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Consequences SMuiNj G OI 1975" U.S. DEPAtZ`L"MIE+NT OF HEALTH. EDtiICATION„AND WELFARE PUBLIC HEALTH SERUICE O

The Health Consequences of SMOKING 1975 U.S. DEPARTMENT OF HEALTH, EIDUCA'1'ION AND WELFf4RE' PUBLIC HEALTH SERVICE Center for Disease Control Atlanta, Georgia130333

July 23; 1975 Honorable Carl Albert Speaker of the House of Representatives Washington, D! C'. 20515 Dear Mr. Speaker: As required by Section 8(a) of the Publie Health Cigarette Smoking;Act of 1969, enclosed is the 1'97$ report, on the health consequences of smol:ing: The recent scientific information reviewedi in the report reaffirms the previous evidence that cigarette smoking is a serious public health problem. It is a major contributor to the development of cardiovascular disease, various types of cancer, and respiratory disease. Dts tolli in illness and premature death is needless and preventable: The: recent literature: further refines our understanding, of the mechanisms by which smoking influences these disease states. Under this Act, I am also required to submit to you such recommendations for legislation as Ii deem appropriate. This Department has previously taken, a, posi'tion in support of 1'egislation~ which would' authorize the regulation of cigarettes through the power to ban the manufacture and sale of cigarettes exceeding what are considered excessively hazardous levels of tar, nicotine, carbon monoxide, and' other ingredients shown to be injurious to health. Thee extent to which the cigarette smoking public has over the years spontaneously moved towards this kind of self protection suggests that it would welcome the additional protection such~ legislation, would' bring, This Department, therefore, recommends to the Congress that it consider, legislation providing, this Departmenti or some other appropriate agency with the authority to set maximum pernussible:level's of hazardous ingredients in cigarettes. Sincerely, Caspar W. Weinberger Secretary For sale by the Superintendent of Documents;, U.S, Government Printing Office; Washington, D.C. 20402'-

PREFACE 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: cardiovascular disease, cancer, respiratory disease, and': the, effects of smoking on, the nonsmoker who shares the environment of those who smoke.. As has been the case with each of the previous reports in the series, the research summarized herein further confirms the relation- ships between cigarette smoking and! disease and premature deatlh and refines our understanding, ofthe: mechanisms underlying these relationships. Clgarette smoking remains the: largest single unnecessary and preventable: cause of illness and early deaM In the eleven years since thereportoftlh~eAdvisoryCommittee: to the Surgeon General in1964, there has been progress toward reducing, this toll. IvTillions of Americans have stopped srnoking, cigarettes, and rnillions more have not takeni up smoking, Even for those who cont'2nue : to smoke, there has been a striking reduction ini the "tar"' and nicotine content off cigarettes used by the vast majority. At the same: time,, however, counter-balancing these gains, there has been an. increase in cigarette smoking, by women and young,people, especially teen-age girls. Toel'iminate theneedllessdeathand disability attributabl'e tio cigarette smoking, the Public Health Service remains committed' today, as in, the past,, to increasing the knowledge about the health consequences of smoking and to educating the American people: a5 to the nature and extent of tlhe hazards of'smoking; This is ai task, not for governmentl al'one; but for the great institutions of society as a whole - the family; the: schools, the health care system. Throughi concertied effort,, a cl'imat'eof respect for our own health and that of others can be createdi. Such a climate must certlainly be conducive to reducing and eventually eliminating the needless burden of disease and premature death imposed by cigarette smoking. ~ eodore Coopef, 14'r. D.. Assistant Secretary for H'ealtli June 1I975 ' O W ~ ~. W iii Ily W

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TABLE OF CONTENTS Pk$e Preface ................................................. . . . . . iii Table of Contents . ......................................... v Preparation of the Report and Acknowledgments ................ vii INTRODUCTION: CHAPTER 1. Overview - The Heal& Consequences of Smoking ...................... Cardiovascular Diseases ..................... I 9 CHAPTER' Z. Cancer ................................ 39, CHAPTER 3. Non-Neoplastic Bronchopulmonary Diseases ...... 57 CHAIP'TER 4. Involuntary Smoking, ...................... 83 Index 1975 ....... ..11i3 Index (Cumulative 1964-1975) .............................. 118

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PREPARATION OF THE REPORT AND~ ACKNOWLEDGMENTS Previous Reports Reviews of the scientific evidence linking smoking; to health effects began in 1964 with Smoking and Health, Report of the. Advisory Committee to the Surgeon General of the Public H'ealth Service or as subsequently referred to "the Surgeon General's Report." After this report, Public Law 89-92 was passed requiring, supplemental reports to Congress on tli2s subject. Zn compliance, three reports were submitted: 1. The Health Consequences of Smoking; AI Public Health Service R'e vie tiu: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to~ the~~ 1~967 P'HS~~ Review, 3. The Health Conseduences of Smoking, 1969 Supplement to the 19b7 PHS Review: In April 1970, Public Law 91-222 amended the previous 1'aw and called for an updated report on the health effects of smoking no l'aterthan January 1, 1971, with annual reports thereafter. The Health Consequences of Smoking, A Report of the Surgeon General: 1971, a comprehensive review of all the scientificl'iterature available to the National Clearinghouse for Smoking and Healthi and with emphasis on the mostl recent additions~ to the literature;wasthat u.pdatedl report.. Since then, the: following annual reports on the health consequences of smoking have been submitted: 1. The~~ Health~ Consequences~ of Smoking, A R~eport~ of the~ Surgeon General, 1972~: 2. The Healtli Consequences of 'Srnolzing, 1973. 3:. The Health Consequences of Smoking, 19~7#~. Each report since the originali "Surgeoni General's Report" has reviewed the scientific literature relevant to the association betvreenn vii

smoking and cardiovascular diseases; non-neoplastic broncho- pulmonary diseases, and cancer. Smoking as related to the following diseases and' conditons has been reviewed periodically in the reports: Pregnancy (1967~, 1969~,,1.9~71~,~ 1972~~„ 19'73~~)'~ P'eptic~Ulcer~Dise~ase (19~~67, 1~97'1„ 1972, ~~1973)' Noncancerouws Omal Disease (1969) Tobacco Amblyopia, (1197 1') Allergy (1972). Publlie! Exposure~ to Air~ Pollutioni From ~ Tobaceo, Snnoke, (1972): ' Harmful Constituents of Cigarette Smoke (1972) Pipe and' Cigar Smoking (197 3). Exercise Tolerance (1973) The 1975, Report The present document, The Health Consequercces 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 broncho- pul'monary diseases, and' cancer. A fourth chapter, "Involuntary Snzoking;°" reviews the effects to: nonsmokers of exposure to sntoke-filled environments. Although emphasis is on the latest additions to the literature, where necessary to provide the back- ground or, framework„research from earlier years is included. This report was prepared by the staff of the National Clearinghouse for Smoking and Health in the following way: 1. The Technical~ Information Cente~~r, of, the: C1'earinghouse~ cont2nuall'y~ monitors~ and collects~ the~ sci~entific~ 1i'terature~~ on the health consequences of smoking; through severaL estab~- l'ished mechanisms: a. An information science corporation is on contract' to extract articles on smoking and health from the scientific literatureoft'heworlde b. The National' Library of Medicine, through the MEDLARS systemy provides a monthly listing of articles on smoking and health. Articles not provided by the information science corporation are ordered., --.. -=~

0 c. Stlaff members review current medical literature and identify pertinent art'icl'es., 2. The literature was reviewed' by the Medical Staff Director who wrote first d'rafts for this report. These draft's were sent to reviewers for criticism and comment regarding the format, the appropriateness of the articles selected for discussion,, andi the conclusions. The final dtafts of the total report were reviewed by the Director of the National Clearinghouse for Smoking and Health,, tihe Director of the National Cancer Institute, the Director of the National Institut'e! of Environ- mental Health Sciences, the Director of the National Heart and Lung Institute, and by additional experts both inside and outside the Public Health Seruice: ACKNOWLEDGEMENTS The National Clearinghouse for Smoking; and Health, Daniel Horn, Ph.D., Director,, and Charles A. Althafer, Acting Director, are responsible: for the preparationi of this report. Medical Staff Director for thereportl was David M. Burns~,, NT.D: Consulting, editors were. Elvin E. Adams,, Pk1.D.,, Daniel P. Asnes,, M.D., John lI. Hiolbrook, IVT.D:,, Paul Schneiderman, 1'Vf.D.,, and H. Stephen Williams, M.D. ~ Technical Editor wasPriscillai B'. Holinan„ and Technical Inforrnation Officer responsible for the literature collection was Donaldl R. Shopland. The professional staff has had' the assistance and advice of' the following experts in the scientific and technical fields whose contributions are gratefully acknowledged. 0 Reviewers c ANDERSON, William H.,, M.D! - Chief, Section of Respiratory andi Environmental Medicine, University of Louisville, Louisville, Ky. AUERBACH, Oscar„ M:D. - Senior Medical investigator, Veterans Administration Hospital, East Orange, N':.Ii BOCK, Fred G.,, Ph.D. - Director, Orchard Park Laboratories, Roswell' Park Memorial Gnstitute, Orchard Park, N.Y. 91 l n r BOREN, Hollis G., M.D. - Assistant Direetor of the Medical Center and Associate Dean of ' the College of7Wledicine, University of South, Florida„Tampa; Fla. ix. .y :... .::.z _,...

FALK, Hans II,.,, Ph.D:, - Associate Director for Program,, National Institute of Environ- mental Health Sciences, Research Triangle Park, N:C. FERRIS, Benjamin G.,,Jr., M.D: - Professor of EnvironmentaliHealth andlSafety,,School of Public,Health, Harvard Uhiversity, Boston„Mass. GOLDSMITH,, John R., M'.D: - Medical Epidemiologist, Epidemiological Studies Labora- tory, California State Department of H'ealth, Berkeley, Calif. GORI„Gio B'.,,Ph.D. - Deputy Director, Division of'Cancer Cause and Prevention„National Cancer Institute,,National lhstitutes of Healtfi, Bethesda,,Md. HARKE„ H:: P:, Ph.D., - Forschunginstitutl der Cigarettenindustrie, e.V:,, Hamburg, Germany. HIGGINS,, Ian T. T., M.D. - Professor of Epidemiology, School of Public Health„Uhiversity ofl Michigan, Ann ~ Arbor, Mich:. HOFFMANN,, Dietrich, Ph.D:, - Member,, and Chief, Division of Environmental Careino- genesis, Naylor Dana Institute for Disease Prevention, American Health Foundation; Valhalla, N.Y. KELLER; Andrew Z., D:M.Di - Chiet, Research, in Geographic Epidemiology Medical Research,Service; Veterans Administration,Central Office„Washingtons D'.C. KRUM1-IOLZ, Richard A., M.'.D:, - Medical Director, Ihstitute of Respiratory Diseases, Kettering Medical Center„Kettering; Ohio. LENFANT, Claude J. M., M'.D: - Associate Diuector for Lung,Progams; National Heart and Lung Institute„National Institutes of Health, Bethesda, Md. MacMAHON, Brian, MID. - Professor; Department of Epidemiology, School of Public Health, Harvard University„Boston, Mass. M'cIvIILLAN, Gardher, C., M'.D; - Associate Director for Etiology of Arteriosclerosis and Hypertension;, National Heart and I6ung; Institute, National Institutes of Health,. Bethesda,, Md. NETTESHEIM, Paul', MID. - Group Leader, Respiratory Carcinogenesis Group, Biology Divisiony, Oak Ridge NationaL Laboratory, Oak Ridge,, Tenn. PAFFENBARGER, Ralph S.,, Jr., M.D. - Epidemiolbgist„ Resource for Cancer Epidemi- ology„California State Department of Health, Berkeley, Califl 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'. - Director, Nationall Institute of EnvironmentaU Health, Sciences, National 1'nstitutes of Health; Research Triangle Park„ N.C. RAUSCHER,, Frank J.,, M.D. - Director, National Cancer Institute, National Institutes of Health, Bethesda, Md., RENZETTI~ Attilio D:, Jt., M.D. - Professor of Medicine and Head, Pulmonary Disease Division; Univ'ersityofUtah~Medical'Center; Salt Lake City„Utah. RINGLER„Robert L., Ph.D. - Acting Director; National Heart and Lung Institute„Nationai Institutes of Health, Bethesda, Md. SAFFIOTTI, Umberto, M.D. - Associate Director for Carcinogenesis, National Cancer Institute; National Institutes of Health, Bethesda„Md.. ~i~ o

SCHMELTZ, IYwin, Ph.D. - Associate Member and Head, Section of Bio-organic Chemistry, Division of Environmental Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation„Valhalla; N.Y. SCHUMtYN,, Leonard M,.,, M.D! - Professor and Director,, Division of Epidemiology, School, of Public Health, University of'Minnesota, Minneapoli's„Minn. SHIMKIN, Michael B., M.D:,- Professor of Community Medicine and Oncology;,School of ' ' Medicine, University of California„ La Jolla, Calif. WYNDER., Ernst L., M.D: - President and Medical Director,, Arnerican, Health Foundationa, Valhalla, N.Y. Special assistance for the Cardiovascular Chapter was provided by: JENNINGS, Michael, M.D. - Epidemic Intelligence: Service Officer„CDC, located at Ohio Department of Health, Columbus„Ohio;,and. MtYNNING, Kathleen, M., R.N. - Department of'Staff Development, Boston City Hospital, Bostons Mass: The following staff inembers: of'the Center for Disease Cbntrali also contributed to the preparation of'this report: Bureau of Training,- JUlia M. Fuller, Winthrop N. Davey, M.D., and Seth N. Leiblers Ed.D.; National Clearinghouse for Smoking,and Health, - Nancy M. Johnston and Sanda Lager. Is, ca~ nal cer xi

I NTRODUCTION Overview - The Heal th Consequences of Snnoking_

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OVERVIEVV~~ - HEALTH C@NSEQUENCES~ OF~S~h1OKIlN~G~ i The statement, "Warning: The Surgeon General Has Determined That CigQrette Srnoking, Is Dangerous to Your Healtlr,," has beenn required by Uaw on cigarette packaging since 1970 as a part of the Public Health Cigarette Smoking Actt of 1969. This Act was ai response by the U.S. Congress to the scientific information on the health consequences of cigarette smoking summarized in reports then available (the Surgeon General's Reporti of 1964 and the subsequent 1967', 1968, and 1969 PHS Health Consequences of Smoking). This Act was passed because a series of irnportianfi questions concerning; cigarette smoking and health had been answered. Thefollovvin~g dl'scussiion summarizes, the basicquestions~, tlhemethodology used to, determine the answers, and the answers themselves. The initial question to be answered concerning the health consequences, of smoking was "Arethereanyharmfuthealth, 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, srnoking; and' these diseases. C'orrcernabout the possible health effects, ofsmoking, started wheni scientists, began looking for an, explanation to account forthe: rapidlyincreasing, death rat~efrom, lung cancer. Thsearlyretrospec- tiive studies showed a link between lung cancer and smoking. The first prospective studies, however,, found' that only one-eighth of the excess overall mortality found among srnokers could be accounted for by lung cancer; the rest was largely due to coronary heart disease, chronic respiratory disease, and other forms of cancer. They also, found that the effect on overall' mortality was largely confined to: cigarette, smokers rather than the users of other forms of tobacco. However„ demonstrating an association by statistical probability, is not enough to establish the causal nature of a relationship: Determining that the association between smoking and exeessdeatlhs rates is cause and effect was a judgment made after a number of criteria had been met, no one of which by itself is sufficient to make this ji.udgcnenti. Th~esecrit~'eriaas listed in the Surgeon Ge~neral"s 3

Advisory Committee Report (1,964) were the consistency, strength, specificity,temporal relationship, and coherence, of the association, Im, addition,, convincing, theories about the mechanisms whereby smoking, contributes to the various diseases responsible for the excess mortality among cigarette smokerswere developed from the evidence on the biochemical, cytologic,, pathologic, and pathophysiologiceffects of cigarette smoking, thereby providing the necessary support for the decision that the relationship was causal. The most important specific health consequence of cigarette smoking in terms of the number of people affected is the development of' premature coronary heart disease (CHD). Both prospective andl retrospective studies: clearly established that cigarette smokers have a greater risk of death due to CHD and have a higherr prevalence of CH'D' than nonsmokers. Long-term followup of healthy populations has confirmed that a cigarette smoker is more likely to have a myocardial infarction and to die from, CHD than a nonsmoker. Cigarette smoking has been shown, to be one of the major independent CHD1 risk factors and to act in combination with other major al'terabl& CHD1 risk factors (high blood pressure andd elevated serurn, cholesterol). Autopsy studies have shown that persons who smoked cigarettes have more severe coronary athero- sclerosis than persons who did no~t'smoke. Physiologic studiesandl animal experiments have indicated several mechanisms whereby these effects can, take place. inhale. As a result lungs of pipe and cigar smokers receive much less Fewer pipe and cigar smokers than cigarette smokers report that they pharynx, larynx,, and esophagus when compared, to nonsmokers.. el'evated, risks, for the developrnent of cancer of the oral cavity, tlhan in nonsmokers. Pipe~~ and cigar s~mokers, were~ found~ to have~ bladder was al'so found' to be significantly higher in cigarette smokers larynx, pharynx, orali cavity, esophagus, pancreas, and urinary above~ thatl for~ nonsmokers~.~ The: risk of~ devel~o~ping; cancer~~ o~f~ the: cancer than smokers of nonfilter cigarettes,, but the: risk remains well cigarettes have been shown to have a lower risk of developing lung who have smoked for a, greater number of years. Smokers of filter smokers who report inhaling, who started smoking; at an early age, or the number of cigarettes smoked per day and' is greater iri cigarettee for nonsmokers. The risk of developing lung cancer increases withh cancer was found to be 10 times greater for cigarette: smokers than as the major risk factor irt lung cancer. The risk of developing lung A second major health consequence of smoking, is the devei'op- ment of cancer in smokers. Cigarette smoking was firmly established! 4

exposure to~ smoke than the lungs of cigarette smokers. This is probably the primary reason for the lower incidence of cancer of the lung,for pipe and cigar smokers compared to cigarette smokers. 1 i Women, have had far lower rates of lung cancer than, men. This has been attribut!edl to the fact that fewer women than men smoke and the fact that women smokers generally select filter and low tar andl nicotine cigarettes.H'owever, the percentage of women smokers in the United Stateslia6increa~sed steadilyini the: last 30 years, and: since 1955 the death rates from lung,cancer in women have increasedd proportionatelymorerapid1y than the rates for m:en, reflectlingthisincreased proportion of women smokers. The tar from cigarette smoke has been found~ to induce malignant changes in the skin and respiratory tract of experimentall animals, and a number of specific chemical compounds contained in cigarette smoke were established as potent carcinogens or co-carcino- gens. Malignant changes including carcinoma in situ were found in, the larynx and in the sputum exfoliative cytology of experimentall animals exposed to cigarette smoke. Nonmalignant respiratory disease: is a third area of smoking- ind'uced morbidity and mortality. Ciigare~tt!esrn:okershavee been shown to have more frequent minor respiratory infections, miss moree days from work due to respiratory illness, and report symptoms of cough and sputum production more frequently than nonsmokers. Retrospective and'' prospective s'tudies with llong-term followup havee fonnd' that cigarette smoking is the primary factor in~ the develop- ment of chronic bronchitis and emphysema in the United States. Cigarette smokers have also been found to be more likely to havee abnormalities of pulmonary function and have higher death rates from~ respiratory diseases than nonsmokers. Data from autopsy studies have shown that cigarette smokers were more likely to have the macroscopic changes of emphysema, and that these changes aree closely related to the number of cigarettes smokedl per day. Mucous cell hyperplasia has been foundl more often ini cigarette smokers, Cigarettesrnoke alsoilnhibitsthe ciliary motion responsiblefore cleansing the respiratory tract. An additional area of healthi concern has been the, effect of cigarette smoking during pregnancy. Mothers who: smoke cigarettes during the lastl two trimesters of their pregnancy have been found to have babies with a lower average birth weight than nonsmoking mothers. lni addition cigarette smoking mothers hadl a higher risk of having a stillborn child,, and their infants hadl higher late fetal and

neonatali death rates. There are some datai to show that these risks due to cigarette smoking; are even 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, the oxygen carrying, capacity of fetal blood.. )}iaving, established that cigarette smoking is a significant causal' factor in a number of seriou.s disease processes, two additionall questions became important. They are "Can the health consequences to the individnal' be avertedl by stopping, smoking or by changing, the cigaret'te, "' and "What are the overall public health consequences of cessation and of the changes made in cigarettes?" The first question is the simpler of the two to answer. In the individual, cessation of cigarette smoking,results inia rapid declane of the carbon monoxide level in the blood over the first 12 hours.. Symptoms of cough, sputum production; and shortness of breath usually improve over the next few weeks. A woman who stops smoking by the fourth month of her pregnancy has no increased risk of stillbirth or perinatal death in her infant related to smoking. Ti he deterioration in pulmonary function tests that occurs in some smokers becomes less rapid than that of continuing, smokers. The death rates from ischerri2c heart disease, chronic bronchitlis;, and emphysema also become less than those of the continuing, smoker. The risk of developing cancer of the lung„ larynx, and oral cavity declines relative to the continuing smoker in the first few years after cessation and 10 to 15 years after stopping smoking approximates that of nonsmokers. A smoker who switches to filter cigarettes and has smoked them for 1'0 years or lbnger has a lower risk of developing, lung cancer than a smoker who continues to smoke nonfilter cigarettes. The risk to a filter cigarette smoker, however,, stlill' remains well above that of a nonsmoker. The public health benef-its of cessation are more difficult to determine than, the: effects of cessation on the~ individual. Just as cause-specific death, rates have reflected the effect of cigarette smoking on certain diseases, they should also reflecti any substantial benefits to be gained by cessation or reduction, in cigarette smoking. Several factors combined to produce a redhiction ini per capita dbsage of tobacco exposure in the United States for the years 1966-1970. First, per capita consumptioni of cigarettes declined fromi 41,287cigarettes per person ini 1966 to 3,985 in 1970. Second, during this period' there was a slow but significant decrease in the average tar and nicotine content of cigarettes as welll as a decrease in the amount of 6

tobacco contained in the average cigarette. The decline in per capitai consumption during those years occurred im the face of a substantiall increase in the proportion of young; women becoming, smokers as compared t& women of previous generationsand so reflected predominantly a decrease in cigarette consumption by men. Since 1970, although the per capita consumption of cigarettes has increased, the average levels of tar and nicotine have continnedl to decline, making it more difficult tlo predict what has happened to per capita dosage.. Examination of cause-specific death rates for the period of this declining per capita consumption reveals that' there was a downturn in the male death rate frorni ischemic hearti disease beginning in 1966 which reversed the: upward trend!thatlhad occurred over the previous two decades. This deciine in, the: death rate from ischernic heartt disease has not occurred in women. The male death, rate from chronic~ bronchitis has also been, declining since 19$7, and the male deathi 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 death rates among males occurring at the same, time that there was ai deciine in per capita cigaretlte consumption, it is.impossibie tlo be certain of the: exact cause of the decline in t!he death rates. These diseases aree influenced by a variety of fact'~orsini ad!dition to cigarette smoking f such as blood pressure and air pollution. Some of these factors have e I also been subject tlo major control efforts which may have contributed to the decline in the death rates. In addition, there have been therapeutic advances in thetreatmentl of theseproblem~s which may also have helped lower the death rates. to as A decline in male death rates from lung cancer should also kte follow the decline in per capita consumption. This rate would not be ial influenced as much by changes ini other etiologic factors or changes im g, therapy because cigarette smoking, causes frorn 85 to 90 percent of ge all lung cancer and' there have been no major improvrnents in survival 7'0. due to changes ini therapy. With lung cancer, however, two !8:'] additional considerations must! be kept in mind. A decline: in death ~his, rates from lung cancer would be expected to lag severaU years behind ~ndl a decline in per eapit'~a~ consumption. Iln addition, the decline in of consumpt!ionand switch m low tar and nicotine cigarettlesoccurred I 1 7

predominantly in the younger age groups where deathi rates from lung cancer are low. For these 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 1'9'71 suggest a decline in the lung, cancer rates for the younger males (under 45), but the confidence limits on _these trends at present remain wide enough that it, is impossible to say whether this is a real decline or merely a leveling off. The national health statistics broken down by 5-year age groups are currently available only through 1971. The dat'a, by age group from a few more years will be: necessary to determine whether the changes in smoking behavior which have taken place have reversed the trend of the preceding; 4'0 years of continually increasing, lung, cancerrates, in, men., In 1971, , the last year for which detailed' mortality statistics are available, the, accumulated exposure to cigarettes reached its peak among men born between 19'15 and 1i919; a group then in their early 50's. Cumulative exposure has continued to decline withi each, successive. 5-year birth cohort borni since, then. The trends of the: last few years offer some hope thatl the peak of the"lung cancerepiderni'c,'"as, someh~ave termed this phenomernon, may have been reached with this group and that future years willi showai slow but consistent d'ecl~ine..

i CHiA P'6E'R I Cardiovascular Diseases

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u CHAPTER 11 Cardiovascular Diseases CONTENTS Pdge Coronary Heart Disease (CHD) ............................... , , , 13,' Introduction ...................................... 13' Cigarette Smoking as aMajor Risk Factor for, Coronary Heart Disease ........................... , 14 Cigarette Smoking, in Relation to Other, Risk Factors for Coronary Heart Disease ................... 1 y Hypertension .............................. 1$' Coffee Drinking ............................. 19. Ventricular Premature Beats ..................... 20 Carbon Nibnoxide ................................... 20 Introduction .................................. 20 Sources of Carbon Monoxide Exposure and Human Absorption .......................... 21 Effects on Healthy Individuals ...................... 26 Effects on Persons With Atherosclerotic Cardiovascular Disease ........................ 27 Studies on the Pathogenesis of' Cardiovascular Dise ase ................................... 28 Nicotine ......................................... 29. Acrolein ......................................... 29. Cerebrovascular Disease .................................... ,29 Effects of Smolking, on the Coagulatiion System ................... 32' Summary of Recent Cardiovascular Findings ..................... 33' Bibliography ........................... ......... 34 I

Page Table 1. - Age-standardized blbod pressure changes (mm~ Hg) at follbwup for continuing cigarette smokers and quitters according to weight changes ....................... , , , 17 Tab1e 2. - Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters .......................................... , 18 Table 3. - Mean percent of carboxyhemoglobin saturation inn smokers and nonsmokers by sex and race .................... 22 Table 4. - Mean percent of carboxyhemoglobin saturation in smokers andl nonsmokers by employment status ................ 23'. Table 5: - Median percent carboxyhemoglobin (COHb)'saturat'ion and 9G percent range for smokers and nonsmokers by location~ ........................................... 24 Table 6. - Mean percent carboxyhemoglobin (COHb) saturation in cigarette smokers 1 hour afterlast cigarette ................. 25 Table 7'. - Age-standardized death rates and mortality ratios for cerebrallvascular lesions for men and women~by type of smoking (lifetime history) and age at start of study ............................................31. I i'

CORONARy'' HEAR'I'.'DISEASE (CHD) Introd'uction 1 Z4 Coronary HeartDisease(CHID)isthernostfrequent cause of deathi in the Uniltedl St'ates and is the most important single cause of excess mortality among cigarette smokers., The evidence relating smoking, to CHD has been reviewedl in previous reports on the heallthh consequences of smoking (6Z, 62, 63;, 64, 65, 66, 67; 68). The following is a brief summary of the relationships betweeni smoking and CHD presented ini these reports, Cigarette smoking, hypertension„ andI elevated serurncholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking actls both independently as a riskk factor and synergistically with the other CHD, risk factors. The rnagnit'udeof therisk increases directly withi the amount smoked. The excess risk of CHID, among smokers has been demonstrated inn some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 50. Cessation of cigarette smoking results ini a reduced& mortality rate from CHD'D compared with the mortality rate for those who continue toisrnoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers, but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking; Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette srnokers than in nonsmokers, and experimentali work in humans and animals has suggested several mechanisms by which smoking may influence the developrnent of atherosclerosis and CHD. The formationi of carboxyhemoglobin, release of cateeholamines; creationi of ani imbalancee betweeni myocardipa' oxygen supply and demand, and increased platelet adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 113

Cigarette Srnoking as aMajor Risk Factor for Coronary Heart Disease The evidence: establishing smoking as a major risk' faetorin, CHD has been reviewed in previous reports (61„ 62, 63, 64, 65; 66, 67; 68). During thelastyearnewepidemiologic data have been published'd on the relationship betweeni coronary artery disease and smoking.. Bengtsson (9, l0)~ studied thesmokinghabitisofwomen, with myocardial infarction (Ml) in Goteborg, Sweden. He foundi that smoking was significantly more common in aigroup of 46 women (80'1 percent smokers), ages 50-54, who had amyo~cardial infarction thann in a control group of 578i healthy: nonhospitalized women (37.2 percent smokers)L Other investigators examined the effect of cigarette smoking onn survivaL of people with acutemyocardiall infarction. In a, study of 400 patients with documented myocardial infarctioni who surviived too be: admitted; to a coronary care unit, Helmers (26, 27, 28) found no significant difference between the: percentages of smokers and' nonsmokers among survivors studied after the: first 24 hours, from 2 days until discharge, and from discharge to 3 years. Reynertson and. Tzagournis (52), in a 5-year prospect'uvestudly of 137 patientswitlh documented CHD: at age 50 or less, wereaUsounableto: find any relationship between CHD~ mortality rates and smoking habits. Smoking habits after entrance into the study were also~ considered and again no difference in mortality rates was found. The Coronary Drug Project (17) found an effect of cigarette smoking on mortality after myocardiall infarction. This group stiudied 2,789 men ages 30-64 years for 3 years after myocardiall infarction and found a statistically: significantl correlation between cigare~ttesmoking determined 3 rnonthsafter a myocardial infarction andi rnort'ality(t-val~ue, of 2.94)~. hloneof these studies (17, 26~ 2 7, ; 28; 52)were able to examine the smoking habits of the group of people who die suddenly as a first rnanifestationi of CHD, and therefore may have excluded that group in whi'ch therei6thehighest excessrnortality dUe to cigarette smoking (31)i. Additional d'a~t~~a~ from tlie~~ Swedish twin study~ of Friberg, et ali., (23) have been reported. They~~ found' ani excess~~ CHD1 mortality~ among smokers ini d[zy~go~tic twins:w~ithi different degrees~ of smoking, but no, similar excess in monozygotic twins. Although the numbers wene~ too~ smalli to be~ significant, the~ aut!hors~ suggest that this tend~s~~ to support the the~~ory~ that, both smoking, and CHD: are~~cons~titutionally 14

11 I determined. These data must be viewed' with caution, however, since the difference was dernonstrabieonlyin theoiderage group (born190'1 - 1910). When the younger, age group (born 1911 - 1925) was considered,, no excess CHD mortality was seen in the dizygotic group but a sm~al'1' excess was noted in the monozygotic group(;tlhreeCHD deaths in the high smoking goup~ and one in the low smoki~nggro~up). Also the: difference ini cigarette consumption between the high and low smoking groups was relatively small (seven cigarettes per day): Consequently, data from this, study are not sufficient to: warrant the conclusion that both smoking and excess CHD mortality are constit'utionally determined rather than smoking being a cause of the excess CHD: mortality. Cigarette Srnoklng in Relation to Other Risk Factorss for Coronary Heart Ll isease. Cigarette smoking, elevated serum cholesterol, and elevated'' blood pressure are generally accepted as the three major modifiable risk factors for CHDi. However;, there is less agreement concerning, other CHD riak factors - obesity, physical inactivity, d'iabetes melditus,, elevated resting heartl rate, psychologic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension,, coffee drinking, and ventricular premature beats. Hypertension Results fromi several studies haveshowni that smokers on the~~ average have slightly lower bloodl pressure than nonsmokers. Somee investigatlorshave attributed this, finding to the fact that smokersoni the average weigh slightly less than nonsmokers. Three current studies(24; 36, 55) discussthisrelationshiip. Gyntelberg and Meyer (24), base& on their evaluation of 5,249 men ages40-59', were of the opinion that lower blood pressure in smokers could not be accountledl for by differences in weight, age,, or physical fitness. Kesteloot andl Van Houte(30), in ai study of 42,804 men, performed a rn~ultlipleregression analysis on age,, weight, and height and found that cigarette smokers had! lower blood pressure than nonsmokers;, however, when they included serum cfiolesterol' values in the analysis, the difference in blood pressure was reduced to approxi- mately1 mm Hg. Although this difference was stat'i6ticallysignifi- cant based' oni the large population, the actual difference in blood pressure was too small to be ofclirnical irnportance: 15

Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight, and blood 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 weightl gain (8 Ib)i among the "'quitt'~ers"than among the: continuingsrnokers(3'_5Ib). B1ood' pressure increased 4 mm, Hg systolic and 2.5 mm, Hg diastolic in the quitters with no change in systolic and ai slight reduction in diastolic (-1.1 mm Hg) in persons who continued to, smoke. In order to examine blood pressure changes in relation to weight change, both continuing srnokers and quitters were grouped according to: their weight changesduring, the period of study ("Tab1e1): The most significant finding was an increase intlhe systolicblood pressure (+1.77 mm 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 (-3.28 mm Hg): Diastolic blood pressure in q,uitters showed an increase with weight gain and no change with weight loss, while continuing smokers showed a decrease in diastolic pressure: with weight loss and no change with, weight gaini. The d!ata on subj~ectswhosebiood, pressure~ had increased to hypertensive leveUs (systolic > 150 and diastolic > 95) were evaluated, and it was found that quitters had a, much higher frequency of becoming hypertensive than, continuing smokers (Table 2). Seltzer, in interpreting these d!ata, suggested that cigarette smoking tends to inhibit blood pressure i'ncreases, with only minimal pressure rises occurring eveni in instances of substantial weight gainL . When this inh2biting; effect of cigarette srnoking is removed as in the case of the quitters, sharp 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 and thatl his data do: not allow an eval,uationi of the degree of blood pressure changes according to how recently cigarettes were: given up. The results of the ischemic heart disease study by Kahn, et al. (34) ) raise: additional questions about Seltzer's data. Kahn foi2owed. 10,000 Israeli male civil service emplo.yeesfor5yearstodetermine what factors were associated' with an increased incidence of hypertension. He presented no data concerning,persons who stopped smoking, but he did show thatthe incidence of hypertensioni increased with age and that theage-adjiusted incidenceofhyper= tension in smokers, was over twice that ofnonsmokers(7'6.9/ 1000 for smokers versus 35.4J 1000: for nonsmokers). Seltzer reported no 16

-o T ~ -_ _ - - -- r TABLE 1. - Age-standardized blood pressure changes (mm Hg)j at followup for continuing cigarette smokers and quitters according to weight changes Weight C hange (LB) Smoking Class Signifi Wt L cant oss No Signi Wt Ch ficant ange Mode Wt G rate ain S igni Wt ficant Gain No. lb -25 to -5 No. lb -4 to +4 No. lb +5 to +12 No. lb +13 to +30 Mean ean systolic BP changes: Continuing smokers 32 -4.00 84 -1.52 71 2.85 24 1.50 Quitters 13 1.77 27 2.22 27 4.04 32 3.69 Mean diastolic BP changes: Continuing smokers 32 -3.28 84 -2.04 71 0.73 24 -0.04 Quitters 13 -0.31 27 -1.96 27 4.30 32 3.94 tStandardized on basis of age distribution of current cigarette smokers. Source: Seltzer, C.C. (55).

TABLE 2. - Number of subjects who had devetoped hypertension at foltowup for continuing cigarette smokers and quitters Blood pressure Continuing cigarette smokers Quitters levels Number Percent Number Percent Systolic blood pressure 150+ 6 2.8 9 8.7 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 95+ 3 1.4 5 4.8 Source: Seltzer, C.C. (55). sMCs4Eo

data oni the incidence of hypertension in nonsmokers, and the age distribution for his group of smokers (the original source of the quitters)'is: heavilyweilghtedtoward younger agegroups (witlh only33 of 214 men age 50! . years or over). According,to Kahn's data, this age group would be expected to have a lower incidence of hypertensiion, andl, in fact,, Seltzer found only small numbers of men whodevelopcd hypertension (eight wilthi di~astoli~chypert.ension)(Table 2)i. Making int'erpretabions based on such small numbers is hazardous; for example, the difference between current smokers andi quitters in the incidence of diastolic hypertension, could have been: produiced& by only three men quitting smoking because they developed hypertension. Coffee Drirrking The Boston Collaborative Drug Study (12) recently reported a correlation between coffee drinking (>~ 6 cups per day) andl myocardial infarction that persisted after controlling ' fortheeffect'' of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis: of myocardial infarction, and 1',,1041 age, sex, and hospital~matched'controlsdischarged with other diagnoses. In additioni to the usual limitations of retrospective studies; tihisstudyhas severall characteristics that make interpretation difficult. In controlli~n~gfor 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! cigarette consumption is highly correlatedl with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokerstlhan those who consumed smaller amounts of coffee. It is also possible that the hospifalized controli; represente& persons who drank less coffee than the general'l 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 the relat~ionshipbetween coffee drinking, and myocardial infarctlionisindep~endent of the relationship of~ both variablestos cigarette smoking. The question of the independent nature of this relationship iss also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocandial infarction who previously had, had multi- phasic health checkups. Both ordinary controls and CHD risk factlor-matched controls were drawn from 2'S0',p00peoplewhoha~d0 undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarctliani when risk-matchedl controlswere used. 19

The: Eramingham Study (18) recently published data on coffee drinking based on ai 12-year followup of 5,209 men and women ages 30-62. An increased risk of death frorn all causes was demonstrat!ed, inn coffee drinkers, but this relationship was accounted for by the associt ation between coffee consumption and, cigarette smoking. No association between coffee drinking, and myocardial infarction or between coffee drinking and thedevelo~pment of CHD, stroke, or intermittent claudicat~ioni was d0monstratedl. Heyden, etal. (29)~ also found no relationship between excessive coff~eeconsumption (> 5, cups per d'ay)l andatheroscl'erotic vascular disease. Ventricular FherrYature Beats Ventricular premature~ bea~tshave been shown, to~ beariskfact~or for sudden death from CHD: Vedin;, et al. (69), in a study of 793 men in Goteborg, S'weden, examined' the frequency of rhythm and conduction disturbances at rest and' during exercise. They found no statistically significant correlat~ionbetween cigarettesmoking, habits and the presence of supraventricular or ventricular premature beats at rest or during exercise. CARBM MONOXIDE Intro~duction Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels, below115to20 percent were tlhou.ghtl tohavelititle effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon~ monoxide (65, 66, 67, 68). Carbon monoxide is present' in concentrations of I to 5' percentt of the gaseous phase of cigarette smoke (11'„4S). The concentration varies with temperature~ of: combustion as well as with factors which control the oxygen supply such as the porosity of the paper and, packing of the tobacco. The amount of carbon, monoxide produced increases as the cigarette burnsdown. Carboxyhemoglobin levels in smokers vary from 2 to 15 percent depending on the amount smoked, degree of inhalat!ion, andl the time elapsedi since smolCingthe lasti cigarette. Carbon monoxid'e, which has 230 times the affinity of oxygen for hemoglobin, impairs oxygen transportation in at least two ways: 20

First, it competes with oxygeni for hemoglbbin binding,sites. Second, it increases the affinity of the remaining hemoglobin for oxygen, thereby requ.iring, a larger gradient in Po2 between the blood andd tissue to deliver a giveni amount of oxygen; this increased gradient is usually produced by a lowering, of the tissue Pb2. I Carbon monoxide also binds to other heme-containing pig- ments, most notably myoglobin, for which i~t'~haseven agreatler affinity than for hernoglobini under conditions, oflowPoz. Thesignifiicance of this binding is unclear, but may be important inn tissues, such as the heart muscle, which have both, high oxygenn requirements and large amounts of myoglobinL . Sources of Carbon Monoxide Exposure and Human Absorption Several' researchers (13, 32, 35, 57, 60, 70)' have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhernoglobin levels (COHb)~ Kahn, et al. (35);, ini a study of 16,649' blood dbnors, determined that smoking was the most important contributing factor, follbwed by industrial' work exposure. Nonsrnoking, industrial workers had COHb levels of 11.38 percent, and nonsmokers without industrial exposure hadl levels of .78 percent. Cigarette smokers, on tlYeotherhand, h~ad' very hi~glt, leuels. Smokers withi industriall exposure had levels of 5.01 percent, while smokers without industriall exposure had levels of 4.44 percent (Tables 3 and' 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However, inn all areas, smokers still had COHb levels two to three times higher thani nonsmokers and had increasing COHb levels with increasing levell of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to automobile exhaust - London taxi drivers (32) and garage and service~ station op~erators~ (1~3)' - have~ higher baseline levels of carboxyhemoglbbin than nonsmokers of the general populat1oni. But even in these~ high~ exposure~ occupation6~~ sm~okers~~ have rmarkedly~ higher~ COHb~ levels~, (8.1 and 10~.8~ percen~~t)~ than nonsmokers (6.3' and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63~~ ppmi CO~~ with peak exposure~ levels~ as~ high as 2~~17~ ppm CO; cigarette smokers still~ maintained much~ higher COHb levels~ (~5~~.0'1 percent)~ than nonsmokers (2.93~~ pereent)~ (8):. 21 qLbl.i'r. ~ . . .

N TABLE 3. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race Total Sample Nonsmokers Smokersl No. X± SX No. X t SX No. X± SX Total tal Sample 16,649 2.30 ± 0.02 10,157 0.85 ± 0.01 6,492 4.58 ± 0.03 Male 10,542 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 0.64 ± 0.01 1,838 4.10 ± 0.06 White - 15,167 - 2.28 ± 0.02 9,474 _ 0.85 ± 0.01 5,693 4.66 ± 0.04 Male 9,669 2.65 ± 0.03 5,508 1.00 ± 0.01 4,161 4.83 ± 0.04 Female 5,498 1.63 t 0.03 3,966 0.64 t 0.01 1,532 4.19 ± 0.06 Black 1,429 2.59 ± 0.06 641 0.86 ± 0.03 788 4.00 ± 0.08 Male 829 2.91 ± 0.10 347 1.07 ± 0.05 482 4.24 ± 0.10 Female 600 2.15 t 0.09 294 0.62 ± 0.04 306 3.63 ± 0.12 tSmokers are defined as those who smoked on the day of giving blood. NOTE. - X = mean percent; Sx = standard error of mean percent. Source: Kahn, A., et al. (35). EVGC94,E0

TABLE 4. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status r VV4esLeo Nonsmokers No. X±SX Smokersl No. 7t *-SX Persons employed 8,478 0.89 ± 0.01 5,962 4.61 ± 0.03 Classed as industrial workerst 1,523 1.38 ± 0.04 1,738 5.01 ± 0.06 Classed as workers other than industrial 6,955 0.78 ± 0.01 4,224 4.44 ± 0.04 Persons not employed 1,678 0.63±0.02 531 4.24 ± 0.11 I Industrial workers are employed in either durable or nondurable goods manufacturing (craftsmen, operatives, or laborers). Smokers are defined as those who smoked on the day of giving blood. NOTE. - X=_ mean percent; SX = standard error of mean percent. Source: Kahn, A., et al. (35).

TABLE 5. - Median percent carboxyhemoglobin (COHb) saturation and 90 percent - rcrnge for smokers and nonsmokers by location Cigarette Smokers Nonsmokers Location Median Range Median Range A nchorage 4.7 0.9 - 9.5 1.5 0.6 - 3.2 Chicago 5.8 2.0 - 9.9 1.7 1.0 - 3.2 Denver 5.5 2.0 - 9.8 2.0 0.9 - 3.7 Detroit 5.6 1.6 - 10.4 1.6 0.7 - 2.7 Ilonolulu 4.9 1.6 - 9.0 1.4 0.7 - 2.5 Houston 3.2 1.0 - 7.8 1.2 0.6 - 3.5 Los A ngeles 6.2 2.0 - 10.3 1.8 1.0 - 3.0 Miami 5.0 1.2 - 9.7 1.2 0.4 - 3.0 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 New York_ 4.8 1.2 - 9.1 1.2 0.6 - 2.5 Phoenix 4.1 0.9 - 8.7 1.2 0.5 - 2.5 St. Louis 5.1 1.7 - 9.2 1.4 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 Vermont, New Hampshire 4.8 1.4 - 9.0 1.2 0.8 - 2.1 Washington, DC 4.9 1.2 - 8.4 1.2 0.6 - 2.5 Source: Stewart, R.D., et al. (57). Sv4[.94~GO

a....: i.. ......--. ~-, TABLE 6. - Mean percent carboxyhemoglobin (C'OHb) saturation in cigarette smokers 1 hour after last cigarette Packs of Cigarettes Smoked Per day Location Nonsmoker < r/i V2-1 1 11/2 2 Milwaukee 1.3 3.0 4.2 5.3 6.2 4.7 New Hampshire, Vermont 1.4 3.3 4.4 5.7 6.7 5.3 New York City 1.4 3.1 4.3 4.7 5.8 6.3 Washington, DC 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 5.4 6.3 7.1 7.7 Source: Stewart, R.D., et al. (37). N

Studkes~ on the CO burd!eni of ea~chi cig~arette~~ have~ determined the~~ body burden of CO, per cigarette to be: 7.110-8.66 ml (40), and the increase in COHb level produced by smoking one cigarette to be .94 to 1.6 percent after 12 hours of abstinence (40; 53). Tihe half-life for the~ washout of CO~ inihealth~y college smokers~(~40)~was~~ calculat~ed~ to~o be: from 31to 5 hours. Effects on HealtJry, lirdividuals i S'everaU studies have been published on the effects of carbonn monoxide on healthy individuals. Small doses of CO' (COHb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (51), in a study of young men exposed during exercise on a treadmill to 50 ppm CO' (COHb levels 2.5 percent in nonsmokers and 4.1, in, smokers), found no decrease ini maximum aerobic capacity wheni the subjects were testedl at 25° C. In a similar experiment conducted at 35° C by the same researchers (20), there was a decrease in maximum aerobic capacity in nonsmokers exposed to 50 ppm CO, but not in, smokers despite an increase in the carboxyhemoglobin levels of 11.5 percent in botfii groups. They postulated a possible: physiologic adaptation of smokers to carbonn monoxide. Ekblom and Huot, (22)1 studied five young men who inhaled CO, to reach given COHb levels. They reported that as COHb levelsincreased!, therewasa decrease in maximall oxygen uptake and lower heart' rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and 1'88 nonsmokers ages 20132,,showed significantly higher values for COHb, red cell mass, hernoglobin, and hematocrit in the smokers. Levels of 2„3' DPG were unaltered while oxyhemoglobin affinity P50 and ATP levels were significantly lower ini the smokers, The three smokers with highestl red cell mass had normal arterial blood gases and one smokerhad very high values of red cell masswh,ich returned t& normal' after he stopped smoking, The authors interpret these data as evidence of tissue hypoxia. 1'hl'il'larand Gregory (43):,, in a study of bothfreshi heparinized blood and ACD-stored blood from a blbod bank, showed a reduction in the oxygen carrying capacity of up to 101 percent in the blood of cigarette smokers;, this reduction persisted for the full 21-day storagee life of blood bank blood. Cole, et al. (16), in a study of pregnantl women, found COHb l,evels, in the fetus to be 1.8tiines as great as those in the 26

simultaneously measured' bloodl of the mother: Fetal blood was exposed to carbon monoxide in vitro,, and fetal hemoglobin wass found to have a shift! of the oxyhemoglobin disassociation curve to: the left as occurs with adultl hernoglobin. The higher fetall COHb levels were attributed to the lower fet'alB'o.z and a resultant decrease in the ability of oxygen tocornpet'e, for the fetal hemoglo~bini. It' wasfeit by the authors that the highi COHb levels may be responsible for the lower birth weight of infants born to mothers who smoke.. Effects~ o~~n~~ Persoxrs~ with ~ Azherosclerotic Cardiovascular Disease I Aronow and' Isbell (5) and Anderson,et al. (1) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50, and 100 ppm)., Carboxyhemoglobin levels were significantly elevated (2_9' percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of systolic blood pressure times heart rate (a measure of cardiac work)' were all significantly lower at onset of angina pectoris, In a continuation ofthiswork,, Aronow„ et al. (2; 3), studie~dd eight patients during two separate: cardiac catheterizations, one during which each patient smoked three cigarettes and one during which each patient'inhaled carbon monoxide until the maximal coronary sinus COHb levell equalled that produced by smoking during the first catheterieation. EYlll eight had angiographically demonstrated CHD (> 7'51 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic bloodd pressure,, heart rate, left ventriculdr end-diastolic pressure (LVEDP), and coronary sinus, arteriall, and venous CO levels. No changes were noted in leftvent'ricular contractility(dp/dt); aorticsystol~icej'ection period, or cardiac index, and decreases were foundl in stroke index and coronary sinus, arterial, and venous Po2. When carbon monoxide was inhaled, increased LVEDP and coronary sinus, arterial~ andd venous CO levels were noted;, there were no changes in systolic andd diastolic blood pressure, heart rate,, or systolic ejection perio&;, andd decreases in left ventricular dp/dt, stroke index, cardiac index andd coronary sinus, arterial, and venous Pa2werefou.nd. These data suggest that carbon monoxide has a negative inotropiic effect onn myocardial tissue resulting in the decrease in contractil'ity(dp/'dt)' and stroke index. When the positive effect of nicotine on contrac- tility and heart rate is added'by cigarette smoking, the net effect is increasedl cardiac work for the same cardiac output. In the heart witlh. 2~7,

coronary artery disease there is a greatly res 'ricted capacity to increase blood flow in response to this increase in cardiac work. The result is, early cardiac decompensatibn manifest'edd byelevat'ion in I:,V'EDP and angina pectoris. Aronow,, et al. have alsolshown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutesorl the 1i.osAngeles Freew~ay(4)L In a related study, they demonstrated a decrease in exercise tiime before claudication in a group of patientswithi intermittent claudi,cation who were exposed, to 50 ppm CO (6)l. Studies on the Path+ogenesis of Cardliavascular Disease Ini a review of somel of theirwork on carbon monoxide, Astrup and Kjeldseni (7)1 noted that ini cholesterol-fed 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 aortai was 2.5 times higher tlhan 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-fedd rabbits made hypoxic at 10' and 16 percent oxygen had 3 to 3.5 tirnestheaorticchol;esterol content, while those exposed to, 26l and. 28 percent oxygen had a considerable decrease in cholesterol accumulatiom Theodore, et al'. (58) s lzdied the aortas of rnonkeys, baboons, dogs, rats, and mice fed al normal diet but exposed to very high levels of C.O, (COHb levels 33' percent) and' found no atheromatous changes in their aortas. Further work by Astrup and, Kieldseni (38) revealed that in rab- bits fed normal diets but exposed to 1I80 ppm carbon monoxide for 22 weeks, there were local' areas in their hearts of partial or total necrosis of myofibril's;~in the: arteries there, was endothelial swelling, formationn of subendothelial edema, and degeneratlion of the myocytes. When the aort'asof these rabbits were examined (37); the~ luminal coats showed pronounced' changes characteriQed' by severe edematous, reaction with ex;tiensiveswellingand formation of subendothelliaL blistersand plaques. The authors postulate that carbon mnoxide~ increasesendothelial permea~bilityt'~oalburninwhich result'~s in formation of ed'erna, leadingt!ochangesindistinguishable from: early atherosclerosis. 28

Evidbnce that this mechanism may occur in humans is provided by the findings of Parving (50) who showed an increased trans- capillary escape rate for 13'1 I-labelbd albumin in humans exposed to .43 percent CO (COHb 20 percent) for 3 to 5 hours,, but not in those made hypoxic to an altitude of 4300 meters (hemoglobin 75 percent saturated). By exposing rabbits to different concentrations of carbonn monoxide (50; 100, and 180 ppm) for varying periods (~.5~,, 2, 4, 8, 24, and 48 hours), Thomsen and Kjeldsen (59) were able to show a tlhresholdl of 100 ppmi of CO for myocardial damage. The dlemonstra- tlion, of damage at this levell of CO (COHb 8-10' percent'.) is possibly explained by the ratio of carboxymyoglobin to carboxyhemoglobin which is about 3 to I in myocardium at ambientl Poz.. Thus, a COHb level of 101 percent would be accompaniedl by a carboxymyo- globin level of 30, percent i:n heart muscle. This ratio is even greater under hypoxic cond'it'ionswi~th a rati&of6t& I when theart~erial Po2; is below 40 mrn Hg,(1'5). Nicozine In a study of the effects of smoking cigarettes with low and high nicotine contlent„ Hill and Wynder (30) noted increasing serum epinephrine levels with increasing nicotine content of the smoke, butt serum norepinephrine levels were unchanged. However, increasing serum epinephrine levels with increasing number of low nirrotine content cigarettes smoked were also noted. A'crolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. I!nhaiationi of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significant increase inn blood''pressure and heart rate in rats. CEREBROYASCULA.R DISEASE There has been conflicting, evidence on whether there is an increased risk of cerebrovascul~r disease due to smoking,(61', 62, 63, 64, 65, 66; 67, 68)L A prospective study by Paffenbarger, et al. (98)of 3,991 longshoremen followed'! for 18 years showed no correlation between fatal strokes and'smoking. However, both the D'orn study of 29,

U_S, veterans (33) an6 Hammond's study of one million men and, womeni (25)1 showed a small but significant increase in the death rates from cerebrovascular disease among cigarette smokers. The Framing- ham 18-year followup of men ages 45 to 54 (42) and Paffenbarger's study of men who entered Harvardi between 1916 and 1940' (49) also showed an excess risk of cerebrovascular disease associated withh cigarette smoking. Two recent studies provided, more data on this topic. Ostfeld, ett al. (46;47), in ai study of 2,748 people ages 65~74 receiving old age assistance in Cook County, Illinois, were unabletofind anyrel'ationi between cigarette smoking, habits at the start of the study and incidence of new strokes or prevalence of transient ischemic atltacks. Nomura,, et al. ('44)S in a study of the population of Washington County; 1Vlaryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. hlomura noted' that "in, atherosclerotic strokes the. Framingham study andl Paffenbarger's investigation of former college students included al great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking, and atherosclerotic strokesandl the present study did not, it may be that the association is age-dependent." Hammond (25) provides some data which may clarify this relatlionship~ Analysis,of his data shows:that thedifference: between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7);, indicating; that the excess death rates associated with cigarette smoking increase with advancing~ age. Theratio~ oftihe death ratlesforsmokers and nonsmokers (mortality ratio), however, decreases with~ age„ reflecting, the fact' that cerebrovascular disease death, rates attributable to other causes increase with age more rapidly than death rates, at'~tributablet'osmoking. Cigarette smoking may wel1i be a risk factor for stroke at all ages, but other causes of strokes become proportionally 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. 30

TAIiLE 7. -;1Ae-.+Iauefiirefiaerf riratftti rates r!rtrl <rturrcililt' ratios fiir cwrebral ra.xvlar lrsiotrs jar rrrrtl and wuttten bY tyltc= uf"sttuttiirrg (lif etinte hislurP) and age at start of study Type of Smoking Men Never smoked regularly Pipe, cigar ~ Cigarette and other Cigarette only Total Women Never smoked regularly Cigarette Total Age Groups 45-54 55-64 65-74 75-84 CV L Death Rates per 100,000 Person-Years 28 92 349 1,358 25 100 369 1,371 28 129 361 990 42 130 477 1,168 35 116 391 1,272 18 57 228 1,082 38 88 315 1,277 25 64 238 1,091 CVL Mortality Ratios Never smoked regularly Men 1.00 1.00 1.00 1.00 Pipe, cigar 0.89 1.09 1.06 1.01 Cigarette and other 1.00 1.40 1.03 0.73 Cigarette only 1.50 1.41 1.37 0.86 Never smoked regularly Women 1.00 1.00 1.00 1.00 Cigarette 2.11 1.54 1.38 1.18 NOTE. - CVL = Cerebral vascular lesions. Source: Hammond, E.C. (25). Mcnc0

EFFECTS OF SMOKING O1r11 THE COAGULATION SYSTEM Several studies have contributed to an understanding of the role of smoking in thronmbogenesis: Levine (41); in a controlled double blind study,, showedl that smoking a single cigarette increased the platelet's response to a standard aggregating stimulus: This phenomenon did notl occur when lettuce leaf cigarettes were smokedd and was ind'ependentl of a rise in free fatty acids in the plasmaL The author postulates that this may be due to increasing epinephrine llevels.. These data may have relevance for two other studies. In the! clinical trial of the possible prevention of heart attackbyhyperlipi'd'emiicdrugsin PNtewcastle, England~ (1I9); it wasfoundl that cigarette smokers were at increased risk of sudden death. This increased risk was not present in smokers, treated with clofibrate. However, the researchers were unable to relate this reduction in risk to any effect of clofibrate on serum lipids. Recently Carvalho, et al.. (14) evaluated 29 patiients with familial hyperbetali'poproteinernia and no~t:edl that theirpl:atel'etshad an iiicreasedl sensitivity to aggregating stimuli (ADP). Treatment with clofibrate returned thheADP sensitivity to normal' withouti significantly altering serumi lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle: study. The reduction in the excess risk of sudden deathi could be due t& a clofibrate induced reversal of increased sensitivity to aggregating stimuli produced by smoking. 32

SUMMARY OF RECENT CARDIQV'ASCUILAR: FI'NDIhIIGS. 1. Data from one recent incidence study suggest' that cigarettee smokers are more likely to develop hypertension, than are nonsmokers. There is some evidence that suggests that stopping, smoking may be accompaniedl by & rise in blood pressure. 2'. Cigarette smoking,has been shown to be the major source of elevat'ed' carboxyhernoglobin levels, witfi occupational exposure and air pollution being, far lessiinportant in most circurnstances~Carboxyhemoglobin levels ini cigarette smokers are two to three times the levels in nonsmokers and increase withi 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 pectoris and intermittent claudication. The carboxyhernoglobin lievels at which these effects take place are well within the range produced by cigarette smoking., 4., Carbon monoxide at levels of exposure! commoniy reached by cigarette smokers has been shown to decrease cardiac contractility in persons with coronary heart disease. S. Carbon monoxide has been shown to produce changes likee those of earlyy atherosclerosis in the aortas~of rabbits.

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31 INTERSOCIETY COMM'ISSIONI FOR HEART DISEASE RESOURCES: Atherosclero- sis Study Group and' Epidemiology Study Group. Primary prevention of the atherosclerotic diseases. Circulation 42(6): A-54LAr95', December 1970. 32' JONES, R. D., COMMINS; B. T., CERNCK, A. A. Blood: lead and carboxyhernoglobin levels in Londomtaxi'dtivers. Lancet2(7772): 302-303, August 12, 1972., 33 KAHN, H. A. The Dorn study of smoking and mortality among U.S: veterans: Report oni 8'yr years of observation. fiz: Haenszel, W. (Editor): Epid'emiological Approaches to the Study ofl Cancer and: Other Chronic Diseases. Bethesda, Md.,. U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966;,pp; 1-125.. 34 KAHN, H. A., MEDALLE, J. H., NEUFELD; H. N., RISS, E:, GOLDBOURT, U. The incidence of'hypertension and associated factors: The Israel ischemic heart disease study. American HearU Journa1184(2): 171-182;,August 1972. 35 KAHN, A., RUTLEDGE„ R. B., DAVIS, G. L.,, ALTES;, J. A., GANTNER, G: E., THORNTON, C. A., WALLACE, N1 D. Carboxyhemoglobin sources in the Metropolitan St. Louis population., Archives of' Environmental Health 29(3): 127-135, September 1974. 36 KESTELOOT, H~, VAN HOUTE,A. Aniepidemiologic survey of arterial blbodlpressure in a large male population group. American Journal of Epidemiology 99(1): 14-29', January 11974. 37 KJELDSEN, K., ASTRUP;, P., WANSTRUP;, J. Ultrastructurali intimal changes in the rabbit aorta, after a modE rate carbon monoxide exposure: Atherosclerosis 16(1)! 67-82„Jtrly-August 1972. 38 KJELDSENs K., THOMSEN, H. K.,, ASTRUP, P. Effects of carbon monoxide onn myocardium. UltrastruclUral changes in rabbits after moderate, chronic exposure., Circulatiom Research 34(3): 339!348, March 1974. 39 KLATSKY, A. L., FRIEDMANi, G. D:, SIEGELAUB, A. B. Coffee dtinking; prior too acute myocardial infarctioni Journal of'the American Medical Association1 226(5):, 540-543, October, 29'; 1973. 4'0, LANDAW, S. A. The, effects of cigarette smoking on total body burden andlexcretion rates of carbon monoxide. Journal of Occupational Medicine 15(3):: 231-2'35, March 1973. 411 LEVdNE; P. H: An acute effect of cigarette smoking on platelet function., A possible link between smoking, and arterial thrombosis. Circulation 48(3): 619-623, September 1973. 42, MeGEE, D. Section 28. The probability of developing;certain cardiovascular diseases in eight years at speeifiedl values of some characteristics. In:, Kannel, W. B., Gordon„ T. (Editors). The Framingham Studyc An epidemiological' investigationi of'f cardiovascular disease. U.S. DepartmentofHealth„Education, and Welfare, Public Health Service, National Institutes of Health, Publication No: (NIH) 74-618; May 43: 44 36 1973, 152 pp. MILLAR, R. A., GREGORY, 1. C: Reduced oxygen contenU in, equilibrated fresh heparinized and' ACD-stored blood from cigarette smokers. British, Journal of Anaesthesia 44(10): 1015 1019,,October 1972. 0 NOMURA, A., COMSTOCK, G.,W., KULLER„L. TONASCIA„J'. A,. Cignrettc smoking andlstrokes. Stroke 5(4):483-486„July-August 19741. W. ~ ~ ~ __,_s;.W; .

45 OSBORNE, J: S.,, ADAMEK, S., HOBBS, LvL E. Some components of gas: phase of cigarette smoke, Analytical Chemistry 28(2)t 211-2115'„February 1956. i f 3 46 OSTFELD„ A. M., SHEKELLE, R. B.,, KLAWANS;, H L. Transient isehemic attacks and risk of' stroke in an elderly poor population. Stroke 4(6): 980-986, November-December 1'973: 47; OSTFELD„ A,. M., SH,EKELLE, R: B:, KLAWANS; H:, TUFO, H. Ml Epidemiolbgy of stroke : in an elderly welfare population. American Journal ofI Public Health 64(5): 450-458, May 1974L 48 PAFFENBARGER, R. S., Jr~ Factors predisposing, to fatal stroke in longshoremen. Preventive Medicine 1(4): 522-528, December 11972. 49 PAFFENBARGER, R. S., Jr., WING, A. L. Chronic disease in former college students, XI. Early precursors ofnonfatal stroke: American Journal of Epidemiology 94(6): 524'-530, December 1971. 50, PARVING;, Hl -H. The effect! of hypoxia and carbon monoxide exposure on plasmaa volume and capillary permeability to albumin. Scandinaviani Journal of Clinical and Laboratory Investigation 30(I): 49-56, September 11972. 51 R'AVEN„P: B., DRINKWATER,,B: L., RUHLIING;,R.O., BOLDUANIN., TAGUCHII, S., GLINER, J., HORVATH, S. M. Effect of carbon monoxide and peroxyacetyl nitrate on, man's maximal aerobic capacity. Journal:of Applied!Physiology 36(3): 288-293; March 1974. 52 REYNERTSON„ R. H:,, TZAGOURNIS',, M. Clinical and metabolic characteristics. Effects on mortality in coronary disease., Archives of Internal Medicine 132(5): 649-65'3; November 1973. 53 RUSSELL, M. A. H. Blood carboxyhaemoglbbin changes during tobacco smoking. Postgraduat'e NI'edical7ournal,49(576): 684-687, October 1973: 54 SAGONE; A. L., Jr., LAWRENCE;,T:, BALCERZAK, S! P. Effect of smoking,on tissue oxygen supply: Blood 41(6):84'5-$5'1, J!une 1973. 55 SELTZER, C. C. Effect of smoking on bloodlpressure. AmericanHeartJournal!87('5): 558-564, May 1974. 56 SHEPHARD, R. J. The influence of small doses of carbon monoxide upon heart rate. Respiration 29(5/6): 516-52i'1, 1971 57 STEWART„ R. D., BAR'ETTA, E. D., PLATTE,, L.,R'., STEWART, E- B., KALBFLEISCH, J. H., VAN YSERLOO, B., RIM',M; A. A., Carboxyhemoglabin levelfi in American blood donors. Journal of the American Medical Association 229(9): 11'87=1195:, August 26, 1974. 58 THEODORE, J., O'DONNELL, R. D., BACK„K. C. Toxicologacallevaluatibn of carbon monoxide in humans and other mammalian, species. Journal of' Occupational. Medicine 13(5): 242-255,,M'ay 1971. 59 60, THOM'SEN,, H. K., KJELDSEN, K. Threshold limit for carbon monoxid'e-induced myocardial damage. An electron microscopic study in rabbits. Archives ot Environmental Health 29(2): 73'•78„August 1974. TTORBATI, 1. D., HAR-KEDAR', 1., BEN-DAVID, A. Carboxyhemoglobin levels in bloodi donors in relation to cigarette smoking and to occupational exposure to carbom monoxide. Israel Journal of Medical Sciences10(3):24'1-244',, M'arch. 1,974:

61 U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Adhisory Committee, to the Surgeon General of the Public Health Service. Washington„U.S., Department of Health, Education, and Welfare,, Public Health Service Publication No. 1103, 1964, 387 pp. 62 U.S. PUBLIC HEALTH' SERVICE. "Ilhe: Health Consequences of Smoking, A Public Health Service Review: 1967: U.S. Department ofl Health~ Education, and, Welfare. Washington, Public Health Service Publicatiom No. 1696; Revised, January 11968, 227 pp. 63 U.S! PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1968., Supplement to the 1967, Public Health Service Review. U!S. Department of Health, Education, and Welfare. Washington, Public Health Shrvice Publicationi 1696, 1968„117 pp: 64 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 Shrvice Publicat'iow 1'696-2„1969; 98 pp. 65 U.S. PUBLIC HEALTHISERVICE. The Health Consequences of Smoking; A R'eport'of the Surgeon General: 19711. U.S. Department of Health, Education, and 1Nelfare: Washington, DH'EWPublication No. (HSM) 71-7513, 1971, 458pp. 66 U.S. PUBLIC HEA,LTHiSERV{CE. The Health Consequences of Smoking. A Reporu ofl the Surgeon General: 1972: UUIS. Department of Healt'h, Education, and Welfare. Washingtony DHEW Publication No. (HSM) 72-6516„11972, I5& pp. 67 U.S. PUBLIC HEALTH SERVICE. The Health Conseqpences of Smoking: 1973. U.S. Department of Health, Education, and Welfare. Washington; DHEW Publication No. (HSM)173-8704',, 1973„24'9 pp. 68' U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 19741 U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication. No. (CDC) 74-8704, 1974, 124 pp. 69 VEDIN, J: A., WILHELM'SSON,, C. E:. WI',LHELMSEN„ L.,, BJURE, 1., EKSTROM- JODAL, B. Relation of resting and, exercise-indhced ectopic beats to other ischemic manifestations and to coronary risk factors. Men born, in 1913. American Journal of'Cardiology 30(1): 25,31, July 11, 1972. 70' WALLACE, N. D., DAVIS, G. L., RUTLEDGE,, R. B., KAHN, A. Smoking, and carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and empiticall considerations. Archives of Environmental Health 29(3): 136,1142, September 1974. #I 1 : 38

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CIHIaPTEIR 2 Cancer CONTENTS Lung Cancer ..................... Epidemiologic Studies .... ...... Smoking and, Air Pollntion ....... Exfoliative Cytology ........... Experimental Carcinogenicity ......... Carcinogens in Cigarette Smoke ... Infection and Carcinogenicity .............. Other Cancers. .................... Oral and Laryngeal Cancer ..... . Genitourinary Cancer ........ Nasopharyngeal Cancer ....... Aryl Hydrocarbon Hyd'roxylase (AHH). ...... Summary of Recent Cancer Eind'ings ........ Bibliography ........................ Pagg ... 44 ... 44 44 ... 4'7' ... 48 ... 48 ••• 49 ••• 49 ..:

List of Figures PPage Figure 1.-Pcodirction of aryl hydrocarbon hydroxylase. (AH'H) in macrophages from one person in responsee to cigarette smoking .................................. 52 List of Tables Page Table 1.-Distribution by type of lung,cancers in a composite series of nonsmokers and a representative hospital series ...................................... 45 Table 2:-Distribut'ion, by type of lung cancer in populations with specific occupational exposures ......................................... 46 Table 3.-Aryl hydrocarbon hydroxylase (:cIHH) inducibility in patients with lung,cancer, with other tumors, and in healthy controls .................................... 53 x.

INTIx,.OIDUCTIOlr1l The major relationships between smoking, and various cancers have been documented in previous reports on the healthh consequences of smoking (18;, 19; 20;, 21, 22, 23, 24, 25). Based on evaluations of detailed epidemiologic, clinical, autopsy, andd experiinent!al data accumulated over the last 3& years,, cigarette smoking has been clearly identifie& as a causative factor for lung; cancer. The risk of developing lung cancer increases directly withh increasing cigarettesrnoke exposure as measured bynumberofcigaretit'es 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 deatfii rates for women aree lower than for men but have: i;ncreasedl dramatically over the last 15: years coincident with the increasing,number of women smokers. This increase has occurred in spite of the fact that women smokers use fewer cigarettes per day, more frequently choose cigarettes withh filter tips and lbw tar and nicotine delivery, and tend to inhale less than men. A person who stops smoking has ai decreased risk of developing lung cancer compared to~ the continuing smoker„ butt the risk remains greater than the nonsmoker's for as long as 10 to 1'~.5 years after the person, stops smoking. Cigarette smoking is a significant etiologic factor in the development of cancerofthelarynx„ oral cavity, pharynx, esophagus;, and urinary bladder and is associated with cancer of the pancreas. Certain occupational exposures have been found to be associatedl withi an increasedl risk of dying frorn lung cancer. Cigarette smoking interacts with these exposures to produce a greater risk of developing lung cancer than from occupationall exposure alone. Uranium mining and the asbestos industries are occupations which have only slightlly increased lung cancer rates for nonsmokers butt dramatically elevated rates for cigarette smokers. Pipe and cigar smokers experience mortality rates from cancer of the oral cavity, l'arynx, pharynx, and esophagus approximately equal to tlhose of cigarette smokers: Their risk of developing, cancer of the lung is 1'ower than the risk of cigarette smokers„ but it is significantly above that of nonsmokers: This is probably due t!o the 43 "A!.

fact that pipe, cigar, and cigarette smokers experience sirnilar smoke exposure ofthe upper respiratory tract, while cigarette smokers (due to~ their greater tend'encytoinhale)! have a greater exposure of their lungs to smoke than pipe or cigar smokers. The bronchial epithellum of smokers often shows premalignant changes such as squamous metaplasia, atypical squamous metaplasia, and carcinomalin situ. T!'he:pathogenesis of these changes is reiated to thevariiouscarcinogenic and co-carcinogenicsubstlances ini cigarette smoke; the exact mechanism of these carcinogens remains under investigation. I:LING,CANCFR Epide-niologic Studies Harris (3) has reviewed the reports of lung cancer in nonsmokers and compared them to a representative hospital series and has shown rnarked, differences in the pathological types between the two groups (Table 1). When only nonsmokers are examined, the excess of squamous and oat cell carcinoma in men compared to womeni is not observed. Adenocarcinoma is by far the most common type of lung carncer, in nonsmokers while squamous cell is by far the most common when smokers are! includedl. The strength of the relationship between smoking, and the development of lung cancer differs markedly with the type ofllung tumor. Sqµarnous and oat cel]' carcinoma are very closely related to smoking behavior while, according to this study, bronchiol:ar carcinoma shows no excess risk attributable to smoking. Harris also presented the percentages of different histologic types, of cancer found in severall industrial exposures (Table 2); t'hesepercent distribution patterns, resembled those found in smokers far more closely than those found in nonsmokers. Wynder, et al'. (26)s in a retrospective study of 350 l'ungcancer patients, and~, hospitalized cont~rols, noted that the relative risk of developing lung cancer was far less in those smokers who had smoked filter cigarettes for more thani 10 years than in smokers of plain cigarettes (26.8, and 46.2, respectively). Even withi smokers' of filter cigarettes, the risk increased with increasing~ number of cigarett!es smoked and was significantly greater than the!risk of nonsmokers. 5rrroking, and AlirPddluti~on Because of the magnitude of the associationi between smoking and the, development of epidermoid lung cancer, it, is difficult to e 44

U, :3 - .7 s.~ i-t' -1 51, TABLE 1. - Distribution by type of lung cancers in a composite series - - - - of nonsmokers and a representative hospital series Distributii n (Perc ent) Type of cancer Nonsmokers All Patients Men Women Men Women Squamous cell carcinoma 14 12 47 22 _ - - - Oat cell carcinoma 4 4 17 11 Bronchiolar carcinoma - 5 €3 2 3 Adenorarcinoma 57 54 10 20 Large cell anaplastic carcinoma 8 8 17 19 Carcinoid 14 16 0.6 4 Other specific types_ < 1 1 2 Undifferentiated 1 4 2 Total number of cases 51 274 1,903 315 l Includes oat cell carcinoma and large cell anaplastic carcinoma. Source: Harris, C.C. (3). 994mc0

TABLE 2. - Distribution by type of lung cancer in populations with specific occupational exposures Distribution (%) in populations with exposure to- Type of cancer Arsenic N ickel Chromium Hematite Asbestos Squamous cell carcinoma_ 40 57 48 33 44 Oat cell carcinoma 13 43 16 60 6 Adenocarcinoma 7 24 25 Oat cell or anaplastic 40 24 carcinoma Anaplastic 12 7 1 Source: Harris, C.C. (3). L94C94.C0

evaluate the effects of'other possible causes oflung cancer such as air pollution. Higgins(4)~ recently analyzed respiratory cancenmortalityin Great Britain andl the United S~t'ates. In theIJnite~d States, although the 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; by contrast, have increased stead'ily since about 1955. If these increases cont'2nue,, the Arnerican~ Cancer Society estimates that lung cancer among,womenwi11i movefromi fourth to third place in 1975 as the site responsible for the greatest number of deaths due to cancer among women (1). In England and Wales, Higgins noted that between 1940 and 1969 lung cancer rates for men declined in the age growp under 55 and' increasedonly in men over 65. After adjusting for cigarette smoking, an independent effect of air pollution was sought. It was foundl that the hing cancer death rates for men ages 2'5-64' ini greater London decreased more than the rates in the rest of the: country; he attributed this decrease to the greater decline in smoke: pollution in London thani elsewhere., Exfolxatiue Cytology Microscopic examinationi of respiratory epithelial cells shed into the sputumi has become a usefull aid in the diagnosis of lhng cancer and has been employed in many lung cancer screening programs for selected high riskgroups.Saccomannio; et all. (1'1'), have conducted': periodic cytiolbgic examinations of the sputum of uraniumi miners and a group of nonmining controls. Many of these individuals developed abnormal squamous ee111 metaplasia that progressed in several cases to become invasive carcinoma. Both cigarette smoking and radiation exposure from uraniumi mining were associatedl with an increased prevalence of these cytologic changes. Of the two, factors, cigaret'tesmkingwasnotledl tlobethsmore important (ini both miners and nonminers) for the development of atypia and carcinomai in situ: Neithercigaret~t'~esmokingnoruranium, mining could be correlated withi the length of time i't took for these changes to progress from one pathoiogic:stage to:the next. Schreiber, et all (15)' studied exfoliative cytology of the lungs of hamsters treated with intratracheal injectioni of the carcinogen benzo(a)pyrene. They noted progression from mild atypia to squamiousmetapiasia, to moderatleandmarkedl atypia, to~ changes indicative of cancer. These cytologic changes in animals exposed to carcinogens are comparable to those found in humans who smoke cigarettes.. 47

EXPERIMENTAL CARCINOiOENICITY Carcinogens in Cigarette Smoke A great deal of effort has been, expended to 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 ai result of smoking can be reduced'. Carcinogenic substances which act as tumor initiators, accelerators„ and promoters in experimentall animal systems have beeni identified in, cigarette smoke. Hoffman andl Wynder (6) conducted an extensive analysis of the tumorigenicit'y of tobacco smoke. Using; the gas phase, of cigarette smoke, they id'entified certain known, carcinogens but were unable to induce carcinoma in the respiratorytract of experimental, ani7nals. They interpreted these results as indicating that the levels of carcinogens present in the gas phase alone are below the concentrations necessary for tumor activity. In, the same study,: Hoffmanni and Wynder examined the part'iculdte phase of tobacco and identified several carcinogens. The maj~orityof tumor initiators intheparticulatlephase were polynuclear aromatic hydrocarbons and alkylatedl polynuclear aromatic hydrocarbons. They found that a significant inhi'bitioni of pyrosynthesis of these substances leads to a significant reduction of thetu~morigenicityof tobaccosmok~e: They also identified several tumor accelerators - substances which accelerate the carcinogenicit'y and tumor initiating activi'ty of the polycyclic aromatic hydro- carbons. The tumor accelerators found were trans-4, 4'-dichloro- stilbene, N-alkyl indoles, and N-alkyit carbazoles., They also reportedd that the~ tumor promoters~ in cigarette sm~ok~eoccurin the acidic portion of the particul'atlematter but did notfurther charact'erize them. H'o~ffrnann, et al. (5), reportledl identifying thenitrosami'ne„ N'-nitrosonomicotine; in concentrations of 11.9 ' to 6:6 micrograms per gram in unburned tobacco and levels of 88'.6 µg/g in one sarnplee of finely cut chewing tobacco. This is one of the highest, concentrations of an environ~mentall nitrosamine (a family of compounds containing several organic carcinogens) yet identified; concentrations in food and drink rarely exceed 0.1 pg/g. This substance isr.eadily extractable from tobaceobywat'~er and so would be present in high concentrations in the saliva of persons wholchew 48

tobacco. As yet, N'-nitrosonornicotine has not been established as carcinogenic,, and even the known carcinogenic nitrosamines are nott felt to act topically.. Asbestos The combinationi of cigarette smoking; and asbestos exposure has been shown to result in a particularly high risk of developing lung cancer: Selikoff, et al. (16')! have shown that asbestos workers who smoke have 90 times greater risk of developing lung cancer than nonsmoking, nonexposed people:. Shabad, et al. (17) recently studied the possible: causes of the synergistic effect of cigarette smoke and' asbestos. Theystiudied the carcinogenic ~ aetivitiyof different types of asbestos in, the UIS.S.R. and noted that all samples of chrysotile asbestos had traces of benzo(a)pyrene (a polycyclic aromatic hydrocarbon carcinogen found ini 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' rnagnesiaarfvedsonite): In these aniinal st'udies, 20 percent of the rats ex osed to chrysotile asbestos developed precancerous lesions; inhalation of chrysotile plus benzo(a)pyrene orofchrysotsleplus cigarette smokeincreasedt!hee frequency of the lesions to 57 and 38~ percent, respectively. Tliesynergism between asbestos and smoking may be tlhe result of thee adsorption of carcinogens onto asbestos, therefore prolonging tfieir retention in the lung. Infection and Carcinogenicit.y There has been some discussion concerning the association between lung cancer and chronic bronchit'is.fl'oth, diseases can be caused by cigarette smoking; however, chronic bronchitis may also inflluence the development of lung cancer by some independent mechanism. Schreiber, etal. (14)adrninistered N-nitrosoheptamethy= ieneimine to germfree rats; specific-pathogen-free rats, and rats withh chronic murine pneumonia. The incidence of lung neoplasms was 117 percentl in germfree males, 37' percent in specific: pathogen4ree malles; and 83' percent in infectled males. An incidence of 90 to 110Qpercent occurred among femal'es in all three experimental groups. They concluded that chronic respiratory infectlion may enhance the neopiastic response of the lungs to a systemic carcinogen. 49

OTHERCAPti1CERS Oral and Laryngeal Cancer Scho.ttenfeId, etall. (13)~havestudied tlheroleof srnoking,on, thed'evelopment of multiple primary cancers of the upper digestive systernS, larynx,, and lung. They followed 733 patients surviving a first primary epidermoid cancer of the oral'i cavity, pharynx,, or larynx for 5 years. The average annual incidence for a second primary was higher in, men, (18,2/1!000): than ini women (15.4/1000). Both meni andl women who: developed a second primary tumor had heavier tobacco exposure prior to their first cancer than those who didl 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 ofa second primary., Theypostuldtethat this failure to show an, association is due to, the lo g inductionn period between presence of a carcinogen and occurrence of the cancer, and~ they expect thatt a relationship; if present,, may become apparent after 7 or 8 years of followup., Genitourinary Cancer Schrnauz and Cole (12), studied~ 43 persons with cancer of thel renal pelvis or ureter and notledl that smoking was onlvai risk factor at very highi levelso~f consumption (over 2'/i packs per day),despit'eits being related to cancer of the bladder at all levels of smoking. They postulate that, due to the rapid transit of urine through the renal pelvis and ureter, very high leveli; of exposure are required too have any effect' whereas the bladder stores urine for some time and even small amounts of carcinogens in the urine may be sufficient to influence the bladder epithelium. Nasoplxaryngeal' Cancer Lin, et al.(14), in al retrospective study of nasopharyngeal cancer in Taiwan using neighborhoodl controls, found smoking to be signvfi'cantlyassociated with thedeveloprnerrt', of nasopharyngeall carcinoma. A person smoking over 20 cigarettes per day had twice the risk of a nonsmoker of developing nasopharyngeal cancer. I ARYL HYDROCARBON HYDROXYLASE (AHH) Due to the great variation in the amount of smoking exposure before the development of lung, cancer, attempts have been rnade! to O .~ 50

identify groups of people who may have a greater sensitivit'y to the carcinogenic effect of cigarette smoke. Interest has developed in the possibility that aryl hydrocarbon hydroxylase (AHH) may be a. genetically determined enzyme that rnedh'ates such increased: susceptibility to certain environmentall carcinogens: AHH is an enzyme system, which metabolizes polycyclic~ arornatichydrocarbons;, some of the resulting metabolites are! carcinogenic. It has been postulated that persons with high levels off this enzyme may be at great'er risk of developing cancer frorni exposure to the polycyclic hydrocarbons in cigarette smoke than those with low levels. The amount of AHH produced iin response to, an inducing stirnulus can be used to separate a population into three: groups (those capable of being induced to produce high, medium,, and low levels ofAHH).Kelllerman, et al.(8)~ studied theinductio.nof AHH activity in 351heallthy suYhjects(67families with 165 children)~. They felt that theenzyrmewas controlled by a si'ngle genelocus with twoalleies (one able to be induced to produce high AHH levels with a gene frequency of .281 and one; to produce lbw levels with ai gene frequency of .717), All six possi!bie crossmatings were found in the families studied, and' no deviatiions from the expected phenotypes were found ini the children. Cantrell, et al. (2), studiedl 119' healthy volunteers and found thatcigaret'~t'esmokershad't higher levels of AHH ini their pulmonary aveolar macrophages than nonsmokers. In one subject they showed an increase in AHH activity starting 1 week after he began to smoke 10, to 15 cigarett'es per day (2, Fig. 1). Hblt and Keast (7) also showed increased levels of AHH activity in homogenates of lnng tissue from mice exposed to cigarette smoke. Kellermann (9) also studied the inducibillity of AHHi in the lymphocytes of 500 patients with bronchogenic carcinoma and compared them to ai healthy white population and' to: a group of patients with nonrespiratory malignancies (Tabie 3). They foundl that, lung cancer patients had a statistically significant, higher percentage of persons homozygous for the high allele; i.e., able to be induced to high AHH levels; than either the healthy or tumor cont'rols. They postuliited that the reason for the greater frequency of persons homozygous for the highi AHH inducibility allele in the: lung cancer group was that this group was more suscept'2bleto:lung cancer dueto, their increased ability to convert polycyclic aromatic hydrocarbons: into carcinogenic metabolites. The incidence of lung cancer,, 51 0 t ~J

however,, does not show a rnarkedly familial occurrence pattern;' therefore, a single genetic locus can not be: the major factor determiniingsu6ceptibi'lity :B'ersonswith increased ability tometaboliize polycyclic aromatic hydrocarbons may well be a group at increased risk of developing, lung cancer if they smoke; however,, prospective studies of random populations controlled for smoking and! environrnentlal'fa¢tlorswilil'be necessary beforethisgeneticsus¢eptibility can beconfirnned. FIIGURE 1i.-Productiion of aeyl hydrocarbon ihydroxylase ('AHKinimacrophages from one personi in response to ciigarette smokiing i 0:05' - L. OL04, ~ E 0 0.03 ~ 2 2 `~ 0.01 r -115 0 110 20, 30 40, 50 60 70 801 90 DAYS NOTiE.-Shadedlbar indicates duration of smoking; the vertical lines indicate the range of duplicate determinations at eachitime period. Source: Cantrell, E.T., et al'. (2). 52

TABLE 3. - Aryl hydrocarbon hydroxylase (AHH) inducibility in patients with lung cancer, with other tumors, and in healthy controls NUMBER IN DISTRIBUTION OF -- GENE FREQUENCIES GROUP GROUP GENOTYPES ( PERCENT)I OF A AND B ALLELES AA AB BB A B Healthy control 85 44.7 45.9 9.4 0.676 0.324 Tumor control 46 43.5 45.6 10.9 0.663 0.337 Lung cancer 50 4.0 66.0 30.0 0.370 0.630 t AA = low inducibility; AB = intermediate inducibility ; BB = high inducibility Source: Kellerman, G., et al. (9).

SUMMARY OF RECENT CANCER FIfNmINIGS 1. Filter cigarette smokens~ have albwer risk of developing lung cancer than nonfilter cigarette smokers,, but thatl riskis~still greater than, the risk to nonsmokers and increases withi increasing number of filtered cigarettes smoked. 2. Cigarette smoking and exposure to radioactivity by uranium mining have been related to eytoibgic changes in the respiratory tract epithelium including~ carcinoma in situ. Cigare~t'~tesmoking has been more strongly related to these changes than mining exposure. 3. Crysotile asbestos has been shown to contain traces of the carcinogen benzo(a)pyrene; and~ the combination of the two has beenn shown to be a more potent carcinogen in rats than either albne: 4. Heavy smoking prior to a first primary oral or respiratory cancer has beeni shown to be related to the dbvelopment of ai second primary in the respiratory tract or oral cavity. 5. Results from one study have shown a greater proportion off lung cancer patients having high levels of aryl hydrocarboni hydroxylase activity than among either healthy persons or persons with other cancers. Persons with high levels of AHH may be a group vrhichi has a geneticallyde~terminedy increased~ riskoflung cancer if they smoke, but nolexcess risk if they do not smoke., 54

' BIBLIOGRAPHY I AMERICAN CANCER SOCITY_ '75 Cancer Facts and Figures. New York„N1Y'., 1974,. 3'1 pp. 2 CANTRELL, E. T., MARTIN, R:. R.,, WARR, G~ A.,,BUSBEE', D:,L., KELLERMANN, G., SHAW„ C. Induction of aryl, hydrocarbon hydroxylase imhuman pulmonary alveolar macrophages' by cigarette: smoking. Transactions of the Association of American Physicians;,86th Session, Atlantic City, New Jersey; May 1-2, 1:973: 86c 121-130. 3 HARRIS, C. C. The epidemiology of differenU histologic types of bronchogenic ,, carcinoma: Cancer Chemotherapy Reports 4'(2„Part 3): 59-61,,March, 1973. 4 HIGGINS, 1. T. T. Trends in respiratory cancer mortality: In the United States andlin England and Wales. Archives of Environmental Health 28(3): 121-129, March 1974: 5' HOFFMANN, D:, HECHT, S. S., ORNAF, R. M:, WYNDER, E. L., M-nitrosonor- nicotine in tobacco: Science 186(4160): 265'-267; October 18; 1974. 6 HOFFM'ANN~ D., WYNDER, E. L. Chemical composition and t'umorigenicity of tobacco smoke. In: Schmeltz;,1. (Editor). The chemistry of tobacco and tobacco smoke. Proceedings of the symposium on the chemical composition ofl tobacco and' tobacco smoke held during the 162nd National Meeting of' the American Chemical Society in Washington,, D.C., September 12-17; 1197'11. PlenumPres's, New York,, 1972, pp. 123-147.. 7 HOLT, P. G.,, KEAST„ D'. Inductioni of aryll hydrocarbon hydroxylase in the lungs of mice in response to cigarette smoke. Experientia 29: 1,004, August 115, 1973. 8 KELLERMANN, 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. 9 KELLERM'ANN~ G., SHAW„C. R., LUYTEN KELLERMANN,,M: Aryl hydrocarbon hydroxylase inducibility andl bronchogenic carcinoma. New Englandl Journal of Medicine 289(18): 934-937, November 1, 1973., 10: LIN„T. M., CHEN, K. P., LIN, C.,C., H:SU;, M. Ml, TU, S. M'.,,CHIANG, T: C., JUNG„ P. F., HIRAYAMA, "h: Retrospective study oninasopharyngeal carcinoma.:Journall of the National Cancer llnstitute 51(5)! 1403-1408, November 1,973. 11 SACCO~M'ANNO~, G,,, A'RCH~,ER'~, V~. E.,, AUERB~A'CHI, 0.,, SAUNDER'~Sa R.~P:, BRENNAN, L. M'., Development of carcinoma of the lung as reflected in, exfoliated cells. Cancer 33(:1); 256-270; January 1974. 12 SCHMAUZ', R., COLE, P. Epidemiology of cancer of the renal pehnis and ureter. Journal of the National Cancer Institute 52(5): L43~1-14'34, May 1974. N ll3' SCHOTTENFELD„ D., GANTT, R. C., WYNDER, E. L. The role of alcohol and ; w tobacco in, multiple primary cancers ofl the upper digestive system, larynx, and lung: A prospective study.,Preventive Medicine 3(2): 277=2~93; June:1'974. ~, ~ 55

14! SCHREIBER, Hl, NETTESHEIM:, P., LIJINSKY,, W., RICHTER, C. B., WALBURG; H. E., Jr, Inductiom of lung cancer in germ-free specific-pathogen-free, and infectedl rats by N-nitrosoheptamethyleneimine: Enhancement by respiratory infection., Journal ofl the: National Cancer Institute 49(4): 1107-1114, October 1972., 15 SCHREIBER, H,, SACCOMANNO, G'., MARTIN D: H,.,, BRENNAN,, L. Sequential cytologicaI changes during development of respiratory tract tumors induced in hamsters by benzo(a)pyrene-ferric oxide. Cancer Research 34(4): 689-698; Apri1, 1974!. 16 SELIKOEIF„ I.,J., HAMMOND,, E. C., CHURG, J. Mortality experiences of asbestos insulation ~ workers 1943-1968. Pneumoconiosis: Proceedings of the International Conference on Pneumoconiosis; 3d„Jbhannesburg, 1969. Oxford University Press, New York, 11970. Pp. 180=186. 17 SHABAD„ L. M!, PYLEV, L. N.,, KRIVOSHEEVA, L. V:,, KULAGINA, T. F.,. NEMENKO, B. A, Experimental studies on asbestos carcinogenicity. Journal of the NationallCancer Institute 52(4);,1175-1187; A;pri1 1974. 18 U.S. PUBLIC HEALTH SERVICE. Smoking, and Htialth. Report of the Advisory Committee to the Surgeon General of the Public,Health,Service: Washington, U.S. Department of Health, Education, and Welfare; Public Health Service Publication No. 1103, 1964, 387 pp. 19 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Sinoking. A Pubhc Health Service Review: 196T U.S., Department of~ Health, Education, and Welfare. Washington, Public Health Service: Publication No. 1696, Revised January 1968, 227'pp. 20 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1968. Supplement to the: 1967 Public Health Service Review. UIS. Department of Healthi Education, and Welfare. Washington, Public Health Service Publication 1696, 1968, 11'7pp. 21 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: Publication 1696-2, 1969 98 pp. 22 U.S! PUBLIC'HEALTH: SERVICE. The Health Consequences of:Smoking: A Report of the Surgeon General: 1971. U.S! Department of Health, Education„and Welfare. Washington„DHEW PublicationNo: (HSM) 71-7513', 1971, 458 pp. 23 U.S. PUBLIC HEALTH SERVIiCE: The Health Consequences of Smoking: A Report of the Surgeon General: 1972. ,U.S. Department of Health„ Education, and Welfare. Washington; DHEW Publication No. (HSM)72-6'516„1972, 158 pp- 24 UIS. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 197,3. U.S. Department of Health„ Education, and Welfare. Washington, DHEW Publicatiom No, (HSM) 73-8~704; 1973; 249pp: 25 U.S, PUBLIC HEALTH SERVICE The Health Consequences of Smoking: 1974: U.S. Department of' Healtht Ed'ucation, and Welfare. Washington, DHEW Publication. No. (CDC) 74-87,04, 1974',,124 pp: 26 WYNDER, E. L., MABUCHI, K., BEATTIE, E. J., Jt: The epidemiology of lung cancer. Journal of the American Medical Association 213(;1'3) 222'1-2228, September 28, 1970. 56.

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CHAPTER 3 INoni-IWeoplastic Bronchopultnonaryr laiseases Contents Introduction ....................... Srnoking,and Respiratory Morbidity ... Page ....... 61 . . 62 Smoking,and Air Pollution ................................. 63. Smoking and Occupationall Disease ............................ 68, Miil Workers - Byssinosis .............................. 68 Firemen ......................................... 68 Smoking andlPulmonary Function Tests ........ al-Antitrypsin ..................... 71 72' Autopsy and Pathophysiologic St'udlies ........................... 74 Autopsy Studies .................................... , 74 Pathophysiologic Studies in Humans. ....................... 76. Pathophysiologic Studies in A;nimalfi....................... 77' Summary of Recent Bronchopuhmonary Findings .................. 7&. Bibliography ............................................ 79 ® P~

List of Figures Page Figure l. Respirat'ory bronchiolitis in smokers andd control groups ..................................... 77 List ~ of ~'1Q'ables ~ Page Table 1.-Leveis~ of sulfur dioxi~de(SQ'~)i andl total suspended particulates (TSP) in four Utahh communities, 1I9711„and in five Rocky Mount'ainn communities, 1970 ................................... 65 Table 2'. Mean annual levels of sulfur dioxide (S0~) andl total suspended particulates (TSP) in four areas - -------------------------_.......,.,....,... 66 Table 3.-Age-adjusted percentage of cigarette smokers and nonsmokers ini each race-sex group: responding, positively to exposure to ehemi;cals; fumes, sprays, and dusts ...................................... 69-70, Table 4.-The al-antitrypsin levels andl frequency of protease inhibitor (Pi) phenotypes in healthy populations ............................... Table 5.-Means of the numerical values given lung, sections at autopsy of male current smokers and non- smokers, standardized for age ........................... 75 Table 6:-M'eans of the numerica11va1ues given lnng,sections at autopsy of female current smokers and nonsmokers, standardized for age ................................. 75. Table.7.-M'eans of the nurnerical'values given lung sections at autopsy of male former cigarette smokers, standardized for age ........................... 76

INTRODUCTION Chronic non+-neoplastic lung diseases are major causes of permanent, and temporary disability in the United Stat'es: Chronic obstructive pulmonary disease (COPD)~ is the largest subgrou~pof these~ diseases and in this report refers to chronic bronchitis and/or emphysema. Relationships between smoking and non-neoplastiic lung diseases have been reviewed in previous reports on the health consequences of smoking (36, 3'7, 38; 39„ 44, 41, 42; 43).. Cigarette smoking is the most important cause: of COPD.. Cigarett'e~, smokers havehigherdeatlYi ratesfromi chronicbronchitiisand emphysema, more frequently report symptoms of pulmonary disease, and have poorer performance on pulmonary function tests than do nonsmokers. These differences become even more marked as the number of cigarettes smoked increases. Tihe rel'ationship~between cigarette smoking, and COPD' has been dirmonstratedl in many different national and ethnic groups andl is more striking in men than in women. Pipe and~ cigar smokers have higher morbidity and mortality rates from COPD than do nonsmokers but are at lower risk than cigaret't'e! smokers. Cessation of cigarette smoking often results in improved pulmonary function tests,, decreased pulmonary symp- toms, and reducedl COPD mortality rates. In addition to an increased' risk of COPD, cigarette smokers are more frequently subject to; andl require longer convalescence from other respiratory infections thani nonsmokers. Also, if they require surgery, they are more: likely to develiop, postoperative respiratory complications. The relative importance of air pollution in the development of COPD' remains controversiali, but it is clearly less significant under most circumstances than cigaretlt'e smoking. The combination of cigarette smoking and polluted air, however, may produce higher rates of CO'PD~ than either factor alone.. Several occupational exposure groups incur an increased riskof COPD, and cigarette srnoking, adds significantly to this risk. Ini particular, exposure to cotton fiber and coal dust appears to acti ini concert with cigarette smoking to promote the~ development of pulmonary disease. I 0 0 0 61.

Autopsy studies have demonstrated a dose-reiated effect of cigarette smoking on the severity of macroscopic emphyserna.. Increased goblet! cell density, alveolar septal rupture,, bronchiall epithelial thickening,, and mucous gland hypertrophy are more commonly found in the lungs of smokers than in those of nonsmokers; Many pathophysiologic mechanisms by which smoking, may cause COPD have beeni proposed. Decreased overall pulmonary clearance; reduced ciliary motion, and impaired alveolarrr,racrophagefianctions have all been related to cigarette smoking and probably play ai rolein, the development of COPD. The exact mechanisms whereby cigarette smoking contributes to the development of COPD, ho~wever„ remaini only partially undcrstood. SMOKING AND RESPIRATORY MORBIDITY An increased' prevalence of respiratory symptoms in srnokerss from early teens to those past the age of 80 ' has been welli established. Bewley, et al. (5), in a study ini Derbyshire County,, England, extended these findings to include younger children. In a questionnaire study of 7,11S schoolchildreni agesl0to111'/i 111/2yeafound that' 6.9 percent of the boys andi 2.6, percent of the girls smoked more than one cigarette per day. The boys who srnoked 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 (18.0% to 4.1%) than their nonsmoking schoolmates. The percentages for the girls, were similar although based, on smalIernurnibersof smokers. As, in many studies of this type, it was impossible to control for air pollution, sociali class, or smoking habits of the parents; nevertheless, theresul'tssuggest that cigarette smokingeven, in thisyoung; age group produces respiratory symptloms. Fridy, et al. (72)~, in a somewhat older population (average age 25 years), examined the effect of smoking on airway function during, mild virall illness. They measured closiingvol'umesfor 2~2' subj~ects(9: cigarette smokers - average age 29:1, and 13' nonsmokers - averagee age 25.7) before onset and at weekly intervals from the beginning,of a mild respiratory illness until all symptoms, had subsided. The closing, volumes forsmokers, 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 astatlisticallysignificanta increase in the closing volumes (from 37.0 to 45.8 percent of their total lung capacity, while nonsmokers had no: change, 32.7 62

and 3!1.7 percent). Smokers remained symptori7atic more than twice as long as nonsmokers (35.7 and 16.5 days,, respectively), and the mean duration of pulmonary function abnorrnalities in smokers was 29.7 days. Nonsmokers had no change in pulmonary function tests during illness. SM O!KIiNG AND ~ AIR POLLUTION The relationships among air pollution, smoking,, and COPD, remain controversial. Reasons for this controversy include difficulties in controlling; such variables as socioeconomic class, degree of crowding, ethnic differences, and age distribution as well as determining the exactl type and amount of individual pollutioni exposure. Measuring individual pollution exposure even within a small area is difficult since both amount and type can vary drarnatiicallyfromstreeti 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 basic approaches in study design have been tried. The first approach is to find areas where pollution levels have been welil measuredl 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 second approachi is to select a populationi that is as uniform as possible, for example, twins, and then measure individual responses to dyfferentl pollution expo- sures. Both approaches have drawbacks as wil'll be: evident from the following studies. Using the first approach, the Community Health and Environ- mental Surveillance System of the Environmentall Protection Agency (6, 1'l'),has conducted surveys in areaswit'h dlifferentl types, andl levels of pollution in four different part'sof the United States: . (Chicago, New York City, the Salt Lake Basiny and the Rocky Mountain area).. Within each part of'the country,, the researchers identified communi- ties of similar socioeconomic status but different pollution levels. They then administered a~ questionnaire through the schooll systiems to determine the: freqµency of lower respiratory tract infection in the children and. their families. They reported an increased incidence of lower respiratory tract illness ini children in high pollution communi- ties compared to children in low pollution cominunit'ies. This differencewasdemonstrabieonlyin, children whose families had livedl in the highi pollution communities fior more than, 3 years. They also reported an increased prevalence of chronic bronchitis in parents 63' >.. ,P~ x.+,

who lived in hi& pollution communities compared to parents from low pollution communities.. They calculated the excess risk of chronic bronchitis produced by air pollution to be one-third of that produced by smoking but to be additive withi smoking: Several major probPemsin these surveys make it difficult t& evaluate the results. The authors describe the areas as having different kinds of pollutionL The Salt Lake Basin andl Rocky Mountain areas were felt to be high in sulfur dioxide (SO2) and low in totall suspended part'icles (TSP)~, while Ncw York and Chicago were high in both these poillutants. As a result, in the Salt Lake Basin and Rocky Mountain areas, communities were separated into low and high pollution communities only on the basis of their SO2 levels. Many communities classified. as low pollution communities on the basis of their S02 levels had higher leveis of total suspended particles than, the~ communities classified as, high pollution communities bySO'Z level (Table I)'. In fact, the average total suspended particles Ievelforthe lowpollution, communiti'esin the Salt Lake Basin was higher than that for the high pol'lut'ioncommunities, ('I"able2') in the Salt Lake Basin. These differences.exempllfy the difficulties of using onlyrone polllutan ~as,a marker oftotalipollutioni exposure. Additionall problems with these studies were the: differences in socioeconomic class measurements between, low and high pollut2oni communities insome of the regions. In the Rocky Mountain area, the percentage of fathers who completed high school varied from 91 percent in one of the lowcommunilt'ies to 58p:ercent in one of the high pollution, communities. There were alsomajiar d'iifferencesbetween 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, 51.2%), Rocky Mountain area (87.0% to 68.0%), and New York (85.0% to 72.0%). Resident'iall stability (percentage: of families living in t'he community for more than 3 years) was different in the high and low pollution communities in Ncw York (58.0% to 36_0%), and Chicago (56.0% to 46.0%)!. The percentage of parents who currentlysmok~ealsodiffered! . for high and l'owpollution, communi- tiesin, New York (53% to 45% for tiliefathersand 47% to 3'7%d for the mothers). These differences raise questions as to: whether the hiigh, and' low pollution communities were really similar enoughh popu~latlionstojustifytheclairn that differences, in incidence of respiratory tract illness could be attributable to differences in air pollution. 64

a TABLE 1. - Levels of sulfur dioxide (Sn2) and total suspended particulates (TSP) in four Utah communities, 1971, and in five Rocky Mountain communities, 1970 Area Community Pollution Pollution levels in µg/m3 Classification S03 TSP Utah (Salt Lake Basin) Low Intermediate 1 Intermediate 2 High 8 15 22 62 78 81 45 66 Rocky Mountain Area Low I 10 50 Low 2 26 68 Low 3 46 110 High 1 109 43 High 2 186 102 Source: Chapman. R.S., et al. (6). 9R4.C94E0

Area Five Rocky Mountain Areas Salt Lake Basin New York t.'hicago TABLE 2. - Mean annual levels of sulfur dioxide (Sn2) and total suspended particulates (TSP) in four areas Pollution levels in µg/ 3 S02 TSP Decade During Study Preceding Study Low High Low High Decade During Study Preceding Study Low High Low High 10 275 10 263 45 110 50 101 9 65 < 20 144 78 66 82 62 23 63 s 30 431 34 104 40 201 57 106 109 250 111 151 121 165 NOTE. - Area includes highest- and lowest-polluted communities. Source: French, J.G., et al. (11). 4s4CJi.dCO

Increasedl prevalence ofCOPD has also been demonstratedl inn areas of high pollution in the Netherlands (44), Yokkaichi, Japan. (25), and Cracow,, Poland (30): Again, however, these studies weree poorlycontrolled for socioeconomic status. Severall recently publishedl studies have used the second major method of investigating the relationship between smoking, air pollution, and COPID; i.e., to select a uniform population and then too measure individual differences to pollution exposure. Comstock, et al. (8)i, in an attempt to controll for occupational exposure andl socioeconomic class;, studied three separate, uniform populations of telephone workers, and used as arneasure of pol'lutdoni the location of the place of work and residence. The populations studied were telephone installers and repairmen in, Baltimore, New York City, Washington, D.C., and rural Westchester County ini 1962' (survey 1), and in 1967 (survey 2); and telephone installers and repairrnen in Tokyo in 1967 (survey 3)!. They were unable to find' any relation between pulmonary symptoms and degree of urbanization of place of work or place: of residence (either current or past). They were, however, able to establish a strong correlation between smoking habits and pulmonary sycnptoms. Given the crude estimationi of pollution exposureused in this study (all workers in each city were treated as though they received the same exposure), a small dlfferenceini symptoms~due to: air pollution could have been missed, whereas the difference due to smoking could be detected both beeauseitwaslarger and because: it was possible todeterrnineindividual exposure more exaetly. Hrubec, et al. (15); in a study of twins from the U.S! Veterans Registry,, were unable to show a difference in respiratory symptoms either between indh'viduals with differentl exposure to air pollution or between members of twinpairs, withi diifferentairpoll,'ution expo- sures. However,, they too used a crude measure of air pollution exposure (by each zip code area), and so could have missed a small difference due to air pollution despite being,able to relate respiratory symptoms to smoking,, socioeconomic status; and alcohol intake. Colley, et al. (7), in a study of 3;899 persons (20-year-olds born during the last week of March 1946 ini the United Kingdom),, were also unable to show a relation between COPD and airpollution. They used as their estimates of air pollution exposure the domestic coal consurnption in the towns where the subjects lived. This method of estimating air pollutioni exposure issu~bject tot!hesame limitation cited for the previous, two st~ud'ies-llimit'edsensi'tivity to small risks due to air pollution.

In summary, if an increasedl risk of COPD due to air pollutioni exists, it i& small compairedl to that due: tocigarettesrnokin~gunder conditions of air polliut'ioni to: which the average person is exposed. The possibilit'y remains that the two different kinds of exposure may interact to increase the tot~al effect beyond that contributed by each, exposure: SMOICII'41GAND OCCUPATIONAL DISEASE Friedrnan, et al. (13), in a study of 70,289 men and womenn who had had Kaiser-Permanente multiphasic health checkups, noted tha~tl srnokerswere morelikelytorep~ort occupational exposure on a questionnaire (Table 3) thani nonsmokers. The differences are small but statistically significant and needl to be considered when investi- gating the relationship of smoking to, occupational diseases: They werenotl able to die termine ~ whether smokers" responsesreflec~ti actual differences in exposure or an, increased awareness of and sensitivity to occupational exposure.. Exposure to coal and granite dust and cotton fiber carries an iincreasedl risk of COPD. This risk is further increased by cigarette smoking. Other new data have been published which clarify the risk iin, certain occupational groups~ t1'-?'il! Workers - Byssinosis Berry, et al. (4), in a study of 595 workers in the Lancashire cotton mills: over a 3-year period, found that the declfne in forced expitatory,volumein one~ second (FEUi)~ was19'ml/year greater in smokers than ini nonsmokers (59' ml/year compared to 40 ml/year, P > .02) but they could not demonstrate aidose-response relationship. 1!r'iremen Sidor and P'eters (32, 33), in a cross-sectional study of 1,768 Boston firemen, were unable to show a signifirrantl relationship between severity of fire exposure andl 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 ini this cross-sec- tional study becausefii-ernen who developed COPD were no longer capabie of meeting the physical demands of the job and had retired, thus removingt'hemfromthe studypopul'ation. They were able, however, to show a higher incidence of CO'PD, in men und'er the age of 35 years who had been on the force more than 6 months whenn compared to persons of the same age who had just been hired. 68

Mv:,YM'Ma/10 TABLE 3. - Age-adjusted percentage of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to chemicals, fumes, sprays, and dusts Whites Blacks ellows Yellows Exposure Time periodl Smoking status Men Women Men Women Men Women Chemicals, cleaning Before efore 1 year ago Smokers 24.0 6.4 26.0 11.8 16.7 4.1 fluids or solvents (or Nonsmokers 18.9 5.1 19.2 6.7 12.9 5.1 chemical sprays)2 In the past year Smokers 12.1 3.0 14.2 5.1 13.1 3.5 Nonsmokers 9.7 2.6 11.6 4.5 9.4 3.8 Insect or plant sprays Before 1 year ago Smokers 4.0 1.0 6.6 2.1 3.8 0.3 Nonsmokers 3.5 0.9 5.1 1.9 2.5 1.0 In the past year Smokers 2.9 2.1 4.8 2.9 3.0 1.3 Nonsmokers 2.9 1.8 4.8 3.0 3.6 1.8 Ammonia, chlorine, Before 1 year ago Smokers 7.9 2.3 10.3 4.8 6.2 0.9 ozone or nitrous gases Nonsmokers 6.2 1.9 7.0 3.2 4.5 1.7 (nitrous oxides or other irritating gases)2 In the past year Smokers 5.4 1.9 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 1year ago Smokers 11.8 1.0 17.6 1.9 4.0 0.0 (more than 2 hours a Nonsmokers 6.9 0.5 13.1 0.6 3.6 0.1 day)2 In the past year Smokers 8.7 0.7 17.6 1.0 4.3 0.5 Nonsmokers 5.2 0.5 13.3 1.2 3.9 0.2 M-M29CCOWN 0GLC94E0

T_ _ABLE 3. - Age-adjusted percentage of cigarette smokers and nonsmokers in each race-sex group responding positively to exposure to chemical, fumes, sprays, and dusts - Continued Whites Blacks Yellows Exposure Time periodl Smoking Status % % % 70 % % Men Women Men Women Men Women 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 1.3 0.3 Lead fumes or metal Before 1 year ago Smokers 8.2 0.9 9.1 1.5 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 Nonsmokers 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 1.2 2.7 0.0 grain (or flour) dusts2 Nonsmokers 4.4 0.3 8.8 0.8 1.6 0.1 In the past year Smokers 2.8 0.4 7.5 1.0 2.7 0.1 Nonsmokers 1.8 0.3 6.2 0.8 0.3 0.8 Silica, sandblasting, Before 1 year ago Smokers 6.9 0.6 10.5 1.3 3.5 0.3 grinding or rock drill- Nonsmokers 4.0 0.5 6.8 0.7 2.9 0.0__ ing dust (sand or - coal)2 In the past year Smokers 3.9 0.5 8.0 1.0 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 2.869 654 446 Nonsmokers 8,282 18,526 1,116 3,218 712 1,313 t With a few slight variations, the questions were worded as follows: Before I year ago: "Before 1 year ago have you ever worked in a place where you were often or daily around - In the past year: "In the past year have you worked in a place where you were often or daily around 2Material in parentheses appears in "past year" question hut not in "before I year ago" question. Source: Friedman. G.V., et al. (/3). ? T6F.1C.7(.aCO

SMOKING AND! P'ULI'4iONARY' FUNCTION TESTS It is recognized that smokers as a group have poorer pulmonary function tests than nonsmokers. The standard pulmonary function te~sts, generally only become abnormal llatein the pathologic process of COPD and u5ua11'y only after irreversible changes in the lungs have occurred. As, a result, tests, are needed that will identiifypersons~at risk of developing COPD before they have irreversible loss of lung function.. Standard tests of pulmonary resistance 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 resistance may be measuredd through evaluating frequency dependent compliance, butt this is often 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 perforn, yet are still able to measure changes in the small airways. Closing volume is the lung volume at whicht!healveoli in thedependentl portions of the lungbegiln tloclose, and it is usually expressedl as a percent of vital capacity. Ellevated closing, volume is considered evidenceof small airway dysfunction.. Maximum expiratory flow rates at 25 and 50' percent of vital capacity measure air flow at low lung volumes where the resistance of the srnalll airwaysmakesuipai muchi larger proportioni of the measured resistance. Several recently published studies contain data on small airway dysfunction in smokers. Lim (20), studiedl 50 smoking andl 50 nonsmoking high school students and found' in smokers a statistically signiificantl reducti~on in, the forced expiratory volume in one second when the test was started at normal end' expiration (i.e:,, low lung volumes). Stanescu, et al. (34) noted elevated closing volumes: in 1,6 healthy asymptomatic smokers when compared to 16 nonsmokers; but were unable to show any difference in maximum expiratory flow rates at 25 and 50 percent vital capacity. Ruff,, et al. (28) studied 500 subjects ages 18 to 82 and showed increasing closing volumes with age and smoking. Martin, ett all (21)1, in a study of 50 subjects ages 12 to 68, found that 25 percent of the smokers had abnormal! closing, volurnes, and Oxhoj, et al. (26)d noted elevatedl closing volumes for 50-year-old smrokerscompared tononsrnokers.Dlinksen, et al. (l'0)1 reportied higher closing volumes in smokers and noted no: changee with cessation, of smoking. Hoeppner, et al. (14) also showed elevated closing volumes: in healthy smokers ages 16 to 61, but found these to: be closely rel'ated to decreases in the static transpulmonary pressure. They postulate: that tiheelevatedclosing volurnesmay be related too decreased elastic recoil rather than changes in small airway resistance.

Tl1edata haveestlablished thefactl that! a greater percentageof smokers than nonsmokers have elevated ciosing volumes,, but the number of smokers with elevated closing volumes who will develop~ COPD remains to be determined. Stebbings (3S); in a further analysis of Densen's data (9) on the changes in pulmonary function test values in male postal workers and transit workers in New York City;,noted'' significantly less decline in FEVi among Blaek smokers when compared to White srnokers.. This difference: persisted' even when corrections were made for differences in amount smoked„ age at which smoking, began,, inhalation patterns, and smaller initial lung volumes in Blacks. Black and Whitenonsmokers, did not d~ifferin therate of de¢lineinFEVi . By age 60 years; Blacks who smoked one pack per day had a .34 liter smaller cumulatlive decrease imi FEVIi than Whites who smoked the: same amount. a t -ANTITRYPSIN It would be useful to identify the populations at excessive risk of developing COPD from smoking. They theni might be: made aware of the hazard before they develop symptomatic lung, disease. Persons with a l-antitrypsin deficiency may be such a population. a l-antitrypsin deficiency is a rare homozygous recessive genetic defect which occurs in approximately one out of every 3,600 people and results in an increased susceptibility to and premature develop- ment of C.OPD_ There is some evidence that srnoking hastens the development of COPD in these people. The heterozygous state (prodhcing intermediate levels of the al-antitnypsin in serum), is far more common than the homozygous state and~ is found in approxi- matelly 10 percent of the: population. It is uncertain whether the heterozygous deficiency state predisposes to COPD. a l;-antitrypsin, inheritance patterns suggest multiple codbminant alleles at one gene locus, some of which (most notably the S and Z alleles) produce lower serum proteaselevells than, thenormall M~alllele (Table 4)!. The pathophysiologic mechanisrn of the deficiency state is felt to be the inability to inhibit the proteases found in the granulocytes and pulmonary macrophages which go on to damage essential eonstituentsoflt~~ngtis~sue: Several recent reviews of the enzyme and the clinical syndrome producedl by its deficiency have C,,; been published (16, 18) Q . all, 4.J 72 Q (D ~ ~

TABLE 4. - The a t,-antitrypsin levels and' freq,uemc}r of protease inhibitor (Pi) phenotypes in healthy populations Healthypoputatlons. Ptotease inhibitor (Pi) type a t-antitrypsin concentration (~`o: nomnal) Expected frequency of Pi types (per 1,000 people). MM 100 898 (FM;FF,[hS',NIV~~,MX) 100 28 Ivl W 80, -a . MP 80, 1 ht5 80 41 (FS;I~S)~ 80! 1 MZ 60, 29 (FZ), 6:0, 1 SS 55 1 SZ 40 li ZZ 15~ CU a Seen,rarely in Spanish populations,. Soures,: Mittman, C, Lieberman,,.l. (22). In most studies of pat~ientswi'thCOPD;investigatorshave found an increased prevalence of the partially deficient heterozygote phenotypes when compared to healthy controll populiations.. In the few studies not finding thisrelatiom5hip;onlyaI -antitrypsin level~swere measured. Because al-antitrypsin is an acute phase protein and increases with infection, it is difficult to separate out the partially deficient heterozygote phenotypes by measuring,only al-antitrypsin levels. It is necessary to identify the products of each aTlele! electrophoretically in order to identify the deficient phenotypes. Two recent studies using this technique showedl an increasedl prevalence of deficient phenotypes in patients with, COPD' but not among control populations. Mittrnan„et al. (23) studied 240 patilents with CO'PU adm2ttedtoLaVinaHospitalin Al'tadena, California, and found that 19.1 percentl hadl deficient phenotypes compared to only 7.1 percent of a control Scandinavian population. Keuppers and. Donhardt (l9)~ found prevalence ratesfon deficient phenotypes, of 3.5 percent in healthy controls, 12.9 percent in, persons ~ retired' from work because of COPD, and 15.7 percent in patients hospitalized for COPD.. 73

Addiitional' population studies,have beeni done to:deterrninetheeffect of the heterozygous st'ate on the development of COPD: Webb, et ai. (47), stud~ied'~500person6visiting aimultiphasic screening clinic in Monroe County, New York, and found that 11.6 percent had deficient phenotypes. Hkr was unable to show differences in symptorns,or in! pulmonaryfunctiontestvalluesbetween personswi~th normal and deficient phenotypes. In a studyof451 randomly selected adults from the same county (31), pulmonary function studies were done on 40' deficient heterozygote phenotypes (2'0, MS and 20, MZ) and on normal phenotype (MM) controls matched for age, sex, and smoking habits. When totiall pulmonary resistance was measured by a forced oscillometric technique, the nonsrnoking, IVIZ subject'shad significant impairment compared to their normal phenotype controls. Al1 cigarette smokers;, regardless of phenotype, had abnormal values. Althougfithedata arest'ill inconclusive, it may well be that heterozygous deficient persons are a group at excessive risk of developing,COPD especially if they smoke. AUTOPSY' AND, P.4THOPHYSIOLOOIC STUDIES'. Autopsy Studies Auerbach, et al. (3) have previously shown dose-related macro- scopic emphysematous: in the lungs of smokers. Now in an autopsy study (2) of 1,582 men andl 388 women, they havee examinedl microscopic lungparenchymall chaniges~ini relationton cigarett'e! smoking. 'I'heywere ablstoshowtfiatruptureofalveolar septa (emphysema), and' fibrosis and t'hickening, of the small arteries and arterioles are far greater in smokers than nonsmokers and increasewith, increasing~ amount smoked (Tables 5and' 6). When these researchers examined former cigarette smokers, they found that those who had stoppedi more than 110 years prior to death had fewer pathologic changes than those who had stoppedl less than 110 years: before d'eath. Butl even in those who had stopped for morethan101 years, therewas a greater degree of pathologicchange in those who had been smoking more thani one pack per day than in those who had been smoking less than one pack per day (Table 7): Niewoehner, et al. (24), in an autopsy study of 39 meni who died suddenly from various~ causes and who were: below40~ years of age (20 nonsmokers and 19 smokers), observed a respiratory 74

j TABLE 5. - Means of tlre numerical values given lung sections at autonsy of male current smokers and nonsmokers, standardized for age 11 Subjects Who Never Smoked Current Pipe or Ci ar Current Cigarette Smokers Regularly g Smokers <.5 .5-1 1-2 >_ 2 Pk. Pk. Pk. Pk. Number of Subjects 175 141 66 115 440 216 Emphysema 0.09 0.90 1.43 1.92 2.17 2.27 Fibrosis 0.40 1.88 2.78 3.73 4.06 4.28 Thickening of arterioles 0.10 1.11 1.35 1.66 1.82 1.89 Thickening of arteries 0.02 0.23 0.42 0.68 0.83 0.90 NOTE. - Numerical values were determined by rating each lung section on scales of 0-4 for emphysema and thickening of arterioles, 0-7 for fibrosis, and 0 3 for thickening of the arteries. Source: Auerbach, 0., et al. (2). TABLE 6. - Means of the numerical values given lung sections at autopsy of female current smokers anrd nonsmokers, standardized for age Number of Subjects Emphysema Fibrosis Thickening of arterioles Thickening of arteries Current Cigarette Smokers <1Pk. >lPk. 252 33 64 0.05 1.37 1.70 0.37 2.89 3.46 0.06 1.26 1.57 0.01 0.40 0.64 NOTE. - Numerical values were determined by rating each lung section on scales of 0-4 for - emphysema and thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries. c~i, Source: Auerbach, 0., et al. (2). Subjects Who Never Smoked Regularly +r..rwww.+~.rrrw~ ss4mco

TABLE 7. - Means of the numerical values given lung sections at autopsy of male former cigqrette smokers, standardized for age Stopped > 10 yr. Stopped' < 1'0 yr. Formerly Smoked <1 Pk. PIL <1'Pk. Pk. Number of'Subjects 35 66 51 131. Emphysema. 0:24 0.70 1.08 1.69' Fibrosis 1.14 1.74' 2.44 3'.30: Thickening or arterioles 0.57 0.93' 1.25' 1.59 Thickening of arteries 0.04 0.16 0.36 0.61. NOTE. - Numerical valiies for each finding were determined by rating,each lung section onn scales ot'o-4 for emphysema and thickening of the arrterioles„0-7 for fibrosis; and!o-3'for thickening,of the ariteries. Source: Auerbach, O:, et al. (Z): bronchiolitis associated with clusters of pigmented alveolar macro- phages' in the! lhngs of smokers': They found'. these changes only rarely in the lungs' of nonsmokers (Fig. 1). The smokers were young (average age 25.7 years), were a heavy smoking population (average 20A pack years), but did not' differ significantly from the non- smokers in age, social class;or polllution exposure. However,, 12ofthe 19' smokers had' had productive cough or freqpent cold compared to only 3' of the 2& nonsmokers: These authors' postulated that'' bronchioli'tis, mayb:eresponsiblefor the abnormalities in thetest's of small airway' function ofsrnokersf Path ophysiol'ogic Studies irt' Humans Yeager, et al. (4'8) showed: decreased' pirrocytosis'in, hurnan~ alveolar nlacrophages obtained from asymptomatic cigarette smoking volunteers when compared to: those obtained from nonsmoking con trois. Warr andl Martin (46) studied alveolar macrophages lavaged from four heallthysrnokersan'd four healthy nonsmokers! Only tiwo, members of each group were reactive to delayed hypersensitivity skin tests for Candida albicans. Macrophages from nonsmokers responded to Migrationi InhibitoryFaetor(;MIF)lbya depression in migration of at least 30 percent, whereas macrophages from smokers did not respond to MIF. "ll'he cells from smokers were not'ed to migrate three times faster than those fromn'onsmokers'. When Candida antigen was added to the medium, cells from the nonreactive subjects (bothi I a 76

FIIGURE 1.-Res'piratory bronchiolitis in smokers and control group 5 z 4 a 01 NONSMOKERS SMOKERS NOTE-The positioniof each symbol represents the number of sections per case in which bronchiolitis was: identified. Source: Niewoehner, D:E., eral. (24). smokers and nonsmokers) were not inhibited,, the cells from thee reactive nonsmokers were inhibited, but the! cells from react'ivee smokers were not~ inhibited. Thus, m~acrophagesfrorn smokersdids not respond normally to either MIIF'or antigenic challenge. Pathophysiologic Studies in Animals Roszman and Rogers (27) noted that either the nicotine or tnee water soluble fraction of whole cigarettes smoked suppressed'tlhe. immunoglobulin response of lymphoid cell cultures. When concentra- tions of over 2'00' micrograrns per milliliter of nicotine of the water soluble fraction were added, they were able to completely suppress the immunoglobulin response and to observe this suppression even in cells exposed for 2 hours prior to the antigenic challenge. Guinea pigs (29) exposed to the' smoke' of five cigarettes a'nd' theni lavaged 2 hours later had': fewer pulmonary macrophages and'd leukocytes in: the lavage fltaid than did controls not exposed to smoke. The decrease: in the number of macrophages was highly correlated with acetaldehyde, tar, nicotine, hydrogen cyanide, and 77' >I „ ~,~...~..

acroleiin concentrations in the cigarette smoke. The decrease in the number ofleukoeyteswas more closely correlated withpHi of'theparticulate phase and concentrations of acetaldehyde and tar. Tracheal mucous velocity has been shown to be decreasedl in purebred beagle dogs (45) exposed to 100 cigarettes per week for 1'3:5 months. In donkeys (1) low levell exposure to whole cigarette smoke accelerated tracheobronchial clearance,, whereas~ at intler- mediatleand high levels, of exposure, clearance was decreased. At high exposure levels wholecigarettlesmokehad twice the effect of filtered smoke in decreasing clearance:, SUMMARY OF RECENT BRONCHOPULMONARY FINDINGS 1. Cigarette smokers: with mild viral respiratory illnesses have been shown to develbp 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 closely related to COPD' than is air pollution under the conditions of air pollution encountered by the average person. The possibility remains thatl the two kinds of exposure may interactl to increase the total effect beyondl that contribut'ed by eachi exposure. 3. Cigarette smokers without respiratory symptoms have evi- dence of small airway dysfunction (elevated closing volumes), more frequently than d'o 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 ini nonsmokers. 5. Rulhroonary macrophages from cigarett'e smokers' lungs have a decreas~edl ability to~ respond t~o~ in vitro: antsg~enic~ stimu~~li~ as, compared to macrophages from smokers. 78

BI BLIIOGRAP'HY ' ALLBERT„ R'. E., BERGER, J.,, SANBORN,, K., LI.PPMANN, M. Effects of cigarettee smoke components on bronchial clearance in the donkey. Archives,of Environ* mental Health 29 (2): 96-101, August 1974. 2 AUERBA'CH„O.,,GARFINKEL, L., HAMM'OND,,E. C. Relation of'smoking and'age to findings ini lung parenchyma:~ A microscopic study. Chest 65(1): 29-35, January 1974. 3' AUERBA'CH:,, O., HAMMOND, E., C., GARFINKEL, L.,, BENANTE, C: Relation of smoking and age to emphysema: Whole-lung section study: New England Journal of Medicine 286(16);, 853'-857, April!20;, 1972. 4 BERRY, G.,, McKERROW, C. B'.,, MOLYNEUX, M'. K. B'., ROSSITER', C. E.`, TOM'BLESON, J. B. L. A study of the acute and chronic changes ini ventilatory capacity of workers in Lancashire cotton mills. British Journal of Industrial. Medicine 30 (1): 25-36, January 11973. 5 BEWLEY,, B. R.,, HALI~L, T., SNAITH, A. H. Smoking by primary school'children - prevalence and associatedlrespiratory'symptoms. British JournallofPreventive and Social Medicine:27 (3): 15'0-15'3;, AugustI 1973:., 6 CHAPMAN, R. S., SHY, C. ML, FINKILEA, J. F., HOUSE;, D: E., GOLDBERGS H. E:, HAYES; C: G. Chronic respiratory disease in military inductees and' parents of schoolchildren. Archives of' Environmental Health 27(3): 138,1I4'2; September , 1973, 7 COLLEY, J. R'. T., DOUGLAS, J. W: B.,, REID, D. D., Respiratory, disease in young adlrl3s:, Influence of early childhood lower respiratory tract illness, social class, air pollution, and smoking,,Btitish:Medical Journal 3(5873): 195-198, JUly 28„1973. 8 COMSTOCK, G. W., STONE, R. W., SAKAI, Y., MATSUYA, T:,, TONASCIA, J. A. Respiratory findings and urban living; Archives of Environmental Health 27(3): 143-150,,September 1971 DENSEN, P. ML, JONES; E. W., BASS, H. E., BREUER, J., REED, E. A survey of respiratory disease among New York City' postal~ and transit workers:, 2. Ventilatory function test results. Environmental Research 2(4): 277-296, July 1969. ll0 DI'RKSEN,, H., JANZONi L., LINDELL, S. E. Influence of smoking and cessation of smoking on lung function. Scandinavian Journal of' Respiratory Diseases (Supplementum,85): 266.274, 1974. . 111 FRENCH, J. G, LOWRIMOR'E, G, NELSON,, W: C., FINKLEA, J.,F., ENGLISH, T., HERTZ, M. The effect of sulfur dioxide: and suspended sulfates on acute respiratory disease. Archives of Environmental Health 27(3): 129-133{ September 12, 1973. 0 : FRIDY, W. W:, Jir., INGRAM, R. H., Jn, HIERHOLZER, J. C., COLEMAN, M. T. Airways function during:miltl viral respiratory illhesses. The effect of rhinovirus infection in cigarette smokers. Annals of Internal Medicine 80(2)'., 150-155, W ~. February 1974. ~ ~ 79 O

13 FRIEDMAN, Gi. D., S[EGELAUB;, A. A,,, SELTZER, C:,C: Cigarette smoking and' exposure to occupational hazards. American Journal of Epidemiology 98(3): 175-183; September 1973'. 141 HOEPPNER, V. H., COOPER, Di M., ZAM'EL,, N., BRYAN, A. C.,, LEVISON,, H., Relationship betweem elastic recoil and closing volume in, smokers an& nonr smokers: American Review of Respiratory Disease 109(1): 81I-86, January 1974'. 15 HRUBEC„ Z:, CEDERLOF, RL„ FRIBERG, L., HORTON, R., OZOLdINS, G. Respiratory symptoms in twins. Archives of Environmental Health, 27(3): ll89-195„September 1973. 16 HUTCHISON, D. C. S. Alpha-l-antitrypsin deficiency and pulmonary emphaysema: The role of proteolytic enzymes andi their, inhibitors. British J!ournal of Diseases of the Chest 67(3): 171-196, July 1973. 17' KUEPPERS, F., (Ll-antitrypsin and its deficiency. American Journal of Human Ger netics 25(6)! 677-686, 1973: 18' KUEPPERS, F., BLACK, L.,F. a', -antitrypsin and its deficiency. American Review of Respiratory Disease 1i10(2):,1176194, August 1974. 19' KUEPPERS, F:, DONHARDT„ A., Obstructive lung, disease in heterozygotes for alphay-antitrypsin deficiency. Annals of Internal Medicine 80(2)i 209-212,, February 11974. 20' LIM„ T. P. K. Airway obstruction among high school students. American Review of. Respiratory Disease : 108(4); 985-988; October 1973; , 21 MARTINi R. R., LEMELIN, C., ZUITER,,M'., A'NTHONISEN, N. R. Measurement of "closing volume": Application and limitations. Bulletin de Physio-Patholbgie Respiratoire 9(4): 979-995;, Jiily-August 1973. 22 MITTMAN, C. LIEBERMAN, J. Screening for a1-antitnypsin deficiency. Israel Journal of Medical Science9(911i0); 1131143'1I8, September=October 1973'.. 23 M'ITTMANy C:, LIEBERMAN, J., RUMSFELD, J'., Prevalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung disease. A,merican Review ofRespii•atory Disease 109(2): 295-296, February 1i974: 24 NIEWOEHNER, D! E:,, KLEINERMAN, J.,, RICE, D. B. Pathologic changes in thel peripheral airways of young cigarette smokers. New'England Journal of Medicine 291(15): 755-758, Oct'olier10, 1974. 25 OSHIMA„ H., IIMAI„ M., KAWAGISHI, T:, Effects of air pollution on the:respiratory symptoms in Yokkaichi, Central,Japan. Mie Igaku 16(1): 25-29, June 11972'. 26 OXHOJ, H., BAKE„B:, WILHELMSEN, L. Closing volume in 50+ and 60-year-old men. A preliminary report:, Scandinavian Journal of Respiratory Diseases (Supplementum 85): 259-265, 1974. 27 ROSZM'ANi T. L., ROGERS, A. S! The immunosuppressive potential of prodhcts derived from cigarette smoke. A'mericam Review ofResp'uatory Disease 1,08(5)~ 1158,1163, November 1973.. 28 RUFF, F:, SALEM, A., BUSY, F:, de VERNEJOUL, Pl, EVEN,,P:, BROUET, G;, La fermeture des voies aeriennes,peripheriques. Son augmentation chez les fumeurs. (Closing of the peripheral airways: Its increase in smokers.) Revue de Tuberculosee et de Pneumologie 36(2): 308=311, March 1972. 80

29 RYLANDER, R. Toxicity of cigarette smoke components: Free lung cell response: in acute exposures., American Review of Respiratory Disease 1i08(5): 1279-1282; Nbvember 1973: 30 SAWICKI, F. Air pollution and prevalence of chronic nonspeeific respiratory diseases. In: Brzezinski, Z., Kopczynski, 1,, Sawicki„ F. (Editors)j Ecology of chronic nonspecific respiratory diseases, Internationall Symposium, September 7-8, 1971,. Warsaw„Poland, Panastwowy Zaklad Wydawnictw Ilekarskich, Warsaw, 1972; pp. 3-13. 31 SCHWARTZ, R'. H. Alpha-l-antitrypsin deficiency and chronic respiratory disease. Annual: Report June 28, 1972=June 20„1973'. University of Rochester,,Roche:sters N.Y., Prepared for Respiratory Diseases Branch„ National Heart and Lung Institute;,National Institutes of Health, Bethesda„M'aryland. 32 SIDOR, R.,, PETERS, J. M'. Fire fighting and pulmonary function. An epidemiologic study. American Review of Respiratory Disease 109(2): 249-254, February. 1974. 33 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. 34 STANESCU„ D! C., VERITER, C., FRANS, A.,, BRASSEUR„ L. Maximal expiratory flow rates and "closing volume" in asymptomatic healthy smokers: Scandinavian, Journal of Respiratory Diseases 54: 264-271„1973'. 35 STEBBINGS',, J. H., JR. A survey of respiratory disease among,New York City postal and transit workers: IV. Racial differences in the FEV1. Environmental Research 6'::14'7-158, June 1973. 36 US. 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, Public Health Service Publication. No. 11103, 1964, 387pp.. 37 U-S. PUBLIC HEALTH SERVICE. The Health Consequences: of Smoking. A Public Health Service Review: 1967. UIS. Deparrtmentl of Health, Educations and Welfare. Washington, Public Health Service: Publication No. 1696, Revised J'anuary1I968, 227 pp. 38', U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1968. Supplement to the 1967 Public Health Service Review. U.S. Department of Health, Educations and Welfare., Washington, Public Health Service Publication. 1696, 1968, 1117pp: 39 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1969'. Supplement, to the 1967 Public Health Service Review. U!S. Department of Healths Education, and Welfare. Washington, Public Health Service Publicatiom. 11696-2; 1969, 98pp- 4'0 U.S. PUBLIC HEA,LTHISERVICE. The HealthiConsequences of Smoking. A,Report of the Surgeon General: 1971. U.S. Department:of Health, Education, andiWelfare. Washington4 DHEW Publication No. (HSM) 71-7513, 1971, 458 pp. 41 UIS. PUBLIC HEALTH SERVICE. The Health, Consequences of Smoking. A Report of' the Surgeon General: 1972. U'.S. Department of Health~ Education, and Welfare: Washington, 1DHEWPublication No. (HSM) 72-6516, 11972, 158,pp. 81 0 0

42' 43 U.S. PUBLIC HEA,LT11 SERVICE: The Health Conseqpences of Smoking: 1973. U.S. Department of Health, Education, and! Welfare. Washington~, DHEW Publication No. (HSM) 73-8704; 1973, 249 pp: U.S., PUBLIC HEALTH SER'VICE: The Health Conseqpences of Smoking: 1974L U.S. Department of Health, Education, andl Welfare. Washington, DHEW' Publication No. (CDC) 74-8704, 1974, 124 pp. VAN DER LENDE, R.,,DE KROONI J. P. M., TAMMELING, G. J., VdS~SER„B. F., DH, ~ VRIIES„ K., WEVER-HESS, J., ORIE, N: G. M. Prevalence of chronic nonspecific lhng disease: in a nonpolluted and, air.polluted area of the Netherlands. In: ~ Brzezinski, Z,, Kopczynski, J.,, Sawicki. F: (Editors). Ecology of chronic ~ nonspecific respiratory diseases, I!nternational Symposium„September 7-8, 1971, Warsaw, Poland; Panstwowy Zaklad Wydawnictw Lekarskich, Warsaw, 1972„ pp. Q 45 WANNER, A,.,, HIRSCH, J. A., GR'EENELTCH, D. E.,, SWENSON; E.,W.,, FORE, T. Tracheal mucous velocity in: beagles: after chronic exposure to cigarette smoke. Archives of Environmental Health 27(6): 370,371„December 1971 46 WARR, G. A., MARTINi R. R. In vitro migrationi of human alveolar, macrophages: Effects of~ cigarette smoking. Infection and Immunity~ 8(2): 222'-2~2'7~, August! 1971 47 WEBB, D. R.,, HYDE„ R. W.,, SCHWARTZ, R. H., HALL, W. JL, CONDEMI, J. J.,, TOWNES, P. L., Serum a,-antitrypsin variants. Prevalence and, clinical spirometry. American Review of Respiratory Disease 108(4): 918-925,,October 1973: 48 YEAGER, Hl., JR., ZIMMET, S! M., SCHIWARTZ„S. L. Pinocytosis by human alveolar macrophages. Comparison of' smokers and nonsmokers. Journal of Clinicall Investigation1 5'4(2); 247-251, August 1974. 82

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CHAPTER 4 lnrrolwntary Smolking. Contents Page Ilnt'roduction .......................................... 87 Constituents of Tobacco! Smoke ............................. 88 Carbon Monoxide .................................... 90 Nicotine ........................................... 97 Other Substances .................................... . . 98 Effects of Exposure to Cigarette Smoke. .................. ...... 98. Cardiovascular Effects of Involuntary Smoking . . . . . . . . ...... 98 Effects of Carbon Monoxide on Psychomotor Tests ..... ...... 99' Pathologic Effects of Exposure to Cigarette Smoke ...... ...... 99 Summary of Involuntary Smoking Findings ........... ........... 1'08' Bibliography .............................. ........... . 109

List o~f~Tab~les~ Page Table 1.-Comparison of mainst'ream and sidestteam cigarette smoke ..................................... 89 Table 2.-Measurements of constituents released by the combustion of tobacco products in various sit'uations ....................................... 91'-94 Table 3.-Median percent' carboxyhernoglobin (COHb) saturationi and 90 percent range for nonsmoker by location ......................................... 96 Table 4.-Effects of carbon monoxide on psychomotor functions ...................................... 100-101 Table 5.-Admission rates (per 1!001infants) by diagnosis„birth weight„and maternal smoking .......................................... 104 s Table 6:-Pneumonia and bronchitis in the fi'rst 5 years of life by parents' smoking habit and morning phlegm .................................. , 106

IhITRaDUCTI10.1'4i The effects of smoking on the smoker have: been extensively studied„ but the effects of tiobace~osmokeon nonsmokers have received much less attention. The 1972 Health Consequences of Smoking (49)~ reviewed' the~ effects of public exposure to the air pollution resulting from tobacco smoke: This: exposure has been, called "passive smoking" bymanyauthons-, but will be referred to in this report as "Involuntary Smoking." The term involuntary smoking will be used t& mean theinhalatianoftobaccocombustionproduets, from, smoke-filledl atmospheres by the nonsmoker. This type of exposure is,, ini a sense, "smoking" because~ it provid!e& exposure to many of the same constituents of tobacco smoke that voluntary smokers experience. It is also "involuntary°° because the exposure occurs as an unavoidable consequence of breathing in a smoke-filledd environment. The chemical constituents found in an atmosphere filled, withh tobacco smoke are derived from two sources - rnainstream and sidestream, smoke. Mainstream smoke emerges from the tobacco product after being, drawn through the tobacco during puffing. Sidestream smoke rises from the burning cone of tobacco. Main=st'ream and sidestream smoke contribute different concentrations of many substlances to the atmosphere for several reasons: Different amounts of tobacco are consumed ine the production of mainstream and sidestream smoke; the temperature of' combustion differs for tobacco dh.iring puffing or while smouldering; and certain substances are partially absorbed from the mainstream smoke by the smoker. The amount of a substance absorbed by the smoker depends on the, characteristiics of the substance and the depth of inhalation, by the smoker. As discussed in the 1972 Report, when the smoker does not inhale the smoke into his lungs,, the smoke he exhales contains less than half its original amount of water-soluble volatile compounds, four-fifths of the original nonwater soIuble compounds andd particulatematter„ and almost all of the carbon monoxide(1'S)'. When the smoker inhales thernainstream smoke, he exhales into the atmosphere lessthan, one-seventh of the amount of voliatile and particulate substancest;hat were originally present in thesmokeand alsoreduees the~ exhaled CO'to less than halfitsoraginal concentra- tioni (16). As a result, d'ifferent concentrations of substances are found in, exhaled mainstream smoke depending on the tobacco product, composition of the tobacco, and degree of inhalat'iion by the smoker. 87 X 00 O

Several minor symptoms (conjunctival irritation, drythro.at,y etc.) are causedl by levels of cigarette smoke encountered in everyday life, and serious allergic-like reactions to cigarette smoke may occur in some sensitive individual§. A major concern,, however, about atmospheric contamination by cigarette smoke has been due to the production of significant levels of carbon~ monoxide. Cigarette srnoking ini poorly ventilatedl enclosed spaces may generate carbon monoxide: levels above the: acceptable 8-hour industrial', exposure li~mits(5~0ppm)- set bytheAmeriCan Conference of Government Industrial Hygienists (T), Exposure to this level of earbon:monoxide even for short periods of time has been shown to reduce significantly the exercise tolerance of some persons witlh symptomatic cardio- vascular disease: There i's also some evidence that prolbnged exposure tothisleveli ofcarb~on monoxide in combination with a highh cholesterol diet can enhance experimental atherosclerosis in animals (Chapter1,,CardiouascularDiseases)s. IIn the present~~ chapt'er, the effects of cigarette smoke on the environment and on the nonsmoker in that environment will be examined by reviewing data on (1) the constituents of cigarette smoke measured under various conditions,, and (2) the physiologic effects of this "involuntary smoking"' oniindividUals.. CONSTITUENTS OF TOBACCCa SIVIOKE Ini a recent workshop on the effects of' environmental tobaccol smoke, on theno.nsmoker (4~1)i, Corn(14)i presentiedl a compilation adapted from Hloegg (32), of some of the substances in rnainstreamm cigarette: smoke and the ratio of si~destream, t'o mainstreamlevels~ forsome of these substances (Tabl'e 1). The actual numerical value of the sidest'reamt'omainstream concentrat'ionrat'~iowill vary with differenti types of tobacco, tested, but Table I gives values generally consistent with those foundl by others (34; 42).. Many of these substances includlingnico.tineand carbon monoxide are found inmuchi higher concentrations in sidestream smoke than in mainstream smoke, establishing that the smoke exposure received by both the smoker and nonsmoker due to, breathing in a smoke-fill'ed environment differs, qualitlativelyas, well asquanti'tativelXfromthesmoke exposure received by the smoker who inhales throughi ai lighted'' cigarette. A, more comprehensive recent review of tlie constituents oP mainstream and sidest'ream~ smoke has also been provided by 8chmelt~z,etal. (42)! andi]ohnson, etal. ('34). 88

A4* TABLE 1. - Comparison of rnainstream anrd sirlestream cigarette smoke 1 ~2 Compound Mainstream (mg/cig) Sidestream (mg/cig) Ratio Sidestream/ Mainstream A General characteristics Duration of smoke production 20 sec 550 sec 27 Tobacco burnt 347 411 1.2 Particulates, no. per cigarette 1.05 X 1012 3.5 X 1012 3.3 B Particulate phase 2Tar (chloroform extract) 20.8 44.1 2.1 10.2 34.5 3.4 Nicotine 92 0 1.69 1.8 - . - 0.46 1.27 2.8 Benzo(a)pyrene 3.5 X 10 5 13.5 X 10 ~ 3.7 Pyrene 13 X 10 5 39 X 10-' 3.0 Total phenols 0.228 0.603 2.6 Cadmium 12.5 X 10 3 45 X 10-5 3.6 C Gases and vapors Water 7.5 298 39.7 Ammonia 0.16 7.4 46 Carbon monoxide_ 31.4 148 4.7 Carbon dioxide 63.5 79.5 1.3 Oxides of Nitrogen 0.014 0.051 3.6 mme_nt Comment Filter cigarette Filter cigarette 3.5 mg of Mainstream and 5.5 mg of Sidestream in particulate phase, rest in vapor phase t A iapted from Hoegg, U.R. (31, 32). 2b'or 35 nil puff volume, 2 sec puff duration, one puff per minute and 23 or 30 mm butt length and 10 percent tobacco moisture. - Source: Corn, M. (14). OTC7 C. J(.a [. o

A number of other researchershave attempted torneasurethe levels of some of the substances ini cigarette smoke encountered in everyday situations (Table 2). They have also tried to determine the factors controlling the atmospheric concentrations of these substances as well as the amount absorbed by nonsmokers under thesecondhtions. Carbon monoxide,nicotine,, benzo(a)pyrene,acrolein, and acetaldehyde have been of particular concern. Carbon M6noxide Leveli; of carboni monoxide (CO), a major product of tobacco combustlion,, have been studied in a variety of situations, and concentrations ranging from 2 to 110' ppm have been measured (Table 2). The major determinants of the CO levels in these situations are size of the space in which the smoking,occurs (dilutionn of CO), the number and type of tobacco products smoked (CO' productlon); and the amount and effectiveness of ventilationi (CO' removal). The type of tobacco product smoked is important as a determinantl of CO exposure because it has beeni found thatl mainstream smoke from regular and small cigars contains more CO'O pre puff and per gram of tobacco burned than filtered or unfiltered cigarettes (8). This greater productioniof CO by cigarss was confirmed by Harke (23). He measured the CO produced by 42' cigarettes, 9 cigars, and 9 pipefuliti of tobacco, eachi product evaluate& separately but: under the same room conditions. The cigars produce d the highestl CO1 levell (60 ppm). In addition to the effect of type of tobacco~ producti onCO'. levels, data on the effects of room siee, amount of tobacco burned, and ventilation are included ini Table 2. Only under conditlions of unusually heavy smoking, and poor ventilation didl C0 levelsexce~eds the maximum permissiible, 8-hour industrial exposure limit of50. ppm CO (1); however, eveni in casese where the ventilation was adequate„ the measured CO levels did exceed' the maximumm acceptable ambient level of 9'ppm (M). Harke (',27)alsoshowed that inismall enclo~sedlventilated spaces (an automobile)~ the C0 level isdeternnined m~orebythenumberofcigarettes being smoked at one given time than by the cumulativee number of cigarettes that have been smoked; also the CO level decreases rapidly once the smoking stops. ; 90

bi 4 ~**~ - TABLE 2. - Measurements oj coits/ittteuts released by ttte cwtrtbttstiutt of tobacco products in variceus situations [Cig == cigarettes; - = unknown; TPM = total particulate matter J Reference, Location, and Dimensions If Known Ilarke, H.-P., et al. (27) Mid-size European car, engine off, in wind tunnel at 50 km/hr wind speed Mid-size European car, engine off, in wind tunnel at zero km/hr wind speed Harke, H.-P., Peters, H. (28) Car in traffic Srch, M. (45) Car, en *ine off- 2.0 9 m~ Seiff, H.E. (44) Intercity buses Ventilation Amount of - Tobacco Burned Constituents None Air jets open & blower off Air jets open & blower on None None Air jets open & blower on - 9 cig 6 cig 6 cig 9 cig 6 cig 6 cig 30 ppm CO 20 ppm CO 10 ppm CO 110 ppm CO 80 ppm CO 8-10 ppm CO None 4 cig 21.4 ppm CO None 10 cig in 1 hr 90 ppm CO, Smokers 10% COHb Nonsmokers 5% COHb 15 air changes per hr 23 cig 33 ppm CO (at driver's seat) (burning continuously) 3 cig 18 ppm CO (at driver's seat) (burning continuously) (i TSM[. 0

TABLE 2. - Measurements of constituents released by the combustion of tobacco products in various situations - Continued [ Cig = cigarettes; -= unknown; TPM = total particulate matter] Reference, Location, and Dimensions If Known Ventilation Amount of Tobacco Burned Constituents U.S. Dept. Transportation, et al. (48) Airplane flights: Overseas-l00% filled 15-20 air changes per hr - 2-5 ppm CO, <.120 mg/m3 TPM Domestic-66% filled do - 120 mg/m3 TPM <2 ppm CO < . . , - Cano, J.P., et al. (11) Submarines-66 m3 Yes 157 cig per day <40 ppm CO, 32 µg/m3 Nicotine 94-103 cig per day <40 ppm CO, 15-35 µg/m3 Nicotine Godin, G., et al. (21) Fe_rry boat compartments: Smoking - 18.4 t8.7 ppm CO Nonsmoking 3.0±2.4 ppm CO Theater: Foyer - - 3.40.8 ppm CO Auditorium - - 1.4±0.8 ppm CO Bridge, D.P., Corn, M._ (7) Party rooms: 145 m3 7 air changes per hr 50 cig & 17 cigars in 1.5 hr 7 ppm CO 101 m3 10.6 air changes per hr 63 cig & 10 cigars in 1.5 hr 9 ppm CO .Tsm(.U

TABLE 2. - Measurements of constituents released bv the combustion of tobacco products in various situations - Continued [ Cig = cigarettes; - = unknown; TPM = total particulate matterJ -~r Reference, Location, and Dimensions If Known Ventilation Amount of Tobacco Burned Constituents Harke, H.-P., et al. (25) Room-38.2 m3 None 30 cig per 13 min (by machine) 5 cig per 13 min (by machine) 64 ppm CO, 510 µg/m3 Nicotine .46 mg/m3 Acrolein 6.5 mg/m3 Acetaldehyde 11.5 ppm CO, 60 µg/rn3 Nicotine, - - .07 mg/m3 Acrolcin, 1.3 mg/m3 Acetaldchyde Harke, H.-P. (24) Office Bldg Air conditioned <5 ppm CO Office Bldg Not air conditioned <5 ppm CO Room-78.3 m3 3 smokers 15.6 ppm CO Harke, H.-P., (23) Room-57 m3 None 42 cig (by machine) 50 ppm CO, 530 ug/m3 Nicotine 7.2 air changes per hr 42 cig do. 10 ppm CO, 120 µg/m3 Nicotine 8.4 air changes per hr 42 cig do. <10 ppm CO, <100 µg/m3 Nicotine None 9 cigars do. 60 ppm CO, 1040 µg/m3 Nicotine 7.2 air changes per hr 9 cigars do. 20 ppm CO, 420 µg/m3 Nicotine None 9 pipes do. 10 ppm CO, 520 µg/m3 Nicotine 7.2 air changes per hr 9 pipes do. <10 ppm CO, <]0(l µg/m3 Nicotine 9 ME94Eo

TABLE 2. - Measurements of constituents released by the combustion of tobacco products in various situartions - Continued - [Cig == cigarettes; -= unknown; TPM = total particulate matter] Reference, Location, and Amount of Dimensions If Known Ventilation Tobacco Burned Constituents - Harke, H.-P. (23) None 105 cig 30 ppm CO, Smokers 7.5% COHb Room-170 m3 Nonsmokers 2.1%COHb 1.2 air changes per hr 107 cig 5 ppm CO, Smokers 5.8% COHb Nonsmokers 1.3z, COHb 2 3 air chan es per hr 101 cig 75 ppm CO Smokers 5 0% COHb . g - - . , - Nonsmokers 1.6% COHb Anderson, G., Dalharrrn, T. (3) Room-80 m3 6.4 air changes per hr 46 cig & 3 pipefuls 4.5 ppm CO, 377 µg/m3 Nicotine, 3.0 mg/m3 TPM Russell, M.A.H., et al. (40) 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. (30) Room-93 m3 None 62 cig in 2 hrs 80 ppm CO, 5200 µg/m3 Nicotine Hoegg, U.R. (31, 32) Sealed test chamber -25 m3 None 4 cig 12.2 ppm CO, 2.28 mg/m3 TPM 8 cig 25.6 ppm CO, 5.39 mg/m3 TPM 16 cig 47.0 ppm CO, 11.41 tng/m3 TPM 24 cig 69.8 ppm CO, 16.65 mg/m3 TPM Srs?E.;7lsIC.O

One must be careful when using the levels recorded in Table 2 as measures of individhal exposure because the CO levels were usually measured at points several feet from the nearest srnoker and probably would have been higher if measured at points correspond- ing to the position of a person sitting, next to someone actively smoking (17; 35). In addition, it is the CO absorbed by the body that! causes the harmful 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 cardio-respiratory function. Several investigators have tried to determine the amount of carbon monoxide absorbed in involuntary smoking situations by measuring changes in carboxyhernoglobin l'evels in nonsmokers exposed to cigarette smoke-filled environments. Anderson and Dalhamn (3) were unable to find any change in the COHb levels of nonsmokersi6 awel ventilated room where the C0 level was 4.5 ppm. When Htirke (23) studied nonsmokers under similar conditions (good ventilation and less than 5 ppmI CO), he was able to show an increase in COHb: level from1.1 to 1.6 percent; withoutventilatilo~n the CO levels rose to 30 ppm and the CO'Hb level increased'' frorn .9 to 2.1 percent in 2 hours. Russell, et al. (40) also found that COHb levels increased from 1.6 to 2.6 percent in nonsmokers exposed to a smoke-filled room where the CO' level was measured at 38 ppm; however, he cautioned that nearlyallll persons ini thero~orn~ felt that the conditions were worse than those experienced in most sociall situations.. Stewart, et al. (46) measured COHb levells in a grou,p of nonsmoking blood donors from severall cities and found that 45 percent exceededl the Clean Air Act's Quality Standard of 1.5 percent with the 90 percentl range: as high as 3.7 percentforindiuidual cities (Table 3). These levels represent the total CO exposure from all sources, involuntary smoking„ and other sources of pol'lutaonaswell as establishing, the levels which wouldl be ad'd~ed to~ any new involuntary smoking exposure. Increases in the COHb levels of this magnitude are proliabl'yfunctionally insignificant in the healthy adult, but in persons with angina pectoris, any reductioni of oxygen-carrying capacity is of great importance. In this disease, the volume of blood able to bed pumped through thediseased'eoronary artery isal'readyunable too meet the d'emands of the heart muscle u:nder exercise stress: Aronow, et al. (4) examined the effect of exposure t& carbon monoxideoni persons with anginai pectoris. They exercised persons with angin& 95

TABLE L_E 3_ .-. Median ia_ n percent carboxyhemoglobin (CQHb ) saturation and 90 percent range for nonsmokers by location Nonsmokers No. of No. Percent of Nonsmokers Nons mokers With COHb Median Range _ > 1.50 Anchorage 1.5 0.6 - 3.2 152 56 Chicago 1.7 1.0 - 3.2 401 74 Denver 2.0 0.9 - 3.7 744 76 Detroit 1.6 0.7 - 2.7 1,172 42 Honolulu 1.4 0.7 - 2.5 503 39 Houston -- - 1.2 - 0.6 - 3.5 - 240 - 30 Los Angeles 1.8 1.0 - 3.0 2,886 76 Miami 1.2 0.4 - 3.0 398 33 Milwaukee 1.2 0.5 - 2.5 2,720 26 New Orleans_ 1.6 1.0 - 3.0 159 59 New York 1.2 0.6 - 2.5 2,291 35 Phoenix 1.2 0.5 - 2.5 147 24 St. Louis 1.4 0.9 - 2.1 671 35 Salt Lake City 1.2 0.6 - 2.5 544 27 San Francisco 1.5 0.8 - 2.7 660 61 Seattle 1.5 0.8 - 2.7 535 55 Vermont, New Hampshire 1.2 0.8 - 2.1 959 18 Washington, D.C. 1.2 0.6 - 2.5 850 35 Source: Stewart, R.D., et al. (46). ..... ..~....., ..... ..a'1:,...JtN ~ ... ....._,. y.. :._..r+/1-ti.W/,MO " !'qC.94UO

pectoris before and after exposure to carbon monoxide. The average amount of exercise that was able to be performed before a person developed chest pain wassignifieantlysh~ortened from 226_7'second§ before exposure to 187.6 seconds after CO exposure. This change occurred after a 2-hour exposure to 50 ppm CO and with, an iincrease in COHb level from 1.03' percent to 2.68 percent', these CO1Hb levels are within the range produced by involuntary smoking. These data indicate that exposure to CO, at levels found in some involuntary smoking situations may well have a significant impact onn the functional capacity of persons with angina pectoris. Carbon monoxide has al'so been shown to decrease cardiac contractility in personswithi coronary heart disease at COHbIevelssiinilar to those produced due to involuntary smoking situations (5). It is reasonable to assume that any significant CO exposure to the diseased heart reduces its functional reserve. Nicotine Nicotine in the: atmosphere! differs fromCO, in that it tends to settle out of the air with or withoun' ventilation (thereby decreasing its atmospheric concentration), whereas the CO level will remaini constant until the CO is removed.. The concentrations of both substances are decreased substantially by ventilationL As can be seen from data in. Table 2, under condltions of adequate ventilation neither exceed's the maximum threshold limit' values for industrial exposure (nicotine;5'00 pg/in3; CO, 50'1 ppm, 1); whereas in conditions without ventilation, smoking produces very highi con- centrations ofbothi (nicotine, u.ptio 1,040'Mg/m3 ; CO~, 11&ppm). Nicotine in the environment is of concern because ni~cot'ineabsorbed bycigarettesrnokers is felt to be one! factor contributing, to the development! of atherosclerotic cardiovascular disease. Several researchers have attempted to measure tfie arnount of nicotine absorbed by nonsmokers ini involunt~arysmokingsituations.Cano„ et al. (11) studied urinary excretion of nicotine by persons on a submarine. Despite very low levels measured in the: air (15 to 32 µg/m3'), nonsmokers did show a smalill rise in nicotine excretion; however, the amount excreted was still less than 1Y percent of tlhee amount excreted by smokers. Harke (23') measured nicotine and its metabolite cotinine in the urine ofsmokers and nonsmokers,exposedd to a smoke-filled environment andl reported that nonsmokers, excreted lessthan 1 percent of1theamo.unt of nicotine and cotiinineexcreted by smokers. I'-lefeelsthat' at this low level'l of absorption nicotine is unlikely to be a hazard to the nonsmoker. 97

Other ~ Substances ~ In two: studies environmental leveis of the experirnentali carcinogen benzo(a)pyrene were measured. Galuskinova (20) foundl levels of benzo(a)pyrene from 2.82 to 14.4 mg'/rn~ in smoky restaurants, but itl is not clear how much of this was dkze to cooking, and how much was due, to smoking. In a study of the concentration of benzo(a)pyrene in the atmosphere of airplanes (48)1, only a fraction of a microgram per cubic meter was detected. The effect: of chronic exposure to very low l'evels of this carcinogen has not beenn established for humans. Acrolein andi acetaldehyde have also been measured in smoke- filled rooms (25, Table 2), andl may contribute to the eye irritation commonly experienced in these situations. EFFECTS OF' EXPOSU RE TO' CIGARETTE SMOKE Cardiovascular Effee~ts~~ of ~lnvo~l'untary~ Sm~~©laing~ The effects of cigarette~~ smoking~ on t~he~ cardiovascular system of tha r.,,nl a+ a+a Sreo11~F,+ h~c}4ofl ~3 ~ uary L+tttla ic lrnnu'rp, abn17t YhP r V

Effects~of~Car6ou~~M'onox~ide~~o~rr~Fsycitomo or~Tests~ Carbon monoxide from tobacco smoke, automobile exliaust, and! industriall pollution is an i'mportantl component of'aia• pollution.. There has been some concern over the effect of relatively low levels of carbon monoxide on psycliomotor functions, (theabilitly to perceive and react to stimuli), especially those functions rel:atedl to driving an automobile (Table 4). Carbonmonoxidelevelsoccasional'ly reaehed~ in some involun- tary smoking situations result ini rneasurable cognitive and' motor effects,, but theseeffectsgeneral'lyrare measurable only at the threshold of stimuli perception. One study (Wright, et al., (S0))found that the safe driving habits measured on a d'riviingsimulator did not improve! as much with practice in a group: exposed to CO as did the habits of a control group. Another study (37)1 with ai different experimental designi but at the same level'sof CO did not find any effect on complex psychornofor activity such as driving a car. Thus,, the role of CO alone in motor vehicle accidents remains unclear. The effect on judgement and reactions of CO, in combina- tion with factors such as fatigue andl alcohol, conditions known to influencejudgement and reaction time, has not been determined. Pathologic Effects of Exposure to Cigarette Smoke The effect of involuntary smoking on ani individual is deter- mined not only by the qualitative and quantitative aspects of the smoke-filled environment, but also largely by the charaeteristicsof tllieindi~vidual. Reactions may vary with age as wel11 as, with the sensitivity of an individual to the components of tobacco smoke. The severity of possible effects range ffom minor eye and throat irritations experienced by most peoplein: smoke-filled roorns,, to t'heanginal attacks of some persons wi'th cardiovascular disease. T'he minor symptomatic irritation experienced by nonsmokers in a smoke'-filled environment is~ inflhenced! by the~ humidity~ of the~ air as well as the concentration, of'irritat'ing substances found in the a~tmosp}trere~. Johansson and~ Ronge~ (33)~ have shown that ~ irritation due to cigarette smoke is~ maximal~ in warm, dry~ air and decre~~ases, with a small rise in reiat'~ive~ liumidity.~ A cha~nge~~ from acceptable to unpleasant was~ reported at 4'~7~ rng/m3~ of~ parti~culate~ matter fo~r~ nonsmokers~~ andl eye~ irritation was~~ noted a~t 9mg/ms' for both sm~o~k~ers~ and nonsmokers. The authors~~ concluded that a venti~lationn rate~~ of~ 1?~ m3/lIr/cig~ was~ necessary to~ avoid eye~~ i'rritat~~iiarr and 50 m3~/~h~r/cig was necessary~ to~avoi'd~ unpleasant odors. 99: .., .~, .:r.. ~

TABLE 4.- Effects of carbon monoxide on psychomotor functions Reference Test or Measurement CO level (ppm) COHb level (Percent) Effect 6 None 11 None 17 None 10 Prolonged 700 17 None 700 17 None 700 17 None 700 17 Decreased 700 17 None 500 20 None McFarland, R.A. Ability of drivers to stay (37) between two-lane markers while being permitted only brief glimpses of the road Ray, A.M., Reaction time to Rockwell, T.H. car taillights (39) McFarland, R.A. Performance of two tasks at (38) same time Dark adaptation and glare recovery Peripheral vision at 1_ 0 and 30' Peripheral vision at 20* Depth perception Stewart, R.D., et al. Time perception (47) -~1,:- ,_.w.~,:.. _ _ • -•,».-. TzS?es4Co

TABLE 4. - Effeets of carbon monoxide on psvchotttotor furrcticzfts - Cruttirttted Reference Test or Measurement CO level pp m COHb level (Percent) Effect Fodor, G.G., Attentiveness to 50 x 5 lus. 2-5 Decreased Winneke, G. (19) auditory stimuli Flicker fusion 50 x 5 hrs. 2-5 No change Speed of motor performance 50x5hrs. 2-5 No change Perception of complex 50 x 5 hrs. 2-5 Improved visual patterns Cognitive function 100 5 Decreased Schulte, .LII. (43) - Reaction time 20 No change Bender, W., et al. Threshold for temporal 100 7.25 Raised (6) resolution of visual stimuli Manual dexterity 100 7.25 Decreased Learning meaningless syllables 100 7.25 Decreased Retention of 10 syllables 100 7.25 No change Groll-Knapp, E., et al. (22) for I hr Attentiveness to auditory stimuli so Deterioration at 50 ppm, worse at 100 150 rs_t 100 ppm, worst at 150 ppm Wright, G., et al. Reaction time 6.3 Prolonged (S0) Glare recovery 6.3 Prolonged Careful driving habits 6.3 Failure to improve with practice zzSCs4Co

Two government sponsored studies fiave attempted to evaluate the degree of minor irritationi due to cigarette smoke experienced by bus andl plane passengers. The U.S. Department of Transportlation. (44) studied the environment on two ventilated~ buses - one with simulated unrestricted smoking and another with, simulated smoking Iimited! to the: rear 20 percent of theseat~s. In one bus, lighted cigaretteswere placed at every other seat (23~ cigaretltes), to simulate a bus filled with smo.ke~rs. In the other bus, cigarettes were placed only in the rear 20 percent of the bus (five cigarettes)' to simulate a bus where smoking~ was limited to the rear 201percent of the seats. When~~ smoking waslirnite~d, the CO, levelatl the driver's seat was only 118, ppmi (ambient air 13' ppm) comparedl to the level of 33' ppm (ambient air 7 ppm) measured ini 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 ag~encies(48), cooperated to survey the symp- toms experienced by travelers on both military and commercial aircraft. They distributed a questionnaire to passengers on 20 military and 8 commercial fliglits:; 57' percent of the passen~gers~ oni the military flights and 45 percent of the passengers on the commercial flights were smokers, The planes were well ventilated aQ1dl CIC.1levelswere alwaysbelbw5 ppm with lowleveis: of other pollutants as well. In: spite of' the low level of measurable pollution, over 60 percent 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 orn thee commercial flightlsand 62~ percent of the nonsmoking passengers on, themilit'aryflightssulggestedthat sorneremedial action be taken; 84 percent of those suggesting remedial action felt that segregating the smokers from nonsmokers would be a satisfactory solhtion. These feelings were even more prevalent among those nonsmokers who had a, history of respiratory disease. Children h~ave~ been found~ to have a higher~ incide~nce~~ of respiratory infections than adults and are thought to be more sensitive to the effects of air pollution due to their greater minute ventilation per body~ weight: than adults. Several researchers~ have~ investigated the~ effects of parental srnoking~ on the~ health of ~ children. Cameron; et' al. conducted two~ telephone surveys~~o~f~Detroi~t families~ to~~ de~termine tihe~ relationship between children~'s~respi~ratory illness and parental smoking habits. In the, first survey~~ (9)~ they~ foundd a~ statistical~ly~ significant relationship between tlre~~ prevalence of~ 102 f t

I children's respiratory infection and parental smoking habits only when all children under 16 were considered (not' when only those under 9 or under 5 were considered). I'ni a larger survey of the same city(Z0), theyfound ai . relationshipbetweeni parental smokingand' prevalence of respiratoryil'lness in the 10- to 116-yearage group and in the birth to 5-year age group. Neither study cont'rolled 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 andi illness. However; the data were consistent with a higher prevalenceofrespiratoryd'iseaseinfamilibswhereAhereare smokers than in, nonsmoking families.. C~olley(L2) alsolfound aireiat~ionship~betlween parental srnoking, habits and the prevalence of respiratory illness in the children. He found ani even stronger relationship between parental', cough and' phlegm production and respiratory infections in childlren. He postulates, this, latter relationship to result fromtlhegreater infec- tivity of theseparentsduet'o their cough andi phlegm prodluction. The: relationship between parental cigarette smoking, and respiratory infection in theirchildren would then occur because cigarette smoking caused the:parents to cough and produce phlegm and wouldd not be indicative of a direct effect of cigarette smoke-filled air on the children. Harlap and Davies (29), studied, infant admissions to Hadassah Hospital ini West Jerusalern and found ai relationship bet'weenn admi6sionsfor bronchitis and pneumonia in the first year of life andmat'ernal smoking habits during pregnancy. Data on rnaternall smoking habits after the birth of the child were not obtained, but it can be assumed that most of the mothers who smoked during pregnancy continnedl to: smoke during the first year of the infant's life. A relationship between infant admission and maternall smoking habits was demonstrable only between the sixthi and ninthi months, of infant life and was more pronounced during the winter months (when the effect of cigarette smoke on the indoor environment would be greatest). Mothers who smoke during pregnancy are known to have infants with a lower average birth weight than the infants of nonsmoking mothers. The relationship, between rnaternali smoking and their infant's~'admission tothe~ hospital found in this study was greater for low birth weight infants, but was also f~ound for normal birth weight infants (Table 5) (29). Harlap and' Davies (29) demonstrated ai dose-response relationship for maternal smoking,and, infant adlmission for bronchitlisand pneumonia;, however,, they also found a relationship between maternal smoking and infant adrnisT sions for poisoning, and inj'pries. This may indicate a bias in the study 103' .... ,cr', ~F.`.

TABLE 5.- Admission rates (per 100 infants) by diagnosis, birth weight, and maternal smoking Birth weight (g) Total Diagnosis <2,999 3,000- 3,499 3,500+ (including unknown) S (297) NS (2,326) S (415) NS (4,098) S (264) NS (3,195) S (986) NS (9,686) Bronchitis and pneumonia 19.2 12.3 9.6 8.2 12.1 9.0 13.1 9.5 All other 22.6 19.9 14.5 14.6 15.2 13.3 16.9 15.5 Total 41.8 32.2 24.1 22.8 27.3 22.3 30.0 24.9 NOTE. - S=Smokers; NSeNonsmokers. Source: Harlap, S., Davies, A.AA. (29). szgMco

dk.ie to relationships which may exist betweeni smoking and factors such as, parent'al neglect or socioeconomic class, Ini ad'dition, hospital admission rates may not be an accurate index of infant morbidity. Colley, etall. (13)~ studied the incidence of pneumonia andd bronchitis in 2,205 children over the first 5 years of life in relation to: the smoking habits of both parents. They found that a relationship: between parentall smoking habits and respiratory infectlion ini children occurre& only during, the first years of life (Table 6). They also showed a relationship between parental cough: and phlegmi productiioni and infant infection (Table!6), which was, found tobeo independent of the effect of parental smoking habits. The relation- ship between parental smoking and infant infection: was greaterwhen, both parents smokedl andl increased with increasing number of cigarettes smoked per day. The relationship persisted after sociall class and birth weight had been controlledl for. Thus, respiratory infections during the first year of life are closely related t&smoking habits independent of parental symptorns„ social class, and': birth weight. Because of the dose-response relation- ship between parental smoking and infant respiratory infection established by Colley, et al. (13), it is reasonabletlo suspect that cigarette smoke in the atmosphere of' the home may be the cause of these infections; however, other factors suchi as parental neglect may also play a role. The above studies exarnined the effects of invol'untlary 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 invollunt'ary smoking situations. In Chapter 1 of this report (Cardiovascular Diseases)evidenee was presented which, showed that levels of CO sometimes experiencedl in smoke-filled environments, (50 ppm) are capable of significantly decreasing the exercise tolerance of persons with angina pectoris and intermittent ciaudication. In addition,, these levels of CO1havebeenshown tod'ecrease cardiac contractility and to raise left ventricular end-diastolic pressur~e, (anind'ication of heart failiure)~ in persons with cardiovascular disease. Persons with chronic bronchitis andi emphysema have consider- able excess mortality under conditions of severe air pollution. In smoke-filled: environments levels of CO and several other pollutants may be ashig~h or higher than occur during air polllu~tionernergencies The effects of short-term exposure of persons, with chronic obstruc- 105

. TABLE 6. - Pneumonia and bronchitis in the first 5 years of life by parents `smoking habit and morning phlegm Annual incidence of pneumonia and bronchitis per 100 children - - (Absolute numbers in parentheses) Both ex-smokers Year of Both nonsmokers One smoker Both smokers or one ex-smoker All Followup or smoking habit changed N O/s N o/B N 0/B N 0/B N 0/B 1 7.6 10.3 10.4 14.8 15.3 23.0 8.2 13.2 10.1 16.7 (343) (29) (424) (128) (339) (139) (546) (129) (1,652) (425) 2 8.1 8.3 _ 7.1 15.5 8.7 9.2 6.5 10.7 7.4 11.3 (322) (36) (365) (129) (286) (152) (599) (159) (1,572) (476) 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) (471) 4 8.0 11.1 7.5 10.8 7.6 11.6 8.2 9.1 7.9 10.3 (287) (36) (306) (102) (236) (121) (695) (187) (1,524) (446) 5 6.7 14.7 5.6 9.4 3.9 10.6 6.4 7.3 5.9 9.1 (285) (34) (267) (107) (208) (132) (737) (219) (1,497) (492) NOTE. - N=neither with winter morning phlegm. O/8=one or both with winter morning phlegm. - - Source: Colley, J.R.T., et al. (13). LzSC94eo

tive bronchopulmonary disease. (COPD) to these conditions have not been evaluated. Persons with COPD are also possibly at increased risk to CO, exposure because of their lowalveol'ar P0z., Due to the reduced amount of oxygen available to compete with the CO for hemoglobin bin.ding sites, these persons might experience a carboxy hemoglobin to oxyhemogl'obin ratio higher than those in healthy subjects under the same conditions of C0 exposure_ The retention of C0 may also be: prolonged! due to both this increased binding of CO'. to hemoglobin under low alveolar P'oz and decreased ventilatory capacity to excrete CO. In summary, the effects of cigarette smoke on healthy nonsmokers eonsists mainly of minor eye and throatl irritation_ H'owever,, people with certain heart and lung diseases (angina~ pectoris, COPD, allergiic! asthma) may suffer exacerbations of their symptoms as a result of exposure to tobacco smoke-filled environ- ments. These effectls are d'ependentl on the degree of individuaU exposure to cigarette smoke which is determined by proximity to! the source of the tobacco smoke, the type and amount of tobacco product smoked, conditions of room size and ventilatlion as well as the amountl of time the individhal spends in, the smoke-filled environment„ and his physiologic condition at the time of exposure.

SLIMMARY' 1. Tobacco smoke can be a significant source of atmospheric poldution in enclosed areas. Occasional'ly under conditions of heavy smoking and poor ventilation, the maximum limit for an 8'-hour work exposure to: carbon monoxide (50 ppm) may be exceeded. The upper limit for C0! in arnbientl air (9 ppm): may be exceeded even in cases wherevent'utationi i6adeqµate. For an individual located close to a cigarette that is being smoked by someone else, the pollution. exposure may be greater than wouldl be expected from atmospheric rneasurements.. 2. Carbon monoxide, at l'evelsoccasionallyfound in cigarette smoke-filled environments, has been shown to produce slight deterioration in some tests of psychomotor performance, especially attentiveness and cognitive function. It is unclear whether these levels impair complex psychomotor activities such as driving a car. The effects, prod'uced by CO rnaybecomeimport!ant wh:eniaddedl tofactorssu.chasfatigue and alcoholwhi& areknowni to1ave an effect on the ability to, operate a motor vehicle. 3'. Unrestricted smoking on buses and' planes is reported to be annoying to t'he majority of nonsinoking passengers, eveni under conditions of adequate ventilation. 4!. Children ofparentswhosrrioke aremore likelyt~ohavebronchitis and pneumoniai during the first year of life, and this is probably at least partly due to their being exposed to cigarette smoke in the atmosphere. 5. Levels of carbon monoxide commonly foundl in cigarette smoke-fillbd environm:entshave been shownt'~odecrea6etheexercise tolerance of patients with angina pectoris. O ~ ~'. W. 108 ~' Cd

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33JOHANSSON; C. R., RONGE„ H. A'cuteirrit'ation effects of tobacco~ smoke in, the room atmosphere. Nordisk Hygienist Tidskrift 46:45-50, 1965. 34 35' 36 37 38' 39 I II 40 t 4'11 I F 42, I! 43 f- ~f 44 Iv 45 g: tg 46 7. i§. n- es 47, JOHNSON, W. R. HALE, J: W:,, NEDLOCK, J. W., GRUBB:S,, H. J., POWELL, D. H. The distribution of products between mainstreamiand sidestream smoke: Tobacco 175(21):43-46', October, 12, 1973. LAWTHER, P. J'., COb4NiINS, B. T. Cigarette smoking andl exposure to carboni monoxide. Annals of the New York Academy of Sciences,174:1,35'-147, October 5s 1970.. LUQUETTE, A. J.,, LANDISS, C:,W.,, MERKI, D:JI Some immediate effects of a~ smoking environment on, children of elementary school age. The Jburnal, of School Health 40(10):533-536, December 1970: McFARLAND, R'. A. A study of the effects of low levels of carbon monoxide upon humans: performing driving tasks at the Harvard School of Public Health: 1973'. Automotive Air Pollution Research Symposium„ Washington„ D:C:, March 7; 9, 1973. McFARLAND, R. A. Low level exposure to carbom monoxide and driving perfor mance:,Archives of Environmental Health 27(6):355-359; December 1973. RAY, A. M:, ROCKWELL, T. H:, An exploratory study ofi automobile driving performance under the influence of low levels of carboxyhemoglobin. Annals of' the New York Academy of Sciences 174:396408, October 5, 1970: RUSSELL, M. A. H., COLE, P. V., BROWN, E. Absorptioniby non,smokersof'carbon monoxide from room air polluted by tobacco smoke. Lancet: 1(7803):576-579, March 17, 197 1. RY:LAND&R', R. (Editor). Environmentall tobacco smoke effects on the non-smoker. Scandinavian Journal of' Respiratory Diseases (Supplementum 91)::1i-90, 1974',. SCHMELTZ, I., HOFFMANN„D., WYNDER, E. L. The influence of tobacco smoke on indoor atmospheres. I. Anoverview, Preventive Medicine 4:66-82, 1975: SCHULTE, L HI Effects of mild carbon monoxide intoxication. Archives of Environmental Health 7(5) 30-36, November 1963. SEIFF, H. E. Carbon monoxide as aniindicator of cigarette:-caused' pollution levels in intercity buses. U.S. Departmentof:Transportation, Federal Highway Administra+ tion, Bureau of'IVlotor Carrier Safety, Apri111973', 11 pp. SRCH, M. Uber die Bedeutung, des Kohlenoxyds beim Zigarettenrauchen im Personen- kraftwageninnern, Deutsche Zeitschriff fur, gerichtliche Ivledi2in,60`.80-89, 1967. STEWART, R. D., BARETTA, E. D., PLATTE, ll. R., STEWART, E. B., KALB- FLEISCH, J:,H., VAN YSERLOO, B., RIMbf„A. A. Carboxyhemoglobin levels,in American blood dbnors. Journal of' the American ivledical Association 229(9)c 1187-1 1I95I, August 26, 1974.. STEWART, R'. D.,, NEWTON, P. E., HOSKO, Jl J.,,PETERSOO N, J. E. EffectoPcarbon monoxide on, time perception. Arehi,vesoflEnvironmenttil Health 27(3):155-160, September 1I97'3. Y.. ~, ~cz

48 U.S. DEPARTMENT OF TRANSPORTATION,, FEDERAL AVI,ATIONI ADMINdS- TRATION, U.S. DEPARTMENT OF HEALTH„EDUCATION, AND WE.LFARE. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. Health, aspects of' smoking, in transport aircraft. Rockville„ Mdl AD-736097, December 1971„85' pp. 49 UIS. PUBLIC HEALTH SERVICE. The Health Consequences of'Smoking. A Report of the Surgeon General: 1972. U.S. Department of Health; Education, and Welfare. Washingtons,DHEW Publication No. (HSM) 72r6516,,1972, 158 pp. 50 WRIGHT, G:,, RANDELL, P., SHEPHARD, R. J. Carbon monoxide and d'riving,skills. Archives of Environmental Health 27(6)c 349-354, December 1973. 0 ~ ~ ~ ~ 112 U

INIDE)I1975 '~ Acetaldehy, de levels, effects of room size„ amount of tobacco burned„ and' ventilation4 , 90, 93, 98 Acrolein , effects of inhalatiomof, in rats; 29 levels, effects of' room size, amount of' tobacco: burned, and ventilation, 90,, 93, 98 AHH activity see Aryl hydrocarbon hydroxylase activity Air pollution effects of exposure levels on respiratory symptoms in,twins,,67 exposure, levels and coal consumption, 67 and human CO burden, 20 ~ levels, exposure of'telephone workers andd pulmonary symptoms, 67 and smoking, in COPD development;, 63!68 andismoking, in lung cancer development, 44,47 summary of recent'i findings, 1'08' survey data for four U.S. locations, 63-66, Airways dysfunctioniof, inismokers, 71 function during viraliillness;,in smokers vs. nonsmokers, 62, 63 Alveolar macrophages decrease in~ pinocytosis, in smokeis vs. nonsmokers, 76 response to migration inhibitioni factor, on antigens, in smokers vs: nonsmakers„76', 77 Angina pectoris, effects of increased carboxyhemoglobinn levels, in passive smokers, 95,97 Antigens effect on alveolar macrophages, in smokers vs. nonsmokers, 76, 77 Antitrypsin dbficiency and' smoking, in COPD etiology„77r74 Arteriess thickening,of, in smokers vs. nonsmokers, 74-76 Arterioles thickening of, in smokers vs. nonsmokers, 74'-76' Aryl hydrocarbon hydroxylase activity role in lung cancendevelopment, 5'0-53' Asbestoss chrysotile, effects on lungs, 49 Atherosclerosis, coronary see Coronary hearrdisease Autopsy findings and smoking:,,74-76 tobacco burned„ and ventilation, 91-94, 98 Birth weight effects of maternal smoking, 27' Bladder, cancer see Genitourinary cancer Blood pressure levels, in smokers, nonsmokers, and ex-smokers, 15,17 Body weight and hypertension, im smokers; non- smokers, and!ex-smokers, 15-17 Bronchiolitis autopsy studies, in male smokers vs. nonsmokers, 74'„76, 77. Bronchitis chronic, incidence of', iw high pollution areas, 63, 64 chronic, and lung cancer development, 49 chronic, summary ofprevious findings, 5, 7,,61, 62 development in infants of maternall smokers, 103 incidence in children of~smokers;,105, 1066 im passive smokers, summary of recent findings, 108 Bronehopulmonary diseases„ chronic ob- structive see also Emphysema„Bronchitis air pollution andi smoking,in etiology of, 63-68 effects of antitrypsim deficiency in smokers vs. nonsmokers, 72'-74 effects of'~ partially deficient'heterozygpte phenotype,s, 73, 74 incidence, in firemen, 68 summary of previous findings, 61', 62' summary of recent, findings, 78' Byssinosis development in, cotton mill workers;, in smokers vs. nonsmokers,,68' Cancer see also specific site,,e:g,,,Lung cancen summary of previous: £indings„ 3-8~ summary of'recent findings, 43, 54 Carbon monoxide cholesterol levels in aorta of' rabbits, after exposure,to, 28 and decrease: in exercise time before cl9udicatlon, 18~ effects on aortas:in animals, 28' effects on healthy smokers vs. non- smokers„26 exposure to, and human~absorption, 21-28 levels, effects of room size, amount, of' tobacco burned, and ventilation, 90-95 levels, effects on exercise performance, 97, Benzo(a)pyrene levels, from smokers in buses and planes, Q W ~ levels, effects of' room size,, amount of 102 ~. ~. ~ 113

myocardial effects on rabbits, 29 summary of' previous findings on relationship to passive smoking, 87; 88, 108' summary'of recent findings, 33 from tobacco smoke, effects of psycho- motor performance, including attentive- ness and cognition function, 99-101 Car'boxyhemoglobin levels in, cigarette smokers; one hour after~ last cigarette„25=26' and CO burden in smokers vs: non- smokers, 211, 26-29 effects, on CO absorption„ in passive smoking, 95'„96 effects on exercise performance, 97 in,f'etuses, 26, 27' in smokers vs. nonsmokers, by sex, race,, employment' status, on urban, location, 22-24 summary of recent findings, 33 in workers exposed to exhaust gases, 21 Carcinogenesis' aryl hydrocarbon hydroxylase activity, and' susceptibility to carcinogens, 50-53 experimental, 48-5'00 summary'of previous findings; 43 Carcinogens benzo(a)pyrene, and exfoliative cytologyy of hamszer lungs,,47' benzo(a)pyrene and chrysotile asbestos, in animals, 49 in cigarette:smoke;,49; 50 Cardiovascular diseasess see also Coronary heart, disease, Ceaebro- vascular, disease atherosclerotic, effects of CO, 27, 28'8 pathogenesis of, 28, 29' Cerebrovascular disease epidemiological studies;,29, 30 mortality by age, sex„and smoking habit, 31 CHD see Coronary heart disease Chemical§ exposure to, in smokers vs. nonsmokers, by race and sex, 69, 70 Children of smokers, incidence of pneumonia and bronchitis, 105, 106; of smokers, prevalence of respiratory symptoms, 102,103 Cholesterol levels after' CO exposure, in rabbits, 28'' and hypertension, in smokers, vs. non- smokers, 15 Chronic bronchitis see Bronchiti's'. Chronic obstructive bronchopulmonary disease see Bronchopultnonary disease, chronic obstructive Cigar smoking autopsy studies, in~ smokers with emphy, sema, fibrosis;,orthickening of arterioles or arteries,,75' CO levels in mainstream~smoke; 90 retationshipto cancea, 43, 44 summary of previous findings' on effects on smokers, 4, 13 Cigarette smoke see Smoke, cigarette Cigarettes,,filter decrease in lung cancen risk, 44 summary of previous findings, 4 Clofibrate and reduction in risk of' sudden death in cigarette smokers, 32' Closing;volume abnormalitiess as' indicator of small airways disease, in smokers vs. nonsmokers, 71„72' CO see Carbon monoxide Coffee, drinking and myoeardial' infarction in smokers vs. nonsmokers, 19, 20 COPD, see Bionchopulmonary' disease, chronic obstructive. Coronary heart diseasee see also Angina pectoris, myocardial infarctionn effects of' coffee dtinking, and cigarette smoking, 20 epidemiological studies,,14, 15' summary of previous findings, 4',,7 Cough of parental smokers, andl respiratory symptoms in children, 103{ 105 in school-age smokers vs. nonsmokers; 62 Cytologic studies exfoliative, and' lung cancer diagnosis; 47 Dust exposure in smokers vs: nonsmokers, by race and sex, 69, 70: and smoking as risk factors, in byssinosiss development, among mill workers;,68' Emphy sema autopsy studies, in smokers vs. non, smokers, 74-76'6 summary of previous findings, 5„7; 6:1', 62. Epidemiological studies cerebrovascular disease and smoking,, 29; 30. CHD and smoking, 1I4„15 lung cancenand smoking, 44 Epinephrine levels effects of nicotine, 29 Epithelium bronchial, and premalignancy in~ smokers, 441 Exercise performance effects of CO' exposure and: increased carboxyhemoglobin levels, 95, 97 Ex-smokers, decrease in risk ofl developing lung cancer, 43 effects ofi cessation on body weight, blood pressure, and' hypertension, develop- ment, 16-19 effects of cessation on dosing volume abnormalities, 71. 114

effects of cessation on pathologic changes,. 74 summary of' previous findings ow health consequences of cessation, 6' summary of previous findings on relationship to COPD, 61, Eye irritation effects of exposure to cigarette smoke, in passive smokers;,99;, 100 Fibrostis autopsy studies';, in smokers: vs. non- smokers, 74-76 Forced expiratory volume decline in smokers, by race, 72' Framingham Study effect of coffee drinking on mortality in smokers vs: nonsmokers, 20 Fume exposure in smokers vs. nonsmokers, by race and sex, 69; 70 Genetics~ role, of antitrypsin deficiency and smoking in COPD development, 72-74 Genitourinary cancer smoking as risk, factor, 50 ~ Histological studies lung cancer and smoking;,44-06' Humidity andl pathologic effects, of exposure too cigarette smoke„99 Hypertension effects of smoking, 15-19 summary of recent findings, 33 Infants maternal smoking, and development of' bronchitis and pneumonia, 103 Ilnhalation patterns summary of previous findings, 4! Immune systemm suppression of immunoglobulin response, by nicotine or water-soluble ftaction of cigarettes, 77 Intermittent' claudicationn decrease in exercise time after exposure to CO;,28' effeet's of' coffee drinking and cigarette smoking, 20 Involuntary smoking see Passive smoking Laryngeal cancer incidence, of' second primary, im smokers vs. nonsmokers, 50 Leukocytes effects of cigarette smoke, in guinea pigs, 77;,78 Lung cancer decreased Irisk of, in ex-smokers, 4'3 and development of chronie bronchitis, 49: effects of aiu' pollution and smoking, 44, 47, effects oflasbestos exposure andlsmoking, 49 epidemiological studies, 44 histologicall types, in smokers vs. non- smokers, 44'-46'6 increase in mortality of, in female smokers, 47 summary of previous findings, 3, 5-8~ su m mary o f'recen t' findings; ,43' Mainstream smoke see Smoke streams Migration inhibition factor effects ofl alveolar macrophages„ in smokers vs. nonsmokers, 76, 77 Morbidity from respiratory symptoms, 6'2; 63 blortalityy from cerebrovascular disease by age,, sex, and smoking habit', 311 from CHD, 14 from lung cancer, of female smokers, 47 ftom myocardial infarction, 14 summary of previous findings, 3-8, 13 hlyocardial, infarction, damage to rabbits after' exposure to carbon monoxide;,29 effects' of coffee drinking and cigarette smoking, 19; 20 mortality, in smokers~vs: nonsmokers, 14 summary of previous findings;,4, 13 in Swedish women;, smokers vs. non+ smokers, 14 Naso phary ngeal cancer in smokers vs. nonsmokers,,in Taiwan, 50 Nicotine effects on epinephrine and' norepinephrine levels, 29 excretion, by passive smokers, 97' levels, effects of' room size, amount of tobacco burned, and ventilation, 91-94, 977 suppression of! immunoglobulin response, in cell cultures', 77 N-Nitrosamines N'-nitrosonornicotine, in tobacco, 48, 49 N-Nitrosoheptamethyleneimine ! incidence ofihng neoplasms, in rats, 49 Norepinephrine effects of nicotine, 29 Occupational diseases byssinosis' in cotton mill workers, 68 ' COPD, in firemen, 68' effects of asbestos exposure andlsmoking on lung cancer development, 49, lung cancer,,in uranium miners, 47 andlrysk of cancer, 4'3' smoking,andi, 68-70 Occupational hazards carboxyhemoglobim levels in workers exposed to exhaust gases, 21

exposure, to ~ chemicals, fumes„sprays, andl dUs;ts; in smokers vs:, nonsmokers, by race and sex, 69, 70 higher, reporting of exposure to, by smokers vs, nonsmokers„68 O:ral!cancer incidence of second I primary, in smokers vs: nonsmokers, 50 Parents cough and phlegm production; and respiratory symptoms in ehildren, 103' incidence of'pneumonia andibronchitis in children of smokers, 1i05'„106' prevalence of, respiratory symptoms in children of smokers, 102„ 103 Particulate matter pollution levels in four UIS. locations, 65, 66 Passive smoking CO, nieotine, benzo(a)pyrene, acrolein, andlacetaldehyde levels, 90-95 effects on bus and plane passengers, 102 effects of carboxyhemoglobin levels, in persons with angina pectoris; 95, 97 effects of carboxyhemoglobin levels on CO' absorption, 95,96 effects of CO in tobacco smoke on psyehomotor performance, 99401 effects of tobacco: smoke constituents, 88-98' excretionof nicotine, 97' exposure to cigarette smoke, and development of eye and' throat~ irrita- tions, 99,,100 incidence of'~ pneumonia and bronchitis in. children of parental smokers; 105'„ 106 maternal smoking, andl development, of bronchitis and pneumonia in infants;. 103'„ 104 parental cough and phlegm, production,, and respiratory symptoms in children,, 103' pathological studies, 99 prevalence of~ respiratory symptoms in, childten of:smokers, 102, 103 summary of:previous findings, 87, 88'' summary of recent findings„107„ 108 Pathological studies effects of exposure : to ~ cigarette smoke, in passive smokers, 99 Pathophysiological studies alveolar macrophages and smoking, 76177 effects of' cigarette smoke on leukocytes, in guinea pigs, 77, 78 effects of cigarette smoke an pulmonary macrophages, in guinea pigs,, 77, 78 effects of' smoking an tracheal mucous velocity, in dog$, 78 suppression of immunoglobulin response by nicotine or water-soliible fraction of cigarettes, 77 Pharyngeal cancer incidence of second primary, in smokers vs. nonsmokers,,SO. ' 1116 Phenotypes partially deficient: heterozygote„in COPD etiology, 73, 74 Phlegm production by parental smokers,, and development of respiratory symptoms in children„103' production, by parental smokers; and' incidence: of' pneumonia and bronchitis in children, 105„106 Pinocytosis decrease in alveolar~ macrophages„ inn smokers vs. nonsmokers, 76 Pipe smoking autopsy studies, in smokers with emphy- sema; fibrosis, or thickening of arterioles or, arteries, 75 summary of previous,fmdings on effects, 4,13 relationship to cancer, 43, 44 Pneumonia incidence in children of smokers, 105s 106 maternal'i smoking„ and development in infants, 103' in passive smokers, summary of recent findings, 108' Polynuclear aromatic hydiocarbons: tumor initiators in tobacco„4'8' Pregnancy carboxyhemoglobin levels in fetuses, 26, 27 maternal smoking, and development~ of' bronchitis and pneumonia in, infants, 103,104 summary of'previous findings, 5, 6 Psychomotor performance effects of CO in tobacco smoke„99-101'' in passive smokers, summary of recent findings, 108' Public transportation, effects of passive smoking ow bus and plane passengers, 102' Pulmonary function abnormalities,, during virali illness, in, smokers vs, nonsmokers, 6'3: closing volume abnormalities, as, indicator of smalliairavaysdiseaae, 71,, 72, decline in f'orced expiratory volume;, in smokers, by race„72 prevalence of deficient heterozygote phenotypes, in smokers vs. nonsmokers, 74 small airways disease,,smoking and,,71,, 72 summary of recent findings, 78 Pulmonary macrophages effects of cigarette: smoke, in guinea pigs, 77„78' summary'of recent findings, 78 Pulmonary symptoms effects of air pollution exposure levels on telephone workers, 67 Respiratory symptoms see also Cough, Phlegm

in~smokers vs: nonsmakers„62, 63 summary of previous findings, 5 summary of previous findings on relationship to passive smoking, 88 summary of recentfindings', 78 Sidestream smoke see Smoke streams Smoke streams CO levels iw mainstream cigar smoke, 90 constituents of'tobacco smoke, 88-98 summary of' previous findings, 87, ,88' Smoke, cigarette carcinogenic content of', 48 and decrease in pulmonary macrophages, in guinea pigs, 77; 78 effects on tracheobronchial clearance, in donkeys, 78 suppression of immunoglobulin response, in cell cultures:, 77' Stnoke, tobacco effects of constituents on passive smokers, 88-98' summary of recent findings, 108 summary of previous findings: on relationship to passive smoking, 87„ 88 Smoking, maternall during pregnancy, and development of bronchitis and pneumonia in infants,,. 103,104 Sudden deathh reductiow of' risk of,,in cigarette smokers, using clofibrate, 32'. Sulfur dioxide pollution levels in four U.S. locations,,65, 66 Tars, cigarette summary of'~ previous frndings on effects on smokers, 5'. Throat irritation effects of' exposure to cigarette smoke, im passive smokers, 99 Thrombogenesis effects of'smoking, 32' Tiracheal, mucous velocityy effects of'smoking, in dogs, 78' Tracheobronchial clearance effects of'cigarette smoke, in donkeys,,78'' Tumorigenic activity in experimental animals„48' of' polynuclear hydrocarbons and tumor accelerators, 4'8 Twins air pollution exposure levels and respira- tory symptoms, 67 mortality from CHD, in smokers vs. nonsmokers, 14, 15' Ventilation effects on constituents of tobacco smoke, 90-95 Ventricular premature beats effect of cigarette s,making; 20 Water soluble fraction of cigarettes, suppressionn of im munoglobu6n response; 77 Women autopsy studies, in smokers vs, non, smokers with emphysema, fibrosis; or thickening of arterioles orart!eries; 75 exposure to chemicals, fumes;,sprays; and! dusts, ini smokers vs. nonsmokers, 69, 70 incidenee, of! lung cancen in, 43 increase in mortality from lung cancer, 47' myocardial infarction, in Swedish smokers vs. nonsmokers, 14 summary of previous findings on effects of smoking, 5-7 117

CUMULATIVE LNIDEX 19fi4-1975 Since the original report on the health consequences of smoking in 1964 entitled Srnakingand'Healtli, Report of' the AdvisoryCorn-rrliz'tee to the Surgeon. General of'the Public Health Service, eight additional reports on the topic have been prepared for the U.S. Con- gress. The nine reports are for the years 1964, 1967', 1968, 1969,, 1971, 1972, 1973, 1974, and 1975. Tofacilit'ateuseof this accumulated scientificeviden¢eon the health consequences of smoking, the following cumulat'iive index of tiheni~nsreports: . was prepared. It should b~enoted that beforet~hiscumul'ativei'nd'ex,, the 1964and 1965: Eteports:.hadl not been indexed; thus, this compilation provides the only indexes for these two re- ports. The concept headings in this index are essentially the:sarne as those used in the individuall report indexes. However,, an effort was made: to use only one terrn, per concept and to select the most corn- monly usedd terrrli'nologyin the scientific literature for the: concept. The, userofthisind'exis referred! to information in the different reports by the reportl year followed by the page numbers in that re- port. The year of the report is set in boldface type to stand out fromi thepagenurnbers. The foTlowing,excerpt from tiheindexexemplsfiesthis: Abortion, comparison of stillbirth and neonatall deathiwith, inismoking and nonsmok- ing mothers year 71 pages, effect' of'maternal smoking, 71:13; 72:5, 84, 85s 73r.123,124 71:390,405-406 (This entry refers the user to the 1971 Report, pages 390, 405s and 406.) 71:13; 72:5,84,85; 73:123-124 (This entry refers the user to the 1971 Report, page13; to the1972'. Report, pages, 5,, 84, and 85; and to the: 1973 Report, pages1i23 and 124.) ils

INDEX (Cumulative 1964-1975) , Abortion comparison, of stillbirth and neonatali death with, in smoking and nonsmok- ing mothers 71:390„405-406' effect of maternal smoking 71:13;J2i5, 84, 85; 73:123, 124 frequency, and cigarette consumption 72:85 Absenteeism smoking,and! 67: l i9 Abstinence, syndrome. 64:352. Aeademic underachievement 641:372, 373 Acenaphthylene in cigar, pipe, and cigarette smoke 73i1178 Acenapthene 64:55 Acetaldehyde 64:52', 60, 61 as ciliatoxic agent inicigarette smoke. 73:5'11 levels, effects of' room size, amount of tobacco:burned and ventilation 75:91-94', 98 as suspected contributor to health,haz- ards of smoking 72:145 Acetic acid as ciliatoxic agent 67:107-108 inSobacco smoke 67:107-108 Acetone 64:52,60 as suspectedlcontiibutor to health haz- ards of smoking 72: 14'5Acetonitrileas suspected!contiibutor to health haz- ards of smoking, 72:145 Acetylcholine effect on,nicotine pharmacology, 67 `.60 sensitivity to 64:69 Acetylene 64:60 Acidosis metabolic, maternal smoking effect on infant. 71:407' Acinus smoke clearance from 64:267', 269 Acrolein; 64':60,61,266,268 ciliastatic effect from, 64:266,267„268' as ciliatoxic agent 67:107-108' effect on Dunaliella bioculata 69':422 effect on respiratory tract. 64:266,267, effecxon respiratory,tract,in rats, 74:104 effects of'inhalation of, in rats 75:29 as irritant in tobacco smoke 72:101 levels, effects of' room size, amount of tobacco burnedland'ventilation 75:91'-94', 98 as probable contributor to health haz- ards of'smoking 72:144 Acrylonitrile as suspected contributor to health haz- ards of'~ smoking 72:145 Additives, tobacco see Tobacco additives Adenocarcinoma beryllium induced' 64:166 classification ofl 64:173 hydrocarbon induced 64:228'8 increased frequency of 64:35, 174, 175, 231 kidney, smoking andl 69:60 nonsmokers incidence of'~ 64;1'60, prevalence in male and female smokers and nonsmokers. 71:25'0 , relationship of' cigarette smoking to: 71:246-249, 296 risk ratio of smokers 69!56 smoking and 64:1 i59 ; 67 :107' 108 smoking,andi, for men. 69!57. Adenoma papillary, induction in rats by exposure to cigaret'tetars71 :348' pulmonary 64;34,165 pulmonary, genetic factors in. 641:34', 167pulmonury, induction in micee by ciga- rette smoke inhalation 7l :34'9 l1]~9 I

pulmonary, induction of'. 641:143 renal, relationship of smoking,to 71:296 Adipose tissue effect:o[ nicotine, in rat's 74:13 Adtenalectomyy effect,on nicotine pharmacology' 67:60 Adrenal glands catecholamine release from, nicotine ef- fects on 71:36' epinephrine discharge f'romi 64:31I8 nicotine effect on 64:69 Advertising curtailment of 64:8 Advisory Committee on, Smoking and Health 64:13',,14,173'. establishment and conclusions of study by 71:3 evaluation of studies by 64:8;9,14,15,19 formation of 64:7', 8', 9 members of 64::9, 10 report on cigarette smoke and!conden- sates effects on oral cavity of animals. 71:288 Aerobic capacity effect of'cessation ofl smoking, 73:243' effect of exercise'andismoking, 73:243, 244 Aerosol irritation by 64;295 tobacco smoke as 64:263 Aflatoxins 64:145 Age atypical nuclei in esophageal epithelium~ arranged by smoking,and 71:379-380, bed days by,,and smoking,history 67:20-21 bladder neoplasm~mortality rates by 67:154 bronchitis mortality rates by. 67:29,92, bronchitis mort'alityratios, by 67:94 cerebrovaseularl disease mortality ratios by' 67:66-b'8 coronary disease excess morbidity rates by' 67:54 120 coronary disease: incidence rates and smoking:history by 69:13-14; 17 coronary, disease incidence, rates by 67<54, 58 coronary disease morbidity ratios by 67:54 coronary'disease mortality rates by 6T.25-26, 50 coronary disease mortality ratios by 67:26, 47, 49, 51-52;;69i 113, 18' coronary thrombosis' mortality by 67:26 current: cigarette smokers by sex and 71!:6; effects on iCH,D7C:27-39 emphysema mortality rates by 67:29, 92, emphysema mortality ratios by' 67:94 esophageali neoplasm mortality' rates by. 67:1500 esophageal neoplasm mortality ratios by 67:150 expiratory flow rate by 64:291 forced expiratory volume by 64':291' increased smoking by. 64:361, 362 laryngeal neoplasm mortality rates by 67:148-149 larnygeal neoplasm mortality ratios by 6J:148-1!49 liver cirrhosis mortality rates by 67:184 liver cirrhosis mortality ratios by 67:184 lung functions for smokers vs. non- smokers,by 67:100 lung neoplasm mortality rates by 67,:134438, 140 lung,neoplasm mortality ratios by' 67:134-1364 138, 14'0mortality ratios by 64:36, 87 mouth neoplasm mortality rates by, 67:146 mouth neoplasm mortality ratios by 67:145'-146' nonsmokers by 6'4:1n 7 pancreatic neoplasm mortality rates by. 67:1'5'8-1599 pancreatic neoplasm mortality ratios by 67':158.1599 peptic uIeer.mortality rates by 67:181 peptic ulcermortality ratios by, 67:181 peptic ulcer mortality ratios for smokers vs. ex-smokers by 67:18'l pharyngeal l neoplasm mortality rates by 67:146 H

pharyngeal neoplasm mortality ratios by 67c146 pulmonary fibrosis by 64!:274 respiratory symptoms in smokers vs. nonsmokers by 67:96•98, 100 restrictedl activity days by„and smoking history 67c2'0-2'1 smokers by 64!:11', 7' smoking and, effecti on clinical labora- tory tests in healthy male veterans. 73:111 statistics, errors in 641:117, 1118 stomach, neoplasm imortality rates by 67:157 stomach neoplasm mortality ratios by 67c157 stroke mortality rates by. 69:13s,17, stroke, mortality ratios by 69:13' urinary tract neoplasm, mortaGty rates by 67:154 urinary tract neoplasm mortality ratioss by 67:154 urogenital neoplasm mortality'ratlos by. 67:154 work-loss days by, and smoking his,tory. 67:20, 211 Age-adjusted death rates 64:31I, 36, 82, 84„100, 101 by country 64:127in,heavy smokers 64:100 in males 64:95; 101,127in,nonrespondents 64:114: sex ratios in 64:133' in,survey respondents 64:1141 in United States 64:127 variables af fecting' 64:100 weighting of 64:1 14! in white males 64:95: Aged prevalence of COPD in, smokers vs. nonsmokers 74:78' Age started smoking'64:89, 111, 361, 36'2', 368, 371-3741, 376 lung neoplasm association with 641:15'8'; 230 mortality rates and 64:29, 158' mortality rates in Japanese by 73:7„8'. socioeconomic factors in 64I:368'. Agricultural workers 64:290 Air pollution 64:150, 177, 186, 195; 232, 295, 296, 297„298' arsenic in 64c611 and bronchitis, in smokers vs. nonsmok- ers 73:36; 37 bronehopulmonary effects on smokers vs. nonsmokers 68:69 carbon monoxide from cigarette smoke 72:7„121-1123', 125 as cause of chronic bionchopulmonary disease 67:29, 108-1100 as cause of'COPD' 71:15'2; 175, 216-217 in chronic bronchitis 64!:297;, 298 ciliastasis: from 64l•26'8'' effect of exposure levels on respiratory symptoms in twins 75:67 effect on mortality rates from lung cancer 73:73 effect on nonsmokers 72:121-125 effect ossmokers 67:108'-110 and emphysema 64:297' in etiology of bronchitis 67 `.108'-110 in etiology'of emphysema 67:108.110 in etiology'of lung,neoplasms 64:172; 67:140;, 68!98„ 99; 71:11,. 276;73:72,7,3 exposure levels and coal consumption 75;67 exposure magnitude in. 64:296;297,298 and' human CO burden. 75:20 levels, exposure of telephone workers and pulmonary symptoms 75;67 lung damagef'rom~ 64:3011 in Osaka,laparr 73:44 prevalence of respiratory diseases and 73:44 relationship off lung, neopiasms, smoking and place of residence 7 I1:252! 255' respiratory diseases in 64:295'-298' I II 0

smoking and, in COPD development 74:82',83;,75:63-68 smoking and„in lung neoplasms develop- ment 741:4'5, 46; 75:44, 47 smoking, and; in military and civilian aircraft 73`.45' sulftrr dioxide in 64:295 summary, of recent findings 75:1I08' survey data for four U:S.locations 75':63-66 tobacco smoke as a factor 72:7, 1'21-124' "Tokyo-Yokohoma asthma" from 64':276 urban-rural effects,of 64:298 Aii~ quality standards for, carbon monoxide 72:128 Airway conductance 64:292 Airway obstruction emphysemalin 64:297 measurement of 64:292 ozone induction of 64:296smoking effect on 64:292, 293, 297, 300 sulfur dioxide effect' on. 64':295 Airway resistance to smoke inhalation in guinea pigs 68:72 Airways, large effect ofl smoking one nonfilter cigarette 74:99 Airways, small abnormalities, in smokers vs, nonsmok- ers, autopsy studies 74:97, 98 dysfunction of; in smokers 75:71 effect ofl smoking one nonfilter cigarette 74:99 function during viral illness; inismokers vs. nonsmoke,rs. 75:62', 63 A'Ibanyprospective studies 64':323,325~ Alcoholl ethanol, penetrability of dissolrfed benzo(a)pyrene in mice esophageal epithelium, 711:293'. Alcohol consumption 64:91, 101, 224, 302, 385 effect on esophageal neoplasms in smok- ers 711:289~ 29~3effect on laryngeal neoplasms in tobacco users 711:2800 effect on mortality rates, from esoph. 12~2' ageal neoplasms in Japanese males 72!:711 effect on tobacco amblyopia 71:435-436' in esophageal neoplasms 64r213;217,218' in heavy smokers 64I:342' and heavy smoking, effect, on, oral neo- plasms 71:288 interaction with smoking and other, risk factors in CHD 1 73:10, in laryngeal neoplasms 641:210, 211 in liver cirrhosis 641:342' in oral neoplasms 641:20+1 smoking and, in esophageal neoplasm etiology 6T:152; 71:3, 68, 70„71; 73:76, 200 smoking and~ in laryngeal neoplasm eti- ology 73:197' smoking and~ in, neoplasm development 73I:76{ 200 smoking and~ in oral neoplasm etiology 68:100,101;,73:193;74':53'-55' smoking' andl, in relation, to cirrhosis: of liver, 67:40;185 in tuberculosis 64:277; 71 :172 see also Alcoholism Alcoholic beverage workers, neoplasm risk ratios in 64:134 Alcoholics Anonymous 64:354 Alcoholism mortality in, relation to:smoking67:10;184 patients, smoking,and ventilatory func- tion,in 7I :21'3' Alcohols, aliphatic 64:51. Aldehydes 64:52, 296 Aldrin 64:62, 145 Alkaline dusts 64:298 Alkaloids 64:541 Alkaloids, tobacco andlexperimentafbladder neoplasms: 69:64 RI-AI kanes 64:51 Alkylbenzenes 64:55 Alky, lphenols641:54 Allergy effect on cardiovasculanabnormalities, 72: l 1I11

tests of 64:276 tobaccoand' 72':7,103-11. tobacco-induced 64:276„301, 319 tobacco smoke irritants and 72:1ai0 Alpha-li-antitrypsin deficiency COPD predisposition from 71':15'0, det'erminationi using, immunoelectro- phoresis 71:151. in emphysema etiology 71:10-11;72;110 smoking and 72;110! smoking,and, in COPD etiology 741:87-90; 75:72-74 Altitude effect on arterial oxygen tension 72;22 Aluminum in main stream~smoke 64:55' Alveolar bone loss smoking and 69:85 :-87 Alveolar macrophages see biacrophages;,alveolar Alveoli see Pultnonary; alveoli Amblyopia, tobacco 64:39,,73', 341,,342' alcohol consumption effect on. 71:435.43i6 characterization of 71:4 35 and cigar smoking 67:39 devedopmen: from cyanide componenti of tobacco smoke 71:14; 72:6 diet and 72:6 effect on optic pathways 67:183 incidenceof79:4'35 pathogenesis 67:183' and pipe smoking 67:39 potentiationW cyanide toxicity by vita- min B-12 deficiency in 67:183' smoking, and 72:6 vitamin B deficiency and tobacco smoke in 67:40, 183 American Cancer Society 64:6, 7,,81, 93', 96, 101, 363 American College of Chest Physicians 64:8' American Heart Association 64:6, 7. pooling project amCHD 71I:23, 28, 30; 39. American,P+~]edical Associat'ion, 64:8 American iThoracic Society 64:275„278' 279 Amino acids 64:54 Aminoazo dyes activity in placenta of smoking mothers 71:410 o-Aminophenols concentration, in urine ofcancer patients and smokers 69t64 experimental bladder neopl9sm induc- tion 67`.1156 Ammonia 64'':60; 61. eiliastatic effect of'. 64:268 as suspected' contributor to health haz- ards, of'smoking 72c145 Am phe tami ne 64:71. Anabasine 64:49 Analytic methods arsenic determination 64`.61, 62 fluorescence properties 64:511 mass spectrometry 64:51 paperchromatography. 64:5ii ultraviolet absorption 64':511 Anger personality traits, smokers 64:326 Angina pectoris 64:275, 319„320, 323„325' carbon monoxide exposure and 74c11,12 carbon monoxide inhalation and 73:17, 18 coffee drinking, smoking„and 74:8 and coronary disease incidence, 67:53' effects of increased, carboxyhemoglobin levels, in passive smoke'rs. 75:95', 97 Health Insurance Plan Study and inci- dence in males 68:19, 20 and heavy cigarette smoking;,findings of Framingham Heart Study 68,19 incidence in iItiJorwegian men 68!L9 incidence inipipe and cigar smokers. 73:215' incidence rates and smoking histon 69:2'1-22 1'_3

morbidity ratios 67:59 morbidity ratios among persons 30-59 years old 68:20 smoking andl 69718;,74c8 smoking,andl intwins 67`.59;,69!25;72`.18 Aniline dyes 64I:2'22' Animals esophageal neoplasms in„ induction by nitrosamines 71:292 experiments, as evidence. 64:26 respiratory tract of, neoplastic changes following cigarette smoke: inhalation 711:23$-239 skin of, carcinogenicity of tobacco tars 711:238, 267, tests of, with smoke carcinogens 71:12 ventilatory function change from smok- ing 71:10 Annandale study, 64!:286 Anoxia 641:70;344 cerebral 64:70 effect on myocardial tissue function 68!3840, 43 relation to smoking 67 `.183 Anthanthrene 641:14 7' Anthracene in cigar, pipe, and cigarette smoke 73:128 oil, carcinogenic activity of 64c147. Anthranilic acid; 3'-hydroxy- urinary excretion of, smoking effects on 711:296 Anticarcinogens 64:143; 144 Antidiuretic hormone 64:69„320 Antigen-antibody reactions allergy and 72:,103-107' smokers vs:. nonsmokers: 72:7, 1105'„Tl1 tobacco andi 72:7, 1104-107Antigenic properties oftobacca 64:319 Antigens effect on alveoiarmacrophages; in smok- ers vs. nonsmokers 75':76„77 Antioch College study 64c370, Antismoking campaigns 64::354 Aortic aneurysm mortality, far, men by amounti smoked. 69:16 mortality rates 64:1,03; 325;67:6'9~ mortality ratios 67:69' nonsyphilitic, mortality rates, smokers: vs., nonsmokers 72:2 smoking and 67:27; 71:9, 67, 71, 75' Aortic arch reflexes 64:70 Aortic bodies, nicotine induced stitnulationiof' 64;317' Appetite reduction 64:71,,355 Arecalnut see Betel,nut Arecoline 64:351. Argon in gas phase,,in ~ smake 64:60 Aromatic alturhols 64'': S 1 Aromatic compounds carcinogenic properties in cigarette smoke from 71':264',265 detection in, urine using chemilumines- cence technique 71':297 polycyclic, carcinogenicity of'~ 64:142, 146, 165, 166, 189, 229, 230: polycyclic, pyrolytic formation of' 64:59 polycyclic, structure of 64:54, 56 stimulation ofl placental' BP-hydroxylase activity in pregnant rats by. 71':414' Aromatic hydrocarbons 64:55 carcinogenicity 67c 1'29; 69:61, rale in lung neoplasm development. 74:49-52 in tobacco smoke, 64:55;67:127 Aromatic hydrocarbons, polycyclic binding,to DNA and RNA 73:86; 87 effect, during pregnancy in laboratory animalS 73~:117', 1118 effect on tobacco carcinogenicity 72:66 maternal-fetal exchange and 73`.119, tumor initiators in tobacco 75:48 ao 124

Arousal effects nicotine induction of 64!:70; 350 Arrhythmias formationi in nicotine stimulated dam- aged myocardium 71:58 nicotine toxicity in 641:73 smoke induction~of 641:319' smoking and 69:4 Arsenic 64:55, 61, 62 carcinogenicityof, 64:167 determination of 64:61, 62 lung neoplasm mortality in smelter workers exposed to 71:257 lung neoplasm risk from 64:193', 194 respiratory tract carcinoma in workers exposed to 71:256; 257 Arterial diseases carboxyhemoglobin levelS and 72:26: smokers vs. nonsmokers 72:26~ smoking and 72c25; 26 see also Arteriosclerosis; Atherosclerosis Arteries 64; 274 aneurysm in aortic, cigarette smoking effectson 71:9„67; 711, 75 atherosclerotic„ increased by cigarette smoking 71:8, 61 flow ofl carotid; cigarette smoking effects on 71:67 hypoxemia, development from cigarette smoking 7P~:9 occlusions o[,,cigarette smoking effects on 71:73 thickening of, in smokers vs: nonsmokers 75:74-76 walls of, mechanism of lipoprotein infil- tration 71:63 walls of,,nieotine-induced necrosis 71:63 Arterioles effect ofsmoking 73:22,23~ thickening of,in smokers vs. nonsmokers 75:74-76 Arteriosclerosis 6:4:321 320-325 in aorta and coronary arteries, cigarette smoking effects on 71:45; 52-56 aortic 69:26 autopsy studies and 72:19;20 cigarette smoking effects on 71:8 cigarsmoking and 72?19, coronary 69:26: coronary, mortality rate in 64:317;320„321 development by increased carboxyhemo- globin formation 71':9 development of, carbon monoxide ef- fects an 71:63 development of, effects ofnicotine on 71:38' and effect ofsmoking on bloodlcircula- tion 67:62 experimentally induced in dogs 72`.19„20 experimental studies 69:26-27 hypoxia and, hyperoholesteTolemia in 69:26 lesion developmenYin, smoking enhance- ment 71:36 mortality rates 64:25;67<26 obliterans 64:326, obliterans,,smokingas a cause 73:19;20 pathogenesis of;relating to smoking 67:65-66 peripherali cigarette smoking effects on 71:72.73I; 73:21 pipe smoking and 72:19 severity of, and smoking 69:26 smokers vs: nonsmokers 72:19, 22, 23„27 smoking and 67:28;69:4-5 smoking classification and 72:19 see also Atherosclerosis Arthritis, rheumatoid pulmonary functiom abnormalities, s,moking;andi 74:92; 93 Aryl hydrocarbon hydroxylase effect ofbenzo(a)pyrenein pregnantrats 73:119 role in lirng neoplasm development 74:49-52; 75:50-53

role in metabolism of'~ chemical'carcin- effects on bronchoconstriction m dogs ogens 71:163'3 73:82; 83 mucus secretion blockage by Asbestos 64;269 chrysotile; effects on lungs 75:49' Atypical cells 64:231 effect on pulmonary, function in smokers vs. nonsmokers. hyperchromatic nuclei in 64,:34 73:41 smoke+induced, in epithelium effect on radiological findings in smokers 641:168', 169,,170, 172, 173 vs. nonsmokers. 73:411 Australia COPD morbidity in,smokers in effect on respiratory symptoms in smok- 71:203' ers vs. nonsmokers 73I:411 coronary death rate in 64:320 pulmonary fibrosis and 72:44 laryngeal neoplasms in, relationship to tobacco use. smoking and, effect, on mortality rates 71:357 from lung neoplasms. 73':73' lung neoplasms death rate, in 64:176 1' synergistic effect with smoking, in lung, retrospective studies lung neoplasms in 4 ' neoplasm ~development 74:41-43 , of Asbestosis 64:167 711:327 peptic ulcer in, methods for retrospecr in, smokers vs. nonsmokers, asbestos workers in Singapore 74:95 tive and cross-sectioni studies of smoking and 71:426, 4'28'. Asbestos workers 64:1'93; 232; 74:95 Automobile driving 64:322 Y 1i Asia 1 Central and Southeas!, relationship of tobacco use and neopVasms of orall Autonomic:nervous system effect of nicotine on 67:60 r cavity 71:366 Autopsy studies. 64:150' f Asthma bronchial, cigarette smoking effects on, arteriosclerosis and 72:19,,20'. 71:10, 175 bronchiolitis development and smoking cigarette smoking in 64:38, 302, definitionlof 64:27 smoking and 67:29;72:37 tobacco allergy in 64:276 "Tokyo-Yokohama" 64:276 Atelectasis 64:272' Atherosclerosis 64;318s319,320 aortic, long,term smoking effeets. 71:52-5'6 coronary blood' flow in, in rabbits 64 ; 3i!8 experimental indbction of, in rats 64c3P9 see also Arteriosclerosis Athletic performance running, effect of smoking 73:243„244 smokers vs. nonsmokers 73:243'„244 swimming„effect of smoking 73:244 Atropine 64:354 126 75!74,,76. COPD and smoking 73A5'48' coronary heart disease and 72`.1I9„20. emphysema development and smoking 74;97;75:74-76 fibrosis development and smoking 75!:74-76 lung neoplasms in U.S: vet0rans 73I:73; 741 mucous gland abnormalities and smoking 741:97' small airway abnormalities and smoking, 74!:97; 98 thickening of arteries, arterioles andd smoking 75:74-76 Aviatorss prevalence of CHD 68:19, smoking effect orcbload!pressure 68': 22' Bacteria effect ofl cigarette smoke on action ofl macrophages. 71 :165' .:.;~*

pneumonia, mice resistance following cigarette inhalation 71:173 Bacterial flora~ in smokers vs. nonsmokers with COPD 73I:54 Ballisrtocardiography 64:319 findings in cardiac disease after cigarette smoking 68:3'7' Bank employees chronic cough in 64:281 Barbiturates 64':352 Bartenders esophageal neoplasms in 64:134 oralineoplasms in 64:134 Bauhinia 64;21'1 Bed dayss by age, sex,and!smoking,his3ory 67:19-21 definition of 67:19. Behavior and coronary disease 67:56; 69':20, 24 of heavy smokers 64:372 patterns, in smokers vs. nonsmokers. 68':26'-28 Behavioral researchh smoking habit. 67':38„188'-192 Belfast lung neoplasm mortality in. 64:195 Benz(e)acephonanthrylene carcinogenic properties in cigarette smoke from 71:264; 265 see also Aromatic hydrocarbons Benzanthracene (9-10 dimethy111, 2-)i 64;203 Benz(a)anthracene alcoholic solution of,, penetrability of mice esophageal epithelium 711:292' carcinogenicity 67:127, carcinogenicity„ as component of ciga- rette smoke 72:66 imtobacco:smoke 67:127 Benz(a)anthracene, 7,12-dimethyl carcinoma induction in hamsters follow- ing instillation of 711:346' skin painting witH, papilloma and carci- noma induction in mice by 71:341 see also Aromatic hydiocarbons, Benzene 64':55,59 as suspectedl contributor to health haz- ards of smoking, 72:145' Benzocaine lozenges 64:35'4 Benzo(b)flhorantHene carcinogenicity 6T:1277 in tobacco smoke 67:1127 see also Aromatic hydrocarbons Benzo(j)fluoranthene 64:57 carcinogenicity. 67:127' carcinogenic properties in cigarette smoke f'rom, 71 i:265' see also Aromatic hydrocarbons. Benzo(k)tluoranthene carcinogenicity 67:127 in tobacco smoke 67:1277 see also Aromatic hydrocarbons Benzo(rst)pentaphene carcinogenic properties in cigarette smoke,from 71:265 see also Aromatic hydrocarbons: Benzo(g;H,i)perylene 64!:147 carcinogenicity 67':ll27 in tobacco smoke 67`.1127 see also Aromatic hydrocarbons Benzo(c)phenanthrene64;56 carcinogenicity 67:127' carcinogenic properties in cigarette smoke from 71i:265in tobacco smoke 67:127 see also Aromatic hydrocarbons Benzo(a)pyrene 64:147,,,148', 233 ability of smoking mothers to, hydroxy- late 71':407 asainpollutant from cigarette smoke, 72:123 and air, pollution„ in lung neoplasm development 74<45', 46 alcoholic solution of, penetration of miceesophagcafepithelium 711:292 carcinogenic effeet, in~lahoratory animals 73:78-80, carcinogenicit'y,of 64:33',144,145',146:67:127 l1_'7

carcinogenicity o[„in relat'ton to asbestos in hamsters 71:2577 carcinogenic properties in cigarette smoke from 711:264„265' carcinoma induction by. 64:1166 in cigar, pipe, and cigarette smoke 73a77, 178 cocarcinogenic effect on respiratory tract in rabbits 72`.67 determination of 64:57 detoxification by lung aryl hydroxylase 71:257 effect on DNA and RNA. 73`.86; 87' effects during pregnancy in,laboratory animals 72:89;73I:117,118 effects of instillation or implantation in animal tracheobronchialltree 71:346-347 effects on animal tissue and organ cul- tures in 71:343•345 effects with i influenza, virus on cigarettee inhalation by mice 7,1:352 iniethanol, effectton esophageal, tissue 67:153-154 hydroxylation by pulmonary benzo• pyrene hydroxylase 69:62 hydroxyl9tion by the placenta 69:80; 72:89 isolationiof' 64:55 levels; effects of room size, amount of' tobacco burned' and' ventilation 75:91-94; 98 in olive oil, effect on esophageal tissue 67:15'2.153oral neoplasm induction by 64:203;204 pyrolytic formation of 64:59 reduction of,,by copper nitrate, 64:60 role in,respiratory tract'carcinogenesis,t in ~ animal9 74:46„47 sarcoma induction in rats following in- stillation of' 71:346 skin, painting, with, papilloma induction in mice by 71:337-338 in smoke streams 72`.123 in soot. 64:148 squamous cell carcinoma from 64;166 structural formula of 64:56 128 threshold levels of 64:143 intobacco smoke. 67:127 fiomvegetable fibers 64:59 see also Aromatic hydrocarbons: Benzo(e)py, reare 64:147 carcinogen icity 67:127 in tobacco smoke 67:127 see alSo Aromatic hydrocarbons Benzopyrene hydroxylas:e inhibition of nickel carbonyl in cigarette smoke 69:62 Beryllium 64!:55 carcinoma~induction by 64c166 epidermoid neoplasms from 64:1666 lung neoplasm risk from 64:193 oxide 64:166 sulfate aerosol 64,:166. Betanaphthylamine content of cigarettes 69:64 Betel nut. 64:203, 349; 351, Betel nuti chewing. 64:2111, 351 in ~Bombay, India72:69. inhead and neck neoplasm etiology 72:699 laryngeal neoplasms from 64:2111 oral neoplasms from 64':197; 711:366; 369-370, smoking and. 72:699 smoking,and oral leukoplakia 69:58 and tobacco chewing, 64:203 Biased measurements 64:36; 98' Bicarbonate in pancreatic secretions, effect of smok- ing 73:159,160 Bieyele, ergometer performance cardiovascular parameters in,smokers,vsn nonsmokers, 73':242-244 Bioassay methods in carcinogenesis 64!:59; 143, 147' Biometry Branch, National Cancer Insrtitute, 64:137, 138; 139 Biri 64':211I

Birth weight, in men„relation to smoking effect of maternal smoking 64:39, 343; 67:39, 185-186; 69t5, 67:153 morbidity; effect of smoking'on 77-80;,71:389,397-399;72:5,,83'.87; 73:103-114, 119-122; 75':27 67:155 mortality rates effect of maternal smoking before and 64;1133',148, 149; 71:293; 294 during current pregnancy by cigarette consumption mortality rates, female 64:132,, 137,, 219,, 220, 221', 224, 73:107-109 225;67:1541 effect of maternal smoking during pre- mortality rates, foreign-born' vious pregnancies 64':134 73:112•11'4' mortality rates, male effect ofl paternal smoking: 64'<130, 132; 137; 67~154 73c1110;,111 mortality ratios effect of tobacco smoke, nicotine, or, 64:148, 149; 222; 6'7:33 carbon monoxide in laboratory ani- mals 73:114-118 gestation duration in smokers vs. nan. smokers 73:103-106 mortality risk of'low birth weigHt,infants: of' smoking vs. nonsmoking mothers 73:126-1322 timing of:influence of smoking: 73:120, 121 Bitters 64:354 Blacks maternal smoking,and infant weight~ 71:397 maternal smoking and prematurity 69:78; 711:400401 Bladder neoplasms 64:37, 218-235 aniline dyes in 64`.222': blood groups in 64:224 carcinogenesis, tobacco smoke canstif- uents and tars 67:15'6~ cotinine and 69:64 dose effecti in 64:223 experimental aspects of'. 69:64 experimental induction by hydto< quinone 67':156 experimental induction by 3-hydroxy- anthranilic acid 67:156 experimental induction by 3-hydroxy- kynurenine 67:156 experimental induction by ortho-amino- phenols 67:156 experimental induction by tars 64<219,223 experimental induction in mice 64:223' frequency in smokers vs. nonsmokers 71':238', 293-295; 73-77, 78' in;heavy smokers 64:219,224 mortality ratios, male smokers by age, 67:1541 mortality trendS, by sex. 64:137' occupational risk 641:134; 222,224 relationship of cigarette smoking to 71:13, 299 relative risk in females by amount smok- ed 72:73' relative risk in males by amount smoked 72c72; 73 relative risk ratios from,,in smokers 641:223 retrospective studies of, and smoking 64:218-222; 71:293, 381-384 sarcoma 64s223 smokers vs.,nonsmokers 72:293-295, 381-384 smoking:and 64:32; 67:33; 69:60, 64;, 72:68„ 72-74 smoking in etiology of'. 72:5 t 73:77„78 and tobacco alkaldids 69:64 and tryptophan metabolites:in urine 67:36, 1156;,71:296•297 urban-rural prevalence of 64:225 U.S. incidence of 64:127' in women 64h132',219,220,221i,224,225 see also Uragenital lneoplasms Bladder stones 64;224: Bloodd gas exchange in' 64:292 groups, in bladder neoplasms 64:224 plasma, and thrombus formation 69;27-28' Blood chemical analysis comparison for, smoking andl nonsmok- ing mothers and their infants 69:80 Blood' eholesterol levels and coronary disease 64:321; 67:58; 7'1:21-22', 23'-24, 43 129

and coronary disease mortality 69! 177 effect of' carbon monoxide in rabbits 73'.1J8; 75:28 effect of diet. 641:3'22 effect of smoking 67:66; 7d1:8', 41, 43; 74c 17, 18 effect of smoking and body weight 73:11 effect of smoking,and clinical parameters in British business executives 73:11I effect of smoking in peripheral vascular disease 71:72 and hypertension, in smokers vs., non- smokers 75:1,5 increase in smokers 64:326' and lung,neoplasms in male smokers. 69:57 myocardial, infarction morbidity ratios in, males from, Framingham, study 68:24 in pipe and cigar smokers 73:215', 216 in smokers vs. nonsmokers 68:22, 23, 29,,43; 711:41, 98-102' see also Cholesterol Blood circulation effect, of cigarette smoke inhalation 67:26, 63; 7l':58 effect of cigarette smoke inhalation, in, dogs: 67:62' effect oflnicotine on, 67`.60-64 effect of'smoking on 67':60-64; 69:11, 27-28; 73:19, 22, 23', effect of' variations in hemoglobin and hematocriU 71I:66 peripheral. 64:3'18Blood!coagulation clotting time 64:31I9 effect of'smoking 67':64;,71:9,,36; 74!:18; 19 Blood lipidss effectiof nicotine in rabbits 68:31 effect of smoking, 71':65-66;, I23-128; 73-11, 12; 74-17' effect of smoking and nicotine 68:30;,31 effect of smoking, and' relative weight, in male Parisianicivil servants 73:11 effect of' smoking in middle-aged pa, tients with angina pectoris 73:1p effect ofl smoking in young Norwegian military recruits 73:11 1!30 elevated, as risk factor in CHD 73:11 elevated„as risk factor in CHD 73:1,11 free fatty acids, effect of'smoking 64:319; 67:64'-65' smokers vs. nonsmokers 71:41, 98-102 and thrombogenesis 68:32, 33 Bloods platelets adhesiveness, effect of cigarette smoking oni 71:9,,36, counts 64:319 effect of smoking 67:64;69:27-28;;71:66„75 survival i 64: 3!19 Blood,pressure coronary disease 67:54-5 5, 5 8; 68:22 coronary disease and smoking 69! 1I4;;71:43, 47 coronary disease mortality and 69c 14, 17' diastolic, cigarette smoking effects 71:8, 23 diastolic, in smokers with CHD 71:21-22, 24; 42 effeet! of catecholamines on 67:60 effect of cigarette smoke inhalation on 67:54 effect of CO exposure 74:1i1, 12' effect of exercise and smoking, 73`.242',244-246 effect of nicotine 64:318!; 67:60; 7,l :36'; 74:13 effect of pipe and!cigar smoking' 73:216 effect1 of smoking. 67: 54' 55'„60; 74:17 effecT of smoking in middle-aged pa- tients with angina pectoris 73c12' high risk in mortality from CVD 71:67 hypertensive vs. nonhypertensivue„ mor- tality rates of CHD in 7'1:42' myacardialiinfarction morbidity ratios inn males. 68:24 risk factors in arteriosclerosis obliterans 71:72 in smokers, nonsmokers, and ex-smokers 75:15-17 smokers vs. nonsmokers. 68:22, 29:; 7,1:41, 42, 103'-1104' smoking and4 effects on pregnancy out- come 69:77-78 systolic, mortality from elevated, with CHD 71:42 i

Blt,od sugar elevation, by tobacco 64:355 Blood vessels effect of'nicotine an. 67:62 effect of'smoking on pultnonary, arterial capillaries 6 Z: 111 Blood viscosity and arteriosclerosis 69:27 Body constitutiow 64:321 and bronchitis 60:30; 102-103, 108 and' cough development. 67:102'-103,,111 and emphysema 67:30;111 and respiratory tract diseases 67:30 i smokers vs. nonsmokers 67:54;99 Body height effect:of maternalis:moking71:407;72:88 interaction with smoking as factor in cerebrovascular disease 7319 in respiratory function tests 64:290 Body size in male smokers vs. nonsmokers 68:28' Bodyweight, 641:3'84, 385 and coronary disease 67:58 andl hypertension, in smokers„nonsmok• ers, and' ex-smokers 75i15-17' increase in, on cessation of smoking 64:326' interaction with, smoking as factor, in, cerebrovascular disease 73:19 relationship to coronary disease mortal- ity rates and smoking 69:14 risk,factor in;CHD 68:29,43' inismokers vs, nonsmokers 68:21 and smoking, as factors in CHD inci- dence 73':4-6 and' smoking, effect on blaad!lipids 73:11 Boilermakerss neoplasm risk in 64:1341 Boston CollAborative Drug Surveillance: Pro- gram role of coffee drinking, and smoking in myocardial infarction 74:8 dowel habit's tobacco effects on 64':355 Bradycardia development'in dogs given nicotine 71,:57 Breast feeding diuationiof 64:368 Breathlessness. 64;27„38; 3011 prevalence of 64:285,2&G,267 Britain chronicbr~onchitis stvdiesin 64:271,280, coronary death rates ini 64:320 curtailment ofl advertising,in. 64:8 lung neoplasm death rate:in 64:1766 mortality rates, in laryngeal neoplasms 64!:2055 risk ratios in 64:127 urban-rurallmortality ratios in 64:186 British agricultural workers forcedlexpiratory flow rates,in 64!:290. British airpollution disease factors in 64;144,195, 2W British doctors study 64!:97; 102, 114, 162, 180, 230, 322' expectedideathsin 64:109 mortality ratios in 641:1(19, 149 nonresponse rates in 64!:113 observed death rates in 64:109' British General Post' Office 64:281,286'Btitish Medical Research Organization 64 :6 British miners: forced expiratory flow rate in 64:290 British Perinatal Mortality'Survey results of 71:390 British smokers age distribution of 64:177 cough prevalence in 641:2811 inhalatiompractices among 64!:177' Bronchii abnormalities in smokers vs. nonsmokers 72:45 histopathologic:changein 64:170 hyperplasia in 64:271

morphology definition of 64:271 641:289; 67:89 mueus secre,tion in„nicotine-induced development in infants: of maternall 64:268 smokers physiology,,imanimals and humans' 75:103' 68:71-74 diagnosis Bronchial epithelium 67:90, changes after nitrogen, dioxide,exposure; and' disability, in smokers vs. nonsmok- in animals ers 74:102,103. 73:43' changes: in, in smokers dust exposure as aifactpr 0 64:1711„1,72' 73':441 disintegrating nuclei in and emphysema 64:170 64:113, 280 effect of~cigarette smoke on etiology of 67:107, 140, 144; 69:40 64:8' effect of filtered' gas-phase' cigarette fibrotic, induction by sulfur' dioxide smoke, in rabbits 64:295 74r.104;105 incidence in British males by cigarette effect of nitrogen dioxide on, in rats. consumption 69!:41I 72:62 effect of smoking on. incidence in children of parental smokers 67:1'04,106 75':105, 106 effecCot tobacco smoke on: incidence of among smokers 67:129 69:37 histological changes at autopsy and morbidity,,and cigar smoking, smoking habit. 67:29-30;941 73:74 morbidity, and pipe smoking histological changes in cigar;, pipe„ ciga- 67:29-30; 941 rette smokers vs: nonsmokers morbidity,,and smoking 73:203, 204, 209 673, 22„96 premalignant changes in smokers morbidity„ in smoking-dis:cordant twin 73:67; 75:44 pairs Bronchial glands 67`.103 64:168 # mortality, and,smokingl Y Bronchial mucosa 67 `.3, 3'0;,90-96 effect of cigarette smoke on~ mortality, in~Uhited States 67:30;104-107;144 6719,90 effect of tobacco smoke, constitutents on mortality rat'es 67:30 67:8 29 , Bronchial Ineoplasms mortality rates by sex and smoking , experimentally induced' by cigarette classification smoke. 67:95 67:144 mortality' rates effect of cessat'ion, of ~ , risk ratio of~smokers ~ smoking,on 96 f 69:56 67c2,29,94 „ Bronchiectasis mortality ratios by amount smoked , 641: Z77-294 i 67:90-92 A inductioniof; inimice mortality ratios, cigar smokers 64:272 67:94 Bronchiolar dilations 64:272 mortality ratios in, male pipe and cigar Bronchiolar neoplasms smokers 73`.21'7',2i9 64;159 mortality ratios male smokers by a- , Bronchiolitis in male smokers vs. mount'smoked autopsy studies , nonsmokers 67:93 77 mortality'ratios, pipe smokers 75:74 76' „ , ozone induction 67:94 occupational diseases and 64:295 purulent, in mice. 72:4'2 64:272' in, passive smokers, summary of recent Bronchiolo-alveolar neoplasms findings. smoking and 75:108 73'71 post-operative, incidence in smokers vs: Btonchitis nonsmokers 64:277-294 74!:92. ' 132

i' 0 prevalence in cement and rubber indus- try workers, smokers vs: nonsmokers 741:95; 96' prevalence in Duisburg, Germany, by age andieigarett'e consumption 73:39' prevalence in ex-coal miners and non- miners by smoking habit 73:42, prevalence iniheavy smokers 641:298 prevalence in male smokers, by smoking patterns 741:79 prevalence in miners and farmers in Hungary,,by, smoking habit. 73:42, prevalence in moderate smokers 641:298 prevalence in pipe and!cigar smokers. 73`.220; 2211 prevalence in rubber industry workers,, smokers vs. nonsmokers 74:96 prevalence in smokers in, Glenwood Springs, Colorado 72'39 prevalknce ini smokers vs. nonsmokers in Bordeaux„France 73:36 prevalence in smokers:vs. nonsmokersin, mountainous and low-lying areas 73:36, 37 prevalence in smokers vs. nonsmokers in Osaka, lapan 73I:44 prevalence in smokers vs, nonsmokers in. Yugoslavia 72'.40 prevalence in smoking vs: nonsmoking yarn mill workers 73`.40 prevalence in the: elderly„ smokers vs. nonsmokers 74;78„79' prevalence in urban vs, rural population in Mongolia, 74;80 prevalence in U.S'.,,statistics 74:75 prevalence in: wool and' cotton textile workers in North Carolina 74':93 prevalence of 64:25, 288 prevalenceof;,bysex, 64:289 prevalence rates by, sex and smoking history 67:96, 99 and'respiratory symptoms 68:74 and' respiratory symptoms by smoking classification. 67:97-98' role of constitutional factors in patho- genesis of 67:30„102-103„108-109 role, of hereditary factorsin pathogenesis of 67:30, 101-104, 108 and small airway abnormalities, in smok- ers vs. nonsmokers 74:97, 98' in smokers vs: nonsmokers 68:69,70i in smokers vs. nonsmokers„ autopsy studies 73:45, 46, smoking and 69:4 smoking and', effect on pulmonary Punc+ tion 74~:80 smoking in etiology of'. 67:29, 31, 96, 103, 104-106; 69:4; 72:37 smoking vs, coal mining in etiology of 73':42 smoking vs: dusu inhalation in etiology of 73':42 summary of' previous findings on rela- tionship to smoking 74:75-78 see also Bronchitis, chronic Bronchitis, chronic 64':31I, 38{ 271, 272„277-302! air pollution in. 64:297, 298 British incidence of 64:280', 297,,298' cigarette smoking cause and effect rela- tionship 71:3; 9 cigarette smoking in 64:31,277-302I definition of 64!:278; 711:139. diagnosis of 64!:278', 280 emphysema relation to 64k279;280,297',298 epidemiology of! 64:280-294, 3011 etiology of 64 64:38, 280-294, 298, 299,, 302' histopathologjc change in 64:271, 272, 300, incidence of', in high pollution areas 75:63,64 lungpeoplasms related to 64;195';75:49 mortality in cigarette smokers 7G:175 mortality rates 64':25;68;66,67;71:139 mortality ratios in 64':29, 277; 293, 3011 mucus production in. 64',:272 occupational lexposure in 64':298,299;300,302', ozone induction of' 64;295. 133 H I I I 0

pathology of 64:271, 272;274, 275 prospective studies in 64:293, 294 risk ratios in 64:31 smokers vs. nonsmokers 71:195-205 symptoms of 64:27, 278-294 Bronchoconstriction from cigarette smoke in animals 68!72 Btonchogenic carcinoma see Carcinoma; bronchogenic Bronchopneumonia development in dogs following cigarette smoke inhalation 71!:271 Bronchopulmonary diseases, chronic ob- structive 64!:272', 277-297, 298 ain pollution relationship in 64:38;,71:15'2, 216-217 alpha+l-antitrypsin deficiency and 72`.3„4'4 autopsy studies 73`.45-48' as cause listed' on death certificates vs. findings at autopsy. 73:47 characterization iof 71:139: cigarette, smoking effects on develop- ment 71:4,9-11,175 definition 67:89-90 disabilities from 64;277 effect of smoking, cessation on develop- ment 71:10, epidemiology 64:280-294, 297, 298; 73`.36.45'5 epidemiology'in Tlecumseh„84ichigan , 72;39,40 genetic factors in : pathogenesis of' 71:148, 150-152, 205 increasedlprevalence, of'heterozygotes in 71:151-15'2, morbidity, smokers vs: nonsmokers in. Berlin, New Hampshire 72:39 mortality 64:277 mortality and morbidity studies 73 736-39 mortality rates 71:139-145'5 mortality rates for ex-smokers, andl smokers vs. nonsmokers 72:3 mortality, rates for pipe/,cigar, smokers vs: cigarette smokers. 72:3 134 mortality rates in, British citizens by migration patterns 73:36 mortality rates in pipe, cigar, and ciga- rette smokers 71:175 mortality rates, smokers vs.,nonsmokers 72:38, 39 mortality ratios in male pipe and cigar, smokers 73:21i6,11:7, 2119 occupational hazards and 72:42-44 prevalence of. 69t38 relation to pulmonary hypertension and cor pulmonale 68! 74-76 smoking,effect on 64;31,,277-302. smoking effects on ventilation-perfusion measurments in, 71:163 smoking in etiology of' 72:3, 37 summary ofl previous findings. 73:35, 36 summary of'recent findings 73:5'5 see also Bronchopulmonary diseases,, non-neoplastic Bronchopulmo nary diseases, non-neoplasticc air pollution and smoking inietiology of 74:82, 83;,75:63-68'. afpha-1'-antitrypsin deficiency and smok- ing in etiology of 74:87-90 closing volume abnormalities, in smokers vs. nonsmokers 74:8487 effects of alpha-L-antitrypsin deficiency in smokers vs. nonsmokers 75:72-74' effects of partially deficient hetero- zygote phenotypes. 75':73, 74 history of respiratory diseases andlsmok- ing in etiology of' 74:90 incidence in autoworkers. 74:80 incidence in firemen 75:68 mortality and morbidity 68:66-71, occupational exposure and smoking 74:80 prevalence in Boston policemen„smokers vs, nonsmokers 74:82, 83 preval'ence in the elderly;, smokers vs,. nonsmokers 74:78 prevalence in urbam vs. , rural I population, iniMongolia 74:80 reference listings 74:107-118 I~

small, airways disease,, pulmonary func- tion, and 741:84;,87small,airways disease,,smoking,,and 74~84-87 summary of previous findings 68:65'; 75:61, 62 summary of recent findings. 74:106;107;75:78 Btonchospasm 64:296' Bliechley, Drake,,andlBreslow study 64:324! B uerger's disease smoke toxicity in 64;73',,326' Bullous dis,ease incidence in men by age, race, and smoking habiv 74:90-92I Blueau of State Services, USPHS 64:13'. Burma methods used in study of' smoking and human pregnancy 71:393 Btuns neoplasm initiation~by 64:14'2. 2,,3-Butadione as suspected contributor; to health haz- ards of'smoking 72`.145' Butane 64:60' Butylamine as suspected contributor; to health haz- ards of'smoking, 72'145 Butylamine, N-rnethyl-nitroso, suspected carcinogenic properties in ciga• rette smoke from. 711:265' B utylmethylnitrosamine, in cigarette smoke 67:29, 31, 96, 1103 Byssinosis developmenC in smoking vs. nonsmoking, cotton milliworkers 75:68 dus,t exposure andl smoking in etiology of 74:94-96 prevalence in men by index of'~ severity and smoking habits 73:40,41. prevalence in smoking vs. nonsmoking, cotton mill workers 73:39, 55 smoking and 73:39-41 Cachexia 64:73 Cadmium in, cigarette smoke; relation to patho- genesis of emphysema 71:154 in emphysema etiology, in animals 74!:104 Caffeine 64;349;351,35'2 California cancer registries 64':1127 California Legion Study expected'deathsin 64:110 mortality ratios in. 64:110,14'9, nonresponse rates in 64:113 California Occupational Study 64:95, 106, 2117, 342 2' bladder neoplasm prevalence in 64:222 expected deaths in 64:109 mortality ratios in. 64:109, 149 nonresponse rates in 64:113 observed deathrin 64:109;1101 Canada. COPD morbidity of! smokers in 71i:204 coronary death rate in 64:320 human, experimental data on smoking and pregnancy 71!:409 infectious res,piratory disease in, relation- ship to smoking 71:228 kidney and bladder neoplasms in smok- ers in 71:294 lung neoplasm death rate in 64:176 mortality rates from COPD 71:139-141,,145 . mortality ratios from COPD 71:143 mortality ratios in smokers and non- smokers from pancreatic neoplasms 71:298 National Department of Health and Wel- fare 64:6 neoplasm risk in 64:127 prospective study„ bladder~ neoplasrn prevalence in 64:222 thrombosis in, smoking relationship. 71:132 Canadian veterans:study 64;91 „94, 342 expected deaths in 64:110 135

lling, neoplasm mortality ratios in,, smok- ers vs. nonsmokers 70:241 mortality ratios in 64':1I10„149 nonresponse rates in 64':11'3 observed deaths in 64:110 Cancer see Neoplasms and' specific neoplasm terms,,e.g., Lung neopiasms Cancer registries 64:128;135 in California 64:127 completeness oE' 64':1'28 in Connecticut'. 64':128 in Denmark 64':220 mortality rates, by site„in 64;1!322 in New York. 64;i 29 Cannibinols 64:349 Capilluries effect of smoking 73:22, Carbazole, 9-methyl~ possible importance in tobacco carcino- genesis 71,:266 Carbon-14 labeled smoke particulate deposition in hamster respiratory tract 71:281-282 Carbon black neoplasm risk from 64:147 Carban idio xide in gas phase, in smoke 64:60 as s,uspeeted contributor to health haz- ards of smoking 72:145' Carbon monoxide, 64:70, 296, 297 as airpollutant from,cigarette smoke 72:7, 1'21 123', 1125 and carboxyhemoglobin levels 69:28-29; 72!:21-23', 127 and carboxyhemoglobin levels in smok- ers vs. nonsmokers. 67:63 cardiovascular effects, experimental studies 73;17-19' cholesterol levels in rabbits, after ex* posure to 75:28 in cigarette smoke 67`63, 1,83' in cigarette smoke, formation of! carboxyhemogiobin, 71:8-9 coronary heart disease and 74;10-12'' and' decrease in exercise time before cluudication 75:28' effect during pregnancy ini laboratory animals 73:116, 1'17, 132, 133'3 effect on aortas in animals 75:28'8 effect on birth, weight and neonatall mortality in animals 73:133' effect on blood circulation in, human beings. 67c63effect on cardiovascular system 72:22;74:10-12 effect on cholesterol biosynthesis, in, vitro. 73:18', effect on cholesterol-fedlrabbits 71:65-66 effect on cholesterol level in aorta inn rabbits! 73:18I effect on coronary hemodYnamics andd ventricular function in dogs 73:18' effect on exercise performance in smok- ers vs. nonsmokers 73:18~ effect, on, healthy smokers vs: nonsmok- ers 75:26: effect on human physiology 71:60+62 effect,on myocardium. 68:3'8:40, 43-44; 69:28; 75:29 effeaon nonsmokers 72;126 effect~ on pl9telet' stickiness im, rabbits , 73':18' effect on ipsy,chomotor performance 72:126 effect on reflex vasoconstrictor re- sponses. 73:18, 23 effect'on vascular resistance 73:22~„23' effect on vision 72:126 exposure to, and human~absorptyon. 75:21-28 from freeway traffic, effect on myocar- dial work capacity and angina 74:11 inhalation of, andleffect on blood circu- lation in dogs 67:63' as most likely contributor to health hazards of smoking 72:8',143' neonatal mortality effect, from 64:343 psychological' and physiological effects 72:125-128'. 136

summary of previous findings on rela- in smokers, and carbon monoxide in tions:hip ~to passive smoking, tobacco smoke 75:87; 88, 108 summary of recent findings 67:183 smokers vs: nonsmokers 75:33 67`.63, 100; 72:21-23' from tobaceo: smoke,,effects on psycho- motor performance, including atten- in smokers vs. nonsmokers, by sex, race, employment status or urban location tiveness and cognition function 75i99-101 75:22-24 summary of recent findings see also Carbon monoxide levels Carbon monoxide levels 75:33 in workers exposed to exhausUgases in cigarette smoke 71:59 effect'V of room size, amounu of tobaceo 75':21. Carboxylic acids as cocarcinogens, burned and ventilation 75:90-95 67:131 Carcinogenesis: effect on exercise performance aryl hydrocarbon hydtoxyl9se activity, 75;97 and susceptibility to carcinogens in fetal blood of smoking mothers 711:4074'1'A0 from smokers in buses and planes 75t5'0~53' bladder neoplasms, andl tobacco smoke constituents 75:102 Carboxyhemoglobin 6'7`156 bladder neoplasms, and tobacco tars effect on fetaltissues. 67 i 1 i56 71:4'07' bladder neoplasms, by o-aminophenols formation from CO in cigarette smoke in laboratory animals 7I:8-9 formation in blood of'smokers, 71:60, 75' 67:156' bladder neoplasms; by hydroquinone in laboratory animals see also Carboxyhemoglobin levels : 67:156 Carboxyhemoglobin levels bladder neoplasms, by 3-hy,droxyan- 69:26, 28 thranilic acid in laboratory animals blood cholesterol and, 72:23 67:156 bladder neoplasms, by 3-hydroxy- blood circulation and kynurenine in laboratory animals 67:63 67 `.15'6 M in cigarette smokers one hour after' last't cell and tissue culture studies , cigarette 73:84-86 : 75:25 ; 26' effect'ofltobacco curing methods , and' CO burden inismokers vs. nonsmok- ers 73:2i12 epidermoid carcinoma, experiments ini 75125 26 laboratory aniinals „ . coronary heart disease and 74 10 12 19 67:35 expenimental. ; - ; 68:90-93; 69:62-64; during and following exposure to carbon 72:65-67; 73:78-87; 74:46, 47;, monoxide. ' ' 75:48, 49, 5'0: 72:124 , 125 effect on CO1 absorption, in passive initiating and promoting agents in ciga- rette smoke smokers 75';95„96 effect on exercise performance 73`.246; 247; 75':97 in fetuses 75 ~126,,27 following, smoking of non-nicotine ciga- rettes 73;117„1,8' in neonates of smoking mothers 73:1118!„119 in nonsmokers exposed' to cigarette, smoke 72: 125occlusive periphe,ral i vascular' disease and' 72:26 in smokers 69;28:29, 80 73:68 init'iating,agents 64:142 initiating agents in cigarette smoke 72:66 lung neoplasms by cigarette smoke in laboratory animals. 67:144 mechanism of action 73:78', 80-87' mechanism of action, in lung neoplasm induction, in animals 74:46, 47 and occupational asbestos exposure of smokers 67c 35 ~ and occupational uranium exposure of smokers 67:35 137

possible role of tobacco alkaloids in 69:61 promo ters 64:142 of respiratory tract in laboratory animals 73:78:80 role ofl cigarette smoke condensate 73.80-84 skin neoplasms by cigarette smoke. 67:1441 summary of recent findings. 75:4'3 by tobacco smoke const'stuents in labora- tory animal5 67'35', 144 Carcinogens 64l•172, action on oral!eavity; effect of saliva 71:288 anthracene oil as 64:172 aromatic hydrocarbons; unspecified 69!:61 benz(a)anthracene 67:127' benzo(b)fluoranthene 67:127 benzo(j)fluoranthene 67:1277 benzo(g,h,i)perylene . 67: 127benzo(c)phenanthrene 67:127 benzo(a)pyrene, and chrysotlle asbestos,, in animals 75:4'9' benzo(a)pyrene, and exfoliative cytology of hamster lungs 75,47 benzo(a)pyrene as 64:55 bladtier, in tobacco smoke 69:64 inicigarette smoke, 67:15, 34; 75':49, 50 in cigarette smoke condensate 74:47' cigar„pipe, and cigarette smoke conden- sate, in skin painting experiments in, animals : 73:210-2'14' creosote oil as 64:147, dibenz(a;h)acridine 67:127 dibenz(a,j)acridine 67:127 dibenz(a,h)ant'hracene 67:127 dibenzanthracene as 64:14'3' dibenzo(a,h)acridine as. 64:59 dibenzo(aj)acridine as 64c59 dibenzo(a;h)anthracene as 64:55, 229 138 711-dibenzo-( c,g)carbazole 67:127 dibenzo(a,i)pyrene67:127 effect on cellltransformations 73`.84'-86 effect' on oral mucosa in laboratory animals 72:70 effect on respiratory tract in laboratory animals 73:78-80 heterocyclics as 64:54I hydrocarbons, extraction ofl 64:147 hydrocarbons, polynucikar;, and tumor' accelerators 75:48 hydrocarbons; reduction of 64:60 implantation 69:64 indeno(1 ,2',3 c,d)pyrene 67:327 listing of'4 in cigarette smoke 71:265-266 metals as, 64:166, 167„189, 193;,194, 232' N-nitrosamines 67:127,128 oral administration of„in imice 64;228' polycyclic aromatic compounds as, 64:26 polycyclic, order of potency 64':56' polycyclic;,structure of 64:56' pyrolytic formation,of 64:59 role in tumor inditction in animals'. 74:46, 47 in smoke, effect'on oralloavity 71:12, sterol, hydtoperoxides as 64:52 tobacco smoke constituents as 64!:26, 33, 34„ 51-60, 141 148, 68:90, 91; 73':210~214! use in, experimental bronchogenic carci+ noma 69:63:64 see also Carcinogenesis, and', specific compound listings Carcinoid' t umor prevalence in, male and female smokers and nonsmokers 711:250 risk ratio of smokers 69i56 Carcinoma 64:165, 166 benzo(a)pyrene induction of 64c166 beryllium induction of 64:166

chromium,induction,of 64:167 classification of, in smokers vs: non- smokers 67:140 formation following animal skin painting, with smoke condensates. 71:337-3422 indltetion in rats exposed to cigarette : tars 7l :34'8 indirotion inshesus monkeys 64:166' insitw 64;172,203 tobacco tar induction of 64:143' undifferentiated, and pipe smoking, 64:143' undifferentiated, and smoking 641:140=14'3 undifferentiated, relationship to ciga- rette,smoking 71:248'-249 see also Specific histologic types Carcinoma, alveolar cell 64I: 1599 induction in mice by cigarette smoke inhalation 71:349: risk ratio of smokers 69:566 and smoking 64:143' Carcinoma, anaplastio 64:231 classification of 64!:173 prevalence in ma{e and female smokers and,nonsmokers : 71:250~ Carcinoma, bronchogenic 64:229 animal models for 69:63-64 development in dogs following cigarette smoke inhalation 71:269, 272'-273 experimental induction of: 64:33, 165; 189;,6'9t63-64in:dogs 64:33 mortality from, relationships to smoking, air pollution and residence 71:253 mortality in smoking vs. nonsmoking:g asbestos workers 71:257 mortality trends in 64:141 multiple primary 67:142-143 risk ratio of's,mokers 69:56'. Carcinoma; epidermoid! 64h 165; ; 23'li experimental induction of'. 69:63-64 mortality from„relationship to smoking, air pollution and,residence 71r254 pipe smoking and 67:143' prevalence in male and female smokers and nonsmokers 71:250 relationship of cigarette smoking to 71:246-249 risk ratio of smokers 69:56 smoking and 67:35, 140-14'3 in women 64;159 Carcinoma, epithelial induction in, mice by cigarette smoke inhalation 71:35'0 Carcinoma, oat cell 64:159; 2311 relationship of'cigarette smoking to. 711:247 smoking and 67i 140-141 Carcinoma; oval'cell 641:175 Carcinoma, small cell risk ratio of smokers 69:56' Carcinoma, squamous cell 64t166;231' development in mice drinking alcoholic benzo(a)pyrene 71:292 increase in 64:175 indhction of' 64,:189,228' in oral cavity, relationship to tobacco use 71:366'-367 smoking in etiology of 72:69 Carcino ma, ,tracheobron chial induction in hamsters by cigarette smoke instillation. 71I: 346-347. Cardiac index effect of exercise and smoking, 73:242-244 Cardiovascular di'seases 64;38', 317-327 atherosclerotic;, cigarette smoking, rela- tionship 71:4 atherosclerotian„effectsof CO: 75:27,,28' g1ucose metabolism 6'8'.40„4'1 mortality rates 64 :25 „317 ; 69:17 mortality ratios in male pipe, and cigar smokers 73:215„216pathogenesis of' 75:28, 29 139

pyschosocial factors in. 64:327 response to smoking and nicotine 68:34'-42 in smokers vs. nonsmokers' 68:37' smoking and 64:32, 38, 317-327; 67:3, 25-28', 4'7=69; 69:3' 5; 73':3-23 ; 74:3-119 smoking,efLects in 64:38, 3!1,7-327 and sudden death 68:36 summary of previous findings' 73':3; 74;3',,4 summary of' prospective epidemiologicall studies for cigar' and pipe smokers 73:216' summary ofl recent findings 73:23; 74:1',9' see also Arteriosclerosis; Atherosclerosis; Coronary diseases Cardiavascul9r system effectiof carbon monoxide exposure. 74:10-13 effect of catecholamines, on 67 `.60 effect' of! cigarette smoke on 711:56-58; 107-118 effect of'nicotine on. 67:60; 71:56-58„107-1118; 74:13 effect~ of smoking on 67:26, 60 Carotid body 64:69, 3!18' Catechal9mine levels' effect of cigar, pipe, and cigarette smoke in dogs 73:216 effect of'nicotine,in rats 74:13 Catecholamines 64:70, 3118' effect of nicotine on release af'~ 67:60; 71I:36, 57, 119 effect of smoking on release of 69:60; 71:8 effect an blood circulation 67:60 effect on bloodl circulation in coronary arteries 71:58 effect on blood pressure. 67:60 effect'on cardiovascular system 67cW effect on heart,rate 67:60, effect an myocardium' 67`.60 and'.thrombogenesis 6'8t32' see also Cateoholamine levels Catholics smoking prevalence in 64:3641 140 Cats cardiovascular function in„smoking and nicotine effects on. 7l':1I10,111' ciliary function in, effect of: cigarette smoke on 71:222-224 lungs of, cigarette smoke effect on sur factant activity 71:225 muaus', secretion in. 64c268 mucus: secretion in, nicotine+inducedl effects 64:318' Cattle ciliary function in, effect, of cigarette smoke on 71:221 Causality definition ofl 64:20;z1 epidemiological methods in determining 64:20 statistical methods in determining 64:20 temporallfactors in 64:185 Cell cultures malignant transformations induced by tobacco tars on carcinogens, 73:84-86' tobacco carcinogenesis and 73':84486 Cells atypical, in, ex-smokers, smokers, and nonsmokers at' autopsy 73:74 pathology of, in smokers 641:26; 27, 167'-173' respiration of„cyanide effect' on 641:266' stimulation of,,by nicotine 64;34'9 Cellulose pyralysis of 64:60 Cembrene 641:4'9 ~ Central nervous system effect of carbon monoxide, in smoke on 7l :60 nicotine effects on 64:69, 70„317, 318 Cerebrovaseular; diseases 64:103 de6nition,of 7l :66 epidemiological studies 74h16;,17;75':29, 30, incidence in longshoremen 74:17 incidence in'men, Framingham study 74;117 incidence in women, smokers vs. non- smokers 74!:16; 17

interactiow of' smoking and, other risk factors 73:19 mortality rates 6'4:325mortality rates by age, sex and smoking classification 67:66; 75':3IP mortality rates, ef'fects of cigarette smoking 71:9 mortality rates, smokers vs. nonsmokers 71:66-70;,72`.2 mortality ratios by agC, sex and!smoking classification 67:66 mortalit'y ratios in pipe,and cigar smok- ers 73:215, 216 oral contraceptives and smoking in etiol- ogy of'. 74:16, 17 smoking and 67:27-28„66, 68; 72:24, 25' thrombosis, smoking and 67:27, 68 see also Arteriosclerosis Ceriumm neoplasm indUction by 64:ll66 Cervix carcinoma in situ iof 64':172 Cesium. 641:137 tobacco plant uptake of 64:146 Cessation of smoking 64:31, 37,,87, 188; 374, 375„376 iniadiilts 64:375 body weight increase following 64:326 comparedl benefits in cigarette vs. pipe/cigar' smokers 73:172, 173 death rate reduction following, 64:29';92 decreased clinical! symptoms following, 64:271, 3011 effect on absolute aerobic power 73`.243~ effect on bladder neoplasm mortality rate 67:15'5' effect anbronchitis mortality rate. 67:29„94, 96 effect' on COPD development'. 711:1r30 effect on COPD development in Britishh physicians. 71:142 effect on COPD morbidity and mortality 71: 175; 72:411, 4'22 effect on COPD:morbidity in smokers vs. nonsmokers 71:14I6' effect on coronary disease mortality rate 6T.25„28', 50;,711:32,,46+48, 106 effect' on emphysema mortality rate 6T29„94 effect on iesophageal neoplasms 67.147 effect on infant birth weight. 73:107-109, 1112-1141 effect' oni laryngeal neoplasm mortality rate 67i149 effect: on lung neoplasm mortality rate 64,:163„ 187„ 188; 67:24,, 33, 137=140 effect on li,ng,neoplasm mortality rate in men 6:7:134,,136' effect on morbidity 67:24 effect on mortality rates 67:4', 7,, ,15-16', 24, 139 effect, on mortality ratios. 64:29,163 effect on mouth neoplasm mortality rate. 67:147 effect on pharyngeal neoplasm mortality rate 67:147 effect on pulmonary surf'aotant levels 73,:55 effect an respiratory symptoms 72'.41 „42 effect on respiratory tract neoplasm mortality rate, 67:14'7 effect on risk of lung,neoplasms. 69t55,,57' effect on stomach neoplasm mortality rate 67:158 effect on tryptophan metabolism dis- orders 67:89-90~ emotional disturbances follow'rng. 64:350 gastric ulcer recovery following 64:337 genetic factors in; 64:191 group psychotherapy iw 64:3b4 health improvement following 64:187; 1'88„271, 294 illness as a reason for 64:9'2' improvements in respiratory system 71:148;149 lung neoplasm~development and 72:62 methodsfor 64:354 myocardial infarct and 72`.1'7,,1'8' as preventive meas,ure in CHD' 72;1I7„1,8'. as preventive measure in occlusive dis- ease 73:211, 22 141 E

psychosocial aspects of 64':374,375;376 reduction of risk following 64<37,163;187,188 reinforcing,factorsin 64;341 relation to incidence of CHD 71:32, 4648; 106' stomatit'rs nicotina resolution following' 64;271;69:87 as :therapy for peptic ulcer 67:182 as therapy in arterial diseases. 72':26' thromboangiitis obliterans treatment by 64:326 Channel, blacks 64':147 Chemicals exposure to, in smokers vs. nonsmokers, by, race and sex 75:69; 70 Chemoreflexx nicotine inductioniof' 64:318' Chest illnesses prevalence of 64:287,288„301 prevalence of, in pipe: and cigar smokers 73:220, 221 prevalence of, in smokers 64:27, 297, 298' in women 641:28y' Chewing,tobacco see Tobacco chewing Chickens cdiary function in, effect of' cigarette smoke on. 71:223 ciBast'asis in 64;268 effect of cigarette smoke on embryos 71:344 effect of'nicotine on~embryosCIVS~ 71:4111i Children effect of'parental smoking, 6'4:369; 72'.129' epithelial tissues in 64:170„1,73' passive smoking and 72:129respiratory illness and 72:129 ofl smokers, incide~nceofe pneumonia and bronchitis 75:105,106, of smokers, prevalence of respiratory symptoms 75:1,02,103 smoking patterns in 64:368',369 Chile atherosclerosis autopsy studies in 711:5'5; 56' Chimney sweeps scrot'aI cancer in 64:147 142 skinicancer ini 64!:147' China ginseng root consumption in 64t3'55 Chlordane. 64:62, 145' Chlorinated hydrocarbons pesticide use of 64t62, 145 Chlorogenic acid 64:54 Chlorpromazine 64:70 Choles,terol 64:326, 385 biosynthesis,, effect of! carbon monoxide, in vitro 73`.18 rabbits fed, carbon monoxide effects on 71:65-66 synergistic relationship of' carbon mon- oxide in coronary atheromatosis 71:63 in tobacco 72:24 in tobacco smoke 72:24 see also Blood cholesterol''levels. Chromaffin tissue 6'4:69,318 Chromium carcinogenesis by 64~:167 lung,neoplasm induction by' 64:189,193;194 lung,neoplasm mortality from 71:257-258 in mainstream smoke. 64:55 neoplasm prevalence in workers exposed to 64:193, 194, 232 respiratory tracU carcinoma in workers exposed,to 71:256 Chronic diseases smokers vs. nonsmokers. 67:22 Chrysene carcinogenicity 67:127 carcinogenicity, as component of ciga- rette smoke 71:265;72:66 in tobacco smoke 67:127 Cigar andlpipe smokers see Smokers, cigar and pipe. Cigarette ash nickel in 641:167 Cigarette butt'slengths 641:17 7' Cigarette filt'erssee Filters H f

Cigarette paper increase of'cigarett'e burning rate 68s91. Cigarettes definition and processing' 73:175 and development, of esophageal neo- plasms 711:12', 293flavor, terpenaids as:souree of' 64:52' low nicotine, and respiratory symptoms 641:289 low nicotine„ciliastatic effect of 64:268 modified~ effect on respiratory sympr toms and ventilatory capacity 73i37,38' portion smoked, dosage score as' func- tion of 67:15 similarities with 4ittle cigars 73:224, 225 tariand nicotine content 72<142,14'3 tar levels of, relationship to lung, neo- plasm development 71:275',, 276 taxation 69:4, 57 see'also Cigarettes, filter; Cigarettes, low- nicotine; Cigarettes, non-nicotine; Cigarettes„ non-tobacco Cigarettes, daily consumption aortic aneurysm mortality by. 69:16 and atypicallnuclei in larynx. 69:59 average, dosage score as ftrnctiornof 67:15 bladder neoplasms mortality rates by 67:1'55~ bronchitis mortality, ratios by 67:901 coronary disease incidence rates 67:58;b9!:15; 21-24 coronary disease mortality rates by 67:511; 69! 13coronary disease mortality ratios by. 67:49 coronary disease mortality ratios for male smokers by 67:48' digestive tract neoplasm mortality rates by 67:147 effect on lung neoplas,m mortality in Poland 72:6'1, 62 esophageal I neoplasm i mortality ratios by 67:15'0 increase in, by women! 64:363 laryngeal neoplasm~mortality rates by 67:147' liveri cirrhosis mortality rates by 67`.1I84 liver cii'rhosis mortality ratios by 67i184 lung,neoplasm morbidity rates by 67:33-34 lung,neoplasm martalityrates 67:135-137 lung neoplasm mortality ratios 67:34,135'-140 mouth neoplasm mortality rates by 67:1',46' mouth neoplasm mortality ratios by 67:146'6 pancreatic neoplasm mortality rates in men by 67:15'9 , pancreatic neoplasm mortality ratios inn memby 67:159 peptic ulcer mortality rates in male smokers by 67:182' peecapita 64;:26, 45, 46„185 pharyngeal neoplasm mortality rates by 67:14'6~ pharyngeal neoplasmi mortality ratios by 67`.146 prevalence, of 64:361-374 respiratory t'ract' neoplasm mortality rates by 67:147 stomach neoplasm mortality rates by. 67:1157 stomach neopl'asm mortality ratios by 67:1577 tracheal Ineoplasm mortality rates by 67:147 inrtuberculars 64:277 uro8enital neoplasm mortality ratios f'or male smokers by' 67:154 Cigarettes„filter decrease initar yieldS 68:91'1 effect~ on respiratory symptoms 73:555 increase in 64:46' and polonium+210 content in tobacco smoke 68:92'' production of, in U.91, by year 641:4'6 1 and risk of'lung neoplasms 69:57; 75:44 s,ummary of'previous findings 75i4 vs. nonfilter, and risk of7ung neoplasms 741:4'0; 41 vs, nonfilter;,comparison of safety 69:57 vs:nonfilter„eEfect onsputumptoduc-tion 73:37, 38 Cigarett es;,lb w•nicotine respiruaory symptoms from 64!:268 143'~

Cigarette smoke see Smoke, cigarette : Cigarette smokers see Smokers, cigarette Cigarette smoking see Smoking Cigarettes, non+nicotine effect on apexcar'diogram~ 72:21 effect'.on carboxyhemoglobin levels 73:17, 118 Cigarettes, non-tobacco 64:59 Cigars: definitioniand processing 73:175, 1176 per capita consumption 64:26;45 Cigars„little ehemical! composition of'. 73c224,, 225„228' evaluation of'~ potential public health impact. 73:222-228 shipment' for' domestic consumption (11970 T972), 73:222-224, 227' similarity to cigarettes 73`.224',225sugar and pH:differences with large cigar' and! cilxarettes 73:222-224 tar andinicotine,content 73:224-226, 228' Cigar smoke see Smoke, cigar Cigar smokers see Smokers, cigar; Smokers, cigar andd p1Qe' Ciliary activity 64t6'1 clearance mechanism by' 64':267,,268' effect of: cigarette smoke in animals . 68174, 72' effect of nitrogen dioxide, in rats 74':103 effect: of pipe/cigar smoke vs. cigarette smoke in cats 73:217,z18 effect of'smoke on 64:27,, 34, 35, 61, 168i 169, 170;. 172',173„267;67:107-108;69t42 effect of'~ smoking on 74:101,102 loss of„imsmokers 64;1168„169', 170; 172, 173 morphological changes in cilia 64:267, 268, 2711 transport. 64;61,267,26:8 Ciliary depressants 64I:27, 33', 34,,61, 267, 268'. acrolein as 64':267,,268 ammonia as. 64:268 cigarette smoke as. 64:33, 35„370 formaldehyde gas as' 64:268 gas' phase as 64:34, hydrogen cyanide as 64:268 nicotine as 64:268 nitrogendioxide as 64:268' ozone as 64:268' sulfur dioxide as 64:268', 295' Ciliatoxic agents acetic acid. 67:108' acrolein 67:107 in cigarette smoke : 67:107 crotonaldehyde 67:1'08' cyanides ~ 67:1'07 effect on adenosine,triphosphatase 67:108' effect on oxidative enzymes 67:108' formaldehyde 6!7:107 formic acid 67:108 phenolt 67:108 propionic acid 67:108 Circulatory diseases 64:113 Circumcision 64':224 Clofibrate and reduction in risk of! sudden death in, cigarette smokers 75:32 Closing volume abnormalities' as indicator of' small airways disease, in smokers vs. nonsmokers 74:84-87; 75:71, 72 Coal dust effect: on pulmonary function in smokers vs:,nonsmoker 73:41-43 effect on respiratory symptoms',in smok- ers vs. nonsmokers 73:4I1113 Coallgas workers 64:232 lung neoplasms in 64;193' Coal miners pneumoconiosis and 72:4244 respiratory function tests in 64:289,293„294I t 144

respiratory symptoms in 64:298,299. Coal tar benzo(a)pyrene content'of 64:14'8 neoplasm induction by 64':33, 147; 167, 229 Cocaine 64':3'4'9 Coca leaves 64:349 Cocarcinogens 64:33, 5'8„142, 14'4',,145' benz(a)anthracene as 641:58 carboxylic acids :as 67:1311 croton oil as 64:58 fatty acids as. 64':58; 59 niekel carbonyl as. 69:62 phenols as 64:54;58,5'9;67:31. in tobacco smoke 64I:3'3; 69:61 in tobacco tars 67:131 Cocoa 641:349' Coffee drinking 6'4;349 angina pectoris, smoking, and' 74:8' myocardial infarction, smoking and, in smokers vs:. nonsmokers 74:8;75i19„20 Cognition and!smoking habit: 67:189-191'. Cologne, autopsy records in 64:150 Colonic polyposis 64:191 Combustion temperature effect on tumorigenic, activity of pipe and cigarette tobacco 73:2i0„21'1 Common colds 64:276 Compensatory behavior, smoking as 64:372 Congenital malformations maternal smoking and 72:87;71:136;137 Congestive heart failure 64:320 Connecticut Cancer Registry 641:127,128 data from 64:135 figures on age-adjusted larynx neoplasm incidence 71:277 figures on incidence of'oral neoplasms 71:284 Constitutional hypothesis 641:190,191,1,92',193 refutation ofl 6'4:192relationship to CHD and smoking 71:4849,1,05-106' Contraceptives, orall incidence of stroke and, in women smok- ers,vss nonsmokers 74!:16; 17 smoking and 72:26 thrombophlebitis andi 72:26 Control'populations bias in selection of 64:1811, 217,231 Copenhagen neoplasm study in 64:220, 222„2241 Tuberculosis Station 64!:141 Copper 64:193' nitrate 64:60 sulfate 64':354 Coppersmiths 64:134 Cornfield method 64:155, 15'9;,160 Cornsilkk s,moking, lack of arterial epinephrine level increase 71:57 Coronary,circulation 64:318; 68:41-43' Coronary diseases 64:8, 29, 36;, 38 103, 106,, 108, 317, 320-327, 384, 385 age-adj usted rates in smokers 71:23' by amount smokedl 69:12-13, 1'8arteriosclerotic;, mortality rates in U.9; 71:21 associated risk factors andlsmoking 74:17 atherosclerosis 64!:3!20 atherosclerosis, effects of'smoking on 71:4, 63 autopsy studies. 72:19, 20; 74!:4 and behavior 67:57 bloodi pressure of'~ smokers vs: nonsmok- ers 71:4'3; 47 carbon dioxide effects on oxygemuptake in 71:62 carbon monoxide and! 74:4 \

carboxyhemoglbbin levelS and'. 72:27 cross-sectional study in Bergen, Norway. 72:16 death ratios~ of paired combinations of high risk 71:25 effect ofl coffee dtinking: and cigarette smoking 75:20 effect of'norepinephrine levelS 68:38 effect of smoking on blood circulation in 67:26, 61-62' effecf on blood circulation 67:62-63 effect~on blood pressure 67:541 epidemiolbgiead studies 64:320, 32U, 322; 69t25;, 72:14-16; 73:4-11; 75':14, 1,5 etiolbgy of 64:320,321„322 excess deaths in 64:113' experimental I s3udies' 73:13•19 heredity as a factor 72:18 high bloo&pressure in, 641:38 high: serum cholesterol in 64:38 incidence and education level. 68:24 incidence and mortality rates' in former smokers 711:46', 4748 incidence in European vs: Americanimen 73:99 incidence in farmers vs. nonfarmers by smoking habit 73':7, incidence in Hawaiian men of Japanese ancestry 73':10 incidence in Japanese male smokers vs: nonsmokers 68:17 incidence in lawyers 68:255 incidence in male bank employees in Brussels, Belgium 73:1'0 incidence in males by smoking, habits or physical activity 68:20, 25 incidence ini male smokers vs, nonsmok- ers. 68s 17, 18, 20„23', 25, 27, 28', 37 incidence in men in Yugoslavia 73:9 incidence in men under 60, in New South Wales 74:6 incidence in men with, and without! ventricular premature beats 74:4-6 incidence in rrtiddleaged men from.var- ious countries 74:6 ineidencein minersim Sardinia, 73:10 incidence in Minnesota men by age and smoking habit' 72:14-1'6 incidence in pipe andlcygar smokers. 73:215, 216 incidence in smokers vs. nonsmokers, Peoples Gas Co. Study 74:6;7 incidence in smokers vs. nonsmokers;, Stockholm Prospective Study 74:6 incidence in tribal population area, New Guinea 74!:9 incidence in twins 68::29' incidence in white males by body weight and!smoking habit 73:5' incidence in whites vs: blacks in Evans County, Georgia 73`.4, 5 incidence in women,, smokers vs: non- smokers 74;9, 10 incidence of;, relation to angana pectoris 67`.53 ineidenee; of, relation4o blood cholester- ol levels. 67:58 incidence of, relation to blbod pressure 67:58 incidence of, relation to body weight 67:58 inc,idence of, relation to electiocardio- graphic abnormalities 67:58 incidence of, relation to hemoglobin levels 67:58 incidence of, relation to myocardial in- farct 67:53'. incidence of, relation to socioenviion- mental stress. 67:56 incidence rates,by age, 67:54, 57-58; 68:21; 69':21-22, 24 incidence rates, by amount smoked 67:54, 57-58 incidence rates, by behavior type 69:20, 24 incidence rates, by smoking and other risk factors 69:23 incidence rates, by smoking history 69:21-24 incidence rates in men 67:65', 69:21-22 incidence rates in twins; smokers vs: nonsmokers 67:59 146

I incidencs rates, smokers vs. nonsmokers 69:18, 20-222 inilndia 73:11 infarction, in NYC' pipe; and cigar smok- ers 711:32', 38-39 infarction, relationship to physical act- ivity„smokers vs: nonsmokers 7l :44 interaction of ' smoking and other risk factors 72:16-18;73:4-11 in I;rish smokers vs. nonsmokers 68;18 morbidity ratios: 67:59;69:19 morbidity ratios,,and blood pressure 67:55' morbidity ratios„and lung function 67:56'6 morbidity ratios, by age 67:54 morbidity ratios, by blood cholesterol levels 67:55 morbidity ratios, by pcrsonality charac- teristics 67:57 morbidity ratios, by sociocultural1 mobil- ity status. 67:57 morbidity ratios, in New Delhi, India, 72:16 morbidity, relationship of smoking to 71:32-35, 37, 39, 93-97 mortality andl morbidity retrospective studies 71:40, 93-97 mortality rates 64:25, 29„32'; 38, 39, 184', 320, 321, 3241;67:8', 25'-26 mortality rates among former college students 69:16, 18 mortality rates and per capita cigarette consumption in several'countries 72:16 mortality rates, by age 67:25, 28, 47, 49-511-,69:1I3-14 mortality rates by blood pressure 69:1,4 mortality rates by relative weight'. 69:14 mortality rates, by sex 67:25 ; 27, 28; 47;, 49-50; 69: l3'-14 mortality rates, by smoking 67:25, 28' 49-5:1; 69`.13-141 mortality rates, effect of associated dis- eases on. 67:51-52'' mortality rates; effect of cessation of smoking on 67:25, 27-28, 50 mortality rates, ex-smokers by smoking: history 67:51i mortality rates in heavy smokers 64;322, mortality' rates in hypertensives vs, non- hypertensives 71:42 , mortality rates in industrial workers 64M3 mortality rates in Japanese men, and womeniby cigarette consumption and age started smoking 73`.7,,8~ mortality rates imlongshoremen 72:14 mortality rates in obese vs. nonobese 71:45' mortality, rates in smokers~vs. nonsmok- ers 71:21-22; 24, 26-29~ mortality, rates in s,moking men in Fin- land 73:9 mortality rates in United States 67:4 7 ; 68:16 mortality rates in, with increased carbon monoxide 71',:62 mortality rates of cigarette smokers from„AHA pooling project 71:28, 30, 39 mortality rates of' paired combinations of high risk 71:25 mortality rates of U1S: veterans 71:26', 38 mortality rates, rel$tionship to electra. cardiographic findings 71:42 mortality ratios,,by age 67:25, 26„28', 49-50; 52; 69:13 mortality ratios, by age and blood pres, sure. 67:53' mortality ratios, by age and smoking, history 67:51-52 mortality ratios, by amount smoked 67:48-49; 69t 113 mortality ratios, by sex 67:25'~, 28; ,69 ~ 13-14 mortality ratios, by smoking history 67:25; 28 mortality ratios, effect of' associated' diseases. 67 :5' 1-5 2 mortality ratios in pipe and cigar smok- ers 73:21,5y216 and multiple risk factors 68::28-30 in Nepal 73':111 in New Zealand 73:111 nicotine and. 74':13 nicotine effect': an coronary blood flow. 71:58 147

obesity in smoking in thrombus formation 64:38 occlusion in 67:26,, 64-65 smoking risk factor 64:320 occupational risks in 71:8' sudden death„and'smoking 64:321, 322 67:53; 71:52 pathophysiology of„ effeet, of carbon, summary of previous findings monoxide exposure. 68:16; 75:4' 7 74~:10 and personalitycharacteristics summary of relationship to s,moking 74:: 3; 4, 19, 64:321', 326;,67:57' symptoms of predisposing characteristics 64:320 67:58 prevalence of twin studies 72:18 64':320,,321. relationship of bl'ood pressure:and smok- ing in women 64':321i see a15o Angina pectori's; Arteriosclerosis; 711:45,,47' relationship ofl heart rate and: smoking 71:45 4'7' Atherosclerosis; Cardiovascular diseases Cbronary Drug ProjecuResearch Gioupp of smoking and idemiologc stUd' e ,, relationship of physical activity and ki y p CHD 1 74:4-6 smo ng, 71:41,,,43', 44 Coronary heart disease relationship of triglycerides to 71:65 see Coronary diseases Coronar vessels relationship, to and i smoking constitutional makeup y effect of cigarette smoking,on 67:65 71:48-49, 105-106 Coronene relationship: to ECG abnormalities and' smoking 64:147 Cor pulmonale 71r4'5; 47 and chronic obsttuctive, pulmonary dis- relationship to obesity and smoking ease 71i:43-4'5 rettospective studies in Goteborg, Swe. den. 6 74:76 Cotinine 64:71 72:1 rettospective studies in Ptague„ Czech, oslbvakia desmethyl 64c72. effect on rats and mice. 72:16 risk factors 69!:61-62' in experimental induction of bladder 71:23-24„40-4111 risk factors and personal characteristics adenomas 69:64 68:26 role of glucose metabolism. 68:40,4'1 in Seventh Day Adventists methonium ion, structure of 64:72 Cough 64:280, 281, 282„283'. 64:322 smokers:' age effects on development chronic 64:27, 280, 281',, 282, 283,,299, 302 711:27,,391 chronic, and cigarette: smoking in males in smokers vs. nonsmokers 68:69 68t26„42;A3 chronic,,in women. in smokers with predisposing,factors. 64:287, 285' ' 71:24 effect of air pollution and smoking smoking and 64!:297; 74:90, 91 ' 67:26{ 54 64-65; 69t3-5', 11„ 20; effect of asbestos exposure in smokers 71:5' , vs. nonsmokers 73:41 smoking and, in individuals under 40 effect of'eoal dust exposure in s,mokers years nonsmoker vs 73:10'0 . s 73:41 42~ smoking and, in myocardial ischemic , effectof'filtered cigarettes patients in Italy 73`.5'5 73:100 effect of modified cigarettes smoking as cause of'death 73:38 67:25-27 epidemiology of smoking as etiologic agent in. 67:97 67:26, 54,,62,,65',,6'6; 69t111; 72:1, ex-smokers vs. nonsmokers 2„13, 14 67:98 148

A I of parental smokers, and respiratory Current! Population Survey of'1955' symptoms in,chiltiren 64I:177; 180,,1',86 75:103„105'. Curschmann's spirals I prevalence in cement and rubber indus, in sputum of smokers try workers, smokers vs. nonsmokers. 69:39-40 74:95', 96 prevalenee,in pipe and' cigar smokers 73':220, 2211 prevalence in smoking vs: nonsmoking women in Bordeaux, France 73:36 prevalence of' 64:38, 280„283',, 284', 289, 291, 301,, 302 prevalence of among smokers 67:103 prevalence of, in smoking-discordant twin pairs 67:103 respiratory function in presence ofl 64;291,292' in school-age smokers vs, nonsmokers 75':62': smokers vs. nonsmokers 67:29;,72:40. and smoking 64.297'; 67:97 and smoking, by sex: 67 `.98 and'sputum 64':283-286 traumatic,injury from 64:279 Coumarin 64':145' Creosote oil carcinogenic activity of! 64:147 Cresols in cigar„pipe„and', eigarette smoke 73:177 as probable: contributors to health haz- ards of smoking 72:144 suspected'carcinogenic agent of cigarette smoke 71:266' Crotonaldehyde ciliatoxic agent 67:108 in tobacco ~smoke 67:108' Croton oil 64!:5'8 Crotononitrilee as suspectedi contributor to health haz- ards of'smoking 72':145 Cuba laryngeal neoplasms in. 64:205; 207 laryngeal neaplasms in, relationship to tobacco use 71:356 oral neoplasms in; by type of smoking, 64':200;201', oral neoplasms in„relationship of'tobac- co use 71':364 Customs and Excise Act of 1952, Great, Britain. 64':62', Cy!anidbs detoxification, im pregnant smokers vs. nons:mokers 7311119 in tobacco amblyopia etiology. 67'.40; 71:14',,435-436;,72:6 in tobacco smoke 67'.40 in tobacco smoke,,and optic atrophy 67:183 toxicity; potentiation by vitamin B121n tobacco amblyopia 67:183 and vitamin B deficiency in tobacco amblyopia 67:40 Cysteine inhibition of' smoke cytotoxic action on macrophages 69:42 Cystitis. 64:224 Cy,tochrome: oxidase 64'c266 Cytologic studies exfoliative, and lung neoplasm diagnosis 75:47 macrophage function andismoking 74:104,105 Czechoslovakia 64':205 laryngeal neoplasms in, rel9tionship to tobacco use. 71':354' 35'7' laryngeal neoplasms in~ retrospective study ofl 64:206 serum lipid difference in smokers vs,, nonsmokers 71I:1'A1 Danish Cancer' Registry 64':1411, 186, 220 Danish Morbidity Study 64:224 Data collection methodss in retrospective studies 64:206, 214', 215, 226 DDT 64<14'' as suspectedi contributor to health haz- ards of smoking 72:65, 14'5' Death certification limitations of, in health statistics 64c1'A1, 127' neoplasm diagnosis in 64`.1',28' 1149' I T 0

Death Registration Act. 64t127 Deaths, accidental 64:39, 344, 345' Deaths, sudden from cardiovascular disease. 68:36, 42 incidence in men with and without ventricular premature beats 74:5 incidence in pipe and cigansmokers. 73:215' incidence in women, smokers vs. non- smokers 74:9, 19' rate by smoking, cholesterol„and blood pressure, 69;17 reduction of risk' of', in cigarette smok- ers, using clofibrate : 75:32 smoking as a risk factor 74':4-6; 19 Defense mechanisms 64:264 Demographic factors in smoking 64:361-365' Denmark adwertising,curtailtnent in 64:8 atherogenic effect~ of carbon monoxide and'hypoxia. 71:64 bladder neoplasms in 64':219; 220, 221 bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and. 71:381, 383 carbon monoxide effects on human blood fipids in 71:129 carbon monoxide effects on rabbit' bltiod lipids in. 71:129 coronary mortality in 64:320 cough prevalence in 64:281. Danish Cancer Registry 64:141,,186, 220 Danish Morbidity Study 64:224 lung,neoplasm mortality in 64:176 respiratory function tests in, 64':291i serum Hpid differences ini smokers vs:. nonsmokers in 71:102 twins in, angina pectoris in smokers vs: nonsmokers 71',:51 Deoxyribonucleic acid see DNA. Dermatitiss among tobacco workers 72:111 150 Dermatologists coronary disease incidence ,in 64:322 Dextroamphetamine 64:352 Diabetes mellitus 64:326' effect on CHD in smokers. 71:24 relationship with cigarette smoking, in peripheral vascular disease 71:72 risk inmortality from CVD 71,:67 Diarrhea smoking'and. 64:71I Dibenz(a;h)acridine. 64'.56 carcinogenicity 67:127, carcinogenic properties in cigarette smoke from 71:265 pyrolytic formation of 64:59 structlrral formulalof 64:59 Dibenz(a,j)acridine carcinogenicity 67:127 carcinogenic properties ~ in cigarette smoke from 71:265 pyrolytic formation of 64:59 strvctural formula of 64:56' in tobacco:smoke 67:127 Dibenzanthracene tumor induction by 64t14'3„167 Dibenz(a~c)anthracene carcinogenicity, as component of ciga+ rette smake. 72:66' Dibenz(a,h)anthracene carcinogenicity' 67:127 carcinoma induction by 64:229 structural formula of'~ 64:56 7H-Dibenzo(c,g)carbazole : carcinogenic effect' in laboratory animals 73:79 carcinogenic effect on respiratory tract in hamsters 72:66, 67 carcinogenicity, as component of ciga- rette smoke 67:127 ; 7 i:265 ; 72:66', 67 structural, formula of 64k56 Dibenzo(a,i)pyrene 64;33; 57 carcinogcnicity 67:127

structural formula.of' 64:26 Dicarbonyl compounds 64:S3 Dieldrin 64`.62. Diet, influence of, in coronary disease 64:322, intervention and' cholesterol levels in postinfarction patients. 68:23 and peptic ulcer 67:182' and smoking 67:666 and smoking, effect on blood lipids 73:1~2' as test constant 64:224 tobacco amblyopia 72:6' Diethylnitrosaminee suspected carcinogenic properties in ciga- rette smoke from 71:265 Digestive tract neoplasms mortality, and smoking 67:10,1,47' Digital blood floww effect of smoking 64:318 Digital temperatures effect afl smoking 64:318' Dihydric aleohols G4:52 Dimethylarn ine as suspected contributor to health haz- ards of smoking 72:145 9-10-Dimethy1-1,2-benzanthraeene. 64:203 7, P2-Dimethylbenz(a)anthracene effect on oral mucosa in~hamsters: 72:70 Diinethyhiitra sam ine suspected carcinogenic properties in ciga+ rette smoke from 71i:265' Dipalmityl ketone 64; 53', Dipentene 64:52' 2, 3-Di pho sp hoglr cerat e effects of carbon monoxide on 71:6M1. Disabihty of emphysema patients 68:66 higher rates of'smokers 68:7 DNA alteration, and oral neoplasm carcino- genesis 68:101 binding,of polycyclic hydtocarbons to 73:86; 87 effect of aromatic hydrocarbons on 69:61i eff'ect, of cigarette smoke on synthesis: 69:62-63 increases in smokers' oral epithelial cells 71:288 levels in mice lung exposed to cigarette smoke 71:161 Dogs atherogenic effects oflnicotine in 71r.120 bladder neoplasms in,, fed! 2-naphthyl- amine amine 71':296 bradycardia and tachycardia in, follow- ing nicotine injection 71 c57-58 bronchogenic carcinoma inductian, in, from cigarette smoke inhalation 71i:269„270 cigarette smoke instillation or implanta- tion effects on tracheabronchial tree afl 71:268,347 death in, causes from cigarette smoke inhalation 71r.271 effect of! cigarette smoke on pulmonary clearance in 711:164, 170 epinephrine release in 64,: 318, 319, experimental neoplasm induction in 64:146, 165y 189 fetal, bronchial tubes of, effect of ciga- rette smoke on 71:345 lung neoplasms following, cigarette smoke inhalation. 71:239;277 lung neoplasms in, types and lobes where found 71:269,, 272-273' lungs of,, cigarette smoke effects on surfactant activity. 71:172, 225 myocardium,,nicotine effects on 71:58 neoplasm development in smoking, per- centages of' 71:274 nicotine effect on. 64:71, 3118, 319 ozone effect on 64:295,296 pulmonary histological! changes in, ciga• rette smoke inhaling 71,:158, 159160 respiratory tract of, cigarette smoke in- halation effects on 71,:2'68, 3'52, 353 smoke deposition in 64:265 smoke-induced bronchoconstriction in, atropine eff'eet's 71:163 15L

smoking and nicotine effects on blood' lipids in potentiating action of nicotine, in ani, mals. 7,1:127-128' 73:161-163 smoking and nicotine effects on cardio~ vascular function in prevalence in smokers, mechanism of action 71:107,112 smoking and nicotine effects ow cate- 73:160: smoking and cholamine levelt in 71:119 72:6,97,98 Dust exposure Doll & Hill study. 64:324 64:298, 299 bronchitis and Donkeys effect, of'cigarette smoke on pulmonary 73:441 COPD development from clearance in~ 711:153', 218 7:1:164, 171 as occupational hazard Darn study 73:43; 44 64:324 Dosage in smokers vs. nonsmokers, by race andd sex measure of, in light and heavy smokers 67:14=415 ' 75:69; 70 smoking and' measure of, immen and women 73 :44I 67:14-155 and mortality among women smokers ' smoking and, as risk factors in bronchitis development: 67:25 74:93; 94 nicot'ine and tarcontent ofeigarette smoke as measurement of smoking and; as risk factors in byssinosis development 67 `.115' score, for smoking 74:94+96; 75t68 Dysphoria 67:1'4-15 smoking,exposure. 64:350 Dyspnea 67:25 Driving habits 64':286 prevalence in cigar and pipe smokers and coronary diseas;e 73:220, 221 64:322 Drug addiction 64:350; 351, 35'2' definition of 64:3511 Ear neoplasm distinction from drug habituation 64!:147' 64:351 psychology of EdentuGsm smoking and 64:35 3' Dry mouth 64:354 Dublinn lung neoplasm mortality in 64:195' Ducks cigarette smoke instillation or implanta- tion effects, on tracheobronchial tree, of 71:346 clearance products in. 64:26'9, Duodenal ulcers 64:8;,337, 340 mortality rates in, 64:37 mortality ratios in 64:103, 337 mortality ratios in male cigar and pipe smokers 73:222 nicotine induced, in,cats 73:158, 159 post-operative complications in smokers vs. nonsmokers. 73:157 69:87;72t6 Educational level, 64:100, 1011 and incidence of CHD, in males 68:24 smoking prevalence by 64:363'. Egypt' reiationship of humani pulmonary his, tology and smoking in 71:161 Electrocardiograms abnormalities„and CHD 67:5'8; 68;29; 71:42; 45, 4'7 effect aflsmoking 64:319;]1:45;47;73:13 effect of smoking; in middle-agedlDutch meni 73:12 effect of smoking, ini young military recruits in Poland 73:12 Electroencephalograms ~ nicotine effect on 64:70 placebo effecfon 64:70 152

smoking effect~ on 64I:70 Electrophoresis use in determining serum level of alpha- 1I-antitrypsin 71:151i Emotional stress 64':373„374' Emphysema 64':35', 3:8; 277-294, 302' air pollution in 64:297 alpha-l-antitrypsin ideficiency and' 71:150, 151; 72:44; 74:87=900 alveolar destruction in 64:294 asthmatic form of 64:294 autopsy studies, in smokers vs. nonsmok- ers. 75:74-76 bronchitic form of 64:294 and bronchitis mortality rates, for men by amount smokedl 67:933' and' bronchitis mortality ratios, by age, amount smoked; andlsex 67:94' and bronchitis mortalityratios,,for meni by amount smoked 67:93 bronchitis relation to 64:278,279;280 cadmium exposure in etiology of, in animals 74~:104 cigarette smoking,effeetsan 71:9 definitionof' 64:278; 67:89;;71:139 development in dogs following, cigarette smoke inhalation, 7d:271 development of, relation of cadmium in smoke to 71:154' diagnosis ofl 64':278,,279, 280; 67:90 disability payments in U.S. 68:66 dyspneic form of'~ 64:297 epidem iology of 64':280-2941 excess mortality from 64':25,277' experimentally'induced in smoking dogs 72:46 grade 11 or I21i smokers vs: nonsmokers 71:162, in horses 69:40 hypersensitivity in development of' 67':1'11', incidence in cigar/pipe smoking coal'l miners vs. cigarette smokers and non- smokers: 73:217' morbidity, and cigar smoking 67:99 morbidity, and pipe smoking 67:99 morbidity,,and smoking 67:3; 22, 29130; 96-98' morbidity, body constitution as a factor in 67:30 morbidity, heredity as a factor in 67:30 mortality, and cigar smoking 67:30 mortality, and pipe smoking, 67:30 mortality, effect of cessation of'smoking on, 67 `.29 mortality, effect of cigarette smoking,on. 711:1175 mortality rates 6'4:25'„ 29:, 301; 67:29, 90=93; 68:66:; 71:139' mortality ratios 64:103; , 293; 67:8, 90, mortality ratios, and smoking 67`.3, 91 mortality ratios, by amount smoked' 67 `.90-93 mortality ratios„by sex in United States. 67:911 mortality ratios', in cigar smokers 67:94 mortality ratios, in male,pipe and' cigar smokers 73:217, 219 mortality ratios, in pipe:smokers 67:94I nonsmokerprevalence, of 64:297 occupationallexposure in 64:298, 299;,300, 3022 pathogenesis of' 69:38-40 phases of 64:294 pigmenYdeposition in~ 64:272, 273 premature development'and: smoking, autopsy studies 74:97 prevalence in males by smoking cate- gory, at autopsy 73:48 prevalence in pipe/cigar, and cigarette smokers vs. nonsmokers, autopsy studies 73:45', 46' prevalence in smokers vs. nonsmokers 73:55 prevalence rates in U.S. 74':755 prospective, studies on 64':29 3 pulmonary'function studies and 74:80 respiratory symptoms, body constitutionn as a factor in 67:30, 102-103, 108,109' 153 0 %J 00b

respiratory symptoms;,by smoking classi- fication 67:99 respiratory symptoms, heredity as a fac-tor in 67:30, 102-103, 108,111 . respiratory symptoms„ in pipe smokers, 67:99 respiratory symptoms,,in smokers 64:27;67:99;68:74 in smokers vs: nonsmokers, autopsy studies. 73:45-47 smoking and etiology of' 64:38, 294, 303; 67:30-31, 96, 104-107, 11'0-1111; 69:37-38; 72:37;, 74:87-90 summary of previous findings on rela- tionship to smoking, 74:75-78!; 75:5, 7, 6'1, 62 Emphysema Registry 64:294 Endrin, 64c 145 as, suspected' contributor to health1 haz- ards of'~ smoking, 72<14'S Enzymess activity, effect of smoking, 71:1fi,S adenosine triphosphatase, effect~ of cilia- toxic agents on 67:108'. aryl hydrocarbon hydroxylase activity in placentas at childbirth 71;4'10, aryl hydroxytase; effeefof nickel in cigarette smoke on induction 71:257' benzo(a)pyrene hydroxyl9se, activity in placentas of smoking mothers 7 t:410 carbonic anhydrase, carbon monoxide inhibition in fetal! cord! blood' off smoking mothers 71:407 carbonic anhydtase, aecrease in activity in fetal card blood in smoking,moth- ers 71,:409 effect, of': cigarette smoke,,in rabbit lungs 74:104, 105~ and macrophage function, im rabbit lungs, 74:104, 105': oxidative enzymes, effect of ciliataxicc agents on 67:108 Epidemiological studies, bladder neoplasms and smoking 72:72-74 bronchopulinonary diseases andismoking,. 72:3841;73:36-45 cerebrovasc ular disease and I smaking , 75:29, 30 COPD:and smoking 74:78-80 154 coronary diseases and smoking 69:12-25; 72:14-16; 73I:4'-13; 23;. 75:14'„15 esophageal neoplasms and smoking 72:70, 7'1 laryngeal neoplasms and smoking 69:58-60; 72':68 lung neoptasms and smoking 69':55,56; 72:60K5; 73:68-72; 74':37;;75:44 lung,neoplasms; by age and'.sex 68:94-99 lung neoplasms, in Iceland' 68:94, 95 lung neoplasms, in Japan 68:95, 96 lung neoplasms,,in Switzerland 68:95 maternall smoking and outcome ofl preg; nancy 69`.77=80;72:83-87 oral neoplasms and smoking 69;58;72:68'-70;74:53 pancreatic neoplasms and smoking 69:60~61; 72:74; 74':57, peptic ulcer and smoking, 73:155,157 urinary tract'neoplasms and smoking 69!60 Epiglottis laryngeal neopl$sms 64:212' Epinephrine 64:318 effect in thrombus formation 67:64-65' effect of nicotine 75r,29, levels in arteries, cigarette smoking ef- fects on 71:57 Epitheliallesions, in smokers 64':1I68„170, 172, 173, 213'~ Epithelial tissues age effects on 64:34 changes in female smakers 64:34 changes in;male smokers, 64:34 cigarette smoking and 64:34, 165, 167,173, 189, 213;. 263r275'5 ciliary loss in. 64:34! in ex-smokers. 64:34 histopathologic changes in ~ 64:167-173, 23!1~ 263-275' hyperplasia in 64:34, 203 hypertrophy caused by nitrogen dioxidb 69:41 in nonsmokers 64:189 pipe and cigar effects on 64:34!

premalignant lesions in 64:34';,75:4'4 see also Bronchial epithelium; Esopha- geal epithelium~ Epithelial tumors classification of 64':174 in man 64':146 Epitheliomas, of lip, relationship of' tobacco use with 71:361 Epoxides suspected carcinogenic agents in ciga- rette smoke 711:265 Ergonovine effect on bldod circulation in laboratory animals with coronary disease 67:62' Esophageal balloon technique 64t292' Esophageal epithelium atypical nuclei in basal cells, mate smok- ers 71:292, 379,380 effect of smokingon 67:36, 150-153' pathological changes by age andismoking, history 67:150-162' pathological changes by amountsmokedi 6T:15'2 pathological changes by smoking classi- fication 67:150-151 pathological changes for male smokers vs: nonsmokers 67:1i50-153'. Esophageal l neop lasm s 64:37;,2112'-218; 234 aleohol consumption and smoking in 67'152-153; 72:4, 5s 71; 73:76, 200 f'requency in ismokers vs. nonsmokers 711:12', 238' geographical factors in 64:133 incidence of, by tobacco use 64:216 incidence of„in Jewish women 64:135 incidence of;in U.S. 64!:127 income class gradients in 64:134 induction in animals by nitrosamine 71:292 inhalation patterns and 64:218; 73':197 methods and results ofl retrospective, studies of tobacco use in 71 :289; 375-378' mortality rates 641:37, 133; 7:11:289 mortality rates;,by amount smoked 67:14'T,150 mortality rates, by smoking classification 67`.147;,150 mortality rates in females 64:131, 11322 mortality rates in, Japanese males by' smoking and drinking characteristics 72:71 mortality rates in males 64:130, 132 mortality rates in migrants 64`.1341 mortality rates in pipe/cigar andl ciga- rette smokers 68:102 mortality ratios, by age 67:150 mortality ratios, by amount' smoked 67:150 mortality ratios, by smoking, classifica- tion. 67:1500 mortality ratios for cigar, pipe, and cigarette smokers vs. nonsmokers 73`197',200 mortality'ratios in 64!148',149,21',7;711:289-291. mortality ratios in cigarette smokers 64:14'9, mortality' ratios in iJapanese male smok- ersvs: nonsmokers 73' 76 mortality ratios in nonwhites. 64:2188 prospective studies of 64:217 relative risk in cigar, pipe, and cigarette: smokers vs: nonsmokers 73:197,2001202 retrospective studies of. 64:212-217 ri'sk gradients ina by amount smoked 64:217, 218 risk ratios in 64:213 smoking in etiology of 64:37; 188; 67:33, 150, 7L293;72:4,70,71 1151;, summary of previous findings on rel9- tionship to smoking 68:89, 90; 74:55' summaryaf retrospective studies 73:201, 202 tobacco tars in 64:218 tobacco use andl 64:32', 217, 218'8 trend in mortality 64:137 urban-ruralldifferences in 64:133I Esophagus effect of benzo(a)py,rene in laboratory animals 67:152-153 histological changes in cigar4 pipe, ciga- rette smokers,vs.~ nonsmokers. 73`.200. Esters in cigarette smoke 64`.52. 155

Ethane 64:60 Ethnic groups neoplasm risks in 64:134, 135 neoplasm sites by 64':134,135 Ethyl alcohol carcinogenic promoter activity of 64:217 Ethylene. 64':60 glycol 64:52 Euphoria 64:350 Executive Office of the, President 64':15. Exercise on bicycle ergometer, eff'ect, of smoking 73:242;243 cardiac index, ePfect'of smoking 73:242, 243 effect of carbon monoxide exposure 74:11,, 12 effect, of smoking and smoking absti- nence. 73:24'1„242, 246, 247 effects of CO exposure and increased carboxyhemoglobin ~levels i 75'195,97' influencing factors 73'.241i„246, 247 and pulmonary f'unction, smokers vs. nonsmokers 74:99 relationship to mortality rates 64':101 summary of findings, and mechanism of action, 73:246,247' on treadmill, effect of' smoking 73:243,245 Ex-smokers atypical l nucl'ei in iesophageal epithelium, in male 71:379-380, chronic cough 67:98 decrease of lung neoplasm risk 69:57; 75:43' effects of cessation on body weight,, blood pressure and hypertension de- veldpment 75:1',6-19 effects of cessation on, closing volumee abnormalities 75:71' effects of' cessation on, patholbgic changes 75:74 histological changes in bronchial epir thelium at autopsy 73:74 low birth weight' infants of 73:1',12-11'4 lung neoplasms ina,lowered'rates 71:11 lungpeoplasms:in, prevalence. 64:192, 191 mortality rates in 64,:36; 64:105' mortality rates in, by smoking,history 67:8r111 mortality rates in, COPD 71`.175 mortality rates in, coronary disease 64:322, 323;,325:; 71',:46-48'8 mortality rates in,, coronary disease, by smoking history 67:51 mortality rates in,,coronary disease, ciga~ rette vs. pipe/cigar smokers 73':172, 173 mortality rates in,, coronary disease, for men by amount smoked 69:15 mortality rates in,,coronary disease„for men, by years stopped smoking, 69:15 mortality rates in, coronary disease,,for men, compared!to nonsmokers 69A5 mortality rates in, gastric uld;er 64':104' mortality rates in, laryngcal,neoplasms 64:104 mortality rates in, lung,neoplagns 64':104; 71:276;]2;5; 73c71~-72 mortality rates in, oral neoplasms 64:104 mortality rates:in, stroke, for men, com- pared to nons,mokers 6'9! 15 mortality ratios in 64:36, 92; 93, 103;,104, 105 mortality ratios in, circulatory disease 64:104 mortality ratios in, ex-cigar smokers. 64:94 mortality ratios in, lung neoplasms 71:241-242 mortality ratios in, respiratory disease 64:104 pneumoconiosis incidence in; in miners 64:298 prevalence of respiratory symptoms 73:39, psychosomatic disorders in 641:367' pulmonary fibrosis in, 64t274 pu lmonary function im 73`.39' relative risk in lring, neoplasms develop- ment, 73'.7]-72 risk ratios in„from neoplasms 641:155„ 158, 188' summary of previous findings on health consequences of cessation 75:6 summary of previous findings on rela- tionship to COPD 75:61. t' 156

t survivall after treatment for pharyngeal, laryngeal, or oral neoplasms 73:75 thickness of vocalicords io 69:60, Extroversion 64':365,366 Eye irritation effects of' exposure to cigarette smoke, in passive smokers 75:99; 100 Face skin neoplasms of 64':147, Factory workers, mean expiratory flow rates' in 64:290 False vocal cords epitheliallhyperplasia in 64:271i hyperkeratosis in 64:271 Farm ers. coronary d isease incidence in, 64:321 decreased smoking by 64:3233 myocardial infarction in 64:323' smoking incidence in 64:187 Fats, saturated 64':322 Fatty acid,levels effect of' cigar, pipe, and cigarette smokee in dogs 73:216' effect of'smoking 73':12' rise in, after, smoking 71:36, 65 in smokers vs. nonsmokers, 711:102 see also Fatty acids; Free fatty acids Fatty acids 64:53 suspected carcinogenic agents of' ciga- rette smoke 71:26'66 see a1So Fatty aoidi levels;, Free fatt'y acids Federal insecticide regulations 64:61 Federal Trade Commission 64:8, 1,5' Fertility and smoking 69:79-80 Fetaldeathl effecUof maternal smoking 64:39, 343; 67:185s 73:123-135' 69:77-78; epidemiological studies, in smokers vs, nonsmokers 73:126-132 Fetuss effecY of maternal smoking 64':39,343;72;5,83-89 heart beats in; increase in smoking moth- ers 71:408 morbidity, effect of maternal smoking on 67:186 tissues of; effects of' elevated carboxy- hemogJobin on. 7'L•407' Fibrosis ~ see Pulmonary frbrosis Filters advantages in reduction ofl particulates 7'1:269,275 cellulose, acetate 64`-59' charcoal, and effect of cigarette smokee on cell cult'ures' 69:62' as a, f'aetor in reducing lung neoplasm risk 74:40-41 reduction of'lung neoplasms from, 74L1'3' Finland blood I p ressure d ifferences in 1 smokers vs; nonsmokers 71:103 COPD morbidity in smokers in, 711:200 coronary death,rate in 64:320 lung neoplasm mortality ina, relationship to 4obacco use 64:176 ; 711:245-246 lung neoplasms in, retrospective study of, methods 71:325, 327 peptic ulcer in, methods and results for retrospective and cross section stud+ ies of smoking 71:426, 4'28' risk ratio in 64':1277 serum lipid differences in smokers vs: nonsmokers in, 71':98, 99~ smokiig, and nicotine effects on human blood Gpids. 71:124Fires smoking as cause of 64':344,345;67:187-588 Fitness tests smokers vs. nonsmokers 73:245 Flavors antismoking measures using, 64:354 Flax mill workers chronic respiratory diseases, in: 64:289; 299 Fluoranthene alcoholic: solution of, penetrability of esophageal epithelium 71:292I 1157

in caffeine solution{ effect on esophageall tissue indaboratory animals. 67:152-153 in carbon black 64:147' in ethanol, effect on esophageal tissue inn laboratory animals 67:152-153 Forced expiratory flow rates 64:288-293 Forced expiratory volume, 641:288;,289, 290; 291I, 293; 294', 298' decline in ismokers, by race 75:72 Formaldehyde 641:60161, 268 ciliastatic action of 64'761, 268'ciliatoxic agent 67:107, as suspected contributor to health haz= ards of smoking 72:145 inrtobacco smoke 67:107 toxic action of' 64:295 tracheobronchial irritation from 64:266 Formic acid ciliatoxic agent. 67:108 in tobacco smoke : 67:108' Formosa acute effect of cigarette smoke on hu- man pulmonary function in 71:1!69 Framingham Study 641:291,323 angina pectoris in 64:325 duration of smoking habitiand incidence of CHD 68:17 effect of' coffee drinking on mortality in smokers:vss nonsmokers 75:20 epidemiolbgic study of'CHD, CDV, in- termittent claudication, and smoking, 74:14+16' interaction of smoking, and other risk factors in CHD 73'.:8'' morbidity ratios for CHD; by smoking habit 68:18;71:24 mortality rates in 64:324: France bladder neoplasms in, methods and re- sults in retrospective,studies of smok- ing 71:381-3'83 bladder neoplasms studies. 64:219, 220,,221 retrospective 158 CHD mortality and morbidity in 71':94;,97, cigarette smoke: effects on animal tissuee in 71:343; 344'„349 COPD mortality of smokers in 71:20i11 esophageal neoplasms in~, retrospectivee studies of tobacco use, 64:214; 711:378 laryngeal neoplasms in, relationship to tobacco:use 641:205, 207,; 71:35'5i 357 lung neoplasms in, methods of' retto- spective study oflsmoking in 71:326 oral neoplasms:in, by type of smoking, 641:199„ 201 oral neoplasms in„relatibnship: of tobac- co use and 71:363' Free fatty acid's 64:52 plasma, effect of nicotine, in rats. 74:13 plasma, effect of'smoking on 69:27, see also Fatty acid levelS; Fatty acids Fried foods 64:100 Fume exposure in smokers vs: nonsmokers, by race and sex 75:69„70' Fungi carcinogenic contamination ofl tobacco 68:92„93' Fungicides concentration in cigarette smoke 71:265,266 Furfurall as suspected' contributor to health haz- ard§ ofl smoking 72:145 Ganglia, parasympathetic 64:69„71, 317,,318' Ganglion cells nicotine effect on. 64:69, 70 ~ paralysis of 64~:69', 70 Gas adsorbents carbon granules as 64:61 Gas phase, cigarette smoke 69t63 effeeUon mucus flow rates:in cats. 72:47 harm ful constituents in 72:143 Gas phase, tobacco smoke 64:60 acetaldehyde in 64:60 {',

x acetone in 64t60 acetylene in 64:60 acrolein in 64:60 ammonia in 64:60 argon in 64:60 butane in 64:60 carbonidioxid'e ini 64:60 carbonimonoxide ini 64:60 ethane in 64:600 ethyl&ne in 64:60 formaldehyde in 6C60hydrogen cyanide in 64:60 hydrogen in 64:60 hydrogen sulfide in, 64:60 methane in 64:60 methanol in. 64:60 methyl chloride in 64:60 methyl ethyl l ketone in 64!:60 methyl nitrate in: 64:60 nitri¢, oxide in 64':266 nitrogen dioxide in. 64:60 nitrogen in 64:60 oxygenlin 64:60 phenol in 64:267 propane in 64:60 propylene ini 64:60 Gastric acidity effect of smoking on 67:1182 Gastric motility' 64:340 Gastric neoplasms 641:37, 38, 225-229, 235' decline immortality from 64:133 geographicfactorsin. 64:133 income class gradients in 64:134 migrant mortality in 64':134 mortality rates in. 64:130, 133 mortality rates in, in smokers 641:149' mortality rates: in, Japanese smokers vs. nonsmokers 74:56,57 mortality ratios in 64;148,149,228' prospective studies of 647227 , retrospective studies of 64:225, 226, 227, 228 retrospective studies of, by smoking pat- tern 64:226, 227 summary of previous findings on rela- tionship to smoking 68:90;74:55' tea drinking,and smoking in,etiology of 74:56, 57 tobacco tars in i 64t228' trends in prevalence of 64:135 U:S, incidence of 64:127 Gastric secretion effect of nicotine 72:97 effecV of nicotine in laboratory animals 73:158, 15'9' effect of smoking 64:340 effect of smoking in~ulcer patients, 73:157, 158 Gastric ulcers 64:8; 37, 337; 340 healing,of; after cessation of'smoking 64:337' mortality ratios in 64:37,,113', 337 Gastrointestinal disorders prevalence in cigarette and pipe/cigarr smokers 73:222 smoking and 72:5; 6, 97,,98 General practitioners, coronary disease incidence in 64:321, 322 Genetic factors 64~: 321, 385 ~ alpha+l~antitrypsin deficiency 72:44 alpha-l-antit'rypsin deficiency'and smok- ing in COPD development 74:87 90; 75:72-74 in bronchitis development 67:102-104, 108-109 cessation~of smoking and' 64':1911 COPD pathogenesis and 71:148, 150-152, 205 coronary disease and 72:18'8 in cough development' 67:102, 111 159

in emphysema developme,nV 67`30, 102-103, 108-109, 111 andiheart disease 67`.53-54, 57 lirng,neoplasms and 64:167, 232' in,respiiatory tract disease development, 67:30,108 short run changes in, in~humans. 641:191 smoking andi 64k190; 319; 711:5; 72:18, 44 smoking and, in lung neoplasm d'evelop- menY 74437 susceptibility in neoplasm epidemiology. 641:190; 191'', 192, 193 twin studies, effects of smoking 71:4'9152, 99 Genitourinary diseases see Urogenital diseases Genitourinary neoplasms see Urogenital neoplasms Geographic factors neoplasnt incidence by 64':133 neoplasm mortalityby. 64:133 Germany CHD morbidity and mortality in 71:95-96, 97 cigarette: smoke inhalation effectk ow animal, resp iratory tract in 71:350 laryngeal neoplasms in 64:205 laryngeal neoplasms in, relationship to tobacco use 71:355 laryngeal neoplasms in4 retrospectivee study ofl 64:206' lung neoplasms in{ methods of retro- spective study of'smoking,in 71:323, 325s 326 polonium-210 levels in lungs of smokers in 71:336 smoking ard nicotine effects on human blood lipids 71:125' Gestational age : effect oni perinatal mortality rates in smoking vs. nonsmoking mothers 73`.126-132 and l6w-birth-weight' infants, effect of maternal smoking 73`.1'03'-106 Gingival neoplasms. 64':197„202' cigar smoking in 64:202 pipe,smoking in 64:202 retrospective study, of, by type of smok- i ng 64:201 1,60' tobacco chewing in 6C207 see also Mouth neoplasms; Orall neo- plasms Gingivitis incidence among, Danish Royal Marlnes. 69`86incidence among,Dutch Navy recruits 69:86 incidence among UIS. Naval trainees 69:86 smoking and 69:85-86; 72:6 Gingivitis, Vincent's relationship to smoking 69:86 Ginseng,root. 6'4 c 35'5 Glo ssary terms used in smoking,andiventilatory function 7 L:215 Glucose intolerance as a risk factorin CHD: 73';8 Glucose m etabolism cardiovascular effects of 68:40; 411 and insulin response„ alteration effects on myocardial response. 71:66 GlUtamic acid'. 64:54 Ghrtamine. 64:54 G1Utathione inhibition of'smoke cytotoxie action on macrophages 69:42 Glycerol'. 64:52„62 Glycogen, levels in mice lung exposed to cigarette smoke 71:161 Glyoxal 64:53. Goblet cellsmorphological'changes in 64:35, 268', 2'71. Graphitee respiratory tract carcinoma imi workers expo sed! to 71:256' Grief;, drug use in 64:353 Grip istrength effect of smoking 73:241, 242 Group psychotherapy cure of tobacco habit by 6C354 Growth inhibitors and carcinogenesis 68:92'

Guanethidine blockage of nicotine cardiac stimulation by 71:57 Guinea pigs 64:296 induced pulmonary damage in 64I:266 lung neoplasm development following chronic rrickel, carbonyl or dust in- halation 7L:256 lungs of, cigarette: smoke effects onn su[factant.activity 711:255 respiratory changes in, exposed to ciga* rette smoke 71:162 sulfur dioxide effect on 64':266 Habituation 64:350, 352, 354 definition of' 641:351 Hamsters benzo(a)pyrene inhalation by, effect of asbestos dust on carcinoma induction 71:162 bladder neoplasms in4 fed 2-naphthyl- amine. 71:296 cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of 71:268',,346-348~ induced carcinogenesis in 641:166 induced oral neoplasms in 64t202„203,204,232' laryngeal neoplasms following smoke in- hal9tion 711:1!22 larynx of, effect of cigarette smoke inhalation on, 71:281„284 lung and embryos, effects of cigarette smoke tars on 71:34'3-344pulmonary changes fromi chronic nitro- gen dioxide inhalation 71':220~ respiratory tract of, C-14 labeled partiou- lates deposition in, 71:281-282 respiratory tract of, cigarette smoke in- halation effects on 71:268, 351 Harvard College alumni study 64s385,386 student study 64:383 Health, Insurance Plan 68':19i 20 myocardial infarction im pipe and' cigar, smokers under 71:32, 38-39 Heartt effect,of CO exposure 74':10-122 effect of nicotine 64:318;67`.60;71:36;74:1,3 effect of'smoking, 64:318;,67`.60-62' see also Mlyocardium Hearu di sease . 64:320' description of 64:320 U.9, mortality rate from 64:25, 317, 320 see also Coronary diseases Heart rate. 64:318; 326 effect of catecholamines on, 67:60 effecG of CO exposure 741:11,,1'2 effecu of exercise and smoking 73':242-24'6 effect of nicotine on. 67:60; 74I:13 effect of smoking andlcoronary disease. 67:61; 71:45, 47 effect of smoking an 6!7:60 fetal~,effect ofl maternal smoking 711:408 Hematite 64:193 dust, respuatorytract neoplasms in ham- sters exposed to 71:348 Hematocrit 64:319 infant, smoking mother effects on. 71:407,4'09 variations in, effeeti on coronary blood flow 71:66 Hemoglobin 64:319 affinity for oxygen; CO' effectS on 2;3di- phosphoglycerate control, of 71:60+61 effect of smoking on oxygen affinity 69:29 levels, relation~ to incidence of coronary disease 67:5'8' risk factor, in CHD 68:29 variations in, effect on coronary blood flow. 71:66 H;epatom as 64;145,321 Heptachlor 64~:62, 145 Heredity see Genetic factors 161 I

Heterocyclic compounds 64:54 carcinogenic properties in cigarette smoke. 71:264, 265'' Heterocyolic nitrogen compounds carcinogenicity 67:127 in tobacco smoke 67 :127' Hexamethaniumn blockage of nicotine cardiac stimulation by 71:57 High school students smoking,in 64:370 Hippocampus nicotine effeet on 64:71. Histiocytes 64:269 Histological Istudles', in, laboratory animals 73:49,50 lu ng, neopiasm s and smoking 74s 38;,75:44'-46. lung neoplasms in U.S. veterans 73:73 macrophage function and 74'c104„1'A5. in smokers vs: nonsmokers 74':8, 49 Holland ltrng,neoplasn morrtality rate in 64:176 smoking habits iw 64':177 Honolulu Heart Study interaction of smoking and other riskk fact'ors,in CHD73'::8, 9. Hookahs smokers of, laryngeal neoplasm induc- tion iin. 7I:355. Humectants 64:52 Humidity and patholdagic; effects of exposure to ci9arette, smoke 75:99 Hungary methods used for retrospective studies of lung neoplasms ini 71:328 Hunger. 64:355' Hydtocyanic acidl as probable contributor to healthi haz- ards of smoking 72:1441 Hydrogen inigasphase, cigarette smoke 64:60 Hydrogen cyanide 64:60 in cigarette smoke, effects on body oxidative metabolism 711:62 ciliastatic action of. 64:61, 268 as respiratory enzyme:poison 64:600 toxicity of'. 64:265', 266 Hydrogen sulfide 64',:60 as: suspected contributor to health haz- ards af smoking 72:1,45' H ydro lases reduction of': inismakers"alveolarimacro- phages 69:42'-43! Hydioperoxidks 64:52, 72 Hydtoquinone 64:54 bladder neoplasm induction in labora- tory animals 67:156 as suspected contributor, to health, haz- ards of smoking, 72:145 3-Hydroxyanthranilic acid bladderi neoplasm induction in labora- tory animals 67:156urlnary excretion, smokers vs: nonsmok- ers 67:156 H yd>•o xy-cot i ni ne structure af'. 64:72 Hydioy-c'oumarin 64:145' 3-Hydroxykynurenine bladder neoplasm indYrction in labora- tory animals 67:156 excretion of, smokers vs: nonsmokers 67:156 excretion of, smoking,effectson 7L296 Hydroxyproline level in mice lung exposed to cigarette smoke 71:1611 Hypercapnia and chronic obstructive bronchopul- monary disease 68:75, 76 Hypercholesterolemia and' hypoxia, in arteriosclerosis 69:26' incidence in Belgian military men 74:17, 18 incidence in imateBiitish businessexecu-tives, by smoking habit' and cfrnicall parameters 73:11 as a risk fuctbr for coronary heart disease 72:16, 17; 73`.8, 9; 11. 162'

Hyperchromatic nuclei in epitheGal cells of smokers 64:168, 173 and arteriosclerosis 69:26 carbon monoxide-induced! Hyperinsulinemia during oral glucose tolerance tests after smoking 68:41. Hyperplasia 64:168, 169;,170, 172', 203, 2311 basal cell 73:18, 23' effecu of nieotine. 72:21 experimentally induced in rats 72:21 postoperative, in smokers 711:1',74', 2'30, 64!:1681 169, 170, 172, 173, 231 postural, mechanism in asymptomatic: basal cell, and smoking smokers vs: nonsmokers 67:36 betel nut chewing and 71:1,47' tissue, carbon monoxide effects on 64!203 brone,hial,mucosa, by smoking history in 71:61. mew 67`.105 nonspecificity of 64:1172 precancerous aspects of' I'celand lUng,neoplasm mortality rate in. 64:166 reversibility of 64:176 lung neoplasms in, relationship to to- 64:1I72 Hyperpnea fiominicotine 64:70 Hypersensitivity bacco smoking 71:244 lntmune,systemm response to benzo(a)pyrene-induced lung, neoplasm s eff'ecu in emphysema development 74I:48, 49 67:1111 Hypertension incidence in male Israeli civil servants suppressiom of immunoglobulin re- sponse, by nicotine or, water soluble fraction of' cigarettes 74:18 interaction with smoking as risk factor in cerebrovascular disease 73:9: pulmonary, and l chronic: obstructive pul- monary disease 68:74-76 as a risk factor fon coronary heart:disease 75:77 Income class lung neaplasm mortality by 64:133, 134 smoking prevalence by 64:362 Indeno(1,2,3-cd)pyrene carcinogenicity 64:32, 321; 72':16, 17; 73`.8,,91 risk of„in smokersvs. nonsmokers 67:127 carcinogenic properties in: smoke 68122,444 smoker mortality ratesini 67:127; 71:265 India '' 647325 smoking effects in 64:205' esophageal neoplasms in, retrospectivee 64:325'; I75 :15-19 summary of recent'findings studies of!tobacco use with 64:214; 21I5;,71s3'78' 75:33 in women smokers with CHD laryngeal neoplasms in, relationship to tobacco use 68:22 Hypnotism cure of tobacco habiti by 71:355;356 laryngeal neaplasms in, retrospective studies of 64:354 Hypothalamus nicotine stimulation 64~:7'1 Hlypoxem ia carbon dioxide effects on 64!:205'5 orallneoplasms in, relationship of tobac- co,use 711:362, 366 oral neoplasms in, retrospective studies 71:61,,75 of, by type of'smoking and chronic obstructive bronchopul.- 641:199', 201! monary disease 68t75, 76 relationship of smoking,to thrombosis in 71:131 smoking and 72:22 relationship of' smoking to tuberculosis in. Hypo xia 71:227 aortic atheromatosisdeve:lopment in rab- bits exposed to 71:64 smoking and nicotine effects on human cardiovascular system 711:1117 163'

r lnd'ole, 1-methyl- possible, initiator in, tobacco carcino- genesis 7l' : 265' Industrial carcinogens 64':166' Industrial,hazards effect of dust on COPD developmenti 71':175 effect'on,COPD development in smokers 71:153, 15'4;,218, 219: Industrial pollution in etiology of bronchitis 67:108 110: in etiologyof'emphysema 67:108,110: Infant mortality black vs: white smoking mothers 73:129, 132.' comparison1 of stillbirth andlabortions inn smoking and nonsmoking,mothers. 71:395', 405,406 differences of birth weight and„in smok- ing and nonsmoking,mothers 71:404 effect of genetic,differenees and smoking 73:132 effect of maternal,smoking, 67:185; 69:77,78; 71I:415; 72:83,. 87t73:123;135 effect' of previous obstetrical experience and smoking 73:132 2 effect of'socioeconomic background and smoking 73:ll31,,132 epidemiological studies in smokers vs. nonsmokers 73':126, 132' factors other than smoking, 73':131'1, 132 low birth weight' and 72:86 risk of low-birth-weight infants of smok- ing,vs: nonsmoking mothers 73:1,26i 132 sudden death, relation of' smoking and nonsmo king mothers 71:4'07' lnfantss development of bronchitis and pneu- monia, and maternal,smoking, 75:103' growth rate, effect of maternal smoking, on 69:78 Infectious diseases 641:38, 276, 277,,302' Influenza 64:195, 277„302 incidence from antibody d'eficiC in smok- ing 72:109 morta6ty ratios in 64:276 prevalence inipipe and''.cigar smokers 73':220; 2211 164 Influenza viruses effect of'cigarette smoke on„in mice 68:70,,71 effect on dogs inhaling cigarette smoke 71:3511 enhancing, effect in, vitro on, oxidized nicotine. 69:4'2, lung neoplasm induction by 64:172 neoplasm inductionby, 64:166 resistance of mice following cigarette smoke inhalation. 71:173 Inhalation i 64':9ai„187, 1188 amount smoked and 64:163' bladder neoplasm prevalence and, 6472119„223, 225' carbon monoxide, effect on blood circu- lation in coronary diseas;e patients 67 `.63 as carcinogen application,method 64k166 cigarette smoke, and chronic cough 67:97 cigarette smoke, and coronary disease 67:54 cigarette smoke, and mortality 67:7;9 cigarette smoke, effect on blood pressure 67:541 coronary mortality and 64!: 324 effect of previous smoking habits onn patt'erns of 73:186'„189 effect on blood circulation indogs 67`.63 esophageal,neoplasms and 64:213s 218 frequency-per-puff in cigar' and cigarettee smokers 73:186, 189 laryngeal neoplasms and 64:209, 212, and lung neoplasms in animals 68:93 lung neoplasms prevalence by 64::159, 230! bymalm smokers, and mortality rate 67:11i as measures of exposure to cigarette smoke 67:15 mortality rate from 6'4:36„91, 92„99; 1d11mortality'rate, inhalers vs. noninhalers 67:7;68:5~ mortality ratios 64<91,111. particulate retentioniin 64:264„350;69:62 personality factors in 64:367

i pipe,, cigar, and cigarette smokers 73rL84;,189 possible determining, factors in patterns of 73':183; 184 of radon 64':14'5 risk in, in lung neoplasms 64:188 stimulatory eff'ect from 64:350 of'thoron 64':145 tobacco: smoke, and bronchogenic carci- noma 67:129 tobaceo smoke, and epidermoid carci- nomal 67:1'29 tobacco smoke, and'papilloma formation 67:129, summary of'previous findings on 75:4 Inorganic compounds 64:141 Ihs;ecticides 64:61, 145 aldrinias 64:62 arsenic as 64:61 chlordane as 64:62, 145' DDT as 64:62, 145 Diazinon as' 64:62 dieldrin as' 64:62 Dylox as 64':62' Endosulfan as 64:622 endrin as 64':62' Guthion as 64:6'2 heptachloras 64t62,145lead arsenate as. 64t61, malathion as 6'4:6Z,145 parathion as 64k6'2;145 paris green as 64:61 Sevin as. 64:62'. TDE as. 64:62, 145 Insoluble particles clearance mechanisms. 64:267 Insufflationn application of carcinogens by 64':166 insurance policyholders breathlessness in 64:287 Intelligence quotient'. 64:370 Intermittent claudication decrease in exercise time after exposuree to C& 75:28' effects' of' coffee drinking and cigarette smoking'. 75:200 smokers vs. nonsmokers. 72':22', 26' smoking and 73:21 smoking as a major~ risk factor 74!:14-16' International,Cooperative Study' interaction, of' smoking and, other risk factors in CHD' 73:9 International Statistical Classification of Diseases, Injuries, and Causes of Death. 64:101 Intestinal neoplasms 64:103 Intestinal tone, tobacco effect on 641:355 Intratracheal injections application of carcinogens by 64':166 Involuntar'y smoking see'Passive smoking, 1'onized radiation neoplasm induction by 64':142„143' threshold levels in 64:143 Ireland acute effect, of cigarette smoke on hu- man pulmonary function in 71:168' CHD mortality and morbidity in 71:96 CHD' mortality and morbidity'in, smok- ers and nonsmokers in 71:94'' lung neoplasms in, methods of retrospec- tive study of' smoking in 71:328 maternal smoking and infant weight' in 76:399 methods used in study of smoking and human pregnancy 71:394, 396 Northern, mortality rates from COPD' 7'1:14'4 occupational exposure and smoking rela- tionships to COPD' in, 71i:21.8 relationship of lung neoplasms to smok- ing, air pollution and residence in 71:218' serum lipid differences in smokers vs. nonsmokers in 7i1:99 t'65

smoking, and' nicotine effect's on humann peripheral vascular system 71:133 smoking relationship to thrombosis in, 71:130 lion oxide. 64:166 Irritants tissue tolerance to 64:353 Isohem ia 1 64:319: lsehemic heart disease see Coronary disease Isomethylnicotinium ion i structure of 64':72 Ikoparaffins 64:51 Isoprene 64:52. I'soprenoids. 64:4'9, 51 structuraliformula of 64:49 Isopropyl, oil lung neoplasm risk fiom. 64:193 Israel cigarette smoke effects on animal em- bryos in 71:343 mortalityrates from COPD in 7I:1400 lSuprel aerosoli kidney and bladder neoplasms of smokr ers in 71:295 lung neoplasms, mortality of smokerss and nonsmokers in 71:243 lung neoplasms, retrospective smoking study; methods of. 71:326,328 mortality ratios, esophageal neoplasms in 7I:2911 mortality' ratios, kidney neoplasms, smokers vsj nonsmokers 73`.77 mortality ratios, pancreatic neoplasms in cigarette smokers 71:298' neoplasm risk in 64:127' relationship of'lung,neoplasms to smok- ing, air pollution, andlresidence in 71:255 "Tokyo-Yokohama asthma"' 64:276 Jena autopsy recordsin 64:150 Jews esophageal neoplasms in, in women 64:135I gastric neoplasms in 64:135'5 increased smoking,amang, in women 64:363 Job changing smokerprevelance of 64:292;293 64:363 Italy Johns Hopkins student study. human experimentall data on smoking 64:384 andlpregnancy Joint Tuberculosis Society of Great, Britain 74I:409 64!6 prohibition of'advertising in 64:8'' serum lipid differences in smokers vs. nonsmokers in 741:1100 tracheobronchial tree changes in smokers Keratin and nonsmokers in oversecretion of, im stomatitis nicotina 71 i:263' 64:271' Keratosis, senile 64:203 Keto-acid9. 64c5:3 Japan Ketoamide bladder neoplasms in, methods and re- structure ofl s,ults in retrospective studies of smok, 64:72 ing Ketones 71:382, 384 64:52 CHD mortality KhgU 64:320 64:34'9 CHD mortality a nd morbidity in Kidney neoplasms 71:96' epidermoid, assooiirtedl with cigarette cigarette smoke efl'ects, on human fetal' smoking lung tissue in 69:60 71:343 mortality rates in U.S:, esophageal neoplasms in, retrospective 71:296 studies of tobacco use in mortality ratios in ~. 71:378 64:148, 149 ~ ~. 6fi 166 ~ ~

' I . I mortality ratios,, Japanese men and wo- men,,smokers vs: nonsmokers 73:77 mortality trends in 64':137,149 relationship of tobacco use and' 71:13, 299' in~smokers and' nonsmokers 71:238, 294-295 smoking and 69:60, 64; 73':77, 78 see also Urogenital neoplasms Korea! relation of human pulmonary histology and smoking in 71:255 ttacheobronehialltree changes in smokers and nonsmokers of 711:259 Kreyberg classification comparison with World Health Oiganiza, tion classification, 64:174 in long neoplasms 64:35, 159, 173 Kreyberg study lung neoplasms and smoking 69 t55'-56 Labeling of tobaceo products 64:8 Laboratory techniques for induction of experimental neoplasms 69:63-641 Laborers coronary incidence in 64:321 Lactate metabolism effect of smoking, in patients with an- gina pectoris 73':1',3' Lactation effect'of maternal smoking 73':138-1I4'1 effect'c of maternal smoking, summary of findings. 73':141I epidemiological studies 73:138 experimental studies 73:138,139 Lactones careinogenicity of 64:14'5' suspected carcinogenic agents in ciga- rette smoke 71:265 Laparotomy postoperative pulmonary complicationss following, in smokers vs. nonsmokers. 71:Y74: Laryngeal neoplasms 64:37, 205-212, 233, 234; 71:12, 237-2391 281; alcoho 1 iconsumption in 64:210 development' in hamsters following cigar rette smoke inhalation 71:239 development in smokers 71:12, 281 dose effect in 64':210„234 effect of cessation of smoking on 67:149 epidemiologicallstudies. 72:68 extrinsic origin~of 6'4:211',212 incidence in males and females, byage. 68`.10T„102 incidence of'secondary primary, in smokers vs. nonsmokers i 75t501 income class gradients in 64t134 inhalation effects in. 641:209 inhalation patterns and, 73:193' intrinsic origin of'~ 64:211,212 mortality rates 64:37; 133, 135, , 210;,71:277 mortality rates; by age. 67:149 mortality rates, by age for men. 67:148 mortality rates, by amount smoked 67:149 mortality rates, by smoking classification 67:147, 14'9: mortality rates, for women 64':134; 67 i 153 3 mortality rates, in smokers vs. nonsmok- ers 71:237-238' mortality rates, in United 8tates,by age 67:148 mortality rates, im, United States by sex 67:148 mortality ratios 64;1'113„1'48, 149;7'1:277=279'mortality,ratios„and smoking 67:33-35s 148-1,4'9' mortality ratios, by age. 67 `.14'9' mortality ratios, by age,for men 67 `.148 mortalityratios, by amount smoked'. 67:149, mortality ratios, by smoking classifi¢a- tion 67 :149: mortality ratios, cigar smokers vs. non- smokers 67:35 mortality ratios for pipe, cigar, and' cigarette smokers vs: nonsmokers 73`.193', 196, 197 mortality ratios in, in females 64:132' 1'67

mortality ratios in, in males 64:130,,132 mortality ratios in, in smokers, 64:149 mortality ratios in, Japanese male smok- ers vs: nonsmokers 73`.76, 77 mortality ratios, pipe smokers vs. non- smokers 67:35 mortality trends in 64:1137 in nonwhites 64:209 recurrent, incidence in smokers vs. ex smokers 73:711„74-77 relationship of'.tobaceo use and develop- ment of 711:354'-357 relative risk for cigar, pipe, and cigarette smokers 72:67; 73:76, 77, 197-199 relative risk ratios from tobacco use 71:277, 358' retrospective studies of 64:205:-209' risk ratios in 64':209 iniSeventh Day Adventists. 64:209 smokers vs. nonsmokers 69:58-59 smoking in etiology of 64:32,,188,189;72:4,67,68 summary af previous findings on rela- tionship to smoking 68!89,,90; 74:57 summary of retrospective studies 73c198, 199 susceptibility to 64:189 in Swedena retrospective study of 64:205, 207' vitamin deficiency in. 64:212 in women 64:234 ILatyngitis , reversibility of 64I:275 Larynx atypical nuclei in cells of smokers 69:58-59 effecr of cessation of smoking on 69:59 epithellallchanges in;,classification of 71'.281,, 283 epithelial changes in, smoke induced, 64:275' hamster, C-'14 labeled!particulate deposi- tion in 71r281-282 histological changes in cigar', pipe, ciga- rette smokers vs: nonsmokers 73:197 premalignant changes in, and smoking 69!:5,,55 168 see also Vocal cords Laws. PL 89-92, reqµirements for smoking hazards literature review. 71:7 PL 91-222, requirements for smoking hazards literature review. 711:7 Lead arsenate 64:61 Leaf constituents hydroxycoumarin as 64:145 Leather workers bladden neoplasm prevalence in 64':222, 224 Leukemia and!cigarette smoke 67'.148 and tobacco tars 67=i48 Leukocytes effects of cigarette smoke on, in guinea pigs. 75:77, 78' Leukoplakia 64I:23'1 experimentally inducedl in rabbits 64:203 oral, neoplasm development in smokers and 72:68, 69' as precancerous lesion, 64:142 prevalence in tobacco chewing, coal' miners 73 :75 reverse smoking and,. 73:76 smoking and betel nut chewing 69:58 smoking in~etiology of' 72:68', 69 see also Stomatitis nicotinal Licorice 64t6'2. Life expectancy U:S1males, by cigarette consumption 68:9,,10 Lip neoplasms chewingtobaeco in, 64:202 cigarette smoking in etiology of 73:190, 191 cigar smoking,in etiology of 73:190;191 mortality rates in UnitediStates 67:145 pipe smoking in etiology of' 64:32, 37; 188; 197,, 204; 67:35, 1,45 k 711:289; 72:4; 73:190, 19 t relative risk in, pipe,,cagar, and cigarette smokers vs. nonsmokers 73:190;,1913 retrospective studies of, by type of smoking 64:201 snuff in 64:202

summary of retrospective studies Luminescence 73:192 techniques of'y, use in determining aro- tobacco use relation to matic hydrocarbons in urine 64':233;,71:361,362,365;367. 71:297 see also: Mouth neoplasms; Oral neo- Lung diseases plasms infections, and smoking;, role in lung lipoproteins neoplasm development' infiltration imarterial walls, carbon mon- 74:47, 4'8~ oxide effects on in rabbits, similar to emphysema 7'1:63 69 t41 in smokers vs. nonsmokers in women 71:99-102 64':289 liquid' paraffins see alsla: Bronchitis; Bronchitis, chronic; 64:51 Emphysema; Respiratory symptoms; Liver Respiratory tract diseases nicotine effects on Lung function 64:34'2' see Pulmonary function;, Respiratoryy function tests Lung neoplasms Llverctrrhosls'64:108,34'2'r and alcohol consumption. 64:143,14'4„1'67air pollution in etiology of 67:40 67:140; 68:98' 99; 711:11; 73I:722 mortality rates, and smoking, amount'smoked in 67:39, 184-185 64:105, 1S5'„1'75 mortality rates;,by age 67:18a1 anaplastic: 64:159, 1160 mortality rates; by amount smoked 67c1841 in animals 68:93'' mortality rates; by sex asbestos exposure and smoking as risk 67:184 factors mortality ratios, by age 74:41-43; 75:49 67:184 in,asbestosworkers,,by smoking,habit. mortality ratios,,by dailj amounU smok- 67:143 ed benzo(a)pyrene induction of' 67:184! 64:147 mortality ratios, by'sex and blood' cholesterol levels in male 67:1841 smokers 69:57 mortality ratios, by smoking: classifica-n tion for men causality 67c 184' 64:30, 31, 37 rates among cigarette smokers cigarette smoking,in 71':5 64':31i, 149; 175-196, 231; 71:11i and smoking andlcigar smoking: 67:39, 184'-185', 67`.34, 138-140 Lobeline classification of, in smokers vs: non- as antitobacco agenU smokers ' 64c70,354 67:140-141', Local anesthetics classification systems compared 64':354' 64':174 London decrease inirisk of'for ex-smokers mortality from smog, 69:57; 75:43 64:295 detection of by sputum analysis of London Transport Executive smokers cough and smoking among: male em- 69:58 ployees ofl development in dogs following cigarette 64:281i,286 smoke inhalation l.ongevity 7,1:239 64:99 and dbvelopmenG of chronic bronchitis constitutional differences in 75':499 64:112 early smoking,factor in Longshorem en 64:158 coronary deathirates in effect of air pollution ~and smoking 64:323 75:44, 47 pulmonary function in effect of cessation of smoking on 64:292 67:15-17,,34;139-1'40 respiratory conditions in effect of'sex, on development: 64:289 71:11i Los Angeles Gounty General HospitalStudy environmental and atmospheric factors 64:173 7,1:252-255 169

epidemiological methods 64`.1754 89 epidemiological studies 69:5'5'-58; 72:6'0'-65';, 73:68>72; 74:37,38;75:44' epidermoid, in male smokers. 69:57 epithelial change in 64:168, 170, 172 etiology of 64:8;72`.59,60 excessive smoking,in 64:7 experimental 67:351 144-145; 74:43-52 experimental induction by cigarette smoke 67:144 experimental induction by radioactive substances 67:128 experimental inductiow by tobacco smoke constituents 67:145 ex.smoker risk in 64:158 filtering of tobacco. 68:97 foreign-born mortality rate in. 64:134 genetic factors and 64:16'7;190,19t,1I2,1'93 genetic factors and smoking as risk fac- tors 74c37 group characteristics of tobacco use ini smokers and nonsmokers. 711:240, 24'4;,329-333 groupings' 71:246•334 in heavy'smokers 64:1'5'1, 196; 230, 232 histology of 64:159, 160, 167-173'; 67:140-144 histoldSgy of; and smoking 71:246-249; 74I:38; 39, 44-46 in human beings and laboratory animals 67c145~ immunologic response to benzo(a)pyr, ene-induced tumor, in animals 7A;48,49, incidence by smoking classification 67:34 incidence in British males, by amount' smoked 72:62 incidence in cigar and/or pipe smokers vs. nonsmokers 74:39,40 incidence in cigarsmokers. 68:95,96 incidence in Czechoslovakian males by amount smoked 72;61 incidence in Jewish vs. non-Jewish wom- en 72:63, 64 incidence in male smokers 69:4 incidence in Norway 69:55-56 incidence in pipe smokers 68 :95 incidence in smokers vs. nonsmokers in India 74:37,,38'. incidtwnce in smokers vs. nonsmokers in. Jersey, Channel Itles : 73:70 incidence in smokers vs. nonsmokers in PaPlata, Alrgentinal 73:70 incidence in smokers vs: nonsmokers in Philadelphia: 73:70 incidence in uranium miners. 72z64', 65 incidence in women 68:97; 69:4; 57 incidence in women smokers vs:, non- smokers 74:39, 40 income class gradients in 64:134 increased mortality from 64':25', 26, 128, 135, 136, 139, 140, 141„1,85; 220,,23E232'. increase in mortality of female smokers 75:47' inhalation patterns and 73:203 Kreyberg,classification of 64:35, 1159„173, 174 Kreyberg study 69`.5'5-56 in men, smoking as cause 67:33;,13i microscopic determination of 64:140 mortality from chromium compounds 7 t:257 258' mortality rates 64:36, 1',051 133, 134, 135, 138, 13'9;. 140, 1411, 176; 67:8,,34; 140;68:68;69:5'7 mortality rates, age-specific 64:36' mortalityrates; by age 67<132'-137;68`.94'-99 mortality rates, b y amou nu smoked' 64`.105 ; 175; 67:134-140. mortality rates by cigarette consump- tion, by country 64:176 mortality rates, by degree of inhalation 67:134-136 mortality rates, by; sex 67:134, 140;68:94-99 mortality rates, by smoking charac- teristics 67:131-140 mortality rates, by smoking classification 67':34,138-14W mortality rates; by smoking,history 67:1134-1,37 mortality rates, effect of'~ cessation of smoking on i 67:4, 15, 34, 139' 17,0

3, mortality rates expected in U.S. in 1970 71:237; 239 mortality'rates;,for men 641:132; 175, 176; 67:132, 134-135, 137, 139-140; 74:43 mortality rates;,for women 64:1,32, 135, 17,5I;, 67:34+35, 133-134, 136, 151 mortality rates: in asbestos workers, smokers vs, nonsmokers 73::73 ~ mortality rates in Britain 64:195' mortality rates in British physicians vs. generalipopulation 67:16-117,;'73'.70 mortality rates', in„errors in measurementt of 64':140 mortality rates in;, occupational differ- ences in. 64:95 mortality rates in„sex:differences in 64:177, 178', 1'79 mortality rates in smelter workers ex- posed to arsenic. 71:257' mortality rates in smokers 64;29;,162' mortality rates in smokers and nonsmok- ers 71: 240-243 mortality rates im smokers in Norwayy and Finland 71': 245 -246 mortality rates in Sweden 64:176 mortality rates in United Stat'es' 67:341, 71:239. mortality rates, smoking and 67:3', 10, 34 mortality rates, smoking duration and 64':36,175;]1:240;244' mortality ratios 64:103, 113; 148, 149, 162, 1:75'mortality ratios, by amount smoked 67:134-1400 mortality ratios, by degree of inhalation 67:134136mortality ratios; by sex 67:134',140 mortality ratios, by smoking characr tertstics 64:164;,67:134-136 mortality ratios, by smoking classifica tion 67:138-140 mortality ratios, by smoking history 67:134+137mortality ratios, for cigar, pipe; and cigarette smokers vs. nonsmokers 73 i 20 3'-205 ~ mortality ratios for women 67:34-35', ,136; 153 mortality ratios in Japanese by'amount smoked and age started'smoking 73:69 mortality ratios in Japanese males by amount smoked 72:61 mortality ratios in Japanese women, 72:63' mortality ratios in, variables affecting 64:163 mortafity studies of; liinitatio ns of' 64:163 multiple primary; autopsy findings 67:141-142 multiple primary; in smokers 67`.35 mustard gas in 641:195, 196 nonrespondent, rates, in surveys of'~ 64':151 oat-cell, inimale smokers. 69:57 observed morta6ty in 64:118 occupatio nal' exposures 64:193, 194; 711:1'2occupational exposures and smoking 73:67 particle deposition in~bronchi and site of'. 74:44, 4'5~ Philadelphia Pulmonary Neoplasm Re- search Project histopathologic study 74:38 pipe and cigar smoking in 64:31, 37, 192, 196, 233'' pipe smoking 67:34', 138-140 and polonium 67:128 prevalence in females 64:37' prevalence in males 64<35, 377 prevalence in males andl females by' tumor type 71:246, 25'0, prevalence in smokers vs. nonsmokers in Ctechoslovakia 73:70 prevalence of, age factors in; 64:1'77, 178; 1'79prevalence of, in smokers 64:1'51i prevalence ratios in 64:182, 184, 185' previous respiratory history in. 64:195, 196prospective ; study in Czechoslovakian, males 72:61 prospective study in Japaneseadults. 72:4, 60, 61; 73:684 699 race as a factor; smokers vs. nonsmokers 73:70 radioactive induction of 64':172 redl<ction in number using filter-type cigarettes 71:275 relationship of asbestos and smoking to. 71:257 1711

relationship of chronic bronchitis and and ulcers, relation to smoking. smoking to 69:57 72:62 in uranium m iners by'smoking:habit relative risk in, cigari, pipe, and cigarette 67:14'3' smokers vs. nonsmokers. World Health Otganization classification 73:203, 206-208 of'' relative risk in ex-smokers by lengthiof 6'4:173, 174 cessation and previous duration of Xenon-133 washout technique for detec- hab it' tion of 72':62-64 74:43, 44 relative risk:in e.x-smokersvs, continuing see also Respiratory tract neoplasm s; and smokers specific histologicalltypes 73`.72 Lungs relative risk in pipe/cigar smokers alveolartissue;,effect of smokingon 73:67, 68' 64:274,275i67:30 retro spective stud ies ofl arterioles, effect of pipe/cigar smoking 64:150-165, 230, 231 vs. cigarette smoking,on retrospective study methods forsmoking 73':217 relationships bactericidal activity, effect of nitrogen 71:240, 323•328 dioxide on;,in mice risk ratios in 74:103' 64:16'0,183', 184', 1I85„1'87, 188 comp lianc e risk redbction with filter vs:, nonfilter 64:292 cigarettes effect of cigarette smoke in laboratory' 74t4'0, 41 animals role: of aryl hydrocarbon hydroxylase 67:106 activity and polYaromatian hydra- effect of cigarette smoke on tissue carbons in 641:274; 71:343-345 74:49-5 2', effect of nitrogen dioxide role of pulmonary infections and smok- 641:266; 69:41 ing in etiology of hamster, C-14 Iibeled particulatesdepo- 74:47, 48 sition in and' selenium in cigarettes 71:281-282 67:128 histology of pipe/cigar smokers vs. ciga- in 9eventh Day Adventists rette smokers 64:322' 731217 sex ratios in histopatholdgical differences in smokerss 64:133'3 vs:,nonsmokers sex ratio st'atistic: 73:48, 49 , 74:400 hygiene smoke inhalation in, urban-rural differ- 64:267, 268 ences in inJury 64:270 64:133, 186, 194, 1I9Sand smokers lesions. 69':4'-5 64:7 3, 295 of smokers, in R'hodesia~ parenchyma~ 69`,5'7 64:27, 35, 167, 263, 264, 272, 3011 smoking in etiology of' parenchyma„effect of'smoking on 67:32-341, 141-144', 7L:3'„ 2'37', 276; 67:144'' 72;4', 5, 59, 60;7 3`:67 pathological changes,in emphysema pa-y tientsby smoking history and sex and'smoking in men 67'34' 67:1,05' and smoking in women pathological effects of! smoking on 67:10, 34; 711:246, 2511 64'.165-172; 69! 5 summary ofl previous findings. physiology, new anirnall modell for test- 75:3; 5-8 ing of summary of previous findings on rela- 74:102'' tionship to smoking polonium-210 levels, smokers vs: non- smokers 68!89,,90; 74:35-37 67:128 summary of recenUfindings scarsand susceptibility to carcinogens 75':48' 69:64 summary of ietrospectivestudies seealso Respiratorysystem 73: 206-208'. Lymphosarcoma ty;pesiinplicated in smoking and cigarette smoke 7P:237. 67':148' tiypingof and tobacco tars 64:35, 159; 173, 174; 175 67:1148' 172

Lysozyme secretion by rabbit pulmonary alveolar macrophages. 69,:4'2'. Macrophages, alveolar decrease in pinocytosis, in smokers vs, nonsmokers 75:76 effect,of cigarette smoke ow 67:110; 69t42; 71:165; 73:52; 53;, 74!:50 , effect of nitrogen dioxide 73`54 effect of tobacco smoke 72!47,,48' lysozyme'secretion in rabbits. 6'9':42 and pathogenesis of chronic bronchopul- monary disease. 64';43 reduction of enzymes in smokers 69:4 2-43 response to migration, inhibition factorr or antigens, in smokers vs, nonsmok- ers 75':76, 77 ini sputum specimens of smokers vs:, nonsmokers 72':48' Macrophages, peritoneal effect of nicotine on, inimice: 74:105 Macrophages, pulmonary effect, ofl cigarette smoke extract, in sheep lungs. 74:105'S effect of cigarette',smoke; in guinea pigs 75:77, 78' effect of cigarette smoke, in rabbits 74c104;105 effect of! smoking 72:3, 4; 47-48;73:55' morphologic differences in smokers vs. nonsmokers. 72:4, 4'7-48' summary of recent findings. 75:78 Mainstream smoke see Smoke streams Malathion 64:62,145 Malaya betellnut-tobacco chewing in 64:203' Mammalk effect:of cigarette smoke, tars on eells 71;343. nicotine metabolism in 64c71,,72, 73„74 M'arihuana 64:349 Marital status bladder neoplasms and 64:224 smoking,prevalenc,e by 64:364 Masculinity 64:383„384,3851 smoking behavior association with, 64!:372, 373'', Massachusett's:General Iliospitall 64:141, 1',741 Mass spectrometry 64:51 Maternal-fetal exchange effecV of nicotine, 72:88 poliycyclie hydrocarbons and 73:119 see also Smoking„maternal Maternal smoking see Smoking, maternal M9ximum breathing capacity 64:290 Mayo Clinic 64!:322 Mean expiratory flow rate 64'':290 Measurement errorss in smoking studies 64:97, 1111 Men arteriosclerosisnbliterans in 64t3266 bladder neoplasms in. 64k219; 222, 224', 255' breathlessness in 64':286, 287 bronchitis prevalence in 64c2891 chest illness in 64:288' chronic cough in 64:281, 282, 285 college students, smoking patterns in 64:369' coronary diseases in 64:321, 3 22, 327 coughiand sputum prevalence in 64:284 epithelial change in 64:170, 173' forced expiratory volume in 64':290,291 increasedllung neoplasm prevalence ini 64:192 irreversible obstructive lung disease in 64':288, 289 laryngeal neoplasms 64:212 lung neoplasms irc. 64:183, 186 lung neoplasms in, by amount smoked 64:155 lung neoplasms in, cigarette smoking in relation to 64:31, 37 lung neoplasms in, early smoking in 64:158' lung neopLisms in, prevalence, of. 64:231. lung neoplasms im prevalence of, in Seventh Day Adventists 641:363 173

mortality rates in, squamous, in stomatitis nicotina 64: 28, 85 ~ 642711 mortality ratios in. 64:28 mortality trends in sqpamous, nickel carbonyl iin 64;:166 Methacrolein 64t133;,135, 192' as suspected contributor to health haz- neoplasm mortality, in; by site ards of smoking; 64:132 neoplasm,mortality, rates,im 72:145' Methane 64:135, 137, 175, 176 in,tobacco smoke neoplasm mortality ratios in 64:60 64:130,132„175 nonsmokers, U.S& incidence of, by age M'ethanol. 64:60 64:178 oral neoplasms 64:202, 2041 risk ratios in Methoxyco um arin 64':145 Methyl alcohoU as suspected' contributor to health haz- 64:161 risk ratios in, in bladder neoplasms ards of smoking 72:14s' 6'4:222, single, mortality trends in , 6'-M'ethy lanthranthrene carcinogenicity, as component of ciga- 641:101 smokers„UIS. incidence of„byage rette smoke 72:66: 64:178 smoking and respiratory symptoms in Methyl chloride 64':60 64:286 smoking habits of' 3' Ititethylcholanthrene 64:166 ~ 64':2311 smoking,patterns in, effects during pregnancy in laboratory animals 64:177, 178, 179' 73:117 smoking;prevalence in 64:363 sputum production in 20-Methy lcho lanthrene 64:203-228' Methyl ethyl ketone 64:283'. Menopause . 64':52, 60 Methylglyceroli and cardiovascular disease,, in women 64:62 smokers vs. nonsmokers N4m eth ylnicatinamide 74:10,19 coronary death,rates following, urinary, excretion, effeet'of smoking; 67:156, 71:297 64:321 1,84p-Menthadiene 64':51. Menthol, 64:62 Mesenchymal tumors, classifieation of Methyl nitrite 64:60 Methyl protoanemonin carcinogeni¢ity of 64:145' M'etrazol' treatm ent of' dep ression with 64:U14 M'esotheliomas 641:352' Metropolitan Life Insurance Company classification of' 64:344 641:174 Metal'mine workers pullnonary function, in Mice bladder, neoplasms in„ induction by tryptophan metabolites 64:299 Metals 71:296 embryo;,lethaleffectsof nicotine on~ as carcinogens 71:411 64:166, 167, 189, 193„ 194;, 230, esophageal' epithelium of, alcoholic ben- 232 zo(a)pyrene penetrability of Metalaworking trades neoplasmirisks in 7 1:292' esophageal epithelium of, oil-dissolved' 64:134 benzo(a)pyrene penetrability of Metaplasia 71:292 64:170 genetic variation, in. anaplasia„llrng neoplasms and 64:1'67, 64:172 induction of bladder neoplasms in as precancerous change 64:219,,223' 64:166 induction of bronchitis in squamous, experimentally induced in 64: 272 , . lungs by cigarette smoke 67 :1441 induction of epidermoidlneoplasms in 64:166 174'

induction of'hepatomas in 64':145' induction of orallneoplasms in 64:202 induction of neoplasms in 64:143, 144, 146 induction of pulmonaryadenomas in, 641:143;,144' induction of skin neoplasms in, 64:14'3 induction of squamous celllcarcinomaiin 64':228 inhibition of phagoc:ytic clearance in 64:269 irritation in;,by formaldehyde 64:260 lung neoplasm incidence in, Prom chro- mium oxide dust exposure 71:25'8 lungs of , effects of'cigarette smoke on 64:165;'71:159', 343, 344 pulmonary carcinoma induction in, fol- lowing asbestos dust inhalation. 71:257 pulmonary' changes from chronic nitro- gewoxide inhaltion 71:161,2~20pulmonary clearance in; cigarette smoke effects on 71:170: resistance to pneumon'ta, bacteria follow- ing cigarette inhalation 7L:173 respiratory tract of's cigarette smoke in- halation leffect on 71: 268-269, , 349-35'3 skin painting of, smoke condensates ef- fects on 71:267;337-342'. spontaneous neoplasms in 64:165' spontaneous pulmonary adenomas in 64:1'65' Migrants W ng,neoplasm rates in 64:194 Migration lung,neoplasm risks in 64:195' Migration inhibition factor effects on alveolar macrophages,, in smokers vs. nonsmokers 75':76', 77 Mill workers breathlessness in 64':286 chronic cough4n 64:280 chronic respiratory disease in 64:289;299M'ineral!oil carcinogenicity of 64:147, 148, 229 Miners forced expiratory flow rates in 64:290 forced expiratory volume in 64:293, 294 impairment of pulmonary function iin 64!:299 mucous glandlhyperplasia in 64:271', respiratory symptoms in 64:298;,299. Minnesota Multiphasic Personality lnven tory 64t3'66: Mitochondria effect of tobacco smoke on, in rat liver. 74:104 Molders neoplasm risk in. 64I:134 Mollusks, ciliaryy function in, effect of cigarettee smoke on 711:223'. Monkeys atherogenic effects of carbon monoxide and hypoxia 71:64 ciliary function inl effect of' cigarette smoke on 71:222 fetal bronchial tubes of, effects of'ciga- rette smoke on 71:345 rhesus, development of bladder neo- plasms from 2-naphthylamine 71:296~ squirrel, nitrogemoxide, effects on resist~ ance to pneumococous 71:173 Monoamine oxidase inhibitors effea on rabbits receiving nicotine 69:27 Mmnohydric alcohols 64':52 Morbidity bladder neoplasms, and smoking 6'7:15'5 bronchitis, and,smoking, 67:3, 30; 96-99 bronchitis, im smoking discordant twin pairs 67:102-103 chronic bronchopulmonary diseases 72:39411; 73:36-39 coronary diseases, smokers~ vs. non- smokers' 67'.5 3-54 emphysema, and cigar smoking 67:97 emphysema, and' pipe smoking 67:97 emphysema, and smoking 67:3,,30, 96-99 lung neopl$sms, and smoking 67:3 peptic ulters, and smoking 67:40 respiratory diseases;, smokers vs. non- smokers among college students 67:98 respiratory symptoms 75 :62'„ 63

and smoking, 67:6, 19' andl smokingj in college students 67:98 and smoking in 4'5'-64I age.group 67:24 studies of 64:127, 133, 293, 294 Morbidity rates bronchitis, by age and smoking history 67:96-98 brcrnchitis,, by sex and smoking history 67:96-98' coronary disease, smokers vs, nonsmokr ersby age 67:54 emphy,sema{ by age and smoking,history 67:96-98 emphysema, by sex and smoking,history 67:96-98 smokers vs. ex-smokers 67:15 smokers vs, nonsmokers; by age 67'19-24 smokers vs. nonsmokers, by amounY smoked 67 c 192+11 smokersvss nonsmokers, by sex 67:19-24 smokers vs. nonsmokers, by smoking, history 67:19-24 Morbidity ratios angina pectoris,, by' smoking habit' inn males 68:20 angjna pectoris, smokersvss nonsmokers, 67:59 coronary diseases 69:19: coionary diseases;,snokers vs: nonsmok- ers 67:5'9; 7i:21-22, 24, 30-35' coronary diseases, smokers vs. nonsmok- ers and lung function, 67:56' coronary diseases, smokers vs: nonsmok ersby age 67:54 coronary diseases, smokers vs. non- smokers by blood cholesterol levels 67:55 coronary diseases, smokers vs. nonsmok- ers by blood pressure values 67:55 coronary diseases, smokers vs, nonsmok- ers by persona0ty characteristics 67`57 coronary dis;eases, smokers with predis- posing factors 71:24 coronary diseases;,smoking,and 71:32-35 s 37, 39 coronary diseases, smoking; habit in males. 68:17, 18 coronary diseases, retrospective studies 7:1:40,93-97' in Danish twins, smoking effects on 71':49 -51' development of' COPD~ in smokers vs: nonsmokers 71:145„ 195-205 myocardial infarction, by risk factors in males 68:23 myocardial' infarction, smokers vs. non- smokers 67:59 myocardial infarction, smokers vs. non- smokers by physical activity 67:56 Mortality rates 64:25 s 27, 30, 35, 36, 37; 84, 101, 162.. 3011 by age 67:9-10„12-13,23 by age, and smoking;history 67`.10;68:6 by age; f'or men 67':9; 10 by age, for women 67:23 age started smoking and' 64:29,11,L alcoholism„relation to smoking 67:10 amount,smoked and 641:111; 67:9; 23 aortic aneurysm, for men by amount smoked 69:16 arteriosclerosis 64:25, 321; 67:28' bladder neoplasms, by amount smoked 67:155 bladder neoplasms„by sex 67:154 bladder neoplasms, by smoking classifi- cation 67,:15 5' bladder neoplasms„ef'fect of cessation of' smoking on 67:1555 bladder neoplasms„for men by age 67:1154 bladder neoplAsms,,in United States 67:154 from bladder neoplasms in U.S. for 1967 74:293' bronchitis 64:25, 297; 67:8; 90-91; 68:66.68' bronchitis, and smoking 67:3, 90~96'6 bronchitis„ e[fect: of cessation of smokr ing on, 67194,96 '. from bronchopulmonary disease 71:141-145 cardiovascular diseases 69:17' cerebrovaseular, diseases, andl athletic ac- tivity 67:68 cerebrovascular diseases, and coronary disease history 67`.68 176

1' cerebrovascular diseases, and parental death history 67:68 cerebrovascular diseases,,and smoking 67:68 cerebrovascular'diseasess„by age 67:66; 75:31', cerebrovascular'diseases, by sex. 67:66;,75:3'1, cerebrovascular' diseases, smokers vs. nonsmokers 71:66-67, 68-70' cerebrovascular diseases, smoking classi- fication 67':66;,75M in chronic bronchopulmonary disease 64:301; 72'.3'8!, 39; 73:36-39 in chronic bronchopulmonary disease, cigar/pipe smokers vs: cigarette smok- ers and nonsmokers 73:21'6„217 cigar'smokers vs. nonsmokers 67:8 in cigar smoking 64':30;,67:7 compared rates for cigarette vs: pipe/ci+ gar ex-smokers 73:172,173' Connecticut data on 64':132' coronary diseases 64:25, 320, 321; 67:8, 25-28, 47; 71:21;75:'14 coronary diseases, ,among'phys;icians 68;17, coronary diseases; and age 67':47„50-51;,69':13'-14;,74c6; 75:14 coronary diseases, by amount' smoked 67:51;69:12-1I3, 1,7' coronary diseases, by blood cholesterol. 69:17' coronary diseases, by blood pressure 69:14, 17 coronary diseases, by relative weight. 69:14 coronary diseases, by sex, 67;47; 50; 69:13-14 coronary diseases, by smoking, habit 67;5'1,; 69':14 coronary diseases,,effecti of cessation of smoking on 67:25, 28, 4749; 50 coronary diseases in Japanese men and women~by cigarette consumption and age started smoking 7357,,8 coronary diseases in middle-aged men inn seven countries 74:6 coronary diseases in survivors of myo- cardial infarction, smokers vs. non- smokers 74:4-6' coronary diseases, male smokers vs. ex- smokers by age' 67':49 coronary' diseases, paired combinations oflhigh risk characteristics in 71:25 coronary diseases, retrospective studies. 71•4n 93-p7' coronary diseases, smokers vs. ex smokers 67:9; 69t 15 coronary diseases, smokers vs: ex-smok+ ers by amount smoked 67:49 coronary' diseases, smokers' vs: ex-smok- ers by smoking history 67:51i coronary diseases, smokers vs, nonsmok- ers 69:12-13, 15-17; 71:24, 26-29; 74:3-6 coronary diseases; s,moking:and! 67:10, 27', 65-66 in Danish twins, smoking effects on, 71:51i differences in rates, defined. 68:7 digestive tract neoplasms, by amount smoked 67 `.147 digestive tract neoplasms, by smoking classification 67 `.147 duration of smoking,in 64; 29„36 early smoking and, excess' in, in ismokers. 64:29, 30, 35, 36, 84, 111, 162, 3011 emphysema 64:25; 67:34, 8', 90-91; 68!:66-68 emphysema„effect of cessation of smok- ing on 67:7:,24,29 esophageal neoplasms 67:150;153;68:102;71:289 esophageal neoplasms, by age 67:1,50 esophageal neoplasms, by amount smok- ed 67':1i50 esophageal neoplasms, by smoking classi- fication 67'.150 esophageal neoplasms; for men by age 67':1i50 esophageal neoplasms; for women 67`.153 esophageal neoplasms in Japanese males by smoking and drinking characteris- tics. 72'.71 in former smokers„relation to CHD 71:46; 47-48 in heavy smokers 64:36, 1107, 111, 163' .nhalation patterns and 64:1,11;68:5 from kidney neoplasms in U:9: for 1967 71:296' in laryngeal neoplasms 64:205;67,:153;68:101,1,02' laryngeal neoplasms, by age 67:1,48'-149 laryngeal neoplasms„by amount smoked 67:149 177.

laryngeal neoplasms, by sex from lung neoplasms in smelter workers 67:148' exposed to'arsenic laryngeal neoplasms,,by smoking classi- 71:257 fication lung neoplasms, pipe smokers 67:149 67':140 laryngeal neoplasms, for women lung neoplasms, redluction in, British 67:148 physicians from laryngeal neoplasms, in Japanese 67:155 smokers vs. nonsmokers, male-female ratios in. 68:102 64:133 lip neoplasms„in~United States mouth neoplasms, by age and amount 67:145' smoked liver cirrhosis, and smoking 67`.1'46' 67:40, 184 mouth neoplasms„by smoking classifica- liver cirrhosis,,by age tion 67:184 67:1466 liver eirrhosis;,by amount smoked mouth neoplasms„fbrwomen, 674.184 67:153' liver cirrhosis, by sex mouth neoplasms, in United States 67:1'84 67:145-146 liver cirrhosis, for men fromimyocardial infarction 67':184 75:14 lung neoplasms neoplasms 64!:25, 29; 67':8, 1534 68:68, 9499; 64;128, 129, 130; 1'31, 1!32„ 136, 69:57' 137,138;139 lung neoplasms, and!smoking neoplasms, by site,,in women 67:3 64:132 lung neoplasms, by age neoplasms, increase in 67`.34,134-137,140 64:127, 136 lung neoplasms, by amount smoked neoplasms, in Japanese smokers vs: non+ 67:137, 140 smokers lung neoplasms, by bicth cohorts 68;10. 67:131-133 in nonwhites lung neoplasms„by sex 64:218 67,:134', 137, 140 occupations lung, neoplasms, by smoking characteris- 64:134;,6T:1Q tics f'romioral neoplasms: in 1967 67:134-136, 140 71:285 lung neoplasms, by smoking classifica- overall rates for cigar smokers vs. pipe tion smokers' 67:136„140 73i179;180 lung,neoplasms, by smoking exposure overall, rates for pipe/cigar smokers and. 67 `.34 dose-response relationships lung neoplasms, by smoking habit 73:180-189 67:13!5'; 140 i' overall rates for pipe/cigar smokers vs. lung neoplasms, by smoking,history nonsmokers 67:134-137 73':179,180', overall rates from cancer' in pipe and lung neoplasms, cigar smokers cigar smokers 67:34, 140 73:189 lung neoplasms, effect of eessatiom of pancreatic neoplasms smoking on 68:103; 72:74 67:34, 140 pancreatic neoplasms by age lung,neoplasms; effect of reduction of 67:158-159 smoking on pancreatic neoplasms, by amount smok 67:41 ed 69:159 f'rom, lung neoplasms expected in 11970 pancreatic neoplasms„by sex 71:237„239 67:153,15'8,159 lYrngneoplasms, ex-smokers pancreatic neoplasms, by smoking classi+ 67 `.140 fication lung neoplasms, for men 67:159 67`.34'„13'1, 1I33-13T, 1139-140 paralysis agitanss from lung neoplasms for 1939 vs. 1967 67:8 in U1S. peptic ulcer 71:239' 67:40, 181-182;,71:423 lung neoplasms:, for women peptic ulcer, by age 67c132'-133 136 47 153 ]5' ` ; ; s ,. 1', ^. 67 1!81 ~t,nO nP/l n~a~~cme.:n~T ~n~.naca~. a _ .. ---a-'-r..__-.._...._.r..___.....,....... r.,r,..,...........,~..., .,.w.~ ~', . ~. 72:63! 67:181,-182 1178 1 on

peptic ulcer, smokers vs. ex-smokers 67`.181 pharyngeal neoplasms 67:15'3 pharyngeallneoplasms; by smoking classi- fication 67:35 pharyngeallneoplasms, for women 67:153 in pipe smokers 64:30; 68:6 pipe smokers vs, nonsmokers 67:10 Poisson distribution of' 64:117, 1,18'' redhction in, effect of cessation of smok- ing 67:16 from renal neoplasms in males, by age, type and smoking habit 68:105,106' respiratory tract neoplasms, and smoking 67`.5'-7, 9-10, 147 rurallvsl urban 64:1133; 67:11, in:selected diseases 64:26 by sex 67 ` 12-13 of smokers, non- and ex-smokers 68t5-8„6'9' smokers vs.,ex-smokers 67:9, 15 smokers vs. ex-smokers, by smoking his- tory 67:9 smokers vs. nonsmokers 67:8-9, 19; 71:3 and smoking: 67:5-9;693 by smoking,history 67:9-110„23' stomach neoplasms, by age 67:157 158' stomach neoplasms, by amount:smoked! 67:157 158' stomach neoplasms, by smoking classi- fication. 67:15'7 158' stomach neoplasms, effect of cessation, of'smoking 67:157 158'. stroke 69:1,7' stroke, by age 67:67; 69:12-13 stroke„by amount smoked. 67:57;69:1,2'-13 stroke,,by sex 69:12'-13 stroke„smokers vs. ex-smokers 69:15 stroke„smokers vs. nonsmokers 69':12'-13, 15' in Swedish twins, smokers vs, nonsmok- ers. 71:511 studies of 64':1,00 study of'Chicago Peoples:Gas Light,and Coke Co: employees. 69! 1I6-17' summary of'previous findings 75:3-8„13'. summary of previous findings on rela- tionship to smoking 68t5-10, trends 64;1I35, 140 urinary tract neoplasms, by age 67`.1154 urinary tract neoplasms; by amount smoked 67 `.1'54 urinary tract, neoplasms„ by smoking classification. 67 `.15'4 urogenitali neoplasms, by age 67:154 U.S. male veterans from CHD 7'1I:26; 38 in veterans 64:88'; 293 in women 64:133 in women smokers 67:7,9;,68':6„8,9 Mortality ratios. 64:36, 84, 99,,101„118, 11',9;69:12-113, 18': after cessationof smoking 64:29,111 age effects on, 64:36'„87' alcohol consumption and 6'4':1112 by amount smoked' 67:150„153 aortic aneurysm; for men by amount smoked 69:16 behavioral factors in 64:101 bladder neoplasms 67:36, 154 bronchi,tis64:28', 29, 293; 67:90, 94 cerebrovascul9ndiseases; by age. 67:66 cerebrovascular diseases, by sex: 67:66 cerebrovascular diseases„ by smoking classification 67:66 in cigarette smokers 64c28, 29, 35' in coronary diseases 64:29„184 coronary diseases, associated with other complicating diseases 67:5'2 coronary diseases, by age 67:25-26',49,51,-52;69:12-13,18' coronary diseases; by amount smoked' 67':49 coronary diseases, by bloodl pressure status 67':52

coronary diseases, by sex 67:49; 69A 2'-13coronarydiseases, by smoking habit 67:51-52 coronary diseases, by smoking history 67:25-26 coronary diseases, by sociocultural mo- bility status 67:57 coronary diseases, for men by age 67:48' coronary diseases, for men, by amountt smokedi 67:4 8' coronary diseases, smokers vs. ex-smok- ers 69:15 coronary diseases, smokers vs. nonsmakers. 69!112-13; 15 coronary diseases, with high risk charac- teristics, es timated 71:25 daily cigarette consumption and 64:89 definition of 64:28; 117; 67:1L; 68t6' duration of'smoking,in 641:111'. educational level' factors. in 64!:1 12' in emphysema 64':28; 299 esophageal neoplasms, by age 67:150 esophageal neoplasms; prospective and retrospective studies 71':289-2911 in ex-smokers~ 64:104 genetic factors in 64:3'6,112,113iniintluenza, in smokers 64:276 inhalation effects oni 64:36', 91, 92 internal consistency of' 64';130 laryngeal neoplasms 67 `.35;,71:2J7-279 laryngeallneoplasms; by age 67'149 laryngeall ncoplasms, by amount' smoked 67:149 laryngeaF neoplasms, by smoking classi- fication 67:149, laryngeaU neoplasms:,, cigar smokers vs. nonsmokers 67:35 laryngealineoplasms; far men by age 67:148.149 laryngeal neoplasms, for women 67:15'3 laryngeal neoplasms, pipe smokers vs. nonsmokers 67:35 liver cirrhosis 64:34'2;67:1,84 liver cirrhasis„by age 67:184 liver'cirrhosis„by sex 67:184 liver cirrhosis, by, smoking classification 67:184 liver cirrhosis, for men 67:184 liver cirrhosis, for men by amount smok- ed 67:184 longevity and 64:99, 100' lung,neoplasms and 64:28, 29„133, 163; 164, 175:189 lung,neopCasms; by age. 67:134-140 lung neoplasms;,by amounti smoked! 67,:135',137=140 lirng, neoplasms, by sex 67:135, 137-140 lung neoplasms; by smoking characteris- tics 67:134-136 lung: neoplasms', by smoking classifica- tion 67:139-149 lung',neoplasms; cigar, smokers 67:140 lung,neoplasms; for men 67,:34', 1'34-13'5, 137-1399 lung neaplasms, for women 67:34, 153 ' lung neoplasms, in Japanese males by amount smoked' 72:61 lung neoplasms, im males by cigarettee smoking duration 71:240;244 lung neoplasms in smokers in Norway andiFinland' 71:246' lung neoplasms,,,pipe smokers 67;140'0 measurement limitations of 64:98 mouth neoplasms 67:35' mouth neoplasms, by age and amountt smoked 67:146 mouthi neoplasms,,by smoking classifica- tion 67`.146' mouth neoplasms, cigar smokers vs.,non- smokers 67:35,146. mouth neaplasms; for,women 67:153 mouth neoplasms, pipe smokers vs. non- smokers 67:35, 1'46, neoplasms,,by site. 64:149 in occasional,smokers. 64:163' occupational exposure and 641:112' 180!

pancreatic neoplasms, by sex 67`.158 pancreatic neoplasms, for men by age 67S1I59 pancreatic neoplasms, for men by amount smoked 67i159 pancreatic neoplasms, for men by smokr ing classification 67:159 pancreatic neoplasms,,,for wamen stroke;,by sex 69`_ 1:2L13 stroke, for mem 67':67' stroke, for men by amount smoked! 67:67 stroke, smokers vs. ex-smokers 69:15 stroke, „smokers vs. nonsmokers 69t 12-13', 115' thrombosis,,by age 0 67:153' 67t36 from pancreatic neoplasms in smokers thrombosis„by'smoking,history and nonsmokers 67`26 7d,:289-299 underestimation of64:1:11. peptic,ulter, for men by age. 67:181 urbarnrural l differencesin from peptic ulcer in smokers and non- 64:99 smo kers urinary tract neoplasms, by age. 71:424 67i1154 peptic ulcer, smokers vs. ex-smokers by urinary tract neoplasms, by smoking age classification 67:181 6'7:154' pharymgeal neoplasms. urogenital neoplasms, by amount smoked 67:35 67:154 pharyngeal neoplasms, by age: andd in white population 1 amount smokedi 64':132 67:146 Motor vehicle exhaustt pharyngeal neoplasms, by smoking class• hydrocarbons as ification 64!:296 67:146 Mouth retention of tar in pharyngeal neoplasms, cigar smokers vs. 64:264 nonsmokers Mouth epithelium 67:35' histopathological change in pharyngeal neoplasms;,f'orwomeni 64;2711 67:153 keratinization of pharyngeal neoplasms, pipe smokers vs: 64',:203'3 nonsmokers smaking effect on 67:355 pharyngeal neoplasms, smokers vs, non, 64:275 Mouth neoplasms smokers and cigar smoking by age. 67:3' 67:146 in, pipe and cigar smokers by age and and cigansmoking in men inhalation 67:146 73:184, 187 experimental indbction by pipe tobacco previous respiratory history and smoke, 64<112' 67:147-148 psychological factors in. frequency in smokers and nonsmokers 64<101 71:238'8 sampling, in mortality rates„by age, 64:95, 98, 99 67:146 smokers vs. nonsmokers, f'rom lung neo- mortality rates,,by amount smokedl plasms 63:146 71:240-24 3' mortality rates, by smoking classification stability of' 67:146 -14!7, 64:1Q7 mortality rates, for women stomach neoplasms; by age 67:15'33 67t 1!57 mortality rates in United States. stomach neoplasms, by amount smoked 67:145 67:15'7 mortality ratias stomach neoplasms, by smoking classi- 67:35 fication mortality ratios, by smoking classifica- 67:15'7 tion stroke, by age 67:35,14K 69:12-13' mortalityrat'iosi cigar smokers, men. by age stroke,hyamount smoked69:12-13'. 67:146 Q ~ 4~I 181. ~. Q

mortality ratios„for men~by age cholesterol,levels andirelapse: rate 67:146 68:23' mortality ratios, for pipe smokers. coffee drinking, smoking:and 67:35, 146 74:8; 75':19, 20 and smoking coronary thrombosis and 67:35, 145-147 64:321 smoking induced' damage to rabbits after exposure to 7d:1'2' carbon monoxide and tobacco use 75:29 67c 145'. in Danish twins in women„smokers': vs„nonsmokers , 71:511 67c 153'. epidemiolbgical study in Goteborg, Swe- see also: Gingival neoplasms;, Lip neo- den plasms; Ora11 neoplasms; Palatal neo- 72:14, 15'„ 1',6 plasms; Salivary glandi neoplasms; etiology of Tongue neoplasms 69:27=28 Mucociliary transport etiology of, smoking as effect of smoking 64:325 74:101, 102 , fatall incidence of, and smoking Mucopolysaccharides 67:59 function as surfactants in lung tissue in German, Japanese, and Norwegian 71':172 smokers vs. nonsmokers Mucous cells 68:18, 19 hyperplasia in incidence in European, vs. American,men 64:272 73:9' hypertrophy ofl incidence in male smokers' vs. nonsmok- 64:271 ers increase,in, number of' 68:18',19,23 64:269 incidence in men in Yugaslavia, Mucous glands 73::9' abnormalities, in smokers vs, nonsmok- incidence in men, with and withoutt ers ventricular premature beats 74:97 74:10'0 morphological changes in incidence in minersin Sardinia 64:35,268;271 73::100 Mucous membranes incidence in Minnesota~ meniby age and effect of cigarette smoke on s,moking habit 67:140 72:14, 15' effect of smoking on. incidence in pipe and cigar smokers 67:144 73:215 irritation of and incidence of coronary disease 64:73 67:53'1 smoking,and neoplasms of incidence rates and smoking 69!58 69:21-22; 72:15 Mucus morbidity ratios; for smokers vs. non- alterations in smokers 64:268' 67:56, 59 reduction of, by smoke mortality, in smokers vs. nonsmokers. 64:270 75:14 secretion. nonfatal, morbidity ratios, smokers vs:. 64:268, 269,,270 nonsmokers Muscles; skeletal 67:59: curariform actiomof nicotine in prevalence in currenT vs, ex-smokers 64':69. 74:8'' Mussels prevalence:in farmers ciliary f'unction in, effects: ofl cigarette 64:323' smoke on prevalence in smoking vs. nonsmoking, 71I:22'1, 222 men in Czechoslovakia M'ustard gas 64:195, 196 73:10', Mutation rate recurrence in smokers vs. nonsmokers, in. hypothesized variation in Buenos Aires: 64;192. 74:9' Myocardialinfarct and smoking 64:320, 323 69:4, 18;,73'19 acute, and smoking effects on blood and smoking in [ndia circulation in coronary disease pa- 74:8 tients summary of previous findings 67:62 75:4, 13 182 '

in Swedish womemsmokersvs, nonsmok- ers 75i14 see also Coronary diseases M'yocardiumn arteriole wall, effects of filtered cigar- ettes in dogs 72:20 arteriol6 walll thickness in smokers vs: nonsmokers 72:2, 19 arteriole wall thickness in smoking and nonsmoking dogs' 72:2; 20 effect of catecholamines on 67:60 effect of cigarette smoking on 67:60; 69:111;,71:5, 8 effect of nicotine on, 67:60 effect of' nicotine on catecholamine re- lease, from 67:60 effect of nicotine on, clinical andiexper- imental studies 67:26 effects of hydtogen cyanide in smoke on 71:62 oxygen consumption in nicotine stimu- latedi 7'1:59 oxygen demand of, nicotine,effects. 7'1 1: 38'. seealsa Heaa Myosmine structural formula ofl 64:49 i 2?Naphthylamine : development of! bladder carcinomas, and papillomas in dogs, hamsters, and monkeys 71:296 / suspected bladder carcinogen in tobacco smoke 71:265 Naphtols 64:54 Nas (tobacco and ashes) and oral neoplasms in the USSR 69:58 Nasopharynge,al neoplasmss in smokers vs:, nonsmokers,,in'haiwan 75:50 National Cancer Institute 641:7 Biometry Branch. 64:137,,138', 1139 National Center for Health Statistics 64:13 survey ofIU.S. smoking habits by 7 C5-6 survey on relationship ofl smoking and' incidence of respiratory disease. 71:173 National Clearinghouse for Smoking and! Health responsibilities. 71:7 survey of smoking, 19 70 71:6 National Cooperative Pooling Project mortality statistics from coronary disr ease 71:21-22 National H'eart' Institute 64:7' National Institutes of' Health. 64:13' NationaliLibrary of Medicine 64:13, 14 assistance, in literature review on smok ing 71:7 National Safety Council 64:344 National,'Puberculosis Association 64:8 National Vital Statistics Division 64:1'34 Naturalgass respiratory tract carcinoma in workers exposed to 71i:256 Neonates effect of maternal smoking on, 67:39, 185-187 rats, LD 50, nicotine determination 71:412 see also Birth weight; Infant mortality; Smoking; maternal. Neop lasm s adanomatous,,induction in micebyciga- rezte smoke inhalation. 71:350 age-adjusted incidenceof 64:183 benign, in mice: 64:165 classification of„ by World Health Or- ganization 64:17 3' deatri statistics in, validation of 64:101 develdtpment' in smoking dogs, per- centages of 71c2741 experimental, bronchogenic carcinoma, 69:63-64 experirnental, epidermoid carcinoma 69:64' experimental, induction by tobacco smoke 67:35 female mortality trends in 64:129, 131, 132, 133„135, 137 induction of' 64:33, 14'3; 146, 1,47; 148, 166 mammalian, cigarette smoke effect'on 79 :343' mortality rates in alhoholics, 73:7di 183 ~ ~ ~ W ~ ~ ~ ie- 0" .,. "W 4 4r..

mortality rates in, international statistics of New Zealandi caronary death rate,in, 64:129, 130;,131 64'.320! martality rates in Japan human experimentall data on smoking, 68:17 mortality ratios in; by site64':137, 148, 149 mortality trends in and pregnancy 71:408-409 1' Nickel, 4 anaplastic changes ftom, q 64':135,137' occupational factors in 64:166' carbonyl; as a cocarcinogen. 64:147 prevalence of, smokers vs: nonsmokers 69:62' chloride 69:56 recurrenti primary; incidence in smokers 64:55 cigarette content of, in iash and' smoke vs: nonsmokers 64:55, 167' 73`.71',74 by sex. compounds,, suspected carcinogenic agents in cigarette, smoke 69:56 sex ratios in,,in mortality 71:265; 72:1,45 metaplasia and 64!132; 133 by site 64:166 : Nickel workers 64!:127, 133, 134, 14'8; 1'49;1'88, 64:193, 194,,232 189, 191, 197, 211 Nicotine. smoke constituents in, as promoters 64:49, 69-75 64:26,229 absorption of smoking, and 64:73; 74, 349 72:4,,5s 59-75 acceleration of alpha rhythm by summary of previous findings on rela- 64:70 tionship to smoking adr,rinistration of' 68:89, 90; 73`.67,,68; 75':3'<8' 64:349 summary of recent~ findings ~on relation- antigenic properties ship to smoking 72:1:04 73:88; 74:58, 59;,75t43, 541 atherogenic effects of by type afltumor and smoking history 71`.120r1i22 69:56 carcinogenic effect'of typing of' 64< 144 64:35 virus induction of in cigar, pipe, and cigarette smoke 64`.142;166 73:177 of smokin on offs rin l li ic ff t see also Cancer registries; and' specific g p g c n a e ec s mothers neoplasm terms e g Lung neoplasms ,, . ., Nephritis 73:140,141 dis d h 64:103 ease an eart coronary Netherlands, cigarette smoke inhalation effects on 74:13, 19 degradation of mice respiratory tract in 64k74 f d 71:349 osage o lung neoplasms, methods of! retro- 641:7;4, 357 spective study of smoking in in duodenal ulcer induction in cats , 7'l :323'. 73:158, 159 ' serum lipid difference, in smokers vs. .as antidiuretia. effect 64 69 nonsmokers of : i l 71:101 ,anox a effeaas cerebra Neuroticism. 64:70 effect as chronic toxicitl> 64:365, 366, 367 New Haven Study 64':32, 73; 74 convulfrant ff t 64:186 e ec as Newton; Massachusetts study. 64:70 6'4'7368, 369, 370 effect as curariform action New York City myocardial infarctions imcigar and pipe 64:69 effect' as depressor action smokers in 64:74 71:32 38•39 effect as digestive disturbance , New York State cancer registry in 64:74 effect as discharge pattern 64:127,,129 neoplasm statistics in 64:70 effect as emetic 64c1'35 64:70 C w. ~ 184 ~ W ~ i l p ~ ~'

t effect as nausea 64k71,,,74' effect as paralysis of ganglia 64:317' effect as stimulation 64:69 effect as stimulation of ganglia 64:317 effect as, tranquilization 64:350 effect as vasomotor activity 64:70, 74 effect during pregnancy 67:186-187 effect during, pregnancy in laboratory animals 72:88; 73 :1115, ,116 effect in "arousal'."action 64':70,350. effect onadipose tissue;,in rats 74:13 effect on apexcardiogram 72'.211 effect on autonomic nervous system 67:60 effect,orrbirth weight: in rats 72:88 effect:on blood circulation 60!:61 effect on, blood circulation in coronary disease patients 67:61 effect on blood'lipids 71:123-128 effeaon blood pressure 64':70;67:6D;71':36 effect on blood vessels 67:62' effect on bronchoconsttictor response inn laboratory animals 72:46 effect' on icardiac rhythm of heart. 7C36. effect on card[ovascular system 67:60; 71:5fi-58', 107-118' effect: on yardiovascular system in dogs 73:17 effect on cateoholamine release 67:60; 71i:36, 119; 75:29 effecYon cats 64:700 effect on chemoreceptor:activity 64:69 effection chemoreflex induction 64:318effeet on chiorpromazine inhiliition, 64:70 effect on ciliary activity 64':268 effect on colon 64':71i effect on dogs 64:70 effect on Petus in laboratory animals 72:88' effection gastric secretion 72:97 effect ongasttic secretion inicats 73:15'8, 159 effect' on gastric secretion in rats 73:1'59' effect on gastrointestinal secretiom in dogs. 72:6 effect on habituation 64:349-354 effecfon heart blood flow in dogs 73:17 effect on heart'i function 67:60 effect on heart: rate 67:60;71:36 effect on hypercholesterolemic rabbits 69:27 effect on immune:response in man 72:109 effect on lactation in laboratory animals, 73:138, 139 effect on lactation in smokers vs, non- smokers. 73:139, 140 effect on lipid biosynthesis imaorta in dogs 73:17 effect onilipid metabolism in rabbits 72:25 effect an.liver 64t 34'2' effect on microeiuculationiin, atrium in cats. 73:17' effect on monkeys. 64:70 eff'ect~on mucus secretion 64:268, 269 effect' on myocardium, 67:26', 60 effect on myocardium, oxygen demand 71:38 effect on myometrial strips inigravidic women 71:4'08' effect on nicotine-sensitive cells 64:69 effect on novice smoker 64:70 effect; on pancreatic secretions in animals 73:1611, 162'' eff'eet,on peripheral vascular system 71:72, 75, 133-134; 72:25i 26 effect oni peritoneali macrophages, inn mice. 74:105 effect on pinocytosis, in mouse perito- neal macrophages 74':105 effect:on pipe/cigar smoke, inhalation 73:183' 1'84 effect on pregnancy 71:411-4'14 effection pregnant laboratory animals 67:187-188 effect on pregnant rats 69,80, 185~ I 0 . Q ~

effect on rabbi4s 64:70: effect on rat and mouse fetus, site of action 73:121 effect on respiration, clinical experi-l mental studies 67:266 effect on respiratory system 64:70 effecUon respiratory tract in rats 74:104 effect on supraopticohypophyseal sys- tem, 64:69 effect' onisympathetic ganglia cells 64:69 effect on systolic pressure rise. 64;74 effect on vaseular, resistance in dogs 67:60' effect„tolerance to 64:353, 354 effect„toxicity fro m 64:74 effect, tremors from 64:70 effect, unpredictability of 64:69 excretion, by passive smokers. 75:97 experimental studies. 7Z:21; 73:16', 17 hypoxia and 72:21 induction,of necrosis: in arterial walls. 7 L:63 as most likely contributor to health hazards of smoking, 72'.8, 143: neurogenic effects of' 71:57 N-oxides, presence in tobacco smoke 69:62 oxidized, in ~vitto ~ciliostatic effects 69:42I as potentiator of' duodcnal ulcers in animals 73':16i1-1'63' pyrolysis of 64:599 secretion, effect of cigar, pipe and ciga- rette smoke in dogs 73:216structural f'ormulalof64:49 substitutes for 64:34, 354 suppression of immunoglobulini re- sponse, in,cell cultures. 75':77 systemic toxicity of 64; 7'1. 73 tissue storage of 64':71. tblerationof 64:352, 35'3; 354 toxicity; of 64:32, 71, 73', 74, 352', 353„35i31 see also Nicotine content;, Nicotine me- tabolism; Nicotine pharmacology. Nicotine contenti in blood,,new assay methodk 73:15, 23 and cigarette smoke. 72:21 and cigarette smoke and tumorigenicity 67:34 effects of room size, amount of'tobacco burned and ventilation 75':91'-94, 97 i nlittle cigars compared to cigaret'tesand cigars 73L223-226', 228 in milk of laboratory'animals. 73c 1138, 139 in milk of smoking mothers 73 t 1'39 smoker awareness,of' 64:349 and tar content; andl tUmorigenicity of cigarette smoke 67':15 and tar content, of cigarette smoke ass measurement of dosage 67:15 Nicotinemeta,bolisrn 64;31,,7'1,72 metabolites 69:61:-62 metabolites, excretion of 64:71,72 pathways o[„inimammals. 64:72 see also Cotinine Nicotine pharmacology 64:32', 69; 70, 71,,72, 31'~7„318, 319; 320, 349 effect of acetylcholine on, 67:60, effect of adrenalectomy on 67':60~ effectof'tetraethylammonium chloridmon 67:60, Nine-State Study expected deaths in 64:109 mortality ratios in. 64':109„149 observed deaths in 64:109 Nitrates in tobacco smoke 67:128' Nitric oxide exposure to 64:266 asproba,ble contributor to health haz- ards of smoking, 72:144 Nitrogen gas phase, cigarette smoke 64:60 Nitrogen bases 64:54 186

Nitrogen dioxide 64;60;266 ciliastatic effeevof 64:268 effect on AldHactivity' 74:52 effect on alveolar wall cells in guinea pigs 73:50 effect on bacterial retention in hamsters 73:54 effect on bactericidal activity in mouse lung 74:103 effect on pulmonary physiolbgy; in ani- mals' 74':102-103' effect on pulhtonary physiology, in mon- keys 74:103effects on rats' lungs 69:41; 72:46, 4'7; 73:4'9, 50 in emphyse,ma etiology 72:46 obliterative fibrosis from 64:266' as' probable contributor to health haz- ards of smoking. 72:144 pultnonary changes in rodents chroni- cally Inhaling 7,1:161, 2200 pulmonary edema fiom 64:266 toxic action ofl 64:295' Nitrogen oxides 64:296, 297as'air pollutants in cigarette smoke 74:124. 1125 in icigarette smoke, 6a:296,297 effects on resistance of squirrellmonke7s to pneumococcus 711:17 3 pharmacolbgy of 64:266 smoke content of 64:266 Nitroglycerine effect on blood circulation in' coronary disease patients 67:61-62 effect on blood circulation in, normal individuals. 67:6 1-624-Nittoquinoline: l -oxide alcoholic s;olution of, development of papillomas in mice drinking 71,:292' Nitrosamines eftect'on lact'ating,hamsters73:139 role in respiratory tract carcinogenesis, in animals 74 :4 7' N-nitrosamines 69:62' carcinogenicity 67:127 carcinogenicity in cigarette smoke 71:264.266 determihatiom in cigarette and tobacco smoke condenstate. 73:87; 88 esophageal neoplasms inducedlin animals by 71:292 in tobacco smoke 67:127 N-nitrosoanabasine, 69:62 N-Nitrosoheptamethyleneimine incidence of lung,neoplasms, in rats 75:49 N-nitrosonornicotine, in tobacco 69:62; 75'48; 49 Nonrespondentsg age adjusted death ratesini 64:114 magnitude of, in surveys64c97 mortality ratios in 64:116 proportion of smokers in 64:114 Nonresponse bias, 64:96, 104, 1115' Nonsmokers age-adj usted mortality'in 64:100 by age and sex, U.S. 6'4:1I78 airway, resistance in. 64:292„293' allergic and irritative reactions to ciga- rette smoke 72;128,129 allergic skin reactions in, 64;319 allergic symptoms in, fiom tobacco smoke exposure 72~1I10; 111 bladder neoplasm risk in 64;2222 bladder neoplasms in 64:223' body weight of 64k3'84, 385 carboxyhemoglbbin effects on oxygen uptake 7i:611 carboxyhemoglbbin levels in 72:125' chronic cough prevalence in 64':299, 302 coronary diseases rate in 64:322„323' emphysema in 64<297 epithelial changes in 64:170, 173, , 1189 epithelial changes in, females 64:170 187 a El I CJ ~'. . 0 . OD

ext'roversion in. mortality rates, by amount smoked 64;366 67:1477 forced expiratory volume in mortality rates, by smoking,classification. 64:290„291 67:147. hemoglobin concentration in Noxious gases 64:319 exposure magnitude of' I.Q,. measurement of' 64:296„297 64:370 in respiratory diseases liver cirrhosis in 64:279 64':342 Nutritional deficienoy hmg,neoplasms in 641: 3'41 64':11'8„184', 191,,193, 230, 232 morphology of 64:385„386 mortality rates in 64':100„102, 1'1I7, 118 Oat cell carcinoma mortality ratios in see Carcinoma, oat cell 64':163„202; 301 Obesity occupational factors ini 64:38, 321, 355' 64:187 coronary diseases mortality and oral neoplasms 64:321;71;43relationship to smoking and CHD 64:202 passive smoking and 71:43-45 72:121'-125' relationship to smoking' in peripheral as percent of' population arteriosclerosis 64:114 71:72 pneumoconiosis in. as risk factor for CHD 64:298 72:16; 73:9 psychosomatic disorders in Occupational diseases: 64:367, asbestosis respiratory conditions in 73:411 64:2899 asbestosis, in asbestos workers„in Singa- risk ratios in pore 64:222, 223', 230, 232 74:95' urban-rural mortality in bronchitis 64;186„1941 72:42 U.S!, by age. bronchitis and respiratory tract irrita« 64:17,8 tion, in rubber industry workers see also Smokers vs: nonsmokers 74::96 Norepinephrine bronchitis, im cementiand rubber in- 64:318' dustry workers effects of nicotine 74:95,,96 75:29 bronchitis, in wool and cotton textile Nornicotine workers 69:62 74:93, 94 structural formula byssinosis. 64:49 73`.3'9, 41 North Dakota~studies byssinosis, in cotton and wool textile 64:323 workers Norway 74:93,94 coronary death ratesim byssinosis in cotton millworkers 64:320 75:68' incidence rates of 11mg,neoplasms chronic obstructive pulmonary disease 69:55-56 72:3', 4244 lung',neoplasms in, for pipe smokers chronic obstructive pulmonary disease, 71:244 in autoworkers 11rng neoplasms mortality in, relationship 74:80 to tobacco use chronic obstructive pulmonary disease, 647176;,71:245-246 in firemen neoplasm risk in 75:68 6'4 ;1127 coal workers"pneumoconiosis tracheobronehialltree changes in smokers 73:42 and nonsmokers ofl lung neoplasms in uranium miners 7 8:259 75:47' Nosee effect of'smoking pneumoconiosis 64:275 72:42-44 Nose neoplasms pulmonary fibrosis 64:193 72:44 1188

and risk of neoplasms 75t43 smoking and 72t3„ 42-44 ; 74I:93-96; 75:68-70 see also Occupational factors; Occupa- tional hazards; Occupations Occupational factors 64:224' chronic bronchitis and 641:298', 299„300, 302 coronary disease and 641:321, 322;,73`.5„7 lung neoplasms and. 64:95, 187„193'; 194„232 mortality and 64:112, 1134 smoking prevalence and! 64:362, 363 see also Occupational diseases;,Oecupa- tional hazards; Occupations. Occupational hazard§. 64:100,10'1,2~32 air polllrtioni exposure in Boston police- men 74:82; 83 asbestos exposure 67:35; 73:4111 asbestos exposure and smoking as factors in lung,neoplasm development 74:41143;,75':49 in bladder neoplasms 64I:222I bladder neoplnsms, and!smoking 73:78 carboxyhemoglobin levels in workers ex- posed to exhaust gases 75:211 coaldusUexposure 73':41-43': from coal tar 64I:147' cotton, flax„andihemp dust exposure 73:39-41 dust exposure 73:43, 44' exposure ~p chemicals; fumes, sprays and dusts, in smokers vs, nonsmokers, byy race, and sex. 75:69; 70 exposure to 100% pure oxygen 73':4'3 higher reporting of exposure to, byy smokers vs, nonsmokers. 75:68 in lung neoplasms, 64!:232' myocardial infarction as 64!:323'nitrogen dioxide, in~ 641:266I pancreatic neoplasms and 73:77' pulmonary disease from 64':266; 298„299, 300„302' radiation exposure in uranium miners 73:72'2 risk ratios in 64:31, 134 rubber industry fumes and smoking 74:96 smoking andi 72`.3„4, 42-44; 73t39-44 smoking as additive risk forCOPD 73 `.5'5' textile:dust exposure and smoking 74;93-966 uranium exposure 67:35 see alsa Occupational diseases; Occupa- tional factors;Accupations Occupations asbestos workers, lung neopl9sm morbid- ity 67;141 asbestos workers, lung neoplasm mortal- ity and smoking, 71:257' asbestos workers, respiratory tract car- cinoma 71:2566 bank employees, smoking and COPD 71:198' coal miners, impaired pulmonary func- tion in smoking 71:163'' coal miners, respiratory tract carcinoma 71:256 coal miners, smoking and COPD 71c153', 197, 218-219 coal miners,, smoking and ventil9tory function 71I:207 flax mill workers„smoking and COPD. 71:1999 government employees, blood pressuree differences in smokers vs., nonsmok- ers 71:99 longshoremen, mortality from smoking- related cerebrovascular disease 71:70 longshoremen„mortality rates from CHD: in 71:28 longshoremen, smoking,and COPD' 71:28 longshoremen, smoking and ventilatory function 71:208 medical students, serum lipid differences in smokers vs. nonsmokers 71:98 medical students, smoking and nicotine effects on blood lipid levels. 71:124 medical students, smoking,and thrombo- sis relationships 71:130 medical students, smoking and ventila- tory function 71:209-21I0 mortality rates„smokers vs- nonsmokers by. 67:11 nickel workers„lung neoplasms in 7,1':256

physicians, bladder and, kidney neo- plasms in smoking 71I:293', 294 physicians, cessation of smoking effect on COPD: 71:142 physicians, COPD' mortality rates 71i:149 physicians„decline in cigarette smoking rates 71'.48' physicians„ mortality from smoking- related cerebrovascular disease 71:68 physicians, mortality rates from CHD 71:26' physicians, mortality ratios from esoph- ageal neoplasms 71:290 physicians, mortality ratios from peptic ulcer in smoking and nonsmoking 71:424 physicians, pulmonary function follow- ing, cessationot smoking 71:149 physicians, smoking and ventilatoryy function 71:209L210, 213 plant, workers, occupational expasure and smoking,relationships to COPD 71i:153', 2'1i8, 219 plant workers, smoking and COPD 71':198' plant' workers, smoking andi ventilatory function 7l :206-208 post office workers, blood pressure dif- ferences in smokers vs. nonsmokers 71:104 post office workers, smokers and ventila- tory function 71:209 post office workers, smoking and COPD 71:200;202 prisoners, serum lipid differences in smokers vs.,nonsmokers 71:1000 prisoners, smoking and nicotine, effeetss on peripheral vascular system. 71:133' railroad employees; mortality and mor- bidity, CHD and smoking 71:28, 34„97' and respiratory symptoms by smoking habit. 67:97 smelter workers„ lung, neoplasm mortal~ ity from,arsenic exposure 71:257 smoking habit for 67`.143 soldiers, smoking and COPD 71 :1I97 steel workers, COPD development from dustiexposure 71:153 students, carbon monoxide effects onn bloodllipids 71:129 students, infectious respiratory disease in smokers vs. nonsmokers 7dI:228-229 students, mortality from smoking-related cerebrovascular disease 71':68' students, mortality rates from CHD 7'1I:28' students, smoking and COPD 71L201 students, smoking and nicotine effects on blood lipid level 711:125 students, smoking and, thrombosis rela- tionships 71':130 students, smoking and ventilatory func- tion 71:211 telephone company employees, smoking and COPD 71:200 textile workers, occupational exposure and smoking relationship to COPD 71:2ii8-219 transportation workers;, air pollution re- lationship to COPD 71:198, 202' transportation, workers, smoking and COPD 71:198s202 transportation, workers, smoking and ventilatory function 71:207, 212 uranium miners, lung neoplasms in, smokers and nonsmokers 71:2566 uranium miners; lung neoplasms morbid- ity by smoking habit for 67:143' utility company employees, CHD mor- bidity in smoking 71:30 veterans, bladder and' kidney neoplasms in smoking 71:294-295 see also Occupational diseases; Occupa- tionali factors;, Occupational' hazards Office of Science and Technology 64:8 Oleic: acid suspected carcinogenic agent inicigarette smoke 71:266 Olive oil penetrability of benzo(a)pyrene in mice esophageal epithelium 71:292. Opium. 64:349 Optic nervee atrophy, and cyanide in tobacco smoke 67:183' sensitivity, amblyopia from 64:341 Oral Idiseases; non-neoplastic smoking and 69:5:61, 85'_87 ; 72:6 3 ,I 1', 90 ~

Oral hygiene, relationship to smoking' and noncancer- ous oral disease. 69:85'-86 smoking and 72:6 Oral mucosa 64:203', effect oflcarcinogens in laboratory ani- mals 72:70 effect of' cigarette smoke 72:6, 69 effect of reverse smoking 72:699 effea of tobacco/bidi~ smoking and chewing, 72:69 Orallneoplasms 64:37,19:6•204,233 alcohol consumptioni and smoking etiology of 73` 193; 74-5'3-55' amount'smoked in 64I:233 cigar smoking in 64:189 epidemioltrgic studies 64;1196-202; 74:53-55 estimatedlincidence iniU_S: for 1970 711:284' experimental indUetion ofl 64:233 incidence of secondary primary, smokers vs. nonsmokers 75:50 income gradients in 64:134 inhalation patterns'and 73:191 mortality rates in 64:37; 133;,71',:285' mortality rates'in, in females 64:131, 132 mortality rates inlin foreign born, 64:131 mortality rates inl in Irish 64;135 mortality rates in„in males, 64:130, 132 mortality rates in Japanese male smokerss vs. nonsmokers 73:74 mortality ratios for pipe, cigar„ and cigarette smokers vs. nonsmokers 73:191-193' mortality ratios in 64:11'3;202 mortality ratios inj in cigarette smokers. 64:149 mortality trends in 641:137' neoplasm site by'tobaccouse in . 64;197' pipe smoking in 64:37„150,1i89:;72'.67 prevalence of, decline in 64:204 recurrent, ineidence ini smokers: vs:, ex- smokers. 73:71, 74'.75 relationship of tobacco use 7L:285, 289, 361-367 relative risk in tobacco smokers and chewers 72:70 relative risk of'~ development in pipe, cigar4 and cigarette smokers vs: non- smokers. 73:191, 194, 195 retrospective studies of 64:198, 199„200, 201 reverse smoking in i 64:203'„204;73`.76 risk gradients in, by amount smoked 64:233 risk ratios' in, in females 64:134 s,moking induced increase in, 64;197 smoking in etiology'of 64:204; 69:58; 71:289; 72:4, 67-70; 73:74-76 snuff in 64'•233 summary of previous fyndings on rela- tionship to smoking 74:52', 53 sum mary of'retrospective studies 73:194, 195~ and tobacco chewing 69:58' urban-rural factors in 64:133' in waiters 64:134 see also Gingival neoplasms; Mbuth neo- plasms; Oropharyngeallneoplasms Orallulceratlonn reverse smoking in 64:203 Organ cultures: cigarette smoke effects on cell' growth and reproduction in 71:267, 343'-345' Oropharyngealneopl9sms 64:201 frequency in smokers and nonsmokers 71:238' Oxidbreductases reduction of, in smokers' alveolar macro- phages 69:42113 Oxygen imcardiac function 64:318' debt, effect of smoking 73:246, 247' debt, exercise perf'ormance and in in 73:246, 2477 myocardial consumption nicotine stimulation 71:58, 75 irrsmoke. 64:60 of, following

tension„smokers vs: nonsmokers 72:22 transport in body, carbon monoxide effects. 71:60, 75' uptake in nonsmokers with specific carboxyhemoglobin levels 71,:61i, 75 Ozonee ciliastasis from 64:268 irritation action of 64;295 Ozonized gasoline 641:166 Pachyderma loralis 64':203 Palatal mucosa 64:275 Palatal l neoplasms 64:204 see also Mouth neoplasms; Oral neo- plasms Palate hamstery C-14 labeled smoke particulates deposition in 71:281'-282smoking and stomatitis:nicotina 69!:87 Pancreatic neaplasms . incidence in cigar/pipe and cigarettee smokers vs: nonsmokers 74:55, 56 mortality rates, by age 67:158-159 mortality rates, by amount smoked. 67:159 mortality rates, by sex, 67:158 mortality rates, by smoking,classification 6761,59 mortality rates„forwomen , 67:153 mortality rates in,Uhited States. 72:74 mortality ratios, by age 67:158 -159 mortality ratios, by age and amount s,moked 67:159 mortality ratios, by s;ex 67:158 mortality ratios, for men by smoking classification 67:159 mortality ratios, for women 67:1153 mortality ratios in Japanese male andd female smokers 72:74 occupational exposure; and 73':77' relationship of smoking, to mortalityy fiom. 71I:298'-299 1922 relative: risk in men by number of'ciga- rettes smoked. 74:55' smoking andl, 67:36, 158-159; 69:60-61;, 71!:113„ 238, 298-299; 72:5, 681 74; 73:77 summary of previous findings on re19- tionship to smoking 74':5'5 Pancreatic secretions bicarbonate content, effect of smoking 73:159,160i effect of nicotine in animals 73:161, 162' Papain, pulmonary effects on rats exposed to cigarette smoke with 71:163Paper chromatography 64.51, 57 Papillomas 64!:142',,165' development in mice drinking alcoholicc benzopyrene 71:292'2 formationi following skin, painting withh smoke tars 71:337-339, 341 induction in hamsters exposed to ben+ zo(a)pyrene 71:346-347' induction of 64':142„143;,144„203, 223 ttansformation,of 64':144. Papillomas, benign 641:142 ' origin of', 64;165' tar induced~,in mice 64; 223. Paraffin 64:147 Paralysis of ganglionic nerve cells 64:69 Paralysis agitans mortality, rates, smokers vs: nonsmokers 67:8' Parasorbic acid!lactone 64:145' Parathion 62:145 Parents incidence of penumoniai and bronchitis in childten of'smokers. 75:105„106 influence 64;369;370 prevalence, of respiratory symptoms in children ofl smokers 75:102;103 smokers cough and phlegm production, and respiratory symptoms in children, 75:103 see also Smoking,,parental Paris green 64:61

g Particulate matter and 1lmgneoplasm development~ 74::44,45' pollution levels in four U.S. locations 75':65, 66 Particulate phase, cigarette smoke 64:51'-60 ; 263, 26'4,, 265 carcinogenic accelerators in 72;5, 65' effeot on pulmonary and cardiac struc- ture and function 727:78 harmful constituents in. 72:143'. Particulate phase, tobacco smoke composition of 64:51 deposition,sites of 64:264, 265' gravitationalisettGng of 64:264 measurement of: 64:263'T removal of' 64:264 respiratory damage from 64': 279 , retention of' 64:264, 300 water content of' 641: S 1. Passive,smokers pathologic studies 75'99 summary of' previous findings 75:87, 88 summary of recent findings 75':107;108 Passive smoking CO;, nicotine, benzo(a)pyrene, acrolein and I acetaldehyde levels 75:90-95' effect on cardiovascular function in dogs. 73:14 effect on children, 72:1z9,: effect on respiratory tract in laboratory animals 72:129;130 effects of carboxyhemoglobin levels, in persons with angina pectoris 75:95, 97 effects of carboxyhemoglobin levels on. CO absorption, 75:95' 96 effects of CO in tobacco smoke onn psychomotor performance . 75;99-101 effects of exposure to cigarette smoke„ in passive smokers. 75:99 effects of tobaceoismoke constituents 75 :88-98' effects on bus and plane passengers 75:102: excretion of nicotine 75':9 7 exposure to cigarette smoke,and!devel- opment of eye and throat irritations 75:99, 100, incidence of pneumonia and' bronchitis in children of parental smokers : 75:105, 106 maternal smoking, and development of bronchitis and pneumonia in infants 75:103,104 in neoplasm induction in laboratory ani- mals. 72:130 parental l cough and': phlegm production, andl respiratory, symptoms in children 75:103' Patliophysiological Ist udies alveolar macrophages and' smoking 75!:76; 77 effects of cigarette smoke on leukocytes, in guinea pigs 75:77, 78' effects of cigarette smake on pulmonary macrophages, in guinea pigs 75 i77, 78': effects of smoking, on tiacheal! mucus velocity, in dogs 75i78 suppression of' immunoglobulin response by nicotine or water soluble fraction of'cigarette 75:77, Patulim 641:14'5 Peak Flow Meten 64:290: Pearl's hypothesis 64:105 Peengroup status. 64;372,373 Penicillic acid. 6'4:1I45 Penis skin neoplasms of' 64:147 Pentacyclic compounds 64:54 Pentolinium blockage of nicotine cardiac stimulation by. 71':57' Peoples Gas Company Study epidemiologic study of smoking and' CHD 74:6, 7 Peoples Gas Light and Cbke,Co. study of CHD, serum cholesterol and smoking relationships 71I;43' Peptic ulcer 64:337-340 antacid efficacy and healing afs effects of cigarette smoking on 71:423 cessation of smaking,as therapy'for, 67:182 cigarette smoking in, 64:39' 0 H 0 I 1 Q 193

clinicalJstudies 73:155-157 development in smokers 71:13 and diet 67:182' duodenal, and,smoking, 67:39 epidemiologicaf studies 73:155'-1I57 gastric, morbidity, and smoking 67:40, 182 gastric, mortality, and smoking 67:40, 1181-182 gastric secretion in smokers vs. nonsmok- ers 73:157, 158'' incidence rates„smokers,vs: nonsmokers, by sex 67:182 increased mortality in Japanese smokers vs: nonsmokers 73:1I5'5'„156 increased prevalence :in male smokers. 72:97 and lung;neoplasms, relation to smoking 69:57 morbidity; and smoking 67:4'0; 18'll mortality rates. 67:40; 71:423' mortality rates, by amountismokedl 67:182 mortality rates, by smoking classification 67:182 mortality rates, smokers vs. ex-smokers. 67:181 mortality ratios:, for men by age 67:181 mortality ratios fh.om. 64:399,340. mortality ratios from„ in smokers andi nonsmo kers 71:424 mortality 'ratios froma, smokers vs: ex- smokers by age: 67i181 mortality ratios in Japanese adults by age started smoking 73i1155„156 mortality ratios in male cigar and pipe smokers 73;2222 predisposing,f'actors 73':157 recurrence inismokers vs, nonsmokers 73:157' retrospective and cross section study methods for smoking relationship to 71I:42542'77 smoking and 67:22', 39130, 181-182; 72:5, 64 97, 98;73:155 smoking as cause, in~dogs. 72:26' Perception ofl health i hazards; and smoking behavior 67:19ai 194 1,8;9-Perinaphthoxanthene: 64:54 Perinatal studies effect of! maternal Ismoking,on mortality; summary of' findings 73':134,,1,35' maternal smoking and' 72:83-88 Periodontal diseases smoking and! 69:85-86;,72:6 smoking and, in Ceylon. 69:85-86' smoking and„ in I+Forwegian Army re cruits 69::85I Peristalsis. 64':71I Peroxides suspected carcinogenic agea in cigarette smoke 71:265 Personality characteristics 64;365-368 and!coronary disease 64; 321; 67:57' coronary disease morbidity ratios, smok- ers vs: nonsmokers by 67;57' drug use and 64:353' relationship to CHD and smoking 71:48-49„ 105-106 in smokers, 64:326„365.368 and smoking Habit' 67:57,,188'192 and' smoking habiU in college students 67:189 Pesticides 64:61, 62', 145' content imcigarette smoke 71:265'„266 pH pipefcigar~smoke inhalation,andI 73t1183 of smoke in, cigarettes, cigars„and little cigars 73:223, 224, 228, Phagocytosis 641:3'5; 267, 269, 270„300 effect of cigarette smoke in laboratoryy animals 73:53', 54 effect of cigarette smoke in rabbits: 72: 109, effect of tobacco smoke 72:47=48' pulmonary alveolar, in smokers vs. non- smokers. 71:165' Pharyngeal fungi smokers vs. nonsmokers in South~ Africa 73:5'4 Pharyngeal Ineoplasms 64:2011„202 frequency in smokers vs. nonsmokers 71k238

4 incidence of secondary primary„smokers vs. nonsmokers 75:5'0 , mortality rates, by smoking,classifioation 67:35„146-147 mortality rates„ cigar smokers vs. non- smokers 67:146: mortality rates; for men by amountt smoked 67:147' mortality rates;,for women i 67:153 mortality rates, pipe: smokers vs. non- smokers 67:146, mortality'ratios 67:35 mortality ratios, by smoking classifica- tion 67:14'6, mortality ratios, for cigEr:smokers 67:35 mortality ratios, for, ciggr, smokers by age 67;1466 mortality ratios, for men by age 67:146' mortality ratios, for, men by amountt smoked 6"1:146-147' mortality ratios; for pipe smokers 67':35 mortality ratios, for pipe smokers by age 67`.146 recurrent, incidence in smokers vs,. ex smokers. 73:74, 75' relationship to tobacco use 71_362.364, 3W retrospective studies of, by type of smoking 64:200, 201 smoking in etiology of 67:35,145'„147 Phenols 64:49;54;58,59,61'„62,145,267' in cigar, pipe, and cigarette smoke 73 ii17,7 ciliat'oxic agents 67'a08 cocarcinogens 67 `.131. as probable contributors to health haz- ards of smoking 72:144 suspectedlcarcinogenic agent of cigarette smoke 71:266 in tobacco smoke 67:1I29 tumor promoting,agents 67:129 Phenotypes partially deficient heterozygote;, in COPD etiology 75:73;741 Phenylmethylbxadiazole (PMO) protection against'adverse effects of ciga- rette smoke,in animals 73'::49, 53 Philadelphia Pulmonary Neoplasm Research~ Projectt lung, neoplasm histopathalogio studies and 74:38 Phlebitis 644:103 Phlegm productionn by occupation and smoking,habit, 67:977 by parental smokers, and development of respiratory symptoms im children 75:103 by parentall smokers„ and incidence af'pneumonia and bronchitis in children 75i105„106 by smoking habit andisex, 67`.98 Phospholipidss function as surfactants in lung tissue, 71:172, smokers vs: nonsmokers 71:99-100,102 . Physical activity. 64;322 as a factor in coronary heart disease 73:4,5 myocardial I infarct morbidity ratios, for smokers vs: nonsmokers by level of 67:566 occupational„and smoking habit. 67:56 relationship to myocardial infarction, smakers vs: nonsmokers 71':44 and risk of cerebrovascular accident 67:68' smoking and, relationship to CHD 71:41, 43,,44 Physiquee smo kers. 64:383-387 Phytadiene 64':5ii Phytoli structural formula.of 64:52 Picoline 64 c59 Pigmentationn induction of 64:14'6 Pi'gments 64:272' in lungs of emphysematous patients, 64:273 Pinocytosis decrease in alveolar macrophages, inn smokers vs; nonsmokers 75:76 effect of nicotine, in mouse peritoneal macrophages 74:105' 195

Piperidine, nitmsa Poisson distribution suspected carcinogenic properties in ciga- in mortality rates rette smoke from. 64:117; 118, 11'9 71:265 Polandd Pipe smoke bladder neoplasms, in„ methods and' re- see Smoke;,pipe sults inretrospective studies of smok- Pipe smokers ing,and see Smokers, cigar and pipe; Smokers, 71:382; 383 pipe CHD mortality and morbidity in, Pipe,smoking 71:96' see Smoking;, pipe esophageallneoplasms in Pblish-born Pipe:tobacco 64:135 see Tobacco, pipe esophageal! neoplasms in„ retrospective Pitch. studies of tobacco use withi 64:147, 229' 64:214; 71:378' skin neoplasms from gastric neoplasms in Polish-born 641:33 64:1135' Placebos laryngeall neoplasms in, retrospective ginseng root as studies of tobaceo use with~ 641:355' 64:205,108:;71,:357 nicotine4ree cigarettes as lung neoplasms, in males 64:70 Placenta 64'aI35 abdity to hydroxylate benzo(a)pyrene in oral neoplasms in, retrospective studies smoking,mothers ofltobacco use with 71:407 64':200,201;71:364 morphology serum lipid differences in smokers vs. 64:343 nonsmokers in Platelets 71:100„102 see Blood platelets smoking and nicotine effects on humann Plethysmogram blood levels in abnormalities, in, smokers vs. nonsmok- 71:124 ers smoking relationship to: thrombosis in ~ 73:22 71:13i Pleural neoplasms Poionium 210 mesothehomas, classification of 64':145' 64:174 carcinogenicity67:128 Pllunbers neoplasm risks in in cigarette smoke 64:13a' 67:128 Pneumoconiosis levels in llmg, tissue,, smokers vs. non- 64:269, 290, 298 smokers in coal miners: 67:128 72:4244 and lung neoplasms in coal miners, smokers vs. nonsmokers 67:128 73:42 suspected carcinogenic agent inicigarette smokers vs. nonsmokers. smoke 72:4244 71:265-267 335'-336' , Pneumonia in tobacco leaf' 64:277, 2941 3022 67:128 epithellal changes in, as tumor initiator 64:170 67:128 incidence in children~of smokers Polyoma virus 75:105',106 64;166 maternall smoking, and development' in Palyphenol9 infants 64:54 75:1,03' Population studies, mortality ratios in British physicians, mortality and smok> 64!:276 , ing (Dall and Hill Study) neoplastic-like pathology in 67:5' 17, 52' 93 139; 15'5' 182-186 , , , , 64t195 bronchitis and smoking in passive smokers, summary of recent't 69:37 findings Canadian: pensioners smoking and health 75:108 study phenol induction of 67:5, 48 93; 138 154' 1159 „ „ , 64;267 U.S. population, mortality and smoking Pneumothorax, spontaneous (Hammond) smoking,andl 67:5, 1,3, 49-54'„66 69 94,,135-1,37 , „ „ 73:37 146-158, 181-189 196

U.S., veterans, mortality and smoking. (Dorn) 67:5', 13, 48-49, 67-69, 92„137-139,, 146'-159,,181-184 Pbrtland!student study 64:368 Postal employees breathlessnessin 64:286 chronic cough in 64:281 Post-operative complications in duodenal ulcer removal, smokers vs. nonsmokers 73:157 incidence in bronchitic and nonbron- chitic smokers vs: nonsmokers 74:92' pulmonary, smokers vs. nonsmokers' 711:174-175';,72 `.38 smoking, obesity, anesthesia and 73:3'9 , Potassium. 64':55 Potassium-40 64':14'5 present in tobacco deaf' 7i1:266' Preeclampsial maternallsmoking,and 69:79;72:84;73:142 in smoking vs:,nonsmoking women 71I:404,407;,73:14'2 Pregnancy carboxyhemoblbbin levels in fetuses 75:26s 27 carboxyhemogJbbin levels oflsmokers.in 69:80i effect of blbodl pressure and smoking habits on. 69:77=78' effect of nicotine on, in rats 69:80, effect,af smoking during 641:343; 67:185-187; 69:4-5, 77-81; 71:4, ~.3, 82:87, 389, 397=399, 415; 73:10~~142 effect of smoking,during; and develop- ment, of bronchitis: and pneumonialinn infants 75:103;104 effect of smoking during; in Hungary, 69:79 effect of smoking during, in Ireland 69:79 effect of smokingduring; in Scotland. 69:79 effect of smoking, during, in Venezuela 69:79 effect of tobacco smoke, nicotine, and carbon monoxide in laboratory ani- mals 73;1114-118' effects of nicotine on uterus during 67 `.1i87 human, methods used in smoking study of 71:391-396' nicotine effects on myometrial strips in 71:408 and previous smoking,habits, effect on infant birth weight 73;112-114 summary of previous findings 75:5, 6 timing' of influence ofl smoking on birth weight 73`.120,121 unsuccessfull smoking effects on 71:13 see:also Maternalfetallexchange; Smoking, maternal Premalignant lesions inibronchi 64:27 in epithelial tissue, 64':2311 in oral' cavity. 64':142 Prematurity' and maternal smoking 64':343;, 67':185-186;, 69:77, 79;. 71:390, 400403; 72'c5y 83-87;. 73:112 and maternal smoking, aman&I9egraes 69:78 Presbyterian Hospital Study 64:14'1,174 Pressure-volume work loops: 64:292' Prevalence studies 64:301 in branchopulmonary disease 64:280-293 pulmonary function, tests in 64:280 sputum productioniin 64:383 Printing ink 64:193 Professional workers smoking;incidence of. 64:187 Promoting agents : 64:26, 142',,146„229 ethyl alcohol as 64;217 urethan as 64:142 Propane 64:60 beta-Propiolactone 64:14'5. Propionaddehy,de 64:52 Propionic acid ciliatoxic agent. 67:108 in tobacco smoke 67`.108 Propylene 64`W Prospective mortality studies age adjustments in. 64:84 197' 0 I fi

alcohol in 64:99, 101 by American Cancer Society 64:81, 96„101 by Best, Josie, and Walker 64:81 British doctors s,tudy as 64:97,102,109 California occupational study as 64:95;106 Canadian study as 64!:91, 92, 94 cause of deathlin 641:109 , certification validity in 64:109;110 city population size,in 64:99 comparison, of 64:83 by Dorn 64:81 by Dunn, Buell, and Breslow 64':8i1 by Dunn, llinden, and' Bteslow, 64:8i1 educational level in. 64':100„101 exercise in 64':1011 in ex-smokers. 64:93 fried foods in 64:100 genetic longevity in 64:99 by Hammond 64:81 by Hammond and Horn 64:81 infectious diseases in. 641:276 inhalation practices ini 641:99 limitations in 641:94;95', 96, 111, 163 maledeath rates in 64:28 maternal smoking in 64:343 mortality ratios in 64:84,118 nonresponse, bias in. 64:96, 97; 104 occupational exposure in 64':100„101 previous disease in 64:100, 101 religious factors in 64~:99, 1011 smoking data in 64:82 socioeconomic factors in. 64:96 tranquilizers in 64:100 twenty five-state study as 64:1'03',104 type of smokers in 64;82 usable,responsesin 64:96 L1.S. veterans study as 64:9'1, 94„96',, 97„PA3'. variables affecting 64:84 weaknesses ofl 64:96 Prospective studies 64':27', 28, 30, 85-116'„ 293, 294, 322, 323' bias in 64:36 by Doll and Hill 64:811 esophageal i neoplasms 64c217' excess deaths in 64:28 in gastric neoplasms 64:227' methodology of 64:81methodology of, in peptic ulcer 64t338', 339 morphology correlations in 64:385, 386 neoplasms 64:231 neoplasms by site 64:149 reliability of 64':1I80 Prostatin:neoplasms 64"135,136 mortality rates in 64':1I31 mortality ratios in 64':148„149 Protesrtants smoking prevalence in 64'c364' Protozoa cillary function in, effect of cigarette smoke on 711:1165, 224 Pseudoep}iedfine 641:3'49 Psychoanalytic theory. 64:367 Psychomotor performance effects of CO in tobacco smoke 75':99-101 in passive smokers„ summary of recent findings 75!:108' Psychosocialfactors in cardiovascular disease, 64:327 smoking habit 67:39, 1188-192 PSychosomatic disorders inheavy smokers 64:367 Psychotherapy cure of tobacco habit by 64:354 1198

Public Health Service 64t6, 13', 127,,341 ' 1967 study of', starting point for new studies 71:4' review of inediea{ literature omsmoking hazards 71:7. Public transportation effects of passive smoking on bus and plane passengers 75:102. Puerto Rico esophageali neoplasms in, retrospective studies of tobacco use with 71:378. relationship, ofl tobacco use and neo- plasms of orallcavity in 71:3'6'7' Puffineten ratios 64,:291,292' Pulmonary alveoli changes in rates after exposure,to nitro- gen dioxide 69:41 effect of smoking on 64:274,275;67:30;107 epithelium 64:165' epithelium, experimentally induced changesin 64:272 fluid' lining,,smoking effects on 64:269,270 rupture; in pipe/cigar smokers vs., ciga- rette smokers and'nonsmokers 73;217 septa„rupture of 64:35, 274!, 275, 301 septa,thickening of. 64': 275 stability, cigarette smoke in 64:35, 300 Pulmonary clearance effeaof heavy smoking 73:52,i53 effect of nitrogen,dioxide,in rats 74':103~ effect of's,moking 72:3,47;73I:55s741:101',102 effect oflsulfur dioxide on 64:295 mechanical vs. baetericidal clearance inn guinea pigs 73:5'3 mechanism, in smokers vs., nonsmokers. 73:5'2, 53 in monozygotic vs. dizygotic twins 73:51 particle deposition in smokers vs. non- smokers, 73:5 3' in smokers; ex-smokers„andinonsmokers with~ and without pulmonary disease 74':100„1,01 see also Pulmonary function Pulmonary diseases see Lung diseases Pulmonary edema nitrogen dioxide in 64!266 Pulmonary embolism. 64:103 Pulmonary emphysema see Emphysema. Pulmonary fibrosis 64':35,301 inasbestos textile workers 72:44' autopsy studies;,smokers,vs, nonsmokers 75':74-76 chronic 64:277-294! in heavy smokers 64:274 in moderate smokers 64:274 obliterating 64;266, in pipe/cigar smokers vs: cigarette smok- ers and nonsmokers: 73:217' smokers vs. nonsmokers 71r.161, smoking and 67:107;72:44 Pulmonary function 64:35' abnormalities, and' rheumatoid arthritis in smokers vs. nonsmokers 74':92,93 abnormalities, during viral ilhtess„ in smokers vs. nonsmokers. 75:63 in asymptomatic young men in Romania 73:39 before and after smoking one non-filter cigarette 74:99 of Boston policemen~ smokers vs. non- smokers 74`.82;83 closing,volume abnormalities as indicator of small aiiways disease 75:71, 72 in coal miners, smokers vs. nonsmokers 73:4'2; 4'3 in coal miners vs: nonminers. 73:42' decline in~forced expiratory volume, in smokers by race 75: 7 2' diffusing capacity, smokers vs. nonsmok- ers in Berlin,, New'Hampshire 73:50, 51 effect: of asbestos exposure and smoking 73:41 effecU of cigarette smoke, in monkeys 74:102 effeeU of coal dust exposure and smoking 73:41-43 effectiof dusTexposure and smoking 74:95 effect of exercise, performance and smoking 74:99 199

effect of isoproterenoL in ~ smokers; non- smokers and bronchitics 74:99, 100 effect of lung hyperinflation in coal miners 73:42, 43 effect of nitrogen dioxide, in animals 741:102, 103 effectof smoking 69:5„42; 72:37, 38; 74:80 , effect on exercise performance in smok- ers vs:nonsmokers 73:246, 247 in ex-smokers 73t39 of insurance company employees, smok- ers vs. nonsmokers 74:80„81 in jet fighter pilots, smokers vs. non- smokers 73c43 of male and female smokers, in New, Guinea 74':81, 82. of male executives, smokers' vs. non- smokers 74':811 in males from industrial town in Hng- land,,smokers vs. nonsmokers 68:69 of pipe and! cigarette smokers„ex«smok- ers; and nonsmokers 74:99 in pipe/cigar smokers vs, nonsmokers 73:217, 221 prevalence of deficient heterozygote phenotypes„in smokers vs. nonsmok- ers 75 :74 pulMonary hypertension and 73:43 respiratory flow,resistance 64:266 smallauways disease, smoking, and 74:84-87; 75:71', 72 in smokers vs. nonsmokers 67:99-101; 72:40; 73:55; 74:80-82 in smokers vs. nonsmokers in Berlin„ New Hampshire 73:50, 511 in smokers vs. nonsmokers, under 30 years ofage 73:50 smoking and 73:38; 39 summary ofirecent findings 75:78 tests 64!:278; 292 volume tests 64:2921 in youngsmokers 67:110=111. see also Pulmonary clearance; Respira- tory function tests Pulmonary heaff disease COPD and 72:24 200 smoking as cause 72:24„27 Pulmonary surfactant effect ofsmoke 67 1'10; 72:48' effect of'smoking 69:42;73`.55 Pyelitis 64:224 Pyrene 64:59,147 in cigar, pipe, and cigarette smoke : 73'.178 Pyridine 64:54,59 as suspected contributor to:health haz- ards, of'smoking 72:145 3-Pyridylacetic acid 64:72' gamma- (3-Pyridyl)-gamma-methylamino butyric acid 64c71, 72 gamma- (3-Pyridyl)-gamma~oxo-butyrio acid 64:72 Pyrolysis 64:50,53„59;62 Pyrrolidine, nitroso. suspected carcinogenic properties in ciga- rette smoke from 71:265 Pyruvic acid 64:51' Quassia 64':354 Quinine 64;354 Quinoline 64:54 Rabbits atherogenic effects of carbon monoxide and hypoxia 71:64 atherogenic :effects of nicotine 71.120-122, bloo& lipidk in, smoking and nicotine effects on 71':127 cardiovascuLir function in, smoking and nicotine effects 711:108, 109 cholesterol fed, carbon monoxide effects on 71 C 65-66 ciliary function in, cigarette smoke ef- fect, on 71:221-222 ciliastasis in 64:268 coronary bloodlflow in~ 64:318

leukoplakia in 64:233 neoplasm inductiondn 64:143, 146, 202, 203 offspring, nicotine and smoke effects on birth weight 7'1:4'07' offspring, smoking effects on stillbirth andlmortality 71r.411. pregnant; tritium.labeled nicotine effects in 71:413'' pultlnonary, changes in cigarette smoking. 71:159 puldnonary elearance in, cigarette srnokee effect on 71:164, 170;,1711 pulmonary damage in 64:266 skin painting„ smoke condensate effects on 71:267,338'. smoke deposition in. 64:265 Race 64:224;,363,364 as a factor in coronary heart disease 73:4, 5,23 as a factor in perinatal mortality in smokingvs: nonsmoking mothers. 73:129-132 as a factor in stillbirth rates 73'.L24;125 Radiation,exposure smoking and~ as cause: of respiratory cancers 73`.72 smoking,andi in uranium miners 72:64'„65 Radioactive carbon 64:166 Radioactive cerium 64:166 Radioactive particles in tobaccp leaf, tobacco smoke, and smokers' lungs 73:72' Radioactive substances epidermoid neopl9sms,from 64:1'66, 230 ~ asttacers 64:265 Radioactivity 64:145'„166, 193, 230 Radlonuclides 64!:193' Radium 64:145 Radbnn inhalation, 64`.145 Rat s. alveolar lining changes in~ 64:269,27U atherosclerosis in;,nicotine induced 64:3i9;71:120,121 blood lipids in; nicotine and smokee effects 71,:12'8 carcinoma, induction in 64':165' ciliary function in, cigarette smoke:on 71:221, 222' clearance mechanisms in 64:269 epidermoid lirng, neoplasm induction in 64':66' hepatoma induction in 64':145' LDg0 nicotine determination in female 71:412 lung neopl9sms,,from intrabronchial im, planting,of chromium compounds 71:258 lung, neoplasms, from nickel carbonyl and dust inhalation 71:256 lungs, cigarette smoke effects on sur- facta~nt~ activity 71:172, 225I mucous cell increase ini 64:269 neoplasm induction in. 64':143 offspring„nicotine and smoke effects an birth weight 71:407 pregnanty aromatic compound stimula, tion of placental BP=hydroxylase ac- tivity 71:4114 pregnant'4 fetal wastage and neonatal death in nicotine and smoking 71:411I pulmonary carcinoma induction follow- ing asbestosdust~inhalationi 71:257 pulmonary changes from chronic nitro- gen dioxide inhalation. 71:1611, 220i pulmonary damage in 64:269 respiratory tract, cigarette smoke:inhala- tion effects 71:268, 3491,353 sarcoma ind'uction in 64:266 skin painting, smoke condensates effect 71:267, 340: tobacco allergy in 64:319 trachea, cigarette smoke effects on 71:343 tracheal ligation, cigarette smoke andd papain effects on. 71:163 tracheobronchial tree, cigarette smokee effects on 711:268, 346•349 Reading ability in children of smoking,mothers 7d :407 Rectal neoplasms 64':103 201

RegistrarGeneral of England and Wales 64:134 Relative risk ratios, amount,smoked in 641:161 Cornfield method in 64t160 measure of 64t183 Religion 64:244 cure of tobacco habit 641: 354 in prospective studies 64::99;,101 and smoking habit'. 67:54, 97 smoking prevalence by 64:364' Reserpine nicotine cardiac stimulation blockage by 71:5'7' Residues 64:145 Resorcinol 64:54 Respiiationn effect' of' nicotine, clinical and experi- mentai studies 67c26, rate. 64:266 Respiratory function tests 64:289-293; 297 body height effect on 64:290 effect of smoking 72:455 in ex-smokers 67:100 smokers 71:146-147; 206-214 smokers vs. nonsmokers by sex. 67:99 smokers vs,. nonsmokers, twins 67:103 of'smokers with mild bronchitis : 69:39 by smoking,history 67:100 using radioactive xenon. 69:39 and young,smokers 67:100-101 seeatso Pulmonary function; Respira- tory system. Respiratory symptoms 68:69,70;7'1 effecUof air pollution and smoking 74:90,91 effectiof air pollution exposure levels in, telephone workers 75:67 effect of asbestos exposure, in smokers vs. nonsmokers 73:41 effect of cigarette smoke 68:73', 74 pipe/cigar smokers and cigarette smokers vs. nonsmokers, 72:3, 40 prevalence in cement and' rubber indus- try workers, smokers vs. nonsmokers 74k95, 96 prevalence in children of parental: smok- ers, 75:102; 103' prevalence in Duisburg, Germany,,by, age and cigarette consumption 73'.39 prevalence imex-smokers 73'.39 prevalence in~pipe andl cigarl smokers 712117, 220, 2211 prevalence in smokersvs: nonsmokers 73t55' prevalence in smokers vs: nonsmokers in Bordeaux, France 73:36 in school,children 6'7:69,70171. inismokersvs: nonsmokers 68:66, 6'7; 71; 75:62, 63 in, smokers vs: nonsmokers by amount, smoked 73:37 summary of previous findings 75':5' summary of previous findings on rela- tionship to passive smoking 75:88 summary of recent findings 75:78' in womeni 64:286 Respiratory system, acute effect of' cigarette smoke on hu- man pulmonary function 71:163, ,166-169animal, cigarette smoke instillation orr impltvntation effects on 71:268,346r348 animal, effect of' cigarette smoke inhala- tion: on 71:268-269, 349-353', defense mechanisms in 64:267, 268' effect of cigarette and cigar smoke on bronchial reactivity 71:164 effecU of cigarette smoke: on human ciliary function 71:165,221-224' effect of cigarette smoke on; human pulmonary clearance 71 :164, 1,70! effecuof smoking,on 67:1411 glossary of terms used in testing, 71:215 histological changes in smokers 64:270-274;71:1,5411157 improvements in function following smoking cessation 71':148, 149 ~ 202'

!i i irritation, prevalence in, rubber industry workers, smokers vs. nonsmokers. 74:96 pathological changes inieigarette smokers 71':175 postoperative complication in, of smok- ers vs. nonsmokers 71:174-1761 230 pulmonary alveolar phagocytosis in smokers vs. nonsmokers 71:165 pulmonary infarction, in dbgs inhaling cigarette smoke. 71:271 surface tension of, effect of cigarette smoke on 71:1n2,225' surfactant activity of'4 in smokers vs: nonsmokers 71:172, 225 surfactants in, definition. 71:172 see also Bronchi;,Lungs Respiratory tract diseases, 64;263-302 by amount smoked 67:97, chronic, definition 64:288 chronic, epidemiology 64:297, 298 cigarette smoking and 64:276 clinical evidence of 64:294 definition of 64'.289 epidemioiogy of 64k297„298 etiology of'~ 64k302' infections, in emphysema development 67:111 infections, prevalence in smokers 71:10;176 infections, smoking and 67':29;71:172;226'-229;72:3;38 non-influenzal„ in smokers vs. nonsmok- ers 72:48 pathological and,cytological changes in, of'smokers vs: nonsmokers 71:258-263 role of constitutional factors in. 67:102-1041 role of heredity factors in 67:102-104 rural vs. urban dwellers 67:97 smokers vs. nonsmokers, by age 67:100 smokers vs. nonsmokers, by occupation, 67:97' by'smoking characteristics 67:97-98 by smoking,cl9ssification. 6'7:97-98 in smoking-discordanti twin pairs. 67:102-104 twin studies 67:102-104 ventilatory function in, smokers vs. non+ smokers 71:175 see also Lung, diseases Respiratory tract neoplasms carcinogenesis induction in animals 74:46;, 477 by country, in females 64!:131' experimental induction of' 69:63-64 mortality rates. 67:147 mortality trends in 64:136' and smoking 67`.10 andismoking classification 67:147 see also Lung neoplasms Respondents age-adjusted death ratesin! 64;1i14 mortality ratios in 64~116 Restricted activity days by age, sex„and smoking,history 67:19-21 definition of 67:19 Reticul6 sarcoma and' cigarette smoke 67:148' and tobacco tars 67:148 Retinal sensitivity to tobacco 64:341 R etinoblastom a 6C 191 Retrospective studies 64!:27; 28-31,,150-157, 160, 161, 198;. 199' association of diseases in 64c160,,161I controlgioups in 6'4:181 definition of 64'.27 inhalation patterns, in. 64k159 laryngeal neoplasms 641:233; 234 lung neoplasms, and smoking, methodk 71:323•328 lung neoplasms, dltration of'smoking,in 64!:15 8' maternal smoking 64:343 methods 64:152, 153„154'„ 198, 199, 200 mortality studies 64:150 203

peptic ulcer 64':337 reliability of 64:1'80 risk ratios in 64:160,161 smoking characteristics in 64:156 Reverse smoking 64:203, 204 effect on orallmucosa 72z6;69,70 heat,effects in. 64: 204 leukoplakia.andi 73;76 nicotine stomatitis and 72:6, 69i 70 oral neoplasms and 73`.76 Rhesus monkeys 64:166 Rheumatic heart, disease mortality from 64:103, 325' Rhinitis 64':275 Rhodesia methods used in retrospective studies of smoking in, relation, to lung nea pl9sms 71:328', Risk factors in coronary heart disease 73:t6-18 Risk,ratios calculation of 64:183, 2300 on cessation of smoking, in lung, neo- plasms 64:187, 188 consistency of 64':1,82; 183 by lifetime cigarette,consumption 64:161 in lung neoplasms 64:187, 188' RNA, binding of polycyclic hydrocarbons to 73:86, 87' synthesis;,effect' of'cigarette smoke on. 69t62, 63 Rodents carcinogenesis tests in 64:142. ozone effect on 64!:14'2' Roswell Park Memorial Institute 64:174, 219: Rubber~ carcinogenic activity, of' 64:147 Rubidium-84 tracing capillary flow in coronary'bloody tlow 71:59 Rum 64:62' Running effect of smoking 73:24'3„244 Rural areas 64!:99' lung neoplasm incidence in, in Switzer- l9nd 7C:24'4 relationships of lung neoplhsm to smok- ing, air pollution and'71:252-255' smokers in 64:99, 364 Rural populations: lung,neoplasms in, suspected etiology ofl increased 71:276 Rural vs. urban populations bladder neoplasm prevalence. 64:225 mortality rates. 67:111 smoking and 67:97 Russia atherogenic effects of nicotine on rabbits in 711:120 atherosclerosis autopsy studies in 71:54 cigarette tar effects on rat tiacheo> bronchial tree,in 71:348 gastric neoplasms, in Russian-born 64:135 gastric neoplasms in Russian Jews 64':1,35 Rutinn structural formula of 64:54! 3aliva. 6'4:203' interference in action of'carcinogens.on oral cavity 71:288'. Salivary gland neoplasms 64:134 see also Mouth neoplasms; Oral neo- plasms Salivarygl$nds. 64:271 Sample selection bias resulting from . 64:180, 181 Sarcomas anaplastic, tar induction of 64:223 classification of' 64:174 formation following animal skin paintingg with smoke condensates. 711:338, 340: induction in rats by cigarette: smoke injection, 71:346-347 204

induction of. 64:1,44', 176 subcutaneous 64:143' Saslow Psychosomatic,Screening Inventory 64':367 Saturated fats 64:322 Scholastic achievemea 64:370, 372' School children smoking and respiratory systems in, 68:69, 70, 71 School grade level smoking prevalence by 64:3611, 36'2' Scotland respiratory symptoms in miners of 64:288,298 Scatoma 64:341, Scottish Home and' Health Department Standing Medical Advisory Committee 64:304 Scrotal neoplasms 6'4:1'47 Secondary infections 64:272. Sedation smoking effect as 64:350 Sedatives withdrawal treatment with 64:352 Selection bias in health studies 64':180,181 Selenium carcinogenicity. 67:1,28' in cigarette smoke 67:128' potential respiratory carcinogenesis 68; 92. Si~•nile keratosis 64:208' Sensory drives 64:354 Seven Countries Study epidemiologic study of smoking, and CHD 74:6 SeventhDay Adventists coronary disease incidence in 64:322' laryngeal neoplasm prevalence in 64:209 Itling,neoplasm prevalence in 64:1'55' Sex acute diseases in smokers and non, smokers by 67:22 ages of cigarette smokers by 711:6 bed days by, andlsmoking,history 6'7:20-21 bladder neoplasm mortality rates in United States by 67:154 bronchitis, prevalence rates by 67:96 cerebrovascular disease mortality rates, by'age and 6'7:66 cerebrovascular disease mortality rates, by'smoking,classification and 67:66 cerebrovascular' disease mortality ratios, by age and'. 6'J `.66 cerebrovascular disease mortality ratios, by smoking,classification and 67 `.66' chronic, diseases in smokers and' non- smokers by 67`.22, coronary disease incidence rates and' smoking history by 69`,21-22', 24 coronary disease mortality rates, by 67:25,47,50,56;69:13',1'7 coronary disease mortality ratios, by 67:49; 69':13~ cough and smoking habit by 67c98', effect of, in alpha-l-antitrypsin defir ciency emphysema 71:1!51 effect of„in lung neoplasms and tobacco u se 71:244, 329-333'' effect,of„in mortality in cigarette smok- ers 7 l i:276 .ffect of, on laryngeal, neoplasm, inci- dence development 71:277' emphysema mortality rates 67:91 esophageal neoplasm mortality rates 67:150 laryngeal neoplasm mortality ratesi 67:148' liver cirrhosis mortality rates, by 67:184 liver cirrhosis mortality ratios, by 67:184 lung neoplasm development by 71:111 lung neoplasm~ mortality ratesby 67:34', 134, 140; 71:252lung neoplasm mortality ratios by 67:33; 1i34'i,140' mortality by, and smoking hisrtory. 67:23'' mortality rates of cigarette smokers by 71':3' pancreatic neoplasm mortality rates, by 67:158 pancreatic neoplasm mortality'ratios, by 67:158 peptic uleermorbidity rates, by 67:182 205 0 G+. ,,I Q ~. ~'

ratio, effect of maternal smoking on 73:135, 136 ratio, in lung neoplasm mortality 74:40, 46 ratio, in lung neoplasm mortality in Norway and Finland' 71:245-2466 restricted activity days by, and smoking history 67:20-211 and smoking habit. 67::4 stroke mortality rates by 69:13, 117 stroke mortality ratios by 69:13' tumor prevalence among smokers by. 69:56' Sex differentials 64':133 in IUng,cancer 64:185, 1i86 in smoking prevalence 64:363 Sheep pregnant, nicotine injection and smoke inhalation effects on 71:414! Sheet metal workers neoplasm risks ini 64:1341 Sheldon somatotyping,method 64,: 383' Shoe repairers bladder neoplasms in. 64:222, 224 Side stream smoke see Smoke, streams Silica 64:271 Silver nitrate 64':354 Singie~breath tests smokers vs. nonsmokers 73:51 Sinusitis 64:275 in smokers and nonsmokers 67c22'. Sitosterols 64:52 Skin benzo(a)pyrene effectnn. 64:146 effect of tobacco extracts 72:105-107 reactions of, tobacco induced 64!:319 tests;of 641:143' tobacco antigens andl 72'.7, 104, 105' Skin neoplasms 64:143, 144 carcinogenic inductioniof 64:229 carcinoma in situ, 64:172 206 experimentally inducedl by cigarette, smoke 67:144 mineral oil indUction of 64:229 ultraviolet'radiationlinduction of 64:144 Skin testing for reactions to tobacco 72:105-107 Stnog' 64:295 S~mo ke; , cigar benzo(a)pyrene content'of 64:58 chemical constitlientsin 73`.177=179 ciliotoxicity 73`.218' effect' of' curing methods 73:218; 219 effect of pH on inhalation of 73:ll83 fittle;, pH, compared to cigarette and cigar smoke 73:224;228 tumorigenic activity in l9boratory ani- mals 73:21i0+2'14 see alsn Smoke, tobacco Smoke, cigarette 64':50<i22 alteration of coronary blood,f7ow 71:58 aromatic hydrocarbons in 67:127,1p$ benzo(a)pyrene contentof 64`.58' and bronchoconstrietion in animalS 68:72'' bronchogenic carcinoma induction in dogs inhaling 71:269,270 butylmethylnitrosamine in 67:128 cadtnium levels in 71!:154 carbon monoxide levels in 71i:59 carcinogenic content of 75:48 carcinoge nic ity 67:15, 34, 144; 72:65, 66 carcinogenicity of components to ani, mals 71:12; 277 cause of death in dogs from inhalation 71:271 chemicall constituents in, compared to pipe/,cigan smoke 73`.177;178 ciliary activity 67:107'108, 140; 68:71, 72; 69:42 ciliary depression by 641:61, 265, , 267; 268, 270 ciliary inhibition 71:267'

ciliatoxio,effect, mechanism of action effect on respiratory tract'4 in rats 67:107 cocarcinogenic effect om respiratory 74'.104 effect,on tissue, cultures. tract in rabbits. 69:4'2; 71:267; 343-345~ 72:67 cocarcinogens in ef'feet, on ~ tracheobronchial clearance,, in donkeys 64':144 composition of 75:78 effect on vascular resistance 64:50-60 and decrease in pulmonary macrophages, in guinea pigs 67':61, effect, on ventricular fibrillation thresh- old in dogs 75':77, 788 deposition patterns of! 73I:13; 14' endcindn 64:265 eff'ect, of curing methods 641:6'2 epidermoid neoplasms,from 7,3:218,21'9 effect of nickel on induction of lung aryl hydroxylase 64t14'4 experimentallinduction of bronchial' neo- plasms 71,:256-257' effect on adenosine triphosphatase 67:108 effect on alveolar macrophages 69:42 effect on apexcardiogram 72:211 effect on bacterial retention in hamsters 73:54 effect on breathing in guineapigs 72:46' effect on bronchial epitheliumi 67:107, 144-145 effeet, on bronchial epithelium, in dogs 69:40; 73:49' effect on bronchial mucosa 67:30, 104-107, 144'-1'45'5 effect, on DNA and RNA synthesis 69:62-63 effect, on Dunallella bioeulata. 69:42' effect on influenza virus in mice 68:70, 71 effect' on lung,AHH-activity 74:50, 51 67:14'4-145 experimentall induction of iung neo- plasms by P 67:144-145 experimentall induetion,of' tracheal neo- ~11 plasrn s b y 67`.14'4-1455 experimentallstudies in dogs 73':13„ 141 experimentall studies in laboratory ani- malt 72k211 exposure magnitude to 64k296; 297, 298' extract, effect on pulmonary macro- phages, in sheep lungs 0 74t1105 formaldehyde gas in 64t266 gaseous deposition of 64:265 harmful constituents of 72:8, 141-146 heterocyclic nitrogen compounds in 67 `.127 effect on luW 67:106 effect on luPg,swrface tension in dogs 72:48 effect on nasociliary mucosa in donkeys 72t47 effect on oxidative, enzymes high:tar, risks in 71:111 inhalation, by dogs, lung neoplasm de- velopm ent. 71:268•269,272=274 inhalation effects on animal respiratoryy tract 67:1088 71:268-269:,349;353 effect on phagocytosis in: laboratory animal9 inhalation effects on hamster larynx 71:281„284 73`.5'3„5a' inhalation methods effect on phagocytosis in rabbits 69t62 72;109 inhalation of, and coronary disease effect on pulmonary clearance 67:54 I'; 73:51-53' inhalation of, effect on bloodl pressure. effect on pulmonary macrophage func- 67 `.5'4 tiona,in rabbits 74:1,04! andileukemia 67`.114'8 Ih effect on pulmonary physiology, in ani- mals 74:102 listing,of identified or suspected tumori- genic agents I I. effect on pulmonary surfactant 67:110;69:42 7 l :264-267 andilymphosarcoma Z C : effect on rat! and mouse fetus site of 67':1I4'8 r ' , actio n metallic constituents of' ~ . 73:121 64".55' ~. ~ 207' ~ ~,

r naphthylamine content, andi bladderr carcinogenes;is 68:105 2-naphthylamine identified in 71:265 negative ions in 64:268 neoplastic,changes in animals inhaling, 71:238-239 nickel carbonyl in 69:62 nickel in, 64!:167 nicotine content in 67:34 nitrosamines in 67:127,128' nonvolatile condensates of 64:50 phenols ini 64:54, 267; 67:127•d28 polonium-210 in 67:128 positive ions, in. 64:268 pyrolysis reactions in 64:50 radioactivity of' 64<1'4'5 reduction of adverse effects in animalss by phenylmethyloxadiazole (PKdO). 73`.49„53' and reticulosarcoma 67:14'8'8 selenium in 67:128' skin neoplasm,induction by 67:1i44 and sulphur dioxide, effect on glands im laboratory animals 73':49 suppression, of immunoglobulin re, sponse, in cell cultures 75:77 TDE contentof 64:62 tobacco amblyopia relationship to cyanide metabolism in 71':435-436 see also Smoke, tobacco Stnoke condensates see Tars, cigarettes; Tars, tobacco Smoke, pipe benzo(a)pyrene in 64t58 carcinogenicity 67 :14'7=148 chemical iconstithients in 73`.1,77;178 ciliotoxicity of 73`218' effect of pH, on inhalation of' 73:183'' mouth neoplasms' experimentally in- duced by 67:1',47=148 208' tumorigenic activity in laboratory ani- m als 73`21'A-214 see also Smoke, tobacco Smokers airway resistance in 641:292, 293 alcohol' consumption by 64!:385' allergic reactions in 641:319 angina pectoris in 641:325 arteriosclerosis in 69:26 behavioral variables in 64:11,2' bladder neoplasms in 641:131, 132; 219, 222, 223; 224, 225 body weight of' 64t326i,384, 385 breathlhssnessin 64:27, 286, 287' bronchitis prevalence in i 64:289' cholesterol levelS in 64:326,,385chronic cough in 64:27, 280, 281, 282, 283, 299, 302 ciliary effects, in 64:27, 34, 35; 61, 168, 169; 170, 172; 173, 267 constitutional differences in 6'4:1'12,,326 coronary disease in. 64':322-325I current, mortality rates in 64':95 current, mortality ratios in 64:93 current„neoplasm risk in 64:158 current, pulmonary fibrosis in, 64': 274 epithelial,changes in, 64:165, ll67-173', 189; 263-275 forced i expiratory flow rate in 64:290, 291 heavy, risk ratios in 64:161, 213, 232 heavy, urban-rural mortality in, 64c186;194 hemoglobindevels in 64':319 hereditary factors in 64:385' LQ. measurements in 64:3701 laryngeal'neoplasms in 64:131,,132',133',209,211 lung,function in, 64!:27 lung neoplasms in, 64`.1181 131, 132, 133', 149-196, 232, morphologic constitution of 64:383'-387

t mortality rates ina from~ gastric neo- plasms 64':132 mortality rates in 64:99, 1,17; 118; 162, 209,,322, 323 mortality rates in, from laryngeal neo- plasms 64:211 nonrespondents among 64"-114 occupational asbestos exposure and car- cinogenesis 67:35 occupational uranium exposure, and car- cinogenesis 67:35 oral neoplasris in 64"131,132,1,33w202,204 as percentage of population 64:114 personality 64:39, 326, 365y 368 physicalieharacteristics, of' 64:326 population ofl 64:45 psychologicaLfactorsin 64:112 reduction of life, expectancy 69:3~ respiratory conditions in 64:289 risk ratios in. 64:160,161,222,223w232 risk ratios in, in bladder neoplasms 64':222 risk ratios in, in lung,neoplasms 6'4:161serum cholesterolin 64:326 smoking patterns in 64':177,,178',179 somatotype, classification of 64:383„385 sputum analysis of 69!39:-40; 57-58 sputum production in 64:27, 283-286 urban-rural differences in 64:99, 101 UIS. incidence of 64!ll78;179 see also Passive smokers;,Smokers, cigar; Smokers, cigar and pipe,;, Smokers, cigarette; Smokers, pipe Smokers, cigarr amblyopia in 64:341, 34'22 atypical nuclei' in male esophageal' epi- thelium i 71:379' bladder neoplasm mortality in 64:219, 222; 223, 224, 235 bladder, neoplasms in 71:29 3-294 body weight of 64':384 carboxyhemoglobindevels in 72:21-23 cell rows and atypical cells in vocal cords of 71:280;359-3600 coal miners as 64t299, COPD morbidity in 71:146, 1,97'-198, 201-202, 204-205 coronary deaths,in 64':323 decreased neoplasm risk in 64:37' duod'enal'ulcers in! 64:37 duration of smoking in 64':36' effects of smoke on bronchial reactivity 71:164 epithelial lesions in 64:170„173', 1!89 esophageal, neoplasm mortality ratios in 711:290 1 esophageal,neoplasms in 64:213, 217, 218, 234' fibrosis in 64k291 forced expiratory volume in 64:291 gastric ulcers in 64:37 gingivallneoplasms in 64:202 inhalation practices in 64:36, 92„188 kidhey neoplasms in 71,:294295 lack of! risk in CVD 711:67 laryngeallneoplasm induction in, 711:12, 354-357 laryngeallneoplasms in 64:37,, 192; 205, 209, 211, 212; 71:281. lip neoplasms im 64:197; 202, 230, 240 lung neoplasms in, 6C3'7, 1150, 155, 159; 163, 170;,173, 175,188';1 lung neoplasms, incidence in rural Swit- zerland 71:244 lung neoplasms, mortality in, 71:11,240-243', morphological constitution ofl 64:385,3$6. mortality rates in 64':30, 36' mortality ratios from COPD in 71:142'-1431 145 mortality ratios from pancreatic neo• plasms, in 71:298 mortality ratios f'rompeptic ulcer in 71:424 mortality ratios in ' 64:86, 87; 107, 1,1'2; 163 myocardial arteriole wall thickness in 72:19 myocardial infarction in 71I :32, 38-39 209 I n

orallneoplasms in 64:37, 189;,192; 202' pharyngeal neoplasms in 64:2022 relations,hip of' neoplasms of oral cavity with 71r12; 361 365; 367 371 relationship to infectious respiratory dis- eases. 71':227 relative risk in esophageal neoplasm drj- velopment 72:68 relative risk in laryngeal neoplasm de- velopment~ 72:67 relative risk in lung neoplnsms develop- ment. 71:276; 73:67, 68 respiratory diseases in 64:274; 289risk: of CHD 71:8' riskof'COPD: 71:10' risk ratios in 64':31, 37„231, 233 tongue neoplasms: in64:1i89„202 U.S. trends in number of' 64':26,,45 see also Smokers, cigar and pipe Smokers, cigar and!pipe causes of death in. 64':107 expected death rate in 64:107 gastric neoplasm mortality in 64:288 gastric ulcer in 64:1i113' incidence of atypical nuclei in.larynx 69:59 incidence of coronary heart disease 69:21,24 incidence of gingivitis 69:86 incidence of'stomatltis nicotina 69:87 liver cirrhosis in 64:11'3 lung,neoplasms in 64:1Q3 mortality ratios in 64`.107' observed deaths in 64:107 oral i neop lasm s in 64:113 thickness of vocal' cords 69:60 see also Smokers,,cigar;,Stnokers, pipe Smokers, cigarette air pollution effects on 64k 194, 195, 276, 295-298, 301, 302 arterial occlusions in 71I:73 ~ atherosclerosis: in, aortic and coronaryy arteries 71:52-56 210 atypical nuclei in male, esophageal epi- thelium thelium 71:379-380 bladder neoplasms in 71:293-295 bladder neoplasms mortality in 64:32',37,,219,234 bronchitis in 64:102, 103; 301 cell rows and atypical cells in vocal cords, of 71:280,359-360 cessation of smoking, effects on COPD morbidity 71':146'„1'97, 199s 2(/3r204cessation of smoking, lowers lung neo- plasm rate in 71:11 changes in ventilatory, function andi puI4 monary histology 7i:175 comparative risk for lung neoplasms 71C237 coronary diseasesin, 64:322' coronary diseases in, AHA pooling pro- ject. 711:28, 30; 399 coronary diseases risk by. 711:8, 23-25 coronary mortality in 64:324 decline in, British physicians 71:4'8': development of altered' ventilatory func- tioniin young 71h 10. development of esophageal neoplasms 71':12,293 development'of laryngeallneoplasms 71:12 development~ of oral neoplasms 71:12' development of second primary oral neoplasms in continuing, 71:287 effect of' filters on, emphysema develop- ment. 71:162' effect on cardiovascular system 71:56-58, 107-118 effects ofl inhalation on bronchial reac- tivity 71:164 effects on uterine activity in gravidic women 71:408 emphysema in 64:277-294 emphy,sema mortality in~ 641:102', 103 epithelial changes in 64:170, 173,,189esophageal neoplasms in 64:102„103, 188, 2112, 213' esophageal neoplasms, mortality ratios in 71:290 -291

excess mortality'in. 64:108 expected mortality in 64:108' forced expiratory volume, in, 64:2911 histology and smoking relationship of lung neoplasms in, 71:246-24'9 , hypertension in 64:325' infant'birth, weight; 71:397-399' inhalation eff'ects on human pulmonary, function 71:163, 166-169 inhalation patterns in 64:159 kidney neoplasms in. 64:102; 71:294-196 laryngeal neoplasm induction in 71:354-357 laryngeal,neoplasm mortafrty in 64:32, 188; 205, 21'2l 234 lung neoplasms, etiology 71:239 ~ lung neoplasms: in, 64:31, 37, 149-196, 229-233' lung neoplasms, mortality in. 711:240-243-Z441 mortality from cerebrovascular disease 71:67-70 mortality from neoplasms, by site 64:149 mortality rates affected by sex 71:3 mortality rates ini 64:35, 102„106, 108, 109, 110; 115, 162,194,3' mortality ratios 64:90, 93, 102, 103 mortality ratios from COPD: 71:142-14'4 mortality ratios from pancreatic nea• plasms in 71:298 mortality ratios from peptic ulcers in 71':424nonresponde,nts, mortality in 64!:115 ~ orallneoplasms; mortality in 64:102, 103, 1!31, 132, 196 205', 233 otolaryngological symptoms,in 64:275' peptic ulcer: 71:427, peptic ulcer in, smoke effects on antaeid therapy 71:423 percent of population as 64':26' percent of women of childbearing age : 7L:389 pharyngeal neoplasms in 64:103, 202 possible processes for increased' mor- tality in 71:4-5 postoperative pulmonary complications, in 711:174', 230, pulmonary surfactant activity in 711:17,2, 225'5 relationship in coronary and lower limb arteriosclerosis 71:72 relationship ~of asbestos in lung neoplasm mortality 71:257 relationship, to infectious respiratory dis= eases. 731:172, 226•229' relationship to laryngeal neopLhsm devel- opmenvin 71:281 relationship to hp or oral cavity neo- plasms 71:361-370 relationship to lung neoplasms 71:275;276 relationship with bladder neoplasms' in men 71 r.299 relationship with dustion COPD develop- ment 71':153 risk gradients in, from bladder neoplasms 64:223 risk gradients in, from esophageal, neo- plasms 64':234 risk gradients in, from laryngeal neo- plasms 64:37, 211, 234 risk gradients in, from lung,neoplasms 64`31, 37; 1i84;,185, 230: risk of COPD in 71:140; stomach ulcers in 64:1'033 survey by age andi sex 71:6 survey of U.S. 71:6 seealSo Smokers, Smokers, pipe amblyopia in 64:39, 341, 342 amount smoked„in mortaGty'ratios 6'4,: 86a 87' atypical muclei in mafe esophageal, epi- thelium 71e379 bladder neoplasms in 64:219; 222; 223; 235;, 71:293-294 bod y weighti in 64:384 carboxyhemoglobini levels in 72:21 cell rows andiatypical cells in vocal cordS ofl 71:280; 359-360 COPD morbidity in 71:146; 197-198, 201-205' coronary mortality in 64:323' 211

development! of chronic bronchopul- monary disease 71:10 development of esophageal neoplasms. 71:13, 291 development'of 7ung neoplasms 71:11 development of oral neoplasms 711:12 duod'enalluleers in, 64:37 epithelial,changes in 64:170, 173„189 esophageal, neoplasms in. 64:37'„2112, 217, 218;,234 esophageal neoplasms, mortality ratios 71I:290 extroversion in 64:366 fibrosis in 64:274! forced'expiratory volume in 64:291 gastric ulcers in 641:37; 337 gingival,neoplasms in 641:202' inhalation by 641:92, 188 kidney neoplasms in' 71:294-295 lack of risk in CVD 71:67 laryngeal neoplasms in 64:37,192, 209„211i 21,2' laryngeal'neoplasms, induction 711:112, 354-357 lip neoplasms in 64:32, 3'7; 188„197; 204 lung neoplasms in 64:31, 37; 196, 233' lung neoplasms, incidence in Norway 71:244 lung neoplasms, incidence in rural Sivit, zerland 71:244 Ivrng,neoplasms; mortality in 71:324.327' morphology of' 64:385, 386 mortality rates 64:30, 36, 74'„ 194',,202, 222„223 mortality rates from COPD 7d :142-143,,145 mortality ratios 64:90, 91„162 mortality,ratios from pancreatic neat plasms 71:298 mortality ratios from peptic ulcer 711:424 myocardial arteriole wall thickness in 72':19 myocardialiinfarction in 7'1:32; 38-39 neoplasm, location in, 64:197' oral changes in 64;302 oral, neoplasms and 64:37, 150, 1189, 192, 202; 72:67 peptic ulcer in 71:427 pharyngeal neoplasms in 64:202 psychosomatic disorders in, 64':3677 relationship to infectious respiratory, dis- eases 71:2277 relationship to laryngeal neoplasmidevel- opment 71:281 relationship to lip neoplasms 71:289 relationship to orallcavity neoplasms 71:361-364, 367' relative risk in esophageal neoplasm de, velopment, 72:68' relative risk in laryngeal neoplasm dt:vel- opment. 71I:677 relative risk in lung neoplasm develop- m enti 711:276; 73:67„68 respiratory diseases in 64:289„299 risk of CHD 71:8 risk ratios, in, fromineoplasms 64:31, 37, 196, 209, 2111, 2311, 233, 235~ tongue neoplasms 6'4:1188„189; 202 see also Smokers; cigar and pipe Smokers vs. ex-smokers atypicallnuclei'in larynx 69:59' coronary disease mortality rates, for menn by age 67:49 coronary disease mortality rates, for men, by years stopped smoking, 67:49; 69:15 coronary disease mortality rates, for men, compared,to nonsmokers 69:1i5 coronary d isease mortality rates, for' men, compared to:nonsmokers 69:15 lung neoplasm mortality rates 67:34„137, 1139 morbidity rates 67:15 mortality rates 67:9, 15' peptic ulcer mortality rates by age. 67:1811 pepticulcer, mort'alityratios by age 64:1811 stroke mortality for' men, compared to, nonsmokers 69:15 212

thickness of vocal cords 69! 60 Smokers v& nonsmokers abortions, stillibirths, and' neonatal death. 71:390 „405-406 acute diseases in 67 `.22 o-aminophenols in urine of 69:64 angina pectoris morbidity ratios 67':59 aortic aneurysm mortality 69c16 arteriosclerosis 67:22;72?19~ arteriosclerosis;,mortality rates 67':26 attitudes 67:190-191 atypical nuclei in,larynx 69:5'9~ bladder neoplasms in. 71.1:293'-295', 381-384 bladder neoplasms, mortality rates, by age. 67:154, 15'5 bldodlcholesterol levels, twin;studies, 67:55'5 blood factors of' mothers and , infants, 69:800 body constitution 67:99 breathlessnes,sin 67:29, 286 bronchitis mortality rates 67:8, 29„90-92 carboxyhemoglobin ilevels 67:100;72;21-23 cardiopuhnonary function, in young male 67:100 cell rows and atypical cells in vocal cords of 71:280; 359-360 cerebrovascular diseases 72;25 cerebrovascul.hr diseases mortality ratesi 67:66;71:67-70 cerebrovascular diseases mortality ratios 67:66 chronic diseases in. 67:22 coronary diseaseincidenee. 69:18, 20-22' coronary disease incidence and behavior type 69:24 coronary disease incidence rates„by age 67:54, 65 coronaryy disease morbidity ratios. 67:59;J1:24 coronary disease morbidity ratios, and blood pressure status, 67:55 coronary disease morbidity ratios, and lung,function 67:5'66 coronary disease morbidity ratios, by age. 67:54' coronary disease morbidity ratios, by blood cholesterol levels 67:55' coronary disease morbidity ratios, by personality characteristics. 67:57 coronary disease morbidity ratios, by sociocultural mobility status 67:57 coronary disease mortality 67:47; 71:21-22; 24, 26-29 coronary disease mortality, by age 67:50; 69:1I3 coronary disease, mortality, by amountt smoked 67'51; 69:13 coronary disease mortality, by sex 67 `.50; 69`,13{ 71:28'-3'1 coronary disease mortality, by smoking history 67 `.5'1. coronary disease mortality, for men 67:27 coronary disease: mortality, for women 67:28 coronary disease mortality, in Swedish twins 71:51 coronary disease,mortality ratios 67:8' coronary disease mortality ratios, by age 67:49, 52; 69:13 coronary disease mortality ratios, by amount smoked 67:47-49; 69`,13' coronary disease mortality ratios; by blood pressure status 67:52 coronary disease, mortality ratios, by sex 67:49; 69:13 cough in 67:29. Curschmann's spiralfi in sputum of 69:39-4'0, development of COPD in 71:141,,145, 195-205 differences in emphysema types in 71A54; 156 digestive ttact neoplasm mortality rates: 67;147' emphysema mortality rates 67:8 emphysema mortality'ratios 67:90-92 esophageal epithefialicells with atypicall nuclei, in 71:292 esophageal neoplasm mortality rates, forr men by age 67:150 esophageal neoplasm mortality ratios 67:35;150-151;71:290-291 excretion of trytophan metabolites in 71:297 frequency of'esophageali neoplasms in 71:238

frequency of'kidney neoplasms in 71:23'8'frequency of mouth and pharyngeal neo- plasms in 71:238'' frequency of', urinary bladder neop4asms in 71:238'. group characteristics: im lung neoplasmss and!smoking,in. 71:240;,244,329-333 3-hydroxyanthranilic,acid urinary excre- tion in 67:156' 3-hydroxykynurenine urinary excretion, in 67:156' incidence of edentulism, 69:87 incidence of gingivitis 69:86' incidence of periodontal disease. 69: 85 -86 incidence of preeclampsia among preg- nant women 69:79 laryngeal neoplasm mortality rates 67:148; 71':237-238' laryngeal neoplasm mortality ratios, 67:35; 71:278-279 laryngeal neoplasms in, relationship too tobacco use 711:354-35'7' lung,fbrosis development in 71:161 lung neoplasm, mortality in uranium miners 71:256 lung neoplasm mortality rates 67:8, 34; 47 lung neoplasm mortality rates, by'age 67:132-138, 1i4'0 lung neoplasm mortality rates„ by sex. 67:1'36, 140 lung neoplasm mortal'ityrates„ for men by age 67:131-132, 134-135, 137' 140 lung neoplasm mortality rates;, formen by amount smoked' 67:1',34-135, 137-140 lung, neoplasm mortality'rat'es, for menn by smoking,characteristics 67:134-135, 139: lung neoplasm mortality rates, for men by smoking history 67'134-135,137=140 lung neoplasm mortality rates„forwom- en, 71; 240 -243 lung neopl9sm mortality ratios, by age 67:134-140 lung neoplasm mortality ratios, by sex 67:136,1b0 lung neoplasm mortality ratios, by smok- ing classification 67:139 214 lung neoplasm mortality ratios, for men by age 67`.134-135,137-140 lung neoplasm mortality ratios, for men by amount smoked 67:1'34-135; 137-140 lung neoplasm mortality ratios, for men by smoking,characteristics. 67 `.1I34-135' lung neoplasm mortality ratios, for men by smoking history 67`.I34-135, 137; 139 lung,neoplasm mortality'ratios, foriwom- en. 67`34'„136' lung, neoplasm occurrence in asbestos workers 67:1W'3 lung neoplasm occurrence in uranium workers 67 `.14'3 N-methylnicotinamide urinary excretion 67 `.15!6 morbidity rates;,in United' 9tates. 67`.3,5 mortality rates : 71:3 mortality rates;,by age 67:79=10 mortality rates; by occupation 67':11 mortality rates, for Canadian pensioners. 67:10, mortality rates;,formen by age. 67:12!13' mortality rates, for UIS. veterans by age 67':12?13 mortality rates, for women by age 67':12?13, 211 mortality ratios, by age and sex 67:12'-13 mortality ratios;,for U.S. veterans by age. 67:12'-13 mortality ratios from pancreatic neo- plasms in 711:298 mortality ratios;,in United States 67`.8 mortality ratios of'COPD in 7 L :1'42-1',44 mouth neoplasm mortality rates 6J:14'& mouthineoplasm mortality ratios 67:35, 146'6 mucous gland abnormalities in 741:97 myocardial infarction morbidity ratios 67:5'9 myocardial infarction morbidity ratios„ by physical activity levels 67:5fi myocardial infarction relationships to physical activity 71:44 oral diseases,and 72;6

pancreatic neoplasm mortality rates;,by, age 67:158-159 pancreatic neoplasm~ mortality rates, by amount smoked 67:159 pancreatic neoplasm, mortality rates; by sex 676158,159 pancreatic neoplasm mortality rates„by smoking classification 67:159, paralysis agitans mortality rates 67:88 pathological and cytological changes in respiratory tract of 71:25 8-263 peptic ulcer ina correlated amounts of tobacco use 71':427-428 peptic ulcer morbidity rates, by sex. 67:182 peptic ulcer mortality rates, for men„by age. 67t181' peptic ulcer mortality ratios„for mena by age. 67: 181 . pharyngeal i neoplasm mortalit y rates 67:146' pharyngeal neoplasm,mortality ratios 67:35,,146 postoperative hypoxemia in 71:174-230 postoperative: pulmonary complications in 71:174-175', 230 postural hypoxemia mee,hanism; in, sympt'omptic 71:147 prevalence of neoplasms, by type of tumor, s;ex,and 69:56 pulmonary alveolar phagocytosis in 71:165 relation between CHD and serum cholesr terollevel 71I:43 relationship to,infectious respiratory dis- ease 71:172, 226-2299 respiratory symptoms 72:40 respiratory symptoms by age. 6'7 `. 29, 1000 respiratory symptoms by occupation 67 :97 respiratory tract'i neoplasm mortality rates 67:147 serum lipids in 71':41, 98-1021 . small airways abnormalities in 74':97, 98 stomach neoplasm mortality rates 67:157-158 stroke mortality, by age 69:13 stroke mortality, by amount': smoked 69:13 sttoke mortality, by sex, 69:13. stroke mortality;, compared' to ex- smokers 69:15 stroke mortality ratios, by age. 69:13 stroke mortality' ratios, by amount smoked' 69:13 stroke mortality ratios, by sex 69:13 surfactant activity in lungs of 71:172, 225 thicknes,s of myocardial arteriole wallS 72:19 thickness of vocal cords 69:60 tracheal neoplasm mortality, rates 67`14'7 type of lung neoplasms in male and' female 71:250 urinary excretionlofl tryptophanimetab- olites 69:641 urinary tract' neoplasm mortality rates; by age 67:154 srealso Smokers vs. nonsmokers, cigar;, Smokers vs, nonsmokers, pipe Smokers vs., nonsmokers;,cigar esophageal neoplasm mortality ratios 67:35-36 laryngeal neoplasm mortality ratios 67:35' mortality rates. 67:8 andlmouth neoplasm~mortality ratios 6735 and' pharyngeal neoplasm mortality ratios 67:35 Stnokers vs. nonsmokers, pipe esophageal, neoplasm mortality ratios 67:355 laryngeal neoplasm mortality ratios 67:35'149 mortality rates 67:8' mortality rates for Canadiani pensioners 67:10 mouth neoplasm mortality rates 67:35'5 pharyngeal neoplasm mortality ratios 67:35 Smo ke streams aluminum in 6'4c55,61,62 arsenic in, 64:55 benzo(a) pyrene content 72?123 bery;lliumin 64!:5'5 chromium in 64':55 2,15

CO ~levels in mainstream cigar smoke 75:90 constituents of tobacco smoke 75:88-98 definition of 64:50 effect on nonsmokers: 72'<122,123 Guthion in 64:62' nickel in, 64:555 potassium in 64:55 Sevin in 64:62' sodium ini 64:55 summarynf previous findings 75:87, 88 tar and nicotine content 72:123' Smoke, tobacco 64:26, 33, 34„ 50-62, 69-75, 142-146, 167, 1'68, 263-267 acenapthenein 64:55 air cured and'tumarigenicity 68:91 as air pollutant. 72:7, 121, 122' alkylbenzene in 64:5'5 allergic and irritative components, effect on nonsmokers 72:2, 128, 129 antigenic properties 72:1041 aromatic hydrocarbons in 64:55;67:127;69:61 arsenic in 64:55, 61! benz(a)anthracenein 67:127 benzenein 64:55 benzo(b)fluoranthene mi 67:127 benzo(j)fluoranthene in. 67:127 benzo(k)fluoranthene in 67`.127 benzo(a)pyrene in 67:127 benzo(e)pyrene in 67:127 beryllium in 64:55 bladder carcinogensin, 69:64 and bronchogenic carcinoma 67:129-130 carcinogenic heterocyclics in 64:54 carcinogenic hydrocarbons in 64:55 carcinogenicity 64':143, 145; 68:90, 91; 69t62 chromium as 64:55 chronic,toxicityof 64:73 chrysene in. 67:127, clearance mechanism for 64;267,269 cocarcinogens in 69:61 composition of 64:50-62; 263, 2641 constituents of 64:5i constituents of;, and' bladder neoplasm carcinogenesis 67 `.1 S6 constituents of, effect on bronchial mu- cosa 67 `.14'4145 constituents of, lung neoplasms induced by 67:14'4 cyanide in, andl vitamin B'-12' deficiency, in tobacco amblyapiai 67:4'0 deposition of'. 641:263-267 dibenz(a,j)acridine in 67:117' effect during pregnancy in, laboratory animals 73:114;115 effect of constituents on.passive smokers 75:88-98 effect on air pollution in aircraft 73:455 effect on bronchial epithelium 67:129 effect on macrophages 72':47 effect on mitochondrial function, in rat liver 74:104 effect on nonsmokers, in aircraft 73:45 effect on stillbirth rate in laboratory animals 73':125 and epidermoid carcinoma. 67:129-130: exposure 64:272' filtration of, effect on bronchoconstric- ton.response in smokers 72':4'5 heterocyclic nitrogen compounds in 67:1277 indeno(1,2;3'-c;d) pyrene in 67:1277 irritants in 72:109, 110 leukoplakia~from 64:233' liver effect of'64:34'2 and lung neoplasms in animals 68:93 216

nicotine content' of 68t9:1' nicotine-N.oxides in 69:622 nitrates in 67:128' N-nitrosamines in 67:127' organ toxicity of 64:73i papilloma formation in tracheobronchiali muco sa l 67:129-130 pH of, effecUof leaf constituents 73:224 polonium-210 content, and carcino- genesis 68:92 polycyclic aromatic:compounds 64:26, 144 potassium 64:55 potential source of N-nitrosamines 68:91 pyrolytic temperature effect!in 64:50 retention of' 64263-267 summary of previous findings on rela tionship to passive smoking 75:87-88summary of'recent findings 75:1088 systemic toxicity of 64:73'3 tar content of' 68:91 in tobacco amblyopia etiology 67:40 toluene 64c55' toxicity of 64':73 tumorigenic activity 68:90; 91; 73:210-214 tumor-promoting agents in„ and neo- plasm pathogenesis 67:35 and vitamim B' deficiency in tobacco amblyopia 67:400 see also Smoke, cigar; Smoke, cigarette; Smoke, p ipe Smoking and ausenteeism 67:19 and adenocarcinoma 67:140-143 and air pollution 64:295-298 and' air pollution, effect on pulmonary function and COPD prevalence 74':82,83 and alcohol consumptionw in esophageal, neoplasmformation. 67:152' andal'veolu bone loss69i 85'-87' and alveolar cell carcinoma 67 `.1'4'2. and angina pectoris 69:18 and anoxia 67:183 and aortic aneurysm 67:1i83 and arrhythmia 69:4 and! arteriosclerosis, 6T28;69.4, 5~ and' asbestos exposure, as factors in lung neoplasm development 74`.4'1,-43' association with other risk factors in. CHD 68:21;74:6;7,17 and' asthma 67:29 and atherogenesis 67:66 and basalicell hyperplasia 67: 30' and bed,days 67:20-22 and behavior type. 69t20, 24 andibladder neoplasms 67:33, 364 69:60; 72:68, 72-74 and bladder neoplasms in men. 67 `.15'3 andibranchitis 69:4;,74:79 and bronchitis morbidity 67:6, 94; 99 and bronchitis mortality 67:3, 29, 90-92 in bronchitis:pathogenesis 67:29=3'1, 96, 108; 69:37-40 and carboxyhemoglobin levels in smok- ers 67:183' and'cardiovascular, diseases 67: 3', 25-28, 47 -69:; 69:3-5 as cause of fires 67:187-188' as cause of traffic accidents 67:187-1,88' and cerebrovascular diseases. 67:27, 66 and cerebrovascular diseases by age 67:68 andl cerebrovascular thrombosis 69:27,68 cigarette sales andiCHD mortality rate: 68:16 and coffee drinking, in myocardial in- farction etiology' 74:88 and COPD etiology. 73:35, 36 and coronary disease 69': 3-5 s 20 and coronary disease, age as factor 74:6 in coronary disease etiology 67:26, 54 2'117'

and coronary disease incidence rates 67:54;68:27 and coronary disease, in womem 74:9, 10 and coronary disease mortahty 67:10, 26-67 imcoronary d isease p atients 67:26, 28 in coronary disease patients„ effect on, blood'.pressure, 67:61 in coronary' disease patients, effect' oni heart function 67:61 in coronary disease patients, effect' on heart' rate 67<611 and coronary thrombosis mortality for men 67:26 and diet 67:66 and digestive tract neoplasms mortality 67:3'0; duration of,. 64t29,3'1,37„187,188. duration of,, and lung, neoplasm, increase. 64t31, 37; 15'8,, 161„ 163„ 170, 187,. 188 duration of habit and incidence of CHD 68:1,7' effect of! abstinence in excercise per- formance : 73:241, 242„246, 247 effect on bladder neoplasm morbidity 67:15 5' effect on b lood' cho lestero l levels 67c55; 56 effect on blood ciiculation i 67:26, 60-61;b9c11 effect on blood circulation„and arterio- sclerosis pathogenesis: 67:61-62 effect on blood circulation; and coro- nary disease pathogenesis 67:62' effect on blood coagulation 67:64I effecuon bloodi l'ipids68:31; 73:11, 1'2 effect'on blood platelets 67:64; 69:27-28;'74t 18; 19, effect'on blood pressure 67:54; 60 effect on blood vessels 67:111 effection bronchial, epithelium67,:104-U06;,144 effect on cardiac lactate metabolism, 73:13 effection cardiovascularsyst'em 67:26, 60;',72t6,13; 14 eff'ecti on coronary vessels 67:65 eff'ection esophageal sphincter. 72:97, 98eff'eeLon esophageal tissue. 67:30,15'0-153 effect on free fatty acids 69':27' effect on gastric acidity 67:182 effect on, gastrointestinall secretions in dogs 72:6 effect'on heart'function 67:60 effecUon heart rate 67:60 :ffecti on hemoglobin oxygen affinity 69:29 effect on huynx and true vocal cords 69:59-60 effect, on leg blood mean-flow capacity 73:22 effect on,leukocytes'in guinea :pigs 72:46 effect onlung,function 67:29, 55;69:5'5 effect on lungs 6'7:104, 140-143 effect' onilungs inidbgs' 72:46 effect' on mortality rates fiom eso- phageal neoplasms in Japanese males 72:71 effect ommucous membranes 67:14'4 effect' onimyocardium 67:60 effect' on neoplasm recurrence at site of' primary 72:69 effect on oxygen tension in arterial blbod 72:45' effect on pentagastrimstimulated gastric secretion 72:977 effect' on peripheral circulatory system 72!25', 26 effect'onipiasma nicotine levels 73: PS-17 effect orrprecapillaryn sphincters 73'.22 effect' on pulmonary clearance 72:47 effect on respiratory tract. 67:14'1 effect on thrombus formation 69: 27-28 effect on thrombus formation in coro- nary disease patients 67:26 effect on tryptophan metabolism 67:36„156' effect on vascular'resistance. 67:60 effect on ventilation/perfusion relation- ships of lung 69:39' effect on vision 6T:1183 electrocardiogram patterns from 64:319 2'118

andlemphysema morbidity. 67:3,,6,:94, 99 and emphysema mortality 67:3,,29, 90-92 in emphysema pathogenesis 67:2913!1, 96, 104, 1I06;'69,:37-38' and'epidermoid carcinoma 67:35,140-143 andiesophageal neoplasms 67:33; 149, 15'0,15L and fertility history 69!:79-80 genetic factors in 64:190, 385 and gingivitis 69:85-86 health hazards of, similarities of ciga- retteswithl'ittle cigars: 73:224„225 heartburn and 72:97„98' histopathologic changes from 64:300', inhalatiomof cigarette smoke as measure, of exposure to 67:15 interaction with other risk factors ini CHD 73:4-11 and intermittent:claudioation 74:14-16 and kidney neoplasms 69i60 in laryngeal neoplasm etiology, 67:3, 148; 69:55' in laryngeal neoplasm etiology in men 67:33 and liver cirrhosis morbidity 67:39 and liverc'urhosis mortality 67:10, 36 and lung;neoplasms. 64:175-196; 69:4; 55-58 and lung neoplasms etiology 6'7133-34; 140-144and lung neoplasms incidence 6'8!94'-99 and lung neoplasms, inmen 69:57 and lung neoplasms;,in women 67:10; 69:67' and lirng,neoplasms morbidity 67:3, 14'22 and,lung neoplasms mortality 67:3, 10;,34 andllung neoplasms, retrospectlve:studies of4 by smoking characteristics 64:156 as a major risk factor in peripheral vascular disease 74`.14-16' and morbidity by age. 67:244 and' morbidity in United States 67:6, 19 and mortality. 69:3' and mortality; British men 67c101 and mortality, British physicians 67:5 mortality, follow-up study 67:8 mortality from esophageal neoplasms 68:102 and mortality in United States 6'7:5 and mortality rates by sex 67:7 and mortality, U.S. veterans 67:5 and' mouth neoplasms 67:145 and myocardial infarction. 69:4, 18 and myocardial infarction incidence rates. 67:57 and noncancerous oral diseases 69:5-6, 85-87 and oat cell carcinoma 67:1'40-1'4' 1' and obesity 67:66 and oral neoplasms 69:58 and'oral neoplasms:incidence 68'.99,100 and pancreatic neoplasms 67c 36, 159;'69:60-61 patterns 64:368,369 and peptic ulcer 67:39;72:6,97,98 and peptic ulcermorbidity. 67'39-40, 1181-182 and peptic ulcer mortality, 67c39140, 1'80-182 pleasure 64:350 population studies 67:&11 and premalignant changes in:larynx 69:5 prevalence;of 64:363, 364 prevalence of, in nonwhites 64:363, 364 prevalence of in UiS. and' Great' Britain 73:173, 174 psychoanalytic explanation of 64';367 and!pulmonary fibrosis. 67 `.107; 7 2:44 rate, 64:98 reduction ofl among British physicians,, and reduced mortality 67:15 redbetion of, effect on lung neoplasmi mortality 67:4 relation to blood cholesterol and lung neo plasm s 69:57' 219

relat;iow to lung, neoplasms and stomach ulcers 69:57 andIrespiiatory tract infections 67:10 and'restricted activity 67:19 status, errors of measurement in 64':1111 and,stomach,neoplasms 67:29, 36; 158 and stroke 67:27 and thrombosis 67:111 tobacco amblyopia and 72:6 trends for U.S. me,na,ton years 1955, 1966, and 1970 74:40 and,tryptophan metabolites in urine. 67:36'6 type, esophageal neoplasms and 64:32,33 type, mortality ratios by 64:90 type, neoplasm sites by 64:188 type, oral neoplasm sites by 64:197 type, retrospective neoplasm studies 64:201 typology 67:189-191I and undifferentiated carcinoma 67:140-143 vasoconstrictive effects ini normal sub- jects. 741:16 wish- for-adult-status as reason for 641:371 withdrawal methods and' 64!:352' in young people, effect onilung function 67 `.1M in young, people, effect on respiratory tract. 6731 See also Reverse smoking; Passive smok- ing;, Smoking,, bidi; Smoking, cigar; Smoking, pipe Smoking, bidr. 641:21,1 esophageal neoplasms fiom 64':21i3 iir neoplasm etiology in Bombay,, India 72:69 Smoking characteristics bronchitis, prevalence rates in men and 74:79 COPD' prevalence rates in Yugoslavialand''74':79 dosage score and 67:14-15 and incidence rates of'lung, neoplasms for; men 69:56 andl incidence rates of' lung neoplasms for women 69:56' and'lung neoplasm mortality tates 69:57 lung neoplasm mortality rates, for men by 67:134-1,35, 139 lung, neoplasm mortality rates, for, women by 67:136' lung neopl9srn mortality ratios, for men by 67:139 lung neoplasm mortality ratios, forr women by' 67:136 patients with~lung or bladder neoplasms 68<104 Stnoking, cigar autopsy studies, in smokers with emphy- sema, fibrosis, or thickening of' arte- rioles or arteries 75:75 and bronchitis morbidity 67:94; 99 and bronchitis mortality 67:30;94 CO' levels in mainstream smoke 75:90, effect an blood lipids 68!:311 effect on mortality and morbidity com pared to cigarette smoking 73`.171-173 an& emphysemalmorbidlty 67`.94' andlemphysema morYality 67`.30„941 in esophageal neoplasm d'evelopment. 731197„200-202 gastrointestinal disorders and 73:222 health consoquences af 73:179 histologieal l effects on bronchial epithe- lium i 73:203, 204, 209' histological effects on esophagus 73:200 histological effeets an larynx 73':197histological effeets on lungs : 73:217 incidence of CHD 68:27 incidence of lung neoplasms in Switzer- land 68:95', 96 inhalation patterns and. 73`.184-1'89 in laryngeal neoplasm development. 73:197-199 in lung neoplasm development 73' 203'-206 ; 74: 39, 40. and lung ne:oplasm mortality 67: 34,,138-140 , 220,

and lung,neaplasm mortality ratios. 67:138-140;73:203'-205 and mortahty. 67:7 mortality from esophageal neoplasms. 68:102 mortality, in smokers vs, nonsmokers 68:5 mortality ratios from cardiovascular dis- eases and 73:215, 216' mortality ratios from COPD and'. 73:21I7, 219 mortality ratios from, esophageal neo- pl9sms and. 73`.197,200 mortality ratios from laryngeal neo- plasms and 73:193;196,197 mortality ratios, from oral neoplasms and 73`.191„ 193 oral neoplasm development and 73:193•195 overall mortality rates by amount smoked 73':1,80<182 overall mortality rates from, neoplasms 73:1,89 prevalence in Great Britain 73:173', 174 prevalence in United'States 73:1731 174 relationship to neoplasms. 75:43, 44 summary of'previous findings on effects. 75:4, 13 and' tobacco amblyopia 67,:39' see also Smoking. Smoking classification, bladder neoplasms mortality rates by 67:155' bronchitis mortality by 67:30 bronchitis respiratory symptoms by 67:98 cerebrovascular disease mortality rates by age and sex 67:66 cerebrovascular disease mortality ratios by age' and sex 67:66 cough by 67:97 digestive tract' mortality rates by 67:147 emphysema mortality by 67:30' esophageal neoplasms mortality rates by 67:50 esophageal neoplasms mortality ratios by 67:150 laryngeal neoplasms mortality rates by 6'7:147-1,49' laryngeali neoplasms mortality ratios by 67 `.14'9 livercin:hosis mortality rates in men 67 `.1'84 liver cirrhosis mortality ratios for men, 67:184 lung neoplasms morbidity by' 67:33, 143 lung neoplasms mortality rates by 67: 34', 137,,139-14'0; 143 lung,neoplasms mortality ratios by 67:137, 139-140 mortality rates by 67:8 mouth neoplasm morbidity by 67`.32 mouth neoplasm mortality by 67:35', 146 pancreatic neoplasms mortality rates for men by 67:159 pancreatic neoplasms mortality rates for. U.S. veterans by 67:159 pancreatic neoplasms mortality ratios for men by 67:159 peptic ulcer mortality rates for men by 67'1i82, pharyngeal neoplasms mortality by 67`.35,146' respiratory tract neoplasms mortality rates by 67`.14'7' stomach neoplasms mortality rates by 67:157=158 stomach neoplasms mortality ratios by. 67:1,57' tracheal neoplasms mortality ratesby 67:147' urinary tract, neoplasms mortality rates by 67:1'54' urinary, tract' neoplasms mortality ratios: by 67:154 Smoking habit 64:36fi appetitite rediretion,by 64:71, 35'5'behavioral research 67188:192' beneficial effects of' 64':32, 355. and body constitution 67'54 Britishi physicians 67:9-10, and cognition 67:189491 compulsive nature of 64:35'2' and cultural characteristics 67 :5'4 demographic factors in 64:361-365 and heredity 67:53-54 intelligence factors in 64:370 measurement of' 64:98' 221.

modification of 64:375;376 mortality rates associated with 64:27 nausea f'rom 64:71 neuroticism and' 64:367 andloccupational physical activity 67`.56 oral hypothesis of. 64k367;363 and'perception 67:189-191 and personality characteristics 67:57' psychologicalldeterminants in 64:40,350, psychosocial aspects, of 67:39, 188?192' reasons for 67:189 and religion 67:54 social determinants in 64:361-374 and socioeconomics. 67:54 seealso Tobacco habit Smoking,history aortic aneurysm mortality rates', by' 69:16 aortic aneurysm mortality; ratios by 69:16 and bronchitis prevalence rates, 67:96, and chronic diseases 67:21 and coronary disease incidence rates 69:21-244 and coronary disease mortality rates 67:25'-26;69:13-14, 17 and coronary disease mortality rates, for ex-smokers 67:51I coronary disease mortality ratios 69:13s15',18 incidence of atypical nuclei'in larynx by 69:59 and' laryngeal neoplasms 67:35'5 and lung,neoplasm morbidity 67:33 and lung neoplasm mortality rates 67:34, 1351137, 139-1'40 and lung neoplasm mortality rates for ex-s:mokers 67:1'37,139' and mortality 67:7-9' and respiratory disease morbidity 67:98 and respiratoryfunction tests 67:100 and stroke 67:688 and stroke mortality rates 69:13, 17 222 andl stroke mortality ratios 69:13,15' Smoking,machines' 64:45 Smoking, maternal and abortion, 69:77-79; 71:1'3; 72:5„84, 85';]3:123;,124 carbo xyhemog lo bin ilevels 69:80 carcinogenic effects onifetus. 72:88 congenital malformations and 73:136,137 and development of bronchitis andi pneu- mania in infants' 75:i03, 104 effect during pregnancy 67 : 1 85-1 8!6'; 7 2 : 5 , 83-87; 73:103-142 effect an~birth weight 67:39-40, 185; 69:5, 77-781 80; 72:5, 83'-87;73'.103-114, 1191122 effect on body height'.of children 72:88 effect on fetallgrowth rate 72:5, 83-87 effect on fetal!morbidity 67 :186' effect on fetal mortality 67:185; 69:77-78; 73:124', 125' effect on gestation duration 73':103-1066 effect on infant mortality 67:185; 69:77-78; 72:84=87 eff'ecf on infants growth rate 69:78 effect on lactation 73':138-1'41 effect' on neonatal carboxyhemoglobin levels 73!118„119 effect onineonate 6739-40, 1185 effect on, neoplasm development in off- spring, 72:87, 88 effect, on placental ability to hydrox- ylate benzo(a)pyrene 69:80: effect,on placental metabolizing activity. 72:89' effect on pregnancy 69:4 5', 77-81 effect'on pregnancy, in lreland! 69:79 effect on pregnancy„in Scotland 69:79 effect on pregnancy;,in Venezuela 69:79 effect on sex ratio 73:135, 136 epidemiologicalistudfes of effects 69:77-80 preeclampsia and 69:79; 72:84;'73!:142' pregnancy toxemias and 69!79 and!prematuritg 67:1i85; 69':77; 79

and'prematurity, among, Negroes. and mortality ratios . 69:78 64:86, 87 selective action on fetus ofl certain wom+ mortality ratios from cardiovascular di- en vs. others seases and' 73:1311 - 73s21',5,216 teratogenic effects mortality ratiosfiom COPD an& 73:217',219 17n•a17timing of influence on birth weight mortality ratios from laryngeal neo- 73:120,121, plasms and'73t1I93, 196, 197; 200 unwanted pregnancy and. 72:84 mortality ratios from oraPneoplasms see also Infant mortality; Neonates 73:1I91 „193 Smoking, parental and mouth, neoplasms effect: on children 67:33 72:129 oral neoplasms development and Smoking„paternal, 73'.:193-195~ eff'ect' on infant b irrth weight overall mortality rates by amount smok- 73':110,11,1 edl Smoking, pipe 73':180,1822 and adenocarcinoma overall mortality rates from neoplasms 67:143' and autopsy studies, in~smokerswith emphy- 73`.189 sema, fibrosis, or, thickening of arte- prevalence in GreatBritain. rioles or arteries 73:173;174 75:75 prevalence,iniUnited States and bronchitis morbidity 73c103,174 67:94,99 pulmonary histological changes andl and bronchitis mortality 73:21'Z 67:94, 99 relationship to cancer effect on mortality and' morbidity com- 75:43, 44 pared to cigarette smoking sedation from 73:171-1I73 64':3'50i and emphysema morbidity stomatiti's nicotina~from 67:94 64:271;'69;87 and emphysema~mortality summary of previous findings on effects 67:34 on smokers and!epidermod carcinoma 75:4; 13 67 :143 and tobacco amblyopia in esophageallneoplasm development 67c39, 73:197, 200-202 see also Stnoking gastrointestinal disorders andl Snuff 73:222 64:73i349 health consequences of effect' on oral mucosa in hamsters 73:179 72:70 histological effects on bronchial epithel- lip neoplasms from ium 64:202 73:203, 204, 209 oralllesions from histologicalleffects on esophagus 64:203 73".200 oral neoplasms histological effects on larynx 64:202, 233;~71:287, 361',,,3'64-365' 73:1977 per capita consumption of'4 in U.S. inhalation patterns and' 64:45 73:184-189' Social adjustments inilaryngeallneoplasm development. in children of' smoking mothers 73:197-199 71:407, and lip neoplasms Social'stimulation i 67:35, 145 64:32' in lung neoplasm etioldagy Socioeconomic level 67:143; 74:39; 40 smoking prevalence by in lung neoplasm etiology by amountt 64:362' smoked Socioeconomios 73:203-206 in COPD and' lu ng neop lasm mortality 71:15!2=153', 216-217 67:34, 139-140 and,smoking,habit. and lkng,neoplasm mortality ratios 67:54 Q 67:139-140t 73':203-205' Sodium and mortality in,main stream smoke ' ~ ~ 67:7 64:55I ~ ~ ~ 223' ~ ~;,

Solanesoli 64I:52 pyrolysis:of 64:53 structural formula of 64:53 Somatotypes 64:372, 383, 384, 385, 386 Soot benzo(a)pyrene content of 64':14'8'' neoplasm induction by 64:33; 147, 229 Sbuth Africa coronary, death rate in 64:320 esophageal neoplasms in;, retrospectivee studies of tobacco use 71:378 healthisurveys in 64:186 methods of retrospective studies of lung neoplasms in 71:328 occupational exposure, and smoking rela- tionship to COPD'in 71:219 serum lipid, differences in smokers vs. nonsmokers in 7ll:99 SpeciCicityy as measure of statistical association 64:182-185',:204, 21Q,225 Spirometric test. 64':292 Sportss smokers' participation in 64:372, 3!73Spray exposure in smokers vs. nonsmokers~ by race and sex 75:69, 70! Sputum 64:38, 282,:283-287, 301 effect of'asbestos exposure in smokers vs, nonsmokers 73:41 effect of filtered cigarettes 73:55'5 effect of modified cigarettes 73':37; 38 effecYof plain vs. filtered' cigarettes 73':37, 38 in males by amount smoked and type of cigarette 73:37, 38 prevalence in pipe, and cigar smokers 73:220, 221 in women 64':231' Squalene 64`.5'1. Status strivingg smoking and, 64:372, 373' Stearic acid suspected carcinogenic agent of cigarette smoke 7d1:266 Steel'workers 64':285, 299 Sterols 64:52 Stigmasterol 64:52 pyrolysis:of 64':59 Stillbirths abortions, and neonatal death and, in smoking and non-smoking mothers 71:390, 405-406 effects of maternal smoking 71:4'15;73:124,125 rates in blacksvs: whites 73:124;,125' in smokers vs. nonsmokers 73'.124, 125' see also Fetal death; Stnoking, maternal. Stimulants 64!:354 nicotine as 64:38, 69, 70, 71, 317-320, 349-350 Stockholm Prospective Study epidpmioiogic study of' smoking, and CHD 74'.6 Stomach,neoplasms mortality rates 67:158 mortality rates; by age and amountt smoked' 67:1i57=158 mortality rates, by age andIdaily tobacco consumption 67:15'8' mortality rates; by smoking classification 67 `.15'7' 15 8 mortality rates, effect of cessation of smoking on 67:158' mortality ratios, by age and amountt smoked 67157-15 8' mortality ratios, by smoking, classifica- tion 67:157, and smoking 67:36 and tobacco use 67:33. Stomatitis nicotina 64:27;5,302 and pipe smoking, 64':271;69;87 reverse smoking and'. 72:6, 69; 700 symptoms of 64:271 see also Leukoplakia Stramonium 64: 35'4 Stress 64!:373; 374 socioenvironmental, and coronary dls- ease incidence 67:56 224I

Stroke mortality rates, by'age 69t13 mortality rates, by age and sex 67:67 mortality rates, by amount smoked' 69:13 mortality rates, by'sex, 69:13 mortality ratios; by amount smoked! 69:13 mortality ratios;,by sex 69:13 and smoking 67:27,28;72;24,25 see also Cerebrovascular diseases Strontium 90 64:146 Students, college smoking patterns in 64':369' Students, highischooll eff'ea of smoking. 72:40, 4'11 pulmonary function of'smokers vs. non- smokers 72:3' respiratory symptoms 72:40; 41 Study populationss representativeness of' 64:941 Subcutaneous neoplasms 64:143„144 Subglottis. 64:271 Suburbs coronary diseases in 64:322 Sugar 64:62' Sulfonamides 64:224I Sulfur dioxide air pollution fiom, 64:295 and I cigarette smoke, effect on ~glandk in laboratory animals 73:49 ciliastatic effect of 64:268 mucus alteration of 64:268 pollutioni levels in four U.S. locations 75:65, 66' toxicity of 64:295 Sulfuric acid carcinogen extraction~by 64':147. Surfactant see Pulmonary surfactant Surgery complications following;, ini smokers vs. nonsmokers 74:92 Survey of Tobacco Smoking Patt'erns in the United! States 64t187 Sweden acute effects of cigarette smoke on human pulmonary function. 711:168 blood' pressure, differences in smokers vs. nonsmokers in 711:104 CHD mortality and'morbidity in 71:97. COPD morbidity in smokers in 71:203, 205' coronary mortality rat'es in, 64':320 effect of' cigarette smoke on animals' ciliary'f'unction in 71:22'1-2241 genetic studies of twins in, smoking effects on, 71:50,99' laryngeal neoplasms in relationship to tobacco use 7d :356 lung neoplasm mortality rates in 64:176 relationship of'tobaeco use and lip nea plasms in 71:3611 relationship of tobacco use and oral cavity neoplasms, 71:364 retrospective studies of esophageal neo• plasms; by tobacco use 64:214;71,:378 retrospective studies, of oral neoplasms; by type of smoking 64:198, 200, 201 retrospective study, of laryngeal neo- plasms 64:205,206 serum lipid differences in smokers' vs, nonsmokers of 71:99' smoking, and nicotine effects on human cardiovascular system. 7'1:11I5. smoking and nicotine effects on,human peripheral vascular system 71:133' tracheobronchiat tree changes in smokers and' nonsmokers in 71':263' Swimming effect of smoking 73`.24'2;244 Switierland CHD morbidity and mortality in, smok- ers vs. nonsmokers 71':95'5 cigarette smoke effects on mioe lung and kidney tissue in 7, t: 344 cigarette smoke inhalation effects on mice respiratory tract 71:351 lung neoplasm incidence in cigar and pipe smokers ofirural 71:244 225 ~ . ....'b'~ , .

lung neoplasm mortality rate in 64:176 lung neoplasms, methods of'retrospec- tive study of'~ smoking in 71:325 semm lipid differences in smokers vs. nonsmokers of' 71:100 bladder neoplasm s and 64:219, 223 buccal retention of' 64:264' carcinogenicity 64:33; 143, 146, 147, 165, 192; 67:128!; 69:61I; 72:65, 66 clearance of 64:269 cocarcinogens in 67:131 condensation temperature of Tachycardia 64:50 development in dogs ~indlieed by nicotine def'inition, 71!:57 72z 143' Tars, cigarette dosage score as function of' carcinogenic effect on, animal oral cav- 67::15 ities effect on, respiratory symptoms and ven- 71:288 tilatory capacity carcinogenicity' 73:38 67:34;69:61;71:11,264,265 esophageal neoplasms and carcinogenic properties on animal skin. 64:212,213i2118 71':337-34'2; 73`.21I0-214 fatty acids in as cause;af bladder neoplasms, in rats 64:53 74:58 gastric neoplasms indirced by content. 64::228 64:50;67:34;68.91 and leukemia effea of instillation or implantation in 67:148 animal tracheabronchial tree in little cigars, compared to cigarettes, 71:346-34'8' and cigars effect, on RNA 73:223-226, 228 73:86 and lymphosarcoma effect on tissue and organ cultures 67:148 71:343-344 mouth , neoplasm experimentally induced as harmful component of cigarette by smoke 67:147 148' 72:142',143 nonvolatile fraction of and nicotine content of cigarette smoke,, 64:50 and' tumorigenieity pulmonary adenoma from 67:15, 34 64:165' and nicotine content of'eigarette smoke,, retention of, in mouth. as measurement of dosage 64I:264 and retioulosarcoma, 67:15' 1+1-nitrosamines in. 67c148' 73:87, 88' sarcoma induction in rats following in, reductiomof stillation 69':61 71:346' retention in mouth skin neoplasm induction by 69:62 6'7': 13 1 ;, 7 1: 2 3 8, 3 37-342; role in experimental carcinogenesis 73:210-214 73!80-84 sterol fraction of' role im respiratory tract carcinogenesis, 64:52 in animals see also Tars, cigarette 74t4'7 Taste bud reflexes summary of previous findings' on effects 64:71 on smokers Taylmr's N4ani[est, Anxiety Scale ~ 75t5 64:367 see also Tars, tobacco TDE Tars, tobacco 64:145 64:50 Tea alkaloid content of 64:349 641:5'4 Tecums;eh Study anticarcinogens in. 64:284 64:143, 144 incidence of CHD in cigarette smokers applicationiof; inicarcinoge,nesis. 68:199 64:165 lung function differences in smokers and ~ and bladder neoplasm carcinogenesis nonsmokers W. 67:156 74':81 Q Q:. c.w 226 I~C ~ ~

Temperature effect smoking and 64:50 Ten-city mortality surveys 67:26, 64, 6'5; 1111; 69:27-28; 71':66,. 1,30-132; 7'2:23; 73:19s 74:18, 19. 64:135 Tension. Thrombus, formation and smoking 64:353 Teratogenesiss maternal smoking implications in 68:3243; 69:27-28; 75:32 Thumbsucking 64:367, 368' 711:407 in mice embryos, nicotine effects on Tidal volume acrolein effects on 71:411 Terpenes 64:51i Terpenoids: 64:51„52' as flavoring agents in cigarettes 64:52 from pyrolysis of solanesal 64k52Tetraethylammonium ~ chloride blockage of nicotine cardiac stimulation, by. 71:57 effect on nicotine pharmacology 67:60 Theobromine 64: 352 64:266, 267' Tissue cultures effect of'cigarette smoke on 69t62-63; 71:267, 343-345 Tobacco advertising, prohibition of 641:8 allergic reaction to 64:302 "angina" 64':319 antigenic;properties of 64:319;72!104 antigens, in ~smokers, vs. nonsmokers. 72:107 anti-obesity eff'ect of ! Thiocyanate 64:266 Thorium. 64:145I Thoron, 64:145 Throatt effect of exposure to cigarette smoke, in passive smokers 75:99 effecti of smoking, 64:275'1lhromboangiitis abliterans allergic skin reactions in 64:319 cessation of smoking, and remission 71:74 cessation of smoking in 64:326 definition 71:73 tobacco allergy, and 72:111 treatment of 64:326 Thrombogenesiss effects afi smoking 68: 32-43 Thrombo phlebitis oral contraeeptives and 72:26 smoking and' 72:26 Thrombosis coronary 64':321I effect of epinephrine an 64:355' arsenic content: ofl 64:61, 62 arsenic spraying of 64:61 beneficial effects of 64I:255; 35'5s 356 carcinogenicity of 64':143 chemical composition of 64:49,,50-60 cholesterol content 72:24' controversy over 64`.5; 6, 7 curing methods, and incidence of respira- tory infections in rats 73 c218, 219 denicotinized 64:34';349 effect an immune responses 72:6,,107-109 tlavoring; in 64`.52; 62 flue,cured' vs: air:cured', effect on respira- tory system in animals 73:217, 218' form used and relation to gingivitis 69:86' history of' 64:5 humectants in 64:62 irritants 64:353 modification of taste of u 67:64 andiemphysema. 64:35'4and'mouth neoplasms 11 67:111 plasma and 67:145 in oral neoplasms . 69':27=28 64:198,199;:200,201 I ~ I w 227 1

and oral submucous fibrosis 69:58 pharmacologic, irritative;,and allergic ef', fects 72:7; 1091111. role in carcinogenesis 69:62 and' stomach neoplasms 67:33', 158' see also Tobacco additives; Tobacco ex- tracts:; Tobacco leaf components; To- bacco; pipe Tobacco Act of 1842 64':62 Tobaceo,additives. 64:62, 145 fl9vorings as 64:62', humectants as 64`.62' proh~bition of 64:62' see also Tobacco Tobacco alkaloidk see Alkaloid's;tobacco Tobacco ambylopia see Ambylopia, tobacco Tobacco chewing 64:45, 2111,,213', 349 decrease of 64:4'5,211 gingival neoplasms fcom, 64:202, laryngeal neoplasms from 64:212 leukoplakia and 73'.75 lip neoplasmsfrom 64:202; 71:3'61-363, 365,366' oral neoplasms from. 64:233; 69':58; 71:361-363, 365-366;72i69 per capita consumption of chewing to- bacco, U.S. 64:45 Tobacco consumption 64:5, 26„29, 30, 35, 36, 45', 46, 85, 86, 87, 89, 155; 187, 188' bladder neoplasms; mortality rates by 67:15'5I bladder neoplasms;,prevalence by 64t22'3: coronary diseases and 64!:10b; 323 coronary diseases, mortality rates by 64!:3'24 cough:and sputum prevalence by 64!:289: epithelia] cell changes by 64h23I errors of measurement ofl 64!:111 esophageallneoplasm risk ratio by 641:2131 2377 factors determining 64!:163: forced expiratory volume by 64':289~ gastric neoplasms mortality rate by 64:22'8;67:158' laryngeal neoplasms risk ratios by 64:209 lung,neoplasms mortality rates by 64:137, 1866 lung neoplasms risk by 64!:37, 196,,232 mortality rates by 64:29, 105, 1',06, 111, 139, 180;,324 mortality ratios by 64:85, 86, 105', 106 oral neoplasms gradients by 64:202, 233 per capita, U.S: 64!:4'5 in pneumoconiosis 64':291,,298 relative risk ratios by 64:1I83' respiratory symptoms by 64:289 stress factors in 64:32, 373, 3741 Tobacco extracts 64:143', 144 antige nic: properties 72t104;,105 caroinogpnesis from ~ 64:143, 144, 165 effect onicell cultures 73:85, 86 effect on skin. 72:105-107 irrittintsin 72:104, 105 thromboangiitis obliterans and I 72:111 see also Tobacco Tobacco habit 64:34'91354 cure of' 64:354 dependence on 64:350 niootine in 64:32, 349: psychological drives in 64::32, 350; 351 see also: Smoking habit. Tobacco Indlistry Research Committee 64:6 Tobacco Institnte;,I'nc. 64:8 Tobacco leaflcomponents antigenic, properties 72:104, 105' polbnium-2'10' in 67:128 presence of potassium 71:266 see also:Tobacco Tobacco, pipe definition and processing 73:176 decrease in consumption 64:45' 228

I per capita consumption, U.S. 64:45 see also Tobacco Tobacco workers coronary diseases in 64:322 healthistudies in. 64:182 laryngeal neoplasms in tobacconists 64:205 Tokyo-Yokohama asthma 641:276 Taluene 64:55s59. Tongue hamster, C-14 labeled particulate depos;i- tion in 71:281-282 Tongue neoplasms cigar smoking in 64:189, 202 pipe and cigar smoking in 64:202 pipe smoking in 64:188, 189: retrospective studies in, by type off smoking 64':201 risk gradients in 64:233 see a1So Mouth neoplasms; OraL neo- plasms Tooth extraction effect of smoking on,healing of socket 69:87 Toxicity birth rate reduction from 64:34'3 from nicotine 64:73 from sulfur dioxide 64:295' threshold i levels in 64<295 Trachea changes in4 in smokers 64':167 172 hamster, C-14 labeled' particulate deposi- tion in 7ll:281-282 histopathologynf 64:167-172; 271 mucus secretion in 64:268 mucus velocity, effects of smoking, in dbgs 75:78 Tracheal! neo plasms experimentally induced by cigarette smo ke 67:144 mortality rates, by; amount smoked 67:147 mortality rates, by smoking classification 67:147 smoking and. 73:711 Tracheobronchial tree clearance, effects of cigarette smoke in donkeys 75:78 epithelial changes in 64:1'67-172 function 64:35' histopathologic changes in 64;16747,3, ,270-274 passim i secondary infection in 64;:27 2 Traffic effect, on air, pollution in iBoston. 74':82, 83. Traffic accidents 64:39; 344„345' Tranquilizers 64:100; 101', 354 nicotine as. 64':350 Transit workers breathlessness in 64:286 chronic cough ini 64:281i Treadmill performance cardiovascular parameters in smokers vs: nonsmokers. 73:243-245 ~ effect of vitamin C 73:245 oxygen intake in smokers vs. nonsmok- ers 73:24'5 Tricaprylin 64::143. 'Priglycerides coronary disease relationship to: 71:65;73'8 smokers vs, nonsmokers 71:99-100, 102'. Trout hepatoma induction in 64:145' Tryptophan metabolismm alteration in,urinary tract neoplasms by smoking 71,:13 alterations by smoking. 71:297 caroinogenicity in mice laladders 71:2966 disorders, and' bladder neoplasms 67:36, 106' d'isorders, effect of'cessation of smoking on 67:156' effect of smoking on 67:36, 1'56' effect' of smoking on„ and bladder neo- plasms 67:36 relation of excretion in smokers and nonsmokers 71:297' 229 E C C.i Q ~ ~ C1a ClT 0

Tryptophan metabolites, carcinogenib,,and smoking genetic and environmentaU factors in angina pectoris in 67:36 carcinogenic, in urine, and bladder neo- plasms 67:366 excretion of„by smokers 69:641 intermediate, and bladder neoplasms 69:25' genetic,studies of smoking,effects on 71:49-52' monozygotio;, ang4nai pectoris incidence, rates in,,by smoking habit 67:59' monozygotic, bronchitis morbidity prev- 67:156 Tuberculbsis alence rates for, with discordant: smoking, habits 64:276{ 302alcoholconsumption~in64:277 cigarette consumption in 67:113 monozygotic, chronic cough in, with discordant smoking,habits 67:103, 113'' 64k277' in smokers vs. nonsmokers monozygotic, respiratory symptoms in, with discordant smoking habits 71:172, 226-228' smoking and 67`.103,113 morbidity rates by smoking habit in 72':41 Tumors 67:103 mortality from: CHD', in smokers vs see Neoplasms; and specific: neoplasm terms Twenty-five State Study expected deaths, in 64:1d0~ lung neoplasm mortality in 64:118' mortality ratios in nonsmokers 75:14,15 neoplasm~ incidence in 64:190 predisposition to smoking,in 64:326 role of heredity factors in, respiratory diseases in 64:110, 11'8, 1'49, observed deaths in 67:102 role of respiratory tract diseases 64:110' Twins air pollution exposure levels and,respira- tory symptoms i 75:67 air, pollution vs. smoking in bronchitis development in 67`.109 aa pollution vs. smoking,in emphysema development, using, 67:109 angina pectoris development, in, smoking effects on 71:50-5 ii blood cholesterol' levels by' smoking habit in 67`20 smoking and'coronary heart:disease in, 72:18' smoking effects on, mortality and mor- I bidity'in 71I:5'1 smoking habits of. I :190' ltraviolet rays absorption determination of 64:51 neoplasm, induction by 67:555 64:144 constitutionalifactors in bronchitis devel- opment in Underachievement 64:372, 373' 67109 Unemployed eonstitutional, factors in emphysema de- velopmenU in smoking in, 64:363 67:1091 United' Ifingdom, coronary disease incidence rates in, with discordant smoking habits 67:103: bladder neoplasms in, methods iniretro- spective studies of smoking and 71:382-384 cough incidence rates, smokers vs: non- smokers by age and sex in 67:102 blood pressure differences in smokers vs:s nonsmokers in 71`.103, 104 dizygotic, bronchitis morbidity prev- British Perinatal Mortality Survey 404 415', 71:390 395' alence rates for, with discordantt smoking habits 67:103 , , , cigarette smoke effects on animal ciliary function in 71:221 dizygotic, chronic cough, in, with di'sr cordant smoking habits 67:103 cigarette smoke effects ow human fetal lung,and mice trachea 71:344 230

cigarette smoke effects on human pul- monary functiow 71:168,169 cigarette smoke effects on mice respira- tory tract 71:352' cigarette, smoke implantation effects on rat tracheobronchial tree in. 7S: 346-34'7 comparison, of abortions,, stillbirths and neonatal d'eaths in smoking and' non+ smoking mothers 71:406 COPD morbidity in smokers in. 71:195-197, 2034 204 human experimental data on, smoking and pregnancy in 71:4'08' kidney and bladder neoplasms in smok- ers in 71:294 lung neoplasms mortality in males in England and Wales 71:240 maternal smoking and' infant weiglrU in 7l :397; 399 methods of retrospective study of lung neoplasms and smoking,in 71:324;326 methods used im smoking study andd human pregnancy. 711:391,, 394395' mortality from cerebrovascular disease, related'to smoking in 71:68 mortality rates fcomi COPD in, lack afl increase 71:140 mortality ratios from, esophageal neo- plasms in 71:290 mortality ratios from laryngeal nea- plasms in 71:278 mortality ratios from peptic : ulcer inn smokers and nonsmokers in 711:424 occupational,exposure and smoking rela- tionships to COPD;in 7d!:218-219 peptic ulcen in, methods and results of ret'rnospective and cross section, studies of smoking and 71:425-428 physicians in, decline in,cigarette smok- ing rates 7L:48 physicians in„mortality from lung nea- plasms in smokers and nonsmokers'. 71:241' pulmonary function in4 cigarette smoke effects an, 71:168 relationship of lung neoplasms to smok• ing„airpollution, and residence in 71:253-254 relationship of smoking and tuberculosis in , 71!:226' serum lipid differences in smokers vs. nonsmokers in 71:101„ 102' smoking and nicotine effects on animal cardiovascular functiomin 71:107' smoking and' nicotine effects omhuman, blood lipids in 71I:126 smoking and nicotine effects on human, cardiovascular system in 71:115 smoking relationships to thrombosis in 71:131 United States acute effect of'~ cigarette smoke on hu- man pulmonary function in 71:166-167, 169; arteriosclerosis mortality in 64:321 atherasclerosis,autopsy studies in 71:53-55 bladder neoplasms, in, methods and results: in retrospective studies of smoking and 711: 381-3 84 blood' pressure differences in smokers vs: nonsmokers in 71:103-104 Bureau of', the Census 64':177. CHD mortality and morbidity in.smok- ers vs. nonsmakers in 71':30-35, 37, 93;941 chewing tobacco consumption; decrease in 64!:45 chronic bronchitis studies in 64:271 cigarette consumption increase in 64:26, 45, 4'6, 185' cigarette smoke effects an animal ciliary function in, 71':221-224 cigarette smoke,effects on animal tissuess in 71!:343-34'5 cigarette smoke effects on pulmonary surfactants and' surface tension 71:172, 225 cigarette smoke implantation effects on animal tracheobronchial tree 71:346-348 cigarette smoke inhalation effects on animal respiratory tracts 71:349-350, 352, 354 comparison of abortions, stillbirth, andl neonatalldeath in smoking and non- smoking mothers 71:405;406 COPD development in 7'1:101 COPD morbidity in smokers 71:195, 196, 198-200, 201-202, 205' 23' 1

Department of Agriculture. 64!:15 Department'of Commerce 64!:15' esophageal neoplasms in, retrospective studies of tobacco use 71:378' esophageal neoplasms mortality in, in~ 1967. 71:289 Food and Drug Administration 64:8, 13,,15 human experimental' data on smoking, and'pregnancy in 711:391-395, 408r410 , human, pulmonary function following cessation of smoking,in 71.:149 inhalation practices in„in smokers 64:177 kidney and bladder neoplasms in smok- ers in, 71:293-295 laryngeal neoplasms incidence in 1967 71:277' laryngeal neoplasms in, relationships to tobacco use 71;278'-279, 354-355' lung neoplasms mortality rates 64:176 lung neoplasms mortality rates in, smok- ers and nonsmokers in 71I: 240-243 maternallsmoking and!infant! weight. 71:397-399 methods: of retrospective stUdy of lung, neoplasms' and smoking in„ 71:323'-328' mortality from aortic aneurysm related, to smoking,in 71:71 mortality fromi cerebrovascular disease related to smoking 71:68-70 mortality rates for bladder neoplasms in 1967' 71~:293 mortality rates for COPD 71,:139-14'00 mortality rates for kidney neoplasms in. 1967' 71:296 mortality rates for lung, neoplasms ex- pected in 1970 71:237„239 mortality rates for lung neoplasms in 1'939 vs. 1967 71:239' mortality ratios for COPD' 71:142-145 mortality ratios for esophageal neo- plasms in. 71:290-294 mortality'ratios for laryngeal neoplasms. 71:278-279 mortality ratios for; pancreatic neoplasms in smokers and nonsmokers in. 711:298' mortality ratios for peptic ulcer in smok- ers and nonsmokers in 71:424 neoplasm mortality increase in 64:229 nonsmokers in, by age and sex. 64:178 occupational exposure and smoking rela- tionships to COPD in 71:21i8-219 Office of Science and Teehnology. 64:8 oral neoplasms incidence in, estimated' for 1970' 711:284 peptic ulcer in, methods and results for retrospective and cross section stud- ies of smoking and 711:425, 426-428 ~ peptic ulcer mortality in 1967 in 71:423 polonium-210 levels~in lungs of smokers in 71:335-336. PublicMealth Service 64':6', 13, 127, 343 relationship of human pulmonary hisr tology and smoking in, 711:155-157 relationship of lung neoplasms to smok- ing, air pollution, and residence in 7L:253r2541 relationship of smoking to infectious respiratory diseasesin 711:227-229 relationship of tobacco, use and lip neo- plasms. 71,:361; 365', 367 relationship of tobacco use and neo- plasms of oral Icavity 711:361-365', 36'7' retrospective studies in, neoplasms 64:150-165', 197-202, 205-209 serum lipid differences in smokers vs:. nonsmokers in 711:98, 100, 101 smokers ina,by age 64:177 smoking and nicotine effects on animal cardiovascular function in 71:107=112' smoking and nicotine effects on,human, blood Gpidfi 71:123-126 smoking and nicotine effects on human cardiovascular system 71i:1i1!3-114, 116'a 117,11,9, smoking and nicotine effects on human catecholamine levels 71:119 smoking and nicotine effects on human peripheral vascular system. 71:133-134 smoking relationship to thombosis in 7111:130, 131 surveys of cigarette smoking in 711:6 232

tracheobronchial tree changes in smokers, Urinary tract neoplasm s , and nonsmokers in see Urogenital'neoplasms 71':259-263 Urogenital diseases white males in, mortality rates in 64:224 64':95' Urogenital neoplasms white population in, mortality ratios in. cigarette smoke condensate:as cause, in 64:132 animals United States veterans 74:58 64:109, 174 excretion of tryptaphan in smokers vs. chronic coughdn. nonsmokers with 64:281, 282„285' 74!: 58 expected deaths in incidence in malesand females by age 64:109 68:104' mortality rates in incidence in smokers vs. nonsmokers 64:88„293' 74:58 mortality ratios in mortality and smoking,factors in bladder 64':1,09; 149, 1,741 neoplasms nonresponse rate in 68:1'04;,105 64:113 mortality rates; by age observed deaths in 67:154 64';109 mortality rates, by amount'smoked' respiratory performance in 67,:154 64I:297 mortality rates, by smoking classification smoker mortality rates in 67:154 64:115 mortality ratios, by age. University of Minnesota Hospital 67':1154 64c1'40, mortality ratios, by amount smoked Unsaturated fats. 67 :1,54 64':322' mortality ratios, by smoking classifica-. Unsaturated fatty acids tion 64:53' 6'7:154 Uranium miners smoking and lung neoplasms in 69t60,64;75':50 64:193;67:1'43;71:25'6 summary of previous findings on rela- Urban areas tionship to smoking; contribution to lung neoplasm mortality 68:89; 90; 74':57 71:1i1, see also Bladder neoplasms; Kidney neo- coronary disease incidence in plasms 64:322 Uterus lung neoplasm rates in cigarette smoking, effects on, in preg- 64:186, 194, 195; 71:276 nancy relationship of, lung,neaplasms; smoking; 71:408 air'pollutiun to 71:252-255 smoking prevalence in, 64!:99; 101, 364 Urbanization Vanillin, 64:186, 232' 64:62 Urban populations Vascu lar diseases; occLVisive lung neoplasms in, suspected etiologyof 64':319 increased. smoking and 71:276 73:21 Urban vs: rural populations Vascular diseases, peripherall bladder neoplasm prevalence carboxyhemoglobin levels and, 64:2251 72:26 mortality rates epidemiologic studies 67:11 74:14-16 smoking and experimental studies. 67:97, 74:16' Urethan, nicotine and neoplasm promotion by 72:25 64`142 smokers vs, nonsmokers neoplasms from. 72:26 64:143, 144 smoking as a risk factor, pulmonary adenomas from 72:2„25„26, 56';'73`.19-23; 74:14.16' 64:144 Vascular reconstructionn Urinary tract diseases effect of smoking Q see Urogenital diseases, 73:22, 23 ~ 233 W ~I9

Vascular resistance effect of cigarette smoke on 67:61 effect of histamine on 67:61 effect of nicotine on 67:60 effect: of'smoking,on 67:60 Vascular system peripheral„ smoking, and' nicotine effectt oni 71:9, 72-73', 75',,133'-134 Vasoconstriction fetal weight' reduction by 64:343 nicotine induction of 64t318' pulmonary, effects of cigarette smoking 68':75i 76. Vegetable fibers 64:59 Venezuela maternal' smoking, andl infant weight in, 711:4'50 methods used, in smoking study andd human pregnancy 71':445 Ventilation effects on constitutents ofl tobacco smoke 75:90-95 Ventilatory function 64':35,292',300,302 effecti.of exercise and!smoking 73:244,24'S Ventricular fibrillation 64:321 death from, nicotine effects on 71:36 effect of cigarette smoke in dogs. 73:131 14 Ventricular hypertrophy as a risk: [actor in CHD 73't8 Ventricular premature beats effect of cigarette smoking 75:20. Veterans see Canadian veterans study; United States veterans Viruses as etiologic agent in cancer 64:ll66,230 influenza, cigarette smoke effects on resistance of mice with, 71:1173 influenza, nitrogeni oxide effects on squirrel monkey resistance to 71:173 neoplasm induction by 64:142' Vision carboxyhemoglobin effect on 64:344' effect'of carbon monoxide 72;126' effect, of smoking ~on. 67:183 Vitamin B'complex deficiency, and tobacco ambylopia 67:40, 1,83'. Vitamin B 12 deficieney; 64:212 deficieney; potentiation of cyanide inn tobacco ambylopia 67i40,1'83in pregnant smokers vs: nonsmokers 73'.119Vitamin iC effect an treadmill,performance in smok- ers vs:,nonsmokers 73`.245 in milk of smoking,mothers 73:141 in pregnant'smokers vs. nonsmokers 73:119 Vitamin D and nicotine, effect on hypercholes- terolemic rabbits 69:27 Vocal cordfi, effectof smoking on thickness 69:59-60 hyperkeratosis in 64:271 seealso Larynx Waiters esophageal neoplasms in 64:134 oral neoplasms in. 64:134 Washington University study 64:174 Water hardness, and smoking as risk factors in CHD: 73':9; 10 soluble fraction of cigarettes, suppres- sion of immunoglobulin response. 75:77' Welsh miners 64:293, 294' Western Collaborative Group Study CHD risk factors, in smokers vs. non- smokers 68:25, 26 incidence of myocardial infarction in younger~male smokers. 68 t 21' White House CQnference on Nareoticsiand Drug Abuse 64:355 White Pekin duck nature of phagocytized clearance prod- ucts in 64:269 Whites caneermortality in 64:135 234

esophageal neoplasms in 64':21i8 laryngeal neoplasm prevalence in 64:209 mortality rates 64':133' mortality ratios by sex. 64:133 smoking patterns in 64:363, 364 Wire implantation 64':166 Withdrawall clinics. 67:191 methods 64:354 symptoms 64:35'2; 354 see also Cessation of smoking Women autapsy studies, in smokers vs. nonsmok- ers with, emphysema„ fibrosis, or thickening af! arterioles or arteries 75:755 blood pressure and smoking habits dur- ing pregnancy 69:77-78' CHD incidence in 74':9; 10: exposure to chemicals, fumes, sprays and dusts,,in smokers vs~: nonsmokers 75:69, 70 hypertension, in cigarette smokers with CHD 68 c22 incidence of lung neoplasms 68:97; 74:39, 40; 75:43' incidence of lung neoplasms and smok- ing; 69':4, 57 increase in mortality, from lung neo- plasms 75i47, mortality fiom lung neoplasms 68':97 mortality; in smokers vs: nonsmokers 68':64 ,8', 99 mortality rates from lung neoplasms andd asbestos exposure 74:42, 43 mortality rates from lung neoplasms„ statistical sex ratio 74:40, 45' mortality rates, in smokers vs. nonsmok- ers 74:9, M myocardial infarction in pre- vs: post', menopausal 74c1'0, myocardial infaretion„in Swedish smok- ers vs. nonsmokers 75:14 secular trends of lung neoplasm develop- ment in. 74':40 sudden deathiratesin. 74:9, 100 summary of previous findings on effects of smoking 75:5-7 trends in neoplasm, incidenee rates for selected sites in 74:411, 4'2 Working classes 6C362' Work-loss days definition 67:19 and smoking 67:20-2i, World Health Organ¢ation. 64':850, 354! classitication of lung,neaplesms 64':17 3, 174 Xenon radioactive, regional pulmonary functionn using 71:147 washout technique for detectioniof lung neoplasms 74':4'3, 44 U.S. GOYERNMENT. PRINTING OFFICE: 1976-848/297 23'5

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