THE HEALTH CONSEQUENCES OF' SMOKING CANCER AND CHRONIC LUNG DISEASE IN THE WORKPLACE a report of the Surgeon General 1985 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Serwce Offlce on Smokrtg and Health RockwIle, Maryland 20857 The Honorable Thanas P. O'Neill, Jr. Speaker of the Haxx of Representatives Washington, D.C. 20515 Dear Mr. Speaker: It is a pleasure to transmit to the Congress the final edition of the Surgeon General's Report on the Health Consequences of -king, as mandated by Section 8(a) of the Public Health Cigarette Swkinq Act of 1969. This is the Public Health Service's 17th Repsrt cn this topic and, like earlier Reports. identifies cigarette smoking as one of this Nation's rmst seriws public health problems. This Reprt, tiicb provides a detailed review of the relationship between snaking and hazardous substances in the workplace, is particularly disturbing because of the added health burden that mny workers carry if they smke cigarettes. As this Report makes clear, for sane mrkers this added burden is substantial. No better example exists to illustrate this interaction than the case of asbestos wxkers. Current scientific evidence indicates that heavily exposed asbestos insulation rorkers who did not snake may expxienne a S-fold increase in lung cancer caped to making, nmexpsed uxkers. Hcw?ver, if this sanrz worker also srraked, his lurq cxcw risk is increased rrore than 5C-fold. Also disturbi- is the mntinued high rate of current cigarette use anrxq blue collar wrkers cmpred to their white collar counterparts. These wxkers are mm apt to he eqosed to dusts and other harmful substances in their wrkplace envir-nts. Prqfan-s to reduce wxkplace hazardous eqx~~res are helping to offset these risks. For the majority of rorkers who make, cigarette smking poses a greater risk to health than does cnxpaticnal exposure. Thus, elimination of cigarette smking zum!q such mrkers can have a profound effect on iiqxoving their health. This Department has a strong commitment to prevention and health pranticn. It is essential that wxkplxe health prcnnticn prcqrams have a strong fans on reducing cigarette smking mm-g enplopes to the extent possible. These efforts can not only have an effect cn the health of the individual, but may also have a substantial impact by reducing absenteeism on the job, thereby improving prcductivity ant! reduciq health care costs. Cigarette inking is associated with an estimated $23 billion in health care costs annually and wer $30 billiar in lost productivity and wages. To a certain degree we all share these cxts whether we mke or not. Prqrams that reduce smoking, therefore, can have a benefit to all cur society. Sincerely, Otis R. Bcwen, M.D. secretary Enclosure w1 1% The Honorable George Bush President of the Senate Washington, D.C. 20510 Gear Mz. President: It is a pleasure to transnit to the Congress the final edition of the Surgecm General's Report cm the Health Cmsequems of Smkirq, as rmrdated by Section 8(a) of the Public Health Cigarette Smking Act of 1969. This is the Public Health Service's 17th Reprt cm this tqic and, like earlier Reports, identifies cigarette smking as me of this Nation's mst sericus @lit health problems. This Repxt, which provides a detailed review of the relationship between smking and hazardcas substames in the wxkplace, is particularly disturbing because of the added health burden that mny workers carry if they snake cigarettes. As this Report ekes clear, for xme workers this added burden is substantial. No better example exists to illustrate this interaction than the case of asbestos hot-kers. Current scientific evidence indicates that heavily exposed asbestos insulation workers who did not m&e may experiexe a 5-fold iirrease in luq cancer canpared to ncmsmking. ncnexpxed workers. Hmever, if this same vorker also smoked. his lung cancer risk is increased mre than SC-fold. Also disturbing is the nntinued high rate of current cigarette use amrg blue collar wxkers rrrrpared to their white collar canterparts. These wxkers are rmre apt to be exposed to dusts and other harmful substances I" their wxkplace envirmuwnts. Prqram to reduce workplace hazardous exposures are helpirq to offset these risks. For the majority of mrkers who mke, cigarette srckirq poses a greater risk to health than dces occupational exposure. Thus, eliminatim of cigarette samking amng such wxkers can have a profound effect cn improving their health. This Ehzpartment has a struq mitment to prevention and health pramtim. It is essential that workplace health prmticn prqrams have a strong focus on reducing cigarette making amxq qloyees to the extent possible. These efforts can not only have an effect on the health of the individual, but my also have a substantial impact by reducing absenteeism on the job, thereby improving productivity and reducing health care costs. Cigarette sawking is assoziated with an estimated $23 billion in health care costs annually and cwer $30 billim in lost productivity and wages. To a certain degree we all share these costs ðer we mke or not. Prqram.5 that reduce mking, therefore, can have a benefit tc all cur society. Sincerely, Otis R. Sam, M.D. secretary FOREWORD Over the past generation, the actions of labor unions, manage- ment, insurers, and Government have made substantial progress in reducing exposure to hazardous substances in the workplace. This Report acknowledges this progress, and demonstrates clearly that these efforts to protect the American worker must continue. There can be no relaxation in our efforts to continue the safeguards already in place or to seek new safeguards as new hazards are identified. This Report also establishes that for these efforts to protect the worker to fully succeed, these same forces of labor, management, insurers, and Government must become equally engaged in attempts to reduce the prevalence of cigarette smoking, particularly among those working populations most at risk. For the majority of workers who smoke, cigarette smoking poses a greater risk to health than does occupational exposure. This 1985 Report of the Surgeon General examines in greater depth than ever before the relationships between cigarette smoking and occupational exposures; it is a document of singular importance. As with previous Reports, a large number of experts and scientists recruited from both within and outside the Federal service have participated in developing and reviewing the content of this Report. I express here my respect and gratitude for their efforts. Donald Ian Macdonald, M.D. Acting Assistant Secretary for Health vii PREFACE The 1985 Report on the Health Consequences of Smoking presents a comprehensive review of the interaction of cigarette smoking with occupational exposures in the production of cancer and chronic lung disease. Cigarette smoking and its relationship to cancer and chronic obstructive lung disease (COLD) were extensively reviewed in the 1982 and 1984 Surgeon General's Reports, respectively. In the 1982 Report, cigarette smoking was judged to be the leading cause of cancer mortality in the United States; a causal association was found between smoking and cancer of the lung, larynx, oral cavity, and esophagus, and smoking was identified as a contributory factor in the development of cancer of the bladder, kidney, and pancreas. In 1984, cigarette smoking was identified as the major cause of COLD, which includes chronic bronchitis and emphysema, among both men and women in the United States. The contribution of other factors in COLD morbidity and mortality was found to be far less important than that of cigarette smoking. This Report examines the evidence available on the role played by cigarette smoking and occupational exposure in the development of cancer and chronic lung disease. Cancer and chronic lung disease are major causes of death in the United States, accounting for well over 25 percent of all deaths annually. Cancer mortality rates have shown a steady increase, unlike rates for the major cardiovascular diseases, which have declined over the last two decades. Chronic lung disease, now the fifth leading cause of mortality, has been increasing more rapidly than other major causes of death. It is estimated that more than 10 million Americans report suffering from these diseases. Findings of the 1985 Report The major overall conclusions of this Report are these: For the majority of American workers who smoke, cigarette smoking represents a greater cause of death and disability than their workplace environment. In those worksites where well-established disease outcomes occur, smoking control and reduction in exposure to hazardous agents are effective, compatible, and occasionally synergistic ix approaches to the reduction of disease risk for the individual worker. Smoking and occupational exposures can interact synergistically to create more disease than the sum of the separate exposures. This kind of interaction is exemplified by the relationship between asbestos exposure and smoking. A study of heavily exposed asbestos insulation workers, more than 20 years after onset of exposure, demonstrated a fivefold increased risk for lung cancer among nonsmoking asbestos workers compared with nonsmokers without asbestos exposure. We know that in non-asbestos-exposed popula- tions, smoking increases the lung cancer risk approximately tenfold. The risk is increased more than fiftyfold if the asbestos workers also smoke. This risk in cigarette-smoking asbestos workers is greater than the sum of the risk of the independent exposures, .and is approximated by multiplying the risks of the two separate expo- sures. In other words, for those workers who both smoke and are exposed to asbestos, the risk of developing and dying from lung cancer is 5,000 percent greater than the risk for individuals who neither smoke nor are exposed. Thus, the interaction of cigarette smoking and asbestos exposure is multiplicative. For asbestos workers, the risk of developing and dying of lung cancer increases with an increasing number of cigarettes smoked per day and with an increasing asbestos exposure. For example, the risk is 87 times greater for those workers who smoke more than one pack per day. The risk declines among workers who are able to stop smoking, compared with the risk for those who continue to smoke. An interaction for the production of lung cancer also exists between cigarette smoking and the radon daughters exposure of miners, although the exact nature of this interaction is not clear. Both cigarette smoking and exposure to certain occupational hazards increase the risk for chronic lung disease. These risks can occur independently or may combine to produce a greater degree of lung injury than would have occurred from either exposure separate- ly. While many exposures are capable of producing chronic lung injury, either independently or in combination, smoking appears to be the more important exposure for the majority of U.S. workers. Differences in Smoking Behavior Between White-Collar Workers and Blue-Collar Workers This Report also presents detailed findings with regard to differ- ences in smoking prevalence between blue-collar workers and white- collar workers. Blue-collar workers are more likely to be exposed to workplace agents, which, in combination with their higher smoking rates, may place these workers at considerable excess risk for cancer X and chronic lung disease. Although these differences exist among both men and women, they are more pronounced among men. The differences in the prevalence of smoking between blue-collar workers and white-collar workers may underestimate the differences found among specific populations of occupationally exposed workers. As noted in this Report, individual studies among certain workers report current smoking rates well in excess of 50 percent. In addition, in one of the largest studies of asbestos workers, more than 80 percent of the men in the cohort had been regular cigarette smokers during their lifetime and only 11 percent were classified as never having smoked regularly. These differences in smoking behavior make the control for smoking behavior an important part of the design of studies of the relationship of occupational exposures and cancer or chronic lung disease. On the average, blue-collar men initiate smoking approximately 14 months earlier than white-collar men. We know from existing studies that an earlier age of initiation is strongly correlated with increased mortality for lung cancer and chronic lung disease as well as for most other smoking-related diseases. Even with this earlier age of initiation, a substantial fraction of blue-collar workers begin smoking coincident with their entry into the workforce, and blue- collar workers are less likely than white-collar workers to be able to successfully quit smoking. Smoking Control in the Workplace The potential role of the workplace in promoting initiation and fostering the continuation of smoking behavior represents a kind of interaction between smoking and the workplace that may affect large numbers of U.S. workers. It seems clear that the responsibility for health in the workplace includes at minimum a work environ- ment that does not promote smoking or interfere with cessation. The worksite offers an opportunity for implementation of smoking cessation programs. A number of studies cited in this Report found worksite-based programs to be more successful than clinic-based programs, probably owing to their more intensive nature and because many employer-sponsored programs offer economic and other incentives, thus enhancing their success. The goal in public health, both in the worksite and outside it, is the reduction and elimination of disease and the promotion of healthy behavior. The content of this Report makes it clear that the elimination of chronic lung disease and cancer from the workplace cannot succeed without a companion effort to alter the smoking behavior of workers. It is precisely those occupations in which the greatest occupational hazards have existed that smoking cessation also yields the greatest return for individual worker's health. It xi should be obvious that smoking cessation efforts are an adjunct to, and not a substitute for, occupational environmental controls. Correspondingly, a concern about workers' health that limits itself to the control of environmental exposure levels disregards the major health benefits of smoking cessation. C. Everett Koop, M.D. Surgeon General xii ACKNOWLEDGMENTS This Report was prepared by the U.S. Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Donald R. Shopland, Acting Director. Manag- ing Editor was William R. Lynn, Acting Technical Information Officer, Office on Smoking and Health. Senior scientific editor was David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, Califor- nia. Consulting scientific editors were Ellen R. Gritz, Ph.D., Asso- ciate Director for Research, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medical Center, Salt Lake City, Utah; and Jonathan M. Samet, M.D., Associate Professor of Medicine, Department of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico. The following individuals prepared draft chapters or portions of the Report. Victor E. Archer, M.D., Clinical Professor, Rocky Mountain Center for Occupational and Environmental Health, The University of Utah Medical Center, Salt Lake City, Utah Michael E. Baser, M.S., Chief, Occupational Health, Bureau of Environmental Epidemiology and Occupational Health, New York State Health Department, Albany, New York David M. Burns, M.D., Associate Professor of Medicine, Divisicn of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, California David B. Coultas, M.D., Instructor of Medicine, Department of Medicine and the New Mexico Tumor Registry, The University of New Mexico School of Medicine, Albuquerque, New Mexico John E. Craighead, M.D., Professor and Chairman, Department of Pathology, The University of Vermont College of Medicine, Burlington, Vermont Lori A. Crane, M.P.H., Staff Research Associate, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California Philip E. Enterline, Ph.D., Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsyl- vania Russell E. Glasgow, Ph.D., Research Scientist, Oregon Research Institute, Eugene, Oregon David F. Goldsmith, Ph.D., Visiting Assistant Professor, Department of Internal Medicine, School of Medicine, University of California at Davis, Davis, California Robert C. Klesges, Ph.D., Associate Professor, Center for Applied Psychological Research, Department of Psychology, Memphis State University, Memphis, Tennessee Alfred C. Marcus, Ph.D., Program Director for Evaluation, Division of Cancer Control, Jonsson Comprehensive Cancer Center, Univer- sity of California at Los Angeles, Los Angeles, California Steven Markowitz, M.D., Environmental Sciences Laboratory, De- partment of Community Medicine, The Mount Sinai Medical Center, The Mount Sinai School of Medicine of the City University of New York, New York, New York James A. Merchant, M.D., Dr.P.H., Professor of Preventive and Internal Medicine, and Director, Institute of Agricultural Medi- cine and Occupational Health, The University of Iowa College of Medicine, Iowa City, Iowa Albert Miller, M.D., Clinical Professor of Medicine (Pulmonary), Clinical Professor of Community Medicine (Environmental), and Director, Pulmonary Function Laboratory, Division of Pulmonary Medicine, Department of Internal Medicine, The Mount Sinai Medical Center, The Mount Sinai School of Medicine of the City University of New York, New York, New York Donald P. Morgan, M.D., Ph.D., Professor, Department of Preventive Medicine and Environmental Health, The University of Iowa College of Medicine, Iowa City, Iowa W.K.C. Morgan, M.D., F.R.C.P.(Edl, F.R.C.P.(C), F.A.C.P., Chest Diseases Unit, University Hospital, London, Ontario, Canada Brooke T. Mossman, Ph.D., Associate Professor of Pathology, and Chairman, Cell Biology Program, Department of Pathology, The University of Vermont College of Medicine, Burlington, Vermont Paul R. Pomrehn, Jr., M.D., Assistant Professor, Department of Preventive Medicine and Environmental Health, and Director, University Occupational Health Service, The University of Iowa College of Medicine, Iowa City, Iowa Howard E. Rockette, Ph.D., Professor of Biostatistics, Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania Jonathan M. Samet, M.D., M.S., Associate Professor of Medicine, Department of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico xiv Cecilia M. Smith, M.D., Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, California Melvyn S. Tockman, M.D., Ph.D., Associate Professor of Environ- mental Health Sciences, with joint appointments in Respiratory Medicine and Epidemiology, Center for Occupational and Environ- mental Health, The Johns Hopkins University, Baltimore, Mary- land Pamela H. Wolf, Dr.P.H., Biostatistician, Contraceptive Evaluation Branch, Center for Population Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Charles A. Althafer, Assistant Director for Health Promotion and Risk Appraisal, Office of Program Planning and Evaluation, National Institute for Occupational Safety and Health, Centers for Disease Control, Atlanta, Georgia Harlan E. Amandus, Ph.D., Statistician, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia Stephen M. Ayres, M.D., Dean, School of Medicine, Medical College of Virginia, Richmond, Virginia Mary A. Ballew, MS., Epidemiologist, Document Development Branch, Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Margaret R. Becklake, M.D., Professor, Departments of Medicine, Epidemiology, and Biostatistics, McGill University, Montreal, Quebec, Canada, on sabbatical, and Career Investigator, Medical Research Council of Canada, Montreal, Quebec, Canada, on leave; Professor (Honorary), Department of Community Health, Univer- sity of the Witwatersrand, and Principal Medical Officer, National Centre for Occupational Health, Department of Health and Welfare, Johannesburg, South Africa Kenneth R. Berger, M.D., Ph.D., Adjunct Assistant Professor, Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland Robert Bernstein, Senior Reviewer, Document Development Branch, Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio xv Donald B. Bishop, Ph.D., Research Associate, Department of Psychol- ogy, Washington University in St. Louis, St. Louis, Missouri Brian A. Boehlecke, M.D., M.P.H., Associate Professor of Medicine, Division of Pulmonary Diseases, Critical Care and Occupational Medicine, Department of Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Lester Breslow, M.D., M.P.H., Co-Director, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California Benjamin Burrows, M.D., Professor of Internal Medicine, and Director, Division of Respiratory Sciences, The University of Arizona College of Medicine, Tucson, Arizona Robert M. Castellan, M.D., Chief, Clinical Section, Clinical Investiga- tions Branch, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia John E. Davies, M.D., M.P.H., Professor and Chairman, Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami, Florida Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland John E. Diem, Ph.D., Professor of Statistics, Tulane University, New Orleans, Louisiana Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Office of the Assistant Secretary for Health, Hyattsville, Maryland Edwin B. Fisher, Jr., Ph.D., Associate Professor of Psychology and Preventive Medicine, Department of Psychology, Washington University in St. Louis, St. Louis, Missouri Lawrence Garfinkel, M.A., Vice President for Epidemiology and Statistics, and Director of Cancer Prevention, American Cancer Society, Incorporated, New York, New York J.C. Gilson, M.D., Hembury Hill Farm, Honiton, Devon, England, United Kingdom William E. Halperin, M.D., M.P.H., Chief, Industrywide Studies Branch, Division of Surveillance Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Peter V.V. Hamill, M.D., M.P.H., Adjunct Professor, Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, Maryland John L. Hankinson, Ph.D., Chief, Clinical Investigations Branch, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia xvi Naomi Harley, Ph.D., Professor, Institute of Environmental Medi- cine, New York University Medical Center, New York, New York Wayland J. Hayes, Jr., M.D., Ph.D., Professor Emeritus of Biochemis- try (Toxicology), School of Medicine, Vanderbilt University, Nash- ville, Tennessee Ian T.T. Higgins, M.D., Professor Emeritus of Epidemiology and of Environmental and Industrial Health, School of Public Health, The University of Michigan, Ann Arbor, Michigan, and Acting Chief of Epidemiology, American Health Foundation, New York, New York Thomas K. Hodous, M.D., Medical Officer, Clinical Investigations Branch, Division of Respiratory Disease Studies, National Insti- tute for Occupational Safety and Health, Centers for Disease Control, and Adjunct Associate Professor, West Virginia Universi- ty School of Medicine, Morgantown, West Virginia Michael Jacobsen, Ph.D., Deputy Director, Institute for Occupational Medicine, Edinburgh, Scotland, United Kingdom Robert N. Jones, M.D., Professor of Medicine, Pulmonary Diseases Section, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana Marcus M. Key, M.D., Professor of Occupational Medicine, Program in Occupational Safety and Health, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas Kaye H. Kilburn, M.D., Ralph Edgington Professor of Medicine, Laboratory for Environmental Sciences, University of Southern California School of Medicine, Los Angeles, California Arthur M. Langer, Ph.D., Associate Professor of Mineralogy, The Mount Sinai School of Medicine of the City University of New York, New York, New York N. LeRoy Lapp, M.D., Professor of Medicine, Pulmonary Disease Section, West Virginia University Medical Center, Morgantown, West Virginia Richard A. Lemen, Director, Division of Standards Development and Technology Transfer, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Trent R. Lewis, Ph.D., Chief, Experimental Toxicology Branch, Division of Biomedical and Behavioral Science, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Edward Lichtenstein, Ph.D., Professor of Psychology, University of Oregon, and Research Scientist, Oregon Research Institute, Eu- gene, Oregon xvii Ruth Lilis, M.D., Professor, Division of Environmental and Occupa- tional Medicine, Department of Community Medicine, The Mount Sinai School of Medicine of the City University of New York, New York, New York Jay H. Lubin, Ph.D., Health Statistician, Biostatistics Branch, Division of Cancer Etiology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland James 0. Mason, M.D., former Acting Assistant Secretary for Health, Washington, D.C., and Director, Centers for Disease Control, Atlanta, Georgia J. Corbett McDonald, M.D., F.R.C.P., Professor, School of Occupa- tional Health, McGill University, Montreal, Quebec, Canada J. Michael McGinnis, M.D., Deputy Assistant Secretary for Health (Disease Prevention and Health Promotion), Office of the Assistant Secretary for Health, Washington, D.C. J. Donald Millar, M.D., Assistant Surgeon General and Director, National Institute for Occupational Safety and Health, Centers for Disease Control, Atlanta, Georgia Anthony B. Miller, M.B., F.R.C.P.(C), Director, Epidemiology Unit, National Cancer Institute of Canada, and Professor of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontar- io, Canada Kenneth M. Moser, M.D., Professor of Medicine, School of Medicine, University of California at San Diego, La Jolla, California, and Director, Division of Pulmonary and Critical Care Medicine, University of California Medical Center, San Diego, California Robert J. Mullan, M.D., Medical Officer, Surveillance Branch, Division of Surveillance Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Muriel Newhouse, M.D., F.R.C.P., Department of Occupational Health and Applied Physiology, London School of Hygiene and Tropical Medicine, University of London, London, England, Unit- ed Kingdom William J. Nicholson, Ph.D., Associate Professor, Division of Envi- ronmental and Occupational Medicine, Department of Community Medicine, The Mount Sinai School of Medicine of the City University of New York, New York, New York Judith K. Ockene, Ph.D., Associate Professor of Medicine, and Director, Division of Preventive and Behavioral Medicine, Depart- ment of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts C. Tracy Orleans, Ph.D., Clinical Assistant Professor, University of Pennsylvania Medical School, Philadelphia, Pennsylvania; Smok- ing and Health Consultants, Incorporated, Princeton, New Jersey . . . xv111 Carl E. Ortmeyer, Ph.D., Public Health Statistician (Retired), National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia John M. Peters, M.D., Professor, and Director, Division of Occupa- tional Health, Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California Richard Peto, M.A., MSc., I.C.R.S., Requis Assessor of Medicine, Radcliffe Infirmary, University of Oxford, Oxford, England, Unit- ed Kingdom Philip C. Pratt, M.D., Professor of Pathology, Department of Pathology, Duke University Medical Center, Durham, North Carolina Edward P. Radford, M.D., Visiting Professor, University of Occupa- tional and Environmental Health, School of Medicine, Yahata Nishi-Ku, Kitakyushu, Japan Robert B. Reger, Ph.D., Chief, Epidemiological Investigations Branch, Division of Respiratory Disease Studies, National Insti- tute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia Attilio D. Renzetti, Jr., M.D., Professor of Medicine, and Chief, Division of Respiratory, Critical Care, and Occupational Pulmo- nary Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah E. Neil Schachter, M.D., Professor of Medicine and Community Medicine, The Mount Sinai School of Medicine, and Director, Respiratory Therapy, The Mount Sinai Medical Center, The Mount Sinai School of Medicine of the City University of New York, New York, New York Richard S. Schilling, M.D., Department of Occupational Health and Applied Physiology, London School of Hygiene and Tropical Medicine, University of London, London, England, United King- dom Irving J. Selikoff, M.D., Professor Emeritus, The Mount Sinai School of Medicine of the City University of New York, New York, New York Kyle N. Steenland, Ph.D., Epidemiologist, Industrywide Studies Branch, Division of Surveillance Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, Ohio Jesse L. Steinfeld, M.D., President, Medical College of Georgia, Augusta, Georgia Arthur C. Upton, M.D., Professor, and Chairman, Institute of Environmental Medicine, New York University Medical Center, New York, New York John Christopher Wagoner, M.D., F.R.C.(Path), Medical Research Council Pneumoconiosis Unit, Llandough Hospital, Penarth, South Glamorgan, Wales, United Kingdom Kenneth E. Warner, Ph.D., Professor, and Chairman, Department of Health Planning and Administration, School of Public Health, The University of Michigan, Ann Arbor, Michigan David H. Wegman, M.D., M.S., Professor, Environmental and Occupational Health Sciences, School of Public Health, University of California at Los Angeles, Los Angeles, California Hans Weill, M.D., Schlieder Foundation Professor of Pulmonary Medicine, Tulane University School of Medicine, New Orleans, Louisiana William Weiss, M.D., Professor Emeritus of Medicine, Hahnemann University, Philadelphia, Pennsylvania *R. Keith Wilson, M.D., Associate Professor of Medicine, Pulmonary Section, Baylor College of Medicine and The Methodist Hospital, Houston, Texas *Ronald W. Wilson, M.A., Director, Division of Epidemiology and Health Promotion, National Center for Health Statistics, Office of the Assistant Secretary for Health, Hyattsville, Maryland James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland Frank E. Young, M.D., Commissioner, Food and Drug Administra- tion, Rockville, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Erica W. Adams, Chief Copy Editor and Assistant Production Manager, Health and Natural Resources Department, Informatics General Corporation, Rockville, Maryland Richard H. Amacher, Director, Health and Natural Resources Department, Informatics General Corporation, Rockville, Mary- land John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Charles A. Brown, Programmer, Automation and Technical Services Department, Informatics General Corporation, Rockville, Mary- land Clarice D. Brown, Statistician, Office on Smoking and Health, Rockville, Maryland Richard C. Brubaker, Information Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Catherine E. Burckhardt, Secretary, Office on Smoking and Health, Rockville, Maryland xx Joanna B. Crichton, Copy Editor, Health and Natural Resources Department, Informatics General Corporation, Rockville, Mary- land Stephanie D. DeVoe, Programmer, Automation and Technical Services Department, Informatics General Corporation, Rockville, Maryland Terri L. Ecker, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Felisa F. Enriquez, Information Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland James N. Ferguson, Reproduction Technician, Office Services De- partment, Informatics General Corporation, Rockville, Maryland Danny A. Goodman, Information Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Leslie J. Headlee, Information Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Patricia E. Healy, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Timothy K. Hensley, Technical Publications Writer, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Ayse N. Hisim, Secretary, Health and Natural Resources Depart- ment, Informatics General Corporation, Rockville, Maryland Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Leena Kang, Data Entry Operator, Health and Natural Resources Department, Informatics General Corporation, Rockville, Mary- land Carl M. Koch, Jr., Information Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Julie Kurz, Graphic Artist, Information Center Management De- partment, Informatics General Corporation, Rockville, Maryland Maureen Mann, Editorial Assistant, Office on Smoking and Health, Rockville, Maryland James G. Oakley, Library Acquisitions Clerk, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland xxi Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland Russell D. Peek, Library Acquisitions Specialist, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Roberta L. Phucas, Secretary, Office on Smoking and Health, Rockville, Maryland Margaret E. Pickerel, Public Information and Publications Special- ist, Office on Smoking and Health, Rockville, Maryland Raymond K. Poole, Production Coordinator, Health and Natural Resources Department, Informatics General Corporation, Rock- ville, Maryland Linda R. Sexton, Information Specialist, Health and Natural Re- sources Department, Informatics General Corporation, Rockville, Maryland Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Automation and Techni- cal Services Department, Informatics General Corporation, Rock- ville, Maryland Debra C. Tate, Publications Systems Specialist, Publishing Systems Division, Informatics General Corporation, Riverdale, Maryland Jerry W. Vaughn, Development Technician, University of California at San Diego, San Diego, California Mary I. Walz, Computer Systems Analyst, Office on Smoking and Health, Rockville, Maryland Louise G. Wiseman, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Pamela Zuniga, Secretary, University of California at San Diego, San Diego, California xxii TABLE OF CONTENTS Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Acknowledgments .................... ................................. x111 1. Introduction, Overview, and Summary and Conclusions ........................................................ 1 2. Occupation and Smoking Behavior in the United States: Current Estimates and Recent Trends . . . . . . . . 19 3. Evaluation of Smoking-Related Cancers in the Workplace.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4. Evaluation of Chronic Lung Disease in the Workplace.. . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 5. Chronic Bronchitis: Interaction of Smoking and Occupation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 6. Asbestos-Exposed Workers ................................. 195 7. Respiratory Disease in Coal Miners .................... 285 8. Silica-Exposed Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 9. Occupational Exposures to Petrochemicals, Aromatic Amines, and Pesticides . . . . . , . . . . . . . . . . . . . . . . . . . . . . . 355 10. Cotton Dust Exposure and Cigarette Smoking ....... 399 11. Ionizing Radiation and Lung Cancer ................... 441 12. Smoking Intervention Programs in the Workplace.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517 xx111 CHAPTER 1 INTRODUCTION, OVERVIEW, AND SUMMARY AND CONCLUSIONS CONTENTS Introduction Development and Organization of the 1985 Report Historical Perspective Overview Summary and Conclusions of the 1985 Report 3 Introduction Development and Organization of the 1985 Report The 1985 Report was prepared by the Office on Smoking and Health of the U.S. Department of Health and Human Services as part of the Department's responsibility, under Public Law 91-222, to report new and current information on smoking and health to the United States Congress. The scientific content of this Report is the collective work of 100 scientists in the fields of both smoking and occupational health. Individual manuscripts were written by experts who are recognized for their understanding of specific content areas. Each chapter was subjected to an intensive peer review, whereby comments were solicited from four to six individuals knowledgeable in that particular area. After these comments were incorporated, the entire Report was submitted to distinguished experts representing a balance of opinion in occupational disease and smoking and health. Concurrent with this latter review, the manuscript was also submit- ted to various U.S. Public Health Service agencies for review. Throughout the entire report compilation process the Office on Smoking and Health had the advice and consultation of four internationally known scientists. These individuals represent exper- tise in the fields of both smoking and occupation. They are Dr. Lester Breslow, University of California at Los Angeles, Dr. Marcus Key, University of Texas Health Science Center, Dr. Irving Selikoff, the Mount Sinai Medical Center, and Dr. Jesse Steinfeld, Medical College of Georgia. From the outset, this panel of experts was instrumental in recommending the Report content and outline, suggesting individual authors and reviewers, and providing overall guidance during each stage of the compilation process. Each also served as an overall reviewer of the completed manuscript. The 1985 Report contains a Foreword by the Acting Assistant Secretary for Health, a Preface by the Surgeon General of the U.S. Public Health Service, and the following chapters: o Chapter 1. Introduction, Overview, and Summary and Con- clusions o Chapter 2. Occupation and Smoking Behavior in the United States o Chapter 3. Evaluation of Smoking-Related Cancers in the Workplace o Chapter 4. Evaluation of Chronic Lung Disease in the Workplace o Chapter 5. Chronic Bronchitis: Interaction of Smoking and Occupation o Chapter 6. Asbestos-Exposed Workers o Chapter 7. Respiratory Disease in Coal Miners o Chapter 8. Silica-Exposed Workers 5 a Chapter 9. Occupational Exposures to Petrochemicals, Aromatic Amines, and Pesticides o Chapter 10. Cotton Dust Exposure and Cigarette Smoking o Chapter 11. Ionizing Radiation and Lung Cancer o Chapter 12. Smoking Intervention Programs in the Work- place Historical Perspective More than two centuries ago, the relationship between occupation- al exposure and health outcome was presented by a noted English practitioner of surgery. Dr. Percival1 Pott (1733-1788), in his Chirugical Observation-s (17751, described this first scientific observa- tion as a "superficial, painful ragged, ill-looking sore with hard and rising edges" that appeared in chimney sweeps, who almost always began working when they were very young and small enough to fit down a chimney. This malady was appropriately tagged "chimney sweep's cancer." Soon after the turn of the 19th century, additional reports confirmed Dr. Pott's observations. Only shortly before Dr. Pott's description was published, Dr. John Hill (1716?-17751, in his Cautions Against the Immoderate Use of Snuff; described an association between tobacco use and cancer. Hill reported on two case histories and observed that "snuff is able to produce . . . swellings and excrescences" in the nose, and he believed them to be cancerous. Although Dr. Pott's startling report and description of the deplorable use of children as chimney sweeps was published in 1775, it was not until nearly a century and a half later, in 1914, that Yamagawa and Ichikawa were able to demonstrate the carcinogenic nature of the hydrocarbons in soot and tar. Almost 20 years later, in 1933, the proximate carcinogen 3,4-benzypyrene was isolated from coal tar by Cook, Hewett, and Hieger. Also in the 1920s and 1930s scientists began investigating the possible association between cigarette smoking and cancer, and near the end of World War II, several scientists had noted the higher percentages of cigarette smokers among cancer patients, particular- ly those with lung cancer. In 1962, when the Surgeon General's Advisory Committee on Smoking and Health began weighing the scientific evidence for its 1964 Report, the causal significance of the association of cigarette smoking and disease was evaluated by strict criteria, none of which taken alone was sufficient for a causal judgment. These criteria today form the basis for the continued judgment that cigarette smoking is causally related to a number of disease processes. Overview Cigarette smoking is clearly the major cause of lung cancer and chronic lung disease identified for the U.S. population. The role that cigarette smoking plays in the development of cancer was extensive- ly reviewed in 1982 Report of the Surgeon General and chronic obstructive lung disease was reviewed in 1984. However, cigarette smoking is not the only cause of lung cancer or chronic lung disease in the U.S. population. A number of occupational exposures are well established as causes of cancer and chronic lung disease, and it is reasonable to expect that ongoing investigation of workplace expo- sures will continue to expand our understanding of the hazards of specific exposures and increase our ability to protect U.S. workers. This Report examines the contributions of cigarette smoking and a number of workplace exposures to lung cancer and chronic lung disease among occupations in which specific hazardous exposures are known to occur. It is possible from the data presented to identify a causal role for both smoking and certain workplace exposures in lung cancer and disability from chronic lung disease. It is also known that the occupational hazards reviewed in this Report frequently occur on a substrate of risk and injury produced by cigarette smoking. The combination of exposures may influence the nature or extent of the disease produced by the isolated exposures (interact); both may act to produce the same disease, or may produce separate injuries to the lung that in combination result in more severe disability than would be expected from the isolated injuries. In addition, the worksite may represent a setting in which a substantial number of workers begin to smoke, and may provide an environment that either supports or discourages the efforts of individual workers to stop smoking. The ability to alter the adverse health outcomes of workers exposed to occupational hazards requires both an under- standing of the disease risks that result from individual and combined exposure and a knowledge of how changes in the worksite can alter the pattern of disease occurrence. Many of the major improvements in public health during the last century and the first part of this century were produced through the control of infectious diseases. The key to this success frequently was the identification of the causal agent, with the subsequent elimina- tion of exposure to the agent or immunization against the agent. The criteria for establishing the causality of an infectious agent were expressed by Robert Koch in 1877 and are commonly referred to as Koch's postulates. They are the following: 1. The agent must be shown to be present in every case of the disease by isolation in pure culture. 2. The agent must not be found in cases of other disease. 7 3. Once isolated, the agent must be capable of reproducing the disease in animal experiments. 4. The agent must be recovered from the experimental disease produced. These postulates served well in identifying the causal agents in acute infectious processes; frequently their identification was a critical part of their successful control. The major diseases responsible for death and disability in the latter half of the 20th century are chronic heart and lung disease and cancer. These diseases, which now account for over half of all deaths in the United States annually, are commonly the result of chronic exposures to noninfectious occupational and lifestyle influ- ences, may be caused by a number of agents acting independently, and may also result from more than one agent contributing to the disease process in any given individual. For these reasons, Koch's postulates have little relevance for establishing causality in lifestyle and occupational exposures, and new criteria for causality have been developed. These criteria rely heavily on epidemiologic data and include an examination of the consistency, strength, specificity, coherence, and temporal relationship of the association between the agent and the disease as well as the evidence of the biologic mechanisms by which the agent produced the disease. The multifactorial etiology and chronic exposures that character- ize cancer and chronic lung disease also have implications for control of these diseases in the worksite. One of the important public health achievements of this century has been the identification of hazard- ous agents in the workplace, with subsequent reductions in these exposures through changes in environmental levels of the agent, modification of work practices, and alteration of manufacturing practices. These changes were the result of regulation and voluntary agreement, and they reflect the action and concern of labor, management, Government, and the insurance industry. The result, in some industries, has been a dramatic reduction in the exposure to hazardous agents in the worksite and in the disease that would have been produced by these exposures. As this Report clearly documents, however, cigarette smoking may alter the amount of disease or level of disability produced by hazardous occupational exposures. For cancer, this alteration may come in the form of adding an additional number of cancer cases, or of the combined exposure synergistically increasing the number of cancers. On an individual level, our understanding of the process of carcinogenesis suggests that both agents may contribute to individu- al cancer rather than some cases being caused exclusively by an occupation exposure and other cases being caused exclusively by cigarette smoking. For lung disease, the combination of cigarette smoking and exposure to a hazardous workplace agent may combine to produce similar injuries or may produce independent disease processes in the same lung that result in greater disability than with either exposure separately. The public health importance of interaction between smoking and an occupational exposure is typified by the relationship between cigarette smoking and asbestos exposure among asbestos workers. A number of studies published in this country and abroad have demonstrated an approximately fivefold excess risk for lung cancer among nonsmoking asbestos insulation workers. Smoking in non- asbestos-exposed populations increases the lung cancer risk by approximately tenfold. However, the risk is more than fiftyfold greater if the asbestos worker also smokes. The risk in cigarette- smoking asbestos workers is greater than the sum of the risk of the independent exposures, and is approximated by multiplying the risks of the two separate exposures. Thus, the interaction of cigarette smoking and asbestos exposure is multiplicative in nature. To state this in another way, for those workers who both smoke and are exposed to asbestos, the risk of developing and dying from lung cancer is 5,000 percent greater than the risk for individuals who neither smoke nor are exposed. Among these asbestos workers, the extent of disease produced by asbestos is conditioned by the smoking habits of the asbestos-exposed population. As is also evident, attempts to control asbestos-related lung cancer can have a maximal impact only if they include successful programs to change smoking behavior as well as efforts aimed at reducing levels of asbestos dust exposure. Elimination of the contribution made by smoking to disease and disability in the worksite is beneficial, even in the absence of synergistic interaction between smoking and workplace exposures. Even with an additive risk for an exposed population, both agents probably contribute to the cancer that develops in an individual, and removing that contribution is an important benefit to that individu- al. In addition, a given degree of impairment produced by an occupational agent will result in less disability in an individual without concomitant lung injury due to smoking than in a worker who has chronic obstructive lung disease due to smoking. The focus on individuals rather than on populations when considering strategies to control occupationally related diseases also helps clarify the concept of a "safe" worksite. The same number of lung cancers may occur in a population with a high smoking prevalence and a low asbestos exposure and ;i population with a low smoking prevalence and a high asbestos exposure. This similarity of population risks does not suggest that the level of acceptable or "safe" dust exposure l:an be adjusted on the basis of the smoking 9 prevalence in the population. It may be reasonable to select nonsmokers for jobs in which smokers would be at much greater risk, but this approach should never be used as a justification for accepting occupational exposure levels that result in risk for those exposed. The goal should always be the elimination of as much of the disease as possible in the working population rather than the lowering of the disease rate to the population norm. Factors in the worksite may also influence smoking initiation and smoking cessation. Chapter 2 of this Report updates the previously reported increased smoking prevalence among blue-collar workers compared with white-collar workers. It also reports two analyses that suggest the workplace may play an important role in smoking behavior. The mean age of initiation reported confirms that the majority of smokers begin smoking prior to or during high school. However, a substantial fraction also begin to smoke after high school. Little is known about the influences that may predispose individuals to become smokers at this age. One of the major life experiences occurring at the same time is entry into the workforce, particularly for blue-collar and clerical workers, and the work environment may be a major factor capable of predisposing an individual toward or away from becoming a smoker. A second important consideration that emerges from chapter 2 is the markedly lower prevalence of successful smoking cessation among blue-collar workers compared with white-collar workers. This difference in cessation is not explained by differences in rates of initiation, and almost equal percentages of current smokers have made a serious attempt to quit and failed. This suggests that the majority of both groups of workers have attempted to become nonsmokers, but blue-collar workers have been less successful. Once again, a potential role for the workplace environment in reinforcing or inhibiting successful cessation may help to explain these differ- ences in the prevalence of former smokers. If a workplace is to be considered "safe," one very important criterion is the absence of exposures to agents that can cause disease. Equally important, however, is that safety should include a work- place that neither encourages initiation nor discourages cessation of cigarette smoking. As demonstrated in the final chapter of this Report, the worksite may provide a focus for the promotion of healthy behavioral change in the workforce, but at a minimum, should not be a focus that encourages behaviors that compromise a worker's health. Summary and Conclusions of the 1985 Report The major conclusions of this Report are clear. They are the following: 10 For the majority of American workers who smoke, cigarette smoking represents a greater cause of death and disability than their workplace environment. In those worksites where well-established disease outcomes occur, smoking control and reduction in exposure to hazardous agents are effective, compatible, and occasionally synergistic approaches to the reduction of disease risk for the individual worker. Individual chapter summaries and conclusions follow. Occupation and Smoking Behavior in the United States: Current Estimates and Recent Trends 1. Among men, a substantially higher percentage of blue-collar workers than white-collar workers currently smoke cigarettes. Operatives and kindred workers have the highest rate of current smoking (approaching 50 percent), with professional, technical, and kindred workers having the lowest rates of current smoking (approximately 26 percent). 2. Among women, blue-collar versus white-collar differences are less pronounced, but still show a higher percentage of current smokers among blue-collar workers. Occupational categories with the highest rates of current smoking include craftsmen and kindred workers (approximately 45 percent current smok- ers) and managers and administrators (38 percent), with the lowest rate of current smoking occurring among women employed in professional, technical, and kindred occupations (26 percent). 3. Occupational differences in daily cigarette consumption are generally modest. For both men and women, the highest daily consumption of cigarettes occurs among managers and admin- istrators and craftsmen and kindred workers. 4. Blue-collar workers (both men and women) report an earlier onset of smoking than white-collar workers. A substantial fraction of smokers report initiation of smoking at ages coincident with their entry into the workforce. 5. Blue-collar occupations have a lower percentage of former smokers than white-collar occupations; this difference is most pronounced among men. Among women, the pattern for homemakers closely parallels that of white-collar women. 6. Black workers have higher smoking rates than white workers, with black male blue-collar workers exhibiting the highest smoking rate. Black workers also have lower quit rates than white workers. In contrast, white workers of both sexes are more likely to be heavy smokers regardless of occupational category. 11 Evaluation of Smoking-Related Cancers in the Workplace 1. Cigarette smoking and occupational exposures may interact biologically, within a given statistical model and in their public health consequences. The demonstration of an interaction at one of these levels does not always characterize the nature of the interaction at the other levels. 2. Information on smoking behaviors should be collected as part of the health screening of all workers and made a part of their permanent exposure record. 3. Examination of the smoking behavior of an exposed population should include measures of smoking prevalence, smoking dose, and duration of smoking. 4. Differences in age of onset of exposure to cigarette smoke and occupational exposures should be considered when evaluating studies of occupational exposure, particularly when the ex- posed population is relatively young or the exposure is of relatively recent onset. Evaluation of Chronic Lung Disease in the Workplace 1. Existing resources for monitoring the occurrence of occupation- al lung diseases are not comprehensive and do not include information on cigarette smoking. Other approaches, such as registries, might offer more accurate data and facilitate research related to occupational lung diseases. Because of the variability in diagnostic criteria for chronic lung disease, in I studies on occupational lung diseases emphasis should be placed on measures of physiological change, roentgenographic abnormality, and other objective measures. 2. Further studies that correlate lung function with histopatholo- gy should be carried out in occupationally exposed smokers and nonsmokers. 3. The effects of cigarette smoking on the chest x ray should be clarified. In particular, the sensitivity of the IL0 classification to smoking-related changes should be further evaluated in healthy populations. 4. To determine if smoking is reported with bias by occupational- ly exposed workers, self-reported histories should be compared with biological markers of smoking in appropriate populations. 5. Mechanisms through which specific occupational agents and cigarette smoking might interact should be systematically considered. Both laboratory and epidemiological approaches should be used to evaluate such interactions. 6. Statistical methods for evaluating interaction require further development. In particular, the biological implications of conventional modeling approaches should be explored. Fur- ther, the limitations posed by sample size for examining 12 independent and interactive effects should be evaluated. The consequences of misclassification by exposure estimates and of the colinearity of exposure variables should also be addressed. 7. The role of cigarette smoking in the "healthy worker effect" requires further evaluation. 8. Approaches for apportioning the impairment in a specific individual between occupational causes and cigarette smoking should be developed and validated. Chronic Bronchitis: Interaction of Smoking and Occupation 1. Chronic simple bronchitis has been associated with occupation- al exposures in both nonsmoking exposed workers and popula- tions of exposed smokers in excess of rates predicted from the smoking habit alone. Among these exposures are coal, grain, silica, the welding environment, and to a lesser extent, sulfur dioxide and cement. 2. The evidence indicates that the effects of smoking and those occupational agents that cause bronchitis are frequently addi- tive in producing symptoms of chronic cough and expectora- tion. Smoking has commonly been demonstrated to be the more important factor in producing these symptoms. Asbestos-Exposed Workers 1. Asbestos exposure can increase the risk of developing lung cancer in both cigarette smokers and nonsmokers. The risk in cigarette-smoking asbestos workers is greater than the sum of the risks of the independent exposures, and is approximated by multiplying the risks of the separate exposures. 2. The risk of developing lung cancer in asbestos workers increases with increasing number of cigarettes smoked per day and increasing cumulative asbestos exposure. 3. The risk of developing lung cancer declines in asbestos workers who stop smoking when compared with asbestos workers who continue to smoke. Cessation of asbestos exposure may result in a lower risk of developing lung cancer than continued exposure, but the risk of developing lung cancer appears to remain significantly elevated even 25 years after cessation of exposure. 4. Cigarette smoking and asbestos exposure appear to have an independent and additive effect on lung function decline. Nonsmoking asbestos workers have decreased total lung capac- ities (restrictive disease). Cigarette-smoking asbestos workers develop both restrictive lung disease and chronic obstructive lung disease (as defined by an abnormal FEV,/FVC), but the evidence does not suggest that cigarette-smoking asbestos 13 workers have a lower FEV,/FVC than would be expected from their smoking habits alone. 5. Both cigarette smoking and asbestos exposure result in an increased resistance to airflow in the small airways. In the absence of cigarette smoking, this increased resistance in the small airways does not appear to result in obstruction on standard spirometry as measured by FEV,/FVC. 6. Asbestos exposure is the predominant cause of interstitial fibrosis in populations with substantial asbestos exposure. Cigarette smokers do have a slightly higher prevalence of chest radiographs interpreted as interstitial fibrosis than nonsmok- ers, but neither the frequency of these changes nor the severity of the changes approach levels found in populations with substantial asbestos exposure. 7. The promotion of smoking cessation should be an intrinsic part of efforts to control asbestos-related death and disability. Respiratory Disease in Coal Miners 1. Coal dust exposure is clearly the major etiologic factor in the production of the radiologic changes of coal workers' pneumo- coniosis (CWP). Cigarette smoking probably increases the prevalence of irregular opacities on the chest roentgenograms of smoking coal miners, but appears to have little effect on the prevalence of small rounded opacities or complicated CWP. 2. Increasing category of simple radiologic CWP is not associated with increasing airflow obstruction, but increasing coal dust exposure is associated with increasing airflow obstruction in both smokers and nonsmokers. 3. Since the introduction of more effective controls to reduce the level of coal dust exposure at the worksite, cigarette smoking has become the more significant contributor to reported cases of disabling airflow obstruction among coal miners. 4. Cigarette smoking and coal dust exposure appear to have an independent and additive effect on the prevalence of chronic cough and phlegm. 5. Increasing coal dust exposure is associated with a form of emphysema known as focal dust emphysema, but there is no definite evidence that extensive centrilobular emphysema occurs in the absence of cigarette smoking. 6. The majority of studies have shown that coal dust exposure is not associated with an increased risk for lung cancer. 7. Reduction in the levels of coal dust exposure is the only method available to reduce the prevalence of simple or complicated CWP. However, the prevalence of ventilatory disabilities in coal miners could be substantially reduced by reducing the prevalence of cigarette smoking, and efforts aimed at reducing 14 ventilatory disability should include efforts to enhance success- ful smoking cessation. Silica-Exposed Workers 1. Silicosis, acute silicosis, mixed-dust silicosis, silicotuberculosis, and diatomaceous earth pneumoconiosis are causally related to silica exposure as a sole or principal etiological agent. 2. Epidemiological evidence, based on both cross-sectional and prospective studies, demonstrates that silica dust is associated with chronic bronchitis and chronic airways obstruction. Silica dust and smoking are major risk factors and appear to be additive in producing chronic bronchitis and chronic airways obstruction. Most studies indicate that the smoking effect is stronger than the silica dust effect. 3. Pathological studies describe mineral dust airways disease, which is morphologically similar to the small airways lesions caused by cigarette smoking. 4. A number of studies have demonstrated an increased risk of lung cancer in workers exposed to silica, but few of these studies have adequately controlled for smoking. Therefore, while the increased standardized mortality ratios for lung cancer in these populations suggest the need for further investigation of a potential carcinogenic effect of silica expo- sure (particularly in a combined exposure with other possible carcinogens), the evidence does not currently establish whether silica exposure increases the risk of developing lung cancer in man. 5. Smoking control efforts should be an important concomitant of efforts to reduce the burden of silica-related illness in working populations. Occupational Exposures to Petrochemicals, Aromatic Amines, and Pesticides 1. The biotransformation of industrial toxicants can be modified at least to some extent by the constituents of tobacco smoke through enzyme induction or possibly inhibition. Both tobacco smoke and some industrial pollutants contain substances capable of initiating and promoting cancer and damaging the airways and lung parenchyma. There is, therefore, an ample biologic basis for suspecting that important interactive effects between some workplace pollutants and tobacco smoke exist. 2. In mortality studies of coke oven workers and gas workers, convincing evidence has indicated that work exposures to oven effluents are causing an excess risk of lung cancer in spite of the lack of adequate information on smoking. Other mortality studies that suggest small increases in smoking-related dis- 15 eases, such as pancreatic cancer in refinery workers, cannot be interpreted without more information on smoking. 3. For bladder cancer, the interactions between smoking and occupational exposure are unclear, with both additive and antagonistic interactions having been demonstrated. 4. The risk of pulmonary disability in rubber workers was increased when smoking and occupational exposure to particu- lates were combined. There are few empirical animal experi- ments that demonstrate interactive effects between cigarette smoking and various industrial chemicals for lung disease. Cotton Dust Exposure and Cigarette Smoking 1. Byssinosis prevalence and severity is increased in cotton textile workers who smoke in comparison with workers who do not smoke. 2. Cigarette smoking seems to facilitate the development of byssinosis in smokers exposed to cotton dust, perhaps by the prior induction of bronchitis. Cotton mill workers of both sexes who smoke have a consistently greater prevalence of bronchitis than nonsmokers. 3. The importance of cigarette smoking to byssinosis prevalence seems to grow with rising dust levels (a smoking-cotton dust interaction). At the highest dust levels, cigarette smoke was found to interact with cotton dust exposure to substantially increase the acute symptom prevalence. 4. Nonsmokers with byssinosis have lower preshift lung function and a greater cross-shift decline in lung function than asymp- tomatic workers, and those workers with bronchitis generally have lower preshift lung function than those without bronchi- tis. In general, smokers have lower lung function than non- smokers among cotton workers, both in those with bronchitis and in those with byssinosis. 5. Although the average forced expiration values measured at the start of a shift are reduced among smokers, the cross-shift decline in function does not seem to be affected by smoking status. 6. The contribution of the acute byssinotic symptoms (grades l/2 and 1) to the subsequent development of what have been termed the chronic forms (grade 3) of byssinosis (which include airways obstruction) is not well documented; however, chronic airflow obstruction has been found more frequently in cotton textile workers than in control populations, and this lung function loss appears to be additive to that caused by cigarette smoking. 7. Cotton dust exposure is significantly associated with mucous gland volume and peripheral goblet cell metaplasia in non- 16 smokers, a pathology consistent with bronchitis. Among ciga- rette smokers, the interaction of cotton textile exposure and smoking is demonstrable for goblet cell hyperplasia. Centrilo- bular emphysema is found only in association with cigarette smoking and pipe smoking. There is no emphysema association found with cotton dust exposure. 8. The evidence does not currently suggest an excess risk of lung cancer among cotton textile workers. Ionizing Radiation and Lung Cancer 1. There is an interaction between radon daughters and cigarette smoke exposures in the production of lung cancer in both man and animals. The nature of this interaction is not entirely clear because of the conflicting results in both epidemiological and animal studies. 2. The interaction between radon daughters and cigarette smoke exposures may consist of two parts. The first is an additive effect on the number of cancers induced by the two agents. The second is the hastening effect of the tumor promoters in cigarette smoke on the appearance of cancers induced by radiation, so that the induction-latent period is shorter among smokers than nonsmokers and the resultant cancers are distributed in time differently between smokers and nonsmok- ers, appearing earlier in smokers. Smoking Intervention Programs in the Workplace 1. Smoking modification and maintenance of nonsmoking status among initial quitters has the promise of being more successful in worksite programs than in clinic-based programs. Higher cessation rates in worksite programs are achieved with more intensive programs. 2. Incentives for nonsmoking appear to be associated with higher participation and better success rates. Further research is needed to specify the optimal types of incentive procedures. 3. Success of a worksite smoking program depends upon three primary factors: the characteristics of the intervention pro- gram, the characteristics of the organization in which the program is offered, and the interaction between these factors. 4. Research is needed on recruitment strategies and participation rates in worksite smoking programs and on Ihe impact of interventions on the entire workforce of a compa :y. 5. More investigations are needed on worksite c:-~arr~~!eristics associated with the success of occupational programs and on comprehensive programs including components such as quit- smoking contests, no-smoking policies, physician messages. and self-help materials in addition to smoking cessation clinics. 6. The implementation of broadly based health promotion efforts in the workplace should be encouraged, with smoking interven- tions representing a major component of the larger effort to improve health through a worksite focus. 18 CHAPTER 2 OCCUPATION AND SMOKING BEHAVIOR IN THE UNITED STATES: CURRENT ESTIMATES AND RECENT TRENDS CONTENTS Introduction Patterns of Employment Smoking Prevalence Daily Cigarette Consumption Age of Initiation Quitting Behavior Recent Changes in Smoking Behavior Birth Cohorts Race Summary and Conclusions Technical Addendum: National Health Interview Survey Estimates References Appendices 21 Introduction Estimates of current smoking behavior reported in this section of the Surgeon General's Report were obtained from the 1978, 1979, and 1980 National Health Interview Surveys (NHIS). A data tape was prepared by the National Center for Health Statistics to allow linkages across surveys, thereby permitting analyses of the com- bined 1978-1980 NHIS (n=49,715). The majority of the analysis presented in this chapter were conducted on the population aged 20 to 64 (n =38,527). Given the large samples and exceptionally high response rates of NHIS, these estimates are generally regarded as the best available estimates of national smoking patterns. To examine recent lo-year changes in smoking behavior by occupation- al category, the 1978-1980 NHIS estimates have also been compared with the 1970 NHIS estimates for selected smoking variables. A more detailed description of the NHIS data base is provided in the Technical Addendum to this section. Patterns of Employment Before characterizing the smoking behavior of the U.S. adult workforce, it will be useful to describe the patterns of employment for men and women. As is shown in Table 1, men are more likely to be employed in professional and technical, management, and blue- collar occupations. Women are more likely to be employed in professional and technical and clerical and service occupations or to be homemakers. Although there was an increase in participation by women in white-collar occupations between 1970 and 1980, the ranking of occupational categories by their relative frequency for both sexes remained about the same in 1980 as it did in 1970. Because of their low relative frequency, farm, sales, and clerical workers, laborers, and service workers have less impact on the smoking behavior of the total male workforce, and female farm workers, laborers, craftsmen and kindred workers, sales workers, and managers and administrators have a modest impact on the smoking behavior of the total female workforce. Smoking Prevalence Surveys have repeatedly shown that blue-collar workers are more likely than white-collar workers to smoke cigarettes (US DHEW 1979). Recent estimates from NHIS continue to substantiate this fimding (Table 2). Overall, smoking rates for blue-collar men (47.1 percent) exceed that of white-collar men (33.0 percent). The same pattern holds for women, but is less pronounced, with smoking rates among blue-collar women (38.1 percent) exceeding that of white- collar women (31.9 percent). Among women, this white-collar-blue- 23 TABLE I.-Estimates of the occupational distribution of men and women, aged 20 to 64 years, United States, 1970-1980 0ccupat10n Men Women 1970 1978-80 1970 197-o Currently employed 87.8 85.1 47 9 57.3 Whitecollar total 39.2 39.2 31.1 40.5 Professional. technical. and kmdred workers Managers and admmistrators. except farm Sales workers Clerical and kmdred workers 14.2 14.9 7.9 11.4 13.3 13 5 2.6 4.9 50 5.3 3.4 3.6 6.8 5.5 17.1 20.6 Blue-collar total Craftsmen and kindred workers Operatives and kindred workers Laborers. except farm Serwce 43.1 40.8 9.0 93 19.9 20 7 0.8 1.5 18.1 14.6 8.0 7.2 5.1 5.5 0.2 0.6 5.4 6.1 10.3 IO.8 Farm 37 2.9 0.5 0.6 Unemployed Usual actwty. homemaking 36 4.1 3.2 4.3 - 52.5 41.7 SOTE The whitecollar. bluecollar. Service. and farm occupational categorres are mutually exclusive. however. those class,fied as "Howmak:ng" or "Unrmployed" may also be classified ,n an occupat,onal group on the baxs of a rrcent or part-tune Job. resulting in a small degree ofoveriap between cate~urles SOURCE Nar~onal Center fur Health Srat~stics. Nat~anal Health Inrenww Surveys. 1970 and 197G1980 `combInedI ,See TechnIcal .4ddendum ) collar difference exists only for the younger age group (aged 20 to 441; for older women (aged 45 to 64) there is virtually no difference in smoking prevalence between these two categories of workers. For men, the highest rates of current smoking occur among craftsmen and kindred workers, operatives and kindred workers, laborers, service workers, and the unemployed. The lowest smoking rates for men occur among professional, technical, and kindred workers, managers and administrators, clerical and kindred work- ers, and farm workers. 24 TABLE 2.-Estimates of the percentage of current smokers by sex, age, and occupation, aged 20 to 64 years, United States, 1978-1980 Occupation Women Men ; otal 20-44 4wz4 Total z&44 45-64 Total 332 34.2 314 409 414 39.8 Currently employed 33.3 34.0 31 a 39 9 409 37 7 Whmz-collar total 319 31.9 319 33 0 33 5 32.2 Professmnal, technical, and kindred workers Managers and administrators, except farm Sales workers Clerical and kmdred workers 26.5 26.1 27 9 257 253 26.6 38.3 37.8 39.2 36 3 38.9 32.2 33.3 33.2 33.5 40.6 42.0 38.0 33.2 33.9 31.4 37.7 36.4 40.4 Blue-collar total 38.1 41.3 31.9 47 1 48.7 43.6 Craftsmen and kmdred workers Operatwes and kindred workers Laborers, except farm 44.6 45.4 43.0' 46.1 47.8 42.6 37.0 40.2 30.8 48.6 50.4 44.5 36.2 43.0' 14.1 o 46.8 47.3 45.1 Service 37.4 39.8 32.7 48.3 46.0 Farm 22.6 28.9 34.5 Unemployed 39.6 33.0 31.3 ' 41.7 351 7.1' 30.4 30.4 47.5 31.5 53.1 Usual actwity. homemakmg 53.9 - 50.8 ' -- 1W cases m the denominator ~unweighted sample8 SOURCE: National Center for Health Statistics. National Health Intenxw Surveys, 1978-1980 icombine& ~See Technical Addendum.1 For women 20 to 64 years of age, the highest smoking rates are found among craftsmen and kindred workers and managers and administrators. Among women 20 to 44 years of age, there are also relatively high smoking rates among operatives and kindred work- ers, service workers, and the unemployed. The lowest rates of current smoking occur among professional, technical, and kindred workers, regardless of age. For homemakers, the category represent- ing nearly 42 percent of all women aged 20 to 64, the prevalence of smoking among those aged 20 to 44 is midway between the 25 prevalence rates for white-collar and blue-collar occupations. How- ever, among women 45 to 64 years of age, smoking rates vary little by occupational group (with the single exception of managers and administrators), with white collar-workers, blue-collar workers, and homemakers all having approximately the same smoking preva- lence. Among men, a more detailed breakdown of smoking by occupation (Table 3) shows that painters, truck drivers, construction workers, carpenters, auto mechanics, and guards and watchmen have the highest rates of current smoking (among occupations having 100 or more cases in the 1978-1980 NHIS), each exceeding 50 percent. In contrast, electrical and electronic engineers, lawyers, and secondary school teachers have the lowest rates of current smoking, all under 25 percent. Among women, waitresses have a noticeably higher rate of current smoking than other groups (Table 4), followed by cashiers, assem- blers, nurses aides, machine operators, practical nurses, and packers and wrappers-all of whom have rates of current smoking that equal or surpass 40 percent. The lowest rates of smoking occur among women employed as elementary school teachers, food service work- ers, bank tellers, and sewers and stitchers. Because of the exemplar role of physicians and nurses in regard to health, their smoking rates are of special interest. Although the sample is relatively small, physicians have among the lowest rates of current smoking (18.1 percent). Among nurses, the pattern of smoking reflects the white-collar-service worker distinction; regis- tered nurses have among the lowest rates of current smoking, but practical nurses have among the highest rates (Table 4). Daily Cigarette Consumption For men, occupational differences in cigarette consumption do not follow the same patterns observed for prevalence. On the average, adult male white-collar smokers consume 24 cigarettes per day, essentially the same as the number of cigarettes consumed by blue- collar smokers (23.3) (Table 5). In virtually all occupational sub- groups, adult men report an average daily consumption exceeding 20 cigarettes. Consumption levels are highest among managers and administrators and sales workers. These numbers represent daily cigarette consumption and need to be interpreted with some caution, as there may be a substantial underreporting of cigarette consump- tion, and the tendency to underreport may not be constant across occupational categories. For women, no difference in consumption is found between white- collar and blue-collar smokers. On the average, white-collar female smokers consume 19.5 cigarettes per day, compared with 19.8 26 `FABLE 3.-Specific occupations with highest and lowest estimates of current smoking, men, aged 20 to 64 years, United States, 1978-1980 Occupatio" Highest rates 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Painters. construction and maintenance (5101 Truck drivers (715) Construction laborers. except carpenters' helpers (7511 Carpenters (4151 Auto mechamcs 14731 Guards and watchmen (9621 Janitors and sextons (903) Assemblers WIZI Electricians 14301 Sales representatives. wholesale trade (282) Lowest rates 1. Electrical and electronic engineers 10121 16.2 2. Lawyers (031) 21.9 3. Secondary school teachers (144) 24.9 4. Accountants (001) 26.8 5. Real estate agents and brokers (270) 27.8 6 Farmers N301) 28.1 55.1 53.6 53.0 50.8 50.5 505 49.8 48.7 48.3 48.1 NOTE: Adapted from Table 22 in Technical Addendum Only thme occupatmns with at least 100 men (aged 20 to 641 in the 197%1980 NHIS are Included Numbers in parentheses denote code values from the U.S. Bureau of the Census 1970 classlticatmn of occupations. SOURCE: National Center for Health Statistics, Natmnal Health Interview Surveys. 197t%1980 (combmed). (See Technical Addendum.) cigarettes for blue-collar smokers, 19.4 cigarettes for homemakers, and 19.0 cigarettes for service workers. Female smokers employed as managers or administrators or as craftsmen or kindred workers report the highest consumption levels, averaging more than 20 cigarettes per day; women employed in professional, technical, or kindred occupations report lower average daily consumption. How- ever, like the men, these differences are not large, averaging fewer than two to four cigarettes per day. The higher the average daily consumption of cigarettes within an occupational group, the more likely it is that this group will also contain a higher percentage of heavy smokers (more than 20 or more than 40 cigarettes a day). Overall, 72 percent of the male smokers employed in white-collar occupations reported smoking more than 20 27 TABLE 4.-Specific occupations with highest and lowest estimates of current smoking, women, aged 20 to 64 years, United States, 1978-1980 OccupatKm Current smokers IpercentageJ Highest rates 1 Wamesses 19151 2 Cashiers 13101 3 Assemblers 1602 4 Nurses aides. orderhes. and attendants ,925) 5 .Machine operatives 16901 6 Practxal nurses 19261 i Packers and wrappers, excluding meat:produce 16431 8 Checkers, exammers. and inspectors; manufacturmg (6101 9 Managers and administrators n e.c. ' 12451 10 Hairdressers and cosmetologtsts 49441 Lowest rates 51.1 44.2 42.9 41.0 41.0 40.3 40.0 39.3 38.0 37.5 I Elementary school teachers (1421 19.8 2. Food service workers 89161 24.6 3 Secondary school teachers 11441 24.8 4 Bank tellers 13011 25.7 5 Sewers and stlrchers 1663: 25.8 6 Regtstered nurses 0751 27.2 7 Child care workers, excludmg prwate households (9421 28.9 SOTE Adapted from Table Z m Technical Addendum Only those occupatmns with at least 1W women (aged 20 to 64 m the lY7&1YR(l SHIS are mciuded Numb+vs m parentheses denote code values from the U S. Bureau of the (`ensus 1970 ciass,ficat~un 01 occupations Sot elsewhere ciawfied SOURCE Satmnal Center for Health Srat,st,cs. National Health Inrerwew Surveys. 1978-1880 ~combmedl See Technical Addendum cigarettes a day, and over 21 percent reported smoking 40 or more cigarettes a day (Table 6). Comparable figures for blue-collar smokers are 72 percent and 18 percent, respectively. Among adult women (Table 71, the percentage of heavy smokers is generally lower than for men, with women employed as craftsmen or kindred workers reporting higher percentages of heavy smoking than other female occupational groups. The pattern for homemakers closely parallels that of white-collar workers, but service workers have slightly lower rates of heavy smoking than white-collar workers. For both men and women, and across virtually all occupational groups, smokers 45 years of age or older are more likely 28 TABLE B.-Estimates of average daily cigarette consumption among current smokers by sex, age, and occupation, aged 20 to 64 years, United States, 1978-1980 Occupatuxl women .Men TOtal 2&44 4%64 Total 2M4 45-a Total 19.3 19.1 19.6 23.2 22.2 25 1 Currently employed 19 2 19 0 19 a 23 4 22 4 25.6 White-collar total 19 5 19 1 20 4 24 0 "2 6 26.9 Professional. technical, and kindred workers Managers and administrators. except farm Sales workers Clerical and kindred workers 18 3 17 9 19 3 215 19 8 25 4 21 1 206 22.0 26 2 25.2 28.1 19.1 18.0 21.0 25.1 22.7 30.3 19.6 19.4 20.1 22.3 21.8 23.2 Blue-collar total 19.8 19.9 19.4 23.3 22.6 25.1 Craftsmen and kindred workers Operatives and kindred workers Laborers, except farm 22.4 22.3 22.5 24.4 23.7 26.1 18.4 22.4 21.7 24.2 25.6 21.5 23.6 service 18.9 21.5 24.7 Farm 19.2 18.9 19.0 18.0 21.2 19.4 19.5 18.1 19.0 18.0 21.2 19.4 18.0 Unemployed Usual activity, homemaking 20.9 215 - 20.9 19.9 20.2 20.1 - 21.7 21.3 26 0 19.4 SOURCE: Natmnal Center for Health Statistln, ?iational Health Internew Surveys. 1978-1980 icomblnedl. (See Technical Addendum.1 to report a higher percentage of heavy smokers than their 20- to 44- year-old counterparts. Age of Initiation Men employed as blue-collar workers initiate smoking approxi- mately 14 months earlier, on the average, than men employed in white-collar occupations (Table 8). The earliest ages of initiation are 29 TABLE 6.-Estimates of the percentage of current smokers who smoke more than 20 or more than 40 cigarettes daily, by age and occupation, men, aged 20 to 64 years, United States, 1978-1980 Total 20.44 45-64 Occupation 220 >a 220 240 220 240 Total 70.6 18.8 66.5 15.7 74.8 24.5 Currently employed 71.4 19.1 69.3 16.1 76.0 25.7 Whit&collar total 72.1 21.1 69.5 16.9 77.6 29.5 Professional, technical, and kindred workers Managers and administrators, except farm Sales workers Clerical and kindred workers 66.5 17.3 61.9 12.9 76.7 26.8 79.1 24.5 77.7 20.0 81.6 33.3 74.2 23.7 70.0 17.8 83.0 36.1 64.2 17.2 64.1 16.2 64.6 19.0 Blue-collar total 11.8 18.3 70.1 16.1 76.3 24.1 Craftsmen and kindred workers Operatives and kindred workers Lalmers. except farm 75.3 21.2 73.6 18.7 79.6 27.2 694 15.6 68.3 13.5 72.1 21.4 65.7 15.1 63.1 14.2 74.6 17.9 Service 66.6 16.0 63.0 11.5 73.6 24.7 Farm 62.1 16.5 56.3 ' 16.6 ' 16.4 ' Unemployed 65.9 16.3 61.3 12.9 68.0 ' 81.1 ' - 27.6 ' Usual actwlty. homemakmg - - - - ' i 1W cases in the denominator lunwelghted sample). SOURCE Natmnal Center for Health Statistics. Natmnal Health lnterv~ew Surveys. 197&1980 icombined &e Techmcal Addendum 1 reported by men employed as laborers (16.5 years), operatives or kindred workers (16.6 years), or craftsmen or kindred workers (16.8 years). Men employed in professional, technical, or kindred occupa- tions, or as managers or administrators, sales workers, or clerical or kindred workers report later onset of smoking, ranging between 17.7 and 18.1 years of age. For women, blue-collar and service workers report a somewhat earlier onset of smoking than white-collar workers or homemakers 30 TABLE `I.-Estimates of the percentage of current smokers who smoke more than 20 or more than 40 cigarettes daily, by age and occupation, women, aged 20 to 64 years, United States, 1978-1980 Total 20-44 45-64 Occupation 2 20 _> 40 > 20 140 120 240 Total 58.6 114 57.1 10.8 61.3 12.4 Currently employed 58.5 113 57.2 10.9 61.7 12.3 White-collar total 59.4 118 57.8 11.0 63.2 13.8 Professional. technical, and kindred workers Managers and administrators. except farm Sales workers Clerical and kindred workers 52 8 10 8 52.0 9.8 55.0 1B.8 63.4 15.6 59.0 14.6 71.8 17.5 56.8 99 55.0 6.5 59.9 * 16.0 o 61.6 11.5 60.6 11.3 11.5 18.2 * 10.5 50' 11.9 5.5 ' 14.4 10.9 643 12.0 Blue-collar total 62.0 11.2 61.2 64.0 10.6 Craftsmen and kindred workers Operatives and kindred workers Laborers, except farm 70.0 18 2 67.4 * 75.5 * 18.1' 60.4 99 60.3 60.7 8.4 56.7 ' 6.0 * 55.2 ' 70.9 * 15.6 o Service FarIll 54.6 11.6 53.6 57 1 65.4 ' 4.9 ' 14.8 113 63.5 ' 802' Unemployed 62.1 61.7 64 4 * Usual activity. homemaking 59.1 58.4 60.0 11.0 0.0 * 17.0 o 11.8 * s: 100 cases in the denommator iunweighti samplel SOURCE. National Center far Health Statmtics Natmnal Health Inrerwew Surveys. 197%1980 lcombmedi (See Technical Addendum 1 (about 6 months). The earliest age of initiation occurs among women employed as laborers (17.4 years of age) or operatives or kindred workers (18.5 years of age), and the latest age of initiation occurs among women employed in professional, technical, or kindred occupations (19.4 years of age). Across all occupational categories, men report an earlier age of initiation than women; this difference is most pronounced within the 45 to 64 age group. 31 TABLE %-Estimates of average age of initiation of smoking among current and former smokers by sex, age, and occupation, aged 20 to 64 years, United States, 1978-1980 0ccupat10n Women Men Total 2M4 45-64 Total 2b44 45-64 Total Currently employed White-collar total Professional. technical, and kindred workers Managers and administrators, except farm Sales workers Clerical and kindred workers Blue-collar total Craftsmen and kindred workers Operatives and kindred workers Laborers, except farm Service Farm Unemployed Usual act1wty. homemaking i9.0 18.6 18.5 18 2 18.1 18.0 18.2 17.6 17.6 21.2 21 .o 20.9 21.2 20.7 21.2 20.9 21.3 22.9 21.1 16.5 21.4 18.4 21.1 21.3 17.2 17.3 17.9 18.1 17.8 17.8 17.7 16.7 16.8 16.6 16.5 17.2 17.0 169 16.9 17.0 17.6 17.6 17.5 16.5 16.5 16.4 16.4 169 16.4 16 4 17 6 18.7 18.0 18.4 18.2 SOURCE Natmnal Center for Health Statistics. Natmnal Health Interview Surveys. 197&1980 tcombinedl. O.O51 samples. As is reported in Table 19, among men one difference was detected for smoking prevalence, but this difference showed an inconsistent pattern across samples. Among women employed as managers or administrators, there was a remarkable 10.7 percentage point decline in smoking prevalence between 1978 and 1980, which is over twice as large as the lo-year net decline between 1970 and 1980 (see Table 11). One possible explanation for this large 3-year decline in smoking prevalence is random fluctuation in the survey estimate. However, if this short-term time trend for female managers and administrators is valid, it would be of considerable interest. Given that the 197C 1978 comparisons already show female managers and administrators to be quitting at a relatively high rate (when compared with other 58 TABLE 20.-Estimates of the percentage of current smokers who smoke 40 or more cigarettes daily by sex, occupation, and NHIS sample (1978, 1979, 19801, aged 20 to 64 years Men Women P P Occupation 1978 1979 1980 value 1978 1979 1980 value Whitecollar total 23.6 21.0 19.3 NS' 10.1 11.4 14.0 NS Professional, technical and kindred workers Managers and administrators, except farm Sales workers Clerical and kindred workers 20.9 17.0 14.2 NS 90 8.6 14.1 NS 25.8 23.9 246 31.0 21.2 2u.5 16.0 15.2 NS 9.4 17.3 .05 16.0 20.5 15.4 11.8 NS Blue-collar total 18.7 11.7 NS Craftsmen and kindred workers Operatives and kindred workers Laborers, except farm 19.4 22.7 16.9 13.9 13.4 20.5 174 19.1 16.6 13.6 15.9 11.5 - 22.2 NS 15 7 NS 3.4 NS 98 NS 11.3 NS 16.1 NS 11.0 NS .2 NS 11.1 NS . 13.0 13.1 10.5 22.9 7.1 . 11.4 , 12.9 NS 13.8 11.1 NS 18.9 o . Service 18.9 10.5 NS Farm 17.2 . o Usual activity, homemaking - - 10.4 10.6 ?? ' Nor statistically significant (p>O.O5) `Not enough cases for valid chisquare test (the expected cell frequency for one or more cells wa8 less than five). female occupational groups), it would seem prudent to closely monitor the smoking patterns of this occupational cohort of women. In regard to heavy smoking (see Table 20), no sample differences were found for men. Among female salesworkers, there was a striking 500 percent proportionate increase between 1978 and 1980 in the percentage of smokers of 40-plus cigarettes a day, which again must be interpreted with caution. Overall, 50 separate chi-square tests were examined, and 3 were statistically significant at p 5 0.05- which would be expected solely on the basis of chance. Detailed presentations of NHIS estimates of smoking prevalence are provided in Table 21 (1978-1980) and Table 22 (1970-1980 net change) for all occupational codes with 100 or more cases in the 59 combined 1978-1980 NHIS (unweighted sample). In Table 23 are provided a comprehensive list of all occupational codes with 100 or more cases in the 1978-1980 NHIS and the estimated percentage of men and women, aged 20 to 64 years, who are employed in each occupation. Figures 13 through 18 depict results from birth cohort analyses that were briefly summarized in the text, including male professional, technical, and kindred workers (Figure 13), managers and administrators (Figure 141, craftsman and kindred workers (Figure 151, and operatives and kindred workers (Figure 161, and female professional, technical, and kindred workers (Figure 17), and clerical and kindred workers (Figure 18). 60 TABLE 21.~Estimates of the percentage of current smokers by selected occupations, aged 20 to 64 years, united states, 197S1980 Occupation Men Women Total WHITEXDLLAR Professional, technical, and kindred workers Accountants (001) Electrical and electronic engineers (012) Law-j-era (031) Personnel and labor relationa workers (056) Physicians, medical and arteopathic #X6) Regard nu- (076) Social workers WO) Elementary school teachers (142) Secondary school teachers (144) Managers and administrators. except farm Bank offxers and fmancial managers (202) office managers n.e.c.' (220) Of?kiels and administrators, public administrators n.e.c. ' (222) Restaurant. cafeteria, and bar managers (230) Sales managers and department heads, retail trade (231) Managers and administrators n.e.c. (246) Sake workers lnsuranw agents, brokers, and underwriters (265) Real estate agents and brokers (270) Sales representatives, manufacturing industries (281) Sales representatives, wholesale trade (282) Sales clerks, retail trade (283) Salesmen, retail trade (284) Clerical and kindred workers Bank tellers (301) Bookkeepemao5) Cashiers (310) Estimators and investigators n.e.c. (321) Expediters and production controllers (323) Computer and peripheral equipment operators (34.3 Postal clerks (361) Receptionists (364) Secretaries n.e.c. (372) Stock clerks and storekeepers (381) Typists (391) Clerical workers, miscellaneous (394) Clerical workers, not specified (395) 26.8 30.4 28.2 16.2 33.0 ' 16.4 21.9 21.4' 21.8 30.9 ' 37.9 ' 34.1 18.1' 18.2' 18.1 46.4 ' 27.2 28.0 42.6' 37.3' 39.0 18.8 ' 19.8 19.6 24.9 24.8 24.9 35.9 43.9 ' 28.1 ' 25.4' 32.9 45.0 22.2' 20.3' 21.6 53.9 ' 52.4' 53.3 28.7 ' 33.8' 30.5 36.2 38.0 36.6 41.1' 21.8 41.0' 48.1' 41.1 36.4 43.2 32.9 ' 41.2 48.1 45.8 1 47.9 39.6 30.5 33.7 42.6' 39.3' 42.4 0.0 ' 42.9 ' 43.4 ' 28.4' 44.9 1 31.3' 38.2' 56.5' 61.7 ' 38.1 10.3 ' 34.9 ' 33.5' 25.7 36.5 44.2 35.9 ' 43.1' 24.7 37.1 44.1 33.1 44.3 44.7 ' 38.5 24.9' 33.9 31.0 31.8 30.9 31.2 31.2' 35.3 33.0 31.7 33.3 33.6 28.4' 29.1 61 TABLE 21.-Continued Occupation Men WOlIX?tl TOtal BLUE-COLLAR Craftamen and kindred workers carpenters (415) Electricians (430) Foremen n.e.c. (441) Machinists (461) Automobile mechanics (473) Heavy equipment mechanics. incl. diesel (481) Painters, cmet~ction and maintenance (510) Plumbers and pipe fitters (522) Operatives, except transport Aeeemblera (602) Checkers, examiners, and inepectore; manufacturing (610) Packers and wrappers. except meat end produce (643) Sewers and stitchers (663) Welders end flamecutters V%O) Machine operatives, miecellaneoua, specified @90) Machine operatives, not specified (692) hGcellaneoue operatives (694) Tramport operatives Bus drivers (703) Deliverymen and routemen (705) Fork lift and tow motor operatives (706) Truck drivers (715) 50.8 70.4 ' 46.3 100.0' 42.7 43.4 53.0 ' 50.5 54.7 L 47.4 49.5 ' 55.1 61.4' 47.1 39.1' 48.7 42.9 45.8 39.3 47.2 1 40.0 42.3 26.9 ' 25.8 25.9 47.8 28.9 ' 46.8 43.7 41.0 42.7 42.9 ' 50.3 ' 44.7 43.3 40.1' 42.4 50.3 ' 35.2 L 42.7 42.4 46.1' 42.7 49.3 ' 35.4 ' 48.7 53.6 62.7 ' 53.7 Workers, except farm Construction laborers, except carpenters' helpers (751) 53.0 52.8 ' Freight and material handlers (753) 42.5 34.6 ' Gardeners end groundskeepers, except farm (755) 46.1 43.7 1 Stock handlers (762) 37.4 ' 34.5 I Laborers, not specitied (785) 38.0 46.3 ' Farm workers Farmers @Ol) Farm laborers, wage workers (822) 28.1 29.9' 28.3 39.0 25.6 ' 34.9 50.9 48.5 44.2 43.7 50.5 47.7 54.0 47.1 45.3 42.3 53.0 41.6 45.9 36.6 39.0 62 TABLE 2l.--Continued Occupation Men women Total Service workers Cleaners and charwomen K102) Janitors and sextons (903) Cooks, except private household (912) waiters (915) Food service workers n.e.c.`, except private household (9161 Nursing aides, orderlies, and attendants (925) Practical numes (926) Child care workers, except private household (942) Hairdressm and cmmetilcgista KM) Guards and watchmen (962) Policemen and detectivea (964) Maids and servants, private household (934) 49.8 ' 49.8 45.0 ' 44.7 ' 42.1' 24.6 27.0 46.2 ' 41.0 42.0 55.3 ' 40.3 41.2 0.0 ' 28.9 63.2 ' 37.5 50.5 35.7 ' 44.5 51.5 ' 55.0 ' 32.1 30.5 39.0 ' 31.1 51.1 38.0 47.1 35.9 50.4 28.4 39.0 47.3 45.1 33.1 ' < 100 caea in the denominator (unweighted sample). `Not elsewhere claarified. SOURCE: National Center for Health Statistics Health Interview Surveya. 1979-1980 kombined). 63 TABLE 22.~Estimates of the net change in smoking prevalence by sex and selected occupations, age 20 to 64 years, United States, 1970-1980 Occupation Men Women Total WHfITrcoLLAR Professional, technical, and kindred workers Accountants @01NOO) Electrical and electronic engineen, @12)~ Personnel and labor relations workers KJ56M154) Physicians, medical and osteopathic @65M153,162) Regietered nuraea (075M150) Social workers (lOOM171) Elementary school teachers (142M182) Secondary school teachera (144)/(163) -6.8 W83) 4.0 Managers and adminiatratars, except farm OtXcinla and administrators, public admhiatrators n.e.c.' (222M270) Managers and administratoza n.e.c. @45M2SO) Sales workers Insurance agents, brokers, and underwriters ww(385) Real estate agents and brokers (27OM393) Clerical end kindred workers Bank tellers (301)/(3051 BaAkeepers @05v(3101 Cashiers (310)/(312) Postal clerks 061M340) lleceptionti 064K?41) Secretaries n.e.c. (372M342) Stock clerks and storekeepers 031M350~ Typists @91v060) BLUECOLLAR -8.9 -8.5 ' + 10.2 ' +3.8 1 -10.5 ' -3.5 16.3 ' -8.1 -9.8 ' 14.6 -45.7' -1.3' +2.6 ' -1.0 ' - -0.8 ' -12.0 -52.8 I Craftsmen end kindred workers Carpenters (415)/(411) -4.1 Electricians (43OM421) +3.9 Foremen n.e.c. M41V(4301 -8.9 Machiniste (46M465) 4.7 Automobile mechanics (473M472) 4.5 Painters. construction and maintenance (510)/(495) -17.1 Plumbers and pipe tittera (522M510) 4.1 -0.4 -18.0 ' -9.2 -29.3 ' -10.0 -12.3 -11.4 + 11.0 ' +7.7 -1.2 -2.6 -1.3 -2.4 A.6 -4.1 -2.0 7.3 ' -15.4 -4.2 -7.3 -22.6 ' -11.3 +3.8' 4.8 -9.0 -11.3 4.2 -3.9 +3.7 +3.5 -15.7' -5.7 -10.6 -9.8 -6.1 -8.0 8.2 ' -12.2 4.9 -7.1 +50.3' -3.7 +33.4 ' -3.9 - -8.9 -7.3 ' -6.5 +22.3' -4.3 + 17.7 ' -17.3 - -4.1 64 TABLE 22.-Continued Occupation Men Women Total Operatives, except transport Assemblers @02)/(631) Checkers, examiners, and inspectors, manufacturing (61OM643) Packera and wrappers, except meat and produce (643)/(693) Sewers and stitchers @63)/(7&V Welders and flame-cutters S8OM721) -7.0 -2.0 -4.6 -8.7 -0.3 -4.4 -8.0 ' -18.8' -3.5 +2.6 -0.5 -12.7' -0.7 -0.8 -3.9 Transport operatives Bus drivers (703N641) Deliverymen and routemen (705V(650) +6.6' +11.2' +4.0 -11.6 f 10.0 ' -10.9 Farm workers Farmers @Ol)/@O) -44 +9.3' 3.4 Farm laborers, wage workers (822M902) -14.5 -6.2 ' -14.8 Service workers Cleaners and charwomen @02V@24) Cooks, except private household (912M825) Janitors and sextona (903)/@34) WaiterE (915)/@75) Practical nursea (926)/(&2) Hairdressers and ccemetolcgiste (944MJ343) Guards and watchmen (962M851) Policemen and detectives G64M853) -14.3' -19.2 ' -1.9 -2.9 ' -31.1' -5.4' 5.5 -3.2 -2.3 -1.6 -5.5 -9.4 +10.4' -0.4 -9.0 -8.7 i4.3 +3.7 -7.4 -8.0 +17.6' -6.9 +24.4' -2.0 ' < 100 - in the denominator (unweighted sample). `Not elsewhere classified. SOURcE: National Center for Health Statistica Health Interview Surveys. 1978-1980 (combined). 65 TABLE 23.~Estimates of percentage of U.S. population, aged 20 to 64 years, in selected occupations, 1978-1980 Occupation Men Women Total Professional, technical, and kindred workers Accountants (001) Electrical and electronic engineers (012) Lawyers (031) Personnel and labor relations workers (058) Physicians, medical and osteopathic (065) Registemd nurse4 (075) Social workers (100) Elementary echo01 teachera (142) Secondmy school teachers (144) Managers and adminiatratora, except farm Bank officers and financial managers (202) G&e managers n.e.c.' (220) Gflkide and administrators; public administratora n.e.c. (222) Restaurant, cafeteria, and bar managem (230) Sales managers and department heads, retail trade (231) Managers and adminintratora n.e.c. (245) S&a workers Insurance age&, brokers, and underwritera w5) Real estate agents and brokers (270) Sale9 representatives, manufacturing industries (281) Sales representatives. wholesale trade (282) S&a clerks, retail trade (283) Salesmen, retail trade (284) Clerical and kindred workers Bank tellers 001) Bcdkeepem 005) Caahiera (310) Estimator, and investigatora n.e.c. (321) Expediters and production controllers (323) Computer and peripheral equipment operatora @43) Postal clerks (361) Receptionist8 (364) Secretark n.e.c. (372) Stock clerks and storekeepers (381) Typll (391) Clerical workers, miscellaneous (394) Clerical workers, not specified (395) 1.2 0.7 1.0 0.6 0.0 0.3 0.7 0.1 0.4 0.5 0.4 0.4 0.5 0.1 0.3 0.1 2.0 1.1 0.2 0.4 0.3 0.5 2.1 1.3 1.0 1.0 1.0 0.7 0.1 0.4 0.3 0.5 0.2 0.4 0.5 0.2 0.3 0.3 0.4 0.4 0.2 0.3 9.4 2.4 5.8 0.6 0.2 0.4 0.6 0.4 0.5 0.9 0.2 0.5 0.9 0.1 0.5 0.5 1.0 1.6 0.5 0.1 0.3 0.0 0.6 0.3 0.3 2.7 1.5 0.2 1.5 0.9 0.3 0.4 0.4 0.4 0.2 0.3 0.4 0.4 0.4 0.4 0.2 0.3 0.0 0.6 0.3 0.1 5.5 2.9 0.6 0.4 0.5 0.1 1.1 0.6 0.3 1.1 0.7 0.1 0.7 0.8 66 TABLE 23.4ntinued Occupation Men Women Total BLUJZ-COLLAR Craftsmen end kindred workers carpenters (415) 2.4 0.0 1.2 Electriciana (430) 1.0 0.0 0.5 Foremen n.e.c. (441) 3.0 0.4 1.7 Machininta (461) 1.1 0.0 0.5 Automobile me&mica (473) 1.7 0.0 0.8 Heavy equipment mechanics, incl. diesel (481) 1.2 0.0 0.6 Paintew, construction and maintenance (510) 0.7 0.1 0.4 Plumbers and pipe fitters (522) 0.8 0.0 0.4 Operativea, except transport Assemblers (602) Checkers, examiners, end inspectors, manufacturing (610) Packers and wrappers, except meat and produce w.3 0.8 1.1 0.9 0.7 0.7 0.7 Sewers and stitchers (663) Welders and flamecutters (680) Machine operatives. mieceIlaneou8. specified SQO) 0.3 0.1 1.0 1.7 0.4 0.7 0.6 1.3 0.1 Machine operatives, not specified (692) Miacellaneoua operatives (694) 0.9 0.1 0.3 0.5 0.7 0.5 1.3 0.2 0.5 Transport operativea Bus drivers (703) Deliverymen and mutemen (705) Fork IiR and tow motor operatives (706) Truck drivers (715) 0.3 0.3 0.3 0.7 0.1 0.4 0.6 0.0 0.3 3.0 0.0 1.5 Workers, except farm Con&uction laborers, except carpenters' helpera (751) Freiiht and material handlers (753) Gardeners and groundskeepers, except farm (756) Stock handlers (762) Not specifd labotera (786) 1.2 0.0 0.6 0.8 0.1 0.4 0.7 0.0 0.4 0.5 0.2 0.3 0.7 0.1 0.4 Farm workers Farmers (801) Farm laborers, wage workers (822) 2.0 0.7 0.2 1.1 0.3 0.5 67 TABLE 23.-Continued Occupation Men Women Total Service workers Cleaners and charwomen @02) 0.5 0.7 0.6 Janitors end sextons WW 1.3 0.4 0.8 Cooke, except private household (912) 0.6 1.0 0.8 waiters (915) 0.2 1.4 0.8 Food service workera n.e.c.. except private household (916) Nursing aides. orderlies, and attendante (925) Practical nurses (926) Child care workers, except private 0.1 0.6 0.4 0.2 1.3 0.8 0.1 0.7 0.4 household (942) Hairdressera and comnetologiste (944) Guards and watchmen (962) Policemen and detectives (964) Maids and servants, private household (984) 0.0 0.6 0.3 0.1 0.8 0.4 0.7 0.2 0.5 0.9 0.1 0.4 0.0 0.7 0.4 All other occupations 30.2 15.9 22.7 Not in labor force 10.9 38.6 25.3 NOTE Includes all occupational codes with at lea& 100 ce&?a (aged 20 to 641 in the 1978-1980 HIS (unweighted aample). `Not ekwhere cla.ktied SOURCE. National Center for Health Statistics Health Interview Surveys, 197B1980 (combined). 68 Year FIGURE 13.-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. men employed in professional, technical, and kindred occupations, 1909-1978 SOURCE. Data from Natmnal Center for Health Statistics. National Health Interview Surveys, 1978-1980 lcombinedl 69 3 / L d 1, 0 `& G ~I//> - ! - f - -.LiLz!zzX- - 2. 1900 1910 19x) 1930 1940 1950 1960 1970 1960 FIGURE 14.-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. men employed as managers and administrators, 1900-1978 SOURCE. Data from Nat,onal Center for Health Statistxs. National Health Inter-&w Surveys, 197b1980 icombmed) 70 53 , i I I I 1931-1940 lso0 1910 1920 1930 1940 1950 1960 1970 1980 FIGURE 15.-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. men employed as craftsmen or in kindred occupations, 190&1978 SOURCE: Data from National Center for Health Statistics. National Health Interview Surveys. 19761980 (combined). 71 .e1901-1910 1 / I / / J j ; 1900 1910 1920 1930 1940 1950 1960 1970 1990 ( j :,I !I I i 1. I ,r--r- `, \lT FIGURE 16.-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. men employed as operatives or in kindred occupations, 1900-1978 SOURCE. Data from National Center far Health Stathtice, National Health fntetiew Surveys. 197b1980 Icombined) 72 1931-1940 -I FIGURE 17.-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. women employed in professional, technical, or kindred occupations, 1900-1978 SOURCE: Data from National Center for Health Statistics. National Health Interview Surveys, 1978-1980 (combmed). 157-964 0 - 86 - 4 73 25 20 15 10 5 0 H-19401 ' --;,,;i 4 / ~1901-1910 A I I FIGURE l&-Changes in the prevalence of cigarette smoking among successive birth cohorts of U.S. women employed in clerical or kindred occupations, 1909-1978 SOURCE: Data from National Center for Health Statistics. National Health Interview Surveys. 19751980 bmhind). References U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health: A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health. DHEW Pub. No. (PHS)79-50066,1979. U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1970. U.S. Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control, National Clearinghouse for Smoking and Health, DHEW Pub. No. (HSMl73-8727, June 1973. U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1975. U.S. Department of Health, Education, and Welfare, Public Health Service, Centers for Disease Control, National Clearinghouse for Smoking and Health, June 1976. 75 APPENDICES Appendix A The two tables in appendix A describe the smoking habits of more than 18,000 employees from 16 components of the General Electric Company in various parts of the United States (personal communica- tion, T. R. Casey and H. R. Richards, General Electric Company, June 1985). The data are presented to demonstrate the differences that can exist by payment category within the same workforce. The employees categorized as exempt are managers and specialists in various professions who are not bound by the provisions of the wage and hours law. Nonexempt personnel are generally clerical and secretarial workers, and hourly personnel are skilled and semi- skilled people who work in manufacturing. It is clear that substan- tial differences in smoking habits exist between men and women, between older and younger workers, and among employees in the three payment classifications. 78 TABLE Al.-Sample of smoking habits of employees of 16 workforce components of the General Electric Company, May 1985 category Nonsmokers Smokers Examokers Women MelI Women Men Women Mel-l - 145 145 545 >45 545 >45 545 >45 545 >45 545 145 Total 5 20 c&/day No. of employees Years of smoking Average years >20 cigs/day No of employees Years of smoking Average years 264 29 1.208 404 53 15 320 286 33 9 252 266 3.139 721 485 5,172 9,979 232 205 2.050 5.106 13.6 32.3 16.2 349 7.0 22.8 6.1 19.2 9 4 122 140 6 3 75 163 522 154 135 2,175 4,363 56 66 820 3,527 17.1 33.8 17.8 31.2 9.3 22.0 10.9 21.6 2 20 eigslday No. of employees Years of smoking Average years >20 cigslday 370 135 528 94 188 79 273 83 75 29 131 91 2,076 2,441 2,376 3,631 2,810 555 518 1,111 1,919 13.0 30.1 13.3 33.9 7.4 17.9 a.5 21.1 No. of employees 47 20 130 35 11 9 57 40 349 Years of smoking 863 666 2.021 1,220 161 226 761 1,092 Average years 18.4 33.3 15.5 34.9 14.6 25.1 13.4 27.3 (x1 0 TABLE Al.-Continued Nonsmokers Smokers Ex-smoken WCllllen Men Women Men Women Men category 545 .45 5 45 -145 545 -,45 145 .45 545 >45 < 45 .45 TVtal Hourly < 20 c&/day No of employees 1.521 1,153 1.779 582 1,211 674 1,556 716 219 168 501 507 10.5x9 Years of smoking 17,247 21,786 22,287 25,942 2,036 3.662 4.579 11.986 Average years 14.2 32.3 14.3 36.2 9.3 21.9 9.1 23.6 :a 20 cigsiday No. of employees 155 91 405 259 35 34 144 233 1,3.x Years of smoking 2,714 3,083 7,520 9,716 482 870 1,706 6,265 Average years 17.5 33.9 113.6 37.5 13.8 25.6 11.8 26.9 Total employees 2,155 1,317 3,515 1.080 1,663 SOURCE: General Electric Campany Corporate Medical Operation (1985) 883 2,608 1,519 379 252 1.160 1,300 18.031 TABLE AL.-Smoking habits of General Electric employees in various employment categories Men Women 545 years old >45 years old <45 years old i45 years old category Never Current Former Never Current Former Never Current Former Never Current Former Exempt Total 61.1 22.4 16.5 32.1 35.1 34.1 72.3 17.0 10.7 48.3 31.7 20 < 20 cigarettes/day 12.4 77.1 67.1 62.0 85.5 84.6 78.9 75 ) 20 ciaarettes/dav 27.6 22.9 32.9 38.0 14.5 15.4 21.1 25 Nonexempt Total 5 20 cigarettes/day > 20 clgaretteslday Hourly Total <' 20 cigarettes/day `,, 20 cigarettes/day 47.2 36.0 16.8 27.4 344 38.2 53.6 34.0 12.4 496 36.4 14.0 67.7 69.7 70.3 69.5 80.0 87.2 79.8 763 32.3 30.3 297 30.5 200 12.8 20.2 23.7 40.6 44.7 14.7 25.7 42.4 32.2 48.4 43.5 8.1 54.4 361 9.5 79.4 77.7 73.4 685 687 862 881 83.2 20.6 22.3 26.6 31.5 11.3 13.8 11.9 168 Appendix B The data in appendix B, portrayed in bar graph format (personal communication, L. Garfinkel, October 19851, represent smoking characteristics by age, occupation, and sex of the more than 1.2 million men and women studied in the American Cancer Society's Cancer Prevention Study II. This study, initiated in 1982, is the largest known prospective study of its kind. The data on smoking and occupation were collected at the time of enrollment. Occupation- al categories were determined from answers to open-ended questions and, therefore, may not correspond to U.S. Department of Labor categories. These data provide comparative information on smoking habits within occupational categories to demonstrate the variability that exists between the estimates derived from individual research designs and the national probability estimates derived from surveys. The number above each bar represents the total population for each age and occupational category. The first graph presents the percent- ages for all occupations; the occupational categories compared are the following. Aide Architect Assembler $$Im$ve pr~e;yan ~l~rlgyService Construction iii%gry Disabled Doctor Education Electrician Engineer Executive Factory Worker Farmer Fire Fighter I??myYparation Heavy Equipment Hospital Worker Housewife Law Enforcement Lawyer l&&me Operator Ea&itetrance Military Miner Nursing Office Worker Painter Pharmacy gmE&yd Printing Postal Service Printing kurogtiorker Sales Social Worker Steel Mill Technician zEFttkne Operator Truck Driver Unemployed gEVfe;/ WElltESS Woodworker 82 00 ALL OCCUPATIONS 00. AIDE M- 10 - B 00 50 40 JO 20 !O 0 Do ARCHITECT I, / / / I / `8 ,* r I-. I I / I I/ j I' llil ASSEMBLER AUTOMOTIVE I-- - Mm W- too BARBER/BEAUTICIAN 1 un W- tm 90 CIVIL SERVKX Mm W- too 91) CONSTRUCTION so CLERGY so DATA ENTRY 80 -' L3 Pmudaw rm 90 EDUCATION 90 ELECTRICIAN I K! ENGINEER m EXECUTIVE ._ m FACTORY WORKER a0 70 1 i:.i Ppdagu IM a3 00 90 FIRE FIGHTER FOREMAN Jb "--' ,i,Y so HEAW EQUIPMENT bl 70 J I-- - tm r'.l WDmdaor 00 HOSPITAL WORKER 90 I I: LAW ENFORCEMENT *,* ( I.`-' I " W 0 LAWYER I MACHINE OPERATOR 90 MAINTENANCE un W- rm MANAGER ./ :, I iiT /- 1 ,- . . ml 557 MILITARY 1 w MINER 80 a0 NURSING w N h - Do OFFICE WORKER co 70 00 00 4 30 20 10 0 lblsSWO-Iccn PAINTER yn - tm 90 PHARMACY PHOTO AND PRINTtNG 1 I-- - 40-e x-60 oo-00 m-m 00 POSTAL SERVICE ml- PRINTING 6.2 RAILROAD WORKER Mm W- tm 00 REAL ESTATE 100 E3 plpmdaor Do SALES Mm W- `ml I SOCIAL WORKER ( 100 00 176 STEEL MILL Mm W- Ial RI TECHNICIAN Men W- Irn w , ,,I TEXTILE TELEPHONE OPERATOR 90 881 TRUCK DRIVER m UNEMPLOYED O"i WAITER/WAITRESS 1 1 WOOD WORKER CHAPTER 3 EVALUATION OF SMOKING-RELATED CANCERS IN THE WORKPLACE CONTENTS Introduction Lung Cancer Death Rates and Smoking Interactions Between Cigarette Smoking and Occupational Exposures Biologic Interactions Statistical Interaction Public Health Interactions Confounding of Occupational Exposures by Smoking Behavior Sources of Confounding Smoking Status Measures of Smoking Intensity Duration of Exposure Control of Confounding Comparisons Using External Control Populations Comparisons Using Internal Control Populations Examination of Occupational Exposures When Smoking Habits Are Not Known Summary and Conclusions References 99 Introduction Cigarette smoking is a major cause of cancer of the lung, larynx, oral cavity, and esophagus and is a contributory factor for cancer of the kidney, urinary bladder, and pancreas (US DHHS 1982). These cancers will cause 278,700 of the estimated 910,000 new cancer cases in the United States during 1985 (ACS 1985), or 30.6 percent of the cancers occurring in the United States other than skin cancer. Exposures to agents in the workplace other than cigarette smoke will also cause some of these new cancers, and a number of cancers will result from the combined effects of cigarette smoking and carcinogenic exposures in the workplace. The role that cigarette smoking plays in causing these cancers is well established and extensively documented (US DHHS 1982). The role that occupational agents play in the development of these same cancers continues to emerge as the effects of more agents are examined both in the laboratory and in the workplace. However, cigarette smoking by exposed workers makes it difficult to separate the effects of smoking from the effects of occupational agents for cancers of sites causally linked to cigarette smoking. For some agents, such as asbestos, both the large numbers of people exposed and the magnitude of the increased cancer risk have allowed a careful examination of the relative contributions of cigarette smok- ing and the workplace exposure. For most agents, the data are more limited. Nevertheless, protection of workers requires that regulatory decisions be made about individual workplace exposures, even in the face of limited data. In assessing the effects of workplace exposures, consideration must be given to the interactions of smoking with agents that increase risk and to the bias introduced into studies of occupational groups by confounding effects of cigarette smoking. This chapter discusses the nature and measurement of interactions between smoking and occupational exposures and the sources and &ntrol of confounding of smoking and occupational exposures. It is not intended to be a comprehensive discussion of the epidemiologic methods used to evaluate workplace exposures, but rather a discus- sion of how smoking behavior in the workforce can effect the evaluation of occupational exposures. The data on smoking and specific occupational exposures are presented in later chapters of this Report. The discussion of these issues is intended to aid in the design and interpretation of studies of occupational exposure and not to criticize those studies in which smoking could not be completely addressed. Lung Cancer Death Rates and Smoking A detailed discussion of the causal relationship between cigarette smoking and the cancers is provided in an earlier Report in this 101 series (US DHHS 1982) and is not repeated here. However, the relationship between smoking and lung cancer is briefly described, as a framework for the discussion of interaction and confounding in subsequent sections of this chapter. Lung cancer was chosen as an example because of its strong link to smoking and because it is the greatest cause of cancer death in both men and women (ACS 1985). Lung cancer will cause an estimated 125,600 deaths in 1985 (ACS 1985): 87,000 men and 38,600 women. For men, this represents more than 8 percent of all deaths. Current U.S. age-specific lung cancer death rates increase with age into the late seventies age range and then decline. However, when death rates for any given birth cohort of men are examined (Figure l), there is no decline in death rates at the older ages. This difference between the cross-sectional mortality statistics and the cohort data is generally attributed to differences in the smoking habits of successive birth cohorts of men (and women) during this century. This Report's chapter on smoking patterns in the U.S. population also carefully documents that cigarette smoking is not uniformly distributed in the U.S. population, but rather varies considerably with both age and occupation. This nonuniform distri- bution of smoking patterns introduces much of the difficulty in controlling for smoking in occupational studies. The relationships among age, lung cancer death rates, and number of cigarettes smoked per day, derived from the mortality study of U.S. veterans (Kahn 1966), are presented in Figure 2. The risk associated with smoking is a function of both the intensity of smoking, as measured by number of cigarettes smoked per day and depth of inhalation, and the duration of smoking as measured by age and age of initiation. The lung cancer mortality ratios derived from the American Cancer Society (ACS) study of 1 million men and women (Hammond 1966) for smokers compared with nonsmokers, stratified by age and by number of cigarettes smoked per day, depth of inhalation, and age of initiation are presented in Table 1. In general, the mortality ratios are greater in the older age groups and increase with increasing dosage measure within each age strata. The data demonstrate that within the broader category of smokers a substantial variation in risk (up to fivefold) occurs between the different levels of dose and duration of smoking. The variation in mortality ratios for each isolated measure in Table 1 almost certainly overestimates the independent contribution of that measure to the actual risk, owing to correlation among the measures of number of cigarettes smoked per day, depth of inhalation, and age of initiation. For example, those who begin to smoke at a young age also smoke more cigarettes per day (Shopland and Brown 1985). However, it is unlikely that this correlation among dosage and duration measures explains all of the variation in mortality ratios with the isolated measures; therefore, it 102 1885 1880 1875 FIGURE I.-Age-specific mortality rates for cancer of the bronchus and lung, by birth cohort and age at death, men, United States, 1959-1975 SOURCE: Data derived from McKay et al. W82). is reasonable to expect that the accuracy of lung cancer risk estimates for a population would improve with the inclusion of a 103 FIGURE 2.-Death rates from cancer of the lung and bronchus in nonsmokers and smokers of various numbers of cigarettes per day SOURCES Kahn (1966). measure of smoking prevalence, a measure of smoking intensity, a measure of smoking duration, and a measure of the duration of cessation for former smokers. Interactions Between Cigarette Smoking and Occupational Exposures Interactions between cigarette smoking and occupational expo- sures may be examined in the context of a biological process, as a statistical phenomenon, or as a problem in public health and individual decisionmaking (Rothman et al. 1980; Saracci 1980; Siemiatycki and Thomas 1981). In each of these contexts the 104 E TABLE l.-Number of lung cancer deaths (men), age-standardized death rates, and mortality ratios, by ;' current number of cigarettes smoked per day, degree of inhalation, and age began if smoking, by age at start of study 0 I Age35-54 Age 55.69 Age 7cH34 All ages, 35-E-4 g Number NUdX?r Number Number I SllKking of Death Mortality of Death Mortality of Death Mortality of Death Mortality cn characteristics deaths rate ration deatha rate ratios deaths rate ratios deaths rate ratios Current number of cigarettes a day l-9 9 lo-19 15 20-39 138 240 26 Degree of inhalation None or slight 19 Moderate 114 D=P 56 Age began cigarette .3moking 2% 5 20-24 31 15-19 112 < 15 36 Never smoked regularly 11 38 6.17 12 68 3.53 5 134 5.32 26 66 4.60 24 3.90 57 168 8.77 10 243 9.62 82 90 7.48 58 9.37 216 264 13.82 27 446 17.62 381 169 13.14 47 7.67 60 334 17.47 6 754 29.84 82 201 16.61 29 4.75 97 203 10.60 14 193 7.66 120 102 8.42 62 8.48 177 224 11.72 20 401 15.88 311 138 11.45 65 9.00 73 266 13.93 13 638 25.26 141 173 14.31 17 2.77 12 36 6.83 72 54 8.71 176 79 12.80 57 6 27 65 212 250 302 19 3.39 11.11 13.06 15.81 3 7 27 9 11 85 3.38 20 39 3.21 306 12.11 110 118 9.72 490 19.37 315 155 12.81 424 16.76 101 183 15.10 25 49 12 NCYI'E: Mortality ration are baeed on death rates carried cut to one more significant fmre than shown SOURCE Hammond (1966). concepts are applied somewhat differently, and confusion results when a move from one context to another is attempted without consideration of these differences in application. Biological interac- tion refers to the presence of one agent influencing the form, availability, or effect of a second agent, and includes physical interaction such as the adsorption of carcinogens to particulates in inspired air, process interactions such as the induction by one agent of an enzyme system capable of converting a second agent into a carcinogenic metabolite, and outcome interactions such as the number of tumors produced by separate and combined exposures in an animal exposure system. Statistical interaction refers to a departure from the mathematical model used to assess the effects of the exposure variables. The model being tested may be additive, multiplicative, or some other form; the outcome of interest may be death rates, relative risks, or other outcome measures; the indepen- dent variables may be intensity of exposure, duration of exposure, a combination of intensity and duration (e.g., pack-years), or a logarithmic or other transformation of these measures. Public health interaction usually refers to the presence or level of one agent influencing the incidence, prevalence, or extent of disease produced by a second agent. An exposure to two agents that resulted in a multiplicative effect on lung cancer death rates might show no interaction using a multiplicative statistical model, but might show a profound interaction in terms of public health and a variety of interactions within the biologic system under consideration (i.e., human carcinogenesis). Biologic Interactions The transformation of normal lung tissue into a clinically mani- fest lung cancer is a complex, incompletely understood process that is generally assumed to require multiple inheritable changes within the cell (Armitage and Doll 1961; Day and Brown 1980). Although cellular changes are assumed to be requisite for carcinogenesis, phenomena taking place outside the cell may influence carcinogene- sis. Cigarette smoke and occupational agents may potentially interact by influencing the fraction of inhaled carcinogen deposited and retained in the lung, the rate of metabolic activation of a procarcinogen into a carcinogenic metabolite, the transfer of agents across mucosal and cellular boundaries, the vulnerability of the cell to carcinogenic change (by increasing the rate of cell replication), or the transformation of the cellular DNA. In addition, cellular DNA repair, humoral or metabolic factors influencing tumor growth, and immunologic recognition or destruction of tumor cells are processes that may influence tumor manifestation and may be affected by occupational exposures and cigarette smoke. A detailed discussion of chemical carcinogenesis is beyond the scope of this chapter and is 106 provided elsewhere (Weinstein 1985; Farber 1982); however, this chapter explores some potential sites of biological interaction between occupational exposure and cigarette smoke to illustrate the biologic interactions that may take place. Cigarette smoking and occupational exposures may interact through effects of smoking on the dose of the carcinogen that reaches the cell. Long-term exposure to cigarette smoke impairs mucociliary clearance (US DHHS 1982) and could alter the dose of an occupation- al agent retained. Carcinogens may adsorb to particulates in smoke or to environmental dusts (Natusch et al. 1974; Mossman et al. 19831, resulting in a higher fractional retention or different distribution in the lung. The adsorption to dust may also facilitate or inhibit transport of carcinogens through th, mucus layer. Cigarette smoke has been shown to increase epithelial permeability in the tracheo- bronchial tree (Simani et al. 1974); the effect may increase the exposure of the underlying cell to an occupational agent. Another potential site of biologic interaction is the metabolic activation of a carcinogen. A number of agents, including the polycyclic aromatic hydrocarbons in cigarette smoke, undergo chem- ical transformation within the body to met,abolites that are consid- ered to be active carcinogens (Gelboin and Tso 1978a, b). The majority of known conversions occur through the mixed function oxygenase system predominately located in the microsomal fraction of the cell. A number of constituents of cigarette smoke have been shown to induce this enzyme system (US DHEW 19791, and its activation may increase the rate of biologic activation of procarcino- gens in the worksite. Cigarette smoking also alters the cellular composition of the lung, increasing the number of neutrophils and activated macrophages in the lung (US DHHS 1984); these cells may also play a role in the metabolic transformation of occupational agents. Much of the consideration of interactions between smoking and occupational exposures has centered on interactions that might influence the response of the cell rather than the "dose" of carcinogen (Siemiatycki and Thomas 1981; Rothman et al. 1980; Rothman 1974, 1978; Walter and Holford 1978). In a widely accepted conceptual model, the process of malignant transformation of a cell into a cancer is considered to be a multistage process requiring multiple inheritable changes (Armitage and Doll 1961; Day and Brown 1980). Individual agents may initiate or promote the process of carcinogenesis. Initiation is thought to be at least a two-stage process that requires cell division before becoming irreversible (Farber 1982). Promotion describes the process by which an agent encourages an initiated tissue to develop focal proliferation. A tumor initiator may exert its effect through a brief exposure, whereas a tumor promoter usually requires repetitive contact with initiated 107 tissue to exert its effect. Cigarette smoke is known to contain a number of compounds that act as tumor initiators and promoters (US DHHS 1982); occupational exposures reflect a similar range of agents. Tumor promoters in smoke may influence the effects of exposure to tumor initiators in the workplace and thus increase the number of cancers that occur, and the presence of tumor initiators in smoke may allow the expression of a tumor promoter in the worksite. The process of carcinogenesis is frequently modeled as a multistep process in which each succeeding step can occur only in those cells that have undergone the preceding step (Armitage and Doll 1961; Day and Brown 1980). In this model, agents may influence one (or more) of these steps, and therefore may have an effect early or late in the carcinogenic transition. Because the later steps in the process can occur only in cells that have undergone the changes of earlier steps, agents that act at separate steps may have multiplicative effects. For example, an agent that results in a fourfold increase in the rate of transition from a hypothetical step 1 to step 2 in the carcinogenic process would result in a fourfold increase in the number of malignant transformations by increasing the number of cells available for step 2 and subsequent steps. Similarly an agent that tripled the rate of transition from step 2 to step 3 would triple the number of malignant transformations. However, exposure to both agents would provide a fourfold (300 percent) increase in the number of cells available for transition from step 2 to step 3 as well as a threefold (200 percent) increase of the rate of transition from step 2 to step 3, with a resultant twelvefold (1,100 percent) increase in the number of malignant transformations. Therefore, the effect of the combined exposure on number of malignant transformations (1,100 percent) would be greater than the sum of the effects of independent exposures (300 percent plus 200 percent). A similar phenomenon may occur with cigarette smoke and an agent that has an independent and additive effect as an initiator of carcinogenesis. The additive effects on tumor initiation may appear as a multiplicative effect on tumor occurrence because of the action of the tumor promoters in cigarette smoke. The tumor promoters in smoke may act on the cells initiated by an occupational agent, as well as on the cells initiated by smoke, to increase the number of the cells that become cancers. The number of tumors produced by a combined exposure could then be greater than the sum of the numbers of tumors produced by the individual exp by questioning next of kin or checking hospital records. Berry and colleagues (1985) examined the comparability of these data sources in a prospective evaluation of asbestos workers in which smoking data were accumulated both at the start of the study period (i.e., prospectively) and at the time of death from lung cancer (i.e., retrospectively). A comparison of the smoking status obtained by the two methods for the same individuals is shown in Table 5. In general, there was good agreement between the two methods, but both methods identified as never smokers individuals who were classified as smokers by the other method. No data were presented to allow determination of which method was more accurate. The random misclassification of smoking status, of itself, should not introduce spurious associations for the population as a whole, or for the smokers in the population (Greenland 19801. However, when the question being asked is whether a risk exists in the absence of smoking and synergism between smoking and the occupational exposure is present, the misclassification of even small numbers of exposed smokers as nonsmokers can lead to the conclusion of increased risk of lung cancer due to an occupational exposure in the absence of cigarette smoking. The potential for misclassification exists and is of greatest concern when decisions are being made on small numbers of cases. The second caveat that may need to be applied in the examination of the effects of occupational exposure among people who have never smoked is the potential effect of involuntary exposure to cigarette smoke. A number of studies have shown increased lung cancer risks in the nonsmoking wives of smokers, raising the question of a carcinogenic risk due to environmental tobacco smoke exposure (IARC, in press). If these studies can be extrapolated to the workplace, then the potential exists for environmental tobacco smoke in the worksite to act as an occupational carcinogen, 126 particularly in those occupations in which there is a high prevalence of active smoking among workers. The considerations raised by examination of smokers with work- place exposures are somewhat different from those raised by examination of nonsmokers. Comparisons of smokers with and without an occupational exposure r. `I- pnqiire careful attention to the correlations among age, duration of exposure, and smoking dose. Age adjustment of the death rates in the exposed group and the control population is generally accepted as more useful than simply compar- ing the mean age of the two populations, because of the rapid rise in lung cancer death rates in the older age groups. It is less widely understood that age adjustment does not eliminate the effects of differences in the age distributions of smokers between the two populations. The smoking-related risk of developing lung cancer occurs disproportionately in older smokers compared with younger smokers. Therefore, in two populations with similar prevalences of smoking, but with different age distributions of that smoking prevalence, the population with the higher prevalence of smoking in the older age group will have the higher number of lung cancer deaths. This difference in number of lung cancers will persist after an age adjustment using the age distributions of the entire popula- tion (smoker and nonsmoker). Therefore, in considering the differ- ences between occupationally exposed smokers and smokers who are not exposed, the lung cancer deaths should be adjusted for age on the basis of the age distribution of the smokers in the two populations rather than the age distribution of the entire population. Several attempts have been made to combine the strengths of large population-based measurements with the detailed measure- ments of smoking status available in cohort studies. Hammond and colleagues (1979) used the American Cancer Society (ACS) study of 1 million men and women to develop a control group for a study of asbestos insulation workers. From the ACS study population, they extracted a group of more than 73,000 men who were white, not a farmer, had no more than high school education; did have a history of occupational exposure to dust, fumes, vapors, gases, chemicals, or radiation; and were alive at the time of the initiation of followup of the insulators. From this control group, they were able to develop age-specific and smoking-specific expected lung cancer death rates for comparison with the observed death rates in the insulation workers. There was a difference in the time period of followup between these two studies; therefore, the expected lung cancer death rates were adjusted upward on the basis of differences in the national lung cancer death rates during the years of differential followup. This approach allowed the expected rates to be calculated from a large enough population to provide stable rates in a number of separate age and smoking categories. The control group and the 127 exposed populations were also matched for a number of those characteristics that raise questions about the comparability of national death rate data to populations of employed workers. A somewhat different approach to the same problem was taken by Berry and colleagues (1985). They used data from a prospective mortality study of British physicians by smoking status (Doll and Peto 1978, 1981) to develop factors that related the risks of smokers, nonsmokers, and ex-smokers separately to the risk in the entire population of physicians. They calculated the expected number of deaths for the exposed workers in each smoking category, using national death rate data, and multiplied this expected number of deaths by the smoking factor to get a smoking-specific expected number of deaths for each category of exposed workers. They also adjusted the number of expected deaths for differences in g-graphic location by multiplying the expected deaths by the ratio of the local lung cancer SMR to the national lung cancer SMR. This approach is obviously quite sensitive to the method by which the smoking- specific factors are developed, and it is not clear that one set of factors can be applied to all ages. When an explicit control population is being used, the differences in smoking behavior can be controlled through the use of a statistical model for lung cancer risk in the population. Models may include a variety of measures of cigarette smoking dosage and duration, and the mortality experienced by the exposed population can be exam- ined by using the risk model developed in the control population. This approach allows the confounding due to smoking to be adjusted through the use of terms for intensity and duration of exposure. Comparisons Using Internal Control Populations The use of an internal control group drawn from the same workforce as the exposed population, but not exposed to the agent of interest, may produce a control group that is more closely matched to the exposed population than the total US. population would be (Breslow et al. 1983; Pasternack and Shore 1976; Redmond and Breslin 1975). Working populations tend to have a lower overall mortality than the U.S. population of the same ages (McMichael 1976; Enterline 1975; Fox and Collier 1976; Shindell et al. 1978; Vinni and Hakama 19801, at least in part because workers with illness tend to drop out of the working population. This lower mortality has been called the healthy worker effect and is one of the reasons the selection of an internal control population may be more appropriate than using SMRs for evaluating occupational exposure risks. External control groups, selected from populations geographi- cally or demographically similar to the exposed population, may also provide a population more similar to the exposed workers than the general U.S. population. 128 That the smoking behaviors of the exposed group and the control population are comparable must still be established. The selection of a control population based on its similarity in one variable (such as worksite) does not allow the assumption of comparability on other variables (such as smoking behaviors). It is possible for a control population to deviate from national measures of smoking behavior in one direction and for the exposed population to deviate in the opposite direction; thus it is important to actually examine the comparability of the smoking behaviors in the exposed group and the control population even when an internal control population is used. The absence of an external control group means that the entire population has some exposure. Potential confounding of cumulative occupational exposure by cumulative smoking exposure can be reduced by stratification of the two exposures in question. The risk with increasing exposure to an occupational agent can then be examined within each strata of smoking exposure. Stratification of smoking by intensity only (cigarettes per day) would lead to a residual confounding of smoking and cumulative dust exposure, owing to the importance of duration of smoking for lung cancer risk and the association of age with both duration of smoking and cumulative dust exposure. The reduction of residual confounding should also guide the selection of the number of strata selected for smoking and the occupational exposure. The larger the risk due to smoking in relation to the risk due to the occupational exposure, the larger the number of smoking strata needed to control the confounding. The use of too few strata may result in the residual confounding producing the appearance of a dose-response relationship with the occupational exposure. A second method of controlling the confounding of occupational exposure by smoking behaviors is through the use of modeling techniques. By using a multiple logistic regression, a model of the smoking variables that contribute to lung cancer risk can be developed. The model should include measures of intensity and duration as well as a factor for cessation. Other factors that may contribute to the model are type of cigarette smoked, use of pipes or cigars, and age of initiation (as separate from duration). Once the model is established for smoking variables, a term or terms for the occupational exposure can be added to the risk prediction equation and tested to see whether the term improves the fit of the model to the observed data. Case-control analyses can also be applied in the absence of an external control group by examining the distribution of exposures in cases of lung cancer and in a control group selected from the sample population of workers, but who have not died of lung cancer. Confounding due to cigarette smoking can then be controlled by 129 stratification (Liddell et al. 1984) or by modeling (Whittemore and McMillan 1983; Pathak et al., in press). This approach is particularly useful when a case-control analysis can be nested within an ongoing study of a cohort of workers. In this setting, the smoking habits of the workforce are often known prior to the development of lung cancer, eliminating the potential for biased recall of smoking habits by the lung cancer patients (or their survivors) compared with the controls. Examination of Occupational Exposures When Smoking Habits Are Not Known In many occupational settings the smoking habits of the workforce are either unavailable or incompletely ascertained. In these cases, the death rates for these workers are compared with rates for a control population or with national mortality data (to generate an SMR). The potential for smoking pattern differences to influence the SMR is then evaluated by calculating the maximal distortion that would be produced, assuming that the exposed population had a very high smoking prevalence. The calculations used are similar to those used in generating Tables 2 and 3. As discussed earlier, extremes of differences in smoking prevalence and dosage could be expected to generate SMRs in excess of 200, and differences in age distribution and type of cigarette smoked may increase this number even more. Once an outer limit for smoking-related distortions of the SMR is estimated, it becomes the value that must be below (outside) the confidence interval surrounding the actual SMR for the exposed population in order to exclude a potential smoking effect. This approach may be useful in settings where smoking data are unobtainable, but should not be used as a substitute for collecting smoking information. When the mortality in a control population is compared with the mortality of an exposed population in the absence of smoking data, the potential for differences between the smoking habits of the two populations may be larger than the differences when using SMRs. The control group and the exposed population may deviate in opposite directions from the mean smoking behaviors represented in the SMR, and correspondingly, the differences in cancer outcome may also be magnified. One method of adjusting for differences in smoking patterns between populations when smoking data are not available, or would be too costly to obtain, is to survey a random sample of the two populations for smoking behavior. The limitation of this technique is that the sample size needed to obtain estimates of usable precision is large and may approximate the size of the two populations com- bined. 130 An additional method of examining the effects of unknown differences in smoking habits on the rates of one smoking-related cancer is to look at the rates of other smoking-related cancers in the same population. The various smoking-associated cancers do not all have the same incidence rates, rate of change in incidence with time, ethnic distribution, cure rate, or age distribution. These differences make cross-comparison between rates of these cancers as a measure of differences in smoking patterns between populations a complex and uncertain exercise at best. This kind of comparison may be useful as a point of discussion, but probably offers little in the way of an estimate of the differences between populations in their smoking behavior. Summary and Conclusions 1. Cigarette smoking and occupational exposures may interact biologically, within a given statistical model and in their public health consequences. The demonstration of an interaction at one of these levels does not always characterize the nature of the interaction at the other levels. 2. Information on smoking behaviors should be collected as part of the health screening of all workers and made a part of their permanent exposure record. 3. Examination of the smoking behavior of an exposed population should include measures of smoking prevalence, smoking dose, and duration of smoking. 4. Differences in age of onset of exposure to cigarette smoke and occupational exposures should be considered when evaluating studies of occupational exposure, particularly when the ex- posed population is relatively young or the exposure is of relatively recent onset. 131 References AMERICAN CANCER SOCIETY. Cancer statistics, 1985. CA-A Cancer Journal for Clinicians 35(1):19-35, January-February 1985. ARCHER, V.E., GILLIAM, J.D., WAGONER, J.K. Respiratory disease mortality among uranium miners. Annals of the New York Academy of Sciences 271:280-293, 1976. ARMITAGE, P., DOLL, R. Stochastic models for carcinogenesis. In: Neyman, J. (ed.). Contributions to Biology and Problems of Medicine. Proceedings of the Fourth Berkeley Symposium on Mathematical Statistics and Probability, Vol. 4. Berkeley, University of California Press, 1961, pp. 19-38. AXELSON, 0. Aspects on confounding in occupational health epidemiology. (letter). Scandinavian Journal of Work, Environment and Health 4(1):98-102, March 1978. BERRY, G., NEWHOUSE, M.L., ANTONIS, P. Combined effect of asbestos and smoking on mortality from lung cancer and mesothelioma in factory workers. British Journal of Industrial Medicine 42(1):12-18, January 1985. BLAIR, A., HOAR, SK., WALRATH, J. Comparison of crude and smoking adjusted standardized mortality ratios. Journal of Occupational Medicine 27(12):881484, December 1985. BLOT, W.J., DAY, N.E. Synergism and interaction: Are they equivalent? American Journal of Epidemiology 110(1):99-100, July 1979. BRESLOW, N. Multivariate cohort analysis. In: Selection, FoZZow-up, and Analysis in Prospective Studies: A Workshop. National Cancer Institute Monograph No. 67. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, NIH Pub. No. 85-2713, 1985, pp. 149-156. BRESLOW, N.E., DAY, N.E. The Analysis of Case-Control Studies. Statistical Methods in Cancer Research, Vol. 1. IARC Scientific Pub. No. 32. Lyon, International Agency for Research on Cancer, 1980,338 pp. BRESLOW, N.E., LUBIN, J.H., MAREK, P., LANGHOLZ, B. Multiplicative models and cohort analysis. Journal of the American Statistical Association 78(381):1-12, March 1983. BRESLOW, N.E., STORER, B.E. General relative risk functions for case-control studies. American Journal ofEpidemiology 122(1):149-162,1985. DAY, N.E., BROWN, CC. Multistage models and primary prevention of cancer. Journal of the National Cancer Institute 64(4):977-989, April 1980. DOLL, R., PETO, R. Cigarette smoking and bronchial carcinoma: Dose and time relationships among regular smokers and lifelong nonsmokers. Journal of Epidemiology and Community Health 32(4):303-313, December 1978. DOLL, R., PETO, R. The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today. Journal of the National Cancer Institute 66(6):1191-1308, June 1981. ENTERLINE, P.E. What do we expect from an occupational cohort? Not uniformly true for each cause of death. Journal of Occupational Medicine 17(2):127-128,1975. FARBER, E. Chemical carcinogenesis: A biologic perspective. American Journal of Pathology 106(2!:271-296, February 1982. FOX, A.J., COLLIER, P.F. Low mortality rates in industrial cohort studies due to selection for work and survival in the industry. British Journal of Preuentiue and Social Medicine 30(4):225-230, December 1976. GELBOIN, H.V.. TS'O, P.O.P. (eds.). Enuironment, Chemistry, and Metabolism. Polycyclic Hydrocarbons and Cancer, Vol. 1. New York, Academic Press, 1978a. GELBOIN, H.V., TS'O, P.O.P. (eds.). Molecular and Cell Biology. Polycyclic Hydrocarbons and Cancer, Vol. 2. New York, Academic Press, 1978b, 397 pp. GREENLAND, S. Limitations of the logistic analysis of epidemiologic data. American JournaZ OfEpidemiology 110(6):693-698, December 1979. 132 GREENLAND, S. The effect of misclassification in the presence of covariates. American Journal ofEpidemiology 112(41:564-569, October 1980. GREENLAND, S. Tests for interaction in epidemiologic studies: A review and a study of power. Statistics in Medicine 2(21:243-251, AprilJune 1983. HAMMOND, E.C. Smoking in relation to the death rates of one million men and women. In: Haenszel, W. (ed.). Epidemiologic& Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, January 1966, pp. 127-204. HAMMOND, E.C., SELIKOFF, I.J., SEIDMAN, H. Asbestos exposure, cigarette smoking and death rates. Annals of the -Vew York Academy of Sciences 330:473- 490,1979. HOGAN, M.D., KUPPER, L.L.. MOST, B.M., HASEMAN, J.K. Alternatives to Rothman's approach for assessing synergism Ior antagonism) in cohort studies. American Journal of Epidemiology 108(11:60-6?. July 1978. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. IARC Monograph No. 38. Lyon, France, International Agency for Research on Cancer, in press. KAHN, H.A. The Dorn study of smoking and mortality among US. veterans: Report on eight and one-half years of observation. In: Haenszel, W. (ed.) Epidemiological Approaches to the Study of Cancer and Other Chronic Diseases. National Cancer Institute Monograph No. 19. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, January 1966, pp. 1-125. KLEINBAUM, D.G., KUPPER, L.L., MORGENSTERN, H. Epidemiologic Research: Principles and Quantitatir:e Methods. Belmont. California, Lifetime Learning Publications, 1982. KUPPER, L.L., HOGAN, M.D. Interaction in epidemiologic studies. American Journal of Epidemiology 108(6):447-453, December 1978. LAST, J.M. (ed.1. A Dictionary of Epidemiology. New York, Oxford University Press, 1983. LIDDELL, F.D.K., THOMAS, D.C., GIBBS, G.W., MCDONALD, J.C. Fibre exposure and mortality from pneumoconiosis, respiratory and abdominal malignancies in chrysotile production in Quebec 192675. Annals of the Academy of Medicine, Singapore 13(2, Supp.):340-344, April 1984. LUNDIN, F.E., Jr., WAGONER, J.K., ARCHER, V.E. Radon Daughter Exposure and Respiratory Cancer, Quantitative and Temporal Aspects. Joint Monograph No. 1. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institute for Occupational Safety and Health and National Institute of Environmental Health Sciences, 1971, 176 pp. MCKAY, F.W., HANSON, M.R., MILLER, R.W. (eds.1. Cancer Mortality in the United States, 1950-1977. National Cancer Institute Monograph No. 59. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, NIH Pub. No. 82-2435. 1982. McMICHAEL, A.J. Standardized mortality ratios and the "healthy worker effect": Scratching beneath the surface. Journal of Occupational Medicine 18(31:165-168, March 1976. MOSSMAN, B., LIGHT, W., WEI, E. Asbestos: Mechanisms of toxicity and carcinoge- nicity in the respiratory tract. Annual ReLjieu- of Pharmacology and Toxicology 23595615, 1983. NATUSCH, D.F.S., WALLACE, J.R., EVANS, CA., Jr. Toxic trace elements: Preferential concentration in respirable particles. Sczence 183(4121):202-204, January 18,1974. NICHOLSON, W.J., PERKEL, G., SELIKOFF, I.J. Occupational exposure to asbestos: Population at risk and projected mortality-198&2030. American Journal of Industrial Medicine 3(4):259-311. 1982. 133 PASTERNACK, B.S., SHORE, R.E. Statistical methods for assessing risk following exposure to environmental carcinogens. In: Whittemore, A. (ed.). Environmental Health: Quantifatitle Methods. Philadelphia, SIAM Institute for Mathematics and Society, 1976, pp. 49-69. PATHAK. D.R., SAMET, J.M., HUMBLE, C.G., SKIPPER, B.J. Determinants of lung cancer risk in cigarette smokers in New Mexico, in press. REDMOND, C.K., BRESLIN, P.P. Comparison of methods for assessing occupational hazards. Journal of Occupational Medicine 17(51:313-317, May 1975. ROTHMAN, K.J. Induction and latent periods. American Journal of Epidemiology 114(2):253-259, August 1981. ROTHMAN. K.J. Synergy and antagonism in cause-effect relationships. American Journal of Epidemiology 99(6): 385-388, June 1974. ROTHMAN, K.J. Occam's razor pares the choice among statistical models. American Journal of Epidemiology 108(5):347-349, November 1978. ROTHMAN. K.J., BOICE, J.D. Epidemiologic Analysis With a Programmable Calculator. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, NIH Pub. No. 79-1649, June 1979. ROTHMAN, K.J., GREENLAND, S., WALKER, A.M. Concepts of interaction. American Journal of Epidemiology 112(4):467-470,1980. SAMET, J.M., LERCHEN, M.L. Proportion of lung cancer caused by occupation: A critical review. In: Gee, J.B.L., Morgan, W.K.C., Brooks, SM. (eds.). Occupational Lung Disease. New York, Raven Press, 1984, pp. 55-67. SARACCI, R. Interaction and synergism. American Journal of Epidemiology 112(4):465466,October 1980. SCHLESSELMAN, J.J.. STOLLEY, P.D. Case-Control Studies; Design, Conduct, Analysis. New York, Oxford University Press, 1982. SELIKOFF, I.J., LEE, D.H.K. Asbestos and Disease New York, Academic Press, 1978, 549 pp. SHINDELL, S., WEISBERG, R.F.. GIEFER, E.E. The "healthy worker effect": Fact or artifact? Journal of Occupational Medicine 20(12):807-811, December 1978. SHOPLAND, D.R., BROWN, CD. Analysis of Cigarette Smoking Behavior by Birth Cohort. Paper presented at the Interagency Committee on Smoking and Health meeting, Washington, D.C., October 1,1985, 12 pp. SIEMIATYCKI, J.. THOMAS, DC. Biological models and statistical interactions: An example from multistage carcinogenesis. International Journal of Epidemiology lOt4):383-387, December 1981. SIMANI, AS'., INOVE, S., HOGG, J.C. Penetration of the respiratory epithelium of guinea pigs following exposure to cigarette smoke. Laboratory Investigation 31(11:75-81, July 1974. US. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health: A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Pub. No. (PHS)79-50066, 1979, 1,136 pp. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Chronic Obstructiue Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Pub. No. IPHS) 84-50205,1984,545 pp. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: The Changing Cigarette. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Pub. No. lPHS)Sl-50156,1981,252 pp. 134 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Cancer. A Report of the Surgeon General. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHHS Pub. No. tPHSX32- 50179,1982,322 pp. VINNI, K., HAKAMA, M. Healthy worker effect in the total Finnish population. British Journal of Zndustrral Medicine 37t2):18G184, May 1980. WALKER, A.M., ROTHMAN. K.J. Model of varying parametric form in case-referent studies. American Journal of Epidemio1og.v 115(11:129-137, 1982. WALTER, SD., HOLFORD, T.R. Additive, multiplicative, and other models for disease risks. American Journal of Epidemiology 108t5~:341-346, November 1978. WEINSTEIN, I.B. Chemical carcinogenesis. In: Calabresi. P., Schein, P.S., Rosenberg, S.A. (eds.). Medical Oncology: Basic Principles and Clinical Management of Cancer. New York, Macmillan Publishing Company. 1985, pp. 63-81. WHI'ITEMORE, AS., McMILLAN, A. Lung cancer mortality among U.S. uranium miners: A reappraisal. Journal of the National Cancer Institute 71(3):489-499, September 1983. 135 CHAPTER 4 EVALUATION OF CHRONIC LUNG DISEASE IN THE WORKPLACE 157-964 0 - 86 - c CONTENTS Introduction Chronic Lung Diseases Sources of Information Occurrence of Chronic Lung Diseases Patterns of Lung Injury Injury From Cigarette Smoke Injury From Occupational Exposures Methods for Evaluating the Effects of Occupational Expo- sures on the Lungs History of Respiratory Symptoms Chest X Ray Physiological Assessment Quantification of Effects of Smoking and Occupation in Populations Concepts of Interaction Study Design Assessment of Exposures Cigarette Smoking Occupational Exposures Data Analysis Specific Investigation Issues Population Selection External Control Populations Colinearity of Aging, Cigarette Smoking, and Oc- cupational Exposure Effects Quantification of Effects in Individuals Summary and Conclusions References 139 Introduction Exposure to harmful agents in the workplace is, and will probably continue to be, an important and avoidable cause of both acute and chronic lung diseases. The major chronic lung diseases associated with workplace exposures can be classified as the pneumoconioses (fibrotic diseases of the lung parenchyma secondary to dust inhala- tion), industrial bronchitis and other processes involving the lung's airways, and occupational asthma. Some of these diseases were recognized long before cigarette smoking became prevalent. During the 16th century, Agricola and Paracelsus described diseases of miners (Hunter 1978); early in the 18th century, Ramazzini (1940) reported further on the respiratory problems of miners and noted that the lungs of stonecutters were full of sand. Occupational lung disease in coal miners was recognized during the 1800s (Morgan 1984a). In the 20th century, many chronic lung diseases caused by workplace exposures have been studied intensively using epidemio- logical, physiological, and clinical approaches. The resulting data have been essential for developing the standards that govern workplace exposures and for evaluating worker safety. In this century, however, assessment of the effects of occupational agents on the lung has been made difficult by the widespread smoking of cigarettes. This behavior has been particularly prevalent among those at high risk for occupational lung diseases-men employed in blue-collar jobs (US DHEW 1979b). The degree of pulmonary impairment in any individual represents the summation of the effects of all harmful environmental factors, including cigarette smoking, occupational agents, and other expo- sures. Cigarette smoking, in the absence of other exposures, causes chronic bronchitis (cough and mucous hypersecretion), airway abnor- malities, and emphysema (abnormal dilation of the distal airspaces with destruction of alveolar walls); together, the last two disease processes underlie the expiratory flow limitation found in chronic obstructive lung disease (COLD) (US DHHS 1984). Cigarette smoking may potentiate the effects of some occupational agents on the lung. This potentiation may occur through an effect of cigarette smoke on the mechanism of lung injury that results from a given occupational exposure, or it may result from a mechanism of lung injury due to cigarette smoke that is independent of the mechanism of occupation- al injury but produces a level of combined lung damage capable of potentiating the level of disability or the level of abnormality detected by pulmonary function tests, x rays, or symptoms. The term "synergism" is used in this chapter to refer to an effect of combined exposure to cigarette smoke and occupational agents that results in a level of abnormality (by whatever measure being used) that is significantly greater than the sum of the levels of abnormality 141 produced by the agents separately. Such interactions are of impor- tance not only for researchers but also for the exposed workers and their employers. Synergism between cigarette smoking and occupa- tional agents may, at the individual level, markedly raise the risk of developing disease and, at the group level, greatly increase the burden of occupational disease in the workforce. Thus, in evaluating the effects of workplace exposures on the lung, consideration must be given not only to the independent effects of cigarette smoking and of the agent of interest but also to the possible interaction of these factors. This chapter describes the techniques used to evaluate chronic lung disease in the workplace and addresses the methodological issues raised by cigarette smoking. The focus of the chapter is largely confined to the chronic, fixed lung injuries that result from these exposures rather than the acute reversible responses that character- ize occupational asthma. This focus was adopted in the interest of clarity and brevity and does not suggest that the issues related to the evaluation of occupational asthma are either unimportant or unrelated to cigarette smoking. Emphasis is placed on methodologi- cal problems; specific exposures are reviewed in other chapters of this Report. Chronic Lung Diseases Sources of Information Although cigarette smoking is the predominant cause of preventa- ble morbidity and mortality from respiratory diseases in the United States (US DHHS 1984), occupational exposures also produce sub- stantial disease. Because the occurrence of nonmalignant respiratory diseases is not directly monitored, its frequency must be estimated from diverse information sources such as the National Center for Health Statistics, the U.S. Bureau of Labor Statistics, the Social Security Administration, and epidemiologic surveys. The extent to which chronic lung diseases are ascertained by these sources is difficult to establish, but coverage is probably not comprehensive. Vital statistics enumerate the numbers of deaths from specific causes. Chronic conditions, such as respiratory diseases, may be listed on the death certificate, but remain uncoded unless they led directly to death. For example, Rank and Bal (1984) reviewed death certificates and found that in comparison with its frequency as an underlying cause of death, emphysema was listed nearly twice as often as an uncoded "other" condition. Vital statistics data cannot readily be used for addressing questions related to the pulmonary effects of cigarette smoking and occupational exposures. Cigarette smoking is not included on the death certificate, and only usual 142 TABLE l.-Number of deaths in selected categories of the International Classification of Diseases (ICD), for three time periods, United States Year (classification) Cause of death 1960 (ICDI 1970 (ICDI 1980 (ICDI COLD Chronic bronchitis 2.287 15021 5,014 (491) 3,269 (491) Emphysema 9.253 (527.11 22,721 (4921 13.677 (4921 Chronic airways obstruction n.e.c. ' - 4,444 1519.31 34,743 (496) Occupational disorders Coal workers' pneumoconiosls 810 1523.1) 1,160 (515.1) 982 mlo) Asbestosis 21 1523.2) 26 (515.2~ 101 will Silicosis 550 1523.01 355 (515.0) 207 (502) Other inorganic dusts 13 (516.01 8 (5031 Other dusts 62 (524) 7 (516.1) 3 (504) Unspecified 210 (523.3) 281 (505) Conditions due to chemical fumes/vapors 5 !516.21 43 (506) Chronic interstitial pneumonia 3,973 (525) 3,351 (517) 202 (516.31 ' Not elsewhere claasifwzd SOURCE, US DHEW (19631; National Center for Health Statista (1974), unpublished data (1980). occupation and industry are noted. Further, the occupational information is not routinely coded by States (Kaminski et al. 1981). Cause of death is coded according to the International Classifica- tion of Diseases, currently in its ninth revision (WHO 1977). For the chronic respiratory diseases, separate categories cover the obstruc- tive disorders, major pneumoconioses, and other interstitial diseases (Table 1). As the International Classification of Diseases has been modified from the seventh through the ninth revisions, major changes in the coding of chronic respiratory diseases have been made. The categories for occupational lung diseases have been expanded and their titles have been made more specific. With the eighth revision (US DHEW 1968), a category (519.3) was added for the diagnosis of chronic obstructive lung disease (COLD). These changes must be considered in examining time trends of mortality. For example, after the introduction of a category for COLD, the number of deaths assigned to this code increased and deaths attributed to emphysema decreased (Table 11. 143 Estimates of disease occurrence based on vital statistics must be interpreted with caution. Some causes of death may be underreport- ed, and mortality rates may not directly reflect incidence. The mortality rate for a particular disease approximates the incidence rate as the case-fatality rate approaches unity (Kleinbaum et al. 1982). Competing causes of death will also influence the relationship between incidence and mortality (Kleinbaum et al. 1982). For example, Berry (1981a) examined the mortality of 665 men certified as having asbestosis by medical boards in England and Wales. Of the 283 deaths, 39 percent were from lung cancer, 9 percent were from mesothelioma, and only 20 percent were from asbestosis. The distribution of competing causes of death should be different in smokers and nonsmokers; thus, even for non-smoking-related occu- pational lung diseases the relationship between incidence and mortality may vary with smoking practices. For several respiratory diseases, vital statistics underestimate mortality. For COLD, Mitchell and colleagues (1971) compared cause of death, as reported on the death certificate, with clinical and autopsy-derived diagnoses. In 211 subjects who died of COLD, as determined by autopsy, another cause of death was listed on the death certificate for 51. For asbestosis, Hammond and colleagues (1979) used "the best available medical information" and identified 160 deaths from this pneumoconiosis in a cohort study of asbestos workers. Only 76 were similarly classified by the death certificate statement of cause of death. State workmen's compensation claims are another source of information about the occurrence of occupational lung diseases. However, most workmen's compensation claims involve acute prob- lems (Whorton 1983) and may more accurately measure conditions associated with irritant gas or vapor inhalation than with the pneumoconioses. Under the Occupational Safety and Health Act, selected employ- ers are required to maintain records of occupational injury and illness (US House of Representatives 1984). In an annual survey, the Bureau of Labor Statistics collects and reports the injury and illness data. During 1982, 2,000 reports for dust diseases of the lungs and 8,800 for respiratory conditions due to toxic agents were filed, but more specific diagnoses were unavailable (US DOL 1984). In the introduction to the 1982 survey, it was acknowledged that "to the extent that occupational illnesses are unrecognized and therefore unreported, the survey estimates understate their occurrence" (US DOL 1984, p. 3). On a national level, the Social Security Administration operates a compensation program for people who have been disabled for at least 5 months (US DHHS 1983). People receiving compensation for chronic lung diseases must meet this criterion as well as stringent 144 requirements for the extent of impairment on lung function testing (US DHEW 1979a). Data from the Social Security Administration probably underestimate the prevalence of most chronic lung dis- eases. For example, Epler and colleagues (1980) showed that approximately 9 percent of a series of clinically diagnosed patients with pneumoconiosis met the Social Security disability criteria. Epidemiological surveys offer the most accurate estimates of disease frequency, though the surveyed populations are generally limited to employed workers and disease frequency may therefore be underestimated. Estimates of disease frequency from a particular survey should be generalized cautiously. Nonrandom selection of occupational groups for study as well as the nonrandom enrollment of workers within a particular workforce may introduce bias. Occurrence of Chronic Lung Diseases Although the available data sources have limitations, they can be used to document the relative frequencies of cigarette-related and occupation-related chronic lung diseases. Most indicate that the diseases associated with cigarette smoking are much more common in the general population than those resulting from occupational exposures. In recent years, mortality from COLD has steadily increased; the number of deaths rose from 32,179 in 1970 to 51,889 in 1980 (Table 1). The 1984 Surgeon General's Report, The Health Consequences of Smoking: Chronic ObstructiveLung Disease (US DHHS 19841, offered the estimate that 60,000 people would die from COLD during that year. Examination of COLD mortality rates for smokers and nonsmokers suggests that 85 to 90 percent of COLD deaths in the United States can be attributed to cigarette smoking (US DHHS 1984). As described in the 1984 Surgeon General's Report, numerous surveys provide estimates of the prevalence of COLD (US DHHS 1984). Representative recent data have been collected in Tucson, Arizona, in six other U.S. cities, and nationwide in the National Health Interview Survey (NHIS). Lebowitz and colleagues (1975) sampled 3,805 subjects in Tucson from 1972 through 1974. In men over 44 years of age, physician-diagnosed chronic bronchitis and emphysema were reported to be 10.2 and 13.3 percent, respectively. In women over 44 years of age, the percentage with chronic bronchitis was 9.0 percent and with emphysema, 4.3 percent. From 1974 through 1977, Ferris and colleagues (1978) surveyed 7,909 men and women in six U.S. cities; 5 percent of the men and 1.9 percent of the women had airway obstruction, defined as a ratio of forced expiratory volume in 1 second (FEV,) to forced vital capacity (FVC) less than or equal to 60 percent. The 1970 NHIS included about 116,000 persons in a nationwide sample (NCHS 1974). Individuals 19 145 years of age and older were asked whether they or other family members not present at the time of the interview had bronchitis or emphysema during the previous 12 months. On the basis of this survey, 3.4 million Americans over 45 years of age were projected as having chronic bronchitis or emphysema. In contrast, data from the Social Security Administration, not included in the 1984 Surgeon General's Report, showed only 20,246 new claimants for COLD receiving disability benefits in 1979 (US DHHS 1983). The available data sources also probably do not comprehensively document the nationwide occurrence of occupational lung diseases. The number of deaths recorded as due to several occupational lung diseases was stable from 1960 to 1980 (Table l), but it is unlikely that these death certificate data provide accurate estimates of the actual prevalence or severity of these disease processes in the U.S. population, owing to the inaccurate reporting of these diseases as cause of death. The Social Security Administration is also an ongoing source of information. In 1977, 820 persons were granted disability for pneumoconiosis; in 1979, the number had decreased to 389 (US DHHS 1983). Data from the 1970 NHIS provide an estimate of the prevalence of work-related chronic lung diseases across the Nation (NCHS 1974). Participants were queried concerning dust in the lungs, silicosis, or pneumoconiosis during the previous 12 months; their responses were used to estimate that 126,000 people nationwide had these conditions. Numerous workforces in the United States and elsewhere have been surveyed to establish the prevalence of occupational and nonoccupational lung diseases. Representative recent surveys of workers in the United States are presented in Table 2, showing the prevalence of disease and of cigarette smoking. Various disease indicators were considered in these studies. Chronic bronchitis was diagnosed on the basis of persistent cough and phlegm as ascertained by questionnaire. For the pneumoconioses, the presence of disease was based on the presence of radiographic abnormality. Of note is the high prevalence of coal workers' pneumoconiosis reported by Morgan and colleagues (1973). A different group of readers subse- quently reinterpreted the chest films reported in the Morgan and colleagues study and found a prevalence of only 12 percent; this lower prevalence suggests overinterpretation on the initial reading (Morring and Attfield 1984). Regardless of the occupational group, cigarette smoking is com- mon, even in workforces exposed to acknowledged respiratory hazards (Tabit: 2). At the time the selected surveys of these workers were conducted, 1966 to 1977 for the asbestos workers (Weiss and Theodos 1978; Samet et al. 1979) and 1981 for the uranium miners (Samet et al. 19841, knowledge of the hazards of these occupations was widely disseminated and information concerning interaction 146 TABLE 2.-Prevalence of cigarette smoking and occupational lung disease in selected survey populations Study, location. years of study Study population Prevalence of smokmg Prevalence of disease Iper 100) cper 1M)l Kibelstis et al 119731, c s.. 1969 Morgan et al 119731, U.S.. 1969 Weiss and Theodos (19781, U.S.. 1975 Samet et al 11979J. U.S.. 196G1977 Theriault et al (19741, U.S., 1971 &met et al 11984), U.S.. 1981 Merchant et al. (1973), U.S., 197M971 Do Pica et al. (19771. U.S., 1974 Gruchow et al. I1981 I, U.S. 8.555 coal miners 9,076 coal m,ners 88 workers from two asbestos manufacturing phIItS 409 workers from two asbestos manufacturing plants and two shtpyards 792 granite shed workers 192 uranium miners 787 male, 473 Smokers 51 Ex-smokers 24 Nonsmokers 25 Smokers 56 Ex-smokers 23 Nonsmokers 21 Smokers 4666 Ex-smokers 27-42 Nonsmokers 10-18 Exposed workers Smokers 61 Ex-smokers 25 Nonsmokers 13 Smokers 43 Exsmokers 39 Nonsmokers 19 M W female cotton textile Smokers 63 44 mill workers Ex-smokers 16 6 Nonsmokers 21 50 300 grain workers Smokers 59 Chronic bronchitis Ex-smokers 22 Smokers 42 Nonsmokers 19 Nonsmokers 30 1,510 farm workers Smokers 15 Ex-smokers 27 Nonsmokers 57 Chronic bronchitis Smokers 3~3 Ex-smokers 30 Nonsmokers 25 Airway obstruction ' Smokers 18 Ex-smokers 14 Nonsmokers 6 Coal workers' pneumoconiosis Simple 30.0 Complicated 2.5 X-ray profusion >l/O 20 X-ray profusion 2110 12-31 2211 513 X-ray profusion l/O 21 210 7 3/o 2 X-ray profusion 2110 8.0 Chronic cough/phlegm < 10 years mining 52 10-19 years mining 46 220 years mining 59 Byssinosls M W Current smokers 25 19 Never smokers 18 15 Farmers lung disease 0.5 147 with cigarette smoking was accumulating. Nevertheless, a large proportion of the participants in these surveys smoked cigarettes. The findings from these surveys with regard to the prevalence of smoking are supported by larger data sets collected from population samples (Friedman et al. 1973; Sterling and Weinkam 1976). Friedman and colleagues (1973) questioned 70,289 participants in the Kaiser-Permanente Multiphasic Health Checkups program and found a higher proportion of smokers in those reporting occupational exposure to asbestos, silica, or fumes. Similarly, Sterling and Weinkam (1976) examined smoking patterns by employment status in data from the 1970 NHIS and found the prevalence of smoking to be highest among blue-collar workers. Association between occupa- tional group and cigarette smoking practices is addressed in detail elsewhere in this Report. Thus, in research and clinical care related to chronic occupational lung diseases, consideration must be given not only to occupational exposures but also to cigarette smoking. The remainder of this chapter describes the general patterns of lung injury by cigarette smoking and occupational exposures and the methods used for evaluating workers who are exposed to both. Patterns of Lung Injury The sites of lung injury caused by cigarette smoke and occupation- al agents may be broadly categorized as the large airways, the small airways, and the parenchyma. The effects of cigarette smoke on these sites are summarized in Table 3. A comparison of injury patterns from cigarette smoke and from selected, but representative, occupational exposures follows. Injury From Cigarette Smoke The pattern of lung injury associated with cigarette smoking has been comprehensively described elsewhere (US DHHS 1984). In the large airways, cigarette smoke causes an increase in mucous gland size and in goblet cell number. These changes result in increased mucus production and the associated symptom of chronic bronchitis. Large airway injury may contribute to airflow obstruction, but the peripheral airways are the predominant site of the increased airflow resistance in COLD (US DHHS 1984). Changes in the small airways are one of the earliest manifesta- tions of cigarette smoking. Niewoehner and colleagues (1974) exam- ined the lungs of 20 smokers and 19 nonsmokers who died suddenly at a mean age of 25 years. A pattern of small airways injury, termed "respiratory bronchiolitis," was readily identified, even in these young smokers. Clusters of brown pigmented macrophages were found in the respiratory bronchioles, which also displayed increased 148 TABLE 3.-Pathologic changes and manifestations of lung injury by cigarette smoke Large airways Small airways Parenchyma Pathologic changes Manifestations Mucous gland hyper- Goblet cell metaplasia. Emphysema, plasia. inflammation inflammation and minimal and edema, ' bronchial fibrosis of the interstital smooth muscle respiratory bronchiole fibrosis Symptoms Cough, phlegm Physical signs None Cough, phlegm Crackles Dyspnea Diminished breath SOUdS X ray None Pulmonary function ? j FEV, testing ? Linear opacities ? Linear opacities FEV,, 1 FEV,%, i FEV,, 1 FEV,%, : TLC, 1 RV. J DLCO `TLC, TRV. LDLCO Accelerated annual Accelerated annual decline of FEV, decline of FEV, numbers of inflammatory cells and denuded epithelium. To charac- terize the physiological consequences of small airways injury associ- ated with smoking cigarettes, Cosio and colleagues (1978) correlated small airways morphology with lung function in 36 patients under- going thoracotomy for a localized lesion. With increasing cumulative consumption, both inflammation and fibrosis of the respiratory bronchioles increased. Furthermore, airflow obstruction, as mea- sured by the ratio of FEV, to FVC or by the maximum midexpirato- ry flow rate (FEFzMNI, progressively decreased and residual volume increased with the amount smoked. Physiological measures of airflow obstruction correlated with the severity of small airways abnormalities. The major parenchymal injury associated with cigarette smoking is emphysema: "abnormal dilation of air spaces distal to the terminal bronchioles accompanied by destruction of air space walls" (US DHHS 1984, p. 119). Emphysema and small airways injury contribute to the physiological impairment found in COLD; in individual patients with COLD, either may be predominant, but both are probably important in most (US DHHS 1984). By itself, emphyse- ma is accompanied by spirometric evidence of airflow obstruction, increased lung compliance, and increased total lung capacity (TLC) and residual volume (RV). The diffusing capacity for carbon monox- ide varies inversely with the extent of emphysema (Park et al. 1970; Cotes 1979). Emphysema is also associated with abnormalities of gas exchange. 149 Cigarette smoking, through its effects on the small airways and lung parenchyma, produces the clinical syndrome of expiratory flow limitation with dyspnea. The chronic airflow obstruction found in COLD develops progressively and insidiously in most cases through a sustained excessive decline of ventilatory function (US DHHS 1984). In COLD, spirometry shows reduced FEV, and a reduced FEV, to FVC ratio; FVC may also be diminished. The airflow obstruction is accompanied by increases in RV and TLC (Boushy et al. 1971; Cotes 1979). Injury From Occupational Exposures For occupational exposures in the absence of cigarette smoking, the patterns of lung injury vary among the agents, presumably on the basis of differences in their physical and chemical properties. Although the clinical and physiological manifestations of occupa- tional lung injury may be distinct from those of cigarette smoking, overlap occurs for some exposures. As with cigarette smoke, chronic irritation of the large airways by dusts and gases is associated with mucous gland enlargement and mucus hypersecretion (Morgan 1978, 1984b). This pattern of injury has been well documented clinically and pathologically for coal and cotton dust (Douglas et al. 1982; Edwards et al. 1975; Kibelstis et al. 1973; Merchant et al. 1972). Gold miners and grain workers also develop chronic bronchitis attributable to occupational dust expo- sure (Irwig and Rocks 1978; Dosman et al. 1980). Industrial bronchitis may be associated with airflow obstruction. Hankinson and colleagues (1977) studied approximately 9,000 coal miners from 1973 to 1974. Among the nonsmoking miners with dust- induced bronchitis, decreased airflow at high lung volumes was demonstrated, a finding suggestive of changes in the larger airways. Abnormalities of the small airways seem to be one of the earliest responses to mineral dust exposure (Churg et al. 1985). In a recent study of hard-rock miners and people employed in the asbestos, construction, and shipyard industries, Churg and colleagues (1985) showed that the abnormalities of the respiratory bronchioles associ- ated with mineral dust are accompanied by airflow abnormalities. The lesions consisted of fibrosis and pigmentation in the small airways and were considered by these researchers to represent a nonspecific response to dust. Involvement of the small airways has also been demonstrated in workers with specific exposures. For example, the coal macule is characterized by the deposition of alveolar macrophages loaded with coal dust in the respiratory bronchioles (Morgan 1984a). Subsequent- ly, the involved respiratory bronchioles dilate, a change termed "focal emphysema" (Morgan 1984a). At this stage, individuals usually are asymptomatic and have no physical findings. The chest x 150 ray may be normal, or rounded nodules, less than 10 mm in diameter, may be present, predominantly in the upper lobes. These findings characterize the simple form of coal workers' pneumoco- niosis. In spite of the presence of roentgenographic and pathologic abnormalities, only subtle abnormalities of small airways function are demonstrable in simple coal workers' pneumoconiosis (Morgan 1984a). In certain chronic occupational lung diseases, parenchymal lung injury may be accompanied by evidence of restriction alone; in others, variable combinations of restriction and obstruction may occur. Relevant examples of these two types of processes are asbestosis (Seaton 1984a) and the complicated forms of coal workers' pneumoconiosis and silicosis (Morgan 1984a; Seaton 1984b). Although asbestos exposure is associated with fibrosis of the respiratory bronchioles, the injury often progresses and involves the alveolar interstitium with the development of parenchymal fibrosis Seaton 1984a). The clinical consequences of this parenchymal injury are cough and dyspnea. Other changes found in asbestosis include crackles, clubbing, and basilar, irregular, linear opacities on chest x ray. Pulmonary function testing shows only a restrictive pattern with reduced FVC, normal FEV/FVC%, and decreased TLC. In contrast, the complicated forms of silicosis and coal workers' pneumoconiosis may be accompanied by obstruction in addition to restriction. In both disorders, large masses of dust and fibrosis replace the normal lung parenchyma and reduce FVC and TLC. Obstruction may also be present, presumably because of increased airways resistance and parenchymal abnormalities. Dyspnea is generally a prominent symptom. Thus, for some occupational agents, the associated lung injury at specific anatomic loci resembles that from cigarette smoking. Large airway irritation, regardless of the exposure, is accompanied by abnormalities of the mucous glands and mucus hypersecretion. Small airways may be affected by occupational agents, and a pattern of injury distinct from that found in cigarette smokers has been described (Churg et al. 1985). However, the parenchymal abnormali- ties of advanced pneumoconiosis can be readily distinguished from emphysema associated with cigarette smoking. Methods for Evaluating the Effects of Occupational Exposures on the Lungs Workers exposed to occupational agents that cause chronic lung disease may be examined for diagnostic reasons, for surveillance, or for research. Regardless of the purpose of the evaluation, the same assessment techniques are generally used: history of respiratory symptoms, physical examination of the chest and extremities, 151 spirometry and other physiological tests, and chest x ray (American Thoracic Society 1982b; Boehlecke 1984; Townsend and Belk 1984). These techniques and their sensitivity to the effects of cigarette smoking are described below. History of Respiratory Symptoms Symptoms of lung disease are nonspecific; the most prevalent are cough, phlegm production, wheezing, and breathlessness or dyspnea (Gandevia 1981). Although a physician may take a conventional history to evaluate these symptoms, standardized questionnaires are generally used for surveillance and research purposes. In the 195Os, the British Medical Research Council developed a standardized respiratory symptoms questionnaire for studies of the epidemiology of chronic bronchitis and chronic obstructive lung disease (Samet 1978; Florey and Leeder 1982). In 1968, this question- naire was adopted for use in the United States by a committee of the American Thoracic Society (1969). Three years later, the National Heart and Lung Institute made available a version that had been modified to improve its suitability for the United States (US DHEW 1971). In 1978, the American Thoracic Society published a further revised respiratory symptoms questionnaire (Ferris 1978). The Medical Research Council questionnaire or one of these modified versions has been used in most studies of chronic lung disease in the workplace. All include a series of questions related to cough, phlegm, wheezing, and dyspnea. The Medical Research Council questionnaire was originally devel- oped for investigating the etiology of chronic bronchitis and airflow obstruction (Fletcher et al. 1959; Samet 1978). The questionnaire was designed, in part, to test one of the prevailing hypotheses about airflow obstruction: that mucus hypersecretion predisposed repeated lower respiratory tract infections and consequent airflow obstruction (Fletcher et al. 1959, 1976). Accordingly, the cough and phlegm questions were worded to be sensitive to the earliest phases of mucus hypersecretion, a condition largely attributable to cigarette smoking (US DHHS 1984). The questions may be less satisfactory for cough and sputum associated with other exposures, particularly if those other exposures produce a pattern of symptoms different from those due to cigarette smoking, such as nocturnal cough or episodic cough. Further, their sensitivity to cigarette-associated mucus hypersecre- tion may hinder separation of an occupational exposure's effect on the occurrence of cough and phlegm from that of cigarette smoking. The dyspnea and wheeze questions probably do not share this sensitivity. In population surveys, cigarette smoking is the major determinant of the prevalence of cough and phlegm (US DHHS 1984). This association has been confirmed in occupational groups as well as in 152 population samples (Gandevia 1981; US DHHS 1984; Petersen and Castellan 1984). Wheezing is also associated with cigarette smoking (Mueller et al. 1971; Samet et al. 1982; Schenker et al. 1982). Dyspnea has multiple determinants that interact in a complex fashion; cigarette smoking and smoking-related impairment of lung function contribub,: to the occurrence of dyspnea (Wasserman and Whipp 1975; Cotes 1979; Killian and Jones 1984). Chest X Ray The pneumoconioses are associated with characteristic radio- graphic abnormalities, although the chest film may be normal in the presence of biopsy-proven disease (Epler, McLoud et al. 1978). A conventional clinical interpretation is usually sufficient for estab- lishing the presence of pneumoconiosis. Preferably, however, the chest x ray should be coded according to the classification estab- lished by the International Labour Office (ILO) (1980). This system, originally published in 1950, categorizes the types of abnormalities on the chest x ray by shape and size, and provides a grading (the profusion) for describing the density of small opacities. The opacities classified as small are grouped as rounded or irregular. If the opacities are less than 1 cm in diameter, they are called small; if equal to or greater than 1 cm, they are called large. The effects of cigarette smoking on chest x-ray findings have been examined, using both conventional interpretations and readings in the IL0 system. Human autopsy evidence and animal exposure studies show that cigarette smoking leads to abnormalities in the airways and parenchyma that might produce radiographic abnor- malities (US DHEW 1979b; Weiss 1984). However, these changes are subtle in comparison with the pathological findings in the pneumo- conioses. Cigarette smoking is associated with modest amounts of interstitial fibrosis in the lungs, in addition to airways abnormalities and emphysema (US DHEW 1979b; Weiss 1984). For example, Auerbach and colleagues (1974) examined lung sections from 1,443 men and 388 women deceased between 1963 and 1970, and found more fibrosis in smokers than in nonsmokers and a dose-response relationship between the degree of fibrosis and the amount smoked. The small airways of cigarette smokers, even at young ages, display inflammation with edema of the bronchiolar walls, smooth muscle hypertrophy, and goblet cell metaplasia (US DHHS 1984). These changes may underlie, at least in part, the pattern of increased lung markings in smokers described anecdotally by clinicians, but are unlikely to be confused with the more extensive fibrosis found in moderate or advanced pneumoconiotic lung disease. Comparisons of chest x-ray findings generally show a higher frequency of abnormalities, interpreted as representing interstitial fibrosis, in smokers than in nonsmokers. These investigations have 153 been based on chest films from both the general population and specific occupational groups. Weiss (1967, 1969) reviewed chest films from two samples of adults-participants in a tuberculosis screening program and hospital employees. In both groups, he identified a pattern of increased lung markings, termed diffuse pulmonary fibrosis, more often in smokers, and showed that the prevalence of this finding increased with the amount and duration of smoking. These studies have been criticized because the films were 70 mm photofluorograms taken for screening purposes and not full sized (Kilburn 1981). Further, the films were not read directly according to the IL0 classification. In another study that did not use the IL0 system, Carilli and colleagues (1973) showed that radiologists could generally distinguish smoking women from nonsmoking women by the presence of linear and nodular fibrotic changes in the smokers. Epstein and colleagues (1984) read the chest x rays of 200 hospital- ized patients according to the IL0 classification. Twenty-two patients with at least category l/O profusion and no documented dust exposure or other explanation for nodular densities were identified, 10 of whom had not smoked cigarettes. Because this study included only hospitalized people, the results may not be generalizable to working populations. The results of investigations involving occupational groups do not show strong effects of cigarette smoking on the profusion of small opacities. Glover and colleagues (19801 read the chest films of slate workers and a nonexposed control group according to the 1971 IL0 classification. In the controls, small irregular opacities were not seen in nonsmokers, but were present in 2 percent of current and former smokers. Investigators from the National Institute for Occupational Safety and Health interpreted chest x rays of 1,422 blue-collar workers whose present and past employment should not have involved exposure to respiratory hazards (Castellan et al. 1984). Only three workers had at least category l/O profusion, two with small rounded opacities and one with small irregular opacities. Sixty-one percent of the subjects were current or former smokers. However, the mean age of subjects in this study was only 33.9 years, substantially lower than the age at which pneumoconiosis or significant cigarette-related airflow obstruction would generally be manifest if exposure began at about age 20. In a much smaller study of similar design, Cordier and colleagues (1984) identified small opacities in only 1 person in a control group of 48 office workers, 31 percent of whom smoked. Studies of workers exposed to hazardous agents show that cigarette smoking may modify the pattern of radiographic abnormal- ity. In coal workers, small rounded opacities predominate in the simple phase of coal workers' pneumoconiosis, but irregular opaci- ties may also be present (Amandus et al. 1976; Cockcroft et al. 1982, 154 1983). The irregular opacities are associated with cigarette smoking and with reductions of FEV1, FVC, and diffusing capacity (Cockcroft et al. 1982). In autopsy specimens obtained from coal workers in the United Kingdom, Ruckley and colleagues (1984) demonstrated that emphysema was present in 90 percent of the lungs with small irregular opacities, but in only 60 percent with small rounded opacities alone. Dick and colleagues (1983) examined the radiographs of a stratified random sample of miners from 10 British coal mines and concluded that smoking did not influence the prevalence of rounded opacities. Smokers had a greater prevalence of irregular opacities, but after adjusting for the effects of differences in age and dust exposure, these results were not statistically significant. Studies of other occupationally exposed groups also demonstrate that cigarette smoking may affect the pattern and extent of radiographic abnormality. In granite workers, Theriault and col- leagues (1974) found that rounded opacities were related to an estimate of lifetime dust exposure, whereas small irregular opacities were more strongly related to smoking. In workers exposed to manmade vitreous fibers, the prevalence of small opacities was determined not only by estimated exposure but also by smoking habits (Weill et al. 1983). Using multiple logistic regression, Peters and colleagues (1984) showed that cigarette smoking, but not particulate exposure, predicted the occurrence of linear opacities in silicon carbide workers. In asbestos workers, the predominance of evidence indicates that cigarette smoking acts independently and additively with asbestos to create radiographic abnormalities (Weiss 1984). The findings of these studies of occupationally exposed and nonexposed individuals indicate that cigarette smoking may affect chest x-ray readings. Cigarette smoking alone is occasionally associ- ated with definite abnormalities classified in the IL0 system. Smoking may also affect the radiographic pattern and independently increase the prevalence of abnormality. In addition, the threshold for detection of an abnormality on chest x ray may be exceeded more frequently or at an earlier age in workers who smoke than in workers who do not smoke. Physiological Assessment An evaluation of workers for diagnosis and surveillance may include auscultation of the chest, for breath sound quality and intensity and for the presence of adventitious sounds including crackles, and examination of the fingernails for evidence of clubbing. Crackles, also referred to as rales or crepitations, are discontinuous, interrupted sounds thought to arise from the sudden opening of small airways or from the bubbling of air through secretions in larger airways (Loudon and Murphy 1984). Fine crackles may be 155 heard in people with diffuse interstitial fibrosis. For example, Epler, Carrington, and colleagues (1978) reported that fine crackles were present in 60 and 65 percent of subjects with biopsy-proven and clinically diagnosed asbestosis, respectively. Some definitions of asbestosis incorporate the presence of crackles as a diagnostic criterion (Murphy et al. 1978). Because crackles may be heard in asbestosis and other occupational lung diseases, auscultation has been advocated as a surveillance technique for monitoring workers exposed to asbestos and other agents (Loudon and Murphy 1984; Murphy et al. 19841. Few studies have addressed the effects of cigarette smoking on auscultatory findings, however. Epler, Carrington, and colleagues (1978) reported the results of a conventional clinical auscultation of patients with various interstitial disorders or with chronic obstruc- tive lung disease, which is largely attributable to cigarette smoking. Fine crackles, characteristic of asbestosis, were heard in only 10 to 12 percent of the latter group, though coarse crackles were more common in those with chronic bronchitis. Two studies of asbestos workers suggest that cigarette smoking may independently increase the frequency of crackles. To quantify the separate effects of asbestos exposure and cigarette smoking on the prevalence of bilateral fine crackles, Samet and colleagues (1979) analyzed data from 409 survey subjects, using multiple logistic regression. Statistically significant effects of both smoking and asbestos exposure were found. In the other study (Murphy et al. 19841, a technician examined each subject with a standardized approach and a summary crackles score was calculated. Multivariate analysis suggested that cigarette smoking was associated with the lower abnormality levels of this score. The consistent findings of these two investigations seem plausible in view of the effects of cigarette smoking on the small airways, the site where fine crackles are presumed to originate (Loudon and Murphy 1984). In 590 employed men not exposed to respiratory hazards, crackles were heard predominantly in the older smokers (Gandevia 1981). This finding further supports a relationship between cigarette smoking and the presence of crackles. Clubbing refers to a change in the configuration of the nail beds, which can be best quantitated by the hyponychial angle (Regan et al. 1967). It has many causes and is a nonspecific manifestation of advanced chronic respiratory diseases, lung cancer, and other disorders (Shneerson 1981). Because clubbing may be occasionally found with COLD, its presence may be related to cigarette smoking as well as to occupational lung disease. Samet and colleagues (1979) found that cigarette smoking and occupational exposure to asbestos were independent determinants of the prevalence of clubbing in four different populations of asbestos workers. 156 Findings on clinical examination, like respiratory symptoms, are nonspecific, and a conventional physical examination alone is an insensitive method for diagnosing chronic occupational lung dis- eases. However, the presence of fine crackles, in the setting of an appropriate exposure, should alert the clinician to the possibility of pneumoconiosis, even if the chest x ray is unremarkable. Clubbing, when attributable to a chronic pulmonary process, is generally a marker for more advanced disease. Diseases associated with ciga- rette smoking may be accompanied by crackles or clubbing. Evaluation of pulmonary function in occupationally exposed individuals, whether for diagnostic or research purposes, should include spirometry, which measures FVC, FEV1, and maximal expiratory flow rates (Ferris 1978; American Thoracic Society 1982b). The effects of smoking on spirometric parameters are discussed elsewhere in this chapter. The diffusing capacity for carbon monoxide may also be measured; it is a sensitive test that may detect early abnormalities in chronic occupational lung diseases (Weinberger et al. 1980). As with FVC, FEVI, and other spirometric measures, cigarette smoking habits must be considered in interpret- ing the level of diffusing capacity, which is reduced by smoking- related lung disease (particularly emphysema) as well as by occupa- tional lung disease (Make et al. 1982; Miller et al. 19831. FVC can be reduced either by restrictive lung diseases, such as asbestosis, or by COLD; therefore, TLC should be measured with a physiological or radiological method in order to establish the presence of a restrictive disorder. In evaluating subjects for occupational asthma, nonspecific bronchial reactivity may be assessed with pharmacologic agents, such as methacholine, or with cold air inhalation (Brooks 1982). Some studies indicate that nonspecific bronchial reactivity is in- creased in cigarette smokers (Kabiraj et al. 1982; Gerrard et al. 1980), though others do not (Kennedy et al. 1984; Wanner et al. 1985). Exercise testing is one of the methods used to assess the degree of impairment resulting from a chronic occupational lung disease (American Thoracic Society 1982a). Exercise testing has been used to characterize the pathophysiology of chronic occupational lung diseases, but is rarely used for establishing clinical diagnoses or for epidemiological studies (Wiedemann et al. 1984) and is not discussed further in this chapter. Cigarette smoking can impair exercise performance through a variety of mechanisms (Cotes 1979). 157 Quantification of Effects of Smoking and Occupation in Populations Concepts of Interaction Interaction has been defined as "the interdependent operation of two or more causes to produce an effect" (Last 1983, p. 51). Epidemiclogists may also apply the term "effect modification" to variation in the magnitude of an exposure's effect as the level of another exposure changes (Last 1983). Synergism refers to an increased effect of the exposures when both are present, and antagonism refers to a reduced effect (Last 1983). Statistical model- ing techniques are generally used to test for the presence and direction of interaction. The most widely applied statistical tech- niques measure interaction on either an additive or a multiplicative scale (Rothman et al. 1980; Kleinbaum et al. 1982). Ideally, the choice of a model should be based on a specific biological formulation of disease pathogenesis; most often, however, the underlying biologi- cal mechanisms are not well established and largely statistical considerations govern the selection of an analytical model. The results of such models must be interpreted not only statistical- ly but also in biological and public health contexts (Rothman et al. 1980). Rothman and colleagues (1980) argued that biological models should be explicitly described; in their view, the labeling of mecha- nisms as synergistic or independent does not advance the under- standing of disease etiology. They broadly described two categories of mechanisms: those with the multiple etiological factors acting interchangeably at the same step and those with the factors acting at different steps. The corresponding statistical models are the additive and the multiplicative, respectively. These authors and others (Blot and Day 1979; Saracci 1980; Kleinbaum et al. 1982) have concluded that, from the public health viewpoint, departure from additivity represents interaction. Both advancing the understanding of disease etiology and the need for protecting public health provide a compelling rationale for assessing interaction between cigarette smoking and workplace exposures. Cigarette smoking may interact with a particular expo- sure through diverse mechanisms that range from behavioral to molecular levels (Table 4). The 1979 Report of the Surgeon General (US DHEW 1979131 partially addressed different forms of interaction between smoking and occupational exposures; other plausible hy- potheses concerning interaction between cigarette smoking and occupational agents can also be postulated. The interactions listed in Table 4 are intended to be illustrative and not exhaustive. Some consequences of cigarette smoking might lead to a reduction of the dose of an inhaled agent. In comparison with nonsmokers, current and former smokers have higher rates of absenteeism from 158 TABLE 4.Come potential interactions between cigarette smoking and occupational exposures in the pathogenesis of chronic occupational lung diseases Source of interactmn Potential consequence Increased absenteeism by smokers from work Reduced mhaled dose in smokers Selection of more fit nonsmokers into aerobically demandmg jobs Contaminated cigarettes act as a vector Reduced inhaled dose in smokers Increased exposure of smokers Workplace chemicals are metabolized to toxic or more toxic agents by cigarettes Increased exposure of smokers Increased tracheobronchial depwtion of particulates m smokers and people with chronic bronchitis Differing regional lung doses in smokers and nonsmoken Reduced mucociliary transport in smokers Increased dose in smokers Reduced alveolar clearance of particulates in smokers Increased dose in smokers Increased numbers of polymorphonuclear leukocytes and other inflammatory cells in lungs of smokers Increased lung injury in smokers work (US DHEW 1979b). Because cigarette smoking and cigarette- related cardiorespiratory diseases are associated with reduced aero- bic capacity, nonsmokers may tend to perform the more strenuous tasks in the workplace. The higher ventilatory requirements of such jobs might increase the amount of dust or other agents inhaled; smokers would be spared to the extent that they are selected for more sedentary jobs. The excess mucus production of chronic bronchitis might protect against soluble agents through the in- creased absorptive capacity of the mucus. Tobacco products might serve as vectors for the transformation of workplace chemicals into more harmful agents. For example, smokers are placed at increased risk for polymer fume fever through contamination of their cigarettes by fluorocarbons; toxic products are generated by the cigarette's heat and are inhaled by the smokers. Reduced pulmonary defenses in smokers might also increase the effects of occupational agents. The mucociliary apparatus of the airways removes particles and absorbed gases by physical transport (Wanner 1977; Lippmann et al. 1980). Both cilia and mucus are affected by tobacco smoke, and direct measurements of mucociliary 159 transport in animals and in humans confirm that long-term smoking impairs particle clearance (Wanner 1977; Lippmann et al. 1980; US DHHS 19841. Cohen and colleagues (1979) have demonstrated impaired alveolar clearance of particulates in smokers, as well. A plausible, though not established, consequence of reduced clearance is the increased pulmonary residence time of harmful agents and an increased dust burden in the lungs. Finally, alterations of lung cell populations and the presence of inflammation in smokers might amplify the effects of inhaled occupational agents. Inflammatory cells are thought to have a central role in lung injury caused by occupational agents (Campbell and Senior 1981; Bitterman et al. 1981). The lungs of smokers yield markedly increased numbers of macrophages and neutrophils in bronchoalveolar lavage fluid in comparison with the lungs of nonsmokers (US DHHS 1984). Thus, synergism between cigarette smoking and an occupational agent could reflect a greater release of enzymes and other toxic products from the large numbers of inflammatory cells that have been recruited into the lung by cigarette smoke. Study Design Several epidemiological study designs are used to assess the independent and interactive effects of smoking and occupational exposures in human populations. The cross-sectional study, or survey, is the most widely used approach, primarily because of its feasibility and low cost. Most surveys involve data collection from samples defined by employment status or union membership. In a cohort study, exposed and nonexposed people are followed over time and monitored for the development of disease. Large-scale cohort investigations of workers exposed to asbestos, silica, and coal dust have been carried out. The case-control design involves the identifi- cation of cases with the disease of interest and a control series of people without the disease who would be potentially selected as cases if they were to develop the disease. The exposure histories of the cases and controls are ascertained and compared. This design has been used infrequently for studying chronic occupational lung diseases. As a minimum, when cigarette smoking and a single occupational agent are of interest, the study should provide estimates of their independent effects and of the combined effect. This minimum is suggested because the impairment observed in a particular popula- tion reflects the consequences not only of the occupational agent but also of all other damaging environmental exposures. Of these, cigarette smoking is by far the most important and the most readily assessed. Cross-sectional, case-control, and cohort designs meet this requirement if the cigarette smoking practices and exposure histo- ries of the subjects can be accurately determined. 160 Assessment of Exposures Cigarette Smoking The American Thoracic Society (Ferris 1978) has recommended that a cigarette smoking questionnaire include smoking status (never, current, or previous), age started smoking, age stopped smoking (for former smokers), current and usual amount smoked, and depth of inhalation. Questions concerned with brand and extent of filter cigarette smoking are optional, but should be used when possible to address research questions related to types of cigarettes smoked. The recommended items provide several measures of exposure to cigarette smoke for data analysis: usual amount smoked, duration of smoking, and cumulative consumption. The items related to cigarette smoking status can be used to stratify a study population into current, former, and never smokers. These simple measures of exposure to cigarette smoking strongly predict the risk of both age-specific overall mortality and COLD mortality (US DHEW 1979b; US DHHS 1984). In the major prospective cohort studies, dose-response relationships between amount smoked and age-specific mortality have been demonstrated; the findings have been similar for duration of smoking (US DHEW 1979b). Associations with self-reported depth of inhalation have been less consistent. Indices of pulmonary morbidity also vary with measures of cigarette smoke exposure (US DHHS 1984). The consistency of these findings for morbidity and mortality emphasizes the importance of collecting information on the parameters of cigarette smoking in epidemiological investigations. Self-reported data may underestimate true cigarette consumption; however, the degree of bias has not been shown to vary with occupational status. For the United States and other countries, estimates of nationwide consumption based on survey data are generally lower than consumption figures calculated with informa- tion from manufacturers and government agencies (Todd 1978; Warner 1978). In the Multiple Risk Factor Intervention Trial (MRFIT), validation of smoking with serum thiocyanate measure- ments documented underreporting of smoking, which was greater in the group randomized to special intervention (Neaton et al. 1981; Ockene et al. 1982). This finding implies that bias in reported smoking may vary with the context in which the information is collected. Workers exposed to agents associated with lung disease might report their smoking habits differently from unexposed workers; both more and less accurate reporting by the exposed population can be postulated. 161 Occupational Exposures For clinical and research purposes, exposure to occupational agents should be documented and both duration and concentration estimated, when possible. The techniques used to establish exposure, duration, and concentration are diverse, and are not considered in detail here. Comprehensive reviews and books about them have been published (Hammad et al. 1981; Dodgson 1984; Cralley and Cralley 1979). The methods include self-report, use of industry, occupation, or job title as a surrogate for exposure, area sampling, personal dosimetry, and biological markers. Data Analysis In an epidemiological investigation of a population at risk for chronic occupational lung disease, information concerning work- place exposures and cigarette smoking is collected and appropriate health outcome measures, such as the chest radiograph and spirome- try, are assessed. Data analysis is directed at characterizing associa- tions between risk factors and disease and at the modifiers of these associations; in studies of chronic occupational lung disease, ciga- rette smoking and exposure to the occupational agent are the primary risk factors to be considered. Data analysis with epidemio- logical methods can provide estimates of the independent effects of smoking and the occupational agent and test for interaction between them (Kleinbaum et al. 1982). These techniques, some quite complex, are not described here, but approaches for assessing interaction are considered. Analysis of data related to a chronic occupational lung disease, regardless of the study design, must address the potential confound- ing and effect modification, or interaction, resulting from cigarette smoking. Confounding refers to the bias introduced when the effects of one factor are not separated from those of another. In studies of chronic occupational lung diseases, confounding may occur when estimates of exposure to the occupational agent are associated with cigarette smoking. For example, in a study of asbestos workers, confounding would be present if the more heavily exposed individu- als were also heavy smokers. Comparisons of blue-collar workers with white-collar employees may be confounded because the former are more often smokers. Confounding can be controlled at the design phase or at analysis by either stratified or multivariate techniques (Kleinbaum et al. 1982). Options in study design include restriction of participants to smokers or to nonsmokers alone and matching of occupationally exposed and nonexposed subjects for smoking habits. At analysis, whether stratified or multivariate, biologically appropriate and valid measures of cigarette smoking are needed. More simplistic variables, 162 such as categorical indicators designating never and ever smokers, may not be satisfactory, and their use may only partially control confounding. In particular, measures of cumulative consumption seem most appropriate for the lung function changes of COLD (Burrows et al. 1977; US DHHS 1984). However, errors in the measurement of smoking may reintroduce confounding and appar- ent effect modification (Kleinbaum et al. 1982). Simple generalizations cannot be offered concerning the potential magnitude of bias that uncontrolled confounding by cigarette smoking can produce. The bias will depend on the strength of the association between the occupational exposure and cigarette smok- ing and on the magnitude of smoking's effects in the population. However, because there is a high prevalence of smoking in the workforce and smoking has a strong association with lung function impairment, it should not be dismissed as a confounder merely because some particular level of effect is found for an occupational exposure. Further, the attainment of statistical significance for the effect of an occupational exposure does not exclude confounding. Either stratified or multivariate statistical techniques can be used to test for interaction. In the first approach, variation in the effects of one factor (e.g., an occupational agent) is examined across strata defined by the second factor (e.g., cigarette smoking). More often, multivariate regression models, either linear or logistic, are used to test for interaction (Kleinbaum et al. 1982). In linear regression models, the dependent variable is a continuous measure, such as FEV,; in the logistic model, the dependent variable is the occurrence or nonoccurrence of a discrete outcome, such as the presence of crackles. In both types of models, the independent variables may include terms for the individual exposures and cross-product terms to test for interaction. The regression coefficients estimate the effects of the exposures on the dependent variables. For example, models developed for an asbestos-exposed study population might include a variable for cumulative asbestos exposure, a variable for cumulative cigarette consumption, and a variable created by multi- plying the two. Statistically, the null hypothesis of no interaction is tested by the cross-product term. Failure to reject this null hypothe- sis indicates that the data are consistent with the two factors acting independently. However, interpretation of such analyses must consider the scale on which interaction is measured; linear models assess departure from additivity, whereas logistic models test departure from a multiplicative interaction (Kleinbaum et al. 1982). The coefficient for the cross-product term specifies the direction and magnitude of the effect of interaction, at various levels of the two interacting factors. The limitations posed by sample size must also be considered in interpreting the results of modeling. In studies of occupational groups, the number of subjects is most often determined by the size of the workforce and by feasibility considerations, and rarely on the basis of more formal sample size calculations with statistical methods. The statistical power of tests for interaction tends to be low (Greenland 19831, and potentially important interactions may not attain conventional levels of statistical significance without a sufficiently large population. Analysis of epidemiological data can also provide estimates of the effects of exposure at the individual level and at the group level (Kleinbaum et al. 1982). Measures of association between exposure and disease estimate the excess risk incurred by exposed individuals. Measures of impact combine measures of association with the prevalence of exposure and estimate the contribution of specific exposures to the disease burden in a population. The most widely used is the population attributable risk or etiologic fraction. These measures can be used to gauge the relative importance of cigarette smoking and occupational agents. Specific Investigation Issues Population Selection The most widely employed design for investigating occupational lung disease, the cross-sectional study or survey, may be biased when subjects are selected from the active workforce. The individuals examined at any particular time in a cross-sectional study may be regarded as survivors from the entire population that entered the particular workplace. Individuals with illness tend to leave the workforce, whereas healthy individuals tend to remain. This bias, often called the healthy worker effect, must be considered in both longitudinal and cross-sectional designs (Fox and Collier 1976; Wen et al. 1983). The implications for surveys of occupational lung disease are evident and have been widely discussed (McDonald 1981; Field 1981; Lebowitz 1981). If only employed workers are considered and individuals with occupational lung disease leave the workforce, the measures of association will underestimate the true effect of exposure. In fact, the leaving of employment by people who are ill has been demonstrated in several industries (Fox and Collier 1976; Musk et al. 1977; McDonald 1981; Soutar and Maclaren 1982; Eisen et al. 1983). The resulting bias should be evaluated by examining retirees and others who have left. The role of cigarette smoking in determining the magnitude of the healthy worker effect has not been fully evaluated. Overall mortality ratios for cigarette smokers are greater below age 65 (US DHEW 1979b), and cardiovascular diseases, respiratory diseases, and lung cancer generally contribute prominently to the reduced all-cause mortality of the healthy worker effect (Fox and Collier 1976; Wen et al. 19831. Thus, cigarette smokers would be anticipated to leave the 164 workforce prematurely more often than nonsmokers. A recent study of Vermont granite workers provides data that conflict with this hypothesis, however. Eisen and colleagues (1983) compared men who remained in the industry during a 5-year followup period with those who terminated. The rate of FEV, loss was greater in those who left the industry, but their cumulative cigarette consumption was not significantly greater than that of those who stayed. These data do illustrate the selection bias that results from differential termina- tion of employment, contingent on the development of disease. Eisen and colleagues (1983, 19841 have explored other sources of bias in respiratory disease surveys. In the granite workers' study, men whose spirometric testing repeatedly failed to meet criteria for acceptability had a more rapid decline of FEV, than those with a better performance. This finding suggests that the exclusion of subjects whose lung function testing is judged unacceptable may introduce bias toward the null. External Control Populations When subjects are selected for an epidemiological investigation, a population, not exposed to the agent of interest but similar in other respects to those who are, may not be available for comparison purposes. In this circumstance, an investigator may consider only the exposed subjects and evaluate the dose-response relationships if the necessary data are available, or identify an external population as controls. If the latter approach is used, the control population must be comparable to the exposed group on potential confounding factors such as age, sex, race, and cigarette smoking. At times, appropriate external populations may not be readily identified. Nevertheless, external control populations are frequently used. In mortality studies, the use of general population rates for calculation of "expected" deaths assumes that the general public is the control group. Frequently, lung function levels in exposed people are compared with those predicted from tests performed on "normal" populations, most often asymptomatic nonsmokers without respira- tory disease (Clausen 1982). Recently, Peterson and Castellan (1984) reported the prevalence of chest symptoms, as measured with a modified Medical Research Council questionnaire, in 1,372 blue- collar workers employed in plants considered to be free of respira- tory hazards. The data are illustrative of the effects of smoking on the prevalence of major respiratory symptoms; even in this young, employed population, all of the symptoms examined were more common in current and former smokers. The authors provided smoking-specific prediction equations and suggested that these data can be used for comparative purposes. 165 Coiinearity of Aging, Cigarette Smoking, and Occupational Exposure Effects From approximately age 25, measures of ventilatory function gradually and progressively decline. In nonsmokers, the rate of loss is approximately 20 to 30 mL annually for FEV, and FVC (US DHHS 1984). The decline in FEV, with age may not be a linear function with a constant decline each year, but rather, the absolute rate of annual decline may vary with age. In addition, the rate of decline in lung function with age derived from cross-sectional studies may be an overestimate of the actual rate of decline because of possible differences in lung function among different birth cohorts in cross-sectional studies. Some cigarette smokers lose function at much more rapid rates and ultimately develop COLD, unless they stop smoking (US DHHS 1984). Presumably, a similar insidious excess loss of function antedates the appearance of clinically evident chronic occupational lung disease. This simultaneous contribution of aging, smoking, and occupation- al exposure to lung function loss represents a formidable analytical problem. Further complicating its solution is the temporal colineari- ty or correlation of these three independent factors; age, cumulative smoking, and cumulative exposure all increase with the passage of time. Failure to address this colinearity may lead to confounding and to an incorrect assessment of the effect of exposure. This problem is most often addressed by using external standard populations to control for aging and, at times, cigarette smoking, or by multiple regression modeling (Berry 1981b). In the first approach, expected lung function levels in the exposed workers are calculated with prediction equations developed in other populations; sex, age, race, and cigarette smoking habits may all be considered in the calculations. For example, Beck and colleagues (1984) conducted a cross-sectional survey of cotton textile workers in Columbia, South Carolina. Spirometric test results for the cotton workers were compared with the expected values calculated from survey data collected in two towns in Connecticut and one town in South Carolina. For each cotton worker, an expected value was predicted on the basis of sex, age, height, and weight, with regression equations derived from asymptomatic nonsmokers in the control communities. Deviations from the expected value were then exam- ined within the strata defined by smoking. This approach is effective when appropriate external populations are available. Prediction equations developed for clinical purposes are frequently used, primarily owing to availability; investigators should, however, consider the comparability of the exposed workers with the "nor- mal" population from which the prediction equations were derived. Multiple regression techniques permit a simultaneous examina- tion of the effects of age, exposure, and smoking, as well as their 166 interactions, on lung function measures. Comprehensive treatments of these methods have been published (Draper and Smith 1966; Kleinbaum and Kupper 1978), and only their use for lung function data is considered here. With this approach, the lung function measures are the dependent variables, and age, smoking, and exposure are the independent variables in a model of this form: Y=a+B,X,+B,X,+BB,X,+ . . . BiX, + E; where Y is a lung function parameter, a is a constant term, X, through X, are the independent variables and B, through B, are their regression coefficients, and E is a term for error. The regression coefficients describe the change in Y per unit change in a particular X,, with all other independent variables held constant. An estimated regression equation is general- ly obtained by the least squares criterion. Most standard statistical packages for computers include this technique, and it can be readily applied to a data set. However, the results of such modeling may be misleading, and the plausibility of such models should be assessed by careful examination of the raw data and residuals and by other formal means. In addition, model development should be guided by biological rather than primarily statistical considerations; that is, the investigator should specify the regression model in the most appropriate fashion biologically, rather than rely on statistical procedures for variable selection. Colinearity of the age, smoking, and exposure effects may limit the multiple regression approach. High correlation in a data set between any two of these factors may prevent assessment of their independent effects. Quantification of Effects in Individuals Properly designed epidemiological investigations can provide essential information about the occurrence of chronic occupational lung diseases in populations. They can establish that an occupational exposure is hazardous, quantify the risk associated with exposure, describe the agent's contribution to the disease burden in the population, and document the consequences of reducing the expo- sures. For an individual, epidemiologically derived estimates of relative risk generally indicate the excess risk incurred by virtue of exposure to a particular agent, as compared with nonexposure. But such a measure of relative risk cannot be interpreted directly as a quantitative indicator of the chance that a particular individual's exposure to the agent was responsible for the occurrence of the disease concerned. Statements concerning causality in an individual case are particularly difficult when the disease of interest has multiple causes and interactions among them are of potential importance. Judgments concerning the causation of disease in specific individu- als are frequently necessary, however, for deciding claims made 167 through workmen's compensation, the courts, or other mechanisms (Hoffman 1984; Hadler 1984). Legal proof of causation hinges on a finding that the exposure more likely than not caused the disease (Danner and Saga11 1977; Hoffman 1984). Allocation of probability of causation when multiple agents interact is particularly problematic (Cox 19841, but frequently necessary. In particular, the evaluation of impairment in cigarette smokers exposed to harmful occupational agents requires judgment concerning the independent and combined effects of all exposures. Accepted methods for accomplishing this quantification have not yet been developed. Enterline (1983) considered the problem for two agents that interact in a multiplicative fashion. Cox (1984) has suggested an approach that covers the situation of joint and interacting causes. Algorithms have been proposed for specific diseases, such as asbestosis (Mitchell et al. 19851, and for specific agents, such as radiation (NRC 1984). However, these approaches have only recently been proposed and their applicability remains to be established. Some guidance can be found, however, in the pattern of physiologi- cal abnormality. For example, the impairment in a smoker with asbestosis, but with no evidence of airflow obstruction, can be attributed mostly to the pneumoconiosis. Correspondingly, the presence of airflow obstruction and an increased TLC in an asbestos worker who smokes and who has a normal chest x ray suggests that the impairment is largely attributable to cigarette smoking. The problem is more complicated in those situations where reduced expiratory airflow is present and TLC is decreased or in those pneumoconioses where reductions in the rate of expiratory airflow are part of the pattern of the pneumoconiosis. For example, reductions of FEV1, FVC, and FEV,/FVC may all be found in complicated silicosis and coal workers' pneumoconiosis, and these patterns are similar to those found in cigarette smokers. Emphyse- ma decreases lung elastic recoil, whereas some pneumoconioses, such as asbestosis, increase it. These competing effects may result in a TLC that is increased, normal, or reduced in a smoker with COLD and pneumoconiosis, depending on which effect predominates. Thus, smokers with COLD and pneumoconiosis display diverse patterns of lung function abnormality. Evidence of airflow obstruction on spirometry may be accompanied by a reduced, normal, or increased TLC, and the diffusing capacity for carbon monoxide will generally be reduced regardless of the cause of the injury. In this setting, the diagnosis of pneumoconiosis can often be established from the chest x ray findings, but responsibility for impairment cannot readily be divided between COLD and pneumoconiosis. For chronic occupation- al lung diseases associated with airflow obstruction, even diagnosis may be difficult in an individual cigarette smoker. 168 A second method of separating the relative effects of two agents in a combined exposure is to use the known dose-response relationships for the agents. This approach is most useful when exposure to one agent has been slight in comparison with the exposure to the second agent. Difficulty arises when an individual has been exposed to biologically equivalent doses of both agents or when exposure to one of the agents cannot accurately be assessed. Summary and Conclusions During the 20th century, cigarette smoking has become prevalent among workers at risk for occupational lung disease. By itself, smoking causes pulmonary impairment; among people exposed to harmful occupational agents, the interactive effects of smoking may increase the number of individuals developing clinically significant impairment. For both clinicians and researchers, cigarette smoking by workers poses difficult and important challenges. 1. Existing resources for monitoring the occurrence of occupation- al lung diseases are not comprehensive and do not include information on cigarette smoking. Other approaches, such as registries, might offer more accurate data and facilitate research related to occupational lung diseases. Because of the variability in diagnostic criteria for chronic lung disease, in studies on occupational lung diseases emphasis should be placed on measures of physiological change, roentgenographic abnormality, and other objective measures. 2. Further studies that correlate lung function with histopatholo- gy should be carried out in occupationally exposed smokers and nonsmokers. 3. The effects of cigarette smoking on the chest x ray should be clarified. In particular, the sensitivity of the IL0 classification to smoking-related changes should be further evaluated in healthy populations. 4. To determine if smoking is reported with bias by occupational- ly exposed workers, self-reported histories should be compared with biological markers of smoking in appropriate populations. 5. Mechanisms through which specific occupational agents and cigarette smoking might interact should be systematically considered. Both laboratory and epidemiological approaches should be used to evaluate such interactions. 6. Statistical methods for evaluating interaction require further development. In particular, the biological implications of conventional modeling approaches should be explored. Fur- ther, the limitations posed by sample size for examining independent and interactive effects should be evaluated. The 169 157-964 3 - 86 - 7 consequences of misclassification by exposure estimates and of the colinearity of exposure variables should also be addressed. 7. The role of cigarette smoking in the "healthy worker effect" requires further evaluation. 8. Approaches for apportioning the impairment in a specific individual between occupational causes and cigarette smoking should be developed and validated. 170 References AMANDUS, H.E., LAPP, N.L., JACOBSON, G., REGER, R.B. Significance of irregular small opacities in radiographs of coalminers in the USA. Brittish Jolrrnal oflndustrial Medicine 33(1):13-17, February 1976. AMERICAN THORACIC SOCIETY. Standards for Epidemiologic Surveys in Chronic Respimtory Disease. New York, National Tuberculosis and Respiratory Disease Association, 1969.32 pp. AMERICAN THORACIC SOCIETY. Evaluation of impairment/disability secondary to respiratory disease American Review of Respiratory Disease 126(5):945951, November 1982a. AMERICAN THORACIC SOCIETY. Surveillance for respiratory hazards in the occupational setting. American Review of Respiratory Disease 126(5):952-956, November 1982b. AUERBACH, 0.. GARFINKEL, L., HAMMOND, E.C. Relation of smoking and age to findings in lung parenchyma: A microscopic study. Chest 65(1):29-35, January 1974. BECK, G.J., MAUNDER, L.R.. SCHACHTER, E.N. Cotton dust and smoking effects on lung function in cotton textile workers. American Journal of Epidemiology 119(1):33-43, January 1984. BERRY, G. Mortality of workers certified by pneumoconiosis medical panels as having asbestosis. British Journal of Industrial Medicine 38(2):130-137, May 1981a. BERRY, G. Statistical analyses. In: Weill, H., Turner-Warwick, M. (eds.). Occupational Lung Diseases: Research Approaches and Methods. Lung Biology in Health and Disease, Vol. 18. New York, Marcel Dekker, 1981b, pp. 427-463. BI'ITERMAN. P.B., RENNARD, S.I., CRYSTAL, R.G. Environmental lung disease and the interstitium. Clinics in Chest Medicine 2(3):393-412, September 1981. BLOT, W.J., DAY, N.E. Synergism and interaction: Are they equivalent? (letter). American Journal of Epidemiology 110(1X99-100, July 1979. BOEHLECKE, B. Medical monitoring of lung disease in the workplace. In: Gee, J.B.L. fed.). Occlrpational Lung Disease. New York, Churchill Livingstone, 1984, pp. 225- 240. BOUSHY, SF., ABOUMRAD, M.H., NORTH, L.B., HELGASON, A.H. Lung recoil pressure, airway resistance, and forced flows related to morphologic emphysema. American Review of Respiratory Disease 104(4):551661, October 1971. BROOKS, S.M. The evaluation of occupational airways disease in the laboratory and workplace. Journal of Allergy and Clinical Immunology 70(1):5&(X, July 1982. BURROWS, B., KNUDSON, R.J., CLINE, M.G., LEBOWITZ, M.D. Quantitative relationships between cigarette smoking and ventilatory function. American Review of Respiratory Disease 115(2):19&205, February 1977. CAMPBELL, E.J., SENIOR, R.M. Cell injury and repair. Clinics in Chest Medicine 2(3):357-375, September 1981. CARILLI, A.D., KOTZEN, L.M., FISCHER, M.J. The chest roentgenogram in smoking females. American Review of Respiratory Disease 107(1):133-136, January 1973. CASTELLAN, R.M., SANDERSON, W.T., PETERSEN, M.R. Prevalence of radio- graphic appearance of pneumoconiosis in an unexposed blue collar population. (abstract). American Review OfRespiratory Disease 129(4):A155, April 1984. CHURG, A., WRIGHT, J.L., WIGGS, B., PARE, P.D., LAZAR, N. Small airways disease and mineral dust exposure: Prevalence, structure, and function. American Review ofRespiratory Disease 131(1):139-143, January 1985. CLAUSEN, J.L. Prediction of normal values. In: Clausen, J.L. (ed.). Pulmonary Function Testing Guidelines and Controversies: Equipment, Methods, and Normal Values. New York, Academic Press, 1982, pp. 49-59. COCKCROFT, A., BERRY, G., COTES, J.E., LYONS, J.P. Shape of small opacities and lung function in coalworkers. Thorax 37(10):765-769, October 1982. 171 COCKCROFT, A., LYONS, J.P., ANDERSSON, N., SAUNDERS, M.J. Prevalence and relation to underground exposure of radiological irregular opacities in South Wales coal workers with pneumoconiosis. British Journal of Industrial Medicine 40(2):169-172, May 1983. COHEN, D., ARAI, S.F.. BRAIN, J.D. Smoking impairs long-term dust clearance from the lung. Science 20414392):514-517, May 4,1979. CORDIER, S., THERIAULT, G., PROVENCHER, S. Radiographic changes in a group of chrysotile miners and millers exposed to low asbestos dust concentrations. British Journal of Industrial Medicine 41(3):384-388, August 1984. COSIO, M., GHEZZO, H., HOGG, J.C., CORBIN, R., LOVELAND, M., DOSMAN, J., MACKLEM, P.T. The relations between structural changes in small airways and pulmonary-function tests. Neu England Journal of Medicine 298(23):1277-1281, June 8,1978. COTES, J.E. Lung Function Assessment and Application in Medicine. 4th ed. Oxford, Blackwell Scientific Publications, 1979,605 pp. COX, L.A., Jr. Probability of causation and the attributable proportion of risk. Risk Anal.@ 4(3):221-230, 1984. CRALLEY. L.J., CRALLEY, L.V. Theory and Rationale of Industrial Hygiene Practice. Patty's Industrial Hygiene and Toxicology, Vol. 3. New York, John Wiley and Sons, 1979,752 pp. DANNER. D., SAGALL, E.L. Medicolegal causation: A source of professional misunderstanding. American Journal of Law and Medicine 3(3):303-308, Fall 1977. DICK, J.A., JACOBSEN, M., GAULD, S., PERN, P.O. The significance of irregular opacities in the chest radiographs of British coal miners. Proceedings of the Sixth International heumoconiosis Conference, 1983. Vol. 1. Geneva, International Labour Office, pp. 283-299. DCDGSON, J. The measurement of dusts and fumes. In: Morgan, W.K.C., Seaton, A. feds.!. Occupational Lung Diseases. 2d ed. Philadelphia, W.B. Saunders Co., 1984, pp. 212-238. DO PICO, G.A., REDDAN, W., FLAHERTY. D., TSIATIS, A., PETERS, M.E., RAO, P., RANKIN, J Respiratory abnormalities among grain handlers: A clinical, physio- logic, and immunologic study. American Reoiew of Respiratov Disease 115(61:915- 927, June 1977. DOSMAN, J.A., COTTON, D.J., GRAHAM, B.L., LI, K.Y.R., FROH, F., BARNE'IT. G.D. Chronic bronchitis and decreased forced expiratory flow rates in lifetime nonsmoking grain workers. American Retlieu' of Respiratov Disease 121(1):11-16, January 1980. DOUGLAS, A.N., LAMB, D., RUCKLEY, V.A. Bronchial gland dimensions in coal miners: Influence of smoking and dust exposure. Thorax 37(103:760-764, October 1982. DRAPER. N.R., SMITH, H. Applied Regression Analysis. New York, John Wiley and Sons, 1966.407 pp. EDWARDS, C., MACARTNEY, J., ROOKE, G., WARD, F. The pathology of the lung in byssinotics. Thorax 30(6):612623, December 1975. EISEN, E.A., ROBINS, J.M., GREAVES, I.A., WEGMAN, D.H. Selection effects of repeatability criteria applied to lung spirometry. American Journal of Epidemiolo- g.v 120(5):734-742, November 1984. EISEN, E.A., WEGMAN, D.H., LOUIS, T.A. Effects of selection in a prospective study of forced expiratory volume in Vermont granite workers. American Review of Respiratory Dzsease 128(4):587-591, October 1983. ENTERLINE, P.E. Sorting out multiple causal factors in individual cases. In: Chiazze, L., Jr., Lundin, F.E., Watkins, D. (eds.1. Methods and Issues in Occupational and Enlaironmental Epidemiologv. Ann Arbor, Ann Arbor Science Publishers, 1983, pp. 177-182. EPLER, G.R., CARRINGTON, C.B., GAENSLER, E.A. Crackles (ralesi in the interstitial pulmonary diseases. Chest 73(31:33%339, March 1978. EPLER, G.R., McLOUD, T.C., GAENSLER, E.A., MIKUS, J.P., CARRINGTON, C.B. Normal chest roentgenograms in chronic diffuse infiltrative lung disease. A&L* England Journal of Medictne 298(17):934-939, April 27,1978. EPLER, G.R., SABER. F.A., GAENSLER, E.A. Determination of severe impairment (disability, in interstitial lung disease. American Revieu of Respiratory Disease 121(4):647-659, April 1980. EPSTEIN, D.M., MILLER. W.T., BRESNITZ. E.A., LEVINE, MS., GEETER, W.B. Application of IL0 classification to a population without industrial exposure: Findings to be differentiated from pneumoconiosis. American Journal of Roentge- nology 142(11:53-58, January 1984. FERRIS, B.G. Epidemiology standardization project. American Review of Respiratory Disease 118(61:1-120, December 1978. FIELD, G.B. Worker surveys. In: Weill, H., Turner-Warwick, M. (eds.). Occupational Lung Diseases: Research Approaches and Methods. Lung Biology in Health and Disease, Vol. 18. New York, Marcel Dekker. 1981, pp. 405-426. FLETCHER, C.M., ELMES. P.C., FAIRBAIRN, A.S., WOOD, C.H. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. British Medical Journal 2(5147):257-266, August 29,1959. FLETCHER, C.M., PETO, R.. TINKER, C., SPEIZER, F.E. The Natural History of Chronic Bronchitis and Emphysema: An Eight-Year Study of Early Chronic Obstructive Lung Disease in Working Men in London. Oxford, Oxford University Press, 1976,272 pp. FLOREY, C. du V., LEEDER, S.R. Methods for Cohort Studies of Chronic Airf7ou Limitation. WHO Regional Publications, European Series No. 12. Copenhagen, World Health Organization, Regional Office for Europe, 1982, 140 pp. FOX, A.J., COLLIER, P.F. Lo w mortality rates in industrial cohort studies due to selection for work and survival in the industry. British Journal of Preuentioe and Social Medicine 3&4):225-230, December 1976. FRIEDMAN, G.D., SIEGELAUB, A.B., SELTZER, CC. Cigarette smoking and exposure to occupational hazards. Amertcan Journal of Epidemiology 98(3?:175- 183, September 1973. GANDEVIA, B.H. Clinical techniques. In: Weill, H.. Turner-Warwick, M. (eds.1. Occupational Lung Diseases: Research Appraaches and Methods. Lung Biology in Health and Disease, Vol. 18. New York, Marcel Dekker, 1981, pp. 11-33. GERRARD, J.W., COCKCROFT, D.W., MINK, J.T., COTTON, D.J., POONAWALA, R., DOSMAN, J.A. Increased nonspecific bronchial reactivity in cigarette smokers with normal lung function, American Review of Respiratory Disease 122(4):577- 581, October 1980. GLOVER, J.R., BEVAN, C., COTES, J.E., ELWOOD, P.C., HODGES, N.G., KELL, R.L., LOWE, CR., MCDERMOTT, M., OLDHAM, P.D. Effects of exposure to slate dust in North Wales. British Journal of Industrial Medicine 3712):152-162, May 1980. GREENLAND, S. Tests for interaction in epidemiologic studies: A review and a study of power. Statistics in Medicine 2(21:243-251, April-June 1983. GRUCHOW, H.W.. HOFFMANN, R.G., MARX. J.J., Jr., EMANUEL, D.A., RIMM, A.A. Precipitating antibodies to farmer's lung antigens in a Wisconsin farming population. American Recieu: of Respiratory Disease 124(4):411-415. October 1981. HADLER, N.M. Occupational illness: The issue of causality. Journal of Occupational Medicine 26(8):587-593, August 1984. HAMMAD, Y., CORN, M., DHARMARAJAN, V. Environmental characterization. In: Weill, H., Turner-Warwick, M. (eds.). Occupational Lung Diseases: Research Approaches and Methods. Lung Biology in Health and Disease, Vol. 18. New York, Marcel Dekker. 1981. pp. 291-371. 178 HAMMOND, E.C., SELIKOFF, I.J., SEIDMAN, H. Asbestos exposure, cigarette smoking and death rates. Annals of the New York Academy of Sciences 330:471 490, December 14,1979. HANKINSON, J.L., REGER, R.B., MORGAN, W.K.C. Maximal expiratory flows in coal miners. American Review of Respiratory Disease 116(2):175-180, August 1977. HOFFMAN, R.E. The use of epidemiologic data in the courts. American Journal of Epidemiology 120(21:19&202, August 1984. HUNTER, D. The Diseases of Occupations. 6th ed. London, Hodder and Stoughton, 1978, 1,257 pp. INTERNATIONAL LABOUR OFFICE. International Classification of Radiographs of Pneumoconioses. Occupational Safety and Health Series, No. 22. (rev.). Geneva, International Labour Office, 1980. IRWIG, L.M., ROCKS, P. Lung function and respiratory symptoms in silicotic and nonsilicotic gold miners. American Review of Respiratory Disease 117(3):429-435, March 1978. KABIRAJ, M.U., SIMONSSON, B.G., GROTH, S., BJORKLUND, A., BULOW, K., LINDELL, S.-E. Bronchial reactivity, smoking, and alpha,-antitrypsin: A popula- tion-based study of middle-aged men. American Review of Respimtory Disease 126f5k864-869, November 1982. KAMINSKI. R., BROCKERT, J., SESTITO, J., FRAZIER, T. Occupational information on death certificates: A survey of state practices. American Journal of Public Health 71(5):525-526, May 1981. KENNEDY, S.M., ELWOOD, R.K., WIGGS, B.J.R., PARE, P.D., HOGG, J.C. Increased airway mucosal permeability of smokers: Relationship to airway reactivity. American Review of Respimtory Disease 129(1):143-148, January 1984. KIBELSTIS, J.A., MORGAN, E.J., REGER, R., LAPP, N.L., SEATON, A., MORGAN, W.K.C. Prevalence of bronchitis and airway obstruction in American bituminous coal miners. American Review of Respiratory Disease 108(41:8X%-893, October 1973. KILBURN, K.H. Cigarette smoking does not produce or enhance the radiologic appearance of pulmonary fibrosis. American Journal of Industrial Medicine 2(4):305-308,198l. KILLIAN, K.J., JONES, N.L. The use of exercise testing and other methods in the investigation of dyspnea. Clinics in Chest Medicine X1):99-108, March 1984. KLEINBAUM, D.G., KUPPER, L.L. Applied Regression Analysis and Other Multi- variable Methods. North Scituate, Massachusetts, Duxbury Press, 1978, 556 pp. KLEINBAUM, D.G., KUPPER, L.L., MORGENSTERN, H. EpidemioZogic Research: Principles and Quantitatioe Methods. Belmont, California, Lifetime Learning Publications, 1982,529 pp. LAST, J.M. (ed.). A Dictionary of Epidemiology New York, Oxford University Press, 1983. LEBOWITZ, M.D. Epidemiological recognition of occupational pulmonary diseases. Clinics in Chest Medicine 2(3):305316, September 1981. LEBOWITZ, M.O., KNUDSON, R.J., BURROWS, B. Tucson epidemiologic study of obstructive lung diseases: I. Methodology and prevalence of disease. American Journal of Epidemiology 102(2):137-152, August 1975. LIPPMANN, M., YEATES, D.B., ALBERT, R.E. Deposition, retention, and clearance of inhaled particles. British Journal of Industrial Medicine 37(4):337-362, Novem- ber 1980. LOUDON, R., MURPHY, R.L.H., Jr. Lung sounds. American Review of Respimtory Disease 130(4):663-673, October 1984. MAKE, B., MILLER, A., EPLER, G., GEE, J.B.L. Single breath diffusing capacity in the industrial setting. Chest 82(3):351-356, September 1982. MCDONALD, J.C. Epidemiology. In: Weill, H., Turner-Warwick, M. (eds.). Occupation- al Lung Diseases: Research Approaches and Methods. Lung Biology in Health and Disease, Vol. 18. New York, Marcel Dekker, 1981, pp. 373-403. 174 MERCHANT, J.A., KILBURN, K.H., O'FALLON, W.M., HAMILTON, J.D., LUMS DEN, J.C. Byssinosis and chronic bronchitis among cotton textile workers. Annals oflnternal Medicine 76(3):423-433, March 1972. MERCHANT, J.A., LUMSDEN, J.C., KILBURN, K.H., O'FALLON, W.M., UJDA, J.R., GERMINO, V.H., Jr., HAMILTON, J.D. An industrial study of the biological effects of cotton dust and cigarette smoke exposure. Journal of Occupational Medicine 15(3):212-221, March 1973. MILLER, A., THORNTON, J.C., WARSHAW, R., ANDERSON, H., TEIRSTEIN, AS., SELIKOFF, I.J. Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state: Predicted values, lower limits of normal, and frequencies of abnormality by smoking history. American Review of Respiratory Disease 127(3):27&277, March 1983. MITCHELL, R.S., CHASE, G.R., KOTIN, P. Evaluation for compensation of asbestos- exposed individuals: I. Detection and quantification of asbestos-related nonmalig- nant impairment. Journal of Occupational Medicine 27(2):95-109, February 1985. MITCHELL, R.S., MAISEL, J.C., DART, G.A., SILVERS, G.W. The accuracy of the death certificate in reporting cause of death in adults, with special reference to chronic bronchitis and emphysema. American Review of Respiratory Disease 104(6):844-850, December 1971. MORGAN, W.K.C. Industrial bronchitis. British Journal of Zndustrial Medicine 35(4):28&291, November 1978. MORGAN, W.K.C. Coal workers' pneumoconiosis. In: Morgan, W.K.C., Seaton, A. (eds.). Occupational Lung Diseases. 2d ed. Philadelphia, W.B. Saunders Co., 1984a, pp. 377-448. MORGAN, W.K.C. Industrial bronchitis and other nonspecific conditions affecting the airways. In: Morgan, W.K.C., Seaton, A. (eds.1. Occupational Lung Diseases. 2d ed. Philadelphia, W.B. Saunders Co., 1984b, pp. 521540. MORGAN, W.K.C., BURGESS, D.B., JACOBSON, G., O'BRIEN, R.J., PENDER- GRASS, E.P., REGER, R.B., SHOUB, E.P. The prevalence of coal workers' pneumoconiosis in U.S. coal miners. Archives ofEnvironmental HeaIth 27(4):221- 226, October 1973. MORRING, K.L., A'lTFIELD, M. Dust Concentrations and Prevalence of Pneumoco- niosis in the United States and Great Bn'tain: A Re-Examination and Comparison of Data Prior to 1970. Paper presented at the Coal Mine Dust Conference, Morgantown, West Virginia, October 8-10,1984. MUELLER, R.E., KEBLE, D.L., PLUMMER, J., WALKER, S.H. The prevalence of chronic bronchitis, chronic airway obstruction, and respiratory symptoms in a Colorado city. American Review of Respiratory Disease 103(2):20%228, February 1971. MURPHY, R.L.H., Jr., GAENSLER, E.A., FERRIS, B.G., FITZGERALD, M., SOLLI- DAY, N., MORRISEY, W. Diagnosis of "asbestosis": Observations from a longitudi- nal survey of shipyard pipe coverers. American Journal of Medicine 65(3):4-g& September 1978. MURPHY, R.L.H., Jr., GAENSLER, E.A., HOLFORD, SK., DEL BONO, E.A., EPLER, G. Crackles in the early detection of asbestosis. American Review of Respimtory Disease 129(3):375379, March 1984. MUSK, A.W., PETERS, J.M., WEGMAN, D.H. Lung function in fire fghters: II. A five year follow-up of retirees. American Journal of Public Health 67(7):630-633, July 1977. NATIONAL CENTER FOR HEALTH STATISTICS. Mortality. Vital Statistics of the United States, 1970, Vol. 2, Part A. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, DHEW Pub. No. (HRA)75-1101,1974,648 pp. 175 NATIONAL RESEARCH COUNCIL. Assigned Share for Radiation as a Cause of Cancer: Review of Radioepidemiologic Tables Assigning Probabilities of Causation. National Research Council, Commission on Life Sciences, Board on Radiation Effects Research, Oversight Committee on Radioepidemiologic Tables, Washing- ton, D.C., National Academy Press, 1984,210 pp. NEATON, J.D., BROSTE, S., COHEN, L., FISHMAN, E.L., KJELSBERG, M.O., SCHOENBERGER, J. The multiple risk factor intervention trial (MRFIT): VII. A comparison of risk factor changes between the two study groups. Preventive Medicine 10(4):519-543, July 1981. NIEWOEHNER, D.E., KLEINERMAN, J., RICE, D.B. Pathologic changes in the peripheral airways of young cigarette smokers. New England Journal of Medicine 291(15):755-758, October 10, 1974. OCKENE. J.K., HYMOWITZ, N., SEXTON, M., BROSTE, SK. Comparison of patterns of smoking behavior change among smokers in the multiple risk factor intervention trial (MRFIT). Preventive Medicine 11(6):621-638, November 1982. PARK, S.S., JANIS, M., SHIM, C.S., WILLIAMS, M.H., Jr. Relationship of bronchitis and emphysema to altered pulmonary function. American Review of Respiratory Disease 102(6):927-936, December 1970. PETERS, J.M., SMITH, T.J., BERNSTEIN, L., WRIGHT, W.E., HAMMOND, SK. Pulmonary effects of exposures in silicon carbide manufacturing. British Journal ofIndustrial Medicine 41(1):109-115, February 1984. PETERSEN, M., CASTELLAN, R.M. Prevalence of chest symptoms in nonexposed blue-collar workers. Journal of Occupational Medicine 26(5):367-374, May 1984. RAMAZZINI, B. Diseases of Workers. Trans. by W.C. Wright. Chicago, University of Chicago Press, 1940. (Originally published as De Morbis Artificum. Geneva, 1713.) RANK, P., BAL, D.G. Chronic obstructive lung disease. Western Journal of Medicine 141(3):404405, September 1984. REGAN, G.M., TAGG, B., THOMSON, M.L. Subjective assessment and objective measurement of finger clubbing. Lancet 1(7489):530-532, March 11, 1967. ROTHMAN, K.J., GREENLAND, S., WALKER, A.M. Concepts of interaction. American Journal of Epidemiology 112(4):467-t70, October 1980. RUCKLEY, V.A., FERNIE, J.M., CHAPMAN, J.S., COLLINGS, P., DAVIS, J.M.G., DOUGLAS, A.N., LAMB, D.. SEATON, A. Comparison of radiographic appear- ances with associated pathology and lung dust content in a group of coalworkers. British Journal of Industrial Medicine 41(4):459-467, November 1984. SAMET, J.M. A historical and epidemiologic perspective on respiratory symptoms questionnaires. American Journal of Epidemiolog-v 108c6k435-446, December 1978. SAMET. J.M., EPLER. G.R.. GAENSLER, E.A., ROSNER, B. Absence of synergism between exposure to asbestos and cigarette smoking in asbestosis. American Recieu' of Respirafon Disease 120(1):75-82, July 1979. SAMET. J.M., SCHRAG, SD., HOWARD, CA., KEY, C.R.. PATHAK, D.R. Respira- tory disease in a New Mexico population sample of Hispanic and non-Hispanic whites. .4merzcan Revieu, of Respiratory Disease 125(2):152-157, February 1982. SAMET, J.M.. YOUNG, R.A., MORGAN, M.V., HUMBLE, C.G., EPLER, G.R.. McLOUD, T.C. Prevalence survey of respiratory abnormalities in New Mexico uranium miners, Health Ph~srcs 46(2):361-370, February 1984. SARACCI, R. Interaction and synergism. American Journal of Epidemiology 11214):465466, October 1980. SCHENKER. M.B., SAMET. J.M., SPEIZER, F.E. Effect of cigarette tar content and smoking habits on respiratory symptoms in women. American Review of Respira- tory Disease 12516):684690, June 1982. SEATON, A. Asbestos-related diseases. In: Morgan, W.K.C., Seaton, A. (eds.). Occupational Lung Diseases. 2d ed. Philadelphia, W.B. Saunders Co., 1984a, pp. 323-376. 176 SEATON, A. Silicosis. In: Morgan, W.K.C., Seaton, A. (eds.1. Occupational Lung Diseases. 2d ed. Philadelphia, W.B. Saunders Co., 1984b, pp. 250-294. SHNEERSON, J.M. Digital clubbing and hypertrophic osteoarthropathy: The under- lying mechanisms. British Journal of Diseases of the Chest 75(2):113-131, 1981. SOUTAR, CA., MACLAREN, W. A follow-up study of pneumoconiosis in miners and ex-miners. (abstract). Thorax 37(10):?8C-781, October 1982. STERLING, T.D., WEINKAM, J.J. Smoking characteristics by type of employment. Journal ofOccupational Medicine 18(11):743-754, November 1976. THERIAULT, G.P., PETERS, J.M., JOHNSON, W.M. Pulmonary function and roentgenographic changes in granite dust exposure. Archives of Environmental Health 28(1):23-27, January 1974. TODD, G.F. Cigarette consumption per adult of each sex in various countries. Journal ofEpidemiology and Community Health 32(4):289-293. December 1978. TOWNSEND, M.C., BELK, H.D. Development of a standardized pulmonary function evaluation program in industry. Journal of Occupational Medicine 26(9):657*1, September 1984. U.S. DEPARTMENT (!I' HEALTH. EDUCATION, AND WELFARE. Mortality. Vital Statistics of the L:nited ?ta(qs, 1960. Vol. 2, Part A. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, 1963. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. International Classification of Diseases: Adapted for Use in the United States. 8th rev. Vol. 2. U.S. Department of Health Education, and Welfare, Public Health Service, Sational Center for Health Statistics, PHS Pub. No. 1693, 1968,671 pp. US DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Proceedings, First NHLBZ Epidemiology Workshop. Washington, D.C., US. Government Print- ing Office, 1971. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Vital Statistics: Instructions for Classifying the Underlying Cause of Death, 1979. U.S. Department of Health, Education, and Welfare, Public Health Service, National Center for Health Statistics, September 1978, 96 pp. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Disability Evaluation Under Social Security: A Handbook for Physicians. US. Department of Health, Education, and Welfare, Social Security Administration, DHEW Pub. No. (SSA)79-10089,1979a, pp. 23-27. U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking and Health: A Report of the Surgeon General. U.S. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHEW Pub. No. (PHS179-50066, 1979b, 1,136 pp. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Characteristics of Social Security Disability Insurance Beneficiaries. U.S. Department of Health and Human Services, Social Security Administration, Office of Policy, Office of Research, Statistics, and International Policy, SSA Pub. No. 13-11947, November 1983,187 pp. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Health Conse- quences of Smoking: Chronic Obstructive Lung Disease. A Report of the Surgeon General. U.S. Department of Health and Human Services, Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHHS Pub. No. (PHS)8&50205,1984,568 pp. U.S. DEPARTMENT OF LABOR. Occupational Injuries and Illnesses in the Unlted States by Industry, 1982. Bulletin 2196. U.S. Department of Labor, Bureau of Labor Statistics Washington, D.C., U.S. Government Printing Office, April 1984. 52 pp. 177 U.S. HOUSE OF REPRESENTATIVES COMMIWEE ON GOVERNMENT OPERA- TIONS. Occupational Illness Data Colkctiolr: Fragmented, Unreliable, and Seventy Years Behind Communicable Disease Surveillance. U.S. House of Representatives, 98th Congress, House Report No. 98-1144, October 5,1984,24 pp. WANNER, A. Clinical aspects of mucociliary transport. American Review of Respiratory Disease 116(1):73-125, July 1977. WANNER, A., BRODNAN, J.M., PEREZ, J., HENKE, K.G., KIM, C.S. Variability of airway responsiveness to histamine aerosol in normal subjects: Role of deposition. American Review of Respiratory Disease 131(1):3-7, January 1985. WARNER, K.E. Possible increases in the underreporting of cigarette consumption. Journal of the American Statistical Association 73(362):314-318, June 1978. WASSERMAN, K., WHIPP, B.J. Exercise physiology in health and disease. American Review ofRespiratory Disease 112(2):2X+249, August 1975. WEILL, H., HUGHES, J.M., HAMMAD, Y.Y., GLINDMEYER, H.W., III, SHARON, G., JONES, R.N. Respiratory health in workers exposed to man-made vitreous fibers. American Review of Respiratory Disease 128(1X1(;++112. July 1983. WEINBERGER, S.E., JOHNSON, T.S., WEISS, S.T rliqical sipificance of pulmo- nary function tests: Use and interpretation of the single-breath diffusing capacity. Chest 78(3):48%@8, September 1980. WEISS, W. Cigarette smoking and diffuse pulmonary fibrosis. Archives of Enuiron- mental Health 14(4):564-568, April 1967. WEISS, W. Cigarette smoking and diffuse pulmonary fibrosis. American Review of Respiratory Disease 99(1):67-72, January 1969. WEISS, W. Cigarette smoke, asbestos, and small irregular opacities. American Review of Respiratory Disease 130(2):293-301, August 1984. WEISS, W., THEODOS, P.A. Pleuropulmonary disease among asbestos workers in relation to smoking and type of exposure. Journal of Occupational Medicine 20(5):341-345, May 1978. WEN, C.P., TSAI, S.P., GIBSON, R.L. Anatomy of the healthy worker effect: A critical review, Journal of Occupational Medicine 25(4X2.83-289, April 1983. WHORTON, M.D. Accurate occupational illness and injury data in the U.S.: Can this enigmatic problem ever be solved? American Journal of Public Health 73(9):1031- 1032, September 1983. WIEDEMANN, H.P., GEE, J.B.L., BALMES, J.R., LOKE, J. Exercise testing in occupational lung diseases. Clinics in Chest Medicine. 5(1):157-171, March 1984. WORLD HEALTH ORGANIZATION. Manual of the International Statistical Classi- fication of Diseases, Injuries, and Causes of Death. Vol. 1. Geneva, World Health Organization, 1977,773 pp. 178 CHAPTER 5 CHRONIC BRONCHITIS: INTERACTION OF SMOKING AND OCCUPATION CONTENTS Introduction Coal Silica Cement Grain Polyvinyl Chloride and Vinyl Chloride Welding Sulfur Dioxide Other Exposures Summary and Conclusions References Introduction Occupational bronchitis is defined as the occurrence of bronchitis caused by worksite chemical or physical agents, whether encoun- tered as gases, fumes, vapors, or dusts. Having derived from a crowded field of overlapping and confusing terms, the term "occupa- tional bronchitis" has inherited a certain inexactitude and has been applied with ambiguity. To complicate the issues further, some industrial substances that cause bronchitis also frequently cause other lung diseases, especially the pneumoconioses and asthma, the symptoms of which may mimic those of occupational bronchitis. Studies of these occupational lung diseases have not always differen- tiated clearly between the development of bronchitis and the development of other lung disorders. Hence, this review begins by briefly applying the customary distinctions in terminology to the area of occupationally derived bronchitis. Whether caused by cigarette smoking, industrial agents, or otherwise, "chronic simple bronchitis" denotes the presence of persistent cough with phlegm production not attributable to a specific pulmonary disease such as bronchiectasis or tuberculosis (Ciba 1959; American Thoracic Society 1962). The operational defini- tion of this form of bronchitis provided by consensus groups of American and British investigators 20 years ago has been widely used in industrial and nonindustrial studies: cough and sputum production on most days for at least 3 months annually for 2 consecutive years (Ciba 1959). Fletcher and coworkers (1976) subse- quently demonstrated that this hypersecretory disorder among cigarette smokers can occur independent of airway obstruction and does not of itself lead to an obstructive disorder. Brinkman and colleagues (1972) confirmed these findings in an occupational setting in a more abbreviated study. Mucus production causes morbidity in that it may lead to increased pulmonary infections, but it does not cause significant dyspnea or potentially disabling obstructive dis- ease. "Chronic obstructive bronchitis" often included in the generic term "chronic obstructive pulmonary disease" (COPD), is defined by the presence of airflow obstruction as measured in most occupational studies by the reduction in the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV,/FVC). More recently, flow rates at low lung volumes obtained from the same forced expiratory maneuver have been used to detect dysfunction of the small airways. In contrast to the mere production of cough and phlegm, the presence of obstruction may have important impact on morbidity and mortality (Fletcher et al. 1976). This subject is reviewed more fully elsewhere in this Report. The term "occupational bronchitis" has been used more often to refer to simple bronchitis than to the airflow obstructive disorder 183 because of the widespread notion that many airborne occupational contaminants produce chronic cough and phlegm, but relatively few agents have been found to lead to measurable airflow obstruction or to clinically significant COPD (Parkes 1982; Casey 1983; Kilburn 1980; Morgan and Seaton 1984). Two related criteria have commonly been used to demonstrate the existence of occupational bronchitis in the presence of a specific exposure or in a specific workplace. First, occupational bronchitis is favored if excessive rates of respiratory symptoms are found in workers who have never smoked. The obvious advantage of such a criterion is the elimination of cigarette smoking, which is a major confounding variable in bronchitis. Unfortunately, this approach could fail to incriminate an occupational agent that produces no respiratory effects by itself but causes higher rates of bronchitis among workers who smoke than are attributable to cigarette smoking alone. Second, the entire exposed population-smokers, former smokers, and nonsmokers-may experience higher rates of chronic cough and phlegm production than a similarly constituted unexposed control population. If the population of exposed nonsmok- ers is small, however, only the interactive effects of smoking and the occupational agent of interest may be evaluated. This chapter describes the impact of smoking and occupational exposures on the prevalence of simple bronchitis. Examining the interaction between smoking and hazardous substances, however, requires documenting the ability of industrial agents alone to produce chronic respiratory disease. The additional or multiplicative effects of cigarette smoking can then be described. Emphasis is placed on evaluating the nature and quality of data rather than on compiling a complete list of agents putatively associated with bronchitis. Coal The role of coal dust in the development of chronic simple bronchitis has been examined (Morgan and Seaton 1984; Parkes 19821, and respiratory disease in coal miners is discussed more fully in a separate chapter of this Report. The specific issue of bronchitis and occupational exposure to coal is reviewed briefly in this section. Evidence supports an independent causal relationship for both cigarette smoking and coal dust in chronic cough and phlegm production (Higgins et al. 1959; Saric and Palaic 1971; Higgins 1972; Lowe and Khosla 1972; Kibelstis et al. 19731. In a series of community-based studies in England and in the United States during the 1950s and 1960s Higgins and colleagues (Higgins et al. 1959; Higgins 1972) found an increased prevalence of chronic simple 184 bronchitis in miners and ex-miners, ranging from 1.2 to 6.4 times the rates in nonminer controls. Lowe and Khosla (19721 studied chronic bronchitis among more than 12,000 Welsh steelworkers, about one-fourth of whom were former coal miners. In the absence of cigarette smoking, previous exposure to coal dust increased the rate of chronic cough and phlegm production from 5.7 percent in nonsmoking nonminers to 13.6 percent in nonsmoking ex-miners. Cigarette smoking was somewhat more important than previous exposure to coal in producing chronic simple bronchitis; 16.6 percent of the nonminers who smoked and 25.5 percent of the ex-miners who smoked had chronic bronchitis. Differences in age among the various subgroups did not account for the varying prevalence of symptoms, which appeared to be additive. Saric and Palaic (1971) compared 904 Yugoslav coal miners with 342 control workers of similar socioeconomic status without occupa- tional exposure to dusts, and found that cigarette smoking and coal dust exposure were multiplicative in the production of chronic simple bronchitis. Of the miners who smoked, 32 percent reported chronic cough and phlegm production, compared with 10 percent of the controls who smoked, 8 percent of the nonsmoking miners, and 2 percent of the nonsmoking controls. However, the rates of chronic simple bronchitis for each exposure subgroup, except the workers who smoked, were below other published rates. Increasing coal dust exposure increased the prevalence of chronic simple bronchitis in both smokers and nonsmokers in the studies by Kibelstis and colleagues (1973) and Rae and colleagues (1971). Neither study included groups not exposed to coal dust. Both studies reported a larger effect of cigarette smoking than of coal dust exposure in causing chronic simple bronchitis, but did demonstrate a substantial coal dust exposure effect. One-third to one-half of the nonsmoking American coal miners over the age of 50 reported chronic cough and phlegm production (Kibelstis et al. 1973). Some- what lower proportions (20 to 40 percent) of the nonsmoking British coal miners with tht highest levels of dust exposure suffered symptoms of chronic cough and phlegm production (Rae et al. 1971). In summary, coal dust exposure causes chronic simple bronchitis independent of cigarette smoking. Although the effects are additive, the effect of smoking is somewhat greater than the effect of coal dust exposure in producing symptoms of chronic bronchitis. Silica Early studies showed no relationship between silica exposure and chronic cough and phlegm production. In 1959, Higgins and col- leagues (19593 found no increase in chronic simple bronchitis in British foundry workers and former foundry workers, regardless of 185 duration of employment, compared with community controls with- out dust exposure. In a cross-sectional study, Brinkman and Coates (1962) found no difference in cough and phlegm production in long- term American foundry workers with normal chest roentgenograms and control workers with no dust exposures. More recently, Glover and colleagues (1980) examined 725 Welsh slate workers and former workers and noted no relation between duration of exposure to slate and presence of chronic simple bronchitis independent of pneumoco- niosis. On the other hand, studies of South African gold miners showed an association between silica and simple bronchitis among smoking miners. White miners were compared with age-matched white nonminers in an area where gold mines had a 50 to 70 percent free silica content (Sluis-Cremer et al. 1967). Nonsmoking miners report- ed an 8.2 percent rate of chronic simple bronchitis, which did not differ from the 6.7 percent rate found among nonsmoking nonmin- ers. However, 50.5 percent of the miners who smoked had chronic cough and phelgm production, almost twice the 28.0 percent found among the nonminers who smoked. Hence, silica dust alone ap- peared not to cause symptoms of simple bronchitis, but magnified the effects of smoking. Wiles and Faure (1977) also studied white South African gold miners and found that they had an increased prevalence of bronchitic symptoms in the absence of cigarette smoking and that there was an additive effect among the workers who did smoke cigarettes. Among the nonsmokers with the lowest dust exposure, no workers had chronic cough with phlegm, but 15 to 20 percent of workers with the highest dust exposures had these symptoms. Twenty-five percent of smokers in the low dust category reported bronchitic symptoms. Among the miners who smoked, 50.5 percent suffered from chronic cough and phlegm production, demonstrating a simple additive effect. A cross-sectional study of 931 Swedish long-term foundry workers with varying exposures to silica was published in 1976 (Karava et al. 1976). Less than 4 percent of the study population had evidence of silicosis on chest x ray. Two percent of the nonsmokers exposed to lesser amounts of dust reported simple chronic bronchitis compared with 9 percent of the nonsmokers with high dust exposure, but the difference was not significant (p>O.lO). However, 16 percent of the smokers exposed to slight or moderate levels of dust had chronic cough and phlegm production, significantly less than the 30 percent of smokers with high dust exposure (p40 years 74 SM 54.6 SM 66.4 64.7 67.2 46.7 NW 13 Ex 22.2 NS1F.X 45.4 EX 26.8 2.2 16.2 28.7 Pipe/cigar 10.5 NS 10.8 pipe/cigar 5.9 ' Never smoked regul=ly o 82.9% smoked >20 cigdday ' 19% smoked >25 cigdday NS 6.9 33.1 16.6 22.7 TABLE 2.-Continued Study Kolonel et al. (1980) Pearle (1982) Number and type of population Male shipyard workers, Hawaii 131 male shipyard workers Smoking characteristics (percent) Comments Asbestosexposed workers 63.8 Nonexpzesd workers 62.5 General population 58.8 75.6 Li et al. 3,991 shipyard workers, (1983) South Carolina SM EX NS 42.9 24.8 32.3 Be&lake et al. (1972) Asheetcm workers, Canada SM' NS 85.3 14.7 Meurman et al. (1973. 1974) Liddell et al. w32) Berry et al. (1972) Meurman et al. (1979) Anthophyllite mine workers, 1936-1967 SM' 66.7 615 asbestos workers, Bueb= 1,203 male asbestos workers Asbestos workers, Finland NS 33.8 SM Ex NS 74.5 19.5 6 Cohort survivors 66.7 Dsceasd workers 79.8 o Smokera=ever smoked 1 cig/day for 2 1 yr.; includes pipe and cigar o 26.1% smoked >15 cigslday TABLE 2.-Continued Study Number and type of population Smoking characteristics (percent) Commmts Weill et al. (1975) and Selikoff et al. (1979) 859 aebest~~~ cement mfg. SM EX NS workers, New Orleans 51 26 23 Greenberg et al. (1976) 890 ssheat-os workers, Texas 84 Weiss and Theodos (1978) 40 ashestce workers 55.7' 22.7 21.6 ' 22.7% smoked >1 pack/day Berry et al. (1979) Asbestos textile factory workers, Great Britain SM EX NS 69.2 13.8 17 Selikoff, Seidman, et al. (1980) 933 am&e asbestoe workers, examined 20 yra. from employment start date SM 61.7 EY 12.1 NS 13.4 Ottlet 12.6 Skerfving et al. 241 a&e&m workers, 64.3 ww Sweden Weiss et al. 45 asheatce workers, aged SM EX NS (1981) 240, reexamined 42.2 31.1 26.7 ~-__- TABLE 2.4ntinued Study McDermott et al. (1982) Number and type of population Two groups of a&?st.cm workers, Swaziland .- Smoking chsrxtetitica (percent) bmments SM EX NS Group 38 10 Group 3.4 4 Acheeon et al. Amosite asbestos workers. (1964) Great Britain Berry et al. 1,253 male and 423 female (1965) asbestos factory workers NOTE: SM = Smoker; EX = Exsmoker; NS = Nonsmoker. 77 5 19 Men 74.5 19.6 5.9 Women 49.4 22.7 27.9 asbestos may result. These associations between asbestos exposure and smoking must be considered when examining the literature and are particularly important when drawing conclusions from studies that either do not control for smoking or control for smoking inadequately. For these reasons, this discussion is limited largely to those studies that have provided data on the smoking habits of their populations. Examination of the relationships among smoking, asbestos expo- sure, and lung cancer includes consideration of a series of separate questions. Does asbestos exposure exert an effect in the absence of active smoking exposure? What are the effects of combined expo- sure? Is there a threshold of exposure below which no effect occurs? What happens to the risk following smoking cessation and after cessation of new asbestos exposure? Lung Cancer in Nonsmoking Asbestos Workers The most direct way to demonstrate that asbestos exposure results in an increased lung cancer risk independent of cigarette smoking is to monitor disease occurrence in asbestos-exposed individuals who have never smoked cigarettes regularly. However, because lung cancer is a relatively rare phenomenon in people who have never smoked cigarettes, even among asbestos-exposed populations, a large population of nonsmokers is required before a statistically signifr- cant number of cases would be expected. The relatively high prevalence of smoking in asbestos-exposed populations decreases even further the number of nonsmoking asbestos-exposed workers available for study, making the evaluation of risks for the nonsmok- ers difficult. For example, no lung cancer deaths were identified among the nonsmokers in the original cohort of asbestos insulation workers reported by Selikoff and colleagues (1968). Some authors have attempted to increase subject numbers in the nonsmoker category by combining ex-smokers or light smokers with never smokers (Blot et al. 1980). However, the risk of developing lung cancer remains elevated in ex-smokers compared with nonsmokers for at least 10 to 15 years after cessation, and the excess risk is proportionate to the amount smoked (US DHHS 1982). Smokers of less than 10 cigarettes per day have less risk than heavy smokers, but the relative risk for lung cancer in these light smokers compared with individuals who have never smoked regularly still varied from 2.3 to 9.5 in the major prospective studies on smoking mortality (US DHHS 1982). Thus, combining people who have never smoked with ex-smokers and light smokers is inappropriate and may introduce bias when the effects of asbestos exposure alone are being assessed. Several studies have examined populations large enough to address the question of the risk of asbestos exposure in individuals who have never smoked regularly. Hammond and colleagues (1979) 210 examined the mortality experience of the 17,800 members of the International Association of Heat and Frost Insulators and Asbestos Workers who were alive on January 1,1967. This group was followed to December 1976, and the mortality of the 12,051 workers more than 20 years after onset of exposure was analyzed. Of this group, smoking histories were available for 8,220, of whom 6,841 (83.2 percent) had been regular smokers at some point and 891 (10.8 percent) had never smoked regularly. Of the 891 workers who had never smoked regularly, death certificates indicated that 4 died of lung cancer. The expected number of deaths was calculated from the mortality experience of a population of blue-collar workers who had never smoked regularly, drawn from the American Cancer Society (ACS) prospective mortality study of 1 million men and women. The resulting expected number of lung cancer deaths of 0.7 and the observed number of 4 yielded a relative risk for asbestos exposure of 5.33. When the deaths were classified according to the best estimate of the cause of death from all available data, rather than from the death certificate alone, one additional case of lung cancer was identified in a worker who had never smoked regularly. Selikoff, Seidman, and Hammond (1980) reported the mortality of 933 men who began working in an amosite asbestos factory between June 1941 and December 1945. Of these men, 78 (8.4 percent) were known to have never smoked regularly; the death certificates of 5 of this group listed lung cancer as the cause of death. When the best estimate of cause of death was used, only three men were believed to have died of lung cancer. The expected number of deaths was 0.2, based on the ACS mortality study. This led to a relative risk of 25 (5/0.2) for workers who had never smoked regularly. McDonald and colleagues (1980) examined the mortality experi- ence of Quebec asbestos miners and millers and reported a dose- response relationship between cumulative asbestos exposure and lung cancer in nonsmokers. They compared the standardized mortal- ity ratio (SMR) for lung cancer in miners who had never smoked, using the mortality rates for the Province of Quebec, which are based on both smokers and nonsmokers. The SMR increased from 0.18 among nonsmoking miners with less than 30 million particles per cubic foot times years (mppcfoy) of exposure to 0.36 in miners with 30 to 299 mppcfey of exposure and 1.24 in nonsmoking miners with more than 300 mppcfoy of exposure. There were 19 lung cancer deaths among nonsmoking asbestos miners. These authors (McDon- ald et al. 1980) also performed a cas+control study of the 245 miners who had died of lung cancer. The distribution of cumulative asbestos exposure among the 20 nonsmoking miners with lung cancer and 20 nonsmoking control miners matched for year of birth and smoking status was examined, and the relative risk for lung cancer was found 211 to have increased from 1 in nonsmoking miners with less than 30 mppcfoy to 10 in nonsmoking miners with more than 1,000 mppcfey. Liddell and colleagues (1984) reexamined the same po~,rlation of Quebec asbestos miners after recording their smoking &tory by pack-years of exposure. They identified 223 cases of lung cancer in men who worked in the asbestos mines and mills of Quebec for a month or more before January 1967 ind who were followed to the end of 1975. The controls were selected from men in the same cohort, born in the same years as the lung cancer cases, but still living. Never smokers represented 23 of the 223 lung cancer cases and 201 of the 715 controls. The relative risks (RR) were calculated on the basis of the mortality experience of the entire asbestos-exposed population (whole population RR, l.O), and the risk in even the most heavily exposed nonsmokers was still lower than the risk in the entire population, which included both smokers and nonsmokers. The RR for lung cancer increased from 0.19 in the nonsmoking miners who had experienced a cumulative exposure of less than 100 fibers per milliliter times years ((f/mL)y) to 0.37 for those with 101 to 1,000 (f/mL)y and 0.87 for those nonsmoking miners with over 1,000 (f/mL)y, thus demonstrating a dose-response relationship with cumulative asbestos exposure for lung cancer in the workers who had never smoked regularly. Berry and colleagues (1972) conducted a retrospective study of the lung cancer mortality in more than 1,300 male and 480 female asbestos factory workers over a lo-year period and compared their mortality with the national lung cancer rates (Table 3). The national lung cancer rates were converted to smoking-specific rates by multiplying them by factors from the study of mortality of British physicians by smoking status (Doll and Hill 1964) in order to develop smoking-specific expected numbers of deaths. No lung cancer deaths were recorded among the men who had never smoked, and only one lung cancer death was recorded among the women who had never smoked. The expected number of deaths was also very low, and so even a single death was greater than expected, and it occurred in the group of women with heavy asbestos exposure. The women in the highest asbestos exposure category who had never smoked had 3.5 times the number of subject years at risk when compared with men in the same exposure category (1,404 to 399) owing to the higher prevalence of never-smoker status among women in the study. This difference in number of individuals at risk may have contributed to the demonstration of a lung cancer death among nonsmoking women but not among men. Subsequently, Berry and colleagues (1985) followed prospectively 1,253 male and 423 female asbestos factory workers from the same plants. Smoking habits were determined in 1971 at the start of the study, and the population was followed through 1980. The expected number of lung cancer deaths was 212 calculated from the death rates for England and Wales multiplied by the lung cancer SMR for greater London, and an adjustment for smoking status was made using the data from the mortality study of British physicians. Observed and expected numbers of lung cancer deaths by smoking status and level of asbestos exposure are presented in Table 4. One lung cancer death occurred among the men who had never smoked (0.1 expected) and three lung cancer deaths occurred among the nonsmoking women (0.2 expected). Meurman and colleagues (1979) reported 1 lung cancer death (of 23 total lung cancer deaths), a nonsmoking male anthophyllite miner. Acheson and colleagues (19841 also reported 1 death from lung cancer among the nonsmokers employed in an amosite manufactur- ing factory, with an expected number of 1.1. However, the expected number was calculated from age-specific population rates that included both smokers and nonsmokers rather than from the rates for a population of nonsmokers. Each of these studies supports an increased risk for lung cancer in nonsmoking asbestos workers, but the conclusions are based on a single death in a population. In summary, the evidence that asbestos exposure results in an increased lung cancer risk in the absence of cigarette smoking is based on a small number of cases, but has been confirmed in several different populations of asbestos workers. The high smoking preva- lence in asbestos workers introduces the possibility that environmen- tal tobacco smoke may increase the risk of lung cancer among the nonsmokers, particularly if the synergism demonstrated between active smoking and asbestos exposure pertains to environmental tobacco smoke as well. In spite of these concerns, the available evidence supports the conclusion that nonsmokers with substantial occupational asbestos exposure are at increased risk of developing lung cancer and that the risk increases with increasing cumulative asbestos exposure. Lung Cancer in Cigarette-Smoking Asbestos Workers The risk of lung cancer in cigarette smokers has been examined in a number of asbestos-exposed populations, and the increased risk of lung cancer in smokers, coupled with the high prevalence of smoking in many of these populations, has generated substantial numbers of lung cancer deaths for analysis. These populations differ in smoking habits, type of asbestos and duration and intensity of exposure, type of activity that resulted in exposure, and duration of the followup of the population. A number of authors have compared the lung cancer rates in asbestos-exposed populations with the rates in control populations (Table 1). This approach can establish an excess mortality in a population, but may not identify the causes of that excess. To establish a causal link between an exposure and lung cancer, specific 213 E TABLE 3.-Comparison of number of observed and expected deaths from cancers of the lung NUDlber Subjecbyeam observed lung Adjusted observed Smoking habits on of at risk Obeerved deaths cancer deaths lung cancer Expected lung January 1,lW Bubjecta (adjusted) (all cauees) WD 162, 163) deaths cancer deaths Men Low/moderate aebeatas expure Never smoked Exsmokers Smokers Not known Severe asbestos exposure Never smoked Exsmokers Smokers Not known Women Low/moderate asbestos exposure Never smoked Smokera Not known Severe a5beatoe exposure Never smoked Smokers Not known 4-i 376 2 38 335 1 509 4,423 32 219 2.122 20 41 399 11 0 0 0.0 39 415 3 2 1.6 0.2 663 6,920 82 3%5) 25.5 9.9 281 2,722 29 4 10.9 2.4 25 271 8 0 0 0.0 45 577 6 1 1 0.3 19 195 0 0 0 0.1 120 1,404 23 2w 1.7 0.2 3,474 52 19(4) 15.5 1.4 1,547 9 0 2.6 0.4 0 :2,1 0 0 0.0 0 0.1 4.6 6.2 3.4 2.0 ' Fires in parentheses indicate number of pleuralmesotheliomas. SOURCE. Berry et al (1972). TABLE I.-Observed and expected deaths from cancer of the lung during 1971-1980 Smoking habits in 1971 Number of subjects Subject-years at risk Total deaths Lung cancer deaths ObkWWd Expected' Low/moderate asbestos exposure Never smoked Exsmokem Smokenr 45 396 6 1 0.10 123 1.092 18 3 1.07 441 3.557 84 17 11.29 Severe anbestce exposure Never smoked 29 273 2 0 0.06 &smokers 123 1,003 343 8 1.25 Smokers 522 4,394 1% 35 14.63 Low/moderate asbestos exposure Never smoked Exsmokers Smokers 17 128 5 0 0.04 12 93 3 0 0.09 27 220 4 0 0.32 Severe ah&on exposure Never smoked 101 Exsmokera 84 Smokers 162 ' Calculated af?.er allowing for the effect of smoking, =x. sge, period, and region. soIJlK!E: Belly et al. (1985). 799 26 3 0.20 659 24 2 0.50 1,413 52 10 2.02 criteria must be applied to the entire body of information available on the exposure. This approach has been carefully and comprehen- sively followed for both cigarette smoking (US DHHS 1982) and asbestos exposure (Selikoff and Lee 1978), and the evidence is sufficient to establish a causal role for both of these agents in producing lung cancer. This section confines itself to an examination of their interaction. Selikoff and colleagues (1968) were the first to demonstrate increased lung cancer risk among asbestos workers in an investiga- tion that assessed smoking habits. In a group of 370 asbestos; insulation workers, none of the 48 workers who had never s: 1~ 1-9~ regularly or of the 39 workers who smoked only pipes or cigt :s developed lung cancer. Of the 283 cigarette-smoking workers, 24 died of lung cancer during the 4 years and 4 months of the followup period, although only 2.98 lung cancer deaths were expected on the basis of smoking-specific death rates. A more extensive evaluation of the risk of cigarette smor;ing for asbestos insulation workers was provided (Hammond et al. 1979) by a prospective evaluaLic,n of the 17,800 members of the International Association of Heat and Frost Insulators and Asbestos Workers discussed earlier. Of this population, 8,220 workers were more than 20 years beyond their onset of asbestos exposure and had a known smoking status. Fifty-four percent of this group were cigarette smokers at the start of the study. The comparison group was drawn from the ACS study of 1 million men and women, and consisted of 73,763 white men with no more than a high school education and not employed as farmers, but with a history of occupational exposure to dust, fumes, vapors, gases, chemicals, or radiation, who were living on January 1, 1967, and were traced thereafter. The control group was followed only until September 30, 1972, and the asbestos workers were followed through 1976; therefore, the lung cancer death rates in the control group were adjusted upward to reflect changes in the U.S. national mortality experience for lung cancer during the time period of differential fol!owup. There were 1,332 deaths among wcrkers more ihan 20 years after onset of exposure whose smoking habits were known; 314 (23.6 percent) deaths were due to lung cancer, using the best estimate of cause of death. Death certificar,e data indicated 272 lung cancer ?eai :A>, Figure 2 portt.:ya the il ,ztality ratios for smokers and :)i,nsmokerx in the col>Lrol and t.iC asbestos-exposed populations, with tne mortality raGo of nonsmokers in the control group set at 1. The lung cancer death rates increased from 11.3 per 100,000 among nonsmokers in the control group to Z3.4 in the nonsmoking asbestos workers, 122.6 for smokers in the contrG1 group, and 601.6 for smoking asbestos workers. The lung cancer relative risk with combined exposure (53.24) is far larger than the sum of the individual risks for cigarette smoking and asbestos exposure sepa- rately, and is quite close to the product of the separate mortality ratios (5.17 and 10.85) together. .\,curate data on the intensity of asbestos exposure for individual workers (dose) were not available for this group of insulation workers, .ld so an asbestos dose-response relationship was not examinea. Dosage data were available for cigarette smokers in this population, however, and the ratio of observed to expected lung cancer deaths (with the expected deaths calculated from the rates in nonsmoking non-asbestos-exposed controls) increased from 5.33 in asbestos workers who never smoked regularly to 7.02 in pipe and cigar smokers, 36.56 in ex-smokers, 50.82 in smokers of fewer than 20 cigarettes per day, and 87.36 in asbestos workers who smoked one pack or more per day. Interaction between smoking and asbestos exposure in the devel- opment of lung cancer has also been explored in other populations. In sonle studies the numbers have been too small to clearly differentiate between an additive and a multiplicative effect with combined exposure; however, the data have been consistent with an effect that is at least more than additive. This interaction of cigarette smoking and asbestos exposure has been demonstrated in asbestos factory workers (Berry et al. 1972, 19851, Quebec miners and millers (McDonald et al. 1980; Liddell et al. 19841, amosite asbestos factory workers (SeXoff, Seidman, and Hammond 1980) and Finn- ish anthophyllite miners and millers (Meurman et al. 1979). A dose-response relationship between cigarette smoking and lung cancer in the general population has been readily demonstrated in a number of prospective mortality studies (US DHHS 1982); however, dose-response relationships for asbestos exposure and lung cancer have been more difficult to establish. The carcinogenicity of asbestos may vary with the type of asbestos, and possibly with the length or diameter of the fiber. There are also potential differences in the carcinogenic risk associated with the different stages and processes of converting asbestos from the raw mineral in the mine into a finished manufactured product. As a result, it is difficult to classify the asbestos exposure of different study populations with a single measurement that quantifies the carcinogenic dose. Even if such a scale were agreed upon, actual measurements of asbestos dust levels in the work environment are often not available. Measures of dust exposures for individual workers are even less frequently available. The quantification of asbestos dust exposure has frequently used estimates of likely exposures based on work conditions and job classification, rather than actual measurements of asbestos dust in the air, because of the absence of these measurements for most workers. This lack of information has been particularly problematic for workers employed more than 20 years ago, a group now at high 217 67.36 53.24 Nonsmokers Nonsmokmg Smokers Smokrq Smoking not exposed asbestos not exposed asbestos ( > 1 pack/day) to asbestos workers to asbestos workers asbestos workers FIGURE 2.-Relative risk of dying of lung cancer for smoking and ntilsmoking asbestos workers and smoking and nonsmoking control group members SOURCE Hammond et al (19791. risk of developing lung cancer. Finally, cumulative asbestos expo- sure, age, and cumulative cigarette smoking exposure are generally 218 correlated. Older employees worked under conditions of much higher asbestos exposure than their younger counterparts, and these same older cohorts probably also had higher prevalences of cigarette smoking, as described in the chapter on smoking patterns by occupation. Confounding between cumulative asbestos exposure and cumulative cigarette smoke exposure may result when dose-re- sponse relationships between cumulative asbestos exposure and lung cancer are examined without a control for differences in smoking habits among the different asbestos exposure groups. Berry and colleagues (1972) examined dose-response relationships in a population of 1,300 male and 480 female asbestos factory workers in Great Britain. Workers were categorized as having low to moderate asbestos exposure or severe asbestos exposure, and the expected number of lung cancer deaths was calculated from stand- ardized mortality rates for lung cancer for the greater London area. An adjustment for cigarette smoking status, derived from the mortality study of British physicians by Doll and Hill (19641, was used to estimate rates for smokers and nonsmokers. The results are presented in Table 3. The small number of lung cancer deaths makes interpretation somewhat difficult, but it appears that the increased lung cancer death rate is limited to smokers with severe asbestos exposure. McDonald and colleagues (1980) examined Quebec miners and presented evidence for a dose-response relationship between cumu- lative asbestos exposure and lung cancer risk in the smoking miners. They compared the lung cancer mortality rates in the Quebec miners with the mortality rates for the Province of Quebec. Table 5 shows the SMRs for lung cancer in miners by level of cumulative asbestos exposure and smoking habits. Heavy smokers consistently had higher SMRs than moderate smokers at the same level of cumulative asbestos exposure, and the SMRs increased with increasing cumula- tive exposure to asbestos in each of the smoking categories. Using the same population of miners, these authors conducted a case- control study of 245 lung cancer victims and a similar number of control miners matched for smoking habits and year of birth. The distribution of cumulative asbestos dust exposure was examined, and the results in cigarette smoking miners showed an increase in relative risk with increasing cumulative exposure. The relative risk of cigarette smokers in the lowest exposure category (< 30 mppcfay) was set at 1.0, and the relative risk increased to 1.12 at 30 to 300 mppcfoy of exposure, 1.58 at 300 to 1,000 mppcfoy, and 1.99 at 2 1,000 mppcfoy of exposure. A more quantitative description of the smoking habits of the same Quebec miners was provided by Liddell and colleagues (1984). Their data are presented in Table 6. The dust exposure measurements were made as particles per cubic foot with midget impingers, and 219 TABLE 5.-Deaths from lung cancer in relation to dust exposure and smoking habit Dust exposure umppcf.yl accumulated to age 45 c 30 3s-299 2300 All Smoking habit 0 SMR 0 SMR 0 SMR 0 SMR Nonsmokers 5 0.18 6 0.36 a 1.24 19 0.38 Mxkratc smokers 73 1.14 64 1.35 52 2.31 189 1.41 Heavy smokers 13 2.12 11 2.39 10 4.50 34 2.63 All smoking habits 91 0.93 81 1.18 70 2.25 242 1.23 SOURCE. LIddell et al 119841 individual exposures were calculated on the basis of the work histories and the measurements of impinger dust counts in the work environment between 1949 and 1966. These counts were then converted to fibers per mL. Two hundred and twenty-three cases of lung cancer were identified and matched to 715 controls born in the same year, and a case-control analysis was conducted. As is shown in Table 6, the relative risk of developing lung cancer increases with increasing asbestos exposure category for each of the cumulative pack-year categories. The analysis also suggests that the interaction between cigarette smoking and asbestos exposure is greater than additive. Thus the studies that have examined the question of a dose- response relationship for asbestos exposure and lung cancer in the face of an adequate control for cigarette smoking have shown an increasing risk of lung cancer as asbestos exposure increases. This suggests that a dose-response relationship for asbestos exposure and lung cancer does exist, and that it is not explained by differences in smoking habits. Threshold The question whether a level of asbestos exposure exists below which an exposure does not result in an increased risk of lung cancer is one that is both technically extremely difficult to answer and extremely important to those required to make policy with regard to asbestos exposure. Current understanding of carcinogenesis and host defenses against cancer are not advanced sufficiently to allow either the acceptance or the rejection of a threshold. It is common practice to assume a linear relationship between the dose of a carcinogen and the development of carcinoma, and to assume that the dose-response relationship does not have a threshold. The linear nonthreshold model allows the extrapolation of data obtained for higher exposures 220 TABLE 6.-Risks of lung cancer, by cigarette smoking and asbestos exposure, relative to all 223 cases and 715 referents for whom smoking histories were reliable; unmatched analysis Expsure accumulated up to 9 years before death of cake mf mL'\ High and Low !&dlUrn very high Pack-years ' " 1001 ,I l.ooo1 / 2 l.ooo' All 0 Nu;nher of cases 6 7 10 23 Number of referentI 103 61 3i 201 Relative risk 0 19 0 3; n ei 0.37 1. ~ 40 Number of case5 29 2; 34 90 Number of referents 123 93 63 279 Relative risk 0.76 0 93 173 1.03 240 Number of cases 40 35 35 110 ?;umber of referents 117 79 33 235 Relative risk 1.10 1.42 2.88 1.50 All Number of cases 75 69 73 223 Xumber of referents 343 233 139 715 Relative risk 0.70 0 35 1.82 1.00 ' Number of cigarettes a day 20 x duration m pan SOURCE: Liddell et al. 119841 to the very low exposures. This extrapolation is substituted for the examination of the very large populations that would have to be examined in order to demonstrate the small expected excess risk with low dose exposure. Such models are particularly attractive for exposures for which human epidemiologic data are limited or absent. As discussed earlier, however, minimal exposure to cigarette smoke and asbestos is probably a nearly universal experience in urbanized society. Because of the large population exposed, more careful examination of the available evidence on the risks of these exposures is necessary. The number of cigarettes smoked per day by an individual is a readily available measure of the dose of smoke exposure in the active cigarette smoker; therefore, it has been possible to examine relative- ly completely the dose-response relationship for cigarette smoking and lung cancer. There is a consistent increased risk for lung cancer among smokers in the lowest category of number of cigarettes smoked per day in the major prospective mortality studies on smoking (US DHHS 1982). In the study of U.S. veterans (Kahn 19661, a relative risk for lung cancer of 3.77 was demonstrated in those who smoked only occasionally compared with those who had never smoked regularly (the relative risk for those who smoked 1 to 9 cigarettes per day was 4.07 compared with those who never smoked 221 regularly). It seems clear that for the active cigarette smoker there is no safe cigarette and no safe level of cigarette smoking (US DHHS 1982). Furthermore, recent data (IARC, in press) suggest that repetitive exposure to environmental tobacco smoke may be accom- panied by an increased risk of lung cancer, thereby suggesting that the dose-response relationship may extend even to those individuals who do not actively smoke cigarettes. The quantification of asbestos exposure is far more difficult. One method is to quantitatively estimate the number of asbestos fibers in digested lung tissue. Asbestos fibers are demonstrable in the lungs of the majority of urban dwellers (Churg and Warnock 1977); however, the number of fibers per gram of lung tissue in urban dwellers without known asbestos exposure is usually several orders of magnitude below that found in occupationally exposed workers, and the type of asbestos varies as well. Churg and Warnock (1979) assessed this urban asbestos exposure as a risk factor for lung cancer by comparing the number of asbestos bodies in 103 patients with lung cancer compared with the number in control patients matched for age, sex, smoking habits, and in some cases, occupation. No differences in the number of asbestos bodies per gram of lung tissue were found between the lung cancer patients and the control population, suggesting that, at this level of exposure, asbestos did not increase the risk of lung cancer in these patients. However, the small number of patients in this study limits the power of the study to find a small effect of asbestos lung burden on lung cancer risk. Confounding by cigarette smoking is another potential source of bias in evaluating the effects of low levels of asbestos exposure. Several of the studies presented in Table 1 do not show excess lung cancer risks at low levels of asbestos exposure, a pattern consistent with the existence of a threshold. However, lung cancer rates in the general population are determined largely by smoking habits, and if the asbestos-exposed populations have even modestly lower lifetime smoking rates, the effect of asbestos exposure may be masked. This bias is of particular importance at the relatively low levels of asbestos exposure at which the effect of cigarette smoking would be expected to predominate. Thus, in interpreting standardized mortali- ty ratios at or below 1, careful consideration must be given to confounding by the smoking habits of the workforce before conclud- ing that the levels of asbestos exposure experienced by these populations do not result in an increased lung cancer risk. In addition, modest differences in the number of cigarettes smoked per day or the age of initiation of regular smoking between the exposed population and the population from which the SMR is derived could counterbalance a modest risk due to asbestos exposure even in populations with similar smoking prevalences. 222 For lung cancer, the measurement of a threshold in epidemiologic studies is further constrained by the certainty with which the absence of an effect can be established. The precision and the accuracy of an estimation of the expected number of deaths in a workforce is heavily influenced by the detail with which the smoking behaviors are determined and the accuracy with which the lung cancer risk of a given smoking history can be estimated. In the U.S. population during 1977,lO percent of the men who died between the ages of 50 and 70 died of lung cancer (McKay et al. 1982). Therefore, a workforce with smoking patterns similar to the U.S. population would be expected to have a similar mortality experience, in the absence of any asbestos exposure. A 10 percent increase in the risk of lung cancer in a workforce (SMR 110, RR 1.1) due to asbestos exposure would mean that 1 percent of the deaths among workers aged 50 to 70 would be excess lung cancers due to asbestos, a level of risk unacceptable as the basis for an industrial hygiene standard. However, even with carefully determined smoking histories for a worksite, no data are currently available that would allow the calculation of expected death rates in smokers and nonsmokers with precision sufficient to establish that an increase of 10 percent was not simply an error in the estimates. In addition, estimates of the smoking habits of the U.S. population are not known with enough precision to adjust national or regional death rates for the smoking patterns of a given workforce so that a 10 percent difference could be considered significant. The result is a dilemma for those who would try to measure a threshold level, or an "acceptable" exposure level, for occupational exposure to asbestos: an effect too small to measure in statistical terms is still too large to be acceptable in human terms. A final caution in the determination of a threshold for lung cancer risk secondary to asbestos exposure, and in the use of such a threshold to establish environmental dust standards, is the potential differences between a threshold for lung cancer and one for mesothelioma or other asbestos-related disease. Mesothelioma, which is not associated with cigarette smoking, may occur following exposure to low levels of asbestos, and a level of dust exposure defined as a "safe" level for lung cancer risk may possibly continue to produce an increased risk of mesothelioma. A pragmatic approach to the problems of defining a threshold or establishing safe levels has been to define asbestos exposure stan- dards on the basis of the lowest level of asbestos dust exposure that can be produced with existing technology. This approach reduces the risk, but does not answer the question whether the exposure of a worker is "safe." An alternate approach has been to use the existing exposure- response data. In the face of uncertainty about the shape of the 223 exposure-response curve for asbestos exposure and lung cancer and whether a threshold exists, an assumption that asbestos has a linear exposure-response relationship with lung cancer and no threshold for effect has been suggested as both reasonable and a way to set standards (Pete 1979; NRC 1984). By definition, in this approach there can be no "safe" level of exposure (i.e., no threshold), only an "acceptable" degree of risk. However, using this method, once an "acceptable" level of lung cancer in a working population has been defined, the level of asbestos exposure that would result in that level of risk can be estimated. A corollary of this approach is that asbestos is assumed to contribute to the lung cancer that develops in populations of workers who have been exposed to asbestos regardless of their level of exposure; by extension, the asbestos found in the lungs of urban dwellers with no known occupational asbestos exposure is assumed to make a small (but finite and definable) contribution to all lung cancers. The evidence that does exist (Churg and Warnock 1977) suggests that asbestos exposure makes no "measurable" contribution to lung cancer in individuals without a definable exposure, but it is impossible to establish the absence of "any" effect. If the issues of liability can be separated from the issue of threshold, then the problem of reducing and eliminating asbestos- related disease and disability could be approached with a broader focus. The focus could be expanded beyond improving technology for reducing exposure to asbestos to include other methods of reducing the cancer risk associated with asbestos exposure. If the goal is to reduce the lung cancer deaths associated with asbestos rather than simply reducing the levels of asbestos dust in the worksite, then the deaths due to the interaction between smoking and asbestos must be dealt with, and the elimination of smoking will be a potent adjunct to environmental asbestos dust control in this task, particularly for those workers who have already received substantial asbestos exposure. A public health "feasibility" threshold could then be defined, not in terms of what dust levels were achievable, but rather in terms of what lung cancer death rates were achievable. This threshold would be the lowest cancer risk achievable, given our current technology, and would include minimizing asbestos expo- sure, maximizing smoking cessation, and applying techniques for early diagnosis and treatment. In summary, although the level of asbestos exposure that occurs in the general population does not appear to be accompanied by an increased risk of lung cancer, the demonstration of a clear threshold below which there is no effect in occupationally exposed populations is not possible. 224 TABLE `I.-Lung cancer mortality ratios with cessation of cigarette smoking in male smokers who smoked more than 20 cigarettes per day compared with those who never smoked regularly Asbestos lnsularlon workers2 10 4 115 42 34 Never smoked regularly 1 I `Data from Hammond 197!? ' Data from Hammond 19791 Cessation of Exposure A decline in the relative risk of developing lung cancer following cessation of cigarette smoking was demonstrated in cigarette-smok- ing asbestos workers by Hammond and colleagues (1979). Table 7 shows the lung cancer mortality ratios in asbestos workers who are current smokers and who have quit for varying periods of time, compared with those workers who have never smoked regularly. A companion set of numbers is provided of the relative risks for lung cancer in men not exposed to asbestos, but who are current smokers or have quit for varying periods of time, derived from the American Cancer Society study of 1 million men and women (Hammond 1972). Several authors have attempted to approach the question of the risk of lung cancer following cessation of asbestos exposure by examining the relative risks of asbestos exposure in workers following retirement (Walker 1984; Selikoff, Hammond et al. 1980). The data in Figure 3 and Table 8 reveal that the relative risk for lung cancer in asbestos workers increases and then declines with the increasing number of years from initial exposure. The workers with the longest interval from onset of exposure are also of the greatest age within the populations examined. Because of this link with age, the interpretation of this decline in relative risk as indicating that cessation of asbestos exposure results in a decline in lung cancer risk must be made with great caution. Examination of national age- specific mortality rates for lung cancer (Figure 4) also shows a decline in male lung cancer death rates with increasing age. This decline with age is an artifact of the cross-sectional nature of data 225 presented in Figure 4. When cancer death rates are examined by birth cohort (Figure 51, no decline with age can be demonstrated. The explanation for this seeming discordance in the data is the differ- ences in pattern of cigarette smoking in different birth cohorts in the U.S. population (Figure 6) (US DHHS 1982). Those birth cohorts that currently represent the oldest age groups have lower smoking prevalences than the birth cohorts in the younger ages (those born between 1910 and 19301, and this decreased smoking prevalence resulted in a decreased lung cancer mortality. The risk ratios presented in Figure 3 are comparisons with the risk in the general population, and therefore represent the combined effect of the increased smoking prevalence among asbestos workers and the increased risk due to the asbestos exposure. To the extent that the age-related changes in smoking prevalence among older asbestos workers presented in Table 9 represent a return toward or below the smoking prevalence in the general population, a decline in the risk ratio among older asbestos workers would be expected. Regardless of the reason for the change in risk ratio among older workers (i.e., either differences in smoking behavior or decline in risk following cessation of asbestos exposure), the magnitude of the decline is modest, particularly when the rapidly increasing baseline risk of lung cancer in the general population with increasing age used to calculate these risk ratios is considered. A somewhat different approach to this question was taken by Seidman and colleagues (19791, who examined the mortality experi- ence of a group of workers exposed to asbestos over a very limited period of time during World War II and followed them for 35 years after the onset of this exposure. These workers had an extremely intense exposure to asbestos, but only very brief exposures with no subsequent asbestos work-exposure history. If the risk of lung cancer declines significantly following the cessation of exposure to asbestos, then these workers would be expected to have a declining risk of developing lung cancer with increasing duration from the onset of asbestos exposure. Figure 7 shows the ratio of observed to expected lung cancer deaths for the lo-year periods beginning 5, 15, and 25 years after the onset of exposure in workers who had worked less than 9 months and those who had worked more than 9 months in this plant. In both cases the risk is greater in workers for the lo-year period beginning 25 years after onset of exposure than for the period beginning 15 years after exposure. The small number of deaths recorded in the study limits its interpretation; however, the data are consistent with the conclusion that cessation of asbestos exposure may not be associated with a decline in the relative risk of developing lung cancer with increasing duration of time since last exposure. 226 6.1 m f 6 h B 5 P 0 4 l-l 5.7 I 5.0 r-l /I I r 4.9 1 3.9 i 3.4 3.5 - 5 % 3- - 2.6 ; 2- a" l-I-r---.-.-II-.--..- .1,- . . . n " of al / 19821 229 , ~~ 30- I 4& 1 1 1 1 5s 60- 70- eo- Age 1885 1990 1875 FIGURE L-Age-specific mortality rates for cancer of the bronchus and lung, by birth cohort and age at death, men, United States, 1950-1975 SOURCE Data derived from McKay et al. 11982). 230 70 - 60---- 50 - 40 - E 0 a" 30 - 20 - 10 o- l-1950 -1960 1900 1910 1920 1930 1940 1950 1960 1970 1980 Year FIGURE 6.-Changes in the prevalence of cigarette smoking among successive birth cohorts of men, 1900-1978 SOTE Calculated from the resulLs of more than 13.ooO lnterwews conduct& dunng the last two quarters of 1978, prowded by the Natmnal Center for Health Statlstlcs. D~vwon of Health Interview Statlstia. SOURCE US DHHS r19821. where asbestos exposure alone is clearly able to produce the tumor and where cigarette smoking does not alter the mesothelioma risk. Laboratory investigations have been undertaken to evaluate the mechanisms through which asbestos interacts with the combustion products of cigarettes to induce neoplasms. In this regard, the carcinogenic properties of polycyclic aromatic hydrocarbons (PAH), documented chemical carcinogens in cigarette smoke, have been 231 TABLE 9.-Prevalence of smoking among asbestos insulation workers whose smoking history was known Age Current Former smokers smokers NWW smoked regularly PW and tiger 25-29 64.8 19.3 13.0 2.5 30-34 61.0 19.3 13.5 6 35-39 60.9 22.2 11.6 4.9 40-44 61.3 25.0 9.2 45 4S-u 55.8 26.8 9.8 56 5M4 53.7 32.2 9.1 5.0 55-59 50.1 34.1 9.8 6.0 6&64 45.4 35.1 10.4 91 65-69 42.3 33.7 12.4 li.6 7&74 30.7 34 3 17.5 17 5 X-79 51.5 34.3 7.1 71 B&84 37.1 33 3 11.1 18.5 2% 30.0 35.0 25 10.0 Source Hammond et al t 19791 evaluated in combination with asbestos both in tissue cultures and in grafts of respiratory tract epithelium (reviewed in Craighead and Mossman 1982; Mossman, Light et al. 1983). This section summarizes the results of these experimental studies. Animal Studies of the Carcinogenic Interactions Between Cigarette Smoke and Asbestos When animals are administered asbestos in inhalation chambers or by intratracheal instillation, differences among species and strains appear to influence the occurrence of lesions. For example, only benign lesions (papillomas and adenomas) are found in ham- sters, guinea pigs, and rabbits after prolonged inhalation of asbestos (Botham and Holt 1972a, b; Gardner 1942; Reeves et al. 19741, whereas cats (Vorwald et al. 1951) and nonhuman primates (Wagner 1963; Webster 1970) develop fibrosis of the lung but not tumors. Small numbers of neoplasms (squamous cell carcinoma., adenocarci- noma, small and large cell carcinoma) have been reported in rats (Davis et al. 1978; Reeves 1976; Reeves et al. 1974; Wagner et al. 1974), but benign neoplasms and fibrosarcomas (tumors rare in the human lung) predominate. Mice also appear to develop both benign and malignant tumors after inhalation of asbestos (Bozelka et al. 1983; Gardner 1942). Bozelka and colleagues (1983) found a large 232 Starting p01llt (Years) 5 15 25 5 15 25 Lung cancer Worked c 9 months Worked > 9 months 0 1 2 3 4 5 6 7 6 9 10 11 12 Rabo of observed lo expected FIGURE 7.-Observed compared with expected weighted average probabilities of lung cancer death in lo-year periods, starting at 5-, 15-, and 25-year points after beginning of work in an amosite asbestos factory, 1941-1945, for men who worked less than or more than 9 months NOTE: Computed by assigmng wwghts of 55 and 45 percent to the prababllitles given in Sadman and colleagues t19791 for men aged 40 to 49 and 60 to 59, respecuvely. at the start of the 1Gyear pen& SOURCE- Sadman et al !19791. number of lesions of questionable malignancy in the lungs of Balb/c mice 12 to 18 months after a 75day exposure to chrysotile asbestos. Unfortunately, it is difficult to evaluate many of these animal studies critically because satisfactory controls were not employed and data on exposure regimens and concentrations of asbestos are often not available. In addition, adequate pathologic documentation of the lesions is often lacking. Benign adenomas could occur spontaneously in many lesser species (Mitruka et al. 19761, and luxuriant squamous metaplasia and bronchiolization of the respira- tory mucosa may be misinterpreted as malignant lesions. These last epithelial changes may occur as a response to injury induced by asbestos (Davis et al. 1978; Mossman et al. 1980; Reeves et al. 1974; Wagner 1963; Woodworth et al. 1983a, b). 233 157-964 0 - 86 - 9 Several investigators have administered chrysotile to rats and hamsters in combination with either cigarette smoke or ben- zo[a]pyrene (BaP), a major polycyclic aromatic hydrocarbon (PAH) in cigarette smoke (Table 101 (Miller et al. 1965; Pylev and Shabad 1973; Shabad et al. 1974; Smith et al. 1968; Wehner et al. 1975). A striking increase in neoplasms (both benign and malignant) of the respiratory tract was observed. In contrast, a synergistic effect on tumor development was not apparent in rats exposed to asbestos and cigarette smoke by inhalation (Shabad et al. 1974; Wehner et al. 1975); however, the majority of the animals in these studies died prematurely of pulmonary fibrosis. The effects of asbestos on the carcinogenicity of PAH in the respiratory tract have been evaluated using grafts of tracheal tissue implanted into syngeneic animals. Two model systems have been developed. In the first, the tracheas of rats are excised and formed into tubular sacs by ligatures at the ends and then transplanted subcutaneously (Topping and Nettesheim 1980; Topping et al. 1980). When relatively large amounts of chrysotile are introduced into the lumina of these grafts, inflammatory changes appear and fibrosarco- mas develop in a substantial proportion of animals (Topping et al. 1980). On the other hand, epithelial tumors (carcinomas) appear when low concentrations of the PAH dimethylbenz[a]anthracene are introduced into the tracheal grafts before chrysotile (Topping and Nettesheim 1980). The amounts of PAH used in these experiments were insufficient to cause tumors; therefore, the asbestos acted as a promoting agent. In the second model system, organ cultures of hamster trachea are exposed to crocidolite asbestos and implanted into syngeneic recipi- ents after various periods of incubation in vitro (Craighead and Mossman 1979; Mossman and Craighead 1979, 1981, 1982). Neo- plasms failed to develop in these experiments. However, tumors, the majority of which were carcinomas, were found when the PAH 3- methylcholanthrene (3MC) was coated on the surface of the crocido- lite fibers and precipitated onto the epithelial surfaces of the tracheal organ cultures prior to transplantation. This tissue served as the nidus for the development of squamous cell carcinomas in the hamsters implanted with the cultures. In these experiments, asbes- tos appeared to be a carrier of PAH, because 3MC also produced tumors when absorbed to nonfibrous particulates such as kaolin, hematite, and carbon (Mossman and Craighead 1979,1982). Concepts of Carcinogenesis The concepts of initiation and promotion were developed to explain the complex, multistep process of chemical carcinogenesis. "Initiation" is defined as the irreversible DNA damage of a cell induced by a carcinogenic agent. In contrast, tumor "promotion" is a 234 TABLE lO.-Tumors occurring in rodents after exposure to asbestos in combination with components of cigarette smoke Number of tumors/Number of animals Chrysotile Agent alone Combination Tumor types Animal Reference Inhalation 5151 12151 (smoke) 9/51 (+smoke) Adenoma, papilloma. carcinoma Rat Wehner et al. (1975) O/46 ND' O/16 (+smoke) O/21 (+BaPY ND Rat Shabad et al. (1974) Intratracheal instillation ND 13137 (BaP) 18135 ( + BaP) Adenoma, papilloma, carcinoma Hamster Smith et al (1966) o/17 lo/34 (BaP) 24/31 (+BaP) Adenoma. papilloma. carcinoma Hamster Smith et al (1966) o/49 0110 O/19 (BaP) 4110 (BaP) 6111 (+Bap mixed) 6/21 (+BaP adsorbed) 15/10" c+BaPj Adenoma, carcinoma, reticulosarcoma, mesothelioma Papilloma, carcinoma Bat Hamster Pylev and Shabad (19731 Miller et al. (1965) ' ND = no details provided z BaP = benzcjalpyrene. ' Anunals developed multiple tumors. sequential process whereby a second, but unrelated, generally noncarcinogenic substance acts to enhance the effect of an initiator. Initiated cells undergo proliferative changes and differentiation that ultimately result in transformation to a malignant lesion. Much of the information that has accumulated on classical tumor promoters and their mechanisms of action was derived from studies with mice in which the animal's skin was painted with PAH, followed by repeated applications of phorbol esters (or related compounds) (reviewed in Slaga et al. 1982). Nonetheless, the concepts of initiation and promotion appear broadly relevant to carcinogenesis in the mammary gland, liver, colon, urinary bladder, brain, and lung (Marx 1978). In this regard, a wide variety of chemical, physical, and infectious agents interact with tissues to induce a constellation of inflammatory and proliferative changes ultimately resulting in malignancy. It is doubtful that the action of asbestos in increasing lung cancer risk is as a tumor initiator (reviewed in Craighead and Mossman 1982; Mossman and Craighead 1981). Few epithelial tumors develop in experimental animals when PAH are not used in conjunction with asbestos. Moreover, chrysotile and crocidolite do not seem to damage the DNA of hamster or human tracheobronchial epithelial cells (Fornace 1982; Mossman, Eastman et al. 1983). In most (but not all) studies using cell culture systems, asbestos is neither mutagenic nor carcinogenic (Chamberlain and Tarmy 1977; Daniel 1983; Kaplan et al. 1980; Reiss et al. 19821, but the malignant transformation of hamster embryo fibroblastic cells by asbestos, glass fibers, and silica particles has been reported recently (Hesterberg and Barrett 1984; Oshimura et al. 19841. Under these circumstances, asbestos may not act like a classical mutagen, but appears to cause alterations in chromosomal structure (Barrett et al. 19831, perhaps consequent to its cytotoxic effects. In contrast, asbestos exhibits many of the properties of classical tumor promoters when introduced into grafts of tracheal tissue (Topping and Nettesheim 1980) and monolayer cultures of hamster and human tracheobronchial tissues (reviewed in Craighead and Mossman 1982; Mossman and Craighead 1981; Mossman, Light et al. 1983). Like the phorbol esters, asbestos appears to induce perturba- tions of the plasma membranes of cells, such as the stimulation of membrane-associated enzymes (Mossman et al. 1979) and the generation of oxygen free radicals (Mossman and Landesman 1983). In addition, both asbestos and fibrous glass induce the biosynthesis of polyamines, important biochemical markers of cell division and proliferative changes in the tracheobronchial mucociliary epitheli- urn (Landesman and Mossman 1982; Marsh and Mossman 1984). This is accompanied by the development of squamous metaplasia, a putative premalignant change. These alterations in cell function and 236 structure are not observed in tissues exposed to nonfibrous mineral analogs of asbestos and glass, an observation indicating that the fibrous geometry of the material is important (Woodworth et al. 1983b). Cigarette smoke contains ciliostatic and toxic chemicals that impair mucociliary transport and the function of phagocytic cells (Warr and Martin 1978). Thus, intrapulmonary deposit,ion and clearance of asbestos might be affected, resulting in increased retention of asbestos in the lungs. In addition, the development of squamous metaplasia consequent to exposure to both PAH and asbestos (Mossman et al. 1984) might contribute to the retention in the respiratory tract of asbestos and the constituents of cigarette smoke. Studies using artificial membranes and cells in culture suggest other possible mechanisms of synergism between PAH and asbestos. PAH are not carcinogenic in their natural state and must be metabolized by a mixed-function, microsomal enzyme system (aryl hydrocarbon hydroxylase, AHH) to degradative products and electro- philic forms interacting with DNA (Freudenthal and Jones 1976). In this regard, the association (adduct formation) of modified metabo- lites of PAH with the DNA of "target" cells is thought to be a critical event in initiation of those cells. A number of studies suggest that the addition of asbestos and PAH to tracheobronchial epithelial cells (Mossman and Craighead 1982), microsomal preparations from lungs (Kandaswami and O'Brien 1981), and phagocytes (McLemore et al. 1979) affects the normal metabolism of PAH as measured by an increase (or decrease) in activity of AHH enzymes. Unfortunately, these results are inconsistent, possibly a reflection of the different experimental systems evaluated. Accordingly, this important area of carcinogenesis needs further exploration. PAH are ubiquitous in the environment and are associated with airborne particulates (Natusch et al. 1974). Thus, the ability of asbestos and other particles to act as "condensation nuclei" for chemical carcinogens has been explored using tracheobronchial epithelial cells (Mossman, Eastman et al. 1983: Eastman et al. 1983) and artificial or isolated cell membranes (Lakowicz and Bevan 1979; Lakowicz et al. 1978). Transfer of PAH to cell membranes by asbestos appears to occur more rapidly than with use of nonfibrous particulates (Lakowicz and Bevan 1979; Lakowicz et al. 1978). Moreover, the normal uptake of BaP and the formation of BaP-DNA adducts by tracheal epithelial cells are increased when BaP is adsorbed to chrysotile and crocidolite asbestos (Mossman, Eastman et al. 1983; Eastman et al. 1983). The pulmonary alveolar macrophage (PAM) is a key cell in the response of the host to asbestos. PAMs accumulate at sites of deposition of asbestos in the tracheobronchial tree (Brody et al. 237 19811, a process associated with activation and release of lysosomal enzymes (Davies et al. 1974) and the generation of oxygen free radicals (McCord and Wong 1979). In addition, these cells possess the enzymatic capability to convert PAH to active metabolites (Autrup et al. 1978) and may facilitate the transfer of hydrocarbons to tracheobronchial epithelial cells and other cell types (Shatos and Mossman 1983). Thus, either damage to or activation of macrophages by asbestos and the components of cigarette smoke could influence the process of carcinogenesis. Conclusions Several mechanisms by which cigarette smoke and asbestos may interact to increase carcinogenic risk are possible, but they remain unproved in man. First, asbestos fibers could serve as carriers of the carcinogens of cigarette smoke into the cell. Physical transport of this type has been demonstrated experimentally, and there is evidence to suggest that asbestos transfers PAH to cell membranes with unusual efficiency in comparison with other particulates. While this mechanism is an intriguing possibility, it presupposes the interaction of smoke constituents with aerosols of asbestos fibers in the atmosphere. Events of this nature remain hypothetical and unproved. A second mechanism is based on experimental evidence accumulated in both animals and cell culture systems. In this schema, asbestos serves as a promoter in the respiratory epithelium to alter the properties of the epithelial cells and to enhance neoplastic transformation in cells initiated by the combustion products of cigarettes. Biological evidence supporting this mecha- nism of carcinogenesis is compelling in experimental models of carcinogenesis, but not easily tested in man. The possible role of macrophages in the metabolism of PAH adsorbed to asbestos is an intriguing consideration. These cells are biologically activated in the smoker and in the lungs of those exposed to asbestos. They frequently accumulate in large numbers in the airspaces of individuals exposed to these and other pollutants. One can only speculate on whether or not the alveolar macrophage contributes to the metabolism of chemical carcinogens under these circumstances. Although obvious information gaps exist, consideration of the experimental results described here and the contemporary concepts of neoplastic transformation suggest several mechanisms of interac- tion between components of cigarette smoke and asbestos. On the one hand, asbestos appears to resemble a classical tumor promoter after initiation of tracheobronchial epithelial cells by the carcinogen- ic chemicals found in cigarette smoke. Alternatively, asbestos appears to act as a vehicle for the transfer of PAH across cell membranes and affects the metabolism of these carcinogens, factors 238 favoring the process of initiation. Finally, asbestos and the toxic constituents of cigarette smoke injure cells, a situation potentially encouraging the retention of these inhalants in the respiratory tract. Chronic Lung Disease Cigarette smoke (US DHHS 1984) and asbestos exposure (Selikoff and Lee 1978) are well-established causes of chronic lung injury. As in the preceding discussion of lung cancer, the enormous body of literature that established the pathogenicity of each of these agents is not presented; rather, this section focuses on the effects of combined exposure. In contrast to their effect on the risk of developing lung cancer, asbestos and cigarette smoke produce different patterns of injury in the lung. The pattern of lung injury associated with cigarette smoking is characterized by inflammation, excess mucus production, narrowing of the airway lumen, and emphysema (US DHHS 1984). The result is a reduction in maximal expiratory flow rates and increased static lung volumes. The pattern of lung injury associated with asbestos is fibrosis of the small airways extending into the alveolar structures with obliteration of alveoli, leading to a reticular nodular pattern of interstitial fibrosis on chest roentgenogram and decreased lung volumes, with relative preservation of the forced expiratory volume in 1 second (FEV,) as a percent of the forced vital capacity (FVC) (Selikoff and Lee 1978). In spite of these relatively distinct patterns of lung injury, interpretation of the pattern of injury in combined exposure is difficult. Both agents may act separately, but simultaneously, to injure the lung. The injury in an individual worker is the combina- tion of the injuries due to cigarette smoke, asbestos and other environmental agents, and all other injurious processes that have occurred during that individual's lifetime. The presence of a lung injury secondary to one agent or process does not prevent the lung from being injured by a second agent. In evaluating impairment in an asbestos-exposed smoker, it may be difficult to apportion the impairment between the two agents because both cigarette smoking and asbestos exposure may alter a given lung function test in the same direction (e.g., both of them reduce the diffusing capacity (DLCO)), or they may change a test in opposite directions (e.g., an increase in total lung capacity (TLC) due to smoking may mask a decline in TLC due to asbestos). When a given physiologic test is influenced in opposite directions by cigarette smoking and asbestos, the degree of injury to the lung may be underestimated by the change in that test. For example, the relative preservation of TLC in cigarette-smoking asbestos workers does not represent a relative protection of the lung in combined exposure, but rather reflects the emphysematous destruction of alveolar walls secondary to cigarette 239 smoking (.which increases TLC) being combined with the asbestos- related fibrosis and obliteration of other alveolar units (which reduces TLC). Interstitial fibrosis of the lung is a well-described and well- established sequel of heavy asbestos exposure. In an individual, the fibrosis is attributed to asbestos when a pattern of lung injury on chest roentgenograph or lung biopsy consistent with that found in asbestos-exposed populations is found in conjunction with a history of significant asbestos exposure or with levels of asbestos in lung tissue consistent with significant asbestos exposure. Fibrosis due to other causes such as exposure to coal dust, silica, or infection needs to be considered in evaluating individual patients, and both diagno- sis and attribution to a specific etiologic agent may be difficult in the very early stages of the fibrotic process. However, by the time the process has progressed to the degree that it causes significant disability or death, the diagnosis is usually readily evident and the substantial asbestos exposure generally necessary to cause this degree of fibrosis is also easily identifiable. Chronic Lung Disease Death Rates Cigarette-induced chronic lung injury does not produce the extensive fibrosis commonly found in individuals dying of asbestos- induced interstitial fibrosis, and therefore does not interfere in the diagnosis, or attribution to asbestos, of the severe fibrotic lung disease in these individuals. However, cigarette smoking can cause significant lung destruction and disability, and therefore it may contribute to the mortality and degree of disability in individuals with asbestos-induced interstitial fibrosis, independent of any effect of cigarette smoking on the degree or extent of fibrosis. In addition, because death and disability occur only after extensive lung injury, the independent (i.e., additive) lung injuries due to smoking and asbestos might sum to produce a level of disability that could exert a synergistic effect on death rates. Frank (1979) presented data on the death rates in smoking and nonsmoking asbestos insulation workers (Table 11). The population was drawn from the 17,800 asbestos insulation workers studied by Hammond and colleagues (1979) and included those workers with more than 20 years of exposure whose smoking habits were known. The age-standardized death rates from chronic lung disease (includ- ing asbestosis) were increased by either cigarette smoking or asbestos exposure, and the rate in cigarette-smoking asbestos workers was well above the sum of the rates for non-asbestos-exposed- smokers and nonsmoking asbestos workers, This "synergism" was- also present when only asbestosis deaths were considered, with them death rate almost three times higher in cigarette-smoking asbestos workers than in nonsmoking asbestos workers. This study revealed a greater than additive effect for cigarette smoking and asbestos exposure on death rates from chronic lung disease and asbestosis. This may reflect a "synergistic" effect on death rates of the "addition" of the two separate injuries, rather than an effect of cigarette smoking on the degree of fibrosis produced by a given dose of asbestos. In addition, these data reflect the fact that a death certification of asbestosis does not rule out the possibility of a second disease process existing in the lungs of that individual. Pulmonary Function Testing The most frequently used measures of lung function are lung volumes and measures of maximal expiratory airflow, either as the volume expired during a given time (e.g., forced expiratory volume in 1 second, FEV,) or as the rate of expiratory airflow at a given lung volume or between two lung volumes (e.g., forced expiratory flow from 25 to 75 percent of the forced vital capacity, FEFzMw). Classically, diseases are divided by their pattern of abnormality on lung function testing into obstructive (processes that predominately limit expiratory airflow) and restrictive (processes that predominate- ly decrease lung volumes and specifically decrease the total lung capacity). Both of these processes may occur in a single individual, resulting in a mixed pattern (both reduced lung volumes and reduction in volume-adjusted expiratory flow rates). Obstructive lung disease is marked by reductions in the rate of expiratory airflow; normal or, more typically, increased TLC; and substantial increases in residual volume (RV) and functional residu- al capacity (FRC) (Figure 8). Restrictive diseases are marked by a reduction in TLC. The flow rates in restrictive disease are usually normal or even increased once an adjustment for the decreased lung volume has been made. FEV, is obviously limited by the total volume that can be expired, as well as by the amount of obstruction to expiratory airflow. For this reason, FEV, is commonly divided by the forced vital capacity (FVC), and expressed as the percentage of the FVC that can be expired in 1 second (FEV,/FVC%). This adjustment of FEV, for reductions in FVC aids in separating the decline in FEV, that is due to a restrictive process (i.e., reduced TLC) from that which represents increased resistance to, and decreased driving pressure for, expiratory airflow. The pattern of lung function change in cigarette smokers has been well described (US DHHS 1984), and consists of a reduced FEV, and FEV,/FVC%, an increased RV and FRC, and an increased TLC (particularly in those individuals with emphysema). In addition, FEFwwG, DLCO, and flows at specific lung volumes are also usually reduced. The pattern of change with the development of interstitial fibrosis due to asbestos is also clear. Figure 9 shows the changes in lung 241 TABLE Il.-Age-standardized death rates for combinations of cigarette smoking, no smoking, asbestos exposure, and no asbestos exposure; selected causes of death Gl-CUp All CfdB?S All cancer Noninfectious pulmonary diseases (total includes aS!J.?ShiS) Asbestosis All other causes Death rates per lOO,C%U man-years I. No adeatos work and no smoking 980.9 208.2 28.6 -' 743.9 II. No asbestos work, but smoking 1580.7 353.1 103.8 -1 1123.8 III. Asbestos work and no smoking 1430.9 563.9 77.1 77.1 789.9 IV. Asbestas work and smoking 2659.0 1317.0 286.5 225.5 1005.5 Mortality ratice No asbestos work and no smoking (I + I) 1.00 1.00 1.00 1.00 No asbestos work, but smoking (II + I) 1.61 1.70 3.60 1.51 Asbestca work and no smoking (III + I) 1.46 2.71 2.68 1.06 Asbestos work and smoking (IV i I) 2.71 6.33 9.95 1.42 Excess in death rates V. Smoking only (II-I) 599.8 144.9 75.0 -1 379.9 VI. Asbestos work only (111-I) 450.0 355.7 48.3 77.1 46.0 VII. Synergism (IV-I-V-W 626.3 608.2 i34.4 148.4 -114.3 Percent excess in death rates Smoking only (1cOV i I) 61 70 260 51 Asbestos work only (lOWI i I) 46 171 -68 6 Synergism WIOVII i I) 64 292 467 -15 NOTFK Rate per 100,ooO man-years standardized for age on the distribution of the man-yearn of all the asbestos msulation workers 2 20 years after onset of asbestos work. Rates for the asbestos work-expoeure groups are based on cause of death coded according to the best available evidence. ' Death rates not available for the no asbestos work-exposure group. SOURCE: Frank (1979). Total lung FlJ~tlO~al esldual capacity volume COLD Total lung capacity Functional rasldual capackty Resrdual volume I Normal Total lung Aestncttve lung dfsease FIGURE &-Lung volumes in normal individuals and in patients with chronic obstructive lung disease and restrictive lung disease volumes and Figure 10 shows the changes in the forced expiratory flow rates for the Quebec asbestos workers at several levels of increasing cumulative exposure to asbestos dust (Becklake et al. 1972). The lung function tests were performed on 1,027 men aged 21 to 65 who represented an age-stratified random sample of the 6,180 men employed in the Quebec asbestos mines and mills on October 31, 1966. An additional 184 men between the ages of 61 and 65 were also studied to increase the number of workers in the highest exposure categories. The data in the figures represent the averages of the test values for smokers and nonsmokers after they had been standard- ized for age, height, and weight. Smokers were defined as those who had ever smoked at least one cigarette per day for 1 year; therefore, this category includes former smokers. The pattern in nonsmoking asbestos workers is that of restriction; there is a steadily declining TLC with increasing dust exposure. 243 t&l: * 2 R 1 d - : ,.,:,, :. .::: No "6 :: 1 :.:.: - ..:.:.:.:,:.: ,- -6 :.,. 1. c 6 2 1 : :.:.: :. :j,..: 1. ..: -+ 0 - z I ,. ,. 0 " " FIGURE 9.-Standardized mean values for subdivisions of lung volume (TLC[SS], IC, FRC, and RV) in nonsmokers and smokers, divided by dust index FEV, also declines with increasing exposure, but this decline can be accounted for by the decline in FVC, as FEV,/FVC% does not decline with increasing exposure in nonsmokers and is above 80 percent in all but the lowest exposure category. FEFzs-75% is also preserved in all but the two highest exposure categories. The FEFs 244 FIGURE lO.-Standardized mean values for flow rates (MMF, FEVTA, FEV,, and FVC) in nonsmokers and smokers, divided by dust index NOTE in,= number of mdividuals m each subgroup SOURCE Becklake et al 11972~ w measurement would also be expected to decline with a fall in FVC, independent of any change in the degree of obstruction to airflow. Thus, in this group of nonsmoking asbestos workers, the pattern of asbestos-induced lung disease is a reduction in lung volumes with preservation of FEV,/FVC%. The changes in lung function in the smoking asbestos workers in this study can be contrasted with those of nonsmoking asbestos workers with comparable cumulative exposure histories (Figures 9 and 10). The static lung volumes (Figure 9) are larger for smokers than nonsmokers at each level of cumulative asbestos exposure. FEFz+x~, and FEV, are lower, as is FEV,/FEV%. There is a progressive decline in FEV,/FVC% with increasing cumulative asbestos exposure in the smokers but not in the nonsmokers. This decline is probably attributable to the increase in cumulative cigarette smoking exposure (and related injury) that occurs with increasing cumulative asbestos exposure (Rossiter and Weill 19741, because of the correlation between these cumulative measures. The picture that evolves from this study of the effect of combined cigarette smoke and asbestos exposure is one of an obstructive process superimposed upon a restrictive process, In addition, in the population of workers with relatively heavy asbestos exposure, TLC is reduced in both smokers and nonsmokers, suggesting that the restrictive pulmonary process exerts a greater effect than those changes that tend to increase TLC (e.g., emphysema). The relative preservation of TLC that occurs in cigarette-smoking asbestos workers in comparison with nonsmoking workers should not be interpreted as a protective effect of smoking, because it almost certainly represents more extensive lung damage (i.e., the combina- tion of emphysematous and fibrotic processes) in the lungs of the cigarette smokers. It is also important to note that the data from this study show a relatively clear dose-response relationship between cumulative asbestos exposure and degree of restrictive impairment. The pattern of lung function response in smoking and nonsmoking workers found in this study is consistent with the premise that asbestos exposure causes a relatively pure restrictive lung disease and cigarette smoking causes a relatively pure obstructive process. In combined exposure, the lung functional changes represent the combination of the effects of these two independent processes. A number of other studies have examined the lung function in smoking and nonsmoking asbestos workers, and the data from these studies can be used to explore this relationship further. A general morbidity study was conducted of civilian naval dockyard workers in Great Britain, and lung function tests were performed on 612 male registered asbestos workers (Harries and Lumley 1977). The measurements were standardized to a height of 1.7 meters and to a constant age within each of five age ranges. Smoking habits were classified as smoker, nonsmoker, or ex-smoker. TLC showed no relationship to age, smoking status, or duration of asbestos exposure. There was a tendency for smokers to have a lower FEV, than nonsmokers, and the difference increased with age. FEV, and duration of asbestos exposure were related only for those aged 246 50 to 59. The differences in FVC between smokers and nonsmokers were less than the differences in FEV1, demonstrating a relative preservation of FEV,/FVC in nonsmokers, and a relationship between duration of exposure and FVC was again present only in the 50- to 59-year-old age group. The absence of a relationship between TLC and duration of exposure may be due to the somewhat lower intensity of asbestos exposure in this population in comparison with the Quebec miners. In a companion study of the same naval dockyards, Rossiter and Harries (1979) examined the lung function in 1,200 men aged 50 to 59. The sample included all men in the register of asbestos workers, 1 in 3 of those currently in occupations where intermittent exposure to asbestos might occur, and 1 in 30 of the remainder. Lung function measurements were standardized to age 55 and a height of 1.7 meters. Smoking was characterized as nonsmoker, ex-smoker, or current smoker, and lung function was analyzed by duration of exposure to asbestos. FEV, was lower in the smokers than in the nonsmokers, and the workers in the registered asbestos-exposure group had lower values than workers in other occupational groups. This was particularly true of the group of asbestos laggers who had been employed prior to 1957. The differences in FVC among the different smoking habits were less than the differences for FEV,. The FEV,/FVC ratio was markedly influenced by smoking. Even among those workers employed before 1957, the FEV,/FVC ratio was preserved in nonsmokers but declined among cigarette smokers. Weill and colleagues (1975) adopted a somewhat different ap- proach by developing predictive equations specific for the smoking status of the worker, as well as age and height, for the individual function tests. FEF2675~ was lower and declined more rapidly in smokers than in nonsmokers (Figure 11) in the population used to develop the predictive equations. The researchers applied these smoking-specific regression equations to 859 workers who were employed in two asbestos manufacturing plants in New Orleans on November 3, 1969. Dust exposure measurements were derived from midget impinger samples taken between 1952 and 1969 and from estimates of exposures derived from interviews with employees who had worked prior to this time period. Figures 12 and 13 reveal a decline in TLC with increasing cumulative asbestos exposure; as would be expected, this decline is accompanied by declines in the vital capacity, FEVI, and FEFzx,~. However, there is no decline in FEV,/FVC with increasing duration of exposure. The decline in TLC and vital capacity at the lower exposure levels occurred entirely in the group with x-ray changes, but for the two highest exposure categories, the decline in TLC and vital capacity occurred even in the group with no roentgenographic changes. Again, this study suggests that the effect of asbestos dust exposure in a manufacturing plant is 247 Nonsmokers (n=57) 35 45 55 Age, years FIGURE Il.-Relationship between FEVB-75% and age for the smokers, ex-smokers, and nonsmokers in the standard group (height taken as 175 cm [5 feet 9 inches]) SOURCE Weill et al G 19751 largely that of a restrictive process producing a decline in TLC, with the decline in FEV, and maximal midexpiratory flow between 25 and 75 percent of FVC (MMF 25-75~) being a reflection of the decline in lung volumes rather than