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. Cigarette smoking has been observed to alter peripheral blood flow and peripheral vascular resistance. CARDIOVASCULAR REFERENCES (1) ACHESON, I?. M., JESSOP, W. J. E. Tobacco smoking and serum lipids in old men. British Medical Journal 2: llOS-1111, October 28, 1961. (2) ADLER, I., HESSEI, 0. Intl,avenous injections of nicotine and their ef- fects uljon the aorta of rabbits. Joul,nal of Medical Research 15: 229-Xl, 1906. 75 (3) ALLISON, R. L)., ROTH, G. M. Central and peripheral vascular effects during cigarette smoking. Archives of Environmental Health 19(2) : 189-198, August 1969. (I) AMBRUS, J. L., MIXK, I. B. Effect of cigarette smoking on blood coagu. lation. Clinical Pharmacology and Therapeutics 5 (4) : 428431, 1964. (5) AKONO~, W. S., KAPLAN, M. A., JACOB, I). Tobacco: A precipitating factor in angina pectoris. Annals of Internal Medicine 69(3) : 52g- 536, September 1968. (6) ARONOW, W. S., SWANSON, A. J. Non-nicotinized cigarettes and angina pectoris. Annals of Internal Medicine 70(6) : 1227, June 1969. (7) ARONOW, W. S., SWANSON, A. J. The effect of low-nicotine cigarettes on angina pectoris. Annals of Internal Medicine 71(3) : 599-691, September 1969. (8) ASHBY, P., DALBY, A. M., MILLAR, J. H. D. Smoking and platelet sticki. ness. Lancet 2: 158-159, July 24, 1965. (9) ASTRUP, P. Effects of hypoxia and of carbon monoxide exposures on experimental atherosclerosis. Annals of Internal Medicine 71(2): 426-427, August 1969. (10) ASTRUP, P., KJELDSEN, K., WANSTRUP, J. Enhancing influence of carbon monoxide on the development of atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis Research 7: 343-354, 1967. (11) ASTRUP, P., PAULI, H. G. (Editors). A Comparison of Prolonged Ex- posure to Carbon Monoxide and Hypoxia in Man. Reports of a Joint Banish-Swiss Study. Scandinavian Journal of Clinical and Labora- tory Investigation 22 (Supplement 103) : 1968. 71 pp. (12) AUERBACH, O., HAMMOND, E. C., GARFINKEL, L. Smoking in relation to atherosclerosis of the coronary arteries. New England Journal of Medicine 273 (15) : 775-779, October 7, 1965. (13) AVTANDILOV, G. G., KOLENOVA, V. I., PONOMARENKO, 0. V. Kureniye tabaka i stepen' ateroskleroticheskogo porazheniya koronarnykh arteriy serdtsa i aorty. (Tobacco smoking and the degree of athero- sclerotic lesions of coronary arteries of the heart and aorta.) Kar- diologiya 5 (1) : 30-34, January-February 1963. (14) AYRES, S. M., GIANNELLI, S., JR., ARMSTRONG, R. G. Carboxyhemoglo- bin: Hemodynamic and respiratory responses to small concentrations, Science 149: 195-194, July 9, 1965. (15) AYRES, S. M., MUELLER, H. S., GREGORY, J. J., GIANNELLI, S., JR., PENNY, J. L. Systemic and myocardial hemodynamic responses to relatively small concentrations of carbosyhemoglobin (COHB). Ar- chives of Environmental Health 18(4) : 699-709, April 1969. (16) BALAZS, T., OHTAKE, S., CUIL~I\IINCS, J. R., NOBLE, J. F. Ventricular extrasystolcs induced by epinephrine, nicotine, ethanol, and vaso- pressin in dogs with myocardial lesions. Toxicology and Applied Pharmacology 15 (1) : 189-205, July 1969. (17) BARGERON, L. M., JR., EHMKE, I)., GONLUBOL, F., CASTELLANOS, A., SIEGEL, A., RING, R. J. Effect of cigarette smoking on coronary blood flow and myocardial metabolism. Circulation 15 : 251-257, February 1957. (18) BARNETT, A. J., BOAKE, W. C. Cigarette smoking and occlusive arterial disease of the legs. Medical Journal of Australia 1: 240-242, Feb- ruary 13, 1960. (19) BEGG, T. B. Characteristics of men with intermittent claudication. Practitioner 194 (2) : 202-207, February 1965. 76 20) (21) (23) !24) (25) (26) (27) (28) (29) (30) (31) (32) (33) (34) (35) (36) BELLET, S., FLEISCHMANN, D., ROMAN, L., DEGUZMAN, N. The effect of cigarette smoke inhalation on the ventricular fibrillation threshold. Circulation (Supplement 3) 42(4) : 135, October 1970. BELLET, S., KERSHBAUM, A., MEADE, R. H., JR., SCHWARTZ, L. The ef- fect of tobacco smoke and nicotine on the normal heart and in the presence of myocardial damage produced by coronary ligation. Amer- ican Journal of the Medical Sciences 201( 1) : 40-51, January 1941. BELLET, S., WEST, J. W., MULLER, 0. F:, MANZOLI, U. C. Effect of nicotine on the coronary blood flow and related circulatory parame- ters. Correlative study in normal dogs and dogs with coronary in- sufficiency. Circulation Research 10 (1) : 27-34, January 1962. BERKSON, D. M., STAMLER, J. LINDBERG, H. A., MILLER, W. A., STEVENS, E. L., SOYUGENIC, R., TOKICH, T. J., STAYV~LEK, R. HEART rate: An important risk factor for coronary mortality--ten-year experience of the Peoples Gas Co. Epidemiologic study (1958-68). IN: Jones, R. J. (Editor). Atherosclerosis. Proceedings of the Second Interna- tional Symposium. New York, Springer-Verlag, 1970. pp. 382-389. BEST, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Department of National Health and Welfare, 1966. 133 pp. BLACKBURN, H., JR., ORMA, E., HARTEL G., PUNSAR, S. Tobacco smoking and blood coagulation: Acute effect on plasma Stypven time. Ameri- can Journal of the Medical Sciences 238: 448-451, October 1959. BLOMSTRAND, R., LUNDMAN, T. Serum lipids, smoking and heredity. Acta Medica Scandinavica 180 (Supplement 455) : 51-60, 1966. BORHANI, N. O., HECHTER, H. H., BRESLOW, L. Report of a lo-year followup study of the San Francisco longshoremen. Mortality from coronary heart disease and from all causes. Journal of Chronic Diseases 16: 1251-1266, 1963. BOYLE, E., Jra., MORALES, I. B., NICHAMAIS, M. Z., TALBERT, C. R., JR., WATKINS, R. S. Serum beta lipoproteins and cholesterol in adult men. Relationships to smoking, age, and body weight. Geriatrics 23 (12) : 102-111, December 1968. BREWER, G. J., EATON, J. W., WEIL, J. V., GROVER, R. F. Studies of red cell glycolysis and interactions with carbon monoxide, smoking, and altitude. Advances in Experimental Medicine and Biology 6: 95-114, 1970. BRODY, J. S., COBURN, R. F. Carbon monoxide-induced arterial hypoxe- mia. Science 164(3885) : 1297-1298, June 13, 1969. BRONTE-STEWART, B. Cigarette smoking and ischaemic heart disease. British Medical Journal 1: 379-384, February 11, 1961. BROWN, H., SELLWOOD, R. A., HARRISON, C. V., MARTIN, P. Throm- boangiitis obliterans. British Journal of Surgery 56 (1) : 59-63, January 1969. BUECHLEY, R. W., DRAKE, R. M., BRESLOW, L. Relationship of amount of cigarette smoking to cornary heart disease mortality rates in men. Circulation 18 (6) : 1085-1090, December 1958. BUNN, H. F., JANDL, J. H. Control of hemoglobin function within the red cell. New England Journal of Medicine 282(25) : 1414-1421, June 18, 1970. BURN, J. H., RAND, M. J. Action of nicotine on the heart. British Medi- cal Journal 1: 137-139, January 18, 1958. CAGANOVA, A., CAGAN, S., SIMKO, V. Lipidy krvneho sera u nefajcia- rov a fajciarov. (Blood serum lipids in nonsmokers and smokers.) Bratislavske Lekarske Listy 50 (3) : 38'7-392, September 3,1968. 77 (.;7) CEDEKLOF, R. The Twin Method in Epidemiological Studies on Chronic Disease. Institute of Hygiene of the Karolinska Institute, Department of Environmental Hygiene of the National Institute of Public Health, Department of Sociology, University of Stockholm, Stockholm, 1966. 71 PP. (38) CEDERLOF, R., FRIBERG, L., HRUBEC, Z. Cardiovascular and respiratory symptoms in relation to tobacco smoking. A study on American twins. Archives of Environmental Health 18(6) : 934-940, June 1969. (59) CEDERLOF, R., FRIBERG, L., JONSSON, E., KAIJ, L. Respiratory symptoms and "angina pectoris" in twins with reference to smoking habits, An epidemiological study with mailed questionnaire. Archives of Environmental Health 13 (6) : 726-737, December 1966. (40) CEDERLOF, R., JONSSON, E., LUNDMAN, T. On the validity of mailed questionnaires in diagnosing "angina pectoris" and "bronchitis". Archives of Environmental Health 13(6) : 738-742, December 1966. (41) CHEVALIER, R. B., KRUMHOLZ, R. A., Ross, J. C. Reaction of non- smokers to carbon monoxide inhalation. Cardiopulmonary responses at rest and during exercise. Journal of the American Medical Asso- ciation 198 (10) : 1061-1064, December 5, 1966. (42) CHOI, Y. Y. Effect of nicotine upon cholesterol-induced atherosclerosis in rabbits. New Medical Journal lO(7) : 685-693, 1967. (43) CLARK, V. A., CHAPMAN, J. M., COULSON, A. H. Effects of various fac- tors on systolic and diastolic blood pressure in the Los Angeles Heart Study. Journal of Chronic Diseases 20: 571-581, 1967. (44) COHEN, S. I., DEANE, M., GOLDSMITH, J. R. Carbon monoxide and sur- vival from myocardial infarction. Archives of Environmental Health 19(10) : 510-517, October 1969. (45) CORNFIELD, J., MITCHELL, S. Selected risk factors in coronary disease. Possible intervention effects. Archives of Environmental Health 19 (3) : 382-394, September 1969. (46) CZOCHRA-LYSANO~I~Z, Z., GORSKI, M., KEDRA, M. Wplyw nikotyny i kofeiny na rozwoj miazdzycy u krolikow. (The effect of nicotine and caffeine on the development of arteriosclerosis in rabbits.) Annales Universitatis Mariae Curie-Sklodowska; Section D: Medicina 14(20): 181-206, 1959. (47) DAWBER, T. R., KANNEL, W. B., REVOTSKIE, N., STOKES, J., KAGAN, A., GORDON, T. Some factors associated with the development of coronary heart disease. Six years' followup experience in the Framingham study. American Journal of Public Health and the Nation's Health 49 (10) : 1349-1356. October 1959. (48) DAYTOX, S., PEARCE, M. L. Diet and atherosclerosis. Lancet l(7644): 473-474, February 28, 1970. (49) DAYTON, S., PEARCE, M. L., HASHIMOTO, S., DIXON, W. J., TOMIYASU, U. A Controlled Clinical Trial of a Diet High in Unsaturated Fat in Preventing Complications of Atherosclerosis. Circulation 40 (1 Sup- plement ll), July 1969. 63 pp. (50) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' ob- servations of British doctors. (Part I) British Medical Journal l(5395) : 1399-1410, May 30, 1964. (51) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' ob- servations of British doctors. (Concluded) British Medical Journal l(5396) : 1460-1467, June 6, 1964. 78 (52) D&KEN, H. Die Rauchgewohnheitenbej jiingeren Herzinfarkt-Pabien- ten. (Smoking habits of younger patients with myocardial infarc- tion. j Miinchrner mrdizinische Wochenschrift 109 (4) ; 187-192 January 27, 1967. (5;') WRKEN, H. I)ie Rauchgewohnheiten bei jiingeren Frauen mit Herzin- farkt. (The smoking habits of younger females with myocardial in- farction.) Miinchener medizinische Wochenschrift 109(41) ; 2129 2134, October 13, 1967. (54) DOYLE, J. T., I)AWRER, T. R., KANNEL, W. B.. KIXCH, S. H. KAHN, H. A. The relationship of cigarette smoking to coronary heart disease. The second report of the combinetl experience of the Albany, N.Y., and E'i,amingham, Mass., studies. Journal of the American Medical Association 190 (10) : 886-890, I ~c*cemi)er 7, 1964. (55) DUNN, J. P., TPSEN, J., ELSOM, K. O., OHTANI, M. Risk factors in coro- nary artery disease, hypertension and diabetes. American Journal of the Medical Sciences 259(5) : 309-322, May 19'70. (56) EDWARDS, F., McK~~wN, T., WHIT~IEID, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, January 24, 1959. (57) EISEN, M. E. Coexistence of thromboangiitis obliterans and arterio- sclerosis: Relationship to smoking. Journal of the American Geria- trics Society 14 (8) : 846-858, August 1966. (58) ENGELBERG, H. Cigarette smoking and the in zsitro thrombosis of hu- man blood. Journal of the American Medical Association 193 (12) : 1033-1035, September 20, 1965. (59) ENGELBERG, H., FUTTERMAN, M. Cigarette smoking and thrombotic co- agulation of human blood. Archives of Environmental Health 14(2) : 266-270, February 1967. (60) ENGLISH, J. P., WILLIUS, F. A., BERKSON, J. Tobacco and coronary disease. Journal of the American Medical Association 115( 16) : 1327-1329, October 19, 1940. (61) EPSTEIN, F. H. Some uses of prospective observations in the Tecumseh Community Health Study. Proceedings of the Royal Society of Medi- cine 60( 1) : 4-8, January 1967. (62) FIDANZA, F., IMBIMBO, B., DI BENEDETTA, C. Indagine epidemiologica delle cardiopatie ischemiche nei reclusi de1 penitenziario di S. Stefano di Ventotene. (Epidemiological investigation of ischemic heart di- sease in prisoners of S. Stefano di Ventotene prison.) Gironale dell' Arteriosclerosi 4 : 255-267 1966. (63) FLETCHER, C. M., HORN, 1). Smoking and health. WHO Chronicle 24(8) : 345-370, August 1970. (64) FOLLE, L. E., SA~IANEK, M., AVIADO, D. M. Cardiopulmonary effects of tobacco and related substances. II. Coronary vascular effects of cigarette smoke and nicotine. Archives of Environmental Health 12(6) : 712-716, June 1966. (65) FORTE, I. E. WILLIAMS, A. J. POTGIETER, L., SCHMITTHENNER, J. E., HAFKENSCHIEL, J. H., RIEGEL, C. Coronary blood flow and cardiac oxygen metabolism during nicotine-induced increases in left ventricu- lar work. Annals of the New York Academy of Sciences 90(l) : 174-185, September 27, 1960. (66) FRANKL, W. S., FRIEDMAN, R., SOLOFF, L. A. Cardiac output, blood pressure and free fatty acid responses to smoking in the nonbasal state. American Journal of the Medical Sciences 252(l) : 39-44, July 1966. 79 (67) (68) (69) (70) (72) (72) (73) (74) (75) (76) (77) (78) (79) (80) (81) FRANKL, W. S., WINTERS, W. L., SOLOFF, L. A. The effects of smoking on the cardiac output at rest and during exercise in patients with healed myocardial infarction. Circulation 31(l) : 42-44, January 1965, FREUND, J., WARD, C. The acute effect of cigarette smoking on the digital circulation in health and disease. Annals of the New York Academy of Sciences 90( 1) : 85-101, September 27, 1960. FRIBERG, L., CEDERLOF, R., LUNDMAN, T., OLSSON, H. Mortality ii smoking discordant monozygotic and dizygotic twins. A study on the Swedish Twin Registry. Archives of Environmental Health 21(4) : 508-513, October 1970. FFUEDELL, &I. T. Effect of cigarette smoke on the peripheral vascular system. Radioactive iodinated albumin used as indicator of volu. metric change. Journal of the American Medical Association 152 (10) : 897-900, July 4, 1953. GLYNN, M. F., MUSTARD, J. F., BUCHANAN, M. R., MURPHY, E. A, Cigarette smoking and platelet aggregation. Canadian Medical Ass+ ciation Journal 95 (11) : 549-553, September 10, 1966. GOFMAN, J. W., LINDGREN, F. T., STRISOWER, B., DELALLA, O., GLAZW, F. TAMPLIN, A. Cigarette smoking, serum lipoproteins, and coronary heart disease. Geriatrics 10 (8) ; 349-354, August 1955. GOLDSMITH, J. R., LANDAU, S. A. Carbon monoxide and human health. Science 162 (3860) : 1352-1359, December 20, 1968. GREENSPAN, K., EDMANDS, R. E., KNOEBEL, S. B., FISCH, C. Some effects of nicotine on cardiac automaticity, conduction, and inotropy. Archives of Internal Medicine 123(6) : 707-712, June 1969. GROSGOGEAT, Y., ANGUERA, G., LELLOUCH, J., JACOTOT, B., BEAUMONT, J.-L., PATOIS, E., MANIER, E. L'intoxication chronique par la nice tine chez le lapin nourri au cholesterol. Effets sur la paroi aortique et sur la lipidemie. (Chronic nicotine poisoning in the rabbit on a cholesterol diet. Effects on the wall of the aorta and on lipidemia.) Journal of Atherosclerosis Research 5(3) : 291-301, 1965. HAMMOND, E. C., GARFINKEL, L. Coronary heart disease, stroke, and aortic aneurysm. Factors in the etiology. Archives of Environmental Health 19(2) : 167-182, August 1969. HAMMOND, E. C., HORN, D. Smoking and death rates--report on forty- four months of follow-up of 187,783 men. I. Total mortality. Journal of the American Medical Association 166 (10) : 1159-1172, March 8, 1958. HAMMOND, E. C., HORN, D. Smoking and death rates-report on forty- four months of follow-up of 187,783 men. II. Death rates by cause. Journal of the American Medical Association 166(11) : 1294-1308, March 15, 1958. HARLAN, W. R., OBERA~AN, A., MITCHELL, R. E., GRAYBIEL, A. Con- stitutional and environmental factors related to serum lipid and lipoprotein levels. Annals of Internal Medicine 66(3) : 540-555, March 1967. HASS, G. M., LANDERHOLM, W., HEMMENS, A. Production of calcific athero-arteriosclerosis and thromboarteritis with nicotine, vitamin I), and dietary cholesterol. American Journal of Pathology 49(4): 739-771, October 1966. HAUCE, M., HARVALD, B., REID, D. D. A twin study of the influence of smoking on morbidity and mortality. Acta Geneticae Medicae et Gemellologiae 19 : 335-336, 1970. 80 (82) (83) (8-h) (85) (8'3) (87) (88) (89) (90) (91) (92) (93) (9.4) (95) HEYDEN-STUCKY, S., SCHIBLER-REICH, S. Kardiologische Risikofaktoren bei Schweizer Mannern. (Cardiological risk factors in Swiss men.) Schweizerische Medizinische Wochenschrift 97 (1) : 20-25, January 7, 1967. HIGGINS, M. W., KJELSBERG, M. Characteristics of smokers and non- smokers in Tecumseh, Michigan. II. The distribution of selected physi- cal measurements and physiologic variables and the prevalence of certain diseases in smokers and nonsmokers. American Journal of Epidemiology 86(l) : 60-77, July 1967. HIRAYAMA, T. Smoking in relation to the death rates of 265,118 men and women in Japan. National Cancer Center, Research Institute. Tokyo, September 1967. 14 pp. HOOD, B., TIBBLIN, G., WELIN, G., ORNDAHL, G., KORSAN-BENGTSEN, K. Myocardial infarction in early age. III. Coronary risk factors and their deficient control. Acta Medica Scandinavica 185(4) : 241-251, April 1969. HUEPER, W. C. Experimental studies in cardiovascular pathology. VII. Chronic nicotine poisoning in rats and in dogs. A.M.A. Archives of Pathology 35: 846-856, 1943. HYAMS, L., SEGI, M., ARCHER, M. Myocardial infarction in the Japan- ese. A retrospective study. American Journal of Cardiology 20(4) : 549-554, October 1967. INTER-SOCIETY COMMISSION FOR HEART DISEASE RESOURCES. Athero- sclerosis Study Group and Epidemiology Study Group. Primary pre- vention of the atherosclerotic diseases. Circulation 42 (6) : A-54-A-95, December 1970. IRVING, D. W., YAMAMOTO, T. Cigarette smoking and cardiac output. British Heart Journal 25: 126132, 1963. JENKINS, C. D., ROSENMAN, R. H., ZYZANSKI, S. J. Cigarette smoking. Its relationship to coronary heart disease and related risk factors in the Western Collaborative Group Study. Circulation 38(6) : 1140- 1155, December 1968. JOUVE, A., ROCHU, P., AVRIL, P. Enquetes epidemiologiques sur l'athero- sclerose dans la region Provencale. (Epidemiological investigations of atherosclerosis in the Provence region.) Union Meclicale du Canada 98(5) : 761-766, May 1969. JUERGENS, J. L., BARKER, N. W., HIKES, E. A., JR. Arteriosclerosis ob- literans: Review of 520 cases with special reference to pathogenic and prognostic factors. Circulation Zl(2) : 188-195, February 1960. KAHN, H. A. The Dorn study of smoking and mortality among U.S. veterans: report on 8% years of observation. IN: Haenszel, W. (Edi- tar). 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. KANNEL, W. B., CASTELLI, W. P., MCNAMAF~A, P. M. Cigarette smoking and risk of coronary heart disease. Epidemiologic clues to patho- genesis. The Framingham study. IN: Wynder, E. L., Hoffmann, D., (Editors). Toward a Less Harmful Cigarette. Bethesda, U.S. Depart- ment of Health, Education, and Welfare, Public Health Service, Na- tional Cancer Institute Monograph No. 28, June 1968. pp. 9-20. KANNEL, W. B., DAWBER, T. R.. SKINNER, J. J., JR., MCNAMARA, M., SHURTLEFF, D. Epidemiological aspects of intermittent claudication: The Framingham Study. Circulation (Supplement II to Vols. 31 and 32) : 121-122, October 1965. (96) (97) (98) (99) (100) (101) (102) (103) (104) (105) (106) (107) (108) (109) (110) (111) KANNEL, W. B., UAWBER, T. R., COHEN, M. E., MCNAMARA, P. M. Vas- cular disease of the brain-epidemiologic aspects, The Framingham study. American Journal of Public Health and the Nation's Health 55 (9) : 1355-1366, September 1965. KARYONEX, IM., ORMA, E., KEYS, A., FIDANZA, F. BROXEK, J. Cigarette smoking, serum-cholesterol, blood-pressure, and body fatness. Obser- vations in Finland. Lancet 1: 492-494, March 7, 1959. KASTL, 0. Berufliche und Umweltanalyse infarktkranker Eisenbahn. bediensteter. (0ccul)ational and environmental analysis of infarct, patients in railway service.) Medizinische Klinik 64 (42) : 1911-1917, October 17, 1969. KEDRA, M., I)MOWSKI, G. The influence of tobacco smoking on the devel- opment of atherosclerosis and on the composition of blood lipids. Polish Medical Journal 5(l) : 37-43, 1966. KEDRA, M., KOROI.KO, A. Tobacco smoking and blood clotting. Bulletin of Polish Medical Science and History 8: 145-148, October 1965. KEDRA, M., POLESZAK, J., PITERA, A. Wplyw palenia tytoniu na poziom tluszczowcow krwi. (Influence of tobacco smoking on the blond lipid levels.) Polski Tygodnik Lekarski 20(39) : 1452-1454, September 27, 1965. KERRIGAN, R., JAIN, A. C., DOYLE, J. T. The circulatory response to cigarette smoking at rest and after exercise. American Journal of the Medical Sciences 255(2) ; 113-119, February 1968. KDRSHBAUM, A., BELLET, S., CAPLAN, R. F., FEINBERC, L. J. Effect of cigarette smoking on free fatty acids in patients with healed myo- cardial infarction. American Journal of Cardiology lO(2) : 204-208, August 1962. KERSHBAUM, A., RELLET, S., DICKSTEIN, E. R., FEINBERG, L. J. Effect of cigarette smoking and nicotine on serum free fatty acids. Based on a study in the human subject and the experimental animal. Circulation Research 9 (3) : 631-638, May 1961. KERSHBAUM, A., BELLET, S., HIRABAYASHI, M., FEINBERG, L. J. Regular filtertip, and modified cigarettes. Nicotine excretion, free fatty acid mobilization and catecholamine excretion. Journal of the American Medical Association 201(7) : 545-546, August 14, 1967. KERSHBAUM, A., BEI.LET, S., JIMENEZ, J., FEINBERG, L. J. Differences in effects of cigar and cigarette smoking on free fatty acid mobilization and catecholamine excretion. Journal of the American Medical Asso- ciation 195 (13) : 1095-1098, March 28, 1966. KERSHBAUM, A., BELLET, S., KHORSANDIAN, R. Elevation of serum cho- lesterol after administration of nicotine. American Heart Journal 69 (2) : 206-210, February 1965. KERSHBAUM, A., JIMENEZ, J., BELLET, S., ZANUTTINI, D. Modification of nicotine-induced hyperlipidemia by anti-adrenergic agents. Journal of Atherosclerosis Research 6: 524-530, 1966. KERSHBAUM, A,, KHORSANDIAN, R., CAPLAN, R. F., BELLET, S., FEIN- BERG, L. J. The role of catecholamines in the free fatty acid response of cigarette smoking. Circulation 28 (1) : 52-57, July 1963. KERSHBAC'M, A., OSADA, H., SCRIABINE, A., BELLET, S., PAPPAJOHN, I). J. Influence of nicotine on the mobilization of free fatty acids from rat adipose tissue in vitro and in the isolated perfused dog limb. Cir- culation 36(4, Supplement 2) : 29, October 1967. KEYS, A. (Editor). Coronary Heart Disease in Seven Countries. Circu- lation 41(4, Supplement 1) : 1970. 211 pp. 82 (112) KIEN, G. A., SHERROD, T. R. Action of nicotine and smoking on coronary circulation and myocardial oxygen utilization. Annals of the New York Academy of Sciences 90( 1) : 161-173, September 27, 1960. (113) KJELDSEN, K. Smoking and Atherosclerosis. Investigations on the sig- nificance of the carbon monoxide content in tobacco smoke in athero- genesis. Copenhagen, Munksgaard, 1969. 145 pp. (114) KJELDSEN, K., ASTRUP, P., WANSTRUP, J. Reversal of rabbit atheroma- tosis by hyperoxia. Journal of Atherosclerosis Research lO(2) : 173- 178, September-October 1969. (115) KJELDSEN, K., DAVGAARD, F. Influence of prolonged carbon monoxide exposure and altitude hypoxia on serum lipids in man. Scandinavian Journal of Clinical and Laboratory Investigation 22 (Supplementum 103) : 16-19,1968. (116) KJELDSEN, K., MOZES, M. Buerger's disease in Israel. Investigations on carboxyhemoglobin and serum cholesterol levels after smoking. Acta Chirurgica Scandinavica 135 (6) : 495-498, 1969. (117) KJELDSEN, K., WANSTRUP, J., ASTRUP, P. Enhancing influence of arte- rial hypoxia on the development of atheromatosis in cholesterol-fed rabbits. Journal of Atherosclerosis Research 8(5) : 835-845, 1968. (118) KLENSCH, H. Blut-Katecholamine und -Fettsauren beim Stress durch Rauchen und durch korperliche Arbeit. (Blood catecholamines and fatty acids under stress induced by smoke and exercise.) Zeitschrift fur Kreislaufforschung 55 (10) : 1035-1044, October 1966. (119) KONTTINEN, A. Cigarette smoking and serum lipids in young men. Brit- ish Medical Journal 1: 1115-1116, April 21, 1962. (1.20) KONTTINEN, A., RAJASALMI, M. Effect of heavy cigarette smoking on post-prandial triglycerides, free fatty acids, and cholesterol. British Medical Journal 1(5334) : 850-852, March 30, 1963. (121) KRUMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. Cardiopulmonary func- tion in young smokers. A comparison of pulmonary function measure- ments and some cardiopulmonary responses to exercise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medicine 60(4) : 603-610, April 1964. (122) KRUMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. Changes in cardiopul- monary functions related to abstinence from smoking. Studies in young cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence. Annals of Internal Medicine 62(2) : 197-207, February 1965. (123) KUHN, R. A. Mode of action of tobacco smoke inhalation upon the cere- bral circulation. Annals of the New York Academy of Sciences 142 (Article 1) : 67-71, March 15, 1967. (12.4) LARSON, R. K., FLJKUDA, P., MURRAY, J. F. Systemic and pulmonary vascular effects of nicotine in anesthetized dogs. American Review of Respiratory Diseases 91(4) : 5.56~,564, April 1965. (125) LEADERS, F. E., LONG, J. P. Action of nicotine on coronary vascular re- sistance in dogs. American Journal of Physiology 203(4) : 621-625, October 1962. (126) LEB, G., DERNTL, F., ROBIN, E., BING, R. J. The effect of nicotine on effective and total coronary blood flow in the anesthetized closed-chest dog. Journal of Pharmacology and Experimental Therapeutics 173 (1) : 138-144, May 1970. (127) LILIENTHAL, J. L., JR. Carbon monoxide. Pharmacological Review 2: 324-354, 1950. 83 (128) MCKUSICK, V. A., HARRIS, W. S., OTTESEN, 0. E., GOODMAN, R. M., SHELLEY, W. M., BLOODWELL, R. D. Buerger's disease: A distinct clin- ical and pathologic entity. Journal of the American Medical Associa. tion 181(l) : 5-12, July 7, 1962. (129) MARSHALL, W. J., JR., STANLEY, E. L., KEZDI, P. Cardiovascular effects of cold pressor tests, 40" head-up tilt, and smoking on smokers and nonsmokers. Diseases of the Chest 56(4) : 290-296, October 1969. (130) MASLOVA, K. K. The influence of nicotine on experimental atherosclero. sis. Bulletin of Experimental Biology and Medicine 41: 20-23, 1956. (131) MILLS, C. A., PORTER, M. M. Tobacco smoking and automobile-driving stress in relation to deaths from cardiac and vascular causes. Ameri- can Journal of the Medical Sciences 234(l) : 35-43, July 1957. (132) MIYAZAKI, M. Circulatory effect of cigarette smoking, with special ref- erence to the effect on cerebral hemodynamics. Japanese Circulation Journal 33 (9) : 907-912, September 1969. (139) MODZELEWSKI, A., MALEC, A. Zachowanie sie niektorych lipidow we krwi u palaczy. (Patterns of certain blood lipids in smokers.) Wiado- mosci Lekarskie 22 (3) : 229-233, February 1,1969. (134) MOYER, C. A., MADDOCK, W. G. Peripheral vasospasm from tobacco, A.M.A. Archives of Surgery 49(2j : 277-285, February 1940. (135) MULCAHY, R., HICKEY, N. J. Cigarette smoking habits of patients with coronary heart disease. British Heart Journal 28: 404-408, 1966. (136) MULCAHY, R,, HICKEY, N. J. The role of cigarette smoking in the cau- sation of atherosclerosis. Geriatrics 22 (2) : 165-174, February 1967. (137) MULCAHY, R., HICKEY, N. J., MAURER, B. J. Coronary heart disease in women. Study of risk factors in 100 patients less than 60 years of age. Circulation 36(4) : 577-586, October 1967. (1.38) MULINOS, M. G., SHULMAN, I. The effects of cigarette smoking and deep breathing on the peripheral vascular system. Studied by five methods. American Journal of the Medical Sciences 199(5): 708-720, May 1940. (139) MURCHISON, L. E., FYFE, T. Effects of cigarette smoking on serum- lipids, blood-glucose, and platelet adhesiveness. Lancet 2(7456) : 182- 184, July 23, 1966. (140) MURPHY, E. A. Thrombozyten, Thrombose und Gerinnung, (Thrombo- cytes, thrombosis and clotting.) IN : Schievelbein, H. (Editor). Niko- tin : Pharmakologie und Toxikologie des Tabakrauches. Stuttgart (West Germany), Georg Thieme Verlag, 1968. pp. 178-192. (141) MUSTARD, J. F., MURPHY, E:. A. Effect of smoking on blood coagulation and platelet survival in man. British Medical Journal l(5334) : 846- 849, March 30, 1963. (142) NADEAU, R. A., JAMES, T. N. Effects of nicotine on heart rate studied by direct perfusion of sinus node. American Journal of Physiology 212(4) : 911-916, April 1967. (143) OSKI, F. A., GOTTLIEB, A. J., MILLER, W. W., L)ELI~ORIA-PAPADOPOULOS, M. The effects of deoxygenation of adult and fetal hemoglobin on the synthesis of red cell 2,3-diphosphoglycerate and its in vi.00 conse- quences. Journal of Clinical Investigation 49 (2) : 400-407, February 1970. (1.44) PAFFENBARGER, R. S., JR., LAUGHLIN, M. E., GIMA, A. S., BLACK, R. A. Work activity of longshoremen as related to death from coronary heart disease and stroke. New England Journal of Medicine 282 (20) : 1109-1114, May 14, 1970. (145) PAFFENBARGER, R. S., JR., WUIAMS, J. L. Chronic disease in former college students. V. Early precursors of fatal stroke. American Jour- nal of Public Health and the Nation's Health 57(8) : 1290-1299, August 1967. (146) PAF~ENBARGER, R. S., JR., WING, A. L. Chronic disease in former college students. X. The effects of single and multiple characteristics on risk of fatal coronary heart disease. American Journal of Epidemiology 90(6) : 527-585, December 1969. (147) PAGE, I. H., LEWIS, L. A., MOINUDDIN, M. Effect of cigarette smoking on serum cholesterol and lipoprotein concentrations. Journal of the American Medical Association 1'71(11) : 1500-1502, November 14, 1959. (148) PAUL, O., LEPPER, M. H., PHELAN, W. H., DUPERTUIS, G. W., MACMIL- LAN, A., MCKEAN, H., PARK, H. A longitudinal study of coronary heart disease. Circulation 28(l) : 20-31, July 1963. (1.49) PENTECOST, B., SHILLINGFORD, J. The acute effects of smoking on myo- cardial performance in patients with coronary arterial disease. Brit- ish Hear% Journal 26: 422-429,1964. (l:io) PIN(.HERLE:, G., WRIGHT, H. B. Screening in the early diagnosis and prevention of cardiovascular disease. Journal of the College of Gen- eral Practitioners 13: 280-289, 1967. (152) POZNER, H., BILLIMORIA, J. D. Effect of smoking on blood-clotting and lipid and lipoprotein levels. Lancet l(7660) : 1318-1321, June 20, 1970. (152) PURI, P. S., ALAMY, D., BING, R. J. Effect of nicotine on contractility of the intact heart. Journal of Clinical Pharmacology S(5) : 295-301, September-October 1968. (153) RAZDAN, A. N., SINGH, R. P., SRIVASTAVA, V. K. Thromboangiitis obli- terans. A clinical study of 125 cases. International Surgery; Bulletin 47 (2) : 122-125, February 1967. (154) REGAN, T. J., HELLEMS, H. K., BINC, R. J. Effect of cigarette smoking on coronary circulation and cardiac work in patients with arterio- sclerotic coronary disease. Annals of the New York Academy of Sci- ences 90(l) : 186-189, September 27, 1960. (155) REID, D. D., HOLLAND, W. W., ROSE, G. A. An Anglo-American cardio- vascular comparison. Lancet 2 (7531) : 1375-1378, December 30, 1967. (156) ROMERO, T., TALESNIK, J. Influence of nicotine on the coronary circula- tion of the isolated heart of the cat. Journal of Pharmacy and Phar- macology 19(5) : 322-328, 1967. (157) ROSE, G. A. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bulletin of the World Health Organiza- tion 27 (6) : 645-658, 1962. (158) ROSE, G. A. Chest pain cprestionnaire. Milbank Memorial Fund Quar- terly 43 (2, part 2) : 32-39, April 1965. (159) ROSENMAN, R. H., FRIEDMAN, M., STR.AUS, R., WURM, M. KOSITCHEK, R., HAHN, W., WERTHESSEN, N. T. A predictive study of coronary heart disease. The Western Collaborative Group Study. Journal of the American Medical Association 189(l) : 15-22, July 6, 1964. (160) ROSS, G., BLESA, M. I. The effect of nicotine on the coronary circulation of dogs. American Heart Journal 79(l) : 96-102, January 1970. (161) ROTH, G. M., SCHICK, R. M. The effects of smoking on the peripheral circulation. Diseases of the Chest 37 (2) : 203-210, February 1960. 85 (16.2) (163) (16-4) (165) (166) (167) (168) (169) (170) (171) (172) (173) (17-4) (175) ROTTENSTEIN, H., PEIRCE, G., Russ, E., FELDER, I)., MONTGOMERY, H. Influence of nicotine on the blood flow of resting skeletal muscle and of the digits in normal subjects. Annals of the New York Academy of Sciences 90 (1) : 102-113, September 27, 1960. RUSSEK, H. I., ZOHMAN, B. L. Relative significance of heredity, diet and occupational stress in coronary heart disease of young adults. Based on an analysis of 100 patients between the ages of 25 and 40 years and a similar group of 100 normal control subjects. American Journal of the Medical Sciences 235(3) : 266-27'7, March 1958. RUSSEK, H. I., ZOHMAN, B. L., DORSET, V. J. Effects of tobacco and whiskey on the cardiovascular system. Journal of the American Med. ical Association 157( 7) : 563-568, February 12, 1955. SACKETT, D. L., GIBSON, R. W., BROSS, I. D. J., PICKREN, J. W. Relation between aortic atherosclerosis and the use of cigarette and alcohol, An autopsy study. New England Journal of Medicine 279(26) : 1413- 1420, December 26, 1968. SAPHIR, R., RAPAPORT, E. Cardiovascular responses of the cat to mesen- teric intra-arterial administration of nicotine, cyanide and venous blood. Circulation Research 25 (6) : 713-724, December 1969. SCHIMMLER, W., NEFF, C., SCHIMERT, G. Risikofaktoren und Herzin- farkt. Eine retrospektive studie. (Risk factors and myocardial in- farct. A retrospective study.) Miinchener Medizinische Wochenschrift liO(27) : X85-1594, July 5, 1968. SCHWARTZ, D., LELLOUCH, J., ANGUERA, G., RICHARD, J. L., BEAUMONT, J. I,. Etiologie comparee de I'arteriopathie obliterante des membres inferieurs et de l'arteriopathie coronarienne. (Comparative etiology of lower limb obliterative arteriopathy and of coronary arteriopathy.) Archives des Maladies du Coeur 58: Supplement No. 3, 24-32, 1965. SCHWARTZ, D., LELLOUCH, J., ANGUERA, G., BEAUMONT, J. L., LENEGFLE, J. Tobacco and other factors in the etiology of ischemic heart disease in man: Results of a retrospective survey. Journal of Chronic Dis- eases 19 (1) : 35-55, January 1966. SELTZER, C. C. The effect of cigarette smoking on coronary heart dis- ease. Where do we stand now? Archives of Environmental Health ZO(3) : 418-423, March 1970. SEN GUPTA, A. N., GHOSH, B. P. Observations on some cardiovascular and biochemical effects of tobacco smoking in health and in ischaemic cardiacs. Bulletin of the Institute of Post-Graduate Medical Educa- tion and Research 9(2) : 45-57, April 1967. SHAPIRO, S., WEINBLATT, E., FRANK, C. W., SAGER, R. V. Incidence of Coronary Heart Disease in a Population Insured for Medical Care (HIP). Myocardial infarction, angina pectoris, and possible myocar- dial infarction. American Journal of Public Health and the Nation's Health 59 (6) : Supplement to June 1969. 101 pp. SHEPHERD, J. T. Effect of cigarette-smoking on blood flow through the hand. British Medical Journal 2: 1007-1010, October 27, 1951. SOGANI, R. K., JOSHI, K. C. Effect of cigarette and biri smoking and tobacco chewing on blood coagulation and fibrinolytic activity. Indian Heart Journal 17: 238-242, July 1966. SPAIN, D. M., BRADESS, V. A. Sudden death from coronary heart dis- ease. Survival time, frequency of thrombi, and cigarette smoking. Chest 58(2) : 10'7-110, August 1970. (176) SPAIN, D. M., NATHAN, D. J. Smoking habits and coronary atheroscle- rotic heart disease. Journal of the American Medical Association 17'7 (10) : 683-688, September 9, 1961. (177) STAMLER, J., BERKSON, D. M., LEVINSON, M., LINDBERG, H. A., MOJON- NIER, L., MILLER, W. -4., HALL, Y., ANDELMAN, S. L. Coronary artery disease. Status of preventive efforts. Archives of Environmental Health 13 (3) : 322-335, September 1966. (178) STEFANOVICH, V., GORE, I., KAJIYAMA, G., IWANAGA, Y. The effect of nicotine on dietary atherogenesis in rabbits. Experimental and Molec- ular Pathology 11(l) : 71-81, August 1969. (179) STEJFA, M., JR. Predictive significance of risk factors in exertional an- gina pectoris. Cardiologia 51(6) : 336-339, 1967. (180) STROBEL, M., GSELL, 0. Mortalitat in Beziehung zum Tabakrauchen: 9 Jahre Beobachtungen bei Arzten in der Schweiz. (Mortality in rela- tion to tobacco smoking. Nine years of observation in Swiss doctors.) Helvetica Medica Acta 32 (6) : 547-592, December 1965. (181) STROMBLAD, B. C. R. Effect of intra-arterially administered nicotine on the blood flow in the hand. British Medical Journal 1: 484-485, February 21, 1959. (182) STRONG, J. P., RICHARDS, M. L., MCGILL, H. C., JR., EGGEN, D. A., MCMURRAY, M. T. On the association of cigarette smoking with coro- nary and aortic atherosclerosis. Journal of Atherosclerosis Research lO(3) : 303-317, November-December 1969. (183) TAYLOR, H. L., BLACKBURN, H., KEYS, A., PARLIN, R. W., VASQUEZ, C., PUCHNER, T. Five-year follow-up of employees of selected U.S. rail- road companies. IN: Keys, A. (Editor). Coronary Heart Disease in Seven Countries. American Heart Association Monograph No. 29, 1970. pp. 2039. (184) THIENES, C. H. Chronic nicotine poisoning. Annals of the New York Academy of Sciences 90 (1) : 239-248, September 27, 1960. (185) THOMAS, C. B. Familial and epidemiologic aspects of coronary disease and hypertension. Journal of Chronic Diseases 7 (3) : 198-208, March 1958. (186) THOMAS, C. B., MURPHY, E. A. Circulatory responses to smoking in healthy young men. Annals of the New York Academy of Sciences 90 (1) : 266-276, September 27, 1960. (187) TIBBLIN, G. High blood pressure in men aged 50. A population study of men born in 1913. Acta Medica Scandinavica (Supplementurn 470) : l-84, 1967. (188) TIBBLIN, G. Kommentar till en svensk tvillingundersBkning. (Comment on research on twins in Sweden.) Lakartidningen 65 (47) : 4654-4655, November 20, 1968. i189) TRAVELL, J., RINZLER, S. H., KARP, I). Cardiac effects of nicotine in the rabbit with experimental coronary atherosclerosis. Annals of the New York Academy of Sciences 90 (1) : 290-301, September 27, 1960. (190) TRUETT, J., CORNFIELD, J., KANNEL, W. A multivariate analysis of the risk of coronary heart disease in Framingham. Journal of Chronic Diseases 20 : 511-524, 1967. (191) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Public Health Service Review: 1967. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696,1967.199 pp, 07 (192) U.S. PUBLIC: HEALTH SERVICE. The Health Consequences of Smoking, 1968 Supplement to the 1967 Public Health Service Review. Washing- ton, U.S. Ijepartment of Health, Education, and Welfare, Public Health Service Publication No. 1696, 1968. 11'7 pp. (193) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. 1969 Supplement to the 1967 Public Health Service Review. Washing- ton, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1696-2, 1969. 98 pp. (194) U.S. PUBLIC HEALTH SERVICE. NATIONAL AIR POLLUTION CON.. TROL ADMINISTRATION. Air Quality Criteria for Carbon Man- oxide. Washington, U.S. Department of Health, Education and Wel- fare, National Air Pollution Control Administration Publication No. AP-62, March 1970. 158 pp. (195) U.S. PUBLIC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATISTICS. Vital and Health Statistics. Data from the National Health Survey. Coronary Heart Disease in Adults-United States- 1960-1962. Washington, U.S. Department of Health, Education and Welfare, National Center for Health Statistics Series 11, No. 10, September 1965. 46 pp. (196) U.S. PUBLIC HEALTH SERVICE. N;ATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics of the United States-1967, Vol. II.- Mortality, Part A. Washington, U.S. Department of Health, Educa- tion and Welfare, Public Health Service Publication, 1969. (1.97) U.S. PUBLIC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics Rates in the United States 1940-1960. Washington, U.S. Department of Health, Education and Welfare, Public Health Service Publication No. 167'7, 1968. 881 pp. (198) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Ad- visory Committee to the Surgeon General of the Public Health Serv- ice. Washington, U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1103, 1964. 387 pp. (199) VAN BUCHEM, F. S. P. Serum lipids, nutrition and atherosclerotic com- plications in man. Acta Medica Scandinavica 181(4) : 403-416, April 1967. (200) VIEL, B., DONOSO, S., SALCEDO, I). Coronary atherosclerosis in persons dying violently. Archives of Internal Medicine 122(2) : 97-103, Au- gust 1968. (201) VILIGER, U., HEYDEN-STUCKY, S. Das Infarktprofil. Unterschiede zwi- schen infarktpatienten und Kontrollpersonen in der Ostschweiz. (The infarct profile. 1)iffrrenccs between infarct patients and controls in East Switzerland.) Schweizerische Medizinische Wochenschrift 96(23) : 748-758, June 11, 1966. (202) VON AHN, B. Tobacco smoking, the electrocardiogram, and angina pec- toris. Annals of the New York Academy of Sciences 90 (1) : 190-198, September 27, 1960. (203) WA-ITS, D. T. The effect of nicotine and smoking on the secretion of epi- nephrine. -4nnals of the New York Academy of Sciences 90(l) : `74- 80, September 27, 1960. (204) WEBSTER, W. S., CLARKSON, T. B., LOFLAND, H. B. Carbon monoxide- aggravated atherosclerosis in the squirrel monkey. Experimental and Molecular Pathology 13 (1) : 36-50, 1970. (205) WEIR, J. M., DUNN, J. E., JR. Smoking and mortality: A prospective study. Cancer 25 (1) : 105-112, January 1970. (m6j WENZEL, D. G. BECKLOFF, G. L. The effect of nicotine on experimental hypercholesterolemia in the rabbit. Journal of the American Phar- maceutical Association ; Scientific Edition 47 (5) : 338-343, May 1958. (,?07) I~ENZEL, I). G., TURNER, J. A., KISSIL, D. Effect of nicotine on choles- terol-induced atherosclerosis in the rabbit. Circulation Research 7: 256-261, March 1959. (208) WEST, J. TV., GUZMAN, S. V., BELLET, S. Cardiac effects of intracoro- nary arterial injections of nicotine. Circulation Research 6: 389-395, May 1958. (20:)) WESTFALL, T. C., CIPOLLONI, P. B., EDMUND~VXZ, A. C. Influence of propranoloi on hemodynamic changes and plasma catecholamine levels following cigarette smoking and nicotine. Proceedings of the Society for Experimental Biology and Medicine 123 : 174-179, 1966. (210) WESTFALL, T. C., WATTS, D. T. Effect of cigarette smoke on epinephrine secretion in the dog. Proceedings of the Society for Experimental Bi- ology and Medicine 1 l%(4) : 843-847, April 1963. (211) WESTFALL, T. C., WATTS, I). T. Catecholamine excretion in smokers and nonsmokers. 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. The effect of acute exposure to cigarette smoke on bronchial clearance in the miniature donkey. Archives of Environmental Health 18 (1) : 30-41, January 1969. ANDERSON, A. E., JR., FURLANETO, J. A.. FORAKER, A. G. Bronchopul- monary derangements in nonsmokers. American Review of Respira- tory Diseases 101(4) : 518-527, April 1970. ANDERSON, A. E., JR., HERNANDEZ, J. A., ECKERT, P., FORAKER. A. G. Emphysema in lung macrosections correlated with smoking habits. Science 144(3621) : 1025-1026, May 22, 1964. ANDERSON, A. E., JR., HERNANDEZ, J. A., HOLMES, W. L., FORAKER, A. G. Pulmonary emphysema. Prevalence, severity, and anatomical patterns in macrosections, with respect to smoking habits. Archives of Environ- mental Health 12(5) : 569-5'7'7, May 1966. ANDERSON, D. 0. Observations on the classification and distribution of pulmonary emphysema in Canada. Canadian Medical Association Journal 89: 709-716, October 5, 1963. ANDERSON, D. O., FERRIS, B. G., JR., ZICKMANTEL, R. The Chilliwack Respiratory Survey, 1963. Part IV. The effect of tobacco smoking on the prevalence of respiratory disease. Canadian Medical Association Journal 92(20) : 1066-1076, May 15, 1965. ANDERSON, W. H., WILLIAMS, J. B. Effects of cigarette smoke on dis- tribution of pulmonary perfusion. In: Current Research in Chronic Respiratory Diseases. Proceedings of the 11th Aspen Emphysema Conference, Aspen, Colo. U.S. Department of Health, Education, and Welfare, Public Health Service Publication No. 1879, 1969. pp. 75-79. ANTHONISEN, N. R., BASS, H., ORIOL, A., PLACE, R. E. G., BATES, D. V. Regional lung function in patients with chronic bronchitis. Clinical Science 35 : 495-511, December 1968. ASHFORD, J. R., BROWN, S., DUFFIELD, D. P., SMITH, C. S., FAY, J. W. J. The relation between smoking habits and physique, respiratory symp- toms, ventilatory function, and radiological pneumoconiosis amongst coal workers at three Scottish collieries. British Journal of Preventive and Social Medicine 15 : 106-117, 1961. 176 (12) ASHLEY, I). .J. B. Environmental factors in thr, aetiolcgy of lung cancer and bronchitis. British Journal of Preventive and Social Xedicine 23 (4) : 258262, November 1969. (13) ATTI~TGER, E. O., GOLDSTEIN;, M. M.. SEGAI., M. S. Effects of smoking upon the mechanics of breathing. I. In nornlal subjects. American Review of Tuberculosis and Pulmonary Diseases 77(l) : l-16, January 1958. (24) AUERBACH, O., HAMZVIOND, E. C., GARFINKEL. I,., Thickening of walls of arterioles and small arteries in relation to age and smoking habits. Ne~v Eligland Journal of Medicine 278( 18) : 980-984, May 2, 1968. (15) AUERBACH, O., HAMRIOND, E. C., KIRMAX, I)., GARFINKEL, L. Emphysema produced in dogs by cigarette smoking. Joui,nal of the American Medical Association 199 (4) : 241-246, January 23, 1967. (16) AUERBACH, O., HAMMOXD, E. C., KIRMAN, I)., GARFINKEL, L. Emphysema llroduced in dogs by cigarette smoking. In: Hanna, 111. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology I)ivision, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 375-387. (17) AUERBACH, O., STOUT, A. P., HAMMOXD, E. C., GARFINKEL, L. Smoking habits and age in relation to pulmonary- changes. Rupture of alreolal septums, fibrosis and thickening of walls of small arteries and arterioles. New England Journal of Medicine 269(20) : 1045-1054, November 14, 1963. (18) AVIADO, D. M., CARRILLO, L. R. Hormones and pulmonary effects of tobacco. I. Corticosteroids and their antiasthmatic action. Archives of Environmental Health X3(6) : 925-933, June 1969. (19) AVIADO, D. M., PALECEK, F. Pulmonary effects of tobacco and related substances. I. Pulmonary compliance and resistance in the anesthetized dog. Archives of Environmental Health 15 (2) : 187-193, August 1967. (20) AVIADO, D. M., SADA~ONG~IVAD, C., CARRILLO, L. R. Cigarette smoke and pulmonary emphysema. Influence of bronchodilators and biogenic amines in experimental induction in rats. Archives of Environmental Health 20 (4) : 483-487, April 1970. (21) AVIADO, I). M., SAMANEK, M. Bronchopulmonary effects of tobacco and related substances. I. Bronchoconstriction and bronchodilatation : In- fluence of lung denervation. Archives of Environmental Health ll(2) : 141-151, August 1965. (22) AVIADO, I). M., SAMANEK, M., FOLLE, L. E. Cardiopulmonary effects of tobacco and related substances. I. The release of histamine during inhalation of cigarette smoke and anoxemia in the heart-lung and intact dog preparation. Archives of Environmental Health 12(6) : 705-724, June 1966. (23) BAIR, W. J., DILLEY, J. V. Pulmonary clearance of `9FE,O, and "CR,O, in rats and dogs exposed to cigarette smoke. In: Davies, C. N. (Edi- tor). Inhaled Particles and Vapors. II. Proceedings of an International Symposium. Cambridge, September 28 to October 1, 1965, Oxford, Pergamon Press, 1967. pp. 251-271. (24) BALCHUM, 0. J., FELTON, J. S., JAMISON, J. N., GAINES, R. S., CLARKE, D. R., OWAN, D., THE INDUSTRIAL HEALTH COMMITTEE, THE TUBERCU- LOSIS AND HEALTH ASSOCIATION OF Los ANGELES COUNTY. A Survey for chronic respiratory disease in an industrial city. Preliminary re- sults. American Review of Respiratory Diseases 86 (5) :675-685, November 1962. 177 (25) BALLENGER, J. J. Experimental effect of cigarette smoke on human respiratory cilia. New England Journal of Medicine 263 (17) : 832-835, October 27, 1960. (26) BALLENGER, J. J., DAWSON, F. W., DERUYTER, M. G., HARDING, H. B. Effects of nicotine on ciliary activity in vitro. Annals of Otology, Rhinology and Laryngology 74(2) : 303-311, June 1965. (27) BATES, D. V., GORDON, C. A., PAUL, G. I., PLACE, R. E. G., SNIDAL, D. p., WOOLF, C. R. Chronic bronchitis. Report on the third and fourth stages of the coordinated study of chronic bronchitis in the Department of Veterans Affairs, Canada. Medical Services Journal, Canada 22(l) : l-59, January 1966. (28) BATTISTA, S. P., KENSLER, C. J. Use of the nonimmersed in vitro chicken tracheal preparation for the study of ciliary transport activity. Cigarette smoke and related components. Archives of Environmental Health 20 (3) : 318-325, March 1970. (29) BATTISTA, S. P., KENSLER, C. J. Mucus production and ciliary transport activity. In uuz`vo studies using the chicken. Archives of Environmental Health 20 (3) : 326-338, March 1970. (30) BEST, E. W. R. A Canadian Study of Smoking and Health. Ottawa, Department of National Health and Welfare, 1966. 13'7 pp. (31) BICKERMAN, H. A., BARACH, A. L. The effect of cigarette smoking on ventilatory function in patients with bronchial asthma and obstructive pulmonary emphysema. Journal of Laboratory and Clinical Medicine 43 (3) : 455-462, March 1964. (32) BLAIR, W. H., HENRY, M. C., EHRLICH, R. Chronic toxicity of nitrogen dioxide. II. Effect on histopathology of lung tissue. Archives of En- vironmental Health 18 (2) : 186-192, February 1969. (33) BOAKE, W. C. -4 Study of illness in a group of Cleveland families. XVIII. Tobacco smoking and respiratory infections. New England Journal of Medicine 259(26) : 1245-1249, December 25, 1958. (34) BONNELL, J. A. Emphysema and proteinuria in men casting copper- cadmium alloys. British Journal of Industrial Medicine 12: 181-195, July 1955. (35) BONNELL, J. A., KAZANTZIS, G.,KING, E. A follow-up study of men ex- posed to cadmium oxide fume. British Journal of Industrial Medicine 16: 135-147, 1959. (36) BOUCOT, K. R., COOPER, D. A., WEISS, W. Smoking and the health of older men. I. Smoking and chronic cough. Archives of Environmental Health 4( 1) : 59-72, January 1962. (37) BOUHUYS, A. PETERS, J. M. Control of environmental lung disease. New England Journal of Medicine 283(11) : 5'73-582, September 10, 1970. (38) BOUHUYS, A., SCHILLING, R. S. F., VAN DE WOESTIJNE, K. P. Cigarette smoking, occupational dust exposure, and ventilatory capacity. Ar- chives of Environmental Health 19(6) : 793-797, December 1969. (39) BOUHUYS, A., WOLFSON, R. L., HORNER, D. W., BRAIN, J. D., ZUSKIN, E. Byssinosis in cotton textile workers. Respiratory survey of a mill with rapid labor turnover. Annals of Internal Medicine 71(Z) : 257-269, August 1969. (40) BOUSHY, S. F., HELGASON, A. H., BILLIG, D. M., GYORKY, F. G. Clinical physiologic, and morphologic examination of the lung in patients with bronchogenic carcinoma and the relation of the findings to postopera- tive deaths. American Review of Respiratory Diseases lOl(5) : 685- 695, May 1970. 178 (41) BOWER, G. Respiratory symptoms and ventilatory function in 1'72 adults employed in a bank. American Review of Respiratory Diseases 83: 684-689, 1961. (42) BRINKMAN, G. L., COATES, E. O., JR. The prevalence of chronic bronchitis in an industrial population. American Review of Respiratory Diseases 86: 47-54, 1962. (43) BROWN, K. E., CAMPBELL, A. H. Tobacco, alcohol and tuberculosis. British Journal of Diseases of the Chest 55(3) : 150-158, 1961. (44) CARSON, S., GOLDHAMER, R., CARPENTER, R. Responses of ciliated epithelium to irritants. Mucus transport in the respiratory tract. American Review of Respiratory Diseases 93 (3, Part 2) : 86-92, March 1966. (45) CEDERLOF, R. FRIBERG, L., HRUBEC, Z. Cardiovascular and respiratory symptoms in relation to tobacco smoking. Archives of Environmental Health 18(6) : 934-940, June 1969. (46) CEDERLOF, R., FRIBERG, L., JONSSON, E., KAIJ, L. Respiratory symptoms and "angina pectoris" in twins with reference to smoking habits. An epidemiological study with mailed questionnaire. Archives of Environ- mental Health 13 (6) : `726-737, December 1966. (47) CHANG, S. C. Microscopic properties of whole mounts and sections of human bronchial epithelium of smokers and nonsmokers. Cancer 10 (6) : 1246-1262, November-December 1957. (48) CHAPMAN, T. T. The acute effect of cigarette smoking on pulmonary function. Journal of the Irish Medical Association 56(333) : 72-74, March 1965. (49) CHESTER, E. H., GILLESPIE, D. G., KRAUSE, F. D. The prevalence of chronic obstructive pulmonary disease in chlorine gas workers. Amer- ican Review of Respiratory Diseases 99 (3) : 365-373, March 1969. (50) CHEVALIER, R. B., KRUMHOLZ, R. A., Ross, J. C. Reaction of nonsmokers to carbon monoxide inhalation. Cardiopulmonary responses at rest and during exercise. Journal of the American Medical Association 198 (10) : 1061-1064, December 5, 1966. (51) CHIANC, S. T., WANG., B. C. Acute effects of cigarette smoking on pul- monary function. American Review of Respiratory Diseases lOl(6) : 860-868, June 1970. (52) CHIVERS, C. P. Respiratory function and disease among workers in alka- line dusts. British Journal of Industrial Medicine 16: 51-60, 1959. (53) COATES, E. O., JR. BOWER, G. C., REINSTEIN, N. Chronic respiratory disease in postal employees. Epidemiologic survey of a group em- ployed in one building. Journal of the American Medical Association 191(3) : 161-166, January 18, 1965. (54) COHEN, J. Chronic bronchitis and emphysema. Observations on trends and distribution according to death certificate data, Israel 1960 to 1964. Israel Journal of Medical Sciences 3(6) : 885-889, November- December 1967. (55) COLLEGE OF GENERAL PRACTITIONERS. Chronic bronchitis in Great Brit- ain. A national survey carried out by the respiratory diseases study group of the College of General Practitioners. British Medical Journal 2: 973-979, October 14, 1961. (56) COMROE, J. H., JR., FORSTER, R. E., II, DUBOIS, A. B., BRISCOE, W. A., CARLSEN, E. The Lung. Clinical Physiology and Pulmonary Function Tests. Chicago, Year Book Medical Publishers, Inc., 1963. 390 pp. (57) COOK, W. A., WEBB, W. R. Surfactant in chronic smokers. Annals of Thoracic Surgery 2 (3) : 327-333, May 1966. 179 (58) COOLEY. J. R. T., REID, D. I). Urban and social origins of childhood bron- chitis in England and Wales. British Medical Journal 2(5703) : 213- 217, April 25, 1970. (59) DALHAMN, T. The effect of cigarette smoke on ciliary activity in the upper respiratory tract. A.M.A. Archives of Otolaryngology 70 : 166 168, 1959. (60) DALHAMN, T. Effect of cigarette smoke on ciliary activity. American Review of Respiratory Diseases 93 (3) : 108-114, March 1966. (61) DALHAMN, T., R~LANDER, R. Ciliastatic action of smoke from filter- tipped and non-tipped cigarettes. Nature 201(4917) : 401-402, Janu- ary 25, 1964. (6.2) DALHAMN, T., RYLANDER, R. Ciliastatic action of cigarette smoke. Vary- ing exposure times. Archives of Otolaryngology 81(4) : 379-382, April 1965. (63) DALHAMN, T., RYLANDER, R. Tar content and ciliotoxicity of cigarette smoke. Acta Pharmacologica et Toxicologica 25 (3) : 369-372, 1967. (64) DALHAMN, T., RYLANDER, R. Ciliotoxicity of cigarette smoke and its volatile components. American Review of Respiratory Diseases 98(3) : 509-511, September 1968. (65) DALHAMN, T., RYLANDER, R. Ciliotoxicity of cigar and cigarette smoke. Archives of Environmental Health 20(2) : 252-253, February 1970. (66) DAVIS, T. R. A., BATTISTA, S. P., KESSLER, C. J. Mechanism of respira- tory effects during exposure of guinea pigs to irritants. Archives of Environmental Health 15 (4) : 412-419, October 1967. (67) DEANE, M., GOLDSMITH, J. R., TUMA, D. Respiratory conditions in out- side workers. Report on outside plant telephone workers in San Fran- cisco and Los Angeles. Archives of Environmental Health lO(2) : 323-331, February 1965. (68) DENSEN, P. M., JONES, E. W., BASS, H. E., BREUER, J. A survey of respi- ratory disease among New York City postal and transit workers. 1. Prevalence of symptoms. Environmental Research 1: 262-286,1967. (69) DENSEN, P. M., JONES, E. W., BASS, H. E., BREUER, J., REED, E. A survey of respiratory disease among New York City postal and transit work- ers. 2. Ventilatory function test results. Environmental Research 2(4) : 277-296, July 1969. (70) DOLL, R., HILL, A. B. Mortality in relation to smoking: Ten years' observations of British doctors. (Part I) British Medical Journal l(5395) : 1399-1410, May 30, 1964. (71) DOLL, R., HILL, A. B. Mortality in relation to smoking: Ten years' observations of British doctors. (Concluded) British Medical Journal l(5396) : 1460-1467, June 6, 1964. (72) DOWLING, H. F., JACKSON, G. G., INOUYE. T. Transmission of the experi- mental common cold in volunteers. II. The effect of certain host factors upon susceptibility. Journal of Laboratory and Clinical Medicine 50(4) : 316-525, October 1957. (73) EDEL~IAN, N. H.. MITTMAN, C., NORRIS, A. H., COHEN, B. H., SHOCK, N. W. The effects of cigarette smoking upon spirometric performance of community dwelling men. American Review of Respiratory Diseases 94 (3) : 421-429, September 1966. (74) EDWARDS, F., RZCKEOWN, T., WHITFIELD, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, January 24, 1959. (75) EHRLICH, R., HENRY, M. C., FENTERS, J. Influence of nitrogen dioxide on resistance to respiratory infections. In: Hanna, M. G., Jr., Nette- 180 sheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Pro- ceedings of a Biology Division, Oak Ridge National Laboratory Con- ference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 243-257. (76) EICH, R. H., GILBERT, R., AUCHINCLOSS, J. H., JR. The acute effects of smoking on the mechanics of respiration in chronic obstructive pul- monary emphysema. American Review of Tuberculosis 76: 22-32, 1957. (77) ELWOOD, P. C., PEMBERTON, J., MERRETT, J. D., CAREY, G. C. R., MCAULAY, I. R. Byssinosis and other respiratory symptoms in flax workers in Northern Ireland. British Journal of Industrial Medicine 22 :27-37, 1965. (78) ERIKSSON, S. Studies in Alpha,-antitrypsin Deficiency. Acta Medica Scandinavica 177 (Supplementum 432) : 1965. 85 pp. (79) FALK, G. A., BRISCOE, W. A. Chronic obstructive pulmonary disease and heterozygous alpha,-antitrypsin deficiency. Annals of Internal Medi- cine 72(4) : 595-596, April 1970. (80) FALK, H. L., TREMER, H. M., KOTIX, P. Effect of cigarette smoke and its constituents on ciliated mucus-secreting epithelium. Journal of the National Cancer Institute 23 (5) : 99991012, November 1959. (81) FERRIS, B. G., JR., ANDERSON, D. 0. The prevalence of chronic respiratory disease in a New Hampshire town. American Review of Respiratory Diseases 86(2) : 165-177, August 1962. (82) FERRIS, B. G., JR., ANDERSON, D. O., BURGESS, W. A. Prevalence of respiratory disease in a flax mill in the United States. British Journal .of Industrial Medicine 19: 180-185, 1962. (83) FINKLEA, J. F., SANDIFER, S. H., SMITH, D. D. Cigarette smoking and epidemic influenza. American Journal of Epidemiology 90(5) : 390- 399, November 1969. (84) FLETCHER, C. M., HORN, D. Smoking and health. WHO Chronicle 24(8) : 345-370, August 1970. (85) FLETCHER, C. M., TINKER, C. M. Chronic bronchitis. A further study of simple diagnostic methods in a working population. British Medical Journal 1: 1491-1498, May 27,196l. (86) FLICK, A. L., PATON, R. R. Obstructive emphysema in cigarette smokers. A.M.A. Archives of Internal Medicine 104: 518-526, 1959. (87) FRANKLIN, W., LOWELL, F. C. Unrecognized airway obstruction associ- ated with smoking. A probable forerunner of obstructive pulmonary emphysema. Annals of Internal Medicine 54 (3) :379-386, March 1961. (88) FRASCA, J. M., AUERBACH, O., PARKS, V. R., JAMIESON, J. D. Electron microscopic observations of the bronchial epithelium of dogs. II. Smok- ing dogs. Experimental and Molecular Pathology 9 (3) : 380-399. December 1968. (89) FREEMAN, G., CRANE, S. C. STEPHENS, R. J., FURIOSI, N. J. Pathogenesis of the nitrogen dioxide-induced lesion in the rat lung: A review and presentation of new observations. American Review of Respiratory Diseases 98 (3) : 429-443, September 1968. (90) FREEMAN, G., HAYDON, G. B. Emphysema after low-level exposure to NO,. Archives of Environmental Health 8 (1) : 123-128, January 1964. (91) FREEMAN, G., STEPHENS, R. J., CRANE, S. C., FURIOSI, N. J. Lesion of the lung in rats continuously exposed to two parts per million of nitrogen dioxide. Archives of Environmental Health 17(2) : 181-192, August 1968. 181 (92) FREOUR, P., COUDRAY, P., ROUSSEL, A., SERISE, A. Les bronchites chroni. ques et l'insuffisance respiratorie dans l'agglomeration de Bordeaux. (Chronic bronchitis and respiratory insufficiency in Bordeaux). Journal de Medecine de Bordeaux 143 (2) : 1865-18'79, December 1966. (98) GANDEVIA, B. A productive cough upon request as an index of chronic bronchitis: The effects of age, sex, smoking habit, and environment upon prevalence in Australian general practice. Medical Journal of Australia l(1) : 16-20, January 4, 1969. (94) GIAMMONA, S. T. Effects of cigarette smoke and plant smoke on pulmo- nary surfactant. American Review of Respiratory Diseases 96(3) : 539-541, September 1967. (95) GOLDSMITH, J. R., HECHTER, H. H., PERKINS, N. M. BORHANI, N. 0. Pulmonary function and respiratory findings among longshoremen. American Review of Respiratory Diseases 86 (6) ;867-874, December 1962. (96) GREEN, G. M., CAROLIN, D. The depressant effect of cigarette smoke on the in vitro antibacterial activity of alveolar macrophages. New Eng- land Journal of Medicine 276(8) : 421-427, February 23, 1967. (97) GREENBERG, M., MILNE, J. F., WATT, A. Survey of workers exposed to dusts containing derivatives of Bacillus s&t&s. British Medical Journal 2: 629-633, June 13,19'70. (98) GUENTER, C. A., WELCH, M. H., RUSSELL, T. R., HYDE, R. M., HAMMAR- STEN, J. F. The pattern of lung disease associated with alpha-l anti- trypsin deficiency. Archives of Internal Medicine 122(3) : 254-257, September 1968. (99) GUILLERM, R., SAINDELLE, A., FALOT, P., HEE, J. Action de la fumee de cigarette et de quelquesuns de ses constituants sur les resistances ventilatoires chez le cobaye. (Action of cigarette smoke and some of its constituents on ventilatory resistance in the guinea pig.) Archives Internationales de Pharmacodynamie et de Therapie 167 (1) : lOl- 114, May 1967. (loo) GUYATT, A. R., BERRY, G., ALPERS, J. H., BRAMLEY, A. C., FLETCHER, C. M. Relationship of airway conductance and its immediate change on smoking to smoking habits and symptoms of chronic bronchitis. Amer- ican Review of Respiratory Diseases 101(l) : 44-54, January 1970. (101) HAMMARSTEN, J. F., WELCH, M. H., RICHARDSON, R. H., PATTERSON, C. I).. GUENTER, C. A. Familial alnhal-antitrypsin deficiency and pul- monary emphysema. Transactions of the American Clinical and Clima- tological Association 80(l) : 7-14, 1968. (102) HAMMOND, E. C. Evidence on the effects of giving up cigarette smoking. American Journal of Public Health and the Nation's Health 55(5) : 682-691, May 1965. (103) HAMMOND, E. C. Smoking in relation to the death rates of 1 million men and women. In: Haenszel, W. (Editor). Epidemiological -4pproaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Monograph No. 19, January 1966. pp. 127-204. (104) HAMMOND, E. C., AUERBACH, O., KIRMAN, D., GARF~NKEL, L. Effects of cigarette smoking on dogs. I. Design of experiment, mortality, and findings in lung :)arenchyma. Archives of Environmental Health 21(6) : 740-753, December 1970. (105) HAMMOND, E. C., HORN, D. Smoking and death rates-report on forty- four months of follow-up of 187,783 men. II. Death rates by cause. Journal of the American Medical Association 166(11) : 1294-1308, March 15, 1958. (106) HAYDON, G. B., DAVIDSON, J. T., LILLINGTON, G. A., WASSERMAN, K. Nitrogen dioxide-induced emphysema in rabbits. American Review of Respiratory Diseases 95 (5) : 797-805, May 1967. (107) HAYDON, G. B., FREEMAN, G., FURIOSI, N. J. Covert pathogenesis of NO, induced emphysema in the rat. Archives of Environmental Health 11(6) : 776-783, December 1965. (108) HAYNES, W. F., JR., KRSTULOVIC, V. J., BELL, A. L. L., JR. Smoking h&it and incidence of respiratory tract infections in a group of adolescent males. American Review of Respiratory Diseases 93 (5) : 730-735, May 1966. (109) HENRY, M. C., FINDLAY, J., SPANGLER, J., EHRLICH, R. Chronic toxicity of NO, in squirrel monkeys. III. Effect on resistance to bacterial and viral infection. Archives of Environmental Health 20(5) : 566-570, May 1970. (110) HEPPER, N. G., HYATT, R. E., FOWLER, W. S. Detection of chronic obstructive lung disease. An evaluation of the medical history and physical examination. Archives of Environmental Health 19 (6) : 806- 813, December 1969. (111) HERXANDEZ, J. A., ANDERSON, A. E., JR., HOLMES, W. L., FORAKER, A. G. Pulmonary parenchymal defects in dogs following prolonged cigarette smoke exposure. American Review of Respiratory Diseases 93 (1) : 78- 83, January 1966. (112) HIGGINS, I. T. T. Respiratory symptoms, bronchitis and ventilatory capacity in random sample of an agricultural population. British Medical Journal 2: 1198-1203, November 23, 1957. (113) HIGGINS, I. T. T. Tobacco smoking, respiratory symptoms, and ventila- tory capacity. Studies in random samples of the population. British Medical Journal 1: 325-329, February 7.1959. (114) HIGGINS, I. T. T., COCHRAN, J. B. Respiratory symptoms, bronchitis and disability in a random sample of an agricultural community in Dumfriesshire. Tubercle 39 : 296-301, 1958. (115) HIGGINS, I. T. T., COCHRANE, A. L. Chronic respiratory disease in a random sample of men and women in the Rhondda Fach in 1958. British Journal of Industrial Medicine 18: 93-102, 1961. (116) HIGGINS, I. T. T.. COCHRANE, A. L., GILSON, J. C., WOOD, C. H. Popula- tion studies of chronic respiratory disease. A comparison of miners, foundryworkers, and others in Staveley, Derbyshire. British Journal of Industrial Medicine 16: 255-268, 1959. (117) HIGGINS, I. T. T., GILSON, J. C., FERRIS, B. G., JR., WATERS, M. E., CAMPBELL, H., HIGGINS, M. \V. Chronic respiratory disease in an industrial town: A nine-year follow-up study. Preliminary report. American Journal of Public Health and the Nation's Health 58(9) : 1667-16'76, September 1968. (118) HIGGINS, I. T. T., HIGGINS, M. W., LOCKSHIN, M. D., CANALE, N. Chronic respiratory disease in mining communities in Marion County, West Virginia. British Journal of Industrial Medicine 25(3) : 165-1'75, July 1968. (119) HIGGINS, I. T. T., OLDHAM, P. D., COCHRANE, A. L., GILSON, J. C. Res- piratory symptoms and pulmonary disability in an industrial town. Survey of a random sample of the population. British Medical Journal 2: 904-909, October 20, 1956. 183 (120) HILDING, A. C. On cigarette smoking, bronchial carcinoma and ciiiary action. II. Experimental study on the filtering action of cow's lungs, the deposition of tar in the bronchial tree and removal by ciliary action. New England Journal of Medicine 254(25) : 1155-1160, June 21, 1956. (121) HOLLAND, W. W., ELLIOTT, A. Cigarette smoking, respiratory symptoms and anti-smoking propaganda. An experiment. Lancet 1(7532) : 41-43, January 6, 1968. (122) HOLLAND, W. W., HALIL, T., BENNETT, A. E., ELLIOTT, A. Indications for measures to be taken in childhood to prevent chronic respiratory disease. Milbank, Memorial Fund Quarterly 47 (3, part 2) : 215-227, July 1969. (123) HOLLAND, R. H., KOZLOWSKI, E. J., BOOKER, L. The effect of cigarette smoke on the respiratory system of the rabbit. A final report. Cancer 16 (5) : 612-615, May 1963. (124) HOLLAND, W. W., REID, D. D. The urban factor in chronic bronchitis. Lancet l(7383) : 445-448, February 2'7, 1965. (1%) HOLMA, B. The acute effect of cigarette smoke on the initial course of lung clearance in rabbits. Archives of Environmental Health 18(Z) : 171-173, February 1969. (126) HUHTI, E. Prevalence of Respiratory Symptoms, Chronic Bronchitis and Pulmonary Emphysema in a Finnish Rural Population. Field survey of age group 40-64 in the HarjavaIta area. Acta Tuberculosea et Pneumologica Scandinavica (Supplementum 61) : 1965. 111 pp. (127) HURST, A. Familial emphysema. American Review of Respiratory Dis- eases 80: 179-180, 1959. (128) HYATT, R. E., KISTIN, A. D., MAHAN, T. K. Respiratory disease in Southern West Virginia coal miners. American Review of Respiratory Diseases 89(3) : 387-401, March 1964. (129) IDE, G., SUNTZEFF, V., COWDRY, E. V. A comparison of the histopathology of tracheal and bronchial epithelium of smokers and nonsmokers. Cancer 12 (3) : 473-484, May-June, 1959. (130) ITO, H., AVIADO, I). M. Pulmonary emphysema and cigarette smoke. Experimental induction and use of bronchodilators in rats. Archives of Environmental Health 16(6) : 865-870, June 1968. (131) JAMES, R. H. Prior smoking as a determinant of the distribution of pulmonary ventilation. American Review of Respiratory Diseases 101(l) : 105-107, January 1970. (132) KAHN, H. A. The Dorn study of smoking and mortality among U.S. veterans: Report on 8% years of observation. In: Haenzel, W. (Edi- tar). 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. (133) ~MINSKI,E.J.,FANCHER, 0. E., CALANDRA, J. C. In ciao studies of the ciliastatic effects of tobacco smoke. Absorption of ciliastatic compo- nents by wet surfaces. Archives of Environmental Health 16 (2) : 188- 193, February 1968. (134) KENNEDY, J. R., ELLIOTT, A. M. Cigarette smoke: The effect of residue on mitochondrial structure. Science 168(3935) : 1097-1098, May 29, 1970. (135) KENSLER, C. J., BATTISTA, S. P. Chemical and physical factors affecting mammalian ciliary activity. American Review of Respiratory Diseases 93(3, Part 2) : 93-102, March 1966. 184 (136) KLEINERMAN, J. Effects of NOz in hamsters: Autoradiographic and electron microscopic aspects. In: Hanna, M. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlin- burg, Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission Symposium Series 18, April 1970. pp. 271-281. (1.37) KORDIK, P., BULBRING, E., BURN, J. H. Ciliary movement and acetyl- choline. British Journal of Pharmacology and Chemotherapy 7: 67- 79, 1952. (138) KRAHL, V. E., BULMASH, M. H. Studies on living ciliated epithelium. American Review of Respiratory Diseases 99 (5) : 711-718, May 1969. (139) KRUGER, A. P., SMITH, R. F. Effects of gaseous ions on tracheal ciliary rate. Proceedings of the Society for Experimental Biology and Medi- cine 98: 41%414,1958. (140) KRUMHOLZ, R. A., CHE~A'ALIER, R. B., Ross, J. C. Cartliopulmonary func- tion in young smokers. A comparison of pulmonary function measure- ments and some cardiopulmonary responses to exercise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medicine 60(4) : 603-610, April 1964. (141) KTUIMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. Changes in cardiopul- monary functions related to abstinence from smoking. Studies in young cigarette smokers at rest and exercise at :< and 6 weeks of ab- stinence. Annals of Internal Medicine 62 (2) : 197-207, February 1965. (142) KRUMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. A comparison of pul- monary compliance in young smokers and nonsmokers. American Review of Respiratory Diseases 92(l) : 102-107, July 1965. (143) KUEPPERS, F. Identification of the heterozygous state for the alpha,-anti- trypsin deficiency gene in man. Biochemical Genetics 3 (3) : 283-288, 1969. (1.44) KUEPPERS, F., FALLAT, R., LARSON, R. K. Obstructive lung disease and alpha,-antitrypsin deficiency gene heterozygosity. Science 165 (3896) : 899-901, August 29,1969. (145) LABELLE, C. W., BEVILACQUA, D. M., BRIEGER, H. The influence of ciga- rette smoke on lung clearance. An experimental approach. Archives of Environmental Health 12(5) : 588-596, May 1966. (146) LAMBERT, P. M., REID, D. D. Smoking, air pollution, and bronchitis in Britain. Lancet l(7652) : 853-857, April 25, 1970. (147) LARSON, R. K., BARMAN, M. L. The familial occurrence of chronic ob- structive pulmonary disease. Annals of Internal Medicine 63 (6) : 1001-1008, December 1965. (148) LARSON, R. K., BARMAN, M. L., KUEPPERS, F., FUDENBERG, H. H. Genetic and environmental determinants of chronic obstructive pulmonary disease. Annals of Internal Medicine 72(5) : 627-632, May 1970. (149) LAURENZI, G. A., GUARNERI, J. J., ENDRIGA, R. B., CAREY, J. P. Clear- ance of bacteria by the lower respiratory tract. Science 142: 1572- 1573, December 20, 1963. (150) LEESE, W. L. B. An investigation into bronchitis. Lancet 2: 762-765, October 13, 1956. (151) LEFCOE, N. M., WONNACOTT, T. H. The prevalence of chronic respiratory disease in the male physicians of London, Ontario. Canadian Medical Association Journal 102(g) : 381-385, February 28, 1970. (152) LEUCHTENBERGER, C., LEUCHTENBERGER, R., ZEBRUX. W., SHAFFER, P. A correlated histological, cytological, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. 185 II. Varying responses of major bronchi to cigarette smoke, absence of bronchogenic carcinoma after prolonged exposure, and disappearance of bronchial lesions after cessation of exposure. Cancer 13(4) : 721- 732, July-August 1960. (153) LEWIS, G. P., LYLE, H., MILLER, S. Association between elevated hepatic water-soluble protein-bound cadmium levels and chronic bronchitis and/or emphysema. Lancet 2(7634) : 1330-1333, December 20, 1969. (154) LIEBERMAN, J. Heterozygous and homozygous alpha,-antitrypsin de6- ciency in patients with pulmonary emphysema. New England Journal of Medicine 281(6) : 279-284, August 7, 1969. (155) LIEBERMAN, J., MITTMAN, C., SCHNEIDER, A. S. Screening for home- zygous and heterozygous alpha,-antitrypsin deficiency. Protein elec- trophoresis on cellulose acetate membranes. Journal of the American Medical Association 210 (11) : 2055-2060, December 15, 1969. (156) LIEBESCHUETZ, H. J. Respiratory signs and symptoms in young soldiers and their relationship to smoking. Journal of the Royal Army Medical Corps 105: 76-81, 1959. (157) LOWE, C. R. An association between smoking and respiratory tubercu- losis. British Medical Journal 2: 1081-1086, November 10, 1956. (158) LOWE, C. R. Chronic bronchitis and occupation. Joint meeting No. 1. Section of Occupational Medicine with Section of Epidemiology and Preventive Medicine. Proceedings of the Royal Society of Medicine 61(l) : 98-102, January 1968. (159) LUNDMAN, T. Smoking in Relation to Coronary Heart Disease and Lung Function in Twins. A Co-twin Study. Acta Medica Scandinavica 180 (Supplement 455) : 1966. 75 pp. (160) MCDERMOTT, M., COLLINS, M. M. Acute effects of smoking on lung air- ways resistance in normal and bronchitic subjects. Thorax 20: 562- 569, 1965. (161) MARTT, J. M. Pulmonary diffusing capacity in cigarette smokers. An- nals of Internal Medicine 56( 1) : 39-45, January 1962. (162) MASIN, F., MASIN, M. Frequencies of alveolar cells in concentrated sputum specimens related to cytologic classes. Acta Cytologica 10 (5) : 362-367, September-October 1966. (163) MEGAHED, G. E., SENNA, G. A., EISSA, M. H., SALEH, S. Z., EISSA, H. A. Smoking versus infection as the aetiology of bronchial mucous gland hypertrophy in chronic bronchitis. Thorax 22 (3) : 271-278, May 1967. (164) MENDENHALL, W. L., SHREEVE, K. E. The effect of cigarette smoke on the tracheal cilia. (Abstract) 28th Annual Meeting, April Zl-24,1937, Memphis, Tennessee. The Scientific Proceedings of the American So- ciety for Pharmacology and Experimental Therapeutics, Inc. Journal of Pharmacology and Experimental Therapeutics 60: ill-112,1937. (16.5) MILLER, D., BONDURANT, S. Effects of cigarette smoke on the surface characteristics of lung extracts. American Review of Respiratory Diseases 85 (5) : 692-696, May 1962. (166) MILLER, J. M., SPROULE, B. J. Acute effects of inhalation of cigarette smoke on mechanical properties of the lungs. American Review of Respiratory Diseases 94 (5) : 721-726, November 1966. (167) MILLS, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio State Medical Journal 46(12) : 1165-1170, December 1950. (168) MITCHELL, R. S., WEBB, N. C., FILLEY, G. F. Chronic obstructive bron- chopulmonary disease. III. Factors influencing prognosis. American Review of Respiratory Diseases 89(6) : 878-896, June 1964. (169) MITCHELL, R. S., SILVERS, G. W., DART, G. -4., PETTY, T. L., VINCENT, T. N., RYAN, S. F., FILLEY, G. F. Clinical and morphologic correla- tions in chronic airway obstruction. American Review of Respiratory Diseases 97 (1) : 54-61, January 1968. (170) MORIYAMA, I. M., DAWBER, T. R., KANNEL, W. B. Evaluation of diag- nostic information supporting medical certification of deaths from cardiovascular disease. In : Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S. Public Health Service, National Cancer Institute Mon- ograph No. 19, January 1966. pp. 405-419. (171) MORK, T. A Comparative Study of Respiratory Disease in England and Wales and Norway. Acta Medica Scandinavica 172 (Supplementum 384)) 1962. 100 pp. (172) MORTON, A. Postoperative hyposaemia. Medical Journal of Australia 2(7) : 341-342, August 16, 1969. (17.3) MORTON, H. J. V. Tobacco smoking and pulmonary complications after operation. Lancet 1: 368-370, March 18,1944. (174) MOTLEY, H. L., KUZMAN, W. J. Cigarette smoke. Its effect on pulmonary function measurements. California Medicine 88 (3) : 211-220, March 1958. (175) MYRVIK, Q. N., EVANS, I). G. Metabolic and immunologic activities of alveolar macrophages. Archives of Environmental Health 14 (1) : 92- 96, January 1967. (176) NADEL, J. A., COMROE, J. H., JR. Acute effects of inhalation of cigarette smoke on airway conductance. Journal of Applied Physiology 16: 713- 716, 1961. (177) NANDI, M., JICK, H., SLONE, I)., SHAPIRO, S., LEWIS, G. P. Cadmium con- tent of cigarettes. Lancet 2(7634) : 1329-1330, December 20, 1969. (178) OSWALD, N. C., MEDVEL, V. C. Chronic bronchitis; the effect of cigarette- smoking. Lancet 2: 843-844, October 22, 1955. (179) PALECEK, F., AVIADO, D. M. Pulmonary effects of tobacco and related sub- stances. II. Comparative effects of cigarette smoke, nicotine, and his- tamine on the anesthetized cat. Archives of Environmental Health 15 (2) : 194-203, August 1967. (180) PALECEK, F., OSKOUI, M., AVIADO, D. M. Pulmonary effects of tobacco and related substances. III. Inhibition of synthesis of histamine in various species. Archives of Environmental Health 15 (2) : 204-213, August 1967. (182) PARNELL, J. L., ANDERSON, D. O., KINNIS, C. Cigarette smoking and respiratory infections in a class of student nurses. New England Journal of Medicine 274(8) : 979-984, May 5, 1966. (182) PETERS, J. M., FERRIS, B. G., JR. Smoking, pulmonary functions and respiratory symptoms in a college-age group. American Review of Respiratory I)iseases 95(5) : 774-782, May 1967. (183) PETERS, J. M., FERRIS, B. G., JR. Smoking and morbidity in a college-age group. American Review of Respiratory Diseases 95(5) : 783-789, May 1967. (184) PETERSON, D. I., LONERGAN, L. H., HARDINGE, M. G. Smoking and pul- monary function. Archives of Environmental Health 16(2) : 215-218, February 1968. (185) PHILLIPS, A. M., PHILLIPS, R. W., THOMPSON, J. L. Chronic cough. Analysis of etiologic factors in a survey of 1,274 men. Annals of In- ternal Medicine 45 (2) : 216-231, August 1956. 187 (186) (187) (188) (189) (190) (191) (192) (193) (194) (195) (196) ( >:,;,) PIPER, D. W. Respiratory complications in the postoperative period, Scottish Medical Journal 3(5) : 193-198, May 1958. PRAW, S. A., FINLEY, T. N., SMITH, M. H., LADMAN, A. J. A comparison of alveolar macrophages and pulmonary surfactant ( ?) obtained from the lungs of human smokers and nonsmokers by endobronchial lavage. Anatomical Record 163(4) : 497-508, April 1969. RAKIETEN, N., RAKIETEN, M. L., FELDMAN, D., BOYKIN, M. J., JR. Mam- malian ciliated respiratory epithelium. Studies with particular rtfer- ence to effects of menthol, nicotine, and smoke of mentholated and nonmentholated cigarettes. A.M.A. Archives of Otolaryngology 66: 494-503,1942. RANKIN, J., GEE., J. B., CHOSY, L. W. The influence of age and smoking on pulmonary diffusing capacity in healthy subjects. Medicina Thora- calis 22(3) : 366-374, 1965. RANKIN, J. G., H&E, G. S., WILKINSON, P., O'DAY, D. M., SANTAMARIA, J. N., BABARCZY, G. Relationship between smoking and pulmonary dis- ease in alcoholism. Medical Journal of Australia l(14) : 730-733, April 5, 1969. READ, J., SELBY, T. Tobacco smoking and ventilator-y function of the lungs. British Medical Journal 2: 1104-1108, October 28, 1961. REVOTSKIE, N., KANNEL, W., GOLDSMITH, J. R., DAWER, T. R. Pul- monary function in a community sample. American Review of Respi- ratory Diseases 86 (6) : 907-911, December 1962. RIMINGTON, J. Chronic bronchitis, smoking and social class. A study among working people in the towns of Mid and East Cheshire. British Journal of Diseases of the Chest 63(4) : 193-205, 1969. ROBERTSON, D. G., WARRELL, D. A., NEWTON-Ho WES, J. S., FLETCHER, C. M. Bronchial reactivity to cigarette and cigar smoke. British Med- ical Journal 3 (5665) : 269-271, August 2,1969. ROQUE, A. L., PICKREN, J. W. Enzymatic changes in fluorescent alveolar macrophages of the lungs of cigarette smokers. Acta Cytologica 12 (6) : 420-429, November-December 1968. ROSENKRANTZ, H., ESBER, H. J., SPRAGUE, R. Lung hydroxyproline lev- els in mice exposed to cigarette smoke. Life Sciences 8( 11, Part 1) : 571-576, June 1, 1969. ROSESKUNTZ, H., SPRAGUE, R. Biochemical screen to investigate whole smoke and vapor phase effects in mice. Archives of Environmental Health 18(6) : 917-924, June 1969. %;-S. .:. c.. LEY. G. D., KRUMHOLZ, R. A., RAHBARI, H. A technique for &- ei:i.Li.~LlL:r: of gas mixing in the lung: Studies in cigarette smokers and nonsn&ers. American Review of Respiratory Diseases 95 (3) : .- - _.z : -._ :L::,p.<.':.,.Yi.ir. 22.. XT-i..\oo, 1,. M. Bronchopulmonary effects of tobacco and ~c:;~cd s-JLisacces. II. Bronchial arterial injections of nicotine and :- . . >r?.r::ine. Archives of Environmental Health 11(2) : 152-159, Au- g.; .t y :;r,s. 1S.~:+ras~s, >I., AYIADO, D. M. Bronchopulmonary effects of tobacco and ~~la.tcri substances. IV. Bronchial vascular and bronchomotor re- . spo:?st!s, their suggested defense function. Archives of Environmental IT -eJ;i;+. I1 (2) : 167-176, August 1965. :.A!GhE6, ar. , -&vrtio, D. RI. Cardiopulmonary effects of tobacco and IL . . . . . L. ~~~~~~-.~ 1 s-.bst;inces. III. Pulmonary vascular effects of cigarette smoke .IL. ;I::: i:.: !:ine. Archives of Environmental Health 12 (6) : 717-724, June 1 2"~-, (20.2) SAMANEK, M., AVIADO, D. PII., PESKIN, G. W. Bronchopu!monary effects of tobacco and related substances. III. Axon reflexes elicited frail: :hc visceral pleura. Archives of Environmental Health 11 (2) : If&166, August 1965. (203) SCARPELLI, E. M. The Surfactant System of the Lung. Philadclphin, Lea & Febiger, 1968. 269 pp. (204) SCHOETTLIN, C. E. The health effect of air pollution on cltlerly males. American Review of Respiratory Diseases 86 (6) : 878-897, I)ec~mbe~ 1962. (205) SHAH, J. R., WARAWADEKAR, M. S., DESHMUKH, P. A., PHUTUX, P. S. Institutional survey of pulmonary tuberculosis with special reference to smoking habits. Indian Journal of Medical Sciences 13 (5) : :;31- 392, May 1959. (206) SHORT, J. J., JOHNSON, H. J., LEY, H. A., JR. The effects of ~O~XCC~ smoking on health. A study of 2,031 medical records. Journal of Laboratory and Clinical Medicine 24 : 586-589, 1933. (207) SIMONSSON, B. Effect of cigarc.ttc smokin g 011 t11v for&d I,X]li I~n1(1,~,V UC'\\- rate. American Review of Rcspilztory Ijiseases 85: 53.1-%!I, 19(;?. (208) SLUIS-CREMER, G. K., SICHEL, H. S. Vcntilatory functions in males in a Wit-watersrand town. Comparison between smokers and nonsmokers. American Review of Respiratory Diseases 98(2) : 229-239, August 1968. (209) SLUIS-CREMER, G. K., WALTERS, L. G., SICHEI., H. S. Chronic bronchitis in miners and nonminers: An epidemiological survey of a community in the gold-mining area in the Transvaal. British Journal of Indus- rial Medicine 24( 1) : 1-12, January 1967. (210) SMITH, J. P., SMITH, J. C., MCCALL, A. J. Chronic l)oisoning from cad- mium fume. Journal of Pathology and Bacteriology 80 : 287-296, 1960. (211) SPURGASH, A., EHRLICH, R., PETZOLD, R. Elt'ect of cigarette smoke on resistance to respiratory infection. Archives of Environmental Health 16(3) : 385-391, March 1968. (212) STANESCU, D. C., TECULESCU, I). B., PA~URAR~, R., GAYRILESCV, h'. Chronic effect of smoking upon pulmonary distribution of ventilation in healthy males. Respiration 25 (6) : 497-504, 1968. (213) STERLING, G. M. Mechanism of bronchoconstriction caused by- cigarcttc smoking. British Medical Joul,nal 3: 275-277, July 29, 19G7. (2.24) STRIEDER, D. J., MURPHY, R., KAZEMI, H. Mechanism of postural hv- poxemia in asymptomatic smokers. .kmcrican Review of Respiratory Diseases 99(5) : 760-766, May 1969. (215) TALAMO, R. C., ALLEN, J. I)., K~~IAN, M. G., A~JSTEX, Ii. F. Hereditary alpha,-antitrypsin deficiency. Scn k;ngland Jou~nnl of ~Ie~licir:~~ 2;s (7) : 345-351, February 15, 1968. (216) TARKOFF, M. P., KUEPPERS, F., MILLER. W. F. Pulmonary em@?-st-ma and alpha,-antitrypsin deficiency. Amk li,,:cn Journal of 11~ 11ic:n: -1; (2) : 220-228, August 1968. (217) THURLBECK, W. M., HENDERSON, J. A., FR&EH, I?. G., B.~Tu.. ! :. V Chronic obstructive lung disease. 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 pr