Th e Health Consequences of Smoking A Report of the Surgeon General: 1971 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service For sale by the Superintendent of Documents, U.S. Government Printing OI%x Washington, D.C. 2040'2 - Price $1.75 This report is a comprehensive review of more than 20 years of research into the problem of smoking and health. This re- search has been carried on under the sponsorship of many groups in this country and abroad, including governments, universities, private research institutions, voluntary health agencies, and the tobacco industry. Seven years ago, an advisory committee to the Surgeon General concluded that cigarette smoking is a serious hazard to health and is related to illness and death from lung cancer, chronic broncho- pulmonary disease, cardiovascular disease and other diseases. In the intervening years, a great deal of new research has been com- pleted. This has resulted in a growing understanding of the bio- mechanisms whereby cigarette smoking adversely affects the hu- `man organism and contributes to the development of serious illness. It is encouraging that cigarette consumption in this country is declining. If this decline can be maintained, it will result in better health for our population and in fewer deaths among those of our @tizens who are in their most productive years of life. JESSE L. STEINFELD, M.D., Surgeon General. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel Horn, Ph.D., Director, was responsible for the preparation of this report. Daniel P. Asnes, M.D., was consulting editor. Staff direc- tor for the report was David G. Cook, M.D. The professional staff has had the assistance and advice of a number of experts in the scientific and technical fields, both in and outside of the government. Their contributions are gratefully acknowledged. Special thanks are due the following: ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Disease Section, University of Louisville School of Medicine, Louisville, Ky. AKTHONISEN, NICHOLAS, R., M.D.-Ph. D.--Associate Professor, Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada. AUERBXH, OSCAR, M.D.-Senior Medical Investigator, VA Hospital, East Orange, N.J. AYRES, STEPHEN M., M.D.-Director, Saint Vincent's Hospital and Medical Center of New York, Cardiopulmonary Laboratory, New York, N.Y. BAKER, CARL, M.l).-Director, National Cancer Institute, National Institutes of Health, Bethesda, Md. BELLET, SAMUEL, M.D.-Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, Pa. BI~`G, RICHARD J., M.D.-Professor, of Medicine, California Institute of Tech- nology, Pasadena, Calif. BOCK, FRED G., Ph. D.-Ijirector, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, N.Y. BOREN, HOLLIS, M.D.-Professor of Medicine, Marquette School of Medicine, Wood VA Hospital, Milwaukee, Wis. BOUTWELL, ROSWELL Ii., M.D.-Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wis. COOPER, THEODORE, MD-1 iirector, National Heart Institute, National In- stitutes of Health, Bethesda, Md. CORNFIELD, JEROME-Research Professor of Biostatistics, University of Pitts- burgh Graduate School of Public Health, Riostatistics Project, Bethesda, Md. EARL, CHRISTOPHER J., M.L).-National Hospital, London, England. EPSTEIX, FREDERICK H., M.D-Professor of Epidemiology, University of Michigan, School of Public Health, Ann Arbor, Mich. FALK, HANS L., Ph. I).--.Associate Ijirector for Laboratory Research, National Institute of Environmental Health Sciences, Research Triangle Park, N. C. FERRIS, BENJAMIN G., JR.. M.I).-Professor, Department of Physiology, Har- vard School of Public Health, Boston, Mass. FITZPATRICK, MARK J., M.D., M.P.H.-Obstetrician, Perinatal Biology and In- fant Mortality, National Institute of Child Health and Human Development, National Institute of Child Health and Human Development, National In- stitutes of Health, Bethesda, Md. FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health and Medical Care, Harvard &ho01 of Public Health, Boston, Mass. GOLDSMITH, JOHN R., M.D.-Head, Environmental Epidemiology Unit, Cali- fornia State Department of Public Health, Berkeley, Calif. HANNA, MICHAEL G., JR., Ph. D.-Biology Division, Oak Ridge National Lab- oratory, Oak Ridge, Tenn. HIGGINS, IAN T. T., M.D., M.R.C.P.-Professor, Department of Epidemiology, University of Michigan Schclol of Public Health, Ann Arbor, Mich. HOFFMANN, DIETRICH, Ph. D.-Division of Environmental Toxicology, Ameri- can Health Foundation, New York, N.Y. ISRAEL, ROBERT A.-Director, Division of Vital Statistics, National Center for Health Statistics, U.S.P.H.S., U.S. Department. of Health, Education and Welfare, Rockville, Md. KELLER, ANDREW Z., D.M.D., M.P.H.-Chief, Research in Geographic Epide- miology, Veterans Administration Central Office, Washington, D.C. KIRSNER, JOSEPH, M.D.-Professor of Medicine, University of Chicago School of Medicine, Chicago, Ill. KNOX, DAVID L., M.D.-Associate Professor, The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Md. KOLBYE, ALBERT C., JR., M.D., J.D.-Deputy Director, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education and Wel- fare, Washington D.C. KOTIN, PAUL, M.D.-Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. KRUMHOLZ, RICHARD A., M.D.--Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, Ohio. LIEBOW, AVERILL A., M.D.-Professor and Chairman, Department of Path- ology, University of California at San Diego, La Jolla, Calif. LILIENFELD, ABRAHAM, M.D.--Professor and Chairman, Department of Chronic Diseases, Johns Hopkins School of Hygiene and Public Health, Baltimore, Md. MACMAHON, BRIAN, M.D.-Professor of Epidemiology, Harvard University School of Public Health, Boston, Mass. MCLEAN, Ross, M.D.-Medical Consultant, Regional Medical Program of Texas, Austin, Tex. MCMILLAN, GARDNER C., M.I).--Chief, Arteriosclerotic Disease Branch, Na- tional Heart and Lung Institute, National Institutes of Health, Bethesda, Md. MITCHELL, ROGER S., M.I).-Director, University of Colorado Medical Center, Webb-Waring Institute for Medical Research, Denver, Colo. MURPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Md. PAFFENBARGER, RALPH S., JR., M.D.-Chief, Bureau of Adult Health and Chronic Diseases, California State Department of Public Health, Berkeley, Calif. PETERS, JOHN M., M.D.-Associate Professor of Occupational Medicine, Har- vard University School of Public Health, Boston, Mass . PETERSON, WILLIAM F., M.D.--Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, D.C. PETTY, THOMAS L., M.D-Associate Professor of Medicine, University of Colorado Medical Center, Denver, Colo. vi SAFFIOTTI, UMBERTO, M.D.--Associate Scientific Director for Carcinogenesis Etiology, National Cancer Institute, National Institutes of Health, Beth- esda, Md. SCHUMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, Minn. SHIIMKIK, MICHAEL B., M.D.-Coordinator, Regional Medical Program, Uni- versity of California at San Diego, La Jolla, Calif. STAMLER, JEREMIAH, M.D.-Executive Director, Chicago Board of Health, Health Research Foundation, Chicago, 111. UNDERWOOD, PAUL B., JR., M.D.--Associate Professor, Department of Ob- stetrics and Gynecology, University of South Carolina Medical School, Charleston, S.C. VAN DUUREN, BENJAMIN L., M.D.-Professor of Environmental Medicine, In- stitute of Environmental Medicine, New York University Medical Center, New York, N.Y. VICTOR, MAURICE, M.D.-Professor of Neurology, Department of Neurology, Case Western Reserve, Cleveland, Ohio. WYNDER, ERNEST L., M.D-President and Medical Director, American Health Foundation, New York, N.Y. The following professional staff of the National Clearinghouse for Smoking and Health contributed to the preparation of this re- port: John H. Holbrook, M.D., Richard W. White, Robert S. Hutch- ings, Elaine Bratic, Annabel W. Hecht, Richard H. Amacher, Donald R. Shopland and Jennie M. Jennings. Special thanks are due Nancy S. Johnston, Kathryn Carlysle, Mary E. Dement, and Mildred H. Ritchie. vii Contents Page PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... 111 ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Chapter 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Chapter 2. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . 15 Chapter 3. Chronic Obstructive Bronchopulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Chapter 4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Chapter 5. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Chapter 6. Peptic Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419 Chapter 7. Tobacco Amblyopia . . . . . . . . . . . . . . . . . . . . . . . 431 CHAPTER 1 General Considerations, Preparation of the Present Document, and Summary of the Report GENERAL CONSIDERATIONS The first major development in the modern history of the effects of smoking on health occurred in 1950 with the publication of four retrospective studies on smoking habits among lung cancer pa- tients and among controls (1, 4, 6, 7). At that time, the question was, "Are smokers more likely to get lung cancer than nonsmok- ers?" Although some epidemiologists were satisfied that the an- swer was in the affirmative, others turned for confirmation to prospective studies in which the smoking habits of large popula- tions were recorded and the populations followed to identify sub- sequent mortality. The first report of Hammond and Horn in 1954 (Z), showed significantly elevated overall death rates for smokers as compared to nonsmokers. This elevation in death rates, almost entirely confined to those who smoked cigarettes, together with the evidence for a gradient according to the amount smoked, changed the question from one concerning only lung cancer to one concern- ing overall death rates and from one concerning smoking to one primarily concerned with cigarette smoking. In effect, the question became, "Do cigarette smokers have higher overall death rates than nonsmokers and smokers of pipes and cigars?" With the publication of the later reports of the major prospec- tive studies in the late 1950's and early 1960's, it became clear that cigarette smokers had higher overall death rates than nonsmokers, as well as higher death rates from a number of individual causes of death. The question then became, "Why?" When the Advisory Committee on Smoking and Health to the Surgeon General was established in 1962, it undertook the evalua- tion of the scientific evidence up to that time. The conclusion of the Committee in its 1964 Report was that: "Cigarette smoking is a health hazard of sufficient importance in the United States to war- rant appropriate remedial action." Not only did the Committee conclude that the evidence clearly showed that male cigarette smokers do in fact have higher death rates than nonsmokers but that the convergence of epidemiological, experimental, and path- ological evidence also clearly indicated a cause-and-effect relation- ship for several of the implicated diseases, particularly cancer of the lung and chronic bronchitis. In several other important dis- eases, the evidence on biomechanisms to explain epidemiological 3 associations was felt to be inadequate at that time to draw firm conclusions about a cause-and-effect relationship. Three and one-half years later, when The Health Consequences of Smoking: A Public Health Service Review, 1967 was published, the conclusions of the 1964 review were taken as a starting point, and the nature of the task of interpreting the scientific evidence was restated as follows : 1. How much mortality and excess disability are associated with smoking? 2. How much of this early mortality and excess disability would not have occurred if people had not taken up cigarette smoking? 3. How much of this early mortality and excess disability could be averted by the cessation or-reduction of cigarette smoking? 4. What are the biomechanisms whereby these effects take place and what are the critical factors in these mechanisms? That and subsequent reviews in 1968 and 1969 have provided some answers to these questions, particularly in summarizing the evidence for various theories as to how cigarette smoking affects the human organism to produce elevated disease and death rates. At least five different processes have been suggested whereby cigarette smokers experience higher mortality or morbidity rates than do nonsmokers. 1. Cigarette smoking initiates a disease process by producing progressive irreversible damage. In this case, the total effect would be approximately proportional to the total accumulated dosage experienced over the years. Cessation of smoking leaves impaired function which does not improve appreciably but does not continue to deteriorate from continued exposure to cigarette smoke. How- ever, such function may deteriorate through aging or through exposure to other harmful agents. It appears that such a relation- ship probably exists for chronic obstructive lung disease and pos- sibly for the development of atherosclerotic heart disease. 2. Cigarette smoking initiates a disease process with continual repair and recovery until some critical point is reached at which the process is no longer reversible. The total effect would therefore be affected to some extent by accumulated exposure but would be affected also by the level of contemporary smoking. Cessation of smoking would result in a rapid reduction of risk provided the critical level initiating an irreversible process has not been reached. The evidence supports this kind of mechanism accounting both for the high dose-response relationship in lung cancer and for the reduction in risk from lung cancer among ex-smokers. 3. Cigarette smoking promotes a disease process either by providing positive support to the development of a pathological condition or by interfering with and diminishing the normal capa- 4 bility of the organism to cope with and defend against a disease process. This may take place by promoting the development of a subclinical disease to a clinically recognizable one, by promoting a mild disease state t.o a more severe form, or by increasing fatality rates of severe disease states. This type of mechanism could ac- count for modestly increased mortality rates for a number of se- vere diseases for which there is no evidence that cigarette smoking itself has a role in initiating the disease. Some of the excess mor- tality from infectious respiratory disease and from coronary heart disease might take place through this kind of mechanism. 4. Cigarette smoking produces a set of temporary conditions which increase the probability that a critical event will occur with attendant disability and possibly fatal consequences. For example, there is evidence to support the theory that each cigarette can pro- duce a set of conditions which increase the probability of myocar- dial damage through increased demand for oxygen at a time when the suppy is diminished. Presumably, once the supply/demand im- balance is alleviated, the probability of myocardial damage would revert to its normal level. Cessation of smoking should have an almost immediate effect of reducing the risk sharply for morbidity or mortality produced through this mechanism. 5. Cigarette smoking may be artificially related to excess dis- ability or death by way of a close association with some other con- dition or exposure which is found at a high level in smokers, but not in nonsmokers, and is itself responsible for the disease. The one cause of death for which cigarette smokers have elevated death rates that is generally interpreted in this way is cirrhosis of the liver. Since most heavy consumers of alcoholic beverages are smok- ers, and since alcohol consumption is an important part of the process that produces cirrhosis of the liver, the high rate of cirrho- sis among cigarette smokers is discounted as resulting from this kind of artificial relationship. Some authors have proposed that there may be genetic factors that link smoking and certain diseases in this fashion. Obviously, the cessation of smoking would have no effect on morbidity or mortality from diseases which are artificially related to smoking. These different ways in which cigarette smoking can be related to elevated morbidity and mortality rates are important considera- tions in attempting to estimate the potential public health benefits of giving up smoking, For some types of relationship, there would be no benefits ; for some, rather small benefits ; for some, substan- tial benefits, taking place over a long period of time; and for others, substantial benefits taking place rather rapidly. During the past few years, a sharp reduction has taken place in the cigarette smoking habits of the U.S. population. The Na- 5 tional Center for Health Statistics has recently published a com- parison of smoking habits in the US. in 1955 and 1966 based on two large scale household surveys (5). These showed a drop in cigarette consumption in men under 55 years of age but no appre- ciable change among those 55 or over. Among women, every age group showed an increase in the eleven year period. A recent sur- vey conducted for the National Clearinghouse for Smoking and Health, based on a much smaller sample (approximately 5,000 interviews), was conducted in the Spring of 1970 (3) (table 1). Even with the smaller number of cases, it is clear that a much larger drop took place in the four years from 1966 to 1970 than in the eleven years from 1955 to 1966. The drop extended to the age group 55-64 among men, again with no appreciable drop among men over age 65. For the first time, the increase in smok- ing among women leveled off, or even dropped slightly among women under 55. The increase among women over 55 was of a lesser magnitude than previously observed. TABLE I.-Percentage of Current Smokers of Cigarettes (regu- larly or occasionally) by sex and age. U.S. Surveys: 1955 and 1966 (CPS-Current Population Surveys) and 1970 (NCSH- Survey conducted for National Clearinghouse for Smoking & Health) .I Male Female CPS CPS NCSH CPS CPS NCSH ALW 1955 1966 1'970 1956 1966 1910 18-24 --__------ 53.0 48.3 247.0 33.3 34.7 231.1 25-34 ---------- 63.6 58.9 46.8 39.2 43.2 40.3 35-44 _---_-__-- 62.1 57.0 48.6 35.4 41.1 39.0 45-54 _-_-___--- 58.0 53.1 43.1 25.7 37.3 36.0 55-64 --~_---~-~ 45.8 46.2 37.4 13.4 23.0 24.3 65+ ----__-_-- 25.8 24.6 23.7 4.7 8.1 11.8 11955 survey based on approximately 46,000 persons; 1966 survey based on approximately 35,000 persons; 1970 survey based on approximately 5,000 persons. 2 Estimated. With the massive changes in smoking behavior which have taken place among adults in the past few years, largely as an expression of the desire to protect health, changes should be ex- pected in mortality rates among those groups which have experi- enced the greatest reduction both in accumulated dosage and in concurrent dosage. An analysis of U.S. mortality rates for 1970 and the years to follow will provide a very valuable addition to the knowledge concerning the effects of smoking on death rates. PREPARATION OF THE PRESENT DOCUMENT Following the publication of Smoking and Health-Report of the Advisory Committee to the Surgeon General-in 1964, the fol- 6 lowing documents were published as reviews of the medical litera- ture concerning the health consequences of smoking, as called for by Public Law 89-92 : 1. The Health Consequences of Smoking, A Public Health Serv- ice Review: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review. 3. The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review. These documents reviewed the medical literature which had been published since the original Surgeon General's Report. This format of publishing a supplement to a supplement has become unwieldy, particularly in the light of the lack of availability of the previous reviews to the general public. Therefore, when Public Law 91-222 was signed into law on April 1, 1970 calling for an eighteen month interval between the last report and the new re- port, the decision was made to review the entire field with em- phasis on the most recent additions to the literature. The National Clearinghouse for Smoking and Health has the responsibility for continuous monitoring and compilation of the medical literature on the health consequences of smoking. This is accomplished through several mechanisms : 1. A scientific review corporation is on contract to extract arti- cles on smoking and health from the medical and scientific litera- ture of the world. This organization provides a semi-weekly acces- sions list with abstracts and copies of the various articles. Trans- lations are called for as needed. Articles of pertinence are identi- fied by a series of code words and phrases. 2. The National Library of Medicine, through the Medlars sys- tem, sends the National Clearinghouse for Smoking and Health a monthly listing of articles in the smoking and health area. These are reviewed, and pertinent articles are ordered. 3. Staff members keep up with the current contents of medical and scientific literature and identify articles of pertinence. Initial drafts of the present review were prepared by Clearing- house staff and consultants who reviewed the previous reports and identified those articles which have been important in the develop- ment of knowledge in this field. These were abstracted and placed into tabular form, and a draft text of the report was prepared. The first drafts of the individual chapters were sent to experts for review, criticism, and comment with respect to the articles re- viewed, those articles not included, and conclusions. The drafts were then revised on the basis of these comments and rewritten until they met with general approval of the reviewers. The final 7 drafts were reviewed as a whole by the Director of the National Clearinghouse for Smoking and Health, the Director of the Na- tional Cancer Institute, the Director of the National Heart and Lung Institute, the Director of the National Institute of Environ- mental Health Sciences, and by six additional experts both within and outside of the Public Health Service. SUMMARY OF THE REPORT CARDIOVASCULAR DISEASES Comnary Heart Disease 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease, including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smoking of pipes and cigars is appreciably less than that incurred by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) show that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. 5. The cessation of smoking is associated with the decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms : a. Cigarette smoking, by contributing to the release of catecho- lamines, causes increased myocardial wall tension, contraction velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in cor- onary blood flow and oxygenation. c. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. Summary Statement of Recent Additions to Knowledge Relating Smoking and Coronary Heart Disease.-A number of epidemi- ologic studies have provided additional evidence concerning ciga- rette smoking as a significant risk factor in the development of CHD. Experimental studies on animals have suggested that ciga- rette smoking, particularly the absorbed nicotine and carbon mon- oxide, contributes to the development of atherosclerosis. Cerebrovascular Disease 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cere- brovascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. Nonsyphilitic Aortic Aneurys,m Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. Peripheral Vascular Disease 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE 1. Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- 9 duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma, although it may increase the frequency and severity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers, while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occu- pational materials and cigarette smoking may act jointly to pro- duce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pul- monary complications more frequently than nonsmokers. Sunzmal'y Statement of Recent Additions of Knowledge Relat- kg to Chronic Obstructive n,,onchopul??zonar!! Disease.-Studies have demonstrated that cigarette smokers show increased symp- toms and pulmonary dysfunction as well as mortality from COPD when compared to nonsmokers. Investigations of alpha,-antitryp- sin deficiency in relationship to pulmonary emphysema have sug- 10 gested that cigarette smoking may act jointly with hereditary fac- tors in the pathogenesis of pulmonary emphysema. A pathological study on animals has shown that long-term inhalation of cigarette smoke produces lesions characteristic of pulmonary emphysema. Lung Cancer. CANCER 1. Epidemiological evidence derived from a number of prospec- tive and retrospective studies, coupled with experimental and pathological evidence, confirms the conclusion that cigarette smok- ing is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases with the number of cigarettes smoked per day, the duration of smoking, and earlier initiation, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller proportion of the cases than in men. The mortality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributable to differences in exposures : the use of fewer cigarettes per day, the use of filtered and low "tar" cigarettes, and lower levels of inhala- tion. Nevertheless, even when women are compared with men who apparently have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing lung cancer appears to be higher among smokers who smoke high "tar" cigarettes, or smoke in such a manner as to produce higher levels of "tar" in the inhaled smoke. 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers. ,There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populations when compared with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of lung cancer is presently inconclusive. Fac- tors such as occupational and smoking habit differences may also contribute to the urban-rural difference observed. Detailed epi- demiologic surveys have shown that the urban factor exerts a small influence compared to the overriding effect of cigarette smok- ing in the development of lung cancer. 11 `7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than 2 years. Cancer of the Laqmx 1. Epidemiological, experimental, and pathological studies support the conclusion that cigarette smoking is a significant fac- tor in the causation of cancer of the larynx. The risk of develop- ing laryngeal cancer among cigarette smokers as well as pipe and/ or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. Oral Cancer 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and to- bacco smoke contain initiators and promoters of cancerous changes in the oral cavity. Cancer- of the Esophagus 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esoph- agus. The risk of developing esophageal cancer among pipe and/ or cigar smokers is greater than for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association between esophageal cancer and alcohol consumption and that alco- hol consumption may interact with cigarette smoking. This com- 12 bination of exposures is associated with especially high rates of cancer of the esophagus. Cancer of the Urinary Bladd,er and. Kidney 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancer of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of tryp- tophan and may in this way contribute thereby to the development of urinary tract cancer. Cancer of the Pancreas Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. Summary Statement of Recent Additions of Knowledge Relating Smoking and Cancer.-Epidemiological studies have confirmed that cigarette smokers incur an increased risk of dying from lung can- cer and that those smokers who switched to filter cigarettes incur a lesser risk. Pathological studies have shown that cancer of the lung and cancer of the larynx have been found in animals exposed to the long-term inhalation of cigarette smoke. SMOKING AND PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birthweight and an increased incidence of prematurity, defined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater number of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insufficient evidence to support a comparable statement for abortions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of Patients, adds further support to the conclusions. PEPTICULCER Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard Peptic ulcer treatment and to slow the rate of ulcer healing. 13 TOBACCO AMBLYOPIA Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in handling the cyanide component of tobacco smoke. INTRODUCTION REFERENCES (I ) DOLL, R., HILL, A. B., Smoking and carcinoma of the lung. Preliminary report. British Medical Journal 2: `739-748, September 23, 1950. (2) HAMMOND, E. C., HORN, D. The relationship between human smoking habits and death rates. Journal of the American Medical Association 155: 1316-1328, August 7, 1954. (3) HORN, D. Address given at National Conference on Smoking and Health, San Diego, Calif., September 9-11, 1970. 13 pp. (4) LEVIN, M. L., GOLDSTEIN, H., GERHARDT, P. R. Cancer and tobacco smok- ing. A preliminary report. Journal of the American Medical Asso- ciation 143(4) : 336-338, May 27, 1950. (5) NATIONAL CENTER FOR HEALTH STATISTICS. Changes in cigarette smoking habits between 1955 and 1966. U.S. Department of Health, Education, and Welfare, April 1970. 33 pp. (6) SCHREK, R., BAKER, L. A., BALLARD, G. P., DOLGOFF, S. Tobacco smoking as an etiologic factor in disease. I. Cancer. Cancer Research 10: 49-58, 1950. (7) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma. A study of six hundred and eighty four proved cases. Journal of the American Medical Association 143(4) : 329-336, May 27, 1950. 14 CHAPTER 2 Cardiovascular Diseases Page 21 38 38 39 40 Introduction ........................................ Epidemiological Studies. .............................. Coronary Heart Disease Mortality ................. Coronary Heart Disease Morbidity ................. Retrospective Studies. ............................ The Interaction of Cigarette Smoking and Other CHD Risk Factors .................................. Smoking and Serum Lipids ................... Smoking and Hypertension. ................... Smoking and Physical Inactivity ............... Smoking and Obesity ......................... Smoking and Electrocardiographic Abnormalities. Smoking and Heart Rate ..................... The Effect of Cessation of Cigarette Smoking on Coronary Heart Disease ..................................... The Constitutional Hypothesis ........................ Autopsy Studies Relating Smoking, Atherosclerosis, and SuddenCHDDeath ................................ Experimental Studies Concerning the Relationship of Coronary Heart Disease and Smoking ................ Cardiovascular Effects of Cigarette Smoke and Nicotine.. .................................... Coronary Blood Flow ............................ Cardiovascular Effects of Carbon Monoxide ......... Effects of Smoking on the Formation of Atherosclerotic Lesions ....................................... The Effect of Smoking on Serum Lipid Levels ........ The Effect of Smoking on Thrombosis .............. Other Areas of Investigation. ..................... Cerebrovascular Disease ............................. Nonsyphilitic Aortic Aneurysm ........................ Peripheral Arteriosclerosis ........................... Experimental Evidence. .......................... Thromboangiitis Obliterans ........................... Summary and Conclusions ............................ 40 41 41 41 43 47 47 47 48 52 56 56 58 59 63 65 66 66 66 67 72 73 73 74 17 Coronary Heart Disease .......................... Cerebrovascular Disease .......................... Nonsyphilitic Aortic Aneurysm .................... Peripheral Vascular Disease ...................... References .......................................... FIGURES 1. National Cooperative Pooling Project, Inter-Society Com- mission for Heart Disease Resources . . . . . . . . . . . . . . . 2. Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of "predisposing factors" (men 30-59 at entry). Framingham Heart Study.......................................... 3. Estimated coronary heart disease death ratios in a 17-51 year follow-up, and frequencies of paired combinations of six high-risk characteristics in college, for all ages at death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Relationship between smoking status and serum choles- terol level at initial examination, and incidence of clin- ical coronary heart disease in men originally age 40-59 free of definite CHD. Peoples Gas Light and Coke Company Study,1958-1962....................... 5. Average annual incidence of first myocardial infarction among men in relation to overall physical activity, class, and smoking habits (age-adjusted rates per 1,000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . LIST OF TABLES (A indicates tables located in Appendix at end of Chapter) 1. Sudden death and acute mortality with first major coronary episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Coronary heart disease mortality ratios related to smoking-prospective studies . . . . . . , . . . . . . . . . . . 3. Sudden death from coronary heart disease related to smoking..................................... 4. Coronary heart disease morbidity as related to smoking..................................... 5. Coronary heart disease morbidity as related to smok- ing-angina pectoris-prospective studies . . . . . . . A 6. Coronary heart disease morbidity and mortality- retrospective studies . . . . . . . . . . . . . . . . . . . . . . . . A 7. Differences in serum lipids between smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 74 75 75 75 75 23 24 25 43 44 23 26 30 32 37 93 98 18 LIST OF TABLES (CONT.) (A indicates tables located in Appendix at end of Chapter) A 8. Blood pressure differences between smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Death rates from coronary heart disease, by systolic blood pressure: ILWU mortality study, 1951-1961 10. Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-1961 11. Death rates from coronary heart disease, among hy- pertensives and nonhypertensives : ILWU mortality study, 1951-1961............................. 12. Death rates from coronary heart disease among men without abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality study, 1951-1961 . . . . . . . . . . . . . . . . . . 13. Death rates from coronary heart disease, by electro- cardiographic findings in 1951: ILWU mortality study, 1951-1961............................. 14. 1958 status with respect to heart rate, blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Com- pany Study,1958-1968....................... 15. The effect of the cessation of cigarette smoking on the incidence of CHD . . . . . . . . . . . . . . . . _........... 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking A 17. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A 18. Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19. Autopsy studies of atherosclerosis . . . . . . . . . . . . . . . . A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function . . . . . . A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans. . -422. Experiments concerning the effect of nicotine or smoking on catecholamine levels . . . . . . . . . . . . . . . x 23. Experiments concerning the atherogenic effect of nicotine administration, . . . . . . . . . . . . . . . . . . . . . Page 103 42 42 42 45 45 45 46 46 105 106 53 107 113 119 120 19 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia . . . . . . . . . A 25. Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) . . . . . . A 25a. Experiments concerning the effect of smoking and nicotine upon blood lipids (Animal Studies) . . . . . . A 26. Experiments concerning the effect of carbon mon- oxide exposure upon blood lipids . . . . . . _ . . . . . . . . A 27. Smoking and thrombosis . . . . . . . . . . . . . . . . . . . . . . . . 28. Deaths from cerebrovascular disease related to smoking..................................... 29. Deaths from nonsyphilitic aortic aneurysm related to smoking-prospective studies . . . . . . . . . . . . . . . . . . A 30. Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system . . . . Page 64 123 127 129 130 68 71 133 20 INTRODUCTION Coronary Heart Disease (CHD) cuts short the lives of many men in the Western World in their prime productive years. More Americans die from heart disease than from any other disease. In 196'7, in this country, a total of 345,154 men and 227,999 women were classified as dying of arteriosclerotic heart disease (ASHD) (196)) a category which consists largely of what is commonly called CHD. During the years from 1950 to 1967, the age-adjusted death rate from ASHD increased 15.1 percent (196, 197). Besides the many deaths attributed to CHD, much morbidity results from this disease. The National Health Examination Sur- vey of 1960-1962 estimated that 3.1 million American adults, ages 18 to 79, had definite CHD and 2.4 million had suspect CHD, togethes representing about 5 percent of the population. It was further estimated that of Americans under age 65, almost 1.8 mil- lion had definite CHD and 1.6 million had suspect CHD (195). `There are several manifestations of CHD, all related in part to the basic process of severe atherosclerosis, a disease of arteries in which fatty materials (lipids) accumulate in the form of plaques in the walls of medium and large arteries. This process, as it occurs in the coronary arteries, leads to stiffening of the wall and narrow- ing of the lumen which, when severe, result in a diminution in the blood supply to the cardiac muscle. Angina pectoris, a major mani- festation of CHD, results from diminution in blood supply relative to the needs of the myocardium. If the blood supply to a portion of the myocardium is completely obstructed, due for example to the formation of a thrombus at the site of atherosclerotic narrowing, necrosis or death of a portion of heart muscle may occur. This occurrence is known as a myocardial infarction. In many cases, a disturbance of cardiac rhythm occurs at the time of thrombosis, and the patient may die immediately. It is estimated that approxi- mately 25 percent of patients suffering coronary artery occlusion die within the first three hours following the occlusion (table 1) (88). Not infrequently, sudden death occurs in patients with severe coronary atherosclerosis but without a demonstrable arterial occlu- sion. In these cases, it is thought that the meager blood flow to a Portion of the myocardium becomes so diminished with respect to cardiac needs as to lead to a fatal arrhythmia, as well as to, per- haps, a myocardial infarction. 21 CIGARIEITE SMOKING(S) AT ENTRY-WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (W-AND TEN YEAR INCIDENCE AND MORTALITY RATES. 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT RATE PER 1.000 150- FIRST MAJOR CORONARY EVENT RATE PER 1,000 150- ALL CHD DEATHS 82 loo- 92 loo- 7 I ,,_(_ 1 ju 50- 45 50- W-I ). .i' (, 20 '*a,,' (_ '.1. /" o- RISK NONE S C OR H S+C OR FACTORS OF 3 ONLY ONLY SSH NUMBER 28 97 74 167 OF EVENTS C+H C+H NONE S +s OF 3 ONLY 31 82 17 50 384 595 1,249 2,018 1,302 1,794 384 595 NUMBER 1,249 2,018 1,302 1.794 OF MEN National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal MI. fatal MI. and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. Al! rates age.adjusted b white male population 1960. Graphs present rates for noncigarette VS. cigarette smokers at entry wdh srmultaneous control o { IO-year age groups to the U.S. blood pressure and serum cho- lesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking S -any use at entry (b) Serum cholesterol C - 250 mg./dl. (c) Diastolic blood pressure H - 90 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). C OR H S+C C+H C+H ONLY OR S-j-H +s 41 90 12 42 FIGURE l-National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960. Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum cholesterol level. For this latter analysis, the following cutting points were used: (a) Cigarette smoking-S-any use at entry (b) Serum cholesterol-C-2250 mg./dl. (c) Diastolic blood pressure-H-290 mm. Hg. SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). TABLE l.-Szcldden death and acute mortality with first major coronary episodes Author. year. Number and country, type of reference population Data collection Event Number of events Proportion per 1,000 events (as calculated on the basis of age- adjusted rates) Comment Pooling Project. American Heart Association, 1970. U.S.A. (88). 7,594 males Medical exam- All first major coronary males 30-59 ination and episodes, nonfatal and fatal. 501 l,ooo.o yem-s of age follow-up. Sudden death (death at entry. within 3 hours of onset Ten-year of acute illness). 123 245.5 experience. All acute deaths with first episodes. 166 329.3 Data from the Pooling Project, Council on Epidemiology. American Heart Association. a national cooperative project for pooling data from the Albany civil servant. Chicago Peoples Gas Co., Chicago Western Electric Co., Framingham Community, Los Angela civil servant, Minneapolis-St. Paul business men, and other prospective epidemiologic studies of adult cardiovascular disease in the United States. SOURCE: Inter-Society Commission for Heart Disease Resources (88). Representative references include: (54. 9L, 14.9. 177) and others listed as 6a-6k in Inter-Society Commission for Heart Disease Resources report. ,- I - I CIGARETTE SMOKING: 0 NONE >l PKG./DAY 196' 123 NONE ANY ONE 12 9.7 PREDISPOSING FACTORS (CHOLESTEROL 3250, HYPERTENSION, DIABETES) `SIGNIFICANTLY DIFFERENT FROM "NONSMOKER" P<.O5 FIGURE 2-Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of "predisposing factors" (men 30-59 at entry). Framingham Heart Study. SOURCE: Kannel, W. B., et al. (94). Numerous epidemiological studies have indicated that cigarette smokers have increased mortality ratios for CHD ; that is, cigarette smokers show significantly increased death rates compared with nonsmokers (table 2). The risk incurred by cigarette smoking in- creases with increasing dosage and, as measured by mortality ratios, is more marked for men in the younger age groups, under age 60, although the absolute increment in death rates experienced by smokers over that of nonsmokers continues to increase with increasing age. Table 2 lists the mortality ratios found in the major studies. Certain of these studies, including those at Framingham, Massachusetts, the He&h Insurance Plan of New York City (HIP), and at Tecumseh, Michigan, have analyzed morbidity as well as mortality from CHD and have indicated that the risk of developing fatal and nonfatal CHD is greater among cigarette smokers than among nonsmokers (tables 3 and 4). Conflicting evidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 24 I I ) I , I 0 2 1 0 Cl#lrcttcr -A No SC-M -6 1.0 1.2 354 1.0 5Zk mL 66 31 483 175 85 1112 Clsarttbr -A M./JK<12.9 -6 20 15 96 1.3 122 10 279 fld 153 391 469 289 978 Cigarettes -A $3. BP 130+ -B Cigarettes -A Height <66 -B 1.5 2.4 i5i 140 2.0 9s 124 Cigarettes -A Parent dead -9 1.6 No sport -A Ht., %40 .2.41 (118) Follow- Number (Yeuaprs, of deaths Cigarettes/day Doyle 2,282 males. Detailed 10 93 NS .l.OO (20) et al., FLW"- medical All smoken .2.40 (73) 1964. ingham. examina- <20 . . .2.00 (17) U.S.A. 30-62 years tio" and 20 .1.70 (20) (54). of age. follow-up. 8 >20 .3.50 (36) 1,913 males. Albany, 39-55 years of age. Doll and Approxi- Question- 10 1.376 NS _. .l.OO Hill. "lately "sire and All smokers .1.35 1964, 41.000 follow-up 1-14 .1.29 Great male British of death 15-24 ,127 Britain physicians. certificate. >25 .1.43 (50). Strobe1 3,749 male Question- s 162 NS . . .l.OO and Gsell Swiss phy- naire and 1965 sicians. follow-UP l-20 .1.48 Switzer- of death >20 . .1.16 land certificate. (180). Best, Approxi- Question- 6 2.000 NS _. .l.OO 1966 mately naire and All smokers .1.60 (1380) Canada 78.000 follow-up - 20 .1.78 (277) veterans. Kahn 1966 U.S.A. (98). U.S. male veterans 2,265,674 person y-2al.S. Hirayama. 265,118 1967. Japanese Japan adults over (84). age 40. Question- naire and follow-up of death certificate. - Trained in- terviewers and follow- up of death certificate. s/r, 10,890 NS .l.OO (2997) Allsmokers .1.74 (4150) l-9 1.39 (439) 10-20 .I.78 (2102) 21-39 . 1.84 (1292) >39 2.00 (266) 1 91 NS .l.OO (17) l-24 __ ., .1.13 (69) >25 .l.OO (5) Kannel 5,127 males Medical ex- 12 52 NS _. .l.OO (27) et al.. and females amination SM>20 ,220 125) 3 (P20 . ..2.51 (203) 2.47 (199) 1.92 (129) 1.56 (73) Data apply only to males aged 40-4s and free of CHD at entry. NS include pipe. cigar and ex-smokers. 35-44 45-64 65-84 NS .l.OO 1.00 1.00 1-14 .3.73 1.40 1.71 16-24 .4.45 1.73 1.27 225 .1.36 1.92 1.68 NS. .l.OO SM. .1.45 Cigars 30-49 50-69 70 and over NS. .I.OO NS .l.OO 1.00 1.00 SM. .0.98 (16) 20 ,. _. __ .1.85 (65) 1.76 (184) 1.73 (28) SM. .0.96 (95) cigar.4 NS. .l.oo 34. .1.04 (628) Pipes NS. .l.oo SM. .1.08 (386) Prefimin- arY report. ' "P" values specified only for those provided by authors. 27 TABLE 2.-Coronary heart disease mortality ratios (Actual number of deaths [SM = Smokers Author, Year. Number and country, b-P.2 of reference population Follow- Number Data of Cigarettes/day collection (Y%) deaths Hammond 358,534 and male!3 Gartinkel, 445,875 1969, females U.S.A. age 40-7s (76). at entry. Question- naire and follow-up of death certificate. - 6 14.819 Make Females NS .l.OO 1.00 1-9 .1.27 0.84 lo-19 .1.60 1.22 20-30 .1.73 1.52 >40 .1.77 0.61 Paffenbar- 50,000 male Baseline 17-51 1,146 NS . . . . .l.OO ger and former interview matched 3M .1.50 (385) (p20 .2.08 (154) (p20 .3.60 (22) U.S.A. 40-59 years exam- (183). of age at ination. entry. Weir and 68,153 Csli- Question- 5-8 1,718 NS .l.OO Dunn. fornia male mire and All smokers .1.60 1970, workers follow-up 210 .1.39 U.S.A. 35-64 years of death 520 1.67 (205). of age at certificate, >30 ,, .I.74 entry. Pooling 7,427 white Medical ex- 10 239 NS .l.OO (27) Project, nK+les amination 20 ._.. .3.00 (68) Associa- entry. GO". 1970, U.S.A. (88). 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional. miscellaneous, mixed. or a-smokers. 28 wleted to snloliing-l)rospective stztdies (cont.) shown in parentheses) ' NS = Nonsmokers] Cigars, pipes Age variation Comments 41/-&Y NS .1.00 1-u .l.fiO IO-19 ,. .2.69 ?ll-30 3.76 >40 5.51 NS 1.00 l-9 .1.31 10-19 .2.08 20-30 .3.62 >40 .t3.31 Ml&d 51,-59 60-CY 1.00 1.00 1.59 1.48 2.13 1.X2 2.40 1.91 2.79 1.79 FtVTll7lCS 1.00 1.00 1.15 1.04 2.37 1.79 2.68 2.08 3.73 t2.02 70-79 1.00 1.14 1.41 1.49 1.47 tBased on 5-S deaths. 1.00 0.76 0.9R 1.27 JO-44 45-5: 55-69 NS .l.OO 1.00 1.00 (P40 ....... .7.93 All ........ .6.24 45-54 55-64 65-69 1.00 1.00 1.00 2.05 1.41 1.17 3.17 1.64 1.26 3.33 1.66 1.36 3.15 1.42 1.42 2.95 1.56 1.24 NS includes pipes and cigars. SM includes ex-smokem 1.00 (27) 1.20 (24) 29 TABLE 3.-Sztdden death frow coronary (Mortality ratios--actual number Author year, country, reference Numbw and type of population Data Follow-up collection years - Number of deaths Pooling Project, American Heart Association, 1970. U.S.A. (b-8). 7,427 white males 30-5s years of age at entry. Medical examination and follow-up. 10 145 TABLE 4.-Coronary heart disease (Risk ratios--actual number of CHD [SM = Smokers NS = Nonsmokers PRCISPECTIVE STUDIES Author, Year. Number and Data Follow- Number of country. type of collection UP incidents reference population years Cigarettes/day Detailed 10 243muo- NS .l.OO (52) medical examina- tion and follow-u*. cardial All smokers ._ .2.36(191) infarc- <20 _. _. .1.98 (44) tions and 20 . . . . . . . . . . ...2.05 (64) CHD >20 3.04 (83) deaths. Doyle 2.282 males et al., Framingham, 1964, 3C-62years U.S.A. of age. (5.4). 1,913 males Albany, 39-55years of sge. stam1er 1,329 CHD- et al., free male 1966, employees of U.S.A. Peoples Gas (177). CompanY 4b-59 years of age. Epstein, 6,565 male 1967, and female U.S.A. residents (61). of Tecumseh. Mich. Interview 4 46 CHD NS ._ ._ .l.oo (27 and exarnin- ation with 20 cigarettes. 3,83 (2S) > 5 cigars. ._ I > 5 pipes..... - Initial medical examinit- tion and repeat follow-up examinlr- tions. 4 96 male. M&8 92 fern& 40-59 CHD in- NS .__... . ..l.OO (1) &ding EX ._. ._..... 6.53 (10) deaths, Cigarettes .5.!20 (36) angina, and Females myocardial NS _. .l.OO (21) infarctions. EX .0.89 (3) Cigarettes .1.02 (14) `Unless otherwise specified. disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous. mixed, or ex-smokers. 30 /,! r11.f rlisease related to smoking ,,f deaths shown in parentheses) Cigarettes/day Cigars, pipes Comment St.v.cr smoked ........... 1.00 (15) 1.00 (15) See table 1 for description of 10 .................. .1.90 (23) 1.36 (13) Pooling Project. 20 ................... .1.90 (50) >2" ................ ..3.3 6 (44) ,uorbidity as related to smoking manifestations shown in parentheses) 1 EX = Exsmokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation CO"l"X"ts Data include CHD deaths, only on males 40-49 years of age and free of CHD on entry. NS includes pipes, cigars. and ex-smokers. NS includes a-smokers. Includez all CHD. Males-Continued 60 and over 1.00 (7) SM 1.27(11) 1.96 (23) SM FCmales-Continued 1.00(47) 1.31 (5) 0.42 (2) M&8 40-59 .1.80(Z) 60 and Gwer . ...0.86(6) Reexamination of patients was spread over l$$-byear period, but data are re- ported in terms of 4-year inci- dence rates. Actual number of CHD inei- dents derived from data on incidence and total in smok- ing class. 31 TABLE 4.-Coronary heart disease (Risk ratios--actual number of CHD [SM I Smokers NS = Nonsmokers PROljPECTIVE STUDIES Author, year. country, Number and type of reference population Jenkins, 3,182 males et al., 39-59 years 1968, of age at U.S.A. entry. (90). Data collectioll Initial medical examina.. tion and follow-up by repeat examina- tions. Follow- UP Years 4:; Number of incidents Cigarettes/day 104 myo- NS . . . . . . . . . . ..I.00 (21) eardial EX ........... .2.47 (15) infarctions. Current ...... .2.78 (68) O-15:day ..... .t1.39 (45) >I6 .......... ..3.0 6 (59) K@.ollel, 5,127 males et al., and females 1968. 30-59 YQB1`S U.S.A. of age. (9.5). Medical 12 examina,.ion and follow- UP. Shapiro 110,000 male Baseline med- 3 et al., and female ical inter- 1969. eor0llee5 view and U.S.A. of Health examination (172). Insurance and regular Plan of follow-up. Greater New York (HIP) 35-64 y-ears of age. 228 myo- Myocardial Infarction cardial M&8 infarc- NS ._ .l.OO (21) tions. All SM 1.51(153) 380CHD. Heavy SM .I.85 (59) Risk of CHD (mwrall) M&8 NS ._ .l.OO (61) l-10 .1.34 (25) 11-20 .1.80 (90) >20 .2.41 (76) - Total Moles unspeci- NS .l.OO fied. All current .2.14 cigarettes ( p20 . . . . . . . . ...2.33/ >40 . . . . ...6.36 Keys 1970 Yugo- slavia Finland Italy Nether- lands GrWCe (Ill). 9,186 males Interviewr. 5 65 deaths. NS, EX in 5 coun- and rcgu- 80 lnYocar- (SM <20) .1.00(305) tries 40-59 lar follow- dial in- All current gears of up examina- farctions. 020) .1.31(103) age at entry. tion by 128 angina local pectoris. physicians. 155 other t428 total. `Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed. or es-smokers. 32 morbidity as related to smoking (cont.) manifestations shown in parentheses)' EX = Ex-smokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation Comments ~PO.Ol) (P20 . . . . . . . . ...1.17 (13) U.S.A. controls in s examina- myoeardial (4% 49). clinical trial of tions. infarctions. a diet high in unsatu- rated fat. DU"" 13,148 male Data only up to 14 Total un- et al.. patients in on new specified. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic records. Pooling 7.427 white Medical 10 538 Project, males 30-59 examinai ion Includes Never smoked .l.OO (53) American years of and follow- fatal and 20 ,328 (154) 1910. infarction U.S.A. and sudden (88). death. Paul et al.. 1,989 western Screening 1963. Electric Co. exami"a:ion COTOWQ/ U.S.A. male workers and cases (87) (148). participating history. NS 23 in a prospec- l-7 2 tive study 8-12 9 for 455 years. 13-17 6 18-22 41 23-27 3 >28 9 `Unless otherwise specified, disparities between the total number of mani- festations and the sum of the individtial smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 34 morbidity as ,related to smoking (cont.) manifestations shown in parentheses)! EX = Ex-smokersl PROSPECTIVE STUDIES-Continued Pipes, cigars Age variation Comments All CHD including EKG diagnoses. No data on NSasa separate group. 30-39 40-49 50-59 t Includes tLow NS, EX, and SM 1.00(25) 1.00(125) 1.00(157) <20 cigarettes/ %High day. SM 2.17(10) 0.90 (31) 1.41 (53) $>2OCiga- rettes/day. Includes all CHD but ezcludes death. No data avail- able comparing smokers and nonsmokers. 1.00(53) 1.25(64) GmmmaTy controls (1,786) 33 7 11 12 30 2 6 (P20 . . .1.15(18) smokers. Albany. 39-55 years of age, Jenkins 3,182 males Initial medical 4% 29 NS ..l.OO (9) NS include et al., wed 39-69 examination All current former pipe 1968, at entru. and follow- cigarettes . ..1.44(16) and ciaal U.S.A. up by repeat >16 ,. ,, ._ ..1.63(14) smokers. (90). examina- tion. KanlWl 5,127 males Medical 12 107 et al.. and females examination NS U.S.A. years of age and follow- Heavy SM. .ZO (94). 30-59 "P. cigarette3 . . NS Cigarette SM M&8 1.00 (16) .2.04(17) FWLflkl .1.00(68) .0.65(16) Shapiro 110.000 male Baseline 3 Total Males Females M&8 M&8 t CP40 . . . . . . ..4.85$ 1.20 >40 ., .10.15 2.m 6.15 follow-up. FlWUdC8 NS .l.OO 1.00 1.00 Current cigarettes .1.56 1.67 0.97 <40 .1,67 1.63 1.04 ": >40 - 4.12 - t Unless otherwise specified, disparities between the total number of to the exclusion of either occasional, miscellaneous. mixed, or ex-smokers. manifestations and the sum of the individual smoking categories are due smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow (due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. EPIDEMIO.LOGICAL STUDIES Numerous epidemiological studies, both retrospective. and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD) . Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of developing CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day, Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers' increased risk of dying from CHD appears to be limited mainly' to those who smoke cigarettes. Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolled in the Health Insurance Plan (HIP) of New York City showed a significantly increased 38 risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de- scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers (table 3). The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- ers continue to rise. CORONARY HEART DISEASE MORBIDITY Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54)) Keys, et al. (111) , and Taylor, et al. (183) include a number of CHD deaths in their data that could not be separated out using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (I?`?) show that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. A recent monograph edited by Keys (111) dealt with the 5-year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population samples which varied in size from 505 to 982 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 39 become available to provide greater statistical stability to the rates, this. intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these differences were not statistically signifi- cant. More recently, Shapiro, et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by myo- cardial infarction. RETROSPECTIVE STUDIES Table A 6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD. Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD RISK FACTORS The preceding section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors, other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids (particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 3 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 40 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and. Serum Lipids The interaction of smoking and serum lipid levels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table A7 presents studies which deal with the association between smoking and lipids, notably cholesterol, triglycerides, and lipoproteins (con- cerned with lipid transport). While some of the studies have indi- cated that smokers show increased serum levels of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the findings difficult. It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly increases the risk of CHD in each of the cholesterol groups. Smoking and Hypertension Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case (table A8). Reid, et al. (155)) in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et al. (27)) demonstrate the following associations : That for both smok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, has been shown to elevate CHD mortality independently both of its effect on blood pressure and of the effect of hypertension on CHD. Smoking and Physical Inactivity The recent study by Shapiro, et al. (272) of more than 110,000 41 TABLE 9.-Death rates from coronary heart disease, by systolic blood pressure: ILWU mortality study 1951-61 (Coronary heart disease rts classified under IX Code 420) Smokers Nonsmokers Systolic blood Person-years Death Person-years Death Age group pleSSure in 1961 of observation rate' of observation rate' 45-54 (130 1,877 27 2.413 8 139-149 2,066 34 2,912 l? 150-169 740 95 1,177 26 >170 369 109 672 45 55-64 . . <130 1,067 84 1.560 26 13&-149 1,380 94 2,401 525 150-169 647 93 1,558 46 >170 524 210 1,117 126 1 Rate per 10,000 person-years of observation. 2 plOO lOO 1,527 26 1,700 6 2,115 47 2,947 17 961 52 1,507 33 448 89 1.020 20 1.059 104 1.447 221 1,521 59 2,704 15 669 194 1,521 346 369 163 954 147 1 Rate per 10,000 person-years of observation. 2 p20 cigarettes/day NWer and Garfinkel, 1969. U.S.A. (76). smoked regularly . . ,_ .1.00(1,841) current cigarette smokers 1.90(1,063) stopped 20 1. .1.08 (70) AI1 ex-cigarette smokers .1.16 (263) l.OO(1.841) Male data only 2.55 (2.822) 1.61 (62) 1.51 (154) 1.16 (135) 1.25 (133) 1.06 (80) 1.28 (564) Shapiro et al.. 1969. U.S.A. (17s). Pooling Project, American Heart Association 1970. U.S.A. (88). Total definite myocardial infarction Never smoked .................................... .l.OO Current cigarette smokers ........................ .1.87 Stopped 25 years ................................. .0.76 AU CHD deaths Never smoked ., .1.00(2'7) >`h pack/day .1.65(34) 1 pack/day ._ ,... _. .1.70(86) >l pack/day .3.00(68) Ex-smokers .0.80(19) First major coronary event 1.00 (53) See table 4 1.65 (72) for description 2.08(205) of Pooling 3.28(X4) Project. 1.25 (51) TABLE 16.-Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking Age started smoking 15-W 20-24 Maximum daiLv number of &a- r&es smoked Current smokers Discontinued Discontinued for five or Current for five or more years smokers more years (Probability X10 s, 56-64 . . ,_. . . 0 601 501 - lo-20 798 568 811 551 21-39 969 766 872 698 65-74 1 . . 0 1.015 1.015 lc-20 1;501 1,169 11478 1,213 21-39 1,710 1,334 1,573 1,098 1 For age group 65-14. probabilities for discontinued smokers are for 10 or more years of dis- continuance since data for the 5-9 year discontinuance group we not given. SOURCE: Cornfield. J., Mitchell. S. (4.5). Based on data derived from Kahn, H. A. (93). 46 Smoking and Electrocardiographic Abnormalities Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically overt CHD manifestations. The results summarized in table IS, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and Heart Rate Recent analysis by Berkson, et al. (23) of the data derived from the Chicago Peoples Gas, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents i`ne interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as Compared with current smokers (51, 76, 88, 90, 93, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western Collab- orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, however, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who stop because of ,ill health and the presence of symptoms are gen- erally at high risk and can bias the group results in one direction; 47 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project (88)) were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (63) have recently presented data derived from the British physicians study of Doll and Hill. Over the past lo-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 35 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesterol (177)) increased blood pressure (27)) elevated resting heart rate (23)) physical in- activity (2 72), obesity (27)) and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It has been suggested by some (39, 170) that the relationship between cigarette smoking and CHD has a constitutional basis. That is people with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and his becoming a cigarette smoker. Two sets of epidemio- logic data bear on this hypothesis. It has been maintained that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 48 of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be- tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and "angina pectoris" among smokers when Group A was analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concluded that this lack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu. tional hypothesis. A major problem in ,these studies is the small number of cases available and, therefore, the statistical instability of the results, In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utilized the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also small so that the differences in rates do not approach statistical significance. Tibblin (288) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (~$0) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having "angina pectoris" by the questionnaire. four were found to be free of symptoms on 50 clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be clinically affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difficulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etiology of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving any conclusions at the present time. Hauge, et al. (81) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- quent in those cotwins with a higher consumption of tobacco than in those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical significance. Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinical, and pathological data relating smoking and CHD, concluded that the evidence from these areas has not "reasonably substantiated" the "hypothesis" of the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular system been shown to be a "clear" and con- sistent one (170). His views are contrary to those of most re- searchers in this field, Although the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it would be surprising if genetic factors did not play such a role. It is open to 51 question whether findings from twin studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors "cause" both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the cigarette smoking habits and the cardiovascular pathology of those individuals dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of 189 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors noted a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The authors also observed that those surviving very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autopsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various countries have been directed towards the relationship of cigarette smoking to the presence of atherosclerotic disease in the aorta and coronary arteries. These are concerned with the long-term effects which smoking has on the cardiovascular system and are sum- marized in table 19. The studies of Auerbach, et al. (12)) Avtan- dilov, et al. (13)) Sackett, et al. (165)) and Strong; et al. (182) found that aortic and coronary atherosclerosis were more common and more severe among smokers than among nonsmokers. Auerbach, et al. (12) noted that this relationship persisted when the cases were matched for both age and cause of death or when the follow- ing cases were excluded; men with a history of diabetes; men who had died of any type of heart disease; and men whose hearts weighed 400 grams or more. Sackett, et al. (165) found that the 52 (Figures in parentheses are number ut individuals in that smoking category)' [SM = smokers NS = nonsmokers] Author. Year. countru, reference Autopsy population Data collection Cigarettes per dny Conclusions Comments Wilens 989 consecutive Routine clinical Severity of am-tic sclerosis The authors conclude that Smoking data unavailable and Plair, male autopsies records of Above average Average Below average in 60 percent of cases. the for 120 cases. 1962, at New York previous and NS . . . 9.9(161) 60.2 29.8 degree of sclerosis at Each aorta specimen given U.S.A. City VA present <20 . 19.1(162) 63.2 17.8 autopsy was e"mme"- an "atherosclerotic age" (214). hospitals. admissions. 20-30 .,,,..... 26.4(288) 62.5 11.1 surate with age of patient. by comparison with a >30 .t25.1(199) 61.3 t13.6 regardless of smoking standard. If "athero- habits. In the remaining sclerotic age" was found 40 percent there is evi- to be 10 years more than dence that cigarette real age. the aorta was smoking may be ass"- said to show above- ciated with an above- average sclerosis. average degree of aortic tp40 . . . . ..0.6(144) 18.1 36.4 45.9 smoking. This relation- have overt CHD ship persisted even at death. when cases were matched for age and cause of death. 1 unless otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the cn w exclusion of either occasional. miscellaneous, mixed, or ex-smokers. TABLE 19.-Autopsy studies of atherosclerosis (cont.) (figures in parentheses are number of individuals in that smoking category)' [SM = smokers NS = nonsmokers] !E Author, year, Autopsy Data cou"trY. population collection Cigarettes per day Conclusions CO"l"l.3h reference Avtandilov. 269 male and Not specified, Comparative size of mean area of alhe+osclerotic ~&WUI The author concludes that Causes of death 96-athero- 1966, 141 female hut there were: in inner coat of eosmkwu a+teriea. the worst changes were sclerotic, lO%accidental. RUSB~IS autopsies. 130 SM and Right ~o?`onaw artery Left cosona~~ artery found in the left and POP-various diseases. (16). 220 NS. SM NS SM NS right coronary arteries tT-test for sjgnificance 30-3s Q5.5(30) 1.3(32) t6.3 2.2 with less severe changes of difference between 40-4s t23.6 (34) 11.6(27) t1e.e 4.4 in circumflex artery means is significant 60-59 ..t36.3(39) 14.8(39) 127.9 9.9 and aorta. at P25 cigarettes/day .12 (9) 31(14) 26(25) 39(20) The authors conclude that: This report concerns o"Iy "Atherosclerotic in- ages 26-64. volvement of aorta and No data on statistical coronary arteries is significance provided. greatest in heavy smokers and least in nonsmokers." NS . Negro 4(14) 3 (3) 16(11) 17(14) l-24 cigarettes/day 3(39) ll(31) 14(30) 28(22) >25 cigarettes/day .17(10) 14(17) 29(12) 16(11) `Unless Otherwise specified, disparities between the total number of in- dividuals and the sum of the individual smoking categories are due to the exclusion of either occasional. miscellaneous, mixed, or a-smokers. severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, Viel, et al. (ZOO) concluded from their study of accidental deaths in Chile that "no relationship between atherosclerotic lesions and the use of tobacco was discernible." Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 192, 193, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular responses. These responses have been observed in human as well as animal subjects, including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardial oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographic changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 56 effects of cigarette smoking by the administration of nicotine intra- venously. Similar results in animals were noted by Kien and Sherrod (112). The mechanism by which cigarette smoke and hence nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long been known as a stimulator of both sympathetic and parasympathetic ganglia. Research has centered, therefore, on the function of catecholamines, mainly epinephrine and norepi- nephrine, as mediators, of these responses. Using isolated rabbit atria1 myocardium, Burn and Rand (35) noted that the prior ad- ministration of reserpine to the perfusate blocked the increased rate and amplitude of contraction seen following the administra- tion of nicotine. West, et al. (208) showed that the in vivo cardiac stimulating effect of nicotine was blocked by tetraethylammonium chloride. Leaders and Long (12.5)) Romero and Talesnik (156), and, more recently, Ross and Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methonium, guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203) and Westfall, et al. (209, 210, ,211) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of standard cigarettes caused significant increases in peripheral arterial epinephrine lev- els, while cornsilk cigarette smoke inhalation evoked no such change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion. The source of these nicotine-released catecholamines, particu- larly those which mediate the immediate and local cardiac re- sponses to intracoronary injections of nicotine, is felt to be the myocardial chromaffin tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of nicotine into the mesenteric circulation of cats were followed within 1 to 2 seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemic resistance. Sectioning of the mesenteric afferent nerves led to a diminished response. The authors concluded that the cardiovascu- lar response to nicotine may also be neurogenic in nature. Nadeau and James (112) injected nicotine directly into the sinus node artery of dogs and noted an initial bradycardia, due probably to direct vagal stimulation, followed by tachycardia, due probably to catecholamine release. 57 That the presence of nicotine may predispose the myocardium, particularly a hypoxic or previously damaged myocardium, to ar- rhythmia formation is suggested by the research of Balazs, et al. (16), Bellet, et al. (21)) and Greenspan, et al. (74). Balazs pro- duced myocardial lesions in dogs either by pretreatment with iso- proterenol or ligation of the anterior descending coronary artery. It was found that while normal animals did not develop arrhy- thmias upon challenge with small doses of intravenous nicotine, the animals with damaged myocardiums responded with increased arrhythmia formation shortly after their spontaneous arrhythmias had ceased. More recently, Bellet, et al. (20) studied the effect of cigarette smoke inhalation on the ventricular fibrillation threshold in anesthetized dogs. They observed a statistically significant de- crease in the threshold following smoke inhalation. Greenspan, et al. (74), using isolated dog right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity. The authors consider that these two nicotine-induced effects probably predispose the myocardium to the initiation of arrhythmias. CORONARY BLOODFLOW Studies in animals and humans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally, exposure of the normal subject to these agents results in an in- crease in flow. Kien and Sherrod (112)) Leb, et al. (126)) Ross and Blesa (160)) Travell, et al. (189)) and West et al. (208)) working with normal animals, and Bargeron, et al. (27)) working with normal humans, have demonstrated this response. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most probably due to the release of catecholamines. Using instantaneous coronary arte- rial flow measurement in dogs, Ross and Blesa (160) were able to reproduce the effects of intracoronary nicotine with the adminis- tration of epinephrine and were able to block the response to nico- tine by pretreatment with pentolinium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CBF seen with cigarette smoking and intravenous nicotine administra- tion. It appears that the catecholamine-induced increase in myo- cardial work and therefore in myocardial oxygen requirement is a prerequisite for the increase in CBF. Kien and Sherrod (112)) using tracheostomized dogs, found that without blood pressure and cardiac output changes CBF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 58 intravenously, although CBF did increase following such changes. Recent work by Leb, et al. (126) has utilized Rb@ as a radioactive marker in order to distinguish capillary flow from overall total CBF. The authors consider that this capillary flow represents that portion of CBF which is effectively involved in nutrient and oxygen exchange. The researchers observed that the increase in effective coronary flow was almost proportional to the nicotine- induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardial shunting was far in excess. Thus, the increased work evoked by the effect of nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22)) working with normal dogs and dogs that had ,under- gone either coronary artery ligation or artificially-induced coro- nary artery narrowing, noted that the increase in CBF following the intravenous administration of nicotine was significantly less among the animals with coronary insufficiency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing in normals. Regan, et al. (154) studied seven men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patients and caused no overall rise in CBF. A number of other investigators have noted that patients with overt CHD do not respond to the stimulus of cigarette smoke as readily as do normals (67, 149, 164). Thus, patients with compromised coronary circulation may not he capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- rette smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maximal level. Any further in- crease in extraction may produce coronary sinus PO, values incom- patible with proper tissue oxygenation. CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE Carbon monoxide (CO) is a colorless and odorless gas, 10~ levels of which have significant effects on human and animal physi- ology which are just now beginning to be understood. According to Wynder and Hoffmann (215)) it is present in cigarette smoke in concentrations of approximately 2.9 to 5.1 percent. The concen- tration of CO in smoke is subject to many factors, among them 59 the type of tobacco and the porosity of cigarette paper. The con. centration of CO in smoke has been found to increase significantly toward the last puffs of the cigarette. According to Chevalier, et al. (41), a concentration of approxi. mately 4 percent CO in cigarette smoke will produce alveolar levels of around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemoglobin (COHb) concentrations of from 3 to 10 per. cent. A number of investigators have compared COHb levels in smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained from 3,311 longshore. men. Using a regression analysis, they calculated the concentra. tion of COHb and found that nonsmokers showed levels of 1.2 per. cent while those smoking over 2 packs per day had levels of 6.8 percent and that smokers of lesser amounts had intermediak levels. Occupational exposure accounted for the mean nonsmokers' level being over 1.0 percent, an unusual finding in comparison with other studies. Kjeldsen (113) interviewed and obtained blood samples from 934 CHD-free smokers and nonsmokers. The mean COHb level for 196 nonsmokers was 0.4 percent while all inhaling smokers had a mean level of 7.3 percent. All 416 cigarette smokers, regardless of inhalation or amount smoked, showed a mean level of 4.0 percent. Carbon monoxide has many varied and significant effects on human physiology. An overall review of these effects may be found in a discussion by Lilienthal (127) or more recently in an exten- sive review by the United States Public Health `Service National Air Pollution Control Administration (194). Apart from its effects on respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effects are probably due to interference by CO with the proper oxygenation and oxidative metabolism of the tissue in question. CO interferes with oxygen transport in a variety of ways. First, the affinity of hemoglobin for CO is approximately 200 times greater than its affinity for oxygen, and thus CO can easily dis- place oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen is bound by hemoglobin, CO interferes with 0, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capillary blood has been reduced to approximately 40 percent saturation. Here the shift can sub- stantially decrease the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by CO with the homeostatic mechanism by which 2, S-diphosphogly- cerate (2, 3-DPG) controls the affinity of hemoglobin for oxygen. Bunn and Jandl (3$) have recently reviewed the various experi- 60 ments concerning this glycolytic intermediate. The question of whether the low levels of CO present in the blood of smokers can affect this homeostasis is presently under investigation (29, 143), and firm conclusions cannot be drawn at this time. Apart from its effect on hemoglobin affinity, CO appears to induce arterial hypoxemia, and this may act as an additional cause of tissue hypoxia. Ayres, et al. (1 4,15) observed unexpectedly that exposure of individuals to CO sufficient to raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial PO,. Greater fall in venous p0, was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brody and Coburn (30) suggested that this COHb-induced arterial hypoxemia was due to the interaction of a number of factors. These authors noted that in the presence of veno-arterial shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial OZ gradient and resulted in arterial hypoxemia. The presence of shunts as small as 2 percent of cardiac output as well as of approximately 10 percent COHb was found to cause an increase in the gradient. Such ventilation-perfusion (V/Q) abnormalities have recently been noted even in asymp- tomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of COHb found in the blood of smokers may interact with these V/Q abnormalities to further decrease available oxygen. In normal individuals, coronary flow can increase to meet the increased oxygen demands of a stressed myocardium (as that under nicotine stimulation), while in individuals with severe CHD coronary flow cannot respond as readily. In such cases, myocardial oxygen extraction must be increased above the almost maximal extraction found at rest. Any interference with arterial oxygen levels or hemoglobin affinity could very well decrease available oxygen supplies below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed below. Chevalier, et al. (41) exposed 10 young nonsmokers to CO con- centrations sufficient to induce COHb levels of approximately 4 Percent. Taking measurements from blood specimens obtained at cardiac catheterization under resting and exercise conditions, the authors noted that the ratio of oxygen debt to oxygen uptake in- creased significantly under conditions of increased COHb. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors (221, 1.22) had previously noted similar findings among smokers and observed 61 that cessation of smoking was associated with a significant im- provement in oxygen debt accumulation. More recent work by Ayres, et al. (15) has focused on the dif- ference in response to CO exposure between 7 normals and 4 pa- tients suffering from CHD (proven arteriographically) . The induc- tion of a COHb concentration of approximately 9 percent in the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen percent extraction and no change in myocardial oxygen consumption, coronary sinus oxygen tension, and lactate and pyruvate extraction ratios. The induction of simi- lar COHb levels in the CHD patients was followed by no change in coronary blood flow, a decrease in the hemoglobin-oxygen ex- traction ratio, and no change in myocardial oxygen consumption. However, these patients did manifest a decrease in coronary sinus p0, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the myocardium was functioning under hypoxic conditions. Because the coronary flow could not in- crease and because the myocardium could not extract O? from HbO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- tive enzyme processes. Thus, the myocardial function of persons with CHD may be unable to compensate for the stresses induced by smoking. Although COHb levels resulting from the CO present in the atmosphere during periods of high air pollution are much lower than those due to the inhalation of cigarette smoke, these concen- trations of COHb might contribute to the manifestations of CHD. Cohen, et al. (44) studied the case fatality rates for patients ad- mitted to 35 Los Angeles area hospitals with myocardial infarction in relation to atmospheric CO pollution. The authors observed an increased MI case fatality rate in areas of increased pollution, and then only during periods of relatively increased CO pollution. An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to Wynder and Hoffmann (215), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that a significant amount of this material is d.etoxified to thiocyanate and excreted as such in the urine or saliva. However, cyanide is a potent inhibitor of oxidative metabolism. Such inhibition of myo- cardial oxidative metabolism may be of importance when combined with the other factors mentioned above which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 62 EFFECTS OF SMOKING ON THE FORMATION OF ATHEROSCLEROTIC LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking and the presence of aortic and coronary artery atherosclerosis, even in men without a his- tory of clinical CHD. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking are discussed in this section. A number of investigators have studied the effect of nicotine administration, either subcutaneously or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A23). When administered alone, nicotine induces certain necrotic changes in the arterial wall. However, in combination with the administration of increased amounts of cholesterol in the diet, nicotine aggravates either subendothelial fibrosis (75) or definite atheromatous lesions (46, 75, 80, 130, 178). Studies by Choi (42) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion m this chapter, carbon monoxide, has also been recently implicated in atherogenesis. Table 24 presents the studies which have related exposure to CO in combination with increased dietary cholesterol to both macroscopic and microscopic aortic and coronary athero- matosis. Astrup, et al. (IO) exposed cholesterol-fed rabbits to CO continually over a period of up to 10 weeks. The experimental group showed increased aortic atheromatosis over that shown by the control group, also cholesterol-fed. Kjeldsen, et al. (114) observed that exposure of rabbits to increased oxygen concentra- tions significantly reduced the amount of cholesterol-induced atheromatosis in rabbits. Most recently, Webster, et al. (204) have extended this research to primates. These investigators found that cholesterol-fed squirrel monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to CO Over a `I-month period than when exposed only to room air. Recent discussion has centered on the mechanisms whereby CO can induce these changes (9, 212). Astrup (9)) referring to pre- vious experiments in humans which had shown increased vascular Permeability for albumin upon chronic exposure to CO (II), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls. This, he con- siders, is a primary cause of intimal and medial lipid accumulation and, therefore, of atherosclerosis. Another point of view has been stressed by Whereat (212)) who considers the filtration theory to be an inadequate hypothesis for 63 TABLE 24.-Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia Author. ye*=. country, reference Number and type of animal Procedure Results Astrup 24 female Regular diet plus 2 percent The experimental group exposed to carbon monoxide showed increased macro- and et al., albino rabbits. cholesterol: microscopic aortic atheromatosis over that show" by control animals. Micro- 1967 I. (12) control. scopic examination revealed intimal lipoid deposition limited in penetration by Denmark II. (12) continual exposure to the internal elastic membrane. Coronary vessels were found to show similar (f0). carbon monoxide: changes. Carboryhemoglobin. (COHb) levels averaged 16-19 percent during the 0.017 percent for 8 weeks. first 8 weeks and 33 percent during the final 2 weeks. 0.035 percent for 2 weeks. - Kjeldsen 24 castrated male Regular diet plus 2 percent The experimental group exposed to hypoxia showed increased macroscopic aortic et al., albino rabbits. cholesterol: atheromatosis over that shown by control animals. Microscopic examination re- 1968, I. (12) control. waled more intimal and subintimal lipid deposition in the aortas of the exposed Denmark II, (12) continual exposure. rabbits than in those of the nonexposed. The total amount of cholesterol de- (117). to hypoxia: posited in the aortas of the experimental group was three times higher than in 10 percent-O2 for 6 weeks. those of the control group. 9 percent O2 for 2 weeks. Kjeldsen 24 castrated male Regular diet plus 2 percent Macroscopically, the experimental group showed significantly fewer atheromatous et al., albino rabbits. cholesterol: changes. Microscopically, the experimental group showed significantly less aortic 1969. I. (12) control. intimal lipid deposition. Denmark II. (12) exposure to 28 percent (114). 0% for 10 weeks. Webster 22 female squirrel Diet containing 0.5 percent The experunental group exposed to carbon monoxide showed a greater mea" per- et al., monkeys. cholesterol and 25 percent fat: centage of coronary arteries with atherosclerotic lesions and more lumen occlu- 1970. I. (10) control. sion among the affected arteries. There were significantly more CO-treated U.S.A. IL (12) experimentaUyexposed to monkeys than control monkeys having 35 percent or more apparent atbero- (204). 200-300 p.p.m. carbon monoxide sclerotic stenosis among the affected arteries. Aortic atherosclerosis was appar- for 20 hours per week for 7 ently not aggravated by exposure to CO. COHb levels at the end of each exposure months. period averaged 16-26 percent during the flnal 24 weeks of the experiment. mural lipid accumulation. The author notes that when the oxida- tion of the pyridine nucleotide, nicotinamideadenine dinucleotide (NAD) , is impaired, the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrial enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mito- chondrial fatty acid synthesis (and decrease fatty acid utilization) in the arterial wall. Carbon monoxide prevents this oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process of NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem, particularly in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. THE EFFECT OF SMOKING ON SERUM LIPID LEVELS In the discussion concerning the epidemiological aspects of CHD, it was noted that increased serum cholesterol was a significant risk factor for the development of overt CHD. Serum triglycerides have also been related to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The studies concerning this immediate effect are presented in tables A25 and A25a. The table is divided into a section concern- ing studies on humans (table A25) and one concerning studies utilizing animals or in vitro systems (table A 25a). Although no consistent response was noted for serum cholesterol, serum free fatty acids were found consistently to rise following smoking. AS with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated by catechol- amine release. This relationship has been observed in a number of experiments by Kershbaum, et al. (105,106,108,109,110) and Klensch (118). That nicotine is primarily responsible for this rise may be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of regular cigarettes. While attention has been centered upon nicotine as the agent inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolism. These studies are listed in table A26. Among rabbits fed increased amounts of cholesterol, 65 the authors observed significant increases in cholesterol and tri. glyceride concentrations in those exposed to CO versus those maintained in a normal atmosphere. THE EFFECT OF SMOKING ON THROMBOSIS In the study of CHD, a number of investigators have turned their attention to thrombosis because myocardial infarction and sudden coronary death frequently result from thrombotic events, A thrombus may be of either gross or microscopic dimensions, and a minute thrombus at a strategic site may precipitate a fatal ar- rhythmia. However, thrombotic and prethrombotic states are dif. ficult to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a secondary role in the consolidation of an arterial thrombus and little if any in initiating the process. The prime mechanism in thrombogenesis appears to be the reaction of the platelet. Several papers have been written about platelet re. activity in vitro but few about the effect of smoking on platelet behavior in vivo. The assay of fibrinolysis, which may also be im- portant, has received scanty treatment. The relevant studies are listed in table A27. Many of these are discussed in the 1968 sup- plement (192) and by Murphy (140). Corroborative data are still inconclusive as to whether smoking shortens platelet survival. OTHER AREAS OF INVESTIGATION Certain other aspects of cardiovascular pathophysiology may be of importance in the relationship of smoking to CHD. Glucose me- tabolism and insulin response, when altered, may alter myocardial response. This topic has been covered in detail in the 1968 Supple- ment to the Health Consequences of Smoking (192). Also, varia- tions in blood hemoglobin and hematocrit may adversely affect coronary blood flow. A number of studies showing a possible rela- tionship of smoking to hemoconcentration have been reviewed pre- viously (192,192), and the reader is referred to those discussions. CEREBROVASCULAR DISEASE The term cerebrovascular disease (CVD) refers to a number of different types of vascular lesions affecting the central nervous system : subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, and thrombosis (ICD Codes 330 to 334). In 1967 in the United States, a total of 93,071 males and 109,113 females were listed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 66 ciated with increased mortality from cerebrovascular disease, whether CVD is listed as the underlying or as a contributory cause of death. Table 28 presents the results of the seven major epidemi- ological studies. The smoking of pipes and cigars does not appear to increase significantly the risk of dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for mor- tality from CVD has recently been noted by Hammond and Gar- tinkel (76). The data from their study, as presented in table 28, also indicate that the mortality ratio for cigarette smokers is greater for persons under 75 years of age than for older individuals. Many of the pathophysiological considerations discussed in the sections concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. In a study reported by Kuhn (123)) 20 habitual smokers re- frained from smoking for one-half day, and base line retrograde brachiocerebral angiograms were taken; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (132) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers as measured indirectly using an ultrasonic D,oppler technique to record internal carotid artery flow. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow and a decrease in cerebral vascular resistance in all subjects. No significant difference in response was observed between the 4 younger and 8 older (over 60 years of age) subjects. More research is needed to clarify the role of cigarette smoking in the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon the cerebral circulation (particu- larly its extracranial portion) is likely to be similar to the effect Of smoking upon the aortic and coronary atherosclerosis. NON-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death. In 1967 in the United States, a total of 8,448 men and 3,173 women were listed as dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to inc.rease the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- ess which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, and the risk increases in proportion to the amount smoked. 67 TABLE B.-Deaths from eerebrovascular disease Telated to smoking (Mortality ratios--actual number of deaths shown in parentheses)' [SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of Author, Follow- deaths due Ye*=* Number and Data UP to CVD as years underlying Cigarettes per day PJt; country, type of collection cigars reference population CB"W Age variation Comments Hsmmond 137.783 white Questionnaire 355 1,050 NS .l.OO (164) t (PZO 1.46 (83) Doll and Hill, 1964, Great Britain (50). Approximately Questionnaire 41,000 male and follow- British up of death physicians. certificate. KlXlIlCl et al.. 1965 U.S.A. (96). 5,127 males Medical and females examination 30-59 year?, and follow- of age. UP. 605 NS . ..l.OO All SM ..I.06 All cigarette 1.12 1-14 . . . ..l.lO 15-24 . .I.09 >25 . 1.26 13 NS .I.00 (6) Data apply only Heavy SM to males 3&59 (>20) .3.23 (8) ye*rs Of me at entry. Data apply only to cerebral infarction. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories arc due to the exclusion of either occasional, miscellaneous, mixed. or ex-smokers. TABLE 28.-Deaths fmm cerebrovascular disease wzltcted to srrrokiag (cont.) (Mortality ratios-actual number of deaths shown in parentheses) [ SM = smokers NS = nonsmokers] PROSPECTIVE STUDIES Number of Author. deaths due Pipes Year. Number and Data Follow- underlying Cigarettes per day and Age variation Comments country, type of collection UP years to CVD as cigars reference population Ca"Be Kahn. U.S. male Questionnaire 1966. veterans and follow- U.S.A. 2,266.674 ~1, of death (93). person certificate. year*. Hammond 358,534 males Questionnaire and 445,875 and follow- Garfinkel. females 40-79 UP of death Sly! 2.008 NS _.. .l.OO (614) All SM current .1.30(1.394) NS current cigarettes .1.52 (692) NS 1-9 1.51 (98) SM lo-20 1.42 (326) 21-39 . . . .1.70 (216) >39 . 1.59 (37) 6 4,099 Pipes .1.06 (82) .1.00(614) Cigare .1.00(614) . .1.08(136) Current tBased on onlg regular M&8 6-9 deaths. riaarettc JO-49 50-59 60-69 70-79 1969, years of age certificate. NCTer U.S.A. at entry. smoked 1.00 (76). l-9 .2.79 10-19 .I.14 20 39 .2.21 >40 .1.64 Never smoked 1.00 l-9 .1.50 lo-19 .2.60 1.00 1.00 1.95 1.30 1.48 t1.44 2.03 1.62' 2.40 1.72 FC7lllllC8 1.00 1.00 1.26 1.26 2.70 2.16 1.00 0.95 0.92 1.22 0.68 1.00 0.83 0.57 20-39 .2.90 2.67 1.83 1.28 >4n .t5.70 t3.52 - - * Unless otherwise specified, disparities between the total number of deaths and the aurn of the individual smoking categories are due to the exclusion of % either occasional. misceIIaneous. mixed, or ex-smokers. TABLE %.-Deaths from ccrc4wvrcsczclnr disease related to smoking (cont.) (Mortality ratios--actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. PROSPECTIVE STUDIES Paffen- 3,263 male Initial multi- 16 67 NSand barger. longshoremen phasic <20 __. 1.00 (42) et al. 35-64 years screening >20 _. ._ .1.15 (26) 1970 of age in and follow- U.S.A. 1951. UI, of death (144). crrtificnte. RETROSPECTIVE STUDY Prlff`Z"- >50,000 male Initial college bsrger University entrance and students medics1 CY- Williams followed up nminations 1967 to 50 ye*rs. with follow- U.S.A. up of death (145). certificate. Controls- surviving classmates age-matched. Death Rates Cases (1.58) Controls (615) SM 45.0 31.3(P10 per day 20.9 11.2 (p39 ,.,............. 7.26 (17) Hammond 358,534 males and 445,875 females Garfinkel. 40-79 years of 1969, nge at entry. U.S.A. (76). Weir and 68,153 California DU"". male workers 1970, 35-64 years of U.S.A. age at entry. (20.5). Questionnaire and follow-up of death certificate. Questionnaire and follow-up uf death certificate. 6 337 NS ........... .l.OO l-9 .2.62 10-19 ......... ,335 20-39 ......... ,454 >40 ........... .R.OO 5-8 51 NS ,. _. ,. ,. .l.OO SM include All _. .2.64 a-smokers. k-10 _. _. .2.44 NS include pipe -c20 __ __ .2.88 and cigar 230 _. ,. . .2.64 smokers. Data apply only to males 50-69 years of age. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual categories are due to the exclusion of either occasional, miscellaneous. mixed. or ex-smokers. PERIPHERAL ARTERIOSCLEROSIS Peripheral arteriosclerosis represents the effects on the vascu- lature of the extremities of the pathophysiologic processes which produce coronary and aortic atherosclerosis. A number of studies have been concerned with smoking as a risk factor in the develop- ment of this disease. Kannel, et al. (95) observed, in the Framing. ham study, that diabetes mellitus and elevated serum cholesterol, as well as cigarette smoking, were also risk factors in the develop. ment of peripheral vascular disease. Juergens, et al. (92) reviewed the records of and contacted 478 male patients with arteriosclerosis obliterans (a severe form of peripheral arteriosclerosis), who had been patients at the Mayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria: the presence of intermittent claudication, the marked diminution or absence of lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of 350 Mayo Clinic patients of similar age who showed no clinical evidence of vascular disease. It was found, for males under the age of 60, that 2.5 percent of the cases and 25 percent of the con- trols were nonsmokers. However, no difference was noted between the percentages of heavy smokers in each group. The authors also implicated high blood pressure and elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted similar findings in a study of 294 male patients with intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotland. ,In comparing the smoking his- tories of 100 patients with this complaint with those of 116 healthy male controls, the author found that 1 percent of the patients and 21 percent of the controls had never smoked. A total of 42 percent of the patients smoked more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of peripheral arterial disease, is a significant cofactor in its develop- ment in almost all cases. The author also noted obesity, high blood pressure, and elevated serum cholesterol as risk factors. Schwartz, et al. (168) compared the prevalence of risk factors in four groups of subjects : 141 cases with arteriosclerotic disease of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite number of control individuals who had been hospitalized for injuries. The in- vestigators reported that certain risk factors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 72 cant in both coronary and lower limb arteriosclerosis. The authors noted that the inhalation of cigarette smoke appeared to be an important risk factor for coronary arteriosclerosis up to age 55 while in arteriosclerosis of the lower extremities, inhalation ap- peared to increase the risk even in the older age groups. Widmer, et al. (213) compared 277 male patients with arterial occlusion of the limbs as demonstrated by aortography or oscillog- raphy with 2,082 men demonstrated by oscillography to be free of arterial disease. The authors found that cigarette smoking, parti- cularly heavy smoking, was significantly more frequent among the cases with arterial occlusion than among the controls. Increased beta-lipoproteins and systolic hypertension were also found to be more common among the cases. EXPERIMENTALEVIDENCE A number of experimenters have investigated the acute effects of smoking or nicotine upon the peripheral circulatory system. These investigators, as listed in table A30, have measured effects in terms of alterations in skin temperature and blood flow as meas- ured by plethysmography, radioactive iodinated albumin clear- ance, or radiosodium clearance from the skin. The majority of these studies have shown significant decreases in peripheral blood flow and skin temperature upon smoking, particularly in persons without manifest peripheral vascular disease. The study of Freund and Ward (68) demonstrates the difference in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of Stromblad (181) on blockade of this response with automatic sys- tem blockers indicates that the reactivity of these vessels is sec- ondary to the local release of catecholamines. Most probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall and prevent rapid alteration, particularly dilatation, in response to the catecholamines liberated by smoking or nicotine. THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger's Disease) (TAO) is an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischemic changes. Much discussion has centered upon the question as to whether this disease is a clin- ical and pathological entity separate from peripheral arterioscle- rosis. McKusick, et al. (128) consider it to be a distinct entity 73 while Eisen (57) concludes that TAO is the acute inflammatory phase of severe arteriosclerosis. Clinically, it has been shown that smoking aggravates this dis. ease and cessation of smoking frequently aids in complete or par. tial remission. Razdan, et al. (153) and Brown, et al. (32) found very few nonsmokers in groups of patients diagnosed as having typical TAO. A recent study from Israel (16) involved a case- control comparison of 46 patients with TAO and 32 matched con- trols. Although the controls were found to smoke less per day than the patients, this difference was not found to be statistically sig- nificant. However, 100 percent of the smoking patients and only 72 percent of the smoking controls were inhalers, a difference sig- nificant at the 0.02 level. CARDIOVASCULAR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) shows that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coro- nary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms : a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wall tension, contraction 74 velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in coro- nary blood flow and oxygenation, c. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULAR DISEASE 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cerebro- vascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction, NON-SYPHILITIC AORTIC ANEURYSM Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. PERIPHERAL VASCULAR DISEASE 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. 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Journal of Applied Physiology 19 (1) : 40-32, January 1964. (21)) WHEREAT, A. F. Is atherosclerosis a disorder of intramitochondrial respiration? Annals of Internal Medicine 73(l) : 125-127, July 1970. (213) WIDMER, L. I(., HARTMANN, G., DUCHOSAL, F., PLECHL, S.-C. Risk fac- tors in arterial occlusion of the limbs. German Medical Monthly 14 (10) : 476-479, October 1969. ($14) WILENS, S. L., PLAIR, C. M. Cigarette smoking and arteriosclerosis. Science 138 : 975-977, November 30,1962. (015) WYNDER, E. L., HOFFMANK, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967. 730 pp. 89 CARDIOVASCULAR APPENDIX TABLES TABLE AG.-Coronary heart disease morbidity and mu?-tality--rctrospcctivc studies Author, Y--P country, reference (Actual number of cases shown in parentheses)' [SM z Smokers NS r Nonsmokers EX = Ex-smokers] Numix F and Data tyr ? ,!f collrction Cases (percent) Controls (llercent) l.rij,uiatlon ._____ -..... Comments English et al., 1940. U.S.A. (60). Mills and Porter. 1957, U.S.A. (281). 1.000 r ,,le: .>ith m:rl:if+' HI), 40 > 3 ,rf age. Con!: L: i.000 mslr r.on-CHD patients. 474 white male coronary deaths. Controls: 606 white males. 1 I,,' Pcrccrrt Smokers Pcrce?d Smolxss .Id /!b 79.7(1X?) 61.9(302) (p"a .1x.5 (21) 120 11.6(14) U.S.A. with matched (33). controls frwn Same S"WfY (included those surviving first myocardial infarction) f TABLE A&-Coronary heart disease morbidity and mortality---retrospective studies (cont.) (Actual number of casa shown in parentheses)* [SM = Smokers NS = Nonsmokers EX = Ex-smokers] Author, Year. Number and Data country, type of collection Cases (percent) Co"trols (percent) Comments reference population ~-. ._ Russek and 97 male nnd 3 Interviews Tobacco usagc>~o cigarettes/day Patients Zohman. female coronary by 50 1,ercent. 35 percent. included 89 195% patients. Controls: authors. with classical U.S.A. 100 healthy controls myocardial (16s). of similar age, in'farction sex. occupation. and 11 with and ethnic origin. angina pectoris. Spain and 269 males identified 3,000 males NS Nathan, as having CHD by in New <40/day 1961. physical examination York City >40./day U.S.A. and history. Controls: inter- EX (176). 2,637/3.000 males viewed and Cigar, pipe identified 8s examined Total not having CHD by medical group. .30.0 (81) 29.0 (772) .29.0 (78) 33.0 (870) 13.0 (33) 9.0 (234) (p20 ........................... .48.6 17.9 t22.2 3.6 Cigar, pipe ..................... .44.4 ... 27.x .. EX ............................. 4.2 ... t15.3 3.6 These are not p"re smoking classes. t (P35 ._ ._ _. .21.8 (42) 100.0(193') (only 28 were mixed or cigar smokers) 18.4 (76) 10.4 (4X) 46.5(192) 22.5 (93) 2.2 (9) 100.0(413) (62 were mixed or cigar smokers) Ex-smokers listed under nonsmokers. Smoking information available only on 193/205. These cigarette categories include mixed or cigar smokers recalculated as to number uf ciga- rettes. No patients or controls smoked pilIes exclusively. Darken. 33 females "D to Death cer- Cigarettes per day 1967, 44 years of age tificates. 0 ,. ,. .,._. 6.1 (2) CR.!? (X4) (1~<0.001) CC~allY with myocardial inter- l-5 17.3(23) (5.3). infarction or sudden views. 6-15 .4x.5 (16) 16.5(22) death. Controls-133 20-30 ._ ._ .__. .39.4 (13) 3.0 (4) females 27-44 years >35 G.l (2) of age from clinic without CVD or lung caneer. 2 t TABLE A6.-Coronary heart disease morbidity and mortality-retrospective studies (cont.) (Actual number of cases .&own in parentheses)' [SM = Smokers NS z Nonsmokers EX = Ex-smokers] Author. Ye==. cou"tly, reference Number and type of population Data collection Hyams et al.. 1967, .J=pa" (87). 79 males surviving Interviews myoeardial infarc- by trained tion. 157 age- personnel. matched controls hospitalized for non- CVD but include hypertensive disease. Cases (percent) -NS . .10.1 (8) l-9 cigarettes Co"trols (percent) 21.0 (33) per day __. 7.0 (6) 10.5 (13) lo-15 . . 25.4 (18) 33.9 (42) 16 20 . . ..35.2 (25) 25.X (32) 21-34 ., ,._. .22.5 (16) 17.7 (22) >35 9.9 (7) 12.1 (15) All SM .lOO.O (71) 100.0(124) Comments Mulcahy et 81.. 1967, Ireland (237). 100 female patients Hospital SM ,. ._ __ .63.0 (63) less than 60 years interviews. NS .33.0 (33) uf age admitted to EX ., ,, t., 4.0 (4) hospital with CHD. Total lOO.O( 100) Stejta. 1967. Poland (179). 70 male and female patients with recent onset exertional angina pectoris. 54 controls of same age. Direct Pre~nlcnce of siak factors interviews. .A rtuinn patient8 60.0 45.6(261) 45.3(259) 9.1 (52) 100.0(572) Smoking on controls obtained from statistics of smoking in Irish Republic. Sudden death not included. Control grollp 48.l(P>O.l) Authors then followed the 70 patients for 3 years and noted that smoking signifi- cantly intluenced the incidence of coronary occlusion. Schimmler 603 males with Hospital NS 9.0 (44) 26.0(1X7) (n20 ,. .42.0(209) 29.0(207) (PI5 cigarettes .22.6 All ., ._ .80.0 Pipe .16.5 1,229 CHD patients: Interview. 43.0 802 males, 427 females. Controls: 743 individuals of both sexes: age. sex, and social class matched. 24.2 I!l.i 27.4 20.0 47.4 X.X 13.0(r1<0.0001) Knstl, 275 mnle railway Interview NS __ ., ., .20.0 (65) 29.x (X2) 1969. employees up to 65 and ex- Z-20 cigarettes or C`Z"l*"Y yc*rs of age sur- amina- UP to 6 cigars. .32.0 (88) 63.X (X2) (9X). viving myocardial tion. >20 cigarettes or infarction. 276 con- >6 cigars. ..48.0(132) R.!) (19) trol employees with minor circulatory disturbances. 1 Unless otherwise specified. disparities between the total number of eases and the sum of the individual smoking categories are due to the exclusion of s either occasional, miscellaneous. mixed. or ex-smokers. Author, year. country, reference TABLE A'i.-Differences in serum lipids between smokers and nonsmokers Number and type of population (Actual number of individuals shown in parentheses)' [SM = Smokers NS = Nonsmokers] Results Comments Gofman et al,. 1955. U.S.A., (72). 401 male e"lplWW?S 20-59 years of zlge. Lipid: tsf c-12 Sf 12-20 Sf 20-100 Sf 100-400 Cholesterol Difference between SM and NS tSf refers to Svedberg Ages 20-29 Ages 80-.79 Ages40-59 flotation units of (NS 56, SM 37) (NS 56, SM 67) (NS 17, SM 44) centrifuged lipoproteins I. +59.9 P250 87/99.6 115/102.4 Chi Square Value = 5.2 p40 ..................................... 229.0(114) 238.5 (68) Piprand cigar ............................. 214.9(128) 227.1(166) Serum cholesterol mg. percent Wcet Finland East Finlatid Helsinki NS ................................. 208.0(64) 226.6 (39) 235.1 (62) SM ................................ 228.7(91) 249.7(103) 257.8 (166) T Increasing amount of cigarette smoking in younger men. The authors state that no trend WBS noted associating increasing amount smoked with increasing serum cholesterol, although smokers and nonsmokers did have different overall kVC,S. TABLE A'?.-Differences in senm lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)' [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of reference population 22 1 rnnd0mly Mean strum cholesterol Mean l3etnlAlpha rh"sen pensioners mg. percent lipoprotein ratio G-X5 yf%L's "f NS _. .._ ._ 214(38) 2.0(36) age. 5 cigarettes/day .X01(12) 2.1(11) 10 213(34) 1.8(33) 20 201(33) 1.9(35) >30 .._._ ._.......... 206 CR) 1.8 (R) Api~rvximately Cholesterol my. percent RctnlAlphn lipoprotein. ratio No data given "n numbers in GOIJ healthy 25-Y!, 40-55 254!) 40-55 each gr"uI). malrs 2s55 tA SE A E A E A E tAPAfrIcan. YERI`S of REC. NS 179 197 222 246 2,x9 3.34 3.75 4.59 %E~~~Euvopenn. "Heavy" SM 1X6 223 204 236 3.82 4.40 4.07 5.40 Results Conments 314 mnlr military Serum cholcstcrol Serum phospholipids No serum lipid differences recruits 14-25 my. perrcat mg. pc rcent f<,und am"ng the rsrinus years of we. NS ,, ,, ,. ,. ,, ,, ,._ ., ., ,(145). ,. __ _. ., 203.8 21R.0 smoking groups. (Cigarettes per day) l-10 (53). 206.8 222.3 11-19 ,., ., ,, ,, _.. (54). _. ,. _. 213.1 224.7 >ZO . . . . . . . . . . . . . . . . . . . ..(62)............. 202.3 210.6 7F monozygotic I. Mimozygotcs discordant for smoking: Smokers showed slightly lower levels The a"th"rs conclude from the twin pairs and of cholesterol, triglycerides, and phospholipids than nonsmokers. differing MZ and DZ results Xi rlizygotir II. Dizygotes discordant for smoking: Smokers showed significantly higher that constitutional factors twin pairs obtained levelv of phospholipids. No differences for cholesterol and triglycerides. are probably m"re importnnt from Swedish Twin than smoking in determining Registry. lipid levels. 8 TABLE A7.--Diferences in serum lipids between smokers and nonsmokers (cont.) (Actual "umber of individuals shown in parentheses)1 [SM = Smokers NS = Nonsmokcrsl Author, year, Number and country, type of Results CO"ll"e"t.8 reference population Fidanza 111 male prisoners Serum cholesterol mg. percent No statistically significant et al., 34-69 years of Agce <39 40-49 SO-59 60-69 differences found between I!)GG. ape. NS 195(E) 189(10) 176 (7) SM nnd NS. Italy <20 cigarettes/day 209 (5) 201(16) 202(13) 196(10) (FL). >20 cigarettes/day 197(6) 175 (7) 171 (7) . . Serum triglyceride8 mg. percent NS x4.7 71.9 86.0 <20 cigarettes/day 84.6 99.4 101.9 89.8 >20 cigarettes/day . 91.0 86.0 66.7 . Kedm and 200 clinically Serum cholcaterol Phospholipids Total lipids Serum cholesterol also noted Dm<,wski, healthy malrs nag. percent mg. pe+cent n&g. percent tn increase with increasing l!lM, 2B-50 years of NS(100) . . . . . 170.2 1,234.8 intensity and duration of Poland 268.11 uge. SM 100) 224.9 (99). 3 Po.os 1.362.1 Beta-lzpoproteina 1 PI0 cigarettes/day _. __ __ __ __ __ 260.0(166) 180.0 TABLE A7.-Differences in serum liln'ds between smokers and nonsmokers (cont.) (Actual "umber of individunls show" in parentheses)' [SM = Smokers NS = Nonsmokers] Author, year, country, reference Number and type of population Rl?Slllts comments Higgins and Kjelsberg, 1967. 1J.S.A. (83). Pinrherly nnd Wright, l!l67. E"gl*"d (1,50). 5,030 male and female residents of Tecumseh. Michigan, 16-79 years of age. 2,000 men participating in executive health examinations 2%70 years of age. M&8 Fe??llZh NS __ __ _. _. _. 209.9 (360) 210.1f1,439) Cigarette 212.5( 1,426) 212.4 (910) Percentage with .wrunz The authors noted that smokers Serum cholesterol choleatcroZ>170 showed significantly higher mg. percent mg. percsnt ( p20 cigarettes/dny(Sll) 249.4 30.0 Van Buchem, 1967, Nethevlands (181)). 918 randomly chose" Semm cholesterol The Ruthors found no meles 4c-59 yearn O-209 mg. pement 210-?4!i mg. Percent >eso nw. Percent correlation between smoking of age for entry NS . . . . . 12.4 (32) 14.0 (44) 14.2 (41) and serum cholesterol levels. into prospective Cigarette SM 71.6 ( 184) 67.8(213) 68.2(197) study. Other ,_....______.._. 16.0 (41) 18.2 (57) 17.6 (51) Hwle et al., 1968, 1J.S.A. (28). 1.104 male factory employees 20-64 yrars nf age. Serum cholcsted Scram Beta-lipoprotein Beta-lipoproteins were found mg. percant my. percent to increase with nge. but NS ,. ._ ._ __ __ _. __ __ _. ._ __ SM 243(519) 1 ,,O.O5 215.0 P40(114) . . . . . ., Pipe and cigar(128) ......... ......... ......... ......... Systolic blood preaaure No association found Ages 29-44 45-59 between systolic blood ................... 138.8 143.0 pressure and smoking. ................... 132.5 140.3 ................... 134.7 144.0 ................... 129.4 141.6 ................... 132.2 138.9 ................... 136.1 141.5 ................... 136.0 141.9 Edwards et al., 1,737 male Proportion of n&err with "Hypmtmion" (~200~100 mm. Hg.) 1959, England patients of NS _. , . . . . . . . . . . 2'7.2 percent (151) (56). general prac- Cigarettes _. . . . . . . . . . . . 20.5 percent (730) titioners over Pipe _. _. 25.9 percent (341) 60 yeTarS of age. Karvonen et al., 526 males in Systolic blood pm.wuw No data on pipe and 1959. Finland various regions West Fixland East Finlund Hebim ki cigar smokers. No (97). of Finland NS ., ._. ,. . 139.2(64) 142.6 (39) 132.8 (62) statistical significance 2s s9 years of SM _. 133.2(91) 135.4 (103) 129.8 (166) noted. BBC. Diastolic blood pmssure NS . _, 84.7 86.8 89.6 SM . . 81.9 84.1 86.8 Clark et al., 1,859 male civil Mean systolic Mean diastolic Nonsmoker and smoker 1967. U.S.A. servants. blood-prcsuwe blood-pressarc groups were of similar (43). NS(728) .,...,.,..,..... .,.. . . . . . . 137.0 (p~O.05) 83.gl (pZO.05) average a???. SM (407) 133.6 R2.5 ( TABLE AS.-Blood pressure differences between smokers and nonsmokers (cont.) (Actual number of individuals show" in parentheses)' [SM = Smokers NS = Nonsmokers] Number and type Results l-ef.Se"Ce of population Comments Higgins and 5.030male and Age adjweted Age adjusted Kjelsburg. female residents mean systolic blood ~msuuw mean diastolic blood pressure 1967. U.S.A. of Tecumseh, Michigan, M&8 F#?l&lJ M&s Females (8s). 16-79 years of age. NS t, .137.9 (360) 84.5 (1439) 136.6 (360) 82J(1439) 1 (p25grams 127.9 (70) 128.1(218) 77.6 77.1 All amounts 129.1(519) 128.6(447) 78.7 773 Tibblin, 1967. 895 males in - Blood pressrcre Sweden 1 l&145/ 150-170/ Numbers in parentheses GGtehorg, Sweden, ~110/~70(89) (187). 75-95(468) born in 1913. loo-110(220) >175/>lI5(75) represent total in blood NS . . . _. . . 18.0 23.0 25.5 34.7 Pressure group. l-14 cigarettes . .29.2 29.2 25.6 18.7 The author noted >I5 cigarettes . 28.1 20.9 15.5 17.3 a stepwise decrease with Pipe and cigar . .11.2 8.6 10.0 4.0 level of blood pressure as smoking increased. `Unless otherwise specified, disparities between the total "umber of i"- dividuals and the sum of the individual smoking categories nre due to the exclusion of either occasional, miscellaneous. mixed, or ex-sm"kem. TABLE A17.-Zmidence of new coronaq heart disease by smoking category and behavior type for men 39-49 years of age (Numbers in parentheses are number of CHD cases in each subgroup) Smoking group FlXlIl.?T Current and Cigarettes Behavior NeVer cigaf;cete former pipe type smoked and cigar only 1-15 16-25 26 and over Total A .._ ., . . `5.3(5) 13.3 (7) 1.3(l) 1.6(l) 15.X(15) 14.9 (16) 9.3(45) B . . . . . . . . 1.3(Z) 5.1 (3) 2.2(Z) 7.3(4) 3.1 (3) 4.9 (4) 3.3(18) Total 2.9 (7) 9.1(10) 1.8(3) 4.9 (5) 9.3(1X) 10.4(20) 6.2(63) Analysis of variance table SOUITC Sum of squares d.f. Mean square F P Within cells _. _. . . _. 59.471 2,245 0.026 . . Regression on age . _. _. _. _. . . . . 0.458 1 0.45R 17.296 0.001 Retwsen smoking groups 2 _. _. . _. 0.504 5 0.101 3.81 0.002 Between behavior types 2 0.329 1 0.329 12.43 0.001 Interaction . 0.396 5 0.079 2.99 0.011 1 Rates are age-adjusted nnnual incidence per 1,000 men. effect but ignoring interaction. thus yielding an estimate of each main ef- `Mean squares for "between smoking grwps" and "between behavior fsct unconfounded by other significant main effects. types" are each computed eliminating the general mean and the other main SOURCE: Jenkins. C. D. rt al. (90). TABLE Al8.--Zncidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age (Numbers in parentheses are number of CHD cases in each subgroup,) Smoking group Behavior NNCT iYPf snmkcd Former cigarette smokers Current and former pipe and cigar only 1-15 Cigarettes 16-25 26 and over Total A _... `12.4(5) B .._... .._ 10.0(4) Total 11.1(g) -. Sourre 1X.6(8) 5.1 II) 14.2(9) 21.8 (8) 8.4 (3) 14.9(11) Sum of S4"BTes 16.4(5) 21.5 (9) 30.0(14) 20.4(49) 4.?(l) 21.1 (7) 19.1 (5) 12.0(21) 11.5(6) 21.3(16) 26.0(19) 16X(70) Analysis of variance table - ..__ d.f. Mean S4"BlY F T- Within cells ............................................. 63.527 Rwression on axe ...................... ., .................... 0.171 Uetween smoking groups - ................................... 0.522 Between behavior types 1 ..................................... 0.296 lnternction .................................................... 0.129 1 Rates are age-r.djusted annual incidence ner 1,000 men. : Mean squares for "between smoking groups" and "between behavior types" are each computed eliminating the acnersl mean and the other main 911 0.070 1 0.171 2.54 0.111 5 0.104 1.496 0.188 1 0.296 4.24 0.040 5 0.026 0.37 0.870 effect but ignoring interaction, thus yielding an estimate of each main ef- fect unconfounded by other significant main effects. SOURCE: Jenkins, C. D. et al. (90). TABLE A20.-Experiments concernixg the cfects of smoking and nicotine OYI unimnl cc~~dio~~asc~~la~ function. Author. Ye**. Number and Smoking Heart Blood Cardiac Coronary country, type of procedure rate pressure output blood Comments reference population flow Bell& 39 experiments Inhalation Definite Definite Coronary artery ligation increased the frwuency et al., on dogs which of tobacco increase. increase. of nicotine-induced severe arrhythmias; these 1941. had undergone smoke in hecame less evident with increasing time since U.S.A. P"ron**y chamber. ligation. (21). artery liga- Nicotine Definite Definite tion up to intravenous increase. increase. 45 days before. 0.2-1.2 mg./kg. Burn and 10 rabbits, Experimental Isolated "trial specimen showed increased rate and Rand. 5 rxperimental, animals pre- incrensed amplitude of contractions with admin- 1958, 6 control, treated with istrati"" of nicotine proportional to pretreat- England isolated atria. intraperitoneal mat. These reactions were blocked by reserpine, (35). nicotine and and the authors consider nicotine effects to be the atria of mediated by catecholamine release from chro- both groups maffin store in myocardium. excised and perfused with nlrotine. ___~ West et al., 33 normal C0*0ll*lY Definite 1. Myocardial contractility increased 40-90 per- l%R, ndult mongrel intra- increase cent in 15/15 animals tested accompanied by U.S.A. dogs. arterial (systolic). ST segment depression and T-wave inversion (?OSi, nicotine: and blacked by tetraethylnmmonium chloride. I. 0.2~2.2 II. Coronary blood flow increased 19 percent upon !a./ka. left circumflex artery injection: coronary blood II. 0.04-l flow showed no change upon left anterior de- wz.lks. scending artery injection, 64 observations on 10 dogs. (Tetmethylammonium chloride blocked CBF in- crc*sc. ) The authors found no evidence of coronary vase- constriction in these healthy animals. s TABLE A20.-- -Experiments concerning the efects of smoking and nicotine on nnimd cardiovascular function (cont.) Author, ye**. country, reference Number and type of population Forte 27 observa- et al., tions on 6 1960. dogs. U.S.A. (65). Smoking Heart procedure rate Blood PRSS"lT Cardiac output c"E3," comments fl"W Intravenous nicotine up to 21.5 mg. given 8s 5-15 ag./kg / minute. Definite initial increase then decrease. No change. No significant change in either left ventricular work or myocardial oxygen extraction. Kicn and 21 ndult doss Cigarette Definite Definite Increase Effects of cigarette smoke were duplicated by in- Sherrod, smoke under increase. increase. following travenoua nicotine and epinephrine. 1960, positive increase During cigarette smoke inhalation. it wns noted U.S.A. pressure via in blood that without blood pressure or output changes. (112). tracheostomy. pressure coronary blood flow did not increase and that Nicotine 20 and cardiac while adverse EKG changes were noted they eor- wg.lkg. intra- output. related morn closely with decreased cardiac oxy- venously. gen utilization than with actual cardiac work. Epinephrine 5 eg./ka. intra- VenouslY. Travel1 14 normal Intravenous Definite Nicotine-induced coronary blood flow and heart et al., rnbbits and nicotine increase rate increase in the atherosclerotic animals re- 1960, 16 rabbits 0.01-0.1 mg. in normals. wired 10 times and 2 times. respectively, the U.S.A. with severe amounts required in the normal animals. (189). cholesterol- induced athero- sclerosis. TABLE AZO.-Experiments concerning the eflects of smoking and nicoline on animal cardiovascular function (cont.) Author. yea=, eoutry, reference Number and type of population Smoking p*0Wdll*e comments Bell& I. 10 normal dogs Intravenous I. 125 percent The authors noted that: et al.. II. 9 dogs at nicotine, increase 1. The response of coronary blood flow to nico- 19G2. varying in- 20 ag./kg.l II. 82.5 percent tine resembled that of anoxemia in the pres- U.S.A. terva1s fol- minute for increase ence of coronary insufficiency. (22). lowing coro- 15-20 minutes. III. 83.3 percent 2. The greater the induced coronary impairment nary artery increase the smaller the increment in coronary blood ligation. flow. III. 7 dogs with varying grades of artilicially- induced coro- nary artery narrowing. Leaders 15 adult Left anterior Nicotine and norepinephrine both increased coro- and mongrel descending nary vascular resistance and myocnrdial contrac- Long. dogs. intracoronary tile force (the former measured by B constant- 19G2. injection of volume variable-pressure system) The action of U.S.A. nicotine or nicotine was blocked by pretreatment with hex- (125). norepinephrine. amethonium. pentolinium, resetpine. or gusme- thidine. Larson 13 adult Intravenous Definite Definite Systrmic vnscular resistance and pulmonary artery et al.. mongrel nicotine. incrense. increase. and left atria1 pressures showed biphasic re- l9G5. dogs. 0.02 mg./kg./ sponses of increase followed by decrease. U.S.A. minute for (194). lo-12 minutes. TABLE ABO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) i; Author, year. Number and Smoking c0untl-Y. type of procedure comments reference population Folle 7 dogs of 30 investigated I. Cigarette smoke inhalation I. No change in coronary vascular resistance. et al., (Remainder experienced to isolated left lower lobe II. 5/6 showed increase in coronary vascular resistance due, according to 1966, catheterization failures). nnd then blood perfused coronnry the author. to general sympathetic nervous system stimulation. U.S.A. arteries. III. 4/5 showed increase in coronary vascular resistance. The authors con- (84). Il. Cigarette smoke to rest of elude that the cardiac effects of tobacco arise almost entirely from lung and then blood passed to the extracardiac actions of smoking instead of the direct response general circulation. of the heart. III. Kieotine perfused directly into left coronary artery. Nadeau and James. 1967. U.S.A. (14P). 26 dogs Nicotine 0.01-10.0 pg. into sinus node artery. Heart rate showed initial slowing (due probably to vagal stimulation) fol- lowed by acceleration (due probably to vagal paralysis and catecholamine release). No systemic blood pressure changes noted. Romero and Talesnik, 1967. U.S.A. (156). 16 experiments on isolated cat heart. Nicotine in varying doses in perfusatr of coronary arteries. Over 5 pg. of nicotine was found to produce an initial bradycardia asso- ciated with increased coronary flow, followed by prolonged tachycardia with an initial decrease in coronary blood flow followed by a prolonged increase. Pretreatment with heramethonium or reserpine prevented both the myocardisl stimulation and the increase in coronary blood flow. The authors consider the action of nicotine to be a combination of a direct vasoconstrictive effect and an indirect catecholamine-releasing vasodilating effect. Put-i et al.. 1968. U.S.A. (252). 22 mongrel dogs I. (14) Intravenous nicotine I. Nicotine produced a definite increase in the force and velocity of left SO &g./kg./minute fur 3-4 ventricular contraction. minutes II. Pretreatment with propranolol produced (relative to results of Group I) : Il. (8) Propranolol pretreat- (a) A further increase in left ventricular systolic pressure. ment, then 50 pg.lkg./minute (bl A decrease iv velocity of Jhortening. nicotine for 3-4 minutes (c) A significant increase in left ventricular end-diastolic pressure. The authors conclude that ~mp,rsnolol probably impairs the norepinephrine- like effects of nicotine on the myocardium while enhancing its peripheral "*80pre880* e*ects. - TABLE AZO.-Experiments concerning the effects oj smoking ad wicotixt OH u)lit)ld co?.dio(.~~scz~l~~~ fwctiox (cont.) Author. year. Number and Smoking country, type of pr"Ced"r.5 Comments reference population ___-. - BalWZs Beagle dogs with lesions I. Normals (3 ~G per experiment) : I. (a) No evidence of nrrhythmins: (b) A single or B few ectopic beats et al., induced in myocardium by (a) 4 Pg./kg. intravenous in 2/3 normal dogs. 1969. either: (1) Isoproterenol nicotine, (b) 40/1g./kg. II. Extrasystoles noted in 2/3 animals during the first day after cessation U.S.A. pretreatment, or (2) intravenous nicotine. of the arrhythmia induced by the lesion alone. but not thereafter. (16). ligation of the anterior 11. Experimental (3). 4 pg./kg. These sod nicotine-induced arrhythmias were of n short duration. descending coronary artery. intravenous nicotine Creensoan Cardiac muscle isolated from Nicotine 2-100 ug.,`cc. in Nicotine perfusion produced: et al., 1969, U.S.A. (74). the right ventricle of 10 adult dogs. Tyrode's solution perfusate. (1) A" increaw in myocardial contractile force apparently independent of adrcnergic innervation. (2) An increased nutomaticity of the Purkinje fiber system apparently due to release of catech"lamin& from rhromaffin tissue stores. (3) A decrease in conduction velocity. The authors conclude that the latter two effects probably predispose to ar- rhythmia formation. Saphir and Rapaport, 1969. U.S.A. (166). SR mongrel cats Nicotine 5-12 Kg. kg. injected intraarterially to mesenteric circulation. I. Mescnteric injection "I nicotine was followed with l-2 seconds by: (a) Increased left ventricular systolic pressure (LVSP). (b) Increased systemic resistance. (c) Enhanced myoeardial performance. II. Left ventricular injection of nicotine was followed by. (a) Increased LVSP. (b) Bradycardia. (c) Enhanced myocardial performance greater than that seen in mesenteric-injected group. III. Pretreatment with phenoxybenznmine diminished the increase in LVSP while proprnnolol pretreatment diminished the enhancement of my- "cardial performance while LVSP still showed a significaut increase. IV. Mesenteric sympathetic nerve section led to a diminished response. The authors conclude that the cnrdiovascular responses to nicotine msy be neurogenic in nature with receptors distributed in certain abdominal arteries. TABLE AZO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) - Author, year. country, reference Leb et al., 1970, U.S.A. (126). Smoking procedure Comments p&&ion 12 mongrel dogs and Nicotine 100 eg.lkg. for Effective Coronary Flow (ECF) is that part of the total coronary flow CBF measured with use of Rb3' and digital counter. 2 minute intravenously. (TCF) which is "effectively ' involved in nutrient exchange. Nicotine injection was followed by: (1) 96.6 percent increase in TCF. (2) 51.1 percent increase in ECF. (3) 73.1 percent increase in myocardial oxygen consumption and analysis revealed that capillary flow increased almost proportionately to my- ocardial oxygen consumption whereas the increase in TCF was far in excess. (4) Definite increases in cardiac output, heart rate. left ventricular work, and aortic pressure. Ross and Bless. 1970. U.S.A. (160). 10 dogs undergoing instantaneous coronary arterial flow measurement. Nicotine 10-100 fig. intra- coronary injection. Nicotine injection ~8s followed by: ( 1) Increased contractile force. (2) Decreased myocardial contraction time. (3) Decreased time necess8ry to reach peak tension. (4) Decreased total stroke systolic CBF. (5) Increased total stroke diastolic CBF. (61 Increased total stroke CBF. (7) Changes similar to intraarterial ppinephrine. (8 1 Changes blocked by pentolinium pretreatment. (9) No change in heart rate or blood pressure. The authors conclude that catecholamines released from the ventricular myocsrdium mediated these responses to nicotine. TABLE A21.-Experiments concerning the effects of smoking. and nicotine on the cardzovascular sy.stcw~ of lm~~tans Author, ye*=* countrY, reference Number and type of population Smoking Heart PlYlCCdUrC rate Blood Electrocardiogram Stroke Cardiac PW2*SUW ballistocardiogram volume output CC&0;d"=Y Comments flow Russek et al., 1955, U.S.A. (164). nargeron et al.. 1957, U.S.A. (17). I. 28 healthy 1 standard and 1 I. Increase. Increase. EKG: Denicotinized cigs- male smokers denicotinized I. 16/2R showed rettcs evoked changes 21-60 years cigarette. significant of a lesser degree of age (aver- changes. in normals and CHD age42). II. No sig- subjects. but in the II. 37 male patients II. Increase. Increase. nificant latter group there with overt changes. was no significant clinical CHD BCG : difference between 42-70 yearsof I. these changes. age (*"erage II. 18/37 showed 64j.6 were significant nonsmokers. change. - 14 of 30 healthy 1 cigarette Insignificant Increase. Definite Corunary vascular adult male vol- inhaled at increase. increase. resistance fell unteer smokers intervals of signifirnntly. and nonsmokers 20 seconds. Myocardial O2 who underwent "Saxl? untler\vent no successful significant change. catheterization Pyruvat< rstraction l&53 years fell slightly. of age. Authors consider lark of increase in heart rate as due to hawlinc nvprehensive tnrhycnrdia. _____ TABLE AZL-h'rperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Ye*=, countrY, reference Nut;;z;f""d population Smoking procedure Heart rstc Blood Electrocardiogram Stroke Cardiac masure ballistocardiogram volume output C-&W Comments flow 2 standard cigarettes in 25 minutes inhaled at minute intervals. Definite increase. Definite increase. - Increase. No signi- Myocardial 0, COI~SUIIIP- flcant tion rose ol?ghtly in change. 3 out of 7. The author considers that the EKG changes noted on smoking are probably due less to decreased coronary blood flow than to increased workload (oxygen need) where uxyuen supply does not increase. Noted no evidence of myocardial ischemia during smoking. Regan et al.. 1960, U.S.A. (1.54). `I males with history of EKG-pr~~en myocardial infsrctiun undergoing cardiac ca- theterization. Thomas and 113 clinically Murphy. healthy young 1060, males. U.S.A. (186). One standard cigarette smoked at own pace. Definite incresse. Definite Definite increase. increase. Definite increase. Pulse pressure showed a decrease. Smokers responded slightly hut signi- ficantly more actively than non- smokers. BCG changes were increasingly common with increasing age. weight, and serum cholesterol. TABLE A21.--Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Year. country, reference Number and type of PoPulation Smoking Heart Procedure rate Blood Electrocardiogram Stroke Cardiac COr0"ZM-Y pressure ballistocardiogram volume output blood Comments flow Van Ah", 1960. Sweden (202). The author reviews a series of experiments performed between 1944-1954. Cigarette smoking. I"CTe*StL EKG: Slight ST segment depression and T-wave flattening. EKC changes more prominent in young, clinically healthy subjects than in older, habitual smokers. Intra- venous nicotine and smoking showed identical cardio- vascular effects. Smohing elicited angina pectoris in a number of CHD patients. Irving and 5 normal males, (a) Shamsmoking. (a) No No change. (a) No change. No change. Cardiac output Yamamoto, 15 patients with change. measured by dye 1963, diseases not de- (h) Non-inhalation (b) No No change. (b) No change. No change. dilution technique. England fined, 19-M years smoking. change. (X0). of age, all mod- (c) 2 standard (c) Definite Widened (c) Definite Definite crate-heavy cigarettes in increase. PUL?. increase. increase. cigarette smokers. 10 minutes. pressure. (d) Nicotine 0.6 (d) Definite Definite (d) Definite Definite mg. intra- increase. increase. increase. change. V~llOUSlY. m `JIAIXE A21.-E.rllc,~i,)lents concerning the effects of smoking and nicotine on the cardiovascular q&em of humans (cont.) Number and type of population Smoking Heart procedure rate Blood Electrocardiogram Stroke Coro"ary P)`ESs"re ballistocardiogrsm volume blood Comments Row I. 14 volLl"trers Single cigarette with clinical CHD, Is/14 smokers, riverap2 axe x0.5. II. 5 patients with nngina pectoris, all smokers, sve- rage *x6! 43.4. III. 14 patients with history of definite myo- cnrdinl infarc- tion, all smok- ers averaxe age 54.1. smoked at own rate in G-7 minutes. - 5 mnlc nnd 3 ? standard female patients cigarettes in with heslrd 10 minutes at myocardinl infarc- rest and under tion 48-69 years graded exercise. of nge Z/B non- smokers. Definite Definite increase increase in all in all groups. groups. I. 10 27 percent percent increase. increase. II. Inter- I"tmme- mediate diste change. change. III. 8 per- 1 percent cent increase. decrease. Definite increase at rest and at exercise. No signifi- No signifi- The author contrasts cant changes cant this response with at rest or changes that see" among during at rest or healthy young exercise. during individuals. exercise. .4uthr. Ye" r, Numlrr nnd Smoking Heart IJlood Electrocerdioarnm Stroke Cardiac country. tyne of procedure ret"2 P~PSB"~`? ballistocnrdiogram "olume OUtPUt C"b,x-&T COTLItleIltS reference nopulatiorr flow Sen Gupta 6 healthy male 1 untipped Increase Increase No change. and Ghosh, nonsmokers. cigarette in in all in all 196'7, 8 healthy male 5-7 minutes. KroIII)s. KP3"I)S. 6/8 showed ST India smokers. rhanges. (171). 6 patients with All showed ST CHD, nonsmokers and T-wave 3 patients with changes. CHD. smokers. All showed ST 36-64 years of age. and T-wave changes. AIXllUW rt al., lY68. U.S.A. (5). 10 male patients 1 rtandard high Definite Definite Product of systolic with classical nicotine cigs- increase. increase. blood pressure and angina pertoris. rctte in 5 hart rate showed a 32%5Y wars of age minutes. significant increase on smoking while left ventricular ejection time vnlurs did not. All patients developed angina more rapidly under a constant exercise load if they had smoked before exercising. Kerrivan 24 male and 1 2 filtered ciga- Delinite Delinite Cardiac The increase in et al., female healthy rettes in 15 increase incrensc index. cardiac index. heart lY68, smokers. average minutes with under under rest Definite rate. and blood U.S.A. age, 45. measures taken rest and and exercise increase pressure during (lfJ2). H male and 2 at rest and during exercise conditions. under rest exercise with smoking female healthy exercise. conditions. and was the sum of such nonsmokers, exercise increases seen with average age 33. conditions. smoking or exercise separately. Neither group showed increases in peri- Y pheral vascular resistance. TABLE APL-Experiments concerning the effects of smoking and nicotine on the cardiovasculw system of humans (cont.) Author, yea=. COU"bY. reference Number and type of population Smoking Heart procedure rate Blood Electrocardiogram Stroke Cardiac pressure ballistocardiogram volume output Cr,;;;=Y Comments flow Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite decrease in and Roth, subjects. rettes smoked increase. lowed by pulmonary blood 1969, 19-59 years of in 12-16 minute decrease .volume as indicated U.S A. age. period. within 20 by impedance methods (3). minutes. of thoracic pulse volume. Aronow and 10 male patients 1 low nicotine Definite Definite All patients developed Swanson. with classical cigarette in increase. increase. angina sooner if 1969, angina pectoris. 5 minutes. they smoked before U.S.A. 32-59 years of exercising. (7). age. Aronow and 10 male patients 1 non-nicotine No change. No change. No difference noted SWZHISO", with classical cigarette in in time or onset 1969, angina pectoris. 5 minutes. of exercise-induced U.S.A. 32-59 years of angina between (6). age. smoking and "on- smoking procedures. Marshall et al.. 1969, U.S.A. (229). 42 normotensive healthy male prisoners 18-50 years of age. 13 nonsmokers. 16 moderate smokers. 13 heavy smokers. 3/4 of one standard Insignificant Insignificant Blood pressure response cigarette. increase. increase. to cold pressor test noted to he greater in heavy smokers. Presyneopal reactions to 40 degree head-up tilt more frequent in smokers. TABLE A22.-Experiments concerning the effect of nicotine or smoking on catecholamine levels Author, year. country, Nu$royd Procedure Results reference subject -. Watts, 11 dogs 0.02-0.60 mg/kg. Nicotine administration was associated with significant increases in peripheral arterial 1960, nicotine intravenously. epinephrine levels. Ganglionic blocking agents prevented this effect. U.S.A. (am). Westfall and Watts, 1963. U.S.A. (210). 22 mongrel dogs Cigarette smoking via tracheal cannula; 1 cigarette/8 minutes for 35 minutes. Regular cigarette smoke evoked a statistically significant increase in adrenal vein, vena CBYB, and femoral artery levels of epinephrine. Cornsilk cigarette smoke evoked no change. W.&fall 21 male vol""teers 3 cigarettes smoked in Smoking at rate noted for 2% hours evoked a significant increase in urinary rpine- and Watts, approximately 25 30 minutes. phrine. but not norepinephrine levels. 1964, ye*4 of age: U.S.A. 11 nonsmokers. WI). 10 smokers. Westfall et al.. Mongrrel dogs Standard cigarette smoke Smoke inhalation evoked a rise in cardiac output, stroke volume, blood pressure. and 1966. exposure via endotracheal plasma cstecholamine levels. Pretreatment with propranolol diminished the cardiac U.S.A. tube. Smoke inhalation output and stroke volume responses hut increased the blood pressure response-the (209). every third inspiration for latter effect due to the release of alpha-receptor activity by beta-blockade. 3 minutes. d TDLE A23.--Experiments concerning the atherogenic effect of nicotine administration Author, year, country, Number and type Procedure Results reference of animal -___- _____ Adler et al.. Rabbits Nicotine 1.5 mg. intravenously in 5 percent The authors noted an artcrionecrosis of the aorta, affecting mainly the 1906, solution C of 7 days per week for more than inner muscular layers. Macroscopically, early changes consisted of U.S.A. 4 months. small areas of caleareous ridging and aneurysmal dilatation without (2). notable fatty degeneration or intimal discontinuity. Microscopically. early changes appear& in the muscle cells of the media, and "chalky" deposits were noted between the elastic fibers. HuePer, 1943, U.S.A. (86). I. 6 mongrel dogs. Nicotine subcutaneously. Increasing dosage up 1. 4/6 animals died of infection and showal marked edema and focal up to 2.5 cc. of 3 percent solution for 1 hyalinization of the media of the aorta and large elastic arteries. month, 2/6 animals were sacrificed and showed thickening and hyalinizs- tion nf the walls of the coronary arteries and edema of the media as well as endothelial proliferation of other arteries. II. 60 rats. Increasing doses up lo 1 cc. of 1 percent II. Much less nortic involvement than that found in the dogs; infre- solution for 1 month. quent arteriolar changes consisting of fibrosis and thickening of the media. Maslova, 1956, USSR (180). Czochra- Lysanowicz et al., 1969, U.S.A. (46). Rabbits 1. (10) Nicotine subcutaneously 1 percent solution 0.2 cc. daily for 115 days. II. (14) Nicotine plus 0.2 grams cholesterol per day. III. (10) Cholesterol only Rnbhits I, (10) 1.0 g. cholesterol/day for 100 days. 11. (10) Cholesterol plus 0.0015 g. nicotine/ day intravenously. IIJ. (4) Nicotineonly. I. Aortic wall---acute swelling of elastic fibers with focal fragmenta- tion and partial disintegration- no intimal fat deposits seen. Coronary vessels--thickening of the vessel wall-no fat deposits. II. Aorta--"massive" deposits of "cholesterol" in the intima and vasa vasorum with "loosening" of the sortie wall. Coronary vessels- the larger vessels showed moderate fat deposition and the smaller vessels showed swelling of the elastica. III. Aorta-isolated lipid deposition in the arch and ascending portions only. Coronary vessels---no fat deposition. Index of aortic lesion density (cholesterol infiltration) : I. 2.5. II. 3.4. III. No aortic lesions noted. Author, year, cnuntry. reference Number and type of animal Procedure Rrsults Wenzel et al., 1959, U.S.A. ( 127). Rabbits Thienes 1960, lJ.S.A. (1X4). Newborn rats and mice. Grosgogeat et al., 1965. Frnnce (75). Male rabbits I. (12) Cuntrol untreated. II. (12) Control diet plus 1 percent cholesterr,l nnd 5 percent cottonseed oil added. 111. (12) Control diet plus oral nicotine 2.28 mg./kg./day. Iv. (12) ncaimen II DIu!; ~711 nicotine 2.28 m~./kg./day. V. (12) Regimen II plus oral nicotine 1.42 mg./kg./day. VI. (12) Regimen II ~,los oral nicotine 0.57 mg./kg./day. Nicotine subcutaneously up to 5 mg./kg. twice daily by the end of 1 month. Animals nntrrpsied at I year. I. ( 10) Nicotine subrutaneoujly 0.15 m,E./day. (10) Controls-saline injected. Sacrificed at from 20-120 days. II. (27) Same as Group I (27) Controls--saline injected. Sacrificed at 90 days. Significant diffrrrnws in a<,rtic subendothclinl fibrosis betwwn control and exw~imental yrwps noted w11y in II and IV. In group IV, the nicotine-treated grcn~~) showed mow srwre change III. (66) Nicotine subcutaneously 0.:3&1.5 mg./dny. Sacrificed at 30 days. IV. (24) Nicotine subcutaneously 0.75 ma./day. (24) Controls--saline injected. One-half of each group ate cholesterol- enriched diet (0.5.-1.0 percent choles- terol added). Sacrificed at 60 days. TABLE A23.-Experiments concerning the atherogenic effect of nicotine administration (cont.) Author. year, countrY, reference Number and type of animal Procedure ReSUlt.3 Hass et al.. 1966, U.S.A. (80). Male rabbits 1. II. III. IV. V. VI. Nicotine Diet Vitamin D (8) Control Control Control I. Infrequent medial calcific disease without lipid locnlization. (7) Control Cholesterol Control II. No medial caleific disease but frequent intimal atheroma formation. 14) Nicotine Control Control III. Rare cnlcific medial degeneration; no intimal atheromatous disrase. 15) Nicotine Cholesterol Control IV. The largest number of atheromatous lesions. (9 1 Control Cholesterol Vitamin D V. No medial calcific disease. 14) Nicotine Cholesterol Vitamin D VI. Consistent medial caleific disease. (Sacrificed at various times) Control-no treatment. Nicotine-subcutaneous injections in oil- increasing amounts 2 times per week. Vitamin D--subcutaneous injections UP to 6-8x 1oJ IU. Cholesterol-250-500 mg. cholesterol added Choi. 1967, Albino rabbits per 100 g. diet. I. Nicotine l-5 mg./kg./day intraperi- toneally. I. Increasing nicotine dosages were associated with decreased atheroma formation (findings not statistically significant). Korea (42). Cholesterol 1 g.lday (in varying II. Nicotine alone produced no atheroma formation but was associated combinations with controls) with the presence of aortic medial calcification and endothelial II. Nicotine alone. hyaerplasia. III. Cholesterol alone. (Sacrificed at 60 days) III. Cholesterol alone was associated with a definite increase in atheroma formation. Stefanovich Female albino, I. (10) Diet supple- Percent of am-tic In both stock and cholesterol-fed animals, nicotine was also noted to et al.. rabbits. mented with 2.0 1969, percent choles- U.S.A. terol. Nicotine in- (178). tramuscularly 2.78 mg./kg./day. 5/7 days. 11. (10) Cholesterol only. III. (10) Nicotine only. IV. (1") Contrul. __ ~- -___- __~ surface involuad with athwoscleTosia I. 9.4 II. 5.7 III. 0.1 TV. increase aortic triglyceride content and to decrease aortic free cho- lesterol content. TABLE A25.-Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) Author. ye**, country, reference Number and type of population Smoking Plasma free procedure fatty acids Serum Serum cholesterol triglycerides Other Comments Page et "I., 1959, U.S.A. (147). 13 male and I female laboratory workers 17-51years of *ge. 2 nonfiltered cigarettes in 10 minutes and blood 1Wels measured over30- minute period. No change. Serum lipoproteins No change (10 subjects). Kershbaum 31 male et al., patients or 1961. staff 16-72 U.S.A. years of age, (104). I normals, 1 CHD. 17 other medical diagnoses. I. 17 subjects smoked 2 "on-filter cigarettes in 10 minutes. II. 9 controls. III. 5 subjects smoked 6 cigarettes in 40 minutes. Mean rise No change. No change. The authors consider the in- I, 351 fiEq./L. crease among controls to be II. 9.X pEq./L. due to fasting. III. 27%2,304 /LEq./L. Kershbaum I. 17 male I., II., III., Mean rise No difference found between re- rt al.. patients 2 non-filter I. 858 fiEq./L. suits following inhalation or 1962, with healed cigarettes in II. 320 &E&L. noninhalation. U.S.A. myocardial 10 minutes. III. 292 /.lEq./L. Statistically significant difference (10.9). infarctions. IV. No smoking. IV. 20 /IEq./L. found between increases in II. 16 non-CHD Groups II and III and patients. Group I. III. 10 normals. 2 IV. 13 normals. TABLE R25.-~;:.cl)cl'iltl(,?ll.s conwwi?lg the effect of srt/ok;ing and nicolim Icpon blood lipids (cont.) Author. yen*. country, Number and Smoking type of prorrdurr (Human Studies) 1 SM - Smokers NS = Nonsmokers] Plasma free fatty acids Serum Serum cholesterol triglycerides Other Comments Definite irlcreasp at start of smoking peri~xl. -. - 3 patients with trimc- Both free and total urinary thaphan camphor- catecholamines increased with sulfanate (Arfonad) smoking and the author pretreatment and 8 considers them as mediators formerly sdrenalecto- of the FFA increase. mizcd patients showed either minimal or no elevation. - ~-___ NS-dcfinitc No change NS- -definite incveasc at 6 hours. SM--definite increase at 6 hours. in either increasr $?roup. at 2 hours. SMslight increase at 2 hours. Author. year, c'ountrg. reference. Number and type of population Serum Serum cholesterol t.riglycerides Other Comments Frank1 5 male and 1 2 stnndnrd No rhanpe. Subjects werr in nonfasting, et al., female riaarettes nonbnsnl state. 1966, healthy inhaled in U.S.A. smokers 10 minutes. (66). 24- 2!l scars rrf age. Kcrshbnum 43 norm"1 male I. Terminal et al., heavy cigarette segment of l!W, or cifial cigar in 20 l1.S.A. smokers. minutes~- 15 (I,,,;) 21 4G years subjects. of ape. II. :i riparettes in 20 minutes 15 subjects (includintz ti from group I). III. Cipnwttr inhalation or nuninhalation G subjects. I. Indefinite increase. II. Dcfinitc inrwesc. III. I"urcaw with inhnlatio" zrcatcr thnn with "on- inhalation in every suhjeci. Cip:u. smoking in 11 subjects hhuwed a" intermediate in- creaw in the excretion of "rin:lry catecholamines as . compalctl to thnt with +a- rvtte smoking. Klensch, 56 observations 1 standard l)eli"itc Ir~mokers all :! biris or CllXLY%3~ wrapped in 1965, regular rhrwrrl 1 (-) (6) I --I (f) l~,bZiCW India tobacco hetcl nut Inrreasc leaf. (174). IlhPI`S. rluid in 20 minutes, Engel- .- ~-___ 40 male and 2 cigarettes berg, 20 female in 20 1 !I 6 5, huspital pa- minutes U.S.A. ticnts. all (5.Y). smokers IT- 6X years of ;ige. sc,n 4 fernalp in 15 ""d patients minutes. Fyfr, with lit UT unlit (t) lOfiR, various cigawttrs. Scotland diseases, all (MD,. heavy smokers 37- 67 years <>f age. ChlWldlCT (in ritm) thrombosis time + decrease Throw& time (*) decrease (f) increase t Smoking both lit and unlit cigarettes caused a rise in platelet adhesiveness which the authors correlated with rise in plasma non- esterified fatty acids. TABLE A27.-Smoking and thrombosis (cont.) z Author, Whole Partial Recalcified Year. Number and Experi- blood Pro- thrombo- plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin clotting adhesive- count survival turnover Other Comments reference population conditions 1 time time time time ness C.lynn 21) male and :i cigarettes Platelet Smokers found et al., li fcmalc in 30 scrotinin to have a 19GG. smokers and minutes. (-) (6) greater C*"*d* 9 male and Plutclet t~ndcncy for (71). 21 frmale adcxosinc platelet nvnsmukcrs nucleotidc aggregation Ii-i6 jears (6) than non- of age. smokers. Engelbrr~ 9.1 male and 1 cinarette and 53 female in 5 minutes Futter- patients and man. mcdicnl l!lGi, h<,uw ~ltatf. U.S.A. (5s). Thmmbuu No relation jormu tion found with time increase in (+) free Patty decrease acids. Platclct ndhwxncc to (i) (2) C-t) sYlsclLlnr increase increase decrease Lndothclircm (+) increase Fibrinolusis (5) decrease Thrombus jormntiom timt (+) decreasr TABLE A30.-Experiments concerning the effect oj nicotine ant1 smoking xpon the peripheral vascular system Author, year country. reference Moyer and Maddock, 20 subjects (including heavy smokers) were studied for the effects of 1940. U.S.A. (I%,). the following procedures on skin temperature: the inhalation of a lit cigarette, inhalation through an empty paper tube. or the ad- ministration of 1 mg. nicotine intravenously. All subjects rrsponded with decreased cutaneous temperature following the smoking and nicotine procedures. No changes were noted following sham smoking. Mulinos and Shulman, A number of experimental groups, each consisting of 6-17 persons, 1940, U.S.A. (198). were studied for the effects of deep breathing and cigarette smoking on skin temperature and digit or limb plethysmography. The au- thors concluded that deep breathing alone could account for the changes in temperature snd blood flow noted upon smoking and noted that denicotinized cigarettes evoked the same or greater vasoconstriction as that noted following the smoking of a standard cigarette. Shepherd, 1951, Ireland (179). 50 young male smokers were studied with plethysmography before and after the normal and rapid inhalation of a standard cigarette. The author noted that rapid inhalation was associated with a pro- longed decrease in extremity blood flow while a more natural rate of inhalation was followed by a momentary deerease in flow. The author considered the former reaction to represent the pharmacolo- gic effect of the smoke and the latter tu represent the physiologic response to deep breathing, as the natural inhalation of r.n unlit cigarette produced the fame transient decrease in flow as did the natural inhalation of the lit cigarette. Friedell. 1953. U.S.A. (70). 52 male and 48 female young smokers and nonsmokers were studied for the effects of smoking on hand blood volume as measured by the use of radioactive iodinated albumin. The inhalation of un- filtered cigarettes was associated with an average decrease in hand blood volume of 19 percent in men and 33 percent in women; while filtered cigarettes showed respective decreases of I1 percent and 21 percent. StrBmhlad. 1959, Sweden (18f ). 11 male and female subjects (smokers and nonsmokers) were studied for the effect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by venous occlusion plethysmogrsphy. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vase- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentolinium. Bamett and Boake 9 male patients with intermittent claudication (7 were heavy smokers) 1960 Australia (~8) were studied for the effect of smoking on blood flow to the leg BS measured hy venous occlusion plethysmography. Smoking an un- filtered cigarette was found not to produce any consistent changes in blood flow to the calf or foot of the affected leg, Freud and Ward, 1960. U.S.A. (68) 15 mde prison inmates (1 ess than 35 years of age) and 14 male patients with peripheral vascular disease (approximately 65 years of age) were studied for the effect of smoking on digital circulation as measured by skin temperature, plethysmography, and radiosodium clrarance from the skin. Smoking was found to adversely affect the first and third measurej in a significant manner (while plethys- mographic values were variable) only in the healthy prisoners and not at all in the parient group. R&h and Schick, 100 normal individuals underwent 425 experimental procedures con- 1960,U.S.A. (161). cerning the effect of smoking on the peripheral circulation. Smok- ing was found to be associated with a decrease in extremity skin temperature. 133 TABLE A30.-Esperiments conwrning the effect of nicotine and smoking upOn the peripkeral vascular system (cont.) Author, year, country. reference Rottenstein et al.. 8 males (18~1 yeam of age) were studied for the effect of intm. 1960, U.S.A. (162). venous .nicotine on extremity temperature and bled flow. Intra. venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began swner and lasted kmger than the latter. Allison and Roth, 1969. U.S.A. (4). 30 healthy indzviduals (19-59 years of age) were studied for the effect of smoking two cigarettes on eXtreIdY Puke vohm?s and ski,, temDerature. Smoking was found to be associated with a 2-6 per. cent deereast, in skin temperature and ZI 45-50 percent decrease in blood pulse volumes to segments of the finger. calf. and toe. 134 CHAPTER 3 Chronic Obstructive Bronchopulmonary Disease Contents Introduction ......................................... Epidemiological Studies .............................. COPD Mortality. ................................ COPD Morbidity. ............................... Ventilatory Function. ............................ Genetic Factors. ................................ Alpha,-antitrypsin ........................... Air Pollution .................................... Occupational Hazards. ........................... Cadmium ................................... Pathological Studies ................................. Experimental Studies ................................ Animal Studies ................................. Studies in Humans .............................. Studies Concerning Pulmonary Clearance .......... Overall Clearance ........................... Ciliary Function ............................ Phagocytosis ................................ Studies Concerning the Surfactant System ......... Other Respiratory Disorders .......................... Infectious Respiratory Diseases .................... Postoperative Complications ...................... Summary and Conclusions ........................... References ......................................... FIGURES 1. Percent of lung sections with Grade IV or V fibrosis . . . 161 2. Percent of lung sections with Grade II or III emphysema 162 LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Page 139 141 141 145 146 148 150 152 153 154 154 158 158 163 164 164 164 165 172 172 172 174 175 1'76 142 137 LIST OF TABLES (Continued) (A indicates tablets located in appendix at end of chapter) A2. Smoking and chronic obstructive pulmonary disease symptoms-percent prevalence. . . . . . . . . . . . . . . . . A3. Smoking and ventilatory function . . . . . . . . . . . . , . . . A4. Glossary of terms used in tables and text on smoking and ventilatory function. . . . . . . . . . . . . . . . . . 5. Cessation of smoking and human pulmonary function A6. Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) . . A7. Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease. . . . . . . . . . . 8. Studies concerning the relation of human pulmonary histology and smoking . . . . . . . . . . . . . . . . . . . . . 9. Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulmonary parenchyma of animals . . . . . . . . . . . . . . AlO. Experiments concerning the effect of the chronic in- halation of NO:> upon the tracheobronchial tree and pulmonary parenchy-ma of animals . . . . . . . . . . . . . 11. Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . 12. Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance. . . . . . . A13. Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function . . . . . . . . A14. Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension . . . . A15. Studies concerning the relationship of smoking to in- fectious respiratory disease in humans . . . . . . . . . A16. Complications developing in the postoperative period in patients undergoing abdominal operations . . A17. Arterial oxygen saturation before and after operation Pafie 195 206 215 l-19 216 218 155 I.59 220 166 170 221 `LP;, 226 230 "30 130 INTRODUCTION Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common respiratory ailments; namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) ,* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the iung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the two ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently difficult to determine whether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,88.5 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals for whom COPD was a contributory cause of death. During the past two decades, a major increase has taken place in the mortality from COPD in the United States. In 1949. the death rate from COPD was 2.1 per lO!J,OOO resident population, while in 1960 it was 6.0 (zz~), and in 1967, 12.9 (221). Although * Because mortality from bronchial asthma does not appear to be related to Cigarette smoking. the term COPD will be used henceforth to refer only to chronic bronchitis and Dulmonam emphysema. Exacerbation of preexisting bronchial asthma has been observed among Cigarette smokers, Further elaboration ,,f this question may be found in a pretiow l'ublic Health Service Review CZ.M). 139 much of this rise is probab y due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gene erally accepted as reflecting a real increase in disease. Similar in- creases over the past `LO to N years have also been observed in Canada (7) and in Israel (54). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD, may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac- curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of hron- chitis and emphysema have differed in the past from those used in the United States. The mortality from and prevalence of COPD is probably under- estimated. In a study of death certificates, Moriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, Mitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe clinical airway obstruction. Hepper, et al. (I 10) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (10) evaluated clinical symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient wa:; free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. Clinicians have long observed that the majority of their patients suffering from COPD lvere cigarette smokers (2, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical obsel-vation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 140 cough, cough with production of phlegm, and dyspnea. By a variety of pulmonary function tests, smokers were shown to have dimin- ished function as compared to nonsmokers and also to have a steeper slope of the expected decline of function with age. Tests of ventilation/perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significantly more changes characteristic of emphysema than nqnsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers. Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional to the total dosage of cig- arette smoke inhaled. In vivo and in v&-o studies have shown that whole cigarette smoke, or certain fractions thereof, inhibit ciliary activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important cause of COPD in man. EPIDEMIOLOGICAL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of POP- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and COPD mortal- ity are presented in table 1. The majority of the studies separate 141 TABLD L-Chronic obstructive bronchopulmonary disease mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Nummyd Data Follow-up Number Cigarettes/day Chronic country, collection Y=WS of deaths pipes. cigars bronchitis Emphysema Other reference population Hammond and Horn, 1958. U.S.A. (1oK). - Doll and Hill 1964 Great Britain (70). 187,783 white Questionnaire males in 9 and follow-up states 50-69 of death year8 of age. certificate. 3% Approximately Questionnaire 41,000 male and follow-up British of death physicians. certificate. 10 338 Cigarettes SM ,308 NS . . . .I.00 (30) NS . 30 20 . .3.64 (40) All . .2.85(231) Pipes NS .l.OO (30) SM . .1.77 (23) Cigars NS .I.00 (30) SM . . . . 1.29 (18) 292 Cigarette8 Chronic NS . .l.OO bsonchitia 1-14 .6.80 111 16-24 .12.80 Other >25 .21.20 181 All . . .11x0 Pipes and Cigars SM _. .3.00 Cigarettes NS _. .l.OO 1-14 .0.66 15-24 .1.08 >26 .0.63 AU .0.81 Pipes and Cigars SM . . ...0.78 TABLE l.-Chronic obstvuctive broncl~opulvvlov~f~~~ disease mortality ratios (cont.) Author, Year, country, reference NutTmyoyd population Data collection (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers Follow-UP Number Cigarettes/day Chronic Years of deaths pipes, cignrs bronchitis PROSPECTIVE STUDIES Emphysema Other Best, Approximately Questionnaire 6 124 Cigarettes Cigarcttcs 1966. 78,000 male and follow-up NS . ..l.OO NS .l.OO Canada Canadian of death 20 t. .14.63(12) >20 ..t. 6.93 (7) All .11.42(78) All .._.. 5.X5(37) Pipe8 Pipe8 SM ,,..,, 2.11 (5) SM .._._. 0.75 (2) Cigars Cignra SM .3.57 (1) SM . ..3.33 (1) Hammond, 440,658 males Interviews by 4 1966, 662,671 ACS volun- U.S.A. females teers. (103). 35-84 years of age in 25 states. Kahn. U.S. male Questionnaire 8 `h 1966, veterans and 1J.S.A. 2.265,674 follow-up (132). person years. of death certificate. 389 SM . . . ...369 NS . . . ...20 nfnks NS .l.OO (20) SM (age 45-64) .6.55(194) SM (age 65-79) .11.41(175) Bronchitis NS .l.OO (31) SM .,...., 64 AllSM . ..6.49(348) NS .13 Current cigs- Emphgsema retk .10.08(229) SM . . . ...284 Pipes NS ..,,.. 18 SM .2.36 (9) Cigars SM _. .0.79 (5) Cursrllt ciga- Current ciga- rcttcn o,dy rrttl27 onlg NS .1.00(13) NS .l.OO (18) l-9 . ..3.63 (5) l-9 .5.33 (10) lo-20 .4.61(22) 10-20 .14.04 (93) 21-39 .4.67(12) 21-39 _. .17.04 (62) >39 . . ...8.31 (4) >39 .25.34 (17) All . ..4.49(43) All .14.17(186) f TABLE l.-Chwnic obstructive bronchopdmonary disease mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers Author. Year, country. reference Num;ebb"f"d population Data FOllOWUP collection Years Number of deaths Cigarettes/ day pipes, cigars Chronic bronchitis Emphysema Other PROSPECTIVE STUDY Weir and 68,163 males Questionnaire S-8 58 Cigarettes Dunn. in various and NS ._ `1.00 1970, occuPstions follow-up &lO . .8.18 U.S.A. in California. of death 220 . . ...11.80 .._. I.zZ.2,. certlticate. ,>30 .20.86 Ail .12.33 RETROSPECTIVE STUDY -- Wicken, 1,189 males. Personal inter- 1,188 obtained Cigarettes 1966, view with retrospec- odu NOtih- relatives of tively. NS . ..1.00(124) em individuals SM . . .1,064 I-10 .2.95(246) Ireland listed on NS ,124 11-22 . . .3.43(300) 017). death >23 . .4.44(168) register. Mixed SM . . ,156 (62) Pipes 07 cigars SM . . . . ..1.84(289) 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. ? NS includes pipe and cigar smokers; SM includes e-x-smokers. the findings for chronic bronchitis and emphysema. Such specific grouping of the mortality data should be viewed with some reser- vations in the light of the difficulties mentioned above in dis- tinguishing the two diseases clinically. The dose relationship of increased mortality ratios with increased consumption of cigarettes is indicated by the results of all the studies which present rates for different levels of smoking. Kahn (132)) for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of .5.33 while those smoking over 39 per day incurred one of 2.5.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dying from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1) . The effect of stopping smoking on COPD mortality is reflected in t.he results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers' group of many who quit for reasons of ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (1.32) aIso noted that the age-specific mortality ratios for ex-smokers were lower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their hea1t.h rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 2~1 percent reduction in bronchitis mortality between 1953-.57 and 1961-65, as compared with a reduction of only 4 percent in all men of t.he same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (85). COPD MORBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) amon, rr smokers and nonsmokers. These studies are outlined in table AZ. Their results indicate that the cigarette 145 smoker is much more 1ikel.v to suffer from respiratory symptoms such as cough, sputum prc'duction, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also shows that pipe and cig.lr smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Mitchell, et al, (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers. Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 5 percent of the continuing smokers did so. Wynder, et al. (237) followed 224 ex-smokers of cigarettes and noted that `7'7 percent reported cessation of persistent cough and an additional 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATORY FUNCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various groups. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table A4. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventila.tion) , expiratory flow rates, forced expiratory volume, and vital capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (117) conducted a nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average decline in FEV,,,;, was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-relationship with increasing amounts of cigarettes smoked. 146 The data contained in table A3 provide two different kinds of information. The majority of the studies were conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz, et al. (140) and Rankin, et al. (189) have shown that pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic college-age group and by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of young asymptomatic physicians and medical students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may be relatively under or overperfused and that, likewise, segments may be under or overventilated. Anthonisen, et al. (IO) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 20 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob- struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance which was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 24 asymptomatic smokers and non- smokers. They found that standard ventilatory tests and lung vol.- umes were normal in both the smoking and nonsmoking groups. However, the arterial ~0' measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 147 nonsmokers (more so in the sllpine than in the erect position). The increase in alveolar-arterial O2 gradients was greater for heavy than for light smokers. The authors concluded that maldistribution of ventilation and perfusion accounted for the observed hypoxemia. They also felt that this mild diffuse airway disease among asympto.. matic smokers is physiologically significant mainly because of in- volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. A similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the more severe alterations found in the long-term smokers. Although of concern in the consideration of COPD, such dis- turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hypoxemia (219). The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arterial exchange as well as on oxygen debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced hypoxemic influences, A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function, Table 5 presents those experjments which deal with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are : diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters showed improvement within 3 to 4 weeks after cessation of smoking. GENE'TIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogenesis of COPD. Earlier studies (127, 147') had noted the existence of kindreds with high incidences of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (1.47') also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (148) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, including forced expiratory volume and residual volume total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 148 TABLE 5.-Cessation of smoh-ing and hman pulmonary function' Author, Ye=-. country, reference Krumholz et al., 1965, U.S.A. (141). 10 physicians 25-33 years of age. Wilhelmsen, 16 smokers. 1967, (43.7 mean U.S.A. e-t`). (130). Following 3 weeks abstinence RoUowing 0 wrcks abstincncc (6 subjects only)t t All subjects were >5 pack Lung volumes--no significant change. Lung volumes: per year smokers. Peak expiratow flow rate-increase Inspiratow reserve volume-increase (g40 cigarettes/day . . . . . . . . . 2.3 Megahed 60 male patients Mucous okmad hypertrophy et al., with chronic Percent 1967. bronchitis under- NS . . . . . . 29 (2/7) Egypt going bronchial SY . . . . . . 77 (33/43) (P10 cigarettes/day (66) _, 1.3 1.4 31.5 45.3 I Nume~~~us eh caeriments. detailing rhangcs iu bronchial epithelium are dctnilcd t~bul~~rl~ in tha C:~ncr~~ ohnrltvr 2.0s 4.4 X.1 20.5 __- EXPERIMENTAL STUDIES ANIMAL STUDIES A number of investigators have studied the effect of the inha]a- tion of cigarette smoke on the macroscopic and microscopic strut- ture of the tracheobronchial tree and pulmonary parenchyma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table Al6 of the cancer chap- ter. Studies more directly concerned with the pathology of COpD are listed in table 9. They show that cigarette smoke exposure is associated with changes similar to those found in humans with COPD, i.e., bronchitis, parenchymal disruption, alveolar septal rupture, alveolar space dilatation, and the loss of cilia and ciliated cells in the bronchial mucosa. The investigations of Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs who inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyma with increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed: In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 420 days or more of exposure, the number of cell layers in the bronchial epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present ; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. Mitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs were exposed to varying doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were "smoked" for 8'75 days, or approxi- mately 29 months. The animals which died during the experiment and the animals sacrificed after day 875 were examined for pul- monary parenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. 158 TARLE 9.-Experiments concerning the effect of the inhalation of cigarette smoke ?Lpon the tmchco-bronchial tree and pulmonary parenchyma of animals' (Actual number of animals shown in parentheses) Author, A. Type of Yes=. country, A::Y exposure B. Duration Results reference strain C. Material Leuchten~ 603 CF1 A. Inhalation. berger, female mice. B. Up to 8 ciga- Number et al., 1960, U.S.A. (1.w). r&es/day for "Pto2yeaI-s. C. Cigarette smoke. Number of mica showing specified chnngca Number Months c?zposu+e 0 l-3 4-R 9-23 l-23 Of of NO Mild cigarettes mice ehangr bronchitis 0 150 146 2 10&200 36 20 9 260-600 36 19 10 600-1600 34 19 7 25-1526 151 xx 33 Severe bronchitis with atyptin 2 (no atypism) 7 7 8 30 Holland et al.. 1963, (121). 60 rabbits. A. Inhalation. R. Up to 20 ciga- rettes/day for 2-5. C. "Normal ciga- rette smoke". N0tTld Controls Exposed Cytology of tmchcobrouchial murosa Focal hypcrplnaia (30)21/30 6/30 (30) 7/30 10130 Gcnerdired hyyerplaaia 3/30 I)/30 Hernander Adult Grey- A. Inhalation. et al.. hound B. Twice daily/ I!lf,f, doas. 5 per week. U.S.A. C. Cigarette (111). smoke. Number of sections I. Controls (8)112 II. All exposed (15) 205 III. Exposed l year CR)107 Mm )s number of mo,zths 10.50 4.60 14.74 Mmn pnrrnchymal Groups disruption/dog W?IlpilTHl P-U&O O.il.50 I-111 insignificnnt 0.!)58:1 II-I insignificant 0.6421 III-IV P <0.05 I.2350 IV-I P <0.02 TABLE 9.--Experiments concerning the effect of the inhalation of ciga,rctte smoke U~O?L tltc tmcheo-l~roncl~ial twc and pulmonary parcncll,z/ttia of animals' (cont.) (Actual number of nnimnls shown in parentheses) huerbach et al.. 1967, U.S.A. (f&16). Results ~- Beagle dogs. A. Active inhalation Controls (lo)-No evidence of pulmonnrv fibrosis or s&al rupture. via tracheostomy. Exposed (lo)-Early (sacrificed) : B. Up to 12 cigRrcttes 1. Alveolar space dilatarion. per day for up 2. I'ad-like attachments to alveolar septa. to 423 days. Medium czpo.wm: Septal wall thickening. C. Cigarette smoke. Latest crposarc: 1. Focal subpleuriil pulmonary fibrosis. 2. Ruptured alveolar septa. 3. Granrtlomata. FrWX& et al.. 1968. U.S.A. (88). Beagle dogs. A, Active inhalation Electron microscopic results: via tracheostomy. After 44 days - Increased number of goblet cells. B. Up to 12 ciaarettes Decreased number of cilia on surface lining cells. per dny for "P After 420 dsys- Increased number of epithelial cell layers. to 423 days. Loss of ciliated columnnr cells. C. Cigarette smoke. Frequent interruptions in basement membrane. lNumerous experiments detailing changes in bronchial epithelium aredetailed tabularly in the Cancer Chapter 80 - 20 12.9 5.7 '. 0 GROUP N: GROUP F: GROUP L: GROUP Ii: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% as many cigmttes) as Group H FIGURE l.-Percent of lung sections with grade IV or V fibrosis. SOURCES: Hammond, et al. (104). Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table AlO. It is clear that chronic exposure to low levels of NO, is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 1.97) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplasia and macrophage infiltration. Similarly, a dose-related increase in lung hydi*oxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 161 98.6 80 - 60 - 24.3 GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (% ss msny cigarettes) ss Group H FIGURE 2.-Percent of lung sections with grade II or III emphysema. SOURCES Hammond, et al. (10.4). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18,1g, 20,21,22,179,180,199, 200,201,202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar to those observed after cigarette smoke inhalation. The bronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory units. 162 Similar experiments in dogs showed that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment with atropine. As a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Most recently, Aviado and his colleagues (20, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as well as to partial tracheal ligation. In 10 rats exposed to cigarette smoke twice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted. Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when compared with animals who underwent only tracheal ligation. STUDIES IN HUMANS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- pliance. Chapman (48) also observed decreases in pulmonary dif- fusing capacity and arterial O? tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (1.~1) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 5 normal young males. Prior smoking of a cigarette in the subject's normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and Williams (9) studied the acute effect of cigarette smoke inhaIation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly liable to these changes. 163 Finally, Robertson, et al. (194) studied the effect of unfiltered and filtered cigarette smoke and cigar smoke upon bronchial re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing he retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers. STUDIES CONCERNING PULMONARY CLEARANCE Overa. Clecirance The ability of the lung to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in table A13. LaBelle, et al. (115) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (125) obtained similar results in rabbits. In a relat.ed study, Albert, et al. (2) studied the bronchial clear- ance times of 9 nonsmokers and 13 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to sulfur dioxide or cigarette smoke. . . . Numerous experiments have shown that cigarette smoke or cer- tain constit.uents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium it/ ~`i?*o and it) ~it,,o in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 164 Ciliary activity has been shown to be affected by particulate matte1 as well as by the gas phase components of cigarette smoke. The rel- ative importance of these two large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 61) consider the particulate phase to be of greater importance while Battista and Kensler (28, 29) con- clude that gas phase components are more important in the induc- tion of ciliastasis. Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (131) studied the effect of the direct exposure of cigarette smoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be toxic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. Phugocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and Masin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells., and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit alveolar macro- phages to clear cultures of S. a?ATeus. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. bovis to cigar- ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly re- versible and was due mainly to gas phase components. Myrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO,. Roque and Pickren (195) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers, They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activity was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought t.o 165 TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function Author, Y-u-, country. reference Bickerman and Barach, 1954, U.S.A. (31). Number and type of A. Method = B. Material 1 C. Duration of RemIta population I. 66 male and 25 female patients with chronic nontuberculous respiratory disenws ( swrage age 50). II. 20 male and 7 female normal suh- jects (average age20). smoking A. Pulmonary function. B. 3 cigarettes. C. 30 minutes. Vital capacity ( VC) I. lo/91 decrease. II. No significant change. Ma&nd breathing capacity B/91 patients showed IO/91 deerease. VC incresse due to No significant change. clearance of secre- tions. All mild or moderate smokers. Eich, et al.. 1957. U.S.A. (76). I. 31 patients with obstructive PUb~OIWY emphysema. II. 14 normal subjects. III. 6 patients with respiratory complaints. All habitual smokers. A. Esophageal balloon technique to mecL9ure pulmonary compliance and resistance. B. 1 cigarette. C. Undefined. Mean airway resistance I. Statiaticslly significant increase. II. No change. III. No change. Mean aimmu compIiance No change. No change. No change. TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulnaonam function (cont.) Author, Ye*=, cou"trY, reference Attinger et al., 1958, U.S.A. (19). Number and type of population I. 20 normal subjects (10 Sm. 10NS). II. 34 patients with various diseases; 9 rheumatic heart diseases, 8 pul- mOn*rY mlPhY- sema, 7 asthma, 5 pulmo"aly fibrosis, 5 undefined. A. Method 1 B. Material 1 C. Duration of smoking A. Esophagal balloon I. No change. Ftesulta CO"l"E"ts No change. technique to meas"re pulmonsry compliance and resistance. B. l-4 cigarettes. II. Expiratory resistance rose No change. C. 10 minute interval signiticantly only among between patients with cigarettes. emphysema. Motley and 125 males and A. Pulmonary 41 smokers Pulmomrg~ compliance Various groups of KUZ"l*", 16 females function. (8 "ornlals, normals and cardio- 1968. (24-70 years of I%. 2 cigarettes. 33 patients Significant decrease after pulmonary patients U.S.A. age-"ormals C Undefined. with cardio- smoking. showed little or no (f74). and patients). pUl"lO"*lY change in arterial disease). p02 during exercise and at rest follow- ing cigarette smoke inhalation. .-. Nadel and I. 22 patients with A. Body plethy- Airwev cmdvctance/thoracic gas vdumC Nicotine hitsrtrate CO"VO& cardiopulmonary smography. I. 18/22 significant decrease (inhibited by pretreatment aerosol evoked no 1961, disease--all B. 15puffs. with isoproterenol aerosol). change. U.S.A. smokers. C. 5 minutes. II. 31/36 significant decrease (inhibited by pretreatment with (176). II. 36 normals (21 isopmtercnol aerosol). smokers, 16 nonsmokers). Author, war, countlY, reference Number and type of population A. Method 1 B. Material ' C D;a&a$";gof - -.. Results Comments Sim""ss"", 1962, Sweden. (207). Zll"ld et al., 1963. England, (240). I. 9 male and 7 female normals (most smokers). II. 15 male nnd 1 female pulmonary disease patients (most smokers). ~ I. 6 male and G female nonsmokers. II. 6 male and 6 female smokers (18-32 years of age.) A. Pulmonary function. B. l-2 cigarettes. C 5-6 minutes PCP cigarette. MmnFEVl o (immediately ejtcr) I. Significant decrease. II. Significant decrease. McanFEVl o (45 minutes letcr) No significant decrease. Significant decrcnse. No siunifirnnt changes ohserved in FEV/FVC. A. Body plethy- smography. B. 1 cigarette. C. Undefined. Airway resistance I. Significant increase. II. Significant increase. 1965. Ireland (48). __- McDermott and Collins, 1965, Wales (160). I. 12 normal v"lu"teers (all smokem). 11. G patients with chronic "on- specific lung disease. I. 32 normals. II. 2X with chronic bronchitis (All ciga- rette smokers 35-GO years of age.) A. Pulmonary function Arterial blood studies. B. 1 cigarette. C. Undetined. I. All showed a decrease in diffusing capacity. II. 4/6-significant decrease in arterial O2 tension. No change in vital capacity or FEV. A. Body plethy- smography. B. Cigarette. C. Undefined. Mean airway resiatancc Light smokers showed I. Significant increase. greater changes than II. Significant increase. heavy smokers. Miller and 10 normal SProule, cigarette 1966, smokers U.S.A. (40 years (1GG). ofage). A. Esophaeeal ballwn technique. B. 1 cigarette. C. One inhalation Pc3-Y ao-FO seconds. FEvo.5 No significant change Dynamic compliance Significant decrease. Inspiretory and erp,iratory rceistmca Significant increase Sterling. 11 normal adults 1967. (E smnkers, England 3 nonsmokers) (219). Chiang and 7 male normal W*nEC. nonsmokers 1970. (L-43 years Formosa of age). (51). A. Body plethy- smography. B. 15 inhalations. C. 5 minutes. Airway rcsiatancc Significant increase (Return to normal in 30 minutes). A. Pulmonary function Nitrogetr roaskcwt L1my clcnrancc Aleeolar dilution All luna volumes, Nitrogen washout. B. 2 cigarettes. C. Undefined. tima Significant increase. A. Body plethy- smography. B. 1 cigarette. C. Undefined. Guvatt 110 subjects; et al.. 50X smoked 1970. between meas- England ures 202 (lml). did not fimoke. - ' All the experiments listed concern studies of sulmonary function be- fore and after smoking the epecified number of cigarettes (unless other- wise specified). illll,.L! Significnnt increase. factor excrpt for residual Significant \-olumr showed no decrense. significant change. No significant change in any of the flow rates. Brunckoconstrictio?~ On the avernge. non- Significant increase with smoking. smokers and es-smokers sh<,wed tnonchodilation and nm<,kers showed I,~~rnch~~constriction. Thr authors postulate that the result among nonsmokers is due to the> rclcnsc of ndrenal hoymonrs in these sub- pxts. ~-_- __ TABLE 12.--Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance Author, Yea=. countru, reference Subjects Method RBUkS Comments Laurenzi Swiss-Webster Mice exposed to Significant increase in S. aureu8 retention in mice expceed to: et al.. male mice. aerosol of s. au7euuB (a) hypoxia-retention ratio 2.5 (10 percent Oa). 1963, and sacrificed at (b) cigarette smoke-retention ratio 4.5. U.S.A. intervals following (149). exposure to various stimuli. LaBelle et al.. 1966, U.S.A. (145). Albino female rabbits. Silver iodide or colloidal gold intratrachesllu. 17-30 hours of exposure to cigarette smoke caused no change in pulmonary clearance as compared with controls breathing room air. Bair and Sprague-Dawley Radioactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic Dilley, female rats. exposure to cigarette smoke (up to 18-20 cigarettes/? hour day/5 day week 1967. male beagle dogs. Radioactive aerosol. for UP to 420 days) had no observable effects. The authors noted, however, U.S.A. that normal clearance rates were too low to reflect anything but complete (2.9). cessation. Albert et al., 1969. U.S.A. (9). -- 36 subjects undergoing 117 experiments. so perct?nt 90 percent t Approximate values. clearance clearance None of 9 nonsmokers Radioactive tagged Number of Average time time had 60 percent times FeOZ particles eubjects age (minutes) (minutes ) over 200 minutes or measured with Nonsmokers . 9 28 88 367 90 percent times over Scintillation All smokers . . . . . . 14 33 172 t496 600 minutes while counter. 20-29 cigarettes/day . . . . 7 29 191 ts19 6/14 smokers exceeded 30-40 cigarettes/day I 36 163 t414 both these limits. Uranium miners . . 3 62 310 580 Cigar and pipe smokers 4 46 81 316 Emphysema patiats . 2 66 330 676 TABLE 12.-Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.) Author, year. country, reference Subjects Method Results Commenta Albert et al., 1969, U.S.A. (8). Holma, 1969, U.S.A. (125). Donkeys exposed to cigarette smoke by nasal cstheter. Rsdiosetive tagged Average Trachael transit Those donkeys exposed Fe02 particles number time to the greatest measured with cigarettes in Perrent clearance Halftime clearance amount of smoke Scintillation .%hour period Control Cigarsttc Control Cigarette Control Cigarette showed residual counter. 1X-24 58 69 1.2 1.9 0.6 1.2 impairment of 36 58 64 1.0 3.4 0.4 6.8 clearance for et least 2 months after acute exposure. Rabbits (anesthetized). C+* monodisperse Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 nuffs/X minutes) caused polystyrene a "significant" increase in lung retention 10 minutes following cessation of aerosol. exposure. originate in tobacco smoke. The authors suggested that the tobacco smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et al. (187) observed that the macrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af- fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phospholipids and mucopolysaccharides which are present in the alveolar lining. Normal pulmonary func- tion is influenced and partly determined by the integrity of this system (203). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated. Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table A14. Exposure of rat and dog lung extracts to cigarette smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165, 2.24). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) in a recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTHER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonar~ disease. Table Al.5 presents a summary of these studies. Lowe (1.57) observed an excess of smokers among `i0.5 tuberculosis patients, but Brown and Campbell (43) in a similar study found that the difference was not present lvhen the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (lOS,181, 183) have reported increased 172 -ates of respiratory illnesses among smokers. Finklea, et al. (83) studied a male college population (prospectively) during the 1968-69 influenza epidemic. They found that smokers of all amounts experienced more clinical illness than did nonsmokers and that this relation was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (220), involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. Male cigarette smokers reported 22 percent more cases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211). Mice were challenged with Klebsiellu pneumoniae or Diplococcus pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke exhibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortality, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (7'5). These investigators exposed squirrel monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klebsiella pneumoniae as demon- strated by increased mortality and reduced lung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p.m. was fatal to all monkeys within three days. Infected controls showed symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased SUS- ceptibility to respiratory disease noted in smokers is presently undefined. 173 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera, tive pulmonary complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop bran. chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table A16). Wiklander and Norlin (229) examined the incidence of post- operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary compli- cations would be at their maximum. These authors found no sig. nificant differences between the frequency of complications in smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported. Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total sample, 66.7 percent developed pulmonary complications during the first postoperative week. All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers. When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for up to four days preoperatively had no apparent effect on the incidence of complications. Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter's use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (178) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, Per- sisting into the second postoperative day (table A17). 174 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUMMARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 3. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. HOW- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- 175 teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pulmo- nary complications more frequently than nonsmokers. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) ABBOTT, 0. A., HOPKINS, W. A., VAN FLEIT, W. E., ROBINSON, J. S. A new approach to pulmonary emphysema. Thorax 8: 116-132, 1953. ALBERT, R. E., LIPPMANN, M., BRISCOE, W. The characteristics of bran- chial clearance in humans and the effects of cigarette smoking. Archives of Environmental Health 18 (5) : `738-755, May 1969. ALBERT, R. E., SPIEGELMAN, J. R., SHATSKY, S., LIPPMANN, M. 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X conlIJ:~ri<~m l)etwt:e!l c~?;~l~i ",II ::I- genologic, functional and morljhologic criteria in chronic l~~ol;cl~:!ir. emphysema, asthma and hronc*!liectu;;is. RIedicil:t~ -1!1 (2 I : ,K 1 :. ! -I - > March 1970. (218) TOKUHATA, G. K., DESSAUER, I'., PF.P;DE~60 ytzars of age. Other NS Il.0 SM ._ _. 6.1 FCVfdCS NS . . . 0.0 SM ._ 6.0 Chronic bronchitis NS _. 16.6 (151) Cigarettes 29.7 (719) l- 9 23.4 (235) lo-19 ._ 31.2 (369) >20 33.7 (175) Pipe 18.5 (340) _______.. Flirk 222 mnle NS .lO.O (61) NS ..25.0 (49) NS 30.0 (4'7) and patients not SM u55.0 (167) SM ..65.0 (156) SM __ 60.0(138) Pato". suffering from 1969, overt cardio- U.S.A. pulmonary (86). discnse, 2&QO years of age. Higgins 716 males in Cough and sputum Chronic bronchitiv et al., various SM __ 7.1 (86) NS 9.4 NS . 7.1 SM 14.3 1969, occupations NS .36.8 (676) SM .24.9 SM 20.2 NS ._ 3.5 England `26-64 years (126). of age. - TABLE A2.-Smoking and chronic obstructive pulmonary disease sy,,zptonzs'-perce,at prccalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author. Year, country, reference Number and type of population Cough Sputum production Breathlessness or dyspnea Chest illnesses Higgins, 393 males in 1959, various England occupations (113). 56-64 years of age. -_ LiebeschuetzJ47 male 1959, soldiers England 20-30 years (156). of age. Other COlIllWSt3 Cough and suutam Chronic bronchitis Chronic NS . . . 6.1 (33) NS _. 18.2 NS _. 3.0 NS 0.0 bronchitis 1-14 g/day 9.7 (173) 1-14 g./day 30.1 l-14 g/day 23.7 1-14 kc/day 13.9 defined as >15 . . . . .42.3 (142) >15. ,. ., ,, ,. 33.8 >I5 .,2x.0 >16 . . . . 17.6 persistent sputum and at least I chest illness in past 3 years. Tobacco gram equivalents ELlY: 1 cigarette = 1 g1'Flm, 1 cigar = 2-5 grams, 1 pipe = lb-25 grams. NS ....... 0.0 (52) SM ....... 13.0 (83) Asbford 4,014 male Rcspiratorg nymntoma Respiratory et al., coal workers. NS . . . . 10.3 (6'77) symptoms- 1961, EX 19.5 (123) "bronchitis England Cigarettes 21.1 (1,504) and/or (11). Pipeonly 36.1 (202) asthma". No Cigarettes dose rcln- and pipe 37.1 (90) tionship : All SM 21.7 (3.214) found. TABLE AZ.-Smoking and chronic obstructive pulmonary disease syw~ptoms'---percent prevalence (Cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author. war. Number and Breathlessness cou"trY, type of Cough Sputum production or dyspnes Chest illnesses Other CO"l"lk?"tS reference population Bower, 96 male and NS ._ 4.1 (49) NS . .20.4 NS . . . f34.7 Chest illneas- 1961, 77 female SM .27.6 (76) SM . . . .34.2 SM .38.2 chest colds U.S.A. hank employees Pipe, cigar (13) Pipe, cigar 16.4 Pipe, cigar during each (41). 40-70 years 63.9 of last 2 of age. winters. Fletcher and 363 male London NS (30) NS . . . . . 8.7 NS NS . . . 4.3 Tinker, transport I-14 B./day 16.6 (166) 1-14 g/day .29.9 l-14 g/day 8.2 1-14 g/day 1961, employees >16 . . .27.3 (116) >16 . .36.9 >16 . . 8.6 8.2 England 40-60 years >16 . 10.7 (35). of lige. Read 170 male and and 132 female NS Selby. individuals SM 1961, interviewed EX Australia in an ou& (291). patient NS clinic (not SM all patients). Male.9 4.4 . . ...23.1 .21.2 Ft?Wl&8 4.9 _. 18.6 BEJChWn 1,461 male NS .10.2 (263) et al., light SM .23.3(1.198) 1962, industry 60 . . . . .60.0 (24) NS .......... 11.0 SM .......... 30.4 60 ....... .62.0 NS .......... 9.8 SM ......... .14.6 fiO ....... .29.0 - `I'ABLE AZ.--Smoking and chronic obstructive pulmonary disease synlptol)ls'--pPrcent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SBl = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, Year, country, Number and type of Cough Sputum production Breathlessness or dyspnea Chest illnesses Other reference population Boucot 6,137 males NS . . . . 13.0 (806) et al., 1962, enrolling SM .31.6(6,951) U.S.A. in pulmonary (36). neoplasm project. Ferris 90 male and Chrmic Nonspecific et al., 71 female Respiratory Diwaee 1962, flax mill- M&8 Ft??S&8 U.S.A. workers. NS .lS.O(ZO) 10.0(60) (82). EX 12.6(16) l-20 .27.3(22) . >20 .53.1(32) 60.0 (4) Ferris 642 male and Chronic bronchitis Age-specific and 625 female M&8 rE&?s. Anderson, residents of NS . . 13.8 (126) 1962. New Hampshire EX Il.9 (71) U.S.A. town chosen Cigarettes 40.3 (340) (81). by random l-10 ..29.8 sampling of 11-20 . .34.2 -XllS"S. 21-30 . .42.3 31-40 ..61.1 >41 . .7&S FeWde8 NS .I..... 9.4 (378) EX . . ulO.8 ($7) Cigarettes 19.8 (208) l-10 .13.1 11-20 .22.2 21-30 . 31-40 . . .27.3 >41 . . . . : H TABLE A2.-b'~~~ol;i~~g and chronic obstructive pulmonar?y disease s?l,,lplottls'-pe~cerLt ~~w~~c~lencc (cont.) (Numbers in parentheses represent total number of irldividuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, ye*=, country, reference Number and type of population Cough Sputum production Breathlessness or dyspnea Chest illnesses Other Comme"ts Goldsmith 3,381 active Revpiratory et al., or retired conditions 1962, longshoremen. NS __ 31.4 (744) U.S.A. Moderate/ heavy (95). smokers 43.0 (1.238) coates 1.342 mole and Cough and chronic phlegm Current et al.. 242 female NS ..11.2 (747) NS 14.7 NS ,. 4.0 smoking 1965. Detroit post 1-14 .12.7 (266) (not aig.) 1-14 28.2(~<0.001) l-14 5.3 (not sig.) data. U.S.A. offirc 15-24 .2'7.6 (402) (p25 . 36.4 (170) (p25 . .34.1(~<0.001) >25 ._ _. 25.3(p25 __ .42.4 (85) >26 .42.4 Fern&s FCT7L&# NS ._ .__ 4.6 (709) EX .13.3 (30) 1;:: .::I.:,":: (:67: >25 . (1) 15-24 b-25 . . .57.0 Males NS _. __ 16.6 NS 29.2 EX ._ .24.8 1-14 EX .26.0 15-24 . . . . .33.3 .26.2 >25 1-14 . .31.8 Females . .14.3 16-24 >25 . ..14.0 Chronic bronchitis Males NS 5.7 EX _. 16.3 l-14 _. 38.0 15-24 . 41.4 >26 .40.0 FW%&8 NS 4.6 EX 13.3 1-14 10.4 15-251 `25 / .....57.0 Es-smokers represent those who have stopped smoking for "lore than 1 month. Dyspnea Grade II only. TABLE A2.-Smoking and chronic obstructive pzclmonary disense s?/,,rpto,t,s'-percent p~c~~vzlenw (cont.) (Numbers ia pnrentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX z Ex-smokers. Author, war, countiT, reference Number and type of population Cough Sputum production Breathlessness or dyspnea Chest illnesses Other Comments Wynder 315 male New York Citg et al., patients in NS .14.0 (44) 1965 New York City Pipe, cigar 33.0 (64) U.S.A. and 315 male Cigarettes: (298). patients in l-10 ..45.0 (44) California. 10-20 .46.0 (38) >20 . .67.0 (86) California NS . . ..22.0 (69) Pipe. cigar 30.0 (32) Cigarettes: l-10 ..45.0 (64) IO-20 . ..74.0 (91) >20 .14.0 (69) Fre0llr 1,055 randomly Cli~iical signs of et al., chosen males in bronchitis and 1966 Bordeaux 3s-70 rcspiratorU Fi-ZUlC.? years of age. insrcficienry (92). NS 25.4 (46) SM ._ 54.4 (4781 Haynes, 179 male Aacmgr number of Hea\ et al.. preparatory *cwrr rrugiratory StIlOkel- 1966 school illrfcsscs per 10 mure than U.S.A. students studcllts (adjuatcd 10 cign- (108). 14.-19 yeam for flw) rettes of nge. NS 0.36 per day. All smokers 2.30 Heavy SM 3.34 : TABLE A2.-Smoking and chronic obstructive pulmonary disease symptoms'-percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, Y-S-. country, reference N,y;F$nd population Cough Sputum production Breathlessness or dyspnea Chest illnesses Other Comments Dellsen 6.313 male Post& Poetal Postal Dyspnea et al.. and 7,291 NS . . . 7.0 (903) 13.1 19.8 represented 1967, female postal Pipe. cigar 12.4 (628) 17.4 24.8 by Grade II U.S.A. and transit Cigarettes Only. (68). workers. only . .27.0(2,687) 28.9 31.7 Transit Transit Transit NS . .,... 6.4(1,012) 9.6 11.7 Pipe, cigar 10.6 (`766) 14.1 14.2 Cigarettes only . . ..23.6(3.'746) 23.7 21.9 Higgins 926 white NS . . . . ...16.4 (162) NS........... 31.1 NS . . . . . . . 6.0 et al., male resi- SM . . . . ...47.2 (613) SM _. . . 46.2 SM . . . .10.7 1968, dents of EX .19.3 (144) EX ,285 EX . . . . . . . . ...16.8 U.S.A. Marion (128). County, West Virginia, 26-69 years of age. Holland 9,786 male M&8 F`DJZ&?~ Males Ft3lWlt% and and female NS . . . . . . 3.8(1,900) 3.2t3.137) 2.4 2.1 Elliott. school SM . . . . 6.3(1,098) 6.3 (664) 6.1 8.3 1968. children. EX . . . . . 2.9(1,782) 4.3(1,161) 39 4.2 England 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . ..9.9(142) 18.8 TAULE A2 .-Smoking and chronic obstmutive pulmonary disease sZ/,)lpto,,rs'-percent pw~vzlence (cont.) (Numbera in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other comments reference pORUlS2tiOZl Gandevia 762 male and M&8 Productive 1969 1,304 female NS . . .10.3 (234) cough upon Australia patients SM .61.3 (628) reuueat. (93). from 13 general Fslnd`S9 practices NS . . .10.6 (867) in all parts of SM . .31.4 (447) Australia. Rimington 41,729 male 1969 and 22,295 England female persons (199). participating in mass miniature radiography screening. Wilhelmsen 313 males et al., 6&64 years 1969, of age randomly Sweden S~lllDkd fro", (251). population of Gateborg. Age-adjusted total Cigarette prevalence of dosage chronic bronchitis gradient M&8 significant NS 5.1 (9.066) to P20 .20.6 Ft2?Mks NS _. 3.4(12.361) EX ., 3.8 (969) Pipe ._ 0.0 Cigarettes (8,986) 1.. 9 6.1 lo-19 10.6 >20 . .18.6 Chkric bronchitis NS ._ 1.0 (88) EX _. 3.0 (61) 1-14 grams/ day 6.0 (94) >16 . . ...17.0 (64) Author, Year, CountrY, reference Number and type of population Sputum production Breathlessness Chest illnesses or dyspnea .___- Lnmhert 9,975 malt I'( rxiatcjlt cough nnd phlegm and and female Alnlrs Reid, reslKmdrrs Rl ............... 27.7 27.7 16.8 Sriences Twin Pipe, ci!z?ar ............. 1.1 7.1 2.7 No ex-smoken included in C.mur, B analysis. The authors conclude that the data indicate R strong probability of a causal connection with smoking. Even Rwistty (of Group R: NS SM NS SM these symptoms. 9,oni) nvial- MZ .,, ., ., _. .._ 2.4 5.4 1.8 4.8 however, seem to be nhlr) nz ., 2.0 9.8 1.6 9.1 influenced by genetic factors. ' Data collected by either dirert interview, questionnaire, review of medical records and/or medical examination. TABLE A3.-Smoking and ventilatory function (Numbers in parcntheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. Author, ye==. country. reference Chivers, 1959, Enaland (52). Number and type of population MBC EFR FEV vc Miscellaneous COllllll~llt6 463 malr Height-in-inches iMean EFR employees Cigarettes/day: 64" 66" 68" 70" in liters of alkaline o-5 . t97(28) 91 (35) 108 (31) lOl(21) per minute. industry 6-20 . . .._ 89(50) xx (75) 101 (112) 109 (76) Regression plant. >20 ..t .._... 63 (6) 88.5 (9) 92.5 (9) 113(12) analysis of data revealed a significant re- lationship between smoking and de- creasing function. Higgins 773 males 25-94 55-a expressed et al., in various NS 145 (66) 101 (29) FEVO 75 as &an indirect 1959, occupations EX 143 (31) 89 (62) MBC. Enaland (25-34 and 1-14 gr*nls (116). 65-64 years .140(193) R7(167) of age). >lS mxms ,133 (89) 80(136) ___- Wilson 28 male RV/TLC et al., residents of NS 6.69 (14)NS . . . . . . 21.1 1960 Dallns, SM a4.44 (14)SM . . . . . 227.01 U.S.A. TtZX*?,, (232). former rural dwellers; matched for hody surface. a$?.?, and height. TABLE A3.-Smoking an,d ventilatorp function (cont.) (Numbers in parentheses represent total number of individusls in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. Author. Ye*=, Number and country, MBC reference type of EFR FEV oooulation vc Miscellaneous CO~llXtllts Ashford 4,014 male et al., gEsv* .o Data represent coal workers Age: SM results after 1961, at 3 Scottish <21-30 4.09(103) 3.96(280) correction for Scotland collieries. 21-30 .3.86(182) 3.77(665) (11). sitting height. 31-40 .3.44(138) 3.88(777) SM includes pipe 41-50 . 3.04 (110) 2.96 (756) smoker. 51-60 .2.71(102) 2.66(610) Data on ex-smoker >60 . ..2.38 (42) 2.21(237) not included. FEVl o found &&cant; lower for SM than NS. Fletcher 363 msle Mean mak EFR and London NS . . __. 670 (30) Tinker, transport 1-14 grams 637(166) 1961, employees. >I6 grams 6!28(116) England EX . . . . . 666 (61) (85). Franklin 213 male Hesvv smoker and factory J-vi .o "",o.;; y.;g Lowell. workers HWNY 2,670 3,611 Light `2,489 2,716 Light . . 3,703 (69) represents *n 1961, 40-60 years *2.666 `2.284 Heavy .`3,678(104) *mount equal to or more U.S.A. of age. than 30 pack (87). ye*lY. TABLE A3.-Smoking and wentilator~ function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. Author. Yew. Number and country, type of MBC reference population EFR FEV vc Miscellaneous Comments Balchum 1.451 male MMEFR et al.. employees NS 16.6 (38) 1962, in Pack/year: U.S.A. California 60 71.0 (24) 7.8(19) 8.0 6.0 12.0 24.0 26.0 40.0 45.0 62.0 Data for: MMEFR given as percent of individrmls with a value of <500 L/M; FEVl.O given as percent of individuals with value of <70 percent of expected. Goldsmith 3,311 active et al., or retired 1962, longshow- U.S.A. men. (95). MEFR NS . . . . . . ..313.63(260) Pipe, cigar 299.26 (126) EX . . 295.23(102) Cigarettes/day: crzo..... 309.73(144) 20-40 . 303.44(346) 240..... 307.63 (67) 2.80 2.84 2.89 2.91 2.90 Authors concluded that cigarette smoke WBS found to have B slight effect on pulmonary function. Martt. 73 healthy 1962. medic"1 per- DLCO Smokers defined U.S.A. sonnel with- NS . . . . . 33.10(30) asthosesmoki"g (162). out signifi- SM 20cigarettes' cant age 6-10 yesrs .328.20(10) day for varyi"a difference >lO years .624.90(25) periods. between smokers and nonsmokers. TABLE A3.-Smoking at&d uetitikLtOv:J function (cont.) (Numbers in parcntheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. .- Author. Ye=-, Number and c0untl-Y. type of MBC EFR FEV vc Miscellaneous Comme"ts reference population Revotskie 1,130 male FEV*.o Data presented et al.. and 1,813 M&8 FETMlt!S in terms of 1962, U.S.A. (192). Krumholz et al., 1964, U.S.A (140). female residents in Framing- ham par- ticipating in the pro- spcctive study. ~. 18 physicians 24-37 years of age. NS . . .0.98 (65) Cigarettes/day: l-10 .0.9? (SO) IO-29 .0.91(163) >30 .0.90 (81) - MEFR NS ........ 680 (9) SM ........ `690 (9) 0.98(255) 0.99 (92) 0.93(157) 0.91 (22) ratio of observed to predicted values. - .-___ ~__ Mean DL NS SM Rest . . . . . . ...36 231 Exercise: 2 minutes .SO 341 4 minutes .60 '43 Zwi 20 medical MMEFR 3 minutes Dost exercise 39 '35 Authors found et al., 1964, U.S.A. (241). studentsor NS _.. 187 (10) graduate SM. .`193 (10) physicians. 4.34 `6.09 6.77 15.53 a sipnifirant difference betwrcn SM and NS for RV `TLC, complianre. and non- elastic resistance. Coates 1,342 male et al., and 242 Age: FEV1.0 Timed VC' FEVl.O/VC NS >SS &/day NS >.25/day NS >25/ahl 1965, female post 40-44 `2.99(186) 2.85 (69) 3.89 3.85 30.77 0.74 U.S.A. office 46-49 52.95(170) 2.64 (42) 3.92 3.83 30.74 0.70 (53). employees 60-64 '2.75(116) 2.62 (22) 3.71 3.74 '0.74 0.70 >40years 66-69 '2.64 (64) 2.44 (18) 3.54 3.61 so.74 0.68 of sge. 60-64 '2.35 (53) 2.30 (8) 3.30 3.33 '0.72 0.70 .- qQ?o! z3 . -. : . . gii :cB p- `d oi 2',0 : *. . . : : : : : : . . . I "F% Zm TABLE A3.-Smoking ad vmtilatory function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. Author, Ye=-, Number and country, type of MBC reference population Edelman et al.. 1966, U.S.A. (79). 410 male community NS . . . . 164 ( 162 ) dwellers current ar- 103 cigarette years of smokers. . 6 161(118) *ge. EX . . . . . . . ., 167 (98, Pipe, cigar . 167 (47) EFR FEV vc Miscellaneous COllllll~!ltS 1.89 7.86 8.09 8.20 yp.0 12.64 2.80 2.91 vitai capacity 4.93 * 4.14 4.17 6.08 Ex-smokers of cigarettes only. Difference signifi- cant between NS and current cigarette smokers fit p26 . 8.30(160) 20-69 years of age. TABLE A3.-Smoking and wentilator~/ function (cont.) Author. (Numbers in parerltheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. year, Number and country. type of reference pornllation Sluis- 53Fwhite Cremrr malr and filrtory Sichel, workers 106X. over 35 South years of Africa REV. (208). MBC EFR FEV vc Miscellaneous J-44 45-54 >55 NY 553(106) 627(101) FEVf .o 444(27) ss-44 45-54 >a5 Crams/day: 3.70 3.22 2.76 l-14 557 (26) 619 (17) 410 (7) 3.64 3.31 2.24 15-24 532 (94) 446 (35) 401(13) 3.66 2.94 2.28 >?,S t52R (66) t494 (31) t380(10) 3.64 3.05 t2.12 Commrnts 1 cigarette: 1 gram. 1 ounce tobacco = 26 granls. 1 cigar = 2 to 5 grams. t Derived slopes found signifi- cantly different from 0. stanescu a7 malt bus F'EV. Nitrogen gradient et al.. drivers; ~ 1." _.. Yow1gcr Older YoNnger Older Younger Older 1963, 27 aged NS 4,470(14) 3,310(40) 6,125 4,290 1.63 2.49 Rumania 20-25, 60 SM 4,500(13) `3,200(20) `5.285 `4.290 11.47 5 3.77 (919). wed 40-60, all without respiratory symptoms. ___- - Dense" 5,287 male Fj:V. _-- FEV expressed as et al., 1969, U.S.A. (89). postal and 7,213 mnle transit workers in New York City. NS All cigarette <25 grams/day 225 awns/day Pos:~~ Wh itr. 3.29 (685) 3.11(2,340) 3.14 (1,292) 3.06 (1.038) Transit White 3.39 (620) 3.11(2.941) 3.15(1.929) 3.02(1,011) NS .................................... All cigarette ............................ <26 grams/dsy ......................... 225 grams/day ........................... - Non-zuhitc 3.05 (204) 2.94 (768) 2.96 (693) 2.93 (161) Now-white 3.08 (298) 2.99(1.041) 3.00 (891) 2.96 (149) standardized for specilied postal and transit workers at age 45 and at sitting height of 35 inches. Includes mixed smokers. TABLE A3.--Smoking md ventilatoq function (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. -- Author, war. count.lY. Nutn$r;nd MRC EFR FEV vc Miscellaneous COltllll~llts reference Dopulation _ FEvl.O FEV expressed as NS _. .`97.6 (12) percent of SM _. 78.4 (58) predicted value for age, sex, and height. Rankin 60 male et al., and 10 1969, female Australia patients (190). with chronic alcoholism 26-66 years of age. Wilhelmsen 313 male et al.. residents 1969, of Giiteburg Sweden 50-54 years (231). of age. __~ Lefcoe 310 male and physicians w<1nna- of London. rott, Ontario. 1970, Canada (151). PEFR VC 1963 values only NS ........................... 525(M) 4.83 EX ........................... 539(67) 3.69 4.71 1-14 grams/day ................ 521(94) 3.62 4.33 >15 grams/day ................ 492 (64) 3.39 4.56 MMFR NS . . 4.09 (88) Cigarette smokers. 3.64(101) EX 3.99 (61) Pipe, cigar 4.17 (33) MMFR has been standardized for age and height. TABLE A3.-Smoking and ventilatorp function (cont.) Author, Year, country, reference (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers. EX = Ex-smokers. FEV Miscellaneous Comments Lundman, 1966. SWNkll (159). 31 MZ and 62 DZ twin pairs selected from Swedish Twin-Pair Registry. FE"1.0 Significant diflerences between smoking discordant twin pairs found for: 1. Group A MZ males and females. N2 washout gradient Significant differences between smoking dis- cordant twin pairs found for: Group B DZ males. MZ = monozygotic. DZ = dizygotie. The author concludes that the degree of ventilation as measured by Nz washout was correlated with cigarette consumption. The FEVleO was significantly lower for smokers and there was a correlation with cigarette consumption. Explanation of analyses for respiratory symptom prevalence: Group A analysis-using each firstborn twin aa one group in an unmatched relationship to each secondhorn twin. Group B analysis-using each twin set as matched pair. All comparisons in Group A and B are between smoking-discor- dant pairs. 2. Group B DZ males. 3. Group A DZ males. 1 Not significant (difference or trend) 2 p- ,)mptoms could not be explained by social class differences. (b) No overail association noted betwpen productive cough and air pollution. Coolev and Reid, 1970. England (58). Lambert and Reid, 1970, England (146). 10.X87 children G-10 years of ape from eon- trasting urban and rural areas. Illnesses considered included chronic cough, past bronchitis, blocked nose. (a) Every geographic area showed a clear gradient of in- creasing illness prevalence with decreasing social class. ,b) Social classes I, II, and III showed no urban:rural gradient while IV and V showed a clear excess in fre- quency of chest illnesses among urban residents over rural residents. 8,975 males and (a 1 The trend of increasing prevalence of bronchitic sump- females tams from rural to urban respondents was not negated responding by adjustment for smoking differencff. to questionnaire ib) After adJuetme"t for age and smoking habits. male S"I`VCY. respondents manifested a clear correlation of persistent cough and phlegm prevalence with increasing air pollu- tion. Correlation was not BS striking in females. (c) Although the proportionate rise in symptom preva- lence increased with air pollution similarly in each smok- ing group, the absolute differences in morbidity risk in- creased with increased cigarette consumption, suggffting synergistic influences of cigarette smoking and air pollu- tion. (d) In the absence of cigarette smoking, the correlation between the prevalence of persistent cough and phlegm and air pollution was slight. ' See GIossary of Terms: Bronrhopulmonary table A4. 217 TABLE A~.--E'l,idr?lriological st1idie.S ConCW?Ling the rehtionship of OCCUpatiOnal ezposwrc and smoking to chronic obstructive bonchopul~~~onary disease Author, Ye=-, c0u"tl-Y. reference Number and type of population Results Higgins 135 males Miners showed increased symptom prevalence (breathless- et al. (84nonminers. ness, cough, sputum). 1956, 101 miners) Miners showed increased prevalence of chronic bronchitis. England without pneumo- Miners showed decreased MBC.' (119). eoniosis. Differences in smoking between the two groups did not a~- count for above differences. Phillips 1.274 males None of the-industrial environments were associated wiz et al.. factory emplowes an increased prevalence of chronic cough. 1956, (coke and Cigarette smoking and age were directly correlated with U.S.A. electrolytic increased prevalence of chronic cough. (18.5). process 1. Higgins 325 males 25-34 Miners as compared to workers in non-dusty occupations: et al., years of age and 25-34 years of age-significantly increased prevalence of 1959, 401 males 55-64 chronic bronchitis and MBC abnormalities. England years of age in X-64 years of age-less significantly increased prevalence (116). various "ccupa- of chronic bronchitis and MBC abnormalities than in tions. 25-34 years of age group. No smoking information available. Chivers, 1959, England (5%). 463 males in No significant differences in PEFR' between dusty and non-dusty and non-dusty Pl`""PS. dusty occupations Cigarette smoking (especially in those >40 years of age) (lime and soda was associated with decreased PEFR values. ash exposure). Higgins 300 male miners Miners showed increased prevalence of symptoms and de- and and 300 male creased MBC values which remained even after standard. Cochrane, nonminers 35-64 ization for smoking habits. 1961, yeal of age. Total dust exposure was not directly correlated with these England findings. (115). Wives of miners showed similar symptom and test change. as compared with wives of nonminers. Brinkman and Coates. 1962, U.S.A. (42). 1.31'7 males 40-65 years of age with various silica exposure histories. Increased silica exposure was associated with an increased prevalence of chmnic bronchitis. Highest prevalence of chronic bronchitis was noted in the non-exposed group; and this group was noted to have the highest number of smokers and highest consumption. Hyatt et al., 1964. U.S.A. (1.28). 261 male miners and ex-miners 4s55years of age. Increased history of underground work was associated with an increased broncbopulmonarv symptom prevalence and decreased pulmonary function values. The impairment of pulmonary function associated with underground work was separate from effect of smoking; but smoking and underground work did show additive effects. ElW""d et al., 1965. Ireland (77). 2,525 male and female flax workers over 35 years of age. Preparing room workers who manifested byssinosis symp- tams also showed an increased prevalence of chronic bronchitis independent of age or smoking when compared with non-preparing room workers. Female workers manifested a significant association be- tween byssinosis symptoms and smoking while msle work- ers did not. Sluis-Cremer 827 miners and et al., nonminers over 1967. 35 years of age. South Africa (ZO9). Those smokers exposed to gold mine dust manifested more symptoms of CQPD 1 than did non-dust exposed smokers. while prevalence of symptoms, among nonsmokers. was similar for the two groups. 218 TABLE A7.-Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease (cont.) Author, Ye==. countlY, reference Number and tYDe Of population Results Sluis-Cramer X27 miners and The dose relationship of cigarettes and COPD 1 symptoms et al., 1967, nonminers over wss much more noticeable among those exposed to dust. South Africa 35 years of age. Thr authors stressed the synergistic actions of cigarette (2OY). (cont.) smoking and dust exposure. Bouhuys et al., 1969, U.S.A. (39). 455 male cotton Those exposed to dust manifested a significantly greater textile workers prevalence of byssinosis symptoms than nonexposed. (214 exposed to Smokers manifested a significantly greater prevalence of dust in carding byssinosis symptoms than nonsmokers. and spinning No significant differences in Monday morning FEV' values rooms, 241 not were observed between smokers and nonsmokers. exposed) Prevalence of byssinosis symptoms did not show any re- lationship to length of employment. Bouhuys et al,. 1969, U.S.A. (38). 216 male hemp Hemp workers (especially the older ones) were noted to workers and 247 have different smoking habits from control group--fewer workers in other heavy smokers. more light smokers, more ex-smokers due industries in to doctor's orders. ssme region, Aged 20-49 - a. No difference in FEV1.9' values. between 20-69 year?, controls and hemp workers in any smok- of sge. ing category. b. No difference in FEV1.o values between men in different smoking categories. Aged 59-69 - 3. Hemp workers manifested decreased FEV1.9 values in all smoking groups except for heaviest smokers. Ex-smok- ers had lowest FEVI.o values. h. Those smoking most had lower FEVI.9 values as compared with light and non- smokers. The authors conclude that: There appears to be no synergism between smoking and hemp exposure as to effect on FEV,.o although the selection process whereby those with symptoms have o greater tendency to stop smoking may obscure such a relationship. Chester et al., 1969. U.S.A. (49). 139 male chlorine Chlorine-exposed group manifested no difference in symp- plant workers toms and a decreased MBC value when compared with (55 with history non-exposed group. ofsevereex- Smokers in chlorine-exposed group had significantly de- posure). creased MBC and FEV values as compared with non- smokers in non-exposed group. Greenberg 121 workers in et al., washing powder Sensitized group manifested lower FEV1.o/FVC' values as compared with nonsensitized group even after smok- 1970. factory (48 found ing habits w'ere controlled for. England to be sensitized (97). to product, 73notj. Tokuhat" et al., 1910, U.S.A. (218). 801 male miners Increased mine exposure was associated with residual vol- "me and FEV abnormalities even after adjustments for age and smoking. A systematic exposure-impairment relationship wss noted only among smokers while relatively few nonsmokers showed COPD impairment, Smoking miners manifffted more X-ray alterations and COPD symptoms than nonsmokers. regardless of num- ber of years of underground exposure. r See Glossary of Terms in Bronchopulmonary table A4. 219 Author. sea=, countrY. reference Animal Results Freeman and Haydon. 1964 U.S.A. (90). Spi-agUe-DaWleY rats. 23 p.g.m.: (a, after 37-41 days-moderate hypertrophy and hyper- plasitl uf bronchial anil bmnchiolar egithelium. (b) after 146-157 days-[ 1) Advanced hypertrophy and hyperplasia of bronchial and bronchi&x epithelium. (2) Increased lung volume. (3) Proliferation of Connective tissue. HlWd@ll et al.. 1965 U.S.A. (107). Haydon et al.. 1967 U.S.A. (106). Sprague-Dawley rats. 12.~ p.p.m. to death: !a) Mrpertrophy and occasional metaplasia of bronchial and hronchiolar epithelium. (b) Increase in number of actively secreting goblet cells. -- ___lll Albino rabbits. g-12 p.p.m. for 4 months: ia) Abnormal dilatation of peripheral air spaces. (b) Decreased density of alveolar walls. (c) Hrpertrophy and hyperDlasia of bronchial epithelium (especially terminal bronchiolar) (d) Increase in size of alveolar ducts. le) Increased elastic tissue staining. (f ) Increased alveolar size. Freeman et al.. 1968. U.S.A. (91). Sprague-Dawley rats. 0.8 p.p.m.-2 p.pm. for entire lifespan: (a) Alveolar distention. (b) Reduction in number of cilia. (c) Epithelial inactivity ("dormancy"). Freeman et al., 1968. U.S.A. (89). Spra!qx-Dawley rats. 18 p.p.m. (a.1 5 days-terminal bronchiolar rpithelial hypertrophy. (b) 4 weeks- ( 1) Widespread bronchiolar epithelial hy- pertrophy. (2) Non-necrotizing emphysema. Blair et al., 1969, U.S.A. (32). Female Swiss Albino mice. Kleinerman, Male Syrian Golden 1970. hamsters. U.S.A. (136). 0.5 p.p.m.: la) 6 hours'dav for 3 months-pneumonitis. (b) 24 hours/day for 3 months- (1) Respiratory bronchi- alar obstruction. (2) Alveolar expansion and brnnchiolar inflammation con- sistent with early focal emphysema. 100 p.p.m. for 5'2 hours: (a) thymidine autoradiography-intense burst of prolif. eration of epithelium returning to normal in 4 days (more persistent distally). (b) electron microscope-( 1) Decreased number of se- cretory cells + secretory granules. (2) Increased number of lyso- somal structures. (3 ) No change in number of ciliated cells. 220 TARLE AlS.---Experimrxts concerning the effect of cigarette smoke or its constituents upon ciliary function Author, ye==, countrr, reference System Method ' Results Mendenhall In vitro: Cigarette smoke ControlsPciliary activity depressed spproxi- and Calf trachea. by direct appli- mateI\. 4 percent. Shreeve. cation or in Experimental&ciliary activity depressed a~- 1937, solution. proximately 40 percent. U.S.A. (164). Rakieten In vitro: I. Nicotine in I. Ciliary activity depressed only upon ea- et al.. (a) rabbit Locke-Ringers posui-e to 100 mg. percent solution. 1942, and rat solution. II. Ciliary activity dwressed after 15-20 min- U.S.A. trachael II. Cigarette smoke utes exposure depending on concentration (188). rings. in solution. of smoke in solution. (b) human nasal Ill"C"llS membrane Kordik III vitro: Nicotine in Locke's Nicotine at 1O--5 g,:cc had no effect on CiliarY et al., Rabbit solution. 1952, trachea England (137). Hilding, In vitro: Cigarette smoke 1956. Cow trachea (direct U.S.A. exposure). (120). Krueger and Smith, 1958, U.S.A. (139). In viuo: Rabbit trachea Cig.arette smoke. Dalhamn, 111 uiz.0: Cigarette smoke. 1959, I. Rat Sweden trachea (59). In t&-o: II. Rabbit trachea III. Humafi ciliated lll"~"SZl &lk In vitro: Cigarette smoke. et al.. Rat and rabbit 1959 tracheal U.S.A. epithelium. (80). Railenger, In i.itro: Cigarette smoke 1960, H11mall in solution. U.S.A. bronchial (25). and tracheal epithelium obtained during anesthesia. activity. All tracheas showed depressed or absent ciliary activity. Cigarette smoke decreased ciliary activity by approximately 200 beats/minute. I. T/10 showed cessation of ciliaw activity after one exposure. II. 6:lO showed cessation of ciliary activity after one exposure. III. fi/T showed cessation of ciliary activity after one cigarette exposure. Decreased ciliary activity noted on exposure to cigarette smoke: (a) Repetitive exposure was associated with persistence of response over longer periods of time. (b f "Tar"-rich cigarette was more inhibitory than "tar'`-poor. (P) Filtered smoke was less inhibitory than unfiltered. Ciliary activity was fully inhibited within 5-28 minutes of exposure depending upon concen- tration <,I smoke in solution. 221 TABLE A13.-Eeperiments concerning the effect of cagarette smoke or its constituents upon diary function (cont.) Author, year. country, reference system Method 1 Results Wynder et al., 1963, U.S.A. (236). In viva: Cigarette smoke; Unfiltered cigarette smoke--eiliastaais by 2ud- Fresh water and its fractions 5th puff. ItlUSSd in solution. Acid (phenolic) fraction solution-immediate ciliated ciliastasis. epithelium. Whole extract fraction solution-no cilia&& Neutral fraction solution-no ciliastasis. 1 percent phenol solution-immediate ciliast+ sis. Dalhamn In viva: Cigarette smoke. Unfiltered cigarettes-ciliastasis in 3/S cati and Cat trachea. after 5 cigarettes. Rylander. Filtered cigarettes-no ciliastasis after 8 cig+ 1964, rettes (5 cats). Sweden Controls-no ciliastasis (5 eats). (61). Ballenger In vitro: Nicotine in solution. Initial stimulation of activity followed by de- et al., Human cline and complete ciliastasis after 12-24 1965, ciliated hours of exposure. U.S.A. tracheal (26). epithelium obtained during. anesthesia. Dslhamn In viva: Cigarette smoke. The longer the time interval between expo- and cat tracklea. sures, the more puffs were required to cause Rylander, ciliastasis. 1965, Sweden (62). Wynder In vim: Various compounds Formic, acetic, propionic, benzoic acids all et al., Fresh water in solution. more ciliatoxic than phenol. 1965, mussel Oxalic acid lass ciliatoxic than phenol. U.S.A. ciliated Formaldehyde, acrolein more ciliatoxic than (235). epithelium phenol. C!XSO" In viva: Cigarette smoke. Percent decrease in ciliamy activity et al.. Cat trachea. Control . . . . 0 1966, Unfiltered smoke . . . 53 U.S.A. cell"lose acetate filter . . 46 (44). Carbon cellulose acetate filter . . 30 Dalhamn. h viva: Cigarette smoke. Mean number of puffs required to produce 1966, Cat trachea. ciIiastiai8 Sweden No filter ................................ 91 (60). Charcoal filter .......................... 170 Commercial cellulose acetate filter ........ 194 Charcoal and acetate filter .............. 512 Cambridge filter ........................ 600 Kensler In vioo: Cigarette smoke Rabbit trachea-Total smoke condensate of 3 and Rabbit and components cigarettes. gas phase condensate of 7 ciga- Battista, trachea, in Tyrode's rettes caused similar ciliastasis. 1966. cat trachea, solution. Other species--All found sensitive to ciliastatic U.S.A. dog trachea, components of cigarette smoke. Bulk of ac- (lS5). monkey tivity noted in gas phase (HCH. formalde- trachea. hyde, acrolein) rat trachea. 222 TABLE A13.-Experiments concerning the effect of cigarette smoke or its constituents upon diary function (cont.) Author, Y-r, countrY. reference system Method 1 Dalhamn In viva: Cellulose aeetate- and Cat trachea. filter cigarettes Rylander, with varying 1967. amounts of Sweden "tar" but simi- C-55). lar gas phases. D*lh*"ln In viva: and Cat trachea. Rylander, 1968, Sweden (64). Unfiltered and Cambridge-filter cigarettes. Resu1t.s Increased amounts of tar were associated with decreased number of puffs required to inhibit eiliary sctivity. Whole smoke found to be markedly more toxic to ciliary activity than volatile (gas) phase at lower dosages (puff volume). This differ- ence diminishes with increasing puff volume. Kaminski In viva: Whole and filtered Wet chamber adsorption significantly reduced et al.. Cat trachea. cigarette smoke the ciliastatic activity of whole smoke, but 1968, exposed or unex- did not affect the ciliastatic activity of smoke U.S.A. posed to "wet previously filtered by Cambridge or charcoal (183). chamber" made filters. to stimulate oral mueosa and saliva. Krahl In viva: Cigarette smoke Significant ciliastasis. reversible. and Common dissolved in Buhnash. molluek sea water. 1969. ciliated U.S.A. epithelium. (188). Battista In vitro: Cigarette smoke The authors observed that: and Chicken or HCN in (1) The more diluted smoke required more Kensler, tracheal TYrode'e puffs to cause ciliastasis. 1970, epithelium. solution. (2) Activated charcoal filtered smoke was U.S.A. less ciliastatic than cellulose acetate filtered (2.3). smoke and also contained less HCN and acrolein. (3) HCN alone was ciliastatic but recovery was more rapid than after cigarette smoke alone. They conclude that the gas phase components are more related to ciliastasis (as particulate matter is not significantly decreased by char- coal filtration while HCN and acrolein are). Battista In viva: Cigarette smoke. The authors observed that: and Hen trachea. (1) Whole smoke acutely depressed ciliarv Kensler, activity in 4-6 puffs. 1970. (2) Gas phase was only slightly less depres- U.S.A. sant than whole smoke. (99). (3) Chronic exposure (1 cigarette/day for 32 days) to smoke resulted in no apparent permanent defect in ciliary activity (al- though mucous production was signifi- cantly increased). 223 TABLE Al.?.-Ezperi~uexts comerning the effect of cigarette smoke or its consLitzcents upon ciliary function (cont.) __- Author. year. country, reference system Method 1 Results Dalhamn In viva: Unfiltered cigarette Average mmzber of pufis required to arve.qt and Cat trachea. and cigar smoke. ciliatu activity Rylander, 1970, Cigarette smoke 13) (p<:o,ol) Cigar smoke . .114J Sweden The authors note that cigar smoke is of a (65). different pH and that it contains more iso- prene, acetone, toluene. and acetonitrile. Kennedy In viva: Mainstream Electron microscopic observations: and Protozoan cigarette smoke. (1) After 7 minutes exposure-alteration of Elliott, (ciliated) mitochondrial structure. 1970. (2) After 42 minutes exposure-destruction U.S.A. of internal mitochondrial membrane atrw- (134). ture. (3) Gas phase alone, while ciliatoxic, did cause mitoehondrial swelling but no dis- ruption of membrane structure. `Unless otherwise stated, method entailed the direct observation of ciliarv activity using markers. 224 TABLE A14.-Experiments concerning the effect of cigarette smoke on pzclmonavy surfactmt aml swfacc tcnsiot? Author, year, country. system Method Results refwence __~ Miller and Rat lung extracts Cigarette smoke: (1) Exposure to cigarette smoke was associated with decreased surface tension in lung extract. Bondurant, (1) Applied to (2) Surface tinsion of rats (lung extracts) exposed to'cigarette smoke was decreased 1962, extract. as compared with those not exposed. U.S.A. (2) Exposure (165) of rats. Cook 40 subjects undergoing Surface tension and Webb hronchoscopy: VdUfS of lrurfactnnt 1966, 14 normal 20 100 Stability in&z (reflectn t Values significantly U.S.A. 1 nonsmokers with percent pcrccnt sxrfactnnt activity) different from (57) pulmonary disease area ama values of normals 19 smokers with and Normal . . 6.6 GO.0 1.61 at pro . . . 9.4 6.7 smokers e.mo"g the cases ~~ Dowling. Individuals Interview and Ezposed to placebo &posed to infeetima agent No statisticnlly et al.. exposed to medical Percent Percent 1967. significant "infectious examination. developing developing differences U.S.A. cold agent" Number "Cow' Number "cold" noted. (76). and placebo. NS . ..t............ 111 10 323 34 SM .,.....,......... `I'8 14 249 36 TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokera NS = Nonsmokers Author. ye*=, countrY, reference Number and type of population Data collection Results Comments Boake, 1958. U.S.A. (9.7). Parents of 59 families. Interview NS . . . . . . . . . . . . . . . . . . . . . . . ..(24) Cigarettes/day: l-10 (19) 11-20 . . . . . . . . . . . . . . . . . ..(25) >20 (19) Pipe. cigar . . . , ,. (14) Number of No statistically Pl38lXt- reepiratory r11nesse.d significant years iam?sees person-year* differences 120 624 6.2 noted. 99 629 6.3 108 486 4.6 99 424 4.3 12 304 4.2 Shah et al.. 1959, India (205). Tuberculosis Survey, X-ray, institute and emploYee8. interview. Tuberculous Normal or t Numbers in bu X-ray nontuberculous parentheses NS .,...................... t10 (19.7) 178 (168.3) represent figures SM _...,,,............_.... 36 (26.3) 215 (224.7) "expected" by use of 2 x 2 contingency table. Tuberculoua employees were found to have significantly fewer nonsmokers and more smokers. TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author. year, Number and countl;y; type of reference vooulation Data collection Results Comments Brown 306 male and et al.. 1961, Australia (4). female tuberculosis clinic pntients, 221 male and female outpatients. Interview Smoking habits prior to diagno& Tuberczdous patients (percent) NS . .._................ ..__... 9.1 Cigarettes/day: l-9 10.5 IO-19 ,,........,.... 34.3 20-29 26.3 30-39 . . . . . . . . 7.2 >ro . . . . . . . ..~~....... 6.2 Pipes ,,..._._. ,..,,_,.....,_.. 5.9 Controls (percent) 19.9 15.4 19.5 25.8 6.4 9.1 4.6 Data presented only on Queensland S8nlplC. The authors noted rhat the significant difference between the patients and controls WBS not present when the groups were matched for alcohol intake. Havnes et *I., 1966. U.S.A. (108). 191 male prep school students. Interview Average number of respiratory illnesses/l0 students (adjusted for age) All 8cucre lower All All smere or combined respiratory respiratory respiratory episodes episodes episodes NS (99) 11.1 1.6 0.36 SM (92) . . . . 20.2 6.7 3.34 P*rIlell et al., 1966 Canada (181). 47 smoking- Interview Median number of illnesses/student The authors noted nonsmoker pairs and health All All that these of student nurses service respiratory other differences were matched for age records. disaasest illnesses stntistically und parents NS (47) . . . . . 2.08 2.99 significant. occupational SM (4'7) . . . . . . . 2.64 5.00 t Particularly C&.5. tracheitis, bronchitis, and pneumonia. TABLE AX.-Studies concerning the relationship of smoking to infectious ,respiratory disease in hmans (conf.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country. type of collection Results Comments reference population Peters 1,496 Harvard Medical his~tory, Number of visita to etudent health unit for rcwimtmy illness/student t p5 .,.,................ 2.60 Finklea 1,811 male Questionnaire Heavy smokers-21 percent more clinical illnesses than nonsmokers: The authors also et al., colll=ae prior to 20 percent more requiring bed rest than nonsmokers noted that: 1969 students. A2/HK/63 Liph't smokers-10 percent more clinical illnesses than nonsmokers; (a) Smokers U.S.A. epidemic and 7 percent more requiring bed rest than nonsmokers. exhibited (83). follow-up on serologic morbidity. evidence of increased subclinical A2/HK/C8 infection. (b) Therewasno difference in the vaccination status between smokers and nonsmokers. .I TABLE AlG.-Complications developing in the postoperative period in patients undergoing abdominal operations Men over 20 Percent Percent Group CCWZS broncho- chest Percent Percent pneumonia t&al Ck&W bronchitis and complicntia" ateleetasis rate Smokera 300 41.7 63.0 6.3 68.3 Light Smokers . 180 68.4 27.7 3.9 31.6 Nonsmokers . . 66 92.6 6.0 1.6 7.6 Women over 20 Smokers . . . . 23 39.1 43.6 11.4 60.9 Light Smokers 62 77.6 20.9 1.6 22.6 Nonsmokers . 518 88.8 8.1 3.1 11.2 SOURCE: Morton. H. J. V. (f7s) TABLE A17.-Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Group CCL% Before number operation Day 1 Day 2 Day 3 1 94 93 94 2 94 93 94 . Nonsmokers . 3 96 93 34 4 95 90 84 . . 6 94 90 33 . . 6 95 91 89 91 7 92 89 81 89 Smokers . . 8 91 89 86 89 9 93 91 88 92 10 90 87 88 92 SOURCE: Morton. A. (171). 230 CHAPTER 4 Cancer Introduction ........................................ Lung Cancer ....................................... Epidemiological Studies .......................... Prospective Studies .......................... Retrospective Studies ........................ Lung Cancer Trends in Other Countries ............ Histology of Lung Tumors ........................ Lung Cancer Relationships in Women .............. Lung Cancer, the Urban Factor, and Air Pollution. ... Lung Cancer and Occupational Hazards ............ Uranium Mining ............................ Other Occupations ............................ Nickel ...................................... Asbestos .................................... Arsenic ..................................... Chromium ................................... Pathological Studies. ............................. Pulmonary Carcinogenesis ........................ General Aspects of Carcinogenesis ............. Polynuclear Aromatic Hydrocarbons ....... Nitrosamine Compounds. .................. Pesticides and Fungicides. ................ Radioactive Isotopes ..................... Inhibitors of Ciliary Movement ........... Experimental Studies ...................... Skin Painting and Subcutaneous Injection. .. Tissue and Organ Culture ................ Tracheobronchial Implantation and Instillation ...................... Inhalation ............................. Reduction in Tumorigenicity .............. Summary and Conclusions ........................ Cancer of the Larynx .................... Epidemiological Studies .............. Pathological Study .................. Experimental Study ................. Summary and Conclusions ............ Oral Cancer ............................ Epidemiological Studies .............. Experimental Studies ................ Summary and Conclusions ............ ........... ........... ........... ........... ........... ............ ........... Page 237 239 240 240 240 244 246 251 252 256 256 256 256 257 257 257 258 258 258 264 264 266 266 267 267 267 267 268 268 275 276 277 277 280 281 281 284 285 288 289 233 Cancer of the Esophagus ............................. Epidemiological Studies .......................... Pathological Study .............................. Experimental Studies ............................ Summary and.Conclusions ........................ Cancer of the Urinary Bladder and Kidney .............. Epidemiological Studies (Bladder) ................. Epidemiological Studies (Kidney) ................. Experimental Studies ............................ Summary and Conclusions ........................ Cancer of the Pancreas ............................... Summary and Conclusions ........................ References ......................................... FIGURES 1. Lung cancer, Finland and Norway . . . . . . . . . . . . . . . . . . . 2. Percent of smoking dogs with tumors . . . . . . . . . . . . . . . . 3. Percent of lung lobes with tumors in smoking dogs . . . . . 4. Effects of chronic cigarette smoke inhalation on the 245 274 274 hamster larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 1. 2. A3. A4. 5. 6. A7. 8. 9. 10. LIST OF TABLES Lung cancer mortality ratios . . . . . . . . . . . . . . . . . . . . Lung cancer mortality ratios for males by duration of cigarette smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . Outline of methods used in retrospective studies of smoking in relation to lung cancer . . . . . . . . . . . . . Group characteristics in retrospective studies on lung cancer and tobacco use . . . . . . . . . . . . . . . . . . . . . . . Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer . . . . . . . Grouping of pulmonary carcinomas . . . . . . . . . . . . . . Tumor prevalence among males and females 35-69 years of age, by t.ype of tumor and smoking category . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence . . . . . . . . . . . . . . . . . . . . . . Pathologic and cytologic findings in the tracheo- bronchial tree of smokers and nonsmokers . . . . . . P age 289 289 292 292 293 293 293 296 296 299 299 299 299 241 244 323 329 246 247 334 250 253 259 234 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) 11. Identified or suspected tumorigenetic agents in cigarette smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A12. Autopsy studies concerning the presence of radio- activity in the lungs of smokers . : . . . . . . . . . . . . . A13. Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals . . . . . A14. Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures . . A15. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals . . . . A16. Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals . . . . . . . . . . . . . . . . . . 1'7. Data on pedigreed male beagle dogs of groups F, L, H,hand N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18. Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h and N 19. Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found . . . . 20. Laryngeal cancer mortality ratios - prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ml. Outline of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . . . . . . . ~422. Summary of results of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . A23. Number and percent distribution by relative fre- quency of atypical nuclei among true vocal cord cells, of men classified by smoking category . . . . , A24 Number and percent distribution, by highest num- ber of cell rows in the basal layer of the true vocal cord, of men classified by smoking category . . . . 25. Deposition of I%-labeled smoke particles in particu- lar regions of the respiratory tract . . . . . . . . . . . . 26. Classification of the five registered stages of epithe- ha1 changes at the larynx . . . . . . . . . . . . . . . . . . 27. Oral cancer mortality ratios-prospective studies. . A%. Outline of retrospective studies of tobacco use and cancer of the oral cavity . . . . . . . . . . . . . . . . . . . . . A%a. Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites. . Page 265 335 337 343 346 349 270 271 272 278 354 358 359 360 282 283 286 361 368 235 429. 30. A31. A::la. A32. A33. 33. A3.5. A35a. ::6. LIST OF TABLES (Continued) (A Indicate5 tables located in appendix at end of chapter) Experimental studies concerning oral carcino- genesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Esophageal cancer mortality ratios-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus . . . . . Summary of results of retrospective studies of to- bacco use and cancer of the esophagus . . . . . . . . . Atypical nuclei in basal cells of epithelium of esoph- agus of males, by smoking habits and age . . . . . . Atypical nuclei in basal cells of epithelium of esoph- agus of males, by amount of smoking and age . . . . Kidney and urinary bladder cancer-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of methods used in l,etrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . Summary of results of retrospective studies of smok- ing and cancer of the bladder . . . . . . . _ . . . . . . . Pancreatic cancer mortality ratios-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pngr 371 290 375 378 379 3% 294 381 383 29e 236 INTRODUCTION During the early years of this century, a number* of pathologists and clinicians reported a dramatic increase in the incidence of lung cancer. Autopsy studies and studies of lung cancer death rates re- vealed a significant increase beginning prior to World War I and continuing during the ensuing years. This epidemic of lung cancel continues to the present day, with nearly 60,000 deaths expected from this disease in the United States during 1970. Beginning in the 1920's, a number of reports appeared which suggested a relationship between lung cancer and tobacco smoking (4, 20.3, 278). Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The 1964 Report (291) contains a thorough review and analysis of the data available at that time as well as an excellent discussion of the considerations necessary for their evaluation. Major epidemiological studies have demonstrated that smokers have greatly increased risks of dying from lung cancer compared to nonsmokers. An increased risk of lung cancer has been found for every type of smoking habit investigated, but two character- istics of the risk are particularly evident : The risk is much greater for cigarette smokers than for smokers of pipes and cigars, and among cigarette smokers a dose relationship exists. That is, the more one smokes, as measured by total pack-years of smoking, present level of smoking, degree of inhalation, or age at start of smoking, the greater is the Csk. It has also been shown that the risk of lung cancer among ex-smokers decreases with time almost to the level of nonsmokers; the time required is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid form of lung cancer is the most prevalent one in cigarette smoking populations and that this form accounts for a major portion of the rise in lung cancer deaths (2.5:). Such studies have also indi- cated a lower prevalence among smokers for oat-cell and adeno- carcinomas of the lung than for the squamous form, but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. Smoking has been implicated in the development of other types of cancer in humans. Among These is cancer of the larynx. A num- 237 ber of epidemiological studies have demonstrated incseased mar- tality rates for laryngeal cancer in smokers, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship exists between smoking and the development of cellular changes in the larynx, including carci- noma in situ. Cancers of the mouth and oropharynx have been found to be more common among users of all types of tobacco than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunction with other factors such as poor nutrition and alcohol consumption has not been fully clarified. Similarly, although smokers are more likely to develop carci- noma of the esophagus than nonsmokers, the relative additional contribution of smoking in conjunction with nutritional factors and alcohol consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that some smoking-induced abnormal meta- bolic product or abnormal concentration of a metabolic product may be responsible for this increased risk. In addition, cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or "tar." This material, when painted on the skin of animals, leads td the development of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these carcinogens are several chemicals which have been identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compounds which promote the neoplastic development of initi- ated cells. Other, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equal that of cigarette smoke condensate. Numerous experiments have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the "tar," are administered by varying methods to animals or to tissue and cell cultures in order to investigate the neoplastic- inducing properties of cigarette smoke. Particular difficulty has been encountered in experiments which have attempted to deliver 238 whole cigarette smoke to the larynx and into the lungs of experi- mental animals. This has resulted in the use of other methods such as the implanting of pellets containing suspected carcinogens and the instilling into the trachea of suspected carcinogens as such, or adsorbed onto fine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second, the upper respiratory tract of experi- mental animals, particularly the nose, is much different from anal- ogous human structures, resulting in a more efficient filtration of smoke in the upper respiratory tract. Nevertheless, in rodents and canines, progressive changes apparently indicative of ultimate neo- plastic transformation have been identified in the respiratory tract. Recently, two studies in different species and in different target organs have been reported concerning the development of early in- vasive cancer following the prolonged inhalation of cigarette smoke. Auerbach and his coworkers (II) trained dogs to inhale cigarette smoke through a tracheostoma. After approximately 29 months of daily exposure, these investigators found a number of cancers of the lung. Dontenwill (7'6) in the second of these two studies, exposed ham- sters to the passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed the development of pre- malignant changes and, ultimately, invasive squamous cell cancer of the larynx. LUNG CANCER Cancer of the lung in the United States accounted for 45,383 deaths among males and 9,024 deaths among females in 1967 (289). It is presently estimated that approximately 60,000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent phenomenon. Death rates for lung cancer (ICD Codes 162, 163) rose from 5.6 (per 100,000 resident population per year) in 1939 to 27.5 in 1967 (289, 290). This rapid increase followed the in- creased use of cigarettes among the United States population. The increase has occurred principally among males, although more re- cently females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is the major cause of lung cancer is derived from varied types Of research including epidemiological, pathological, and laboratory investigations. 239 EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in different parts of the world to investigate the relationship between smoking and cancer of the lung. These studies are outlined in tables 1, 2, A3, and A4. Prospective Studies The major prospective studies concerning the relationship of smoking and lung cancer are presented in table 1. In all, these investigations have studied more than a million persons from a number of different populations for up to 10 years. These studies show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.61 to 14.20 among male smokers as compared to nonsmoking males. The one major prospective study of female cigarette smokers reveaIs an overall mortality ratio of 2.20 (118). Also uniformly present in these studies is a dose-related increase in the mortality from lung cancer with increasing amounts of cigar- ettes smoked per day. Other measures of exposure show similar trends. Hammond (118) reported increased mortality ratios asso- ciated with increased inhalation (table 1) as well as with increased duration of smoking (table 2). Ex-smokers show significantly lower lung cancer death rates than continuing smokers. In their study of more than 40,000 British physicians, Doll and Hill (74, 75) noted a decrease in lung cancer mortality rates with increasing time since smoking stopped (table 1). During the past 20 years, half of all the physicians in Britain who used to smoke cigarettes have stopped smoking. While the death rates from lung cancer rose by `7 percent among all men from England and Wales during the period from 1953-57 through 1961- 65, the rates for male doctors of the same ages fell by 38 percent (96). Pipe and cigar smokers have been shown in the prospective stud- ies to have lung cancer mortality rates higher than those of non- smokers, although these are generally substantially lower than those of cigarette smokers (table 1). Retrospective Studies More than 30 retrospective (case-control) studies have been re- ported concerning the relationship of smoking and lung cancer. These studies are outlined in tables A3 and A4. Table A4 presents the percent of nonsmokers and of heavy smokers among both cases and controls as well as the relative risk ratios for all smokers. 240 TABLE I.-Lung cancer wwrtality mtios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number ye*=. and type COUntrY, of col$;don Follow- Number Regular cigarette Pipe UP of smoking only cigar Inhalation reference pooulation years deaths (cigarettes/daY) Exsmokers CODUll@Xd.9 _ - -_- Hammond 187.783 Qucstion- 31/& 448 Pipe No data Bso7xhogcnic 341/448 and white naire and SM 443 NS ,.., 1.00 (15) NS 1.00 (15) (1Szcluding adenocarcinma) deaths with Horn, males interview. NS 16 20 . ..23.40(117) NS 1.00 (15) Continuing .16.94 eludes those (120). ages All . . .t10.73(397) SM . 1.00 (7) Duration 60-69. of i <1 year .16.50 regular l-10 years (10.44 cigarette cessation >lO years 1.51 smokers who Previously >I pack/day also smoked Continuing .46.21 pipes and Durntion] lO years .17.79 without microscopic proof. Doll and Approxi- Question- 10 212 NS ..I.. 1.00 (3) Pipe and Cigar No data Cigarette smokers Hill, matelv mire and SM 209 1-14 . . . 8.14 (22) NS 1.00 (3) NS ._ ,t ._... . . . 1.00 (3) 1964, 41,000 followup NS 8 15-24 .19.86 (63) Gmmsldw Continuing _. .18.29(124) Great Illale of death >25 ,, .32.43 (57) l-14.. 6.00 (12) Duration 25 .13.71 (3) I cessation lo-20yean 2.57 (3) >zoyears 2.71 (2) Best, Approxi- Question- 6 331 NS . . . . 1.00 (7) Pips No data t Refers 1966. mately naire and tSM 324 <10 . . . 10.00 (67) NS . . . 1.00 (7) NS ,. _, 1.00 (7) toeur- 1966, 78,000 followuP NS . 7 lo-20 .16.41(204) SM .4.36 (18) Ex-smokers of rent Canada male of death >20 .17.31 (63) cigar cigarettes only _. . 6.06 (18) cigarette (21). Canadian certificate. All . .14.20(246) NS .l.OO (7) smokers !z V&3C%C3. SM . ..2.94 (2) only. -- TABLE l.-Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)~ SM = Smokers. NS = Nonsmokers. Prospective studies Author. Nlllllber Ye*=, and,4'" Data Follow- Number collection Regular cigarette Pipe country, UP d2hs smoking only cigar Inhal&i0n reference population Exsmokers Comme"ts Ye*!3 (cigarettes/day ) Kahn U.S. male Question- 8% 1,266 Pipe (Do="). veterans mire and SM .1,178 NS . . . 1.00 (78) NS . .l.OO (73) Nodata 1966, 2.266.674 followup NS. 78 l-9 . . . . 6.49 (45) SM . . . .1.34 (17) NS . . . . . . . . 1.00 (78) U.S.A. person of death 10-20 . . 9.91(303) Ciga+ Number of eigarettcs/dau: (189). ye**s. certificate. 21-39 . . .17.41(315) NS . , .l.OO (73) l-9 . . . . . . 0.96 (4) >39 . . .23.93 (82) SM . . ..1.69 (6) 10-20 . . . . . . . 3.43 (39) All . . .12.14(749) Pipe and cigar 21-39 . . . . . . . 9.33 (67) NS . . . .l.OO (78) >39 . . . . . . . . 3.24 (19) SM . . . .1.66 (20) Hammond.440.563 Interviews 4 Males Current cigarettes Pipe Males ICD code 1966, III&e by ACS 1.169 OdU NS .l.OO (49) NS . . . . 1.00 (49) 162 only. U.S.A. 662,671 volunteers. srd .l,llO Males SM . . .2.24 (21) Slight . . 8.42(120) (118). females NS 49 NS . . . 1.00 (49) Cigar Moderate .11.46(311) 35-84 FtWtaL% l-9 . . . . 4.60 (26) NS . .l.OO (49) Deep . . .14.31(141) years of 183 10-19 7.48 (32) SM . . ..1.86 (22) FOUL% age in 25 SM . 81 20-39 . .13.14(381) Pipe and cigar NS . . . . . 1.00(102) states. NS . 102 >40 . .16.61 (82) NS . .l.OO (49) Slight . . . . . 1.78 (251 -All .~., . . . . . 9.20(719) SM . ..0.90 (11; F.Z?iWh~ 3.70 (46) NS . . . . . l.OO(l02, J 1-19 . . . 1.06 (20) >20 . . 4.76 (60) All . , 2.20 (81) TABLE I.-Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smoker%. NS = Nonsmokers. Prospective studies Author, Number Follow- year, andow Dats "P Number count.lY. Eollection Regular cigarette Pipe reference population years de% smoking only cigar Inhalation Exsmokers (cigarettes/day) COllUlWlt5 Bllell 69,866 et al., American `l?$ind 3 1967, Legion- followup U.S.A. naires of death (49). 36-76 certificate. years of age and older. 804 NS , . . . 1.00 <20 . . . . 2.90 20 . . . 3.60 >20 4.90 Hirayama. 266,118 Trained 1?4 43 NS . . . . . 1.90 (3) Preliminnry 1967, male and PIIS SM 40 l-24 . 2.69 (29) report. JC3p8n female nurse >26 . . . 6.68 (6) (1.25). adults interview 40 years and fol- of age and lowup of older. death certificate. Weir and 68,163 Question- 6-S 368 NS . . . . 1.00 DUIIII, males in naire and 5~10 . 3.12 1970, various followup *20 . . . 9.06 U.S.A. OCC"PB- of death >30 . . . 9.66 (SO6). tions in certificate. All . . . . . 7.61 California. 1 Un1ee.a otherwise specified, diaparitiea between the total number of deaths and the hum of the individual smoking categories are due to the exclusion NS include pipe and cigar smokers SN include ex-smokers. E of either occasional. miscellaneous, mixed, or exemokem. TABLE Z.-Lung cancer mortality ratios for males by duration of cigarette smoking (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-54 25 or older 2.Ti (5) 20-24 5.83 (31) 15-19 8.71(112) <15 12.80 (35) SOURCE: Hammond.E. C. (118,. 55-69 70-84 35-84 3.39 (12) 3.38 (3) 3.21 (20) 11.11 (72) 12.11 (7) 9.72(110) 13.06 (176) 19.37 (27) 12.81(315) 15.81 (57) 16.76 (9) 15.10(101) These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for males and from 0.2 to 5.3 for females. Although not presented in tabular form, the data concerning lung cancer and pipe or cigar smoking are similar to those found by the prospective studies mentioned above. However, a study by Abelin and Gsell (1) conducted on a rural Swiss population noted that an increased risk of lung cancer was present among heavy cigar and pipe smokers (as well as cigarette smokers) to a greater degree than previously reported. The authors suggest that their findings might be due to differences in either the amount smoked or the car- cinogenicity of Swiss and German cigars. The difference might also be explained by the greater use and more frequent inhalation of small cigars in Switzerland as compared to other countries where large cigars are more commonly smoked but rarely inhaled. Kreyberg (15.$), in a review of 887 cases of lung cancer in Norway, noted that pipe smokers showed an increased risk of lung cancer, although this risk was substantially lower than that for cigarette smokers. LUNG CANCER TRENDS IN OTHER COUNTRIES Several studies of particular interest are those in which the changing mortality from lung cancer has been investigated in countries in which cigarette smoking has become popular and wide- spread only in recent years. In those countries where accurate statistics for lung cancer mortality are available for both t.he pre- smoking and post-smoking periods, long-term trends can be studied in some detail, Two such studies have dealt with lung cancer mortality trends in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare disease in Iceland and felt that this rarity could be explained by the relatively late onset of heavy tobacco smoking in the Icelandic population when compared to that of Great Britain and Finland. He observed that the annual per capita consumption of tobacco did not reach one pound in Iceland until 1945, while Great Britain and Finland passed that amount before 1920. In 1967, Thorarinsson, et al. (276) noted a sharp rise in the incidence of lung cancer in Ice- 244 60- 50- 40- 30- 4- 3- 2- -Finland I I -Norway I I 1934-36 1939-41 1944-46 1949-51 1954-56 1959-61 1963-64 Calendar Years FIGURE I.-Lung cancer, Finland and Norway. SOURCE: Kreyberg, L. (154). land after 1950 and found a correlation between that increase and the increasing sale of cigarettes in that country. Kreyberg (154) analyzed the lung cancer death rates of both Norway and Finland in relation to the use of tobacco in those two countries over the past 100 years. Figure 1 shows the substantial difference in lung cancer mortality between the two countries. Kreyberg observed that cigarettes came into use in Norway in 1886 Mile the Finnish population (more closely allied to Russia socio- economically) was consuming more than 100 million cigarettes per Year during the decade of the 1880's. Cigarettes remained scarce in Norway until after World War I, and this 30-year lag in consump- 245 TABLE EL-Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Year 1936-38 ................... 192 33 34 30 Sex ratio ................ 6.8 : 1 1.1 : 1 1963-66 ................... 1,319 121 366 79 Sex ratio ................. 10.9 : 1 4.6 : 1 SOURCE: Kreuberg. L. (154) tion behind that of Finland is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HISTOLOGY OF LUNGTUMORS A number of investigators have focused their interest upon the relationship of cigarette smoking to the varied histology of lung tumors. The major histological types of lung cancer include squa- mous cell (epidermoid) carcinoma, small and large cell anaplastic carcinomas, adenocarcinoma (including bronchiolar and alveolar types), and undifferentiated carcinoma (153). A review of these studies (table 6) indicates a closer relationship between cigarette smoking and epidermoid carcinoma than between cigarette smok- ing and adenocarcinoma (42, 22 3). The work of Kreyberg (153) in Norway, over the past 20 years, provides evidence of a specific histologic relationship. This inves- tigator noted that a clearer association is obtained if the various types of pulmonary carcinomas are grouped. Table A7 presents his groupings of the specific histologic types. Using this classification as a basis for analysis of lung cancer sex-ratios in Norway, Kreyberg has observed that Group I carcinomas are significantly more frequent among males while Group II carcinomas show an approximately equal distribution among males and females. The author considers the recent rise in lung cancer in Norway to be a reflection of the increased prevalence of Group I carcinomas. Table 8 presents a summary of Kreyberg's investigation concerning 793 male and female cases of lung cancer. Among both males and fe- males, the risk ratio among smokers is substantially higher for Group I types than for those of Group II. However, adenocarcinoma among males shows a risk ratio of 2.9, signifying a relationship with smoking. Kreyberg attributes the lower rates noted among females to their significantly lower consumption of tobacco in all forms. 246 TABLE B.-Epidemiologic and pathologic investigations concerning smoking and the histology of lung ca.nce+ (Actual number of cases shown in parentheses) Author, Number of yea=, persons and country. case selection ReaUlt.3 Comments reference method Wynder 644 autopsies on Percent ca8es by histologic type and smoking history The percentage of chain and males with AU lung cance+8 other than smokers in the general Graham, confirmed adenocorcinoma (605) Adenocarcinoma ( 39 ) population (7.6) was 1950, lung cancer. Nonsmokers .._.._............t...... 1.3 10.3 significantly less than U.S.A. Light cigarette smokers . 2.3 7.7 among the patients with (316). Moderate ,.._,........................ 10.1 16.4 adenocarcinoma. The Heavy ,,___.,_........................ 36.2 38.6 authors refrained from Excessive 30.9 10.3 making any definite Chain ,,...._.._____._................ 20.3 18.7 conclusions due to the insufficient number of ease-s. DO11 916 male and 79 Percent patients with lung can.ce~ by average amount smoked daily ower 10 ~a~8 No statistically and female cases Male.4 significant difference Hill. with histologically Oat-cell 07 was found between 1952, confirmed Epidennoid ( 475 ) anaplastie (303) Admocarcinoma (33) the amounts smoked by England lung cancer. Nonsmokers 0.2 (1) 0.7 (2) 6.1 (2) the patients in the (Y3). Smokers: different histological <5 cigarettes/day 2.9 (14) 3.9 (12) 6.1 (2) groups. Number of 6-14 35.6 (169) 36.3(110) 21.2 (7) proven adenocarcinomas 15-25 . . . . . 36.8(175) 34.7(105) 48.5(16) too small for >25 24.4(116) 24.4 (74) 18.2 (6) conclusions. Ft3tWl.e8 Oat-cell 07 Epidermoid ( 18 ) wuzplastic (38) Adenocarcinoma (10) Males-105 unclassified Nonsmokers 61.1 (11) 31.6(12) 50.0 (6) tumors. Smokers : Females -13 unclassified <5 cigarettes/day 5.6 (1) 16.8 (6) 20.0 (2) tumors. 5-14 22.2 (4) 23.7 (9) 10.0 (1) 16-25 6.6 (1) 18.4 (7) . >25 . . . . . . . . . . 6.6 (1) 10.6 (4) 20.0 (2) TABLE 6. Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer' (cont.) (Actual number of cases shown in parentheses) -~-. --. -~~. Author, Number of Y`ZU, pcrsn': :klld country, case :;e*c c,ion Results Comments reference mc:h~.d Brrslow 493 male and 25 Pcrccnt of patients with specific lung cancers by tobacco umgc during the 20 ye~m prior to study Nonsmokers include pipe et nl., female cabe~ end cigar smokers only. I!#64 with histnloyically All lung cancers other tharl The authors conclude U.S.A. proven lung adcnocarcinoma Adenocarcinoma Controls that cigarette smoking (43). cancer. (472) (46) (518) appears to affect the 51x age and Nonsmokers 6.9 13.0 24.4 development of sex-matched Cigarette smokers _. . . 94.1 87.0 75.6 withelial carcinoma COlll~OlS. more than that of adenocarcinoma. ~--___ SChWElrtZ 430 male and Pexewt of amokers by hi8tdoQic tupe and 8'TllOki?LQ historv et nl., female cases 1957, with histologically Epidermoid Anaplastic Unknown type Cylindrical + Difference FlYLnCe confirmed lung Cases 96.0 97.0 96.0 100.0 significant (247). cancer. 4 matched Controls 79.ot 83.01 79.0t 96.0 et PZO.05 level. control gL'o",,s. -.. __. Hal?Il%Xl 158 female Relative risk for specified tumors (smokers/n~?~~mokers) 134 cases with final et al., CaYPS of histological 1958, lung cancer. Group I (Kreybwg) Adenocarcinoma determination. U.S.A. Adjusted for ege and occuyation. 3.0t 1.19 (ff3). t Difference from unity significant at p~O.01. Hae"s7.Cl 2,191 male Standardized mortality ratios Cases obtained from a and casm of Shimkin. 10 rwcent saml&s of lung cancel Epidcrmoid and mdiffemntiated lung ceneer deaths in 1962, with aderwatc carcinomas Adenocarcinoma U.S.A. doring 1958. U.S.A. histologic data. White males total _, . . . . 100 100 The authors noted an (II?). Never smoked . . . . .._._.. 6 18 Ex-smokers absence of important ..I.................... 34 46 differentials by (1 pack/day _. _, 123 116 histologic type. >l I,aek/day _. .._.....,I...._.....___......_ 499 467 -__ ___-- : ' Dtlta obtained from patient. interview and other sourscs. _---.---.-.----- ~-~~~- TABLE K-Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category (Smokers constituted 85 percent of populations studied) Sex and type of tumor Total Smoking category Smoking all methods NO"- smokers Risk ratio among smokers Males Epidermoid carcinoma ............................................ 434 431 3 17.0 26.4 Small cell anaplastic carcinoma .................................. 117 116 1 6.7 20.4 Adenocarcinoma .................................................. 88 83 6 28.3 2.9 B~~,nchiolol-nlvrola~. carcinoma ...................................................... Carcinoid ...... .................................................. 46 39 7 39.7 1.0 Bronchial gland tumor ...................................... .... ................... Total . . . 685 669 16 90.7 7.4 Females Epidennoid carcinoma ............................................ Small cell anaplastic carcinoma ................................... Adenocarcinoma .................................................. Rronchiolol-alveolar carcinoma ................................... Carcinoid ......................................................... Bronchial gland tumor ............................................ 12 9 3 .75 12.0 8 6 3 ,785 6.6 66 14 42 to.5 1.3 . . . . . . 32 I 25 6.3 1.1 . . . . . . . . Total . . . . . . . . . . . . . 108 35 73 18.3 1.9 `Number that would be expected if incidence rate among smokers were SOURCE: Kreyberg, L. (154) equal to that of nonsmokers. LUNG CANCER RELATIONSHIPS IN WOMEN Lung cancer death rates for women are presently much lower than the corresponding rates for men. In addition, it has been ob- served that among certain strains of mice exposed to carcinogenic agents, the male animals show a greater tendency to develop lung tumors than do the females (200, XV) although there are strains for which this is apparently not so. The extent of the influence of endocrine factors in the sex variation in the incidence of lung tumors is unknown. As of 1967 in the United States, women accounted for only about one-sixth of the total deaths from lung cancer (289). However, the lung cancer death rate in women has risen by over 400 percent in the past 40 years. From 1950 to 1967 alone, the rate per 100,000 population doubled, increasing from 4.5 to 8.9 (289,290). A number of retrospective studies concerning lung cancer and cigarette smoking among women have found that the difference in the prevalence of lung cancer between males and females is ac- counted for principally by those tumors classified as Kreyberg's Group I (154,311) . These, as was noted above, are the tumors, par- ticularly in males, which show the closest relationship with smok- ing. Haenszel, et al. (123), in a study of 158 women with lung cancer, observed that the sex differential for lung cancer death rates diminishes, but does not fully disappear when only non- smokers are considered, Hammond (118) found that the death rate for lung cancer in nonsmoking males was somewhat higher than for nonsmoking fe- males. However, the difference in male-female rates was much greater when smokers were compared. It appears that a substantial part of the difference in death rates between male smokers and fe- male smokers can be explained mainly by differences in their smok- ing habits. These differences in smoking habits between males and females are of two types. First, overall consumption among females is still significantly lower than that among males. In 1966 (,%?I), 30 per- cent of males reported that they had never smoked while for fe- males the corresponding figure was 59 percent. This study also noted that nearly three times as many males as females reported consuming more than 20 cigarettes per day. Second, it has been shown that women smoke differently than men (303) : They begin smoking later than men (114) and do not smoke cigarettes as close to the end, where proportionally more nicotine and "tar" are in- haled. Women smoke more filter-tip and "low tar and nicotine" cigarettes than men. Furthermore, cigarette smoking still tends to be heavily concentrated among women under the age at which lung cancer is most likely to occur. 251 Finally, analysis of the ratio of male and female lung cancer death rates (283, 284, 285, 286, 287, 288, 289, 2.90) reveals that since 1960 this ratio has shown a steady decline, reflecting the greater relative rise in mortality from lung cancer in the female population. LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION A number of studies have been concerned with the relative influ- ences of smoking, urban residence, and air pollution in the etiology of lung cancer. Table 9 lists studies performed in the United States, Great Britain, and Japan which have dealt with this question. Kotin and Falk (149, 250) and more recently the Royal College of Physi- cians (228) have reviewed the literature concerning the influence of atmospheric and environmental factors in the pathogenesis of lung cancer. The studies listed in table 9 show a number of important trends. Lung cancer death rates are found to be higher among urban popu- lations than among rural populations. It is not known to what ex- tent this urban factor in the etiology of lung cancer is due to differences in the levels of air pollution. Other factors associated with urban residence which may influence the etiology of lung cancer are : differences in smoking habits between the two popula- tions, occupational differences, and possible differences in the re- porting of lung cancer deaths (228). The studies also uniformly show that within each urban/rural grouping, lung cancer death rates increase with increased smoking. Whether air pollution acts with cigarette smoking to influence lung cancer death rates in a combined manner is presently unclear (112, 126, 261, 265), and the evidence concerning a separate role of air pollution in the etiology of lung cancer is still inconclusive (228). The recent report of the Royal College of Physicians on air pollu- tion and health (228) concluded that "the study of time trends in the death rates of lung cancer in urban areas demonstrates the overwhelming effect of cigarette smoking on the distribution of the disease. Indeed, only the detailed surveys that have taken individual smoking histories into account have succeeded in separating the relatively very small influence of the `urban factor' on the over- riding effect of cigarette smoking in the development of cancer of the lung." 252 TABLE 9.-Epidemiologic investigations conwxing the wlationsl,ip of hng cancer to smoking, air polhtion, and urban or rural residence (Actual "umber of deaths shown in parentheses) Author, Population Ye*=. studied and country. method of Results reference data collection Comme"ts Doll, Estimated death rates Lung canecr mortality (1950) per 1,000 Authors noted that 1953, from lung cllncer M&.9 FC?Tl&S Nonsmokers estimates are based on England in English London Other urban Rural Londo?~ Other urban Rum4 All area8 very few deaths. (70). population and Age: among nonsmokers 25-44 0.126 0.095 0.070 0.028 0.028 0.012 0.020 obtained from 45-64 1.672 1.264 0.861 0.194 0.162 0.120 0 090 general register. 65-74 3.124 2.00G 1.164 0.440 0.32F 0.288 `219 Stocks and Death rates in Male lung cancer death rates 195161 (prr 100.000) ngctl 51-74 The authors noted the Campbell, England and upward gradient among 1955, Northern Wales. Rural (68) Mixed (118) Urban (5.79) nonsmokers. pipe England Review of patient Nonsmokers __.............._.......,......_ 14 131 (8.55). smokers and light chart or interview Pipe .._.........__... 41 25 143 c.igerette smokers and the with kin or Cigarettes: Light 87 153 297 lack of a similar physicians. Moderate ,,.,,........._....._,.......,... 183 132 287 gradient among Heavy ._....................,.......... 363 303 394 moderate and heavy cigarette smokers. Hammond 187,783 white males Age etandardized death rates dve to bronchogcnic carcinoma (males) - Data excluded and Horn, in 9 states. adcnocarcinoma. when 1958. Questionnaire Suburb City of City of standardized for age and U.S.A. and interview. Rural or town 10,300-50,000 (120). >SO.OOO smoking, rural rate was Nonsmokers . 4.7 (2) 9.3 (3) 14.7 (4) still noted to be 26 Cigarette smokers 66.2 (62) 71.7 (67) 70.9(69) 85.2(83) percent less than urban. .~ TABLE g.-Epidemiologic investigations concerning the relationship of lung Cancer to smoking, air pollution, and wban or rural residence (cont.) (Actual number of deaths shown in parentheses) Author, Population Ye-. studied snd country. method of Results comments reference data collection HW"SZ.4 10 percent of all Age- md emoking-standardized lung cancer mOrt&tU rsaQtii% Standardized Mortality et al.. white male lung (epidermoid and undifferentiated carcinontas mh) Ratio = IOO for U.S. 1962, canwr deaths in U.S.A. white males age 35 and U.S.A. for 1958 Metropolitan counties Nonmetropolitan counties (11.3). over in 1958. The authors for whom next of >50,000 ,119 2.600-50.000 . .QO kin or physicians *ISO noted ". . joint lO,OOO-50.000 .I61 Rural nonfarm .74 eff'Xt.s Of residence and supplied smoking 2.600-10.000 . .99 Farm . . . . . . . . . ...57 smoking histories in the data. 2.191 cases @chedule of hng-cancer with adequate =ateS far greater than information. those expected on the a.%umption of additivity of the separate effects. . :' DOU 41,000 male British Standardized death rates for lung cancer The authors noted that and Hill, physicians. 1964. Questionnaire and rural mortality data England Conurbation(49) Large Towns (34) Small Towns (ad) follow-up of death Rural (IS) Nonsmokers 0.03 were affected by a (74). 0.00 0.11 0.12 certificate. Cigarette smokers: significant number of 1-14 . . . . . . . . . . . . . .._ 0.48 city residents 0.32 0.87 0.52 16-24 .._.......... 1.31 retiring to the country. 1.66 1.06 1.16 >25 . . . . .._......... 1.90 4.43 2.20 1.17 Wicken, 1,908 male and 1966. Lung tamer death rate pe+ lOO,OOO--age- and smoking-standardized femalelu"gcs"eer Total number of deaths Northern deathsover 35 Inner outer Belfast urtmn noted under method of STlUdl Ireland data collection include Years of *ge from Belfaet Belfast Environs AT.X8 TOWM (308). RUTal register. Personal 964 contTob3. Males X7(241) 139(167) 136(46) 118(185) 137(26) 47(149) interviews with Females 22 (38) 17 (24) 12 (6) 23 (35) kin or physicians. 22 (6) 12 (43) TABLE 9.-Epidemiologic in.vestigations concerning the relationship of lung cancer to smoking, air pollution, and urban or rural residence (con&) (Actual number of deaths shown in parentheses) Author. Population Yea=, studied and COUIltrV. method of Results referenee Buell et al.. 1967. U.S.A. (49). Hitosugi, 1968, Japan (126). data collection 304 lung cancer Age-adjusted lung cancer death rates per 100.000 man years and mottalitg ratios The authors noted the lack deaths among of death-rate difference American San Francisco/ AU other between Los Angeles and Legionnaires Los Angeles San Diego California countiee San Francisco regions aged 25 and over. Rate Ratio Rate Ratio Rate Ratio and concluded that Questionnaires to Nonsmokers _,.,..._.__..... 28.1 2.6 43.9 3.9 11.2 1.0 photochemical smog ia next of kin. Smokers : not related to l . . 241.3 21.6 226.0 20.2 137.6 12.3 185 male and Lung caacer death rate per 100,000 The authors postulated a female lung cancer slight synergistic deaths and 4,191 PoUution region effect between smoking matched controls Males LOW Intermediate High and air pollution. aged 36-14. Data Nonsmokers .._.......,.,...,........... . . . . . 11.6 3.8 4.9 from Smokers : questionnaires 1-14 cigarettes/day _. . . 10.6 14.2 23.6 and interviews. >16 ,,,,,.................................... 21.3 18.6 31.4 Fern&a Nonsmokers ,,.,...__.._._._..._............... 4.6 6.9 3.8 Smokers: 1-14 cigarettes/day . 19.7 16.6 16.3 >16 . . . . . . 12.4 20.6 17.1 Age- and smoking-adjusted lung cancer death rate per 100,000 E Males . . ..___._................................. Females . . . . . . . . . . . . . . . . . _.._.._............... LOW Intermediate High 16.1 22.4 28.4 7.6 11.6 8.1 LUNG CANCER AND OCCUPATIONAL HAZARDS Uranium Mining The excess risk for the development of lung cancer among uran- ium and fluorspar miners has been known for more than 30 years. In a recent review, Bair (17) noted that radon and radon-decay products are the only inhaled radionuclides to be epidemiologically related to lung cancer. Lundin, et al. (178), in a continuation of the work initiated by Wagoner, et al. (299, 300, 301)) have re- cently reported on a l7-year follow-up of 3,414 white underground uranium miners. The authors estimated that smoking uranium miners experienced an excess of lung cancer ten times greater than did nonsmoking miners. Saccomanno (231)) in recent testimony, analyzed the data of the United States Public Health Service (USPHS) Study Group as presented by Lundin, et al. (178) above. He reported that cigar- ette smoking uranium miners incurred lung cancer rates four times greater than those of other cigarette smokers. Of the 62 lung cancer deaths in this population, 60 occurred in smokers. He also observed that among 100,000 uranium miners 700 lung cancer deaths per year would be expected to occur among cigarette smokers compared with only 4 among nonsmokers. Other Occupations Nelson (199) has recently reviewed certain environmental and occupational hazards as they relate to inhalation carcinogenesis. He observed that cancer of the respiratory tract has been linked epidemiologically and, in some cases, experimentally with occupa- tional exposure to the following materials: chromium, nickel, arsenic, and asbestos. Doll (72) and Goldblatt (100)) in earlier reviews, also noted an association with coal, natural gas, and graphite exposures. Nickel Morgan (194) noted that much of the nasal and lung cancer at- tributed to nickel exposure may have been due to arsenical impuri- ties found in processed nickel prior to 1925. Doll (69) found that the number of excess deaths among nickel workers under 50 years of age had declined following the change in nickel manufacturing processes. The experiments of Hueper (1.~1) and Sunderman, et al. ( 267,268,26.9) have shown that both guinea pigs and rats develop lung cancer following chronic exposure to nickel carbonyl or nickel dust. Sunderman and Sunderman (270) also reported that ciga- rette smoke contains nickel and that this concentration of nickel 256 may be capable of inhibiting the induction of lung aryl hydroxylase, an enzyme which is able to detoxify aromatic hydrocarbons includ- ing known carcinogens such as benzo[a]pyrene. Asbestos In 1955, Doll (71) found that lung cancer was a definite hazard among asbestos workers, In a more recent study, Selikoff, et al. (Zl,ZnZ) examined the relationship of smoking and asbestos ex- posure to lung cancer. These authors followed 370 people who had been asbestos workers during the years 1942-1962. Over a 5-year follow-up period, 94 deaths occurred in this group, of which 24 were due to bronchogenic carcinoma. The authors noted that according to data obtained from Hammond (118), only 3.16 deaths from lung cancer would have been expected among smokers, and calculated a 7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87 nonsmokers or pipe and cigar smokers died of lung cancer. When the expected number of nonsmoker deaths (0.26) is compared with the actual number (~4) which occurred among the smoking asbes- tos workers, an extremely high mortality ratio of 92 to 1 is obtained, thus reflecting the possible interaction of asbestos exposure and cigarette smoking. Exposure of mice (179) and rats (106) to asbestos dust or the intratracheal injection of chrysotile asbestos dust has resulted in the production of significant numbers of primary pulmonary car- cinomas. Miller, et al, (181) exposed hamsters to intractracheal injections of benzo[a]pyrene. These authors observed that the addi- tion of the chrysotile variety of asbestos to the injections appeared to promote benzo[a]pyrene carcinogenesis in the respiratory tract, as determined by the time of appearance and yields of papillomas and carcinomas. Auenic A recent epidemiologic study by Lee and Fraumeni (16.3) has indicated an excess of lung cancer deaths among smelter workers exposed to arsenic for more than one year. Cigarette smoking was not taken into account in their computations. Experimental work on the induction of cancer in animals using arsenic has yielded either negative or inconclusive results (133,135). Chromium Exposure to industrial bichromate compounds has been associ- ated with an excess of lung cancer deaths (22,25cJ). Laskin, et al. (159) have recently reported that intrabronchial pellet implanta- 257 tion of various chromium compounds in rats is associated with the development of squamous cell carcinomas and adenocarcinomas. However, Nettesheim, et al. (ZOO) exposed mice to chromium oxide dust and observed that it had no discernible effect on lung tumor incidence. PATHOLOGICALSTUDIES Investigators who have conducted detailed autopsy studies on patients who died of lung cancer have reported the increased pres- ence, when compared to noncancer patients, of bronchial epithelial changes which they considered to be precursors of bronchogenic carcinoma (7, 8, 23, 51,. 101, 208, 220, 279, 309). Such changes include squamous metaplasia, atypical squamous metaplasia (with acanthosis, dyskeratosis, and numerous mitotic figures), and car- cinoma in situ. Carnes (51) noted that carcinoma in situ was pres- ent in 119 cases of lung cancer but not in any of the 119 controls who were matched for age, sex, and race. Autopsy studies comparing the frequency of these cancer- related changes in the lungs of smokers and nonsmokers are pre- sented in table 10. Virtually all the studies noted an increased prevalence of these epithelial alterations among smokers as com- pared with nonsmokers. Definite dosage-dependent relationships were evident in the results of many of the reports. Also, Auerbach, et al. (14) observed that the number of cells with atypical nuclei decreases progressively in the bronchial mucosa of ex-cigarette smokers, depending upon the number of years between cessation of smoking and death, although it usually remains above that found in nonsmokers. The cytologic studies included in this table (182, 198, 222) all noted an increased percentage of sputum specimens showing meta- plasia among smokers as compared with nonsmokers. PULMONARYCARCINOGENESIS General Aspects of Carcinogenesis Agents found in cigarette smoke which have been identified as, or are suspected of being carcinogenic, are listed in table 11. The list includes certain compounds which most probably contribute to the pathogenesis of the various cancers discussed in the other sec- tions of this chapter. Many other agents have been identified in tobacco and tobacco smoke. At the present time, they do not appear to bear a direct relationship to carcinogenesis. Stedman (262) and Wynder and Hoffmann (319) provide detailed listings and discus- sions concerning these materials. 258 TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (Actual number of cases show" in parentheses) Author. Y==, countrY, reference NuIu""`,";f method of selection R.?sllIts Comments Chang. 1967, U.S.A. and K0rell (55). 105 males and females 40-86 years of age. Percent of cases with brmachid basal cell hyperactivity Nonsmokers . . . . . . . . . . , . . . 23.6 (34) smokers . . . . . . . . . . . . . 43.7 (71) Heavy smokers . . . . . . . . . . . . . . . , . . . . . . . . . t61.3 (31) Smokers included pipe snd cigar smokers. t psO.01 in com- parison with nonsmokers. Hamilton et al.. 1957. U.S.A. (117). Selected autopsy material. Number Age range Smokers . . . . . . . . . . . . . . . . 16 39-71 Nonsmokers 20 26-83 Percent of cues with: Bad cell SQuamoua hyperplasia metaplaaia 86.6 20.0 40.0 15.0 Tsmaitional metaplaaia 40.0 36.0 No lung cancer patienta included. Sanderud, 100 males Percent of case6 with bronchial ag~arno~n epithelial netaplaia Nonsmokers in- 1956. autopsied at Nonsmokers . . . . . . . . . . . . . . . . . 64.0 (39) elude those Norway Gade Institute Pipe . . . . . . . . . . . . . . . . . . . . . . . . .._.........._.................. 80.6 (20) smoking less (240). on whom All cigarette . . . . . . . . . . . , . . . . . . . . . 79.0 (38) than or equal to smoking data Cigarettes per day: 6 grams per day. was available. E&14 . . . , . . . 70.0 (23) 16-26 . . . . . . . . . . , . . . . . 90.0 (10) >ZS . . . . . . . . . . . . . . . . , . . . . , . . . . . . , . . . 100.0 (6) Knudtaon, 100 persons Percent of cases with: Atupical Age, occupation, 1960, 23-86 years No. of NO Basal cell SQWtnOU8 proliferative and site of U.S.A. of age P+%WWd change hgperplasia metapIa.& ?"dWAlsia residence were (1.47). autopsied at Nonsmokers . . . . . . (21) 41.6 23.6 14.3 9.6 found to have no Seattle Cigarettes/day: appreciable Veterans 1-9 . . , . . . . . . . (9) 17.8 11.1 11.1 . . effect. Hospital on 10-16 . . . . . . . . . . . . . . . . . (11) 18.2 18.2 64.6 9.1 whom 16-20 . . .._........._.. (44) 20.4 29.6 29.6 29.6 smoking >21 . . . . . . . . . , . (9) 11.1 33.3 44.4 11.1 it data was Pipe or cigar , . , . , . (6) . . 100.0 . . available. rg TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokevs (cont.) (Actual "umber of cases shown in parentheses) Author. year, country, refrrenee Results COlllllle"tS Auerbach 339 persons et al.. 22-m years 1961, of age U.S.A. autopsied at (f2). East Orange Veterans Hospital (excludes lung Wl"C.X) Nonsmokers: <40 years of age 40-59 . 60-69 . >70 . . . . Smokers 70 . . Smokers >l pack/day: <40 years of age 4rk69 6lL69 . . . . . . >70 . ........ ........ ........ ........ ........ ........ ........ ........ . . 8 11 28 18 14 . . . 24 36 22 17 ._.. 63 . . . . 84 . . . . 15 Number of sections of bronchial epithelium 333 560 1,463 918 727 1,240 1.772 1,101 880 3,027 4,136 756 Percent sectimla Percent sections with cilia absent with bone and sntirel~ atypical cells atypical cell8 and cilia absent 0.3 0.1 0.6 0.1 4.7 1.0 16.9 0.5 10.8 0.6 9.4 1.5 12.5 4.5 17.4 6.9 20.5 9.8 23.7 The suthors noted a dose-response re- lation of smoking to: a. loss of cilia, b. increase in number of atypical cells, c. carcinoma in situ. Average "umber of sections per case equaled 62.3. Cross et al.. 1961, U.S.A. (64). 140 persons Percent aectiom showing changes in bronchial epithcltum (number of sectiona) t The authors noted autopsied at Squamow Atypicd Carcinoma that the differ- Iowa City NW??tld Hyperplmia metapimia ?fWtUplLISG in situ Carcinoma ence between Veterans Nonsmokers (31) . . 61(562) 36(137) 8 (33) t15 (68) . . . . smokers and "on- Hospital Smokers ( 109 ) . . . . . . . . . . . . . 44(570) 43(662) 16(197) 20(263) l(12) 2.6(34) smokers was on whom statistically smoking significant. data was available. TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.) (Actual "umber of cases show" in parentheses) Author. ye.8=, c0u*t.rY, reference %:k;oaf method of selection Results comments Auerbach et al., 1962. U.S.A. (14). 72 autopsied former ciga- rette smokers who had been smoking for 210 yc*lg and had ceased 25 years ago. Number of Percent sections Percent s&ions Percent sectiona Each a-smoker sectimu of with cilia absent with mmc atypi- with 50 percent matched with a brachial and entirely cd celk and atypical eel& current smoker Number epithelium atypical cells cilia absent and cilia preeent plus "ever-smoker Nonsmokers 72 3,166 0.0 0.1 0.6 for age. OCC"PB- Rx-smokers . 12 3,436 0.2 0.9 2.5 tion. and resi- Current smokers . 72 3,537 8.0 19.0 80.8 dence. There was an average of 50.3 sections per subject and none had less than 18 sections. TABLE IO.--Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, Number of Year, cases and country, method of ResU1t.S COllUIl.Xlts reference selection Auerbach 456 male and Percent *ec- Percent sec- Percent *ec- Major findings et al.. 302 female Number of tima with timw with tiom with 50 noted: 1962. smokers and wctiona of cilia absent wme atypi- percmt atypical Urban nonsmokers U.S.A. nonsmokers bronchial and entirely cd cells and ceUs and showed more (13). autopsied and Number epithelium atypical cell.9 cilia absent cilia present lesion than rural. matched for Males : Both lesions and rage. oceu- Nonsmokers . . . . . 41 2,346 0.1 0.7 atypical nuclei pation. and Cigarette smokers . . . . . . 75 3,393 6.9 21.2 78.6 were much less residence. Females: . . frequent in non- Nonsmokers . . . . . . . . 47 2,379 . . 0.1 0.5 smokers and less Cigarette smokers . 76 3,607 2.5 13.3 62.6 frequent in pipe Males : and cigar smokers Nonsmokers . . . 36 1.106 0.3 0.2 0.6 than in cigarette Cigar smokers . . . . . . . 36 1,733 10.0 10.7 smokers. Cigarette smokers . . . . . . 35 1.626 12.8 27.3 83.1 57.1% of cases bad 60-55 sections 31.5% of eases had 40-49 sections 7.3% of cases had 30-b9 sections 4.6% of cases had 16-29 sections Robbins, 1966, U.S.A. (2.22). 103 students Percent in each cytologic clads Smokers defined as 17-24 years Slight& Moderat& strmg1y those having eon- of age who Normal atypicd &p&l atypical sumd 210 ciga- underwent Nonsmokers (45) . . . . . . . . 86.7 4.4 8.9 . rettes a day for WXOSOl Smokers (58) . . . . . 55.2 32.8 10.3 1.7 21 year. sputum induction. TARI E lO.---Pathologic md cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.) (Actual number of crises shown in parentheses) Author. Number of year. cases and country, method of reference selection Results Maltoni 1,000 healthy Number Percent ahowinp mctaplasia et al., males who Nonsmokers . . 294 41.16 1968, underwent Smokers: Italy sputum l-10 cigarettes/day _. . ". 189 47.09 (182). induction. 11-20 . 385 51.43 21-30 . . 93 61.29 >30 . . 39 69.23 -~~- __ Nasiell, 50 nonsmoking Sputum crtologic changes Percent with t Regarded by 1968. outpatients, Percent Percent with utupical author 89 "real SWdCn 39X smokers Number M&S Mean age metaplasia metap1naiat premalignant (198). wrtmpatmg Nonsmokers 50 42 57.1 18 4 change." in general Smokers _. 393 73 46.6 62 27 health exam- ination who underwent SPUtUm induction. Spain et nl., 1970, U.S.A. (258). 15'7 males and TX females nutopsied fol- lowing sudden or accidentnl death fol whom smok- ina data were available (ex- smokers ex- cluded from female data). Males : Nonsmokers . Ex-smokers l pack Females: Nonsmokers l pack - ......... ......... ......... ......... ......... ........ ....... . . ,... ........ ........ ........ Number 36 . 21 32 6.8 34 . 18 . 26 Percent with metaplasia The authors found no evidence af 50.0 carcinomn in situ 67.7 or pwneoplastic 62.5 atypicnl changes. 73.5 34.1 33.3 46.1 In order to facilitate understanding of the relationships of the various compounds to one another, the third column presents the presently underst.ood relative importance of each of the various groups of compounds. These compounds have been tested only in animals or tissue cultures, and it should be stressed that the rela- tive importance of one compound may not be the same in man as it is in animals. Table 11 is divided into two major sections. The first section details those compounds which are considered to be or are suspected of being cancer initiators. These are compounds which induce irreversible changes in responsive cells. In the second section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the malrg- nant reproduction of cells in which neoplastic changes have been initiated. A number of these initiators may also act as complete carcinogens in their own right. The evidence concerning the two stage initiation-promotion mechanism is still rather limited for respiratory tract carcinogenesis. The pol~nuclear aromatic hydrocarbons (PAH) listed are pres- ently considered to play a very significant role in pulmonary car- cinogenesis due to tobacco smoking. These compounds act as tumor initiators or complete carcinogens. The particular role of these agents in environmental and occupational carcinogenesis has been reviewed by Falk, et al. (93). That such hydrocarbons are pro- duced from tobacco during human smoking has been shown by Kiryu and Kuratsune (2-N). These authors reported the presence of benz[ a] anthracene, chrysene, benzo[ alpyrene, and benzo- [blfluoranthene in the "tar" produced by normal smoking and measured in either filters or stubs. Two hydrocarbons which have frequently appeared in the litera- ture on experimental tobacco carcinogenesis may not actually be present in tobacco smoke. They have been used as representatives of carcinogenic PAH, a class which includes many constituents that have been ident.ified in cigarette smoke condensate. They are `Y,?C!-dimethy!benz[a]anthracene and 3-methylcholanthrene and have been frequently used as tumor initiators or complete carcino- gens, particularly in skin painting and tracheal implantation experiments. The nitrosumine compounds listed are potent carcinogens affect- ing many organ systems, including the respiratory tract (188, 199). Nagee and Barnes (181) have presented a detailed account of experiments in this area. Xitrosamines have been identified in trace amounts in tobacco "tar" and the conditions required for their formation (the presence of secondary amines and nitric oxide) are 264 TABLE Il.-Identified or suspected tumorigenic agents in cigurette smoke' Estimated concentrs- tion in 100 cigarettes (85 mm. "onfilter) Presently understood relative importance in experimental tobacco carcinogen&s I. Complete carcinogens and tumor initiators: Polynuclear aromatic hydrocarbons ........ 1. Benzo (a) pyrene .................. 2. Dibe"z(a,hlanthracene .......... 3. Be"zo(b)fluora"thene ............. 4,Benzo(j)fluoranthene .............. 6. Dibenzo(a,iJ pyrene ............... 6. Benz(a)anthracene .............. 7. Cbrysene .......................... 8. Indeno(l,2,3-cd),,yrene ........... 9. Be"zo(ciphenanthrene' ............. 10. MethyIbenzo(a)pyre"es .......... 11. Methylchrysenes .................... N-heterocyclic hydrocarbons .......... l-2 1. Dibenz(a,h)acridine ............ 0.01 2,Dibenz(a,j)acridine ................ 1.0 3. `IH-dibenzo (c&z) carbazole ........... 0.07 N-nitrosamines" l-10 1. Dimethylnitrosamine ............. 0.4 2. Diethyinitrosamine ............... TKXe 3. Methyl-n-butylnitrosamine .......... TlYWe 4. Nitrosopyrrolidine .................. 0.4 5. Nitrosopiperidine .................. TP3C-Z Epoxides, peroxy compounds. and la&ones: 1. Epoxides ........................... 2. Peroxides ................... 3. LarAones ........................... a. a-Leva"re"olide ................ b. a-Levantenolide ................ No data PRSe"t 20.0 2.0 N-alkyl-heterocyclics: 1. I-methylindoie ..................... Pesticides and fungicides :< 1. TDE ............................. 2.o,l;-DDD ....................... 3. DDT ...................... 4. Maleic hydrazide ................. 10-100 10.?OO IO-IOF 10-100 2-3 1.5" Beta-naphthyiamine ..,.,,,,.. Polonium 210 10-30 "I3 3.9 0.4 0.3 0.6 TlYSe 0.3 2.0 0.5 TCDX 0.1 2.0 Tumor initiators Tumor initiators. suspected carcinogens of possible importance (presence in fresh smoke possible). Certain of these compounds 8~ know" carcinogens; presence in smoke condensate not established. Possib!e initiator. No essentiai contribution suspected. Suspected b!adder carcinogen: of doubtf"i significance at reported ievels. Of some importance on!y in the -;irocuries case of relatively high conten- tration. but not important at reported levels. Nickelcompounds . Present Suspected carcinogens of some importance. 265 TABLE Il.-Identified or suspected tumorigenic agents in cigarette smoke' (cont.) Estimated concentra- tion in 100 cigarettes (85 mm. nonfilter) Presently understood relative importance in experimental tobacco carcinogenesis II. Tumor promoting agents: Neutral promoters (polymers) (unknown structures.) No data Of possible importance. Volatile phenols 20-30 mg. Of possible importance. 1. Phenol 2. Cresol Nonvolatile fatty acids 20.100 mg. Of minor importance. 1. Stearic acid 2. Oleic acid N-alkyl heterocyelics: Of possible importance. 1. I)-methylcarbazole . . . . . . . . . . . Present 1 Modified and expanded from (319. 320) with reference to (52, 60, 89. Ill. 149. 402. 261. 299,494.295). 2 Has not been tested as an initiator, but is a known complete carcinogen. 3 See Neurath. (9X), `See (112,128). found in tobacco smoke (38). However, nitrosamines may be arti- facts dependent on the method of smoke collection (201). Neurath (202) considers the nitrosamines listed in table 11 as being present in fresh cigarette smoke (253, 254). However, con- clusive confirmation of their presence in fresh smoke is not available (38,138,15.5,319). Certain of the pesticides and fungicides presently in use on tobacco have been found to be carcinogenic (91,273,280). A num- ber of these, such as DDT, are now being phased out of regular domestic use. The compounds listed have been shown to be present in trace amounts in mainstream tobacco smoke (I 11,128). A recent, extensive review by Guthrie (2 12 ) provides more detailed informa- tion concerning these agents. Radioactive isotopes can be found in tobacco and tobacco smoke (105). Potassium-40, while present in tobacco leaf, is not trans- mitted in any substantial amount to mainstream smoke (230). Polonium-210 (PO,,,,), however, is transmitted into the mainstream smoke (94, 123, 142, 145, 215, 217). A number of autopsy studies (table A12) have shown that the bronchial epithelium of smokers contains significantly more Po~,~ than that of nonsmokers. LitBe, et al. (172, 173, 17s) have also noted that the concentration of polonium was markedly higher at sites of bronchial bifurcation. These authors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic carcinomas are fre- 266 quently located at bifurcations and that the polonium levels which they found in those regions probably have biologic significance (~16). Other investigators (11.1, 217') have not observed this excess at bifurcations, and in a recent discussion Wynder and Hoff- mann (8.20) concluded that it appears unlikely that PO?,,, in the amounts present in cigarette smoke plays a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in cigarette smoke which are potent inhibitors of ciliary movement. Their importance in cnrcinogenesis derives from the increased amount of time which they afford the kno1v-n carcinogens to be present on the surface of the bronchial epithelium. These inhibitors include volatile aldehydes, hydrogen cyanide, nitrogen oxides, volatile phenols, and certain volatile acids such as formic and acetic (1.29). In some respects, the animal and tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in ot,her tissues in which tobacco smoke, particularly cigarette smoke, is believed to play a role. These general experiments will be presented here, however, with the experiments which bear on lung tissue directly. Skin Painting a,nd Shxtaneous Injection Numerous animal studies on rats, mice, and rabbits, have been performed utilizing known carcinogens, whole tobacco "tar," and various tobacco condensate subfractions, or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved animal skin. A selected number of these studies js presented in table A13. Numerous other studies, performed prior to and following 19.5:3, are reviewed by lvynder and Hoffmann (319). The skin painting method is still considered to be a valid pro- cedure for the identification of agents suspected of participating in Pulmonary carcinogenesis, as well as for the quantification of the reduction in tumorgenicity of specific agents, The exposure of tissue and organ cultures to cigarette smoke, its condensates, or its conhtituent compounds has been shown to sig- nificantly alter patterns of cell growth and reproduction. Table A14 Presents an outline of these experiments. Once again, less severe effects have been noted lvhen filtered smoke was used (165). 267 Tracheobronchial Implantation and Instillation. More complex experiments concerning the carcinogenicity of cigarette and tobacco smoke are represented by those which involve the direct implantation, instillation, or fixation of suspected ma- terials into the tracheobronchial tree of animals. Certain of these experiments are outlined in table AX. Recent reviews by Saffiotti (233,234) Laskin, et al. (159)) and Montesano, et al. (189) as well as that by Wynder and Hoffmann (319) provide more detailed and extensive accounts of these experiments. Of note among the results outlined in this table are the following : The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P) is combined with a carrier such as hematite dust (235)) and the definite increase in bronchial epithelial preneoplastic and neo- plastic changes among dogs treated with smoke condensate as com- pared with those undergoing only physical bronchial stimulation (224). Inhalation Various species, including mice, rats, hamsters, and dogs, have been exposed to cigarette smoke or aerosols of its constituents. These inhalation experiments are outlined in table A16. It must be noted that the majority of the studies listed involve the passive inhalation of the material presented usually in a chamber. Active inhalation experiments, exemplified by the work of Rockey and Speer (223) and Auerbach and his colleagues (11, 129) involved animals which were trained to inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Miihlbock (195) observed that cigarette smoke inhalation en- hances the already substantial rate of spontaneous alveolar cell carcinoma format.ion in hybrid mice, and various investigators in- duced adenomas in experimental animals (108, 168, 206). Harris and Negroni (I 21) found that exposure to cigarette smoke achieved some enhancement of adenocarcinoma formation in mice but did not observe proven squamous cell carcinoma. Some of their mice had also been exposed to Swine influenza virus aerosol. In a related study, Boren (32) exposed hamsters to cigarette smoke at set inter- vals over a 4%hour period. The author observed alterations in pul- monary cell kinetics (the pattern of DNA synthesis) as demon- strated by H"-thymidine autoradiography. The pattern of the label- ing response to cigarette smoke was significantly different from that of the response to high oxygen concentrations. Auerbach, et al. (22) have reported the development of early 268 invasive squamous cell bronchogenic carcinoma in dogs following a period of direct inhalation of cigarette smoke. These investiga- tors trained beagle dogs to inhale cigarette smoke through a tracheostoma (50) and divided the animals into groups according to dosage as detailed in table 17. A number of dogs died during the course of the experiment which ran for 875 days, or approximately 29 months. The causes of death are listed in table 18. All of the remaining dogs, with the exception of group "h" (high exposure, heavy weight), were sacrificed shortly after day 875 ; the survivors among the heavier dogs are continuing to smoke. Examination of the respiratory tree of the animals revealed a number of tumors (table 19). Most of these were similar to the type of tumor which in man is referred to as bronchiole-alveolar. This tumor arises in the bronchiolar and alveolar epithelium and tends to be multicentric. Two striking characteristics of these bronchiolo- alveolar tumors were the existence of a histologic spectrum (from a tumor resembling the benign condition of adenosis to frankly malignant tumors with invasion of the pleura and surrounding parenchyma) and the marked tendency to squamous change. Inva- sive bronchiole-alveolar tumors were found in 12 dogs in the group which had been exposed to the largest dosage of cigarette smoke. Several had tumors of more than one category. Ten of these dogs had invasive bronchiole-alveolar tumors which did not extend into the pleura, one dog had an invasive bronchiole-alveolar tumor which extended to the pleura, and four had invasive bronchiolo- alveolar tumors extending into the pleura beyond the pleural- pulmonary junctions. In addition, two bronchogenic squamous cell carcinomas were found in this group (table 19). The dosage de- pendence of tumor formation is shown in figures 2 and 3. Major findings of the study were twofold. First, that smoking filter-tip cigarettes was less harmful, both in terms of pulmonary parenchymal damage and lung tumors, than smoking identical cigarettes without filters. This supports the generally held view that total particulate matter is a meaningful indicator of the car- cinogenic potential of a cigarette, Second, lung cancer of two types found in man was produced by the inhalation of cigarette smoke. TWO of the dogs were found to have early invasive squamous cell carcinoma of the bronchus, and both belonged to the high-dosage group. These carcinomas were indistinguishable from early invasive squamous cell carcinomas found in the bronchial tubes of human beings who smoke cigarettes. The majority of tumors found in the dogs were of a bronchiole-alveolar type, which although not as common as squamous cell cancer in man, is not rare in humans. This type is often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 269 TABLE IT.-Datu on pedigreed m& beagle dogs of groups F, L, H, h, and N (Some of the figures apply only to dogs surviving 8'76 days or longer) Filter **O"p F NO filter gri?p NO filter grour, H fE* Nonsmokers group grO"P h N Number of doss on day No. 67' Weight at start (day No. 1) mean weight (pounds) Cigar&e s per dog II, 875 days _. t.. Mcarr numlwr of c~ynrettes per day _. _. Eauivalertt number of cigarettes per day for 150 pound man Type of cigarettes:' ___- 12 12 24 38 R 25.0 26.1 26.0 31.9 30.7 6,143 3,103 6,129 6.129 none 7.02 3.64 7.0 7.0 - 42.1 21.2 42.0 32.9 Milligrams of tar per cigarette . Milligrams of nicotine per cigarette Total dosage in 875 days: Grams of tar per dog _. Grams of niecrtinp per dog Dosage in Xi5 days relative to starting weight: Grams tar/pounds weight Grams nicotine/pounds weight _. _, 17.8 1.17 109.3 7.19 4.31 4.12 8.31 0.29 0.22 0.44 34.8 34.8 34.8 - 1.85 1.85 1.85 103.5 207.8 6.56 11.12 207.8 - 11.12 - 6.61 - 0.35 - -_I ____ ' The smoking dogs were divided into CLOUDS F. L. H. and h on dav No. 67. ? Dogs of groups L, H. and h smoked filter-tip cigarettes during a training period at the start of ,the experiment, but smoked nonfilter cigarettes thereafter. SOI'H~~~S: Adapted from Hammond, E. C. et al. (119). TABLE I%-Swmnary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, atztl N (Each death classified according to most severe condition-some dogs mbinnti25 _. ._ _. _. ,, 7.60 Pipe and cigart t Includes data on ex- NS . 1.00 smokers of pipes and cigars. SM 5.00 No NS died of laryngeo- tracheal cancer. therefore l-14 gram SM set as 1.00 standard. Data combine laryngeal and tracheal carcinoma. R IL 54 NS ..__.....__. 1.00 (3) Pipe Refers to current cigarette I_ SM .51 l-9 ..__._._..... 3.27 (1) NS 1.00 (3) smokers only. NS 3 l&20 8.45(10) SM .10.33 (6) 21-39 .13.62(11) Pipe and cigar >39 ,............ 18.85 (3) NS 1.00 (3) All ,. 9.95(25) SM .._. 7.28(11) 4 57 NS ._..__._... 1.00 (3) Pipe and cigar Male data only. SM ..54 SM (age 45-64) 6.09(32) NS 1.00 (3) Pipe and cigar data refer to NS 3 SM (age 65-79) 8.99(18) SM 3.37 (4) males 55-84 years of age. TABLE ZO.-Loyi~~gcnl cmccr 7nwtalitjj ratios (cont.) (Actual number of deaths shown in parentheses)' SM - Smokes. NS = Nonsmokers. I'rosyective studies Author, year, country, reference Number and type of population Data collection Number of lawngeal caneel deaths Cigawttrslday Pipes, cigars C""l"lZ?"tS Wrir and Dunn, 1970, U.S.A. (906). 68,153 males Questionnaire 5-8 11 NS - No nonsmokers died of in various and follow- SM ..ll *lo 1.00 Inryn~.eal carcinoma, occupations up of death NS 0 220 ., . 5.00 therefore -cl0 smoker set in California. certificnt~. >30 5.84 as 1.00 standard. NS includes pipe and cigar smokers. SM includes ex-smokers. ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, 01' ex-smokers. t.he hypopharynx. These authors noted that the percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls. However, it is of interest that the excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of laryngeal cancer. Wynder, et al. (872) reported a significantly increased risk of extrinsic cancer among those with alcohol intake above 7 ounces of whiskey per day. With less than this amount, no increased risk wa,s evident. Schwartz, et al. (&8), noted no effect in relation to alcohol intake. Further research into the interaction of these two variables is necessary. Auerbach, et al. (9) studied histological changes in the larynges of 942 men, age 21 to 95, who were autopsied at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained inter- viewers. The randomized histological sections were graded by one observer. Tables A23 and A21 summarize the findings in the true vocal cord. Of the men who never smoked, 7.5 percent had no cells with atypical nuclei, only -1.3 percent had sections with areas con- taining 60 to 69 percent of cells lvith atypical nuclei, and none had a higher percentage. The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. HoLvever, disintegrating nuclei \vere found in JO.5 per- cent of the ex-cigarette smokers and in only ()..I percent of the remaining cases. Only one of the 9 1 cigar and or pipe smokers had no atypical cells. Three had carcinoma irl sitrc, and one case had a section showing early invasive primary carcinoma. The highest percentage of atypical cells IVWS found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers n-as free of atypical nuclei in the laryngeal epithelium. Of those ivho smoked t\vo or more packs per day, 85 percent had 1eGons xvith 60 percent or more atypical cells as compared to -1 percent of the nonsmokers. Between 10 and 18 percent of the cigarette smokers had areas of carcinoma irz sitl(, and .I of the 64-I cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directl! related to the amount smoked. 280 EXPERIMESTAL STUDY Dontenwill (76) has recently reported the development of an effective and practicable method 1)~ n-hi& small rodents (ham- sters. rats? mice) can be exposed to long-term passive inhalation of cigarette smoke in a mannel' nhich circumvents the fatal effects of acute toxicity. which ruincc! earlie:, attempts but allows for a dosage of smoke great enough to induce the development of chronic patho- logical changes. The SJ.rian Golden hamster was found to be the most suitable species for such inhalation experiments for several reasons : its resistance to pulmonar!- infections, its resistance to the effects of nicotine a.5 compared to that of rats or certain strains of mice, and, especially, its susceptibility to develop tracheobronchial cancers after treatment nith carcinogens, in contrast to its almost total freedom from the spontaneous development of these tumors. Dontenwill demonstl*atecl that the concentration of deposited cigarette smoke uas greatest in the hamster's larynx as compared to the other portions of the exposed respiratory tract (table 25)) and that the lar\-ngeal epithelium was the tissue which underwent the greatest smoke-induced histological changes. In studying the changes in the larynx, the author differentiated five stages of epithelial change, using as his reference the Atlas of Tumor Pathology of the Armed Forces Institute of Pathology (5). Table 26, quoted by Dontenwill, describes the five types of change. They range from benign. such as epithelial hyperplasia, to pre- malignant. exemplified by pseudoepitheliomatous leukoplakia. The results of the inhalation experiment are presented in figure -1 in which a dosage-related increase in the severity of the epithelial changes is represented in graphic form. The author also reported, and depicted with photomicrographs, the finding of an early inva- sive squamous cell carcinoma. This form of cancer is the predomi- nant type involving the human larynx. SUMMARY AND CONCLUSIONS 1. Epidemiological, experimental, and pathological studies sup- port the conclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. The risk of developing laryngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same ol.cler as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 281 TABLE 25.~Deposition of `"C-lubeled smoke pwticies in particular regions of the respimtoq tract' Organ Traced radio- activity 01-g?in CnCi) Head and palate 6.11 Head. palate Tongue 0.41 Oral cavity in total. Larynx (r 39 Trachea 0.26 Lungs 6.35 1 Total 14.12 Eitimated Deposition radio- of activity particles (nCi) ( % 1 Traced Proportional depwsition area of the in relatirm respiratory to the tract ProPortional j-3 1.6 0.1-0.3 X561-187 1 ,Zl.i 0.6 X62.3 1000 Xl 1~11).0 282 TABLE 26.-Classification of the five registeredstages of epithelial charzgcs at the lwynx'.' stage -.-__~ --__~ __-- ~- ~.-. . ~~ - ..--. .~ Drskerntosis (we- mature atypical Acanthosis (thickm- H, ,,erkr,xt<& Pnrakeratosis (in- cornification ing of stratum increased complete cornifica- changes in the Mitosis spinosum multi- cornificntion tion of nuclei in nucleus prolifern- cellular layer) (stratum corneum) the stratum corneum) tion of the basal 1. t'nchvdwmia (epithelial hywrplasia) + + t t t 2. Leuroplakin + +- 1 r t 4. t'apillrnnntou~ kwruplakia + t t +it f TOTAL 146 34 35 8 6 10 7 11 4 5 17 4 5 . . . . . . . . . . . . . . . 5 . . . . . . . 4 . . . . . . . . 3 2 . . . . . . . . . . . . . 52 c " ,I I I I 2 4 6 8 10 12 14 16 18 20 22-28 SMOKE EXPOSURE, months . ZONE ANIMAL &=ANIMAL LIVING O=LARYNX CANNIBALIZED FIGURE 4.-Effects of chronic cigarette smoke inhalation on the hamster larynx. Review of the results of the inhalation experiments: number of smoke-ex- posed animals with and without changes in the larynx, duration of smoke exposure, and number of animals still alive. SOURCE: Dontenwill, W. (7G). ORAL CANCER The cancers included in this category are those of the lips, tongue, floor of the mouth, hard and soft palate, gingiva, alveolar mucosa, buccal mucosa, and oropharyns. It is estimated that 15,000 of these cancers will be diagnosed in the United States in 1970, accounting for about 2.5 percent of the estimated 600,000 malignant neo- plasms reported (289). A variety of histological types of malig- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the cancers. The incidence of and mortality from oral cancers has remained steady over the past 20 to 30 years. The Connecticut Cancer Reg- istry (88)) which is a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 and 16.3 per 100,000 population during the years from 1950-1961. Examination of mortality rates over the past 20 to 30 years (882, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 284 contrast to the sharp increase that took place in lung cancer rates in those years is probably due to serreral of the following factors. First, pipe and cigar smoking are both significantly related to can- cer of the oral cavity, and the increase in cigarette smoking among men, noted between 193r and 1955, has been, to a large degree, accompanied by corresponding l,eduetions in the use of pipe.; and cigars. Second, aside from the V:CYiOUS changes which the Interna- tional Classification of Diseases (ICD) had undergone during t.hat period, the diseases discussed above are recorded in ICD Codes 140-148 which include some neoplwms not found to he related to the use of tobacco. The various sites of cancer themselves do not contribute equally to the o\~e~all 1,atc and are subject to nidely dif- ferent cure rates, so that their contl.i1)ution. to the total incidence rate is different from their colltri~Jiltil~ll to the c~vt>rall mortality rate from oral cancer. Although more than 31,000 cancers of the oral cavit)- were estimated ;1~ nelvl:- di:cyno.& ill 1967, the total number of individual5 rcco~~ierl ;is tlJ,ing front oral wncer during that year was only 6,71 x (~8:)). Oral cancer occurs predominantly in people of the middle and older age groups. More than 90 percent of all oral cancers occur in persons over age -15, with the average age at time of diagnosis approximating 60. Although the majority of oral cancers occur in men, there is recent evidence that the ratio of males affected to females affected is decreasing (2.57). ~EPII,E?~~IOI,~)GIC.L\L STUDIES The use of tobacco in various forms has been associated with the development of cancer of the oral cavity and pharynx. The studies in this area of concer1, at-t' ?rul~- international, many having been carried out in Asian :" :ll~ns as well as in the M'est. The major pr(J~im,: ; t' u!~i:lumic~logic~~l htudies have found in- creased rates of fhcw .`::I "`.:rs for cigarette smokers as well as for pipe and cigar sni:)kei~:: (see table 27). Pipe smoking, per se, has long been recognizt:cl :~s a cause (Jf lip cancer (?!I1 ) . The methodol- ogy and results of the numerous retrospective studies are sum- marized in tal,lti:.i X28 ar:d AZ&. These studies almost uniformly show significant relalionships between the various forms of tobacco use and )`.' `::"-c'-: 1,; -1 P c:`.:: ;:t\-ity and pharynx. Studir5 !I; .`$-. :!: ,t' 1;~: h:~~e examined the prevalence or inci- dence of pl'enliijJ~J:,.!.. :i~n& , ,G;lrch as oral lettkoplakia, as well as that of cancer of the oral cavitp. In many of thwe studies, forms of tobacco use not prevalent in lyestern countries have been investi- gated, including reverse smoking (in which the lighted end of t.he cigarette is kept in the mouth close to the palate) and the chewing 285 TABLE 27.-Oral cancer mortality ratios-prospective studies Author year. country, reference Number and type of population Data collection (Actual number of deaths shown in parentheses) SM= Smokers. NS = Nonsmokers. FOllOW- Number UP Years of Cigarettes deaths Pipes, cigars Comments Hammond 187.783 white Questionnaire 3 $6 20/56 Pipe MiXCd Data referring to mortality and males in 9 and follow-up 5/M 21/56 ratio do not include cancer of HOlYI, states 50-69 of death NS ..3 Cigar larynx and esophagus. 195R, years of aEe. certificate. 6/66 t Excludes two occasional U.S.A. only smokers. (110). Doll nnd Approximately Questionnaire 10 19 All smokera by amount Pipe and cigar No NS died of oral CBIICCI', Hill, 41,000 male and follow-up SM .19 in gram.9 NS ....... 1.00 therefore 1-14 gram 1964. British of death NS .. . NS - .............. SM ....... 1.00 smoker set as 1.00 Great physicians. certificate. 1-4 ............. 1.00 standard. Britain 15-24 ............ 0.25 (74). >25 ............. 5.25 - .... ..-- . Kahn U.S. male Questionnaire Xl/, 61 NS .............. l.OO(ll) Pipe Data do not include pharynx. (Darn), wternns. and follow-up SM .50 tCias/day 1-9 .... 0.86 (1) NS ....... l.OO(ll) t Refers to current cigarette 1966, 2.265.674 of death NS .ll lo-20 ............ 2.93(13) SM ....... 3.12 (4) smokers only. U.S.A. ,:cI`:ioll YCBTS. cel~tifirnte. 21-39 ............ 7.34(20) Cigar (139). >39 ............. 5.73 (3) NS ....... l.OO(ll) All .............. 4.09(37) SM ........ 4.11 (9) H~~IllOlld. 410,65;: males Interviews by 4 95 NS .............. 1.00 (`7) t Pipeand/or t Male data only. Pipe and 1966, T,C2,1;71 females ACS volunteers SM .33 SM (age 45-64) ... 9.90(63) cigar. cigar data refer to males U.S.A. :ii-' I ycnrs "f NS .. . SM (sge65-`79) .. 2.!33(25) NS ....... 1.00 (7) 55-84 years of age. (118). apt ill 25 states. SM ....... 4.94(15) Weir and FR,lS:i lN.ales Questionnaire 5-R 19 NS .............. 1.00 SM includes ex-smokers. Dunn, in vat ious and follow-up -10 ............. 3.69 NS includes pipe and 1970, occupations of death -t20 ............. 1.17 cigar smokers. U.S.A. in California. certificate. >3n ............. 6.62 (.W(i). All .............. 2.76 of "pan" or "Nass," which are mixtures of tobacco with either betel nut or lime ash, and other ingredients (241, 2.55, 256). Snuff dipping, a habit in which snuff is placed in the gum and ret.ained there for prolonged periods, has also been associated with the development of oral cancer (1118, 210)) as has the chewing of tobacco (124, 193,211,298). The risk of developing a second primary mouth or throat cancer, after the recognition of the first primary cancer, has been found to be greater in continuing smokers than in those who quit smok- ing. All of the patients studied by Moore (190) were asymptomatic for at least three years following the treatment of the first cancer. Of the 117 patients with adequate smoking histories, only 4 of 33 (9 percent) who quit smoking developed a new primary cancer. On the other hand, 27 of 74 (36 percent) who continued to smoke developed a second primary cancer. However, a study by Castigliano (53) of patients treated fol oral cancer did not show a greater risk of a second primary among continuing smokers. In this study, 5 of 26 (19 percent) of those patients who did not quit smoking developed a second primary cancer as compared to 9 of 51 (18 percent) of those who did quit. The rate of quitting smoking in the two studies is markedly dif- ferent (36 percent in the Moore study and 62 percent in the Casti- gliano study). From the data presented in the two papers, it is not possible to evaluate the other significant ways in which the pop- ulations may have differed. Keller (1~0) studied 408 males with histologically confirmed squamous cell cancer of the mouth or pharynx. This author dealt with the question of recurrent tumors in a somewhat different manner. The patients were observed for the development of a sec- ond or third primary cancer at an anatomically discrete site of the mouth and pharynx within a median period of three years after the first cancer. He found that a second or third cancer (termed a coexisting cancer) developed in 28 of the 408 cases. Among these 23 cases with 32 coexisting neoplasms, 21.7 percent were heavy smokers, but among their matched controls, there were no heavy smokers. Coexisting cancers were most commonly found on the soft Palate, an anatomical site that is in direct contact with the main- stream of tobacco smoke. More recently, Wynder, et al. (S1S) studied 62 male and 23 female patients with multiple primary cancers of the mouth and pharynx. They observed that heavy smoking prior to the develop- ment of the oral cancer was associated with a greater likelihood of developing a second primary. Also, continued smoking after t.he fil'st primary was found to have a significant association with the occurrence of a second primary. 287 With or without smoking, use of alcohol appears to contribute to the development of oral cancer (124, lJ0, 183, 2.97, 322). In a study of male veterans, Keller (110) found that heavy smoking and heavy drinking were associated with cancer of the mouth and pharynx. X:0 studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrent nutritional deficiencies in the etiol- ogy of these cancers. EXPERIMENTAL STUDIES In 1964, the Advisory Committee to the Surgeon General on Smoking and Health (291) reported that cigarette smoke and ciga- rette smoke condensates had failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate of hamsters and t.hat the oral mucosa appears to be resistant in general to can- cer induction even when highly active carcinogens such as benzo- [alpyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanical factors, such as secretion of saliva, interfere with the retention of applied carcino- genic agents on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch, but it has also been pointed out that the cheek pouch lacks salivary glands and that its structure and func- tion differ from those of the oral mucosa. The majority of these studies are outlined in table AZ9. Although cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (319) supports the concept that cigarette smoke contains cancer promoters that may be of special importance, particularly in oral carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch. More importantly, regarding the chewing of tobacco, Bock, et al. (27. .30), Van Duuren, et al. (.Z!1$), and Wynder and Hoffmann ($21) have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting activity of the smoke. Roth, et al. (d?li , ~27) have shown that the dye-binding capacity of the DNA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DXA content of oral epithelial cells in smokers. Smokers had values of dye-binding capacity intermediate between nonsmokers and "1 patients with proven oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal values. SUMMARYANDCONCLUSIONS 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 deaths among American males in 1967 and 1,321 deaths among females. The death rate from esophageal cancer has remained relatively constant since 1939. EPIDEMIOLOGICAL STUDIES The major prospective epidemiological studies (table 30) have indicated a significant relationship between smoking and esopha- gea! cancer. Overall mortality ratios for male cigarette smokers range from 1.74 to 6.17. There are insufficient data concerning females for establishing firm conclusions. A number of retrospective studies concerning the relationship of smoking and esophageal cancer are outlined in table A31 and &la. Smokers incur risk ratios ranging from 1.3 to 6.6 when compared with nonsmokers. As in studies of oral cancer, the effect of alcohol consumption must be taken into account in studies of esophageal cancer. Because a relationship between alcohol consumption and tobacco use is kno1v-n to exist, Wynder and Bross (310) analyzed the association between tobacco consumption and esophageal cancer after adjust- ing for alcohol intake. They found that in the absence of alcohol consumption, there was no association between the use of tobacco and esophageal cancer but that in the presence of alcohol consump- tion, an increasing relative risk with increasing number of ciga- rettes smoked was apparent, as well as an association between cigar and pipe smoking and esophageal cancer. More recently, Takano, et al. (Z'6), in a retrospective study of `?(I0 patients with esophageal carcinoma, found an increased risk mith smoking which was magnified by increased alcohol consump- tion. Martinez ( 183) analyzed the association of tobacco usage and esophageal cancer after controlling fol. age, sex, and alcohol consumption. Increasing relative risks with increasing tobacco use 209 TABLE 30.-Esophageal cancer mortu& ratios-prospective studies (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, year, countrY, reference Number and type of population Data Follow- collection up years Number of esophageal cancer deaths Cigarettes/day pipes, cigars Commmts Hammond and HOlTl, 1958. U.S.A. (120). 1X7.783 white males in 9 states EDIM!, yenrs of age. Questionnaire and follow-up of death certificate. 3% 34 Cigarette smokers Pipe Mticd Data referring to NS ___ 1 15/33. 2/33 cigarette mortality ratios SM . ..33 Cigar smokers included cancer 2/3.1 13/33 of mouth and larynx. Doll and Approximately Questionnaire 10 29 All smokers bu amount tl'ipe and cigar t Includes ex- Hill, 41,000 mnlc and follow-up in grama NS 1.00 smokers of pipe 1964, British of death NS , ._ 1.00 SM 2.00 and cigars. Great physicians. certificate. 1-14 2.00 Britain 15-24 3.60 (74). >25 5.00 All 3.00 -____- __ Katm U.S. male Questionnaire 8 `A 111 NS l.OO(tl) Pipe t Refers to (Darn), veterans and follow-up NS 11 t1-9 1.76 (2) 1.99 (3) cigarette 1966. 2,265,674 of death SM . ..lOO 10-19 4.71(18) Cigar smoking U.S.A. person years. certificate. 20-39 .11.50(24) 5.33(12) OdY. (139). >25 7.65 (3) All 6.17(47) Hammond, 440.sj5X malrs Interviews by 4 46 NS 1.00 (6) Pipe and Cigar 1966. 562,671 females ACS volunteers. NS . 6 SM (age NS 1.00 U.S.A. 35 a4 years of SM 40 45-64) 4.1'7(32) SM 3.97(14) (118). age in 25 States. SM (age 65-79) 1.74 (8) (Actual number of deaths shown in parentheses) SM= Smokers. NS = Nonsmokers. . Author year. country. reference Number and type of population Data Follow- collection up years HirElYalIla, 265,118 male Trained PHS II/& SM . ..21 NS l.OO(p30 l.f?2 (SUB). All 1.82 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellnncous, mixed, or ex-smokers. Comments Refers to all forms of smoking. NS includes pipe and cigar smokers. were noted. The consumption of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGICALSTUDY Autopsy studies of smokers as compared with nonsmokers, spe- cifically observing the pathological changes in esophageal tissue, have been performed by Auerbach, et al. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epithelium. Esophageal epithelial cells with atypical nuclei (having an irregular distribution of chromatin) were found far more frequently in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers. An increase in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasia. Tables A32 and A33 summarize these findings. EXPERIMENTALSTUDIES Kuratsune, et al. (156) investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studied by fluorescence microscopy. Deeper penetration and a different distribution were found when B[a]P was dissolved in aqueous ethanol as compared to B[a]P in olive oil. It was also found that benzo[a]anthracene and fluoran- thene dissolved in ethanol solution or aqueous caffeine solution could penetrate the epithelium of the esophagus. Horie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink a solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also developed in a group of 63 mice to which 4nitroquinoline l-oxide was administered in the same way. None of the 67 control animals given only diluted ethanol developed neoplasms. Several other authors have reported nitrosamine-induced esopha- geal cancer in experimental animals (56, 79, 80, 81) . As noted above, the presence of nitrosamines in cigarette smoke is still a subject of debate. 292 SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esopha- gus. The risk of developing esophageal cancer among pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association be- tween esophageal cancer and alcohol consumption and tthat alcohol consumption may interact with cigarette smoking. This combina- tion of exposures is associated with especially high rates of cancer of the esophagus. CANCER OF THE URINARY BLADDER AND KIDNEY EPIDEMIOLOGICAL STUDIES (BLADDER) Cancer of the urinary bladder accounted for 6,019 deaths among American males and 2,743 deaths among American females in 1967 (289). Incidence rates have increased from 1949 to 1962 (88)) but the death rates from bladder cancer have remained relatively stable during that period. Improvements in early diagnosis and therapy may have masked the increasing incidence of this disease. A number of epidemiological studies have indicated that smokers have an increased risk of contracting or of dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney cancer mortality in the results. The major prospective stud- ies, with the exception of that of British physicians, have shown bladder cancer mortality ratios among cigarette smokers ranging from 1.40 to 2.89. Smokers of more than 1 pack per day were shown to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 7'5) of British physicians, on the other hand, reports death rates for smokers to be lower than those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers are substantially lower than those among cigarette smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (139) to incur ratios approximating 1.20. Retrospective studies (table A35a) have also shown an increased proportion of smokers among bladder cancer patients when com- pared with matched controls. Relative risk ratios for bladder can- cer among smokers range from 1.0 to 7.3 among all smokers and up to 10.3 among heavy smokers of all types. 293 TABLE 34.-Kidney and urinary bladder cancer--prospective studies-Mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, yen=. Number ar.d Data Follow- Number country, type of collection up years of Cigarette/day Kidney Bladder Comments reference population deaths Pipe. cigar Hammond 187,783 white Questionnaire 3 I/(? and Horn, 1958. U.S.A. (120). males in 9 and states. intrrview. 287 NS 1.00(383 Pipe 20 3.42(41) Cigar NS .1.00(38) SM .1.06(19) Data include patients dying of prostatic carcinoma. Data refer to microscopically PlW"Wl carcinomas. Doll and Approximately Questionnaire 10 Hill, 41,000 male and follow- 1964, British UP of death Cl-eat physicians. certificate. Britain (74). Best, Approximately Questionnaire 10 1966, 78,000 male and follow- Canada Canadian UP of death (21). veterans. certificnte. Hammond, 440,66X males Interviews by 4 1966. 562.671 ACS U.S.A. females volunteers. (11X). 35-84 years of age in 25 states. 38 NS ..l.OO SM ..0.41 All SM bg amount in grams NS . ..l.OO l-14 .0.59 15-24 .0.65 >25 .0.76 All .0.`71 114 NS 1.00 Pipe Refers to 20 1.43(16) Cigar group. All 1.40(10) NS ..I.00 SM .1.16 (3) Bladder 138 SM ,115 NS 23 Kidney 104 SM 82 NS 22 Cigarettes Cigarettes Male data onl2/. NS .1.00(22) 1.00(23) Bladderincludes SM (age 45-64) .1.42(64) 2.00(59) other urinary SM (we 65-79) .1.57(28) 2.96(S) tract cancers. `I'ABLE 34.-KicOlc7!y und wimry hladdcr cancer-prospective studies--Mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Number and Data Follow- Number type of collection pom&ition "I) Years de:ftha Cigarette/day Pipe, cigar Kidney Bladder comments Kahn U.S. malt Questionnaire (Darn), vetcrnns and folluw- 13FF, 2,265,G74 up of death U.S.A. person certificate. (138). years. Hirayama, 265,118 male Trained PHS 1067, ana female nurse inter- Japan adults 40 view and (125). yea,? of age follow-up and older. of death certificate. Weir and FR,lRR males Questionnaire DlIIlll. in various pnd follnw- 1070, occupations up of death 1J.S.A. in California. certificate. (sns). -.- .___ S'/, Bladder NS _... .1.00(38) 1.00(52) Bladder includes 224 Pipe .1.32 (6) 1.20 (8) other urinary SM ,112 Cigar .O.W (6) 0.94 (10) tract calleers. NS . 52 Ciaarettes/day: Kidwey l-9 .a.97 (4) 1.10 (6) 141 10-19 .1.34(21) 1.93(U) SM ,102 20-38 l&8(16) 3.20(34) NS 39 >39 .2.76 (5) 2.62 (6) All . .1.45(46) 2.15(82) _.--. -___ l',$ SM 6 NS 1.00 Bladder cancer only. SM . . ..lO.OO (6) Refers to all forms of smoking. 6-8 Bladder 27 Kidney 27 NS a10 ?20 >30 All 1.0" NS . ..l.OO SM include ex- .0.&i .3.30 .2.57 .2.46 ?lO .1.52 smokers. 520 .2.81 NS include pipe >30 .5.41 and cigar A11 .2.89 smokers. ' Unless otherwise specified, disparities between the total number of deaths and thr sum nf the individual smoking categories are due to the exclusion of either wcasional. miscellaneous, mixed, or w-smokers. EPIDEMIOLOGICAL STUDIES (KIDNEY) A total of 5,894 Americans died of cancer of the kidney during 1967. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies. The three major studies which separately examine the relationship of kidney cancer to smoking (table 34), namely those of Hammond (II 8)) Kahn (139), and Weir and Dunn (306)) have shown mortality ratios for all cigarette smokers to range from 1.42 to 2.46. Retrospective studies by Bennington, et al. (18, 19) have indicated a significant association between all forms of smoking and renal adenoma and adenocarcinoma. EXPERIMENTAL STUDIES Numerous experiments have been undertaken by many investi- gators to elucidate the relationship of tobacco smoking to bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladder carcinogen, beta naphthylamine, in cigarette smoke and the presence of abnormal tryptophan me- tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial exposure of workers, beta naphthylamine has long been known as a bladder carcinogen. Complementing such data was the work of Hueper, et al. (136) who subjected mongrel dogs to daily subcutaneous injec- tions and oral administration of commercial beta naphthylamine. Thirteen of the 16 animals developed bladder papillomas and car- cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet containing up to 1.0 percent beta naphthylamine and observed that 18 of 39 animals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et al. (5.9) ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional cell carcinomas of the urinary blad- der were induced in 9 of the animals, and a dose-response relation- ship was apparent. Pailer, et al. (207') and Miller and Stedman (185) failed to find this amine in cigarette smoke. However, more recently, Hoffmann, et al. (127) identified it in cigarette smoke. The authors, noting the minute quantity present in each cigarette (2.2 x l&`g), hesi- tated to attach a biological significance to the finding. Of more recent interest have been the metabolites of tryptophan present in certain patients with bladder cancer. A number of nor- mal and abnormal metabolites of tryptophan have been found to be carcinogenic when tested by implantation in the bladders of mice. These include 3hydroxykynurenine (OHKy), 3-hydroxyanthranilic 196 acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino- phenols), the g-methyl ether of xanthurenic acid (CHXa) , xanthu- renic acid (Xa) , L-kynurenine (KY), quinaldic acid, and 3-meth- oxyanthranilic acid (3CHOA) (2, 36, 37, 39, 47, $8). OHKy and OHA are frequently present in human urine, as is kynurenic acid (WA). Certain investigators have concentrated their attention on the presence of abnormal tryptophan metabolites and increased amounts of normal tryptophan metabolites in the urine of patients with bladder cancer as compared with selected controls (1, 10, $6, 97, 148, 211, 2;3, 32.9). These authors have observed the increased excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky- nurenine in such patients. Yoshida, et al. (Jz!?), in a recent study concerning the relationship between tryptophan metabolism and heterotopic recurrences of human urinary bladder tumors, reported that those patients with recurrences showed abnormal metabolfte excretion more often than those without recurrences. The relationship of smoking to these biochemical findings is presently uncertain. Kerr, et al. (123)) in 30 experiments on 3 smokers and 3 nonsmokers who were given large doses of trypto- phan, found that smoking increased the urinary excretion of OHKy and OHA and decreased that of N'methylnicotinamide (an end product of tryptophan metabolism). Kerr concluded that smoking interferes with the normal metabolism of tryptophan. Recently, Brown, et al. (is) studied 15 adults under smoking and abstinence conditions and found that except for the basal excretion of acetylky- nurenine, tryptophan metabolite excretion did not change with smoking or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers under basal and tryptophan- loaded conditions. No differences were observed in the excretion of the measured tryptophan metabolites. However, due to its instabil- ity, OHA was not measured. The authors concluded that the rela- tionship of smoking to urinary bladder cancer was probably not via its effect on the kynurenine pathway of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel, et al. (241, 215). The authors observed an elevated concentration of certain ortho-aminophenols in the urine of bladder cancer patients and cigarette smokers, when compared with nonsmokers (241). More recently (215) , the same group compared the chemilumines- cence of the urines of smokers, nonsmokers, and bladder tumor patients. They noted that nonsmokers showed the lowest level of luminescence (which they relate to the presence of aromatic hydro- carbons) and the bladder tumor patients the highest level. The normal cigarette smokers' level was found to be intermediate. 297 TABLE 36.-Pancreatic cancer mortality ratiosqrospective studies (Actual number of deaths shown in parentheses)' S.M x Smokers. NS = Nonsmokers. .____- Author. year, Number and Data I+llOW-UP Number Comments country, type of collection years of deaths Cigarettes Pipes, cigars reference population ___~ Best. Appro\imntelp Queutionnni;~ F SM 35 Currntt ~cigarcttes OnLY) Pipes -- 7x.000 male Canadian vrternns. and folk,w-up of death crrtiiicate. NS 1.00 NS .l.OO 20 .,.. 2.37 (7) NS .l.OO SM .2.63 (1) -~ ~-___ -: Hammond 140,55X male5 Intcrvicms b, 4 262 NS~.. 1.00 (29) Male data only. 19GG St;L'.liil fcmnies ACS SM . ..a233 SM (age U.S.A. .15-x4 )Iw,w v~,ln"tre~.s. NS 29 45-64 ) Z.G9(158) (IIY). of nge in 25 SM (age stntrs. 65-79) 2.17 (75) Kahn (Darn ) 10 c G __ 344 NS 1.00 (88) Pipes ~~~ t Refers to current smokers tSM . ..256 1-9 0x7 (8) NS .1.00(88) of all types. NS X8 lo-20 1.93 (65) SM ..0.74 (8) 1J.S.A. per`s,," yr?ll'b. certifiratc. 21-39 2.18 (43) Cigar8 ( I.79 , >39 1.87 (7) NS .l.OO(SS) All 1.84(125) SM .1.52(27) Both NS .l.OU(RUt SM .0.93;13; Hirasrima, 265.11~ malr Trained PHS 111 SM 14 NS t. 1.00 - l!lCi, and femnle nurse inter- 1 (Pa0 1.44 All 2.43 NS includes pipe and cigar smokers. At present, no definite conclusions can IX: rlra\vn concerning the interrelationships of bladder cancer, abnormal tryptophan metab- olism, and tobacco smoking. Further study is required in this and the other areas of bladder cancer pathophysiology. SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancel' of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of trypto- phan and may in this way contribute to the development of urinary tract cancer. CANCER OF THE PANCREAS Several prospective epidemiologic studies have suggested a rela- tionship between cigarette smoking and cancer of the pancreas (table 36). A retrospective study of 465 cases of pancreatic cancer by Ishii, et al. (137) has shown a dose-related increased risk of pancreatic cancer in association with smoking. Analysis of dietary data revealed that the relative risk for pancreatic cancer from smoking was considerably greater than from dietary factors. No experimental studies relating to this question have been reported. SUMMARY AND CONCLUSIONS Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. 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Cancer 5 (2) : ::R!l-:n- heavy non- heavy ratio IlO"- heavy Iloll- heavy ratio N umlwr srnllhcl,b smokers' Number, smokers smokers' SM:NS" Number smokers smokrrs' Number smokers smokers' SM:NS? ~_____ ~... - - - nirchnell 93 5.4 3X.5 IRF 6.5 23.2 1.2 7 57.1 14 7X.6 . . . 2.8 et al., 1!,6'2 (180), 25.1 1,357 4.5 13.4 9.4 10X 37.0 11.1 10X 54.6 0.9 2.1 Percentage "heavy" smokers understated. __--~~ ~__ ___-. __. Sndowsky 477 :3.X 615 13.2 .,. 3.9 (1) (1) (1) (1) (1) (`1 Gradient et ill., with amount 1953 (IOS,). smoked. _____ ~~~ Wyndrr and (i :3 4.1 67.6 133 20.6 29.3 36.1 (`) (9 -(a) (`) v ) (4) COlVlfit?kl, ,053 (314). Watson and 265 1.9 71.7 287 9.7 61.6 35.6 36 58.3 2.x 181 32.0 1.1 3.3 Conte, 1954 (305). -~ (;stdl, 135 0.7 6X.1 135 16.9 14.0 326.8 t') (1). (`) (`1 (1) (0 1954 (107). TABLE A4.-Group characteristics in retrospective stzcrlies on lung cancer and tobacco use (cont.) SM z Smokers. NS = Nonsmokers. Md.3 Females Author. CCiSC?S Controls Cases Controls Year. R%ve - Relative Comments reference Percent Percent Percent pc;t Percent Percent Percent Percent risk 2 non- heavy non- ratio Num- non- heavy non- ratio smokers smokers' Number smokers smokers' SM:NF heavy ber smokers smokers' Number smokers smokers' SM:NS? Randig, 415 1.2 34.2 381 6.8 17.9 35.1 33 51.5 3.0 131 70.3 0 2.2 1954 (218). Wynder et al., (`) (4) (`) (4) (4) (`) . . . 105 56.2 16.2 1,304 66.0 3.4 1.4 1956 (911). Segi et al., 166 .~I . . . 2,124 . . . . ,. . Quantities 1957 (?50). smoked stated as averages only. Differences are statistically significant. Mills and PlTter, 1957 (187). 434 x.4 26.0 1,588 27.6 5.3 4.2 94 83.0 4.3 1,722 73.3 0.5 0.6 Percent "heavy" smokers under- stated. Only 50:; S"1`YLIJ response among female cLlscs. Stocks, 2.101 1.9 28.2 6.960 8.7 22.3 4.9 255 57.6 17.2 3,402 68.6 10.7 1.6 1957 (268). Schwartz and 602 1.0 53.2 1,204 9.6 36.2 10.4 (`1 (4) (4) (`) (1) (4) Denoix, 1957 (147). Haenszel and (*) (`) (6) (`) (4) (4) 15x 51.9 14.6 339 694 8.2 2.6 Shimkin, E 1968 (113). d TARLE A4.--Group characteristics in mtyospective sfrc.tlics OPL lung camcr and tobacco MC (cont.) SM = Smokers. NS = Nonsmokers. M&S FelI%-&S Author, CFXSCS Controls CCiSf3 Controls war, R&W reference Percent Percent Percent Percent Relative Commrnts Percent Num- non- heavy Percent heavy Percent Percent risk non- ber ratio heavy smokers smokers' "all- Number non- heavy ratio smokers smokers' SM:NS? Number smokers smokers' Number smokers smokers' SM:NS' Lombard and 500 1.6 4,238 11.0 7.9 (4) (4) (1) (J) (1) Snegireff, (`1 Authors' 1959 (176). calculations for heavy smoking based on lifetime number of packs of cigarettes. PLWlU, 1,477 6.6 34.5 713 37.2 20.8 8.4 129 85.3 26.4- 1,060 91.6 ; 0.7 1960 (211). 1.9 Quantities given only in grams per day. Hal?llSZel 2,191 3.4 41.9 (4) 16.2 12.0 6.2 (4) (1) (1) - (1) (4) (`) . . Population et al., 1962 (212). sample of R1.516 used as base. Not a case- control study. Lancaster, 23x 2.5 86.1 476 20.1 11.2 9.8 (`)T (`1 (4) (4) (4) 1962 (158). (4) . Haenszel and (`) (4) (4) (4) (4) (4) . . . 749 60.9 11.5 (&I 67.3 Taeuber. 2.5 1.3 Population 1964 (11.5). sample of 34.33S used 88 base. Not a case-control study. TAHLE Al.-Grout cltaructeristics in retrospective studies on lung cancw nnd tobacco usr (cwt.) SM = Smokers. NS = Nonsmokers. M&S Females Author. Cases controls Cases Co"trols Ye==, *fitiF Relative Comments reference Percent Percent Percent ?erc;t Percent Percent Percent percent risk %?- "On- heavy non- ratio non- heavy non- smokers smokers' Number smokers smokenl SM:NS Number smokers smokers' Number heavy ratio smokers smokers' SM:NS? Wicken, 803 4.0 40.0 803 14.0 22.0 8.9 151 58.0 29.0 151 80.0 17.0 2.9 Heavy smokers- 1966 (308). greater than 23 a day. Gelfand et al., 32 6.3 . . 32 63.0 . . . `26.3 (4) (`) (`) (4) (4) (1) . 1968 (98). -- Hitosugi. 124 6.6 67.8 1,839 13.2 66.0 2.6 61 54.1 6.6 2,352 80.5 2.9 2.3 Air pollution 1968 (225). fou"d to have no effect on lU"Y Cancel rates of non- smokers. Heavy amokers-great- er than 15 a day. Bradshaw and 45 0.0 341 31.7 . . (4) (`1 (`1 (`1 (4) (4) . . Schonland. 1969 (41). Or"los et al., 94 7.5 58.5 1,811 42.9 58.9 9.3 24 95.R 0.0 1,278 Xl.7 9.7 0.2 Heavy smokers- 1969 (204). greater than 15 R day. Wynder et al.. 210 1.4 67.5 420 21.0 40.9 320.8 30 16.7 44.0 132 57.6 23.3 6.18 Heavy 1970 (334). sm<,kers- grenter than 20 II day. ' For this table, heavy smokers are defined BS those smoking 20 or more 3 Based upon fewer than 5 case nonsmokers ii cigarettes per day, unless otherwise stated. 4 Does not apply. w `Computed according to method of Cornfield. J. (61). TABLE A?`.-Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Small cell anaplastic carcinoma ("oat-cell" carcinoma). Group II: A. Adenocarcinoma. B. Bronchiole-alveolar cell carcinoma. C. Carcinoid tumor. D. Mucous gland tumor. Extra (not included in I and II): A. Large cell undifferentiated exrcinoma. B. Combined epidermoid and adenocarcinoma. Unsuitable for diagnosis. SOURCE: Kreyberg, L. (15.3). 334 TABLE AlB.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers NS = Nonsmokers. SM = Smokers. AlIthOt+, Year. Number country. of Results Comments reference cases Little et al.. 1964, U.S.A. (175). NS . . . . . . 5 SM _. . . . . . . .1!2 Port0 level.3 in vavioue tisauelr (pclg tissue) Vertebral bodies, renal Peribronchia! Bronchial cortex. spleen, and lymph nodes Lung (average) epithelium urinary bladder showed 0.011 0.001-2 negligible no differences. 0.011 0.008 0.028-1.25 Hill, 1965, U.S.A. (1%`). Mcaw Pd'o levels in variown tiswrss (pc/kg tissue) The authors found no Brmchial tree AlVLdZC Total lung Liver Kidneu excessive concentrations NS . . . . . . 6 3.1 3.4 3.2 14.8 15.0 at bronchial bifurca- SM . . . . . . . . . . . . 4 7.3 9.9 8.6 20.0 20.5 tions. Little et al.. 1966, U.S.A. (274). NS . . . . . . . . 8 SM . . . . . . .26 P&O levela in variou.4 epithelial tiusw regions of lung (pc/g)t Site: Mainstem bronchus . l year. tc. 112 51 O/61 O/61 f Experimental group. strain.) C. Whole condensate. SE. 672 . . . 220 10/220 6/220 TABLE AIS.-Experiments concerning the efects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, A%Y' A. Method, year. B. Frequency and/ country, strain or duration. Results Comments reference C. Material Wynder Swiss mice A. Painting skin. Percent Percent et al.. B. Varied for 12 Treatment: Number papillomw carcinomas 1967, months. S/week ..,................ 60 12.0 8.0 U.S.A. C. Whole condensate B/week . . . . . . 50 38.0 16.0 (828). in acetone. Z/week . . . . . . . . 40 10.0 3.0 l/week . . 40 6.0 . Wynder and CAFl or A. Painting shaved skin. Percent Percent Swiss mice noted Wright, Swiss B. S/week for lifespan. Treatment CAFI: Number papillomaa carcino7naa to be more smt- 1951, mice. C. Whole "tar" or nicotine Whole "tar" . . . . . . . 30 53.0 27.0 ceptible. U.S.A. free "tar" derived Nicotine free "tar" . 40 13.0 26.0 Majority of carcino- (S28). from pipe and Cigarette "tar" . 30 30.0 30.0 gem noted to be cigarette tobacco. Pipe "tar" .__.._......... 30 60.0 20.0 in neutral fraction Treatment Swiss: of condensate. Whole "tar" 30 53.0 10.0 Nicotine free "tar" . 40 43.0 20.0 Cigarette "tar" . 30 63.0 33.0 Pipe "tar" . . 30 63.0 60.0 Gellhorn, Paris R III A. Painting shaved skin. Treatment: Popillumalr Carcinomas 1958, mice B. Varied for l-2 years. Benzpyrene (twice only) 20/529 6/629 U.S.A. C. "Tar" in acetone. Croton oil (5/6 week) 4/26 O/26 (99). benzpyrene. "Tar" (5/6 week) . 3/659 Z/559 eroton oil. Acetone (E/6 week) o/30 o/30 "Tar" and croton oil (5/6 week) 10/175 O/176 Bock and Swiss A. Painting skin. Percent Moore, female B. S/week for lifespan. Group: Number living at 6 mo?tths Skin tumors at 64 weeks 1959. mice C. Whole condensate Painted . . . 49 13.0 U.S.A. irradiation. Painted and irradiated 65 44.0 (28). Irradiated . . . . . . . 36 . . . 3 TABLE A13.-Erpwimnts concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its comtituents u~)ot~ nni),lrrls (uIw~.) Author, Animal A. Method. Year. and a. Frequency and/ country. strain or duration, Results reference C. Material Comments Druekrey, Rats A. Subcutaneous G70up: 1961, Sarcowm.3 t Control group. inlectiu". tc . . . . . . . . . l/75 GW"l?2"Y 13. l/week for 60 weeks. i Expeumental group. $E ..._........_..._............,,, 15/75 (7.9). C. Smoke condensate in trirauwli" nnd alcohol. Bock et al., ICR Swiss A. PRintins shaved skin. - Sllr?~iz~illg Pcrcc n t Z'urcnt Sl;iu 1962, mice R. IO/week for 1 year. Trcutment: nt 1x WCT/,~S Skin Cnnccr U.S.A. neoplasia (`. Ciwrette "tar". Standard ciaarette 24/30 (Sl). 25.0 54.0 Standard cigsrette 21i30 5.0 57.0 Stnndard cigercttc 18130 33.0 44.0 Standnrd cigarette 13'30 23.0 62.0 Filter cigarette 30/30 7.0 27.0 Filter cigarette 30130 3.0 23.0 Acetcme only fin/fit? Control . . . 65/65 Roe, Albino mice A. Painting shaved skin. Trer.tment: 1962. Sur~iwws Pcrccnt skin twnors H. S/week for 84 weeks. Author concluded "Tar"a"d0.025mg.B~o~P .._. 26 1J.S.A. 12.0 C. Whole smoke "tar" that cigarette "Tar"and0.06mg.B(a)P 15 (225). 27.0 smoke contains with added B(a)P "Tar" and 0.25 mg. B(a)P 15 13.0 cocarcinogens. in acetone. "Tar" and 1.25 mg. B(a) P 14 64.0 B(a)P 1.25 mg. ,. _. 14 Druekrey and Rats A. Subcutaneous Treatment (BP mg.:wecli): Schildbach. Snrconln.9 injection. 30 1963. s/30 Il. l/week for 700 days. 10 Ger"L_"Y 14140 C. Benzpyrene in (82). 3 X/60 trirapwlin. - (solvent) ,. ,, ,. ,, Z/75 Author, yeal-9 country, reference TABLE Al3.-Ezperinwnts concerning th effects of the skin painting OT subcutaneous injectiorr of cigarette smoke condensate or its constitzen,ts upon, animals (co~f.) ~___ ..__~~ Animal A. Method, ana 13. Frenuency and/ strain or duration, C. Material Results Comments __- Hornburger CAFl mice A. Painting shaved skin. CO"l,h2Ll~ Percent et al., B. Z-3/week for 2 years. Condensate: autopaiea Papillomaa 1963. C. Various tobacco Pipe tobacco 77 35.0 U.S.A. (131). cOndensates in acetone. Cigar tobacco x4 Cigarette tobncco x2 Benzpyrene 54 Acetone only _. 62 27.5 27.0 10.0 Bock et al., 1965, U.S.A. (29). Swiss ICR A. Painting clipped skin. mice B. lo/week for 11 weeks. C. Various smoke condensates in acetone. Percent concentration of ta, (type cigsrette) : 8.2 (standard) 8.3 (standard) 7.9 (English standnrd) 8.7 (king) 4.0 (filter) ,.. 4.4 (filter) 2.5 (filter) Acetone control untreated cOntlol Z'wrcnt szcr7,ivitz.u 1 I zrr~cka !)(i.O !)3.0 90.0 100.0 9X.0 100.0 97.0 94.0 100.0 . . Pcrwnt CLl?LC-<`? 30.0 27.0 24.0 28.0 9.0 10.0 4.0 ____ Pwccnt Carcinomas 15.0 16.0 15.0 20.0 Prrcent cancer ana papillama 67.0 67.0 58.0 69.0 36.0 41.0 16.0 .___ ____.___ Van Duuren Swiss ICR/ ___. A. Painting shaved ski". et al.. Cumulative ?~wnbcr of mice: roith t 7.12-dimethyl- Ha mice B. Initiating agent once- Initiator Promotor Par~illoma.9 Carcinomas 1966. benz ( B ) anthraccne. Promoter 3/week for DMBA .Ether tobacc,) leaf ,`strnet 4120 U.S.A. o/20 12-14 months. 0 . .Ether tobncco leaf wtrxt _. o/20 (296). O/20 C. DMBAt. tobacco DMBA .Choloroform tubacro leaf extract l/20 O/20 extracts riga- 0 . .Choloroform tobnrw lenf extract _ o/20 o/20 rette "bd'. DMBA Cigarette "tar" 11120 4/20 0 . .Ciunrctte "tnr" O/20 o/20 0 . . .Awtone E o/20 o/20 ~ ~~~~___ .I__.__~~ ~-~. __- ~~ ~___~~ _-__ TABLE AlS.-Experiments concerning the effects of the skin painting or subcutaucous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, yeal'. country. reference Animal and strain A. Method l3. Frequency and/ or duration. C. Material Results C0ltlllleTlts Munoz et al . . Swiss ICR/ A. Painting shaved skin. Dark tobacco "tat" 1968. 48 mire B. Varied. 4.0 percent ................. U.S.A. C. "Tar" from dark 8.0 percent ................. and (Colombian ) and Light tobacco tar: Colombia light (U.S.A.) 4.0 percent ................. (197). tobaccos. 8.0 percent ................. Acetone ..................... I At risk TUWUJKi 81 SO 71 46 95 26 98 64 91 0 Carcinomas The authors noted 17 a shortened latent 16 period for dark tobacc". 6 20 0 Davies and Day. 1969. Great Britain (65). Albino mice A. Painting shaved skin. IS. Varied regimen. C. Cigarette and cigar condensate. Percent of carcinoma-bearing animals at 116 weeks The authors concluded Tmatmcnt: (actual number of animnln in parentheses) that the lack of 300 mg. 1.50 n&g. 75 mg. 37.5 mg. difference in re- Standard cigarette . . . 20.1(29) 13.2(19) 0.7 (1) sulta from the first Cigar 27.1(39) 11.1(16) 2.1(3) and third groups Cigar tobacco cigarette 13.9(10) . under treatment suggests that the increased tumori- g&city of cigar tobacco is due to physical processing tsctors. TABLE A14.-Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures Author, Ye*=, country, reference Tissue or org*n culture Material/delivery Results Bouchard and May. 1960, France (35). Mouse lung. Tobacco smoke condensate perfusion for 24 hours and subsequent grafting under renal capsule of mice. Increased number of mitotic abnormalities in the treated cultures: particularly in the first 5-10 days after grafting. Awa et al.. 1961, Japan (16). Human fetal lung. Direct exposure to smoke from: a. Whole cigarettes. b. Tobacco alone. c. Paper alone. Paper smoke induced the most severe changes, consisting of cytoplasmic vacu- olization and nuclear pyknosis. Also noted were a decrease in the mitotic index and an increase in abnormal divisions, more so with paper smoke than with the other two. Thayer and Ke"Sler, 1964, U.S.A. (275). KR mammalian tumor cells. Cigarette smoke condensate applica- tion; filtered and unfiltered cigareftes. Significant growth inhibition was shown in unfiltered smoke. Cytotoxic compo- nents were noted in hoth the gas and particulate phases. Berwald and Sachs, 1965. Israel ( 1" ) SWR mice and golden hamster embryos. Direct application of benzo(a)pyrene IB(a)PI. Benzo(a) pyrene caused increased cell transformation as manifested by: a. Hereditary random growth pattern. b. Progressive growth as tumors after subcutaneous injection into adults. c. Ability to grow continuously in culture. Cracker et al., 1965, U.S.A. (63). Diamond. 1965. U.S.A. (68). Suckling rat trachea in orgnn culture. Variuus con- tinuous cell strains (mammalian). Application of B(a) P in acetone. Application of II (a) P in either dimethylsulfoxide (DMSOI or paraffin. Treated cultures revealed cellular metaplasia. basal cell hyperplasia. increased mitotic rate, and increased H"-thymidine incorporation proportional to the con- centration of material and duration of application. Inhibition of cell growth. TABLE A14.--Ercprri)tlents concerning the effect of cigarette smoke OT its constituents on tissue and organ cultures (cont.) Author, year. CXJ""tl-Y, refercnw Material/delivery Results Il,,renfreund et al., Hamster lung Application of a. increased appearance of new small chromosomes and telocentric chromosomes. 1%x, tissue. B(a) I' in either b. Increased ability to grow in hamster cheek pouch and there become spindle- U.S.A. (89). DMSO or dimethyl- cell sarcomas. fc~rmamide. Chickerl embryo ~. Application of .-.~__ Increased mitotic activity and increased incidence of anomalous mitoses. 1:1(x. muxular tobar?,, extract. F'wlnre (110). explants. Lxhnitzki. Mice nronatnl Application of a hy- a. Increased basal cell hyperplasia and pleomorphism of newly formed cells. l!KX. t, achra. drocarbun-enriched b. Increased epithelial mitosis. EnKland (160). fraction of whole smoke cundensate. I,us"itzki, Human fetal lung Application of a hy- a. Cellular enlargement and promotion of growth of new bronchi. 196x, in organ culture. dmcarbon-enriched b. Increased mitoses, bronchial epithelial hyperplasia. and 8c1uamous metaplasia. E"gla"d (161) fraction of whole c. Inhibition of stromal growth. smoke condensate. - - Char, et al., Muuse lung Application of a. Cellular disorganization. I!l6!l. burl embryonic B(nlP in DMSO. b. Cellular pyknosis: nuclear shape and size irregularities. U.S.A. (54). cultures. c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in those cultures exposed to B(a) P versus those exposed to pyrene or DMSO. Leurhter,bergel Mouse lung Exposure to fresh smoke: and and kidney a. Unfiltered. a. Decreased RNA production, pyknosis, and death of cells. Leuchtenberger, tissue and b. Activated b. Similar results, hut changes were of minimal severity. l!f68. t3I'&?an cultures. charcoal filter. Switzerland (165). c. Cigarette or c. Similar effects as group a., but less swerc. cigar tobacco. __- TABLE Al4.--Ezf,c,rit,crt/ts cowcerning the effect of cigarette ,ytttol<(' 01' its constit/(ents 0~1 tissue and organ cf(ltures (cont.) __~ ~~..____ ~_____~__-~~~ Author, ______- YCBI`, Tissue OP country. urgan culture Mntcrial/delivery reference Hr5ults ~-__~ Cracker, Various organ ~__~ __~ -- Ayplirntion of ___~ -__ Squamous metnplasia: frwuent pleumuuphic cells: dedifferentiation of epithelium 1910. cultures: I%(n)P in scrutn. (inhibited by Vitamin A). U.S.A. C/X?), a. Wholr suck- lina hamster tracheas. 1). Whole brvn- rhinl tubes from late fetal doas and monkeys. ~__~ ~--__~ ~ ---~ ~._~~~ ~ ..--~ ~. -~__ L v. Author. war, countlY. reference -__ Blacklock. 1051. GlY*t Britain 124). - Della Porta et al.. 195X, U.S.A. (67). TABLE A15.--Ezpm-iments concerning the effect of the instillation or implantation of cigarcttc> smoke or its constituents into the tracheobronchial tree of animals Animal and strain CR white rats. A. Method B. Frequency and/ or duration Results C. Material .- A. Injection into 4.46bcnzpyrene: Number with tumors/number czposed lung parenchyms a. 3 mg. in olive oil 5/6 **rconl*. by thol.ncotomy. b. :: mg. in olive oil with dead Tb bacilli Z/4 sarcoma. 4/8 squamous cell carcinoma. I{. once. c. 5.75 mg. in cholesterol pellet l/R squamous cell carcinoma. (`. 3.4~ber,zp.vrene Cigarette "tar": in olive oil, a. In olive oil O/10. with dead Tb b. In olive oil with dead Tb bacilli l/X sarroma. l/R squamous cell carcinoma. bacilli or in Controls: cholesterol. a. 0.15 cc. olive oil o/4. cipnrette "tar". b 0.15 cc. olive oil with dead Tb bacilli n/4 c. Cholesterol pellets o/4. - Syrian golden hamsters. A. Direct tracheal instilllation. B. Weekly up to 45 weeks. C. 1 percent 7,12-dime- thylbenz(a)anthra- cene (DMBA). cigarette "tar" roncmtrate. Mate&l: a. DMBA 50 pg./week b. "Tar" 200 pg./week c. DMBA 50 ,*g./week then "tar" 200. WFEka 45 32 12 ,& week d. DMBA 100 fig./week e. DMBA 100 pg.lweek 1 and "t.al." 500 \ pg./week ) 30 17 20 Survivors at 20 twskslosiginal number exposed 10/20 11/21 9/20 l/20 9/20 Number of hamsters with tracheobrmwhial carcinomas at death 2 4 3 Rigdon. 1060. U.S.A. (221). White Pekin A. Intrntrarheal No neoplastic changes noted in either the experimental or control groups. ducks. injection. Controls: 99 B. Daily for 721 days. Experimental C. Tobncro condensate group: 52 in liquid p&r&turn. TABLE A15.-Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.) Author, A. Method Year. B. Frequency and/ country, A:iIT' or duration Results reference strain C. Material ___. Blacklock. CB white rats. A. Inoculation at Number Percent with 1961, thoracotomy. of rats malignant tumo+e Great B. Once and sacrificed C""tr"ls . . . . ~. . . . . . ~. 276 1.5 (1 carcinoma, 3 sarcomas) Britain at 1 week-2 years. Cigarette condensate _. _. . 72 11.1 (6 carcinomas. 2 sarcomas). (15). C. Cigarette tobacco Eucerin alone _. _, 44 2.3 (1 sarcoma). smoke condensate rn eucerin. Herrold and Syrian golden A. Intratracheal Number of Number with Number of tracheo- Dunham, hamsters. inoculation. Material: hameters tumors bronchial tumors 1962, B. 0.5 ct./week for B(a) in TweenGO 6 3 5 (3 pspillomas, 2 carcinomas). U.S.A. 5/6 months. B(a)P in TweenFO' 6 3 9 (4 pspillomas, 5 carcinomas). (121,. c. Benz0 (a) pyrene Tween60 6 0 I" Tween60 B(a) P in olive oil 6 0 or olive oil. Olive oil _. 6 0 Rockw et al.. Doas. 1962, U.S.A. (azr). A. Bronchial inoculation 0~' stimulation. B. 3-5 times/week for rr* to 5 years. c. Cigarette smoke condensate. Sqlcamous P7C- metapluaia Number Invasive Carcinoma- enneeroua with atypical lnflam- Procedure: of dog.9 carcinoma ii1 sit76 changes changea mation Controls 27 6 24 Manipulation of bronchus 25 - - 7 26 Smoke condensate 130 1 3 25 98 128 ____. ______ __- Tipton and Mongrel dogs. A. Bronchial Crockw, Control proup and inoculation. 1964, experimental B. Daily for 8 days. U.S.A. Kl`OllP--19. C. Cigarette smoke (177). condensate. iz _____ ._I_ .-____- Y Rapid induction of swamous metaplasia in condensate-exposed animals. No tabular data is presented. TABLE A15.-Experiments concerning the eflect of the instillation or implantation of cigarette smoke or its constituents into the tracl~eobronchial tree of animals (cont.) Author, year, country, reference Animal and strain A. Method B. Frequency and/ or duration C. Material Results Saffiotti et al., Syrian golden 1966, hamsters. 1J.S.A. (237). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a)P (3mg.j attarhed to fine hematite dust. Number autopsied: Male 23 Female _. _. 17 Percent tumor- Nwmber of bearing of tmnor-bearing auruivors at animal8 15 zoecks 15 100.0 11 100.0 Total Total number nscmbcr of rcspiratorv of turnore tract ca?wPT* 24 18 17 16 Kuschner, 1968. U.S.A. (1.57). Hamsters A. Wire mesh pellet implantation into bronchus. B. Lifetime. c. B(a)P. methylrholan- thwnr (MCA). Number of surrivors/original Implant: number in group Wire mesh only _. __ __ _. _. _. _. 34135 MCA RR/91 D(a)P x9/91 Number of animals with lung canecr -- 43 57 Saffiotti et al., Syrian golden 196X. hamsters. U.S.A. (235). Borisyuk, Wistnr rats. 1969, Russia (J4). A. Intratracheal inoculation. B. Weekly for 15 weeks. C. B(a) I' attached to a fine hrmatite dust. A. Intratrarheal intubation. B. Monthly up to IO months. C. Cigarette "tar". Number of hamster8 with Number alctopaied respiratory Inoculate: tract tumor.3 Control 176 B(a)P in hematite 55 36 Hematite only _. _. _. 41 Number final/ Dumtiou of initial inocz&tion Inoculate: (months) Controls 11/20 12 Unfractionated "tar" 24/200 10 Denicotinized "tar" 9/45 R (l/9 metaplasia) Neutral "tar" fraction 14/100 8 (Z/14 carcinomas, l/14 papillary adenoma). TABLE Al&-ll'xperiments concerning the eflect of the inhalntion of cigarette smoke or its constituents upon the respiratory tract of animals (Figures in parentheses represent total number survivors in specific group) - -~-~__~~ Author, war. At%=' A. Type of exposure c0untl-Y. B. Duration Hesults reference strain C. Material Comments Lorenz et al.. Strain A mice: A. Chamber. -~ 1943, E. No increase in tumor formation over that noted in controls.This strain of mice does tc. 97. R. Up to 693 hours. U.S.A. (177). have a hereditnw IE. 97. C. Cigarette smoke. tendency t<, tumol formntion. tc'. Crs were Netherlands c. 32. up to 684 days. E. 79.0 found. (295). E. 29. C. Cigarette smoke. - Leuchtenberaer CF, albino mice: A. Chamber. 23 of tkc espr~imcntnl mice showrd: et rd., C. snd E. 275. B. To 8 cinarettes 15 basal cell hyperplasin. 1958. per day from 14 atypical bnsnl cell byperplasiu. U.S.A. (166). 11-201 days. 7 dynplnsia. C. Cigarette smoke. 2 squamous cell metnplasia. .~ Cuerin, .__ IC and Wistar A. Chamber. Pmwutrrgc of rats with t~trlmo~rr~rti tamom 1969. strain rats. B. 45 minlltes C. 2.4 percent of :(!I survivors. Frence (loa). c. 40. per day from E. 5.1 yercent of 68 survivors. Ix. 100. Z-6 months. C. Cigarette smoke. ~. -___.__ -~~ -~ TABLE AlG.-Experiments concerning the eflect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, Year. country, reference Animal A. Type of exposure and B. Duration strain C. Material Results Comments Leuchtenberger Female CFI mice: A. Chamber. et. al.. c. 243. B. 54-G cigarettes 1960. E. 360. per day for 1 U.S.A. (167). month to 2 years. Namber C. Cigarette smoke. of mice 151 150 36 __.... 36 . . . 34 ,..... 51 . . . 63 __.... Number of cigaseltes 25-1.626 0 loo- 200 25& 500 600-1.600 loo- 400 IO& 400 Ezposwc length (months ) 1-23 0 l- 3 4- 8 9-23 3- 6 3- 6 Number with wvcfe bronchitis; pcribronchilis; atypical &the- lial prolifcrntion 30 2 7 7 8 4 17 Leuehtenberger Female CFI mice: A. Chamber. Number Pcrcsnt of mice Presence of tumors et al.. c. 166. B. l/+3 cigarettes of mice Ezpomre with pulmom+y showed an age. 1960, E. 231. per day for examined ( daua I adenomatous tumom relationship U.S.A. (168). 17-600 days. 81 0 66 independent of C. Cigarette smoke. 39 17- 99 41 smoking exposure. 35 , 100-199 37 61 _. _. . . , 20&600 66 Otto. 1963, Ger"la"Y (206). Albino mice. C. 60. E. 169. A. Chamber. B. Approximately 12 cigarettes per day for varying intervals. C. Ciaarette smoke. Number of mice examined C. 60 E. 189 Ew~osrre Number with NO"& lung tulnorr Varying 3 pulmonary adenomas. upto 21 pulmonary adenomas. months. 2 epithelisl carcinomas. TABLE A16.-Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, war. country, reference Animal A. Type of exposure and B. Duration strain C. Material Results Dontenwill and Golden hamsters. A. Chamber. Number of D&l Wiebecke, c. - B. Up to 4 cigarettes animals average 1966. E. 320 per day for up dead at ezpomre Germany to 2 years. 640 dags (cigaretlea) (77). C. Cigarette smoke. 40 . . . . . . . . . . . . . . 1 40 . . . . . . . . . . . . . . 2 80 . . l-2 143 . . . . . . . . . . .._ . l-4 Comments MET des = desquams- Histologic tive metaplasia. findings in MET branch = bron- dead animals chial papillary 8/ 40 MET des metaplasia. S/ 40 MET des PAP tracb = tracheal 44/ RO MET des (3 MET papillomat* or branch. 2 PAP trseh) intense tracheal 67/143 MET des (13 MET metaplasia. branch. 8 PAP trach) Leuchtenberger CF, mice. A. Chamber. and B. Up to 1,000 hours. Leuchten- C. Cigarette smoke, Marked sguanous berger 1966, exposure to in- cell metaplasia Switzerland fluenza virus (percent) (1.54). (PRR). Controls (100) : Male Female Smoke exposed (59) : Male Female Virus exposed (59) : Malt 11.0 Female - Smoke and virus exposed (88) : Male 9.0 Female 29.0 Marked dgsplaaia (percent f 6.0 21.0 - 43.0 54.0 Marked tmnsgression of lung parolchyma (percent) 3.0 13.0 5.0 t1tJ.o t33.0 tEpithelia1 tissues of these animals showed an increased frequency of cellular atypism. The authors concluded that PRB influenza virus may act as a cofactor in malig- nant transformation. TARLE A16.--Ezpo`iments concerning the effect of t//t, inldntion of cigarette smoke 0~ its constituents upon the respiratory fvxct of animals (cont.) (Figures in parentheses represent total number survivors in srxcific group) -~___~~ Animal A. Type of exposure and 13. I)ur*tion Results Comments Author, war. countrv. reference strain Kockey and Mongrel dogs: SPCW, c. 11. 1966. E. l!l. U.S.A. (CBY). ~-~-----~ Aucrbnch Heagle dogs: C. Material .\. Trnrhral fenestra- Sqlcamous tCarcinom* in situ tisl" (IO). Hyprrplnsin metapln- noted in 5 seppnrate NsoI. henz- Influenzn and smoking 165 3 those noted by pyrene aerosol. Leuchtenberger. -~ ~___ TABLE AlG.-Ezpeviments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of cmhals (font.) (Figures in parentheses represent total number survivors in specific group) _____- .___~ ___~ ._____ Author. year, country, reference Animal A. Type of ~XPOSUFP and B. Duration strain C. Material - ___~ ~__~~ -- Wynder et al.. Male C57BL6 A. Chamber. 1%X, mice: 1~. Up to 315 rJ.S.A. (3~7). c. and E.- cinarettes. more than 40. C. Cigarette smoke, nitrogen dioxide, volatile acids and aldehydes fuund in ciza- rette smoke, swine influenza virus. Results comments -___ Cnnclusions: t tResults not provided No squamous cell respiratory cancer noted. This is attributed in tabular form. to the limitation of inhalation time (CO and nicotine acute effects) and to the anatomically and physiologically intricate nasal passn~e defense system. Expusurr to cigarette smoke, NOZ, or wlatile wide and alde- hrdes leads to reactive hypewlasia and metaplasia, both of which wcw nrjted to be reversible. Swine influenza virus esposurc produced hyperplastic and metaplastic effects which could not be enhanced by subse- quent cx~osu~e to cigarette smoke. Laskin et al.. Rats: A. Chamber. Squamous cell 1070, c. 45. B. 1 hour per day ISL?)msir,e Number carcinoma8 U.S.A. (1%). E. 3. for up to Atmospherr controls . . 3 o/ 3 680 days. Atmnrphcrc plus benzo(n)- c. Benz0 (a) pyrene pyrcnc exp0sure 21 2121 aerosol, so, so, rontlols 3 o./ 3 atmosphere SO, plus benzo(a)- (3.5 P.P.rn.). pyrene exp,E"rr 21 5121 ____-. -._____ Hammond Heagle dogs. See text See tex1. et al., 1970, U.S.A. (II!?). TABLE A21.-Outline of retrospective studies of tobacco use and cancer of the larynx Author, ye==. country, reference CiWZS Controls - Collection of data St?X Number Method of selection Number Method of selection Schrek et al.. 1950. U.S.A. (246). M. 73 Referrals from V.A. hospitals in "entire midwest" to V.A. Cancer Center, Hines. Illinois, during 1942-44; patients with larynx-pharynx tumors clinically or his- tologically diagnosed: Percent Nonsmokers . 13.7 Cigarettes 79.6 Cigars _. 3.7 Pipes _. _. 6.8 522 From same set of referrals. patients Random sample of 6.003 with tumors other than lip, lung, lar- admissions; question- ynx-pharynx: naires from Hines re- ferrals for 1942-44; records included Percent smoking history. Nonsmokers _. _. 23.9 Cigarettes . . . 63.2 Cigars . . . . 10.0 Pipes __. ,_, . . . . . 11.6 Valko, M-F 226 Clinic patients with cancer of the larynx: 108 Clinic patients of same age group with Medical history and pues- 1962. other diagnoses: tionnaire in clinic. Czechoslovakia Percent Percent (Pi%?). Nonsmokers . . 7.6 N onsmokera . 22.2 Cigarettes _. . . . . . . . . . 83.2 Cigars . . . . 4.4 Pipes _. . . . . . . . 10.6 Sadowsky et al., 1963, U.S.A. (P9B). M. 273 White male admissions to hospitals in New York City, Missouri. New Orleans, Chicago; patients with diagnosed laryn- geal tumors. 1938-43: Percent Nonsmokers _. _. . 4.0 Cigarettes only . . 60.1 Cigars only . 2.2 Pipe only . . 4.8 Some combination . . . . . 28.9 616 From same set of admissions, patients Sample of 2.605 out of with illnesses other than cancer: 2,347 interviews (in- cluding smoking his- tory ) by trained lay Percent interviewers. Nonsmokers 13.2 Cigarettes only . . 63.3 Cigars oniy . . . 3.4 Pipe only . . . . . 7.0 Some combination . 23.1 TABLE A21.-Outline of retrospective studies of tobacco we and cancer of the larynx (cont.) Author. year. C*XS countrY, Controls reference S&X Number Method of selection Number Collection of data Method of selection Bliimlein, M. 241 Clinic patients with cancer of larynx: 200 Patients with no laryngeal disease: Personal history taken in 1956. Percent GY"8llY Percent clinic. Patients and Nonsmokera . _. 0.8 Nonsmokers _. _. 18.0 controls -aver 40 years (26). Heavy smokers 79.3 Heavy smokers 4.3 of age. Inhalers 95.0 Inhalers _. 17.0 Wynder et al.. M. 209 White male inpatients Memorial Cancer 209 Patients with other than epidermoid Trained lay interviewers. 1956, Research Center during 1962 to 1954. ClNlCW, U.S.A. ($12). individually matched controls with benign or malignant epidermoid in same institutions: tumors of larynx: Percent Pwcent Nonsmokers _. 0.5 Nonsmokers 10.5 Cigarettes X6.0 Cigarettes _. 13.7 Cigars 7.5 Cigars 10.1 Pipes _. 5.0 Pipes _. 3.8 Cigars/pipes . _. _. __ _, 1.0 Cigars/pipes _. ._ /. 1.9 Wynder et al.. M. 132 Laryngeal cancer patients at Tata Mem- -. 132 Controls individually matched as for Interviews for smoking 1956, orial Hospital, 1962-54: U.S.A. data above: India (.sfZ). and medical histories. Percent Percent Nonsmokers . 13.6 Nonsmokers _. _. 30.3 Bidis _, _. `78.8 Bidis 62.1 Cigarettes _, _. . 5.3 Cigarettes __ 4.6 Hookah _. 1.6 Hookah _. 0.8 Chilum . . 0.8 Chilum 2.3 Schwartz et al.. M. 121 Patients hospitalized from 1954 through 242 1957, Same time and sources; patients hospital- Cases and controls indi- 1956 with laryngeal cancer. in Paris ized for non-cancerous conditions or France (248). vidually matched within and other large cities: trauma: institutions; each mem- Percent Percent ber of a set questioned Smokers 96 Smokers (p20 cigarettes per day 23.4 >20 cigarettes per day . , 18.6 when smoking is con- trolled. -~ _____~ Wynder et al., M. 543 Patients with cancer of oral cavity: 207 Patients with cancer of other sites and 1957, F. 116 232 benign diseases: U.S.A. (SIS). Percent Perce?l t Male Female Mals Fcmnlr Nonsmokers 3 47 Nonsmokers 10 70 Cigars _. . 20 - Cigars _. _. 13 - Pipes . . . 11 - Pipes 6 - Mixed _. R - Mixed 8 - Chew _. 17 - Chew H - Cigarettes 57 53 Cigarettes 63 30 >35 cigarettes >35 rivarettes per day 29 - per day -~ 17 >I6 cigarettes >16 cigarettes per day _. - 34 per day 11 - ~~~..._~ Schwnrtz et al., M. 332 Hospital patients with cancer of oral CBV- 60X Hospitnl patients with non-czmcer ill- 1957. ity and pharynx: ness and accident CISCS. matched by France (248). *ge: Percent Perccn t Nonsmokers 16.4 Nonsmokers 23.4 Cigarettes only 62.7 Cigarettes only 58.2 Pipes only . . . . . . 3.3 Pipes only 3.0 __- ~-~ w L TARLE A28.-Ozctlinc, of retrospcctirlc studies of iol~ctccr~ I(SP red cunccr of the oral cnvitg (conf.) (Data obtained from patient interview and other sources) Author, Yt?ZW, country, reference Cases Controls ___ .-~ __._____~ -~ Srs NUl?lb?l Method of selection Number Method of selection COl""lC"tS Wynder et al., 1951, Cuba (8.25). -__ M. , Ii': Hospital rlinic Datients with cancer of 220 Patients in same clinics with non-malig- F. :34 I,L.RI cavity and pharynx: 214 nnnt conditions, matched by sex and age: PCTCtXlt Percent Male F~malc Male Female Nonsmokers 4 24 Nonsmokers 16 66 Cigarettes Cigarettes jtreduminantly 45 62 predominantly . . 45 21 Cigars predominantly 33 12 Cigars predominantly 22 6 Wynder et al., M. 115 Male patients with cancer of oral cavity 115 Male patients in same hospital with can- Alcohol data significant 1957, and pharynx: cer of sites other than oral, pharynx, only for hypopharynx. Sweden ( 822 ) larynx. lung, esophagus, breast: PeTcent Pdrcent Cigarettes 36.6 Cigarettes 36 Cigars _. . 13.0 Cigars . 9 Pipes . . 12.2 Pipes . . . . 16 Mixed _. _. . . . 15.7 Mixed _. 13 Peacock et al.. 1960, U.S.A. (210). M. F. 25 Hospital r>atients with oral cancer: 14 Patients in same hospital without oral 20 72 cancer and 111 male and 100 female out-patients. randomly selected. Percent 32.6 percent of first group, and 43.3 per- Chewed or used snuff over 20 cent of second group chewed or used years (all patients) . 56.6 snuff over 20 years. Staszewski, 1960, Poland (259). M. 3R3 Male patients with oral cancer: Percent Nonsmokers . _. _. 5.7 "Heavy" smoking index 72.8 Cigarettes only . 72.3 Pipes and/or cigars . 12.8 912 Male patients with other cancerous and non-cancerous conditions: Percent Nonsmokers . . . 17.3 "Heavy" smoking index . . . 49.0 Cigarettes only 60.5 Pipes and/or cigars 11.1 TABLE A28.-Outline of retrospective studies of tobacco MSE and cnmw of tlic ora1 cnvit!! (coTat.) (Data obtained from patient interview and other sources) Author, year, country, reference Vogler et al.. 1962. U.S.A. (698). Cases Controls Comments S-X% Number Method of selection Number Method of selection .__ M. 188 Clinic patients with cancer of lip and oral 521 Patients of same clinic with other can- t Due to varying tabular E'. 92 cavity: 1,064 cer or non-malignant conditions: treatment of data, per- Percent centages of tobacco Male Fsmale users are not all based Chewers _. $32.9 - Percent on the same number of Excessivechewers 22.9 - Male Fern& eases. Snuff dippers - . 72.0 Snuff dippers t6.1 Excessive snuff dippers - 41.3 Tobacco users . 90.0 90.0 Tobacco users 56.0 56.0 Vincent and March&s. 1963, U.S.A. (997). M. F. 66 Successive patients with lesions of buccal 16 cavity and oropharynx: Percent Od OTO- Males : Cavity pharynz Nonsmokers 3.0 - <20 cigarettes per day t. 1X.3 15.1 >20 cigarettes per day 78.1 84.9 Females: Nonsmokers 55.5 26.6 <20 cigarettes per day - --~ >20 riaarettes per day . . ._ 44.5 71.4 100 Successive patients attending gastroin- Male patients used con- 50 lestinnl clinic, age-matched: siderably more alcohol than male controls. Data refers to all forms Pcrccnt of smoking expressed 27.0 as cigarette equivalents. t`icawttt. equivalents: 24.0 1 cigar r= 5 cigarettes 1 Pipe = 2 cigarettes 4!l.O t BN-Betel nut. R2.0 8.0 10.0 __---- - H TABLE A28.-Outline of retrospective studies of tobacco use and cancer of the oral cavitsf (Cont.) (Data obtained from patient interview and other sources) Author, Year. Cases controls c0untl-Y. Comments reference Sex Number Method of selection Number Yethod of SelEetion Sbantr and M. 662 Patients with oral and phawngeal eaneer 300 Controls residing in Krishnamurthi, F. 206 (unsure of confirmation) : 100 same area matched 1964, Percent for we. sex, and India (I&?). BlLCCd Anterior P0&rio+ ehas: Males: Lip mueomz tongue tongue Phownz males No tobacco habit - 2.0 7.2 2.0 6.3 89.1 Smokers 50.0 46.7 66.6 76.0 72.8 62.7 Number of eases . (12) (293) (69) (48) (130) (800) Females: Fanal@ No tobacco habit . . . 14.3 11.0 33.3 - 40.0 88.8 Smokers . . . . . - 4.7 - 8.8 - Number of cases (7) (162) (Iif (4) (26) (100) Wahi et al.. M. 589 Patients with oral and pharyngeal car- 689 Patients matched for age, sex. religion, 1966. F. 232 cinema: 232 and social class. India (sOa). Percent Pwcent Nonsmokers . . . . . . , . 9.62 66.6 Smokers . . . . . . 17.06 21.2 Chewers (Betel nut) . . . . 86.44 6.9 Both . . . . . 37.88 6.4 Hirayama. M. 369 Patients with oral and pharyngeal card- 277 Patients with other (unspecified) dis- Found only a suggestive 1966, F. 176 IUXllP.: I63 eaws: association between Central and Percent Pemmt alcohol-drinking and South East Male Female Male Female oral cancer in non- Asia ( 1 24) Nonusers . 1.6 2.6 17.0 33.0 chewers only. Smokers . _. . 17.1 2.6 23.3 1.2 t BN-Betel nut. Smokers. tBN and tobacco chewers 46.7 6.6 24.9 1.8 TABLE A28.-Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from patient interview and other sources) Author, year. country, reference - Keller, 1967, U.S.A. (140). CSS.3 Controb Sex Number Method of selection Commenta Number Method of selection M. 408 Patients with waumnow cell cw&uxna of 406 Next male patient admitted to same hos- Excessive alcohol con- oral cavity and oropharynx confirmed pita1 within 5 year we range. aumption noted for histologically. Three New York City VA c*spJ involving floor, Hospitals 196368: meaophwynx. and Percent Percent tongue. Nonusers , . . . . . . . . . . . . . 6.1 14.2 Findings indicate tbe Cigarettee . . . . . . . . . . . . . 68.6 66.4 (p2.500 grams (Caucasians). All preg- nancies with B"Y complicntion were excluded. Ceserean sections and induced delivery were ex- cluded. Robinson, 1965. Burma (37). P. 1,614 Interview. Regular attendees at prenatal clinic. 46.X percent of women smoked cheroots. Underwood et al., 1965, U.S.A. (50) R. 4,440 interview by obstetrical resident. Data was obtained on 16.158 preg- nancies from the 4,440 women. Puerperal wonw" from Roper Hos- pital and Medical College Hospi- tal. Only infants weighing >I,000 rrams WEI`P included. Women from Roper Hospital were of above average eco- nnmic status. Women from Medical College Hospital in- cluded Negro and white patients. Downing and Chapman. 1966. U.S.A. (7). R. 5,659 Review of clinic records from 1952 to 1958. Six-year tot"1 of obstetrical patients at clinic. TAULE l.-Szcmmar~/ of ~trclhock used tn study of smoking and huwlan pregnancy (cont.) Number of *erson': 2.02:1 Data collection Epidemiologic questionnaire. Much data collected uver telephone. Ad- ditional datn obtained from birth certificates. Rcinkr nnrl Hrndrrso" 14fX. U.S.A. (SG). Ii. 3.151; Registration data of prenatal clinic. Case selection Study population was identified by the listing of newborn infants in ii Seattle newspaper during May. June. and July of 1964. Twins were excluded. Comme"ts 95.4 percent of mothers were white. Negru women who delivered single, live infant- from 1962-64. Patients receiving care at "concep- cion palncias" in Caracas. Underwood et al.. Illfii. U.S.A. (51). I' 4X.605 Code sheets submitted from 44 world- wide navel installations. Code sheets were completed by the at- tending physician upon the mo- ther's admission to the labor room. Women with single pregnancies de- livered of infants weighing more than 500 grams between July 1, 1963, and June 30, 1965. Duffw and MacCillivray, I'JFX. Scotland, (8). Mulcahy and Knaugs, 1YliP. Ireland (28). .- II 2,543 Antenatalclinic records. All "booked" marriezl city primi- gravidae attending the antenatal clinics during 1960. 1964. and 1965. The number of cigarettes smoked was not considered. 3.6X1 Mothers admitted to the Coombe Hospital from April 1963 to Oc- tober 1964. Author. TABLE I.-Summary of methods used in study of smoking and human pregnancy (cont.) year, Retrospective Number country. Or of Datn collection reference Case selectio" Comments prospective persons - Russell et al., P 1968, England (89). Tokuhata, 1968, U.S.A. (49). R. Ihmcher, 1969, U.S.A. (4). R. Butler and 1' Alberman, 1969. Great Britain (5). ~~~-__ Terris and R. Gold, 1969. U.S.A. (47). 2.110 2.016 49.R97 17.000 197 - - Data collected by Senior resesrch midwives over a 4- to fi-year period. Women attending the two main ma- ternity units in Sheffield, who "comprised n reasonably repre- sentative sample." Multiple preg- nancies were omitted. Personal interview or mail question- naire of surviving family members. Women selected from Memphis and Shelby County death registry who died of cnncer of genitalia or breast since 1950 and who had been married. Included some threatened abor- tions and some with "bad" obstetrical histories. Control group taken from same registry. They died of causes other then cancer and were matched for rnce, age at death, and year of death. Data obtained from U.S. Naw ob- stetrical study from 1963 to 1965. Smoking dats obtained by physician at the time of mother's admission to labor room. Women with single pregnancies de- livered of infants weighing more than 500 grams between July 1. 1963, and June 30, 1965. Includes cases reported by Underwood et al. (47) in 1967. The British Perinetal Mortality Sur- vey of 1958 when n large amount of obstetric and sociobiologic in- formation wns obtained from birth sttendants, records, and nt inter- view with the mothers. -- Public Health Nurse interviewed each mother on first or second post- partum day. 98 percent of the total births reg- istered during 1 week in Msrch 1958 throughout England, Scot- land, and Wales. Another 7,000 perinatal deaths were surveyed by identical methods over a &month period. Premature Negro ward births (<`&SO0 grams) with no known cause of prematurity. Controls were matched by sex, birth order of infant, nge, and marital status of the mother. TABLE I.-~Summary of methods used in study of smoking and Izunlan pregnancy (cont.) Author. year, Retrospective Nlllllber coontry, ;f Data I0 cigarettes Effect on infant weight WBS independent per day Per day of maternal sge, parity, or complica- Male . . . . . 7.43 lbs. (607) 7.1x (187) 7.05 (165) tions of pregnancy. Female 7.23 Ibs. (539) 6.74 (163) 6.67 (147) Total 7.33 lbs. (1,146) 6.38 (350) 6.87 (312) 170 g. (6 oz.) Frazier 3,osog. (1.717) 2,924 g. (1.019) 156 8. (5.5 OZ.) Nonsmokers include occasional smokers. et al.. (12). Herriot No data (1,473) No data (1.272) 160 g. (6.6 oz.) Effect on infant weight was independ- et al.. ent of maternal age, parity. height, (16). or social class. Save1 and White . 3,374 g. (383) 3,141 g. (428) 233g. (8.2 oz.) Ciy*Tc.ttC# Roth Negro .._... 3,173g. (364) 3.031g. (240) 142 g. (5.002.) per day Infant weight (41). White smokers: l-10 3,ZlOg. (161) 11-20 ._ 3,198g. (184) >zo . . 3,OlOg. (83) Negro smokers: l-10 3,042g. (169) 11 20 3.012g. (57) >ZO ._ _. _. _. 2,968 g. (14) Murdoch 7 Ibs. 7.5 oz. (243) 6 Ibs. 15 oz. (258) 8.5 oz. Cigasrttce (30). PCT duy Infant weight l-10 t.. 7 lbs. 2 oz. 11-20 _. 6 lbs. 11 oz. >20 .._........ 6lbs.lOoz. >40 . . . 61bs. $02. O'Lane 2.9'78 g. (666) 2,938 g. (465) 40 g. (1.4 OZ.) li: C-w). -4 TABLE 2.-Maternal smoking and infant weight (cont.) (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mea" weight Author, of infant of smoker Comments reference Nonsmoker Smoker versus nonsmoker Zabriskie 3,320 g. (1,043) 3,091 g. (967) 229 8. (8.1 OZ.) Cigarettes (58). per day Infant weight 30 3,190s. (38) MacMahon Male 124.00~. (3,063) 116.3 oz. (3,173) 7.1 oz. Cigarettes Infant weig%t et al., Female . . . 119.9 oz. (2.906) 111.9 oz. (3,011) 8.0 oz. ,WT day ( oumx?s ) (24). Male Fe"l& /In 1." Y21.2 ($59) ??C,.E (595) lo-20 115.2 (1.262) 112.2 (1.259) 20-40 114.6( 1,166) 108.9 (1,088) >40 113.2 (66) 111.7 (49) McDonald Light smoker Heavy emoker No significant difference be- and Lanford (26). 111.68 oz. (81) 110.83 oz.(42) 109.38 oz.(48) tween mea" birthweights. Underwood et al., Group: (50). I 3,622g. (2,406) Cigarettes pe+ day 20 20 20 Fm >20 cigarettes per day 3,349 g. 353 g. (12.5 oz.) (p4.000 cigarettes during preg- et al.. Female . 7.60 lbs. (160) 7.05 lbs. t(171) .46 lbs. (7.2 oz.) "*"W. (35). TABLE 2.-Maternal smoking and infant weight (cozt.) (Numbers in parentheses indicate absolute number of infants in respective groups) Infant weight Difference in mea" weight Author, of infant of smoker Comme"ts reference Nonsmoker Smoker versus nonsmoker Reinke and 3.135 g. (1,542) 2.987 8. (1.614) 14R g. (5.2 oz.) (p30 3,182g. (1,570) 213 g. (7.502.) .___ Mulcahy 113.3 oz. Cigalettee and per day Knaggs l- 4 111.4oz. 1.9 oz. (28). 5- 9 102.30%. 11.0 oz. 10-14 . 102.0 oz. 11.3 oz. 16-19 I.. 102.9 oz. 10.4 oz. >20 . 102.40% 10.9 or.. Russell BP The effect of ma&al smoking on fetal et al., <140/ 90 117.2 2 .7 oz. (9R4) 107.2 !I 1.0 oz. (496) 10.0 oz. weight ~8s independent of maternal (39). 140/ 90 114.2 3- 1.2 oz. (340) 103.9 & 2.4 oz. (117) 5.3 oz. parity. age. height, educational level, >150/100 99.3 -c 2.6 oz. (138) 90.8 15.3 oz. (35) 8.5 07.. attitude to pregnancy or work during pregnancy, father's social class, con- sort's social class. and sex of the child or premature delivery. Butler and Alberman (5). 3,375 g. (11,146) 3,205 g. (4.660) 170 g. (6;~) fieductio" of mean birthweight of babies born to smokers WBS independent of unduly high proportion of babies born preterm, and maternal factors includ- ing social class and maternal height. Mulcahy 3.83 kg. (50) 3.43 kg. (50) 396 g. (14 oz.) 2 et *I., (29). 9 TABLE 3.-Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Author. reference Simpson (44). Lowe (43). Premature by Percent of premature infants Mean duration of pregnancy Duration of ~ ~---- Comments Weight gestation Nonsmokers Smokers Nonsmokers Smokers <2.600 B. Name of hospital: Number and percent of County 7.77 (144) 11.48 (96) premature infants: Loma Linda 6.16 (86) 12.13 (49) Nonsmokers 6.39 (328) St. Bernnrdines 5.21 (98) 10.50 (119) Cigarettes per day: l-5 . . 7.06 (47) 6-10 .11.18 (89) 11-15 .11.36 (31) lfi-20 .13.6 21-m ._ ._ .25.0 I::; >30 .33.3 (9) ___- <260 days 6.4 (57) 10.6 (58) 279.9 days 278.5, days At each week of gestation, the mean birthweight was lower in babies of smokers. Frazier et al.. (12). <2,500 8. 11.2 (175) 18.6 (179) 38.7 weeks 3X.4 weeks Infants of smokers weighed less than infants of nonsmokers for a wide range of preg- nancy duration. Herriot No data No data Social class: 2,745 patients in the study. et al .. I and II ......... 4.0 4.8 At each week of gestation, the (16). III .............. 3.5 6.8 mean birthweight was lower IV andV ........ 6.3 12.6 in babies of smokers. Save1 and 36 weeks White ............... 2.6 (10) 4.9 (21) White .39.8 39.4 Roth Near,, .............. .13.7 (50) 11.3 (27) Negro .38.X 38.8 (41). t37 weeks). TABLE 3.-Maternal smoking and prematurity (Figures in parentheses are the absolutr number of premature birth?) Author. reference Premature by Duration of - Weight gestation Percent of premature infants Nonsmokers Smokers Mean duration of pregnancy ___~ - Nonsmokers Smokers Yerushalmy <5',C. lbs. (54). 5.9 (36) 8.1 (30) Murdoch (30). <2.500 g. 3.3 (R) 13.6 (35) O'L&ine <2,500 B. 5.1 (29) 11.x (55) (83). Zabriskie <2,500 g. 3.83 (40) 9.93 (95) Ciparette.s (58). per day: Prematurity 30 .10.53 (38) ___ ~~ -~~~___ Yerushalmy <5 Ibs. 8 oz. White 3.5 (112) 6.4 (138) (plO 8.3 (4) (LO). Pctersnn <2,600 g. Cigarettes pm day Overall incidence of prematurity rt al., 2.5 (111) I-10 3.0 (35) in smokers vs. nonsmokers (54). 11-20 4.x (80) significant at p20 3.4 (16) .- TABLE 3.-Maternal smoking and prematutity (cont.) (Figures in parentheses are the absolute number of premature births) Author, reference Premature by Duration of ~ Weiaht gestation Percent of premature infants Mean duration of pregnancy Nonsmokers Smokers Nonsmokers Smokera Comme"ts Peterson et al., (contd.) t.14 ) <37 weeks Cigarettes ncr day 1.3 (58) l--l0 1.4 (16) 11-20 2.3 (36) >20 2.4 (11) Robinson <2.500s. (37). Underwood <2,500 g. et al.. (50). Group: I II III Downing No data No data and Chapman (7). 16.5 (152) 31.0 (181) Cigarettes per day 4.5 (108) 20 16.9 9.9 (770) 20 10.2 Percentages and absolute num- ber of premature births 8re based on 16.158 pregnancies recorded in 4,440 women. Group I. Smokers vs. "on- smokers po.o5 (3-C). TABLE 3.-Maternal smoking and prematurity (cont.) (Figures in parentheses are the absolute number of premature births) Premature by Author, ~ reference Duration of __ Weight gestation Percent of premature infants Nonsmokers Smokers Mean duration of pregnancy Nonsmokers Smokers Underwood <2,500 K. et al.. 5.7 (51). <36 weeks 5.R Iluncher (4). Cigarette8 .wec day 1,417) l-10 7.6 (671) 1 l-30 9.4 (1,358) >30 11.2 (176) 1,442) l-10 6.9 (525) 11-30 7.5 (1,084) >30 7.5 (118) Prematurity by birth weight ro8e directly to B significant degree (p0.05). Russell iBI': t Includes abortion. et al., <14Oi90 984 496 t27 t32 t27 t65 stillbirth, and (39). =140/90 340 117 t14 ts 63 neonatal death. >140/90 133 35 tzo t11 { 41 145 1 314 t Blood pressure. Tokutata White Data based on use of (49). 2.555 743 t246 tll2 t96 t151 cigarettes only. Nonwhite t Includes stillbirths 1,236 350 t174 t64 t141 t1s3 and miscarriages. Rutler 11,145 4,660 215 129 146 80 19.3 27.6 13.1 17.2 and Alberman (5). Source: Modified and expanded from Butler and Alberman (5). preeclampsia, smoking appears to increase the risk to the fetus be- cause of low birthweight and increased perinatal mortality (8). In a case-control study of sudden, unexpected death in infancy, Steele, et al. (46) observed that the percentage of smokers among mothers of cases of sudden, unexpected death, 61.2 percent, was significantly greater than the percentage among mothers of con- trols, 39.5 percent. The possible teratogenic effect of maternal smoking has not been adequately evaluated. Although it does not appear to be a major factor, there have been too few studies to determine whether ma- ternal smoking is a significant teratogenic risk (5, 23, 28, 50). Concern has been expressed about the possible long-term effects on the children of women who smoke during pregnancy. Butler (6) recently reported the results of a follow-up at age seven of the babies studied in the British Perinatal study of 1958. He found that the children of the mothers who were "heavy" smokers during pregnancy showed significantly decreased height, retardation of reading ability, and lower ratings on "social adjustment" than the children of nonsmoking mothers. The differences were independent of such factors as social class, age of mother, and parity. EXPERIMENTAL STUDIES In the past decade, research on the effect of smoking on pregnancy has increased. Summaries of human and animal experimental data in this area of study are found in tables 5 and 6. Elevated carbon monoxide levels have been found in maternal and fetal blood in women who smoke. Carbon monoxide is an inhibitor of carbonic anhydrase and as might be expected the activity of this enzyme is decreased in the cord blood of infants whose mothers smoke. The significance of elevated fetal carbon monoxide is not clear; how- ever, in an extensive monograph on this subject, Longo, (22) has concluded that ". . . the decreased availability of oxygen resulting from elevated (fetal) carboxyhemoglobin levels is probably in- jurious to fetal tissues." Other changes noted in the infants of smoking mothers have included a mild metabolic acidosis and a higher mean hematocrit (56). Two studies (9,52) have shown that placentas of women who smoke have a significantly greater ability to hydroxylate benzo[a]pyrene than the placentas from nonsmok- ers. Such findings suggest the possibility of fetal exposure to car- cinogens; however, the significance of these findings is presently speculative. Early animal studies (10, 42) showed that rats and rabbits ex- posed to nicotine or cigarette smoke have smaller offspring and more unsuccessful pregnancies than control animals. Recent radio- 407 % m TABLE 5.--Human experimental data on smoking and pregnancy Author. ear. country, reference Design of study Results comments Sontag and Wallace. 1935. U.S.A. (45). Fetal heart rate beforr and after smoking was Average fetal heart rate before smoking ~8s 144.0. studied Ii1 times in 5 patients. The average fetal heart rate for the eighth to the twelfth minute after starting to smoke was 149.0. Hlrddon et al., 1961. U.S.A. (14). Carbon monoxide levels were measured in 50 (,I, Carbon monoxide levels were significantly smokers and nonsmokers in a prenatal clinic. (p20 cigarettes a day. Both Canada (56). of the cigarette smoking mothers at the time of groups of women had normal deliveries and delivery was 8.3 percent and in the nonsmoking healthy infants. Biochemical changes in the first mothers 1.2 percent. The corrffponding mean um- 48 hours of life were studied in the infants. hilical vein blood levels were 1.3 percent and .I percent. (b) The blood Ph. pCOz and bicarbonate and lac- tate values in both groups of infants were within normal limits. (c) The infants of smoking mothers showed a higher mean hematocrit and mild metabolic acid- osis. __ Engel et al., 37 experiments were performed on placental blood Human placental blood has a lower relative affinity 1969, samples obtained from 15 pregnancies to detcr- for CO than adult hiowl. It was calculated that the U.S.A. (9). mint relative affinity of human fetal Hb for CO affinity constant of fetal Hb was approximately and Oz. 20 percent less than that of Hb A. TABLE 5.-Human experimental data on smoking and pregnancy (cont.) Author, Year, country. reference Nebert et al.. 1969, U.S.A. (92). Welch et al., 1969, U.S.A. (51). Design of study Results Comment.8 Aryl hydrocarbon hydroxylase activity was de- Significantly higher (p25 7.33 Hammond, 440.658 Interviews by G-83 11 NS 1.00 (11) 1.00 (22) ,966. males 35- ACS volunteers D-93 .22 SM (aae 45-64) 2.95) -.. 2.861 ^I. U.S.A. 84 years of SM (age65-79) 4.061 ""' 1.50]`= (11). age in 26 states. Kahn, U.S. male Questionnaire 678 . ,. .12 NS . 1.00(12) l.OO(26) l.OO(12) 1.00(26) l.OO(12) 1.00(26) 1966, veterans and follow-up D-119 . . ...26 SM 2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8) U.S.A. 2.265.674 of death Allcigarette 4.13(39) 2.98(57) (Id). person years. certificate. l-9 __._. 3.96 (6) 2.30 (6) lo-20 __________ 2.77(13) 2.74(26) 21-39 . :. 6.46(X) 3.98(22) >39 . . . . . . . ..11.6? (6) 2.89 (3) Weir and 68,163 males Questionnaire 44 NS . 1.00 No deaths from Dunn. in various and follow-up All cigarette 0.53 gastric ulcer oc- 1970. occupations of death 210 1.00 0.40 curred in "on- U.S.A. in California. certificate. -c20 . 1.67 0.69 smokers and risk (IS). 230 _. 2.38 0.32 of those smoking z?lO/day wss set at 1.00. NS in- cluded pipe. cigar, and .x-smokers. Author, Year, e"u"trY, reference SW Number CZWes Method of selection Numhrr C"ntr"ls C"mme"ts Method of selection Barn&t, M 66 Gastric. Patients admitted between 1913 and 500 Selected at random from the gen- 1. Retrospective review 1927. 178 Duodenal 1926. Only cases with complete eral admissions-males. 20-60 years records at Peter Bent U.S.A. (2). smoking history selected. of age. Brigham Hospital. 2. Ulcer diagnosis prob- ably well established. Trowell, 1934, England (31). M 50 Duodenal Not stated Allibone and Flint, 195% England (I). MandF 107 Consecutive admissions to hospital of patients with gastric and du- odenal hemorrhage or perforation. Doll et al., 1958, England (7). M and F 327 Gastric. Ulcer patients in Doll and Hill Lung 33X Duodenal. Cancer Study plus additional pa- tients in Central Middlesex Hospi- tal. Edwards et al., M 1,137 Men aged 60 and over on 11 General 1959, Practioners' lists were examined England and interviewed by these practi- (8). tioners. Represents about 84 per- cent of all such me" on these lists. (9 percent "on-response due to death and/or untraced.) 400 Selected at random from wards of 1. Interviewed by inves- a general hospital. tigator. 2. Ulcer diagnosis con- firmed by X-ray and/or S"Tgery. 107 Matched by we, sex. and time of Patients and controls in- admission from acute general sur- twviewed by same pical emergency admissions. observer. -~-.___~ ~~ 1.143 Patients with non-ulcer diseases. 1. Same interviewers and Each case matched with 2 co"- questionnaire in cases trol patients of same sex, B-year and controls. am ProuP, and 5llr"c type of 2. Ulcer diagnosis proh- place of residence. Male patients ably well established. matched by social class. Of 143 considered to have a peptic ulcer. 53 were confirmed by X-ray. TABLE 2. Methods used in retrospective and cross sectionat studies of peptic ulcer and smoking (cont.) Author, Year. country. reference Sex Number Method of selection Number Contlnls Method of selection Comme"ts Kasanen and M ForsstrSm. 1966. Finland (18). 43 Gastric. Successive male admissions with pep- 100 Successive men treated at medical A special questionnaire 67 Duodenal. tic ulcer treated at medical clinic clinic who had no gastrointestinal wes used for the or outpatient department of Uni- symptoms or signs of CHD. interview. versity Hospital. Only patients under 66 years of age or those who had been working were in- cluded. Gillies and Skyring. 1968, 196R. Australia (9). M and F 100 Gastric. Patients with peptic ulcer were se- 150 Matched by age and sex from the Diagnosis well established 60 Duodenal. lected from hospital admissions in seme ward at the same time and with X-ray, gastros- 1967. with absence of signs or symp- copy. or surgery. toms or past history of upper gastrointestinal disease. Gillies and M and F 10 Gastric. 1,405 workers from a broadcasting 100 Two control groups: All information obtained Skyring. 48 Duodenal. company, a manufacturing corn- 1. 100 peptic ulcer patients we- by question card. All 1969, 1R Uncertain peny, and a bus company were viously reported by authors. ulcers were proved by Australia location. interviewed for a history of pep- 1,329 2. 1.329 workers without ulcer. X-ray or surgery. (IO). tic ulcer. Monson. M and F 62 Gastric. 643 physicians fmm Massachusetts 625 Controls were physicians without Diagnosis established by 1970. 462 Duodenal. who responded a5irmatively to I) ulcer disease who were matched X-ray or SUrgelY except U.S.A. (15). 139 Not questionnaire sent to them in 1967 to ulcer patients by year of birth. for 46 "clinical" cases. specified. asking how many had had LL pep- tic ueer. TABLE 3.-Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking Author, ye*c co""trY. reference Barnett, 1927, U.S.A. (2). Percent nonsmoker ChS.33 controls Total . . 18.0 26.0 Gastric . . . . 16.0 Duodenal . . . 20.0 Amount of tobacco used C*WS Co"trols Trowel& 1934. England (91). Duodenal 8.0 17.0 Average number: Cigarettes 12.0 per day. .ll.l per day Pipe 1.6 ounces per week. 2.16 ounces per week Allibone and Flint, 1958. England (1). 38.0 64.0 Doll et sl., 1968. Englend (7). Gastric: Males . 1.3 Females . 61.1 Duodenal: Males 2.1 Females 53.7 4.7 66.8 5.8 62.0 Gastric: Percent emoking >25 cigarette8 per day Males . . 10.6 11.3 Females 1.1 1.1 Duodenal: Males ._ ._ 10.2 12.1 Females 1.9 1.9 Edwards Percent of peptic ulcer bu et al.. smoking category 1959, Never smoked . . . . . . . 6.0 England Formerly smoked . . . . . . . . . . *..* 6.7 (8). Cigarettes: l-9 per day _. _. . 9.4 lo-19 per day _. . . . . . . 9.3 >?Operday . . . 12.0 Pipe . . . . . . . . . . . . . . . . . . . . . 6.6 e Pipe end cigarettes . . . . . . . 8.5 v TABLE 3.-Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking (cont.) Author, year, Percent nonsmoker eountrY. ~ reference Cases Co"trols "Peptic" . . 10.0 40.0 Kasanen end ForsstrSm. 1966, Finland (IS). Amount of tobarco used ~-. Cases Co"trols Cigarettes per dsy: 20 . 19.0 10.0 Gillies end Skyring, 1968. Australia (9). Gastric 18.0 44.0 Duodenal 62.0 71.0 Mean number cigarettes per day: Gastric . 23.3 Duodenal 23.2 Duration of smoking (years) : Gastric 30.2 Duodenal 24.2 17.1 23.0 28.0 28.2 Gillies end Skyring, 1969. Australia (10). Gastric ........ 17.9 55.6 Duodenal ...... 36.6 Monson. 1910. U.S.A. (15). Duodenal ...... 32.1 Gastric ........ 19.2 Not Specified . 43.2 46.7 Percent smoking >20 cigarettes per day Age: Gastric DUOlhWl 20 ......... 38.8 21.3 30.1 30 ......... 45,.7 43.0 41.1 45 ......... 60.2 49.6 46.3 60 ......... 64.1 40.4 44.0 REFERENCES (1) ALLIBONE, A., FLINT, F. J. Bronchitis, aspirin, smoking, and other fac- tors in the aetiology of peptic ulcer. Lancet 2: 179-182, July 26, 1958. (2) BARNETT, C. W. Tobacco smoking as a factor in the production of peptic ulcer and gastric neurosis. Boston Medical and Surgical Journal 197(12) : 457459, September 22, 1927. (3) BATTERMAN, R. C , EHRENFELD, I., The influence of smoking upon the management of the peptic ulcer patient. Gastroenterology 12 (4) : 575- 585, April 1949. (4) COOPER, P., KNIGHT, J. B., JR. Effect of cigarette smoking on gastric secretions of patients with duodenal ulcer. New England Journal of Medicine 255(l) : 17-21, July 5, 1956. (5) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' obser- vations of British doctors. Part I. British Medical Journal l(5395) : 1399-1410, May 30, 1964. (6) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' obser- vations of British doctors (concluded). British Medical Journal l(5396) : 1460-1467, June-G, 1964. (7) DOLL, R., JONES, F. A., PYGOTT, F. Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1: 657-662, March 29,1958. (8) EDWARDS, F., MCKEOWN, T., WHITFIELD, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-201, January 24, 1959. (9) GILLIES, M., SKYRING, A. Gastric ulcer, duodenal ulcer and gastric car- cinoma: A case-control study of certain social and environmental fac- tors. Medical Journal of Australia 2(25) : 1132-1136, December 21, 1968. (10) GILLIES, M. A., SKYRING, A. Gastric and duodenal ulcer. The association between aspirin ingestion, smoking and family history of ulcer. Medi- cal Journal of Australia 2(6) : 280-285, August 9, 1969. (11) HAMMOND, E. C. Smoking in relation to the death rates of 1 million men and women. IN : Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 12'7-204. (12) KAHN, H. A. The Dorn study of smoking and mortality among U.S. veterans: Report on 8% years of observation. IN: Haenszel, W. (Edi- tor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 1-125. (IS) KASANEN, A., FORSSTROM, J. Social stress and living habits in the etiology of peptic ulcer. Annales Medicinae Internal Fenniae 55(l) : 13-22, 1966. (14) MITTY, W. F., JR., ROUSSELOT, L. M., DELANY, G. J. Smoking and its relation to nutritional status of patients following gastrectomy; a five-year follow-up survey of 171 patients. Annals of Surgery 150 (1) : 76-84, July 1959. (15) MONSON, R. R. Cigarette smoking and body form in peptic ulcer. Gastro- enterology 58 (3) : 337-344, March 1970. 429 (16) PACKARD, R. S. Smoking and the alimentary tract: A review. Gut 1: 171-174, 1960. (17) PALMER, W. L. Peptic ulcer. Chapter 32. IN: Paulson, M. (Editor). Gastroenterologic Medicine. Philadelphia, Lea & Febiger, 1969, pp. 710-757. (16) SCHNEDORF, J. G., Iw, A. C. The effect of tobacco smoking on the alimentary tract. An experimental study of man and animals. Journal of the American Medical Association 112(10) : 898-904, March 11, 1939. (19) STEIGMANN, F., DOLEHIDE, R. H., KAMINSKI, L. Effects of tobacco smok- ing on gastric acidity and motility of hospital controls and patients with peptic ulcer. American Journal of Gastroenterology 22 : 399-409, 1954. (20) THOMPSON, J. H. Effects of nicotine and tobacco smoke on gastric secre- tion in rats with gastric fistulas. American Journal of Digestive Diseases 15(3) : 209-217, March 1970. (21) TROUTELL, 0. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 808-809, April 14,1934. (12) U.S. PUBLIC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATIS- TICS. Vital Statistics of the United States-1967. Vol. II-Mortality, Part A. Washington, U.S. Department of Health, Education and Wel- fare, Public Health Service Publication, 1969. (28) WEIR, J. M., DUNN, J. E., JR. Smoking and mortality: A prospective study. Cancer 25( 1) : 105-112, January 1970. 430 CHAPTER 7 Tobacco Amblyopia Contents Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436 433 TOBACCO AMBLYOPIA Tobacco amblyopia (tobacco-alcohol amblyopia) is that syn- drome of visual failure occurring in association with the use of tobacco, with or without the concurrent use of alcohol, and with or without concurrent nutritional deficits. The disease has a subacute onset, leading to a loss of visual acuity and color perception (12). It is characterized by centrocecal scotomas which are bilateral but not necessarily symmetrical and which have sloping diffuse edges and by the presence of nuclei of denser visual loss within the large scotomas (22,23). Such visual impairment is not unique to tobacco amblyopia, as it is also seen in neurodegenerative disorders, such as Leber's hereditary optic atrophy (7,25). Clinical information on tobacco amblyopia has appeared in nu- merous articles throughout the past century. This information has been reviewed by Silvette, et al. (17) and, more recently, by Dunphy (5). Pure tobacco amblyopia (TA) , that is amblyopia unassociated with excessive alcohol intake or the exposure to other toxins, is rarely seen in the United States today (12). Walsh, et al. (23) have observed that when TA is found it is usually present in association with nutritional or idiopathic vitamin deficiencies. Victor (22) recently observed that the type of visual defect seen in tobacco amblyopia may be found in clinical circumstances in which tobacco is clearly not a causative factor. He questions whether TA is distinguishable from other forms of amblyopia. The prevalence of this disorder has been variously estimated in the past at from 0.5 to 1.5 percent of all eye clinic patients (20,23). However, currently in the United States, it appears to be a rare condition. Silvette, et al. (17) have observed that the incidence of tobacco amblyopia appears to have decreased substantially during the past decades. Other authors (3, 15) have also commented on this trend. Although reference has been made to the increased fre- quency of certain types of tobacco usage in patients with this dis- order, adequate population studies with proper controls have yet to be performed. The association of this disorder with the use of tobacco is strengthened by the frequent clinical observations of improvement following the cessation of smoking although improve- ment has been noted by some to occur without cessation. Research into the pathogenesis of tobacco amblyopia has cen- 435 tered upon the interrelationships of cyanide metabolism, vitamin B,,, and other vitamin deficiencies. Three reviews of this material have recently appeared (1, 12, 2.2). Numerous studies reviewed in these articles suggest that tobacco amblyopia may result from the incomplete detoxification of the cyanide present in tobacco smoke. This failure of detoxification may stem from or be intensified by inadequate dietary intake of necessary nutritional factors. This may be the reason for the association of this disorder with exces- sive alcohol intake and with its related nutritional deficits (2, 4, 6, 8,9,10,11,13,14,16,18, 19,21,24,26,27,28). SUMMARY AND CONCLUSIONS Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mechan- isms, particularly in handling the cyanide component of tobacco smoke. REFERENCES (1) CANADIAN MEDICAL ASSOCIATION JOURNAL. Tobacco amblyopia. (Edi- torial) Canadian Medical Association Journal 102(4) : 420, February 28, 1970. (2) CHISHOLM, I. A., BRONTE-STEWART, J., FOULDS, W. S. Hydroxocobalamin versus cyanocobalamin in the treatment of tobacco amblyopia. Lancet 2(7513) : 450-451, August 26, 1967. (5) DARBY, P. W., WILSON, J. Cyanide, smoking, and tobacco amblyopia. Observations on the cyanide content of tobacco smoke. British Journal of Ophthalmology 51(5) : 336-338, May 1967. (4) DREYFUS, P. M. Blood transketolase levels in tobacco-alcohol amblyopia Archives of Ophthalmology `74(5) : 617-620, November 1965. (5) DUNPHY, E. B. Alcohol and tobacco amblyopia: A historical survey. American Journal of Ophthalmology 68(4) : 569-578, October 1969. (6) FOULDS, W. S., BRONTE-STEWART, J. M., CHISHOLM, I. A. Serum thio- cyanate concentrations in tobacco amblyopia. Nature 218 (5141) : 586, May 11, 1968. (7) FOULDS, W. S., CANT, J. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, J. Hydroxocobalamin in the treatment of Leber's hereditary optic atrophy. Lancet l(7548) : 896-897, April 27, 1968. (8) FOULDS, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, T. M. Vitamin B,, absorption in tobacco amblyopia. British Journal of Ophthalmology 53 (6) : 393-397, June 1969. (9) FOULDS, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, T. M. The optic neuropathy of pernicious anemia. Archives of Ophthalmol- ogy 82(4) : 427-432, October 1969. (10) FREEMAN, A. G., HEATON, J. M. The aetiology of retrobulbar neuritis in Addisonian pernicious anaemia. Lancet l(7183) : 908-911, April 29, 1961. 436 (11) HEATON, J. M., MCCORMICK, A. J. A., FREEMAN, A. G. Tobacco amblyo- pia : A clinical manifestation of vitamin-B,, deficiency. Lancet 2(7041) : 286-290, August 9, 1958. (12) KNOX, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(l) : 103-127, January 1970. (13) LINDSTRAND, K., WILSON, J., MATTHEWS, D. M. Chromatography and microbiological assay of vitamin B1? in smokers. British Medical Journal 2 (5520) : 988-990, October 22, 1966. (14) LINNELL, J. C., SMITH, A. D. M., SMITH, C. L., WILSON, J., MATTHEWS, D. M. Effects of smoking on metabolism and excretion of vitamin B,,. British Medical Journal 2(5599) : 215-216, April 27, 1968. (15) SCHEPENS, C. L. Is tobacco amblyopia a deficiency disease- Transactions of the Ophthalmological Society of the United Kingdom 66: 309-331, 1946. (16) SCHIEVELBEIN, H., WERLE, E., SCHULZ, E. K., BAUMEISTER, R. The influ- ence of tobacco smoke and nicotine on thiocyanate metabolism. Naunyn-Schmiedebergs Archiv fiir Pharmakologie und Experimentelle Pathologie 262(3) : 358-365, February 5, 1969. (17) SILVETTE, H., HAAG, H. B., LARSON, P. S. Tobacco amblyopia. The evolu- tion and natural history of a "tobaccogenic" disease. American Journal of Ophthalmology 50( 1) : 71-100, January 1960. (18) SMITH, A. D. M. Retrobulbar neuritis in Addisonian pernicious anae- mia. (Letter) Lancet l(7184) : 1001-1002, May 6, 1961. (19) SMITH, A. D. M., DUCKETT, S. Cyanide, vitamine B,,, experimental demyelination and tobacco amblyopia. British Journal of Experimen- tal Pathology 46(6) : 615-622, December 1965. (20) TRAQUAIR, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans- actions of the Ophthalmological Society of the United Kingdom 50: 351385, 1930. (21) VICTOR, M. Tobacco-alcohol amblyopia. A critique of current concepts of this disorder, with special reference to the role of nutritional deficiency in its causation. Archives of Ophthalmology 70(3) : 313-318, Septem- ber 1963. (22) VICTOR, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de- ficiency. A critique of current concepts. Chapter 3. IN: Smith, J. L. (Editor) Neuro-Ophthlamology. Symposium of the University of Miami and the Bascom Palmer Eye Institute. Hallandale, Florida, Huffman Publishing Co., 1970. pp. 3348. (2s) WALSH, F. B., HOYT, W. F. (Editors) Neurotoxic substances affecting the visual and ocular motor systems. Chapter 15: IN: Clinical Neuro- Ophthalmology, Volume 3, 3rd Edition. Baltimore, The Williams & Wilkins Company, 1969. pp. 2613-2616. (24) WATSON-WILLIAMS, E. J., BOTTOMLEY, A. C., AINLEY, R. G., PHILLIPS, C. I. Absorption of vitamin B12 in tobacco amblyopia. British Journal of Ophthalmology 53 (8) : 549-552, August 1969. (85) WILSON, J. Leber's hereditary optic atrophy: A possible defect of cya- nide metabolism. Clinical Science 29(3) : 505-515, December 1965. (26) WILSON, J., MATTHEWS, D. M. Metabolic inter-relationships between cyanide, thiocyanate and vitamin B,, in smokers and nonsmokers. Clinical Science 31(l) : l-7, January 1966. 437 (27) WOKES, F., PICARD, C. W. The role of vitamin B,, in human nutrition. Clinical Nutrition 3 (5) : 383-390, September-October 1955. (28) WYNDER, E. L., HOFFMANN, I). Certain constituents of tobacco products. Chapter 8. K. Vapor phase of tobacco smoke. IN: Wynder, E. L., Hoffmann, I). (b:ditors). Tobacco and Tobacco Smoke. Studies in Ex- perimental Carcinogenesis. New York, Academic Press, 1967. pp. 451-453. 43.3 Index Abortions smoking effects on, 13 Abortions, spontaneous comparison of stillbirth and neonatal death with, in smoking and nonsmok- ing mothers, 390,405406 Acidosis metabolic, smoking mother effects on in- fant, 407 Adenocarcinoma prevalence in male and female smokers and nonsmokers, 250 relationship of cigarette smoking to, 246-249,296 Adenoma papillary, induction in rats by exposure to cigarette tars, 348 pulmonary, induction in mice by ciga- rette smoke inhalation, 349 renal, relationship of smoking to, 296 Adrenal gland catecholamine release from, nicotine effects on. 36 Advelvt;y Committee on Smoking and establishment and conclusions of study by, 3 report on cigarette smoke and conden- sates effects on oral cavity of animals, 288 Age atypical nuclei in esophageal epithehum arranged by smoking and, 379-31 current cigarette smokers by sex and, 6 effects on CHD, 27.39 AHA see American Heart Association Air pollution as cause of COPD, 152,216-217 effect on COPD development, 175 relationship of lung neoplasms, smoking and place of residence, 252-255 role in etiology of lung cancer, 11, 276 Alcohol effect of consumption on esophageal neoplasms in smokers, 289,293 effect of consumption on laryngeal neo- plasms among tobacco users, 280 effect of consumption on tobacco am- blyopia 435436 effect of heavy consumption and heavy smoking on oral neoplasms, 288 ethanol, penetrability of dissolved benzo(o)pyrene in mice esophageal epi- thelium,, 293 relationship of smoking and, in human tuberculosis, 172 Alcoholism patients with, smoking and ventilatory function in, 213 Amblyopia characterization of, 435 development from cyanide component of tobacco smoke, 14 incidence of, 435 American Heart Association pooling project on CHD, 23, 28, 30, 39 Aminoazo dyes activity in placenta of smoking mothers, 410 Angina pectoris cause bf, 21 incidence with cigarette smoking, 24,37 in Danish twins. smokers vs. nonsmok- ers,.51 in twms, constitutional factors, 50-51 prospective studies of, CHD morbidity relation to smoking 37,39 Animals see ulso specific animals e.g., cats, dogs, rabbits, etc. atherosclerotic lesion development in, smoking enhancement, 36 carcinoma induction in, from arsenic, 257 cigarette smoke effect on pulmonary physiology and structure in, 162 development of lesions from cigarette smoke inhalation, 11 effects of nicotine on cardiovascular system of, 57, 107-112 esophageal neoplasms in, induction by nitrosamines, 292 respiratory tract of, neoplastic changes following cigarette smoke inhalation, 238-239 ski of, carcinogenicity of tobacco tars, 238.267 tests of, -4th smoke carcinogens, 12 ventilatory function change from smok- ing, 10 Anti-trypsin, alphat COPD predisposition from genetic ab- sence of, 150 determination using immunoelectro- phoresis, 151 relationship in pulmonary emphysema, 10-l 1 Anthranihc acid, 3hydroxy- urinary excretron of, smoking effects on, 296 Aorta aneurysms of, cigarette smoking effect on.9.61.71.15 atherosclerosis' in, long term smoking effects, 52-56 Areca nut see Betel nut Aromatic compounds carcinogenic properties in cigarette 439 smoke from, 264,265 detection in urine using chemilumi- nescence technique, 297 stimulation of placental BP-hydroxylase activity in pregnant rats by, 414 Arrhythmia formation in nicotine stimulated dam- aged myocardium, 58 Arsenic lung neoplasm mortality in smelter workers exposed to, 257 respiratory tract carcinoma in workers exposed to, 256,257 Arteries aneurysm in aortic, cigarette smoking ef- fects on. 9.67,71,75 atherosclerotic, increased by cigarette smoking, 8,63 flow of carotid, cigarette smoking effects on, 67 hypoxemia, development from cigarette smoking, 9 occlusions of, cigarette smoking effects on, 73 walls of, mechanism of lipoprotein infii- tration, 63 walls of nicotine-induced necrosis, 63 Arteriosclerosis see also Thromboangiitis obliterans in aorta and coronary arteries, cigarette smoking effects on, 45.52-56 cigarette smoking effects on, 8 development by increased carboxyhemo- globin formation, 9 development of, carbon monoxide ef- fects on, 63 de$opment of, effects of nicotine on, lece;tde3v;lopment in, smoking enhance- periphdral, cigarette smoking effects on, 72-73 Arteriosclerotic heart disease (ASHD) see Coronary disease Asbestos workers see Occupations ASHD see Coronary disease Asia see also specific countries of Asia Central and Southeast. relationship of tobacco use and neoplasms of oraicav- ity, 366 Asthma bronchial, cigarette smoking effects on, 10,175 Atherosclerosis see Arteriosclerosis Atropine effects on bronchoconstriction in dogs, 163 Australia COPD morbidity in smokers in, 203 laryngeal neoplasms in, relationship to tobacco use, 357 lung neoplasm in, retrospective studies of,.327 peptic ulcer in, methods for retrospec- tive and cross-section studies of smoking and, 426,428 Bacteria effect of cigarette smoke on acuon ,,f macrophages on, 165 pneumonia, mice resistance fogowrng cigarette mhalatron, 173 Bank employees see Occupations Benz(e)acephenanthrylene carcrnogenic properties in cigarette smoke from. 264.265 Benz(o)anthrackne alcoholic sohrtion of, penetrabihry of mice esophageal epithelium, 292 Benz(u)anthracene, 7,12dimethyl carcinoma induction in hamsters follow. ing instillation of, 346 skin painting with, Papihoma and talc,. noma induction m mice by, 341 Benzo(b)fluoranthene see Benz(e)acephenanthrylene Benzo(i)fluoroanthene carcinogenic properties in cigarette smoke from. 265 Benzo(c)phenanthrene carcinogenic properties in Cigarette smoke from, 265 Benzo(rsr)pentaphene carcinogenic properties in cigarette smoke from. 265 3,4-Benzopyrene see Benzo(u)pyrene Benzo(a)pyrene ability of smoking mothers to hydroxy). ate, 407 alcoholic solution of, penetration of mice esophageal epithelium, 292 carcinogenicity of, in relation to asbestos in hamsters,, 257 carcinogenrc properties in CQarette smoke from, 264,265 detoxification by lung aryl hydroxyiase, 257 effects of instillation or implantation in animal tracheobronchial tree, 346-347 effects on animal tissue and organ cul- tures in? 343-345 effects wtth influenza virus on cigarette inhalation by mice, 352 sarcoma induction in rats following in- stillation of, 346 skin painting with, papilloma induction in mice by, 337-338 Benzo(a)pyrene, l-methyl- carcinogenic properties in cigarette smoke from, 265 Betel nut chewers of, relationship with oral cavity neoplasms, 366,369-370 Birth weight see Neonate Blacks maternal smoking and infant weight, 397 m;;;fqnga: smoking and prematurity, Bladder neoplasms frequency in smokers vs. nonsmokers, 238. 293-295 methods of retrospective studies of smoking and, 293,381-384 presence of tryptophan metabolites in 440 urine of patients with, 296-297 relationship of cigarette smoking to, 299 urinary, cigarette smoking relationship, 13 U.S. mortality in 1967, 294 Blood see also specific components of blood, e.g., cholesterol, lipids, platelets carboxyhemoglobin formation in, from smoking, 60,75 clotting, cigarette smoking effects on, 9, 36 Blood circulation. coronarv alteration foUo&ing cigarette smoke in- halation, 58 effect of variations in hemoglobin and hematocrit, 66 Blood pressure diastolic, cigarette smoking effects, 8, 23 diastolic, in smokers with CHD, 21-22, 24,42 high, risk factor in arteriosclerosis ob- literans. 72 hiah. risk.in mortalitv from CVD. 67 hypertensive vs. nori-hyperten&ey mor- talitv rates of CHD in 42 nicotine effects on, 36 relationship of smoking and CHD, 43,47 smokers vs. nonsmokers. 41.42. 103-104 - . - _ _ systolic, mortality from elevated, with CHD. 42 BP-hydroxylase see under Enzymes Bradycardia development in dogs given nicotine, 57 British Perinatal Mortality Survey results of, 390 Bronchitis. chronic cigarette'smoking cause and effect rela- tionship, 3,9 definition, 139 mortality in cigarette smokers, 175 mortality rates in 1967.139 smokers-vs. nonsmokers, 195-205 Bronchogenic carcinoma see Carcinoma, bronchogenic Bronchopneumonia development in dogs following cigarette smoke inhalation, 271 Bronchopulmonary disease, chronic ob- structive see also Asthma, bronchitis, emphysema, respiratory diseases ai;16p;ll17ution relationship in, 152, characterization of, 139 cigarette smoking effects on develop- ment, 4,9-l 1: 175 effect of smokma cessation on develou- increased prevalence of heterozygotes in, ment, 10 - genetic factors in pathogenesis of, 148, 151-152 150-152.205 mortality in pipe, cigar, and cigarette smokers, 175 mortality rates from, 139-145 smoking effects on ventilation-perfusion measurements in, 163 Buerger's disease see Thromboangiitis obliterans Burma methods used in smoking study and human pregnancy, 393 - Butylamine. N-methyl-nitroso suspected ~carcinogknic properties in ciga- rette smoke from, 265 Cadmium in cigarette smoke, relation to emphy- sema pathogenesis, 154 Calves see Cattle Canada COPD morbidity of smokers in, 204 human experimental data on smoking and pregnancy, 409 infectious resuiratorv disease in. relation- ship to smoking, 228 kidney and bladder neoplasms in smok- ers in. 294 mortality rates from COPD, 139-141, 145 mortality ratios from COPD, 143 mortality ratios in smokers and non- smokers from pancreatic neoplasms, 298 thrombosis in, smoking relationship, 132 veterans of, lung neoplasm mortality ratios in smokers and nonsmokers, 24 1 Carbazole, 9-methyl- possible importance in tobacco carcino- genesis, 266 Carbon-14 labeled smoke particulate deposition in hamster respiratory tract, 281-282 Carbonic anhydrase see Enzymes Carbon monoxide in cigarette smoke, formation of car- boxyhemoglobin, 8-9 effects on cholesterol-fed rabbits, 6566 effects on human physiology, 6062 levels in ciaarette smoke. 59 levels in fe'tal blood of smoking mothers, 407410 Carboxyhemoglobin effects of elevated, on fetal tissues, 407 formation in blood of smokers, 60, 75 formation from CO in cigarette smoke, 8-9 Carcinogens action on oral cavity, effect of saliva, 288 listing of, in cigarette smoke, 265-266 in smoke, effect on oral cavity, 12 Carcinoid prevalence in male and female smokers and nonsmokers. 250 Carcinoma formation following animal skin painting induction in rats exposed to cigarette with smoke condensates. 337-342 tars, 348 undifferential, relationship to cigarette smoking, 248-249 Carcinoma, alveolar induction in mice by cigarette smoke in- halation, 349 441 Carcinoma, anaplastic prevalence in male and female smokers and nonsmokers, 250 Carcinoma, bronchogenic development in dogs following cigarette smoke inhalation, 269,272-273 mortality from, relationships to smok- ing, air pollutton and residence, 253 mortality in smokers vs. nonsmokers as- bestos workers, 257 Carcinoma, epidermoid mortality from, relationship to smoking, air pollution and residence, 254 prevalence in male and female smokers and nonsmokers, 250 relationship of cigarette smoking to, _ 246-249 Carcinoma, epithelial induction in mice by cigarette smoke in- halation, 350 Carcinoma, oat cell relationship of cigarette smoking to, 247 Carcinoma, squamous cell development in mice drinking alcoholic benzo(u)pyrene, 292 in oral cavity, relationship to tobacco use, 366-367 Carcinoma, tracheobronchial induction in hamsters by cigarette smoke instillation, 346-347 Cardiovascular diseases see also Coronary disease atherosclerotic, cigarette smoking rela- tionship, 4 Cardiovascular system nicotine and cigarette smoke effects on, 56-58, 107-l 18 Catecholamines adrenal gland release, effect of nicotine on, 36 effect on blood flow in coronary arte- ries, 58 release by cigarette smoking, 8 release in animals by nicotine, 57, 119 Cats cardiovascular function in, smoking and nicotine effects on, 110, 111 ciliary function in, effect of cigarette smoke on, 222-224 lungs of, ngarette smoke effect on sur- factant activity, 225 Cattle ciharv function in. effect of ciearette smoke on, 221 ' CRF --- see Blood circulation coronary Central nervous system effects of carbon monoxide in smoke on, 60 Cerebrovascular disease definition of, 66 mortality from, effects of cigarette smoking on, 9 mortality rates from, smokers vs. non- smokers, 66-70 Cessation of smoking effect on COPD development in British physicians, 142 effect on COPD morbidity in smokers vs. nonsmokers, 146 effect on development of COPD, 140 442 effect on mortality from COPD from, 175 improvements in respiratory system, 148,149 relation to incidence and mortality from CHD, 32,4648,106 CHD see Coronary disease Chemiluminescence see Luminescence Chewing see Betel nut and tobacco Chickens ciliary function in, effect of Cigarette smoke on, 223 embryos of, effect of cigarette smoke on, 344 embryo of, nicotine effects on CNS, 411 Chile atherosclerosis autopsy studies in, 55 atherosclerosis in, no smoking effect found, 56 Cholesterol rabbits fed, carbon monoxide effects on, 65-66 secrufnh' 8cigarette smoking relationship serum, control in coronary disease, 21-22 serum, relationship of cigarette smoking to levels of, 41,43 serum, relationship of elevated with ciga- rette smoking in peripheral vascular disease, 72 serum, m smokers vs. nonsmokers, 41, 98-102 serum, in smokers with CHD, 23-24, 43 synergistic relationship of carbon mon- oxide in coronary atheromatosis, 63 Chromium respiratory tract carcinoma in workers exposed to, 256 Chromium compounds lung neoplasm mortality from, 257-258 Chronic obstructive pulmonary disease see Bronchopulmonary disease, chronic obstructive Chrysene carcinogenic properties in cigarette smoke from, 265 Chrysene, lmethyl- carcinogenic properties in cigarette smoke from, 265 Cigarette filters ad;6ytag;; m reduction of particulates, reduciion of lung neoplasms from, 13 Cigarette smoke alteration of coronary blood flow, 58 bronchogenic carcinoma induction in dogs inhaling, 269,270 cadmium levels in, 154 carbon monoxide levels in, 59 carcinogenicity of components to ani- mals, 12,277 cause of death in dogs from inhalation, 271 ciliary movement inhibition, 267 efF4;tS;;5tissue and organ cultures, 267, effect of nickel on induction of lung aryl hydroxylase, 256-257 high tar, risks in, 11 inhalation by dogs, lung neoplasm devel- opment, 268-269,212-214 inhalation effects on animal respiratory tract,, 268-269, 349-353 inhafatron effects on hamster larynx, 281,284 listing of identified or suspected tumori- genie agents, 264261 2-naphthylamine identified in. 265 neoplastic changes in animals inhaling, 238-239 tobacco amblyopia relationship to cyan- ide metabolism in, 435436 Cigarette smoke condensates carcinogenic effect on animal oral cav- ities, 288 carcinogenic properties on animal skin, 331-342 effects of instillation or implantation in animal tracheobronchial tree, 346-348 effects on tissue and organ cultures, 343-344 painting skin of animals with, 331-342 Cigarette smokers arterial occlusions in, 73 atherosclerosis in aortic and coronary ar teries, 52-56 atypical nuclei in male esophageal epi- thelium, 379-380 bladder neoplasms in, 293-295 cell rows and atypical cells in vocal cords of, 280, 359-360 cessation effects on COPD morbidity, 146,197,199,203-204 cessation lowers lung neoplasm rate in, 11 changes in vent&tory function and pul- monarv histologv. 115 CHD mAHA po%ng project, 28, 30, 39 CHD risk by, 23-25 comparative risk for lung neoplasms, 237 decline in British physicians, 48 development of altered ventilatory func- tion H young, 10 de;;l;$ynt of esophageal neoplasms, development of laryngeal neoplasms, 12 development of oral neoplasms, 12 development of second primary oral neo- plasms in continuing, 287 effect of filters on emphysema develop- ment, 162 effects of inhalation on bronchial reacti- vity, 164 effect on cardiovascular system, 56-58, 107-118 effects on uterine activity in gravidic women, 408 esophageal neoplasm mortality ratios in, 290-29 1 etiological cause of lung neoplasms? 239 histology and smoking relationshrp of lung neoplasms in 246-249 infant birth weight, 397-399 inhalation effects on human pulmonary function, 163,166-169 kidney neoplasms in, 294-296 laryngeal neoplasm induction in, 354-351 lu2n4~-2nrplasm mortality in, 240, mortality from cerebrovascular disease, 61-70 mortality rates affected by sex, 3 mortality ratios from COPD, 142-144 mortality ratios from pancreatic neo- plasms in, 298 mortality ratios from peptic ulcers in, 424 peptic ulcer in, smoke effects on antacid therapy, 423 percentage of women of child-bearing age, 389 possible processes for increased mortal- ity in, 4-5 postoperative pulmonary complications in, 174,230 pulmonary surfactant activity in, 172, 225 relationship of asbestos in lung neoplasm mortality, 257 relationship in coronary and lower limb arteriosclerosis, 72 relationship of former to lung neoplasm development, 276 relationship to infectious respiratory dis- ease, 172,226-229 relationship to laryngeal neoplasm devel- opment in, 28 1 relationship to lip or oral cavity neo- plasms, 36 l-370 relationship to lung neoplasms, 275 relationship with bladder neoplasms in men, 299 relationship with dust on COPD develop.. ment. 153 with peptic ulcer, 427 risk in CHD, 8 risk of COPD in, 140 survey by age and sex, 6 survey of U.S.. 6 Cigarettes development of esophageal neoplasms ~ bv. 12.293 tar levels of, relationship to lung neo- plasm development, 276 Cigar smokers atypical nuclei in male esophageal epi- thelium, 319 bladders neoplasms in, 293-294 cell rows and atypical cells in vocal cords of, 280, 359-360 COPD morbidity in, 146, 197-198, 201.202,204-205 effects of smoke on bronchial reactivity, 164 esophageal neoplasm mortality ratios in, 290 kidney neoplasms in, 294-295 lack of risk in CVD, 67 laryngeal neoplasm induction in, 12, 354-357 lung neoplasm incidence in rural Switzer- land. 244 lung neoplasm mortality in, 11,240-243 mortality ratios from COPD in, 142-143, 145 443 myocardial infarction in, 32, 38-39 relationship to infectious respiratory dis- ease, 227 relationship of laryngeal neoplasms de- velopment in, 281 relationship of neoplasms of oral cavity with,, 12, 361-365.367-371 mortahty ratios from pancreatic neo- plasms in, 298 mortality ratios from peptic ulcer in, 424 risk of CHD, 8 risk of COPD, 10 risk of lung neoplasm development, 276 Ciliary activity see Respiratory system Circulation see Blood circulation Cirrhoses see Liver Civil servants see Government employees under Occu- pations Coal miners see Occupations Congressional legislation see Laws Connecticut Cancer Registry figures on age-adjusted larynx neoplasm incidence,.277 fifm~ on mcidence of oral neoplasms, Constitutional hypothesis relationship to CHD and smoking, 4849, 105-106 COPD see Bronchopulmonary disease, chronic obstructive Cornsilk smoking, tack of arterial epinephrine level increase, 57 Coronary blood flow see Blood circulation, coronary Coronary disease see also Angina pectoris age- adjusted rates in smokers, 23 arFLriosclerotic, mortality rates in U.S., atherosclerosis in, effects of smoking on, 4,63 bl;r;d4y;me of smokers vs. nonsmok- carbon dioxide effects on oxygen uptake in, 62 cigarette smoking relationship, 5 death ratios of paired combinations of high risk, 25 fist, mortality rates in smokers vs. non- smokers, 24, 26-29 incidence and mortahty rates in former smokers, 46.4748 infarction in NYC pipe and cigar smok- ers, 32.38-39 infarction relationship to physical activ- ity, smokers vs. nonsmokers, 44 in smokers with predisposing factors, 24 morbidity relationship of smoking to, 32-35,37,39,93-91 mortality and morbidity retrospective studies, 40,93-97 444 mortality from, relationship to electre cardiographic findings, 42 mortality in obese vs. non-obese, 45 mortality rates in, hypertensives vs. non- hypertensives, 42 mortality rates in, smokers vs. non- smokers, 21-22 mortality rates in, with increased carbon monoxide, 62 mortality rates of paired combinations of high risk, 25 mortality rates of cigarette smokers from? AHA pooling project, 28,30,3V mortahty rates of U.S. veterans, 26, 38 myocardial infarction in Danish twins, 51 ni;;tin; effect on coronary blood flow relaiion of triglycerides to, 65 relationship of blood presure and smok- ing, 45,41 relattonship of heart rate and smoking, 45,.47 relatronship of physical activity and smoking41,43,44 relationship to constitutional makeup and smoking, 4849, 105-106 relationship to ECG abnormalities and smoking, 45,47 relationship to obesity and smoking, 4345 risk factors, 23-24,4041 smokers age effects on development, 27, 39 smoking risk factor, 8 sudden mortality in, smoking effects on, 52 Coronary heart disease See Coronary disease cows see Cattle Cresol suspected carcinogenic agent of cigarette smoke, 266 Cuba laryngeal neoplasms in, relationship to tobacco use, 356 relationship of tobacco use and neo- plasms of oral cavity, 364 CVD see Cerebrovascular disease Cyanides metabolism of, pathogenesis of tobacco amblyopia relationship to, 435436 in tobacco amblyopia etiology, 14 Czechoslovakia laryngeal neoplasms in, relationship to tobacco use, 354,357 serum lipid difference in smokers vs. nonsmokers in. 101 Death rates see Mortality rates Denmark atherogenic effect of carbon monoxide and hypoxia, 64 bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 381,383 carbon monoxide effects on human blood lipids in, 129 carbon monoxide effects on rabbit blood lipids in, 129 serum lipid differences in smokers vs. nonsmokers in, 102 twins in, angina pectoris in smokers vs. nonsmokers,.51 Deoxyribonucleic acid content increase in smokers oral epi- thelial cells, 288 levels in mice lung exposed to cigarette smoke, 161 Diabetes effect on CHD in smokers, 24 risk in mortality from CVD, 67 Diabetes mellitus relationship with cigarette smoking in peripheral vascular disease, 72 Dibenz(a,h)acridine carcinogenic properties in cigarette smoke from,.265 Dibenz(aj)acridme carcinogenic properties in cigarette smoke from, 265 7H-Dibenzo(c,g)carbazole carcinogenic properties in cigarette smoke from, 265 Dibenzo(a,i)pyrene see Benzo(rst)pentaphene Diethylnitrosamine suspected carcinogenic properties in ciga- rette smoke from, 265 7,12-Dimethylbenz(a)anthracene see Benz(a)anthracene, 7,12dimethyl- Dimethylnitrosamine suspected carcinogenic properties in ciga- rette smoke from, 265 2,3-Diphosphoglycerate effects of carbon monoxide on, 6061 DNA see Deoxyribonucleic acid DO&E atherogenic effects of nicotine in, 120 bt&d;; rrrplasms in, fed 2-naphthyl- brady&dia and tachycardia in, follow- ing nicotine injection, 57-58 bronchogenic carcinoma induction in, from cigarette smoke inhalation, 269, 210 cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of. 268,347 death in, causes from cigarette smoke m- halation, 271 effect of cigarette smoke on pulmonary clearance in, 164, 170 fetal bronchial tubes of, effect of ciga- rette smoke on, 345 lungs of, cigarette smoke effects on sur- factant activity, 112, 225 lung neoplasms following cigarette smoke inhalation, 239,277 lung neoplasms in, types and lobes where found. 269.272-273 myocardium of, nicotine effects on, 58 neoplasm development in smoking, per- centages of, 274 activity of, effect of smoking, 165 aryl hydrocarbon hydroxyiase activity in placentas at childbirth, 410 aryl hydroxylase, effect of nickel in ciga- rette smoke on induction of, 257 benzo(a)pyrene hydroxylase, activity in placentas of smoking mothers, 410 carbonic anhydrase, carbon monoxide inhibition in fetal cord blood of smok- ing mothers, 407 carbonic anhydrase, decrease in activity in fetal cord blood in smoking mothers. 409 pulmonary histological changes in ciga- Epidermoid carcinoma rette smoke inhaling, 158, 159160 see Carcinoma, epidermoid respiratory tract of, cigarette smoke in- halation effects on, 268,352, 353 smoke induced bronchoconstriction in, atropine effects, 163 smoking and nicotine effects on blood lipids in, 127-128 smoking and nicotine effects on cardio- vascular function in, 101-l 12 smoking and nicotine effects on cate- cholamine levels in, 119 Donkeys effect of cigarette smoke on pulmonary clearance in, 164, 111 Ducks cigarette smoke instillation or implanta- tion effects on tracheobronchial tree of, 346 Duodenal ulcer see Peptic ulcer Dusts COPD development from, 153, 218 Egypt relation of human pulmonary histology and smoking, 163 - Electrocardiograph -. findings on, CHD mortality relationship to,.42 readmg abnormalities, relationship to smoking and CHD, 45.47 Electroph&esis use in determining serum levelof alphar- antitrypsin, 151 Emphysema alphar-antitrypsin absence type genetic factors, 150 cigarette smoking effects on, 9 development in dogs following cigarette smoke inhalation, 27 1 development of, relation of cadmium in smoke to, 154 grade II or III, smokers vs. nonsmokers, 162 mechanism inalphar-antitrypsin absence type of, 151 mortality from, effect of cigarette smok- ing on, 175 mortality rates from, in 1967, 139 pulmonary, definition, 139 Employment see Occupations England see United Kingdom Enzymes see also Papain 445 Epinephrine levels in arteries, cigarette smoking ef- fects on, 51 Epitheliomas tip, relationship of tobacco use with, 361 Epoxides suspected carcinogenic agents in ciga- rette smoke, 265 Esophageal neoplasms frequency in smokers vs. nonsmokers, 12,238 induction in animals by nitrosamine, 292 methods and results of retrospective studies of tobacco use, 289, 375-378 mortality rates in U.S. for 1967, 289 relationship to smoking, 293 Esophagus basal cells of epithelium of, atypical nuclei in male smokers 292, 379-380 Ethanol see Alcohol Ex-smokers see Smokers (former) Factory workers see plant workers under Occupations Fatty acids blood, effect of smoking on levels of, 65 levels in smokers vs. nonsmokers, 102 rise in blood serum after smoking, 36 suspected carcinogenic agents of ciga- rette smoke, 266 Fetus heart beats in, increase in smoking mothers, 408 tissues of, effects of elevated carboxy- hemoglobin on, 407 Fibrosis in lung, smokers vs. nonsmokers, 161 Fibrillation ventricular, death from, 36 Filters see Cigarette fitters Finland blood pressure differences in smokers vs. nonsmokers in, 103 COPD morbidity in smokers of,, 200 lung neoplasms in, restrospectrve smok- ing study of methods in, 325,327 lung neoplasm mortality in, relationship to tobacco use, 245-246 peptic ulcer in, methods and results for retrospective and cross section studies of smoking and, 426,428 serum lipid differences in smokers vs. nonsmokers of, 98.99 smoking and nicotine effects on human blood lipids in, 124 Fluoranthene alcoholic solution of, penetrability of esophageal epithelium, 292 Flax mill workers see Occupations Former smokers see Smokers (former) Formosa acute effect of cigarette smoke on human pulmonary function in, 169 France bladder neoplasms in, methods and re- suits in retrospective studies of smok- ing and, 381-383 CHD mortality and morbidity in, 94,97 COPD mortality of smokers in, 201 cigarette smoke effects on animal lung tissue in, 343 cigarette smoke effects on chicken em- bryos in, 344 cigarette smoke inhalation effects on rat respiratory tract, 349 esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 355,357 lung neoplasms in, retrospective smoking study of methods in, 326 relationship of tobacco use and neo- plasms of oral cavity, 363 Framingham Heart Study morbidity ratios in CHD, 24 Fungicides concentration in cigarette smoke, 265, 266 Gastric ulcer see Pentic ulcer Genetics factors of. cigarette smoking relation- ship, S ' factors of, in COPD pathogenesis, 148, 150-152,205 twin-studies, effects of smoking, 49-52, 99 Germany CHD morbidity and mortality in, 95-96, 97 cigarette smoke inhalation effects on ani- mal respiratory tract in, 350 laryngeal neoplasms in, relationship to ^-- tobacco use, 355 lung neoplasms in, retrospective smoking study of methods in, 323,325,326 polonium-210 levels in lungs of smokers in, 336 smoking and nicotine effects on human blood lipids, 125 Glossary of terms used in smoking and ventilatory function, 215 Glucose metabolism and insulin response, altera- tion effects on myocardial response, 66 Glycogen levels in mice lung exposed to cigarette smoke, 161 Government employees see Occupations Graphite respiratory tract carcinoma in workers exposed to, 256 Great Britain see United Kingdom Guanethidine blockage of nicotine cardiac stimulation by, 57 Guinea pigs lung neoplasm development following chronic nickel carbonyl or dust inhala- tion, 256 446 bv s-l lungs of, cigarette smoke effects on sur- factant activity, 225 respiratory changes in, exposed to ciga- rette smoke, 162 Hamsters benzo(a)pyrene inhalation by, effect of asbestos dust on carcinoma induction, 257 bt$; ;;plasms in, fed 2-naphthyl- cigarettd smoke instillation or implanta- tion effects on tracheobronchial tree of, 268, 346-348 laryngeal malignancies in, following smoke inhalation, 12 laryngeal neoplasms following cigarette smoke inhalation, 239 larynx `of, effect of cigarette smoke in- halation on, 28 1, 284 lung and embryos, effects of cigarette smoke tars on, 343-344 pulmonary changes from chronic nitro- gen dioxide inhalation, 220 respiratory tract of, C-14 labeled particu- lates deposition in, 281-282 respiratory tract of, cigarette smoke in- halation effects on, 268,35 1 Health Insurance Plan (NYC) myocardial infarction in ipe and cigar smokers under, 32.38-3 4) Heart see also Arrhythmia. brachycardia, myo- cardium and tachy&rdia cardiac rhythm of, effect of nicotine on, 36 fetal, increased rate by maternal smok- ing, 408 myocardium of, nicotine effects on oxy- gen demand, 38 myocardium of, cigarette smoking effect on, 5,8 rate, relationship to smoking and CHD, 45.47 Heart disease see Cardiovascular diseases and coronary disease Heights decreased, in children of smoking mothers, 407 Hematite dust respiratory tract neoplasms in hamsters exposed to, 348 Hematocrit infant, smoking mother effects on, 407, 409 variations in, effect on coronary blood flow, 66 Hemoglobin see also Carboxyhemoglobin affinity for oxygen, CO effects on 2,3di- phosphoglycerate control of, 6061 varia$~sg in, effect on coronary blood Hens ' see Chickens Heterocyclc compounds carcinogenic properties in cigarette smoke, 264,265 Hexamethonium blockage of nicotine cardiac stimulation -.r>-. HIP of NYC see Health Insurance Plan (NYC) Hookahs smokers of, laryngeal neoplasm induc- tion in, 355 Hungary retrospective smoking study of methods for lung neoplasms in, 328 Hydrocarbons see Aromatic compounds heterocyclic compounds Hydrogen cyanide in cigarette smoke, effects on body oxi- dative metabolism, 62 3-Hydroxyanthranilic acid see Anthranilic acid, 3-hydroxy- 3-Hydroxykynurenine excretion of, smoking effects on, 296 Hydroxyproline level in mice lung exposed to cigarette smoke,. 161 Hypertension see Blood pressure Hypoxemia arterial, carbon dioxide effects on, 61,' 15 Hypoxia aortic atheromatosis development in rabbits exposed to, 64 postoperative, development in smokers, 174,230 postural, mechanism in asymptomatic smokers vs. nonsmokers, 147 Iceland lung neoplasms in, relationship to tobac- co smoking, 244 Indeno( 1,2,3 ,-cd)pyrene carcinogenic properties in cigarette smoke from, 265 lndia esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 355,356 relationship of smoking to tuberculosis in, 227 relationship of tobacco use and neo- plasms of oral cavity in, 362,366 smoking and nicotine effects on human cardiovascular system, 117 smoking relationship to thrombosis in, 131 Indole, l-methyl- possible initiator in tobacco carcinogene- sis, 265 Industrial workers see plant workers under Occupations Industrial hazards effect of dust on COPD development, 17s - .- effects on COPD development in smok- ers, 153-154, 218-219 Infant see also Neonate sudden death in, relation of smoking and nonsmoking mothers, 407 Influenza virus effect on dogs inhaling cigarette smoke, 351 447 resistance of mice following cigarette smoke inhalation, 173 Inhalation studies see under Cigarette smoke Ireland acute effect of cigarette smoke on human pulmonary function, 168 CHD mortality and morbidity in smok- ers and nonsmokers in, 94 CHD mortality and morbidity in, 96 lung neoplasms in, retrospective smoking study of methods in, 328 maternal smoking and infant weight, 399 methods used in smoking study and human pregnancy, 394,396 northern, mortality rates from COPD, 144 occupational exposure and smoking rela- tionships to COPD in, 218 relationship of lung neoplasms to smok- ing, air pollution and residence in, 254 serum lipid differences in smokers vs. nonsmokers in, 99 smoking and nicotine effects on human peripheral vascular system, 133 smoking relationship to thrombosis in, 130 Israel cigarette smoke effects on animal em- bryos in, 343 mortality rates from COPD in, increase, 140 Italy human experimental data on smoking and pregnancy, 409 serum lipid differences in smokers vs. nonsmokers in, 100 tracheobronchial tree changes in smokers and nonsmokers in, 263 Japan bladder neoplasms in, methods and re- suits in retrospective studies of smok- ing and, 382,384 CHD mortality and morbidity in, 96 cigarette smoke effects on human fetal lung tissue in, 343 esophageal neoplasms in retrospective studies of tobacco use in, 378 kidney and bladder neoplasms of smok- ers in, 295 lung neoplasms in, retrospective smoking study of methods in, 326,328 lung neoplasm mortahty of smokers and nonsmokers in, 243 mortality ratios from esophageal neo- plasms in, 291 mortality ratios from pancreatic neo- plasms in cigarette smokers in, 298 relationships of lung neoptasms to smok- ing, air pollution, and residence in, 255 Kidney neoptasms mortality rates in U.S. for 1967,296 relationship of tobacco use, 13, 299 in29;;;cers and nonsmokers, 238, Korea relation of human pulmonary histology and smoking in, 255 tracheobronchial tree changes in smokers and nonsmokers of, 259 Lactones suspected carcinogenic agents in ciga- rette smoke, 265 Laparotomy postoperative pulmonary complications following, in smokers vs. nonsmokers, 174 Laryngeal neoplasms development in hamsters following ciga- rette smoke inhalation, 239 development in smokers, 12,281 mortality in smokers vs. nonsmokers, 237-238 mortality ratios from, 277-279 relationship to tobacco use and develop- ment of,, 354-357 relative risk ratios from tobacco use, 277,358 U.S. mortality in 1967,277 Larynx epithelial changes in, classification of: 281,283 hamster, C-14 labeled particulate deposi- tion in, 281-282 Laws PL 89-92, requirements for smoking haz- ards literature review, 7 PL 91-222, requirements for smoking hazards review, 7 Lip neoplasms relationship of tobacco use, 361, 362, 365,367 relationship to pipe smoking, 289 Lipids blood effect of smoking on levels of, 65-66,123-128 serum, differences in smokers vs. non- smokers, 4 1,98-102 Lipoproteins infiltration in arterial walls, carbon mon- oxide effects on, 63 in smokers vs. nonsmokers, 99-102 Liver cirrhosis of, rates among cigarette smokers, 5 Longshoremen see Occupations Luminescence techniques of, use in determining aro- matic hydrocarbon in urine, 297 Lung diseases see Bronchopulmonary diseases, adeno- carcinoma, carcinoma, tuberculosis Lungs tibroses in, smokers vs. nonsmokers, 16 1 hamster, C-14 labeled particulates depo- sition in, 281-282 human, effects of cigarette smoke on tis- sue from, 343-345 Lung neoplasms, air polhrtion role in etiology of, 11 cause and effect relationship of smoking, 276 cigarette smoking risks, 11 development in dogs following cigarette smoke inhalation, 239 effect of sex on development, 11 448 environmental and atmospheric factors of, 252-255 groupings, 246-334 group characteristics of tobacco use in smokers and nonsmokers, 240, 244, 329-333 h;;,9';;; and smoking relationships, mortality expected in U.S. in 1970,237, 219 --- mortality from chromium compounds, 257-258 mortality in cigarette smokers by dura- tion, 240,244 mortality in smelter workers exposed to arsenic. 257 mortality in smokers and nonsmokers, 240-243 mortality, in smokers in Norway and Finland, 245-246 occupational exposure effects on patho- genesis of, 12 prevalence in males and females by tumor type, 246,250 reduction in number using filter-type cigarettes, 275 relationship of asbestos and smoking to, 257 relationship of female smoking, 246,251 relationship of smoking to, 237 retrospective study methods for smoking relationships, 240,323-328 smoking cause and effect relationship, 3 smoking habit study of patients with, 3 types implicated in smoking, 237 U.S. mortality rates for 1939 vs. 1967, 239 Macrophages effect of cigarette smoke of action on staphylococcus, 165 Mammals see also specific mammals cells of, effect of cigarette smoke tars on, 343 Medical students see Occupations Methylbenzo(a)pyrene see Benzo(a)pyrene, l-methyl- 9-Methyl carbazole see Carbazole, 9-methyl- Methylchrysenes see Chrysene, 1 methyl- Methyl-indole see Indole, lmethyl- Methyl-n-butymitrosamine Fe Butylamine, nmethyl-nitroso- N -Methylnicotinamide see Pyridinium compounds, 3carba- moyl-l-methyl- Mice bladder neoplasms in, induction by tryptophan metabohtes, 296 embryo, lethal effects of nicotine on, 411 esophageal epithelium of, alcoholic benzo(a)pyrene penetrability of, 292 esophageal epithelium of, oil desolved benzo(a)pyrene penetrability of, 292 lungs of, effects of cigarette smoke on, 343.344 lung neoplasm incidence in, from chrom- ium oxide dust exposure, 258 pulmonary carcinoma induction in, following asbestos dust inhalation, 257 pulmonary changes from chronic nitro- gen oxide inhalation, 16 1,220 pulmonary changes in cigarette smoke inhaling, 159 pulmonary clearance in, cigarette smoke effects on, 170 resistance to pneumonia bacteria follow- ing cigarette inhalation, 173 respiratory tract of, cigarette smoke in- halation effect on, 268-269, 349-353 skin painting of, smoke condensates ef- fects on, 267, 337-342 Miscarriages see Abortion, spontaneous Mollusks ciliary function in, effect of cigarette smoke on, 223 Monkeys atherogenic effects of carbon monoxide and hypoxia, 64 ciliary function in, effect of cigarette smoke on, 222 fetal bronchial tubes of, effects of ciga- rette smoke on, 345 Rhesus, development of bladder neo- plasms from 2-naphthylamine, 296 squirrel, nitrogen oxide effects on resis- tance to pneumococcus, 173 Morbidity ratio Cyoys in4smokers with predisposing fac- CHD `in smokers vs. nonsmokers, 21-22, 24,30-35 CHD, relation to smoking, 32-35,37, 39 CHD, retrospective studies, 40,93-97 in Danish twins, smoking effects on, 49-s 1 development of COPD in smokers vs. nonsmokers, 145, 195-205 Mortalitv rates from bladder neoplasms in U.S. for 1967,293 from bronchopulmonary disease, 141-145 cerebrovascular disease, smokers vs. non- smokers, 66-67,68-70 CHD, paired combinations of high risk characteristics in, 25 CHD, retrospective studies, 40,93-97 CHD in smokers vs. nonsmokers, 24, 26-29 CHD in U.S., 21 in Danish twins, smoking effects on, 51 fr;y67es;f;ghageal neoplasms in U.S. in from &dney neoplasms in U.S. for 1967, 296 from lung neoplasms for 1939 vs. 1967 in U.S., 239 from lung neoplasms expected in 1970, 237,239 from lung neoplasms in smelter workers exposed to arsenic, 251 from oral neoplasms in 1967,285 449 from peptic ulcer in U.S. in 1967,423 in former smokers, relation to CHD, 46, 4748 in Swedish twins, smokers vs. non- smokers, 5 1 smokers vs. nonsmokers, 3 U.S. male veterans from CHD, 26,38 Mortality ratios CHD with high risk characteristics, esti- mated, 25 from esophageal neoplasms, prospective and retrospective studies, 289-291 from laryngeal neoplasm, 277-279 from lung neoplasms in smokers in Nor- way and Finland, 246 from lung neoplasms,, in males by ciga- rette smoking duratton, 240,244 from pancreatic neoplasms in smokers and nonsmokers, 298-299 from peptic ulcer in smokers and non- smokers, 424 smokers vs. nonsmokers, from lung neo- plasms, 240-243 Mouth neoplasms frequency in smokers and nonsmokers, 238 . smoking induced, 12 Mucopolysaccharides function as surfactants in lung tissue, 172 Mussels ciliary function in, effects of cigarette smoke on, 221,222 Myocardium effects of hydrogen cyanide in smoke on. 62 oxygen consumption in nicotine stimu- lated, 59 oxygen requirements for, nicotine ef- fects, 58 2-Naphthylamine development of bladder carcinomas and papillomas in dogs, hamsters and mon- keys given, 296 suspected bladder carcinogen in tobacco smoke, 265 National Center for Health Statistics survey of U.S. smoking habits by. 56 survey on relationship of smoking and incidence of respiratory disease,. 173 National Clearinghouse for Smoktng and Health responsibilities, 7 1970 survey of smoking, 6 National Cooperative Pooling Project mortality statistics from coronary dis- ease, 21-22 National Library of Medicine assistance in literature review on smok- a, 7 llatudE= rwatory tract carcinoma in workers exposed to, 256 NW- St-ZlZhCkS Neonate see also Fetus. pregnancy, prematurity birth weight, effect of maternal smoking on, 389, 397-399 450 death, comparison of stillbirth and abor- tions in smoking and nonsmoking mothers, 395,405406 death, differences of birth weight and, in smoking and nonsmoking mothers, 404 death, smoking mothers effects on 415 rats, LDso nicotine determination, 412 Neoplasms see also specific neoplasms, adenocarci- noma, carcinoma, lung neoplasms, etc. adenomatous, induction in mice by ciga- rette smoke inhalation, 350 bladder, in smokers and nonsmokers, 293-295,381-384 bladder, methods of retrospective studies of smoking and, 293,381-384 bl;$I;;9 relationship of tobacco usage bladder. relation&u to ciaarette smok- ing, 13,299 - - bladder. U.S. mortalitv in 1967.293 development in smoking dogs, percent- ages of, 274 esophageal, frequency in smokers and nonsmokers, 12, 238 esophageal, methods and results of retro- spective studies of tobacco use in, 289, 375-378 esophageal, mortality ratios, 289-291 esophageal, mortality rates for U.S. in 1967,289 esophageal, relationship to smoking, 293 kidney, mortality rates in U.S. for 1967, 296 kidney, relationship to tobacco use, 13, 299 kidney, in smokers and nonsmokers, 238,294-295 laryngeal, 12,237-239,281 laryngeal, relationship of tobacco use and development of, 354-357 laryngeal, relative risk ratios from tobac- co use, 277,358 laryngeal, U.S. mortality in 1967, 277 ho. relationshin to smokine. 289 lip; relationship to tobaico use, 361, 362,365,367 mammalian, cigarette smoke effect on, 343 oral cavity, relationship of tobacco use, 285,36 l-367 oral cavity, relationship to smoking, 289 pancreas, relationship to smoking, 298-299 Netherlands cigarette smoke inhalation effects on mice respiratory tract in, 349 lung neoplasms in, retrospective smoking study of methods for, 323 serum lipid difference. in smokers vs. nonsmokers of, 101 New York City myocardial infarctions in cigar and pipe smokers in, 32,38-39 New Zealand human experimental data on smoking and pregnancy, 408409 Nickel compounds suspected carcinogenic agents in ciga- rette smoke, 265 Nickel workers see Occupations Nicotine atherogenic effects of 120-122 effect on blood lipids, 123-l 28 effect on blood pressure, 36 effects on cardiac rhythm of heart, 36 effects on cardiovascular system, 56-58, 107-118 effects on catecholamine release from adrenals, 36,119 effects on heart rate., 36 effects on myocardmm oxygen demand, 38 effects on myometrial strips in gravidic women, 408 effects on peripheral vascular system, 72, 75.133-134 effects on pregnancy, 411414 induction of necrosis in arterial walls, 63 neurogenic effects of, 57 Nitrogen dioxide pulmonary changes in rodents chron- ically inhaling, 161,220 Nitrogen oxide effects on resistance of squirrel monkeys to pneumococcus, 173 4-Nitroquinohne l-oxide alcoholic solution of, development of papillomas in mice drinking, 292 N-Nibosamines carcinogenicity in cigarettes smoke, 264-266 esophageal neoplasms induced in animals by. 292 Nitrdsopiperidine see Piperidine, nitroso- Nitrosopyrrolidine see Pyrrolidine, nitroso- N'methyhticotinamide urinary excretion of, smoking effects on, 297 Nonsmokers see also Smokers vs. nonsmokers carboxyhemoglobin effects on oxygen uptake, 61 Norway lung neoplasms in, for pipe smokers, 244 lung neoplasm mortality in, relationship to tobacco use, 245-246 tracheobronchial tree changes in smokers and nonsmokers of, 259 Oat cell carcinoma see Carcinoma, oat cell Obesity relationship to CHD mortality, 43 relationship to smoking and CHD,4345 relationship with smoking in peripheral arteriosclerosis, 72 Occupations see also Industrial hazards asbestos workers, respiratory tract carci- noma, 256 asbestos workers, lung neoplasm mortal- ity in smoking, 257 bank employees, smoking and COPD, 198 coal miners, impaired pulmonary func- tion in smoking, 163 coal miners, respiratory tract carcinoma, 256 coal miners, smoking and COPD, 153, 197,218-219 coal miners, smoking and ventilatory function, 207 flax mill workers, smoking and COPD, 199 government employees, blood pressure differences in smokers vs. nonsmokers, 99 longshoremen, mortality from smoking- related cerebrovascular disease, 70 longshoremen, mortality rates from CHD in, 28 longshoremen, smoking and COPD, 200 longshoremen, smoking and ventilatory function, 208 medical students, serum lipid differences in smokers vs. nonsmokers, 98 medical students, smoking and nicotine effects on blood lipid levels, 124 medical students, smoking and thrombo- sis relationships, 130 medical students, smoking and ventila- tory function, 209-210 nickel workers, lung neoplasms in, 256 physicians, bladder and kidney neo- plasms in smoking, 293,294 physicians, cessation of smoking effect on COPD, 142 physicians, COPD mortality rates, 149 plt;t;"4;s, decline in cigarette smoking physi&s, mortality from srnoking- related cerebrovascular disease, 68 physicians, mortality rates from CHD, 26 physicians, mortality ratios from esopha- geal neoplasms, 290 physicians, mortality ratios from peptic ulcer in smoking and nonsmoking, 424 physicians, pulmonary function follow- ing cessation of smoking, 149 physicians, smoking and ventilatory function. 209-210. 213 plant workers, occupational exposure and smoking relationships to COPD, 153,218,219 plant workers, smoking and COPD, 198 plant workers, smoking and ventilatory function, 206-208 post office workers, blood pressure dif- ferences in smokers vs. nonsmokers, 104 post office workers, smokers and ventila- tory function, 209 post office workers, smoking and COPD, 200,202 prisoners, serum lipid differences in smokers vs. nonsmokers, 100 prisoners, smoking and nicotine effects on peripheral vascular system, 133 railroad employees, coronary heart dis- ease, morbidity in smoking, 34 railroad employees, mortality and mor- bidity from CHD, 97 railroad employees, mortality rates from CHD, 28 smelter workers, lung neoplasm mortal- 451 ity from arsenic exposure, 257 soldiers, smoking and COPD. 197 steel workers, COPD development from dust exposure, 153 students,, carbon monoxide effects on blood hpids, 129 students, infectious respiratory disease in smokers vs. nonsmokers, 228-229 students, mortality from smoking-related cerebrovascular disease, 68 students, mortality rates from CHD, 28 students, smoking and COPD, 201 students, smoking and nicotine effects on blood lipid level, 125 students, smoking and thrombosis rela- tionships, 130 students, smoking and ventilatory func- tion, 211 telephone company employees smoking and COPD, 200 textile workers, occupational exposure and smoking relationship to COPD, 218-219 transportation employees, smoking and COPD, 198.202 transportation workers, air pollution re- lationship to COPD, 216 transportation workers, smoking and vent&tory function, 207,212 utility company employees, CHD mor- bidity in smoking, 30 uranium miners, lung neoplasms in smokers and nonsmokers, 256 veterans, bladder and kidney neoplasms in smoking, 294-295 veterans, COPD mortality rates, 143 veterans, CHD morbidity in smoking, 32 veterans, effects of smoking on twin, 50 veterans, lung neoplasm mortality in smoker and nonsmoker, 24 l-243 veterans, mortality rates from CHD, 26, 38 veterans, mortality from smoking-related cerebrovascular disease, 69 veterans, mortality ratios from esopha- geal neoplasms, 290 veterans, mortality ratios from peptic ulcer in smokers vs. nonsmokers, 424 Oleic acid suspected carcinogenic agent in cigarette smoke, 266 Olive oil penetrabihty of benzo(a)pyrene in mice esophageal epithelium, 292 Oral cavity neoplasms estimated incidence in U.S. for 1970, 284 mortality from in 1967,285 relationship of tobacco use. 285, 289, 361-367 Organs cultures of, cigarette smoke effects on cell growth and reproduction, 267, 343-345 Oropharynx neoplasms frequency in smokers and nonsmokers, 238 Oxygen see also Hypoxemia myocardial consumption of, following nicotine stimulation, 58,75 transport in body, carbon monoxide effects,, 60,75 uptake m nonsmokers with specific car- boxyhemoglobin levels, 6 I,75 Palate hamster, C-14 labeled smoke particulates deposition in, 281-282 Pancreatic neoplasms relationship to smoking, 13,238 relationship of smokmg to mortality from, 298-299 Papain pulmonary effects on rats exposed to ciarette smoke with. 163 Papiliimas development in mice drinking alcoholic benzopyrene, 292 formation following skin painting with smoke tars, 337-339,341 induction in hamsters exposed to ben- zo(a)pyrene, 346-347 Pentolinium blockage of nicotine cardiac stimulation by, 57 Peoples Gas Light and Coke Co. study of CHD, serum cholesterol and smoking relatronships, 43 Peptic ulcer antacid efficacy and healing of, effects of cigarette smoking on, 423 development in smokers, 13 mortality from, in U.S. m 1967,423 mortality ratios from, in smokers and nonsmokers, 424 retrospective and cross section study methods for smoking relationship to, 425427 Peroxides suspected carcinogenic agent in cigarette smoke, 265 Personality characteristics re~$u$ip to CHD and smoking, 4849, Pesticides content in cigarette smoke, 265, 266 Phagocytosis pulmonary alveolar, in smokers vs. non- smokers, 165 Pharyngeal neoplasms fr;y8ency in smokers vs. nonsmokers, relaltnship to tobacco use, 362-364, Phenol suspected carcinogenic agent of cigarette smoke, 266 Phosphohpids function as surfactants in lung tissue, 172 smokers vs. nonsmokers, 99-100, 102 Physical activity relationship to CHD and smoking, 41, 43!44 relattonship to myocardial infarction, smokers vs. nonsmokers, 44 Physicians see Occupations Piperidine, nitroso- 452 suspected carcinogenic properties in ciga- rette smoke from, 265 Pioe smokers atypical nuclei in male esophageal epi- thelium, 379 bladder neoplasms in. 293-294 cell rows and atypical cells in vocal cords of, 280,359-360 COPD morbidity in, 146, 197-198, 201-205 development of chronic bronchopulmo- nary disease, 10 development of esophageal neoplasms, 13,293 development of lung cancer, 11 development of oral neoplasms, 12 esophageal neoplasm mortahty ratios, 290 kidney neoplasms in, 294-295 lack of risk in CVD, 67 laryngeal neoplasms induction, 12, 354-357 lung neoplasm incidence in Norway, 244 lung neoplasm incidence in rural Switzer- land, 244 lung neoplasm mortality in, 324-327 m;$Gty rates from COPD, 142-143, mortality ratios from pancreatic neo- plasms, 298 mortality ratios from peptic ulcer, 424 myocardial infarction in, 32, 38-39 peptic ulcer in, 427 relationship to infectious respiratory dis- ease, 227 relationship to laryngeal neoplasm devel- opment, 281 relationship to lip neoplasms, 289 relationship to oral cavity neoplasms, 361-364,367 risk of CHD, 8 risks on lung neoplasm development, 276 Placenta ability to hydroxylate benzo(a)pyrene in smoking mothers, 407 Platelets adhesiveness of increased, from cigarette smoking, 9 aggregation of, cigarette smoking effects on, 36 blood, effect of smoking, 66,75 Poland bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 382,383 CHD mortality and morbidity in, 96 esophageal neoplasms in, retrospective studies of tobacco use with, 378 laryngeal neoplasms in, relationship to tobacco use, 357 relationship of tobacco use and neo- plasms of oral cavity in, 364 serum lipid differences in smokers vs. nonsmokers in, 100,102 smoking and nicotine effects on human blood levels in, 124 yo3pg relattonships to thrombosis in, Pollution see Air pollution Polonium-2 10 suspected carcinogenic agent in cigarette smoke, 265-267, 335-336 Post office workers see Occupations Postoperative pulmonary complications see Respiratory system Potassrum40 present in tobacco leaf, 266 Pregnancy see also Abortion (spontaneous), pla- centa, stillbirth, neonate human, methods used in smoking study of, 391-396 maternal smoking during, effect on fetal growth and weight, 389,397-399 maternal smoking during, effects on fetal growth, 13,415 nicotine effects on myometrial strips in, 408 unsuccessful, smoking effects on, 13 Prematurity maternal smoking and, 390,400403 Prisoners see Occupations Proteins see Lipoproteins Pro tozoae ciliary function in, effect of cigarette smoke on, 165,224 Public Health Service review of medical literature on smoking hazards, 7 1967 study of, starting point for new studies, 4 Public laws see Laws Puerto Rico esophageal neoplasms in, retrospective studies of tobacco use with, 378 relationship of tobacco use and neo- plasms of oral cavity in, 367 Pulmonary system see Respiratory system Pyrrolidine, nitroso- suspected carcinogenic properties in ciga- rette smoke from. 265 Rabbits atherogenic effects of carbon monoxide and hypoxia, 64 atherogenic effects of nicotine, 120-122 blood lipids in, smoking and nicotine effects on 127 cardiovascular function in, smoking and nicotine effects,, 108, 109 ciliary function m, cigarette smoke ef- fect on, 221-222 cholesterol fed, carbon monoxide effects on, 65-66 offspring of, nicotine and smoke effects on birth weight, 407 offspring, smoking effects on stillbirth and mortality, 411 pregnant, tritium-labeled nicotine effects in, 413 p;\nnary changes in cigarette smoking, pulmonary clearance in, cigarette smoke effect on, 164, 170. 171 453 skin painting, smoke condensate effects on, 267,338 Railroad employees see Occupations Rats atherogenic effects of nicotine in, 120, 121 blood liuids in. nicotine and smoke ef- fects, i28 ciliary function in, cigarette smoke on, 221,222 LDso. nicotine determination in female, 412 lung neoplasms, from intrabronchial im- planting of chromium compounds, 258 lung neoplasms, from nickel carbonyl and dust inhalation, 256 lungs, cigarette smoke effects on surfac- tant activity, 172,225 offspring, nicotine and smoke effects on birth weight, 407 pregnant, aromatic compound stimula- tion of placental BPhydroxylase activ- ity, 414 pregnant, fetal wastage and neonate death in nicotine and smoking, 411 pulmonary carcinoma induction follow- ing asbestos dust inhalation, 257 pulmonary changes from chronic nitro- gen dioxide inhalation, 161,220 respiratory tract of, cigarette smoke in- halation effects, 268,349,353 sk227py4y, smoke condensates effects, trachia of, cigarette smoke effects, 343 tracheal ligation of, cigarette smoke and papain effects on, 163 tracheobronchial tree of, cigarette smoke effects on, 268.346-349 Reading ability in children of smoking mothers, 407 Reserpine nicotine cardiac stimulation blockage by, 57 Respiratory system see also Bronchopulmonary disease, larynx, lungs, trachea acute effect of cigarette smoke on human pulmonary function, 163, 166-169 animal, cigarette smoke instillation or implantation effects on, 268,346-348 animal, effect of cigarette smoke inhala- tion on, 268-269,349-353 effect of cigarette and cigar smoke on bronchial reactivity, 164 effect of cigarette smoke on human cili- ary function, 165,221-224 effect of cigarette smoke on human pul- monary clearance, 164,170 glossary of terms used in testing, 215 histological changes in smokers, 154-157 improvements in function following smoking cessation, 148,149 pathological changes in cigarette smokers,.1 75 postoperatrve complication in, of smok- ers vs. nonsmokers, 174-176.230 pulmonary alveolar phagocytosis in smokers vs. nonsmokers, 165 pulmonary infarction in dogs inhaling cigarette smoke, 271 surface tension of, effect of cigarette smoke on, 172,225 surfactant activity of, in smokers vs. nonsmokers, 172,225 surfactants in, definition, 172 tests of function of, in smokers, 146-147,206-214 Respiratory tract diseases see also Asthma. bronchitis. broncho- pulmonary disease, emphysema, pneu- monia, tuberculosis infectious, 226-229 smoking effects on, 172, infections, prevalency among smokers, 10.176 pathological and cytological changes in, of smokers vs. nonsmokers, 258-263 ventilatory function in, smokers vs. non- smokers, 175 Rhodesia retrospective smoking study of methods for lung neoplasms in, 328 Rubidium-84 tracing capillary flow in coronary blood flow, 59 Rural populationsr lung neoplasms 111, suspected etiology of increased, 276 Rural residences lung neoplasm incidence in, in Switzer- land, 244 relationships of lung neoplasm to smok- ing, ah pollution, and, 252-255 Russia atherogenic effects of nicotine on rabbits in, 120 atherosclerosis autopsy studies in, 54 cigarette tar effects on rat tracheobron- chial tree in, 348 Saccharides see Mucopolysaccharides Saliva interference in action of carcinogens on oral cavity, 288 sarcoma formation following animal skin painting with smoke condensates, 338,340 induction in rats by cigarette smoke in- jection, 346-347 Scotland see United Kingdom Sex ages of cigarette smokers by, 6 effect of, in alphaantitrypsm deficiency emphysema, 151 effect of, on laryngeal neoplasm inci- dence development, 277 effect of, in mortality in cigarette smokers,.276 effect of, m lung neoplasms and tobacco use, 244,329-333 lung cancer mortality by, 252 lung neoplasm development by, 11 mortality rates of cigarette smokers by, 3 ratios of, in lung neoplasm mortality in Norway and Finland, 245-246 454 Sheep pregnant, nicotine injection and smoke inhalation effects on, 414 Smelter workers see Occupations Smokers (former) see nlso Cessation of smoking atypical nuclei in male esophageal epi- thelium in? 379-380 CHD mortahty probability in, 46 incidence of CHD and mortality in, 4648 lung neoplasm mortality ratios in, 241-242 lung neopksms in, lowered rates, 11 mortality rates from COPD, 175 mortality rates from lung neoplasms, 276 Smokers vs. nonsmokers see also Nonsmokers bladder neoplasxns in, 293-295, 381-384 cell rows and atypical cells in vocal cord of, 280, 359-360 CHD mortality in, 21-22 comparison of abortions, stillbirth and neonatal deatli in, 390.405406 development of COPD in, 141, 145, 195-205 differences in emphysema types in, 154, 156 effect of cigarette smoke on post-opera- tive pulmonary complications, 175 effect of sex on mortality from CHD, 28-31 esophageal e nuclei in, 2 % ithelial cells with atypical 2 esophageal neoplasm mortality ratios in, 290-29 1 excretion of tryptophan metabolites in, 297 frequency of esophageal neoplasms in, 238 frequency of kidney neoplasms in, 238 frequency of mouth and pharyngeal neo- plasms in, 238 fr;r;;;y of urinary bladder neoplasms grodp characteristics in lung neoplasms and smoking in, 240,244,329-333 laryngeal neoplasms in, relationship to tobacco use, 354-357 lung fibrosis development F, 161 1u2n4~-2~30plasm mortahty ratios in, lung neoplasm mortality in uranium miners, 256 morbidity ratios from CHD. 24 mortality from cerebrovascular disease, 67-70 mortality from CHD, 24, 26-29 mortality from CHD in Swedish twins. 51 - mortality from laryngeal neoplasms in, 237-238 mortality rates, 3 mortality ratios of COPD in, 142-144 mortality ratio from laryngeal neo- plasms, 278-279 mortality ratios from pancreatic neo- plasms in, 298 myocardial infarction relationships to physical activity, 44 pathological and cytological changes in respiratory tract of, 258-263 peptic ulcer in, correlated amounts of tobacco use, 427428 postoperative hypoxemia in, 174,230 postural hypoxemia mechanism in asymptomatic, 147 postoperative pulmonary complications in, 174-175,230 pulmonary alveolar phagocytosis in, 165 relation between CHD and serum choles- terol level, 43 relationship to infectious respiratory dis- ease, 172,226-229 serum lipids in, 41,98-102 surfactant activity in lungs of, 172, 225 type of lung neoplasms in male and fe- male. 250 Snuff dippers of, relationship to neoplasms of oral cavitv. 287.361.364-365 Social adjustments ' ' in children of smoking mothers, 407 Socioeconomic relationships in COPD, 152-153,216-217 Soldiers see Occupations South Africa esophageal neoplasms in, retrospective studies of tobacco use. 378 occupational exposure &d.smoking rela- tionship to COPD in, 219 retrospective study of methods for lung neoplasms in, 328 Serum lipid differences in smokers vs. nonsmokers in, 99 Spontaneous abortions see Abortions, spontaneous Squamous cell carcinoma see Carcinoma, epidermoid Steel workers see Occupations Stearic acid suspected carcinogenic agent of cigarette smoke, 266 Stillbirths abortions and neonatal death and, in smoking and nonsmoking mothers, 390,405 406 effects of maternal smoking, 41.5 Students see Occupations Sugars see Glucose. mucopolwaccharides Surface tens&n a - see Respiratory system Surfactants see Respiratory system Sweden acute effects of cigarette smoke on human pulmonary function, 168 blood pressure differences in smokers vs. nonsmokers in, 104 CHD mortality and morbidity in, 97 COPD morbidity in smokers in, 203,205 effect of cigarette smoke on animals cili- ary function in, 221-224 esophageal neoplasms in, retrospective 455 studies of tobacco use with, 378 genetic studies of twins in, smoking ef- fects on, 50.99 laryngeal neoplasms inJe1ationship to tobacco use, 356 relationship of tobacco use and lip neo- plasms in, 361 relationship of tobacco use and neo- plasms of oral cavity, 364 serum lipid differences in smokers vs. nonsmokers of, 99 smoking and nicotine effects on human cardiovascular system, 115 smoking and nicotine effects on human peripheral vascular system, 133 tracheobronchial tree changes in smokers and nonsmokers in, 263 Switzerland CHD morbidity and mortality in, smokers vs. nonsmokers, 95 cigarette smoke effects on mice lung and kidney tissue in, 344 cigarette smoke inhalation effects on mice respiratory tract, 351 lung neoplasm incidence in cigar and pipe smokers of rural, 244 retrospective smoking study of methods for lung neoplasms in, 325 serum lipid differences in smokers vs. nonsmokers of, 100 Tachycardia development in dogs induced by nico- tine, 57 TAO see Thromboangiitis obliterans Tars, tobacco carcinogenicity on animal skin, 238 carcinogenic properties from cigarette smoke, 1 l! 264,265 content m cigarettes, relationship to lung neoplasm development, 275,276 sarcoma induction in rats following in- stillation,, 346 skin paintmg with, carcinoma induction from, 337-342 Telephone company employees see Occupations Teratogenesis maternal smoking implications in, 407 m mice embryos, nicotine effects on, 411 Tetraethylammonium chloride bl;;k;g7e of nicotine cardiac stimulation Textile workers see Occupations Thromboangiitis obliterans definition, 73 remission of. cessation of smoking ef- fects. 74 Thrombosis smoking effects on, 66, 130-l 32 Tissues cultures of, cigarette smoke effects on ceie-g;;wth and reproduction. 267, hypoxia of, carbon monoxide effects on, 61 Tobacco see also all forms, e.g. Cigarettes, etc. 456 chewing of, relationship to lip and oral cavity neoplasms, 361-363,365366 leaves, presence of potassium40 in, 266 Tobacco amblyopia see Amblyopia Tobacco tars see Tars, tobacco Tongue hamster, C-14 labeled particulate depo. sition in, 281-282 Toxemia preeclamptic, incidence in smoking and nonsmoking mothers, 404,407 Trachea hamster, C-14 labeled particulate depo- sition in, 281-282 Transportation employees see Occupations Triglycerides CHD incidence relationship to, 65 smokers vs. nonsmokers, 99-100, 102 Trypsin see Anti-trypsin, alpha, Tryptophan metabolism alterations by smoking, 297 alteration in UriIWy tract neoplasms by smoking, 13 carcinogenicity in mice bladders, 2"' relation of excretion in smoke rs and nonsmokers. 297 Tuberculosis relationship of smokers vs. nonsmokers to, 172,226-228 Tumorigenic agents see Carcinogens Twins angina pectoris development in, smoking effects on, 50-5 1 genetic studies of smoking effects on, 49-52 smoking effects on mortality and mor- bidity in, 5 1 Ulcers see Peptic ulcers United Kingdom bladder neoplasms in, methods in retro- spective studies of smoking and. 382-384 blood pressure differences in smokers vs. nonsmokers in, 103. 104 British Perinatal Mortality Survey of. 390,395,404,415 cigarette smoke effects on human fetal lung and mice trachea, 344 cigarette smoke effects on human pul- monary function, 168, 169 cigarette smoke effects on mice respira- tory tract. 352 cigarette smoke implantation effects on rat tracheobronchial tree in, 346-347 comparison of abortions, stillbirths and neonatal deaths in smoking and non- smoking mothers, 406 "3,`,9 tnoqrbidity in smokers in, 195-197. effect. of cigarette smoke on animal cili- acv function in. 221 human experimental data on smoking and pregnancy, 408 kidney and bladder neoplasms in smokers in, 294 lung cancer mortality in males in Eng- land and Wales, 240 maternal smoking and infant weight in, 397,399 methods used in smoking study and human pregnancy, 391,394-395 mortality from cerebrovascular disease related to smoking in, 68 mortality rates from COPD in, lack of increase, 140 mortality ratios from esophageal neo- plasms in, 290 mortality ratios from laryngeal neo- plasms in, 278 mortality ratios from peptic ulcer in smokers and nonsmokers in, 424 occupational exposure and smoking rela- tionships to COPD in 218-219 peptic ulcer in, methods and results of retrospective and cross section studies of smoking and, 425428 physicians in, decline in cigarette smok- ing rates, 48 physicians in, mortality from lung neo- plasms in smokers and nonsmokers, 241 pulmonary function in, cigarette smoke effects on, 168 relationships of lung neoplasms to smok- k, air pollution, and residence in, 253-254 relationship of smoking tuberculosis in, 226 retrospective smoking study of methods for lung neoplasms in, 324,326 serum lipid differences in smokers vs. nonsmokersin, 101, 102 smoking and nicotine effects on animal cardiovascular function in, 107 smoking and nicotine effects on human blood lipids in, 126 smoking and nicotine effects on human cardiovascular system in, 115 smoking relationships to thrombosis in, 131 United States acute effect of cigarette smoke on human pulmonary function in, 166-167,169 atherosclerosis autopsy studies in, 53- 55 bladder neoplasms in, methods and re- sults in retrospective studies of smok- ing and, 381-384 blood pressure differences in smokers vs. nonsmokers in, 103-104 CHD mortality and morbidity in smokers vs. nonsmokers in, 30-35, 37, 93-94 comparison of abortions, stillbirth and neonatal death in smoking and non- smoking mothers, 405406 cigarette smoke effects on animal tissues in, 343-345 cigarette smoke effects pulmonary sur- factants and surface tension, 172, 225 cigarette smoke implantation effects on animals tracheobronchial tree, 346-348 cigarette smoke inhalation effects on ani- mal respiratory tracts, 349-350, 352, 354 Co&D morbidity in smokers in, 195, 196,198-200,201-202,205 effects of cigarette smoke on animal cili- ary function in, 221-224 esophageal neoplasms in, retrospective studies of tobacco use, 378 esophageal neoplasm mortality in, in 1967, 289 human experimental data on smoking and pregnancy in, 4084 10 human pulmonary function following cessation of smoking in, 149 kidney and bladder neoplasms in smokers in, 293-295 laryngeal neoplasm incidence in 1967, 277 laryngeal neoplasm in, relationships to tobacco use, 278-279,354-355 lung neoplasm mortality in smokers and nonsmokers in, 240-243 maternal smoking and infant weight, 397-399 methods used in smoking study and human pregnancy, 391-395 mortality from aortic aneurysm related to smoking in, 7 I mortality from cerebrovascular disease related to smoking, 68-70 mortality from lung neoplasms expected in 1970,237,239 mortality rates for bladder neoplasms in 1967,293 mortahty rates for COPD, increase of 139-140 mortality rates for kidney neoplasms in 1967,296 mortahty rates for lung neoplasms in 1939 vs. 1967,239 mortality ratios for COPD, 142-145 mortality ratios for esophageal neo- plasms in, 290-294 mortality ratios for laryngeal neoplasms, 278-279 mortality ratios for pancreatic neoplasms in smokers and nonsmokers in, 298 mortality ratios for peptic ulcer in smokers and nonsmokers in, 424 occupational exposure and smoking rela- tionships to COPD in, 218-219 oral neoplasm incidence in, estimated for 1970,284 peptic ulcer mortality in 1967 in, 423 peptic ulcer in, methods and results for retrospective and cross section studies of smoking and, 425.426428 polonium-210 levels in lungs of smokers in, 335-336 populations of, COPD development in, 10 relationship of human pulmonary histol- ogy and smoking in, 155-157 relationship of tobacco use and lip neo- plasms, 361-365,367 relationship of tobacco use and neo- plasms of oral cavity, 36 l-365, 367 relationship of lung neoplasm to smok- ing, air pollution, and residence in, 253-254 457 relationship of smoking to infectious res- piratory disease in, 227-229 retrospective smoking study methods for luna neoolasms in. 323-328 serum l&d differences in smokers vs. nonsmokers in, 98,100,101 smoking relationship to thrombosis in, 130,131 smoking and nicotine effects on animal cardiovascular function in, 107-112 smoking and nicotine effects on human blood lipids, 123-l 26 smokinn or nicotine effects on human cate&olamine levels, 119 smoking and nicotine effects on human cardiovascular system, 113-l 14, 116, 117-119 smoking and nicotine effects on human peripheral vascular system, 133-134 surveys of cigarette smoking in,, 6 tracheobroncbial tree changes m smokers and nonsmokers in, 259-263 Uranium miners see Occupations Urban environment contribution to lung cancer mortality, 11 relationship of lung neoplasms, smoking, air pollution to, 252-255 Urban populations lung neoplasms in, suspected etiology of increased, 276 Urinary bladder see Bladder Uterus cigarette smoking effects on gravidic, 408 Utility Company employees see Occupations Vascular system see also Blood circulation, cardiovascular system, cerebrovascular system, throm- boangiitis obliterans peripheral, smoking and nicotine effect on, 9,72-73,75, 133-134 Venezuela maternal smoking and infant weight in, 450 methods used in smoking study and human pregnancy, 445 Ventricular fibrillation death from, nicotine effects on, 36 Ventilatory function tests see Respiratory system Veterans see Occupations virus influenza, cigarette smoke effects on re- sistance of mice with, 173 influenza, nitrogen oxide effects on squirrel monkey resistance to, 173 Vitamin deficiency relationship to tobacco amblyopia Xenon radioactive, regional pulmonary function using, 147 458 z!z U. 5. GOVERNMENT PRINTING OFFICE: 1971 O-420-719