TIIE HEALTH CONSEQUENCES OF SMOKING FOR WOMEN a report of the Surgeon Genera/ u S DEPARTMENT 0~ Pbllc Health serv,ce HEALTH AND HUMAN SERVlCES o'flce of the AssIstant Secretary for Health onw on Smoking and Health c. The Honorable Thomas P. O'Neill,Jr. Speaker of the Rouse of Representatives Washington, D.C. 20515 Dear Mr. Speaker: I hereby submit the 12th annual report that the Department of Health, Education, and Welfare (DHEW) has prepared for Congress as required by the Public Health Cigarette Smoking Act of 1969, Public Law 91-222, and its predecessor, the Federal Cigarette Labeling and Advertising Act. This report is one of the most alarming in the series. It clearly establishes that women smokers face the same risks as men smokers of lung cancer, heart disease, lung disease and other consequences. Perhaps more disheartening is the harm which mothers' smoking causes to their unborn babies and infants. The report is not all bad news. It presents recent data showing that women are turning away from smoking in response to the warnings of government, voluntary agencies and physicians. The precipitate rise in women's deaths from lung cancer and chronic lung disease demand that this trend away from cigarettes be accelerated. Our scientists expect that by 1983, the lung cancer death rate will exceed that of any other type of cancer among women. Citizens of our free society may decide for themselves whether to smoke cigarettes. The health consequences of this decision make it imperative for their government to assure that the decision is an informed one. This series of reports is one way in which DHEW is striving to meet this critical responsibility. Patricia Roberts Harris PREFACE This report is more than a factual review of the health conse- quences of smoking for women. It is a document which chal- lenges our society and, in particular, our medical and public health communities. This report points out that the first signs of an epidemic of smoking-related disease among women are now appearing. Be- cause women's cigarette use did not become widespread until the onset of World War II, those women with the greatest inten- sity of smoking are now only in their thirties, forties, and fifties. As these women grow older, and continue to smoke, their bur- den of smoking-related disease will grow larger. Cigarette smok- ing now contributes to one-fifth of the newly diagnosed cases of cancer and one-quarter of all cancer deaths among women- more cancer and more cancer deaths among women than can be attributed to any other known agent. Within three years, the lung cancer death rate is expected to surpass that for breast cancer. A similar epidemic of chronic obstructive lung disease among women has also begun. Four main themes emerge from this report to guide future public health efforts. First, women are not immune to the damaging effects of smoking already documented for men. The apparently lower susceptibility to smoking-related diseases among women smok- ers is an illusion reflecting the fact that women lagged one- quarter century behind men in their widespread use of cigar- ettes. Second, cigarette smoking is a major threat to the outcome of pregnancy and well-being of the newborn baby. Third, women may not start smoking, continue to smoke, quit smoking, or fail to quit smoking for precisely the same reasons as men. Unless future research clarifies these differences, we will find it difficult to prevent initiation or to promote cessation of cigarette smoking among women. Fourth, the reduction of cigarette smoking is the keystone in our nation's long term strategy to promote a healthy lifestyle for women and men of all races and ethnic groups. `lhe Fallacy of Women's Immunity All of the major prospective studies of smoking and mortality have reached consistent conclusions. Death rates from coronary heart disease, chronic lung disease, lung cancer, and overall mortality rates are significantly increased among both women and men smokers. These risks increase with the amount smoked, duration of smoking, depth of inhalation, and the "tar" V and nicotine delivery of the cigarette smoked. In these studies, conducted during the past three decades, relative mortality risks among female smokers appeared to be less than those of male smokers. It is now clear, however, that these studies were comparing the death rates of a generation of established, lifelong male smokers with a generation of women who had not yet taken up smoking with full intensity. Even those older women who reported smoking a large number of cigarettes per day had not smoked cigarettes in the same way as their male counterparts. Now that the cigarette smoking char- acteristics of women and men are becoming increasingly simi- lar, their relative risks of smoking-related illness will become increasingly similar. This fallacy of women's apparent immunity is clearly illus- trated by differences in the timing of the growth in lung cancer among men and women in this century. Lung cancer deaths among males began to increase during the 193Os, as those men who had converted from other forms of tobacco to cigarette smoking before the turn of the century gradually accumulated decades of inhaled tobacco exposure. By the time of the first retrospective studies of smoking and lung cancer in 1950, two entire generations of men had already become lifelong cigarette smokers. Relatively few women from these generations smoked cigarettes, and even fewer had smoked cigarettes since their adolescence. Those young women who had taken up smoking intensively during World War II were only in their twenties and thirties. In 1950, women accounted for less than one in twelve deaths from lung cancer. Thereafter, the age adjusted lung cancer death rate among women accelerated, and the male predominance in lung cancer declined. Lung cancer surpassed uterine cervical cancer as a cause of death in women. By 1968, as the findings of many large population prospective studies were being published, women accounted for one-sixth of all lung cancer deaths. These studies found that women cigarette smokers had 2.5 to 5 times greater death rates from lung cancer than women nonsmokers. By 1979, women accounted for fully one-fourth of all lung cancer deaths. Over the next few years, women cigarette smokers' risk of lung cancer death will approach 8 to 12 times that of women nonsmokers, the same relative risk as that of men. Lung cancer has four main histological types: epidermoid, small cell, adenocarcinoma, and large cell carcinoma, As several studies have shown, the incidence of each of these types of lung cancer displays a clear relationship to cigarette smoking among both men and women. Epidermoid and small cell lung cancer appear to be more prominent among men, while adenocar- vi cinema of the lung now appears to be more prominent among women. The recent acceleration of lung cancer incidence among women has in fact been more rapid than the corresponding growth of lung cancer among men in the 1930s. Again, this dif- ference in the initial rate of acceleration of lung cancer inci- dence does not refute the demonstrated causal relation between cigarette smoking and lung cancer among both sexes. Instead, differences in the rate of increase of lung cancer incidence may reflect changes in the carcinogenic properties of cigarette smoke, the style of cigarette smoking, or the interaction of cigarette smoking with other environmental hazards. It is noteworthy that those men who died of lung cancer in the 1930s came from a generation that had gradually converted to cigarettes from other, non-inhaled forms of tobacco. By con- trast, the first regular tobacco users among women were almost exclusively cigarette smokers. The 1979 Report on Smoking and Health documented numer- ous instances where cigarette smoking adds to the hazards of the workplace environment among men. Among women, this report reveals two such occupational exposures- asbestos and cotton dust-which have been clearly demonstrated to interact with cigarette smoking. The fact that evidence is limited among women does not imply that women are protected from the dangerous interactions of smoking and occupational exposures. Pregnancy, Infant Health, and Reproduction Scientific studies encompassing various races and ethnic groups, cultures and countries, involving hundreds of thousands of pregnancies, have shown that cigarette smoking during pregnancy significantly affects the unborn fetus and the newborn baby. These damaging effects have been repeatedly shown to operate independently of all other factors that influ- ence the outcome of pregnancy. The effects are increased by heavier smoking and are reduced if a woman stops smoking during pregnancy. Numerous toxic substances in cigarette smoke, such as nicotine and hydrogen cyanide, cross the placenta to affect the fetus directly. The carbon monoxide from cigarette smoke is transported into the fetal blood and deprives the growing baby of oxygen. Fetal growth is directly retarded. The resulting re- duction in fetal weight and size has many unfortunate conse- quences. Women who smoke cigarettes during pregnancy have more spontaneous abortions, and a greater incidence of bleed- ing during pregnancy, premature and prolonged rupture of am- vii niotic membranes, abruptio placentae and placenta previa. Women who smoke cigarettes during pregnancy have more fetal and neonatal deaths than nonsmoking pregnant women. A rela- tion between maternal smoking and Sudden Infant Death Syn- drome has now been established. The direct harmful effects of smoking on the fetus have long term consequences. Children of mothers who smoked during pregnancy lag measurably in physical growth; there may also be effects on behavior and cognitive development. The extent of these deficiencies increases with the number of cigaret- tes smoked. The damaging effects of maternal smoking on infants are not restricted to pregnancy. Nicotine, a known poison, is found in the breast milk of smoking mothers. Children whose parents smoke cigarettes have more respiratory infections and more hospitalizations in the first year of life. Women who smoke cigarettes have more than three times the risk of dying of stroke due to subarachnoid hemorrhage, and as much as two times the risk of dying of heart attack in compari- son to nonsmoking women. The use of oral contraceptives in addition to smoking, however, causes a markedly increased risk, including a 22-fold increase in the risk of subarachnoid hemor- rhagic stroke and a 20-fold increase in heart attack in heavy smokers. Why Do Women Smoke? Cigarette consumption in this country is now declining. An- nual per capita consumption has decreased from 4,258 in 1965 to an estimated 3,900 in 1979. From 1965 to 1979, the proportion of adult male cigarette smokers declined from 51 to 37 percent. Not only have millions of men quit smoking, but the rate of initia- tion of smoking among adolescent males has now slowed. From 1965 to 1976, the proportion of adult women cigarette smokers remained virtually unchanged at 32 to 33 percent. Since 1976, however, the proportion of adult women cigarette smokers appears to have declined to 28 percent. Although adult women are now beginning to quit smoking at rates comparable to adult men, the rate of initiation of smoking among younger women has not declined. This report documents numerous differences by sex in the perceived role of cigarette smoking, in attitudes toward health and lifestyle, and in methods of coping with stress, anger, and boredom. Yet the significance of these differences, and their relation to differences in smoking patterns, remains poorly un- derstood. **. Vlll Although it is frequently observed that women in organized smoking cessation programs have more severe withdrawal symptoms and lower rates of successful quitting than men, these observations have not been systematically confirmed for the general population. In the past, women may have attempted to quit or succeeded in quitting smoking less frequently than men. The recent decline in the proportion of women smokers, however, suggests that women's attempted and successful quit- ting rates have now increased. Although weight gain is a frequently cited consequence of quitting smoking, the association of weight gain with cessation of smoking has not been the subject of sufficient scrutiny. Con- trolled studies with careful measurement on representative populations of women do not exist. The impact of the fear of weight gain after quitting has not been adequately examined. If weight gain does result from cessation of smoking, its exact mechanism must be determined. Even more problematic are marked differences by sex in the distribution of smoking prevalence by occupation. Men with ad- vanced education and professional occupations have taken the lead in quitting smoking, but women in administrative and managerial positions have relatively high smoking prevalence rates. Although 20 percent or fewer male physicians smoke, the proportions of cigarette smokers among women health profes- sionals, especially nurses and psychologists, remain disturb- ingly high. Recent changes in smoking prevalence among black women and men have paralleled those of the general population. From 1965 to 1979, the proportion of black women cigarette smokers declined from 34 to 29 percent, while the proportion of black men smokers declined from 61 to 42 percent. However, differences by race in the onset, maintenance, and cessation of smoking have not been adequately explored. Little is known about cigarette smoking among other ethnic and minority groups. Adolescent Smoking The health consequences of smoking evolve over a lifetime. Evidence continues to accumulate, for example, that cigarette smoking produces measurable lung changes in adolescence and young adulthood. Young cigarette smokers of both sexes show more evidence of small airway dysfunction, and a higher preva- lence of cough, wheezing, phlegm production, and other respira- tory symptoms. The health damage due to cigarette smoking increases when an individual begins regular smoking earlier in life. Yet, as this report documents, the average age of onset of ix regular smoking among women has continuously declined dur- ing the last 50 years, and continues to decline. According to a recent survey by the National Institute of Education, cigarette smoking among adolescent girls now ex- ceeds that among adolescent boys. In the 17-19 year age group, there are almost 5 female cigarette smokers for every 4 male cigarette smokers. The causes of this inversion are far from clear. We do not yet understand the signal events in the initia- tion of smoking among young women. It is possible that parents set examples concerning lifestyle, health attitude, and risk- taking much earlier in childhood. The beginning of junior high school or entrance into the work force may be equally critical events. We do not know enough about an adolescent's sense of competence and self-mastery, and how these roles differ among women and men. Although smoking patterns among girls corre- late with parental, peer and sibling smoking habits, educational level, type of school curriculum, academic performance, socioeconomic status, and other forms of substance abuse, the practical significance of these empirical correlations is unclear. Women and the Changing Cigarette As this report documents, the proportion of men and women smokers using brands with lowered "tar" and nicotine con- tinues to grow. Adolescents of both sexes have followed this trend, to the point where nonfilter cigarettes are relatively rare among young adults. Although the preponderance of scientific evidence continues to suggest that cigarettes with lower "tar" and nicotine are less hazardous, four serious warnings are in order. First, the reported "tar" and nicotine deliveries of cigarettes are standardized machine measurements. They do not neces- sarily represent the smoker's actual intake of these substances. Evidence is now mounting that individuals who switch to cigarettes with lowered "tar" and nicotine inhale more deeply, smoke a greater proportion of their cigarettes, and in some cases smoke more cigarettes. Second, "tar" and nicotine are not the only dangerous chemi- cal components of cigarette smoke. Many conventional filter cigarettes, in fact, may deliver more carbon monoxide than non- filter cigarettes. Third, it has not been established that lower "tar" and nicotine cigarettes have less harmful effects on the unborn fetus and baby; on women and men at high risk for developing coronary heart disease, such as those with elevated cholesterol or high blood pressure; or on workers with adverse occupational X exposures. It has not been established that switching to a lower "tar" and nicotine cigarette has any salutary effect on indi- viduals who already have smoking-related illnesses, such as coronary heart disease, chronic bronchitis, and emphysema. Fourth, even the lowest yield cigarettes present health hazards for both women and men that are very much higher than smoking no cigarettes at all. The single most effective way for both women and men smok- ers to reduce the hazards associated with cigarettes is to quit smoking. As this report demonstrates, little is known about the effects of these product changes on the initiation, maintenance and cessation of smoking, particularly among women. It has not been determined whether the availability of cigarettes with lowered "tar" and nicotine has made it easier for young women to experiment with and besome addicted to cigarettes. It is not known whether smokers of the lowest yield cigarettes are more or less likely to attempt to quit, or to succeed in quitting, than smokers of conventional filtertip or nonfilter cigarettes. The extent to which the act of switching to a lower "tar" cigarette serves as a substitute for quitting may differ among women and men. Public Health Responsibilities This report, which includes data compiled by individuals from both inside and outside the Government, has confirmed in every way the judgement of the World Health Organization that there can no longer be any doubt among informed people that cigarette smoking is a major and removable cause of ill health and premature death. Each individual woman must make her own decision about this significant health issue. Secretary Harris has noted that the role of the Government, and all responsible health profes- sionals, is to assure that this decision is an informed one. In issuing this report, we hope to help the public health community accomplish this purpose. Julius B. Richmond, M.D. Assistant Secretary for Health and Surgeon General xi ACKNOWLEDGEMENTS This report was prepared by agencies of the U.S. Department of Health, Education, and Welfare under the general editorship of the Office on Smoking and Health, John M. Pinney, Director. Consulting scientific editors were David M. Burns, M.D., As- sistant Clinical Professor of Medicine, Pulmonary Division, University of California at San Diego, San Diego, California, and John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medical School, Salt Lake City, Utah. Contributing scientific editors were Joanne Luoto, M.D., M.P.H., Medical Officer, Office on Smoking and Health, Rockville, Maryland, and Kelley L. Phillips, M.D., M.P.H., Ex- pert Consultant, Office on Smoking and Health, Rockville, Maryland. Introduction and Summary Office on Smoking and Health Patterns of Cigarette Smoking Office on Smoking and Health Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Depart- ment of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts; Clinical Associate, Medical Serv- ices, Massachusetts General Hospital, Boston, Mas- sachusetts. Mortality National Heart, Lung, and Blood Institute Eugene Rogot, M.A., Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Insti- tutes of Health, Bethesda, Maryland. Thomas J. Thorn, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, National Insti- tutes of Health, Bethesda, Maryland. Morbidity National Center for Health Statistics Ronald W. Wilson, M.A., Chief, Health Status and Demo- graphic Analysis Branch, Division of Analysis, National Cen- ter for Health Statistics, Hyattsville, Maryland. Cardiovascular Diseases National Heart, Lung, and Blood Institute G. C. McMillan, M.D., Ph.D., Associate Director for Etiology of Arteriosclerosis and Hypertension, Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Insti- tute, National Institutes of Health, Bethesda, Maryland. . . . x111 Cancer National Cancer Institute Jesse L. Steinfeld, M.D., Dean, School of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia. Non-Neoplastic Bronchopulmonary Diseases National Heart, Lung, and Blood Institute Richard A. Bordow, M.D., Associate Director of Respiratory Medicine, Brookside Hospital, San Pablo, California. Claude J. M. Lenfant, M.D., Director, Division of Lung Dis- eases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Barbara Marzetta Liu, S.M., Division of Lung Diseases, Na- tional Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Eric R. Jurrus, Ph.D., Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Interaction Between Smoking and Occupational Exposures National Institute of Occupational Safety and Health Jeanne M. Stellman, Ph.D., Associate Professor, Columbia University, School of Public Health, New York, New York. Steven D. Stellman, Ph.D., Assistant Vice-President for Epidemiology, American Cancer Society, New York, New York. Pregnancy and Infant Health National Institute of Child Health and Human Development Eileen G. Hasselmeyer, Ph.D., R.N., Associate Director for Scientific Review, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Mary B. Meyer, Sc.M., Associate Professor of Epidemiology, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland. Lawrence D. Longo, M.D., Professor of Physiology and of Obstetrics and Gynecology, Loma Linda University School of Medicine, Loma Linda, California. Donald R. Mattison, M.D., Medical Officer, Pregnancy Re- search Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Peptic Ulcer Disease National Institute of Arthritis, Metabolism and Digestive Diseases Travis E. Solomon, M.D., Ph.D., Center for Ulcer Research xiv and Education, Veterans Administration Wadsworth Medical Center, and University of California, Los Angeles School of Medicine, Los Angeles, California. Janet D. Elashoff, Ph.D., Center for Ulcer Research and Edu- cation, Veterans Administration Wadsworth Medical Center and University of California, Los Angeles School of Medicine, Los Angeles, California. Interactions of Smoking with Drugs, Food Constituents, and Responses to Diagnostic Tests Food and Drug Administration Cheryl Fossum Graham, M.D., Division of Drug Experience, Office of Biometrics and Epidemiology, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland. Psychosocial and Behavioral Aspects of Smoking in Women National Institute on Drug Abuse and National Institute of Child Health and Human Development Initiation Ellen R. Gritz, Ph.D., Research Psychologist, Veterans Ad- ministration Medical Center, Brentwood, and Associate Re- search Psychologist, Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, California. Ann F. Brunswick, Ph.D., Senior Research Associate (Public Health, Sociomedical Sciences), Center for Sociocultural Re- search on Drug Use, Columbia University, New York, New York. Maintenance and Cessation Karen L. Bierman, M.A., Department of Psycholo,ay, Univer- sity of California, Los Angeles, California. Ellen R. Gritz, Ph.D., Research Psychologist, Veterans Ad- ministration Medical Center, Brentwood, and Associate Re- search Psychologist, Department of Psychiatry and Biobehavioral Sciences, School of Medicine, University of California, Los Angeles, California. The editors acknowledge with gratitude the many distin- guished scientists, physicians, and others who assisted in the preparation of this report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscripts or helping in other ways. Elvin E. Adams, M.D., M.P.H., Chairman, Texas Interagency Council on Smoking and Health, Practicing Internal Medicine, Fort Worth, Texas. Josephine D. Arasteh, Ph.D., Health Scientist Administrator, xv Human Learning and Behavior Branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Lester Breslow, M.D., M.P.H., Dean, School of Public Health, University of California at Los Angeles, Los Angeles, Califor- nia. A. Sonia Buist, M.D., Associate Professor of Medicine and Physiology, University of Oregon Health Sciences Center, Portland, Oregon. David M. Burns, M.D., Assistant Clinical Professor of Medicine, Pulmonary Division, University of California at San Diego, San Diego, California. Thomas C. Chalmers, M.D., President and Dean, Mount Sinai Medical Center, New York, New York. Florence L. Denmark, Ph.D., Professor of Psychology, Hunter College of the City University of New York, and President of the American Psychological Association, New York, New York. Robert M. Donaldson, Jr., M.D., Chief, Medical Services, Westhaven Veterans Hospital, and Vice-Chairman, Depart- ment of Internal Medicin.e, Yale University School of Medicine, New Haven, Connecticut. Joseph T. Doyle, M.D., Professor of Medicine and Head, Divi- sion of Cardiology of the Department of Medicine, Albany Medical College of Union University, Albany, New York. Elizabeth M. Earley, Ph.D., Chief, Section of Cytogenetics, Division of Pathology, Bureau of Biologics, Food and Drug Administration, Rockville, Maryland. Bernard H. Ellis, Jr., Program Director for Smoking and Oc- cupational Activities, Office of Cancer Communications, Na- tional Cancer Institute, National Institutes of Health, Bethesda, Maryland. Diane Fink, M.D., Associate Director, National Cancer Insti- tute, and Coordinator, Smoking, Cancer, and Health Program, National Institutes of Health, Bethesda, Maryland. Harold E. Fox, M.D., Associate Professor of Clinical Obstetrics and Gynecology, Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, and Medical Director, Western and Upper Manhattan Perinatal Network, New York, New York. Joseph H. Gainer, D.V.M., Veterinary Medical Officer, Divi- sion of Veterinary Medical Research, Bureau of Veterinary Medicine, Food and Drug Administration, Beltsville, Mary- land. Stanley N. Gershoff, Ph.D., Director, Nutrition Institute and xvi Chairman, Graduate Department of Nutrition, Tufts Univer- sity, Medford, Massachusetts. Mary E. Guinan, M.D., Clinical Research Investigator, Clini- cal Studies Section, Venereal Disease Control Division, Cen- ter for Disease Control, Atlanta, Georgia. Sharon M. Hall, Ph.D., Assistant Professor in Residence, Uni- versity of California at San Francisco, Langley Porter Psy- chiatric Institute, San Francisco, California. Jane Halpern, M.D., Assistant Secretary for Policy Evalua- tion and Research, Office of Health and Disability, United States Department of Labor, Washington, D.C. Beatrix A. Hamburg, M.D., Senior Research Psychiatrist, Laboratory of Developmental Psychology, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland. Virginia G. Harris, M.D., Director, Maternal and Child Health, Onondaga County Health Department, Syracuse, New York. John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medical School, Salt Lake City, Utah. L. Stanley James, M.D., Professor of Pediatrics, and of Obstet- rics and Gynecology, and Director, Division of Perinatal Medicine, College of Physicians and Surgeons, Columbia Uni- versity, New York, New York. Hershel Jick, M.D., Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Waltham, Mas- sachusetts. Reese T. Jones, M.D., Professor of Psychiatry, Department of Psychiatry, University of California at San Francisco, Langley Porter Psychiatric Institute, San Francisco, California. Philip Kimbel, M.D., Chairman, Department of Medicine, Graduate Hospital, Philadelphia, Pennsylvania. Jan W. Kuzma, Ph.D., Chairman and Professor of Biostatis- tics, Department of Biostatistics and Epidemiology, Loma Linda University, Loma Linda, California. Abraham Lilienfeld, M.D., M.P.H., D.Sc., University Distin- guished Service Professor, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland. Harold A. Menkes, M.D., Associate Professor of Medicine and Environmental Health Sciences, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. Kenneth Moser, M.D., Professor of Medicine and Director, Pulmonary Division, University of California at San Diego, San Diego, California. Mariquita Mullan, B.S.N., M.P.H., Special Assistant to the Di- xvii rector, National Institute of Occupational Safety and Health, Center for Disease Control, Rockville, Maryland. Janyce E. Notopoulos, Program Analyst, Office of Planning and Evaluation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Albert Oberman, M.D., Director, Division of Preventive Medicine, University of Alabama in Birmingham Medical Center, Birmingham, Alabama. Ralph S. Paffenbarger, M.D., D.R.P.H., Professor of Epidemiology, Stanford University, School of Medicine, Stan- ford, California, and Adjunct Professor of Epidemiology at the University of California, School of Public Health, Berkeley, California. Richard Peto, M.D., Radcliff Clinic, Oxford University, Ox- ford, England. Malcolm C. Pike, Ph.D., Professor, Community and Family Medicine, School of Medicine, University of Southern Califor- nia at Los Angeles, Los Angeles, California. Ovide F. Pomerleau, Ph.D., Professor of Psychology and Psy- chiatry, University of Connecticut, School of Medicine, Far- mington, Connecticut. Phil1 H. Price, M.D., Medical Officer, Metabolic Products Branch, Division of Metabolism and Endocrine Drugs, Bureau of Drugs, Food and Drug Administration, Rockville, Maryland. Dorothy P. Rice, Director, National Center for Health Statis- tics, Office of the Assistant Secretary for Health, Hyattsville, Maryland. Anthony Robbins, M.D., Director, National Institute of Occu- pational Safety and Health, Center for Disease Control, Rockville, Maryland. Judith B. Rooks, C.N.M., M.P.H., M.S., Office of the Assistant Secretary for Health, Washington, D.C. Harold P. Roth, M.D., Associate Director for Digestive Dis- eases and Nutrition, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland. Philip Sapir, Special Assistant to the Director for Behavioral and Social Sciences and Chief, Human Learning and Behavior Branch, Center for Research for Mothers and Children, Na- tional Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. Marvin A. Schniederman, Ph.D., Associate Director for Sci- ence Policy, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. . . . Xvlll Irving J. Selikoff, M.D., Professor of Community Medicine and Professor of Medicine, and Director of Environmental Sci- ences Laboratory, Mount Sinai Medical Center, New York, New York. S. I. Shibko, Ph.D., Chief, Contaminants and Natural Toxic- ants Branch, Division of Toxicology, Bureau of Foods, Food and Drug Administration, Washington, D.C. Jeremiah Stamler, M.D., Chairman, Department of Commu- nity Health and Preventive Medicine, Northwestern Univer- sity Medical School, Chicago, Illinois. John E. Vanderveen, Ph.D., Director, Division of Nutrition, Bureau of Foods, Food and Drug Administration, Washington, D.C. Eve Weinblatt, Assistant Director for Research, Department of Research and Statistics, Health Insurance Plan of Greater New York, New York, New York. Samuel S. C. Yen, M.D., Professor and Chairman, Department of Reproductive Medicine, University of California, San Di- ego, LaJolla, California. The editors also acknowledge the help of the following staff who among others assisted in the preparation of the report. John L. Bagrosky, Associate Director for Program Opera- tions, Office on Smoking and Health, Rockville, Maryland. Jacqueline 0. Blandford, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland. Betty Budd, Secretary, Office on Smoking and Health, Rockville, Maryland. John F. Hardesty, Jr., Public Information Officer, Office on Smoking and Health, Rockville, Maryland. Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland. Robert S. Hutchings, Associate Director for Information and Program Development, Office on Smoking and Health, Rockville, Maryland. &Margaret E. Ketterman, Secretary, Office on Smoking and Health, Rockville, Maryland. Richard A. La SCO, Ph.D., Bureau of Health Education, Center for Disease Control, Atlanta, Georgia. Joanne Luoto, M.D., M.P.H., Medical Officer, Office on Smok- ing and Health, Rockville, Maryland. Judith L. Mullaney, M.L.S., Tephnical Information Specialist, Office on Smoking and Health, Rockville, Maryland. Marjorie L. Olson, Secretary, Office on Smoking and Health, Rockville, Maryland. xix Kelley L. Phillips, M.D., M.P.H., Expert Consultant, Office on Smoking and Health, Rockville, Maryland. David L. Pitts, Public Health Advisor, Operations Branch, Nutrition Division, Bureau of Smallpox Eradication, Center for Disease Control, Atlanta, Georgia. Donald R. Shopland, Technical Information Officer, Office on Smoking and Health, Rockville, Maryland. Linda R. Spiegelman, Administrative Assistant, Office on I Smoking and Health, Rockville, Maryland. Carol M. Sussman, Technical Publication Writer/Editor, Of- fice on Smoking and Health, Rockville, Maryland. Ronald G. Thomas, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland. Selwyn M. Waingrow, Public Health Analyst, Office on Smok- ing and Health, Rockville, Maryland. Ann E. Wessel, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland. Carole L. Winn, Assistant Chief, Clinical Chemistry Stand- ardization Section, Clinical Chemistry Division, Metabolic Biochemistry Branch, Bureau of Laboratories, Center for Disease Control, Atlanta, Georgia. xx TABLE OF CONTENTS INTRODUCTION AND SUMMARY . . . . . . . . . . . . . . . . . . . . . 1 PART I PATTERNS OF CIGARETTE SMOKING . . . . . . . . . . . . . . . . 15 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 The Rise of Cigarette Smoking: 1900-1950 . . . . . , . . . . . 17 The Emergence of Filtertip Cigarettes: 1951-1963 . . 21 Increasing Public Health Awareness: 1964-1979 . . . . . 21 Exposure to Cigarette Smoking Among Successive Birth Cohorts . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Cigarette Smoking Among Young Women . . . . . . . . . . . 33 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 PART II BIOMEDICAL ASPECTS OF SMOKING MORTALITY ............................................ 44 Introduction and Background ....................... 45 Mortality Trends .................................... 45 Epidemiological Studies ............................. 46 The American Cancer Society 25-State Study ................................. 47 The Swedish Study .............................. 51 The Canadian Veterans Study ................... 51 Japanese Study of 29 Health Districts ........... 51 The British Doctors Study ....................... 51 The Framingham Heart Study .................. 52 The British-Norwegian Migrant Study ................................. 52 Overall Mortality for Females-Cigarette Smokers Versus Nonsmokers ............................... 53 Mortality Ratios ................................. 53 Amount Smoked and Age ........................ 54 Duration of Smoking ............................ 57 Age Began Smoking ............................. 58 Inhalation ....................................... 59 "Tar" and Nicotine Content of Cigarettes ..................................... 59 xxi Comments ........................................... Summary ............................................ References .......................................... MORBIDITY ............................................ Days Lost from Work ................................ Limitation of Activity ............................... Cigarette Smoking and Occupation .................. Summary ............................................ References .......................................... CARDIOVASCULAR DISEASES ........................ Introduction ......................................... Mortality Rates ..................................... Atherosclerosis ...................................... RiskFactors ......................................... The Effect of Smoking ............................... Atherosclerosis .................................. Coronary Heart Disease ......................... Cessation of Smoking and "Tar" and Nicotine Content of Cigarettes ................................. Angina Pectoris ................................. Cerebrovascular Disease ......................... Arteriosclerotic Peripheral Vascular Disease .............................. Aortic Aneurysm ................................ Hypertension .................................... Venous Thrombosis .............................. High-Density Lipoprotein ........................ Oral Contraceptive Use, Smoking, and Cardiovascular Disease ............................ 61 61 62 65 67 68 69 70 75 77 79 79 84 86 86 86 88 92 93 93 95 96 96 97 98 98 Carbon Monoxide .................................... 101 Comment ............................................ 101 Summary ............................................ 102 References .......................................... 103 CANCER ................................................ 107 Introduction ......................................... 109 Lung ................................................ 111 Geographic Differences .......................... 116 Smoking Patterns Among Women ............... 117 Cessation of Smoking ............................ 120 Experimental Carcinogensis ..................... 121 Larynx .............................................. 121 Oral ................................................. 122 Esophagus ........................................... 123 xxii Urinary Bladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Non-neoplastic Bronchopulmonary Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 Smoking and Respiratory Mortality . . . . . . . . . . . . . . . . . 137 Smoking and the Epidemiology and Pathology of Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141 Smoking and Respiratory Morbidity . . . . . . . . . . . . . . . . . 146 Smoking and Pulmonary Function . . . . . . . . . . . . . . . . . . . 156 Smoking and "Early" Functional Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Smoking and Ventilatory Function . . . . . . . . . . . . . . 160 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 Interaction Between Smoking and Occupational Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Smoking Patterns in Women . . . . . . . . . . . , . . . . . . . . . . . . , 172 Patterns of Employment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 The Reproductive Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 Specific Interactions Between Occupational Exposure and Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Asbestos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Cotton Dust . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 PREGNANCY AND INFANT HEALTH . . . . . . . . . . . . . . . . . 189 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 Smoking, Birth Weight, and Fetal Growth . . . . . . . . . . . 191 Placental Ratios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 Gestation and Fetal Growth . . . . . . . . . . . . . . . . . . . . . 195 Long-Term Growth and Development . . . . . . . . . . . . 196 Role of Maternal Weight Gain . . . . . . . . . . . . . . . . . . . 202 Smoking, Fetal and Infant Mortality, and Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 Spontaneous Abortion . . . . . . . . . . . . . . . . . . . . . . . . . . . 206 Congential Malformations . . . . . . . . . . . . . . . . . . . . , . , 207 Perinatal Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 CauseofDeath . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 Complications of Pregnancy and Labor . . . . . . . . . . . . . . 214 . . . xx111 Preeclampsia .................................... LII Preterm Delivery, Pregnancy Complications, and Perinatal Mortality by Gestation ........................ 217 Long-Term Morbidity and Mortality ................. 221 Sudden Infant Death Syndrome ................. 225 Mechanisms ......................................... 226 Experimental Studies ............................... 229 Tobacco Smoke ................................... 229 Nicotine ......................................... 229 Carbon Monoxide ................................ 231 Polycyclic Aromatic Hydrocarbons ............... 233 Other Components ............................... 234 Fertility ............................................. 235 Smoking and Reproduction in Women ........... 235 Smoking and Age of Menopause ................. 236 Smoking and Reproduction in Men .............. 236 Fertilization and Conceptus Transport ..................................... 237 Summary ............................................ 238 References .......................................... 239 PEPTIC ULCER DISEASE ............................. 251 Summary ............................................ 254 References .......................................... 254 INTERACTIONS OF SMOKING WITH DRUGS, FOOD CONSTITUENTS, AND RESPONSES TO DIAGNOSTIC TESTS .............................. 259 Women Smokers and Nonsmokers and Drug Consumption Patterns ....................... 259 Altered Clinical Response to Drug Therapy by Smokers as Compared to Nonsmokers .......... 261 Oral Contraceptives and Smoking ................... 262 Alterations in Normal Clinical Laboratory Values in Women Smokers ......................... 263 The Influence of Smoking on the Nutritional Needs of Women ....................... 264 Summary ............................................ 265 References .......................................... 265 PART III PSYCHOSOCIAL AND BEHAVIORAL ASPECTS OF SMOKING IN WOMEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 xxiv Initiation of Smoking in Adolescent Girls . . . . . . . . . . . . 271 Concepts of Adolescent Behavior . . . . . . . . . . . . . . . . . 272 Prevalence and Patterns of Adolescent Cigarette Use . . . . . . . . . . . . . . . . . . . . . . 273 Prevalence . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . 273 Age at Initiation of Smoking . . . . . . . . . . . . . . . . 275 Number of Cigarettes Smoked . . . . . . . . . . . . . . . 277 Type of Cigarette Smoked . . . . . . . . . . . . . . . . . . . 278 Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . 278 Smoking Prevalence and Ethnicity . . . . . . . . . . 280 Alcohol and Marihuana Use . . . . . . . . . . . . . . . . . 280 Demographic and Psychosocial Correlates of Smoking in Adolescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281 Socioeconomic Influences . . . . . . . . . . . . . . . . . . . . 281 Family Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 Smoking Among Parents and Siblings . . . . . . . 282 Peer Group Influence . . . . . . . . . . . . . . . . . . . . . . . . 284 Scholastic Achievement and Aspirations . . . . . 285 Dynamic/Personality Factors . . . . . . . . . . . . . . . . 286 Prediction of Future Smoking Behavior . . . . . 288 Prevention of Smoking and Considerations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Prevention of the Initiation of Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290 Research Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291 Maintenance of Smoking Behavior ..,............... 293 Patterns of Cigarette Smoking . . . . . . . . . . . . . . . . . . . 293 Smoking Prevalence and Ethnicity . . , . . . . . . . 296 Pharmacological Effects of Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Peripheral Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 Central Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298 A Possible Role for Nicotine in Smoking Maintenance . . . . ..**.a........... 298 Differences in Nicotine Metabolism . . . . . . . . . . 300 Smoking and Stimulation Effects . . . . . . . . . . . . . . . . 300 Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 Education . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . 303 Income . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Occupation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 Psychology of Changing Smoking Habits . . . . . . . . 305 xxv Treatment Studies ............................... 306 The Smoking Withdrawal Syndrome ............. 315 Smoking and Weight Control .................... 315 Treatment Recommendations .................... 319 Conclusions ...................................... 321 Dissemination of Information About Smoking ....... 321 Health Attitudes and Behaviors ................. 321 Sources of Information .......................... 322 Health Care Providers ....................... 322 Educators ................................... 324 Peer Group .................................. 324 Family ...................................... 325 Media: Television, Radio, Film, Newspapers, Magazines ................... 325 Advertising .................................. 325 The Failure to Disseminate Information ................................... 327 Stress at Work ....................................... 327 Smoking Habits of Health Professionals ............. 329 Physicians ....................................... 329 Psychologists .................................... 332 Nurses .......................................... 333 The Pregnant Smoker-A Special Target ............ 336 Sources of Information .......................... 336 Physician Advice ............................ 337 Prevalence of Smoking and Quitting During Pregnancy ............................. 340 Psychosocial Factors in Quitting ................. 344 Recommendations ............................... 345 Summary ............................................ 346 References .......................................... 347 xxvi INTRODUCTION AND SUMMARY. INTRQDUCTION AND SUMMAFtY The 1980 Report on the Health Consequences of Smoking fo- cuses upon the evidence relating cigarette smoking to health effects in women. It is not presented as a detailed discussion of the entire range of effects of smoking on health. Such a detailed review of all existing evidence can be found in the 1979 Report of the Surgeon General on Smoking and Health. Instead, this volume on smoking and women's health is offered as a review and reappraisal of smoking and major health relationships spe- cifically in women. It is intended to serve the medical commu- nity as a unified source of existing scientific evidence about health effects of smoking cigarettes for women. As an examina- tion of current knowledge, it will logically lend itself to applica- tion in both the personal and public health arenas. Its content is the work of numerous scientists within the De- partment of aealth, Education, and Welfare, as well as scien- tific experts outside that organization. This volume examines the major issues relating tobacco use -to women's health including trends in consumption, the biomed- ical evidence of the health effects of cigarette usage by women, and determinants of smoking initiation, maintenance, and ces- sation. This section summarizes the principal findings of this report. lt is hoped that the entire volume will serve to highlight the established risks of smoking for women and their children, as well as to define the areas in need of further investigation. PM.ems of Cigarette Smoking 1. Women have differed from men in their historical onset of widespread cigarette use, in the rate of diffusion of smoking among each new birth cohort, in their intensity of cigarette smoking and their use of various types of cigarettes. 2. Men took up cigarette smoking rapidly at the beginning of the twentieth century, especially during World War I. Cigar- ettes rapidly replaced other forms of tobacco. BY 1925 , approximately 50 percent of adult males were cigar@tte smokers. Smoking among men accelerated rapidly during World War II By 1950, the prevalence of cigarette use among men~approached 70 percent in some urban areas. 3. The onset of widespread cigarette use among women `qged behind that of men by 25 to 30 years. The proportion of o dult women smoking cigarettes did not exceed one-quarter unti1 the onset of World War II. `. Between 1951 and 1963, increasing proportions of women 3 and men smokers converted to filtertip cigarettes. By 1964, 79 percent of adult women smokers and 54 percent of adult men smokers used filter cigarettes. 5. After reaching a peak value of 4,336 in 1963, annual per capita consumption of cigarettes declined in 1964,1968-70, and in the period since 1975. The most recent estimate of 3,900 cigarettes per capita in 1979 is approximately equal to that ob- served in 1952. 6. From 1965 to 1978, the proportion of adult men cigarette smokers declined from 51 to 37 percent. The preliminary esti- mate of adult men's smoking prevalence for 1979 is 36.9 percent. From 1965 to 1976, the proportion of adult women smokers re- mained virtually unchanged at 32 to 33 percent. Since 1976, the proportion of women smokers has declined to below 30 percent. For 1979, the preliminary estimate of adult women's smoking prevalence is 28.2 percent. The overall. smoking prevalence of 32.3 percent for both sexes in 1979 represents the lowest re- corded value in at least 45 years. 7. The proportion of adult smokers attempting to quit smok- ing declined from 1970 to 1975, but increased in 1978-1979. In contrast to past years, the proportions of women and men now attempting to quit smoking, and their reported quitting rates, are indistinguishable. Approximately one in three adult smok- ers now makes a serious attempt to quit smoking during the course of a year. Approximately one in five of those who attempt to quit subsequently succeed. 8. The proportion of adult smokers using lower "tar" and nicotine brands has increased substantially. In 1979,39 percent of adult women smokers and 28 percent of adult men smokers reported primary brands with F.T.C. "tar" delivery less than 15.0 milligrams. It is not known whether smokers of the lowest "tar" cigarettes are more or less likely to attempt to quit smok- ing, or to succeed in quitting, than smokers of conventional fil- tertip or non-filter cigarettes. 9. The average number of cigarettes smoked by women and men current smokers has increased. The relationship of this finding to recent declines in the average F.T.C. "tar" and nicotine deliveries of cigarettes is not well understood. 10. With each successive generation, the smoking character- istics of women and men have become increasingly similar. 11. Among women, the average age of onset of regular smok- ing progressively declined with each successive birth cohort- from 35 years of age for those born before 1900, to 16 years of age among those born 1951 to 1960. The average age of onset of regular smoking among young women is now virtually identical to that of young men. 4 12. Maximum smoking prevalence rates have declined sub- stantially in recent birth cohorts of men. Men born 1931 to 1940 reached a peak smoking proportion of 61 percent during 1960- 62, while men born 1941 to 1950 reached a peak smoking propor- tion of 58 percent in 1968-69. Men born 1951 to 1960 reached a peak smoking proportion of 40 percent in 1976. Among recent cohorts of women, peak smoking prevalence rates have declined to a much smaller extent. Women born 1931 to 1940 reached a peak smoking proportion of 45 percent in 1966-68, while women born 1941 to 1950 reached a peak smoking proportion of 41 per- cent in 1970-73. Women born 1951 to 1960 reached a peak smok- ing proportion of 38 percent in 1976. Among the generation born 1951 to 1960, the porportions of women and men smoking cigarettes are now virtually identical. 13. The proportions of women and men smokers in each age group have declined. Among those born before 1951, this decline in smoking prevalence resulted mainly from smoking cessation. By contrast, the observed decline in smoking prevalence among younger men born 1951 to 1960 has resulted from both smoking cessation and a lower rate of smoking initiation. This decline in the rate of onset of smoking among young men has not been observed for young women. 14. Recent survey data on adolescent smoking habits reveal that by ages 17 to 19, smoking prevalence among women ex- ceeds that of men. This finding supports the conclusion that the rate of initiation of smoking among young men- but not that of young women-is declining. The future cigarette use of the youngest generations of women is uncertain. 15. With each successive birth cohort, the accumulated years of cigarette smoking per woman has progressively approached the accumulated years of cigarette smoking per man. Each suc- cessive birth cohort has also experienced progressively smaller sex differences in the fraction of lifetime years of smoking that represents filtertip cigarette use. 16. Among men born during this century, each successive birth cohort has thus far experienced fewer cumulative years of cigarette smoking, higher proportionate exposure to filtertip cigarettes, and lower smoking prevalence rates. This relation- ship between birth date and cigarette smoke exposure does not hold for women. Women born 1921 to 1940 have experienced substantially higher smoking prevalence rates than earlier generations. Unless they quit smoking in substantial numbers, these women, currently aged 40 to 59, will surpass older women in total years of cigarette smoking per capita, the total years of nonfilter cigarette smoking per capita, and in the total number of cigarettes smoked. The health consequences of this enhanced 5 exposure to cigarette smoke among women are likely to be more prominent in the coming decades. Mortality 1. The mortality ratio for women who smoke cigarettes is about 1.2 or 1.3. 2. Mortality ratios for women increase with the amount smoked. In the largest prospective study the mortality ratio was 1.63 for the two-pack-a-day smoker as compared to nonsmokers. 3. Mortality ratios are generally proportional to the duration of cigarette smoking; the longer a woman smokes, the greater the excess risk of dying. 4. Mortality ratios tend to be higher for those women who begin smoking at a young age as compared to those who begin smoking later. 5. Mortality ratios are higher for those women who report they inhale smoke than for those who do not inhale. 6. Mortality ratios for women tend to increase with the tar and nicotine content of the cigarette. 7. Mortality ratios for female smokers are somewhat less than for male smokers. This may reflect differences in exposure to cigarette smoke, such as starting smoking later, smoking cigarettes with lower "tar" and nicotine content, and smoking fewer cigarettes per day than men. 8. Women demonstrate the same dose-response relationships with cigarette smoking as men. An increase in mortality occurs with an increase in number of cigarettes smoked per day, an earlier age of beginning cigarette smoking, a longer duration of smoking, inhalation of cigarette smoke, and a higher tar and nicotine content of the cigarette. Women who have smoking characteristics similar to men may experience mortality rates similar to men. Morbidity The 1979 Report of the Surgeon General summarized the in- formation on smoking and morbidity as follows: 1. In general, female current cigarette smokers report more acute and chronic conditions including chronic bronchitis and/or emphysema, chronic sinusitis, peptic ulcer disease, and arteriosclerotic heart disease, than women who never smoked. 2. There is a dose-response relationship between the number of cigarettes smoked per day and the frequency of reporting for most of the chronic conditions. 6 3. The age-adjusted incidence of acute conditions (e.g., in- fluenza) for women smokers is 20 percent higher for women who had ever smoked than for nonsmokers. Additional data from the Health Interview Survey (HIS) is presented: 1. Currently employed women who smoke cigarettes report more days lost from work due to illness and injury than working women who do not smoke. 2. Limitation of activity is reported more commonly among women under the age of 65 who have ever smoked than among those who never smoked. Cardiovascular Diseases Coronary heart disease is the major cause of death among both males and females in the U.S. population. The 1979 Sur- geon General's Report clearly demonstrated the close associa- tion of cigarette smoking and increased coronary heart disease among males. This report reviews the evidence associating cigarette smoking and cardiovascular disease in women: 1. Coronary heart disease, including acute myocardial infarc- tion and chronic ischemic heart disease, occurs more frequently in women who smoke. In general, cigarette smoking increases the risk by a factor of about two, and in younger women cigarette smoking may increase the risk several fold. 2. Cigarette smoking is a major independent risk factor for coronary heart disease in women; it also acts synergistically with other coronary heart disease risk factors producing a risk greater than the sum of the individual risks. 3. The use of oral contraceptives by women cigarette smokers increases the risk of a myocardial infarction by a factor of ap- Proximately ten. 4. Women who smoke low "tar" and nit-tine cigarettes expe- rience less risk for coronary heart disease than women who smoke high "tar" and nicotine cigarettes, but their risk is still considerably greater than that of nonsmokers. 5. Increased levels of high-density lipoprotein (HDL) are cor- related with a reduced risk for an acute myocardial infarction; women cigarette smokers have decreased levels of HDL. 6. Cigarette smoking is a major, independent risk factor for the development of arteriosclerotic peripheral vascular disease in women. Smoking cessation improves the prognosis of the dis- order and has a favorable impact on vascular patency following reconstructive surgery. 7. Women cigarette smokers experience an increased risk for subarachnoid hemorrhage; the use of both cigarettes and oral 7 contraceptives appears to synergistically increase the risk for subarachnoid hemorrhage. 8. Women who smoke cigarettes may be more likely to de- velop severe or malignant hypertension than nonsmoking women. Cancer 1. Cigarette smoking is causally associated with cancer of the lung, larynx, oral cavity, and esophagus in women as well as in men; it is also associated with kidney cancer in women. 2. Cigarette smoking accounts for 18 percent of all cancers newly diagnosed and 25 percent of all cancer deaths in women. In 1980, 26,500 of the estimated 101,000 deaths, or over one- quarter of the deaths expected from lung cancer, will occur in women. 3. Women cigarette smokers have been reported to have be- tween 2.5 and 5 times greater likelihood of developing lung cancer than nonsmoking women. 4. Among women the risk of developing lung cancer increases with increasing number of cigarettes smoked per day, duration of the smoking habit, depth of inhalation, and tar and nicotine content of the cigarette smoked. The risk is inversely related to the age at which smoking began. 5. A dose-response relationship has been demonstrated be- tween cigarette smoking and cancer of the lung, larynx, oral cavity, and urinary bladder in women. 6. The rise in lung cancer death rates is currently much steeper in women than in men. It is projected that the age ad- justed lung cancer death rate will surpass that of breast cancer in the early 1980s. 7. The rapid increase`in lung cancer rates in women is similar to but steeper than the rise seen in men approximately 25 years earlier. This probably reflects the fact that women first began to smoke in large numbers 25-30 years after the increase in cigarette smoking among men. Thus, neither men nor women are protected from developing lung cancer caused by cigarette smoking. 8. Cigarette smoking has been causally related to all four of the major histologic types of lung cancer in both women and men, including epidermoid, small cell, large cell and adenocar- cinema. 9. The use of filter cigarettes and cigarettes with lower levels of "tar" and nicotine by women is correlated with a lower risk of cancer of the lung and larynx compared to the use of high-"tar" and-nicotine or unfiltered cigarettes. The risk posed by smoking 8 low-"tar" cigarettes, however, is clearly greater than that among females who never smoked. 10. After cessation of cigarette smoking, a woman's risk of developing lung and laryngeal cancer has been shown to drop slowly, equalling that of nonsmokers after lo-15 years. 11. Excessive ingestion of alcohol acts synergistically with cigarette smoking to increase the incidence of oral and laryngeal cancer in women. Non-Neoplastic Bronchopulmonary Diseases 1. Recent statistics indicate a rising death rate due to chronic obstructive lung disease (COLD) among women. The data avail- able demonstrate an excess risk of death from COLD among smoking women over that of nonsmoking women. This excess risk is much greater for heavy smokers than for light smokers. 2. Women's total risk of COLD appears to be somewhat lower than men's, a difference which may be due to differences in prior smoking habits. 3. The prevalence of chronic bronchitis varies directly with cigarette smoking, increasing with the number of cigarettes smoked per day. 4. There is conflicting evidence regarding differences in the prevalence of chronic bronchitis in women and men. Several recent studies suggest that there is no significant difference in the prevalence of chronic bronchitis between male and female smokers. This may be the result, however, of increasingly simi- lar smoking behavior of women and men. 5. The presence of emphysema at autopsy exhibits a dose- response relationship with cigarette smoking during life. 6. There is a close relationship between cigarette smoking and chronic cough or chronic sputum production in women, which increases with total pack-years smoked. 7. Women current smokers have poorer pulmonary function by spirometric testing than do female ex-smokers or nonsmok- ers, a relationship which is dose-related to the number of cigarettes smoked. Interaction Between Smoking ad Occupational Exposures 1. The 1979 Surgeon General's Report identified the ways in which smoking cigarettes may interact with the occupational environment. They include: a) Facilitation of absorption of physical contamination of cigarettes, b) Transformation of workplace chemicals into more toxic substances, 9 c) Addition of the exposure to a toxic constituent of to- bacco smoke to a concurrent exposure to the same con- stituent present in the workplace, d) Addition of a health effect due to environmental expo- sure to a similar health effect due to smoking, el Synergy of exposures, and f) Causation of accidents. 2. Women are entering occupational environments with greater frequency, and thus may be experiencing greater expo- sures to physical and chemical agents. 3. Cohorts of women with a greater prevalence of smoking are currently reaching the ages of maximal disease occurrence, re- placing earlier cohorts with lower cigarette exposures. 4. Physiologic differences in hormonal status between males and females constitute a potential source of differing responses. 5. In the workplace women who are pregnant present a nine-month exposure opportunity, including potential teratogenic and perinatal mortality effects. 6. Concurrent exposure of women to smoking and asbestos resulted in a clear excess of cancer of the lung. 7. Women smokers exposed to cotton dust run a higher risk of developing byssinosis, bronchitic syndromes, and abnormal pulmonary function tests than nonsmoking women. Pregnancy and Infant Health 1. Babies born to women who smoke during pregnancy are, on the average, 200 grams lighter than babies born to comparable nonsmoking women. 2. The relationship between maternal smoking and reduced birth weight is independent of all other factors that influence birth weight including race, parity, maternal size, socioeconomic status, and sex of child; it is also independent of gestational age. 3. There -is a dose-response relationship between maternal smoking and reduced birth weight; the more the woman smokes during pregnancy, the greater the reduction in birth weight. 4. If a woman gives up smoking early during pregnancy, her risk of delivering a low-birth-weight baby approaches that of a nonsmoker. 5. The ratio of placental weight to birth weight increases with increasing levels of maternal smoking, reflecting a considerable decrease in mean birth weight and a slight increase in mean placental mass; this may represent an adaptation to relative fetal hypoxia. 10 6. The pattern of fetal growth retardation that occurs with maternal smoking is a decrease in all dimensions including body length, chest circumference, and head circumference. 7. Maternal smoking during pregnancy may adversely affect the child's long-term growth, intellectual development, and be- havioral characteristics. 8. Maternal smoking during pregnancy exerts a direct growth-retarding effect on the fetus; this effect does not appear to be mediated by reduced maternal appetite, eating or weight gain. 9. The risk of spontaneous abortion, fetal death, and neonatal death increases directly with increasing levels of maternal smoking during pregnancy; interaction of maternal smoking with other factors which increase perinatal mortality may re- sult in an even greater risk. 10. Excess deaths of smokers' infants are found mainly in the coded cause categories of "unknown" and "anoxia" for fetal deaths, and the categories of "prematurity alone" and "respira- tory difficulty" for neonatal deaths; this suggests that the ex- cess deaths are due to problems of the pregnancy, rather than to abnormalities of the fetus or neonate. 11. Increasing levels of maternal smoking result in a highly significant increase in the risk of abruptio placentae, placenta previa, bleeding early or late in pregnancy, premature and pro- longed rupture of membranes, and preterm delivery-all of which carry high risks of perinatal loss. 12. Although there is little effect of maternal smoking on mean gestation, the proportion of fetal deaths and live births that occur before term increases directly with maternal smok- ing level. Up to 14 percent of all preterm deliveries in the United States may be attributable to maternal smoking. 13. The incidence of preeclampsia is decreased among women who smoke during pregnancy; however, if preeclampsia devel- ops in a smoking woman, the risk of perinatal mortality is markedly increased compared to preeclamptic nonsmokers. 14. An infant's risk of developing the "sudden infant death syndrome" is increased by maternal smoking during pregnancy. 15. There are insufficient data to support a judgement on whether maternal and/or paternal cigarette smoking increases ,he risk of congenital malformations. 16. Infants and children born to smoking mothers may expe- -ience more long-term morbidity than those born to non- smoking mothers; however, studies usually cannot distinguish jetween the effects of smoking during pregnancy and the ef- `e&s of the infant's or child's passive exposure to cigarette smoke after birth. 11 17. Studies in women and men suggest that cigarette smok- ing may impair fertility. 18. Experimental studies on tobacco smoke, nicotine, carbon monoxide, polynuclear aromatic hydrocarbons, and other con- stituents of smoke help define pathways by which maternal smoking during pregnancy may exert its aforementioned ef- fects. Peptic Ulcer Disease The 1979 Surgeon General's Report included evidence that cigarette smoking in males was significantly associated with the incidence of peptic ulcer disease and increased the risk of dying from peptic ulcer disease by approximately two-fold. The effect of smoking on pancreatic secretion and pyloric reflux demonstrated among men may provide a mechanism by which peptic ulcers develop. 1. Female smokers show a prevalence of peptic ulcer higher than that of nonsmokers by approximately two-fold. 2. The effect of cessation on healing is not known. Interactions of Smoking with Drugs, Food Constituents and Responses to Diagnostic Tests Most published studies investigating the effects of cigarette smoking on drug use have been performed on mixed popula- tions; factors specific for women have not been demonstrated to date. It has, however, been clearly demonstrated that women are prescribed and consume more prescription drugs than men. 1. Studies of selected drugs indicate that smoking may affect clinical responses and alter the dose required for an effective therapeutic result. 2. Smoking interacts with oral contraceptive use to increase the risk of myocardial infarction and subarachnoid hemor- rhage. 3. Common clinical laboratory parameters are altered in smokers compared to nonsmokers; the health significance of these changes is unknown. 4. Insufficient information exists for assessment of the im- pact of smoking on the nutritional needs of women. Psychosocial and Behavioral Aspects of Smoking in Women 1. The percentage of 17-18 year old women who smoke has shown a steady rise between 1968 and 1979. It now appears, however, that the increase in smoking prevalence among all 12-18 year old females has leveled off and begun to decline. Young women born after 1962 show a substantially reduced 12 initiation of smoking and will probably have a much lower pre- valence of smoking as adults. 2. Those young women who do begin to smoke are starting to smoke regularly at a younger age, with more than half of the male and female adolescents who begin to smoke starting before the 10th grade. 3. The earlier tobacco is used and the greater the number of cigarettes smoked per day, the less likely an attempt to quit will be successful. 4. The percentage of women smokers who smoke more than one pack per day is increasing. 5. Adolescent and adult women are more likely to use low-tar and-nicotine cigarettes, smoke fewer cigarettes per day and in- hale less deeply than do men, but the difference between the sexes in these patterns of smoking is decreasing. Adolescent and adult black women are more likely to be smokers than their white peers, but they smoke fewer cigarettes per day. 6. Adolescents from low income families, single parent families, and families with lower parental educational levels are more likely to become smokers. 7. Female and male adolescents are more likely to begin smoking if a parent or older sibling also smokes. 8. Adolescent smokers associate with peers who smoke and nonsmokers associate with nonsmoking peers. 9. Adolescent girls overestimate the percentage of their peers who smoke and they have a very positive image of the people in cigarette advertisements, but they are less likely than adoles- cent boys to see smoking as a social asset. 10. Adolescent girls who smoke tend to be more outgoing but feel less able to influence their future. 11. Adolescents experience stress due to feelings of unattrac- tiveness, incompetency in school achievement and personal re- lations, limited opportunity for personal growth and concern over future social and economic roles. This stress may be the common mechanism producing the increased rates of smoking in some groups. 12. The factors associated with successful quitting by adoles- cents of either sex are lower number of cigarettes smoked per day, higher educational aspirations and achievement, greater acceptance of the health risk of smoking, and having more nonsmokers among their friends. 13. It is possible that women and men modify their smoking in order to maintain a constant nicotine level. 14. Women are more likely than men to smoke in order to reduce stress. 15. Women at higher education and income levels are more 13 likely to succeed in quitting. Additional factors associated with successful quitting are a strong commitment to change, the use of behavioral techniques and reliable social support for quit- ting. Women have been reported to show lower rates than men of successful cessation following organized cessation programs, a difference which is less apparent in those programs that in- clude social support. 14 PART I: PATTERNS OF CIGARETTE SMOKING. PA'ITERNS OF CIGARETTE SMOKING Introduction This chapter traces the evolution of cigarette smoking among successive generations of American women and men during the twentieth century. The available evidence demonstrates that women have differed from men in their historical onset of wide- spread cigarette use, in the rate of diffusion of smoking among each new birth cohort, in their intensity of cigarette smoking, and in their use of various types of cigarettes. Four main conclusions emerge from this analysis. First, al- though men rapidly took up smoking during the early decades of this century, the proportion of adult female cigarette smokers did not exceed one-quarter until the onset of World War II. The peak intensity of smoking occurred among women born after 1920. Second, as a result of higher past rates of quitting and lower past rates of initiation -among men, as well as changes in the type of cigarette consumed, the smoking characteristics of women and men are now becoming increasingly similar. Third, the prevalence of cigarette smoking among adult American women and men is declining. This conclusion applies to all age groups, but with less certainty to the youngest generation of women. Fourth, increasing public awareness of the health con- sequences of smoking has resulted in significant changes in the nature of the cigarette product. Yet little is known about the effects of these product changes on the initiation, maintenance and cessation of smoking, particularly among women. Since the last review of cigarette smoking in the 1979 Report of the Surgeon General (24), two new national surveys have been performed under the sponsorship of the National Center for Health Statistics and the National Institute of Education. This chapter relies in part on the recent, preliminary results of these surveys. The Rise of Cigarette Smoking: 1900-1950 Although the use of cigarettes in the United States was ob- served as early as 1854 (42,48), consumption did not increase dramatically until after 1909. As shown in Figure 1, per capita consumption of all types of cigarettes increased by more than tenfold from 1900 to 1920. Despite a transient decline during the Great Depression, consumption increased from 665 cigarettes per capita in 1920 to 3,522 cigarettes per capita in 1950 (50). A continuous, nationally representative series of smoking prevalence rates during the period 1900 to 1950 is not publicly available. Nevertheless, numerous sources can be pieced to- 17 gether to characterize the differential growth of cigarette smoking among women and men. Figure 2 depicts estimates of the percentage of male and female current cigarette smokers in the greater Milwaukee area, as compiled by the Milwaukee Journal (38). In 1923, the first reported year of this survey, 51.8 percent of males aged 18 years and over smoked cigarettes. Sixty percent of male cigarette smokers also smoked pipes or cigars. In total, 87 per- cent of adult males used some type of tobacco (38). Although earlier survey estimates of male smoking rates are unavailable, it appears that the rise of cigarette consumption prior to 1923 reflected both the conversion of established male non-cigarette tobacco users to cigarette smoking and the re- cruitment of a new generatibn of younger male smokers during World War I. Innovations in cigarette production and market- ing have been cited as influential factors in this rapid growth (39,48,67). Camel cigarettes, a blend of lighter Burley smoking tobaccos with previously dominant Turkish cigarette tobaccos, were introduced in 1913 and within months attained a national market. Two similar brands, Lucky Strike and Chesterfield, fol- lowed in 1916 and 1919, respectively (39,48,67). During World War I, the War Industries Board estimated that soldiers of the Allied Armies consumed 60 to 70 percent more tobacco than they had used in civilian life (28,29). Cigarettes continued to dominate other forms of tobacco among male smokers throughout the 1920s and 1930s. By 1935, 62.5 percent of adult males in the greater Milwaukee area smoked cigarettes (Figure 2), while the percentages of pipe and cigar users had declined substantially. Average cigarette con- sumption frequency among men smokers increased from 3.7 packs per week in 1923 to 4.8 packs per week in 1935 (38). Consumption among men accelerated during World War II (Figures 1 and 2). In 1944, more than 25 percent of cigarettes produced in the U.S. were distributed to overseas forces (29), typically for free or at low cost (39), to the point where sub- sequent shortages developed in the domestic market. By 1948, 67.1 percent of adult males in the Milwaukee area smoked cigarettes (Figure 2). This estimate of the prevalence of cigarette use among urban men is confirmed by other local con- sumer surveys performed in that year. For example, in 1948, adult male smoking rates were 69.1 percent in Omaha, 67.4 per- cent in Birmingham, 69.4 percent in Philadelphia, 63.9 percent in Seattle, and 63.4 percent in San Jose (37). The growth of cigarette smoking among women occurred much later in the face of strong social taboos. Gottsegen noted that "the ultra smart set and women social leaders began to 18 smoke at the turn of the century" (13). By 1906, American "girl stenographers" were reported smoking cigarettes clandestinely (5). By 1919, some younger women in New York were reported smoking at dinner parties "with a trace of defiance" (48). By 1922, New York women were smoking openly on the streets and in bus tops (48). The first advertisement showing a woman smoking was Loril- lard's 1919 publicity for Helmar cigarettes (43,48). In 1926, a young women in a Liggett and Myers' Chesterfield advertise- ment did not smoke but pleaded, "Blow some my way" (6). In April, 1927, a Philip Morris advertisement for Marlboro cigar- ettes noted that "women, when they smoke at all, quickly de- velop discriminating taste," and that Marlboro cigarettes were as "mild as May" (2). In 1928, a Lucky Strike advertisement urged women to "reach for a Lucky instead of a sweet" (31,39,48). In 1934, Eleanor Roosevelt smoked cigarettes pub- licly (26). By 1940, handbags and cosmetic compacts were typi- cally designed to hold cigarettes (13). Although the Milwaukee Journal (38) reported that 16.7 per- cent of adult women smoked cigarettes in 1934 (Figure 2), prior estimates of women's smoking prevalence are sporadic. Wessel estimated that women consumed 5 percent of all cigarettes in 1924 (66). Moody's Investors Service estimated that women smoked 12 percent of all cigarettes smoked in 1929 (44). The average daily consumption of women smokers, as compared to men smokers, is not documented for that period. If men smokers consumed approximately twice as many cigarettes per day as women smokers (cf. the Milwaukee Journal's 1934 survey report that women's consumption frequency was 135 packs per year as compared to 244 packs per year for male smokers), and if the estimates of male smoking prevalence rates in Figure 2 are taken as nationally representative, and if there were approxi- mately 5 percent more adult males than adult females during the 1920 to 1930 decade (51), then Wessel's estimate yields a 6 percent adult female smoking prevalence in 1924 and Moody's estimate yields a 16 percent prevalence in 1929. The Milwaukee Journal series in Figure 2 must be interpreted in light of changes in the type of survey respondent and the wording of questions designed to elicit smoking practices (see caption to Figure 2). Moreover, this urban population series may not be representative of all American women. Neverthe- less, the publicly available survey data sources are consistent with the conclusion that smoking rates among women did not exceed one-quarter until the onset of World War II. Based on 10,000 applications for insurance policies during 1930 to 1940, Ley (32) estimated age-standardized smoking rates 19 of 63.9 percent of men and 20.8 percent of women aged 15 years and over. In 1935, Fortune Magazine, in the first nation-wide survey (12), reported that 52.5 percent of adult men and 18.1 percent of adult women smoked cigarettes. (See Table 1). Among those under 40 years of age, 65.5 percent of men and 26.2 percent of women were smokers. Among those over 40 years, 39.7 per- cent of men and 9.3 percent of women were smokers. Urban- rural differences in smoking were significant. The proportion of smokers ranged from 61.4 percent of men and 31.2 percent of women in cities with population over one million, to 44.1 percent of men and 8.6 percent of women in rural areas with population under 2,500. A survey of 250 urban women by the Market Re- search Corporation in 1937 reported 26 percent regular smokers and an additional 23 percent occasional smokers (47). After 1940, women's smoking rates accelerated, as new gen- erations of women, particularly younger women in urban areas, entered the labor force (see also title "Occupation and Envi- ronment" in this Report). In 1944, the Gallup Poll reported 48 percent adult male smokers and 36 percent adult female smok- ers (4). In 1949, the Gallup findings were 54 percent male and 33 percent female (4). Local consumer surveys of urban areas in 1948 revealed 37.6 percent adult women cigarette smokers in Milwaukee (see also Figure 2), 34.3 percent in Omaha, 35.6 per- cent in Birmingham, 46.7 percent in Philadelphia, 38.3 percent in Seattle, and 34.0 percent in San Jose (37). Conover, citing "trade journal" surveys in the three or four years prior to 1950, reported smoking prevalence rates of 65 to 70 percent among men and 40 to 45 percent among women (9). Although the differential growth of cigarette use among vari- ous socioeconomic groups is not well documented, the available data during this period suggest that male smoking rates de- clined with increasing income, while the relation of women's smoking to income was less clear. The Milwaukee Journal in 1945 noted 58 percent of men with monthly rents over $50 were smokers, and 75 percent of men with rents under $30 per month were smokers (38). Among women, the corresponding progor- tions were 32 and 37 percent respectively. In Mills and Porter's 1947 survey of Columbus, Ohio (36), 28.3 percent of white females and 64.9 percent white males smoked cigarettes, whereas 36.4 percent black females and 68.9 percent black males smoked cigarettes (estimates calculated from the age distribu- tion data provided in Table 6 of (36)). Kirchoff and Rigdon, in a survey of over 21,000 patients, visitors, and employees of hospi- tals in Houston and Galveston, noted that 63.2 percent white males, and 33.4 percent white females, 66.3 percent black males, and 32.2 black females smoked cigarettes (30). 20 All of the above findings reinforce the conclusion that the onset of widespread cigarette use among women lagged behind that of men by 25 to 30 years. This historical delay in the growth of cigarette smoking among women has also been documented for the United Kingdom (8,46,49). The Emergence of Filtertip Cigarettes: 1951-1963 As shown in Figure 1, total per capita consumption of cigar- ettes declined during 1953 to 1954. This decline was coincident with the appearance in the popular press of reports seriously suggesting a link between cigarette smoking and lung cancer (10,33,34,40). Thereafter, the consumption of filtertip cigarettes increased rapidly (Figure 1). In 1953 filtertip cigarettes consti- tuted 2.9 percent of cigarette production. By 1958, their share of production had increased to 45.3 percent, and by 1963 it was 58.0 percent (50). The transient decline during 1953 to 1954 in the number of cigarettes consumed was not clearly matched by a decrease in the proportion of cigarette smokers (27). At least in urban areas, the proportion of women smokers continued to increase. From 1953 to 1958, the prevalence of adult female smoking increased from 42.9 to 45;4 percent in Milwaukee (Figure 2), from 38.4 to 42.6 percent in Omaha, from 47.0 to 50.2 in Washington, D.C., and from 39.6 to 44.4 percent in San Jose (37). At the same time, both women and men rapidly converted to filtertip cigarettes. By 1958, filter cigarette use prevailed among 61 percent of women smokers and 42 percent of men smokers in Milwaukee, 54 percent of women smokers and 43 percent of men smokers in Omaha, 53 percent of women smokers and 47 percent of men smokers in Washington, D.C., and 59 per- cent of women smokers and 42 percent of men smokers in San Jose (37). In a nation-wide 1964 survey reported by the National Clearinghouse for Smoking and Health (64), 79 percent of adult female smokers and 54 percent of adult male smokers used filter cigarettes. Increasing Public Health Awareness: 1964- 1979 Per capita consumption reached a peak of 4,336 in 1963 (Fig- ure 1). It declined transiently after the appearance in January 1964 of the first Report of the Advisory Committee to the Sur- geon General (52). Per capita consumption continued to decline during the subsequent period of increased publicity concerning the health hazards of smoking (24,27). Since 1975, per capita consumption has declined at an average rate of 1.4 percent an- 21 .- 0 1900 `10 `20 `30 `40 `50 `E I total , I filter year FIGURE l.-Annual consumption of cigarettes and filtertip cigarettes per person aged 18 years and over, 1900- 1979* *Total per capita consumption data for 1917-19 and 1940-79 include overseas forces. Total per capita consumption for 1979 is preliminary estimate. Per capita consumption of filtertip cigarettes derived from annual data on the filtertip share of total cigarette production. SOURCE: U.S. Department of Agriculture (50). nually. The most recent 1979 estimate of 3,900 cigarettes per capita closely approximates that observed in 1952. Table 1 summarizes the results of selected, nationally repre- sentative surveys of adult cigarette use during the period 1935 to 1979. Except for the Fortune survey of 1935 (12) and the sup- plement to the Current Population Survey in 1955 (16), these data were collected under the sponsorship of the National Cen- ter for Health Statistics. The results of other recent national surveys of adult cigarette use (34,57,58,61,62,64), revealing very similar trends in the prevalence of smoking, were described in the 1979 Surgeon General's Report (24). Among adult males, the prevalence of regular cigarette use has declined continuously since 1965, with more marked de- creases in the intervals 1965 to 1970 and 1976 to 1978. (The abso- lute standard errors for the National Center for Health Statis- 22 tics estimates for 1970 to 1976 are less than 0.3 percent. The absolute standard errors for 1978 and 1979 are 0.6 percent.) Among adult women, the direction of change in smoking preva- lence is less clear. The estimates for the interval 1976 to 1979, however, suggest a recent downturn. The preliminary 1979 es- timate of 32.3 percent for the overall prevalence of adult cigarette smoking among both sexes represents the lowest re- corded value in at least 45 years. (The overall prevalence of cigarette smoking in the 1935 Fortune Magazine survey was 37.3 percent among adults of both sexes.) TABLE 1 .-Estimates of the prevalence of regular cigarette smoking among adults, United States, selected national surveys, 1935- 1979 Year Females Males 1935 18.1 52.5 1955 24.5 52.6 1965 33.3 51.1 1970 31.1 43.5 1974 31.9 42.7 1976 32.0 41.9 1978 29.9 37.0 1979 28.2 36.9 Data for 1978 are revisions of preliminary estimates reported in Harris (26). Data for 1979 are preliminary estimates based on a sample of over 13,000 interviews conducted during January-June 1979, provided by Health Interview Survey, National Center for Health Statistics. 1955 data represent persons 18 years and over. 1976 data represent persons 20 years and over. Estimates for the years 1965, 1970, 1974, 1978 and 1979 represent persons 17 years and over. SOURCE: Fortune Magazine (12), Haenszel, W. (16), U.S. Department of Health, Education, and Welfare (54-56, 58-59). These patterns of change in smoking prevalence applied to both white and black adults. For white men, the prevalence of regular smoking declined from 51.5 percent in 1965 to 36.3 per- cent in 1979. For black men, the prevalence of regular smoking declined from 60.8 percent in 1965 to 42.0 percent in 1979. For white women, smoking prevalence declined from 34.2 percent in 1965 to 28.2 percent in 1979. For black women smoking preva- lence declined from 34.4 percent in 1965 to 28.9 percent in 1979. Racial differences in cigarette use are discussed in greater de- tail in the chapter in this report entitled "Psychosocial and Be- havioral Aspects of Smoking in Women." Although the Milwaukee area data for 1964 to 1979 do not closely match these national estimates, Figure 2 does show a marked decline in smoking rates for both sexes during 1964 to 23 sco 19x) t920 1930 l940 l950 1960 1970 wcl YEAR FIGURE 2.-Percentage of adult current cigarette smokers in the greater Milwaukee area, 1924-1979* `Prior to 1941, the wording of the question eliciting cigarette use and the type of respondent are not recorded. From 1941 to 1954, men were asked, "Do you smoke cigarets?" From 1955 to 1959, all respondents were asked, "Do any men (women) in your household smoke cigarets with (without) a filter tip?" From 1960 to 1965 and in 1967, both men and women were asked "Have you bought, for your own use, cigarets with (without) a filter tip in the past 30 days?" In 1966 and from 1968 to 1979, both men and women were asked, "Have you bought, for your own use, cigarets with (without) a filtertip in the past 7 days?" All percentages reflect adults aged 18 years and over. Data for women from 1976 to 1979 (open circles) represent filtertip cigarette smokers only. SOURCE: Milwaukee Journal (38). 1970, a deceleration in the decline of smoking prevalence during 1971 to 1975, and a resumption of the decline in prevalence among men in the last four years. The cessation of cigarette smoking has been a significant fac- tor in explaining this overall decline in smoking prevalence (24). Column (i) of Table 2 presents estimates of the percentage of recent smokers who made a "fairly serious attempt to quit" 24 TABLE 2.-Estimated rates of attempted and successful quitting among adult, recent cigarette smokers, United States, 1970-1979 0) Percent of All Recent Smokers Who Attempted to Quit in Past Year (ii) Percent of Smokers Attempting to Quit in Past Year Who Reported Successfully Quitting (iii) Percent of All Recent Smokers Who Reported Successfully Quitting in Past Year Women 1970 1975 1978 `1979 Men 1970 1975 1978 1979 40.8 21.3 8.7 30.2 19.5 5.9 32.7 18.8 6.2 32.9 21.6 7.0 44.4 26.4 11.7 28.3 20.1 5.7 29.1 21.5 6.3 31.4 21.3 6.7 1970 and 1975 data from surveys of persons aged 21 years and over, conducted by National Clearinghouse for Smoking and Health. 1978 and 1979 data from the Health Interview Survey of persons aged 17 years and over, conducted by the U.S. National Center for Health Statistics. 1979 data are preliminary estimates based on interviews during January-June of that year. SOURCE: U.S. Department of Health, Education, and Welfare (54,61,62). within one year of the interview date. (Recent smokers include all current smokers plus those former smokers reported to have stopped within one year of interview.) Column (ii) shows what proportion of those attempting to quit regarded themselves as former smokers. Column (iii) shows the proportion of all recent smokers (whether or not they attempted or succeeded quitting) who reported themselves as recent former smokers. These data necessarily reflect respondents' self-assessment of both the seriousness of a quit attempt and their degree of success. Nevertheless, they do provide an indication of the representa- tive smoker's annual probability of attempting to quit, the probability of successful cessation given a quit attempt, and the overall annual smoking cessation rate. (The absolute standard errors in Table 4 are approximately 1.0 percent, 1.5 percent, and 0.3-0.5 percent for columns (i), (ii), and (iii), respectively.) All three indicators of smoking cessation were highest for men in 1970. Although a relatively large proportion of women smokers attempted to quit smoking in 1970 (column (i)), their 25 probability of success in that year was significantly lower than that of men (column (ii)). Quit attempt rates for both sexes (col- umn (i)) declined by 1975, but have increased in 1978 to 1979. With respect to the probability of attempting to quit and the success rate, adult men and women cigarette smokers are now indistinguishable. Table 3 displays recent changes in the distribution of cigarette brands according to F.T.C. "tar" contents. The propor- tion of adults smoking cigarettes with F.T.C. "tar" delivery less than 15 milligrams has increased from 9.5 percent of women and 2.9 percent of men in 1970 to 38.5 percent of women and 28.1 percent of me in the first half of 1979. A corresponding increase in the proportion of smokers of cigarettes with F.T.C. nicotine delivery less than 1.0 milligram was also observed. TABLE 3.-Estimated percentage distribution of adult current regular cigarette smokers according to F.T.C. "tar" content of primary brand, United States 1970-1979 Year Women 1970 1975 1978 1979 Men 1970 1975 1978 1979 Less Than 5.0 to 10.0 to 15.0 to 20.0 mg 5.0 mg 9.9 mg 14.9 mg 19.9 mg or More 0.7 2.0 6.8 67.1 23.4 1.2 1.2 15.0 75.1 7.5 5.3 8.8 21.1 59.2 5.7 5.6 9.5 23.4 55.4 6.1 0.2 0.9 1.8 61.3 28.1 0.6 1.1 11.0 68.1 19.2 3.3 6.2 13.5 63.5 13.6 2.6 8.5 17.0 60.1 11.8 1979 data are preliminary estimates provided by the National Center for Health Statistics. 1970 and 1975 data represent adults aged 21 years and over. 1978 and 1979 data represent adults aged 17 years and over. Estimates exclude those with unknown primary cigarette brand. SOURCE: U.S. Department of Health, Education, and Welfare (54,61,62). At the same time, the average daily cigarette consumption of adult smokers has increased. Table 4 shows recent changes in the distribution of reported daily cigarette consumption among current smokers. These data must be interpreted in light of possible underreporting biases (65) and, in particular, a strong tendency for respondents to round off their reported daily con- sumption to one pack. Nevertheless, the percent of women smoking less than one pack per day has declined, while the pro- portion smoking more than one pack per day has increased. Ex- cept for 1979, a similar trend is observed for men. (The absolute 26 standard errors of the 1978 and 1979 estimates are approxi- mately 1.0 percent.) The data of Table 4 represent the more recent portion of an apparently long run trend toward increasing daily cigarette consumption among regular smokers. In 1924, Milwaukee men smokers consumed an average of 10 cigarettes per day (38). In 1934, male smokers in Milwaukee consumed an average of 13.4 cigarettes per day, while women smokers consumed 7 per day (38). If cigarette consumption in 1935 was 1,564 per adult (Fig- ure 1 and (50)), and if the overall percentage of adult smokers was 37.3 percent (121, then mean consumption per adult smoker was 11.5 cigarettes per day. If consumption per adult was 3,597 in 1955 and if the prevalence of regular smoking was 37.6 per- cent (161, then mean consumption per adult in that year was 26.2 cigarettes. The corresponding calculation based on 1979 per capita consumption data and adult prevalence data (Figure 1 and Table 1) yields 33.3 cigarettes per day. Numerous epidemiological studies and other surveys per- formed during the period 1950 to 1965 have shown that for both TABLE I.-Estimated percentage distribution of adult current cigarette smokers according to reported daily consumption frequency, United States, 1965-1979 Year Women 1965 1970 1974 1976 1978 1979 Men 1965 1970 1974 1976 1978 1979 Percent Smoking Percent Smoking Less Than 15 25 Cigarettes or Cigarettes per Day More per Day 44.5 13.7 39.1 18.0 38.7 18.5 36.5 19.6 36.0 21.0 34.6 22.4 29.6 24.5 27.8 27.7 26.3 30.6 24.2 31.1 23.4 34.2 26.4 32.2 Data for 1976 represent persons aged 20 years and over. All other years represent persons aged 17 years and over. Data for 1979 are preliminary estimates based on interviews conducted during January-June of that year, provided by the Health Interview Survey, National Center for Health Statistics. SOURCE: Harris, J. E. (26), U.S. Department of Health, Education, and Welfare (54-56,58-59). 27 sexes, especially for women, the proportion of heavy smokers was larger among the younger age groups (14,16,19,20,22, 30,36,61,64). These findings applied to current daily cigarette consumption and lifetime maximum cigarette consumption. They are consistent with the hypothesis that regular smokers in past decades consumed fewer cigarettes per day than con- temporary smokers. The empirical relationships between rates of smoking cessa- tion (Table 2), changes in F.T.C. "tar" and nicotine delivery of cigarettes (Table 3), and increases in daily cigarette consump- tion (Table 4) are poorly understood (25). It is not known whether smokers of the lowest "tar" cigarettes are more or less likely to attempt to quit, or to succeed in quitting, than smokers of conventional filtertip or nonfilter cigarettes. The extent to which the act of switching to a lower "tar" cigarette may serve as a substitute for quitting may differ among women and men. The observed increase in daily cigarette consumption among current smokers could represent the effect of: higher cessation rates among lighter smokers; an increase in the daily cigarette consumption of continuing smokers; or an increased daily cigarette consumption of new entrants into the smoking popu- lation; or a combination of these effects (24). The relationship of these possible mechanisms to the observed increase in the pro- portion of filtertip cigarette and low "tar" cigarette smokers is not well elucidated. Exposure to Cigarette Smoke Among Successive Birth Cohorts Figures 3 and 4 depict estimates of the prevalence of current cigarette smoking from 1900 to 1978 among successive birth cohorts of men and women. Each continuously graphed time series corresponds to individuals born during a particular dec- ade. For example, among women born from 1931 to 1940 (Figure 4), who are now 40 to 49 years old, the prevalence of smoking rose rapidly during the post World War II period and reached a peak of 45 percent by 1963. Thereafter, their overall prevalence of smoking declined to 39 percent in 1978. These prevalence data were constructed from the reported lifetime smoking histories of over 13,000 respondents to the Health Interview Survey during July to December, 1978. (For related applications of this methodology, see 7,15,27). Although the accuracy of survey recollection of age started smoking, age of smoking cessation, and the duration of significant, temporary periods of abstinence is not known, no particular source of recall bias has been identified (15,16). However, the significantly higher mortality rates of continuing smokers, as compared to 28 70 60 50 k 40 z 8 E a 30. 20 10 k 0 1900 l9m MEN 1911- 2r 1920 YEAR FIGURE 3.-Changes in the prevalence of cigarette smoking among successive birth cohorts of men, 1900-1978 Calculated from the results of over 13,000 interviews conducted during the last two quarters of 1978, provided by Division of Health Interview Statistics, U.S. National Center for Health Statistics. SOURCE: U.S. Department of Health, Education, and Welfare (60). nonsmokers or former smokers (1,11,1'7,18,41,45,46,52), intro- duces a selection bias that may understate the prevalence of past smoking for the oldest cohorts. For example, on the basis of the insurance life tables recently reported by Cowell and Hirst (ll), a male cigarette smoker at age 32 has an estimated 25 Percent probability of surviving to age 80, as compared to 49 29 YEAR FIGURE I.-Changes in the prevalence of cigarette smoking among successive birth cohorts of women, 1900-1978 Calculated from the results of over 13,000 interviews conducted during the last two quarters of 1978, provided by Division of Health Interview Statistics, U.S. National Center for Health Statistics. SOURCE: U.S. Department of Health, Education, and Welfare (60). percent for a nonsmoker. The estimated probabilities of surviv- ing to age 60 are 80 percent for smokers and 93 percent for nonsmokers, respectively. Therefore, the peak smoking preva- lence rate of men born before 1900, calculated from 1978 survey responses to be 46 percent in 1937, could actually have been as high as 65 percent. Since individuals who quit smoking have a higher survival than continuing smokers (18,45), the actual point in time at which smoking rates peaked in this cohort may have been later than 1937. This effect is less likely to be impor- tant among men born after 1910, who are now approaching 70 years old. A similar calculation for men born, for example, be- tween 1911 and 1920 reveals that their peak smoking rate may have been understated by at most 2 or 3 percentage points. This source of bias is likely to be less important for older women. On the basis of age-specific mortality data reported by 30 Hammond in 1966 (18, Appendix Table 2b), women continuing to smoke cigarettes from age 35 would have an estimated 48 per- cent chance of surviving to age 80 years, as compared to 54 percent for nonsmokers. The estimated probabihties of survival to age 60 would be 91 percent for smokers and 93 percent for nonsmokers. If these survival data are currently applicable to women smokers and nonsmokers, then the estimated peak pre- valence rate of smoking among women born before 1910 could be understated by only one to two percentage points. Despite these possible biases, the predicted percentages of current smokers in Figures 3 and 4 are consistent with past survey and epidemiological data on the smoking habits of dif- ferent age groups (12,14-16,19-23,30,35,36,55). Comparison of Figures 3 and 4 reveals the following conclu- sions. (a) The most marked differences in smoking prevalence among men and women appeared in those individuals born be- fore 1910, who are now over `70 years of age. (b) Women born between 1921 and 1940, who are now approaching 40 to 59 years of age, experienced the highest smoking prevalence rates. These women have not yet reached the age where the absolute excess deaths of smokers over nonsmokers are expected to be- come substantial (1). (c) Among successive cohorts of men and women, the age of peak smoking prevalence has declined. Among younger cohorts, the peak smoking prevalence rates are declining, although the effect is less marked for women. Men born between 1911 and 1920 reached a peak smoking prevalence of 71 percent during 1946 to 1948, while those born 1941 to 1950 reached a peak smoking prevalence of 58 percent in 1968 to 1969. Women born 1921 to 1930 reached a peak prevalence of 44 per- cent in 1958 to 1960, while those born in 1941 to 1950 reached a peak smoking prevalence of 41 percent in 1970 to 1973. (d) Among men born 1951 to 1960, the rate of increase of smoking prevalence was slower than in previous cohorts. This slowing of the diffusion of smoking practices was coincident with the in- creased publicity concerning the health risks of smoking and the relatively high rate of quitting smoking among adult males in the late 1960s. A similar effect is not clearly discernible for young women in this cohort. In both sexes, among individuals who are now approaching ages 20 to 29, the prevalence of smok- ing has apparently peaked. Smoking rates among men and women in this age group are now nearly indistinguishable. Figure 5 depicts the mean age of starting regular smoking among successive birth cohorts, calculated from the same data as for Figures 3 and 4. The age of onset of smoking among women declined continuously during this century, to the point where it is nearly indistinguishable from that of men. As a re- 31 1 1 I 1 I * -l9ocl 1901-10 l9ll-20 193140 1921-30 &&l-6( Birth Cohort FIGURE 5.-Mean age of onset of regular smoking among successive birth cohorts of women and men SOURCE: U.S. Department of Health, Education, and Welfare (60). sult, each successive cohort of lifelong continuing women smok- ers will have an increasing number of years of exposure to cigarette smoke. Figure 6 depicts the accumulated years of cigarette smoking per capita, up to 1978, for each birth cohort. These magnitudes correspond to the total areas under each cohort prevalence curve in Figures 3 and 4. Among women, individuals born 1911 to 1920 have thus far experienced the largest total exposure per capita. However, as seen from Figure 4, unless the smoking pre- valence rates of women born during 1921 to 1940 decline more rapidly in the future, the lifetime exposure of these latter cohorts is likely to exceed that of the 1911 to 1920 cohort. It is not clear, however, whether the lifetime exposure of men born 32 from 1921 to 1940, now 50 to 69 years of age, will exceed that of previous generations. With each successive cohort, the ratio of female to male exposure increasingly approaches one. As a result of the rapid diffusion of filtertip cigarettes after 1950 (Figure l), each successive birth cohort was exposed to a different proportion of filtertip and nonfilter cigarettes. Details of the respondent's past history of cigarette brand use were not obtained in the 1978 Health Interview Survey. Such data, how- ever, are available from a series of over 2,000 interviews of cur- rent and former smokers aged 21 years and over, conducted by the Nationals Clearinghouse for Smoking and Health in 1975 (62). Figure 7 depicts, for the same birth cohorts, the proportion of lifetime years of smoking that represents filtertip cigarette. use. (The birth dates of the youngest cohorts in Figures 6 and 7 do not match due to differences in survey date and eligible age group.) Among men, there is a distinct, monotonically increas- ing relation between the proportion of filtertip cigarette expo-. sure and birth date. The corresponding relationship among women born before 1930 reflects their lower smoking cessation rates and, therefore, their continued use of filter cigarettes (62). A woman born in 1925, for example, who began smoking at age 21 (Figure 5), and who switched to filtertip cigarettes in 1957 (Figure 11, has now been smoking filtertip cigarettes for over two thirds of her smoking career and 40 percent of her entire life. The prevalence of cigarette smoking, age of initiation, lifetime duration of smoking, and the extent of use of various types of cigarettes are not the only measures of cigarette smoke expo- sure among a particular population. Trends in depth of inhala- tion, fraction of cigarette actually smoked, and other dimen- sions of the style of smoking also affect smoke exposure. How- ever, as discussed in the 1979 Surgeon General's Report (241, these are difficult to determine from survey data. In view of the concern over the accuracy of contemporaneous survey reports of daily cigarette consumption (65); past accounts of the time course of daily cigarette consumption would be difficult to as- sess accurately. Nevertheless, the evidence presented in the previous section is consistent with the conclusion that the aver- age daily cigarette consumption among regular cigarette users has increased among each successive birth cohort. Cigarette Smoking Among Young Women The more marked decline in peak smoking prevalence among men born between 1951 and 1960, now approaching 20 to 29 years of age, reflected a slowing in the rate of initiation of smok- 33 .-. .s- - ,-- - - - -1900-1901-x) 1911-x)-1921-301931-40 1941-50 1951-60 Birth Cohort FIGURE 6.-Accumulated years of cigarette smoking per person among successive birth cohorts of women and men, 1978 SOURCE: U.S. Department of Health, Education, and Welfare (60). ing that was not observed in women of the same age group. This trend appears to be continuing in the next birth cohort. Table 5 reports the results of nation-wide surveys of teenage cigarette smoking during 1968 to 1979. The most recent survey, conducted by the National Institute of Education during late 1978 and early 1979, presents the preliminary results of over 2,600 telephone interviews of individuals aged 12 to 18 years. In this survey, but not in the others reported in Table 5, women and men 19 years of age were also interviewed. Otherwise, the survey sampling techniques and interview questions regarding smoking practices were the same for all the surveys. (See notes to Table 5). The data in Table 5 support the conclusion that the rate of initiation of smoking among even the youngest men is declining, 34 - - W-I - - -1900 1901-K) 1911-20 X32-30 1931-4011-50-1951-54 Birth Cohort - FIGURE 7.-Proportion of years smoking filtertip cigarettes among successive birth cohorts of women and men, 1975 Calculated from the results of over 2,000 smoking histories of men and women who had ever smoked, collected by National Clearinghouse for Smoking and Health. SOURCE: U.S. Department of Health, Education, and Welfare (62). an effect that is not present among young women. These results must be interpreted in light of sampling variability. (The abso- lute standard errors on the 1979 estimates for ages 15-16 and 17-18 are about 2 percent.) As in adult surveys, non-response biases must also be considered. Nevertheless, the findings in Table 5 are consistent with other nation-wide estimates of smoking rates among young women and men. The prevalence of current regular smoking among respondents 17 to 19 years of age in this survey was 28.1 percent for females and 22.8 percent for males. The comparable rates for women and men aged 17 to l9 from the Health Interview Survey were 29.2 percent and 27.5 percent, respectively. An analysis of the growth of smoking Prevalence among this group, performed in the same manner as 35 TABLE 5 .-Estimated percentage of current, regular cigarette smokers, ages 12-18, United States, 1968-1979 Year Ages 12-14 Ages 15-16 - Ages 17-18 Females 1968 1970 1972 1974 1979 Males 1968 1970 1972 1974 1979 - 0.6 9.6 18.6 3.0 14.4 22.8 2.8 16.3 25.3 4.9 20.2 25.9 4.4 11.8 26.2 2.9 17.0 30.2 5.7 19.5 37.3 4.6 17.8 30.2 4.2 18.1 31.0 3.2 13.5 19.3 Nation-wide surveys performed by National Clearinghouse for Smoking and Health, 1968-1974, and National Institute of Education, 1979. Current regular smokers in all surveys include all those who smoke cigarettes at least weekly. In 1979, approximately SO percent of current regular smokers used cigarettes on a daily basis. For 1979 only, 29.7 percent males and 31.9 percent females, aged 19, were reported as regular smokers. SOURCE: US. Department of Health, Education, and Welfare (63). that of Figures 3 and 4, suggested that smoking rates among this group of women grew rapidly and exceeded those of men by 1975. The future smoking habits of this generation of young women cannot be accurately predicted. Smoking among adolescent women is discussed in greater de- tail in the chapter entitled "Psychosocial and Behavioral As- pects of Smoking in Women" in this Report. Summary 1. Women have differed from men in their historical onset of widespread cigarette use, in the rate of diffusion of smoking among each new birth cohort, in their intensity of cigarette smoking and their use of various types of cigarettes. 2. Men took up cigarette smoking rapidly at the beginning of the twentieth century, especially during World War I. Cigar- ettes rapidly replaced other forms of tobacco. By 1925, approxi- mately 50 percent of adult males were cigarette smokers. Smok- ing among men accelerated rapidly during World War II. By 1950, the prevalence of cigarette use among men approached 70 percent in some urban areas. 3. The onset of widespread cigarette use among women lag- ged behind that of men by 25 to 30 years. The proportion of adult 36 women smoking cigarettes did not exceed one-quarter until the onset of World War II. 4. Between 1951 and 1963, increasing proportions of women and men smokers converted to filter-tip cigarettes. By 1964, 79 percent of adult women smokers and 54 percent of adult men smokers used filter cigarettes. 5. After reaching a peak value of 4,336 in 1963, annual per capita consumption of cigarettes declined in 1964, 1968-70, and in the period since 1975. The most recent estimate of 3,900 cigarettes per capita in 1979 is approximately equal to that ob- served in 1952. 6. From 1965 to 1978, the proportion of adult men cigarette smokers declined from 51 to 37 percent. The preliminary esti- mate of adult men's smoking prevalence for 1979 is 36.9 percent. From 1965 to 1976, the proportion of adult women smokers re- mained virtually unchanged at 32 to 33 percent. Since 1976, the proportion of women smokers has declined to below 30 percent. For 1979, the preliminary estimate of adult women's smoking prevalence is 28.2 percent. The overall smoking prevalence of 32.3 percent for both sexes in 1979 represents the lowest re- corded value in at least 45 years. 7. The proportion of adult smokers attempting to quit smok- ing declined from 1970 to 1975, but increased in 1978-1979. In contrast to past years, the proportions of women and men now attempting to quit smoking, and their reported quitting rates, are indistinguishable. Approximately one in three adult smok- ers now makes a serious attempt to quit smoking during the course of a year. Approximately one in five of those who attempt to quit subsequently succeed. 8. The proportion of adult smokers using lower "tar" and nicotine brands has increased substantially. In 1979,39 percent of adult women smokers and 28 percent of adult men smokers reported primary brands with F.T.C. "tar" delivery less than 15.0 milligrams. It is not known whether smokers of the lowest "tar" cigarettes are more or less likely to attempt to quit smok- ing, or to succeed in quitting, than smokers of conventional fil- tertip or non-filter cigarettes. 9. The average number of cigarettes smoked by women and men current smokers has increased. The relationship of this finding to recent declines in the average F.T.C. "tar" and nicotine deliveries of cigarettes is not well understood. 10. With each successive generation, the smoking character- istics of women and men have become increasingly similar. 11. Among women, the average age of onset of regular smok- ing progressively declined with each successive birth cohort- from 35 years of age for those born before 1900, to 16 years of 37 age among those born 1951 to 1960. The average age of onset of regular smoking among young women is now virtually identical to that of young men. 12. Maximum smoking prevalence rates have declined sub- stantially in recent birth cohorts of men. Men born 1931 to 1940 reached a peak smoking proportion of 61 percent during 1960- 62, while men born 1941 to 1950 reached a peak smoking propor- tion of 58 percent in 1968-69. Men born 1951 to 1960 reached a peak smoking proportion of 40 percent in 1976. Among recent cohorts of women, peak smoking prevalence rates have declined to a much smaller extent. Women bo% 1931 to 1940 reached a peak smoking proportion of 45 percent in 1966-68, while women born 1941 to 1950 reached a peak smoking proportion of 41 per- cent in 1970-73. Women born 1951 to 1960 reached a peak smok- ing proportion of 38 percent in 1976. Among the generation born 1951 to 1960, the proportions of women and men smoking cigarettes are now virtually identical. 13. The proportions of women and men smokers in each age group have declined. Among those born before 1951, this decline in smoking prevalence resulted mainly from smoking cessation. By contrast, the observed decline in smoking prevalence among younger men born 1951 to 1960 has resulted from both smo!cing cessation and a lower rate of smoking initiation. This decline in the rate of onset of smoking among young men has not been observed for young women. 14. Recent survey data on adolescent smoking habits reveal that by ages 17 to 19, smoking prevalence among women ex- ceeds that of men. This finding supports the conclusion that the rate of initiation of smoking among young men-but not that of young women-is declining. The future cigarette use of the youngest generations of women is uncertain. 15. With each successive birth cohort, the accumulated years of cigarette smoking per woman has progressively approached the accumulated years of cigarette smoking per man. Each suc- cessive birth cohort has also experienced progressively smaller sex differences in the fraction of lifetime years of smoking that represents filtertip cigarette use. 16. Among men born during this century, each successive birth cohort has thus far experienced fewer cumulative years of cigarette smoking, higher proportionate exposure to filter-tip cigarettes, and lower smoking prevalence rates. This relation- ship between birth date and cigarette smoke exposure does not hold for women. Women born 1921 to 1940 have experienced substantially higher smoking prevalence rates than earlier generations. Unless they quit smoking in substantial numbers, these women, currently aged 40 to 59, will surpass older women 38 in total years of cigarette smoking per capita, the total years of nonfilter cigarette smoking per capita, and in the total number of cigarettes smoked. 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Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1980, pp. 333-340. (26) HOOVER, I.H. Hail to the chief. Saturday Evening Post, May 5, 1934. (27) IPPOLITO, R.A., MURPHY, R.D., SANT, D. Staff Report on Consumer Responses to Cigarette Health Information. U.S. Federal Trade Com- mission, Bureau of Economics, August 1979. (28) JACKSON, E.L. The Consumption of Tobacco Products: A Descriptive Economic Analysis, United States 1900- 1940. Doctoral Dissertation, Harvard University, Cambridge, Massachusetts, 1942. (29) JACKSON, E.L. Trends in the consumption of tobacco products, United States, 1900-1950. Journal of Farm Economics 32(4, Part 2): 881-893, November 1950. (SO) KIRCHOFF, H., RIGDON, R.H. Smoking habits of 21,612 indivi luals in Texas. Journal of the National Cancer Institute 16(5): 128'7-1304, April 1956. (31) LEWINE, H. Good-Bye to All That. New York, McGraw-Hill Book Co., 1970. (32) LEY, H.A., Jr. The incidence of smoking and drinking among 10,000 examinees. 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July 1974. (64) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, PUBLIC HEALTH SERVICE, NATIONAL CLEARINGHOUSE FOR SMOKING AND HEALTH. Use of Tobacco, Practices, Attitudes, Knowledge, and Beliefs, United States, Fall 1964 and Spring 1966. July 1969. (65) WARNER, K. E. Possible increases in the underreporting of cigarette consumption. Journal of the American Statistical Association 73(362): 314-318, June 1978. (66) WESSEL, C.A. The first sixty billions are the hardest for the cigarette industry. Printers' Ink 120(5): 3-6,137-146, January 31, 1924. (67) WHITTEN, I.T. Brand Performance in the Cigarette Industry and the Advantage of Early Entry, 1913-74. U.S. Federal Trade Commission, June 1979. 42 PART II: 3lOMEDICAL ASPECTS OF SMOKING. MORTALITY. MORTALITY Idroduction and Background Cigarette smoking has been cited as the single most impor- tant environmental factor contributing to premature mortality in the United States (17). A great many epidemiological studies support this statement. The emphasis, in general, has been to study males rather than females. Perhaps the main reason for this discrepancy is that,. in the past, relatively few women smoked whereas smoking was common among men. The upward trend in lung cancer death rates in males observed in the 1950s by Dorn and others stimulated epidemiologic studies of smoking and health, especially among males (2,3). According to the 1979 Surgeon General's Report: It is important that attention be called specifically to the mortality that females experience as a result of cigarette smoking. There has been an increase in smoking among teen- age girls over the past 10 years. At present, the percentages of teenage boys smoking and teenage girls smoking are nearly identical. For some ages,.there are more teenage girl smokers than boy smokers. Over the past 10 years, there has been a gradual reduction in the percentage of the adult population that is smoking. Men have quit in greater numbers than women. There has been only a modest drop in the percentage of women who are smoking. In Canada and several European countries, smoking is decreasing among men but increasing among women. The present report reviews some of the more important pro- spective epidemiological studies on cigarette smoking and mor- tality among women. MortaIityTrenda As background, this section reviews mortality levels by sex and color in the United States, by examining recent trends in overall mortality and in three causes of death which have been strongly linked to cigarette smoking-ischemic heart disease, lung cancer and the combined category of bronchitis, em- physema and asthma.*. These trends are displayed in Figures 1 through 4. For all causes of death (Figure l), the trend for females was downwards over the entire period from 1950 to 1977 with a somewhat steeper decline in recent years. The trend in death rates among males was essentially flat during most of the 1950s and 196Os, but has been sharply downwards since the late 1960s. *The category, chronic obstructive lung disease, may include asthma, a dis- ease which is not causally related to smoking. 45 `-..m..* Nonwhite Males o ? ? ? ? ???????? ???? o ? ? ? ??? o ? ? ? ? ?????? Nonwhite Females `White Females 1950 1955 1960 1965 1970 1975 FIGURE 1 .-Age-adjusted death rates* for all causes of death by color and sex; United States, 1950-1977 *Adjusted by the direct method to the U.S. population, 1940. SOURCE: National Center for Health Statistics (9). For ischemic heart disease, the death rate trend for all sex and color groups was upwards until it flattened in the 1960s. It has been sharply downward since then (Figure 2). For lung cancer the trend was sharply upwards during the entire period, especially for females (Figure 3). For bronchitis, emphysema and asthma, the death rate has been sharply upwards for all sex and color groups except non- white females. In recent years there appears to be a leveling off for males but not for white females (Figure 4). Other inves- tigators have studied these trends, especially in relation to changes in cigarette smoking habits in the United States and their potential effect upon mortality from the smoking-related diseases (8,12). There are inherent difficulties in interpreting trend data and in particular in relating one trend to another. Epidemiological Studies During the past 30 years, there have been eight large pro- 46 jnwhite Females ) 100 50 1950 1955 1960 1965 1970 1975 e- 6th Rev. - -7th Rev.--- 8th Rev.& FIGURE 2.-Age-adjusted death rates* for ischemic heart disease** by color and sex, United States, 1950-1977 *Adjusted by the direct method to the U.S. population, 1940. **ICD 6th and 7th Rev. No. 420 and 8th Rev. Nos. 410, 413. SOURCE: National Center for Health Statistics (9). spective epidemiological studies specifically designed to de- lineate the relationship between tobacco smoking and the de- velopment of disease. In five of these studies data are available on women as well as men. These studies are outlined below and in Table 1 (1,2,4,5,7,10). To these published results are added unpublished data from two other studies conducted by the Na- tional Heart, Lung, and Blood Institute, and from the British Doctors Study. THE AMERICAN CANCER SOCIETY 25STATE STUDY (6) The largest study by far is the American Cancer Society study of men and women in 25 states. In late 1959 and early 1960, the American Cancer Society enrolled 1,078,894 men and women in a prospective study. All segments of the population were 47 g TABLE I.-Outline of prospective studies of smoking and mortality among women Authors Hammond (5) Cederlof Friberg Hrubec Lorich (1) Best Josie Walker (4) Hirayama (7) Doll Gray Pet0 (2) Framingham Heart Study (10) British-Norwegian Migrant Study British Norwegian (10) Type of subjects Probability Total pop. Sample plus Probability sample Volunteers sample of Canadian of 29 health volunteers of British & Norwe- in 25 the Swedish pensioners districts British from Framingham, gian migrants to states population & dependents in Japan doctors Mass. (whites) U.S. in 12 states Number of female subjects Age range at baseline Year of enrollment Years of follow-up reported Number of female deaths Basic statisti- cal measure 562,671 27,732 14,226 142,857 6,192 2,873 9,057 5,337 35-84 la-69 ~30 t0 80 + 1959 1963 1955 40 t 25 to 75 t 29-62 45-74 45-74 1951 1948 1962 1962 4 10 6 5 22 26 5 5 16,773 1,955 1,794 1,508 1,090 Person-yrs. Probability Probability Person-yrs. Person-yrs. death of death of death death death rate in 10 yrs. in 6 yrs. rate rate 662 Probability of death in 26 yrs. 588 354 Probability of death in in 5 years White Males Nonwhite Females White Females 50 1950 1955 1960 1965 1970 1975 -6th Rev. -7th Rev.-6th Rev.- FIGURE 3.-Age-adjusted death rates* for malignant neoplasm of trachea, bronchus, and lung,** by color and sex, United States, 1950-1977 *Adjusted by the direct method to the U.S. population, 1940. o *ICD 6th and 7th Rev. Nos. 162, 163 and 8th Rev. No. 162. SOURCE: National Center for Health Statistics (9). included except groups that could not be traced easily. A lengthy initial questionnaire contained information on age, sex, race, 49 Nonwhiie Males Nonwhite Females -(- r White Females 30 20 10 5 2 1950 1955 1960 1965 1970 1975 -6th Rev. -7th f%?V.~8th Rev.-----, FIGURE 4.-Age-adjusted death rates* for bronchitis, emphysema, and asthma ** by color and sex, United States, 1950- 1977 *Adjusted by the direct method to the U.S. population, 1940. **ICD 6th and 7th Rev. Nos. 241,501,502,527.1 and 8th Rev. Nos. 490,493,549.3. SOURCE: National Center for Health Statistics (9). education, place of residence, family history, past diseases, present physical complaints, occupational exposures, and vari- ous habits. Information on smoking included: type of tobacco used, number of cigarettes smoked per day, degree of inhala- tion, age at which smoking began, and the brand of cigarettes used from which the "tar" and nicotine content of the cigarette could be calculated. Nearly 93 percent of the survivors were successfully followed for a 12-year period. Only limited data 50 have been published for the l&year period for women; the main body of published data for women is based on the first 4-year period of the follow-up. THE SWEDISH STUDY (1) A national probability sample of 55,000 Swedish men and women was surveyed in 1963, by a mailed questionnaire to which 89 percent of the sample responded. Information was col- lected on smoking status at the time of the query and at specified intervals during the previous 9 years according to type and amount of smoking and degree of inhalation. The question- naire identified age, sex, location (urban, nonurban), income, and occuption of each subject. A IO-year follow-up on smoking- related mortality was published in 1975. THE CANADIAN VETERANS STUDY (4) Beginning in 1955, the Department of National Health and Welfare, Canada, enrolled 78,000 men (veterans on pension) and 14,000 women (mostly widows of veterans) in a study of smoking-related mortality. Information was obtained on age, detailed smoking history, residence, and occupation. During the 6 years of follow-up, 9,491 of the men and 1,794 of the women died. No recent follow-up has been reported. JAPANESE STUDY OF 29 HEALTH DISTRICTS (7) In late 1965, a total of 265,118 men and women in 29 health districts in Japan were enrolled in a prospective study. This represented from 91 to 99 percent of the population aged 40 and older in these districts. This study provides a unique opportu- nity to examine the relationship of cigarette smoking to death rates in a population with genetic, dietary, and other cultural differences from previously examined Western populations. At the time of the eighth year of follow-up 11,858 deaths had oc- curred and there were 1,269,382 person-years of observation. For women, however, the main body of published data is based on 5 years of follow-up. THE BRITISH DOCTORS STUDY (2) In 1951, the British Medical Association forwarded to all British doctors a questionnaire about their smoking habits. A total of 34,400 men and 6,207 women responded. With few excep- tions, all men who replied in 1951 have been followed for 20 years. Further inquiries about changes in tobacco use and some additional demographic characteristics of the men were made in 51 1957, 1966, and 1972. More than 10,000 deaths have occurred in this population during the past 20 years. For women, published data are available for 11 years of follow-up, and unpublished data are available for 22 years of follow-up. THE FRAMINGHAM HEART STUDY (10) The Framingham Study began in 1948 with a cohort of 2,336 white men and 2,873 white women who were age 29 to 62 at the beginning of the study and were residents of Framingham, Massachusetts. Persons were selected by a sample of house- holds plus enlistment of volunteers. These individuals were re- called and examined every 2 years thereafter. The routine cardiovascular examination consisted of a medi- cal history, physical examination, blood chemistries, body measurements, vital capacity, chest x-ray and a 12-lead elec- trocardiogram. Mortality and morbidity were documented in detail from the routine biennial examination, hospital records, death certificates, physician records and the next-of-kin. Information on smoking was obtained at the first examina- tion (and at several thereafter). A series of monographs and over 200 articles on the Framingham Study have now become part of the scientific literature. Data on the relationship of cigarette smoking to cardiovascu- lar morbidity and mortality, for both men and women, have been reported in the Framingham literature, but the longest reported follow-up period has been 18 years with relatively few deaths having occurred by then, especially among the women (11). Data given below are based on a longer follow-up period, 26 years, and have not been published. The study is presently in its 16th biennial cycle. THE BRITISH-NORWEGIAN MIGRANT STUDY(10) In October 1962, morbidity questionnaires requesting infor- mation on personal and demographic characteristics, including cigarette smoking, as well as symptoms of cardiorespiratory disease were sent to approximately 32,000 British migrants and 18,000 Norwegian migrants to the United States residing in 12 states. These samples were drawn from the 25 percent random sample of the entire population for which country of birth was recorded in the 1960 United States Census. The 12 states in- volved contained about three-fourths of the British and Norwe- gian immigrants to the United States. The response rate to the questionnaire was 86 percent. The respondents were then fol- lowed for survivorship and cause of death data for 5 years, from January 1, 1963 through December 31, 1967. The number of 52 morbidity questionnaire respondents and deaths occurring among them from 1963 to 1967 for ages 45 to 74, by sex, were as follows. Males Females Respondents Deaths Respondents Deaths British 10,103 1,181 9,057 588 Norwegian 5,902 643 5,337 354 Several reports dealing with the prevalence survey and with a related cross-sectional study of mortality, including data on cigarette smoking for women as well as for men, have been pub- lished (13,14,15,16). The main results of the prevalence study may be briefly summarized. Four syndromes were considered: "persistent cough and phlegm," "chronic bronchitis," "angina," and "possible infarction." The relation of smoking to the preva- lence of these symptoms was clearly demonstrated for women as well as for men. The main results of the cross-sectional mor- tality study indicated substantial excess mortality for cigarette smokers, as compared to nonsmokers, for both women and men. Overall Mortality for Females-Cigarette Smokers Versus Nonsmokers MORTALITY RATIOS In this report the mortality ratio is the basic means of com- paring cigarette smokers with nonsmokers. It is usually ob- tained by dividing a "death rate" (or other mortality measure) for a classification of smokers by the "death rate" (or other mortality measure) of a comparable group of nonsmokers. The "death rate" may differ markedly from one study to another. In some studies it is calculated by means of person-years and is a l-year measure; in others it is a probability measure; it may be a 5-year, lo-year or, as in the Framingham Study, a 26-year measure. Differences in mortality ratios may arise because of these factors. Because of the arithmetic nature of this ratio, there is a tend- ency for lower ratios to result with higher underlying levels of mortality. For example, with an underlying mortality level of 10 Percent per year for nonsmokers, the mortality ratio for a group of smokers can at most be 10 if all the smokers died within the Year. With a mortality level of 50 percent for nonsmokers, the maximum possible ratio is 2. Since "death rates" increase with age, there is a tendency for the mortality ratios to decline with age, since its range is restricted. 53 TABLE 2.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; females in 24 states Number of cigarettes per day Nonsmokers l-9 10-19 20-39 40+ All Smokers Age Total, 35-84 35-44 45-54 55-64 65-74 75-84 Age-adjusted' 1.00 1.00 1.00 1.00 1.00 1.00 .90 .95 .99 1.09 1.07 .97 .97 1.22 1.31 1.18 1.21 1.19 1.35 1.54 1.46 1.51 .85 1.45 1.56 1.96 1.23 1.42 * 1.63 1.12 1.31 1.27 1.31 1.14 1.26 `Adjusted by the direct method using as standard the age distribution of all women. *Not shown--less than 5 expected deaths. SOURCE: Hammond, E.C. (5). TABLE 3.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; females in the Swedish study Number of cigarettes Age Total, 18-69 per day 18-39 40-49 50-59 60-69 Age-adjusted Nonsmokers 1.0 1.0 1.0 1.0 1.0 l-7 1.0 1.6 1.1 .9 1.0 8-15 2.3 2.2 1.7 1.4 1.5 16+ 4.5 2.2 1.5 2.2 2.0 All Smokers 1.8 1.9 1.3 1.1 1.2 SOURCE: Cederlof, R. (2). For simplicity, however, mortality ratios are used throughout this review; it is recognized that these ratios are not strictly comparable from one study to another nor from one age group to another. AMOUNT SMOKED AND AGE Overall mortality ratios by amount smoked and age are pres- ented for several of the studies in Tables 2-7. Except for the Swedish study (Table 3), age-adjusted ratios were calculated for each level of smoking in each study. Adjustment was by the direct method, using as standard the age distribution of all 54 TABLE 4.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; females in the Canadian study Number of cigarettes per day Age Total, 30+ 30-54 55-64 65-74 75+ Age-adjusted' Nonsmokers 1.00 1.00 1.00 1.00 1.00 l-9 1.59 1.09 1.05 .92 1.20 10+ 2.25 .93 1.20 * 1.43 All Smokers 1.95 1.03 1.10 .95 1.31 `Adjusted by the direct method using as standard the age distribution of all women. *Not shown-less than 5 expected deaths. SOURCE: Best, E.W.R. (1). TABLE 5.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; females in the Framingham Heart Study Number of cigarettes per day 29-44 Age 45-54 55-62 Total, 29-62 Age-Adjusted' Nonsmokers 1.00 1.00 1.00 1.00 <20 1.42 1.21 1.07 1.30 20 1.84 1.48 1.13 1.62 21+ 2.25 1.14 * 1.72 All Smokers 1.62 1.28 1.07 1.43 `Adjusted by the direct method using as standard the age distribution of all women. *Not shown-less than 5 expected deaths. SOURCE: National Heart, Lung, and Blood Institute (10). women in the particular study. For the Swedish study the age- adjusted values were taken directly from the report. Mortality ratios shown in Table 2 are considered especially important since they are derived from the study with the largest survivorship experience. Mortality ratios generally rose with the amount smoked for each age group except for the 75 to 84 age group. The age-ratios were .97 for the l-to-g-cigarettes per day group, 1.19 for the lo-to-19 per day group, 1.45 for the 20-39 group, and 1.63 for the IO-plus group. For all cigarette smokers the age-adjusted mortality ratio was 1.26. By age group, mortality ratios were 1.12 for the 35-to-44 age group, 55 TABLE S.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; British females Number of cigarettes per day 45-54 Age 55-64 65-74 Total, 45-74 Age-adjusted' Nonsmokers 1.00 1.00 1.00 1.00 <20 1.49 1.09 .79 1.08 20+ 1.86 1.51 1.55 1.60 All Smokers 1.66 1.25 .98 1.25 `Adjusted by the direct method using as standard the age distribution of all women. SOURCE: National Heart, Lung, and Blood Institute (10). TABLE 7.-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day and age; Norwegian females Number of cigarettes per day Age Total, 45-74 45-64 65-74 Age-adjusted' Nonsmokers 1.00 1.00 1.00 <20 1.54 1.07 1.33 20+ 1.41 .89 1.18 All smokers 1.49 1.02 1.28 `Adjusted by the direct method using as standard the age distribution of all women. SOURCE: National Heart, Lung, and Blood Institute (10). 1.31 for the 45-to-54 age group, 1.27 for the 55-to-65 group, 1.31 for the 65-to-74 group and 1.14 for the 75-to-84 age group. Data from the Swedish study (Table 3) appear to be rea- sonably consistent with the ACS data in Table 2. The l-to-7- cigarettes-per-day group had an age-adjusted mortality ratio of 1.0 (compared with .97 for the l-to-9 group above) and 2.0 for the 16-plus group (compared with 1.63 for the 40-plus group above). For three of the four age groups, the mortality ratios were directly associated with level of smoking. By age group, the highest mortality ratios were observed for the two youngest age groups and the lowest for the two oldest groups. The overall ratio for all cigarette smokers was 1.2. For the other studies (Tables 4-7) mortality patterns were generally similar in that mortality ratios tended to be highest 56 TABLE K-Mortality ratios for female cigarette smokers by number of cigarettes smoked per day; females in the British Doctors Study Number of cigarettes per day Total, Age-adjusted' Nonsmokers 1.00 1-14 0.94 15-24 1.54 25+ 1.66 All Smokers `Based on annual death rates standardized for age. SOURCE: Cederlof, R. (2). 1.23 with heaviest smoking and tended to be lowest at the oldest ages. For the Japanese study and the British Doctors Study, mor- tality ratios by amount smoked and age were not reported. However, an overall age-adjusted mortality ratio for female cigarette smokers was reported in the Japanese study, while in the British Doctors Study this ratio was obtained from unpub- lished data based on 22 years of follow-up (Table 8). We list these along with the overall ratios for the other studies: Study Total mortality ratio age-adjusted American Cancer Society 1.26 Swedish 1.20 Canadian 1.31 Japanese 1.28 British Doctors 1.23 Framingham 1.43 British Migrants 1.25 Norwegian Migrants 1.28 All ratios here are greater than unity. The largest ratio is 1.43 for Framingham. The other seven ratios are close to one another, ranging from 1.2 for the Swedish study to 1.31 for the Canadian study. DURATION OF SMOKING Overall mortality ratios for women increased with duration of the smoking habit based on data from the Canadian and 57 TABLE 9.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and age began smoking; subjects aged 45-54 at start of study. 25State Study Number of cigarettes per day Age began smoking 25+ 15-24 Nonsmokers 1.00 1.00 l-9 0.95 0.88 10-19 1.17 1.23 20-39 1.33 1.61 40+ ** 1.85 **Ratio not shown-less than 10 expected deaths. SOURCE: Hammond, E.C. (5). TABLE lO.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and degree of inhalation. Subjects aged 45-54 at start of study. 25-State Study Number of cigarettes per day Degree of inhalation of smoke None-Slight Moderate- Deep l-9 0.85 1.04 10-19 1.27 1.17 20-39 1.41 1.58 40+ ** 2.19 **Ratio not shown-less than 10 expected deaths. SOURCE: Hammond, E.C. (5). Swedish studies (1,4). Among Canadian women who smoked for 10 or more years the mortality ratio, adjusted for age, was 1.37 compared to a ratio of 1.08 for women smoking less than 10 years. In the Swedish study an excess risk was found for women smoking 30 or more years (1.4). For those smoking less than 30 years the ratio was 1.0. AGE BEGAN SMOKING Table 9 shows mortality ratios for women who were 45 to 54 by number of cigarettes smoked per day and age began smoking (5). Except for the light cigarette smokers (1-to-g-per-day), those taking up the habit at ages 15 to 24 had higher mortality ratios than those who started smoking at older ages. 58 TABLE Il.-Age-adjusted mortality ratios of female cigarette smokers, by number of cigarettes smoked per day and degree of inhalation and age. 25-State Study Degree Age of Inhalation 35-44 45-54 55-64 65-74 75-84 Nonsmokers 1.00 1.00 1.00 1.00 1.00 None o ? 1.01 1.11 1.12 0.96 Slight 1.22 1.21 1.28 1.26 1.21 Moderate 1.05 1.30 1.32 1.41 ** Deep 1.40 1.78 1.64 ** ** **Ratio not shown-less than 10 expected deaths. SOURCE: Hammond, E.C. (5). Mortality data for women smokers, according to age started, are also available from the Swedish study (1); age-adjusted ratios were reported as 1.7, 1.6, and 1.1 for age started less than 17, 17 to 18, and 19 plus, respectively. INHALATION Table 10 shows mortality ratios for female cigarette smokers who were 45 to 54 years of age according to number of cigarettes smoked per day and degree of inhalation of smoke (5). No clear pattern emerges. The "moderate-deep" group had higher mor- tality ratios than the "none-slight" group in two of three com- parisons. Table 11 shows mortality ratios for female cigarette smokers by degree of inhalation and age (5). A fairly consistent general pattern emerges; mortality ratios vary directly with degree of inhalation. This is seen in each age group, except perhaps the 35-to-44 age group. Mortality data for female cigarette smokers according to in- halation are also available from the Swedish study (1); age- adjusted ratios were reported as 1.1,1.2, and 1.6 for the no inha- lation, light inhalation, and deep inhalation groups, respec- tively. "TAR" AND NICOTINE CONTENT OF CIGARETTES The relationship between overall mortality and the "tar" and nicotine content of cigarette smoke was recently examined by Hammond, et al. (6). In this study, "tar" and nicotine levels (T/N) were defined as follows: "high" T/N, 25.8 to 35.7 mg "tar" and 2.0 to 2.7 mg nicotine; "medium" T/N, 17.6 to 25.7 mg "tar" 59 TABLE 12.-Adjusted mortality ratios for males and females, by 9ar" and nicotine content of cigarettes usually smoked Mortality Ratios Sex "High" T/N "Medium" T/N "LOW" T/N Males 1.00 0.94 0.85 Females 1.00 0.88 0.83 Total 1.00 0.91 0.84 SOURCE: Hammond, E.C. (6). TABLE 13.-Adjusted mortality ratios for males and females smokiug km "tar" and nicotine cigarettes and subjects who never smoked regularly Sex Mortality ratios "Low" T/N Nonsmokers Males 1.00 0.61 Females 1.00 0.74 Total SOURCE: Hammond, E.C. (6). 1.90 0.66 TABLE 14.-Overall mortality ratios of cigarette smokers compared to nonsmokers, by sex and by Yar" and nicotine content of cigarettes usually smoked Sex Non- "LOW" "Medium" "High" smokers T/N T/N TIN Males 1.00 1.66 1.85 1.96 Females 1.00 1.37 1.45 1.65 Total 1.00 SOURCE: Hammond, E.C. (6). 1.52 1.64 1.80 and 1.2 to 1.9 mg nicotine; "low" T/N, less than 17.6 mg "tar" and less than 1.2 mg nicotine. Table 12 shows the overall mortality ratios of male and female smokers by these "tar" and nicotine levels. In this instance, the mortality ratio of the "high" T/N smokers was represented as 1.00 to illustrate the reduction in overall mortality that occurred with lower T/N cigarettes. There was a small reduction in the risk of dying with the use of lower T/N cigarettes. The mortality 60 ratio was reduced to 0.91 for the "medium" T/N smokers and was further reduced to 0.84 for the "low" T/N smokers. The mor- tality ratios were lower for women than for men. In a separate analysis, a comparison was also made between the mortality ratios of "low" T/N smokers and nonsmokers. These data are presented in Table 13. The mortality ratio of the "low" T/N group was designated as 1.00. Nonsmokers had over- all mortality ratios that were considerably less than those of "low" T/N smokers. The combined data from Tables 12 and 13 are shown in Table 14 where mortality ratios were calculated using nonsmokers as the reference. Combining these data from two separate analyses that are not exactly comparable results in figures that are only approximate. Hammond also compared death rates of smokers of relatively few (1 to 9) "high" T/N cigarettes with those of smokers who smoked relatively large numbers (20 to 39) of "low" T/N cigar- ettes (17). The death rates of these two groups were very simi- lar. comments Mortality ratios for women who smoke cigarettes ranged from 1.2 in the Swedish study to 1.43 in the Framingham study. As with men, mortality ratios for women who smoke cigarettes var- ied directly with amount smoked, depth of inhalation, "tar" and nicotine content of the cigarette and duration of smoking, and varied inversely with the age when smoking was started. In attempting to study cigarette smoking and mortality among women, a major difficulty is the lack of large-scale epidemiological studies addressed specifically to female popula- tions. The main findings of this review depend heavily on one study, that of the American Cancer Society. For the other studies reviewed here, the numbers of women-and of deaths among them -are often too sparse to permit meaningful statis- tical analyses. Thus, for example, little can be said about the survivorship experience of women who give up cigarette smok- ing. We strongly recommend, where possible, extending the length of follow-up of women who are already enrolled in these prospective studies. It is also highly recommended that new studies be conducted that are specifically addressed to women and smoking-related mortality. 1. The mortality ratio for women who smoke cigarettes is about 1.2 or 1.3. 61 2. Mortality ratios for women increase with the amount smoked. In the largest prospective study the mortality ratio was 1.63 for the two-pack-a-day smoker as compared to nonsmokers. 3. Mortality ratios are generally proportional to the duration of cigarette smoking; the longer a woman smokes, the greater the excess risk of dying. 4. Mortality ratios tend to be higher for those women who begin smoking at a young age as compared to those who begin smoking later. 5. Mortality ratios are higher for those women who report they inhale smoke than for those who do not inhale. 6. Mortality ratios for women tend to increase with the tar and nicotine content of the cigarette. 7. Mortality ratios for female smokers are somewhat less than for male smokers. This may reflect differences in exposure to cigarette smoke, such as starting smoking later, smoking cigarettes with lower "tar" and nicotine content, and smoking fewer cigarettes per day than men. 8. Women demonstrate the same dose-response relationships with cigarette smoking as men. An increase in mortality occurs with an increase in number of cigarettes smoked per day, an earlier age of beginning cigarette smoking, a longer duration of smoking, inhalation of cigarette smoke, and a higher "tar" and nicotine content of the cigarette. Women who have smok- ing characteristics similar to men may experience mortality rates similar to men. References (1) BEST, E.W.R. A Canadian Study of Smoking and Health. Department of National Health and Welfare, Epidemiology Division, Health Services Branch, Biostatistics Division, Research and Statistics Directorate, 1966, 137 pp. (2) CEDERLOF, R., FRIBERG, L., HRUBEC, Z., LORICH, U. The Rela- tionship of Smoking and Some Social Covariables to Mortality and Cancer Morbidity. A Ten Year Follow-up in a Probability Sample of 55,000 Swedish Subjects Age 18 to 69. Part I and II. Stockholm, Karolinska Institute, Department of Environmental Hygiene, 1975. 201 pp. (3) DOLL, R., GRAY, R., PETO, R. Mortality in Relation to Smoking: Ob- servations on Female Doctors. (Unpublished manuscript) (4) DORN, H.F. The relationship of cancer of the lung and the use of to- bacco. The American Statistician g(5): 7-13, December 1954. (5) HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel, W. (Editor). Epidemiological Ap- proaches to the Study of Cancer and Other Chronic Diseases, National Cancer Institute Monograph 19. Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, January 1966, pp. 127-204. 62 (6) HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. "Tar" and nicotine content of cigarette smoke in relation to death rates. En- vironmental Research 12(3): 263-274, December 1976. (7) HIRAYAMA, T. Smoking in relation to the death rates of 265,118 men and women in Japan. A report of 5 years of follow-up. Presented at the American Cancer Society's 14th Science Writers' Seminar, Clear-water Beach, Florida, March 24-29, 1972, 15 pp. (8) NATIONAL CENTER FOR HEALTH STATISTICS. Mortality from Diseases Associated with Smoking: United States, 1950-1964. De- partment of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, Public Health Service Publica- tion No. 1006Series 20, 50. 4, October 1966, 45 pp. (9) NATIONAL CENTER FOR HEALTH STATISTICS, Office of Health Research, Statistics, and Technology, Public Health Service, Depart- ment of Health Service, Department of Health, Education, and Wel- fare. (Unpublished data) (10) NATIONAL HEART, LUNG, AND BLOOD INSTITUTE. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, NIH Publication No. 79-1610, May 1979, 399 pp. (11) NATIONAL HEART, LUNG, AND BLOOD INSTITUTE. Some charac- teristics related to the incidence of cardiovascular disease and death: Framingham Study, 18-year follow-up. In: The Framingham Study: An Epidemiological Investigation of Cardiovascular Disease. Kannel, W.B., Gordon, T. (Editors). DHEW Publication No. (NIH) 74-599, Feb- ruary 1974. (12) NATIONAL HEART, LUNG, AND BLOOD INSTITUTE. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, 1979. (Unpublished data) (1.9) PEARL, R.B., LEVINE, D.B., GERSON, E.J. Studies of Disease Among Migrants and Native Populations in Great Britain, Norway, and the United States. II. Conduct of Field Work in the United States. National Cancer Institute Monograph 19. Department of Health, Education, and Welfare, U.S. Public Health Service, National Cancer Institute, 1966, pp. 301-320. (14) REID, D.D. Studies of Diseases Among Migrants and Native Popula- tions in Great Britain, Norway, and the United States. I. Background and Design. National Cancer Institute Monograph 19. Department of Health, Education, and Welfare, Public Health Service, National Cancer Institute, 1966, pp. 287-199. (15) REID, D.D., CONFIELD, J., MARKUSH, R.E., et al. Studies of Disease among Migrants and Native Population in Great Britain, Norway, and the United States. III. Prevalence of Cardiorespiratory Symptoms Among Migrants and Native Born in United States. National Cancer Institute Monograph 19. Department of Health, Education, and Wel- fare, Public Health Service, National Cancer Institute, 1966, pp. 321- 346. (16) ROGOT, E. Cardiorespiratory disease mortality among British Norwe- gian migrants to the United States. American Journal of Epidemiology 108(3): 181-191, 1978. (17) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. A Report of the Surgeon General. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Publication No. (PHS) 79-50066, 1979, 1251 pp. MORBIDITY. MORBIDITY The relationship between cigarette smoking and morbidity has been summarized in the 1979 Surgeon General's Report. That report contained data from the National Center for Health Statistics Health Interview Survey (HIS) showing the relation- ship for both men and women between smoking and the preva- lence of selected chronic diseases, the incidence of acute illness, days lost from work, days of bed disability, and perceived health status. This section will present additional data from the Health Interview Survey on trends in days lost from work and limita- tion of activity. Days bat from Work Workers who smoke report losing more work days due to ill- ness and injury than do nonsmokers. This relationship has been observed for both men and women every year that the National Health Interview Survey has included questions on cigarette smoking. For example, in 1965 working women who smoked re- ported 6.6 work-loss days; working women who had never smoked reported only 4.8 work-loss days (see Table 1). Similarly, in the 1977 HIS women who smoked reported 6.6 days lost from work compared to 5.7 days lost from work by those who never smoked. The National Clearinghouse for Smoking and Health used the earlier 1965 data to estimate the number of "excess" days lost from work among cigarette smokers. This estimation was ob- tained by calculating the expected number of work-loss days if all workers had the same work-loss experience as those who had never smoked cigarettes. It was estimated that approximately 20 percent of all work-loss days due to illness and injury could be attributed to the higher rates of loss among current and former smokers (2). The 1979 Surgeon General's Report presented simi- lar calculations, based on 1974 data, and again the estimate was about 20 percent of all work-loss days. These calculations were not sex specific. Certain modifications in the collection proce- dures have lowered the male response rate for the smoking data and may, thus, make comparisons of more recent data by sex less than ideal. However, the data do show that in 1977 the work-loss rate among women who never smoked was higher than in 1965, while the rates among current smokers remained about the same. This would tend to reduce the number of "ex- cess" days among women attributable to smoking. There has been a slight decrease in work loss among males who never smoked. Former smokers reported fewer work-loss days in 1977 than in 1965. Although the difference in work-loss days between 67 TABLE l.-Days lost from work per year due to illness and injury, per currently employed persons 17 years old and older, by smoking status, sex and age: United States, 1965 and 1977 Total' Present Former Smoker Smoker Percent.of work-loss days 1965 - Never Smoked Female 17 +a 17-44 45-64 Male 17+3 17-44 45-64 Female 20 +3 20-44 45-64 Male 20 +3 20-44 45-64 5.6 6.6 6.7 4.8 5.5 6.6 6.0 4.5 6.0 6.7 7.7 5.3 5.7 5.9 6.8 4.6 4.1 4.7 3.6 3.4 7.8 7.9 9.8 5.6 6.0 6.6 5.4 5.7 6.1 6.8 5.4 5.4 6.4 6.5 5.92 6.5 5.3 5.9 6.1 4.2 5.1 6.0 5.5 4.4 5.6 5.9 6.2 3.9 `Includes unknown smoking status. `Figure does not meet standards of reliability or precision. Yncludes ages 65 and over. SOURCE: National Center for Health Statistics (1). 1965 and 1977 is small, it could be attributed to the assumption that in recent years the former smoker groups have a greater proportion of people who stopped smoking for preventive rea- sons, that is, before they had experienced serious health conse- quences. Further study is needed to determine the association between "excess" days lost from work by smokers and specific diseases. Such an analysis would help explain the economic impact of smoking in the work place. Limitation of Activity The Health Interview Survey also regularly collects data on the long-term impact of chronic illness. Respondents were asked if chronic illness limited their activities (3). Estimates of the percent of the population with limitation of activity by cigarette 68 smoking status are shown in Table 2 for 1965 and 1977. Detailed interpretation of trend data is difficult; however, there appears to be a relationship between smoking and the impact of chronic illness. In general, the 1977 data indicate that women under 65 who have ever smoked are more likely to have a limitation of activity than those who never smoked. There are no marked differences between current and former smokers. Among eld- erly women in 1977, there were no differences in limitations of activity by smoking status. TABLE 2.-Percent of persons with limitation of activity due to chronic conditions, by cigarette smoking status, sex and age: United States, 1985 and 1977 Total' Present Former Smoker Smoker Percent with limitation Never Smoked Female 17 + 17-44 45-64 65 + Male 17+ 17-44 45-64 65 + Female 20 + 20-44 45-64 65 + Male 20 +. 20-44 45-64 65+ 17.3 12.7 17.3 19.8 8.3 8.8 9.8 7.7 19.5 17.4 22.1 20.2 45.1 39.8 48.6 45.4 17.3 15.3 23.0 17.7 7.3 7.7 8.0 6.2 20.0 20.9 22.1 15.7 53.7 52.7 56.3 52.9 17.6 16.0 18.1 18.3 8.0 9.2 8.4 7.0 21.5 24.2 23.9 19.8 39.2 36.3 35.5 38.8 20.0 20.5 24.1 17.6 9.6 12.4 8.3 7.5 25.7 27.6 25.7 25.7 47.6 52.7 47.6 42.5 1977 "Includes known smoking status. SOURCE: National Center for Health Statistics (1). Cigarette Smdcing ad Occuption* The Health Interview Survey provides a considerable data base on cigarette smoking behavior and occupational status. *See: "Interaction Between Smoking and Occupational Exposures" in this Report. 69 The data are available from a national probability sample of about 40,000 households for the years 1965, 1966, 1970, 1974, 1976, 1977,1978, and 1979. However, only minimal analysis has been conducted on this potentially valuable data base (4). This brief section presents data on smoking patterns for only two of these periods- 1970 and 1976. Researchers are encouraged to investigate these data more fully through the purchase of pub- lic use data tapes (1). The importance of this data base increases as new evidence becomes available on the increased health risks experienced by smokers in certain occupations. The problems of relatively small sample sizes in high-risk occupations can be partially overcome by combining several years of the HIS data tapes. Tables 3 and 4 show smoking characteristics of broad occupa- tional groups - i.e., white collar, blue collar, service and farm workers-for 1970 and 1976, respectively. Service and blue col- lar workers, both women and men, are more likely to smoke than are white collar and farm workers, but the differences are much less among female workers. In 1970, there were virtually no differences among female white collar, blue collar, and serv- ice workers; more recently, however, there has been a slight increase in smoking among the latter two groups. Caution should be used in drawing conclusions from these data based on differences of only a few percentage points since such dif- ferences can be well within sampling error. White collar work- ers who smoke tend to be heavier smokers than other types of workers, and this pattern is more marked among female white collar workers. The proportions of cigarette smokers by more detailed occu- pational classes are shown in Tables 5 and 6 for 1970 and 1976. Within three of four subgroups of white collar workers- professionals, managers, and sales people -the proportion of smokers among women is the same as for men in the same occu- pational group. This also appears to be true for laborers, who show the highest levels of smoking among both women and men. The 1979 Report of the Surgeon General summarized the in- formation on smoking and morbidity as follows: 1. In general, female current cigarette smokers report more acute and chronic conditions including chronic bronchitis and/or emphysema, chronic sinusitis, peptic ulcer disease, and arteriosclerotic heart disease, than women who never smoked. 2. There is a dose-response relationship between the number 70 TABLE 3 .-Percent distribution of the population 17 years and over by cigarette smoking status, according to sex and occupation category, United States, 1970 Sex and occupation category Total Never Former population' smoked smokers Percent distribution Present Present smokers-no. of cigarettes per day* smokers Total2 < 15 15-24 25+ Female Total population Total currently employed White collar workers Blue collar workers Service workers Farm workers Male Total population Total currently employed White collar workers Blue collar workers Service workers Farm workers 100.0 54.0 11.2 34.9 100.0 39.3 42.4 18.2 100.0 54.3 11.1 34.6 100.0 3x.7 43.3 18.0 100.0 53.2 12.6 34.2 100.0 37.6 42.8 19.6 100.0 55.1 8.5 36.5 100.0 40.7 44.4 14.9 100.0 55.7 9.2 35.2 100.0 41.6 41.0 17.4 100.0 74.3 V.5 18.6 100.0 *49.2 r33.3 *19.0 100.0 28.8 24.9 46.2 100.0 25.8 45.1 29.1 100.0 28.8 25.2 46.0 100.0 25.5 4.5.3 29.3 100.0 31.6 29.1 39.3 100.0 23.8 43.4 32.8 100.0 24.8 22.4 52.8 100.0 25.5 46.4 2X.0 100.0 31.1 20.8 48.1 100.0 31.1 43.3 25.6 100.0 40.7 24.8 34.4 100.0 35.5 45.1 19.4 `Excludes unknown if ever smoked. *Excludes unknown amount of cigarettes smoked. *Figure does not meet standards of reliability or precision. SOURCE: National Center for Health Statistics (1). TABLE 4-Percent distribution of the population 20 years and over by cigarette smoking status, according to sex and occupation category, United States, 1976 Sex and Total Never Former Present Present smokers-no. of cigarettes per daya occupation category population' smoked smokers smokers Total2 <15 15-24 25 + Female Total population 100.0 54.3 13.8 Total currently employed 100.0 50.8 13.3 White collar workers 100.0 51.1 14.6 Blue collar workers 100.0 50.7 10.2 Service workers 100.0 49.1 11.9 Farm workers 100.0 59.8 * Male Total population 100.0 29.2 28.9 Total currently employed 100.0 29.5 27.1 White collar workers 100.0 34.0 29.4 Blue collar workers 100.0 24.3 25.3 Service workers 100.0 29.4 23.4 Farm workers 100.0 34.9 28.2 `Excludes unknown if ever smoked. *Excludes unknown amount of cigarettes smoked. *Figure does not meet standards of reliability or precision. SOURCE: National Center for Health Statistics (1). 32.0 100.0 36.5 43.8 19.6 35.9 100.0 36.5 44.0 19.5 34.3 100.0 35.3 42.4 22.3 39.0 100.0 38.0 44.3 17.6 39.0 100.0 37.9 48.3 13.7 31.3 100.0 34.6 o ? 41.9 100.0 24.2 44.8 31.1 43.4 100.0 21.9 45.4 32.8 36.6 100.0 20.8 43.6 35.6 50.4 100.0 21.2 47.4 31.5 47.2 100.0 27.6 40.0 32.4 36.9 100.0 29.4 44.9 25.7 TABLE 5 .-Estimates of the percentage of current, regular cigarette smokers, adult ages 17 years and over, according to labor force status, occupation, and sex, United States, 1970 Female Male Total Total 17+ 17-44 45-64 17+ 17-44 45-64 Total 34.9 36.8 33.7 46.2 49.0 44.4 Currently employed 34.6 36.4 33.7 46.0 48.7 44.1 White collar total 34.2 34.9 34.3 39.3 41.1 38.4 Professional, technical and kindred 28.1 29.4 26.3 31.7 32.8 30.6 Managers & administrators except farm 40.8 48.4 38.3 42.8 47.4 40.0 Sales workers 34.6 35.3 35.7 44.9 46.8 46.1 Clerical & kindred workers 35.8 35.9 36.4 43.3 45.2 41.5 Blue collar total 36.5 39.9 33.5 52.8 56.1 49.2 Craftsmen & kindred workers 40.4 44.4 37.0 51.7 56.1 47.2 Operatives and kindred workers 36.5 40.0 33.5 54.7 57.5 50.7 Laborers, except farm *23.3 *25.6 *20.9 50.9 52.0 52.9 Service 35.2 39.3 33.5 48.1 48.3 51.7 Farm 18.6 *25.9 *15.5 34.4 38.7 37.7 Unemployed 38.4 40.8 32.9 52.3 54.4 53.0 Homemakers 29.7 37.3 32.3 NA NA NA NOTE: Unknown if ever smoked excluded from calculation. *Figure does not meet standards of reliability or precision. w" SOURCE: National Center for Health Statistics (1). 2 TABLE 6.-Estimates of the percentage of current, regular cigarette smokers, adults ages 20 years and over, according to labor force status, occupation, and sex, United States, 1976 Total 20+ Female 20-44 45-64 Total 20+ Male 20-44 45-64 Total Currently employed White collar total Professional, technical and kindred Managers & administrators except farm Sales workers Clerical & kindred workers Blue collar total Craftsmen & kindred workers Operatives and kindred workers Laborers, except farm Service Farm Unemployed Usual activity-homemakers 32.0 36.9 34.8 41.9 47.6 41.3 35.9 37.0 36.1 43.4 46.8 39.7 34.3 33.8 36.9 36.6 38.6 35.3 29.1 28.6 32.7 30.0 31.1 29.9 41.6 42.7 40.8 41.0 46.4 36.1 38.1 37.0 42.6 39.9 42.6 38.0 34.8 34.7 36.0 40.4 40.1 44.2 39.0 43.7 33.6 50.4 54.1 44.3 40.5 46.9 35.6 48.0 52.1 41.6 37.6 42.5 31.2 52.3 55.3 46.2 56.3 52.6 * 53.7 56.9 51.7 39.0 42.8 37.2 47.2 51.1 44.8 31.3' 51.0 * 36.9 45.4 35.0 40.0 41.0 39.2 56.8 59.9 53.8 29.0 37.1 32.2 NA NA NA NOTE: Unknown if ever smoked excluded from calculation. *Figure does not meet standards of reliability or precision. SOURCE: National Center for Health Statistics (1). of cigarettes smoked per day and the frequency of reporting for most of the chronic conditions. 3. The age-adjusted incidence of acute conditions (e.g., in- fluenza) for women smokers is 20 percent higher for women who had ever smoked than for nonsmokers. Additional data from the Health Interview Survey (HIS) is presented: 1. Currently employed women who smoke cigarettes report more days lost from work due to illness and injury than working women who do not smoke. 2. Limitation of activity is reported more commonly among women under the age of 65 who have ever smoked than among those who never smoked. References (1) NATIONAL CENTER FOR HEALTH STATISTICS. Standardized Micro-Data Tape Transcript. Department of Health, Education, and Welfare, Public Health Service, DHEW Publication No. 781-213, June 1978. (2) NATIONAL CLEARINGHOUSE FOR SMOKING AND HEALTH. Smok- ing and Illness. Department of Health, Education, and Welfare, Public Health Service, Bureau of Disease Prevention and Environmental Con- trol, National Center for Chronic Disease Control, National Clearing- house for Smoking and Health, PHS Publication No. 1662, July 1967, 6 PP. (3) WILDER, C.S. Limitation of activity due to chronic conditions, U.S. 1974. Department of Health, Education, and Welfare, Public Health Service, Health Resource Administration, National Center for Health Statistics, Series 10, No. 111, Public Health Service Pub. No. (HRA) 77-1537, June 1977, 65 pp. (4) WILSON, R.W. Cigarette smoking, disability days and respiratory condi- tions. Journal of Occupational Medicine 15(3): 236-240, March 1973. 75 CARDIOVASCULAR DISEASES. CARDIOVASCULAR DISEASES Introduction While the mortality and morbidity rates of coronary heart disease (acute myocardial infarction and chronic ischemic heart disease) (CHD) are lower for women than men, CHD still repre- sents the major cause of death among women in the U.S. In 1976 the United States recorded 284,055 female deaths as attributa- ble to this cause (Table 2). The difference in mortality rates between the sexes is more marked for acute myocardial infarc- tion, with males of all ages experiencing 189 deaths and females 111 deaths per 100,000 (Table 1). Observed differences by sex in susceptibility to coronary heart disease are not fully understood but appear to be affected by multiple specific risk factors within any demographic group. McGill and Stern have recently provided an extensive review of sex differences in susceptibility to atherosclerosis in humans and in experimental animals, including an analysis of factors known to predispose to atherosclerosis and its dependent dis- eases (25). Mortality Rates In the United States, the National Center for Health Statis- tics has reported mortality rates from acute myocardial infarc- tion and chronic ischemic heart disease classified by age, sex, and race, for the years 1968 and 1976 (Tables 1-3) (33). These tables show that mortality rates for acute myocardial infarction among adults up to age 64 are highest for white men and are succeeded by progressively lower rates for other men, other women, and finally, white women. Mortality rates for chronic ischemic heart diseases vary. The rates for white men are sec- ond to those for other men and close to those for nonwhite women; again, however, rates for white women are by far the lowest. Both white and nonwhite women show consistently lower rates until extreme old age. However, the differences nar- row markedly in age in comparison with those in young adult- hood and middle life (Table 1). Male-to-female mortality ratios for acute myocardial infarc- tion among adults in their 30's and 40's are approximately 5 to 6 for whites and 2 to 3 for nonwhites; among adults in their 70's and 80's, they are roughly 1.6 and 1.4. The actual number of deaths involved is very large; their distribution by age, sex, and race is shown in Table 2. Between 1968 and 1976, a striking decline occurred in the acute myocardial infarction mortality rate for men and women of all ages and races. These are shown 79 TABLE l.-Death rates* for acute myocardial infarction and chronic ischemic heart disease for specified age groups, by color and sex; United States, 1968-1976 Year and age Both sexes Total Male Female Both sexes White Male Female Both sexes All Other Male Female 1976 All ages . . . . . . . . . . . . . 25-34 years ....... 35-44 years ....... 45-54 years ....... 55-64 years ....... 65-74 years ....... 75-84 years ....... 85 years and over . . . . . . . . . . . . . . . . . . . . . . ..,.. . . . . . ,.... 148.8 189.0 110.8 2.8 4.6 1.1 27.0 46.2 8.8 111.7 186.9 41.3 309.5 490.3 147.2 660.1 989.8 406.8 1,328.O 1,806.7 1,035.7 2.038.0 2,564.`7 1,790.3 Acute myocardial infarction 158.7 202.2 117.3 2.6 4.3 0.9 26.6 46.1 7.6 111.8 190.1 37.7 312.2 501.1 142.1 674.5 1,024.7 406.5 1,364.8 1,881.4 1,054.3 2,135.0 2,709.6 1,869.g 84.0 100.3 69.0 4.2 6.4 2.3 30.4 47.5 10.3 111.2 159.8 68.9 283.2 386.5 194.8 524.6 667.9 409.9 917.0 1,061.l 813.0 lJ26.5 1,369.l 990.1 All ages ............. 25-34 years ............. 35-44 years ............. 45-54 years ............. 55-64 years ............. 65-74 years ............. 75-84 years ............. 85 years and over ........ 185.4 243.0 130.6 4.6 7.2 2.2 42.3 70.9 15.2 158.5 267.1 56.8 420.8 668.3 197.1 900.5 1,315.0 574.1 1,687.l 2,228.4 1,316.5 2,911.8 3,570.7 2,553.0 195.9 258.0 136.7 4.1 6.5 1.7 40.3 69.6 12.1 157.6 270.4 51.3 423.9 684.3 188.4 919.8 1,360.8 574.4 1,732.l 2,306.5 1,342.8 3,012.g 3,715.3 2,637.8 109.5 133.2 87.7 8.7 13.1 5.0 57.9 81.6 37.9 166.6 236.2 105.3 390.5 512.5 281.0 706.7 870.1 571.2 1,103.l 1,291.4 961.1 1,782.4 2,163.4 1,526.2 TABLE l.-Death rates* for acute myocardial infarction and chronic ischemic heart disease for specified age groups, by color and sex; United States, 1968-1976~(Continued) Year and age Both sexes Total Male Female Both sexes White Male Female Both sexes All Other Male Female 1976 Chronic ischemic heart disease All ages ........... 25-34 years ......... 35-44 years ......... 45-54 years ......... 55-64 years ......... 65-74 years ......... 75-84 years ......... 85 years and over .... 1968 150.2 153.5 147.0 115.4 125.4 106.4 1.6 2.4 0.8 12.8 20.3 5.6 57.7 90.9 26.7 173.3 258.5 96.8 487.4 674.8 343.4 1,621.5 1,947.4 1,422.6 4,647.4 4,945.8 4.507.0 155.5 157.7 153.4 1.2 1.9 0.5 10.6 17.5 3.9 50.4 82.6 20.1 159.5 244.3 83.2 467.8 660.5 320.4 1,626.0 1,968.0 1,420.4 4,859.8 5,208.O 4,699.l 4.2 6.1 2.5 27.5 41.0 16.3 116.1 160.7 77.4 302.2 396.1 222.0 672.1 805.8 565.2 1.572.0 1,742.7 1,448.8 2,650.8 2.782.4 2.576.9 All ages ........... 150.6 156.3 145.1 153.1 158.3 148.2 132.0 141.6 123.3 25-34 years . . . . . . . . . . . . . 1.6 2.3 1.1 1.0 1.6 0.4 6.2 7.2 5.3 31-44 years *.. . . . . . . . . . 13.6 20.5 7.1 10.4 17.0 4.0 38.8 49.8 29.5 45-54 years . . . . . . . . . . . . . 57.0 85.6 30.2 47.5 76.0 20.7 142.6 175.8 113.3 55-64 years . ..*......... 190.6 273.4 115.7 169.2 253.4 93.0 393.1 468.6 334.8 65-74 years . . . . . . . . . . . . . 590.4 769.1 449.7 560.6 742.8 417.9 889.5 1,025.O 777.2 75-84 years . . . . . . . . . . . . . 1,826.0 2,075.5 1,655.3 1,833.g 2,093.7 1,657.g 1,724.6 1,858.l 1,628.0 85 and years over . . . . . . . . 5,523.6 5,636.6 5,468.4 5,695.3 5,831.8 5,629.4 3,605.g 3,736.6 k 518.0 *Rates are deaths per 100,000 population. For acute myocardial infarction, rates are based on deaths assigned to category number 410 of the Eighth Revision of the International Classification of Diseases, adapted for use in the United States, adopted in 1965, and for 00 c chronic ischemic heart disease, to category number 412 of this revision I SOURCE: Rosenberg, H.M. (33). g TABLE 2.-Number of deaths* for acute myocardial infarction and chronic ischemic heart disease for specified age groups, by color and sex; United States, 1966 and 1976 Total White All other Year and age Both sexes Male Female Both sexes Male Female 1976 Acute myocardial infarction All ages . . . . . 25-34 years . . . . . 35-44 years . . . 45-54 years . . . . . 55-64 years . . . . . 65-74 years . ...* 75-84 years . . . . . 85 years and over 1968 . . 319,477 . . 890 . . 6,223 . . 26,405 . 62,091 . . 93,695 . . 89,969 . . 40,068 197,429 122,048 295,613 183,820 111,793 23,864 13,609 10,255 718 172 720 598 122 170 120 50 5,182 1,041 5,338 4,558 780 885 624 261 21,361 5,044 23,479 19,407 4,072 2,926 1,954 972 46,516 15,575 56,623 43,072 13,551 5,468 3,444 2,024 61,038 32,657 86,566 57,004 29,562 7,129 4,034 3,095 46,395 43,574 84,852 43,912 40,940 5,117 2,483 2,634 16,132 23,936 37,939 15,201 22,738 2,129 931 1.198 All ages . . . . . 25-34 years . . . . . 35-44 years . . . . 45-54 years . . . . . 55-64 years . . . . . 65-74 years . . . . . 75-84 years . . . . . 85 years and over . . 369,610 . 1,099 . . 9,980 . . 36,032 . 76,108 . . 109,672 . . 100,312 . . 36,135 236,017 133,593 838 261 8,132 1,848 29,368 6,664 57,387 18,721 70,564 39,108 53,838 46,474 15,711 20,424 342,999 220,517 122,482 846 664 182 8,412 7,122 1,290 32,261 26,860 5,401 69,504 53,287 16,217 101,863 66,205 35,658 95,613 51,436 44,177 34,317 14,824 19,493 Chronic ischemic heart disease 26,611 15,500 11,111 253 174 79 1,563 1,010 558 3,771 2,508 1,263 6,604 4,100 2,504 7,809 4,359 3,450 4,699 2,402 2,297 1,818 887 931 1976 All ages . . . . . . . 322,382 160,375 162,007 289,572 143,372 146,200 32,810 17,003 15,807 25-34 years . . . . . . . 502 381 121 332 266 66 170 115 55 35-44 years . . . . . . . 2,937 2,273 664 2,137 1,734 403 800 539 261 Both sexes Male Female - age groups, by color and sex; United States, 1968 and 19764Continued) Total White All other Both Year and age sexes Male Female 45-54 years ............. 13,649 10,391 3,258 55-64 years ............. 34,765 24,525 10,240 65-74 years ............. 69,176 41,612 27,564 75-84 years ............. 109,860 50,010 59,850 85 years and over ........ 91,368 31,109 60,259 1968 Both sexes 10,593 28,929 60,042 101,088 86,358 Male Female 8,426 2,167 20,996 7,933 36,745 23,297 45,932 55,156 29,217 57,141 Both sexes 3,056 5,836 9,134 8,772 5,010 Male 1,965 3,529 4,867 4,078 1,892 Ail ages ............. 300,216 151,815 148,401 268,124 135,333 132,791 32,092 16,482 25-34 years ............. 390 262 128 211 166 45 179 96 35-44 years ............. 3,212 2,350 862 2,162 1,734 428 1.050 616 45-54 years ............. 12,953 9,412 3,541 9,727 7,545 2,182 3,226 1,867 55-64 years ............. 34,475 23,481 10,994 27,743 19,732 8,011 6,732 3,749 65-74 years ............. 71,905 41,270 30,635 62,076 36,135 24,941 9,829 5,135 75-84 years ............. 108,576 50,145 58,431 101,229 46,689 54,540 7,347 3,456 85 years and over ........ 68,548 24,801 43,747 64,870 23,269 41,601 3,678 1,532 - Female 1,091 2,307 4,267 4,694 3,118 15,610 83 434 1,359 2,983 4,694 3,891 2,146 *Number of deaths due to acute myocardial infarction are those assigned to category number 410 of the Eighth Revision of the International Classification of Diseases, adapted for use in the United States, adopted in 1965; and for chronic ischemic heart disease to category number 412 of this revision SOURCE: Rosenberg, H.M. (33). as percent changes in rate in Table 3. The percent change has been larger at younger ages (Tables 2 and 3). The changes for chronic ischemic heart disease are similar but less dramatic (Table 3). Atherosclemsis Differences in heart attack mortality rates among men and women parallel pathology data concerning atherosclerotic plaques of the coronary arteries. The International Atherosclerosis Project systematically collected autopsy obser- vations on persons from 14 geographic locations and 19 ethnic groups in different parts of the world, and found that women from 11 of the 19 groups, when compared to their male counter- parts, had as much or even more aortic atherosclerosis. Men over age 39 had more raised plaques in their coronary arteries than women (24). These findings indicate that the occurrence of coronary plaques was parallel to heart attack rates, but that the occur- rence of aortic lesions was not. Coronary plaque severity had a male-to-female ratio of 1.61 among whites and of 1.14 among blacks. Studies of a white population in Sweden (40) and of west- ern Europeans from five locations (18) demonstrate similar find- ings: a clear excess of coronary atherosclerosis among men and a similar severity of aortic atherosclerosis among men com- pared to women. Autopsy studies thus show a selective liability of the male coronary arterial bed for atherosclerosis, as compared to the female, especially among white men but also among men of other races. The pathological findings are congruent with the clinical data on heart attack mortality rates. Autopsy studies also show that, among men or women with manifest coronary heart disease, women patients have roughly the same preva- lence of advanced atherosclerotic lesions of the coronaries as men (41). These data suggest that the amount of atherosclerosis necessary to precipitate a heart attack is the same, on the aver- age, in both sexes. This generalization about the amount of coronary atherosclerosis appears to hold for heart attacks at younger and older ages, for recent and old infarcts, and coro- nary occlusion without infarct, and for stenosis, as well as for complicated and calcified lesions and raised plaques in the coro- nary arteries (41). It should be noted that the grading of atherosclerosis at au- topsy is not a simple matter because there are several types of lesions and several ways of evaluating or measuring them. Moreover, the development of the different sorts of lesions is 84 TABLE 3.-Percent change* between 1968 and 1976 in death rates for acute myacardial infarction and chronic ischemic heart diseases for specified age groups, by color and sex: United States Age Both Sexes Total Male Female Both Sexes White Male Female Both Sexes All Other Male Female Acute myocardial infarction All ages ............. -19.7 -22.2 -15.2 -19.0 -21.6 -14.2 -23.3 -24.7 -21.3 25-34 years ............. -39.1 -36.1 -50.0 -36.6 -33.8 -47.1 -51.7 -51.1 -54.0 35-44 years ............. -36.2 -34.8 -42.1 -34.0 -33.8 -37.2 -47.5 -41.8 -57.0 45-54 years ............. -29.5 -30.0 -27.3 -29.1 -29.7 -26.5 -33.3 -32.3 -34.6 55-64 years ............. -26.4 -26.6 -25.3 -26.4 -26.8 -24.6 -27.5 -24.6 -30.7 65-74 years ............. -26.7 -24.7 -29.1 -26.7 -24.7 -29.2 -25.8 -23.2 -28.2 75-84 years ............. -21.3 -18.9 -21.3 -21.2 -18.4 -21.5 -16.9 -17.8 -16.4 85 years and over ........ -30.0 -28.2 -29.9 -29.1 -27.1 -29.1 -36.8 -36.7 -35.1 Chronic ischemic heart diseases All ages ............. -0.3 -1.8 1.3 1.6 -0.4 3.5 -12.6 -11.4 -13.7 25-34 years ............. 4.3 -27.3 20.0 18.8 25.0 -32.3 -15.3 -52.8 35-44 years ............. -5.9 -1.0 -21.1 1.9 2.9 -2.5 -29.1 -17.7 -44.7 45-54 years ............. 1.2 6.2 -11.6 6.1 8.7 -2.3 -19.6 -8.6 -31.7 56-64 years ............. -9.1 -5.4 -16.3 -5.7 -3.6 -10.5 -24.1 -15.5 -33.7 65-74 years ............. -17.4 -12.3 -23.6 -16.6 -11.1 -23.3 -24.4 -21.4 -27.3 75-84 years ............. -11.2 -6.2 -14.1 -11.3 -6.0 -14.3 -8.8 -6.2 -11.0 85 years and over ........ -15.9 -12.3 -17.6 -14.7 -10.7 -16.5 -26.5 -25.5 -26.8 *Percent changes are based on rates per 100,000 population. For 1968 and 1976, rates for acute myocardial infarction are based on deaths assigned to category number 410 of the Eighth Revision of the International Classification of Diseases, adapted for use in the W cn United States, adopted in 1965, and for chronic ischemic heart disease, on category number 412 of this revision SOURCE: Rosenberg, H.M. (33). not necessarily parallel. Sternby provides a useful discussion of issues in the grading of atherosclerosis (40). Nevertheless, the major studies noted above provide strong evidence that women have less coronary atherosclerosis on the average than men of the same age in the same population Risk Factors Factors present in individuals which correlate with future liability to disease are risk factors for that disease. In the case of heart attack, for example, it has been shown that age, male sex, cigarette smoking, hypertension, elevated blood cholesterol, and several other conditions are positively and independently associated with the probability of heart attack. The level of high-density lipoprotein cholesterol in the serum has a negative correlation with heart attack; that is, higher levels are protec- tive. The various risk factors have been identified for both men and women and have been shown on multivariate analysis to be independent. A combination of risk factors is synergistic, pro- ducing an associated risk greater than the simple sum of the individual risks. Although the data for women are much less extensive than for men, they indicate that cigarette smoking is a major risk factor for heart attack in women. `Ibe Effect of Smoking ATHEROSCLEROSIS There is little autopsy information about the amount of atherosclerosis in women smokers. Sackett and his associates reported on aortic atherosclerosis among both men and women: of their 450 female subjects, 309 were nonsmokers, 52 smoked less than a half pack per day, and 89 smoked more (34). Mean, age-adjusted aortic atherosclerosis was found to increase in conjunction with the amount and duration of smoking. A study of the intramyocardial arteries and arterioles of the heart in 13 women and 21 men who were nonsmokers, and 16 women and 27 men who were smokers, indicated that prolifera- tive lesions in intramyocardial arteries were more advanced relative to age in smokers than nonsmokers. It was also found that subendocardial arterioles were thickened in smokers. A separate analysis by sex was not performed, but the authors remarked that the lesions developed as rapidly and as exten- sively in women as in men in both smoking and nonsmoking groups (28). Studies of the severity of atherosclerotic plaques in the ar- teries of women who smoked in comparison with those who did 86 TABLE 4.-Coronary heart disease mortality ratios related to smoking-prospective study Author, year, country Number and Follow- Number type of Data populations collection (yeUars) of deaths Cigarettes/day Age Variation Hammond and Garfinkel, 1969, U.S.A. 358,584 Questionnaire 6 14,819 males and follow-up NS . 445,875 of death certi- l-9 * females age cate 10-19 40-70 at 20-30 entry. >40 M F . 1.00 1.00 . 1.27 0.81 . * * . 1.00 1.22 1.75 1.52 r"; . ..* . 10-19 . 1.77 0.61 20-30 >40 . . Males 40-49 50-59 60-69 70-79 1.00 1.00 1.00 1.00 1.00 1.50 1.48 1.14 2.39 2.13 1.82 1.41 3.76 2.40 1.91 1.49 3.51 2.79 1.71 1.47 Females 40-49 50-59 60-69 70-79 NS . . . . , . 1.00 1.00 1.00 1.00 1.9 . . . . . 1.31 1.15 1.04 0.74 IO-1Y . . . 2.04 2.37 1.79 0.98 20-30 . . . 3.62 2.69 2.00 1.27 240 . . . . . +3.31 3.73 +2.02 Based on 5-9 deaths NS = nonsmokers, M = males, F = females SOURCE: U.S. Public Health Service (44,45). not smoke involve too few subjects to be satisfactory. Inves- tigating the relationship of these arterial lesions and cigarette smoking in women is fundamental to understanding the occur- rence of heart attack and other ischemic diseases. CORONARY HEART DISEASE Coronary heart disease (acute myocardial infarction and chronic ischemic heart disease) occurs with greater frequency in smoking than in nonsmoking women. The prospective study of Hammond and Garfinkel, published in 1969, included data on approximately 446,000 women between the ages of 40 and 79 (10). The increase in mortality ratios in conjunction with in- creasing numbers of cigarettes smoked per day for various ages is shown below in Table 4 (43,44). Mortality ratios were higher for younger ages and lower for older ages. The one-pack-a-day smoker's risk of death from heart attack was approximately twice that of the nonsmoker. The prospective data of Shapiro and colleagues are based on a population of 120,000 men and women (36). Using a sampling factor of about one-thirtieth, they examined 4,301 women at risk of a first myocardial infarction between the years 1962 and 1964. The smokers compared with nonsmokers had roughly twice as many rapidly fatal heart at- tacks and heart attacks that were not fatal within 48 hours. The ratio was approximately 2.9 among younger women aged 45 to 54 and 1.8 for the subjects aged 55 to 64. Heavy smokers had higher ratios, but the data did not permit a detailed study of dose relationships or of the experience of female ex-smokers. A recent study examined the cause-specific mortality of 6,194 British women physicians over the period 1951 to 1973 (6). Table 5 presents the results of this study in conjunction with the pre- viously published results among male physicians during the same period (7). The clear association of cigarette smoking and ischemic heart disease previously described in males was con- firmed in female physicians. For women who reported smoking 15 or more cigarettes per day, mortality due to ischemic heart disease was more than double that of nonsmokers. Although the results demonstrated a similar effect of smok- ing in the development of ischemic heart disease in both male and female physicians, the association of smoking with heart disease was less striking in women physicians. Ischemic heart disease was less prominent as a proportional cause of death in this population of women than in male colleagues (16 percent vs. 32 percent of all deaths). Ischemic heart disease mortality was only 26 percent higher for all ever-smoked women than for never-smoked women. However, for females who smoked heav- 88 TABLE 5.-Death from ischemic heart disease and smoking habits when last asked, British physicians 1951- 1973 Number Annual Death Rate per 100,000 Persons Standardized for Age Current Smokers - Dose Per Dav X2 Nonsmokers Total of Popul. Deaths Nonsmokers Ex-smokers l-14 15-24 > 25 vs. others Trend Women Men 6194 179 138 126 132 304 292 __- 21.14' (number of cigarettes) 34,440 3191 413 533 501 598 677 22.59* 53.56* (any tobacco-grams) (1 gram = 1 cigarette) *p40 . . . . . . . . . Age 40-4s 50-59 60-69 70-7s Males 1.00 1.00 1.00 1.00 . 2.79 1.95 1.30 0.95 . 1.14 1.48 +1.44 0.92 . 2.21 2.03 1.62 1.22 . 1.64 2.40 1.72 +0.68 Females Never smoked 1.00 1.00 1.00 1.00 l-9 . . . . . . . . . . . . . . . 1.50 1.26 1.26 0.83 10-1s . . . . . . . . . . . . . . 2.60 2.70 2.15 +0.57 20-30 . . . . . . . . . , . . . . 2.90 2.67 1.83 1.28 > 40 . . . . . . . . . . . . . . . +5.70+3.52 - - SOURCE: U.S. Public Health Service (44,45). correlation between the incidence of atherothrombotic stroke and cigarette smoking in men but not in women. The extensive prospective study of Hammond and Garfinkel, which involved almost 446,000 women and recorded 1,905 deaths from cere- brovascular disease during a six-year period, found that smok- ing was a positive correlate for such mortality (10); in both men and women, the mortality ratio was increased by roughly 2 or 2.5 times (Table 7) (44,45). That some of these deaths may have involved subarachnoid hemorrhage rather than brain infarction, is suggested by a re- cent report that found the incidence of subarachnoid hemor- rhage to be positively associated with smoking for both men and women (2). The relative risk for men was 3.9 and for women, 3.7. The association appeared to relate to hemorrhage from rup- tured cerebral aneurysms rather than to other conditions that may give rise to subarachnoid hemorrhage. A synergism be- tween smoking and the use of oral contraceptives and sub- arachnoid hemorrhage is noted below (31). The Japanese study cited in the discussion of ischemic heart disease has also re- ported on 366 deaths from cerebrovascular disease among women who smoked (29). The risk ratios for subarachnoid hemorrhage and cerebral hemorrhage were both significantly increased among women smokers (PC .OOl) as was the risk rate for the category, "other forms of cerebrovascular disease" (p < .05). ARTERIOSCLEROTIC PERIPHERAL VASCULAR DISEASE Clinicians have noted that arteriosclerotic peripheral vascu- lar disease is more common in men than women. Sternby has reported from autopsy studies that men generally have some- what more atherosclerosis of the femoral and pelvic arteries than women (40). Kannel has reviewed the relationship of smoking to the inci- dence of arteriosclerotic peripheral vascular disease (19). In the Framingham Heart Study the incidence of peripheral vascular disease was increased among smokers of both sexes; cigarette smoking was as strong an independent risk factor in women as in men. Heavy smokers had a threefold increased incidence. Weiss studied 245 women with arteriosclerotic peripheral vascular disease (49). Ex-smokers who had not smoked for 5 years or more had nearly a normal risk ratio of 1.06; those who had not smoked for the last 1 to 5 years had a risk of 1.70; continuing smokers of less than a pack a day, 5.15; pack a day smokers, 11.53; and those smoking more than a pack a day, 15.56 (relative to nonsmokers, 1.00). The increased risk was particu- 95 larly associated with proximal (aortoiliac) disease, and there was less association with distal (femoropopliteal) disease. Age- standardized relative risk ratios for those smoking a pack a day were 30.06 for proximal and combined proximal and distal dis- ease and 6.32 for distal disease alone. A retrospective study of 217 patients who underwent arterial reconstructive procedures of various kinds for peripheral vascu- lar disease has been reported by Myers and colleagues (27). Diabetics were excluded from the report. There were 164 male and 53 female patients. The late patency rate of the vascular reconstruction was followed for 1 to 4 years. The authors re- ported that the number of cigarettes smoked before surgery did not influence the outcome, but cessation of smoking after surgery had a favorable impact. There were no significant dif- ferences in outcome between men and women. The patency rate 4 years after aortofemoral surgery was 90 percent in those who smoked five or fewer cigarettes per day after surgery and 75 percent in those who smoked a greater amount. Following femoropopliteal reconstruction, the 2year patency rates were 95 percent for those who stopped smoking, 75 percent for those smoking as many as 15 cigarettes per day, and 65 percent for those who continued to smoke more than 15 cigarettes per day. AORTIC ANEURYSM Studies have not been reported for women with respect to atherosclerotic aortic aneurysm and smoking. Deaths for women are about one-fifth those for men (10). HYPERTENSION Smoking is not associated with an increased prevalence of essential hypertension in men or women (39). However, smoking does combine with hypertension (and other risk factors) as a risk factor for heart attack, synergistically compounding the risk. Two recent case control studies of rapidly progressive, severe or malignant hypertension have found that there is an overrep- resentation of smokers among patients with this uncommon phase of hypertension (3,13). In one study of 82 patients who developed malignant hypertension, 67 were smokers. Thirty- three of those were women. In the study, 77 percent of the female patients with malignant hypertension smoked, and only about 44 percent of those with essential hypertension and of the general female population smoked. The difference is highly sig- nificant. A similar and parallel study of 48 patients with malig- nant hypertension contained 33 men and 15 women; 25 men (76 96 percent) and 8 women (53 percent) were smokers compared with 44 percent and 30 percent, respectively, of a group of 44 men and 44 women with nonmalignant hypertension. The difference is significant for men but does not reach significance for women. VENOUS THROMBOSIS The section of the 1979 Surgeon General's Report dealing with venous thrombosis noted a case control study by Vessey and Doll of 84 women who had venous thromboembolism (45). There was no significant relationship to smoking, although there was a trend (p=O.O8) reasonably attributable to chance (46). Simi- larly, Lawson, Davidson, and Jick reported no association with smoking among 60 premenopausal women who used oral con- traceptives and who had uncomplicated venous thromboem- bolism (22). The issue is reopened, however, by a recent paper derived from the Walnut Creek Contraceptive Drug Study. The authors analyzed 38 cases of venous thromboembolic events among the approximately 16,700 women followed in the study. These women were matched with 8,174 controls from the same cohort, providing each case with 61 to 559 comparison subjects. The relative risk of cigarette smoking was 2.6 with a one-sided p value of less than 0.01. On multivariate analysis, the smoking effect was independent and remained significant. Of the 17 idiopathic cases of thromboembolic disease, 65 percent occurred in smokers, while 33 percent of the controls were smokers. The relative risk for smokers was 4.2. Both smoking and oral con- traceptive use were independent risk factors for venous throm- boembolic disease in this cohort of women (32). The same section of the 1979 Surgeon General's Report noted a controversy about whether smokers who suffered myocardial infarction had a relative protective effect from leg vein throm- bosis in the immediate post infarction period (45). The authors did not provide an analysis for each sex. A recent investigation of women undergoing gynecologic op- erations has studied the incidence of deep vein thrombosis of the leg in relation to smoking. In the prospective study of 231 women, their smoking habits during the month before the oper- ation were determined. The occurrence of deep vein thrombosis (DVT) was assessed by the radioactive fibrinogen technique, with routine scans on the first, third, and sixth postoperative days. Of the 231 patients, 99 smoked and 132 did not smoke. Eight of the smokers (8.1 percent) and 29 of the nonsmokers (22 Percent) developed DVT. Following an analysis of other factors, the authors concluded that smoking provided an apparent "pro- 97 tective" effect against postoperative DVT, based on the fact that smokers constituted only 21 percent of the patients with DVT. They also noted that the women who developed DVT weighed more than those who did not and that smokers who developed CVT were more overweight than nonsmokers with DVT (5). In a continuing prospective study of the relationship of blood clotting and blood thrombogenic properties to ischemic heart disease, Meade and associates have reported on a number of blood coagulation variables and their relationship to smoking among 1,426 men and 638 women in England (26). Forty-three percent of the men and 36 percent of the women were smokers. Smoking was not found to have an effect in women on factors V or VII, fibrinogen, fibrinolytic activity, antithrombin III, platelet adhesiveness, or platelet count. Smoking decreased fib- rinolytic activity in men and decreased factor VIII activity in both men and women. Oral contraceptive users were found to show an increase in fibrinolytic activity only if the women were nonsmokers. HIGH-DENSITY LIPOPROTEIN High-density lipoprotein (HDL) is a protein complex that transports cholesterol in the blood. A higher level of HDL is correlated with a reduced risk of heart attack. It has been ob- served that women who smoke have lower levels of HDL than expected (1,4,9). Oral Contraceptive Use, Smoking, and Cardiovascular Disease The association of oral contraceptive use and an increased incidence of certain cardiovascular disorders has attracted much interest. Smoking has emerged as a strong synergistic risk factor, and an additional study has focused on smoking as an independent risk factor. The effects of smoking and of estrogen and progestin con- traceptives on the level of high-density lipoprotein in women have been studied by Bradley and associates. They measured serum HDL among almost 5,000 women between the ages of 21 and 62 (4). They reported that the use of oral estrogens raised the level of HDL significantly above the level in nonusers while progestin use lowered it. Combination drugs tended to change the HDL level according to their relative estrogen-progestin formulation. The average HDL concentration was reduced by smoking. Among nonsmoking women the HDL concentration was 63.7 + 16.8 mg/dl. This was reduced by 2.2 mg/dl for those smcking half a pack per day; and by 7.3 mg/dl for those smoking 98 one or more packs per day. A reduction in the HDL level among women who smoked was also reported from Holland. This study found an independent negative association with the HDL level among oral contraceptive users (1). It has been reported from long-term studies that women using oral contraception have a two to threefold statistically significant increase in risk of venous thromboembolic disease when compared to those using other forms of contraception (47). This study concluded that smoking did not significantly in- crease the incidence of venous thromboembolism (46). By con- trast, the Walnut Creek Study reported that smoking contrib- uted to venous thromboembolism among both users and nonus- ers of oral contraceptives (32). Conclusions about the effect of smoking on venous thromboembolic phenomena, therefore, must be regarded as uncertain at this time since there are few relevant studies and they provide somewhat contrary conclu- sions. In 1973, the Collaborative Group for the Study of Stroke in Young Women estimated that the relative risk of cerebral is- chemia or thrombosis was approximately nine times greater for women who use oral contraceptives than for those who do not. A detailed analysis of smoking was not presented, but one of the study's striking findings was the high proportion of women with stroke who currently or at some time smoked cigarettes regu- larly (73.8 percent), compared with smoking rates of 43.4 percent among neighborhood controls aged 17 to 44. The study also found an increase in hemorrhagic strokes among white women. Almost half of the hemorrhagic strokes were attributable to bleeding from congenital aneurysms leading to subarachnoid hemorrhage (5). Recently an association between smoking and aneurysmal subarachnoid hemorrhage in both men and women has been documented (2). The Walnut Creek Contraceptive Drug Study reported that in a cohort of approximately 16,700 women, the risk of sub- arachnoid hemorrhage for smokers was 5.7 times that of nonsmokers; the risk for oral contraceptive users was 6.5 times that of nonusers; and the relative risk for women who used both cigarettes and oral contraceptives was 22 times as great. Past users of oral contraceptives also had an increase in relative risk, but an analysis of risk was not possible because of the small number of cases (31). The risk of myocardial infarction in women is increased by cigarette smoking and by the use of oral contraceptives; it is compounded when both are used together. For example, Mann and associates reported a retrospective study of 63 women below the age of 45 with acute myocardial infarction. The pro- 99 portion of heart attack patients who had used oral contracep- tives in the previous months was significantly higher than ex- pected. The relative risk for myocardial infarction among women smoking 25 or more cigarettes per day was 11.3 times greater than that among nonsmokers. Moreover, there was evi- dence for synergism of the two risks (23). Jick, et al. reported a case control study of 107 women under age 46 who were discharged from the hospital after suffering nonfatal, acute myocardial infarctions (15,16,17). The annual risk of nonfatal myocardial infarction (MI) among healthy women aged 39 to 45 who both smoked and used estrogens for noncontraceptive purposes was approximately 1 in 750. They noted that although an acute myocardial infarction is uncom- mon in healthy young women, the risk appears to be substantial in women over the age of 38 who both use estrogens and smoke cigarettes (17). In this same study, a relative risk of 14 was reported for oral contraceptive users compared with nonusers (90 percent confi- dence limits of relative risk from 5.5 to 37) (16). In women smok- ing more than 25 cigarettes per day the relative risk rose to 34 times that of women who were both nonusers and nonsmokers. While the number of subjects was small, the authors calculated that for wamen exposed to either oral contraceptives or smok- ing, but not both, the annual age-specific risks for nonfatal MI were roughly 1 per 190,000 at ages 27 to 37; 1 per 47,000 at ages 38 to 40; 1 per 23,000 at ages 40 to 43; and 1 per 16,000 at ages 44 and 45. If, however, both cigarettes and oral contraceptives are used, the annual age-specific risk is .estimated to be much higher and the respective risks become 1 in 8,400; 1 in 920,l in 540, and 1 in 250. The authors report that a dose-response rela- tionship exists between smoking and risk among their popula- tion of female myocardial infarction patients, such that smok- ing 1 to 14 cigarettes per day carried a relative risk of nonfatal myocardial infarction of 9.2; 15 to 25 cigarettes of 7.9; and 26 or more cigarettes of 21, relative to those who never smoked (15). In another recent study of 234 pre-menopausal women.who had suffered a first myocardial infarction and 1,742 control pa- tients drawn from the hospital population, Shapiro and his co- workers found an association between recent oral contraceptive. use and smoking (35). They found- no evidence that past use of oral contraceptives was related to heart attack or that heightened risk was associated with increased duration of use of the oral contraceptives. For nonsmokers who used oral con- traceptives, the rate of myocardial infarction increased fourfold compared to nonusers and nonsmokers; in those women who smoked 25 or more cigarettes a day but did not use oral con- 100 traceptives, the rate increased more than sevenfold; and in those women who both smoked heavily and used oral contracep- tives the rate increased at least twentyfold. Carbon Monoxide A study of male and female office workers found no sex dif- ference in the relationship between carboxyhemoglobin (COHb) levels and daily consumption of cigarettes. However, women smoked fewer cigarettes on the average than men. The study found that the COHb levels in smokers were higher among the sedentary office workers than among physically active meat porters and that both had higher levels of COHb than pregnant women who smoked (12). The latter had COHb levels approxi- mately three times higher than that of nonsmokers. Wald re- ported from a cross-sectional study that carboxyhemoglobin levels of smokers are a better indicator of the risk of atherosclerotic cardiovascular disease than a reported smoking history (48). The proportion of both men and women with atherosclerotic disease increased with increasing levels of COHb. Comment Women are less likely to experience a myocardial infarction than men. Nevertheless, coronary heart disease is still a leading cause of death and disability in women. The lower mortality rates from acute myocardial infarction and chronic ischemic heart disease of women as compared to men are paralleled by less extensive and severe atherosclerosis in the coronary ar- tieries of adult women. The severity of aortic atherosclerosis, however, is about the same in both sexes. The relationship of cigarette smoking to atherosclerosis, heart attack,and other ischemic diseases secondary to atherosclerosis has not been studied among women as exten- sively as among men; moreover, most studies have been limited to white women. It is not known whether atherosclerotic plaques observed at autopsy are more extensive and severe in women smokers than in nonsmokers. No data are available con- cerning the incidence of death from atherosclerotic aneurysms of the aorta among women who smoke relative to those who do not, and inadequate data exist to indicate whether cessation of smoking by women is associated with a beneficial reduction in the risk of heart attack, as has been demonstrated in men. The effect of smoking on the threshold for the onset of angina pec- toris and on cardiac function in women with coronary heart disease has not been studied. 101 Nevertheless, compelling data from prospective cohort studies and from case control investigations indicate that cigarette smoking is a major risk factor for fatal and nonfatal heart attacks in women. In general, cigarette smoking in- creases the risk by a factor of about two, and in younger women cigarette smoking may increase the risk several fold. Women who smoke low-"tar" and low-nicotine cigarettes have a greater risk of suffering heart attacks than nonsmokers but appear to have a smaller risk than women smoking moderate-to-high "tar" and nicotine products. Smoking is a major risk factor for arteriosclerotic peripheral vascular disease in women, as it is in men. For both men and women the successful outcome of surgical repair of this disorder is enhanced by cessation of smoking. Smoking is a major risk factor for subarachnoid hemorrhage and for the development of malignant hypertension. Smoking is reported to depress the natural relative elevation of high-density lipoprotein choles- terol enjoyed by women. In women who use oral contraceptives, smoking is a powerful synergistic risk factor for subarachnoid hemorrhage and for myocardial infarction. While data implicating smoking as a risk factor for various cardiovascular diseases in women are neither as extensive nor as complete as for men, the evidence nonetheless clearly estab- lishes cigarette smoking as a major correlate for myocardial infarction, arteriosclerotic peripheral vascular disease and subarachnoid hemorrhage in women (45). Coronary heart disease is the major cause of death among both males and females in the U.S. population. The 1979 Sur- geon General's Report clearly demonstrated the close associa- tion of cigarette smoking and increased coronary heart disease among males. This report reviews the evidence associating cigarette smoking and cardiovascular disease in women: 1. Coronary heart disease, including acute myocardial infarc- tion and chronic ischemic heart disease, occurs more frequently in women who smoke. In general, cigarette smoking increases the risk by a factor of about two, and in younger women cigarette smoking may increase the risk several fold. 2. Cigarette smoking is a major independent risk factor for coronary heart disease in women; it also acts synergistically with other coronary heart disease risk factors producing a risk greater than the sum of the individual risks. 3. The use of oral contraceptives by women cigarette smokers 102 increases the risk of a myocardial infarction by a factor of ap- proximately ten. 4. Women who smoke low "tar" and nicotine cigarettes expe- rience less risk for coronary heart disease than women who smoke high "tar" and nicotine cigarettes, but their risk is still considerably greater than that of nonsmokers. 5. Increased levels of high-density lipoprotein (HDL) are cor- related with a reduced risk for an acute myocardial infarction; women cigarette smokers have decreased levels of HDL. 6. Cigarette smoking is a major, independent risk factor for the development of arteriosclerotic peripheral vascular disease in women. Smoking cessation improves the prognosis of the dis- order and has a favorable impact on vascular patency following reconstructive surgery. 7. Women cigarette smokers experience an increased risk for subarachnoid hemorrhage; the use of both cigarettes and oral contraceptives appears to increase synergistically the risk for subarachnoid hemorrhage. 8. Women who smoke cigarettes may be more likely to de- velop severe or malignant hypertension than nonsmoking women. References (11 ARNTZENIUS, A.C., VAN GENT, C.M., VAN DER VOORT, H., STEGERHOEK, C.I., STYBLO, K. Reduced high-density lipoprotein in women aged 40-41 using contraceptives. Consultation Bureau Heart Project. Lancet: 1221-1223, June 10, 19'78. (2) BELL, B.A., SYMON, L. Smoking and subarachnoid haemorrhage. British Medical Journal 1: 577-578, March 3, 1979. (9) BLOXHAN, C.A., BEEVERS, D.G., WALKER, J.M. Malignant hyper- tension and cigarette smoking. British Medical Journal 1:581-583, March 3,1979. (4) BRADLEY, D.D., WINGERD, J., PETITTI, D.B., KRAUSS, R.M., RAM- CHARAN, S. Serum high-density lipoprotein cholesterol in women using oral contraceptives, estrogens, and progestins. New England Journal of Medicine 299(l): 17-20, July 6, 1978. (5) COLLABORATIVE GROUP FOR THE STUDY OF STROKE IN YOUNG WOMEN. Oral contraceptive and increased risk of cerebral ischemia or thrombosis. New England Journal of Medicine 28&17): 871-878, April 26, 1973. (6) DOLL, R., et al. Mortality in relation to smoking: 20 years' observations on male British doctors. British Medical Journal 2: 1525-1536, De- cember 25, 1976. (7) DOLL, R., GRAY, R., PETO, R. Mortality in Relation to Smoking: Ob- servations on Female Doctors. (Unpublished manuscript) (8) EPSTEIN, F.H. Some uses of prospective observations in the Tecumseh Community Health Study. Proceedings of the Royal Society of Medicine 60(l): 56-60, January 196'7. (9) GARRISON, R.J., KANNEL, W.B., FEINLEIB, M., CASTELLI, W.P., MCNAMARA, P.M., PADGETT, S.J. Cigarette smoking and 103 (10) (11) (12) (13) (14) (16) (17) (18) (19) t20) (21) (22) 104 HDL cholesterol: the Framingham Offspring Study. Atherosclerosis 30: 17-25, 1978. HAMMOND, E.C., GARFINKEL, L. Coronary heart disease, stroke, and aortic aneurysm: factors in the etiology. Archives of Environmen- tal Health 19(2): 16'7-182, August 1969. HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. "Tar" and nicotine content of cigarette smoke in relation to death rates. En- vironmental Research 12(3): 263-274, December 1976. HAWKINS, L.H. Blood carbon monoxide levels as a function of daily cigarette consumption and physical activity. British Journal of Indus- trial Medicine 33(2): 123-125, May 1976. ISLES, C., BROWN, J.J., CUMMING, A.M.M., LEVER, A.F., MCAREAVEY, D., ROBERTSON, J.I.S., HAWTHORNE, V.M., STEWART, G.M., ROBERTSON, J.W.K., WAPSHAW, J. Excess smok- ingin malignant-phase hypertension. British Medical Journal 1: 579-581, March 3, 1979. JAIN, A.K. Cigarette smoking, use of oral contraceptives, and myocar- dial infarction. American Journal of Obstetrics and Gynecology 126(3): 301-307. October 1, 1976. JICK, H., DINAN, B., HERMAN, R., ROTHMAN, K.J. Myocardial in- farction and other vascular diseases in young women. Role of estro- gens and other factors. Journal of the American Medical Association 24q23): 2548-2552, December 1, 1978. JICK, H., DINAN, B., ROTHMAN, K.J. Oral contraceptives and nonfatal myocardial infarction. Journal of the American Medical Association 239(14): 1403-1406, April 3, 1978. JICK, H., DINAN, B., ROTHMAN, K.J. Noncontraceptive estrogens and non-fatal myocardial infarction. Journal of the American Medical As- sociation 239(14): 1407-1408, April 3, 1978. KAGAN, A.R., STERNBY, N.H., UEMURA, K., VANECEK, R., VIH- ERT, A.M., LIFSIC, A.M., MATOVA, E.E., ZAHOR, Z., ZDANOV, V.S. Atherosclerosis of the aorta and coronary arteries in five towns. Bulle- tin of the World Health Organization 53(5-6): 501-530, 1976. KANNEL, W.B. Epidemiologic studies on smoking in cerebral and peripheral vascular disease. In: Wynder, E.L., Hoffmann, D., Gori, G.B. (Editors). Proceedings of the Third World Conference on Smoking and Health, New York, June 2-5, 1975. Volume I. Modifying the Risk for the Smoker. U.S. Department of Health, Education, and Welfare, Pub- lic Health Service, National Institutes of Health, National Cancer In- stitute, DHEW Publication No. (NIH) 76-1221, 1976, pp. 257-274. KANNEL, W.B., CASTELLI, W.P., MCNAMARA, P.M. Cigarette smok- ing and risk of coronary heart disease. Epidemiologic clues to pathogenesis. The Framingham Study. In: Wynder, E.L., Hoffmann, D. 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(37) SLONE, D., SHAPIRO, S., ROSENBERG, L., KAUFMAN, D.W., HARTZ, S.C., ROSSI, A.C., STOLLEY, P.D., MIETTINEN, O.S. Rela- tion of cigarette smoking to myocardial infarction in young women. New England Journal of Medicine 298(23): 1273-1276, June 8, 1978. (`88) SPAIN, D.M., SIEGEL, H., BRADESS, V.A. Women smokers and sudden 105 (891 (40) (41) (421 143) (441 (45) (461 (471 (48) (49) (501 death. The relationship of cigarette smoking to coronary disease. Journal of the American Medical Association 224(7): 1005-1007, May 14, 1973. STAMLER,J.,RHOMBERG, P.,SCHOENBERGER,J.A.,SHEKELLE, R.B., DYER, A., SHEKELLE, S., STAMLER, R., WANNAMAKER, J. Multivariate analysis of the relationship of seven variables to blood pressure. Findings of the Chicago Heart Association Detection Project in Industry, 1967-1972. Journal of Chronic Diseases 28(10): 527-548, November 1975. STERNBY, N.H. Atherosclerosis in a defined population. An autopsy survey in Malmo, Sweden. Acta Pathologica et Microbiologica Scan- dinavica. Supplement 194: 16-194, 1968. STRONG, J.P., SOLBERG, L..4., RESTREPO, C. Atherosclerosis in per- sons with coronary heart disease. Laboratory Investigation 18(s): 527-537, May 1968. TALBOTT, E., KULLER, L.H., DETRE, K., PERPER, J. Biologic and psychosocial risk factors of sudden death from coronary disease in white women. American Journal of Cardiology 3X6): 858-864, May 26, 1977. THE EPIDEMIOLOGY STUDY GROUP. Epidemiology for stroke facilities planning. Report of the Joint Committee for Stroke Facilities. Stroke 3: 360-371, May-June 1972. U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smok- ing. A Reference Edition. Department of Health, Education, and Wel- fare, Public Health Service, Center for Disease Control, DHEW Publi- cation No. (CD0 78-8357, 1976, 657 pp. U.S. PUBLIC HEALTH SERVICE. Smoking and Health. A Report of the Surgeon General. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Publication No. (PHS) 79-50066, 1979, 1241 pp. VESSEY, M.P., DOLL, R. Investigation of relation between use of oral contraceptives and thromboembolic disease. A further report. British Medical Journal 2(5658): 651-657, June 14, 1969. VESSEY, M., DOLL, R., PETO, R., JOHNSON, B., WIGGINS, P. Along- term follow-up study of women using different methods of contracep- tion. An interim report. Journal of Biosocial Sciences 8: 373-427,1976. WALD, N., HOWARD, S., SMITH, P.G., KJELDSEN, K. Association between atherosclerotic diseases and carboxyhaemoglobin levels in to- bacco smokers. British Medical Journal 1: 761-765, March 31, 1973. WEISS, N.S. Cigarette smoking and arteriosclerosis obliterans: an epidemiologic approach. American Journal of Epidemiology 95(l): 17-25, 1972. WILHELMSEN, L. Recent studies on smoking and CVD epidemiology: Scandinavia and some other Western European countries. In: Stein- feld, J., Griffiths, W., Ball, K., Taylor, R.M. (Editors). Proceedings of the Third World Conference on Smoking and Health, New York, June 2-5, 1975. Volume II. Health Consequences, Education, Cessation Activities and Social Action. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, DHEW Publication No. (NIH) 77-1413, 1977, pp. 171-177. 106 CANCER. CANCER Introduction For more than 40 years cancer has been second only to car- diovascular disease as a cause of death in the United States. With the exception of the very elderly, the death rate for adult men exceeds that for adult women for both groups of diseases, implying a difference in genetic susceptibility, environmental exposures or lifestyles between the sexes, or a combination of genetic and environmental factors. Placing these generalizations about cause of death in per- spective, current data from the National Center for Health Statistics (28) reveal the following statistics: There are 105 male births each year in the United States for every 100 female births, but the higher death rate for males results in a ratio of 100 men to 100 women at ages 20 to 24 and of 79:lOO at ages 65 to 69, and of 47:lOO at age 85. Life expectancy in the United States in 1976 was 68.7 years for males compared to 76.1 years for females. Heart disease and cancer currently account for 60 percent of deaths in the United States. In contrast to the decline in the age-adjusted death rates for ischemic heart disease, the age- adjusted death rate for cancer has increased. Hidden in this small rise in the overall cancer statistics is a remarkable increase -a veritable epidemic-of cancer of the lung in both men and women. In the past quarter century, deaths from cancer of the respiratory tract tripled in the white population and quadrupled in the black population. The remarkable male- to-female preponderence of lung cancer in the 1940s and 1950s has been decreasing in the 1960s and 1970s; the rate of increase in lung cancer in males is slowing while the rate of increase of lung cancer in females is accelerating. As a cause of death, lung cancer in women is now second only to mammary carcinoma and will likely displace breast cancer as thekading cause of cancer mortality in women in the 1980s (1) (see Figure 1). The 1964 Surgeon General's Report reached the following conclusion: "Cigarette smoking is causally related to lung cancer in men; the magnitude of the effects of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction" (33). Since then, a number of retrospective and prospective epidemiologic studies, experimental animal carcinogenesis studies, and studies of human tissues at surgery and autopsy have confirmed and ex- tended those conclusions. Cigarette smoking is the major cause of cancer of the lung in women. The risk increases with the number of years the individual smoked, the number of ciga- 109 27 r .*%otiwhite Males I I I A!' 7 6 5 r Whiteemales- ] 5 1950 1955 1960 1965 1970 1975 46th Rev. -7th Rev. --++ 8th Rev. + 1980 , g&985 FIGURE l.-Age-adjusted death rates* for malignant neoplasm of trachea, bronchus and lung,** by color and sex compared to rates for malignant breast neoplasm, United States, 1950-1977; projection for white females to 1985.*** *Adjusted by the direct method to the U.S. population, 1940. o *ICD 6th and 7th Rev. Nos. 162, 163 and 8th Rev. No. 162. ***Projection based on average annual rate of increase over last 10 years. SOURCE: National Cancer Institute (25), National Center for Health Statis- tics (27). rettes smoked, the "tar" and nicotine level of the cigarette smoked and the degree of inhalation, and is inversely related to the age at which the individual began smoking, being higher for those who begin smoking at younger ages. The risk of developing 110 cancer is diminished significantly by quitting smoking and is lessened somewhat by switching to low-tar, low-nicotine filter- tip cigarettes (43,45). Considerable evidence has also shown that cigarette smoking is a significant cause-for women and men-of cancer of the larynx, oral cavity, esophagus, urinary bladder, kidney, and pancreas. Much of this information has been summarized in previous issues of "The Health Conse- quences of Smoking" or the Surgeon General's Reports (33-43). Table 1 Iists the new cases and deaths estimated to occur in 1980 for those cancers which are causally associated with cigarette smoking (1). Smoking will contribute to 43 percent of the male and 18 percent of the female newly diagnosed cancer cases in the United States in 1980 and to 51 percent of the male and 26 percent of the female cancer deaths. This table does not imply that cigarette smoking causes each of these individual cancers. It does, however, identify the impact of cigarette smok- ing on the major cancers now known to be associated with cigarette smoking. Most of the cases of cancer of the lung and larynx could have been prevented, as could a substantial pro- portion of the cancer deaths at the other sites listed. In this chapter, selected data on cancer and smoking among women will be reviewed and summarized. Where necessary for clarity, data previously reported will be summarized briefly. Lung The lung is a complex organ lined by at least five types of epithelial cells, each of which theoretically might give rise to one or more types of neoplasm. In addition to the epithelial cells, blood vessels and connective tissue are prominent in the lungs. Both visceral and parietal portions of the lung are covered by synovlal membranes, which also are subject to neoplastic trans- formation. The World Health Organization's classification of malignant tumors (Table 2) includes multiple histologic types, of which epidermoid, small cell, adenocarcinoma, and large cell carcinoma are causally related to cigarette smoking and display significant dose-response relationships in epidemiologic studies (7,43). These four tumors are the most common histologic types of lung cancer in both men and women. However, there are differences in the distribution of the different types of lung cancer in men and women and in smokers and nonsmokers. Epidermoid carcinoma was the most common histologic 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 3) (31). 111 TABLE l.-Estimated new cancer cases and deaths for sites associated with cigarette smoking, 1980 Site Total Estimated New Cases Estimated Deaths Male Female Total Male Female All Sites 785,000' 38'7,000* 398,000* 405,000 219,500 185,500 Lung 117,000 85,000 32,000 101,300 74,800 26,500 Pancreas 24,000 12,500 11,500 20,900 11,100 9,800 Urinary Bladder 35,500 26,000 9,500 10,300 7,000 3,300 Oral 25,500 17,900 7,600 8,800 6,100 2,700 Kidney & Other Urinary 16,900 10,500 6,400 7,900 4,800 3,100 Esophagus 8,800 6,200 2,600 7,600 5,500 2,100 Larynx 10,700 9,000 1,700 3,500 2,900 600 All Tobacco Related 238,400 167,100 71,300 160,300 112,200 48,100 *Carcinoma in situ is not included. There are 45,000 new cases of uterine cervical carcinoma in situ each year. Non-melanoma skin cancer is not included. Approximately 400,000 new cases of non-melanoma skin cancer occur annually. SOURCE: American Cancer Society (1). TABLE 2.-World Health Organization classification of malignant pleuro-pulmonary neoplasms I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. Epidermoid Carcinomas Small Cell Anaplastic Carcinomas Adenocarcinomas 1. Bronchogenic a. acinar b. papillary with or without mucin formation Large Cell Carcinomas Combined Epidermoid and Adenocarcinomas Carcinoid Tumors Bronchial Gland Tumors 1. Cylindromas 2. Mucoepidermoid tumors Papillary Tumors of the Surface Epithelium Mixed Tumors and Carinosarcomas Sarcomas Unclassified Melanoma Mesotheliomas SOURCE: Kreyberg, L. (22). TABLE 3.-Histologic types of pulmonary cancers in smokers and nonsmokers Male Female Non- Non- Type Total Smokers Smokers 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 Bronchioloalveolar 68 35 4 13 16 TOTAL 2,926 2,341 70 367 148 SOURCE: Resenow, E.C. (31). Other centers have similar data, although the proportions by histologic type may vary with the pathologic criteria used, pa- tient population, geographic location, and other factors. Earlier epidemiologic studies suggested that cigarette smok- ers were more likely to develop squamous-cell and small-cell lung carcinoma than other types. However, more recent inves- tigations indicate that all four major histologic types of lung cancer- including adenocarcinoma, which appears to be in- creasing rapidly in recent years- are related to cigarette smok- ing in both men and women (43). 113 In 1980, of the estimated 117,000 newly diagnosed cancers of the lung in the United States, 32,000 will be among women. There will be an estimated 25,500 deaths from lung cancer in women (1). In 1950, women accounted for approximately 1 in 12 of all lung cancer deaths. By 1968 the proportion was 1 in 6; in 1979 women dying of lung cancer will represent over one-quarter of all lung cancer victims. White women have death rates from lung cancer which are similar to those of nonwhite women, while the rates of white males remain below those of nonwhite males. These dif- ferences may be due to differences in the smoking habits of blacks and whites described elsewhere in this report. Many prospective studies have found that the lung cancer death rate for smokers was far in excess of the rates for nonsmokers in both sexes; as previously mentioned, the rates for male smokers dramatically exceeded the rates for female smokers. However, even the nonsmoking male had a higher in- cidence of, and death rate from, lung cancer than the nonsmok- ing female (9). This evidence suggested that women might have a decreased susceptibility to lung cancer. A more careful examination of the data indicates that most of the differences between male and female lung cancer rates can be explained by differences in smoking habits and occupational exposures. As discussed in other sections of this report, a smaller per- centage of women than men smoke and, when they do smoke, they are more likely to adopt smoking behaviors that have been shown to have a lower risk of developing lung cancer. That is, they smoke fewer cigarettes per day, inhale less, start smoking later in life, and are more likely to smoke low-tar and low- nicotine and filter cigarettes. In addition, it is important to con> sider the cohort effects on the differences in rates between males and females. Over 85 percent of those who smoke regu- larly began between the ages of 12 and 25 (29). Men first began to smoke in large numbers just before and during the First World War. As each succeeding birth cohort passed through the age of initiation (12 to 25), a larger percentage began smoking until the groups born between 1915 and 1930 were reached (1'7). In the birth cohorts born after 1930, fewer began to smoke regu- larly. The risk of developing lung cancer increases exponen- tially with age and duration of smoking, with the increase start- ing 15 to 20 years after the beginning of regular smoking. This accounts for the dramatic rise in the male lung cancer death rates noted in the 1930s. As those birth cohorts with. higher smoking rates replaced those with lower smoking rates, the age-specific lung cancer rates rose steadily; and as each of the heavy-smoking birth cohorts grew older, their lung cancer risk 114 continued to accelerate, resulting in a very steep rise in the overall male lung cancer death rate. The overall cancer rates among men will continue to rise (albeit more slowly) as those birth cohorts with the heaviest smoking prevalence replace those with lower prevalence in the older age groups where the lung cancer death rates are the highest. As these birth cohorts with high smoking prevalence pass through the age groups and are replaced by birth cohorts with lower smoking prevalence, declines in lung cancer rates should be noted. They should be noted first in the age-specific death rates for the younger age groups and later in the overall lung cancer death rates. The first indications of this change have been noted with a decline in the age-specific death rates in males born after 1930. It is therefore important to consider this cohort effect when examining the differences between lung cancer rates of men and women. Women began to take up smoking in large numbers 20 to 30 years later than men (in the early 1940s). This rise in smoking prevalence was produced by predominantly young women first using tobacco as cigarettes. This is in contrast to the rise in men which included a substantial percentage of men of all ages who switched from other forms of tobacco use to cigarettes. The rise in lung cancer rates in women occurred as those cohorts with high smoking prevalence reached the ages where lung cancer occurs with significant frequency (age 45 and over). Since most of these women began smoking cigarettes prior to age 25 they would have at least 20 years of exposure by age 45 in contrast to the shorter durations of exposure at age 45 for those men who switched to cigarettes from other forms of tobacco around the time cigarettes first came into widespread use. This greater du- ration of exposure at any given age for women in these first heavy smoking birth cohorts compared to the first cohorts in men, should result in a more abrupt rise in lung cancer rates in women. This rapid rise in female lung cancer death rates began to be observed in the late 1950s. As birth cohorts with higher smoking prevalence continued to replace those with lower smok- ing prevalence, the rates rose steeply, reproducing the phenomenon noted in males 20 to 30 years earlier with some indication that the rise is even steeper for women. If one sub- tracts 25 years from the female cancer death rates in Figure 1, the rates for women are only slightly below the rates for men. This small difference is explained by lower prevalence of smok- ing and less hazardous smoking patterns of women and their less frequent exposure to occupational carcinogens. Thus, close scrutiny of the trends reveals no substantial protective effect for women on the risk of developing lung cancer but rather leads to a 115 TABLE 4.-Age-adjusted lung cancer mortality ratios-age began smoking and degree of inhalation Age Began Smoking 15 15-19 20-24 25+ Depth of Inhalation None Slight Moderate Heavy SOURCE: Hammond, E.C. (11). Male Female 16.8 2.5 14.7 5.0 1O.l 3.4 4.1 2.3 Male Female 8.0 2.0 8.9 2.3 13.1 3.5 17.0 7.1 TABLE 5.-Age-adjusted relative risks of lung cancer by number of cigarettes smoked Number of Cigarettes Smoked Daily l-9 10-19 20-39 40+ ACS Study Male 4.6 8.6 14.1 18.8 Female 1.3 2.4 4.9 7.5 1-14 15-24 25+ British Male 7.8 Physicians Female 1.3 SOURCE: Doll, R. (6,8), Hammond, E.C. (11). 12.7 25.1 6.4 29.7 sobering projection of a reproduction of the male lung cancer epidemic in women (Figure 1). GEOGRAPHIC DIFFERENCES Lung cancer death rates, including all histologic types, are highest in industrialized countries where there has been a higher smoking prevalence for a longer time. Women in Scotland have one of the highest death rates from lung cancer of women of any country. Their tobacco consumption per smoker approaches that of English and Welsh men (19). Current tobacco consump- tion by Scottish women is only a little lower than the consump- tion of Scottish men 20 years ago. In England and Scotland, where the upper socioeconomic classes have reduced their 116 TABLE 6.-Lung cancer mortality ratios for females by duration of smoking: Swedish study Duration of Smoking in Years Nonsmokers l-29 years 30+ years SOURCE: Cederlof, R. (4). Mortality Ratios 1.0 1.6 9.6 cigarette consumption in recent decades, there is a significantly greater lung cancer mortality rate in the lower socioeconomic classes among women (19). Age-adjusted death rates for lung cancer in women in select countries indicate that women in Hong Kong have the highest rates, while those in Scotland are second and those in England and Wales are third. The United States ranked sixth world wide (1). Amongnonsmokers, lungcancer is found slightly more often in urban than in rural areas; however, the marked increase in lung cancer among smokers in urban areas suggests that urban living exerts a potentiating rather than an additive effect on the inci- dence of lung cancer. Urban living has little independent effect on lung cancer induction in comparison with even modest smok- ing of filtered low-tar and low-nicotine cigarettes (5,lO). SMOKING PATTERNS AMONG WOMEN Although women tend to have different patterns of smoking than men, the relative relationships between smoking and lung cancer are the same. Lung cancer rates for women who smoke increase with increased dosage as measured by several dosage measures, including number of cigarettes smoked per day, dura- tion of smoking habit, degree of inhalation, age of initiation of smoking, and the "tar" and nicotine level of the cigarettes smoked. These data, obtained from several prospective investi- gations, are examined in Tables 4, 5, 6, 7, 9, and 10. The more cigarettes an individual smokes, the more likely that individual will die of lung cancer (Table 5). Overall, female cigarette smok- ers have 2.5 to 5.0 times greater likelihood of dying from lung cancer than nonsmokers (Table 7). As discussed earlier, when the full impact of the cohort effect is felt, this ratio will probably approach that for men (8 to 12). Doll, et al. studied the cause-specific mortality experience among approximately 6,200 female physicians in England during 117 TABLE 7.-Lung cancer mortality prospective studies - Age Adjusted Lung Cancer Death-Relative Risks Cigarette Nonsmokers Smokers ACS Male 1.0 10.1 Female 1.0 2.6 British Male 1.0 14.0 Physicians Female 1.0 5.0 Swedish Study Male 1.0 8.2 Female 1.0 4.5 SOURCE: Cederlof, R. (4), Doll, R. (6,8), Hammond, E.C. (11). the period 1951 to 1973 (6). The results of this study are presented in detail in Table 8, which also includes data from a previous report on male physicians (8). It is apparent that smoking and lung cancer are similarly related in men and women. In both sexes, lung cancer mortality was at least three times as high in ever-smokers as in never- smokers, at least twice as high in current heavy smokers (more than 25 cigarettes) as in light smokers (less than 15 cigarettes), and exhibited a significant dose-response relationship. The magnitude of the smoking effect on lung cancer for females and males was approximately the same. The relative risks for mortal- ity from lung cancer for moderate (15 to 24 cigarettes per day) and heavy (more than 25 cigarettes) smokers were 6.3 and 29.7 among females, and 10.6 and 22.4 for males. The authors emphasize, however, that no conclusions can be drawn from this data about the magnitude of the biologic effects of smoking in men compared to women. Since the authors doc- umented differences in lifetime smoke exposure (later age at initiation and lower prevalence of inhalation among females), lifetime smoking exposures between the sexes were not directly comparable. This issue will be resolved only when studies examine the effect of smoking in cohorts of women whose lifetime smoking behavior more closely matches that of the men to whom they are compared. A number of retrospective studies have examined the rela- tionship of smoking and lung cancer in women. The 1971 Health Consequences of Smoking reviewed many of these investiga- tions and showed a smoker-to-nonsmoker risk ratio ranging from 0.2 to 6.8 for females. The reader is referred to this volume for a more detailed discussion of these studies. Results of these investigations reveal sex differentials similar to those found in 118 TABLE 8.-Death rates from lung cancer and smoking habit when last asked, British physicians 1951-1973 Women Men Annual Death Rate per 100,000 Persons Standardized for Age X* Current Smokers-Dose Per Day Nonsmokers Trend Total vs. (Dose/ Popul. # Deaths Nonsmokers Ex-Smokers 1-14 15-26 25-F Others Response) 6,194 27 7 23 9 45 208 13.47* 61.59* (cigarettes only) 34,440 441 10 43 52 106 224 41.9* 197.04* (any tobacco/grams) (1 gram = 1 cigarette) *(PC .OOl) SOURCE: Doll, R. (6,8). TABLE 9.-Age-adjusted lung cancer mortality ratios* for males and females, by tar and nicotine (T/N) in cigarettes smoked Males Females High T/N 1.00 1.00 Medium T/N 0.95 0.79 Low T/N 0.81 0.60 *The mortality ratio for the category with highest risk was made 1.00 so that the relative reductions in risk with the use of lower T/N cigarettes could be visualized. SOURCE: Hammond, E.C. (11). the larger prospective studies, with males having higher overall lung cancer rates compared to females. However, the lung cancer rates of smokers are significantly higher than those of nonsmokers for both sexes. The women who smoke low-"tar", low-nicotine cigarettes have a lower age-adjusted lung cancer mortality rate than women who smoke high-"tar", high-nicotine cigarettes. Women who smoke medium-"tar", medium-nicotine cigarettes have mortal- ity rates in between (12) (Table 9). However, even the low-"tar" and low-nicotine cigarette smoker has a rate substantially higher than the nonsmoker. These data suggest some benefit from smoking low-"tar", low-nicotine cigarettes. However, a further comparison of women who smoked less than one pack of high-"tar", high- nicotine cigarettes daily with women who smoked more than one pack of low-"tar", low-nicotine cigarettes daily revealed that the smoker of more than a pack a day of low-"tar", low- nicotine cigarettes had over twice the age-adjusted lung cancer mortality rate of the woman who smoked fewer cigarettes, but with high "tar" and nicotine (Table 10). In a retrospective study standardized for duration of smok- ing, number of cigarettes smoked, inhalation and butt length, long-term female smokers of filter cigarettes had a lower rela- tive risk of developing cancer than smokers of non-filter cigarettes (46). CESSATION OF SMOKING Although the risk of developing lung cancer increases with age, both for smokers and nonsmokers alike, women in good health who quit smoking will, over a period of years, experience a reduction in their relative risk of developing lung cancer. About 15 years after they have quit smoking, the risk of devel- oping lung cancer approximates that of the nonsmoker. 120 TABLE lO.-Age-adjusted lung cancer mortality ratios* for males and females, comparing those who smoked a few high tar and nicotine (T/N) cigarettes with those who smoked many-low T/N cigarettes 1-19 high TIN 20-39 low T/N cigarettes/day cigarettes/day Males 1.00 1.6 Females 1.00 2.1 *The mortality ratio for the category with lowest risk was made 1.00 so the increase in risk with smoking more cigarettes/day could be illustrated. SOURCE: Hammond, E.C. (11). EXPERIMENTAL CARCINOGENESIS Tobacco tars, tobacco smoke, and single or mixtures of chemi- cals found iri tobacco smoke have been used with various species of animals in carcinogenesis experiments involving skin paint- ing, subcutaneous injections, tracheobronchial implantation, and/or instillation and inhalation. Some experiments have re- ported sex differences in the occurrence of lung tumors follow- ing exposure to chromium oxide (26). However, in a recent monograph on lung cancer, separate re; views on tobacco carcinogenesis, radiation carcinogenesis in the respiratory tract, and experimental models for studies of respi- ratory tract carcinogenesis did not yield information suggesting that the male lung of any of the species studied was more sus- ceptible than the female lung to carcinogenic action by either tobacco products or radiation (16). The reader is referred to pre- vious Smoking and Health Reports for summaries of experi- mental tobacco carcinogenesis studies. Larynx The larynx is a small, complex structure, which produces speech, controls the flow of air in and out of the lungs, and prevents aspiration during swallowing. In 1980 there will be an estimated 1,700 new cases of laryngeal cancer and 600 deaths from that tumor in U.S. women (Table 1). Laryngeal cancer has occurred predominantly in men, but more and more women are developing laryngeal cancer as their smoking and drinking habits come to approximate those of men. The male-to-female ratio for laryngeal cancer exceeds that of lung cancer. Laryngeal cancer occurs in the fifth, sixth, and seventh decades both in men and women. While the disease is uncommon, its incidence has continued to rise over the past quarter century, 121 especially in women, substantially because of changes in their smoking habits. Cancer can occur either in the glottis (true cord, 70 percent of cases), or in the subglottic or supraglottic region (false cord, 25 percent of cases). Usually the neoplasm is epidermoid car- cinoma when examined histologically. Since a tumor that inter. feres with speech gives rise to early symptoms, glottic cancers are usually diagnosed at an early stage and are curable in over 60 percent of the cases. When the tumor arises in the subglottic or supraglottic region, interference with phonation or speech may not occur as early as when neoplasm begins on the glottis. The tumor may, therefore, reach a greater size and be accom- panied by significant local tissue invasion and destruction as well as metastasis. Patients with tumors discovered when they are still localized in the larynx have approximately an 80 per- cent cure rate, while advanced lesions have a 33 percent 5-year survival rate. Laryngeal cancer displays a strong dose-response relation- ship with smoking, increasing with the number of cigarettes smoked per day, the "tar" and nicotine content of the cigarettes smoked, the depth of inhalation and number of years cigarettes were smoked. The risk of developing laryngeal cancer is in- versely related to the age at which smoking began (43). A lower risk for laryngeal cancer has been demonstrated in women who used filtered cigarettes for 10 years or more compared to those who smoked non-filtered cigarettes. Nonetheless, the risk re- mained well in excess of that experienced by nonsmokers (45). Excessive use of alcohol by nonsmokers also results in an in- creased incidence of laryngeal cancer. Heavy drinkers of alcohol-that is, greater than seven ounces of whiskey or its equivalent per day-who also smoke cigarettes have a greater risk of developing laryngeal cancer than if they either smoked or drank to excess alone. There is a synergistic effect of smoking and drinking on laryngeal cancer development (43,44). When women quit smoking, their relative risk of developing laryngeal cancer decreases until 10 years after cessation when their risk approaches that of the nonsmoker (45). A number of investigators have found an association between exposure to asbestos and the subsequent development of laryngeal carcinoma (43). Oral Oral neoplasms include cancer of the lip, tongue, gums, buccal mucosa, hard and soft palate, salivary glands, floor of the mouth, and oropharynx. In the United States for 1980, there 122 will be 17,900 new cases in men and 7,600 in women, resulting in 6,100 deaths in men and 2,700 deaths in women (1). While dif- ferent histological types of cancer can occur in this group, squamous cell carcinoma is by far the most common, except for the tumors of the salivary glands. Five-year survival rates range from 25 percent in those patients whose tumor is ad- vanced when first diagnosed to 67 percent for those whose tumor is localized at diagnosis. In women, oral cancers account for 1.9 percent of all neoplasms, while they account for 4.7 percent of all cancer occurring in men. Deaths from the various oral cancers account for 1.4 percent of cancer deaths in women and 2.8 percent of all cancer deaths in men. Cigarette, pipe and/or cigar smoking are all associated with increased oral cancers. Heavy alcohol use (over 7 ounces per day) has been shown to be an independent causative factor (32,42). When both are used together by women or men, synergism results in an even greater incidence of oral cancer (3). Poor oral hygiene or inadequate dentition is also a risk factor (15). Most of the prospective epidemiologic studies have concen- trated on men. In Japan a large prospective study showed the mortality ratio for oral cancer to be 2.88 for the male cigarette smoker and 1.22 for the female cigarette smoker compared with the nonsmoker. Leukoplakia or an abnormal thickening and keratinization of the oral mucous membrane is recognized as a precancerous condition. While found in the western world, it is most common in Asian countries where a mixture of tobacco and betel nut or lime ash chewing is common, and in those countries where re- verse chutta (cigar) smoking occurs. Women in certain regions of India are more likely to engage in reverse chutta smoking than men, although both women and men develop carcinoma of the hard palate after years of reverse chutta smoking (30). Women and men with mouth, pharynx, and larynx cancer who continue smoking after surgical treatment of the first neoplasm have a 40 percent probability of developing another neoplasm of the head and neck. Only 6 percent of the patients who quit smoking develop a second cancer in the region. Less than 10 percent of oral cancer patients are nonusers of tobacco; almost all have a well-differentiated carcinoma and a relatively high cure rate (23). Esophagus Carcinoma of the esophagus will be diagnosed in 6,200 men and 2,600 women in the United States in 1980 (1). The American Cancer Society estimates that there will be 5,500 deaths in men 123 and 2,100 deaths in women from this disease (1). Median survi- val time once esophageal carcinoma is diagnosed is 6 months, The 5-year survival rate is only 3 percent. Esophageal car- cinoma rates have declined in the white population over the past 25 years. However, they have increased in the black popu- lation in both sexes. This may reflect genetic or environmental factors. In the Caspian littoral, there is a remarkable difference in esophageal carcinoma incidence in people of comparable background and socioeconomic status living only 400 kilometers apart. There is a 30-fold higher incidence in women living in the desert northwest section of Mazandran, Iran, compared with the fertile Caspian rainbelt 400 kilometers to the west (20). Data from a number of retrospective studies show that smok- ing increases the risk of developing esophageal carcinoma. Neither the relative risk of developing esophageal carcinoma nor the steepness of the dose-response relationship with cigarette smoking is as great as it is for carcinoma of the lung or larynx (45). Individuals who stop smoking or switch to low-tar, low-nicotine cigarettes will, after a lag period, experience lower relative risks of developing esophageal carcinoma, although the fall-off is not as steep as with lung and laryngeal cancer. In the male, both retrospective and prospective studies show that pipe and cigar smokers have mortality rates from esophageal car- cinoma similar to cigarette smokers. There are no prospective epidemiologic studies of female smokers in this country large enough to permit development of a mortality ratio comparison to nonsmoking females. Ingestion of alcohol is also a major etiological factor in esophageal carcinoma. A dose-response relationship exists, with increasing alcohol ingestion resulting in an increased inci- dence of esophageal carcinoma. As in the larynx, synergism of the carcinogenic effect on the esophagus occurs with the use of both tobacco and alcohol (45). Whether or not nutritional de- ficiencies, which occur frequently with severe, chronic al- coholism, play a role in carcinogenesis remains unknown, as does the possible contribution of chronic iron deficiency found in Plummer Vinson's syndrome (Paterson-Kelly syndrome, sid- eropenic dysphagia). Ninety-eight percent of esophageal cancers are histologically squamous cell in type. In an autopsy study, Auerbach found more abnormalities of the esophageal tissues-including atypi- cal nuclei, disintegrated nuclei, hyperplasia and hyperactive esophageal glands-of tobacco smokers as compared with nonsmokers (2). Esophageal carcinoma can be produced experimentally by both benz(a)pyrene and the nitrosamines. Both benz(a)pyrene 124 and a group of nitrosamines have been identified in tobacco smoke. The appearance of experimentally-produced squamous cell carcinomas can be accelerated by dissolving the carcinogen in alcohol, a laboratory experiment duplicated daily by thousands if not millions of our citizens (43). Urinary Bladder Cancer of the urinary bladder will occur in 26,000 men and 9,500 women in the United States during 1980 and it will kill 7,000 men and 3,300 women (1). Cancer of the urinary bladder is frequently multicentric in origin. If found while still localized in the bladder wall, the 5-year survival rate is 72 percent, in con- trast to 14 percent for those patients whose disease had already spread when the diagnosis was first established (1). Bladder cancer has been associated with occupational expo- sure to aniline dyes, leading to the study of aromatic amines as potential carcinogens. 2-Naphthylamine, xenylamine, ben- zidine, and 4-nitrobiphenyl have all been implicated (43). Numerous retrospective studies have shown a relationship between smoking and urinary bladder carcinoma in both men and women (17). The likelihood of either women or men develop- ing bladder cancer increases with the number of cigarettes smoked, the duration of smoking, and tar and nicotine content of the cigarette smoked. Changing to low-tar, low-nicotine cigarettes or more clearly, cessation of smoking, decreases the relative risk of developing bladder cancer. The risk of an ex- smoker developing urinary bladder cancer approaches that of the nonsmoker years after cessation (46). In prospective studies in Japan and Sweden, women who smoke are 1.6 to 2.7 times as likely to develop bladder cancer as nonsmokers (3,14). In an international study of successive birth cohorts in the United States, United Kingdom, and Denmark, Hoover and Cole found increasing rates of bladder cancer as- sociated with increased cigarette smoking in men and women in both suburban and rural areas and in all nationalities studied (17). It has been estimated that 30 percent of urinary bladder cancer in women can be attributed to cigarette smoking (43). Kidney Cancer of the kidney will occur in 10,500 men and 6,400 women in the United States during 1980 (1). Some 4,800 men and 3,100 women will die of renal carcinoma (1). The 5-year survival rate is between 40 and 50 percent (1). While the overall classification of kidney carcinoma includes tumors of the renal pelvis and 125 ureter, the largest number of kidney carcinomas occur in the renal parenchyma and are adenocarcinomas. In retrospective studies, adenocarcinomas of the kidney are found more frequently in smokers compared with non-smokers in both men and women (43,44). In a large prospective study among U.S. veterans, the kidney cancer mortality ratio in- creased from 1.0 (the baseline for nonsmokers) to 1.34 for those who smoked 10 to 19 cigarettes daily and to 2.75 for men who smoked two packs or more each day (18). No large scale prospective study of women and kidney cancer has been reported to date. Pancreas Carcinoma of the pancreas will occur in 12,500 men and 11;500 women in the United States during 1980, and 11,100 men and 9,800 women will die of pancreatic carcinoma (1). During the past 25 years, there has been a steady increase in both the inci- dence and mortality due to pancreatic cancer in both men and women (1,211. Among the common human neoplasms, the rate of increase of pancreatic cancer over the past quarter century has been second only to that of the lung. Most pancreatic carcinomas are adenocarcinomas, arising from ductal cells (24). Most are relatively undifferentiated in cell type. The median survival time from histologic proof of diagnosis to death is 3.5 months in men and 4.5 months in women. Survival time varies little with age at time of diagnosis, duration of symptoms, location of primary lesion (head, body, or tail of pancreas) or even degree of differentiation. The 5-year survival rate is one percent, the most dismal survival rate for any of the common neoplasms of either men or women (1). Retrospective studies relating smoking to pancreatic car- cinema have been reviewed in previou.s reports. In a prospective study of 143,000 women, the pancreatic cancer mortality ratio was 1.94 for Japanese women smokers compared to nonsmokers (14). In Sweden, a smaller prospective study showed that the mortality ratio for pancreatic cancer was 2.5 for women smokers compared to women nonsmokers (4). In the United States, the male to female ratio of pancreatic cancer was 1.6 in the 1940s. It has- decreased to the current estimate of 1.17 for 1979 and is consistent with the decreasing male to female ratios of lung and laryngeal carcinomas.. Summary 1. Cigarette smoking is causally associated with cancer of the lung, larynx, oral cavity, and esophagus in women as well as in men; it is also associated with kidney cancer in women. 126 2. Cigarette smoking accounts for 18 percent of all newly diag- nosed cancers and 25 percent of all cancer deaths in women. In 1980,26,500 of the estimated 101,000 deaths, or over one-quarter of the deaths expected from lung cancer, will occur in women. 3. Women cigarette smokers have been reported to have be- tween 2.5 and 5 times greater likelihood of developing lung cancer than nonsmoking women. 4. Among women the risk of developing lung cancer increases with increasing number of cigarettes smoked per day, duration of the smoking habit, depth of inhalation, and tar and nicotine content of the cigarette smoked. The risk is inversely related to the age at which smoking began. 5. A dose-response relationship has been demonstrated be- tween cigarette smoking and cancer of the lung, larynx, oral cavity, and urinary bladder in women. 6. The rise in lung cancer death rates is currently much steeper in women than in men. It is projected that the age ad- justed lung cancer death rate will surpass that of breast cancer in the early 1980s. 7. The rapid increase in lung cancer rates in women is similar to but steeper than the rise seen in men approximately 25 years earlier. This probably reflects the fact that women first began to smoke in large numbers 25-30 years after the increase in cigarette smoking among men. Thus, neither men nor women are protected from developing lung cancer caused by cigarette smoking. 8. Cigarette smoking has been causally related to all four of the major histologic types of lung cancer in both women and men, including epidermoid, small cell, large cell and adenocar- cinema. 9. The use of filter cigarettes and cigarettes with lower levels of "tar" and nicotine by women is correlated with a lower risk of cancer of the lung and larynx compared to the use of high-"tar" and nicotine or unfiltered cigarettes. The risk posed by smoking low-"tar" cigarettes, however, is clearly greater than that among females who never smoked. 10. After cessation of cigarette smoking, a woman's risk of developing lung and laryngeal cancer has been shown to drop slowly, equalling that of nonsmokers after lo-15 years. 11. Excessive ingestion of alcohol acts synergistically with cigarette smoking to increase the incidence of oral and laryngeal cancer in women. References (1) AMERICAN CANCER SOCIETY. 1979 Cancer Facts and Figures. 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(Un- published manuscript) DOLL, R., PETO, R. Cigarette smoking and bronchial carcinoma dose and time relationships among regular and lifelong nonsmokers. Jour- nal of Epidemiology and Community Health 32: 303-313, 1978. DOLL, R., PETO, R. Mortality in relation to smoking: 20 years' observa- tions on male British doctors. British Medical Journal 2(6051): 1525- 1536, December 25, 1976. FRAUMENI, J. Genetic Factors in Cancer. In: Holland, J.F., Frei, E. (Editors). Philadelphia, Lea and Febiger, 19'73, pp. 7-15. HAENSZEL, W., TAUBER, K.E. Lung-cancer mortality as related to residence and smoking histories. II. White females. Journal of the Na- tional Cancer Institute 324: 803-838, April 1964. HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel, W. (Editor). Epidemiological Ap- proaches to the Study of Cancer and Other Chronic Diseases. National Cancer Monograph No. 19. 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Population trends in cigarette smoking and bladder cancer. American Journal of Epidemiology 94(5): 409-418, 1971. HORN, D. The benefits of stopping smoking. In: Steinfeld, J., Griffiths, W., Ball, K., Taylor, R.M. (Editors). Proceedings of the Third World Conference on Smoking and Health. Volume II. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, DHEW Publication No. (NIH) 77- 1413, 1977, pp. 59-64. 128 (18) KAHN, H.A. The Dorn study of smoking and mortality among U.S. vet- erans. Report on eight and one-half years of observations. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monog- raph No. 19. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Insti- tute, January 1966, pp. l-27, 124-125. (19) KEMP, I.W., RUTHVEN, H.E. Cancer of the lungs in Scotland. Health Bulletin, pp. 259-268, 1979. (20) KMET, J.A. AND MAHBOUBI, E. Esophageal cancer in the Caspian littoral of Iran: initial studies. Science 175: 846, February 25, 1972. (21) KRAIN, L.S. The rising incidence of carcinoma of the pancreas, real or apparent? Journal of Surgical Oncology 2(2): 115-124, 1970. (22) KREYBERG, L. Histologic typing of lung tumors. International His- tological Classification of Tumors No. 1. Geneva, Switzerland, World Health Organization, 1967. (25) MOORE, C. Smoking related to cancer of the mouth, tongue and lip. In: Steinfield, J., Griffiths, W., Ball, K., Taylor, R.M. (Editors). Proceedings of the Third World Conference on Smoking and Health, New York, June 2-5, 1975. Volume II. Health Consequences, Education, Cessation Activities, and Social Action. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Na- tional Cancer Institute. DHEW Publication No. (NIH) 77-1413,1977, pp. 101-104. (24) MORTEL, C. 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Journal of the National Cancer Insti- tute 53(6): 1619-1634, December 1974. (4.5) WYNDER, E.L., STELLMAN, S.D. Comparative epidemiology of tobacco-related cancers. Cancer Research 37: 4608-4622, December 1977. 130 (46) WYNDER, E.L., STELLMAN, S.D. The impact of long-term filter cigarette usage on lung and larynx cancer. Journal of the National Cancer Institute 62(13): 471-477, March 1979. 131 JON-NEOPLASTIC 3RONCHOPULMONARY DISEASES. Introduction Chronic non-neoplastic bronchopulmonary disorders are a major cause of death and disability in the United States. Chronic obstructive lung diseases (COLD), including chronic bronchitis and emphysema, comprise the majority of these illnesses. In 1977, they were responsible for nearly 46,000 deaths and millions of dollars in social security disability payments, ranking second in economic cost only to heart disease (42). Previous U.S. Public Health Service reports on the health consequences of smoking have presented evidence that cigarette smoking is the major cause of COLD (55-64). The studies on which this is based have focused primarily on male populations. This reflects the scientific interest generated by the overwhelming male-to-female ratio in the prevalence of COLD at the time these studies began. However, recent mortal- ity statistics indicate a substantial increase in the death rate from COLD among women (see Mortality section). Although this increased death rate may partially reflect a greater aware- ness and recognition of COLD, its magnitude suggests a true increase in frequency of COLD among women. The following text reviews a large number of studies analyzing the relation- ship of smoking to COLD. These studies include appreciable numbers of women, and many suggest that smoking may affect men and women differently. Nevertheless, cigarette smoking remains the most important cause of COLD regardless of sex or other variables. Definitions The terms chronic bronchitis and emphysema have been used diagnostically for many years. Physicians often use these terms interchangeably to describe a patient with chronic airflow obstruction. These conditions are, however, difficult to distin- guish from each other in patients with chronic airflow obstruc- tion because (a) both conditions may be present in the same patient; (b) both disorders are characterized by expiratory flow obstruction; and (c) patients with either disorder frequently have the same symptom-dyspnea on exertion. Consequently, the clinician often labels the patient with chronic airflow obstruction as having chronic obstructive lung disease (COLD). Many attempts have been made to establish criteria for the diagnosis of chronic bronchitis and emphysema (1,27,28). The most widely accepted definitions in the United States are those 135 TABLE l.-Age-adjusted death rates from COLD (ICDA 490-492 and 519.3) 1960 - 1977 (per 109,000) 1977 1976 1975 1974 1973 1972 1971 1970 1969 1968 1967 1966 1965 1964 1963 1962 1961 1960 - White Nonwhite Male Female Male Female 33.4 10.7 14.8 3.5 33.5 10.1 14.9 3.2 32.1 9.1 13.5 3.3 31.1 8.4 13.7 2.8 31.4 7.8 14.1 3.0 29.9 7.0 14.0 2.9 28.6 6.5 13.2 3.0 28.2 6.0 13.3 2.6 27.3 5.4 12.8 2.4 22.3 3.8 13.7 2.5 19.9 3.1 11.5 2.0 19.7 3.0 11.0 1.9 18.4 2.7 10.4 1.8 16.1 2.4 9.2 1.6 15.9 2.3 9.5 1.9 13.1 2.0 7.7 1.8 10.9 1.7 7.0 1.3 10.4 1.7 6.7 1.4 SOURCE: National Center for Health Statistics (42). of a joint committee of the American College of Chest Physi- cians and the American Thoracic Society (1). "Bronchitis: A non-neoplastic disorder of structure or func- tion of the bronchi resulting from infectious or noninfectious irritation. The term bronchitis should be modified by appropri- ate words or phrases to indicate its etiology, its chronicity, the presence of associated airways dysfunction or type of anatomic change. The term chronic bronchitis, when unqualified, refers to a condition associated with prolonged exposure to nonspecific bronchial irritants and accompanied by mucous hypersecretion and certain structural alterations in the bronchi. Anatomic changes may include hypertrophy of the mucous-secreting ap- paratus and epithelial-metaplasia, as well as more classic evi- dence of inflammation. In epidemiologic studies, the presence of cough or sputum production on most days for at least 3 months of the year has sometimes been accepted as a criterion for diag- nosis." "Pulmonary Emphysema: An abnormal enlargement of the air spaces distal to the terminal nonrespiratory bronchiole, ac- companied by destructive changes of the alveolar walls. The term emphysema may be modified by words or phrases to indi- cate its etiology, its anatomic subtype, or any associated airway dysfunction." 136 "Chronic Obstructive Lung Disease: This term refers to a dis- ease of uncertain etiology characterized by persistent slowing of airflow during forced expiration. It is recommended that a more specific term, such as chronic obstructive bronchitis or chronic obstructive .emphysema, be used whenever possible." It should be noted that these definitions i-nay have serious inadequacies, particularly when applied to longitudinal studies assessing the natural history of COLD (29,52). In the following discussion, these limitations are recognized. Smoking and Respiratory Mortality Recent mortality statistics indicate a striking increase in death rate from COLD among women (42). These data presented in Table 1 indicate a nearly fivefold increase in reported mor- talities due to COLD from 1962 to 1977 among white females and a twofold increase among nonwhite females. Mortality rates from these conditions for white and nonwhite males have also increased since 1967 (by factors bf 1.9 and. 1.5, respectively), but the rate of increase has not been as steep as that for women. Seven large prospective studies have shown a greatly in- creased mortality from COLD among smokers as compared to nonsmokers (14,18,19,31,32,37). These studies, presented in Table 2, represent over 13 million subject years of observation and approximately 270,000 deaths from all causes. The number of deaths related to COLD is probably underestimated since some of the deaths attributed to pneumonia or myocardial dis- ease may have been due to complications of COLD. In addition, these mortality figures do not include an appreciable number of individuals for whom COLD may have been a major contribut- ory cause of death. For example, it is not uncommon for indi- viduals to have COLD and lung cancer simultaneously. Two of these prospective studies have included significant numbers of women. Hammond prospectively followed 1,003,229 subjects aged 35 to 84 (31). Nearly 93 percent of the survivors were observed for a 12-year period. Death rates from em- physema among women were much higher in cigarette smokers than nonsmokers. "Heavier" smokers (defined as either smok- ers of 20 or more cigarettes a day regardless of age when smok- ing was begun, or smokers of 10 or more cigarettes a day who had begun smoking before age 25) had a sevenfold increased mortality rate as compared to nonsmokers. Cederlof et al. fol- lowed 55,000 Swedish subjects aged 10 to 69 for 10 years (14). The overall mortality rate from all causes among female smok- ers was 1.2 times higher than that of female nonsmokers. The death rate from bronchitis, emphysema, and asthma among 137 TABLE 2.-COLD mortality ratios + in seven prospective studies Study (Reference) Women in 25 Men in 25 British States States U.S. Canadian Men in California Swedish Subjects Doctors 45-65 45-64 65-79 Veterans Veterans 9 States Occupations Females Males (18) (31) (31) (37) 03) (32) (19) (14) Emphysema and/or bronchitis 24.7 - - - 10.08 - 2.30 4.3 - - Emphysema without bronchitis - Bronchitis - 4.89 6.55 11.41 14.17 - - - 4.49 7.7 11.3 - - - - - - - Bronchitis, emphysema and asthma - - - - - - - - 2.2 3.7* + Death rate for smokers divided by death rate of a comparable group of nonsmokers. *For all ages combined; increased mortality rate significant only for former smokers. female smokers was 2.2 times that of female nonsmokers. How- ever, the number of deaths due to COLD among women was small in both of these studies; consequently, the relationship with smoking is more difficult to evaluate. Nevertheless, a sig- nificant excess risk for reported mortality from COLD was pres- ent for female cigarette smokers as compared to female nonsmokers. Data collected by Doll et al. examine the association of smok- ing and cause-specific mortality in 6,194 women physicians in England, observed prospectively over the period 1951 to 1973 (17). Table 3 presents the results of this study, including previ- ously published results of a similar study among male physi- cians over the same period (18). The association of smoking and chronic bronchitis clearly observed in males was confirmed in women physicians. For both women and men who reported smoking 15 or more cigarettes per day, the mortality rate due to emphysema and chronic bronchitis was more than five times as great as in nonsmokers. In both sexes, mortality due to em- physema and chronic bronchitis was more than double that of nonsmokers, was at least three times as high in ever-smokers as in never-smokers, and was at least twice as high in current heavy smokers ( ~25 cigarettes) as in light smokers ( ~15 cigarettes). The risk of death from emphysema and chronic bronchitis as- sociated with smoking was approximately similar in men and women. For moderate (1 to 14 cigarettes per day) and heavy ( X25 cigarettes per day) smokers, compared with nonsmokers, the relative risk of death was 28.5 and 32 for women, respec- tively, versus 16.7 and 29.3 for men. In this data, as well as that for lung cancer, there is no support for the contention that women are less susceptible to harmful effects of smoking than are men. The authors emphasize that no conclusions can be drawn from this data about the magnitude of the biologic effects of smoking in men compared to women. Attempts to document differences in lifetime smoke exposure (later age at initiation and lower prevalence of inhalation among females) demonstrate that lifetime smoking exposures between the sexes are not comparable. This issue will be resolved only when studies examine the effect of smoking in cohorts of women whose lifetime smoking behavior more closely matches that of the men to whom they are compared. In comparing the relative risks for mortality from COLD in female and male smokers (Table 2), it is apparent that female smokers have lower reported mortality rates than their male counterparts. This difference in mortality rates may be due to differences in female smoking patterns (31). Women tend to 139 TABLE 3.-Death rates from chronic bronchitis and emphysema by smoking habit when last asked, British physicians 1951- 1973 Total Popul. Annual Death Rate Per 100,000 Persons Standardized for Age X2 Current Smokers-Dose Per Day Nonsmokers Trend Non- Ex- VS. (Dose/ # Deaths Smokers Smokers 1-14 15-25 >25 All Others Response) Women 6,194 13 2 10 Men 34,440 254 3 44 21 57 64 12.34* 26.64; (cigarettes only) 38 50 88 25.58* 47.23* (any tobacco/grams) (1 gram = 1 cigarette) *(P >O.OOl) SOURCE: Doll, R. (17,18). smoke fewer cigarettes, inhale less deeply, and begin smoking later in life than men. They more frequently smoke filtered and low-tar and -nicotine cigarettes and have less occupational ex- posure to lung irritants than men. Recent data suggest that women are manifesting smoking patterns similar to those of men. Moreover, more women are joining the labor force, includ- ing occupations where exposure to lung irritants may occur. (See section on Occupational Exposures.) Whether these women will continue to have mortality rates different from those of men remains to be determined. In summary, recent statistics indicate a rise in the reported death rate due to COLD among women. The two large prospec- tive studies that included appreciable numbers of women found significantly higher mortality rates due to COLD among women smokers as compared to women nonsmokers. This relationship was accentuated in heavier smokers. Mortality rates from COLD among female smokers are considerably lower than among male smokers. This may be due to different smoking pat- terns and work exposure among men and women. Smoking and the Epidemiology and Pathology of COLD The prevalence of chronic bronchitis has been determined in several populations in the United States and in other countries (24,25,26,34,36,41,43,44,46,51). Table 4 lists several studies which have included appreciable numbers of women. These studies have documented a close relationship between cigarette smok- ing and an increased prevalence of chronic bronchitis, and when looked for, a dose-response relationship was also present (Table 3). The prevalence of chronic bronchitis in the United States was determined in four cohort studies and ranged from 4 to 10 percent among women and 14 to 18 percent among men (24,25,26,41,44,51). In both men and women a dose-response re- lationship between the number of cigarettes smoked and the prevalence of chronic bronchitis was apparent. The observed differences between men and women noted in these studies may be due in part to the smaller percentage of women than men who were smokers in the population studied. Moreover these women smoked fewer cigarettes than men. When comparing current smokers, several studies of different populations in the United States and in England did not find significant differences in the prevalence of chronic bronchitis between men and women (21,33,41). The relationship between smoking and pathologic changes in the lung have largely been obtained by necropsy studies. These investigations are often skewed by physician and/or hospital 141 z TABLE 4.- Prevalence of chronic bronchitis by smoking classification (numbers in parentheses represent total E3 number of individuals in particular smoking group) S = Smokers NS = Nonsmokers EX = Ex-Smokers Author, Year Number and Type Country (Reference) of Population Men Women Comment Higgins, 1958 England (34) 94 men and 92 women NS . . . . . . . . . . . . . . . . . 0.0 NS . . . . . . . . . . . . . . . . . 0.0 randomly chosen from S . . . . . . . . . . . . . . . . . . 6.7 S . . . . . . . . . . . . . . . . . . 5.0 agricultural communities Oswald, 1955 England (43) 3,602 males and 2,242 NS . . . . . . . . . . 15.8 (474) NS . . . . . . . . . . 12.1 (619) Chronic bronchitis female clerical workers S . . . . . . . . . . 18.4 (1,940) S . . . . . . . . . . . . 18.8 (5'79) defined by habitual 40-65 yrs. of age cough and sputum production Hubti, 1965 England (36) 663 men and 823 women in a Finnish rural community 40-60 yrs. of age Remington, 1969 England (46) 41,729 men and 22,295 women participating in mass miniature radiography screening NS ................ 5.7 EX ............... 16.3 S 1-14 .......... .38.0 15-24 .......... .41.4 >25 ............. 4.0 NS .......... 5.1 (9,055) EX ........ .9.8 (6,510) Cigarettes ..... (23,243) s 1-19 ............ 9.1 lo-19 .......... .15.0 >20 ............ .20.6 NS ................ 4.5 Ex-smokers represent EX ............... 13.3 those who have stopped s 1-14 ........... 10.4 for more than 1 month 15-24. ........... >25 ............. 57.0 NS ......... 3.4 (12,351) Age-adjusted total EX ........... 3.9 (959) prevalence. Cigarette Cigarettes ...... (8,985) dosage gradient s l-9 ............. 5.1 significant to P 20 ............. 18.5 Ferris, 1962 U.S.A. (23,25,26) 542 men and 625 women Overall residents of New NS .......... 13.8 (125) Hampshire town chosen EX ........... 11.9 (77) by random sampling of Cigarettes .. .40.3 (340) census l-10 ............. 29.8 11-20 ............ .34.2 21-30 ............ .42.3 31-40 ............. 61.1 >41 .............. .75.3 Overall Age-specific rates NS .......... 9.4 (378) EX ........... 10.8 (37) Cigarettes ... 19.8 (208) l-10 ............. 13.1 11-20 ............ .22.2 21-30 ............... . 31-40 ............ .27.3 >41 ................ - Payne, 1964 5,140 adult residents of Overall . . . . . . . . . . . . .8 U.S.A. (44) Tecumseh, Mich. Mueller, 1971 U.S.A. (41) 281 men and 328 women Overall ........ 17 (281) residents of Glenwood NS .............. 3 (2) Springs, Colo. EX .............. 13 (7) s 1-14 .......... 11 (3) 15-24 ........ .20 (13) >25 ......... .38 (21) Overall . . . . . . . . . , , . . .4 Prevalence rates estimated from line graph Overall . ..*... 10 (328) NS . . . . . . . . . . *.. 2 (3) EX . . . . . . . . . . . . . 5 (1) s 1-14 . . . . . . . . . 14 (7) 15-24 . , , , . . . . 25 (14) >25 . . . . . . . . . . 33 (9) Tager, 1976 U.S.A. (51) 227 men and 280 women Overall ...... 14.7 (227) Overall ...... 7.5 (285) Age-adjusted in East Boston, Mass. NS ................ 5.8 NS ................ 1.8 prevalence rate age 15 or greater S ................. 24.2 S ................. 17.6 interest and may not accurately represent a random popula- tion. Moreover, observer variation occurs frequently, even among "experts." Data regarding smoking history are usually derived from a hospital record or from close relatives and friends; thus they may be unreliable. Only a few of the studies examining the relationship of cigarette smoking to the frequency and severity of pathological changes have included significant numbers of female subjects. Thurlbeck recently reviewed 30 reported surveys of the fre- quency of emphysema at necropsy (53). Emphysema of some degree was found in about 65 percent of men and 15 percent of women. The emphysema found was also more severe in men than in women. The predominant pathological finding in chronic bronchitis is the hypertrophied mucous gland in the submucosa of the large cartilaginous bronchi. The ratio of bronchial gland thickness to bronchial wall thickness (Reid index) is usually increased. In a recent survey of 179 consecutive necropsies, Ryder et al. found significantly greater bronchial mucous gland volume in smok- ers compared to nonsmokers. There was no significant dif- ference in mucous gland volume between male and female smokers or male and female nonsmokers (48). Mueller et al. examined the prevalence of chronic bronchitis in one-fifth of the adult population of Glenwood Springs, Col- orado (41). Among current smokers of varying smoking categories (Table 4) there were no significant differences in the prevalence of chronic bronchitis. Higgins and Cochran found no significant difference in the prevalence of chronic bronchitis between men and women smokers in 186 subjects randomly chosen from an agricultural community (Table 4) (34). Similarly, Oswald and Medvel found no significant difference in the preva- lence of chronic bronchitis between men and women smokers in 5,844 clerical workers in England (Table 4) (43). Auerbach et al. examined the relationship of smoking to em- physema in whole-lung and microscopic sections at necropsy in 1,436 men and 388 women (4,5). Among the women, there were 97 current smokers, 16 of whom smoked two packs a day or more. Data regarding smoking habits were obtained through interviews with relatives. Female smokers had a significantly higher rate of emphysema than female nonsmokers (Table 5). Furthermore, the severity of the emphysema was dose-related to the number of cigarettes smoked. The authors found similar relationships in men. Spain et al. examined consecutive whole-lung mounts from necropsies of adult victims (49 women, 85 men) of sudden and unexpected death (50). Smoking habits were ascertained by a 144 letter and questionnaire to the next of kin. The degree of em- physema was graded from 0 to 100 by two observers independ- ently and without prior knowledge of the source of the specimen or any previous grading. There was a close relationship between cigarette smoking and the degree of emphysema in both men and women. Furthermore, the data (Table 6) demonstrated a dose-response effect between the number of cigarettes smoked and the severity of pathological changes. Thurlbeck et al. examined whole-lung sections in 1,742 ran- dom necropsies in three different cities in different countries with varying climates and environments (54). Using a standard panel of grading pictures, pathologic changes in the lung were graded from 0 to 100 by the three readers. In men and women emphysema was more frequent and more severe in smokers than nonsmokers; however, male smokers had higher average emphysema scores and greater frequency of emphysema than female smokers and nonsmokers. This difference between men and women was also true when heavy smokers and ex-smokers of both sexes were compared. The authors speculate that male- female differences may exist because: (a) women are protected by hormonal factors; (b) men may smoke more heavily than women; (c) men may have different smoking patterns than women, e.g., inhalation; and (d) men may be exposed to damag- ing environmental factors at work. TABLE 5.-Means of average degrees of findings* in nonsmokers and current smokers standardized for age of total study population, women Subjects Who Current Cigarette Never Smoked Smokers Regularly 20 41 14 (O-50) 16 (39%) 52 Women 0 21 2 (O-10) 0 - <21 6 6 (O-20) 1(17%) 70+ >20 22 8 (O-30) 5 (23%) 40 *x2 test shows significance at the 1% level for the heavy smokers and nonsmokers. **Each whole lung paper mounted section was graded from 0 to 100 in denominations of 5 up to grade 50 and then in denominations of 10 up to grade 100. `One case. SOURCE: Spain, D.M. (50). 146 of these studies have included appreciable numbers of women (9,11,15,38,39,40,45,47,65). These investigations have examined populations varying in age, geographic location, social class, and exposure to air pollution. Leibowitz and Burrows examined the quantitative relation- ships between cigarette smoking and chronic productive cough in a large randomized sample of the white non-Mexican Ameri- can population of Tucson, Arizona (38). Their data (Table 7) con- firm the close relationship between cigarette smoking and chronic cough and/or chronic sputum production in men and women. The effect of cigarette smoking was closely related to the total pack-years smoked (Table 7). These data support the male to female preponderance in prevalence of chronic bron- chitis noted in several other epidemiologic surveys (24,25,26,41,44,51). However, these data also indicate that males and females with equivalent smoking histories have similar rates of chronic cough and/or sputum production. Woolf examined the frequency of respiratory symptoms in women volunteers, aged 25 to 54, drawn from several large commercial firms (Table 8) (65,66). The prevalence of cough and sputum production was significantly greater in smokers than in nonsmokers (p< 0.001). Heavier smokers complained of cough and/or sputum production more frequently than nonsmokers or ex-smokers. The prevalence of wheezing and exertional dysp- nea increased progressively with the number of cigarettes smoked. In addition, colds that "went to the chest" occurred more frequently in moderate and heavy smokers than in nonsmokers (p < 0.005 and p < 0.001, respectively). Woolf com- pared his data with previously reported data among men (Table 9) and concluded that the relationship of cigarette smoking to respiratory symptoms was similar among men and women. Ferris resurveyed a 1967 sample of Berlin, New Hampshire, residents in 1973 (22). As in 1967, the prevalence of cough and/or sputum production in females and males was directly related to the number of cigarettes smoked daily. When the group evalu- ated in 1967 was examined by current inhaling and smoking status (Figure l), inhalers had a higher prevalence of symptoms than noninhalers (22). Furthermore, the frequency of symptoms was dose-related to the number of cigarettes smoked. Manfreda et al. studied population samples in an urban and a rural com- munity in Manitoba, Canada (39). Their data presented in Table 10 demonstrate a higher prevalence of cough, phlegm, and wheezing among men and women who smoked than in nonsmokers or ex-smokers. However, no significant differences in the prevalence of symptoms were apparent in the two com- munities. 147 L m TABLE 7.-Comparison of prevalence of chronic cough+ and/or chronic sputum production+ in men and women, by smoking habits* Never Smoked - (Number of Subjects) % With Symptoms Ex-Smokers Presently 1-2Olday Presently > 20lday A. By age group Males Females Males Females Males Females Males Females 15-29 years (156) 7.2 (182) 8.2 (36) 8.3 (45) 17.7 (78) 25.7 (82) 20.8 (34) 41.2 (17) 41.1 30-44 years (43) 2.3 (82) 12.2 (45) 11.1 (41) 4.8 (43) 39.5 (40) 35.0 (40) 47.5 (30) 56.7 45-59 years (45) 11.1 (119) 10.9 (61) 21.3 (63) 20.6 (57) 43.8 (83) 36.2 (54) 61.1 (39) 51.3 60+ years (105) 18.1 (336) 14.6 (186) 36.0 (77) 20.8 (62) 51.6 (82) 34.1 (16) 81.3 (14) 57.1 B. By pack-years of smoking Present Smokers Ex-Smokers Never smoked (350) 10.3 (719) 12.1 (350) 10.3 (719) 12.1 Smoked < 6 pack-years (69) 29.0 (81) 21.0 (59) 5.3 (69) 15.9 6-20 pack-years (106) 35.8 (127) 33.1 (77) 14.3 (69) 15.9 21-40 pack-years (96) 47.9 (126) 40.5 (86) 34.9 (27) 18.5 40+ pack-years (113) 61.1 (53) 60.4 (106) 35.8 (30) 16.7 *Subjects with a history of childhood respiratory problems have been excluded from the analysis. Differences in rates by smoking significant within each age-sex group (X2 and z differences between proportions) and trend with smoking significant within age-sex groups (X2 trend). Trend of symptoms by pack-years significant for male present and ex-smokers and female present smokers (X2 trend). Never smokers always significantly different from present or ex-smokers (X2 and z). +Symptoms are those reported on a self-completion questionnaire and are derived from the National Heart and Lung Institute modification of the British Medical Research Council respiratory questions. " Chronicity" of cough or sputum production refers to the presence of the symptom "on most days for at least three months of the year." SOURCE: Leibowitz, M. (38). TABLE B.-Prevalence of cough and sputum production in 500 women related to smoking habit Nonsmokers Ex-smokers Light Smokers Moderate Smokers Heavy Smokers No. % No. % No. % No. % No. % a. Cough* b. Sputum** c. Sputum volume None Morning blob Tablespoonful More than one tablespoonful 11 6.0 1 1.6 11 27.5 32 34.8 66 53.7 14 7.7 1 1.6 12 30.0 27 29.3 60 48.8 169 92.3 61 98.4 28 70.0 65 70.7 63 31.2 10 5.5 0 0.0 7 17.5 11 12.0 29 23.6 3 1.6 0 0.0 5 12.5 12 13.0 17 13.8 1 0.5 0 0.0 0 0.0 4 4.4 12 9.8 *Includes women with cough with or without sputum. **Includes women with sputum with or without cough. SOURCE: Woolf, C.R. (65). TABLE 9.-Prevalence of respiratory symptoms in men compared with women* Cough Men (Published Data) Percent Women (Present Investigation) Percent Nonsmokers 4 (46) 6 14-22 (47) Light smokers Moderate smokers Heavy smokers Sputum Heavy smokers Dyspnea All smokers Heavy smokers 24 (48) 28 48-52 (48) 35 42 (46) 54 67-74 (47) 58-78 (48) 42 (46) 49 21 (49) 27 33 (50) 33 *Numbers in parentheses are reference numbers. SOURCE: Woolf, C.R. (65). The relationship between smoking and several respiratory symptoms was examined by Buist et al. in population samples of three North American cities (11). Cough, sputum production, and wheezing occurred more frequently among smokers than nonsmokers regardless of sex. Bewley and Bland examined the relationships between smok- ing and the prevalence of respiratory symptoms in 14,033 chil- dren aged 10 to 12% in two separate urban areas of the United Kingdom (9). In this questionnaire survey, 2.5 percent of the girls acknowledged smoking at least one cigarette per week ("smoker"). Boys who smoked outnumbered girls who smoked by 3: 1 and were more frequent smokers of at least one cigarette a day than were females by 11:l. Table 11 shows that, even in this young age group, smokers have a higher frequency of morn- ing cough, cough during the day and night, and cough for 3-months duration than their nonsmoking classmates. In a questionnaire study of a large group of American high school students in Rochester, New York, Rush found a strong association between current smoking and respiratory symptoms in both sexes (47). There were minor differences be- tween sexes in the frequency of respiratory symptoms when 150 70 60 50 E 5 40 9 2 n cs 30 20 10 0 Males 1-14 15-34 .:.: F,{ v. :::: v. :.:. .:: Q A 1 0:: 2* `s: y 0.' ::: :- . ) . . 35+ 1-14 15-34 Cigarettes/Day FIGURE l--Age-standardized rates (percent) of chronic nonspecific respiratory disease* by inhaling and current cigarette smoking *Criteria for diagnosis were as follows: (1) Chronic bronchitis: Affirmative response to the question-Do you bring up phlegm from chest six or more times a day for four days a week for three months a year for the past three years or more? (2) Asthma: Affirmative response that bronchial asthma had been diagnosed and was still present. (3) Chronic obstructive lung disease: Affirmative response to one or more of the following: wheezing or whistling in the chest occurred most days or nights; the subject had to stop for breath when walking at his own pace on the level; FEVI less than 60 per cent of the FVC. These could occur in various combinations and were not mutually exclusive. SOURCE: Ferris, B.G., Jr. (22). smoking histories were comparable. Rawbone et al., in a ques- tionnaire survey of 10,498 secondary school children aged 11 to 17 in London, found a significantly higher frequency of cough, 151 TABLE lO.-Respiratory symptoms and diseases in male (M) and female (F) participants in Charleswood (C)-urban-and in Portage La Prairie (P&rural-expressed as percent of respondents Respiratory Nonsmokers Ex-Smokers Smokers Symptom/Disease C P C P C P Cough on most days, at least 3 months/year M F Phlegm on most days, at least 3 months/year M F Wheezing apart from colds M F Attack of short- ness of breath and wheezing M F Shortness of breath compared to per- sons of same sex and age M F 8.3 - - - 4.2 3.5 4.2 - 8.3 7.0 SOURCE: Manfreda, J. (39). 4.0 8.1 2.9 25.4 31.5 4.0 - 10.0 20.3 31.7 4.0 10.8 5.7 16.9 24.7 4.0 - 5.0 10.2 25.4 8.0 10.8 14.3 26.8 31.5 8.0 12.1 20.0 25.4 30.2 8.0 12.0 4.0 12.0 13.5 11.4 11.3 17.8 6.1 15.0 13.5 20.6 5.4 5.8 5.6 12.3 6.1 5.0 22.1 17.5 colds, and exertional dyspnea in regular smokers as compared to nonsmokers (45). There was no appreciable difference in the frequency of cough between male and female smokers or be- tween male and female nonsmokers. Colley et al. examined the influence of smoking, lower respiratory tract illness under 2 years of age, social class of father, and air pollution on respira- tory symptoms in a cohort of 20-year-olds followed since birth (15). Their data (Table 12) suggest that respiratory symptoms were closely related to current smoking. Symptoms were also related to a history of lower respiratory tract infection in the first 2 years of life but were not related to social class or air pollution. 152 TABLE ll.-Smoking and the prevalence of respiratory symptoms in girls from two different cities in England Prevalence of Symptom With Each Group - Experimental Smoker + Smokert Nonsmoker Symptom Residence N % N % N % Significance* Cough in the morning Kent 10 31.3 51 9.8 73 6.9 P . Thirty-nine percent of the cases were nonsmokers ver- sus 60 percent of controls; 36 percent of the cases and 27 percent of the controls smoked less than a pack per day; 24 percent of the cases and 10 percent of the controls smoked a pack per day or more. The habits of the remaining 1 to 2 percent of mothers were unknown (139). Bergman and Wiesner studied 56 families who lost babies to the sudden infant death syndrome and 86 control families. They reported that a higher proportion of SIDS mothers smoked dur- ing pregnancy than controls (61 percent versus 42 percent), more smoked after pregnancy (59 percent versus 42 percent), and SIDS mothers smoked a significantly greater number of cigarettes than controls. These authors indicate that exposure to cigarette smoke (passive smoking) appears to enhance the risk for SIDS for reasons not yet known (8). However, whether prenatal or postnatal exposure is more important cannot be de- termined. Naeye, et al., in their analysis of 125 SIDS victims from the population of the Collaborative Perinatal Project of the 225 NINCDS, stated: "The gestations that produced the SIDS vic- tims were characterized by a greater frequency of mothers who smoked cigarettes and had anemia" than was true for the whole population of 53,721 infants or for a set of 375 controls matched for important factors (96). Rhead, commenting on studies pub- lished to date which demonstrate an increased incidence of maternal cigarette smoking in SIDS, states: "It is now . . . clear that maternal cigarette smoking contributes to an infant's risk of dying from SIDS" (123). Analysis of data from the prospective study of 19,047 births to members of the Kaiser Foundation Health Plan (1960-1967) also showed a strong association of SIDS with maternal smok- ing. In the SIDS group, 70.6 percent of mothers smoked during pregnancy, compared with only 35.3 percent of mothers of babies who did not die of SIDS (p < .OOl>. The relative risk of SIDS for smokers versus nonsmokers was 4.4 (67). Clues to the mechanisms by which smoking may increase the risk of pregnancy complications are available from pathological and physiological studies of placentas, membranes, blood ves- sels, circulatory patterns, and serum levels of substances im- portant for cell and tissue integrity. For example, it is possible that placental changes in smokers that serve as adaptations to the hypoxic effects of carbon monoxide may also increase the risk of placental complications. Christianson has reported findings from carefully stand- ardized gross examinations of 7,651 placentas from smokers and nonsmokers. These examinations revealed that smokers' placentas were thinner and larger in their minimum diameter than those of nonsmokers. This significant change effectively increased the surface area of the smokers' placentas and must, therefore, have increased their area of attachment to the uterine wall. The distance from the edge of membrane rupture to the placental margin was also less for smokers, and signifi- cantly more smokers than nonsmokers had zero distance, which is consistent with the diagnosis of placenta previa (19). These findings suggest a possible mechanism to account for the signif- icant dose-related increase in the frequency of the clinical diag- nosis of placenta previa that accompanies maternal smoking (86). A similar increase in this condition occurs with increasing altitude (75). Christianson's study also revealed that smokers had signifi- cantly more placental calcification, primarily of the maternal surface, and patchy subchorionic fibrin, as shown in Table 11. 226 TABLE Il.--Selected results of gross examinations of placentas from smokers and nonsmokers Percent of Placentas with Stated Condition White Black Nonsmoker Smoker Nonsmoker Smoker N=3,461 N=2,239 P N= 1,300 N=652 P Calcification 49.5 60.8 < .OOOl 43.5 59.0 < .0001 Patchy Subchorionic Fibrin 26.2 35.3 < .OOOl 30.8 37.0 < .Ol Infarcts 24.6 22.3 -c .05 14.4 14.5 NS Thickness (mean cm) 2.16 2.12 < .OOl 2.11 2.06 c.01 Ratio of smallest diameter to thickness 8.19 8.40 < .OOl 8.39 8.68 < .Ol Shortest distance, edge of rupture of membranes to placental margin (mean cm) 4.32 4.09 < .025 5.08 4.83 NS Percent with zero distance 26.6 27.9 NS 18.6 20.3 < .05 SOURCE: Christianson, R.E. (19). These changes are characteristic of maturation and aging of the placenta and occur as normal gestation proceeds; however, they occurred earlier in smokers than in nonsmokers (19). This find- ingis compatible with other manifestations of accelerated aging reported to be associated with cigarette smoking (28,108). Asmussen compared placental vessels in smoking and nonsmoking mothers by electron microscopy. In the smoking group these vessels were characterized by subintimal edema with destruction of the intimal elastic membranes, a marked decrease in collagen content, and proliferation of myocytes. Asmussen postulated that similar damage may occur in the fetal and infant vascular system. To what extent such changes may predispose to the subsequent development of vascular dis- ease remains unknown. The author regarded most of the changes observed in smokers' vessels as degenerative, but men- tioned the possibility that the thickening of the basement mem- brane observed in smokers might be an attempt at repair (4,5). Naeye (93) has described an increased frequency of placental microscopic lesions associated with smoking. These include: cytotrophoblastic hyperplasia, obliterative endarteritis, stromal fibrosis, and small villous infarction. Smokers also demonstrated an increased frequency of necrosis and inflam- mation in the decidua capsularis and in the decidua basalis at the placental margin. Placental features observed less fre- quently in smokers' placentas were excessive syncytial knots and various thrombotic phenomena. Naeye found increasing placental enlargement with smoking level, accompanied by decreasing birth weight and a consequent increase in the placental ratio. The author stated that "as smok- ing increased, placentas developed microscopic lesions charac- teristic of underperfusion of the uterus." Naeye's data showed positive trends with maternal smoking level for some findings and negative trends for others (93). Many of the changes cited were of low frequency in all groups, and no clear pattern of possible mechanisms of action emerged. Other studies that may shed light on these complex interrela- tionships include the report by Goujard and colleagues that heavy alcohol consumption as well as smoking contributes to the risk of stillbirth caused by abruptio placentae. In a prospec- tive survey of 9,169 women, the risk of stillbirth was 21 per 1,000 in smokers who were light or nondrinkers, 20 per 1,000 in nonsmoking drinkers of 45 ml equivalents or more of absolute alcohol per day, and 8.5 per thousand for nonsmokers who drank less than 45 ml per day. The small number of smokers who were also heavy drinkers had stillbirth rates of 50.5 per 1,000 (95 women with 5 stillbirths). The proportions of these deaths that 228 were attributable to abruptio placentae increased with smoking and with drinking, based on data unadjusted for the effects of age, parity, and other factors (122): More research is needed to define possible pathways of action by which the active components of cigarette smoke affect preg- nancy complications that may lead, in turn, to fetal death or to preterm birth with or without survival. Experimental Studies TOBACCO SMOKE Tobacco smoke contains more than 2,000 compounds includ- ing: carbon monoxide, oxides of nitrogen, ammonia, polycyclic aromatic hydrocarbons, hydrogen cyanide, vinyl chloride, and nicotine. For the pregnant woman and fetus the most important of these appear to be nicotine, carbon monoxide, and the polycyclic aromatic hydrocarbons. NICOTINE The effect of nicotine on sympathetic and parasympathetic ganglia, skeletal muscles, and the central nervous system is similar to that of acetylcholine. At all three sites it first stimu- lates, then depresses. Minute doses of nicotine stimulate the chemoreceptors of the carotid and aortic bodies, causing reflex hypertension. Nicotine also releases epinephrine from the ad- renal medulla, thereby producing cardiovascular changes. Thus, it can produce widely differing effects depending upon the dosage and the particular site that is most sensitive to stimula- tion. Nicotine rapidly crosses the placenta to affect the fetus (142). Relatively mature rhesus monkey fetuses respond to nicotine infusion with a rise in blood pressure, bradycardia, acidosis, hypercarbia, and hypoxia (141). Maternal nicotine administra- tion in rats also has been shown to affect the fetal central ner- vous system and its response to electrical stimulation during the newborn period (56,78). Quigley, et al. noted that in moderate to heavy smokers, after 34 weeks gestation, smoking two cigarettes in 10 minutes was associated with a 60 percent increase in maternal plasma norepinephrine and epinephrine and a 20 percent increase in serum cortisol concentrations (118). These changes also were associated with an increase in maternal pulse and blood pressure. Lehtovirta and Forss measured changes in placental intervillous blood flow using the 133 xenon method (66). Im- mediately after smoking, intervillous flow decreased 22 percent. 229 These data correlate with the studies of Resnik, et al. (122), showing nicotine-induced increases in catecholamines and de- creased uterine blood flow in sheep, and of Haberman, demon- strating decreased uteroplacental blood flow in women, using thermography (48). Sastry and his colleagues have carried out a series of studies on the effect of nicotine on the human placenta. Nicotine added to a calcium-containing medium caused a 33 percent increase in the rate of acetylcholine release from isolated placental villi (131). The authors postulated that this effect could account for the decrease in placental amino acid transport (125,154) pro- duced by nicotine-mediated cholinergic blockade (105). Rowe11 and Sastry also demonstrated that nicotine caused a 41 percent decrease in uptake of alpha amino isobutyric acid in an experi- mental placental system (126). Their studies indicate that under normal circumstances acetylcholine exhibits a muscarinic ef- fect facilitating placental amino acid uptake. Nicotine blockade of the facilitating effects of acetylcholine on amino acid uptake may result in fetal growth retardation (126). These data agree with the 1977 work of Crosby, et al. in humans (26). Nicotine injection in rats results in prolonged gestation with lower than normal newborn weights. A possible cause of this prolonged gestation is nicotine-induced delay in ovum implan- tation. Yoshinaga, et al. tested this hypothesis, administering 7.5 mg nicotine tartrate twice daily from the morning of proes- trus until the day of sacrifice on days 1 to 5 of pregnancy (161). The nicotine-injected animals demonstrated a delay of about 12 hours in ovum cleavage from the two- to the four-cell stage, and each step of development after the four-cell stage was thereby delayed. In addition, ovum entry into the uterus, blastocyst formation, shedding of the zona pellucida, and implantation were delayed. Nicotine injection also was associated with a "crowding" of implantation sites toward the tubal ends of the uterine horns. During the preimplantation period the serum concentrations of progesterone, luteinizing hormone, and prolactin were lower, while the concentrations of estrogen and follicle stimulating hormone were higher than in control animals. These workers suggested that the delayed ovum implanation followed a de- layed increase in progesterone secretion required to prepare the uterus for the implanting blastocyst, and that the delayed progesterone secretion results in part from nicotine-induced disturbed hypothalamus pituitary balance. Hamosh, et al. observed that, while administration of 100 mg kg-`day-* nicotine to pregnant rats from day 14 gestation onward failed to affect the mother or fetus, administration of 1 mg kg-`day-l 230 (a dose "comparable" to that of a 20 cigarette-per-day smoker) re- sulted in a decrease in litter size and an increase in stillbirth rate. Although administration of 100 mg kg-`day-' nicotine failed to affect newborn birth weight by 12 days of age continued maternal nicotine administration resulted in a 9 percent decrease in body weight and a 40 percent decrease in weight of the stomach contents. These de- creases presumably resulted from lower milk production by the nicotine-treated animals (51). CARBON MONOXIDE (CO) Carboxyhemoglobin concentrations of 4 to 5 percent are as- sociated with numerous physiologic alterations in adults. Cigarette smoking raises the carboxyhemoglobin concentration 4 to 5 percent per pack smoked per day. Although CO diffuses across the placenta relatively slowly [ the half time equals 1.5 to 2 hr (72)], fetal carboxyhemoglobin concentrations reflect those of the mother, and under steady state conditions are 10 to 15 percent higher than maternal levels (71). Elevated car- boxyhemoglobin concentrations in the fetus are associated with decreased fetal blood oxygen tensions. These decreased oxygen tensions are associated with a redistribution of fetal blood flow to the brain, heart, and adrenal glands (146). Carboxyhemoglobin concentrations have been described under several conditions of pregnancy. Davies, et al. (31) com- pared earboxyhemoglobin concentrations and "available oxy- gen" (a function of 0, content in ml dl blood-`) in women who stopped smoking for 48 hours during the last trimester of preg- nancy, with women who did not stop smoking, and with nonsmoking women. In those women who stopped smoking, car- boxyhemoglobin concentrations decreased. "Available oxygen" increased about 8 percent due both to an increase in functioning hemoglobin and a shift in the oxyhemoglobin saturation curve; this increase in "available oxygen" should contribute to im- proved fetal oxygenation. Exposure of rabbits (6) and rats (39) to CO during gestation resulted in decreased fetal weights and increased perinatal mortality. Such CO-exposed newborn animals showed less activ- ity as well as decreased lung weights and decreased concentra- tions of brain protein, DNA, and the neurotransmitters norepinephrine and serotonin (45). Cellular hypoxia is the final common pathway mediating the adverse effect of CO on the developing fetus. Recent experimental studies have explored various aspects of CO-induced biochemical changes in the fetus and the newborn. Newby, et al. demonstrated a persistent effect of CO exposure in 8- and 13-day-old rats following a single 5-hour exposure to 1,500 231 120 r -co~n=a c *=*COc3+n=15 010 CONT $?n=9 100 c-o=o CONTdn=9 T I I I I I 1 2 4 16 Intensity (CandlepowerI9.4 x 104) FIGURE 12.-Effect of prenatal CO upon peak-to-peak amplitudes of the first positiive to the first negative component of the flash evoked potential recorded from the rat visual cortex. Vertical bars represent * standard error of the means SOURCE: Dyer, R.S. (36). parts per million (0.15 percent CO) (100). In these animals alpha methyl-p-tyrosine, a potent inhibitor of the enzyme tyrosine hydroxylase, was injected 1 hour before the CO exposure, and the extent of catecholamine depletion was taken as an index of the rate of catecholamine turnover. CO-treated rats showed in- creased steady state dopamine concentrations with decreased rates of dopamine turnover. In addition, the CO effect on dopamine turnover persisted for at least 3 to 6 weeks after a single exposure of 8-day-old rats. There was no CO effect on norepinephrine concentrations or turnover rates, and the effect was not produced in rats exposed to 8 percent oxygen instead of carbon monoxide. This is consistent with the data of Coyle and Campochiaro, which indicates that a maturational event occurs in the striatum of the 8-day-old rat (25). Whether this event represents the age of functional maturity, initiation of 232 dopaminergic transmission, or maturation of cholinergic inter- neurons is unclear. Prenatal CO exposure may have long-term consequences on central nervous system function. For instance, Dyer, et al. ex- posed female Long-Evans hooded rats to 150 ppm CO through- out pregnancy (36). At birth the litters and mothers were placed in room air without CO. On day 65 electrodes were placed in the young rats' skulls, and 2 weeks later visually evoked potentials were recorded. Figure 12 illustrates the effect of such prenatal exposure on the peak-to-peak amplitudes of the Pl-Nl (first pos- itive to first negative) component of the visual evoked potential from the cortex. Females showed a significant increase in Pl-Nl amplitude at each of four flash intensities. Although the exact nature of this amplitude increase could not be determined, it suggests altered cell populations at the retinal, geniculate, and cortical levels, and may represent impaired inhibitory mecha- nisms, rendering other neurons more excitable. The question of the posible teratogenicity of CO has never been resolved. Schwetz, et al. exposed mice to 250 ppm CO for 7 or 24 hours per day, from days 6 through 15 of gestation, and rabbits to the same concentration from days 6 through 18 (137). Blood carboxyhemoglobin concentration ranged from 10 to 15 percent. The fetuses of mice exposed to CO for 7 and 24 hours per day were slightly heavier and lighter, respectively, than those of the control animals. The only increase in teratogenic effects were minor skeletal variants such as extra lumbar ribs and spurs. POLYCYCLIC AROMATIC HYDROCARBONS The polycyclic aromatic hydrocarbons (PAH), such as ben- zo(a)pyrene, are widely distributed mutagens and carcinogens. These substances, produced by incomplete combustion of or- ganic material, are important constituents of tobacco smoke. Exposure of cells to PAH induces the enzyme, aryl hydrocarbon hydroxylase. The inducibility of this enzyme system has been used by some workers to demonstrate, indirectly, that ben- zo(a)pyrene and other polycyclic hydrocarbons reach the placenta and fetus. The placental concentration of benzo(a)pyrene is highly corre- lated with the amount which a pregnant woman smokes (97, 111). In pregnant rats exposed to this substance higher doses were required to induce enzyme activity in the fetus as com- pared with the dose required to stimulate placental enzyme ac- tivity (153), suggesting that the placenta may protect the fetus from these substances. However, the placenta is not imperme- 233 able to benzo(a)pyrene (134). The placenta is involved in com- plex hormonal interrelations between mother and fetus, and oxidative enzyme pathways in the placenta are important in maintaining hormonal and nutrient balance for normal fetal development. The hydroxylation of polycyclic hydrocarbons and the active transport of various compounds by trophoblast cells may share common enzyme systems. Thus, the induction of var- ious enzymes by polycyclic hydrocarbons may interfere with normal transport systems. Another unanswered question concerns the carcinogenic risk for progeny exposed in utero to polycyclic aromatic hydrocar- bons. The offspring of mice that were injected with ben- zo(a)pyrene late in gestation showed an increased incidence of neoplasms of the lungs, liver, and mammary glands (101). Pel- konen, et al. determined that placental aryl hydrocarbon hyd- roxylase activity correlated closely with both the amount the mother smoked and newborn weight (112). These authors suggested that the placental concentration of this enzyme may be used as a measure of fetal exposure to maternal cigarette smoking. Vaught, et al. also reported much higher aryl hyd- rocarbon hydroxylase activity in the placental microsomes of smokers compared with nonsmokers (148), Although currently available data do not allow a quantitative assessment of the genetic risk to man from cigarette smoking, such risk may occur since so many components of cigarette smoke are mutagens (as well as carcinogens) (11). Male cigarette smokers may have an increased number of abnormal spermatozoa (150). Paternal and maternal chromosomal aber- rations (103) and sister chromatid exchanges may be increased in smokers (62). Because the proportion of smokers in the popu- lation is so high (between 30 and 50 percent), even a relatively weak mutagenic effect could have a significant effect on the gene p00i (11). OTHER COMPONENTS Cyanide, another constituent of cigarette smoke, may con- tribute to retarded infant growth and increased perinatal mor- tality. Smokers have increas-ed levels of cyanide and thiocyan- ate in body fluids. Serum concentrations of vitamin Blz, used in cyanide metabolism, are decreased as well. Several workers have recorded increased thiocyanate concentrations in both women who smoke and in their fetuses (2,140,154). Pettigrew, et al. compared cyanide and thiocyanate concentrations in smok- ers and nonsmokers,. matched for age, height, parity, and socioeconomic status (116). Cyanide and thiocyanate concentra- 234 tions were two to four times greater in the blood and urine of smokers and in the urine of smokers' infants as compared with controls. Meberg, et al. reported that thiocyanate concentra- tions were correlated with cigarette consumption and inversely correlated with birth weight (81). Cadmium, another constituent of tobacco smoke, is concen- trated in the placenta of smokers (124). Webster exposed preg- nant mice to 10 to 40 ppm cadmium and noted an inverse corre- lation between cadmium concentration and fetal weight (152). Lauwerys, et al. examined the effects of epidemiology factors on heavy metal and CO concentrations in the blood, placenta, and fetus of smoking women (65). Cadmium concentrations in maternal blood were twofold greater than concentrations in fetal blood, suggesting that the placenta acts as a barrier to this metal. They reported a correlation between maternal cadmium and carboxyhemoglobin concentrations (13,65). They also found that the cadmium concentration of smokers' placentas was about 25 percent greater than in a control group and that the placental cadmium concentration exceeded that of maternal blood about tenfold (124). Fertility Fertility results from the successful completion of a complex step-wise process beginning with gametogenesis (sperm and egg production), continuing through gamete release (ejaculation and ovaluation), gamete interaction (fertilization), conceptus transport through the fallopian tube into the uterus, and end- ing with implantation of the embyro into the endometrial wall. An adverse effect of smoking on any of these steps may impair fertility. SMOKING AND REPRODUCTION IN WOMEN Several epidemiologic studies have suggested that smoking decreases fertility in women (50,115,143,149). The retrospective study of Tokuhata demonstrated that 21 percent of women who regularly smoked cigarettes were infertile while only 14