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. 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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. 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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 an indication of the presence of airflow obstruction. Several analyses have focused on the pattern of pulmonary function response rather than on isolated test values (Fornier- Massey and Becklake 1975, Becklake et al. 1976; Muldoon and Turner-Warwick 1972; Murphy et al. 1972, 1978). These authors were attempting to determine whether asbestos exposure results in chronic obstructive lung disease, either in the absence of cigarette smoking or in excess of the level to be expected solely from smoking. The stratified sample of 1,027 Quebec asbestos miners and millers described earlier in this section was also analyzed by the pattern of pulmonary function response (Fornier-Massey and Becklake 1975; 248 Total lung capaccty Percent standardlzed All sublects No x-ray Any x-ray change V~tal capacity . . . . . 100 Percent standardmd All subjects No x-ray Any x-ray change change Functmal residual CapaCitY 100 Percent standardnzed All subjects No x-ray change Any x-ray change FIGURE 12.-Relationship between lung volumes and dust exposure SOURCE We111 et al t 19751 Becklake et al. 1976). These workers were categorized as having a normal, undifferentiated, obstructive, or restrictive pulmonary func- tion picture on the basis of a combined score of the percentage deviations from the predicted value of five pulmonary function tests FEV, Percent standardzed All subjects No x-ray Any x-ray change change FEV,lVC 105 Percent standardzed change Any x-ray change Percent standardmed All sublects No x-ray change Any x-ray change FIGURE 13.-Relationship between expiratory flow and dust exposure SOURCE We,ll et a, 119751. (Table 12). The deviation of the percentage predicted value was scored from 7 through 13 for each value, with lower numbers representing those measurements indicative of restrictive disease 250 and higher codes representing those values indicative of obstructive disease. Scores of 45 to 55 were considered consistent with a normal profile when all five coded values were between 9 and 11, and consistent with an undifferentiated profile when a mathematical balance of codes under, equal to, and over 10 resulted in a score of 45 to 55. Scores under 45 were assumed to represent restrictive profiles and scores over 55 to represent obstructive profiles. Forty-three percent of the population had normal lung function profiles, and 26.5 percent had undifferentiated lung profiles. The remainder was divided relatively evenly between the restrictive and obstructive lung profiles, with 14.9 percent having a restrictive defect and 14.3 percent having an obstructive picture. In Table 13 are revealed the results in smokers and nonsmokers, stratified by increasing asbestos exposure category. The data seem to suggest that neither obstructive nor restrictive lung disease occurs in nonsmoking asbestos workers and that restrictive and obstructive lung disease occur with equal frequency in asbestos miners who smoke. In addition, it appears that there is, if anything, a negative dose-response relationship between restrictive lung disease and increasing cumulative asbestos expo- sure. These results are particularly remarkable in the face of data from the same group of workers presented earlier in this section, which show a relatively clear dose-response relationship between cumulative asbestos exposure and decline in TLC and FEV, in both smokers and nonsmokers. The authors have interpreted this data to suggest that an association between smoking habit and the develop- ment of asbestos-related fibrosis may exist and that asbestos workers who smoke may develop either obstructive or restrictive lung disease. The inconsistencies between the data on pattern pulmonary function tests and the measures of individual test responses de- scribed earlier may be explained by the effects of changes in lung volumes on some of the measurements used to code the lung function profile. FEVY,Q and MMEFzw~~~ are measurements that, when reduced, are used in this coding scheme to define an individual as being obstructed. Both of these are measurements of airflow obstruction in the presence of normal lung volumes, but may also be reduced in the presence of diminished lung volumes secondary to restrictive lung disease. Indeed, examination of the pattern of pulmonary function response in nonsmoking asbestos miners (Figure 10) reveals that with increasing cumulative asbestos exposure, the decline in TLC in these workers was accompanied by a decline in FEVW and MMEFz~-w+. This pattern, consistent with progressive restrictive lung disease, would define the worker by the coding scheme as having obstruction, or would counterbalance those scores for a restrictive category, thereby placing the worker in the undifferentiated category. A similar effect would occur in asbestos miners who smoke. As can be seen in Figure 10, the decline in FEV,, 251 TABLE 12.-Coding of lung function profile code Volumes Flow rates (RI'. TLC) (FEVw MMF) (FEV, PVC)% percent predicted 7 <70 > 130 >116 8 70-79 121-130 111-115 9 80-89 111-120 llo-106 10 90-110 90-110 95105 11 111-120 80439 90-94 12 121-130 7iL79 ass9 13 > 130 <70 <84 SOURCE Fornw-kiasey and Becklake (19751 FEVX~, and MMEFzs-75o is greater in smoking asbestos miners than in nonsmoking miners. This pattern, which is consistent with a combination of restriction and obstruction in these workers, would result in a progressive increase in the coding scheme obstructive score, and therefore may account for the absence of a dose-response relationship between asbestos exposure and restrictive lung disease in the asbestos workers who smoke. With increasing severity of restrictive lung disease, more and more workers would be catego- rized as having an obstructive or undifferentiated pattern and thus would drop out of the restrictive category. A similar approach was taken by Muldoon and Turner-Warwick (1972), who categorized the lung function results in a consecutive series of 75 subjects with a history of exposure to asbestos who were referred to the Pneumoconiosis Medical Panel of London. The researchers categorized workers as having obstructive, restrictive, mixed, or normal lung function. They reported that the workers with obstruction did not have heavier smoking histories than the subjects with restrictive or normal lung function. However, examination of the data presented in their report reveals that, although the percentage of current smokers in the obstructive and restrictive groups was somewhat similar, there were marked differences in the frequency of former smokers. Indeed, all of the workers who had obstructive disease had a history of cigarette smoking. There were 13 workers in the group; 8 were current cigarette smokers and 5 were former cigarette smokers, of whom 3 had stopped smoking less than 1 year prior to the study. Of the entire group examined, there were only four workers who had never smoked cigarettes, and all of these workers fell into the restrictive category. Murphy and colleagues (1972, 1978) also attempted to answer the question whether an increased prevalence of obstructive lung disease occurs in asbestos workers. They examined a group of 101 shipyard 252 TABLE 13.-Effects of chrysotile exposure on the health of 1,015 current Quebec asbestos workers Dust index 1 c 10 lo-99 10x199 2cc-399 4c&799 >a00 Prevalence percent2 Chronic bronchitis Dyspnea Function profile3 prevalence percent Restrictive Obstructive Percentage fall in function' vc FEV, DLCO,, rest DLCO,, exercise Prevalence percent' Chronic bronchitis l&pIlea Fun&on profile-3 prevalence percent Restrictive Obstructive Percentage fall In function' vc FEV, DUO,, rest DLCO,, exercise 10 0 3 0 0 0 0 0 23 4 8 12 0 0 0 0 Konsmokers 19 19 46 21 49 19 24 31 13 44 3 3 1 0 -10 -16 -9 -9 -11 -15 -8 -9 Smokers 22 30 29 46 45 15 18 21 30 32 14 16 10 4 13 12 13 12 23 12 -3 -7 -3 -8 -4 13 0 -2 1 -18 -19 -23 -13 -15 -22 -18 -12 -15 -18 -18 -20 -10 -10 1-5 0 -13 -15 -3 -5 1 -14 -15 0 -7 SOTE For all measurements. prevalence percent has been age-standardized to the total working population BS of October 31. 1966 This was to allow for the smaller of number of men for whom function profiles were analyzed ' Expressed in mllhon particles per cubic foot years ' 1 Based on a total sample of 1.015 men I "Basedon995men 2 SOURCE Becklake et al 119761 pipe coverers and compared them with 95 control subjects. The prevalence of smoking in these two populations was approximately the same. There were significant differences between the asbestos- exposed workers and the control population in vital capacity and FEV, in measurements taken both in 1966 and in 1972. However, there was no difference between the two groups in FEV, as a percent of FVC at either time point. In 1972, there was a significant difference between the two groups in the reported symptom of wheezing apart from colds. When this symptom was combined with the prevalence of an abnormal FEV,/FVC%, using the criteria of Ferris and Anderson (1962) for obstructive lung disease, the asbestos workers had a significant higher prevalence of obstructive lung disease in comparison with the control population. However, this 253 increased prevalence resulted from their reported symptoms and not from differences in measured pulmonary function. In summary, lung function has been examined in several popula- tions of smoking and nonsmoking asbestos workers. In populations of nonsmoking asbestos workers, a dose-related decline in TLC and a decline in FEV, and in FEFZMSS consistent with the decline in TLC can be identified, a pattern consistent with a primarily restrictive lung function profile. In populations of cigarette-smoking asbestos workers, the decline in TLC is somewhat less than in nonsmoking asbestos workers and the decline in FEV, and FEFXJSS is somewhat more. The percentage decline in FEV, compared with the percentage decline in FVC is greater in smoking asbestos workers, but not in nonsmoking asbestos workers. When smoking asbestos workers are compared with control populations with similar smoking habits, there is a significantly greater decline in FVC and TLC, but the ratio of FEV, to FVC is similar in the asbestos-exposed and the non- asbestos-exposed populations. The data are therefore consistent with independent effects of asbestos and cigarette smoking on lung function. This issue has been examined statistically by Samet and colleagues (1979) and by Rossiter and Weill (1974); an additive effect of smoking and asbestos exposure on the FVC was present, but there was no statistically demonstrable synergism. Regan and colleagues (1971) evaluated the relative power of 16 clinical-radiological-pulmonary function variables in evaluating as- bestosis and chronic airway disease. A decreased diffusing capacity for carbon monoxide (DLCO) and a decrease in the vital capacity had the greatest power to measure the severity of either obstructive or restrictive lung disease in workers with both smoking and asbestos exposure, but had little ability to distinguish between the two processes. The best indicator for distinguishing between restrictive lung disease and obstructive airway disease was FEV, as a percent- age of the vital capacity. This variable had a better ability to distinguish between obstructive and restrictive disease than either the clinical or the chest roentgenogram findings or other tests of pulmonary function. The absence of an effect of asbestos exposure on FEV,/FVC% must be interpreted with caution. Although this test is the best measure of the presence of airflow obstruction in the presence of restrictive lung disease, it is not sensitive to changes in the small airways. Because both cigarette smoking and asbestos exposure have been shown to result in changes in the small airways of the lung, it is important to examine the effects of these two exposures on tests of small airway function. 254 Small Airways Function Airways in the lung with diameters of 2 mm or less are considered small airways and consist of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls). Considerable obstruction can be present in these airways without significantly altering the airway resistance or lung mechan- ics. In addition, abnormalities in the small airways are a prominent part of the abnormality present in chronic obstructive lung disease (COLD). The relationship of cigarette smoking to abnormalities in tests of small airways function, and of pathologic abnormalities of the small airways to functional changes, was reviewed in a previous Report of the Surgeon General (US DHHS 1984). Changes in the small airways of cigarette smokers may occur within the first few years of smoking, are more prevalent in heavy smokers, and increase in frequency with increasing duration of the smoking habit. Because the small airways are also involved in people who develop cigarette- induced COLD, tests of small airways function are usually abnormal in people with chronic airflow obstruction on conventional spirome- try; however, it is not yet clear whether the early and reversible inflammatory changes in the small airways of smokers are the first stage in the pathophysiologic process of developing COLD or are merely a nonspecific irritant response to smoke that does not predispose to the development of COLD. The response of the lung to asbestos also involves the small airways, and there has been considerable interest in functional changes of the small airways of asbestos workers. Relevant questions are these: Does asbestos cause changes in the small airways independent of smoking? Do the morphologic changes in the small airways caused by smoking differ from those caused by asbestos? Do the changes in the small airways of asbestos workers progress to airflow obstruction, as measured by standard spirometry, indepen- dent of cigarette smoking? Woolcock and colleagues (1969) demonstrated that a group of bronchitic subjects with normal lung volumes and flow rates had abnormal tests of small airways function. Cosio and colleagues (1978) and Berend and colleagues (1979) were able to correlate abnormali- ties of tests of small airways function with morphologic changes in the small airways. The morphologic changes consisted of a respira- tory bronchiolitis with goblet cell metaplasia, inflammation of the bronchiolar wall, smooth muscle hypertrophy, peribronchiolar fibro- sis, and pigmentation of the bronchiole. Tests of small airways function (closing capacity and slope of the single breath nitrogen washout) were abnormal, with lower degrees of pathologic change; however, abnormalities on spirometric testing (FEV,/FVC and FEF25-754r) were also correlated with more severe morphologic changes in the small airways. The changes in the small airways of asbestos workers have been examined (Wright and Churg 1984; Churg and Wright 1984), and differences in the pattern of injury from that produced by cigarette smoking alone were identified. The researchers examined lung sections from 15 patients who had been exposed to asbestos and had abnormalities of the respiratory bronchioles, and compared these individuals with 15 control subjects matched for age, sex, and smoking status. Almost all of the subjects smoked (13 of 151, so it was not possible to examine the differences between smoking and nonsmoking asbestos workers or to rule out an interaction between smoking and asbestos. However, two distinct patterns seem to emerge. Churg and Wright found changes in the membranous bronchioles of the cigarette-smoking controls similar to those found by others (Casio et al. 1978; Berend et al. 1979), including inflamma- tion, pigmentation, and periobronchiolar fibrosis. The changes in the membranous bronchioles of the asbestos workers (almost all of whom were smokers) were qualitatively identical to those in the non- asbestos-exposed smokers; but quantitatively, the degree of fibrosis, the amount of pigmentation, and the percentage of membranous bronchioles involved was greater in the asbestos-exposed individuals. In the asbestos-exposed group, 67 percent of the membranous bronchioles showed marked fibrosis in comparison with 19 percent in the control population of smokers. The clearest distinction and the most diagnostically useful lesions occurred in the respiratory bronchioles and alveolar ducts. Forty-eight percent of the respiratory bronchioles and 35 percent of the alveolar ducts showed marked fibrosis in the asbestos-exposed group in contrast to 4 percent of the respiratory bronchioles and 0 percent of the alveolar ducts in the control population. These data suggest that cigarette smoking produces an inflammatory response with only modest amounts of fibrosis in the membranous bronchioles, and that the addition of asbestos exposure results in a marked increase in the fibrosis around the membranous bronchioles and an extension of this fibrosis to the respiratory bronchioles and alveolar ducts. Because there were so few nonsmokers examined in this study, the questions whether asbestos exposure alone causes an inflammatory response and whether the fibrotic lesions characteristic of asbestos exposure are influenced by smoking could not be addressed. Given this description of the pathologic response of the small airways to cigarette smoke and asbestos dust, examination of the physiologic testing of the small airways in asbestos workers should focus on several questions: Does asbestos exposure alter the function of the small airways in people who have never smoked? Does this alteration in small airways function result in reductions in the rate of expiratory airflow (as occurs in cigarette smokers) independent of the reductions in lung volume that occur secondary to asbestos 256 exposure? (The increased resistance in the small airways may be compensated for by an increased elastic recoil of the lung available to drive expiratory airflow.) Does asbestos exposure increase the prevalence of abnormalities on tests of small airways function above that expected from smoking alone? A number of researchers have examined small airways function in asbestos workers. Jodoin and colleagues (1971) examined 24 workers with normal chest roentgenograms whose asbestos exposure ranged from 6 months to 24 years. Two groups with comparable age and smoking prevalence, but with differing exposure to asbestos dust, were defined among those 24 workers. The more heavily exposed group had a 30 percent increase in lung static recoil pressure and had reduced rates of expiratory airflow for any given transpulmo- nary pressure, suggesting increased resistance in the small airways. This increased resistance did not result in obstruction on spirometric testing, as both FEV,/FVC% and FEFz+xc~ actually increased in the workers with heavier asbestos exposure. In five of the subjects with heavier exposure, but with a normal FEV, and FEV,/FVC%, the maximal expiratory flow was reduced throughout the entire range of lung volume despite an increased driving pressure, suggesting that the degree of small airway obstruction was greater than the degree of increase in driving pressure. However, all five of the subjects were cigarette smokers; therefore, the reduced airflow could not be identified as due to the asbestos. The authors provided no separate analysis of the data for the nonsmokers in the study. Several other authors (Harless et al. 1978; Cohen et al. 1984; Rodriguez-Roisin et al. 1980; Siracusa et al. 1983) have also presented evidence suggesting that asbestos exposure results in small airway dysfunction; however, the data on nonsmokers were not presented in a manner to allow evaluation as a separate group, or included ex-smokers with never smokers, making interpretation difficult. Begin and colleagues (1983) examined airways function in 17 lifetime nonsmoking asbestos workers with an average of 28 years of exposure in the asbestos mines and mills of Quebec. Seven workers met the diagnostic criteria for asbestosis and 10 did not; none of the workers met the diagnostic criteria for chronic bronchitis, emphyse- ma, or asthma. The lifetime nonsmokers without asbestosis had relatively normal lung function, but there was a slightly lower maximal expiratory flow at 25 percent of the vital capacity and a significantly elevated isoflow volume, suggesting dysfunction in the small airways. The seven workers with asbestosis had clear evidence of smali airway obstruction with a threefold or fourfold increase in upstream resistance at low lung volumes. These data were supported by histologic evidence of peripheral airway obstruction and narrow- ing on lung biopsies in three of these men. However, this obstruction in the small airways was not severe enough to significantly reduce the usual spirometric parameters of airflow obstruction, and none of these men had a significant reduction in FEV,/FVC%. The authors attributed this phenomenon to the higher pressures available to drive airflow in these workers with restrictive lung disease. Cohen and colleagues (1984) attempted to examine the relation- ship of smoking and asbestos exposure in a cross-sectional study of a group of asbestos litigants. Unfortunately, ex-smokers were included with the group of nonsmokers. This results in an increasing prevalence of ex-smokers with increasing age, and ex-smokers have reduced lung function (US DHHS 1984); correspondingly, with increasing duration of asbestos exposure, there would also be an increasing prevalence of ex-smokers. This confounding of their exposure data makes meaningful interpretation impossible. In summary, the evidence suggests that asbestos exposure can result in small airways dysfunction in nonsmoking workers, but this small airways dysfunction does not result in obstruction on standard spirometric testing. FEV,/FVC% remains normal in these non- smoking asbestos workers even in the presence of substantial increases in the airway resistance at low lung volumes and decreases in TLC. This picture differs from that in small airway dysfunction in cigarette smokers, where there is a decline in the FEV,/FVC%. This difference may be accounted for by the differences in elastic recoil pressure of the lung produced by these two injuries. Asbestos exposure results in increased elastic recoil of the lung, which provides an increased driving pressure that compensates for the increased resistance in the small airways. Thus, the rate of expirato- ry airflow is preserved. In contrast, the elastic recoil either remains normal or frequently decreases (in emphysema) with cigarette- induced lung injury, and therefore there is no compensatory increase in driving pressure to maintain the rate of expiratory airflow in the presence of an increased resistance in the small airways. In combined exposure to cigarette smoke and asbestos, the largely inflammatory response in the small airways due to smoking may occur conjointly with the largely fibrotic response in the same airways due to asbestos, and the resultant increase in the resistance in the small airways may be large enough to reduce expiratory airflow even in the presence of an increased elastic recoil. In conclusion, asbestos exposure can result in reduced lung volumes in both smoking and nonsmoking workers, and may result in small airway dysfunction. However, the evidence does not suggest that airflow obstruction, as measured by a reduced FEV,/FVC, is a result of asbestos exposure in nonsmoking asbestos workers or that it is worse than would be expected from the smoking habits of asbestos workers who smoke. Chest Roentgenographic Changes One of the hallmarks of interstitial fibrosis due to asbestos is an abnormal chest roentgenogram, and despite the fact that biopsy- proven disease may be present with a normal roentgenogram (Epler et al. 1978), the x ray commonly reflects both the presence and the extent of fibrosis. Occasionally, particularly in early asbestos-in- duced lung disease, the chest roentgenogram may not be abnormal and the only abnormalities may be a reduced diffusing capacity or decreased lung volumes. The chest roentgenogram is less frequently abnormal in cigarette-induced chronic obstructive lung disease, but roentgenographic abnormalities can occur, particularly in advanced disease or when extensive emphysema is present. The abnormalities produced by these two processes are usually quite different on chest roentgenogram once the disease process is sufficiently advanced, and confusion about the roentgenographic diagnosis in severe disease is unusual. The radiographic changes associated with asbestos include small irregular opacities, which commonly begin as a reticular pattern in the lower lung fields and may progress to diffuse interstitial densities throughout the entire lung with reduced lung volumes (Selikoff and Lee 1978; Fraser and Pare 1979). The abnormalities that have been reported with COLD include overinflation, promi- nence of lung markings ("dirty lungs"), tubular shadows, and in the presence of significant emphysema, oligemia, and bullae (Fraser and Pare 19791. Roentgenographic Changes in Non-Asbestos-Exposed Populations The literature establishing asbestos as a cause of interstitial fibrosis is extensive, and no significant scientific debate remains over the potential for occupational asbestos exposure to result in intersti- tial fibrosis; substantial numbers of asbestos workers have developed interstitial fibrosis as a direct consequence of their inhalation of asbestos dust. A review of this evidence is beyond the scope of this chapter and can be found elsewhere (Selikoff and Lee 1978). The questions raised by the combination of cigarette smoking and asbestos exposure do not include whether cigarette smoking is an independent competing cause of the extensive fibrotic process found in many workers following prolonged heavy exposure to asbestos. Cigarette smoking has not been shown to independently cause this kind of reaction in the lung. Therefore, this section focuses on three questions concerning the relationship of cigarette smoking to the roentgenographic changes caused by asbestos. In the absence of asbestos exposure, are the chest roentgenograms of cigarette smok- ers more likely to be interpreted as positive for interstitial fibrosis than those of nonsmokers? Do cigarette-smoking asbestos workers 259 have a higher prevalence of chest roentgenograms interpreted as positive for interstitial fibrosis than nonsmoking asbestos workers? Do cigarette-smoking asbestos workers have more severe interstitial fibrosis on chest roentgenograms than nonsmoking asbestos workers for comparable asbestos exposures? The determination of whether radiologic findings consistent with interstitial fibrosis are present is part of the standard clinical interpretation of the chest roentgenogram. However, the Interna- tional Labour Office (ILO) (1980) developed a classification by which the roentogenographic changes of pneumonconiosis can be measured and reported in a standardized way. Small opacities are character- ized as rounded or irregular, and the profusion of the opacities is also described and quantitated on a numerical scale (from O/O to 3/4). This classification was designed as a descriptive rather than a clinical tool; as such, it is structured to be sensitive to the earliest roentgenographic changes. This sensitivity allows the investigation of early or mild disease, but also may reduce specificity. Using this classification, other mild, but not pneumoconiotic, disease in the general population may be interpreted as positive. Indeed, given the variety of causes of interstitial fibrosis other than inhalation of inorganic dust, the absence of any false positives by this classifica- tion would be surprising, and therefore the questions are the magnitude of this false positive rate and whether cigarette smoking influences that rate. The semiquantitative IL0 classification system can have substan- tial variability of interpretation, particularly at the lower levels of abnormality (Werner 1980). Table 14 shows the differences between the highest and lowest categorizations of 32,695 chest roentgeno- grams interpreted according to the IL0 classification by three different readers as part of a study of asbestos-related disease. In general, there was good agreement, but in a number of cases marked differences of interpretations occurred, including the same radio- graphs being interpreted by different readers as negative (O/O) and as substantially positive (2/2). Werner discussed some of the problems generated by these differences in interpretation and offered some potential remedies, but the data pointed out that a system designed to be sensitive to low levels of abnormality may be expected to have a some variability of classification, particularly around the threshold of abnormality. Weiss (1967, 1969) published a pair of studies evaluating the prevalence of a roentgenographic interpretation of interstitial fibrosis in smokers and nonsmokers drawn from the general population. The first study involved the examination of 70 mm chest photofluorograms of 999 men and women who came consecutively to the central survey unit of the Philadelphia Tuberculosis and Health Association. The films were evaluated for increased bronchovascular 260 TABLE 14.-Analysis of x rays of asbestos workers, lowest readings by highest readings (IL0 U/C scale) L0wee.t reading 01. o/o O/l l/O l/l l/2 211 212 213 312 313 314 01. 2 o/o 857 20449 O/l 94 3406 46 l/O 47 2162 149 29 l/l 56 2699 385 189 53 Highest reading l/2 2/l 212 213 312 313 3f4 TOtal 15 2 6 2 2 1063 693 153 283 47 18 29910 152 39 85 12 1 2 871 100 43 69 10 1 2 443 55 39 101 32 6 7 1 294 1 3 25 10 6 1 46 8 5 3 16 3 9 3 6 2 23 2 6 8 0 1 1 0 TOtd 2 21306 3546 2387 3382 1016 219 580 129 11 53 4 32695 SOURCE: Werner (1980) markings or diffuse pulmonary fibrosis; 3.1 percent of the subjects had abnormal films, with a prevalence of 1.5 percent in nonsmokers and 4.4 percent in cigarette smokers. Dose-response relationships were present for the number of cigarettes smoked per day and for the duration of smoking. A second study evaluated 2,825 adults, again using 70 mm photofluorograms; this time interpretation was by readers other than the author, and the purpose of the evaluation was to examine the population for COLD rather than for interstitial fibrosis. The prevalence of diffuse interstitial fibrosis was 0.6 percent in nonsmokers and 2.1 percent in smokers. Kilburn (1981) criticized these studies on the basis of their use of `70 mm films and the failure to use the IL0 criteria for grading the roentgenographs. Epstein and colleagues (1984) applied the IL0 criteria to 200 admission chest roentgenograms at an urban universi- ty medical center. Small opacities with profusions of l/O or greater were found in 22 (11 percent) of the subjects, none of whom had a documentable dust exposure or any known medical disease that caused interstitial lung disease. Of the 22, 12 (55 percent) were current or former cigarette smokers. Murphy and colleagues (1978) also used the IL0 criteria in examining 68 shipfitters and pipefitters without known exposure to asbestos who were selected to serve as a control group for a study of similar workers with known exposure to asbestos. Of the control workers, 60 had chest roentgenograms classified as O/l or less, 6 (8.8 percent) had readings of l/O to l/2, and 1 had a reading higher than l/2. A previous study of the same group of workers (Murphy et al. 1972) had classified 14 percent of the controls as having slight abnormalities (l/O to l/2) and 2 percent as has having moderately advanced abnormalities (2/l to 213). None of the control group were classified has having more advanced disease, and the results were not presented by smoking status. In summary, the data suggest that a small percentage of chest roentgenograms of the general population may have changes that can be interpreted as interstitial fibrosis, and that slightly larger percentages of hospitalized patients and shipyard workers with no known asbestos exposure may have chest roentgenograms read as positive for interstitial fibrosis by the IL0 criteria. Both the prevalence in these populations and the severity of the changes are far lower than those found in populations with significant asbestos exposures (Murphy et al. 19781, and they may reflect the sensitivity of the chest roentgenogram and the IL0 classification to other causes of lung injury. The "dirty lung" described in smokers (Fraser and Pare 1979) may contribute to the smoking-related prevalence of "diffuse interstitial fibrosis" described by Weiss (1969) in the general population, but it is unlikely to be confused with the more advanced forms of fibrosis found in severe asbestos-related lung injury. However, the prevalence of changes in the general population, 262 particularly in the population of shipyard workers with no known asbestos exposure, suggests that classifying a mildly positive chest roentgenogram as asbestosis in the absence of a clear exposure history should require other confirming evidence of asbestos-induced lung injury. This caution may be particularly true for cigarette smokers. Interstitial Fibrosis in Asbestos-Exposed Populations As was mentioned earlier, cigarette smoking is not a competing cause of the diffuse severe interstitial fibrosis that occurs in some workers secondary to their inhalation of asbestos dust. However, modest peribronchiolar fibrosis (Cosio et al. 1978; Berend et al. 1979) and occasional fibrosis of respiratory bronchioles (Wright and Churg 1984) do occur as a response of the small airways to cigarette smoking, in addition to the periobronchiolar inflammation that is the predominant early response to cigarette smoking. These bron- chioles are also the site of the early response to asbestos dust (Craighead et al. 1982J and therefore the threshold for radiologic perception of an abnormality may be crossed more frequently, or earlier, or at a lower dose of asbestos exposure in cigarette-smoking asbestos workers than in nonsmoking workers. In addition, the inflammatory response to cigarette smoke may enable or facilitate the fibrotic response to asbestos dust. Therefore, the question of a different exposure-response relationship between asbestos exposure and roentgenographic changes for smoking and nonsmoking asbestos workers should be considered. Weiss (1984) recently reviewed the evidence relating cigarette smoking and roentgenographic fibrosis in asbestos-exposed popula- tions. In Table 15, drawn from this review, is shown the prevalence of radiologic "asbestosis" in studies of asbestos-exposed populations. In general, the prevalence was higher in smokers than in nonsmok- ers; in several studies the difference was statistically significant. The highest prevalence ratios for smokers compared with nonsmokers are recorded in the populations with the lowest overall prevalence of roentgenographic fibrosis, and it is the studies where a high prevalence of disease is present that show similar rates of roentgeno- graphic fibrosis among smokers and nonsmokers (if studies of populations of less than 100 are ignored). This observation is in part an obligatory result of the mathematics involved (a given difference in prevalence between smokers and nonsmokers produces a smaller prevalence ratio when there is a high prevalence than when there is a low prevalence), but it is also the effect that would be expected if the effect of smoking were a small independent risk of radiologic fibrosis or if the effect was to increase the frequency with which 263 smoking asbestos workers cross the threshold for perception of roentgenologic abnormality. The demonstration of an increased prevalence of roentgenographic changes interpreted as fibrosis in cigarette smokers does not establish that the changes are produced by smoking. As has been discussed earlier, cigarette smokers may have had a different cumulative asbestos exposure than nonsmokers in some of the populations studied. Liddell and colleagues (1982) examined the prevalence of roentgenographic fibrosis in a group of 515 asbestos miners born between 1891 and 1920 and found an increased prevalence of roentgenographic fibrosis with increasing age and cumulative asbestos exposure. Smokers and nonsmokers had similar prevalences of changes, but the smokers had marginally lower cumulative asbestos exposure. Harries and colleagues (1976) exam- ined a younger population of shipyard workers with a lower prevalence of roentgenographic fibrosis (Table 16). The prevalence of changes was slightly higher in smokers than in nonsmokers, and seemed to increase in smokers after 10 to 14 years of asbestos exposure in comparison with after 20 to 24 years of asbestos exposure for nonsmokers. Dosage measures were not available for this study. Samet and colleagues (1979) examined a population of 383 asbestos workers with a prevalence of roentgenographic fibrosis (l/O or greater) of 33.7 percent. They tested for interaction between smoking and asbestos exposure and found a small additive effect for roentgenographic changes, but no synergism between cigarette smoking and asbestos exposure. Rossiter and Berry (1978) examined the interaction of smoking and duration of asbestos exposure in a population with a lower prevalence of roentgenographic fibrosis and found a duration-response relationship for asbestos exposure only among cigarette smokers. The number of workers at risk in the nonsmoking category was small, however, making it difficult to determine whether the absence of a dose-response relationship in nonsmokers resulted from differences between smokers and non- smokers or was simply a reflection of the low rate of disease in the population. In summary, cigarette smokers appear to have a higher prevalence of radiologic abnormality compatible with interstitial fibrosis than nonsmokers among populations of asbestos-exposed individuals with low prevalence of roentgenographic fibrosis (and presumably low levels of asbestos exposure). This difference is not apparent in populations with higher prevalences of roentgenographic fibrosis (and presumably higher asbestos exposures). One study (Harries et al. 1976) suggested that cigarette smokers develop an abnormal chest roentgenogram after a shorter duration of asbestos exposure than nonsmokers. There is little evidence to suggest that smokers develop more severe fibrosis (in contrast with a higher prevalence of fibrosis) 264 =; TABLE 15.-Results of prevalence studies of the cigarette factor in asbestosis I : Smokers Nonsmokers 0 Asbestosis Asbestosis 95% confidence limits I PFf&llC~ EE Study Number Number Percent Number Number Percent ratio ' Lower UPF I z Weiss (1971) Langlands et al. (1971) Harries et al. (1972) Harries et al. (1976) Weiss and The&s (197RI Chrysotile Chrysotile + amosite Hedenberg et al. 11978) Rossiter and Harnes (1979) McMillan et al. (1960) Selikoff et al. (19Ro) Pea& (1982) Liddell (1982) 73 29 91 35 1,635 49 17.788 181 39.73 38.46 3.00 1.02 25 6 24.00 1.66 0.81 3.76 33 9 27.27 1.41 0.56 2.53 em 20 2.48 1.21 0.72 2.03 5.552 11 0.20 5.10 2.9R 8.65 31 8 25.81 9 2 22.22 33 26 42.11 10 0 0.00 103 7 6.80 94 1 1.06 944 39 4.13 142 3 2.11 1,346 18 1.34 3n5 0 0.00 228 180 78.95 56 44 78.57 99 9 9.09 32 1 3 13 341 89 26.10 174 46 26.44 1.16 m 6.42 1.96 m 100 2.90 099 0.29 4.57 1.26' 56.31 z 1.07 38.34 O.fTl 6.30 1.092 102.232 0.43 2006 0.61 1.59 1 Smokers to nonsmokers `Calculated by substitutmg 0 5 for 0 casea of pulmonary fibrow in the nonsmoker group SOURCE Weiss (1984) TABLE 16.-Prevalence (percentage) of suspected or definite pulmonary fibrosis among 23,340 male in-yard British dockyard workers during 1972 and 1973, by smoking habit and duration of asbestos exposure Nonsmokers With fibrosis Yumber rpercent I Smoking hablt Ex-smokers With fibrosis NLldEr lpercenti Smokers With fibrosle Number ipercelr j' 5 3,516 0.1 2,746 04 7,300 06 5-9 784 02 581 03 1.666 0.5 lo-14 392 00 442 11 979 1.5 15-19 293 03 320 1.6 869 2.5 20-24 20R 10 330 1.7 66: 31 2w29 140 1.1 214 2.6 486 2.8 230 219 0.9 357 2.2 811 3.1 Total 5.552 02 4,990 0.8 12,798 1.1 than nonsmokers. These data are consistent either with a small independent risk of interstitial fibrosis on chest roentgenogram produced by smoking (as suggested by the studies in non-asbestos- exposed populations) being added to the risk of fibrosis due to asbestos exposure or with the combination of asbestos-induced and smoking-induced changes in the small airways resulting in asbestos workers who smoke crossing the threshold for perceptible abnormali- ty earlier than nonsmokers. However, it is clear that if cigarette smoking contributes to the development of interstitial fibrosis in asbestos-exposed workers, the contribution is a minor one in comparison with the effect of asbestos dust exposure. Immunologic Response to Cigarette Smoke and Asbestos Dust There is an extensive literature on both animal models and humans regarding alterations in the immune system following exposure to either asbestos or cigarette smoke; however, clinical and laboratory studies of combined exposure to asbestos and cigarette smoke are more limited. 266 Humoral Immunity Two independent studies (Kagan et al. 1977; Huuskonen et al. 1978) reported elevated polyclonal immunoglobulin (Ig) levels in populations of workers with asbestosis. Lange (1980) also correlated serum Ig levels with asbestosis. This study differentiated groups by sex and age, characteristics that can also affect the immune system. Cigarette smoking did not significantly correlate with serum Ig levels, whereas individuals with roentgenographically demonstrated asbestosis had increased levels of IgA and IgG. Asbestos workers, including those with interstitial fibrosis, were also evaluated for symptoms of chronic bronchitis. Male workers exhibiting symptoms for longer than 5 years had lower IgG and IgA values than asbestos workers without chronic bronchitis or with symptoms of bronchitis present for less than 5 years. Elevated IgA or IgM levels were found in a subgroup of male asbestos workers who were heavy smokers, as assessed by the duration of smoking multiplied by the average number of cigarettes smoked per day. The authors concluded that the asbestotic process and not the presence of chronic bronchitis was responsible for the high serum IgA and IgG levels (variable results have been reported regarding the level of serum IgA with chronic bronchitis) (Falk et al. 1970; Medici and Buergi 1971; Varpela et al. 1977). The immunoglobulin level alterations were found in workers with demonstrable lung disease. Therefore, it is unclear whether this alteration is involved in the pathogenesis of the disease or is an epiphenomenon, because the measurements were made when dis- ease was already present. Cellular Immunity Wagner and colleagues (1979) evaluated factors affecting the peripheral blood leukocytes and T lymphocytes in 138 asbestos- exposed men. T lymphocyte subsets were identified by the ability of lymphocytes to rosette with erythrocytes, after incubation either for 1 l/2 hours (T helper cells) or overnight (T suppressor cells). Age, length of asbestos exposure, smoking history, evidence of roentgeno- graphic fibrosis or pleural changes, and spirometric abnormalities were assessed. The smoking history in these asbestos-exposed workers was the factor that correlated best with lymphocyte changes. The group with roentgenographic changes of asbestosis and a history of smoking had an increased percentage in E-rosettes after 1 l/2 hours. This suggests an increase in the number of the T helper cells. Among workers with parenchymal chest roentgenographic changes, those who smoked had an increased number of the T helper cells compared with those who did not smoke. The number of T suppressor cells was not affected by the smoking history or by roentgenographic change. 267 Age and smoking as individual factors affecting lymphocyte percentage or number have also been assessed. There is some controversy about the effects on T lymphocytes. Silverman and colleagues (1975) showed no correlation between percentage of T lymphocytes and smoking or aging. Friedman and colleagues (1973) and Alexopoulos and Babitis (1976) did not demonstrate the effect of age on the percentage of T lymphocytes, but the absolute number of lymphocytes declined with age. Teasdale and colleagues (1976) and Smith and colleagues (1974) demonstrated a decline in the percent- age and total number of T lymphocytes with age. Friedman and colleagues (1973) showed that the total number of leukocytes, including lymphocytes, increased in smokers until age 50, and then declined. The effect of asbestos exposure on lymphocytes was studied by Kang and colleagues (1974) and by Kagan and colleagues (1977). The findings of both groups of investigators were similar. Kang and colleagues reported decreased erythrocyte-binding lymphocytes. Ka- gan and colleagues showed a decrease in percentage and in absolute number of T lymphocytes in a group of workers with asbestos exposure. Smoking as a contributing factor was not reported in these two studies. More recently, these findings were substantiated by Miller and colleagues (1983) with the use of monoclonal antibody markers to differentiate T lymphocyte subsets. Smoking, length of asbestos exposure, and chest x-ray findings were evaluated. A decrease in percentage of T lymphocytes (OKRsub3)+) and in the suppressor subset of T lymphocytes (OKmb a~+), with an increase in the ratio of helper T Cells to suppressor cells (OKmub 4i-/OKTcSub a~+), was found in the group of 40 asbestos-exposed individuals compared with nonexposed inGviduals. Those with short asbestos exposure (less than 5 years) u~re similar to controls, and those with more than 5 years of exposure had the abnormalities. When assessing radiographic changes, those without chest roentgenographic changes had lympho- cyte parameters similar to nonexposed individuals, those with pleural plaques had increased circulating helper cells (OKTcsub 41+), and those with interstitial changes had decreased percentages of T lymphocytes (OKnsub 31-j and suppressor cells (OKn,,,b s)+) and an increased ratio of helper to suppressor cells (OKmb 4)+/0Kkb a,+). Smoking habit did not influence these results. Miller and colleagues (1983) theorized several possibilities to explain the findings. The asbestos exposure may initially stimulate the immune system, accounting for the increase in the helper cells in subjects with pleural plaques. There may be an isolated toxic effect to suppressor cells affecting the percentage of this subset, and thus the total percentage of T lymphocytes. Lymphocytes may be distributed in organs (i.e., the lung) once fibers are inhaled, and thus the peripheral blood lymphocyte parameters are altered. Although the differences are most striking in subjects with roentgenographic changes, the lymphocyte alterations may not be related to the pathogenesis of these changes, but may be a secondary change due to chronic disease. In other studies (Ginns et al. 1982; Miller et al. 1982), smoking was also found to cause T lymphocyte subset changes. These changes were found in heavy smokers (50 to 120 pack-years) and not in light to moderate smokers (10 to 49 pack-years). Heavy smokers had increased total T lymphocytes (GR.riiub 3'- ), a decreased percentage of T helper cells (GKTtSUb 4)+), an increased total number of T suppressor cells tORnsUb st-), and a decreased ratio of helper to suppressor cells. De Shazo and colleagues (1983) also examined lymphocyte subsets in 31 current and former asbestos-cement workers compared with 52 healthy controls after adjustments had been made for possible confounding effects of age, race, and smoking. The asbestos workers had significantly decreased percentages and numbers of B and T lymphocytes in the peripheral blood. Analysis of T lymphocyte subpopulations revealed that total T cell numbers (OKn,,t, 31-j and helper-inducer T cell numbers (OKTtsub aI* ) were decreased by similar proportions. These decreases were negatively correlated with time since the end of exposure to asbestos. In both workers and controls, lymphocyte proliferative response to phytohemagglutinin was corre- lated positively with the number of (OKnBUb 4,-j cells and negatively with age. No relationship was detected between any of the immuno- logic aberrations noted in the workers and the radiographic category of pneumoconiosis, estimates of cumulative asbestos exposure, or abnormalities of pulmonary function. Lymphocyte function was assessed by Campbell and colleagues (1980) by the mitogen lymphocyte transformation response of peripheral blood lymphocytes. Allowing for the decline in response seen with increasing age, there was an increase in response to phytohemagglutinin (PHA) and pokeweed mitogen (PWM) in asbes- tos workers who smoked compared with ex-smokers and nonsmok- ers These findings were in agreement with those reported by Haslam and colleagues (1978). Sister Chromatid Exchange Frequency An in vitro cytogenetic assay, sister chromatid exchange (SCE) frequency, has been utilized to demonstrate chromosomal breakage in different mammalian cell lines following exposure to asbestos. In a study reported by Rom and colleagues (1983), 25 asbestos insulators had a small increase in frequency of SCE in peripheral blood lymphocytes compared with controls. The SCE rate increased slightly with increasing years of exposure to asbestos, when age and smoking were controlled. Smokers had similar rates of occurrence of SCE among both controls and asbestos workers. In nonsmokers, 269 those with asbestos exposure had a significantly increased SCE rate compared with controls. Butler (1980) and Crossen and Morgan (1980) did not detect a difference in SCE frequency. Public Health Implications The data are unequivocal that cige.rette smoking and asbestos exposure have produced substantial death and disability. The residual public health questions generated by these data focus on how to reduce the future risk of illness and death. As asbestos exposures are reduced, clinically disabling interstitial fibrosis should become a rare phenomenon in workers currently beginning their work careers. As asbestos exposures are reduced, it will become increasingly difficult to identify an increase in lung cancer death rates among asbestos workers that is greater than those of the general population. While the risk of developing mesothelioma is not associated with smoking, the risk of developing mesothelioma should be reduced by the lower exposure levels that currently exist, but persists even at very low levels of exposure. A reduction in the current U.S. standard (2f/cc) is being considered; once adequate asbestos dust controls are applied and enforced, future gains in reducing asbestos exposure are likely to come from reducing the exposure of workers employed in jobs other than asbestos mining and manufacturing. These jobs include construction workers who may be exposed during the demolition or remodeling of existing structures constructed with asbestos materials, and maintenance workers who may be similarly exposed to existing asbestos-contain- ing materials. Current concerns are the risk involved in removing asbestos from existing buildings in order to reduce environmental contamination and the need to educate the workers involved in these tasks to prevent their exposure as they remove these materials. Unfortunately, little can be done to reduce the current asbestos burden in workers exposed prior to the introduction of environmen- tal controls. For these workers, it is clear that the single most important intervention that would alter their future disease risk is the cessation of cigarette smoking. The elimination of cigarette smoking in this population would not only substantially reduce the number of future lung cancer deaths but also moderate the contribution of cigarette-induced COLD to the restrictive ventilatory limitation that may develop in these workers. The issues of liability and responsibility for the disease that is occurring in these workers will continue to be argued for an extended period of time, but these arguments should not confuse or impede the efforts to alter the future disease risk in these workers. The goal is not, and should not be, to eliminate only that disease burden attributable to future asbestos exposure, but rather to reduce as much as possible, by any 270 means possible, the enormous risk of death and disability that currently exists for these workers. Smoking cessation is therefore an intrinsic and essential part of any effort to reduce asbestos-related disease and disability. Summary and Conclusions 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 !ung 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 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. 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Annals of the New York Academy of Sciences 330:701-709, December 14, 1979. `283 CHAPTER 7 RESPIRATORY DISEASE IN COAL MINERS CONTENTS Introduction Prevalence of Smoking in Coal Miners Coal Workers' Pneumoconiosis Prevalence of Coal Workers' Pneumoconiosis Pulmonary Function Abnormalities in Simple and Complicated Coal Workers' Pneumoconiosis Relationship of Small Opacities to Emphysema and Airways Obstruction Lung Function in Subjects With Rounded or Regular Opacities Lung Function in Subjects With Irregular Opaci- ties Respiratory Symptoms and Exposure to Coal Dust Bronchitis and Dust Exposure Respiratory Mortality in Coal Miners Lung Function in Coal Miners Emphysema, Exposure to Coal Dust, and Cigarette Smoking Dust Exposure, Cigarette Smoking, and Ventilatory Function Summary and Conclusions References 287 Introduction An association between respiratory disease and coal mining has been recognized since the 16th century, when Agricola and Paracel- sus wrote of the diseases of miners (Hunter 1978). The first description of coal workers' pneumoconiosis (CWP! was given in the early 1800s by Laennec (Meiklejohn 1951) when he described cystic and noncystic melanotic masses in the lung, and in addition, melanotic parenchymal infiltrates in the lung. The melanotic masses were almost certainly progressive massive fibrosis (PMF) and the black infiltrates, simple CWP. It is clear from Laennec's description that he recognized an association between coal mining and the deposition of "la matiere noire pulmonaire." An excellent history of coal miners' lung disease in Great Britain can be found in a series of articles by Meiklejohn (1951, 1952a, 195213). Over the years, a large number of names have been attached to the conditions that affect the lungs of coal miners. Many early physi- cians assumed that there was a single respiratory condition arising from coal dust exposure, which was variously referred to as spurious melanosis, miners' asthma, anthracosis, miners' phthisis, and silico- sis. With the passage of time, it became evident that, aside from the lung diseases that commonly affect the general population, coal miners are prone to develop occupationally related lung diseases, namely coal workers' pneumoconiosis, silicosis, and chronic bronchi- tis (Morgan and Lapp 1976). Silicosis is covered elsewhere in this Report; therefore this chapter discusses coal workers' pneumoco- niosis and chronic bronchitis. The paramount importance of exposure to coal dust in the development of CWP is generally accepted, and complicated CWP is clearly associated with significant and often disabling chronic airflow limitation as well as with other respiratory impairments (Morgan and Seaton 1984; Morgan and Lapp 1976). Less certain is the magnitude of the role of coal mine dust as a cause or contributory factor in the development of bronchitis and emphyse- ma. The effects of long-continued inhalation of coal and other dusts are currently of major interest to epidemiologists and to those practicing occupational medicine. Clearly the results of the studies designed to characterize the effects of coal dust on lung function are of vital importance to officials concerned with compensation for occupationally related pulmonary disability. In these studies it is important to evaluate as potentially independent effects the role of coal dust in producing radiologic CWP and the role of coal dust in producing physiologic airflow obstruction (Weeks and Wagner 1986). This separation of the radiologic and physiologic responses to coal dust is even more critical when considering the effects of combined exposure to coal dust and cigarette smoke. 289 The respective contributions of cigarette smoking, dust exposure, and other environmental and occupational factors in the develop- ment of respiratory impairment in coal miners are examined in this chapter by reviewing the evidence currently available from mortali- ty and morbidity studies of coal miners compared with appropriate reference populations and the evidence on the frequency and extent of pulmonary impairment in coal miners. The roles of dust, cigarette smoking, and various confounding factors are taken into account and apportioned where possible. At the present time, there are approximately 150,000 underground coal miners in the United States. Ten years ago, the figure was about 170,000, but the closure of a number of mines in Appalachia has reduced the number of employed underground miners, In addition, 60,000 to 70,000 workers are employed in open cast or surface mines, but this number is constantly changing. Exposure to coal mine dust is greater in those employed underground; miners working at the face or in transportation are the most heavily exposed. Miners employed underground on maintenance and other activities are less exposed, and surface miners are the least exposed (Doyle 19701. Prevalence of Smoking in Coal Miners The prevalence of smoking for various populations of miners in different countries and during different time periods is presented in Table 1. In general, the prevalence of smoking among U.S. coal miners is currently similar to, or slightly higher than, the rates in the overall U.S. male population. However, coal mining as an occupation introduces a distortion in the pattern of smoking because of the prohibition against smoking while in the mine. As a result, the entire consumption of cigarettes by miners is limited to those periods when they are not underground; for a given number of cigarettes smoked per day, the pattern among miners would consist of periods of more intense smoking interspersed with long periods of not smoking (i.e., during working hours), in contrast to the more even consumption of cigarettes throughout the day that characterizes most cigarette smokers. Coal Workers' Pneumoconiosis Coal workers' pneumoconiosis (CWP) is defined as the deposition of coal mine dust in the lungs and the reaction of tissue to its presence (Morgan and Seaton 1984). However, the term is commonly applied only to the chest roentgenographic changes produced by coal dust, and the other tissue responses to coal dust are classified by their symptomatic, physiologic, or pathologic manifestations (e.g., chronic bronchitis, airflow obstruction, or emphysema). The radiologic 290 TABLE l.-Smoking characteristics of coal workers Study Higgins et al. (1968) Number and type of population 755 mining town residents. Great Britain Smoking characteristics (percent) SM NSIEX 15 25 Cammenta Tokuhata et al. (1970) 801 anthracite coal miners, Pennsylvania Ashford et al. ( 1970) 30.@30 underground and surface workers. Great Britain SM NS EX 78.7 15.3 6 Rae et al. 3,379 workers, 20 SM NS (1971) colleries. Great Britain 19.2 208 Large colleries Age 140 40-49 250 Independent Age <40 40-49 250 64.1 15.9 74.0 26.0 71.6 28.4 76.4 23.6 60.5 19.5 71.3 22.7 Ex-smokers not differentiated from smokers SWIG and Pelaic 119711 Lignite and brown coal miners, Yugoslavia SM NS EX 64.7 23.6 11.7 M TABLE k-Continued Study Number and type of population Smoking characteristics (percent1 Comments Mlnette (1972) 204 cd miners, Belgium SM 70.6 NS' 29.4 o Nonsmokers include smoken who did not inhale Phelpe (1972) 256 miners, U.S. Rocky Mountain region SM 65.6 Skrabski-Kopp et al. (1972) 1,066 coal miners, Hungary SM 75.6 Lowe and Khosla (1972) 3.012 excoal miners, 9,361 controls, Great Britain Ex-miners 86.6 Controls 80.7 NS 34.3 NSIEX 24.4 KibdstiE et al. (1973) Bituminous coal miners. United States SM NS 50.8 25.4 Ortmeyer et al. Coal miners and ex-miners, Coal miners, 60.9 19.7 (1974) Appalachia Ex-miners 47.1 52.3 EX 23.8 19.4 2039year-old miners smoked at a rate above 65% Fairman et al. (1977) 987 surface coal miners, six U.S. states 70.7 29.3 TABLE l.-Continued Study Number and type of population Smoking characteristica (percent) Comments Armstrong et al. Cod and gold miners, (1979) Australia Szymaykiewia (1979) Miners, Poland Potkonjak 970 cd nunera, 536 (1979) controls with no dust exposure Cochrane and Moore Coal miners, Great Britain (1960) Ram et al. 242 active and retired (1981) miners, Utah Love and Miller 1,677 colliery workers, (1982) Great Britain Cod miners Gold miners Miners Controls Age 2x34 SM/cigs 1-14 b 14 Age 55-64 SM/cigs 1-14 `-a 14 54 52.1 NSIEX 24.3 Pipe only 3.6 16 SM NWEX 56.7 41.3 66.3 33.7 13.7 46 47.9 SM 71.3 32 39.3 60 32 2a SM NS EX 38 23.6 36.4 SM NS EX 66.1 12.8 4.5 16.5% were intermittent smokers NCYIIC SM=Smoker; EX=Exsmoker: NS=Nonsmoker. manifestations of CWP are classified into two forms: simple, and complicated (often known as progressive massive fibrosis, PMF). Simple CWP is a reaction solely to the inhalation of coal dust. Although the efficiency and integrity of the lung defenses are important factors in the development of disease, cumulative dust exposure is of paramount importance. Characteristically, after a period of exposure, i.e., 10 to 15 years, small rounded opacities begin to appear in the upper lung fields of some miners. With continued exposure, they gradually spread to the middle and lower zones, and the increasing profusion of these opacities is used to categorize simple CWP on a 0 to 3 scale. The opacities are indistinguishable from those seen in silicosis. Simple CWP does not progress in the absence of further exposure. Moreover, increasing category of simple CWP is not associated with a decrement in ventilatory capacity (Cochrane et al. 1961; Gilson and Hugh-Jones 1955; Morgan et al. 1974). Complicated CWP is defined as the presence of an opacity greater than 1 cm in diameter on the chest radiograph of a subject who already has simple CWP (IL0 19801, and the volume of lung occupied by the large opacities on the radiograph is used to categorize complicated CWP into category A, B, or C. For the most part, complicated CWP develops on a background of category 2 or category 3 simple CWP. Necessary for its development is the presence of a fairly high dust burden in the lungs, plus some other factor or factors as yet not fully recognized or understood. Prevalence of Coal Workers' Pneumoconiosis In 1969 the National Coal Study was commenced by the National Institute for Occupational Safety and Health (NIOSH) (Morgan et al. 1972). Selected for study were workers at 31 coal mines, of which 2 were anthracite and 29 were bituminous. In the initial survey, an overall CWP prevalence of nearly 30 percent was found; 2.5 percent had PMF. A decreasing prevalence was noted from east to west, and there was a clear-cut relationship between the years spent under- ground and radiographic category. The disease was much more common in workers at the face than in surface workers. The prevalence of CWP in this study was undoubtedly overestimated, however. Part of the reason was that the early films were interpre- ted according to the 1958 International Labour Office (ILO) classifi- cation. In addition, some of the readers were inexperienced and tended to overread. The second round of the National Coal Study revealed a prevalence of 8 percent; the findings at the third round were just under 5 percent, with 3.85 percent having category 1; 0.48 percent, category 2; 0.04 percent, category 3; and 0.17 percent, PMF. The decline in the prevalence of pneumoconiosis noted between the first and third rounds of the National Coal Study is partly 294 accounted for by the use of different readers, partly by more stringent reading criteria, partly from the use of the IL0 standard films as yardsticks, and partly from improved coal dust control. An exodus of workers with higher categories of disease between the first and subsequent accumulations of subjects with radiographic evi- dence of pneumoconiosis also played a role, since those with CWP qualified for compensation. Both simple CWP and PMF are related to cumulative lifetime exposure to coal dust. The reduction or elimination of category 2 and category 3 simple CWP through effective dust control not only is possible but is rapidly being achieved in the United States and Great Britain (Jacobsen 1980). Since complicated pneumoconiosis develops almost entirely in subjects who have the higher categories of simple CWP (i.e., those with a high dust burden), the effective prevention of category 2 and category 3 simple CWP should almost completely eliminate PMF as well. The removal from further coal dust exposure of miners with early categories of simple CWP should also aid in reducing the incidence of PMF. Pulmonary Function Abnormalities in Simple and Complicated Coal Workers' Pneumoconiosis The radiologic changes of simple CWP are associated with the development of certain relatively minor pulmonary impairments. These include an increased alveolar-arterial gradient for oxygen, abnormalities of the distribution of inspired gas, and a modest increase in lung volumes (Morgan and Lapp 1976). The increase in lung volumes is a consequence of the focal emphysema that is an integral part of the pathology found with simple CWP (Morgan and Seaton 19841. Complicated pneumoconiosis is associated with a reduction in lung volume and diffusing capacity, ventilation perfusion mismatching, an obliteration and destruction of the pulmonary vascular bed that leads to nonhypoxic pulmonary hypertension and car pulmonale, and with the presence of generalized airways obstruction (Gilson and Hugh-Jones and Seaton 1955; Lyons et al. and Seaton 1981; Morgan and Seaton 19841. Relationship of Small Opacities to Emphysema and Airways Obstruction The small opacities present in the lung in the various pneumocon- ioses can be classified as either rounded (regular) or irregular. Small rounded opacities have a fairly rounded and regular margin. They are classified according to their size into p, q, and r types: p is up to 1.5 mm in diameter, q is between 1.5 and 3 mm, and r is between 3 and 10 mm. Usually only one type of opacity is present, 295 but mixtures are occasionally found in the same lung. The reading of the film should be based on the predominant opacity noted. Irregular opacities are also classified according to size: s opacities are up to 1.5 mm in width, t opacities are between 1.5 and 3 mm wide, and u opacities are between 3 and 10 mm. Irregular opaciti,s are characteristically seen in asbestosis. In some smokers scanty irregular opacities may be observed. Rounded and irregular opacities occasionally occur together, usually in a person who has experienced various exposures or in a person with either silicosis or coal workers' pneumoconiosis who also is a heavy smoker. Lung Function in Subjects With Rounded or Regular Opacities A number of investigations have shown that the p, or punctate, type of opacity seen in simple CWP is associated with a reduced diffusing capacity (Sartorelli et al. 1963; Lyons et al. 1967; Seaton et al. 1972; Musk et al. 1981). In addition, an increased parenchymal air space size has also been observed in subjects with a p type of opacity (Hankinson et al. 1979). No detectable difference in lung function between subjects with the p, q, or r type of opacity was observed in this study. These physiological changes have also been demonstrated in nonsmoking miners with simple CWP (Hankinson et al. 1979; Seaton et al. 1972). The indices of lung function that were tested in the miners with the p and q opacities were similar (Hankinson et al. 1979) except for the diffusing capacity, which was significantly lower in those with the p type of lesion (Seaton et al. 1972). Static compliance was reduced marginally, but not significantly, with the q type of opacity. The type of opacity was not significantly related to differences in dynamic compliance at increased rates of breathing (Seaton et al. 19721. Musk and colleagues (1981) examined the lung function in 125 coal miners identified in 1968 as having the simple pneumoconiosis of coal workers and reexamined 9 years later. Pulmonary function was related to both smoking history and coal dust exposure. Miners who smoked in 1978 had lower forced expiratory volume in 1 second (FEVJ, forced vital capacity (FVC), and FEV,/FVC ratio and a higher ratio of residual volume to total lung capacity (RV/TLC) compared with nonsmokers. Ex-smokers had a lower carbon monox- ide diffusing capacity (DLCO) than nonsmokers. Total dust exposure was inversely related to FVC and lung elastic recoil at TLC. After correcting for the effects of age, height, and smoking category, miners whose radiographs showed predominantly p and r types of opacities had a reduced DLCO when compared with miners with the q type of opacity. In the researchers' experience, irregular opacities were also associated with a reduced DLCO, and were thought to 296 reflect the presence of both emphysema and diffuse fibrosis. In addition, the r type of opacity, but not the p type, was associated with reduced maximal recoil at TLC, and reduced recoil at 50 percent of TLC and at 1 L below TLC, and with an increased RV and RV/TLC percent compared with miners with the q type of opacity. The decreased compliance in subjects with the r type of opacities noted by Musk and colleagues (1981) may be a consequence of the exposure of some of these subjects to silica. Irregular opacities were not associated with increased obstruction or with smoking; here the results of Musk and colleagues differ from almost all other studies. Lung Function in Subjects With Irregular Opacities The significance of irregular opacities in the lungs of coal miners has been the subject of a number of investigations. Lyons and colleagues (1974) pointed out that there was a positive association between the presence of irregular opacities and emphysema and impairment of FEV,. Unfortunately, this was a post-mortem study in which no smoking histories were available. Subsequently, Aman- dus and colleagues (1976) investigated the significance of irregular opacities in the lungs of 6,166 working U.S. coal miners for whom complete smoking histories were available. Irregular opacities on the chest radiographs were shown to be associated with smoking, bronchitis, age, and years worked underground. Smoking was not associated with the presence of regular opacities. Although irregular opacities were observed in nonsmokers, they were 2.5 times more common in those who smoked. Among nonsmoking miners, there were no significant differences in the lung volumes or flow rates of the men with normal chest x rays, irregular opacities, rounded opacities, or mixed opacities. Smokers had similar FVCs in each of the radiologic categories when compared with nonsmokers, but FEV, and FEV,/FVC were lower and RV and TLC were higher. In addition, smokers with irregular opacities had a lower FEV, and a higher RV and TLC than smokers with normal chest x rays or rounded opacities. A study by Cockroft, Berry, and colleagues (1982) of coal workers and ex-workers showed that irregular opacities were related to age, smoking, and underground exposure in those receiv- ing disability benefits. Cockcroft, Seal, and colleagues (1982) examined the relationships among lung function tests, irregular opacities on chest radiograph, and the pathologic changes of emphysema in 46 men who had been referred for lung function tests during life and who had died between 1970 and 1979. Irregular opacities on radiograph were associated with a reduced DLCO and reduced TLC, an increased pathologic score for emphysema, and to a lesser extent, an increased pathologic score for fibrosis. Smoking histories were obtained in all but five of these workers, and there was no association of smoking with any 297 157-964 0 - 86 - 11 particular lung function or pathologic finding. However, almost all of the subjects in the study were current smokers (two were nonsmokers and two were former smokers), which limited the ability of the study to examine the effects of smoking. The majority of the evidence indicates that simple CWP is associated with mild overdistension or hyperinflation of the lungs. There is some evidence, especially in miners with the p type of opacity. that there is also a reduction in DLCO. The decreased DLCO does not appear to be associated with increasing airways obstruction, but with focal dust emphysema. The available data indicate that cigarette smoking plays a much greater role in reducing DLCO than does the presence of simple CWP (Frans et al. 1975). Irregular opacities occur occasionally in the lungs of coal miners and former miners. For the most part, they are associated with smoking, age, bronchitis, and years spent underground. Bronchitis may be the common denominator in the production of irregular opacities, and the increased prevalence of bronchitis in smoking coal miners may be the reason for the increased prevalence of irregular opacities found among smokers in some studies. Irregular opacities are seen in nonoccupationally exposed groups (Carilli et al. 1973), in subjects exposed to silica, in asbestos miners and millers (Morgan 1978), in workers who manufacture manmade fibers (Weill et al. 1983), and in workers with other conditions, suggesting that irregu- lar opacities may be a nonspecific response associated with the presence of bronchitis, regardless of its etiology. Respiratory Symptoms and Exposure to Coal Dust The relationship between dust exposure and bronchitis was noted by Thackrah (1832) and Greenhow (1860) in the 19th century. Although these pioneer workers noted a higher prevalence of bronchitis and other respiratory ailments in the dusty trades as a whole, they particularly emphasized the importance of textile dust as a cause of bronchitis. Until recently the use of the terms "chronic bronchitis" and "emphysema" implied that these two conditions were invariably associated and that both, for the most part, were related to cigarette smoking. In this context, "bronchitis" implied a condition character- ized by cough and sputum, usually associated with a reduction in ventilatory capacity or frequently leading to one (Fletcher et al. 1959). Subjects with these symptoms who also had concomitant chronic airflow obstruction were usually diagnosed as having chronic bronchitis and emphysema, assuming from the association of the two diseases that they were part of the same process. At the time the committee appointed by the Medical Research Council (MRC) of Great Britain published its statement (British Medical Journal 298 1966), it was known that not all subjects with chronic bronchitis showed an associated reduction of FEV1, but the committee did not elaborate fully on the implications of the term "bronchitis." It was assumed, moreover, that there was a relationship between the symptoms of cough and sputum and a decreased ventilatory capaci- ty, and that sooner or later most or all subjects with chronic bronchitis would develop some degree of irreversible airways ob- struction. The MRC's (1965) division of bronchitis into obstructive bronchitis and simple bronchitis, a condition characterized by the presence of cough and sputum in the absence of airways obstruction, was the first step taken toward a better understanding of the implications of a diagnosis of bronchitis. Subsequently, the general use of the MRC questionnaire on chronic bronchitis for symptoms without reference to lung function led to an appreciation of the pathophysiology of this condition (MRC 1965), and the pathological features of bronchitis as described by Reid (1960) in her studies provided a means of quantitating the severity of the condition. Bronchitis and Dust Exposure Many of the studies showing an association between dust exposure and an increased prevalence of chronic bronchitis have been carried out with coal miners. Coal miners represent a clearly defined and relatively large group of subjects who seldom change their occupa- tion, and thus present an ideal study population. Ashford and colleagues (1970) showed that the prevalence of cough and sputum increased with age and, it may be inferred, with cumulative dust exposure. Shortly thereafter, Rae and colleagues (1971) demon- strated a relationship to dust exposure. Kibelstis and colleagues (1973) showed, in a U.S. population of more than 9,000 working coal miners, that cough and sputum were related to dust exposure and also to cigarette smoking. When only nonsmokers were considered, there was a gradient in the prevalence of bronchitis from the least to the most dusty jobs. This occurred independent of age. In smokers, the effect of cigarette smoking almost completely overwhelmed the effects of dust and age, at least as far as symptoms were concerned. Similar findings have been reported in Belgian coal miners (Minette 1976; Vuylsteek and Depoorter 1978). The effect of dust and cigarette smoke on bronchial gland dimensions in coal miners has recently been investigated (Douglas et al. 1982). These investigators demonstrated that both dust and cigarette smoking had an effect on the Reid index and that they led to mucous gland hypertrophy. There is thus a fairly widespread acceptance that the long-continued inhalation of coal dust and other dusts may lead to an increased prevalence of cough and sputum in the absence of cigarette smoking. Moreover, it has been demon- strated that the prevalence of dust-induced bronchitis is related to cumulative dust exposure (Rogan et al. 1973; Kibelstis et al. 1973). The topic of industrial bronchitis is more fully discussed in another chapter of this Report, but the data suggest that there is an independent and additive effect of coal dust exposure and cigarette smoking on the prevalence of chronic bronchitis. Respiratory Mortality in Coal Miners Early mortality data of coal miners showed a high death rate from respiratory disease. This was true for both Great Britain (Registrar General 1958) and the United States (Enterline 1964; Guralnick 1963). Although there may be some doubt as to the precise accuracy of such data, it is probably true that there was an increased standardized mortality ratio (SMR) for respiratory disease among coal miners. There was, however, little convincing evidence to establish that coal dust was a major causative factor in this increase. Tuberculosis, emphysema, and bronchiectasis were more common in coal miners, and most of the increased mortality could be explained by an increased prevalence of these diseases. In addition, Enterline (1964, 1972) had shown in a series of retrospective analyses that the SMR for coal miners as a group was elevated, but a substantial portion of the excess was a consequence of trauma and accidents. When deaths due to these excesses were excluded, excess mortality still persisted. Much of the excess was due to respiratory disease, and although the death rate for chronic bronchitis and emphysema was reported to be increased, so also were the death rates for tuberculosis and lung cancer. While it is easy to postulate a relationship between occupation and bronchitis, it is also clear that bronchitis and lung cancer have a common causative agent, namely cigarette smoke. In addition, coal miners, particularly in the United States, constituted a distinctly underprivileged group during the early part of this century, and as such suffered from overcrowding and poor medical care, both of which contributed significantly to a higher death rate from bronchiectasis and tuberculosis and other infectious diseases. Over the past two decades, a number of well-controlled epidemio- logical studies of morbidity and mortality of coal miners have been carried out in both Great Britain and the United States. Liddell (1973a) looked at the frequency of time off from work because of illness in a cohort of 29,084 men. He showed that miners spent more time off work than nonminers. The highest rate of incapacity was present in the lowest paid workers; this applied as much to coal face miners as to surface workers. Pneumoconiosis was associated with greater time off work. An additional investigation of the mortality of 5,362 British miners who died in 1961 showed that they had higher death rates for accidents and pneumoconiosis than the general population, but lower death rates for cancer in general and for lung 300 cancer in particular (Liddell 1973b). There was a wide disparity between the SMR of miners employed at the face (49) and the SMR of those working on the surface (82). This disparity can be explained in that surface miners may smoke while at work, but underground miners cannot, and that the less healthy miners tend to move away from coal face work and to be employed in easier jobs on the surface. Ortmeyer and colleagues (1973; Lainhart et al. 1969) studied the death rate of Pennsylvania coal miners who had been awarded compensation for occupationally related respiratory disability. The overall SMR was the same as that of white men in Pennsylvania. Excess death rates were found in subjects with a reduced ventilatory capacity, in particular when the FEV,/FVC was below 50 percent, and in ex-miners with stage B and C complicated CWP. "Disabled" miners with simple CWP had a normal SMR. Later, Ortmeyer and colleagues (1974) studied a group of randomly selected Appalachian miners and ex-miners. They showed that the overall life expectancy for miners and ex-miners combined was the same as that for the general U.S. population and for the States from which the cohort originated. The effects on mortality of the years worked under- ground, cigarette smoking, and airways obstruction were investi- gated. Ex-miners had a slightly but significantly increased death rate. Simple CWP had no effect on life expectancy; however, complicated CWP was associated with decreased longevity. Although both cigarette smoking and airways obstruction were associated with an increased SMR, the number of years of work underground had no discernible effect. About the same time these reports were published, Cochrane (1973) described his findings from a 20-year followup of the male population of the Rhondda Fach in Wales. Survival rates for miners and ex-miners were independent of the radiographic presence of simple CWP or category A complicated pneumoconiosis. Further studies of the same cohort from the Rhondda Fach showed a normal life expectancy in those with simple CWP and category A complicat- ed CWP (Cochrane et al. 1979). The death rate for bronchitis and other respiratory diseases was elevated. The smoking habits of this population were not examined. A 20-year followup of a population sample from Derbyshire (Cochrane and Moore 19801, aged 25 to 34, included four groups of workers whose work was categorized as nondusty, pure coal mining, pure foundry, or other and mixed. There were no significant differences in the SMRs of the dust-exposed group of miners, compared with the non-dust-exposed group of miners; however, only 20 deaths were recorded in the study. Rockette (19771, in a NIOSH-supported study, investigated the mortality rates among coal miners covered by the United Mine Workers of America (UMW) Health and Retirement Fund. Unfortu- 301 nately, unlike the studies of Ortmeyer and colleagues (1973,1974), in this investigation the population was not randomly chosen and smoking histories were not available. A 10 percent sample of miners eligible for benefits in January 1959 was randomly selected from the original 550,000. Doubt exists whether miners covered by the UMW Health and Retirement Fund are necessarily representative of U.S. coal miners as a whole. The SMR for all causes was 101.6 and for all cancer, 97.7. The SMRs for asthma, emphysema, and tuberculosis were significantly elevated at 174, 144, and 145, respectively. The SMR for lung cancer was minimally but significantly elevated at 112; however, a disproportionate number of miners from southwest- ern West Virginia were subsequently shown to have been included in the cohort. The death rate for lung cancer in this part of the United States is significantly higher than the rate for the United States as a whole and for other parts of West Virginia. In the absence of smoking histories, little can be made of such a small increment in mortality. Deaths due to accidents were high (SMR 144). The SMR for bronchitis was 89.7, but, as previously mentioned, the SMR for emphysema was elevated. There was a significantly increased death rate for stomach cancer, but the SMR for pneumoconiosis could not be determined because of difficulties with death certification and classification. A lengthy report of coal miners' morbidity in relation to x-ray category, lung function, and exposure to airborne dust (Miller et al. 1981) described the findings for 31,611 British miners who were surveyed at 24 pits from 1953 to 1958. Again, the coal miners had a lower mortality than British men in general. Although this was attributed to the healthy worker effect, no supporting evidence for this conclusion was given. Miners with PMF had an increased death rate. Mortality from bronchitis was associated with increased dust exposure, but it is apparent that with increased dust exposure, there would also be an increased cumulative exposure to cigarette smoke. Appropriate data whereby the two effects could be separated were not available, since cumulative cigarette smoking history or, indeed, a smoking history of any kind was not available. Deaths from lung cancer were not increased. Higgins and colleagues (19811, in a followup study of a group of miners from Richwood and Mullens, West Virginia, were unable to show any significant difference in the mortality of miners and ex- miners as compared with nonminers. The death rates from respira- tory diseases were appreciably higher in coal miners; however, there are doubts as to the accuracy of the cause of death on the death certificates because compensation was often awarded to ex-miners' families solely on the basis of a death certificate that mentioned respiratory disease (Comptroller General 1980, 1982). Another problem encountered was that some miners had moved away from 302 the district and could not be traced. In many instances, their status proved impossible to determine. A clear-cut effect of smoking on mortality was evident in nonminers, but was less evident in miners and ex-miners. Here again the advent of black lung compensation may have been an incentive for disability applicants to underesti- mate their smoking habits. The publication of the Registrar General's Decennial Supplement (1970-1972) on occupational mortality (1978) indicated that mortali- ty rates for coal miners were somewhat increased for both under- ground and surface workers. The SMR for most respiratory diseases other than lung cancer showed a mild to moderate increase. Jacobsen (1976,1977) concluded that coal miners as a group have a normal SMR. He also indicated that there was no excess death rate from bronchitis and emphysema among coal miners, nor was there an increase in mortality from these conditions with increasing time worked in dusty occupations. Among men with no pneumoconiosis, there was a clear and significant mortality gradient with increases in estimates of cumulative exposures to airborne dust. However, the decision to study the SMR of selected subgroups of miners whose cigarette smoking habits were unknown, and in whom other possible confounding factors may have been present, detracts from his conclusions. The demonstration that the presence of bronchitis in coal miners is associated with increased mortality and morbidity is of little special significance for coal miners because the same situation applies to the general population. The increased mortality and morbidity are for the most part attributable to cigarette smoking in the general population, and only if it were possible to show an increased death rate in nonsmoking bronchitic coal miners would this observation be convincing evidence that the presence of bronchitis of itself portends premature disability and death. In conclusion, the majority of recent mortality studies have shown that coal miners have a normal life expectancy. Although there is an increased SMR in miners with PMF, the overall prevalence of PMF in working miners is so low that any effect it has on the SMR is more than counterbalanced by decreased death rates from lung cancer and heart disease. Although in certain studies, death rates from bronchi- tis and emphysema have been found to be elevated, this has not been a consistent finding; in other studies, especially those in which it has been possible to quantitate the effects of cigarette smoking, no increased death rates have been demonstrable. There is little or no evidence that the inhalation of coal mine dust contributes to excess morbidity or mortality in regard to lung conditions other than PMF, such as emphysema, asthma, tuberculosis, or pneumonia. By way of contrast, cigarette smoking has repeatedly been shown to have a clear and easily demonstrable effect on the death rate of both miners and nonminers. There is some recent suggestion that cigarette 303 smoking prevalence increased in British coal miners between 1965 and 1975, possibly related to their increased standard of living, but it is too early for any discernible changes in cigarette consumption to be reflected in mortality and morbidity statistics. Lung Function in Coal Miners Although there is no substantial clinical effect of an increasing category of simple CWP on the ventilatory capacity of coal miners, most studies in which coal miners have been compared with a suitable reference population of nonminers have demonstrated a significant decrement in the ventilatory capacity of the miners (Higgins 1972). Regardless of radiographic evidence of simple CWP, FEV, of coal miners--or any other suitable index of ventilator-y capacity-is generally reduced in comparison with FEV, of nonmin- ers. This suggests that decrements in FEV, and simple CWP are both related to dust exposure, but the two measures represent separate biologic responses in the lung to the inhalation of coal dust. Higgins studied three populations in the United Kingdom, all of which contained a significant proportion of miners and ex-miners, along with a comparable reference population. The areas chosen were Leigh, the Rhondda Fach, and Stavely (Higgins 1960; Cochrane et al. 1961). The reduction in the ventilatory capacity of miners that was observed could not be explained on the basis of cigarette smoking; indeed, coal miners at that time generally smoked less than nonminers. Since then, several other studies have found similar results and the data have been reviewed by Higgins (1972). Possible explanations for the observation that coal miners have a lower ventilatory capacity and that this finding is unrelated to radiograph- ic findings are. that (1) coal dust can produce or exacerbate emphysema or airway narrowing and that these changes occur independent of the changes that result in an abnormal radiograph, or (2) the lower ventilatory capacity in miners results from either industrial selection or differential migration. Thus, were the more healthy miners to leave their employment and move to other parts of the country to seek new jobs, those who remain would be less healthy and almost certainly have lower lung function. Although the second hypothesis is a consideration, especially during hard times when unemployment in the coal mines is high, recent studies have shown that it is the weaker and the less muscular man who is more likely to leave the coal mine within the first few months of his employment (McLintock 1971). Thus, the first hypothesis seems much more probable and requires further consideration. 304 Emphysema, Exposure to Coal Dust, and Cigarette Smoking The pathology associated with CWP, both simple and complicated, has been well described, and it is generally accepted that simple CWP has a relatively specific set of histological findings (College of American Pathologists 1979). Initially, dust starts to accumulate around the second division of respiratory bronchioles. As this occurs, there may be a little reticulin or, exceptionally, some collagenous fibrosis. Subsequently, the respiratory bronchiole dilates to form a condition known as focal emphysema. Gough (1947) and Heppleston (1947, 1954) suggested that this condition develops as a result of weakening and atrophy of the smooth muscle in the bronchiolar wall. The site at which focal emphysema develops is identical to that of the centrilobular emphysema found in cigarette smokers. Some researchers, however, believe that the focal emphysema of coal workers seldom extends to involve the gas-exchanging regions of the lung, namely, the respiratory bronchioles and alveoli (Heppleston 1972). Heppleston (1972) and Gough (1968), moreover, claimed to be able to distinguish focal emphysema from centrilobular emphysema, and suggested that the former is characterized by an absence of bronchiolitis in the smaller airways. Not all researchers accept these opinions (Cockcroft, Seal et al. 1982). Dust exposure has long been associated with increasing severity of focal emphysema. Gough (1968) wrote that in a young coal miner with short exposure to dust, dying of accident or of nonpulmonary disease, there is an accumulation of coal dust specifically related to the terminal and respiratory bronchioles. The lungs can evidently withstand this deposition without harm for some years. Emphysema then develops, and in miners who have been exposed for 20 years, some degree of dilatation of the proximal order of the respiratory bronchiole is usual and may be marked. After 40 years of dust exposure, the majority of miners will show focal dust emphysema (FDE), although there is a surprising range in the quantity of dust deposited, and in the degree of emphysema, in miners working under similar conditions. FDE refers to dilatation of the respiratory bronchioles and there can be no doubt, because of the time sequence, that the dust deposition precedes the emphysema. Although Gough's remarks imply that there is a direct relationship between dust exposure and the development of focal emphysema, until recently his views were not entirely accepted. In a similar context, there is a clear-cut relationship between coal dust exposure and the develop- ment and progression of simple CWP (Jacobsen 1980). Ryder and colleagues (1970) reported the results of a survey in which they correlated pathological, physiological, and radiological findings from the lungs of 247 deceased South Wales miners and ex- miners, most of whom had been diagnosed as suffering from coal workers' pneumoconiosis during life. The researchers were particu- iarly ;,oncerned with the relationship of emphysema to dust exposure and TO the radiological findings present antemortem in these subjects. A control series of autopsies was drawn from nonmining nlen autopsied at the same hospital and matched for age `by decade. Whole lung sections were made and emphysema was quantified with standard techniques. Virtually all of the mining population had been examined by the Pneumoconiosis Panel during life, and most were receiving benefits. Post-mortem findings of emphysema were then related to clinical findings, ventilatory capacity measurements, and radiological findings. Emphysema was much more common among the disabled coal miners than among the control population of nonminers, but it is difficult to interpret this observation, as the miners were largely selected from among those who had respiratory disability and the control population was not selected in anv similar way. They also found that miners with the punctate type of opacity were more likely to have emphysema than those with nodular or micronodular lesions. Lung function showed no correlation to progressive x-ray changes for simple pneumoconiosis, but declined with increasing severity of progressive massive fibrosis. The mean emphysema score increased with increasing age in the control population, but not in the miners. The absence of a relationship between emphysema score and age in the miners may be secondary to their having been selected (even at the younger ages) because they presented with respiratory disability. The mean emphysema score correlated well with antemortem measurements of FEV1, but was not greater in those miners with categories B and C of progressive massive fibrosis than in miners with lesser degrees of radiologic change. The absence of smoking data in this population of disabled miners and the poor correlation of emphysema score with radiologic change makes it difficult to ascertain the relative contributions that cigarette smoking and coal dust exposure may have made to the emphysema found in this population. A later publication on the same population of disabled miners (Lyons et al. 1972) included some smoking data. Lung function declined with increasing severity of radiologic progressive massive fibrosis, but actually improved with increasing severity of radiologic simple pneumoconiosis. This dichotomy of lung function and radio- graph may be due to the selection of the autopsy population largely from those who had been disabled from pneumoconiosis in life, as the certification of disability may require more severe functional abnor- malities in the absence of radiographic abnormalities than it would in the presence of advanced simple pneumoconiosis on the radio- graph. They again showed a correlation of lower FEV, with increasing emphysema score, but not with the Reid index of bronchitis. Smokers had lower mean FEV, values than nonsmokers and ex-smokers among miners with simple pneumoconiosis and 306 grade A PMF, but there was no difference in mean FEV, for smokers and nonsmokers among workers with more advanced PMF. The authors suggested that the emphysema is a more important determi- nant of ventilatory impairment than the radiograph and that the emphysema is due to coal dust in both simple pneumoconiosis and progressive massive fibrosis. However, they presented no data to evaluate the possibility that emphysematous change due to cigarette smoking may have been responsible for the link between emphyse- ma score and lung function and for the absence of a correlation with the radiologic changes of pneumoconiosis. Leigh and colleagues (1983) described the results of 886 post- mortem examinations of Australian miners, relating years spent underground at the coal face to bronchial gland wall ratio, the presence and extent of emphysema in the lungs, radiographic findings, and cigarette smoking history. Emphysema was related to years spent underground at the coal face and to radiological evidence of CWP. Radiological evidence of pneumoconiosis was negatively associated with smoking. Even more surprisingly, smoking was not correlated with gland wall ratio or emphysema. This absence of any relationship between cigarette smoking and emphysema is unique in the published literature and suggests a bias in the selection of subjects who underwent post-mortem examination or in the manner in which smoking habits were analyzed. A relatively recent post-mortem study of coal miners and nonmin- ers from South Wales compared the prevalence and extent of emphysema in subjects who had died of ischemic heart disease (Cockcroft, Berry et al. 1982). A greater percentage of smokers and ex-smokers had emphysema (17/34) than never smokers (l/5) among the coal miners, but there were too few cases of emphysema among the nonminers to compare smokers and nonsmokers. Coal miners were noted to have more emphysema than nonminers, but the frequency of emphysema in the control population was very low. While the degree of emphysema in these subjects was quantitated in the absence of knowledge of the deceased subject's occupation, the characteristic features of coal miners' lungs (i.e., the formation of macules and the presence of pigment and the accompanying focal emphysema) would invariably indicate the deceased subject's occupa- tion during life. There was a legal requirement for a post-mortem examination for coal miners. Whether the pigment present also highlighted and accentuated the emphysema is unknown. Ruckley and colleagues (1984) examined the lungs of 460 British coal miners at post-mortem examination for signs of dust-related fibrosis and emphysema. Smoking habits had been determined previously by questionnaire. The prevalence of emphysema was 9 percent in the nonsmoking miners whose lungs showed only circumscribed dust accumulations of which any solid center was less 307 than 1 mm in size, 33 percent in nonsmoking miners with lungs showing one or more palpable lesions between 1 and 10 mm in size, and 75 percent in nonsmokers with PMF. The corresponding prevalences of emphysema among smokers with similar pathologic findings were 52.7 percent, 70.3 percent, and 85.3 percent, respec- tively. Ex-smokers generally had intermediate percentages. The percentage of the population with any emphysema increased with the increasing content of dust in the lung, but the percentage of the population with more than one-third of the lung affected showed no increase with increasing concentration of dust in the lung. These data suggest that both smoking and coal dust contribute to emphyse- ma, but that extensive emphysematous change is more closely related to extent of cigarette smoking. Morgan and colleagues (1971) examined lung volumes in coal miners and showed that both cigarette smoking and increasing simple CWP grade increased the TLC and RV, and the effects appeared to be additive. This suggests that simple coal workers' pneumoconiosis is associated with a slight loss of the elastic recoil. Such an observation is best explained by the presence of so-called focal dust emphysema (FDE). In summary, there is little doubt that simple CWP and dust exposure may lead to the development of focal dust emphysema. The type of emphysema seen in coal miners is probably still best referred to as focal dust emphysema, since there is some evidence that it does not progress to severe centrilobular emphysema (Ruckley et al. 1984) in the absence of cigarette smoking. Whether a morbid anatomical distinction between the two conditions is possible is not certain. Studies of right ventricular function in coal miners and ex-miners both during life and at post-mortem examination (Morgan and Seaton 1984) have shown that car pulmonale or right ventricular hypertrophy do not occur except in cigarette smokers or in miners who have PMF (Fernie et al. 1983). Dust Exposure, Cigarette Smoking, and Ventilatory Function In a long-term prospective study of 3,581 miners who worked at the coal face, Rogan and colleagues (1973) showed that dust exposure was inversely related to ventilatory capacity. Lifetime cumulative exposures to coal dust were available. The researchers were able to demonstrate a progressive reduction in ventilatory capacity with increasing exposure to dust. The presence of pneumoconiosis was not associated with an additional decrement of ventilatory capacity beyond that due to cumulative dust exposure, smoking habits, and stature. Smokers showed a more rapid decline in FEV, than nonsmokers, but an effect of cumulative dust exposure was apparent in both smoking and nonsmoking miners. Among the nonsmokers, 308 FEV, was generally lower in the most dust-exposed group than in the low exposure group, but the rate of decline per year remained the same from age 30 to age 60 in both exposure groups. The age- related regression coefficients were the same in the heavily and lightly dust-exposed nonsmokers. Subjects with PMF were excluded from the analysis. Among smokers, the rate of decline in FEV, with age was greater than for the nonsmokers in each exposure category, but the absolute FEV, in smokers at a given age was uniformly lower for the group with high dust exposure than the group with low dust exposure. Kibelstis and colleagues (1973) were also able to demonstrate a slight effect of dust exposure on the ventilatory capacity of their nonsmoking miners. These investigators divided their population according to whether the men had worked at the face, in transporta- tion, in miscellaneous other jobs, or on the surface. Dust measure- ments performed for these various jobs and work places had shown a gradient, with the greatest exposure at the coal face and least on the surface (Doyle 1970). Nevertheless, individual cumulative dust exposure measurements were not available for the subjects. When the nonsmoking coal face workers were compared with the non- smoking surface workers, there was a slight but significant differ- ence in FEV,. Thus, the coal face workers had an FEV, of 98 percent of the predicted value; that of the surface workers was 102.4 percent. The difference in FEV, for the smoking and the nonsmoking coal face workers was 6 percent; the difference between the smoking surface workers and the nonsmoking surface workers was 10.5 percent. The effects of cigarette smoking were therefore substantial- ly larger than those of dust exposure. Among the ex-smokers and nonsmokers, there was a significant difference in function between coal face workers and transportation workers and their counterparts who worked on the surface. Among the smokers, no such difference was present, with smoking apparently overwhelming the effects of dust. Airways obstruction was three times more common in the smokers than in the nonsmokers. An extensive West German study of 6,700 workers employed in coal mines, steel works, cement works, asbestos factories, and other heavy industry related dust exposure to smoking habits and other factors (Deutsche Forschungsgemeinschaft 1978). Each subject un- derwent a clinical examination, chest radiograph, and spirometry along with measurements of airways resistance and arterial blood gas analyses. The study showed that the most important factors related to the prevalence of bronchitis and airways obstruction were age and smoking habits. Among younger workers, there seemed to be an additive effect of smoking, age, and dust, with the combined effect of all three equaling the sum of their separate effects. Among older 309 workers, smoking appeared to play a relatively greater role in the production of airways obstruction. Hankinson and colleagues (1977) characterized the physiological impairments that are associated with the inhalation of coal dust and cigarette smoke. This study relied on flow volume curves as a method of assessing ventilatory capacity, but in addition to the standard spirometric measurements, lung volumes were calculated by a radiological method using posteroanterior and lateral chest films. Since TLC could be calculated, it was possible to express the flow rates, not only as a percentage of vital capacity (VC) but also at absolute lung volumes. Four age- and height-matched groups were selected on the basis of their smoking history and on the presence of bronchitis, that is, cough and sputum. Thus the four groups consisted of smokers with bronchitis, smokers without bronchitis, nonsmokers with bronchitis, and nonsmokers without bronchitis. Flow-volume curves of the four groups are shown in Figures 1 and 2. The differences between the four groups reveal that cigarette smoking effects the flows at all lung volumes. In contrast, nonsmoking bronchitics for the most part showed decreased flows at high lung volumes, although there was some mean reduction in flows at lower lung volumes, indicating that the small airways were not entirely spared. When the flows were expressed at absolute lung volumes, it became evident that smokers had an increased RV and an increased TLC. In contrast, the nonsmoking subjects with and without bronchitis had a normal TLC and RV. The increased TLC suggests a loss of retractive forces in the lung and the presence of subclinical emphysema. Bronchitis in nonsmoking subjects was not associated with an increase in TLC. A number of longitudinal studies have been carried out with groups of coal miners. Love and Miller (1982) followed 1,677 men from five British collieries for 11 years. Loss of FEV, was found to increase with cumulative dust exposure, after allowing for age, smoking, and colliery effect. The investigators classified smoking according to the smoking status that was recorded in all three surveys, that is, as nonsmokers, ex-smokers, or current smokers. Miners who were recorded as smokers at the first survey and as ex- smokers at the second and third surveys were designated as intermittent smokers. According to Love and Miller (1982), the average decrement in FEV, from the effects of dust was about one- third of that due to smoking. They further stated that if men left the industry because of ill health and respiratory impairment, the average loss of FEV, would have been underestimated. This could apply to men who retired from the workforce because of the effects of dust, cigarette smoking, or both in combination. There are several problems with this study. First, only 1,677 subjects were studied, 29 percent of the population of 6,191 in the 310 (n)= 428 d G 30 40 50 60 70 Volume, percent forced wtal capacity FIGURE l.-Mean flow volume curves expressed as percentage of forced vital capacity SOYRCE Hankmson et al lYT:i first survey. No data were provided to establish that the 1,677 survivors had similar characteristics to the original 6,191 subjects. It is essential to know that the ventilatory capacities, age, height, and smoking habits of the survivors did not differ from those of the original cohort. Second, no quantification of smoking was available. FEV, was regressed against age, regular smoking habit, and dust. Unfortunately, smoking was treated as an unchanging variable such as height, although Fletcher and colleagues (1976) had shown that the effects of cigarette smoking increase with pack-years. Similarly, Kibelstis and colleagues (1973) showed that while cough and sputum relate well to current smoking habits, pack-years are a better predictor of the prevalence of airways obstruction. Attfield (1985) examined changes in ventilatory function among smoking and nonsmoking miners in the United States. They recorded the decline in FEV, over an ll-year period in a group of 1,072 U.S. miners. Over that time the loss in FEV, was 0.1 L more in 311 (n)=426 7 - 6t P 8 5- P 2 1 = 4 4 Il. 3 2 ; 1 i " I / 6 7 6 5 4 3 2 1 Absolute lung volume. lhS FIGURE 2.-Mean flow volume curves expressed as absolute lung volumes SOCRCE Hankrnson et al 119771. the smoking miners than in the nonsmoking miners, in a multiple regression model. The effect of coal dust exposure over the 11-year period ranged from 0.036 to 0.084 L, depending on the regression model used for the coal dust exposure. The relative importance of cigarette smoking versus dust and other factors in occupational lung disease has been reviewed by Elmes (1981). He concluded that while control of occupational exposure to coal dust remains critical, substantial future improve- ment in respiratory health can be achieved by reducing the prevalence of smoking among miners. Summary and Conclusions 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 312 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 levels 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. 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American Review of Respiratory Disease 12@1):104-112, July 1983. 318 CHAPTER 8 SILICA-EXPOSED WORKERS CONTENTS Silica Exposure Population at Risk Smoking Behavior of Silica-Exposed Workers Definitions of Health Effects Epidemiological Findings Pathogenesis of Silica-Related Health Effects Silica Exposure and Cancer Epidemiologic Studies of Smoking, Silica Exposure, Silicosis, and Cancer Silica-Exposed Cohort Studies Metal Ore Mining Steel Industry Workplaces With Exposure to Silica Only Followup of Silicotics Research Recommendations Summary and Conclusions References 321 Silica Exposure The oxides of silicon (SiO,) are found in a number of polymorphic structures consisting of three-dimensional networks of silica tetrahe- dra (Zoltai and Stout 1984). When SiO, is bound with cations, it is considered to be "combined" silica. When not combined, it exists in its "free" forms-polymorphic crystalline, cryptocrystalline (minute crystals), and amorphous (noncrystalline) (Parkes 1982). Whether SiO, is in a free form is important from the standpoint of occupational toxicity. The crystalline phases of SiOz, including quartz, tridymite, and cristobalite, are recognized as causative agents in silicosis. Diatomite tends to form amorphous silica, and crystalline lenses are found in diatomaceous earth deposits. Diatom- ite is converted to the biologically active cristobalite with calcining at temperatures from 1000" C to 1723" C (Parkes 1982). Occupational exposures to free silica are diverse. Major industries with recognized significant silica exposures include metal mining, coal mining, and nonmetallic mineral extraction, stone, clay, and glass processing, iron and steel foundries, and nonferrous foundries. A more complete listing of occupations with potential exposure to silica is found in Table 1. Some of these exposures, including silica flour production and use, sandblasting and certain mining, quarry- ing and tunneling operations, result in exposure predominantly to silica. However, many silica exposures, including most mining operations and foundry exposures, are mixed-dust exposures, which has implications for the type and extent of biological response seen among exposed workers. A general pattern of noncompliance with the current permissible exposure limit (PEL) for free silica has been documented in recent papers appearing in the American medical literature. These reports have included the Occupational Safety and Health Administration (OSHA) compliance data for 205 foundries in which 40.6 percent of samples exceeded the PEL (Oudiz et al. 1983); OSHA data showing a 53 percent rate of noncompliance with the silica PEL in 27 silica flour mills (Banks, Morring, Boehlecke 1981; Banks, Morring, Boehlecke et al. 1981); and gross excesses (greater than hundredfold) of the silica standard in sandblasting operations, which remain a poorly regulated industrial process in the United States but are banned in several other developed countries (Samimi et al. 1974). Population at Risk Estimates of the population at risk for potential silica exposure are available from the National Institute for Occupational Safety and Health (NIOSH) National Occupational Hazard Survey, which was based on a probability sample of 5,000 industries between 1972 and 1974 (NIOSH 1978). From these survey results, NIOSH estimated TABLE l.-Occupations with potential exposure to silica Abrasive blasters Abrasive makers Auu, garage workers Bisque-kiln workers Brick layers Buffers Burhstone workers Carborundum makers Casting cleaners (foundry) Cement makers Cement mixers Ceramic workers Chemical glass makers Chippers Coal miners Construct workers Cosmetic makers Cutlery makers Diatomaceous earth calciners Electronic equipment makers Enamellers Fertilizer makers Flint workers Foundry workers Furnace liners Fused quartz workers class makers Glaze mixers (pottery) Granite cutters Granite workers Grinding wheel makers Grindstone workers Hard rock miners Insecticide makers Insulators Jewelers Jute workers Kiln liners Masons Metal buffers Metal burnishers Metal polishers Miners Mortar mixers Mortarmen Oil purifiers Oilstone workers Optical equipment makers Paint mixers Polishing soap makers Porcelain workers Pottery workers Pouncers (felt hat) Pulpstone workers Quarry workers Quartz workers Refractory makers Road constructors Rock crushers Rock cutters Rock drillers Rock grinders Rock screeners Rubber compound mixers Sand cutters Sand pulverizers Sand blasters Sandpaper makers Sandstone grinders Sawyers Scouring soap workers Silica brick workers Silicon alloy makers Silver polishers Slate workers Smelters Sodium silicate makers Spacecraft workers Stone bedrubbers Stone cutters Stone planners Street sweepers Subway construction workers Tile makers Toothpaste makers Tube mill liners Tumbline barrel workers Tunnel construction workers Whetstone workers Wood tiller workers SOCRCE Aspen Systems 119781 that 3,200,OOO active workers in 238,000 plants were potentially exposed to silica; however, this estimate was based on workers in an area where free silica is used, and the number of workers with clinically significant exposures would be appreciably lower. This estimate excluded former workers who were retired, working elsewhere, or disabled and the large industrial sector of agriculture where some silica dust exposure occurs (Popendorf et al. 1982). 324 Significant physical factors for occupational respiratory disease risk include the percentage of free silica, the respirable fraction of the mineral dust (which may have a higher silica content (Ayer et al. 197311, and the concentration of dust (total and respirable) in the worker's breathing zone. In addition, other workplace contaminants may combine with silica particles to alter the toxicity of the given mineral dust exposure. Individual factors such as pulmonary deposi- tion and clearance, atopic status, genetic constitution, and immune response may also be important risk factors in silica-related disease; however, they are sometimes difficult to measure and have been less well studied. Hence, studies of workers exposed to silica must provide clear documentation of the exposures in the workplace as well as documentation of other personal and environmental factors that may influence biological response. Smoking Behavior of Silica-Exposed Workers The smoking behavior of workers in a variety of settings where silica exposure can occur is detailed in Table 2. These studies in the United States and abroad indicate that a very large proportion of people who are exposed to silica are also smokers. Definitions of Health Effects Several health effects are associated with occupational exposure to silica dust. The causal role silica plays in some disease responses, namely silicosis and silica-induced alveolar lipoproteinosis ("acute silicosis"), is quite clear and widely accepted. Silica is recognized as playing an important causal contributing role in a second group of pulmonary responses-silicotuberculosis, mixed-dust fibrosis (usual- ly mixed with iron oxides), and the fibrosing alveolitis arising from exposure to calcined diatomaceous earth (diatomite pneumoconiosis) (Parkes 1982). Smoking appears to play no significant causal role in the etiology of the first two categories of silica-induced diseases. In a third group of health effects, silica dust appears to be a risk factor in simple chronic bronchitis as characterized by mucus hypersecretion and in chronic airways obstruction, which is often associated with a progressive decline in expiratory flow rates and is largely irrevers- ible. This last group of pulmonary responses is nonspecific, recog- nized to be multifactorial and causally linked to cigarette smoking. A causal relationship between silica dust and chronic bronchitis or chronic airways obstruction is less clear. This issue is of considerable importance because of the prevalence of chronic bronchitis and chronic airways obstruction in modern society and the large size of the population at potential risk of silica exposure. E TABLE 2.-Smoking characteristics of silicaexposed workers Number and type Study of population Smoking characteristics (percent) Comments Prow 240 gold miners. (1970) South Africa Brinkman et al. 301 automotive industry (1972) workers. aged 40-65 SluisCremer Men expmed to dust, (1972) Carletonville. South Africa Theriault et al. (3 papers) (1974) 792 granite workers. Vermont Armstrong et al. Coal and gold miners, (1979) Australia . Born et al. (1963) Trona miners. Wyoming Light (I-200)' Moderate (2Olm) Heavy (>6CO) Exposed workers Nonexpcmed workers SM 65.8 11 22.3 32.5 70 60.7 SM 60.4 SM EX' NS `Not smoked in 57 30 12 last 6 months Gold miners SM 66.3 42.6 NS/EX 34.2 ' Numerical rating of cigs/day x years smoked 30 39.3 EX NS 25.6 13.9 NSIEX 33.7 33.6 23.6 NOTJZ.: S.M=Smoker; EX=Ehsmoker; NS=Nonsmoker. Epidemiological Findings Early observers of occupational diseases, including Ramazzini in 1713 (1964), wrote about the respiratory problems of miners and stone cutters, and recognized silicosis among miners, stone cutters or hewers, and potters. Silicosis, and its previously described associated health effects, have been given a variety of names that reflect the several faces of silica exposur&ust consumption, ganister disease, grinders' asthma, grinders' consumption, grinders' rot, grit consump- tion, masons' disease, miners' asthma, miners' phthisis, potters' rot, rock tuberculosis, stonehewers' phthisis, and stonemasons' disease (Hunter 1955). Greenhow (18781, in his treatise on bronchitis, recognized that "irritants which act immediately upon the bronchial membrane may produce inflammation by means of either mechani- cal or chemical irritation. Fine coal and metal dust, stone and porcelain grit, and even the flue of cotton wool . inhaled into the lungs during various industrial processes are all of them mechanical irritants which become fruitful causes of bronchitis in certain classes of operatives" (p. 30). Mortality studies of silica-exposed cohorts have consistently shown increased mortality rates for tuberculosis and nonmalignant respira- tory disease, largely accounted for by silicosis (Guralnick 1962; Registrar General 1958, 1978; Davis et al. 1983; Armstrong et al. 1979; McDonald et al. 1978; Fox et al. 1981). Although none of these studies accounted for the effects of smoking, the consistency and magnitude of the increased rates suggest a causal relationship between silica exposure and these cause-specific mortality rates. Davis and colleagues (1983) demonstrated dose-response relation- ships between exposure category, tuberculosis, and silicosis, but found no excess mortality from bronchitis and pneumonia. Finkel- stein and colleagues (1982) investigated mortality among 1,190 Ontario miners receiving compensation awards for silicosis and found nonmalignant respiratory disease (excluding tuberculosis) to be the most frequent cause of death (standard mortality rate, 765). NIOSH recently assessed causes of disability among employees of the mining industry, based on the Social Security Disability Benefit Awards and Allowances to Workers for 1969-1973 and 1975-1976 (Osborne and Fischbach 1985). The observed proportional morbidity rate (PMR) for pneumoconiosis from silica and silicates (they were not distinguished) was found to be somewhat higher (4,894) than for other mining occupations. Workers employed in boring, drilling, and cutting jobs appeared to experience increased disability from respira- tory diseases, specifically pneumoconiosis including silicosis. These findings, based on somewhat more recent exposures than the previously cited mortality studies, confirm the major mortality findings, but suffer from the same methodological problems. Again, smoking data were not available or analyzed, and it is recognized 327 that those disabled in the mid-1970s very likely were exposed to silica three or four decades previously; therefore, their disabilities reflected previous dust exposures. Early morbidity studies of workers exposed to silica dust focused on rates of sickness, respiratory symptoms, and physical findings, supplemented in the 1920s with chest radiography. The U.S. Public Health Service (US PHS) conducted the first major U.S. silicosis study of the hard-rock mining industry in 1913-1915 (Higgins et al. 1917; Lanza and Higgins 1915). Their studies reported that 60.4 percent of the 720 miners examined suffered from pulmonary diseases attributable to mine rock-dust exposure. Dust samples collected with a Draeger liter bag-granulated sugar filter apparatus were reported to average from 30 to 50 mg/m3 (Higgins et al. 1917). Although these concentrations would appear to be quite high, they are difficult to interpret according to modern-day respirable dust sampling and analysis (x-ray diffraction for free silica content). Subsequent US PHS silica studies included Harrington and Lanza's (1921) 1916-1919 study of copper miners in Butte, Montana, in which 42.4 percent were judged to have some dust-induced lung injury and 25.5 percent to have advanced disease. Dreessen and colleagues (1942) studied 727 metal miners in 1939, and Flinn and colleagues (1963) studied 67 underground mines employing 20,500 miners from 1958 to 1961, but found varying silicosis prevalence from mine to mine and widely divergent exposures to free silica. The silicosis prevalences of 9.1 percent and 3.4 percent, respectively, were found to be associated with longer duration of exposure and especially with face work exposures (Dreessen et al. 1942; Flinn et al. 1963). Earlier, Flinn and colleagues (1939) had reported an impor- tant study (19361937) of West Virginia potteries that included 2,516 workers with an overall silicosis prevalence of 7.8 percent. Free silica content ranged from 1 to 39 percent, dust concentrations varied from 3 to 440 million particles per cubic foot (mppcfl, and mean particle diameters were judged to be 1.2 pm (but without data on the concentration of respirable dust). A strong dose-response relation- ship between dust concentration, duration of pottery exposure, and silicosis prevalence was documented. It was suggested that no new cases of silicosis would occur if dust concentrations in this industry were brought below 4 mppcf. Renes and colleagues (1950) studied 18 ferrous foundries in 1948-1949, and found 9.2 percent of 1,937 foundrymen to have pulmonary fibrosis. Free silica content averaged 30 percent, with a mean particle size of 3 pm, and 82 percent of the samples had levels below 6.9 mppcf. Mechanical shakeout operations were found to have the highest dust concentrations (10 to 75 mppcfl, and silicosis was noted to be more prevalent among foundrymen with 20 or more years of exposure. It was suggested that conditions had improved in foundries and that most of the pulmonary fibrosis was 328 due to previous exposures. Early studies of the refractory (silica) brick industry documented high percentages of free silica, often in the form of cristobalite and tridymite from burned bricks. Keatinge and Potter (1949) and Fulton and colleagues (1941) studied 1,035 exposed workers in this industry, finding 52 percent to have some stage of silicosis. A relationship with dust concentration and duration of exposure was again documented, as was an apparent increased risk among men exposed to burned brick dust (Keatinge and Potter 1949; Fulton et al. 1941). Epidemiological studies of workers in the Vermont granite indus- try have provided an important and interesting chronology of data on the natural history of silica-associated respiratory diseases. Early US PHS studies of this industry (Russell et al. 1929) documented high dust concentrations (37 to 59 mppcf) and a very high prevalence of silicosis. On the basis of dust with a free silica content of 35 percent, a presumptive "safe limit" of dustiness was suggested to lie between 9 and 20 mppcf. A subsequent US PHS study (Russell 1941) essentially confirmed the findings of the original study, noted an increased progression of silicosis among the highly exposed cutters, and concluded that a limit below 10 mppcf for this industry would be desirable. Subsequent followup studies in 1955 by the US PHS and the Vermont State Board of Health (Hosey et al. 1957) found that the prevalence of silicosis had decreased from 45 percent in 1937-1938 to 15 percent in 1956, that the silica content of the dust averaged a somewhat lower 22 to 25 percent free silica, and that nearly all workers with silicosis had been exposed prior to implementation of dust controls in 1937. This report was consistent with an earlier report by Ashe (19551, and was subsequently supported by a further followup study by Ashe and Bergstrom (19651, which reported no cases of silicosis among 1,478 granite workers employed after 1937, and a study by Davis and colleagues (1983) that reported only one case in the same population. All of these early studies of silica exposure concentrated on radiographic evidence of silicosis and tuberculosis and the associa- tion with silica content and concentration. These studies formed the basis for environmental control of silica exposures, demonstrated the effectiveness of dust control, and provided a widely held impression that silica exposures, and hence disease arising from silica expo- sures, were well controlled. Beginning in the 195Os, British epidemiologists introduced stand- ardized respiratory questionnaires, field spirometry, and sound epidemiological methodology to the study of bronchitis and chronic obstructive lung disease, and were the first to use these methods to assess respiratory effects among industrial workers. This allowed assessment of other risk factors, including cigarette smokmg, and quantitation of major risk factors compared with appropriate 329 157-5L.4 3 - 66 - 1,' reference populations. At the same time, on the basis of clinical case series, it was becoming clear that bronchitis and nonspecific airways obstruction were more common than pneumoconiosis among work- ers exposed to coal mine dust and silica dust. The significance of these health effects was not clear. Modern epidemiological studies began with the Higgins and colleagues (1959) investigation of Stavely, an English industrial town of 18,000 and home to a significant number of coal miners and foundry workers. This study and other cross-sectional studies of silica exposure that have assessed standardized respiratory symptoms, lung function, smoking, and occupation (only those with non-coal-mining silica exposures) are summarized in Table 3. Review of these studies has found them to be heterogeneous in regard to workforce composition, free silica content and dust concentration (if reported), and other associated occupational expo- sures that may contribute to respiratory symptoms and declines in lung function. In some instances associated occupational exposures other than silica dust appear to be as important or more important than silica dust (Higgins et al. 1959; Gamble et al. 1979; Manfreda et al. 1982; Graham et al. 1984). Two of these studies found lung function to be somewhat better among exposed workers than among reference subjects (Clark et al. 1980; Graham et al. 1984). However, in both of these studies, one of potash miners and one of taconite miners, it is very likely that the free silica exposure, although not documented, was low. One study of fluorspar miners (Parsons et al. 1964) and one of copper miners (Federspiel et al. 1980) suggest a significant dust effect on bronchitis prevalence and a somewhat lower lung function among exposed miners. Specific environmental data on free silica content or dust concentration were not provided in either study, although most likely some of the dust exposure in these mines was silica. Four of the studies reviewed in Table 3 have documented significant exposures to free silica with the relative absence of other exposures: the Welsh slate workers study (Glover et al. 19801, the Vermont granite workers study (Theriault, Burgess et al. 1974; Theriault, Peters, Fine 1974; Theriault, Peters, Johnson 1974) and two studies of South African gold miners (Sluis-Cremer et al. 1967; Wiles and Faure 1977). Silicosis was reported in all four study populations, ranging from 5 to 33 percent. Sluis-Cremer and colleagues (1967) surveyed the prevalence of chronic bronchitis in a mixed mining and nonmining population in Carletonville on the Witwatersrand, South Africa. Chronic bronchitis was more common among miners who smoked than among nonminers who smoked, but there were no significant differences in prevalence of bronchitis between miners and nonminers who did not smoke. The prevalence of bronchitis was substantially higher among smokers than among 330 Study, country Number and Age type of (mean or population range) Bronchitis (ratio) S/NS Exp/Not Lung function P"eum* conic& S NS A EXP Not A (percent) Comment Higgine et al. (1959), United Kingdom Current and ex- 55 to foundry workera; 64 105 exposed, 81 nondusty occupations Not available for foundry workera alone 1.2 Not available for foundry 82.1 90 -7.9 14.0 Foundry workera both "pure" workers alone with free silica exposure and (Indirect MBC based on "mixed" with chemical fumes FEVd (HCI. H,SQ, caustic soda, and benzol) and other dusts; increased respiratory symptoms and decreased lung function mainly in "mixed" foundry workers suggests other dusts and fumes likely more important than "pure" foundry work Parsons et al. (1964), Canada Fluorspar mining; 301 ev-4 5% co"trola ,383 (20 to 70) Not available 5.5 Generally higher for nonminers; decreased lung function in chronic bronchitic me" appeara more important than dust eategory @a.& on indlrect MBC, MMF, PFR) 1.93 No specific SiO, expasurea or dust measurements available; exposure determined from job category and tenure Sluis Cold mining; 35 and 1.8 1.22 Not studied 5 Free silica content range 5& Cremer et 582 expceed, 285 older 70%, but generally low dust al. (19871, community levels; smoking somewhat South controls more common among miners; Africa significant increase in chronic bronchitis prevalence among smoking and ex-smoking but not nonsmoking miners suggests possible interaction between smoking and E "underground aerial w pollution" TABLE 3.-Continued Number and Age Bronchiti 3 (ratio) Lung function Pneume Study, type or (mean or --- coniosie country population range) SINS l&p/Not S NS h EXP Not h (percent) Comment Higgins et 60 foundry 25 to Not Not Not reported separately 3.49 3.55 -.c6 23.1 No environmental al. w66), workers, 100 34 reported reported for foundrymen measurements, but typical United "nondusty" SiO, foundry exposures; 9- Kingdom workers year followup mortality higher among foundry 43 foundry 55 to 2.27 2.36 -39 workers than others, workers, 52 64' appreciably higher among "nondusty" (FEV7S%) foundry workers with silicwis workers Theriault 792 granite 44 Not Not 4.2 4.1 + IO 4.2 4.1 +.10 31 Single "A" radiograph reader; L al. (3 workers =pod repoti dow+response relationship PapeM (FVC) between FVC and granite (1974). 189 marble 41 duet and quartz dust; 2 mL United workers FVClduetyear decline, 9 mL States F'VC/smoking-year decline Wilea and 2,209 gold 4.5ta 2.3 5.3 2.53 3.77 -1.24 3.60 3.64 -.24 6.7 7@-250 particles/cm' dust Fare miners with 54 (1977). counts; 75% free BO,; 2 10 years' (low duet (MMEF) flow duet significant dust South service YS. exposure/chronic bronchitis Africa highYsbust high dust doee-reeponee relationship in C&gOries) C&gOrieS) all smoking categories; much stronger smoking effect on lung function, but no dase- response &lationehip TABLE 3.-Continued Number and Age Bronchitis (ratio) Lung function Pneume Study, type of (mean or - conk& country population range) SINS Exp/Not S NS A EXP Not A (percent) Comment Gamble et 121 talc miners 39.7 3.5 1.2 3.74 4.13 -.39 3.66 3.64 -.14 2.2 2040 w/m' free silica; 0.2% al. (1979), talc, 2.96 mg/m' respirable dust; United 1,077 potash 39.2 (FEV,) .I07 anthophyllite, tremolite, and States miners potash crysotile asbestos fibers found; (reference group) 17/24 jobs ;,2f/cc; decrea.. lung function and pleural thickening significantly aesaciated Clark et 240 iron ore 49.3 None 1.0 c478.5 61.4 -2.9 861.4 80.0 t1.4 c2 Taconite has iron. quartz. al. (198X, miners. 220 among and numerous silicates, esp. United yE2X-S nonsmoking mv,/Fvc) grunerite-cummingtonite; 25- States underground miner8 40% total dust quartz; repxted significant smoking effect, no 86 not exposed 50.1 dust effect on lung function - Federspiel 133 surface Not 98.4 None GM.5 92.5 -7.0 492.5 98.0 -5.5 Not No dust level or SiO,% data; et al. workers given among reported no SO, miner exposure. little (196OJ nonsmoking FEV,) or no surface worker SO, United 112 copper nonminers exposure; mining and States miners smoking additive effect on bronchitis; signiticantly reduced nonsmoking miner FEV, and FVC and smoking miner FVC i% TABLE 3.-Continued 6 Number and Age Bronchitis (ratio) Lung function Pneumw Study, type of (mean or conioaia country population range) SINS Exp/Not S NS A Exp Not A (percent) Comment Glover et al. (19801, United Kingdom 725 slate workers 530 nonexposed 1.8 4.4 3.06 3.23 mv,1 -.17 3.23 3.53 -30 33 13-325 reepirable quartz in reapirable dust; no smoking category/radiographic opacity association; no dust concentrations available, but thought "high"; respiratory symptoms dependent on pneumonconiceie category per multiple regression, except nonsmokers with previous TB (in 4&50% of slate workew age >w Manfreda et al. (1982). Canada 241 hardrock 25to 9.0 9.5 23 7 +16 0 7 -7 TLV; some 382 nonexposed percentile of nonsmoking general population) underground worker (95) NO, men (community exposure, some smelter sample) worker (107) SO, exposure (10% >TLV); low sulfm? worker (39) duet exposure; nonsmoking miner bronchitis significantly increased; significantly reduced lung function in smelter workers, not miners; probable selection processes noted NOTE: Bronchitin rat& and lung function comparisons are of nonexpwed smokers 6) and nonsmokers (NS) to 888e88 smoking effect and of nonamokiing exposed workers (Exp) and nonexpoeed worken, (Not) to BBBBBB exposure effezt. Combined smoking and exposure et&& are not shown, but are add- under omxnent. nonsmokers in both the dust-exposed and the nonexposed popula- tions. Evaluation of Vermont granite shed workers (Theriault, Burgess et al. 1974; Theriault, Peters, Fine 1974; Theriault, Peters, Johnson 1974) revealed that both smoking and cumulative dust exposure contributed to the differences in FVC and FEV, among these workers, but the effect of smoking was larger than the effect of dust exposure, using a multiple regression technique. A dose-re- sponse relationship between silica dust exposure and decreased lung function was demonstrated in both the Vermont granite shed workers and the South African gold miners (Wiles and Faure 1977). Glover and colleagues (1980) examined 725 workers and former workers from the slate mines and quarries of North Wales and 530 men from the same area who had never been exposed. The prevalence of chronic cough ranged from 5.2 percent in the nonsmok- ers not exposed to dust to 19.4 percent in the nonsmokers with dust exposure. Smokers with no exposure to dust had a prevalence of cough of 27.5 percent; the prevalence was 38.9 percent among the smokers with dust exposure. FEV, (standardized to a fixed height) was lower in the smokers than in the nonsmokers. The dust-exposed nonsmoking workers had a lower mean FEV,, but the values for the dust-exposed and the nonexposed smokers were similar. The regres- sion coefficients for FEV, with age were 20 mL per year in the nonexposed nonsmokers and 38 mL per year in the dust-exposed nonsmokers, but the coefficients for smokers were similar between the dust-exposed (40 ml/year) and nonexposed (46 ml/year) men. The absence of an effect of dust exposure among the smokers in some of these studies may be the result of the cessation of smoking by those workers with declining lung function, as suggested by the observation that the mean FEV, and regression coefficient for decline in FEV, with age among slate workers was worse in ex- smokers than in either current smokers or nonsmokers. In contrast, the values for ex-smokers in the general population were between those for smokers and those for nonsmokers. Only a few prospective studies of silica-exposed workers have been reported in the literature. Four of these studies are summarized in Table 4 (Higgins et al. 1968; Pham et al. 1979; Kauffmann et al. 1982; Manfreda et al. 1984). Two other prospective studies of silicaexposed workers are not included in this table because of methodological questions. Brinkman and colleagues (1972) followed a group of foundry workers with silica exposure and with silicosis over an ll- year period. Only a third of the men known not to have died in that interval were restudied, however, raising questions about the validity of the finding of no apparent difference between the silica- exposed workers and the unexposed workers in decline in lung function over time. The original cross-sectional study found poorer lung function among silica-exposed workers and silicotics. Musk and 335 colleagues (1977) conducted a 4-year followup study of Vermont granite workers and reported a substantially higher annual loss in lung function than predicted from previous cross-sectional studies of this population. However, reassessment of some of these data has raised questions about the adequacy of the pulmonary function testing (Graham et al. 1981). Reana!ysis of the population revealed that Vermont granite workers had an annual decline in FEV, of 44 mL per year and those who had left the industry had a decline of 72 mL per year (Eisen et al. 1983). The smoking habits of those who continued working (20 pack-years) and those who had left the industry (27 pack-years) were similar. There was no statistically significant relationship between lifetime dust exposure and decline in FEV, for either the workers who were still working or those who had left the industry. One of the four studies reviewed in Table 4 found no increased decline in lung function over time among silica-exposed workers (Higgins et al. 1968). On followup, however, the mortality rate among the foundrymen in the original study (Table 3) was appreci- ably higher, particularly among those with silicosis and among older workers. Smoking habits were recorded in this study, and the foundry workers who smoked had lower mean FEV, values than the nonsmoking foundry workers in both the 25 to 34 and the 55 to 64 age groups. Pham and colleagues (1979) found consistently increased declines with age in all measures of lung function studied (FEV,, FVC/FEV,, RV/TLC, and fractional uptake of CO) among silica- exposed steel workers compared with unexposed workers. Results for smoking and nonsmoking workers were not reported separately. Lung function of the exposed men in the original survey was somewhat higher than in the unexposed workers (although they had much more bronchitis), suggesting that selection processes (healthy worker effect) occurred in this study. Kauffmann and colleagues (1979, 1982) also found increased declines in smoking-adjusted lung function over time among workers exposed to mineral dust (especial- ly silica), and argued that the mineral dust and silica exposures were most likely to be causal. Their findings are consistent with this conclusion, but exposures were assessed by type of job, and informa- tion on silica dose or interval progression over the 12 years of study is lacking. Manfreda and colleagues (1984), in a 5-year followup study of hard-rock miners and smelter workers, reported significant declines in FEV,/FVC for both smoking and mining industry exposure. These effects were quantitatively similar, but may reflect more of a smelter effect than a mining (silica dust) effect, as that was the finding on their original cross-sectional study. The prospective study abstract does not address this question. 336 TABLE 4.-Prospective studies of workers occupationally exposed to silica Study, country Number and Age type of (mean or population range) Annual decline in lung function s NS A EXP Not A Comments Higgins et al. (19661. United Kingdom 60 foundry workers, 100 "nondusty" workers 43 foundry workers, 100 "nondusty" workers 25-34 5574 (Ages in 1957) 36' 21 -17 29 30 -1 Somewhat higher increased annual lung function decline in older men, not strongly associated with occupation, but strongly influenced by smoking 32' 54 -22 37 34 +3 ' Heavy smokers only (FEV 76) Pham et al. 119791, France 196 steel (foundry and roll sheet) workers 166 unexposed workers 49.5 49.6 (Ages at first exam) 7.4% 0.6% -6.6% At baseline, bronchitis prevalence significantly higher in steel vs. unexposed workers (37.8 vs. 17.51, lung function somewhat higher in steel workers; over Byear followup. somewhat more (%FEV increased steel worker bronchitis prevalence predicted) (45.3121.9); more steelworker than unexposed worker all-parameter lung function consistent Matched for age, decline; no silica content or dust concentration height, smoking environmental data status TABLE 4.-Continued Number and Age Annual decline in lung function Study, type of (mean or country population range) S NS A Exp Not A Comments Kauffmann 178 mineral dust 41 No smokingspecific lung 52 42 -10 la-year followup study of 11 factories, including et al. expmd workers (55 function decline given several mineral dust exposures, of which only ww, expoeed to silica) (41) o (57) (42) C-15) silica is separable; no silica monitoring data; France significant FEV, annual adjusted declines in 177 unexpceed 41 CFEV,) mineral dust exposed workers (esp. silica exposed) workers interpreted a~ work related and consistent with Annual declines silicaexposed worker original crw-aectional adjusted for decreased lung function assessment smoking statue and amount `Numbers in parentheses, of 55 silica-expceed workers only Manfreda 179 hard rock 2544 3.4% 2.0% -1.4% 3.1% 1.6% -1.5% (See Table 2 for crowsectional results) et al. miners, 254 Cough and phlegm prevalence greater among (19&o. unexpcwd (Percentage decrease in (Percentage decrease in miners at baseline, no change over time; adjusted Canada (community sample) FJW,/FVC, over 5 years, FEV,/FVC, over 5 years, FEV, and FJW,/FVC declines significant for adjusted for age and adjusted for age, height, smoking and FEV,/FVC decline significant for height) and smoking) mining expoeure; data suggest FEV,/FVC more sensitive indicator; data con.&.ent with mining and smelter exposure and smoking additive effect NCFlW S=Smoker; NS=Nonemoker; Exp=Expaeed; Not=Not exposed. Pathogenesis of Silica-Related Health Effects The characteristic pathology of the various forms of silicosis are well described in recent texts dealing with occupational respiratory diseases (Parkes 1982; Kleinerman and Merchant 1983). The mature lesion of silicosis is the hyalinized nodule that is spherical and typically varies in size from 3 to 12 mm. The nodules are more commonly found in upper lobes, but are found throughout the lung and are frequently subpleural. Microscopically, the nodules have a whorled appearance composed of lamina of acellular hyalin. The borders of the lesions are typically serpiginous and are composed of pigment (especially if associated with a coal exposure), chronic inflammatory cells (mainly lymphocytes and plasmacytes), and connective tissue extending into the surrounding lung parenchyma. With phase microscopy, doubly refractile silica particles 1 to 5 urn in size may be observed within the lesions and within macrophages in the surrounding infiltrate. Acute silicosis, or acute silicoproteinosis, differs from classical nodular silicosis in that the principal finding is alveolar proteinosis associated with a diffuse interstitial reaction. Scanning electron microscopy and x-ray microanalysis have demonstrated small bire- fringent silica and silicate particles (less than 1 urn in diameter) in these processes (Abraham 1978,1984). Progressive massive fibrosis may develop on a background of silicosis through the enlargement and sometimes the coalescence of the nodular lesions of silicosis into conglomerate silicosis. These lesions form most commonly in the apical or middle portion of the upper lobes and are frequently complicated by tuberculosis. Cavita- tion of these lesions may occur with or without tuberculous infection (Kleinerman and Merchant 1983). The mechanisms that produce silicosis, and particularly conglom- erate silicosis, are still not fully understood. The cellular events leading to lung injury appear to arise from the cytotoxicity of the respirable silica particle for a principal lung defender, the alveolar macrophage. Upon phagocytosis of the silica particle, cell death is caused by the release of proteolytic and hydrolytic enzymes into macrophage cytoplasm. The release of these cytoplasmic constitu- ents, including the still biologically active silica particle and fibroblast stimulating factor, may then lead to fibrosis (Allison et al. 1966,1977). As has been noted with other types of pneumoconiosis, silicosis (and particularly conglomerate silicosis) is associated with a high prevalence of circulating autoantibodies (ANA and RF) (Jones et al. 1976; Turner-Warwick et al. 1977). Although silica exposure and particularly silicosis may be associated with rheumatoid arthritis and several other collagen-vascular diseases, the role of these antibodies in the etiology, onset, and progression of silicosis is not 339 clear (Parkes 1982). Angiotensin,-converting enzyme (ACE) elevation has also been reported among silicotics (Gronhagen-Riska 1979; Nordman et al. 1984). Nordman and colleagues (1984), in a case- reference study of the Finnish Occupational Diseases Register from 1965 to 1977, reported an association between ACE activity and progression of silicosis. Smoking, age, and bronchitis .were not related to ACE activity, which was thought to reflect accumulation and increased degradation of macrophages. Histocompatibility anti- gens (HLA) have also been studied as possible genetic risk factors for silicosis, but with variable results. Koskinen and colleagues (1983) found that the prevalence of HLA-Awl9 was higher in their Finnish silicosis patients than in the silica-exposed referent population and that the highest risk of developing advanced silicosis was associated with the phenotypic combination Awl9 and B18. However, Sluis- Cremer and Maier (1984) reported only a decrease in HLA-B40 among 45 South African gold miners. These variable associations are statistically weak and may be related to the number of statistical tests performed on the multiple HLA antigens. The pathogenesis of airways obstruction in silica-exposed workers is less well understood. Although increased rates of bronchitis and decreased lung function have been observed in epidemiological studies comparing silica-exposed and unexposed workers, it appears that these findings are largely separate from the clinical and epidemiological picture of silicosis. In the largest and best controlled study of a reasonably pure silica-exposed sample of 1,973 white gold miners (Irwig and Rocks 1978), chronic bronchitis was found to be equally common among those with radiographic evidence of silicosis and those without. The smoking habits of miners with radiographic silicosis and of those without silicosis were not significantly different statistically. Silicotics reported only more days away from work, a finding the authors suggested may have been as related to their compensation status as to their disease. Comparison of lung function between silicotics and their silica-exposed referants revealed equiva- lent FVC, FEV,, and FEFz~:~~ among silicotics. Recent pathological evidence of a nonfibrous mineral dust small airway lesion has been provided by Churg and Wright (1983). This pathological process, which they labeled mineral dust airways disease (MDAD), is similar to that produced by tobacco smoke. This pathological process involves primarily respiratory bronchioles, with a lesser extension into alveolar ducts. This lesion generally involves more pigmentation and more thickening of the bronchiole walls than is typically found in cigarette smokers. In a recent study by Churg and colleagues (1985) of 13 cases of patients with MDAD, 7 had occupational histories consistent with a primary silica exposure. Only 1 of 121 cases without a clear history of dust exposure was found to have MDAD. Those. with MDAD, matched for age and 340 smoking habit with 13 cases without MDAD, were found to have significantly poorer lung function, including clinically relevant lower mean levels of FEVI, FEF25-75~1, and FVC and increased RV/TLC and AN, per liter as percentages of that predicted. It was also noted that significantly more membranous and respiratory bronchiole fibrosis occurred among subjects with MDAD. The similarity in location, morphology, and physiological impairment between the pathology induced by mineral dust and that observed with cigarette smoking suggests that the cellular events giving rise to them may be similar. Although a good deal is known about the pathogenesis of the process arising from cigarette smoke (US DHHS 1984), systematic experimental studies of mineral dust airways disease have not been reported. Silica Exposure and Cancer Initial concerns about the association between silica exposure and cancer arose during the 1930s among investigators in England, Canada, and South Africa. In the early research on this topic, the focus was on the proportion of lung cancers arising among autopsied cases of silicosis compared with that among nonsilicotics or members of the general public. All of the early research (Dible 1934: Anderson and Dible 1938; Kennaway and Kennaway 1947; Klotz 1939; Irvine 1939) was characterized by the lack of any data on smoking. Early assessments of the association between silicosis and lung cancer were summarized by Hueper (1966). More recently, Hepple- ston (1985) summarized the autopsy findings from South Africa (Becker and Chatgidakis 1960; Chatgidakis 19631, from Switzerland (Ruttner and Heer 19691, and from Germany (Otto and Hinuber 19721, but again no smoking data were presented. The reports from South Africa and Switzerland showed no differences in the ratio of lung cancers between silicotics and controls. However, Otto and Hinuber (1972) showed that porcelain workers with silicosis had more than twice the proportion of lung cancers as the noncases. Early studies suggested that silicotics have an increased lung cancer risk (Dible 1934; Klotz 1939; Mittmann 1959) or that silicotics with respiratory cancer have greater concentrations of silica in lung tissue (Anderson and Dible 1938). However, data from Bridge (19381, Heppleston (19851, Hueper (1966), and Irvine (1939) suggested that lung cancer risk among silicotics is less than or equal to that of men without silicosis, regardless of their occupation. In reviewing the evidence, Hueper (1966) observed that the data support the idea that lung cancer is a coincidental finding among silicotics and that there is no etiological relationship. None of these studies addressed the smoking status of the subjects, a crucial omission in any study of lung cancer. Furthermore, age was 341 not adjusted, nor were there any quantitative estimates of the silica exposure or assessments of the severity of the silicotic lesions. Epidemiologic Studies of Smoking, Silica Exposure, Silicosis, and Cancer Silica-Exposed Cohort Studies Occupational silica dust exposure is common in many industries; therefore this section is organized so that exposure studies in work settings that are similar can be examined together, i.e., metal ore mining, the steel industry, and workplaces where exposures are to silica only. Metal Ore Mining McDonald and colleagues (1978) conducted an enlarged followup study from 1937 to 1973 of the Homestake Veterans Association cohort that included 1,321 men with at least 21 years of employment at the mine. Standardized mortality ratios (SMRs) were calculated using South Dakota mortality rates as opposed to U.S. rates. The South Dakota lung cancer rates were lower than those for the United States as a whole. Using dust exposure data from company midget impinger samples, the authors examined the pneumoconiosis (mostly silicosis) and cancer risks in five categories of dustiness, collapsing them when indicated owing to small numbers. The data showed striking trends for pneumoconiosis and tuberculosis, but no gradi- ents emerged for respiratory cancer. Brown and colleagues (1985) also conducted an assessment of the Homestake gold miners. The cohort included 3,328 white male miners employed at least 1 year between 1940 and 1965 and followed until June 1, 1977. The authors calculated SMRs using person-years and contrasted mine mortality rates with rates for U.S. white men. An index of dust exposure by job location was assembled for the purpose of assessing dose-response gradients. The SMR for malig- nant neoplasms of the trachea, bronchus, and lung was 100, with no trends in latency or dust exposure by length of employment. Katsnelson and Mokronosova (1979) examined the mortality at a U.S.S.R. gold mine and at several brick plants from 1948 to 1974. Dust concentrations were not specifically stated for workers in the gold mine, and an approximation of the SMR (which the authors termed "relative risk") was calculated to compare the cancer risk among gold miners with the cancer risk of residents of a nearby town (excluding those who worked with chromate dusts and adding to the comparison group those who worked less than 3 years in the plants under study). The authors reported a relative risk (RR) of 7.9 (p < 0.001) for lung cancer among the male underground gold miners; without the silicotics, the RR was 3.1 (~~0.02). Surface workers had 342 a nonsignificant RR of 1.6. No lung cancer deaths occurred among women during these years. No smoking data were presented for gold mine workers, although data presented for workers at a silica firebrick plant and an aluminosilicate brick plant indicated that two- thirds to three-fourths of the men smoked, whereas only 0 to 15 percent of the women did. There appeared to be an inverse gradient of the proportion of lung cancers by stage of silicosis or silicotubercu- losis (although no standard classification such as that of Internation- al Labour Office (1980) is given). Armstrong and colleagues (1979) followed 1,974 Kalgoorlie gold miners from Western Australia (whose smoking habits were mea- sured between 1960 and 1962) for silicosis incidence and mortality through 1975. Expected death rates were obtained from the age- specific death rates of Western Australia during 1963-1967, 1968- 1972, and 1972-1976. There were significant (p29 years, RR 10.5). The chemical nature of the dyes to which workers were actually exposed was not discussed. A case+control study of 212 cases of bladder cancer in rural Denmark drew upon general population controls matched to cases by sex, age, and region of residence (Mommsen et al. 1982, 1983). Multivariate logistic regression was used to identify factors (evalu- ated by questionnaire) associated statistically with the malignancy. Significant relative risk ratios were found for tobacco use (l&2.1), work with petroleum, asphalt, oil, or gasoline (2.9-3.8), industrial work (2.21, work with chemical materials (2.0), alcohol use (2.3), and previous venereal disease (2.9). Farmers, who were presumably exposed to pesticides, were at less than average risk of developing bladder cancer. The report did not explore the interactive effects of occupation and tobacco use. 392 A case-control study in the greater New Orleans area, wherein 82 patients with bladder cancer and 169 matched general population controls were interviewed by telephone, was used to identify smoking of filter cigarettes (but not of unfiltered cigarettes or other tobacco products) as a risk factor for bladder cancer (Sullivan 1982). Matching criteria were not specified. A large number of employment categories and chemical exposures appeared to involve risks, most prominently mechanical engineers and people exposed to paint thinners, coal, petroleum, metals, welding materials, office supplies, and industrial equipment. In a study in northern New Jersey (Najem et al. 1982), 75 cases were compared with 150 patient controls, matched by age, sex, race, place of birth (in New Jersey or elsewhere), current residence, and the clinic providing care. Occupations were recorded only when job tenure was more than 1 year. Smoking habits were characterized as never smoked, former smoker, or current smoker. Several criteria were used to test the significance of associations, and significant risks were analyzed to test for the confounding effects of smoking. Significant risk ratios were identified for cigarette smoking (2.0) and work in dye (3.1), petroleum (2.5), and plastics (3.4) industries, but not for employment in rubber, textile, printing, rodenticide, or cable industries, although some ratios did exceed 1. When the significant occupational risk ratios were analyzed within the three strata of smoking status, ratios for current smokers were essentially the same as those calculated without controlling for smoking. Curiously, the occupational risk ratios for nonsmokers in the dye, plastics, and petroleum industries consistently exceeded the ratios for current smokers, but the ratios for ex-smokers were consistently lower (1.3 to 1.5). Some ratios were based on only a single case in a smoking- occupation cell. In a recently reported case-control study at Turin, Italy, 512 male bladder cancer patients diagnosed from 1978 to 1983 were compared with 596 patient controls (225 urologic, 371 surgical) (Vineis et al. 1984). Smoking and occupational information was assembled by interview. Highly significant relative risk ratios were found for cigarette smoking, the magnitude depending on smoking intensity, on age when smoking started, and possibly on brand of cigarettes smoked. Occupational risk analysis was based on 64 patients classified as "exposed": 14 cases and 2 controls employed more than 6 months in dye production (said to include exposure to benzidine and betanaphthylamine), plus 28 cases and 20 controls employed in the rubber industry. From this, the authors calculated risk ratios strongly suggesting interactive effects of occupational exposure and smoking, most striking in workers less than 50 years of age, and dependent on smoking intensity (relative risk was 144.0 for hazar- dously employed workers who smoked). The relative risk for 383 hazardous occupation among nonsmokers of all ages (there were only five chemically exposed: two cases, three controls) was 3.7. The relative risk for smoking among the nonexposed of all ages was 5.2. The risk for the occupationally exposed who smoked was 11.6 relative to nonexposed nonsmokers. The risk ratio relationships based on all age groups are more suggestive of an additive overall effect than of synergy. The small number of occupat,ionally exposed nonsmokers in the study limits the confidence that can be placed in the analysis. Smith and colleagues (1985) recently examined relationships of occupational solvent exposure and smoking to incident cases of bladder cancer in regions of the United States served by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program and included in the National Bladder Cancer Study (NBCS) of 1978. Controls selected from the NBCS study were frequency-matched to the cases by age and sex. Among nonsmokers reporting at least 6 month's exposure to chlorinated and simple hydrocarbon solvents used in dry cleaning and in other industries, the relative risk of bladder cancer was significantly elevated only in women (RR 1.38), and this was not significantly related to duration of exposure. In both men and women chemically exposed, however, the risk of bladder cancer increased progressively and significantly from nonsmokers to former smokers to current smokers. There was no evidence of interaction between the effects of occupation and smoking. The evidence of a smoking effect was consistent and substantial in this study (highest RR 4.681, but indications of a solvent exposure effect were weak and of borderline statistical significance. Inhalation of combustion effluents is thought to pose a risk of cancer at various sites, including the bladder. For a case-control study of 81 male bladder cancer patients in Quebec (1970-19751, age- and sex-matched individuals living in the patients' neighborhoods were recruited to serve as controls (Theriault et al. 1981). Detailed histories were taken covering lifetime employment and residence, medications, personal habits, and water supply. Smoking habit was characterized qualitatively and quantitatively. Information on de- ceased cases was received from next of kin. These authors calculated a mean relative risk of bladder cancer of 5.70 among currently smoking workers in the electrolysis department of an aluminum reduction plant. Relative risk for smoking among other workers was 1.82, and risk associated with electrolysis department employment alone was 1.90. (It was necessary to base the latter estimate on ex- smokers because there were no nonsmokers so employed.) The independent risk ratios are not statistically significant, but the range of values for electrolysis workers who smoked extended from 2.0 to 12.30. To the extent that the ratio estimates can be relied 384 upon, they suggest a strong interaction between smoking and occupational exposure. Silverman and colleagues (19831, in a population-based case- control study of 303 white male bladder cancer cases in Detroit (1977-19781, explored occupational, dietary, and personal habit associations. Controls under 65 years of age were chosen from the Detroit population by random digit dialing, operating with a pool of 2,110 households. Controls of retirement age were selected at random from Health Care Financing Administration lists. A total of 296 controls were recruited for home interviews. Analysis of occupational associations relied on an "ever employed" query, and responses were classified according to the industry identified and by occupation. An apparent strong interaction involved truck driving as an occupation and cigarette smoking. Among people who had never been truck drivers, smoking one or two packs of cigarettes per day increased the risk of bladder cancer by a factor of 1.6; smoking more than two packs increased the risk ratio to 2.1. The ratio for truck drivers smoking less than one pack per day was 1.3; for smokers of one or two packs per day, the ratio was 6.8. The risk ratio for heavy smokers could not be calculated because none of the controls reported smoking more than two packs per day. A relationship with the inhalation of diesel exhaust was suspected, but could not be confirmed from the data. Not unexpectedly, the case-control studies used to test a relation- ship of pesticide exposure to urinary tract cancer are inconclusive. Pesticides are chemically and toxicologically diverse; worker expo sures to them are equally varied. It is unlikely that in epidemiologic studies based on broad occupational categories carcinogenic risk would be detected, if indeed it exists. Several case-control studies of bladder cancer have indicated that as an occupational group, people "working in agriculture" are at no more than average risk of urinary tract cancer, or are actually at less than average risk (Anthony and Thomas 1970b; Cole et al. 1972; Howe et al. 1980). In some studies of exposures to pesticides, specifically, nonsignificantly elevated risk ratios have been shown (Najem et al. 1982; McLaughlin et al. 1983). In Canada, bladder cancer was found to be significantly associated with crop spraying and nursery work as occupations (Howe et al. 1980). These associations were said to be unaffected by controlling for smoking. Other Specific Cancer Sites Cancer of the kidney and upper urinary tract has received less attention than bladder cancer. In a nationwide case-control study of 202 patients with renal adenocarcinoma (Wynder et al. 19741, the past personal and occupational histories of the patients were examined in relation to histories from other hospitalized patients. 385 Relative risk among heavy smokers (more than one pack per day) under 50 years of age was 8.0, but only 2.1 in patients over age 50. Moderate smokers (up to one pack per day) were at intermediate risk. Except for a tentative identification of employment in textiles as a risk factor, no associations with occupational exposures to metals, dyes, or other organic chemicals were found. In the Boston area, 43 cases of cancer of the renal pelvis and ureter were studied in relation to bladder cancer cases and randomly chosen general population controls (Schmauz and Cole 1974). Only among smokers of more than two and one-half packs of cigarettes per day did a significant risk appear (RR 10.0). Of the occupational categories identified, only leather working exhibited a suspect relationship to cancer at these sites. Occurrences of renal cell carcinoma (495) and cancer of the renal pelvis (74) in the Minneapolis-St. Paul area from 1974 to 1979 were studied for heritable and environmental risk factors (McLaughlin et al. 1983, 1984). Controls were chosen randomly from the metropoli- tan area population. Because half of the cases were already deceased, background data had to be obtained through next-of-kin interviews. With respect to cancer of the renal pelvis, the risk of disease increased steadily in both men and women in relation to smoking intensity (maximum RR 10.7 in men, 11.1 in women). The only links to occupation appeared in relation to exposures to hydrocarbons: coal, natural gas, and mineral and cutting oils. There were not enough cases to permit analyses for smoking risk within occupations. Renal cell carcinoma also appeared to be related to cigarette smoking, but relative risk ratios were much lower (2.3 in male, 2.1 in female heavy smokers), and the dose-response relationship was not as consistent as in the case of renal pelvis or bladder cancer. Analysis for "usual industry of employment" failed to identify any significant occupational associations. Musicco and colleagues (1982), in a case-control study of brain neoplasms in Italy, sought to associate the occurrence of gliomas (various types and grades) with occupations of victims prior to diagnosis during 1979 and 1980. Forty-two cases were matched with nonglioma patients at the Neurological Institute C. Besta of Milan. The controls were matched by age, sex, and area of residence. They suffered from a variety of chronic diseases, some probably character- ized by physical and or mental disability from a relatively early age. Smoking was defined as a minimum l-year usage, and total lifetime usage was estimated. More than 20 pack-years was considered heavy smoking. The authors found a significantly elevated risk ratio (5.0) for "agricultural work after 1960" when the data were analyzed without stratification. When stratified by sex, age, and residence, the ratio was 1.9 (not significant). The relative risk was 1.3 for smoking and 1.6 for heavy smoking, neither statistically significant. No occupational risk ratios for nonsmokers were calculated. Particular- ly with respect to occupational risk calculations, the appropriateness of neurologically afflicted patients as controls must be questioned. Nonetheless, the authors were inclined to indict modern pesticides and fertilizers as causal factors for gliomas. Austin and Schnatter (19831, in a followup case-control study of 21 patients dying from a brain tumor in a Texas petrochemical worker cohort, indicated that the tumors were of several different types. Efforts to identify unique past chemical exposures of brain tumor victims were not successful. Using case-control methodology in reviewing 142 cases of pancre- atic adenocarcinoma in several large U.S. clinical centers, Wynder and colleagues (1973) demonstrated that cigarette smokers were at increased risk of developing this disease. Risk ratios increased progressively with the number of cigarettes smoked per day. Controls for this study were patients in the same hospitals who had been interviewed for other epidemiologic studies. Controls did not include patients suffering from tobacco-related cancers (mouth, larynx, lung, esophagus, bladder, kidney) or other tobacco-related diseases (bronchitis, emphysema, coronary heart disease). Fifteen male cancer patients reported having been occupationally exposed to "dyes, chemicals, metal dust, saw dust, grease, oil, or gas fumes," but there was no difference between cases and controls with respect to the frequency with which this exposure was reported. A case-control study in New Jersey (Stemhagen et al. 1983) of 265 victims of primary liver cancer occurring from 1975 to 1980 was conducted by interview of family members. Controls were selected from hospital records and death certificates, and were matched by age, sex, race, and county of residence. No evidence was adduced to indict smoking as a factor in causing this disease. Significantly elevated risk ratios were derived for farm laborers but not for farm owners or farm managers or for people engaged in manufacturing pesticides. Other people apparently at risk were gasoline service station employees, those employed at eating and drinking establish- ments, and those providing laundry and dry cleaning services. It was not possible to identify specific past chemical exposures that might have contributed to the risk. A recent study of 102 cases of primary liver cancer in Sweden utilized controls matched by age, sex, race, year of death, and municipality where the decedent had lived (Hardell et al. 1984). No association with smoking history was found. Occupational exposure to solvents appeared to double the risk of liver cancer. No other occupations or chemical exposures were identified as risk factors, although a strong association with alcoholism was indicated. Investigation of 207 cases of large bowel cancer in a Quebec community explored several risk factors in cases and controls, the 387 latter selected from the communities where the cases resided, and matched by age and sex (Vobecky et al. 1983). Smoking was not identified as a significant risk factor, although a slightly elevated risk ratio (1.2) for smoking (alone) was calculated. Industrial exposure at a local synthetic fiber factory did appear to be a significant association (RR 2.2). When the risk of industrial exposure and smoking were considered in combination, a higher risk was evident (2.81, at a stronger level of significance. A moderate degree of smoking+ccupation interaction is suggested. Chronic Lung Disease The likelihood that exposure to dusts and fumes in rubber product manufacture plays a causative role in the chronic obstructive lung disease encountered in this industry was examined in two studies. Fine and Peters (1976) assessed symptomatology and pulmonary function in 65 white male workers engaged an average of 7 years in rubber processing at three Akron tire plants. Air sampling showed 1 to 3 mg/m3 of respirable dust in the work environments. Smoking habits were classified as never smoker, former smoker, current cigarette smoker, and current and former pipe and cigar smoker. Controls (189) were chosen from plant workers not exposed to polluted air. Processing workers reported a much higher prevalence of cough and phlegm than controls; this was true among nonsmokers as well as smokers in the various categories. Smoking nearly doubled the frequency of this symptom complex in the processing workers. However, dyspnea and wheeze, generally considered indicative of chronic obstructive lung disease, were no more prevalent among processing workers than among controls. Reported frequencies of bronchitis, pneumonia, asthma, and winter colds were not signifi- cantly greater among these workers than among controls. Pulmo- nary function testing yielded important findings. In comparing all workers with all controls, only the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV,/FVC) was significantly lower in the particulate-exposed workers. However, the exposed group and the control group were subdivided according to whether they had been employed in their respective jobs for more or less than 10 years. Although the long-term processing workers were older and had smoked longer than the controls, decrements in flow rates and FEV, /FVC were not significantly correlated with years of cigarette smoking. Using appropriate adjustments for age, the long-term- exposed employees exhibited significant deficits in FEVI, FEV,/FVC, and flow rates at 50 and 25 percent of FVC. Multiple regression analysis confirmed that duration of employment in rubber processing was a significant predictor of reduced FEV, and FVC. Employment for more than 10 years appeared to cause a significant decline in FEV,/FVC and the FVC-standardized flow rate at 50 percent FVC. These results were independent of smoking variables, ethnicity, socioeconomic status, and age. The absence of a correlation between decrement in lung function and cigarette smoking and the small number of workers in this study raise questions about the generalizability of the data in this study. Lednar and colleagues (1977) examined the work history and smoking habit backgrounds of 73 former rubber workers who were retired prematurely between 1964 and 1973 with medically docu- mented, disabling pulmonary disease. They were members of a cohort of 4,302 workers employed in 1964 at an Akron plant. Thirty- nine were retired with emphysema, 10 with lung cancer, 8 with asthma, and 16 with other pulmonary conditions. Work background and likely exposure to dusts and fumes were determined from company records; smoking histories were obtained from question- naires mailed to retirees or relatives. The investigators utilized two control groups, the first consisting of disabled employees retired because of diseases other than pulmonary (disabled controls) and the second of currently employed workers and early retirees free of acknowledged pulmonary disease (nondisabled controls). Relative risk ratios were calculated for smoking and for occupational exposures to dusts and fumes. Relative risks for pulmonary disability retirement in relation to smoking and various occupational titles were also calculated. Risk ratios for smoking alone (based on smokers and nonsmokers at worksites not otherwise contaminated) were consistently greater than 1.0, but they were significant only in the case of maintenance workers. For all workers combined, the smoking risk ratio was 2.95 (p24 2.6 SM EX NS 54.7 12.0 33.3 SM 45.2 35.6 Syn. wool workers Cottonmill workers Men Women 60.5 6.9 SM NS EX 62 31.6 6.3 36.2 21 SM 36 EX/NS Percent smoking ~1 pack/day not available 16.9 39.8 14.1 9.0 5.0 63.1 >53% began smoking at 15-19 years of age E TABLE L-Continued Number and type Study of population Smoking characteristics (percent) Cmnmenta Imbus and Suh 10,133 cotton workers. 11973) North Carolina Men 78 Women 43 Smokers include ever smoked 1 cig/day for 1 Y-r Berry et al. (1974) 14 cotton and 2 manmade fiber milla. Great Britain Men 75.6 Women 56.5 Former smokers not reported Zwkin et al. (1976) Wool workers and controls Workers Men 47 Women 0 Controls Men 55 Women 0 Khogali (1976) 271 ginnery workers, Sudan SM 36.5 Jones et al. (1977) 153 cottonmill workers, southeast United States SMIEX 70 Almost l/2 smoken said smoked <5 cigs/day Bouhuys et al. (1977) Card and weave room workers, South Carolina SM Men X-41 Women 15-25 TABLE l.-Continued Study Number and type of population Smoking characteristics (percent) Comments Palmer et al. (1978) Bouhuys et al. (1979) 203 gin workers Textile workers, aged 245, South Carolina Ginnera Pressmen Others Controls Women Carding SM EX 51.1 25.5 (16.0)' (9.6) 57.1 19.1 (7.3) (4.1) 45.5 15.1 (15.3) (8.0) 52.3 19.2 (11.4) (9.1) SM EX NS 18 14 68 20 10 70 17 14 69 20 10 69 15 11 74 Jones et al. Cotton and wool/synthetic (1979) mill workers &,rii,g Weaving Others' Men Carding . - Preparing Weaving Others' Mill 1 Mill 2 Mill 3 Mill 4 38.0 62.0 SM' NS 52.6 47.2 66.9 33.1 64.8 35.2 26 44 26 37 4.5 16 50 42 8 38 37 16 20 3.5 30 NS 23.4 23.8 39.4 28.5 `( )=mean pack-years (1 pk/day/year) * Includes cloth room workers and miscellaneous job CAgOrieS ' Smokers include ex-smokera TABLE k-Continued Study Number and type of population Smoking characteristics (percent) Comments Barman (1979) - 70 cottonmill workers MUI Women Sparks and Peters (1960) Grimard and Adams (1981) Becketal (19821 Cotton duetexposed workers Men Women Textile workers, Canada Men Women 118 male and 162 female cottm textile workers Men Workers Controls Women Workers Controls SM EX 44 28 58 44 28 55 - 76.6 60.4 27 16 31 43 NOTE SW Smoker; EX Exnmoker. NS. Nonrmoker greater frequency than do American workers, with many studies showing the proportion of smokers to be well over 70 percent. Acute Effects of Smoking and Cotton Dust Exposure on Respiratory Symptoms The symptoms 01 ?ilonddy ches t t;,htness begin gradually, S or 4 hours after the cotton texrile worker returns to work. A dry cough and shortness of breath on exertion frequently accompany the sensation of chest tightness. However. the physiologic reaction associated with Monday chest tightness is not confine2 to the chest. X low grade temperature. a 20 to 3n percen: increase in the peripheral white blood cell I polymorphonuclear ieukocyte 1 count, and a general malaise have been frequently reported These systemic symptoms suggest the presence of a host in!lammarory response; however, the relationship between these systemic symptoms and the symptom of che?t tightness is not well defined. By 1936, an association had heen recognized between Monday chest tightness and detectable loss of ventilatory capacity and increased breathlessness iPrausnltz 19361. Recognition that in sus- ceptible cotton mill workers. Monday chest tightness may be followed by permanent respiratory disabi!ity led to the evolution of a standard byssinosis case definition. Schilling and colleagues (19551 developed specific questions concerning Monday chest tightness for the British Medical Research Council's respiratory symptom survey questionnaire (British Medical Journal 1960). A positive response to the standardized questions regarding Monday chest tightness de- fined the presence of byssinosis. Molyneux and Tombleson (19701 conducted one of the first prospective studies of byssinosis. 4t the initial examination, these investigators interviewed 1.359 workers from 14 cotton spinning miZc and 227 -xorkers from 2 manmade fiber spinning mills in Lancashire. United Kingdom. Followup examinations were conduct- ed at 6-month intervals over 3 J.ears, from 1963 to 1966. Byssinosis and bronchitis prel-alence were :Ieterl..A ~;ned by the use of the Jledical Research Council's questionnaire on respiratory sy!:iptoms [British .Medicai .Journal 196Oi, to which :t.e Roach and Schilling t1960) questions on chest tightness wert- added. Bjs;inosis bvas graded as follows (Molyneux and Tombleson 197Oj.' Grade 0: No evidence of chest tightness or breathing diffi- culty on the first day of the workweek Grade 1 `2: Occasional chest tightness on !`rlondays Grade 1: Chest tightness or difficulty in breathing on Mondays only Grade 2: Chest tightness or difficulty in breathing on Monday and other days Age, length of exposure to cotton dust, and smoking habit were determined by questionnaire. Individuals were considered smokers if they regularly smoked one or more cigarettes per day. Hexlet and total dust air samplers were used to measure the mass concentration of the respirable, medium, and fly components of the total airborne dust. Byssinosis prevalence (adjusted for age, sex, and mill type) showed a progressive increase with increasing duration of cotton dust exposure (Table 2) (Molyneux and Tombleson 1970). A rearrange- ment of the data from this Lancashire mill workers study and calculation of the Mantel-Haenszel (weighted) odds ratios (Mantel 1963) shows an interesting relationship between smoking, byssinosis, bronchitis, and sex. A similar relationship is demonstrated by data from studies of American cotton mill workers (Merchant et al. 1972; Imbus and Suh 1973). Cigarette smoking was associated with an overall 2.21-fold excess risk of bronchitis in the Lancashire cotton mill workers (Table 3). Cotton mill workers of both sexes who smoked had a consistently greater prevalence of bronchitis than did non- smokers. The magnitude of the smoking effect was similar for men 12.2%fold) and women (2.16-fold). The presence of bronchitis con- ferred an approximately twofold excess risk of developing byssinosis (Table 4). This risk was significant for men and for women, for smokers as well as for nonsmokers. Once the presence of bronchitis had been controlled for, however (Table 51, cigarette smoking did not add significant additional risk for developing byssinosis. One may interpret these observations to show that among cotton mill workers both cotton dust exposure and cigarette smoking produced the symptoms of bronchitis. Bronchitis, in turn, seemed to confer additional risk for the development of acute chest tightness (byssinosis). Cigarette smoking, therefore, seems to facilitate the development of byssinosis in smokers exposed to cotton dust, perhaps by the prior induction of bronchitis. Applying an additive logit model (6 dust levels x 3 lengths of exposure x 4 combinations of sex and smoking habit) to these data, Berry and colleagues (1974) found that cigarette smokers had a modest (1.4-fold) increase in the adjusted prevalence of byssinosis when compared with nonsmokers and ex- smokers. Two years after the initial questionnaire survey, these investigators were able to reinterview about half of the original population (669 cotton workers and 127 manmade fiber workers). Incidence and remission rates were tabulated for byssinosis and bronchitis by length of exposure, sex, and smoking status. The incidence of both bronchitis and byssinosis was greater among 410 TABLE 2.-Prevalence (percent) of byssinosis in nine exposure groups Number in group Prevalence adjusted for age. mill type. and sex CL4 305 52 8.8 8.0 %9 155 23 3 20.5 19.2 l&14 168 28 0 22 3 21.0 15-19 187 35.8 29 5 27.5 20-24 117 36.8 30 9 31.1 2529 115 43.5 40 2 42 4 30-34 94 30.9 302 35 1 3639 99 35 4 36.5 414 140 119 33 6 37.7 418 SOURCE Malyneux and Tombleson (19701 TABLE 3.-Age-adjusted association of bronchitis and smoking, by byssinosis status and sex Smoker Bronchitis Bronchitis Chi square and with byssinosis without byssinosis odds ratio for the association of N Present Absent N Present Absent smoking/bronchitis' Yes 127 No 33 557c 554 45% 45% Men 301 46% 54% X*=15.20 105 21% 79% OR = 2.28 cptX among smokers Ten times more lung cancer in smokers then nonsmokers Smoker I-L period shorter; histologic type distribution came in smokers and nonamokere Smoker I-L period much shorter Smoking not large factor in exceea lung cancera Smoking little role in Navajo lung cancers Smoker I-L period shorter Smoker I-L period shorter Smoker I-L periods slightly shorter 447 TABLE l.-Continued Study Archer 09851 Samet, Kuh%t et al. 0984) Group studied U.S. uranium miners U.S. Navajo uranium miners Type of analysis cllsecontro1 Case-control cancer site Lung Lung ResUlts Smoker I-L period significantly shorter Smoking little role in Navajo lung cancers Hinds et al. Hospital (1979) patients cLk?e-mntr01 Larynx Prior dental x rays Prentice et al. ww A-bomb survivors Cohort Esophagus and lung TABLE 2.-Cigarette smoking habits of white U.S. uranium miners at study entry and of U.S. nonminer men Smoking status Uranium miners (percent) Nonminers (percent) Nonsmokers ' 28.8 45.4 11 pack/day 54.2 39.8 > 1 pack:day 16.9 14.8 Includes smokers of pipes or qars only and ex-smokers SOURCE Adapted from Lundm et al 119711 TABLE 3.-Cigarette smoking habits of Navajos in U.S. uranium miner study group, at entry Packs'day Percentage smoking at entry Percentage former smokers Percentage never smoked 000 - 001419 15.1 0 24.59 14.6 0 6499 07 210 2.7 SOURCE Adapted from Archer et al 11976~ - 62.8 2.3 - 17 - 0.000 - 0001 - nearly 80 lung cancer deaths among cigarette-smoking U.S. uranium miners (Archer 1985). Because approximately one-third of the miners did not smoke cigarettes, the discrepancy was so striking that 448 it led some observers to blame cigarette smoking for the entire problem and to conclude that if uranium miners did not smoke, they would rarely develop lung cancer. A second lung cancer among nonsmoking uranium miners was observed in a mortality analysis of the U.S. uranium miner cohort published in 1969 (Lundin et al. 1969). These two cases represented a fourfold excess of lung cancers (only 0.5 case was expect.ed among nonsmokers&the same relative risk noted for cigarette smokers (15 expected versus 60 observed). Since the U.S uranium miners were known to smoke at a somewhat higher rate than other U.S. men (Table 2), in an analysis of how much extra cancer could be due to this extra smoking, Lundin and colleagues (1971) concluded that this extra smoking could account for no more than a 50 percent increase; a fivefold to tenfold increase had been observed. The discrepancy between smoker and nonsmoker lung cancer rates suggested an interaction between the two agents. A later study of white U.S. uranium miners reported that the incidence of lung cancer varied both by cumulative amount of radiation exposure and by the intensity of cigarette smoking (Figure 1) (Archer et al. 1978). The mean exposure of these miners was about 870 WLM. Approximately 780 of the uranium miners in the U.S. study group were Navajo Indians. They had a much lower smoking prevalence than white miners (Table 31, but nevertheless had elevated lung cancer rates (Archer et al. 1976; Gottlieb and Husen 1982; Samet, Kutvirt et al. 1984). Many of those who developed lung cancer had smoked little or not at all (Table 4). Most of the lung cancers were therefore attributed to mining exposure (Samet, Kutvirt et al. 1984). The role of other factors in the lung cancers of U.S. uranium miners was also studied. The induction-latent (I-L) period (time from start of mining to diagnosis of cancer) was shortened by increased age at the start of mining, by cigarette smoking, and by high exposure rates (Archer 1981). The attributable lung cancer risk tended to decline among miners who had reached the age of 65 and had 25 or more years of latency (Roscoe et al. 1983). An updated analysis of these data, using deaths occurring through 1982 and an adjustment of expected numbers of deaths for smoking habits, indicated that the drop in attributable risk appeared to occur mainly among the smokers, not the nonsmokers (Figure 2) (Roscoe et al., in press). Because the I-L period is dependent on factors other than cigarette smoking (Archer 1981) and the smoking-related shortening of the I-L period was minimal in miners exposed to low radiation dose rates (Radford 19841, a more detailed case-control study was done of U.S. uranium miners (Archer 1985). There were 35 lung cancer cases among nonsmoking underground uranium miners (defined as smok- 443 0 180 600 1080 1600 Cumulabve exposure (working level months) 2400 FIGURE l.-Influence of cigarette smoking and radiation exposure on bronchogenic cancer incidence among U.S. uranium miners SOCRCE Adapted lrom Archer et al 119% ing a total of less than four pack-years of cigarettes and not smoking within 10 years of cancer diagnosis) whose lung cancer was diag- nosed between January 1964 and January 1984. A few of them had smoked a pipe or cigars occasionally, but not regularly. Because not all of the lung cancer cases were members of the study group, supplemental smoking information was obtained from hospital records and relatives. Two controls were chosen for each case from among 334 smoking U.S. uranium miners. Controls were matched on 450 TABLE 4.-Smoking habits of 21 Navajo uranium miners with lung cancer Cv+wettes:day Number of men 00 8 1 2 1-3 6 4-8 5 SOURCE Adapted from Samet. Kutwrt er al 11984i `\ \ \ \ i k 1 i i I 1 ) I ra- l- c5 5-99 IO-149 15-24.9 >25<5 599 lc-14 9 15-249 225 interval bn years after start 01 mmg T FIGURE 2.-Influence of age at observation and induction- latent period on attributable lung cancer deaths among U.S. uranium miners NOTE Error bars are 90 percent confidence intervals SOURCE Adaw+d from Roxoe et al `III press) birthdate, on year when their mining started, and on the magnitude and rate of exposure to radon daughters. The mean I-L period was 23.f' and 18.5 years for nonsmokers and smokers, respectively (p of Respirable Particles. 19th Annual Hanford Life Sciences Symposium, DOE Symposium Series No. 53,1980, pp. 551-557. CHAMEAUD, J., PERRAUD, R.. CHRETIEN. J., MASSE, R.. LAFUMA. J. Lung carcinogenesis during in viva cigarette smoking and radon daughter exposure in rats. Recent Results in Cancer Research 82:11-20. 1982. CHAMEAUD, J., PERRAUD. R., MASSE, R., LAFUMA, J. 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Environmental Health Z'erspectiL,es 50:15-21, April 1983. 471 CHAPTER 12 SMOKING INTERVENTION PROGRAMS IN THE WORKPLACE CONTENTS Introduction Criteria for Evaluating Worksite Programs Changes in Participants' Smoking Behavior Worksitewide Program Effects General Effects General Review of Worksite Programs Uncontrolled Studies Controlled Studies Remaining Issues Special Issues Relevant to Worksite Programs Social Support Physician Advice Incentives High Risk Populations Multiple Risk Factor Reduction Programs Organizational Characteristics and Other Factors Implementation of Worksite Smoking Programs Promotion and Recruitment Program Characteristics Recommendations for Future Research Methodological Issues Substantive Areas Summary and Conclusions References 475 Introduction Cigarette smoking by employees results in increased expenses for employers. Smokers use the health care system up to 50 percent more than nonsmokers (Fielding 1984); this means higher health insurance costs for companies. Studies have reported higher rates of work-related accidents, disability reimbursement payments, and absenteeism among employees who smoke than among those who do not (Terry 1971). Although it is difficult to assess exact dollar amounts because of the variety of circumstances and assumptions involved (Warner 1983), estimates of excess annual costs to employ- ers per smoking employee generally run from $200 to $500 (Lute and Schweitzer 1978; Kristein 1982). Costs attributable to smoking among employees in the high risk occupations discussed in this Report are likely to be considerably higher than these overall estimates. These data, as well as consideration for the welfare of their employees, have led a number of businesses to establish workplace antismoking programs. Because of the magnitude of the health effects of smoking and the benefits of cessation, smoking cessation programs are likely to yield a higher return on investment than worksite health promotion programs targeting other risk factors such as obesity and lack of exercise (Fielding 1984). Surveys reveal that 11 to 15 percent of American businesses provide smoking reduction programs and many more are considering such programs (Dartnell Inst. 1977; NICSH 1980). In response to the recommenda- tions of a panel of experts concerning priorities for health promotion activities, the Health Insurance Association of America has estab- lished a smoking reduction program that is available to its members (Fielding 1984). From one-third to one-half of the large organizations have designated no-smoking areas (Dartnell Inst. 1977; NICSH 1980). A great variety of worksite smoking-modification approaches have been devised, including monetary incentives and contests for not smoking, distribution of self-help materials, physician messages and health education lectures on the adverse effects of smoking, and stop-smoking clinics (Chesney and Feuerstein 1979; Danaher 1980; Klesges and Glasgow 1985; Orleans and Shipley 1982). Stop-smoking sessions have been led by coworkers, volunteers from health organizations, commercial cessation consultants, and health profes- sionals. Ongoing multiple risk factor intervention programs, either for the entire workforce or for individuals at especially high risk of developing cardiovascular disease, have been offered. The purpose of this chapter is to critically review the literature on such programs. First, however, it is helpful to consider both the potential advantages and the possible disadvantages of worksite smoking modification programs versus the more traditional, clinic-based programs. 477 The potential advantages of worksite-based smoking modification programs can be considered from the perspective of employees, employers, and public health researchers. For employees, the primary potential advantages appear to be increased convenience (particularly if the program is held during work hours), reduced expenditure if the company pays all or part of the program fee, and the opportunity to participate with friends and coworkers rather than a group of strangers. For the employer, potential benefits include increased worker productivity, better employee morale, and better employee and public relations from health promotion efforts. The potential monetary savings from reduced absenteeism and medical costs are also appealing. For public health researchers, worksite programs offer the advan- tages of a much larger number (and possibly different types) of smokers involved in efforts to quit than would otherwise be the case, greater ease in obtaining long-term followup data, and the opportu- nity to provide sustained or ongoing programs rather than one-time offerings. In worksite programs, treatment is conducted in the environment in which participants spend a large portion of their day, which should facilitate generalization of treatment effects and potentially lead to the establishment of nonsmoking norms. Possibly the greatest potential resource available in worksite programs from all three perspectives is the additional incentive and motivational components that can be brought to bear through both monetary and social support manipulations. It is important to realize, however, that these potential benefits do not occur automatically (Klesges and Glasgow 1985), and that they may be offset by possible disadvantages of worksite smoking modification programs. From an employee perspective, participation may interfere with work activities or be outwardly condoned, but not supported, by a supervisor. Meetings may be held at inconvenient times or in inconvenient locations. If promotional activities are not handled appropriately, workers may feel coerced to participate. From an employer's perspective, there are the direct costs of the program, such as advertising, counselor time, and materials, as well as indirect costs, such as time off work for employees to participate. Sponsoring an antismoking program can also create employee relations problems. Nonsmoking employees may resent the time off work available to smokers and may demand that their own participation in health promotion programs be subsidized. The critical issue here may be company norms, whether time off is consistent with previous company practice regarding other programs for employee benefit. In organizations in which workers are exposed to hazardous substances such as asbestos, unions may view smoking cessation programs as attempts by management to absolve them- 478 selves of responsibility for occupationally related disabilities (Ellis 1980). There are also problems from the perspective of public health researchers in conducting programs in the workplace. Most of these potential disadvantages result from a reduced degree of control over variables that can influence outcome. For example, company pro- gram planners (organizational steering committee) might decide to conduct additional stop-smoking activities (e.g., changes in company smoking policies, added incentives for not smoking, participation in other health promotion activities, a contest with a rival business) that are not part of the study design. Finally, some participants may take part solely as a way of getting out of work rather than from a desire to change their smoking behavior. Criteria for Evaluating Worksite Programs The criteria for evaluating program effects are considered under three general headings: changes in participants' smoking behavior, effects on smoking and health-related variables for all employees in t.he organization, and "secondary" effects of a program on nonhealth variables of concern to employers. Most reports on worksite-based programs assess only one or two of these areas. Changes in Participants' Smoking Behavior The same considerations that apply to the measurement of adult smoking behavior in clinic settings apply also to worksite smoking modification programs. Specification of reported smoking data is particularly important. Following a program, there is often a bimodal distribution of smoking rate, with a number of individuals successfully quitting and many nonquitters smoking at close to their baseline rate. Presentation of reductions in the "average" number of cigarettes smoked can therefore be misleading. It is important to separate data about subjects who are abstinent from data about those who are still smoking, albeit at a reduced rate, when reporting either reductions in smoking behavior or biochemical indices of smoking exposure. It is critical, of course, to have information about the long-term (6 to 12 months minimum) effects of smoking modification programs (Lichtenstein and Brown 1982; McFall 1978). Interest in research in the "dynamics of cessation and relapse" is much more recent (US DHHS 1983, p. 246; Ockene et al. 1982). It is helpful to know, for example, whether a 30 percent long-term abstinence rate resulted from the same 30 percent of participants remaining abstinent throughout the followup period or from IO percent new quitters, IO percent previous relapsers, and.10 percent who remained abstinent throughout the assessment periods. 479 Objective verification of changes in smoking behavior has become the standard for defining smoking behavior. Recent reviews have been conducted of several biochemical measures of smoking status, including carbon monoxide, saliva thiocyanate, and cotinine (Freder- iksen and Martin 1979; Leupker et al. 1981; Benowitz 1983; Bliss and O'Connell 1984). Simply having an informant, usually a spouse or coworker, "confirm" a participant's smoking status may not be sufficient corroboration. Such people are not in a position to continuously observe a participant's smoking behavior throughout the day and may be persuaded to falsify their report on the participant's smoking behavior. Worksitewide Program Effects The impact of a worksite program may include effects on workers other than those enrolled in the program and effects other than smoking cessation. The localized nature of a worksite program and the repetitive interactions of workers in the program with those who did not participate may produce changes in the attitudes and behaviors of the active workforce that promote smoking cessation and improve employee morale and productivity. For these reasons, one criterion for evaluating worksite programs should be the fraction of the workforce whose smoking behavior is altered in addition to the fraction of the participants who quit. All of these effects are important in evaluating the reported success rate of a program because a very high cessation rate for a program may have little overall impact if only small numbers of employees are willing to participate (Kanzler et al. 1976). Whenever possible, program costs should be reported in addition to data on the effects on smoking patterns of nonparticipating smokers. In the same vein, ongoing worksite programs conducted over a number of years should attempt to document the effects of a smoking modification program on variables such as absenteeism, medical care expenses, and health services utilization. General Effects Variables such as employee morale and productivity, commitment to the organization, turnover, and employee-employer relations are important potential secondary effects of a worksite program. Be- cause these issues do not directly concern the topic of smoking and health and have been infrequently assessed, they are not considered in this review. It should be noted, however, that Brownell (1985) makes a convincing case that if the field of worksite health promotion is to prosper, concerted attention needs to be directed toward demonstrating the effects of worksite programs on these organization management issues. He argues that managers may be more interested in such results than in changes in health status. 480 General Review of Worksite Programs A large number of worksite smoking control programs have been conducted. Unfortunately, only a small percentage of these programs have been evaluated. The characteristics and results of experimental investigations of occupational smoking control programs that have presented more than anecdotal data are outlined in Tables 1 through 3. Many of these studies have consisted of pretest-posttest or post- test-only evaluations without control conditions and have not reported objective measures to validate self-reports of smoking status. The sample size, type of worksite setting, and reported results of such uncontrolled studies are listed in Table 1. Because of the absence of comparison conditions, the lack of verification of smoking status, and the general sparsity of information about program procedures and treatment effectiveness in these reports, there are a host of alternative explanations of their results. Therefore, they are only briefly summarized. Uncontrolled Studies Although programs have been conducted in a variety of worksite settings (Table l), the majority have been either conducted in companies of small to moderate size with white-collar employees or offered only to supervisory personnel. The number of participants is generally small. Self-reported abstinence rates for these uncon- trolled studies ranged from 25 to 90 percent (median, 60 percent) at posttreatment and from 6.5 to 91 percent (median, 33 percent) at 6- month or l-year followup. These figures, while encouraging, must be interpreted with caution because it is often unclear whether the reported rates have excluded subjects who dropped out of treatment or followup, and because, in several studies, subjects received sizable monetary rewards based upon reports of abstinence that were not corroborated by objective measures of smoking. Not known is the impact of the programs listed in Table 1 on overall rates of smoking in the worksites in which they were conducted (see Bishop and Fisher 1984). The majority of investiga- tions do not report rates of participation in their programs, but the studies that have reported (other than in very small companies as noted below) have been discouraging. For example, Kanzler and colleagues (1976) found that despite an intensive promotional campaign, only 4 percent of smokers in their workplace began the cessation program. Grove and colleagues (1979) found that of 409 smokers in their worksite, only 101 attended the first meeting, and only 33 (8 percent of the smokers in the workforce) completed treatment. Of these 33 subjects, only 9 were abstinent at 6-month followup. Stachnik and Stoffelmayr (1981), noting these generally low participation rates, stated: "The question of how one can TABLE I.--Uncontrolled studies without objective measures of smoking status Stud> Number of WbJ`Xk type of worksite Cessatmn rate cpercent I Followup Posttreatment INO. months) Andrew (19831 965 hospital employees Bauer 119781 81 Bell Laboratorm employees Not reported 90 26 (201 30 161 Bishop and Fisher 119841 lW6 employees in each of six companies 254x 6X33 1121 Dawley et al 119841 15 VA hospztal employees and 2 patlents 88 50 16, Elhs (19WI Asbestos company employees Not reported 30 (48) Grove et al 119i91 33 Blue Cross employees 33 27 161 Heckler 119801 16 Thomas Llpton, Inc. employees Not reported 50 (1) Kanzler et al (19761 9 psychiatric institute employees and 21 commumty members 67 40 1121 33 engine manufacturing company employees Not repmtea 55 1121 Rosen and Lichtenstein ,197:) 12 ambulance company employees 58 33 112, lat worki Shepard 119801 26 electromcs mfg. company employees Not reported 35 148) fat work1 Sorman i19791 Not reported 31 112, Stachmk and Stoffelmayr ,19831 Employees in three compames bank, manufacturer, and health services Nat reported a&91 (61 increase participation in smoking cessation programs should receive the same attention that the more standard question of which cessation technique is most effective has received in the past" (p. 49). The exceptions to these low participation rates are seen in studies in the companies with fewer than 100 employees that have employed incentive procedures (e.g., Rosen and Lichtenstein 1977; Sorman 1979; Shepard 1980; Stachnik and Stoffelmayr 1983). 482 Controlled Studies Studies that have included control or comparison conditions are presented in Tables 2 and 3'. To emphasize the importance of worksite and participant characteristics, these characteristics as well as data on the public health issues of recruitment strategies employed and on the participation and attrition rates experienced are listed in Table 2. The type of intervention and experimental design employed, short- and long-term cessation rates, and type of biochemical validation of smoking status obtained, if any, are described in Table 3. In this section, a general discussion of the status of the worksite smoking modification literature with emphasis on the characteristics of the most successful programs is followed by a more detailed review and discussion of several important subtopics within the occupational smoking modification field-the role of social support, physician assistance, incentive approaches, employ- ees at particularly high risk for the development of cardiovascular or respiratory disease, multiple risk factor reduction programs, and organizational characteristics that affect program success. The varied programs conducted have ranged in intensity from a brief physician message (e.g., Li et al. 1984) to ongoing programs involving multiple components over a 4- to 5year period (e.g., Rose et al. 1980). Recent programs have offered participants a variety of behavior change options. In particular, 7 of the 14 studies outlined in Tables 2 and 3 allowed subjects to select as goals either smoking reduction or abstinence. The most encouraging finding is that the long-term success rates of the programs reviewed are relatively high. Although initial cessa- tion rates do not appear to differ from those typically produced by community-based smoking clinics, the longer term followup data are more positive if viewed as a percentage of posttreatment cessation outcome. Abstinence rates at 6 to 24 months after a program are approximately 60 to 65 percent of those observed at posttest, in contrast to the 20 to 30 percent figures classically cited for clinic programs (Hunt and Bespalec 1974; McFall 1978). In fact, the lowest maintenance rate in the studies summarized in Tables 1 and 3 was 26 percent of the posttest rate, and some studies report followup results equal to or better than posttest (e.g., Malott et al. 1984; Meyer and Henderson 1974; Schlegel et al. 1983). On the other hand, much higher long-term abstinence rates, 50 percent or better of all subjects, have recently been reported from a number of treatment programs (US DHHS 19821, and results from the 22-center Multiple 483 lb $ TABLE 2.-Worksite, subject, and procedural characteristics of controlled outcome studies Participation rate Characteristics of Attrition rate Study Size and type of worksite (percent) participants @aTent) Recruitment slrategies Abrams et al. (1985) WO-employee medical manufacturing company and 1.6Wemployee insurance carrier Gleegow et al. 6OGemployee telephone we4 company Glasgow et al. (in VA hospital. health care Pm) services company, and savings and loan Klesgee et al. w35) Four banks and one savings and loan, 11%180 workers each Kornitzer. oramaix et al. U980) 30 Belgian factories Li et al. (1984) Naval shipyard Not reported (estimated 6) Not reported 25 female, 11 male (estimated i8) employees Not reported 20 female, 9 male employees 88 with competition; 53 without CP mokmg hab- it and asbestos ~X~OSUP. 866 fibrosing alveolitis in silica-exposed xorkrrs. smoking role. 325 nonexposed vs. exposed asbestos workers. smoking relationship, 259-260. 262 INDEX PULMONARY FIBROSIS-Contd. silica exposure as factor, enzyme activity in pathogenesis, 339 uranium miners, exposure effects, with smoking, 463464 Pulmonary function See LUNG FUNCTION PULMONARY MACROPHAGES enzymatic activity, influence in carcinogenesis, 237-238 silica cytotoxicity in pathogenesis of fibrosis. 339 small airways of smokers, pattern of lung injury, 148-149 RACE FACTORS black blue-collar workers, smoking rates, 11 smoking prevalence, birth cohort, sex, occupation as factors, 42-46, 48-55 RADIATION (See also OCCUPATIONAL EXPO- SURES, bladder cancer risk, with smoking, 381 bronchial cancer risk in uranium miners, with smoking, 450 cancer risk, with smoking, sum- mary and conclusions, 465 human exposure levels from radon daughters, 445-446 Japanese A-bomb survivors, cancer risk in smokers vs. nonsmokers, 455 lung cancer epidemiology, studies on interactive effects with smok- ing, 455-456 lung cancer in Swedish miners, risk factor with smoking, 452- 453 polonium 210 from tobacco smoke as cancer risk, 46@461 pulmonary effects in uranium min- ers, with smoking, 463464 radon daughters, interactive effects with cigarette smoke exposure, 17 residential exposure, lung cancer risk with smoking, 454 REDUCTION OF SMOKING t&e also CESSATION OF SMOK- ING; SMOKING CONTROL 536 REDUCTION OF SMOKING-Contd. PROGRAMS; WORKPLACE IN- TERVENTION PROGRAMS) biochemical verification in control- led worksite modification studies, 486-488 birth cohorts, by race, sex, and oc- cupation. 41-52 controlled studies, data by worksite type, procedural characteristics, 484-485 controlled studies, design and out- come data of smoking modifica- tion programs, 486-488 worksite participants, controlled studies, 483, 489-490 worksite program effects, evalua- tion criteria, 479-480 worksite program participants, long-term effects, 491 RESEARCH RECOMMENDATIONS (See also WORKPLACE EXPO- SURE STUDIES) animal studies of health effects of tobacco smoke and industrial pollutants, 391 cancer risk with occupational expo- sure and smoking, 12 chronic lung disease risk with oc- cupational exposure and smok- ing, 12-13 health effects of occupational expo- sures and smoking, epidemiologic studies, 391 industrial pollutants, identifying constituents as cancer initia- tors/promoters, 391 lung cancer risk in occupationally exposed workers, 464 lung function effects in occupation- ally exposed smokers, 169 lung impairment, apportioning risk between occupational exposure and smoking, 170 methodology and evaluation issues in worksite smoking modifica- tion, 507-509 occupational exposure to specific agents, interactive effects with smoking, 169 -occupational exposures, 347-348 passive smoking risks, 464 INDEX RESEARCH RECOMMENDATIONS Contd. statistical analysis of occupational exposure and smoking interec- tions, 169 workplace smoking intervention programs, 17, 507-509 RESPIRATORY FUNCTION TESTS LSee also LUNG FUNCTION) asbestos workers and smokers, pat- terns of lung function changes. 241. 243-254 chrysotile asbestos workers, percen- tage decline in smokers vs. non- smokers, 253 coal miners, 296297, 311-312 coal workers, dust exposure and smoking effects, 308-312 coal workers, face workers vs. sur- face workers, 309 cotton dust exposure and smoking, effects, 415419 expiratory volume in cotton work- ers, smokers vs. nonsmokers, 416-418 expiratory volume in men, byssino- sis, bronchitis, and smoking ef- fects, 418 expiratory volume in women, byssi- nosis, bronchitis, and smoking effects, 419 flow rates in asbestos workers, by dust index in smokers vs. non- smokers, 245 rubber workers, duration of em- ployment as factor, 388 silica-exposed foundry workers, 336 ventilatory capacity in coal work- ers, 304 RESPIRATORY SYMPTOMS (See al.so COUGH1 chronic cough and phlegm in coal miners, smoking as factor, 14, 313 coal dust exposure relationship, 298-300 cotton dust exposure and smoking, acute effects, 409-410, 412-415 cough and phlegm in rubber curing workers, smoking as factor. 191 rubber processing workers, duration of employment as factor. 388 389 RESPIRATORY SYMPTOMSsontd. silica-exposed workers, chronic bronchitis risk factor with smok- ing, 186 silica-exposed workers, dust expo- sure and smoking as factors, 330, 335 standardized questionnaire to eval- uate occupation and smoking ef- fects, efficacy, 152-153 workplace exposures in non- smokers, occupational bronchitis criteria, 184 RESPIRATORY SYSTEM (See also BRONCHI; BRONCHI- OLES; LARYNX; LUNGS) airflow obstruction as symptom of chronic obstructive bronchitis, 183 occupationally exposed workers, patterns of injury, 151 pulmonary responses to silica expo- sure, smoking as factor, 325 radiation and cigarette smoke, in- teractive effects, 463464 smokers, patterns of injury in large and small airways and parenchyma, 148-151 ventilatory function in coal work- ers, dust exposure and smoking effects, 308-312 RESPIRATORY TRACT DISEASES (See also BRONCHIAL DISEASES; EMPHYSEMA; LUNG DIS- EASES; OCCUPATIONAL DIS- EASES) coal miners, dust exposure and smoking as factors, 14-15 historical association with coal mining, 289 morbidity and mortality, smoking as predominant cause, 142 mortality from nonmalignant dis- eases in silica-exposed workers, 327 mortality in coal workers, 300-304 mortality in cotton workers, 429, 431 mortality in refinery and chemical workers, study data, 362-363 mortality, underestimation with vi- tal statistics, 144 537 INDEX RESPIRATORY TRACT DISEASES Contd. silica-induced, dust concentration and exposure duration in risk, 328-329 silica-related, physical factors of OC- cupational exposure. 325 ventilatory disability in coal work- ers, cessation of smoking for re- duction, 313 RISK THRESHOLD asbestos exposure, confounding by cigarette smoking as source of bias. 222 lung cancer in asbestos workers, smoking as source of bias, 222- 224 RISK REDUCTION lung cancer, cessation of asbestos exposure effect, 225-228 respiratory disease in coal miners, dust control and smoking cessa- tion, 312-313 SEX RATIO (See also OCCUPATIONAL GROUPS: OCCUPATIONS; SMOKING HABIT; WOMEN1 bladder cancer risk, by smoking habit and occupation, 379-380 changes in smoking prevalence for selected occupations, 64-65 cotton workers, smoking habits, 404 current smokers by sex, occupation, amount smoked, 5863 daily cigarette consumption by age and occupation, 27-31 employment patterns and smoking prevalence, 23-26 General Electric Company employ- ees, smoking status by occupa- tional category and age. 78-81 lung cancer in asbestos-exposed workers, observed vs. expected deaths, 214 occupation and smoking behavior, current estimates and trends, 11 occupational categories, smoking habits by age, 83-96 selected occupations, 66-68 SILICA (See also OCCUPATIONAL EXPO- SURES) 538 SILICA-Contd. cancer risk in exposed workers, 341-348 definitions of health effects, 325 disease risk in exposed smokers vs. nonsmokers, 331-334 disease risk in exposed workers, summary and conclusions, 348 epidemiological findings among ex- posed workers, 327-330, 335-336 "free" vs. "combined" forms, impor- tance to occupational toxicity, 323 industries with significant silica or mixed dust exposures, 323 pathogenesis of related health ef- fects, 339-341 population at risk for exposure, NIOSH survev 323-324 prospective study' data on exposed workers, 337-338 pulmonary effects in uranium min- ers, with radiation and smoking, 463-464 research recommendations on health effects, with other expo- sures and smoking, 347-348 sILIcOsIs (See also OCCUPATIONAL DIS- EASES; PNEUMOCONIOSISl coal miners, occupational relation- ship, 289 dust concentration and exposure duration, risk relationship, 329 dust exposure as risk factor, smok- ing role, 325 lung cancer in patients, 341-342 lung cancer proportional morbidity rate in followup of silicotics, 345-346 lung injury mechanisms in exposed workers, 339-341 pottery workers, early studies of risk relationship, 328 workers exposed to "pure" silica, standard mortality ratios, 345 SKIN CANCER radiation and cigarette smoke con- densate in induction in animals, 456458 SMALL AIRWAYS (See also RESPIRATORY SYSTEM1 INDEX SMALL AIRWAYS-Contd. abnormalities in chronic obstructive lung disease, 255 asbestos exposure and smoking, ef- fects, 271 changes in smokers, consumption and duration of habit as factors, 255 dysfunction in asbestos workers, differences in exposure and smoking effects, 258 pattern of injury in asbestos-ex- posed workers, 256 SMALL AIRWAYS DISEASE (See also OCCUPATIONAL DIS- EASES; RESPIRATORY TRACT DISEASES) silica-exposed workers, research re- commendations, 347 SMOKE INHALATION, ANIMAL emphysema induction in dogs, with radon daughters and uranium ore dust, 458 lung cancer induction in rats, with radon daughter exposure, 458 SMOKING (See also WORKPLACE SMOKING] statistical analysis of independent and interactive effects with occu- pational exposures, 162-164 synergistic vs. additive effect with occupational exposures, 360-361 workplace, environment as factor in initiation, 32 SMOKING CONTROL PROGRAMS (See also WORKPLACE INTER- VENTION PROGRAMS1 clinic-based vs. worksite programs, validity of comparisons, 489 design and outcome of controlled worksite smoking modification studies, 486-488 organizational characteristics, other factors in program success, 502- 504 primary objectives of worksite smoking modification programs, 508-509 recruitment strategies of various worksite programs, participa- tion/attrition rates, 484-485 SMOKING CONTROL PROGRAMS-Contd silica-exposed populations to reduce disease risk. 348 social support, physician's advice, nicotine gum, incentives, effica- cy, 491498 worksite. evaluation criteria, 479- 480 worksite. implementation. 504-506 worksite. overview of advantages vs. disadvantages, 477-479 worksite programs to modify smok- ing. three approaches, 503-504 worksite. review of uncontrolled vs. controlled studies, 481483, 489- 490 SMOKING HABIT (See also OCCUPATIONAL GROUPS; OCCUPATIONS; SMOKING PREVALENCE; WORKPLACE SMOKING1 asbestos-exposed workers, multipli- cative interactive effects, 9 asbestos workers, controlling for differences to reduce confound- ing. 219 asbestos workers, synergistic effect on chronic lung disease mortali- ty, 246-241 birth cohorts, race- and sex-related changes in prevalence, 38-53 blue-collar vs. white-collar workers, by sex and age, 23-26 blue-collar vs. white-collar workers, initiation by age and sex, 29-32 coal miners. chronic simple bronch- itis risk factor, with occupational exposure. 185 coal miners, study data on smoking characteristics, 291-293 cotton dust-exposed workers, 404, 409 cotton workers, disease risks. 1617 General Electric Company employ- ees 1985. by occupational catego- ry, age, sex. 7%81 gold miners, effect with silica expo- sure on bronchitis symptoms, 186 male birth cohorts 1900-1978. changes in prevalence. 231 Navajos in U.S. uranium miner study group. 448. 451 INDEX SMOKING HABIT-Contd. pancreatic cancer patients, daily consumption as factor, 387 white U.S. uranium miners vs. nonminer men, 448 SMOKING PREVALENCE (See also OCCUPATIONAL GROUPS; OCCUPATIONS; SMOKING HABIT; WORK- PLACE SMOKING) asbestos-exposed workers, study data, 206-209 blue-collar vs. white-collar workers, 11 coal miners vs. US. male popu- lation, 290 coal workers, 291 cotton workers, study data, 405-408 male birth cohorts 1900-1978, 230 radiation-exposed miners, 446 uranium miners, 448 SMOKING SURVEYS American Cancer Society, by occu- pation, sex, age, 82-96 coal miners, prevalence data, 291- 293 daily cigarette consumption by oc- cupation for men and women, 27-31 General Electric Company employ ees 1985, by sex, age, amount smoked, 7%81 National Health Interview Surveys, employment patterns and smok- ing prevalence, 23-26 National Health Interview Surveys for 197%1980, by sex and occu- pation, 58 National Health Interview Surveys, occupations by category and code, 57 petrochemical, aromatic amine, and pesticide industries, prevalence, 360 silica-exposed workers, study data, 325-326 SOCIOECONOMIC STATUS bladder cancer risk relationship, 381-382 540 STATISTICAL ANALYSIS independent and interactive effects of smoking and occupational ex- posures, 162-164 interactions between occupational exposures and smoking, 104, 109-113 occupational exposure effect on dis- ease risk, confounding by smok- ing, 114-123 occupational exposures and smok- ing, quantifying interactive ef- fects, 158 occupational exposures, confounding of risk by smoking, use of com- parison groups, 122-130 occupational risks, comparability of internal and external control groups, 166 THIOCYANATES serum level measurement to docu- ment smoking status in work- place studies, 161 TOBACCO SMOKE aromatic amines, possible role in carcinogenesis, 371-372 environmental levels as risk factor in nonsmokers, 199-200 TUBERCULOSIS (See also OCCUPATIONAL DIS- EASES) mortality in silica-exposed workers, 327 silica-induced, smoking role, 325 workers exposed to "pure" silica, standard mortality ratios, 345 Tumorigenesis See CARCINOGENE SIS Tumors See CANCER URANIUM (See also OCCUPATIONAL EXPO- SURES; RADIATION; SILICA) dust, carcinogenic effects in dogs, 458 lung cancer in miners, exposure and smoking risks, 446-452 miners, smoking habits, 448 pulmonary effects of exposures, with smoking, 463-464 WOMEN lung cancer risks, 377 INDEX Workplace See OCCUPATIONAL GROUPS; OCCUPATIONS WORKPLACE EXPOSURE STUD- IES (See also RESEARCH RECOMMEN- DATIONS) asbestos, establishing risk thres- hold, smoking as factor, 224-225 asbestos-related mortality, data by type of exposure, 206-209 cancer mortality relationship, smoking status as source of con- founding, 114-122 case-control analyses to control confounding by smoking, 129-130 chest x ray abnormalities in work- ers, smoking effect, 154-155 chronic lung disease in occupation- ally exposed workers, 142-148 confounding by smoking behavior, sources and control, 114130 control of potential confounding by smoking, use of comparison groups, 123 cotton workers, respiratory system effects, with smoking, 403431 duration and concentration of expo- sure, determination methods, 162 external control populations, com- parability with exposed group, 165 healthy worker effect in cross-sec- tional design, smoking role, 164 healthy worker effect on mortality risk evaluation, 128 high-risk populations, need for data on smoking intervention efficacy, 498-500 internal controls, comparable smok- ing status to control confound- ing, 129 lung disease risk, with smoking, summary and conclusions, 169- 170 mortality risk, adjustments when smoking habits not known, 130- 131 occupation and smoking risks, use of external vs. internal controls, 123-130 occupational lung disease and ciga- rette smoking, prevalence in sur- vey populations, 147 WORKPLACE EXPOSURE STUDIES-Contd physiological assessment of work- ers, independent effects of smok- ing, 156 quantification of relative risk in in- dividuals, 167 quantifying effects in populations, concepts of smoking interactions, 15%160 quantifying occupational and smok- ing risks, 160-168 questionnaire to establish smoking status recommended, 161 relative risk of cancer, smoking status as source of confounding, 115-122 silica, prospective study data on ex- posed workers, 337-338 silica, research recommendations on health effects, with other ex- posures and smoking, 347-348 statistical analysis of independent and interactive effects of smok- ing, 162-164 WORKPLACE INTERVENTION PROGRAMS (See also RESEARCH RECOMMEN- DATIONS; SMOKING CON- TROL PROGRAMS) asbestos workers, efficacy for smok- ing reduction/cessation, 499-500 controlled, characteristics, 483, 489- 490 controlled studies, data by worksite type, procedural characteristics. 484-485 design and outcome data from con- trolled smoking modification studies, 486488 evaluation criteria, 479480 general results and research needs, 17-18 high-risk populations, large-scale studies needed, 49&500 implementation, 504-506 methodological deficiencies in com- parison conditions, participation rates, 491 methodological issues in program design, evaluation criteria, 507- 508 monetary incentives and competi- tion, efficacy, 495498 541 WORKPLACE INTERVENTION PROGRAMS-Contd. multiple risk factor intervention programs, efficacy for smoking cessation, 490 organizational characteristics, other factors in program success, 502- 504 overview of smoking control pro- grams, advantages vs. disadvan- tages, 477479 participant characteristics, program intensity, worksite size, outcome effects, 489490 physician's advice, efficacy, 493-495 program characteristics, advan- tages/disadvantages of various approaches, 505306 recommendations for future re- search, 507-509 research needed on variables that affect program success, 504 review, uncontrolled vs. controlled studies, 481483, 489490 social support for nonsmoking, rele- vancy in worksite programs, 491493 summary and conclusions, 509 uncontrolled, without objective measures of smoking status, ces- INDEX WORKPLACE SMOKING (See also SMOKING; SMOKING HABIT: SMOKING PREVA- LENCE) asbestos workers, multiplicative in- teractive effects, 9 biological, statistical, and public health interactions with occupa- tional exposures, 104-113 cotton workers, disease risks, l&17 lung disease risk, independent and interactive effects with occupa- tional exposures, 142 occupational categories, by age and sex, 83-96 occupational environment as factor in initiation, 32 occupational exposure studies, po- tential for confounding, 114-130 occupationally exposed workers, control groups to reduce poten- tial confounding effect, 123 recent changes by occupation, age, and sex, 33-38 workers exposed to respiratory haz- ards, lung disease risk, 146150 WORKSITE See OCCUPATIONAL GROUPS; OCCUPATIONS sation rates. 482 542