY F'IND'INGS' l. Cigarette smokers with mild viral respiratory illnesses have been shown to develop abnormal but reversible changes in certain pulmonary function tests while nonsmokers show no changes in these tests. Cigarette smokers have also been shown to have a significantly longer duration of respiratory symptoms following mild viral illness than nonsmokers.. 2'. Cigarette smoking is more cl'osely related to COPD' than is air pollution under the conditions of air pollution encountered by the average person. The possibility remains that the two kinds of exposure may interact. to increase the total effect beyond that contributed by each exposure. 3. Cigarette smokers without respiratory symptoms have evidence of' small airway disfunction (',elevated closing,vol!umes) more frequently than do nonsmokers without respiratory symptoms. 4. Autopsy studies have shown a dose-response relationship between cigarette smoking and the microscopic changes of COPD.. Data from one study indicate that bronchiolitis may be a far more common finding in cigarette smokers than in nonsmokers. 5'. Pulmonary macrophages from cigarette smokers' Iungs have a decreased ability to respond to in vitro antigenic stimuli. 83'.

BIBLIOGRAPI'IY (BP' 297) ALBERT, R., E. , BERGER, J. , SAfiIBORIV', k. , LIPPHANN'„ Iyf. Effectsf of cigarette smoke components.on bronchial clearance in thee donkey. Archives of Environmental Health 29(2): 96-101, August 19'71. (',BP 105) AUERBACIi,, 0~.,, GARFINKEL, L., HAMMOND, E. C. Relati'on~ of smoking,and age to findings' in lung parenchXma: a micro- scopi'c study., Chest 65(,1): 29-35, Janua~ry~ 1974.~ (Ref . 1) AUERBACIi',, 0. , HAMtSOND„ E. C., GARFINKEL, L., BENANTE, C. Relation of smoking and aoe to emphysema: whole-lung section study. The New England Journal of Medicine 286 (16): 853-857, April 201, 19Z2'. (BP' 41) BERRY,, G. , McKERROW, C. B':. , MOLYNEUX, M. K. B., ROSSITER, C. E. , TO.riBLESW, J. B. L. A studylof' the acute and chronic changes in ventilatory capacity of workers in Lancashire cotton mills. British ,Tournal of Industrial Medicine 30!: 2'5-36 ,, January 19 73' . ($P' 33')BET,dLEY',, B~.~ R., HALIL,, T.,,, SNA~~ITH~, A. 11111. Smoking~ by p~~rima~,ry~ sch~oolch~ildren--preva~llenceandlassociated resp~~iratory: symptoms. British J'ournal of'P'r.eventive and' Social Medicine 27'(3): 150"153, August 1973. . (BP 29'), CHAPMAN,, R'., S. ,, SIIY,, C. M'. „ FINKLEA, J. F'., IiOUSE,, D. E.. , GOLDBERG, H'. E., HAYES',,C. G. Chronic respiratory disease in military inductees and'parents of school- children. Archives of Environmental! Iiealth 27'(,3): 138-142, September 19'73'.. (BP 232) COLLEY, J. R. T., DOUGLAS,, J. W. 8., REIDi„ D., D. Respiratory disease in young adults: influence of early childhood d lower respiratory tract illness, social class, air pollution,, and smoking. British Medical Journal 3(5873)1: 195-198, July 28, 1973, Eng,lish,., (BP 13)! COMSTOCK', G. W., STONE, R. W.„ SAKAI!„ Y., MATSUYA,, T., TO'NASCZA,,J'. A.Respiratoryfind'ings and'urban living. Archives of Environmental Health 27: 143-150, September 1973. (BP' 86) DENSEN,, P. M. ,, JONES,, E. W. , BASS, H. E. , BREUER,, J., REED:,, E. A survey of respiratory disease among N'ew York City postal and'transit workers. 2. Ventilatory function test results. Environmental Research 2(4): 277-296, July 1969~. 84 lW N W

(BP' 306) DIRKSEN, H. , JANZON, L.,, LINDELL, SI. E. Influence of smoking and cessation of smoking on lung function. Scandinavian Journal of Respiratory Diseases (Supp1!ementum~85): 266-274,, 19'74. (BP 14) FRENCH, J. G.,; LOWRIMORE, G., NELSON', W. C., FINICLEA, J. F., ENGLISH, T.„ HERTZ, M. The effect of sulfur dioxide andd suspended'sulfates on acute respiratory disease. Archives of Environmental Health 27: 129-133, September 197'3'. (BP' 171) FRIDY, W. W. , Jir., INGRAM, R. Hi. „ Jr.„ HIERHOLZER, J. C., COLEMAN, M. T. A~irwaysfunction duringmil&vi'ra1 respiratory! illnesses~. The effect of rhinovirus infectionlin cigarette smokers. Annals of Internal Medicine 80(2)': 150-155, February 1974.. (BP' 31) FRIEDMAN, G. D'., SIEGELAUB, A. A.,,. SELTZER, C. C. Cigarette smoking and exposure to occupational hazard's. Ameri!can Journal of Epidemiology 9'8(',3) r 175-183, September 19'73'. (B'P' 244)~ HOEPPNER, V., H., COOPER, D. IWI!.,,ZAMEL„ N., BRyAN',A.C'., LEV'IS0N',, H'. Relationship between elastic recoil and closing volume,in smokers and nornsmokers,., American Review of Respiratory Disease 109 (l) : 81-8'6',, January 1974. (13P 12')' HRUBEC, Z'. , CEDERII.OF', R., FRIBERG, L., HORTON'„ R.,, 0'Z'OLIN'S, G, Respiratory symptoms in twins. Archives of Environmental Health 27':189-195,S'eptember1973'. QP' 227) HUTCHISON,, D. C. S. Alpha-l-antitrypsin deficiency andi puhonary emphysema: the role of proteolytic enzymes and their inhibitors. BritishiJournal of'Diseases of' the Chest 67(3): 171-196, July 1971. (BP' 165) KfJEPPERS,, F'. q 1-antitrypsi'n. American Journal of Human Genetics 25 (6 ) : 677-686 ,, 1973. (BP' 318) KUEPPERS, F.,, BLACK, L. F. 4 1-antitrypsin and its deficiency. American R'eviewofRespiratory Disease 110(2): 176'-194,August 19'74. (BP 170')MJEPPERS,F.,DONHA'RDT„ A.ObstructiveIung~disease in hetero- zygotes for aliphal-antitrypsin deficiency. Annals of Internal Medicine 80(2): 209-212',, February 19'74.

C (BP 19) LIM, T. P. K. Airway obstruction among high school students. American Review of Respiratory Disease 108(4): 985-988, October 1973'. (BP' 285)i MARTIN, R. R. , LEMELIX„ 0'. , ZUTTER, M. ,, ANTHONISEN, N. R. Measurementof"closing, volume/R1:~ application,and d limitations. Bulletin de Phys3o-Pathologie Respiratoire 9: : 979-995, July-August 1973. (BP 264) MITTMAN, C., LIEBERMAN,, Ji. Screening, for Of 1-antitrypsin deficiency. Israel Journal of Medical Science9:. 13'11-131&, September-October 1973'. (BP 93) MITTM'AN,, C., LIEBERMAN, J., RU:wtSFELD, J. P'revalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung d3sease. American Review of Respiratory Disease 10.9'(2) : 295-296, February 1974. (BP' 322) NIEWOEHNER, D. E. „ KLEINERMAN, J.,, RICE,, D. B. Pathologic changes in the peripheral airways of young cigarette smokers. New Englan&Journal of Medicine 291(15):. 755-758, October 10, 1974. ~ ($P' 78) OSHIMA, H. , IMAI, M., KAWAGISHI, T. Effects of air pollution on the respiratory symptoms in Yokkaichi, Central Japan. a'i'e Igaku 16 (1)1: 25-29 , June 19'72'. (BP~~ 307)' OXHG,-#~~,, H~.,,, BAKE, B.~,~ WILHELMSEN, L. Closing volume in 50- and 60-year-old'men. A preliminary report. Scand'inavi'an Journal of Respiratory Diseases (Supplementum 85) :.'.59-2'65, . 1974. (BP' 4T)' ROSZrsA-N„ T'. L., RUGERSI, A. S. The immunosuppressive potential of products derl".ved fromicigarette smoke. AmericaniR'eview, of' Respiratory Disease 108(5)': 1158'-1163, November 1973'. (BP' 73), R'UFF, F.,, SALEM, A., BUSY, F.,, de VERNEJOUL, P. ,, EV'ENi P'. , BROUET, G. La fermeture des voi'es aeriennes peripheriques. Sonlaugmentation chez les fumeurs. (',Closing, of the peripheral airways. Its increase in smokers.) Revue d'e Tuberculose et de Pneumologie 36(2): 308'-311,, March 19'72'. (,BP 48) RYLANDER, R. Toxicity of cigarette smoke components: free lung, ce711 response in acute exposures. American Revieww of Respiratory Disease 108'S): 1279-1282, November 1973'. 86

(BP' 112')i SAWICKI, F'., Air pollution ande prevalenceofchronic nonspecific respiratory diseases. In: Brzezinski, Z., Kopczynski, J.i, Sawicki, F. (Editor),. Ecology of chronic nonspecific respiratory diseases, International Sumposium, September 7-8, 1971,W'arsaw, P'oland,PanstwowyZaklad WydawnictwLekarskich,. Warsaw, 1972, pp. 3-13. (8P 128) SCHWARTZ,, R. H. Alpha-l-antitrypsin deficiency and chronic respiratory disease. Annual Report June 28', 1972'- Jiune 20, 19'73'. Unfiversity of Rochester,, Rochester, N. Y. Prepared for Respiratory Diseases Branch,, National Heart and Lung Institute, National Institutes of Health, Bethesd'a,, Maryland. (BP' 95)' SIDOR, R'., PETERS, J., M. Fire fighting and pulmonary functi'on. An epid'emiologic study. American Review of Respiratory Disease, 109~(2)!: 249-254, February1974. (BP 94) SIDOR, R'.„ PETERS, J. M. Prevalence rates of chronic nonspecific respiratory disease in fire fighters. American Review of Respiratory Disease 109(2): 255-261, February 1974. (BP' 58) STANESCU, D. C, , VERITER, C. , FBAN',S,; A., BRASSEUR, L. Maximal expiratory flow rates and "'closing vol:ume"' in asymptomatic healthy smokers.Scandi'navian Journal of Respiratory Diseases 54: 264-2'71, 1973.. (BP'49') STEBB'INGSI, J. H., JR. A survey of respiratory disease among New~ York City postal andd transit wo~~r~ker~s~~., IV. Racial differences in the FEVli. Environmental Research 6: 147=1L.58!, June 1973'. (HCS~1)1 U.S. PUBLIC HEALTH SERVICE. Smoking, and Health. Report of' the Advisory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Department of'Health, Education,, andWelfare, Public Health Service Publication IV1o. 1103, 1964, . 387 pp. (HCS 2), U'. S. PUBLIC' HEALTH SERVICE. The Health Consequences of Smoking,. A P'ublic Health Service Review: 1967. U. S. Department of Health, Education, andiWelfare. Washington, Public Health Service Publication No. 1696,, Revised January 1968, 222' pp. 0)

M S 3) U.S. P'UBLIC' HEALTH SERVICE. The Health,Consequences of Smoking. 1968. Supplement to the 19'67'Public Health Service Review. U.S. Department of Health, Education, and' Welfare. Washington,, Public Health Service P'ublication 1696, 1968, 117 pp. (HCS4)~ U.S~. PtlB.hICHEAI.TH SERVICE. The Health~ Conseq,uences ofSmoking,.196'9.Supplement to the 1967'Public Health Service Review. U.S. Department of Health, Educationi, and Welfare. Washington, Public Health Service Publication 1696-2, 1969, 98i pp. (~HCS~ 5~~)~, U~. S'. PUBLIGHEALTR SERVICE~. Th~e~~ Health Con~~sequencesof Smoking. A Report of the Surgeon General: 1971. UU.S. Department of Health~,, Education, and~ We~l!fare., Washing,ton,, DHEGZ~ Pub,lica~tion! No. (HSM) 7~1-7513', 19'71, 45&pp. (HCS 6) U.S'. PUBLIGHEALTH SERVICE.The Health,Consequences,of Smoking. . A Report of the Surge=General: 1972. U.S. Department of Health, Education, and We~lfare., Washington, D'H~EGJ~ Publicati'on; No~. (HSM) 72-6516, 1972, 158 pp. (HC~S~~ 7), U.,S~~.~ PU~BLZC~ HEALTH SERVICE. The~~ Health Consequences of~ S~moki~ng:. 1973. U'.S.~ Dep~artment~ of Health, Ed!ucation,,, and W'e~~lfare~., ~ WashingZon„ DHEW Publication No. (H2,f) 73-8704, 1973, 249' pp. (HCS~ 8) U.S~., PU'BLIC' HEALTH~SERV'ICE. The~~Health~ Consequences o~f~ Smoki'ng; 1974. U.~S.~ Department of Health, E~ducationi, and' Welfare. Washington, DHEW Publication No. (CDC) 74-87C14. ($P 119) VAN' DER LEITDE', R'. , DE KROON, J. P. M., T?.Ml`ELING, G. J.„ VISSER, B. F. , DE VRI!ES,, K., WEVER-HESS, J., ORIE, N. G. M'. PYevalence of chronic nonspecific lunddisease in a,non- polluted,and an air-polluted area.of' theNetherlands. In: Brzezinski, Z., KopczynsKi:, J., Sawcki, F'. (Editors). Ecology of chronic nonspecific respiratory diseases, International Symposium, September 7-8', 1971, Warsaw, P'oland,, Panstwowy Zaklad Wydawnictw Lekarskich, Warsaw, 1972, pp. 27-33. (BP 56), WANhER, A., HIRSCH, J. A,, GREENELTCH, D. E., SWENSJV, E'. W., FORE,, T. Tracheal mucous velocity in beagles after chronic exposure to cigarette smoke. Archives of Environmental Health 27(6) : 370-371, December 1973. (BP 217) WARR, G. A., MARTIN, R. R. In vitro migration of human alveolar macrophag,es,: effects of cigarette suioking., Infectipn and Iuununity 8(2) : 222-22'7', August 19'73. 88

(BP1!8)'k1EB'B,D.R. , HYDE, R. W., SCHWARTZ,, R. H., HAI:.L,W., J., COND .F~~tI, J. J., TOWNES, P. L. Serum 1-antitrypsin variants. Prevalence and clinical spirometry. American Review of Respiratory Disease 108(4) : 918-925, October 1973. (BP 303) YEAGER„ H., JR., Z'I2O1ET, S. M., SCHWARTZ,, S. L. Pinocytosis by human alveolar macroph,ages~., Comparison of'smokers and nonsmokers. Journal of Clinical Investigattion 54(2'): 247-251, August 1974. i 89

CNAPTER' 4 INVOLUNTARY SMOKING

Contents Pa e Introdtiction.. . . . . . . . . . . « . . . . . . . . . . . 95 Constituents of Tobacco Smoke« . . . . . . . . « . . . . . 96'. Carbon M'onoxide. . . . . . . . « . . . . . . . . . . . 96 Nicotine . . . . . . . . . . . . . . ... . . . . . . . 101 Other Substances.., . . . . . . . ., . . . . . . . . . 102 Effects of Exposure to Cigarette Smoke. . . . . . . . . . 102 Cardiovascular Effects of Involuntary Smoking. .... 102 Effects of Carbon Monoxide on Psychomotor Tests. ..« 103 Pathologic Effects of Exposure to Cigarette Smoke. . . 103 Summary of Involuntary Smoking,Find'ings. . . . . ., . . ., . 111 Bib] iogzaphy. . . . . . . .1 . . . . . . .. . « . . . . . . . 112 List of Tables Page Tab1e 1.--Comparison of mainstream and sidestream cigarette smoke. . . . . . . . . . . .. . « . . Table 2.--Measurements of constituents released by the combustionof tobacco~ products in various s ituations . . . . . . . . . . . . . « . . . . . . 97 . ., ., . 9'.8 Table 3!.--Effects of carbon monoxide on psychomotor functions . . . . . . . . . . . . . . « . . . . . . Table 4.--Admission rates (per 100 infants)by diagnosis, birth weight, and maternal smoking. . . . . . . . . . . . . . . « . . . . « . « . 1014 Table 5.--P'rieumonia and bronchitis in the first 5 years of life by parents" smoking habitt and' morning. phlegTn. « . . . . . . . . . . . . . . . . .109~ 93'

0 w ~ ~ ~ N GJ W

C 1 INTRODUCTION The effects of smoking, on the smoker have been extensively studied, but the effects of tobacco smoke on nonsmokers have received much less attention. Ttie 1972 Health Consequences of Smoking (IS 38)' reviewed the effects of public exposure to the~air pollution resulting,from tobacco smoke. This exposure has been called "passiivesmoking'°by: many!authorities~, but will be referred to in this report as "Involuntary Smoking." The term involuntary smoking will be used to mean the inhalation of tobacco!combustion products from smoke-filSed atmospheres by the nonsmoker. This type of exposure is, iM a sense, "''smoking"'because it provides exposure to many of the same constituents of tobacco smoke that voluntary smokers experience. It is also "invol!untary"' because the exposure occurs as an unavoidable consequence:of breathing in a smoke-filledienvironment. Tihe~ chemical constituents found in~ an atmosphere filled with tobaccoo smoke are derived from two sources-mainstream and sidestream smoke. Main- stream smoke emerg;es from the tobacco product after being drawnithrough the tobacco during puffing,. Sid'estream smoke rises from the burning, cone of tobacco. 1°tainstream and sidestream smoke contribute different concentrations of many substances to the atmosphere for several reasons: Different amounts. of tobacco are consumed in the production of mainstream and side3tream smoke; the temperature of'combustion differs for tobacco during,puffing,or while smoul'dering; and certain substances are partially absorbed from.the mainstream smoke by the.smoker., The amount of a substance absorbed by the smoker depends arn the characteri!stics of the substance and the depth of inhalation bythe smoker. As discussed in the 19'72'Report,, when the smoker do~esnot inhalethe smoke intohislungs,, the smoke he exhales contains lessthan half its original amount of water-soluble volatile compound's, four-fifths of the original nonwater-solubile compounds and particulate matter, andialmost all of the carbon monoxide (',IS 15). Wfienithe smoker inhales the mainstream smoke, he exhales into the atmosphere less thanione-seventh olf the amount of volatile and particulate substances that were originally presentt in the smoke and also reduces the exhaledi C01to less than half' its original concentration (IS 14). As alresu3t,, vastly different concentrations of substances Are found in exhaled mainstream smoke depending on the tobacco .product, compositionof the tobacco, and degree of inhalation by the smoker. Several minor symptoms: (conjunctival irritation., dry throat,, etc.) are caused byLevels of cigarette smoke encounteredlin everyd'ay life,,and'iserious allergic-like reactions to cigarette smoke may occur in some sensitive individuals. A major conce~rni, however, about atmosphericcontam~ination byrcigarette smoke has been due:to the producti'on!of significant levels of carbon monoxide. Cigarette smoking in poorly ventilated enclosed spaces

may generate carbon monoxide levels above the acceptable 8-hour industrial exposure limits (50' ppm)--set by the American Conference of Government Industrial Hyg,ienists (IS' 1)'. Exposure to this level of carbon monoxidee even for short period's of time has been shown to reduce significantly the exercise tolerance of some persons with symptomatic cardiovascular disease. There is also some evidence that prolonged exposure to this level of' carbommonoxide in combination with a high cholesterol diet can enhance experimental atherosclerosis in animals (Chapter 1, Cardiovascular Diseases). In the present chapter, the effects of cigarette smoke on the environment and on the nonsmoker in that environment will be examinediby reviewing data on (1) the constituents of cigarette smoke measured under various conditions and (2)' the physiologic effects of this "involuntary smoking"' on individuals. CONSTITiJENTS OF' TOBACCO S:fOKE In a recent workshop on the effects of environmental tobaccoismoke on the nonsmoker (IS 49)', Corn (IS' 41) presented a compilation ad'apted' ~/ from Hoegg (IS 47)i of some of the substances in mainstream cigarette smoke and the ratio of sidestream to mainstream levels for some of'these substances (Table 1)'. Many-of these substances including, nicotine and carbonimonox~ide:are found inimuchihigher concentrations in sidestream smoke than in mainstream smoke, establishing that the smoke exposure of the involuntary smoker differs qualitatively as wel1 as quantitatively from the smoke exposure of' the voluntary smoker. A more comprehensive recent _ review of the constituents of mainstream and'sid'estreamismoke has also been provided by Schmeitz, et al. (IIS' 32). w A number of other researchers have attempted to measure the levels of some of the substances in cigarette smoke encountered in everyday V situations (Table 2). They have alsoitried to determine the factors controlling the atmospheric concentrations of these substances as well as the amount absorbed by nonsmokers under these conditions. Carbon monoxide, nicotiney bienzol(a)pyrene, acrolein, and acetaldehyde have been of particular concern. Carbon Monoxid'e. Levels of'carbon monoxide (CO), a major product of tobacco combustion, have been studied in a variety of situations, and concentrations ranging from 2 to 11fJ ppm have been measured (Table 2) . The major determinants of the COlevels in these situations are size of the space in which the smoking occurs (dilution of CO), the number and type of tobacco products smoked (CO production), and the amount and effectiveness of ventilation (CO' removal). ! 96

C TABLE ' D. - eomparison of mainstrearn and'sid'estream cigarette sntoJce ",2i Compound Mainstream (mg/cig) Sidestream (rng/cig) Ratio Sidestreamf' Mainstream A General characteristics Duration of smoke production 20'sec SS0isec 2'7' 'fobacco burnt' 347 411 1.2' Par'tiiculat'es, no. per cigarette 11.0S X 1011 3'.S X 1i01' 2 3.3 B Particulate phase 2Tar (chloroform extract) 20•$ 44'.1 2'.1 10! 2 343 3'.4I Nicotine 0:92' 1'.6'9 1' 8! 0.46 1'.27' 2'.8' Benza(a~)Pyrene~~ 3:5~~ X~1Iq"s~~ 13!5~~ X~l0 ~ IT Pyrene 13' X 1I0-s' 3;9 X 1,0-s' 3~ 0! Total phenols 0.228 0:603 2.6 Cadmium 12:5 X 1Qi 4'S X 10-s 3 6 C Gases and vapors Water 7:5 298' 39.7' Ammonia 0:16' 7.41 46 Carbon monoxide 31.41 148' 4.7. Carbon dioxide 63.5' 79.5' 1.3. Nrtrous oxides 0.0i1'4' 0:05'11 16 Comment Filter cigarette Filter cigarette 3:S' mg of Mainstream and! S'.5 mg of Sidestream in particulate phase, tesCin vapor phase t Adapted from Hoegg, U.R'., (IS 46, 47) 2For 3S':mI pufff volumay 2' sec puff'diirzt',ion„ona puff per minute and 23 or 30 mm, butt' length, and 10 per'cent, tobacco mouture. Source: Corn, RMI. (IS 4I')L 0 9'7

TABLE 2. - Measurements of constituents released by the combustion of tobacco products tit various situations [Cig = cigarettes; -= unknown; TPM = total particulate matter] Reference, I.ocation, and Dimensions If Known Harke, H.-e., et ai. (IS 44) Mid-size European car, engine off, In wind tunnel at 50 krn/hr wind speed Ventilation Amount of Tobacco Burned Constituents None AIr jets open & blower off 9 cig 6 cig AirJEtsoptnd: 6cig blower on 30 ppm CO 20 ppm CO 10 ppm CO 110 ppm CO Mid-size European car, None 9 cig engine off, in wind ~ tunnel at zero kmfhr None 6 cig wind speed 90 ppm CO Air jEts open dc -6 cig 8-10 pptn CO blower on 'Harke, H.-P., Peters, H. (IS 43) Car in traffic None 4 cig 21.4 ppm CO Srch, M. (IS 35) Car, engine off-. None 10 cig in 1 hr 90 ppm CO, Smokers 5-1096 COHb 2.09 m3 Nonsmokers 2-5% COHb S_e_Iff, H.E. (IS 34) Intercity buses 15 air changes per hr 23 cig 33 ppm CO (at driver's scat) (burning continuously) ~ 3 cig (burning continuously) 18 ppm CO (at driver's scat) U.S. Dept. 3'ransportation, et al. (lS.ll) Airplane flights: Overseas-100% filled 15-20 air changes per hr - 2-5 ppm CO, <. 120 mg/m3 TPM Domestic-6696 filled do. - <2 ppm CO, <.12U mg/n13 TPIM 4iCZV94C0

TABLE 2. - Measurements of constituents released by the combustion of tobacco products In various situations - Continued [Cis = cigarettes; -= unknown; TPM =_ total particulate matter] Reference, Location, and Dimenaions If Known Cano, J.P., et al. (IS 12) Submarines-66 m3 Godin, G„ et al. (IS 20) Ferry boat compartments: Smoking Nonsmoking T-heater: Foy er Auditorium Bridge, D.P., Corn, M. (IS 9) Party rooms: 145 m3 101 m3 Harke, H.-P., et al. (IS 24) Room-38.2 m3 Harke, H.-P. (IS 50) Office Bldg Office Bldg Room-78.3 m3 SM94c0 Amount of Ventilation Tobacco Burned Constituents Yes 157 cig per day <40 ppm CO, 32 µg/m3 Nicotine 94-103 cig per day <40 ppm CQ, 15-35 µg/rn3 Nicotine ' 18.4 t8.7 ppm CO 3.012.4 ppm CO 3.4t0.8 ppm CO 1.4±0.8 ppm CO 7 air changes per hr 50 cig & 17 cigars in 1.5 hr 7 ppm CO 10.6 air changes per hr 63 cig & 10 cigars in 1.5 hr 9 ppm CO None 30 cig per 13 min (by machine) 64 ppm CO, 510 Ng/m3 Nicotine .46 m%/m3 Acrolcin 6.5 mg/rrt3 Acetaldehyde 5 cig per 13 min (by machine) 11.5 ppm CO, 60 µg/m3 Nicotine, .07 mg/m3 Acrolein, 1.3 mg/m3 Acetaldchyde Air conditioned - <5 ppm CO Not air conditioned -. <S-ppm CO - -- - - - 3 smokers 15.6 ppm CO

TABLE 2. -Measurements of constituents released by the combustion of tobacco products in various situations -(.1ontinued [Cig = cigarettes; -=. unknown; TPM = total particulate matter] I Reference, Location, and Dimensions If Known Harke, H.-P., (IS 22) Room-57 m3 Room-.170 m3 Anderson, G., Dalhamn, T. (IS 2) Room-80 m3 Ventilation None 7.2 air changes per hr 8.4 air changes per hr None 7.2 air changes per hr None 7.2 air changes per hr None 1.2 air changes per hr 2.3 air changes per hr 6.4 air changes per hr Amount of Tobacco Burned 42 cig 42 cig 42 cig 9 cigars 9 cigars 9 pipes 9 pipes 105 cig 107 cig 101 cig 46 cig & 3 pipcfuls Constituents 50 ppm CO, 530 Mg/m3 Nicotine 10 ppm CO, 120 µg/m3 Nicotine <10 ppm C0, <100 µg/m3 Nicotine 60 ppm CO. 1040 ug/m3 Nicotine 20 ppm CO, 420 µg/m3 Nicotine 10 ppm CO, 520 µg/rn3 Nicotine <10 ppm C(), <100 vg/m3 Nicotine 30 ppm CO. Smokers 7.5% COIIb Nonsmokers 2.1%COHb S ppm CO, Smokers 5.8%COHb Nonsmokers 1.3% COHb 75 ppm C_O_ , Smokers 5.0% COlib Nonsmokers 1.6% COHb 4.5 ppm CO, 377 ; g/m3 Nicotine, 3.0 mg/m TPM Russell, M.A.H., et al. (IS 31) Room-43 m3 None 80 cig & 2 cigars per hr 38 ppm CO, Smokers 9.6% COHb Nonsmokers 2.6% COHb Harmsen, H., Effenberger, E. (IS 4S) Room-93 m3 None 62 cig in 2 hrs 80 ppm CO, 52100 µg/m3 Nicotine Hoegg, U. R. (IS 46, 4 T-) 3 Scaled test chambcr-.25 m3 None 4 cig TPM 12.2 ppm ( (). :'.28 mg/rn 8 cig 25.6 ppm CO, 5.39 mg/m3 TPM 16 cig 47.0 ppm CO, 11.41 mg/mTTPM 24 cig 69.8 ppm CO, 16.65 mg/m8 TPM 6M94c©

The' type of tobacco product smoked as a ae'terminant of C0 exposure . ~:5 ..+T 'J ... important because'it has been found' that mainstream smoke from regular and small cigars contains more CO' per puff and per gram of tobac¢o' burned', l4 ' n f1 than fi]itered or unfiltered cigarettes (,IS 40) . This g,reater production1P of CO by cigars was confirmed by Harke (IS 22). He measured the CO produced by 42' cigarettes, 9' cigars,, and 9 pipefuls of tobacco, each product evaluated separately' but under the same room conditions.' . 7Phe cigars produced the highest C0 level .(60' ppm). }. '' ..{* ' In additionto ttle' effect of type, of tobacco' product on C0 leuels, , . data on the effects of room size, amount of tobacco burned, and ventilation 1. are included in Table 2. Only underconditions of unusually heavy smoking and poor ventilation did CO levels exceed' the' maximum pe'rm3ssible, 8'-liour .: .industrial exposure limit of 50 ppm CO (IS 1); however, even in cases .r1 where the ventilation was adequate, the measured C0 levels did exceed I j~,. ~,st ~~ the~ maximuml acceptable ambient level of~~ 9 ppm (YS~ 17). ~ One must~ be careful k'when using the levels recorded in Table 2 as measures of individual exposure because the' CO levels were usually measured at points several feet from hkdbbld' h b hifi te neares t smoer an proaly wouaveeenger if measured at as. . to the pasi'tiom of a person sitting next to the smok points corresponding,er ,; r; ~ ZS' 16)'. In addition, it is the CO absorbed by the body that causes the' harmful 4 Ci: ,.effects and not that which is' measured' in the atmosphere._ This absorption can vary from individual to individual, depending on factors such as duration of exposure,, volume of air breathed per minute, and card;:o-re'spiratory function. Several investigators have tried to de'termine the amount of carbon,`y._. ,~., monoxide absorbed' in involuntary smok3n;, situations by measuring ch'anges : in carboxyhemoglobin levels in nonsmokers exposed to ci'garette smoke-filled environments. Anderson and Dalhamn (IS 2) were unable' to find any change in the COh-b levels of nonsmokers in a well ventilated roon where the ., . CO level was 4.5 ppm. When Harke (IS 22) studied nonsmokers under similar ;, conditions (good venti]iationand less than 5' ppm CO)' ,, he was able , to show an F increase in COIIb level fromi1.1 to 1.6 percent; without ventilation the '' CO levels rose to 30 ppm and!the COHb level increased from .9 to 2'.1 percent ~ .aY.. in 2 hours. Russell, et al. (IS 31) also found that COHb levels i'ncreased ,, from 1.6 to 2.6 percent in nonsmokers exposed to a smoke-filLed room where the CO level was measured at 3!8'ppm; however, he cautioned that 1nearly all p'ersons in the room felt that the conditions were'worse than those experien'ced in most social situations. The levels of COHb measured by both Harke and Russell, et al. (IS 22', IS 31) are well within 'the range' that has been shown to decrease the exercise tolerance of patients with angina pectoris (IS 3,, 4, 5, 6, 7,--Chapter' 1, Cardiovascular Diseases)!._ Nicotine Nicotine in the atmosphere'differs from CO'in that it'tends to' settle. out of the ain with or without ventilation (thereby decreasing,its

., . ' .. . , , ;4~ - .. . . . ~ . . . . •~,• atmospherzc concentration)'', whereas the.CO level! will remain constant until the CO is removed. The concentrations of both substances are decreased '' substantially by ventilation. As can be seen from data, iu Table 2, ' under conditions ' of adequate ventilation neither exceed's the maximum `'"' threshold limit values for industrial exposure (nico'tine,, 500 Ag/m3;, CO, 501 ppm,, ('IS~~ 1)i; whereas in~~cond~itions without~~ ventilation,,~ smoking produces very high concentrations of both (nicotine, up to 5,200/t g/m3', CO!, 110, ppm) .^'-j ;`'. ~ .~Y+IT . . .,. ~ , ...,~ ., . ; . . . ' . .', - ~; Ni cotine in the enviro~ament is of concern because nicotin~ abs©rbed by cigarette smokers is felt to be one factor contributing to the development of atherosclerotic cardiovas'cular disease: Several researchers have 'attempted' to measure the' amounti of nicotine absorbed' by~ nonsmokers in' involuntar~ 'smoking situations. "'-Canol, et al. (IS' 12)i studied urinary excretion of nicotine by persons on a submarine." Despite very low levels measured in the air (15 to' 32 /Z g/m3)', nonsmokers did show a small rise in nicotine ;° excretion; however, the amount•excreted wasistill less than 1 percent of'the''' amount excreted bY smokers.``•Harke (IS'22)i measured nicotine and its `~' metabolite cotininein the urine of smolcersi and nonsmokers' exposed to a'' smoke-filled environment and'reported'that nonsmokers excreted' less than : .1' percent af' the -amount of nicotine and cotinine excreted' by smokers. -----`-:- H'e feels that' at this~ low level of absorption nic+otine is' unlikely to '; be a hazard to the }'nonsmoker.f` , l.di?~y~+'~' ~,,a. Other Substancee 4~''~J.~~~ ~ 4lr,. ;; 4~. ~f.; In two studies environmental levels of the experimental carcinogen benzo(a)pyrene were`measured. Galuskinova aS 19) found' levels'` - of benzo(a)pyren'e from'2.82 ' to 14.4 mg/m3 in smoky" restaurants, but it isnotclearhawTauchofthiis~ was dtiueto'cooking and, hoRamuch, was due to smoking, - In a study of' the concentration of benza(a)!pyrene in the atmosphere of airplanes (IS 37)'',' only a fraction of a microgram per cubic meter was detected, The effect of chronic exposure to very lowlevels o£ this carcinogen hasnot been established for ~~ I .. . . . . _ - ' ~ -. . " - . . . . ~ . . ,. - .. . Acrolein. and acetaldehydehave also-been measured in' smoke-filled rooms (IS 24, Table 2) and'may Eontribute to the•eye firritation commonly experienced in these EFF'ECTS OF' EXPOSITRE TO CIGARETTE SMOKE ' Cardiovascular Effects of Ihvo'luntary Smoking y The effects "of cigarette smoking on the'cardiovascul''ar 'system' of the smoker are well established, but vary little is known about th'e cardio- vascular response of the nonsmoker to cigarette smoke. Harke and Bleichert

s ~ (IS2'3)! studied,]18adults (11 smokers and' 7 nonsmokers) in a room 17Gm3larg,e in which 150 cigarettes were smoked or allowed to burn in ashtrays for 30' minutes. They noted'that the subjects whoismoked during thee experiment had' alsi'gnificant lowering of skin temperature and a riseM/ in blood pressure. Nonsmokers who were exposed to the same smolie- contaminated'environment showed no change in either of these parameters.. L.uqiuette, et al. (IiS' 27) performed' a similar experiment with 40 children exposed' alternately to smolte-contaminated' and clean~ atmospheres, buf' other- wise under identical experimental condi'tions.They,f~ound that exposure to the smoke caused increases in heart rate (5 beats per minute)' and in systolic (4 mm Hg)~ and diastolic (5 mm Hg) blood pressures. The d'ifferences in results between these studi'es may be d'ue,, in part, to the age of the subjects--i.e., children may be more sensitive to the cardiovascular effects,of involuntarysmokingth~an adults,, or the increase in heart rate and blood pressure may be due to a difference between chil'dren and adults in~ the psychologic response to being, in a smoke- filled atmosphere. Effects of Carbon Monoxide on P'svchomotor Tests Carbon monoxide from tobacco smoke, automobile exhaust, and' industrial poSlution is an important component of air pollution. f'iere has been some: concern over the effect of'relatively low l:evels of carbon monoxide on psychomotor functions (the ability to perceive andireact to stiznuli), especially those functions related' to driving an automobile (Table 3). Carbon monoxide levels occasionally reached' in some involuntary smoking situations result in measurable cognitive and'motor effects, but these effects generally are measurable only at thie threshold of stimuli perception. One study (Wright, et al., (IS 39) found'that the safe driving habits,measur'ed on,a driving, simulator did not improve as!much~with practice in a group exposed' to CU' as did the habits of a control group. Another study (IS' 2'8), with a different experimental design but'at the same levels of CO did not find any effect on complex psycho- motor activity such as driving,a car. Thus, thie role of CO alone in motor vehicle accidents remains unclear. The effect on judgement and reactions of COn in combination with factors such as fatigue!and alcohol, conditi'onsknown to influence judgement and' reaction time, has not been d'etermined. Paithoiogi'c Effects of Exposure to Cigarette Smoke The effect of involuntary smoking on an indi'vidual is determined not only by the qualitative and' quantitativeaspectsofthesmoke-f~illedenvironment,, but also largely by the characteristics of the individual. Reacti'ons may vary wi'thiage as well as with the sensitivity of an individual to the components of tobacco smoke. The severity of possible effects range from minor eye and throat irritations experiencediby most people in smoke-filled rooms„ to the incapacitating anginal attacks of some persons with cardiovascular d'isease. 3 101

Ti ABL,E 3~. - Effects of carbon nsonl.~ le on psychomotor functions c 0 Reference Test or Measurement CO level (ppm)' COHb tevel' (Percent) ffect . M'cFarland„R.A. Ability of'd'ri;vers to stay 6. None (IS28) between two-lane markers i11 None while being permitted only 17' None Ray, A.M., brief glimpses of the road Reaction time to 10 Prolonged! Rockwell, T.H. (IS 30) car taillights McFarland, R.A. Performance of two tasks at 700 17' None US 29) same time Dark adaptationi and glaree 7'00, 17 PVone. recovery Peripheral vision at 16' 700' 117 ' Idone and 30' Peripheral vision at' 2D` 700! 117 Decreased Depth perceptilorr, 7001 17 None, Stewart, R'.D:,, et' al. Time perception 500, 20' None (ifS 3'6) Fodor; (;,.G., Attentiveness to 50'x, 5 hrs: 2-5' Decreased Winneke, G: (iS L8) auditory stiinulil Flicker fusion 50 x 5 hrs., 2•5 hirchange Speed' of motor performance 50 x 5'hrs.. 2'-5' No change Perception of complex 50x5hn 2-5 1'mproved visual I patt'erns Cognitive function 100 5 Decreased' Schulte, I:H. US 33) Reaction time 20' No change Bender„tiV_, et all Tlnreskiold' for temporal' 100, 7.25 Raised (IS 8) resolution of visual'stimulii Manuall dexterity 100, 7.25 Decreased. Il.earning,m eaningless syllables 100' 7.25 Decreased, Retention of 10 syllables 100! 7:25 No change Gtoll-lCnapp; R:,,et'al. forlhr Attentiveness to audit'ory 50' Deterioration at (IS 2l) stimuli 100, 50 ppm, worse at 150! 100 ppm, worst' at 1'50'ppm Wright, G:,, et al. Reactionitime 6.3 Ptol'onged. US34) Glare recovery 6.3 Prolonged Careful driving habits 6.3 Failure to improve with practice 1fl4

C e The minor symptomatic irritation experienced'by nonsmokers in a smoke- filled environment is influenced by the humidity of the air as well as the concentration of irritating substances found in the atmosphere. Johansson and Ronge (IS' 48) have shown that irritation d'ue to cigarette smoke is maximal in warm, dry air and decreases with a small rise in relative humidity. A change from acceptable to unpleasant was reported at 4.7 mg/m3 of particulate matter for nonsmokers and eye irritation was noted at 9 mg/'m3 for both smokers and nonsmokers. The authors concluded that a ventilation rate of 12'm3/hr/cig was necessary to avoid' eye irritation and'50 m3/hr/cig was necessary to avoid unpleasant od'ors. Two government sponsored studies have attempted! to evaluate the degree of minor irritation due to cigarette smoke experiencediby bus and plane passengers. The U'.S'. Department of Transportation,(IS 34) studi'edi the environment on two ventilated buses--one with simulated unrestricted smoking and another with simulated smoking limited to the rear 20 percent of the seats. In one bus„ lighted cigarettes were placed at every other seat (23 cigarettes) to s3mulate a bus filled with smokers. In the other bus, cigarettes were placed only in the rear 2'0' percent of the bus (,five cigarettes) to simulate a bus where smoking,was llimited'to the rear 20 percent of the seats. When smoking,was limited, the C0 level at the driver"s seat was only ]i$ ppm compared to~the level of 33 ppm measured in the unrestricted smoking situation. Four of the six subjects seated in the bus reported eye irritation during,the unrestricted smoking simulation.. None of the six subjects reported any eye irritation in the restricted smoking situation (not even those seated in the rear 20 percent of the bus). Several Federal agencies (IS 37) cooperated to survey the symptoms experienced by travelers on both military and commercial aircraft. They distributedia questionnaire to passengers on 20 military and 8'commercial flights; 57 percent of the passengers on the military flights and 45, percent of the passengers on the commerciall flights were smokers. The planes were well ventilated, and CO levels were always below 5 ppm with low levels of'other pollutants as well. In spite of the low level of measurable pollution, over 6'01percent of the nonsmoking passengers and 15 to 22 percent of the smokers reported'being annoyed'by the other passengers' smoking. Seventy- three percent of the nonsmoking passengers on the commercial flights and 62' percent of the nonsmoking passengers on the military flights suggested that some remedial action be taken;, 84 percent of those suggesting remedial action felt that segregrating the smokers from nonsmokers would be a satisfactory solution. These feelings were even more prevalent among those nonsmokers who had ahistory of respiratory disease.. Children have been found to have a higher incidence of respiratory infections and are thought to be more sensitive to the effects of air pollution due to their greater minute ventilation per body weight than edults. Several researchers have investigated the effects of parental O. ~ d~S , - i0s , ~

c smoking on the health of children. Cameron, et al. conducted two telephone surveys of Detroit families to determine the relationship between children''s respiratory il:lnessandi parental smoking, habits.In th~efirst survey(IS11) they found a statistically significant relationship betweenithe prevalencee of children"s respiratory infection and parental smoking,habits only when all children under 16 were considered (not whenionly those under 9 or under 5 were considered). Inia larger survey of the same city (IS 101) they foundd a relationship between parental smoking and prevalence of respiratory illness in the 10- to 16-year age group and in the birth to 5-year age group. Neither study controlled for smoking by the children which might be a factor in the 10- to 16'-year age group or for socioeconomic status which has an effect on both, smoking habits and illness. However,, the data were consistent with a higher prevalenceof'respiratorydiseese in~familieswhiere~there aresmokers than in nonsmoking families. Colley (IS 13) also found a relationship between parental smoking, habits and the prevalence of respiratory illness in the children. He found an even stronger relationship between parental cough and phlegm production and respiratory infections in children,. He postulates this latter relation- ship toiresult from the greater infectivity of these parents due to their cough and phlegm production. The relationship between parental cigarette smoking, and respiratory infection in their children would then occur because cigarette smoking, caused the parents to cough andiproduce phlegm and would not be indicative of'a direct effect of cigarette smoke-filled air on the child'ren. Harlap and Davies CIS 25) studiedli'nfant admissions to Hadassah Hospital in West Jerusalem and found a relationship between admissions for bronchitis and pneumonia in the first year of life andimaternal smoking habits during, pregnancy. Data on maternal smoking habits after the birth of' the ckild were not obtained, but it can be assumed that most of the mothers who smoked during,pregnancy continued to smoke during,the first year of the infant"slife., A relationshipbetweenlinfant admission andimaternal smoking habits was demonstrable only between the sixth and ninth months of infant life and~was more pronounced during,the winter months (whenthe effect of cigarette smoke on the indoor environment would be greatesu;. Mothers who smoke duringg pregnancy are known to have infants with a lower average birth weight than the infants of nonsaaokfng,mothers. The relationship between maternal smoking, and their infants' admission to the hospital found in this study was greater for lowbfrthweight i.nfan~ts,but wasalso!fo~und for normal birth wej!ghtinfants(Table 4) (IS 25). Harlap, and Davies (IS 25) demonstrated' a dose-response relationship for maternal smo?cing, and infant admission for bronchitis and pneumoniai, however„ theyr also found a relationshl;p betweenimaternal smoking, O ¢a CJT,

C 0 TABLE 4:- AdmiWon rates (per 100 infants) by'diagnosis, bdrth weight, andmaternalsrnoking B'irth we;ght (g) Total IDingnosiu cs~gg; 3,p00- 3,499' 3,Spp+ (including unknown) S, (297) -NS (2',316)i S (4'15) NS (4,098) S (264) NS (3,1'95) S (986} NS' (9,686). Bronchit'i.s and pneumonia 19.2 1',2.3 9'.6 8.2 1!2'.1, 9'A 13:1 9.5' All other 22.6 19.9' 1i4'.5 14'.6 15'.2' 13.3 16.9' 15:5 T.otall 41.8 32'.2' 24.1 22.8 27.3 22'.3' 30:0 24.9' NOTE. - S=Smokars;; NS=N'onsmokers. Source:: Harlip, S:, Davies; A.M. (IS 24

` and infant admissions for poisoning and!in,juries. This may indicate a bias in the study due to relationships whi'ch may exist between smoking and'factors such~as parental neglect or socioeconomic class. •,In ad'd'ition, hospital admission rates may not: be an accurate index of infant morbidity. Colley,, et al. (IS 42) studied the incidence of pneur.ionia and'bronchitis . in2',205 chil'dren overtheFirs~t 5: years of' llifein relation to~ the smokingg habits of both parents. They found that a relationship between parental smoking habits and respiratoryinfectioninch,ildrenoccurred only during the first years of life (Table 5). They also showed a relationship between parental cough and phlegm production and infant infection (Table 5) which~was found to be independent of'the effect of parental smoking habits. The relationship betwe~en parental smoking and infant infection was greater when both parents smoked and increased with increasing number of cigarettes smoked per d'ay. The relationship persisted after social class and birth, weight had been controlled' for. Thus, respiratory infections during the first year of life are closely related to smoking,habits independent of parental symptoms, sociali class,, and birth weight. Because of the dose-response reliationship~between parental smoki'ngand':infantrespiratoryinfection established by Colley, et al. (IS 42), it is reasonable to suspect that cigarette smoke in the atmosphere of the home may be the cause of these infectionsy however, other factors such as parental neglect may also play a role. The above studies examined the effects of involuntary smoking on relatively healthy people. A substantial proportion of the U.S. population suffers from chronic cardiovascular and pulmonary diseases, however,,and they represent the segment of the population most seriously jeopardized by conditions found in involuntary smoking situations. In Chapter 1 of this report (Cardiovascular Diseases)' evidence was presented whichishowed, that levels of CO' sometimes experienced in smoke-filled environments (',50 ppm)' are capable of significantly decreasing the exercise tolerance of persons with angina pectoris and intermittent claudication. In addition, these levels of CO have been shown to decrease cardiac contractility and to raise left ventricular end-dias:tolic press~ure(~an,indi'cation:of heart faiLure)in personswi'th cardiovascular disease. Persons,w.Lth chronic bronchitis and emphysema have considerable excesss mortality under conditions of severe air pollution. In smoke-filled environments lievels of C0 and several other pollutants may be as high or higher than occur during air pollution emergencies. The effects of short- term exposure of'persons with chronic obstrucCive bronchopulmonary disease (COPD) to these condi:ti,)ns have not been evaluated!. Persons with COPD are also possibly at increased' risk to'CO exposure because of their low alveolar pp2. Due to the reduced'amount of'oxygen available to compete with the CO for hemoglobin binding sites, these persons might experience a carboxy- hemoglobin tooxyhemoglobinratiohi'gher than those in health~ysubjects

M r C Ta BLE 5. - Pneumonia and bronchitis in the,first Syears of life by parents'smoking habit and morning phlegra Atnnual!ihcidertce of pneumonia snd'~ bronchitis per 100 childiaen (Albsolu2e numbers in iparentheses)' - Both ex-unoiters • Year of I Both nonsmokers One smoker Both amoken or one ex-smolcer All FollowuR ~ om'amoking habit changed IY~ OI!B' 19~ 0YB' N O/B I+I~ Ol/B~ I N ~ 018 1 7:6' 10.3 10!4 1 4 1 15.3 23'.0' 8.2 13.2' 10:1 16'.7' (343) (29) (424) 1 , 8 ()' (339) (139) (546) (129) (1,65'2) (425). 2' 8.1 8.3' 7:~1 ~ 1'5~.5 8,7'~ 9.2~ 6.5~ ~ 10:7~ 7.4'~ ~ T1'i.3' ! (322) (36) (365)' (129)' (286) (152) (599) (159) (1,572), (4~76). 3 6.9 8.1 10.5'. 9.4 7:9 11.0 8'.2' 11.6 8.4 10.6 (305) (37) (353) ~ (107)' ~ (242): (154) ~ ('661), ~~ (173~~)~ ~~ (1,561), (47~11)~. 4 8.01 11.1 7.5' 1'0.8' 7.6 11.6 8,2' 9.1 7:91 j 10.3 (287) (36) (306) (1102)~ (2'36)1 (1211)', (69S'Y (187) (1,524) (4'46)i 5' 6.7 14':T 5.6 9:41 3.9 10.6 6.4 7.3 5'.9' 1 9.11 (285) (34) (267) I (107)~ (208): (132) (737): (219) (1,497) I (492)' NOTE. - N=neither with winter morning phlegm. A/,B:=one or both with winter morning, phlegm., 5ource: Cottey, 1lR.T., et all (IS,42) 109 i

under the same conditions of C4 exposure. The retention of Wmay also be prolonged due to both this increased bindi~ngof CO to hemoglobin underlcrw alveolar P02,and decreased ventilatory capacity to excrete C!0. In summary, the effects of cigarette smoke on healthy nonsmokers consists mainly of minor eye and throat irritation. However, people with certain heart and lung diseases (angina pectoris, COPD, allergic asthma) may suffer exacerbations of their symptoms as a result of exposure to tobacco smo&e- filLed enui'ronments. These effects are dependent on the degree of individual exposure to cigarette smoke which is d'etermined'by proximity to the source of the tobacco smoke, the type andd amount of tobacco product smoked'„ conditions of room size and ventilation as well as tiie amount of time the individuall spends in the smoke-filled environment, andihis physiologic condition at the time of exposure. 0

M 1. Tobacco smoke can be a significant source of atmospheric pollution in enclosed areas. Occasionally under conditions of heavy smoking, and poor ventilation, the:maximum limit for an 8-hour work exposure to carb=monoxide (501ppm) may be exceeded., 2. Carbon monoxide,, at levels occasionally foundiin cigarette smoke- filled environments, has been shown to produce slight deterioration in, some tests of psychomotor performance, especially attenti'venessand cognitive function. It is unclear whether these levels impair complex psychomotor activities such as driving a car. The!effects produced by CO may become important when added to.factors such as fatigue and alcohol which are knownn to have anieffect on the ability to safely operate almotor vehicle. 3., Unrestricted smoking on buses: and planes is reported tolbe annoying to the majority of nonsmoking passengers under conditions of adequrateven~tilation. 4i. Children ofparen~ts whoismoke are more, likely to~havebronchitisand pneumonia during the first year of life, and this is probably at least partly °due to their being exposed1to cigarette smoke in the atmosphere. 5. Levels of carbon monoxide couanonly found in cigarette smoke-filled environments have been shown to decrease the exercise tolerance of patients with angina pectoris and probably have an adverse affect on persons with chronic obstructive pulmonarydisease.

r BIBLIOGRAPHY (Is 1) A2vIER'ICAN CONFERENCE OF GpVERNi+tENT' INDUSTRIAL HYGIEN'ISTS. TLi) threshold limit values for chemical substancess in workroomiair adopted by the American conference of '. government industrial hyg~ienistsfor1973. Journal of Occupational Med'icine, 16:(',1)': 3'9-49,JanuarX19'74. (IS 3) ANDERSO~T~, E. W., ANDELMAN, R., J., STRAUCH, J. M.,, FORTUIN, N. J'. , KNELSONi„ J. H. Effect of low-level carbon monoxide exposure on onsefi and dkirata:on of' angina pectoris. A study of' tenipatients with ischemic heart disease. Annals of Internal Med'icine 79'(1): 46-50, July 19!73. (IS 2) ANDERSON',, G.„ DALHAM!1„ T. The risks to health of passive -- 8 A smoking. Lakartidningen 70: 2833'-236,ugust 15, 1973. (IS' 7) ARONOW, W. S.„ CASSIDY, J., V'ANGROW,, J. S'., MARCH, H., KERNI, J. C., GOLDSMITH',, J. R.,, EOiFMICA, M'., PAGANO, J. VAWTER, Mi. Effect of' cigarette smoking and breathing carbon monoxide on cardiovascular hemodynamics inn anginal patients. Circulation 50 (2)I : 340-347, August 19'74. (IS 5) ARONOW, W'. S., GOLD6'MITH,„ J. R.i, KERi~i', J. C., JOTNSON', L. L. Effect of smoking cigarettes on cardiovascular hemo- dynami'cs. Archives of Environmental Health 28(6): 3I30~- 332',IJLme 1974. (IS' 6) ARON'OWi, W. S'. , HARRIS, C. N. ,, ISBELL, M. W'. , ROKAW, S. N'. , IMPARATO,, B. Effect of freeway travel on angina pectoris. Annals of Internal Medicine 77(5): 669-676, November 1972. (IS 4) ARONOt+T„ W. S'. , ISBELL, M. W. Carbon monoxide effect on exercise-induced angina pectoris. Annals of Internal Medicine 79 (3) : 39'2-395, Seg `ember 1973. (IS 8) BENDER, W'. , GOTHERT, M., MALORNY,, G. Effect of low carbon monoxide concentrations on psychological functions. S~taub R~einhaStung, der Luft 32(4): 5:4-60!,April 1972., (IS 9)i BRIDGE, D. P.„ CORN, M'. Contributionito: the assessment of , exposure of nonsmokers to air pollution from cigaret~te and cigar smoke in occupied spaces. Environmental Research 5: 192-209, 1972.

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(IS 49) RYLAND(:.,, R., Ed. Environmental tobacC smoke ef f ects on the non-smoker. Scandinavian Journal of Respiratory Diseases Supplementum 91:1-90, 1974. (IS~~ 32) SCHMELTZ~, I., HOFFMANN, D~. ,[MTDER'~, E. L.~ Th~e~~ infl!uence~ of tobacco smoke on-indoor atmospheres. I. An overview. Preventive Medicine 4:6'6-82',, 19'75. (IS 33)i SCHULTE, J. K.Effectsofraildl carbon mono~xideintoxicationi. Archives of Environmental Health 7(5) :30-3'6, November 1963. (IS 34) SEIFF, H. E. Carbon monoxide as an indicator of cigarette- caused pollution levels i'n intercity buses. U.S'. Depart- ment of T'ransportation, Federal Highway Administration, Bureau of Motor Carrier Safety„ April 19'73„ 11 pp. (IS 35) SRCH, M. Uber die Bedeutung, des Kohlenoxyds beim Z'igaretten- rauchemim Pers'onenkr~aftwageninnern.Deutsclie Zeitschriftfiir gerichtliche Medizin 60:80-89, 1967. (IS 36)' STEWART, R. D., N'EWTON, P. E. ,, HOSKO, J. J., PETERS'ON,, J. E. Effect of carbon monoxide on time perception. Archives of Environmental Health 27(3') :155'-160', September 1973. (IS 37')~ U.S. DEPA'RTMENT' OF TRANSPORTATION, FEDERAL AVIATION ADMIiNISTRA- TION, U.S. DEPAR'TMENT'OF HEALTH', EDUCATION„ AND WELFARE. NATIONAL INSTIiTUTE' FOR OCCUPATIONAL SAFETY AND~ HEALTH'.. Health aspects of smoking in transport aircraft. Rockville, Md'. AD-736097, December 1971, 85 pp. (IS 38) U.S. PUBLIC HEALTH SERVICE. The Health~ Consequences of Smoking. A Report of the Surgeon G'eneral: 19'72'. U.S. Department of Health, Education, and Welfare. Washington,, DHELJ. Publication No. (HSrT)'~ 7'2-65~16,1972, 158 pp. (IS 39) WRIGHT, G., RA,DELLa P., SHEPHARD, R. J. Carbon monoxide and driving skills. Archives of Environmental Health 27:349-354, December 1973. , r

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