The Health Consequences Of Smoking CANCER a report of the Surgeon Genera1 1982 U.S. DEPARTMENT OF HEALTti AND HUMAN SERVICES Pubkc Health Serwce Offace on Smoking and Health RockwIle. Maryland 20857 The !ionorable Thomas P. O'PJelll, Jr. Speaker of the tiouse of Representatives Washlnqton, D.C. 20?15 Dear Mr. Speaker: I hereby submit to you the 1982 Report on the Health Consequences of Smoking, prepared I" accordance with the Public Health Clqarette Smoklna Act of 1969 and its predecessor, the Federal Clqarerte Labellnq and Advertlsinq Act. This 1s the first report in the series to focus on a slnqle disease entity--cancer. Scientists lnslde and outslde of Govrrnmen~ have evaluated the evidence presenteo 1" this report. It )olns this Deparrment's previous reports on smoklnq and health in maklnq publicly avallabie information about one of the mayor health risks of smoklnq. These reports reflect the important responslblllty of tiovernment to Inform its citizens in order that they can make a consldered decision about whether to smoke. Rlchard S. Schwetker secretary The Honorable George Bush President of the Sena+.e Wash:nq+on, D. C. 20510 Dear Mr. President: I hereby submit to you the 1982 Report on +.he Health Consequences of Smoking, prepared in accordance with the Public Health Cigarette Smoking AC? of 1969 and its prede- cessor, the Federal Cigarette Labeling and Advertising Act. This is the first report in the series to focus on a single disease entity--cancer. Scientists inside and outslde of Government have evaluated the evidence presented in this report. It loins this Department's previous reports on smoking and health in :nakinq publicly avallable information about one of the major health risks of smoking. These reports reflect the important responsibility of Government to inform its citizens in order that they can make a considered decision about whether t-0 smoke. Sincerely, &4igLL%ia 'chard S. Schweiker FOREWORD The 1982 report on The Health C'onseyuencrs of`Sn?ofziqq presents ;I comprehensive evaluation of the relationship between cigarette smoking and cancer. - Since 1937, cancer has been the second most important cause of death in the United States and will account for an estimated 430,000 deaths this year. Surveys have shown that Americans fear dying of cancer more than any other disease. We have yet to observe, however, a decline in the cancer mortality rate as is currently occurring for other chronic diseases, such as the 30 percent decline in the cardiovascular disease mortality rate and the 50 percent decline in the cerebrovascular disease mortality rate observed over the last three decades. The mortality rate for cancer has changed little over two decades, and that change has been a small, but measurable, increase. This increase in mortality has occurred in the f'cjre of remarkable improvements in survival rates for some cancer sites through earlier or better diagnosis and treatment. Unfortunate- ly. however, these advances have failed to counter the remarkable increases in mortality from smoking-related cancers, many of which have a poor prognosis for long-term survival or cures. The Public Health Significance of this Report Cigarette smoking is the major single cause of cancer mortality in the United States. Tobacco's contribution to all c:lncer deaths is estimated to be 30 percent. This means we can expect that 129,000 Americans will die of cancer this year because of the higher overall cancer death rates that exist among smokers as c'etnpared with nonsmokers. Cigarette smokers have total cancer (lc:lth rates two times greater than do nonsmokers. Heavy smokers hirve a three to four times greater excess risk of cancer mortality. If ILlrge numbers of our population did not smoke, the cancer death rate in this countrv could be reduced, and instead of the small but continued increasedin the total cancer death rate. there could be a substantial decline. There is no single action an individual can take to reduce the risk of cancer more ef'fectively than quitting smoking, PLrrticularlv cigarettes. Cigarette smoking is a major cause of cancers of the lung, larynx, oral cavity, and esophagus, and is a contributory factor for the development of cancers of the bladder, pancreas, and kidney. The term contributory factor by no means excludes the possibility of a causal role for smoking in cancer of these sites. Lung Cancer Lung cancer. f'irst correlated with smoking over 50 years ago, is the single largest contributor to the total cancer death rate. Lung cancer alone accounts for fully 25 percent of all cancer deaths in this country; it is estimated that 85 percent of lung cancer cases are due to cigarette smoking. Overall, smokers are 10 times more likely to die f'rom lung cancer than are nonsmokers. Heavy smokers are 15 to 25 times more at risk than nonsmokers. The total number of lung cancer deaths in the United States increased from 18,313 in 1950 to 90,828 in 1977. The lung cancer death rate for women is currently rising faster than the lung cancer death rate for men, a fact that reflects the later adoption of smoking by large numbers of women. The lung cancer death rate for women will soon surpass that of breast cancer (perhaps as eariy as next. year), currently the leading cause of cancer mortality in women. This remarkable increase in lung cancer mortality for women mimics that observed among men some 30 years ago. However, since the early 196Os, ,large numbers of men have given up cigarette smoking or have not begun to smoke, whereas only recently has the prevalence of cigarette smoking by women started to decline. These differences in patterns of smoking have a decided eff'ect on lung cancer mortality trends in this country, with a decline in lung cancer mortality already apparent for younger men. These differences will clearly affect future lung cancer mortality experience by sex in the United States. The American Cancer Society estimates there will be 111,000 lung cancer-related deaths in 1982, of'which 80.000 will be in men and 31,000 in women. The 5-year survival rate for cancer of the lung is less than 10 percent. This rate has not changed in 20 years. Early diagnosis and treatment do not appreciably alter this dismal survival rate-the best preventive measure a smoker can take to reduce the risk of lung cancer is to quit smoking, and for a nonsmoker, to not take up the habit. Larynx and Oral Cavity Cancer Laryngeal and oral cancers will strike an estimated 40,000 individuals and will be responsible for approximately 13,000 deaths this ~-c':rr in the United States. These sites have 5-year survival rates 01` 60 and 40 percent. respectively. An estimated 50 to 70 percent of vi oral and laryngeal cancer deaths are associated with smoking. These cancers are strongly associated with the use of cigars and pipes in addition to cigarettes. All carry approximately the same excess relative risk of at least fivefold. The use of alcohol in conjunction with smoking acts synergistically to greatly increase the risk of these cancers. Esophageal Cancer This year, 8,300 deaths due to cancer of the esophagus are expected. Cancer of the esophagus has one of the poorest survival rates of all cancers-only about 4 percent of esophageal cancer patients live 5 years after diagnosis and most die within 6 months. Cigarette smoking is estimated to be a factor in over half of esophageal cancer deaths. Smokers have mortality ratios approxi- mately 4 to 5 times higher than nonsmokers. The use of alcohol has a synergistic interaction with smoking that greatly increases this risk. Bladder and Kidney Cancers Over 50,000 Americans are expected to develop bladder and kidney cancer this year. Bladder and kidney cancers will be responsible for a total of 20,000 deaths this year. The 5-year survival rates are approximately 50 to 60 percent. Various investigators have estimated that between 30 and 40 percent of bladder cancers are smoking related, with slightly higher estimates for males than for females. Pancreatic Cancer Approximately 24,000 people will develop cancer of the pancreas this year, and there will be an estimated 22,000 deaths. Like cancers of the lung and esophagus, cancer of the pancreas is often fatal, with a 5-year survival of less than 3 percent. While few estimates are available as to the proportion of these deaths attributable to smoking, it would appear to be about 30 percent. Pancreatic cancer appears to be increasing at a more rapid rate than most other cancer sites. Stomach and Uterine Cervix Cancer A link between smoking and stomach cancer and cancer of the uterine cervix is noted. However, no judgment can be reached on the significance of any association, because of insufficient data. vii Involuntary Smoking and Lung Cancer In recent months, the popular press has generated interest in the controversy of whether passive or involuntary smoking causes lung cancer in nonsmokers. Three epidemiological studies examined this issue in the past year. Evidence from two of the studies demon- strated a statistically significant correlation between involuntary smoking and lung cancer risk in nonsmoking wives of husbands who smoked. A third noted a positive association, but it was not statistically significant. While the nature of this association is unresolved, it does raise the concern that involuntary smoking may pose a carcinogenic risk to the nonsmoker. Any health risk resulting from involuntary smoke exposure is a serious public health concern because of the large numbers of nonsmokers in the population who are potentially exposed. Therefore, for the purpose of preventive medicine, prudence dictates that nonsmokers avoid exposure to second-hand tobacco smoke to the extent possible. Lower Tar Cigarettes This report also notes that smokers who use filtered or `lower tar cigarettes have statistically lower death rates from lung cancer than do cigarette smokers who use nonfiltered or higher tar brands. This reduced risk was also noted for laryngeal cancer. However, cancer death rates for smokers of lower tar cigarettes were still significantly higher than those noted for nonsmokers. Cessation of Smoking Since cigarette smoking is a cause of many cancers, encouraging data about cessation are presented in this Report. Quitting smoking reduces one's cancer risk substantially, compared with the continu- ing smoker, even after many years of cigarette smoking. The more years one is off cigarettes, the greater the reduction in excess cancer risk. Fifteen years after quitting cigarette smoking, the former smoker's lung cancer risk, for example, is reduced close to that observed in nonsmokers. This same reduction in cancer risk is observed for the other cancer sites associated with smoking. Part V of this Report contains a review of cessation research among adults and adolescents. In summary, many promising tech- niques are available to smokers who have been unable to quit on their own. It is nonetheless interesting to note that the vast majority of former smokers, probably close to 95 percent, quit on their own, without the aid of formal smoking cessation programs. As a physician, I encourage all health care providers, particularly other physicians, to counsel cigarette smokers to quit and to give them as much support as possible. As this Report notes, a Sew . . . Vlll minutes' discussion with patients about their smoking behavior can have a decisive impact on whether they quit smoking or continue the habit. Trends in Smoking Prevalence I am encouraged by the recent decline in cigarette smoking rates in this country. Today, only one-third of adults smoke, a decline from 42 percent in 1965. Teenage smoking, particularly among adolescent girls, also appears to be declining. While these figures are encouraging, there are still 53 million cigarette smokers in this country-about the same number of smokers as 20 years ago. Furthermore, while per capita use of cigarettes has declined to its lowest level since 1957, there has been a substantial increase in the consumption of chewing tobacco and snuff, particularly among the young. What impact the use of these products will have on future cancer mortality is unclear; knowledge of the type and extent of the health effects of these tobacco products is limited. Current evidence indicates, however, that their use is not without risk. Studies conducted in this country and others have demonstrated an in- creased risk for oral cancer and other noncancerous oral diseases. Educational Efforts This Department is committed to continuing the programs of education and information for all our citizenry regarding the adverse health consequences of smoking. There is no more important aspect of this than the health education of our young, to convince them not to start smoking, or to quit the habit before it becomes difficult to break. This problem cannot be left solely to government to solve. I call upon the rest of the health care community, the voluntary health agencies, and our schools to increase their efforts to control one of this country's most pressing health problems. Reducing smoking will reduce the devastating toll that cancer, as well as other smoking- related diseases, exacts on this Nation's health. Edward N. Brandt, Jr., M.D. Assistant Secretary for Health ix PREFACE In July 1957, Dr. Leroy E. Burney issued the Public Health Service's first statement on cigarette smoking: it identified smoking as a cause of lung cancer. Each succeeding Surgeon General has had occasion to issue additional and stronger warnings. These have linked smoking with lung cancer, with heart disease, with chronic lung disease, with other cancers, and with increases in overall mortality. With this 1982 statement on cigarette smoking and cancer, I am joining my distinguished predecessors, Drs. Burney, Luther Terry, William Stewart, Jesse Steinfeld, and Julius Richmond. Cigarette smoking, as this Report again makes clear, is the chief, single, avoidable cause of death in our society and the most important public health issue of our time. Over the years, 14 reports on the health consequences of smoking have been prepared by the Public Health Service under the Federal Cigarette Labelling and Advertising Act and its successor, the Public Health Cigarette Smoking Act of 1969. These reports have contrib- uted greatly to public understanding of the hazards that cigarette smoking poses to the health of this Nation. In contrast with previous Public Health Service reports on smoking and health, the present document examines the relation- ship between smoking and a single category of disease, cancer. The relationships between smoking and lung cancer, as well as cancer of other sites, are carefully examined. This should not distract atten- tion from the fact that smoking is related to many diseases, including cardiovascular disease, which exacts a greater toll than does cancer in disease and death. Cancer, however, was the first disease to be linked with tobacco use, and its association with smoking has been the subject of the most intense research: Much of the research within the past few years has not previously been examined in the detail presented here. As in previous years, this Report has been prepared with the aid and critical review of experts from within and outside the Govern- ment. On behalf of the Public Health Service, I express here my respect for their expertise and gratitude for their help. C. Everett Koop, M.D. Surgeon General xi ACKNOWLEDGEMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Joanne Luoto, M.D., M.P.H., Acting Director. Managing Editor was Donald R. Shopland, Technical Information Officer, Office on Smoking and Health. Consulting scientific editors were David M. Burns, M.D., Assistant Professor of Medicine, Pulmonary Division, University of California at San Diego, San Diego, California; John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medi- cal School, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Prevention Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. The editors wish to acknowledge the assistance of the National Cancer Institute, particularly the Clinical Epidemiology Branch, for making available the computer-generated three dimensional graphs of cancer mortality, and the National Center for Health Statistics, for making available the cancer mortality data extracted from the publication by A. Joan Klebba, Mortality From Diseases Associated with Smoking, United States, 1960 to 1977. The following individuals authored sections within the Parts of the Report as indicated: Part I. Introduction and Conclusions Office on Smoking and Health Part II. Biomedical Evidence for Determining Causality Richard A. Bordow, M.D., Associate Director of Respiratory Medi- cine, Brookside Hospital, San Pablo, California; and Assistant Clinical Professor of Medicine, University of California at San Francisco, San Francisco, California Abraham M. Lilienfeld, M.D., M.P.H., D.&Z., University Distin- guished Service Professor, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Part III. Mechanisms of Carcinogenesis Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York x111 Ilse Hoffmann, Research Coordinator, Naylor Dana Institute foi Disease Prevention, American Health Foundation, Valhalla, New York Stanley E. Shackney, M.D., Head, Section of Cellular Kinetics. Clinical Pharmacology Branch, Division of Cancer Treatment. National Cancer Institute, Bethesda, Maryland Elizabeth K. Weisburger, Ph.D., Assistant Director for Chemical Carcinogenesis, Division of Cancer Control and Prevention, Na- tional Cancer Institute, Bethesda, Maryland Part IV. Involuntary Smoking and Lung Cancer Aristide Y. Apostolides, D.V.M., M.P.H., Associate Professor 01 Epidemiology, Department of Preventive Medicine and Biometry, Uniformed Services University of the Health Sciences, Depart- ment of Defense, Bethesda, Maryland Michael D. Lebowitz, Ph.D., Professor of Internal Medicine, College of Medicine, the University of Arizona Health Sciences Center, Tucson, Arizona Part V. Cessation of Smoking E. B. Fisher, Jr., Ph.D., Associate Professor of Psychology, Associate Director of the Washington University Diabetes Research and Training Center, Washington University in St. Louis, St. Louis, Missouri Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Preven- tion Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Associate Research Psychologist, Department of Psychiatry and Biobehavioral Sciences, School of Medicine, Neuropsychiatric Institute, University of California, Los Angeles, California; and Research Psychologist, Veterans Administration Medical Center, Brentwood, Los Angeles, California C. Anderson Johnson, Ph.D., Associate Professor and Director, Health Behavior Research Institute, University of Southern California, Los Angeles, California The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Elvin E. Adams, M.D., M.P.H., P.A., Huguley Medical Arts Clinic, Fort Worth, Texas Sam P. Battista, Ph.D., Senior Staff Pharmacologist, Arthur D. Little, Inc., Cambridge, Massachusetts Fred G. Bock, Ph.D., Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Buffalo, New York Vincent T. DeVita, M.D., Director, National Cancer Institute, Bethesda, Maryland Hans L. Falk, Ph.D., Associate Director, Health Hazard Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina William Foege, M.D., Director, Centers for Disease Control, Atlanta, Georgia Robert A. Goyer, M.D., Deputy Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Dorothy E. Green, Ph.D., Consulting Research Psychologist, Arling- ton, Virginia Michael R,. Guerin, Ph.D., Section Head, Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Sharon M. Hall, Ph.D., Associate Professor, Langley Porter Psychiat- ric Institute, University of California at San Francisco, San Francisco, California Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Arthur Hull Hayes, Jr., M.D., Commissioner, Food and Drug Administration, Rockville, Maryland Maureen M. Henderson, M.D., Professor of Medicine and Epidemiol- ogy, School of Public Health and Community Medicine, University of Washington, Seattle, Washington Harry A. Lando, Ph.D., Professor, Department of Psychology, Iowa State University, Ames, Iowa Alex Langmuir, M.D., Chilmark, Massachusetts Edward Lichtenstein, Ph.D., Department of Psychology, University of Oregon and Oregon Research Institute, Eugene, Oregon Abraham M. Lilienfeld, M.D., M.P.H., DSc., University Distin- guished Service Professor, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Anthony B. Miller, M.D., Director, Epidemiology Unit, National Cancer Institute of Canada, University of Toronto, Ontario, Canada Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of California at San Diego, San Diego, California Richard Peto, M.A., M.Sc., I.C.R.S., Reader in Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, England Richard D. Remington, Ph.D., Dean, School of Public Health, University of Michigan, Ann Arbor, Michigan xv 377-310 c - 82 - 2 Dorothy P. Rice, Director, National Center for Health Statistics, Hyattsville, Maryland David Schottenfeld, M.D., Chief of Epidemiology and Preventive Medicine, Director of Cancer Control, Memorial Sloan-Kettering Cancer Center, New York, New York; and Professor of Public Health, Cornell University Medical College, New York, New York Marvin A. Schneiderman, Ph.D., Bethesda, Maryland Irving J. Selikoff, M.D., Professor of Community Medicine and `Medicine, and Director, Environmental Sciences Laboratory, Mt. Sinai School of Medicine, City University of New York, New York, New York Saul Shiffman, Ph.D., Assistant Professor, Department of Psycholo- gy, College of Social and Behavioral Sciences, University of South Florida, Tampa, Florida Michael B. Shimkin, M.D., Professor Emeritus, Department of Community and Family Medicine, School of Medicine, University of California at San Diego, La Jolla, California Jesse L. Steinfeld, M.D., Dean, School of Medicine, Medical College of Virginia, Richmond, Virginia The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of the Report. Erica W. Adams, Copy Editor, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Richard J. Bast, Medical Translation Consultant, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Jacqueline 0. Blandford, Secretary, Office on Smoking and Health, Rockville, Maryland Marsha Clay, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Melissa R. Colbert, Applications Manager, Publishing Services Division, Informatics Incorporated, Riverdale, Maryland Karen M. Cox, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Information and Technology Transfer Department, Informatics Incorporated, Rockville, Mary- land Denise M. Cross, Data Entry Manager, Publishing Services Division, Informatics Incorporated, Riverdale, Maryland Martha E. Davis, Technical Illustrator, Informatics Incorporated, Rockville, Maryland xvi Stephanie D. DeVoe, Data Entry Operator, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Andrea L. Dykstra, Senior Technical Editor, Biospherics Incorporat- ed, Rockville, Maryland Susan H. Fenton, Table Coder, Publishing Services Division, Infor- matics Incorporated, Riverdale, Maryland Judy Fernandes, Writer-Editor, Office on Smoking and Health, Rockville, Maryland Sandy ,Gibson, Copy Editor and Indexer, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Wendy S. Goldin, Secretary, Information and Technology Transfer Department, Informatics Incorporated, Rockville, Maryland Rebecca C. Harmon, Manager, Graphics Unit, Clearinghouse Ser- vices Division, Informatics Incorporated, Rockville, Maryland Reginald V. Hawkins, M.P.H., Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Douglas Hayes, Applications Manager, Information Processing Ser- vices Division, Informatics Incorporated, Riverdale, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Leslie J. Headlee, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, .Rockville, Maryland Lisa A. Katz, Graphic Artist, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Assis- tant, Office on Smoking and Health, Rockville, Maryland John J. Kourilo, Senior Information Analyst, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Julie Kurz, Graphic Artist, Clearinghouse Services Division, Infor- matics Incorporated, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Marilynn H. Meinke, Copy Editor, Clearinghouse Projects Depart- ment, Informatics Incorporated, Rockville, Maryland Jacquelene Mudrock, Technical Illustrator, Informatics Incorporat- ed, Rockville, Maryland Judith L. Mullaney, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Douglas F. Pepin, Statistical Analyst, Clearinghouse Projects De- partment, Informatics Incorporated, Rockville, Maryland xvii Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland' Carol A. Sherrer, Technical Consultant, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Scott Smith, Editor, Biospherics, Incorporated, Rockville, Maryland Linda Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Sol Su, Sc.D., Statistician, Office on Smoking and Health, Rockville, Maryland Selwyn Waingrow, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Melissa L. Yorks, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland xv111 TABLE OF CONTENTS Foreword ...... .I ......................................................... v Preface .................................................................. xi Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 1. Introduction and Conclusions .................................. 1 2. Biomedical Evidence for Determining Causality ....... 13 3. Mechanisms of Carcinogenesis . . . . . . . . . _. . . . . . . . . . . . 171 4. Involuntary Smoking and Lung Cancer ................. 237 5. Cessation of Smoking.. ....................................... 255 Index . . . . . . . . . . . . . . _. _. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ _. . . . . . . . . . 305 xix PART I. INTRODUCTION AND CONCLUSIONS Introduction Development and Organization of the 1982 Report The content of this Report is the work of numerous scientists within the Department of Health and Human Services, as well as scientific experts outside the organization. Individual manuscripts were reviewed by experts, both outside and within the Public Health Service, and the entire Report was reviewed by a broad-based panel of 12 distinguished scientists. Many of these scientists are, or have been, directly involved in research on the health effects of smoking. The 1982 Report consists of a Preface by the Surgeon General, a Foreword by the Assistant Secretary for Health of the Department of Health and Human Services, and five Parts, as follows: o Part I. Introduction and Conclusions 0 Part II. Biomedical Evidence for Determining Causality 0 Part III. Mechanisms of Carcinogenesis o Part IV. Involuntary Smoking and Lung Cancer o Part V. Cessation of Smoking Historical Perspective Tobacco use was associated with the possible development of cancer as early as 1761. According to one medical historian, Dr. John Hill (1716?-1775) should be credited with the first report document- ing an association between tobacco use and cancer for his work Cautions Against the Immoderate Use of Snuff: Hill reported on two case histories and observed that "snuff is able to produce...swellings and excrescences" in the nose, and he believed these to be cancerous. Others credit Soemmerring in 1795 for noting a relationship between cancer of the lip and tobacco use. It was not until the 1920s and 1930s that investigators began to examine scientifically the possible association of smoking and cancer. In 1928, Lombard and Doering, in the United States, found an association between heavy smoking and cancer in general. Muller and Schairer (Germany) in 1939 and 1944 respectively, and Porter (USA) in 1945, and others, noted higher percentages of smokers among lung cancer patients than among controls. The first major developments in the modern history of investigation of the effects of smoking on health occurred in 1950 with the publication of four retrospective studies on smoking habits of lung cancer patients and controls in the United States by Schrek et al., Mills and Porter, Levin et al., and Wynder and Graham. Each of these noted a consistent, statistically significant association between smoking and cancer of the lung. Other investigators proceeded to further examine the relationship by initiating prospective studies in which large numbers of healthy persons were followed over time and their subsequent mortality noted. 3 The first major prospective study encompassing total and cause- specific mortality was initiated in October 1951 by Doll and Hill in the United Kingdom among 40,000 British physicians. Hammond and Horn followed 188,000 males beginning in January 1952 in the United States. These and subsequent prospective studies conducted in the United States, Sweden, Canada, and Japan, found not only that smokers have substantially elevated cancer mortality rates, but also that smokers experience significantly elevated overall death rates. Cancer has been the second ranking cause of death in the United States since 1937. Provisional vital statistics data for 1980 indicate cancer accounted for almost 21 percent of all deaths in the United States. This compares to 17 percent of all deaths in 1970 and 14.5 percent of all deaths in 1950. Various investigators have suggested that 22 to 38 percent of these deaths can be attributed to smoking, and therefore, are potentially "avoidable" if smoking did not exist as a human behavior. Since 1950, the age-adjusted overall cancer death rate has changed little, whereas the lung cancer death rate has increased dramatically for both males and females. The male age-adjusted lung cancer rate increased 192 percent during the period 1950-1952 thru 1976-1978. Female lung cancer death rates during this same period increased even more: 263 percent. Since the 1950s lung cancer has been the leading cause of cancer death among males in the United States, `and if present trends continue, will become the leading cause of cancer death in females during this decade; the age-adjusted female lung cancer death rate is projected to possibly surpass the death rate for breast cancer next year. Today, deaths from cancer of the lung represent fully one quarter of &l deaths due to cancer in the United States. In 1962, the year when the Surgeon General's Advisory Committee on Smoking and Health began deliberating the evidence presented in its landmark report, slightly more than 41,000 persons died of lung cancer annually, compared to 18,300 lung cancer deaths in 1950. In 1982, the American Cancer Society estimates 111,000 Americans will die of lung cancer, nearly a three-fold increase in the number of deaths in a 20-year time span. The Advisory Committee's Report of 1964 judged the causal significance of the association of cigarette smoking and disease by rigid criteria, no one of which alone was sufficient for a causal judgment. The epidemiologic criteria included: a. The consistency of the association b. The strength of the association c. The specificity of the association d. The temporal relationship of the association, and e. The coherence of the association 4 Corroboration was also sought from other sources, such as clinical autopsy and experimental evidence. Significant additional scientific evidence linking smoking to cancer, as well as to other tobacco-related diseases, has accumulated since the issuance of that Advisory Committee's Report in 1964. Much of this has been collected, reviewed, and published in annual reports by the L)epartment of Health and Human Services. The purpose of this Report is to review in depth the many sources of scientific evidence relating cigarette smoking to each cancer by anatomic site, and to evaluate this evidence by the same criteria first established by the Advisory Committee in its 1964 Report, including experimental carcinogenesis and human epidemiologic studies. Conclusions of the 1982 Report Overall Cancer Mortality 1. Cigarette smokers have overall mortality rates substantially greater than those of nonsmokers. Overall cancer death rates of male smokers are approximately double those of nonsmok- ers; overall cancer death rates of female smokers are approxi- mately 30 percent higher than nonsmokers, and are increasing. 2. Overall cancer mortality rates among smokers are dose-related as measured by the number of cigarettes smoked per day. Heavy smokers (over one pack per day) have more than three times the overall cancer death rate of nonsmokers. 3. With increasing duration of smoking cessation, overall cancer death rates decline, approaching the death rate of nonsmokers. SiteSpecific Cancer Mortality Lung Cancer 1. Cigarette smoking is the major cause of lung cancer in the United States. 2. Lung cancer mortality increases with increasing dosage of smoke exposure (as measured by the number of cigarettes smoked daily, the duration of smoking, and inhalation pat- terns) and is inversely related to age of initiation. Smokers who consume two or more packs of cigarettes daily have lung cancer mortality rates 15 to 25 times greater than nonsmokers. 3. Cigar and pipe smoking are also causal factors for lung cancer. However, the majority of lung cancer mortality in the United States is due to cigarette smoking. 4. Cessation of smoking reduces the risk of lung cancer mortality compared to that of the continuing smoker. Former smokers who have quit 15 or more years have lung cancer mortality rates only slightly above those for nonsmokers (about two times 5 greater). The residual risk of developing lung cancer is directly proportional to overall life-time exposure to cigarette smoke. 5. Filtered lower tar cigarette smokers have a lower lung cancer risk compared to nonfiltered, higher tar cigarette smokers. However, the risk for these smokers is still substantially elevated above the risk of nonsmokers. 6. Since the early 195Os, lung cancer has been the leading cause of cancer death among males in the United States. Among females, the lung cancer death rate is accelerating and will likely surpass that of breast cancer in the 1980s. 7. The economic impact of lung cancer to the nation is consider- able. It is estimated that in 1975, lung cancer cost $3.8 billion in lost earnings, $379.5 million in short-term hospital costs, and $78 million in physician fees. 8. Lung cancer is largely a preventable disease. It is estimated that 85 percent of lung cancer mortality could have been avoided if individuals never took up smoking. Furthermore, substantial reductions in the number of deaths from lung cancer could be achieved if a major portion of the smoking population (particularly young persons) could be persuaded not to smoke. Laryngeal Cancer 9. Cigarette smoking is the major cause of laryngeal cancer in the United States. Cigar and pipe smokers experience a risk for laryngeal cancer similar to that of a cigarette smoker. 10. The risk of developing laryngeal cancer increases with in- creased exposure as measured by the number of cigarettes smoked daily as well as other dose measurements. Heavy smokers have laryngeal cancer mortality risks 20 to 30 times greater than nonsmokers. 11. Cessation of smoking reduces the risk of laryngeal cancer mortality compared to that of the continuing smoker. The longer a former smoker is off cigarettes the lower the risk. 12. Smokers who use filtered lower tar cigarettes have lower laryngeal cancer risks than those who use unfiltered higher tar cigarettes. 13. The use of alcohol in combination with cigarette smoking appears to act synergistically to greatly increase the risk for cancer of the larynx. Oral Cancer 14. Cigarette smoking is a major cause of cancers of the oral cavity in the United States. Individuals who smoke pipes or cigars experience a risk for oral cancer similar to that of the cigarette smoker. 15. Mortality ratios for oral cancer increase with the number of cigarettes smoked daily and diminish with cessation of smok- ing. 16. Cigarette smoking and alcohol use act synergistically to increase the risk of oral cavity cancers. 17. Long term use of snuff appears to be a factor in the develop- ment of cancers of the oral cavity, particularly cancers of the cheek and gum. Esophageal Cancer 18. Cigarette smoking is a major cause of esophageal cancer in the United States. Cigar and pipe smokers experience a risk of esophageal cancer similar to that of cigarette smokers. 19. The risk of esophageal cancer increases with increased smoke exposure, as measured by the number of cigarettes smoked daily, and is diminished by discontinuing the habit. 20. The use of alcohol in combination with smoking acts synergisti- cally to greatly increase the risk for esophageal cancer mortality. Bladder Cancer 21. Cigarette smoking is a contributory factor in the development of bladder cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. Kidney Cancer 22. Cigarette smoking is a contributory factor in the development of kidney cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. Pancreatic Cancer 23. Cigarette smoking is a contributory factor in the development of pancreatic cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. 7 Stomach Cancer 24. In epidemiological studies, an association between cigarette smoking and stomach cancer has been noted. The association is small in comparison with that noted for smoking and some other cancers. Uterine Cervix Cancer 25. There are conflicting results in studies published to date on the existence of a relationship between smoking and cervical cancer; further research is necessary to define whether an association exists and, if so, whether that association is direct or indirect. Mechanisms of Carcinogenesis This overview presents evidence and observations on tobacco carcinogenesis primarily developed since 1978. 1. The biological activity of whole cigarette smoke and its tar and tar fractions can now be measured by improved inhalation assays in addition to tests for tumor-initiating, tumor-promot- ing, and cocarcinogenic activities on mouse skin. 2. Studies on smoke inhalation with the hamster now appear suitable for estimating the relative tumorigenic potential of whole smoke from commercial and experimental cigarettes. The identification of the smoke constituents that contribute to tumor induction in the respiratory tract is best achieved by fractionations of tar and by assays on mouse epidermis that determine the type and potency of the carcinogens. In combina- tion with biochemical tests, mouse skin assays should also aid in evaluating the possible role of nicotine as a cocarcinogen. 3. The identification, formation, and metabolic activation of organ-specific carcinogens have been studied which help ex- plain the increased risk to cigarette smokers of cancer of the esophagus, pancreas, kidney, and urinary bladder. In addition to certain aromatic amines, tobacco-specific N-nitrosamines appear to be an important group of organ specific carcinogens in tobacco and tobacco smoke. Little is known of the in uiuo formation of organ-specific carcinogens from nicotine and other Nicotiana alkaloids. The modification of their enzymatic activation to ultimate carcinogenic forms needs to be explored by chemopreventive approaches. 4. Transplacental carcinogenesis as it may relate to effects of cigarette smoking should be investigated more fully. It has been known for some time that inhalation of tobacco smoke activates enzymes in the placenta and fetus and the conse- quences of such changes need to be studied. 5. The continuing modification of U.S. cigarettes has led to changes in the quantitative and perhaps also the qualitative composition of the smoke. This ongoing development requires continued monitoring of the toxic and carcinogenic potential of the smoke of new cigarettes. 6. The changes in cigarette composition lead generally to reduced emission of major toxic mainstream smoke constituents as measured in analytical laboratories under machine-smoking conditions. Many smokers intensify puff volume and degree of inhalation when smoking a lower-yield cigarette. Therefore, it should be determined what effect different techniques of air dilution and filtration have in counteracting the increased smoke exposure that results from intensified smoking. 7. Snuff tobaccos are increasingly used as an alternative to cigarette smoking. More information is needed regarding the carcinogenic activity of snuff tobaccos and the presence of tumorigenic agents in these products. Involuntary Smoking and Lung Cancer 1. Mainstream and sidestream cigarette smoke contain similar chemical constituents. (Mainstream smoke is smoke that the smoker inhales directly during puffing. Sidestream smoke is smoke emitted from a smoldering cigarette into the ambient air.) These constituents include known carcinogens, some of which are present in higher concentrations in sidestream smoke than they are in mainstream smoke. Passive or involun- tary smoking differs from voluntary cigarette smoking with respect to the concentration of smoke components inhaled, the duration and frequency of smoke exposure, and the pattern of inhalation. 2. In two epidemiologic studies, an increased risk of lung cancer in nonsmoking wives of smoking husbands was found. In these studies, the nonsmoking wife's risk of lung cancer increased in relation to the extent. of the husband's smoking. In a third study, the risk of lung cancer among nonsmoking wives of smoking husbands was also increased, but the difference was not statistically significant. 3. Although the currently available evidence is not sufficient to conclude that passive or involuntary smoking causes lung cancer in nonsmokers, the evidence does raise concern about a possible serious public health problem. Cessation of Smoking 1. Ninety-five percent of those who have quit smoking have done so without the aid of an organized smoking cessation program, and most current smokers indicate a preference for quitting 9 with a procedure they may use on their own, and a disinclina- tion to enter an organized, comprehensive program. 2. Research evaluations of self-help aids have reported success rates up to 50 percent cessation at extended followups (6 to 15 months). Most estimates, however, fall below this, around 5 to 20 percent. 3. Brief and simple advice to quit smoking delivered by a physician has substantial potential for producing cessation in a cost-effective manner. 4. Televised smoking cessation clinics result in variable rates of abstinence at followup. The use of television and other mass media are a cost-effective intervention because of their large potential audiences. 5. Retrospective studies revealed greater use of self-reward and active problem-solving strategies among those who quit or reduced smoking on their own than among those who were unsuccessful in quitting or reducing smoking. 6. Until recently, the long-term outcome of intensive smoking cessation clinics has remained at 25 to 30 percent abstinence. New emphasis on techniques to improve the maintenance phase of cessation promises to improve these rates, with several reports of greater than 50 percent abstinence at followups of 6 months or longer. 7. To improve maintenance of nonsmoking after intensive treat- ment programs have ended, reinforcement should be built into the, natural environment. Smoking cessation programs in the workplace may offer an opportunity for this. 8. Comprehensive self-management packages that have been shown to boost maintenance rates include a wide variety of techniques. 9. Treatment outcome may be improved by focusing on the antecedents of relapse. These include feelings of frustration, anxiety, anger, and depression as well as social models and smoking-related cues and settings. Behavioral and cognitive skills for dealing with such antecedents should be developed. 10. Social support interventions are promising. Reliable findings link social cues, smoking friends, and smoking spouses to relapse, whereas the presence of group support, nonsmoking spouses, and professional contact decreases recidivism. 11. Spontaneous smoking cessation among regular users (approxi- mately once a week or more often) is estimated to be on the order of 25 percent during adolescence. 12. Probability of quitting was greater for those adolescent smok- ers first interviewed in 1974 who had at least started to attend college by 1979 than for those smokers who did not attend college (42.0 percent vs. 24.6 percent). 10 13. Probability of quitting decreases linearly with duration of the smoking practice, changing from 64.5 percent in the first year of smoking to 14.3 percent after 7 years. 14. Quitting "cold turkey" appears to be a more effective cessation strategy than cutting down without trying to stop entirely. 15. Success at quitting increased with the number of efforts made: about 73.4 percent of adolescents who kept trying eventually succeeded. 16. Smoking prevention programs are desirable alternatives to cessation programs aimed at youth. Successful programs have been based on social psychological theory and research, and are school based. Results have shown a 50 percent or more reduction in smoking onset. 17. The most successful programs were those emphasizing the social and immediate consequences of smoking rather than long-term health consequences. These programs have placed special emphasis on teaching skills in recognizing and resisting social pressures to smoke. 377-330 0 - 82 - 3 11 PART II. BIOMEDICAL EVIDENCE FOR DETERMINING CAUSALITY INTRODUCTION Provisional mortality data for 1980 indicate that cancer was responsible for approximately 412,000 deaths in the United States (199). It is estimated that in 1982 there will be 430,000 deaths due to cancer, 233,000 among men and 197,090 among women (2). Various investigators (70, 78, 106) have suggested that 22 to 38 percent of these deaths can be attributed to smoking, and therefore are potentially "avoidable" if smoking did not exist as a human behavior. A relationship between smoking and cancer was first suggested for neoplasms of the lung in scientific reports from the 1920s and early 1930s (203, 266). Muller (192) in 1935 and Schairer and Schoeniger (237) in 1943 reported that most lung cancer patients were smokers. Subsequently, 8 major prospective studies and more than 50 retrospective studies have examined this relationship. In 1964, the Advisory Committee to the Surgeon General of the U.S. Public Health Service (272) published a comprehensive review of the then available data. They concluded that "cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. Data for women, though less extensive, point in the same direction. The risk of developing lung cancer increases with the duration of smoking and the number of cigarettes smoked per day and is diminished by discontinuing smoking." Over the last 17 years, thousands of scientific investigations have confirmed the Committee's conclusion and provided additional evidence concerning the relationship of cigarette smoking to lung cancers. Smoking has been implicated as a cause of cancer of the larynx, oral cavity, and esophagus, and associated with cancer of the urinary bladder, kidney, and pancreas. This is the first report devoted exclusively to a comprehensive assessment of the associa- tions reported between smoking and various cancers. In the follow- ing sections of this Part of the Report, the nature 0%' these associations is appraised in the light of currently available knowl- edge. 15 EPIDEMIOLOGIC CRITERIA FOR CAUSALITY The concept of causality has been debated by students of philoso- phy since the days of Aristotle. David Hume (1711-1776) and John Stuart Mill (1806-1873) are credited with major contributions to contemporary insight and theory of causality. More recently, mem- bers of the Advisory Committee to the Surgeon General (272), Hill (1121, MacMahon and Pugh (1681, Susser (2601, Evans (801, and Lilienfeld (158) have examined the concept of causality in the health sciences. The ability to totally control the experimental environ- ment, to randomize exposure, and to measure discrete outcomes allows a clear experimental demonstration of causality. However, the application of these rigid laboratory techniques for establishing causality to the study of cancer in humans is clearly impossible. The idea of exposing human subjects to potentially cancer-producing agents in order to establish causality is mcrally and ethically unacceptable. Therefore, other criteria have been developed to establish causality with a very high degree of scientific probability (80, 112, 158, 260, 272, 280). In practice, epidemiologic methods have been employed to study cancer in man. These studies result in observational data that may establish a statistically significant association between variables or attributes. This association may be artifactual, indirect, or direct. The possibility of an artifactual (or spurious) result can be eliminat- ed if the design and conduct of the studies are adequate, and if studies conducted in different geographical areas and among differ- ent population groups produce the same or similar statistical associations. Once an artifactual association has been ruled out, it is then necessary to determine whether the association is an indirect or direct (causal) one. Randomization is an attempt to eliminate the effect of all variables other than the one under study. However, a personal choice behavior such as smoking is impossible to randomize (i.e., to dictate smoking behavior). Therefore, in order to establish that an association between smoking and a disease is not due to a confound- ing variable, an entire body of data must exist to satisfy specific criteria, none of which by itself is an all-sufficient basis for judgment. Thus, when a scientific judgment is made that all plausible confounding variables have been considered, an association may be considered to be direct. In this Report, the same definition of the term "cause" that was used in the Report of the Advisory Committee to the Surgeon General in 1964 has been adopted. "The word cause is the one in general usage in connection with matters considered in this study, and it is capable of conveying the notion of a significant, effectual relationship between an agent and an associated disorder or disease in the host" (272). The term "cause" should not be construed to 16 exclude other agents as causes; rather, it is used in full recognition that biological processes are complex and multiple in etiologies. In this Report, as in the earlier one, the attribution of "causality" to a disease-associated variable (e.g., smoking) includes full recogni- tion that "the causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. To judge or evaluate the causal significance of the association between an attribute or agent and the disease, or the effect upon health, a number of criteria must be utilized, no one of which is an all-sufficient basis for judgment. These criteria include: a. The consistency of the association b. The strength of the association c. The specificity of the association d. The temporal relationship of the association, and e. The coherence of the association" These criteria are utilized herein for evaluation of the reported associations between cigarette smoking and cancers of various sites in humans. Consistency of the Association This criterion implies that diverse methods of approach in the study of an association will provide similar conclusions. Consistency requires that the association be repeatedly observed by multiple investigators, in different locations and situations, at different times, using different methods of study. Such replication assures that the association is not likely to be an artifact due to bias in study methodology or subject selection, and that it is not indirect due to confounding variables such as diet, occupation, or genetics. Strength of the Association The most direct measure of the strength of the association is the ratio of cancer rates for smokers to the rates for nonsmokers. The relative risk ratio yields evidence on the size of the effect of a factor on disease occurrence and which, even in the presence of another associated factor without causal effect but coincident with the causal agent, will not be obscured by the presence of the non-causal agent. A relative risk ratio measures the strength of an association and provides an evaluation of the importance of that factor in the production of a disease. If all cases of the disease under study, but none of the controls, have a history of exposure to the suspected etiologic agent or characteristic (assuming that an adequate number of cases and controls exist in the population under study), a one-to-one correspon- dence between the disease and the factor exists, and a causal hypothesis would be credible. Most diseases are influenced by many 17 factors, however, and therefore a one-to-one correspondence would not be expected. The strength of an association is measured by relative risk ratios, incidence ratios, or mortality ratios. The greater the relative risk ratio or the mortality ratio, the stronger the relationship between the etiologic agent and the disease. Prospective studies have shown that the death rate from cancer of the lung among cigarette smokers is approximately 10 times the rate in nonsmokers, and the rate in heavy cigarette smokers is 20 to 30 times greater than in nonsmokers. To account for such high relative risk in terms of an indirect association would require that an unknown causal factor be present at least 10 times more frequently in the smokers and 20 to 30 times more frequently among heavy smokers than among nonsmokers. Such a confounding factor should be easily detectable, and if it cannot be detected or reasonably inferred, the finding of such a strong association makes a conclusion concerning causality more probable. Important to the strength, as well as to the coherence of the association, is the presence of a dose- response phenomenon in which a positive gradient between degree of exposure to the agent and incidence or mortality rates of the disease can be demonstrated. Specificity of the Association This concept cannot be entirely dissociated from the concept inherent in the strength of the association. It implies the precision with which one component of an associated pair can be utilized to predict the occurrence of the other, i.e., how frequently the presence of one variable will predict, in the same individual, the presence of another. Specificity implies t,hat a causal agent invariably leads to a single specific disease, an event rarely observed. A one-to-one relationship between the presence of an etiologic agent and disease would reflect a causal relationship. However, several points must be kept in mind in interpreting specificity in biological systems. First, an agent may be associated with multiple diseases. Second, many responses considered to be disease states have multiple causes. Congenital malformations, for example, result from prenatal radiation as well as from some drugs administered during pregnancy and other factors. Variations in the relative risk of disease may be produced by variations in the number of causal agents as well as by the specificity of a given causal agent. Third, a single pure substance in the environment may produce a number of different diseases. The experimental production of a variety of diseases in mice by exposure to X-rays is a good example of this. Fourth, a single factor may be the vehicle for several different substances. Tobacco smoke is a complex mixture of several thousand individual constituents, and therefore it would not be surprising to find that these diverse substances are able 18 to produce more than one adverse biologic response. It is also not surprising that these constituents may have possible additive, synergistic, or competitive actions with each other and with other agents in the environment. And fifth, there is'no reason to assume that the relationships between one factor and different diseases have similar explanations. The association between smoking and lung cancer, for example, is considered direct and causal, whereas that between cigarette smoking and cirrhosis of the liver is thought to be indirect, reflecting the association of cigarette smoking and heavy alcohol use by some segments of the population. In summary, despite the fact that the demonstration of specificity in an association makes a causal hypothesis more acceptable, lack of specificity does not negate such an hypothesis, since many biologic and epidemiologic aspects of the association must be considered. Temporal Relationship of the Association In chronic diseases, insidious onset and the lack of knowledge of precise induction periods automatically present problems on which came first-the suspected agent or the disease. In any evaluation of the significance of an association, exposure to an agent presumed to be causal must precede, temporally, the onset of a disease which it is purported to produce. The criterion of temporal relationship requires that exposure to the suspect etiologic factor precede the disease. Temporality is more difficult to establish for diseases with long latency periods, such as cancer. Prospective studies minimize this difficulty, although even prospective studies do not exclude the possibility that the disease was present in an undetected form prior to exposure to the agent. Histologic evidence demonstrating premalignant changes among individuals exposed to the agent, but not among unexposed controls, provides evidence that temporality is present. Experimental studies may also demonstrate a temporal association. Coherence of the Association The final criterion for the appraisal of causal significance of an association is its coherence with known facts in the natural history and biology of the disease. Coherence requires that descriptive epidemiologic results on disease occurrence correlate with measures of exposure to the suspected agent. Perhaps the most important consideration here is the observation of a dose-response relationship between agent and disease, that is, the progressively increasing occurrence of disease in increasingly heavily exposed groups. In some cases, multiple mea- sures of dosage are available. The natural history of disease would include observations on the progression of disease with continuing 19 exposure differing from its progression in those whose exposure is discontinued. In order to establish the coherence of a specific association, other possible explanations for the association must be systematically considered and excluded or taken into account. Coherence is clearly established when the actual mechanism of disease production is defined. Coherence exists, nonetheless, although of a lesser magni- tude, when there is enough evidence to support a plausible mecha- nism, but not a detailed understanding of each step in the chain of events by which a given etiologic agent produces disease. Causality for Specific Forms of Cancer The causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. In the following section, the relationship between smoking and several cancers is reappraised. Epidemiologic, pathologic, and experi- mental data form the basis for review. When a significant associa- tion between cigarette smoking and a specific cancer is noted, the nature of the association was assessed by applying the judgment criteria noted above. If all epidemiologic criteria were judged to be satisfied and pathological and experimental data are supportive, the term "causal" is applied to the association. The designation "major cause" is used when the relative risk for the cancer in cigarette smokers is high. The term "contributory factor" is used when the body of evidence is less compelling, the relative risk is lower, or the ancillary evidence (pathologic and experimental data) is not suffi- cient for a judgment of causality. The term "contributory factor" by no means excludes the possibility of a causal role for smoking in cancers of those sites. The term "association" is used when a relationship between smoking and a cancer site exists, but the data are inadequate for an assessment of the character of that relation- ship. 20 SMOKING-RELATED CANCERS BY SITE Lung Cancer Introduction Since the early 1950s lung cancer has been the leading cause of cancer death among males in the United States; among females, the lung cancer death rate is accelerating faster than all other cancer death rates and, if present trends continue, will likely surpass that of breast cancer by the mid-1980s (2) (Figure 1). Between 1950 and 1977 in the United State~,~ the total number of lung cancer deaths increased from 18,313 in 1950 to 90,828 in 1977 (the figure for 1977 includes ICD (International Classification of Diseases) Nos. 162-163.0). The American Cancer Society estimates there will be 129,000 new lung cancer cases diagnosed in 1982 and 111,000 deaths. Of this number, 80,000 will be men and 31,000 women. The age-adjusted lung cancer mortality rate for the total population nearly tripled, rising from 11.1 to 32.7. (All age-adjusted death rates, unless stated otherwise, were derived by applying the age-specific rates to the standard population distributed by age as enumerated in 1940.) Overall lung cancer mortality rates increased over this period at a decelerating pace. Thus, in the 1950-1957 interval, the average annual increase in the age-adjusted death rate was 5.2 percent; over the next 10 years, the average annual increase was 4.0 percent; and in the final lo-year interval, 1968-1977, the rate of increase was 3.1 percent. These sex-aggregated figures hide differences in the lung cancer mortality trends of males and females (Figures 2,3, and 4). In the 28 year period from 1950 to 1977, the age-adjusted lung cancer rate increased almost 200 percent for men' and over 250 percent for women. The most striking aspect of this trend is the acceleration in lung cancer mortality among females. The age-adjusted death rate of white females increased by an average of 1.0 percent per year between 1950 and 1957,5.5 percent per year between 1958 and 1967, and 6.7 percent per year between 1968 and 1977. The corresponding increases for all other females were 3.0,5.1, and 6.6 percent per year. (The term "nonwhite" represents all races other than white and is used in most graphics throughout this Report for the sake of brevity.) In contrast to this trend in females, the rate of increase slowed down in males. After climbing an average of 6.1 percent a year from 1950 to 1957, the rate among white males rose 4.0 percent annually from I958 to 1967, and 2.1 percent a year from 1968 to 1977. The rate of increase among all other males fell from 8.7 to 6.2 to 3.6 percent per year over these intervals. Even with this deceleration in the rising ' Unless otherwise stated, all cancer mortahty data cited in thrs Report were extracted from the volume "Mortality From Diseases Assocmted With Smoking: Umti States, 196677" 1200). For a detaled dlscussmn oi these data as well as trends for other diseases related to smoking the reader is referred to that volume. 21 FEMALE 90 60 MALE` 7-r FIGURE I.-Male and female cancer death rates* by site, United States, 1930-1978 * Age-adjusted to the U.S. population as enumerated in 1970. SOURCE American Cancer Society (21 22 male lung cancer rate, an examination of the age-specific rates in Figures 3 and 4 reveals that the lung cancer rates are still markedly greater in males than in females. In the white population, these trends resulted in a decrease in the sex ratio of lung cancer mortality rates between males and females. In 1950, the age-adjusted lung cancer death rate was 4.7 times higher in white males than in white females. By 1977, the mortality sex ratio had dropped to 3.6. In the white population 35 to 44 years of age, the mortality sex ratio decreased from 3.74 to 1.72 over this period. In contrast, the mortality sex ratio (male/female) of the other than white group increased from 4.11 to 4.54 from 1950 to 1977. Particularly in the early part of the study period, mortality among males other than white climbed sharply. In 1950, the ratio of the,age- adjusted death rate of all other males to that of white males was 0.77; by 1977, age-adjusted death rates of all other males had surpassed those of white males. The mortality color ratio (other- than-white/white) had risen to 1.25. Among females, the mortality color ratio shifted from 0.88 in 1950 to 1.00 in 1957, after which it remained stable. In females 35 to 44 years of age, however, rates were consistently higher in the other than white group than in the white group. When age-specific lung cancer death rates are plotted by calendar year and age, a three-dimensional graph is produced (Figures 5 and 6) which can be examined from 1950-1977, or from the reverse (back side) perspective. The broad, ascending peaks reflect the dramatic rise in lung cancer rates for men and women over this time interval. The lower age-specific lung cancer death rates seen in the oldest age group (Figures 5 and 6) reflect changing cohort patterns of exposure. Thus, what appears to be a decline in mortality rates with old age is actually an artifact arising from the combining of cohorts with different cigarette smoke exposure and mortality experiences. As will be discussed later, the age-specific mortality rate for each specific birth cohort actually continues to increase steadily with increasing age in both men and women (Figures 13 and 15). Lung cancer has a considerable economic impact. Rice and Hodgson (218) estimate that the health cost of lung cancer in 1975 was $3.8 billion in lost earnings, $379.5 million in short-term hospital charges, and $78 million in physician fees. Less than 10 percent of patients with lung cancer will survive 5 or more years. This bleak survival rate has not changed significantly over the last 15 years. Hence, the prevention of lung cancer is of paramount importance. According to a recent study.for the Congres- sional Office of Technology Assessment, approximately 85 percent of United States lung cancer deaths in 1978 were attributable to smoking, and thus were "avoidable" if individuals had not smoked cigarettes (70). 23 RRiES/lOO.OOO FIGURE L-Age-adjusted* mortality rates for cancer of the bronchus, trachea, and lung, by race and sex, United States, 1950-1977 ' This graph is ageadJusted to the U.S. population as enumerated in 1970; all rates cited withm the text of the Report, however. are adjur.kd to the popula~mn as enumerated in 1940 SOURCE. National Cancer Instkute ,198). 24 K F: I2 " : N N RATES/lOO.OOO FIGURE 3.-Age-specific mortality rates for whites in the United States for cancer of the bronchus, trachea, and lung SOURCE Nat,onalCancerInstltute,19XI. 25 0 P z : " 0 N N RRTES/lOO.OOO FIGURE 4.-Age-specific mortality rates for nonwhites in the United States for cancer of the bronchus, trachea, and lung SOURCE: Nst~onal Cancer Institute (1981. 26 I I I I 1 IIIIIIIIIII llll~llllllllllll~ ~llIIIIlIIIIIIlI Id IGO ?IGURE B.-Age-specific mortality rates by &year age groups for cancer of the bronchus, trachea, and lung for white males, United States, 1950- 1977 SOURCE: Natronal Cancer Institute ,198) The term "lung cancer" refers to a number of specific malignant iseases involving the lungs. Several systems of classifying lung ancer have been proposed (Table 1). Four cell types constitute the majority of lung cancers: epidermoid r squamous, adenocarcinoma, small cell (oat cell), and large cell. `here are differences in the frequency distribution of the different 27 377-310 0 - 82 - 4 FIGURE 6.-Age-specific mortality rates by B-year age groups for cancer of the bronchus, trachea, and lung for white females, United States, 1950-1977 SOURCE Natmnal (`ancer Instltute~ 198IHI types of lung cancer in males and females and in smokers and nonsmokers. Epidermoid carcinoma was the most common histologi- cal type of lung cancer in the male smoker, while adenocarcinoma was most common in the female smoker and in nonsmokers of both sexes in a series recently published from the Mayo Clinic (Table 2) (225). Other centers have reported similar data, although the 28 FABLE l.-Comparison of the World Health Organization (WHO), Veterans Administration Lung Cancer Chemotherapy Study Group (VALG), and Working Party for Therapy of Lung Cancer (WP-L) Lung Cancer Classifications WHO -_ I. Epidermoid carcinoma VALG WP-L 11' Small cell carcincma 1. Fusiform 2. Polygonal 1. Squamous cell carcinoma 10. Epidermoid carcinoma a. With abundant keratin 11. Well differentiated b. With intercellular bridges 12. Moderately differentiated c Without keratin or 13. Poorly differentiated bridges 2. Sma:! cell carcinoma 20. Small cell carcinoma a With oatcell structure 21. Lymphocytelike h. With polygonal cell 22. Intermediate cell structure 3. Lymphocytelike 4. Others III. Adenocarcinoma 1. Bronchogenic a. Acinar h. Papillary 2. Bronchoalveolar IV. Large cell carcinoma 1. Solid tuaor with mucin 2. Solid tumor without mucin 3. Giant cell 4. Clear cell 3. Adenwarcinoma 30. Adenocarcinoma a. Acinar 31 Well differentiated b. Papillary 32. hloderately differentiated c. Poorly differentiated 33. Poorly differentiated 34. Bronchiolopapillary 4. Iarge cell undifferentiated 40. Large cell carcinoma 41. With stratification 42. Giant cell 43. With mu& formation 44. Clear cell SOURCE: Matthews and Gordon (176). proportions by histological type vary with the pathological criteria used, the patient population, the geographic location, and other factors. Earlier epidemiologic studies suggested that cigarette smok- ers were more likely to develop squamous cell, large cell, and small cell lung carcinoma than other types (67, 148). This view has been supported by some investigators (54, 284) and disputed by others (6, 18, 19, 137, 293. 329). More recent investigations indicate that all four major histological types of lung cancer-including adenocarci- noma, which appears to be increasing in recent years-are related to cigarette smoking in both males and females (8, 284, 293). Establishment of the Association Between Smoking and Lung Cancer It is not ethical or feasible to perform a controlled experiment in humans to establish a causal relationship between tobacco smoking and lung cancer. Practically, epidemiological methods are employed to test a causal hypothesis. These methods, as discussed previously, when coupled with pathological and experimental data, provide the framework for a judgment of causality. 29 TABLE Z.-Histologic types of pulmonary cancers in smokers and nonsmokers Type TOtal Smokers Smokers Epidermoid 992 892 7 80 13 Small cell 640 533 4 100 3 Adenocarcinoma 760 492 39 128 101 Large cell 466 389 16 46 15 Bronchi&alveolar 68 35 4 13 16 TOtal 2,926 2,341 70 367 148 SOURCE: Rosenow 1225) Numerous retrospective studies have examined smoking patterns among established cases of lung cancer and a variety of matched controls. These studies have been summarized and reviewed in previous reports from the Department of Health and Human Services (270,272-281). Eight prospective studies have measured lung cancer mortality rates among smokers and nonsmokers followed over various time intervals. In October 1951, Doll and Hill (62, 63) initiated the first major prospective study of the relationship between smoking habits and mortality in a cohort of more than 40,000 male and female physicians. By 1965, seven other major prospective studies in four countries had been initiated. These studies cumulatively represent more than 17 million person-years of observation and over 330,000 deaths. The study designs are summarized below and in Table 3. The number of years of followup reported for the various major prospective studies ranges from a low of 4 years in the American Cancer Society Nine-State Study to 22 years for females in the British Physicians Study. Published reports for the varying followup periods differ substantially for each study with respect to the amount of information provided. Data from the Japanese study have been published presenting 5, 8, 10, and 13 years' results. For each followup period, site-specific cancer mortality is fragmented. Data for specific cancer sites are available only for males from the 13-year followup study; dosage analyses for other cancer sites for either males or females are intermittent among the many published reports cited. In all cases, the most current data from each of the prospective investigations are cited. In some instances, mortality rates (or ratios) for all smokers for a specific site may be from one study period while dosage information (usually expressed as the number of cigarettes smoked per day) may be from another (followup) period. The reader is referred to the references cited at the end of each study description for a complete bibliography. 30 The British Physicians Study In.1951, the British Medical Association forwarded to all British doctor% a questionnaire about their smoking habits. A total of 34,400 men and 6,207 women responded. With few exceptions, all physi- cians who replied in 1951 were followed to their deaths or for a minimum of 20 years (males) or 22 years (females). Further inquiries about changes in tobacco use and some additional demographic characteristics of the men were made in 1957,1966, and 1972 and of the women in 1961 and 1973. By 1973 more than 11,000 deaths from all causes had occurred in this population (62-66, 68, 69, 71). The American Cancer Society 25State Study In late 1959 and early 1960, the American Cancer Society enrolled 1,078,894 men and women in a prospective st.udy (97-102, 155). Although this was not a representative sample of the United States population, all segments of the population were included except groups that the planners believed could not be traced easily. An initial questionnaire was administered that contained information on age, sex, race, education, place of residence, family history, past diseases, present physical complaints, occupational exposures, and various habits. Information on smoking included type of tobacco used, number of cigarettes smoked per day, inhalation, age started smoking, and the brand of cigarettes used. Nearly 93 percent of the survivors were successfully followed for a la-year period. Early reports of this study examined lung cancer mortality in relationship to several parameters of smoke exposure, including duration of habit and age at onset, among others. Two recent reports have examined the effects of general air pollution (101), the type of cigarette smoked (155), and lung cancer mortality. Cancer mortality data for 483,000 white females and 358,006 white males for the period 1967 to 1971 were also recently reported (106). The U.S. Veterans Study The U.S. Veterans study (74, 131, 222-224) followed the mortality experience of 290,000 U.S. veterans who held government, life insurance policies in December 1953. Almost all policyholders were white males. The data for specific causes of death during a 16year period were recently reported by Rogot (224) and are similar to earlier data published after only S'/, years of observation of this population (131). Over 107,000 deaths have occurred in this popula- tion. The Japanese Study of 29 Health Districts In late 1965, a total of 265,118 men and women in 29 districts in Japan were enrolled in a prospective study (115-120). This represent- 31 ed from 91 to 99 percent of the population aged 40 and older in these districts. This study provided the unique opportunity to examine the relationship of cigarette smoking to death rates in a population with genetic, dietary, and cultural differences from previously examined Western populations. By the end of the 13th year of followup, almost 40,000 deaths had occurred, including 10,300 cancer deaths, and there were over 3,000,OOO person-years of observation. For females, the main body of published data is based on 5 to 8 years of followup. The Canadian Veterans Study Beginning in 1955, the Canadian Department of National Health and Welfare enrolled 78,000 men and 14,000 women in a study of smoking-related mortality (26, 27). Information was obtained on age, detailed smoking history, residence, and occupation. During the first 6 years of followup, 9,491 males and 1,794 females died. No more recent followup has been reported. The American Cancer Society Nine-State Study In the American Cancer Society Nine-State Study (104, 105), 187,783 white males were followed for an average of 44 months. This study began in early 1952. There were 11,870 deaths in the age 50 to 70 population. The last major report of this study was published in 1958. The California Men in Various Occupations Study This study (76, 290) examined the mortality experience of 68,153 men, 35 to 64 years of age, over a period of 482,650 person-years of observation. A total of 4,706 deaths occurred. These men were in nine occupational groups. The last published report from this study was in 1970. The Swedish Study A national probability sample (42) of 55,000 Swedish men and women was surveyed in 1963 by mailed questionnaires, to which 89 percent of the sample responded. Information was collected on smoking status at the time of the initial query and for specific intervals during the previous 9 years according to type and amount of smoking and degree of inhalation. The questionnaire identified age, sex, location (urban, nonurban), income, and occupation of subjects. A lo-year followup on smoking-related mortality was published in 1975. 32 TABLE 3.-Outlin9 of eight major prospective studies Doll Dorn Best Weir cederlof Authors Hill Hammond Kahn Himyama Joeie Hammond Dunn fiberg Pet0 Ronot Walker Horn Linden Hrubec Pike Breelow lmich Males end Total population California Probability British fern&e U.S. of Canadian White malee sample of Subjects in 29 health males in doctors in the 25 veterans districts in various pensioners nine states Swedish States Japan urupetiona population Population size w@o WW@J 2%m -2%~ 92.~ 187.ou) woo %ooo Females 6,~ 562,671 1.78 13.06 17.00 > 3.70 Comments Swedish Study Nonsmoker None Light DeeP 1.00 1.00 Female data 3.70 - based on only 7.80 7.20 9 total lung 9.20 .l.SO cancer deaths Temporal Relationship of the Association The criterion of temporality requires that cigarette smoking antedate the onset of cancer. Suppdrt for this criterion is provided by all the major prospective studies in which an enormous number of initially disease-free subjects were followed over varying time intervals. 39 LUNG CANCER I. MALES 80 70 60 xl 40 30 20 10 N: CASES CONTROLS NON F NF F NF F NF F NF F NF SMOKER l-10 11-20 21-30 3140 41+ NO. OF CtGARETTES SMOKED PER DAY xl 25 126 iz FIGURE 7.-Relative risk of lung cancer for males, by number of cigarettes smoked per day and long-term use of filter (F) or nonfilter (NF) cigarettes SOURCE: W'ynder (3271 Indirect support for the temporality of the association is provided by other studies (57, 70). One study (57) examined the relationship between per capita tobacco consumption in 1930 and male lung cancer death rates in 1950 in I.1 different countries (Figure 9). This study encompassed the era prior to the advent of filter cigarettes. Assuming that the majority of tobacco consumption in 1930 occurred among males and that there was a 20-year latency period for the development of lung cancer, there was a strong positive correlation between tobacco consumption in 1930 and lung cancer death rates in 1950. 40 LUNG CANCER I. FEMALES CASES N: CONTROLS NON F NF SMOKER l-10 F NF F NF F NF 11-20 21-30 31+ NO. OF CIGARETTES SMOKED PER DAY FIGURE 8.-Relative risk of lung cancer for females, by number of cigarettes smoked per day and long-term use of filter (F) and nonfilter (NF) cigarettes SOURCE: Wynder (327). A later study (70) examined the relationship between manufac- tured cigarette consumption per adult in 1950 and lung cancer death rates in males and females who were in the 35- to 44-year-old age group in the mid-1970s (who had entered adult life in 1950). There Was a consistent correlation between cigarette consumption and lung cancer death rates in different countries (Figure IO), a finding which WaS "better than...expected in view of the possible international differences in cigarette composition, puff frequency, style of inhala- tion, butt length, additional use of nonmanufactured cigarettes (and other forms of tobacco), and national consumption of cigarettes in intervening years between 1950 and 1975." 41 TABLE 9.-Age-adjusted lung cancer mortality ratios for males and females, by tar and nicotine in cigarettes smoked M&S Females - -. High T/N 1.00 1.00 \ Medium T/S 0.95 0.79 Low T/N 0.81 0.60 the *The mortality rstm for the category with highest risk was made 1.00 90 that the relative reductions in fia nJ use of lower T/N cigarettes could be visualiud. SOURCE: Hammond et al. c 1031 Additional evidence for the temporality of this association b advanced by a number of histological studies showing that smoke& develop histologic changes interpreted by most pathologists a premalignant lesions in bronchial epithelium in much greater proportions than nonsmokers, and that these changes progra toward cancer in continuing smokers but reverse in ex-smokers (9 14, 15) (Table 14). Coherence of the Association The final criterion is the coherence of the association betwwc smoking and lung cancer with known facts in the biology and natural history of lung cancer. Coherence of the association has been noted with the following facts: Dose-Response Relationship Between Smoking and Lung Cancer Mortality The finding of a dose-response relationship between cigarette smoking and lung cancer provides great coherence with the known facts of the disease. Regardless of the measure of tobacco consump tion employed (i.e., number of cigarettes smoked, inhalation practice, duration of smoking, age when smoking began, or type of cigarettes smoked), there was a gradierut of disease consistent with a true dose response relationship in ever:y study. Sex Differences in Lung Cancer Mortality Correlating With Corresponding Differences in Smoking Habits Males have had higher lung cancer death rates than females. This observation has been interpreted by some as contradictory to the causal role of smoking in lung cancer (8.2, 167). However, a careful examination of smoking patterns and age-specific mortality data ha 42 GREAT BkTAIN # I I I I I CIGARETTE CONSUMPTION FIGURE 9.-Crude male death rate for lung cancer in 1950 and per capita consumption of cigarettes in 1930 in various countries SOURCE. DOII 1.57, been interpreted by most observers as support for the causality of smoking in lung cancer. Historically, males began to smoke in large numbers in the World War I period, and much of the increased cigarette use noted during this period reflected switching from other forms of tobacco (e.g., smokeless tobaccos, pipes, and cigars) to cigarettes. Females began to smoke in larger numbers about 20 to 25 Years later, in the World War II era (270); at that time, a smaller Proportion of females smoked compared to males, and those who did, generally smoked fewer cigarettes per day, inhaled less, started later in life, and were more likely to smoke lower tar and nicotine and filtered cigarettes. These differences in smoking habits of males and 43 377-310 0 - 82 - 5 a Ratesbasedcmow100~~ 0 Rateabased0n25-1OOdeah 0 U.S. non-smokers 19%197p SMOKED 0` 1 t 1 1 500 1000 lWC! 2ooo 2500 3aoo MANUFACTUREIY ClGARElTES PER AWLT IN 1950 FIGURE lo.-International correlation between manufactured cigarette consumption per adult in 1959 while one particular generation was entering adult life (in 19501, and lung cancer rates in that generation as it enters middle age (in the mid-i97Os) NOTE Comparison has been restricted to developed countries (i.e.. excluding Africa, all of Asia except Japan. and all except North Amencsl. with populations > 1 million, Lo impmve the accuracy of the &sewed death certification rates aa indicators of the underlying riskn of lung cancer among people aged 3&44. `Lung cancer death certification rates per million. adults aged 3544 are from WHO 003,304l These rates are the means of the male and female rates for all yews (1973.1974. or 1975) reported in WHO (303). except for Greece (which was not reported in WHO (3031 and thus was taken from WHO (Xl0 and Norway for which the rates in WHO 130.X and WHO 1304I were based on only 11 and 14 cases, respectively; for statistical stability, these welp averaged. "Manufactured cigarettes per adult are from Lee (Jw for the year 1950 Iexcept for Italy. where consumption data are available in 5-year groups onlyl; to avoid tl'le temporary postwar shortages. data for 1951-55 have been used. This excludes handrolled cigarettes, which in most countries accounted for only a small fraction of all cigarette tobacco in 1950. `U.S. nonsmoker rates were estimated by fitting straight lines (on a double logarithmic eeale) to the relationship between lung cancer mortality and age reported for male and for female lifelong nonsmokers by Gartinkel(86) and averaging the plpdicted values at age 40. (Although the average of the male and female rati actually observed at these ages is sinular to this estimated value. thew observed rates are each based on fewer than five c~dc8 tGarfinkell(86l and so might have been inaccurate.l SOURCE: Doll and Peto( 70). females correlate well with the observed sex differences in lung cancer mortality rates. In fact, the rise in female lung cancer mortality rates observed in the late 1950s and early 1960s appears to be reproducing the phenomena noted among males 20 to 30 years earlier. If one subtracts 25 years from the female cancer death rate, as noted previously in Figure 1, the rates for women are only slightly below the rates for men. Thus, close scrutiny of these trends reveals 44 no substantial difference in the risk of developing lung cancer between men and women. Lung Cancer Mortality and Cessation of Smoking Since cigarette smoking is significantly associated with lung cancer, it is logical to expect that cessation of smoking would lead to a decrease in mortality rates from lung cancer among quitters compared to persons who continue to smoke cigarettes. In fact, all of the major studies which examined cessation showed this decrease in lung cancer risk. Data from four of the major prospective studies are presented in Table 10 for illustration. After 15 to 20 years, the ex- smoker's risk of dying from lung cancer gradually decreases to a point where it more closely approximates the risk of the nonsmoker (68, 224), whereas for the continuing cigarette smoker, the lung cancer risk is more than 10 times that of the nonsmoker. The magnitude of the residual risk that ex-smokers experience is largely determined by the cumulative exposure to tobacco prior to smoking cessation (i.e., total amount the individual smoked, age when smoking began, and degree of inhalation), and varies with number of years since quitting smoking, as well as with the reasons for quitting smoking (e.g., quitting due to symptoms of disease). Differences in Lung Cancer Mortality by Site of Residence (Urban Versus Rural) A number of studies have examined the relationship of smoking to lung cancer mortality by site of residence (urban or rural) and air quality of a community. Eight of the earlier studies were reviewed in the 1971 Report of the Surgeon General (276). More recent publica- tions include "Epidemiological Review of Lung Cancer in Man" (111) and the report of a task group, "Air Pollution and Cancer" (41). There have been studies in England and Wales (59), in 20 countries combined (40, 291), as well as in the United States (101, 146, 164, 258). The majority of these studies has found that lung cancer mortality is more common in urban than rural areas. This urban to rural gradient is primarily, but not exclusively, found among smokers. Since cigarette consumption is generally greater in urban areas than in rural areas, it is difficult to define conclusively what proportion, if any, of the excess lung cancer mortality in city dwellers can be accounted for by urban living independent of smoking. One study (164) examined the risk of several cancers by religion and place of residence in 20,379 cases in the State of Utah. Members of the Church of Jesus Christ of Latter-Day Saints (Mormons) composed approximately 70 percent of the state's population in 1970. The use of tobacco and alcohol is prohibited by religious tenets, and it is documented that Mormons have a very low proportion of 45 TABLE IO.-Lung cancer mortality ratios in ex-cigarette smokers, by number of years stopped smoking U.S. Veterans ' `Years stopped Study smoking Mortality ratio British Physicians 14 16.0 5-9 5.9 10-14 5.3 15 + 2.0 Current smokers 14.0 l-4 18.83 5-9 7.73 lo-14 4.71 15-1s 4.81 20+ 2.10 Current smokers 11.28 l-4 4.65 5-9 2.56 10 + 1.35 Current smokers 3.76 ACS 2.5-Stat.e Study (males 50-69) - 600 - 500 - g 400 - 4 ii 30.0 - i 200 - mz 2 c" 2 10.0 - 90 - 80 - 7.0 - 6.0 - 50 - 40 - 3.0 - 20 - 10 - 09 - 06 - 07 - 06 - 05 - WHlTE MEN 5054 *err FIGUflE 16.-Mortality rates for malignant neoplasm of the trachea, bronchus, and lung, for white men and white women, by birth cohort and age at death, United States, 5-year intervals during 1947-1977 SOURCE!National Center for Health Statistics 1200). 56 WWTE WOMEN ICOO - So0 - WI0 - 700 - 600 - 500 - 400 - 3Jo - M.0 - 100 - so - 6.0 - 70 - 60 - 50 - 40 - 30 - 20 - FIGURE 16, continued.-Mortality rates for malignant neoplasm of the trachea, bronchus, and lung, for white men and white women, by birth cohort and age at death, United States, Byear intervals during 1947-1977 SOURCE. Natmnal Center for Health StatistmG?GOI. 57 16 years NON- SMOKERS I I I I I I I I I I I I 0 2 4 6 0 10 12 14 16 18 20 22 24 MORTALITY RATIO FIGURE 17.-Lung cancer