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Asbestiform Fibers Nonoccupational Health Risks Committee on Nonoccupational Health Risks of Asbestiform Fibers Board on Toxicology and Environmental Health Hazards Commission on Life Sciences National Research Council NATIONAL ACADEMY PRESS Washington D C. 1984 i National Academy Press 2101 Constitution Avenue, NV Washington, DC 20418 NOTICE: The project that Is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Research Council was established by the National Academy of Sciences In 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. The Council operates in accordance with general policies determined by the Academy under the authority of its congressional charter of 1863, which establishes the Academy as a private, nonprofit, self-governing membership corporation. The Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in the conduct of their services to the government, the public, and the scientific and engineering communities. It is administered jointly by both Academies and the Institute of Medicine. The National Academy of Engineering and the Institute of Medicine were established in 1964 and 1970, respectively, under the charter of the National Academy of Sciences. The study reported here was supported by Contract EPA 68-01-4655 between the National Academy of Sciences and the Environmental Protection Agency. Library of Congress Catalog Card Number 84-60249 International Standard Book Number 0-309-03446-9 Printed in the United States of America Committee on Nonoccupationai Health Risks of Asbestiform Fibers Lester Breslow, Chairman School of Public Health University of California Los Angeles, Calif. Richard Bates Health Effects Institute Cambridge, Mass. Henrik Bendizen Department of Anesthesiology Columbia University College of Physicians and Surgeons New York, N.Y. Strephen L. Brown Independent Consultant Portola Valley, Calif. Patricia A. Buffler University of Texas Health Science Center School of Public Health University of Texas at Houston Houston, Texas Arthur M. Langer Department of Community . Medicine Environmental Sciences Laboratory Mt. Sinai School of Medicine New York, N.Y. Jeremiah Lynch Exxon Chemical Company East Millstone, N.J. James A. Merchant Department of Preventive Medicine and Environmental Health and the Department of Internal Medicine College of Medicine University of Iowa Iowa City, la. Richard Monson Department of Epidemiology Harvard School of Public Health Boston, Mass. Brooke T. Mossman Department of Pathology College of Medicine University of Vermont Burlington, Vt. James E. Trosko Department of Pediatrics and Human Development College of Human Medicine Michigan State University East Lansing, Mich. John Van Ryzln Division.of Blostatlstlcs School of Public Health Columbia University New York, N.Y. . Tlbor Zoltal Department of Geology and Geophysics University of Minnesota Minneapolis, Minn. iii Consultant Warren Muir Departaent of Envlronaental Health Sciences School of Hygiene and Aibllc Health The Johns Hopkins University Baltlaore, Md. National Research Council Staff Barbara Mandula, Study Director Frances M. Peter, Editor Pamela Smith, Research Assistant Valdena Banks, Adainlstratlve Secretary Board on Toxicology and Environmental Health Hazards Gerald N. Wogan, Chairman .Department of Nutrition and Food Science Massachusetts Institute of Technology Cambridge, Mass. Ronald Estabrook Departaent of Biochemistry University of Texas Medical School Dallas, Texas Philip Landrlgan, Co-Vice-Chairman National Institute for Occupational Safety and Health Robert Taft laboratories Cincinnati, Ohio Qomanuel Farber Department of Rathology University of Toronto Toronto, Ontario Donald Horaig, Co-Vice-Chairman School of Public Health Harvard University Boston, Mass. David G. Hoel Biometry and Risk Assessment Program National Institute of Environmental Health Sciences Research Triangle fork, N.C. Edward Bresnlck Eppley Institute for Cancer Research University of Nebraska Medical Center Omaha, Nebraska Michael V. Lieberman Departaent of Pathology Washington University School of Medicine . St. Louis, Missouri Herman N. Elsen Departaent of Biology Massachusetts Institute of Technology Cambridge, Mass. Abraham M. Lllienfeld School of Hygiene and Public health The Johns Hopkins University Baltlaore, Maryland IV BOARD ON TOXICOLOGY AND ENVIRONMENTAL HEALTH HAZARDS (Continued) Richard Merrill School of Law Univeraity of Virginia Charlottesville, Virginia Joseph V, Rodrlcks Environ Corporation Washington, D.C. Vaun A. Nevlll Exxon Corporation Medicine and Environmental Health Department New York, New York Liane B. Russell Biology Division Oak Ridge National Laboratory Oak Ridge, Tennessee John Peters Department of Family and Preventive Medicine University of Southern California School of Medicine Los Angeles, California Ellen Sllbergeld Toxics Program Environmental Defense Fund Washington, D.C. Ex Officio Members Gary P. Carlson Purdue University School of Pharmacy and Pharmacal Science Department of Pharmacology and Toxicology Lafayette, Indiana Maureen Henderson School of Public Health and Community Medicine Department of Epidemiology University of Washington Seattle, Washington Roger 0. McClellan Lovelace Inhalation Toxicology Research Institute Albuquerque, New Mexico Daniel B. Menzel Department of Pharmacology Duke University Medical Center Durham, North Carolina Norton Nelson Institute of Environmental Medicine New York University Medical Center New York, New York National Research Council Staff Robert G. Tardiff, Executive Director, until June 1983 Devra L. Davis, Executive Director, September 1983 to present Jacqueline K. Prince, Staff Assistant v Preface Industrial progress during the twentieth century has contributed to our well-being, but has also resulted In environmental changes that have Increased risks to human health. Not only are greater quantities and varieties of hazardous materials being taken from the earth and used In many ways, but the use of synthetic materials with similar physical and chemical properties has also been growing. Adverse health effects from many of these new exposures have been receiving considerable attention. Radioactive substances, cigarette smoke, petrochemicals, and asbestos, for example, are well known for their potential to harm health. The health risks from exposure to these and other materials are provoking some alarm because of several characteristics that they have In common. Relatively small, sometimes minute, amounts may cause severe damage to health. People are often not aware of their exposure at the time it occurs. Cancer, a particularly feared disease, can result. Cancer and other adverse health effects typically occur many years after exposure began. Evidence linking the particular substance to subsequent disease may appear--and be accepted--only decades after millions of people have been exposed. Asbestlform fibers, which for purposes of this report include both natural materials such as asbestos and synthetic materials such as fibrous glass, typify the problem. Although asbestos and some of its uses had been known for centuries, twentieth century industry brought a vast increase in mining and distribution of that material. Then, some years after hundreds of thousands of workers had been exposed. It became apparent that considerable damage to health, including cancer, was occurring as a result. Ascertaining the harm precisely was complicated because other factors, especially cigarette smoking, often contributed to the same effects. As the hazard became more widely known in recent years, annual use of asbestos In the United States has dropped. However, asbestos had already been widely distributed in schools and other buildings, in the general outdoor air, and in some water supplies. Thus, tens of millions of people are still being exposed--although usually to very small amounts. The usefulness of asbestos was so great that substitutes with some similar physical properties were developed for commercial purposes. Do these synthetic materials carry the same, or some, health risk because of the characteristics they share with the naturally occurring asbestos? . Given the widespread occurrence of these materials, concerned federal agencies commissioned studies to examine the potential health risk from vii nonoccupatlonal exposure Co asbescos. In one such study, the Safe Drinking Water Committee of the National Research Council sought to determine whether health damage was occurring because drinking water was contaminated with asbestos fibers. The committee found that the epidemiological studies of asbestos in drinking water had major limitations in design, but that the committee's risk estimates were compatible with the results of the epidemiological studies (National Research Council, 1983). Generally, the amount of asbestos in the drinking waters studied would be likely to yield an Increased risk too 8mall to detect. The U.S. Consumer Product Safety Commission, in carrying out its responsibility for protecting consumers, sought guidance from a Chronic Hazard Advisory Panel on Asbestos. The latter body concluded that "asbestos at all levels of exposure ...[should be regarded] ... as a potential human carcinogen." Furthermore, the panel wrote, "It is , prudent to behave as if asbestos fibers may be carcinogenic at low exposure levels and at small particle sizes" (U.S. Consumer Product Safety Commission, 1983). There has also been concern about asbescos in schools, as evidenced by reports from the U.S. Environmental Protection Agency (1980) and the U.S. General Accounting Office (1982). In a more general approach to the issue, broadening it beyond asbestos, the Environmental Protection Agency asked the National Academy of Sciences: to evaluate the human health risks associated with nonoccupaclonal exposure to asbestlform fibers, with emphasis on inhalation of outdoor and indoor air, and to determine the extent to which the physicalchemical properties of the fibers may be associated with the development of various human diseases and the extent to which such information may be Incorporated into assessing health risks resulting from exposure to the fibers. To conduct that study, the National Research Council established the Committee on Nonoccupatlonal Health Risks of Asbestlform Fibers in August 1982. This is the report of that committee. . I personally would like to thank the committee members, who worked extremely hard and persistently to bring the project to fruition. I could not imagine a more thoughtful, energetic, and cooperative group for approaching this complex problem. Op behalf of the committee, 1 would also like to thank the many persons from various groups and agencies who viii provided che committee with unpublished draft documents, or who took the time to answer questions and offer suggestions. They are too numerous to mention individually. However, Or. Dennis Kotchmar, EPA project officer, deserves special mention, as do Mr. Golin Church, Dr. Bobert Clifton, Or. Jon Konzen, Dr. James Leineweber, Dr. Marvin Schneiderman, and Mr. Paul White. The committee is also grateful to the capable and devoted NRC project staff, including Dr. Barbara Mandula, Ms. Pamela Smith, Ms. Dena Banks, Ms. Frances Peter, and the many others who assisted them at various times, especially Ms. Shirley Ash, Ms. Leslye Ciese, Ms. Jacqueline Prince, Ms. Mary Ellen Scheckenbach, and Ms. Bernidean Williams. Special thanks are also due Dr. Warren Muir, who was a consultant to the committee. Finally, I wish to thank Dr. Robert Tardiff, who was executive director of BOTEHH when the project began; Dr. Devra Davis, present executive director of BOTEHH, who energetically shepherded the project through its final stages; and Drs. Frederick Robbins and Alvin Lazen of the Commission on Life Sciences for their continued interest and support. Chairman Committee on Monoccupational Health Risks of Asbestiform Fibers Il ix REFERENCES National Research Council. 1983. Drinking Water and Health. Vol. 5. A report of the Safe Drinking Water Committee, Commission on Life Sciences. National Academy Press, Washington, D.C. U.S. Consumer Product Safety Commission. 1983* Chronic Hazard Advisory Panel on Asbestos. Consumer Product Safety Commission, Washington, D.C. U.S. Environmental Protection Agency. 1980. Asbestos-Containing Materials in Schools. Health Effects and Magnitude of Exposure. Support document for proposed rule 6 on friable asbestos-containing materials in school buildings. Environmental Protection Agency, Washington, D.C. U.S. General Accounting Office. 1982. Asbestos in Schools: A Dilemma. General Accounting Office, Washington, D.C. x Contents EXECUTIVE SUMMARY ................................................................................................... 1 Origin of Che Study .............................................................................................. 1 Major Findings and Recoannendations........................................................ 2 Evaluation of Risk................................................................................... 2 Physicochemical Properties and Health Effects ....................... 4 Recommendations .......................................................................................... 4 Summary of the Study......................................................... 5 Background.................................................................. 5 Materials of Concern ................................................................................. 7 Relationship of Fiber Characteristics to Health Effects ......................................................................................8 Measurement and Extent of Exposure .................................................. 9 Health Effects Methodology ................................................................... 10 Health Effects of Asbestos ................................................................... 11 Health Effects of Nonasbestos Asbestiform Fibers ................................................................................ 12 Evidence Associating Fiber Properties with Adverse Health Effects .......................................................... 13 Risk Assessments......................................................................................... 13 1 INTRODUCTION ........................................................................................................... 16 Concurrent National Research Council and Government Activities Related to Asbestos ......................................... 19 The Committee's Approach................................................................................... 20 References............................................................................................. .... 22 2 ASBESTIFORM FIBERS: HISTORICAL BACKGROUND, TERMINOLOGY, AND PHYSICOCHEMICAL PROPERTIES..................................................................25 Asbestos in History.................................................... 25 Mineraloglcal Terminology................................................................................... 26 Sources of Mineral Particles ....................................................................... 31 Physical Properties of Asbestiform Fibers .... ................................ 31 Flberllke Morphology ................................................................................ 32 Enhanced Strength and Flexibility ................................................. 33 Diameter-Dependent Strength . .......................................................... 33 Increased Physical and Chemical Durability ................................ 33 Defect-Free Surface Structure ........................... 34 Growth-Dependent Fiber Quality ........................................................ 35 xi CONTENTS 2 (cont.) Biologically Relevant PhysicochemicalProperties ................................ 36 Respirabillty ................................................................................................ 36 Size and Aspect Ratio (Length:Diameter)................................ 36 Durability....................................................................................................... 37 Flexibility and Tensile Strength ............................................. 38 Chemical Composition............................................................................38 Surface Area............................................................................................. 39 Surface Charge......................................................................................... 39 Standardized Asbestos Samples.............................................. . . 39 Summary.................................... .... .... '.V. ; ; . 40 Recommendations.................................................................................................. 42 References............................................................................................................... 43 3 ASSESSING NONOCCUPATIONAL EXPOSURES TO ASBESTIFORM FIBERS.........................................................................................48 Definitions of Exposure ........... .................................. 48 Asbestiform Fibers and Their Sources....................................................... 52 Exposure Potential for Asbestos .............................................................. 55 Types of Exposure.............................................................. ..................... 55 Quantitative Exposure Estimates. . . . ..... . . . 61 Exposure to Other Natural Mineral Fibers ............................................... 68 Attapulgite....................................................................................................... 69 Erionite....................................................... .... ............................................70 Exposure to Man-Made Fibers .......................................................................... 71 Man-Made Mineral Fibers............................................................ Exposure to Other Man-Made Fibers.................. '............................75 Summary and Recommendations.................................................................................76 References............................................................................................. .... 77 71 4 MEASUREMENT OF EXPOSURE TO ASBESTIFORM FIBERS . .82 Measurement Techniques.......................................................................................... 82 Measuring Asbestos Dust In the Workplace.................................................. 85 The Impinge r Technique.............................................................. The Membrane Filter Technique ...............................................................85 Measuring Asbestos Dust in the Ambient Environment ............................86 Relationships Among Various Exposure Measurement Methods................................................................................ Exposure to Chzysotlle in the Ambient Environment . . .... .90 Complicating Factors in Environmental Assays.......................................... 91 Fhture Measurement of Exposure to Asbestiform Fibers........................ 91 Recommendations.......................................................................................................... 93 References .................................................................................................................... 93 85 xii 87 CONTENTS 5 EFFECTS OF ASBESTIFORM FIBERS ON HUMAN HEALTH ................................ 97 Nature of Evidence.......................................................... ................................... 97 Biodlsposltioa of Fibers ................................................................................ 100 Fiber Deposition....................................................................................... 103 Clearance and Transport ........................................................................ 106 Clinical Aspects of Asbestos-Associated Diseases ........................... 107 Necessary Assumptions Used in Determining Health Effects . .'............................................................................107 Sensitivity and Specificity of Clinical Evidence............................................................ ....................................... 108 General Diagnostic Measures ............................................................... 109 Disease Associated with Nonoccupational Inhalation Exposures to Asbestifora Fibers .......................................................... 114 Asbestos Exposure froa Household Contacts ................................ 116 Neighborhood Exposure to Asbestos .................................................. 116 Natural Sources of Asbestifora Fibers ......................................... 117 Suoaary............................................................................................................. 119 Epidemiological Studies of Effects Resulting from the Ingestion of Asbestos in Drinking Water. . .................................... 119 Occupational Epidemiological Studies--Methodological Considerations .................................................................................................... 123 Cancer Mortality in Occupational Cohorts Exposed to Asbestos......................................................................................................... 125 Mining and Milling ................................................................................ 128 Manufacturing.................................................................. 128 Insulation.....................................................................................................131 Shipyards......................................................................................................... 131 Relative Carcinogenicity of Different Types of Asbestos ................................................................................... 132 Effects of Saoklng .......................................................... ..... 133 Summary..............................................................................................................133 Asbestosis and Asbestos-Associated Pleural Disease in Occupational Cohorts............................... ............................................135 Mortality Studies......................................................................................... 135 Morbidity Studies .................................................................................. 136 Summary............................................. ........................................ .... . . . 140 Health Effects of Occupational Exposure to Man-Made Mineral Fibers ........................... ...... .................. 141 Morbidity......................................................................................................... 141 Mortality .................................................... 143 Summary................................................ 145 Additional Occupational Epidemiological Studies ....... 146 Attapulgite.................................................................................................. 146 Talc..................................................................................................................146 Recommendations.................................................................................................... 148 References ............................................................................................................. 149 xiii CONTENTS 6 LABORATORY STUDIES OF THE EFFECTS OF ASBEST IFORM FIBERS ... 165 Studies in Animals.......................... 165 Lung Cancer................................................................................................... 165 Mesothelioma...................... 167 Fibrosis ............................... 168 Events In the Gastrointestinal Tract After Exposure to Asbestos ........................................................................ 169 In Vitro Studies................................................................................................... 170 Hemolytic Assays ....................................................................................... 170 Cytotoxicity Studies .............................................................................. 171 Alterations In Cells of the Immune System . After Exposure to Asbestiform Fibers......................................... 172 Effects on Fibroblasts In Vitro ...................................................... 173 Initiation-Promotion Model of Carcinogenesis .................................. 173 Interaction of Asbestiform Fibers withDNA...................................175 Tumor Promotion..........................................................................................176 In Vitro Studies with Mesothellal Cells ............................... 177 Interactions Between Fibers and Polycyclic Aromatic Hydrocarbons (PAHs) ........................................................ 177 Conclusions...........................................................................................................177 Asbestiform Fibers: Initiators and/or Promoters of LungTumors?.................................................................... 177 Asbestiform Fibers: Initiators and/or Promoters of MalignantMesothelioma? ..................................... 179 Asbestiform Fibers: Possible Mechanisms of Fibrosis..................................................... 180 Summary......................................................................................................................... 180 Recommendations .................................................................................................. 183 References............................................................................................ 184 7 RISK ASSESSMENT....................................................................................................... 200 The Process of Risk Assessment ....... ... . .... 200 Quantitative Risk Assessment ................................................................... 205 Mathematical Model for Carcinogenic Risk Estimate ............................................ 206 Published Risk Assessments ....................................................................... 208 Lung Cancer Risk From Nonoccupatlonal Environmental Exposures....................................................................208 Mesothelioma Risk From Nonoccupatlonal Environmental Exposures.......................... 209 Quantitative Risk Assessment for Nonoccupatlonal Environmental Exposures ........................................................................... 211 Lifetime Risk Estimates for Lung Cancer and Mesothelioma............................................ 211 Risk Assessments for Special Subpopulations ....................... 221 xiv CONTENTS 7 (cone.) Comparative Risk Assessment ........................................ 222 Methods............................................................................................................. 222 General Methodological Considerations.......................................223 Scoring Considerations...........................................................................226 Discussion of Comparative Risks............................................................228 Summary and Recommendations........................................ 230 References...............................................................................................................232 APPENDIX A: Asbestos Exposure and Human Disease. Hallmark Observations and Studies from 1898-1979 ...................237 APPENDIX B: Natural and Synthetic Fibrous Substances and Some of their Known Biological Effects . . . .244 APPENDIX C: Fiber-Quality Parameters of Selected Asbestos, Whisker, and Glass Fibers...........................253 APPENDIX D: Conceptual Model of Fiber Exposure............................... 261 APPENDIX E: Epidemiological Studies Among Cohorts Exposed to Asbestos....................................................................267 APPENDIX F: Effects of Administering Asbestiform Fibers to Animals....................................................................... 300 APPENDIX G: Development of Some Equations Used for Quantitative Risk Assessment.............................................311 APPENDIX H: Comparative Risk Assessment Score Sheets..................314 APPENDIX I: Background Information on Members of the Committee on Nonoccupational Health Risks of Asbestiform Fibers...........................................................332 xv Executive Summary ORIGIN OF THE STUDY Nonoccupational health risks associated with exposure to airborne asbestlfonr fibers have aroused concern because the adverse effects from occupational exposure to some types of these fibers have been well documented and because asbestos as well as other mineral and synthetic particles with similar properties are widespread In the environment. Moreover, an excess occurrence of asbestos-related disease has been found among people who were not themselves occupationally exposed but who lived either near industrial facilities where asbestos was used or in households with asbestos workers. In this report, the Committee on Nonoccupational Health Risks of Asbestlform Fibers considers the health risks posed by nonoccupational airborne exposures to asbestos and other natural or synthetic asbestlform fibers. The Issue is Important because many people may be exposed to these materials, although at relatively low levels. To reach a better understanding of the relationship between charac teristics of asbestlform fibers and possible adverse health effects from nonoccupational exposures, the U.S. Environmental Protection Agency asked the National Academy of Sciences to undertake a study with two goals: to evaluate the human health risks associated with nonoccupational exposure to asbestlform fibers, with emphasis on inhalation of outdoor and indoor air, and to determine the extent to which the physicalchemical properties of the fibers may be associated with the development of various human diseases and the extent to which such information may be Incorporated Into assessing health risks resulting from exposure to the fibers. The committee found that much more information is available about asbestos than about the other materials of concern. Wherever possible, the committee compared data on the nonasbestos fibers with data on asbestos. This comparison required assessment of information on asbestos as well as on other materials. ^The term "asbestlform*' in this report refers to fibers that share some specific physical properties with asbestos. These are described later in this summary and in Chapter 2. The term is a mineralogical one that has been used for more than a century. 1 2 major findings and recommendations Evaluation of Risk Nonoccupational exposure to asbestifora fibers in air presents a risk to human health. The extent of this risk is highly uncertain, depending on the nature and amount of exposure and other factors. Evidence for the existence of the risk includes the following: Large excesses of lung cancer, mesothelioma, pulmonary fibrosis, and other pleural abnormalities have been found among workers occupa tionally exposed to asbestos. Presumably, nonoccupational exposures would result in qualitatively similar effects. Both a statistically excessive number of cases of mesothelioma and an excess frequency of pleural abnormalities have been observed among household contacts of asbestos workers. Asbestiform fibers are distributed extensively outside the work place, although usually in minute quantities. The major pathological effects associated with human exposure to airborne asbestos have been duplicated experimentally in animals. Increases in cell replication and other abnormalities have been seen in cultures of tracheal lining cells from humans and animals after the cells were exposed to synthetic or natural asbestiform materials. Estimating the extent of health risks from nonoccupational exposure to asbestiform fibers is fraught with uncertainty. Factors contributing to that uncertainty include the following: A great variety of asbestiform fibers has been found in the non occupational environment. These fibers occur in a range of sizes and vary in physicochemical characteristics, such as flexibility and durability. It is difficult to standardize methods for measuring amounts and characteristics of asbestiform fibers. A long time is required for health effects in humans to become detectable after exposure begins (often 20 to 40 years). . There is inadequate knowledge of the mechanisms by which asbestiform fibers lead to cancer and other health effects. There are uncertainties.in determining dose-response relationships from the occupational environment and then extrapolating them to the nonoccupational environment, where both exposure and population characteristics are usually very different and doses are typically much lower. 3 Hie couiitCee made estimates of comparative risk of adverse health effects chat might result from exposures to various asbestiform substances. It concluded that population risks from exposure Co the ocher materials considered vould generally be lover chan Che risks from exposure to chrysotile asbestos because the opportunities for airborne exposure to particles of respirable size vere generally less for the ocher substances than for chrysotile. The nonasbestos materials considered vere attapulgite (the trade name for the mineral palygorskice, vhich exists in asbestiform and nonasbestiform varieties); several man-made mineral fibers, such as fibrous glass, mineral wool, and ceramic fibers; carbon fibers; and fibrous erionite. These vere selected because they seemed likely to have, or are knovn to have, at least some of the properties of asbestiform fibers. The committee made a quantitative estimate of Che risk of excess lung cancer and mesothelioma that might occur in persons breathing low levels of asbestos in the air. A concentration of 0.0004 fibers/cm^ vas deemed reasonable to use in such calculations because a variety of measurements of indoor and outdoor air indicated that 0.0004 fibers/cm-3 is the approximate average level that may be encountered. If a person inhaled air containing asbestos at that level throughout a 73-year lifetime, the committee's best judgment is that the lifetime risk of mesothelioma vould be approximately nine in a million (range 0 to 330 per million, depending on assumptions regarding che relationship of dose to risk). Others have produced different estimates that are discussed in this report. Risks for continuous lifetime exposures to higher or lever levels vould be proportionately higher or lover. Epidemiological data and the estimates derived from them indicate that the corresponding lifetime risk for lung cancer vould be about 64 in a million for male smokers (range 0 to 290), 23 in a million for female smokers (0 to 110), and 6 and 3 in a million, respectively, for male and female nonsmokers. The risk to nonsmokers appears greater for mesothelioma chan for lung cancer. Because of Che great reliance on assumptions and on clearly deficient exposure and effects data, the committee vievs these risk estimates as guides to che qualitative assessment of nonoccupational health risks from asbestos and asbestiform fibers--not as definitive estimates of the amount of disease to be anticipated. These estimates and other considerations lead to the folloving five conclusions about risk: Some deaths from mesothelioma and lung cancer will probably result from current and past levels of exposure to asbestos in ambient air. Excess deaths from ocher diseases, such as asbestosis, and from exposures to ocher asbestiform fibers are also possible but are not likely to be as numerous as those from asbestos-induced mesotheliomas or lung cancer. The numbers of annual or cumulative deaths expected to result from such exposures are very uncertain, but they are virtually certain to be lover, and probably much lover, than those resulting from past, heavier occupational exposures to asbestos. 4 Death* from past occupational exposures to aabestoa can reasonably be estimated to total several thousand per year in the United States during the next few years. Among these, store deaths from lung cancer than from mesothelioma can be expected. a The greatest risks of continuous lifetime exposure to asbestos vould be to smokers, who would be most at risk of lung cancer. However, the risks to nonsmokers might well be greater for mesothelioma than for lung cancer, because of the strong dependence of mesothelioma rates on time from first exposure. The time dependence factor also implies that restricting exposures of children to asbestos vould be even more effective chan a corresponding restriction for adults in reducing the lifetime risk of mesothelioma. Physicochemical Properties and Health Effects Some of the physical properties of asbestiform fibers appear to be important in causing adverse health effects, but the specific properties Chat are necessary and sufficient are not known. One clearly important characteristic is respirability. In addition, longer, thinner fibers appear to be more pathogenic than shorter, thicker fibers, but there is not a minimum size below which no effects vould be expected. However, nonfibrous particles generally do not induce mesotheliomas in animals. Number, rather than mass, and durability of fibers also seem to be significant factors in pathogenicity of asbestiform fibers. -- All major commercial types of asbestos fibers used in the United States have been associated with lung cancer, mesothelioma, and asbestosis in humans. It is not known whether the physicochemical fiber properties responsible for fibrosis are similar to those involved in carcinogenesis. Recommendations The committee's findings and analysis led to the following recommendations: - 1. Systematic monitoring and characterization of asbestiform fibers with standardized methods should be undertaken in nonoccupational environments, including urban, rural, indoor, and outdoor locations where exposure may be of special concern. 2. A program of systematic surveillance should be undertaken to determine the extent to which the occurrence of mesothelioma and lung cancer is associated with exposure to asbestiform fibers. 3. Cessation of cigarette smoking should be encouraged in view of the multiplicative effect of smoking and asbestos exposure in increasing Che risk for lung cancer. 4. Steps should be taken to educate both the medical profession and the general public concerning possible exposures to asbestiform fibers and the resulting health effects. 5 The committee also made several recommendations concerning future research to resolve the many questions about the health risks of nonoccupational exposure to asbestiform fibers. 1. A standardized terminology for asbestiform fibers should be adopted. The terminology should be based on mineralogical analysis and should distinguish these fibers from other types of particles. 2. The various characteristics of asbestiform fibers or ocher particles used in experiments should be described as completely as possible. 3. Standardized methods for measuring and characterizing asbestiform fibers should be improved. 4. Ln vivo and irj vitro laboratory studies with asbestiform fibers and nonfibrous substances should be conducted to investigate the physico chemical properties chat are responsible for the biological effects. 5. Clinical studies of lung cancer, mesothelioma, and fibrosis should be continued with emphasis on the possible role of asbestiform fibers. 6. Epidemiological studies are needed to clarify further the rela tionships between exposure to fibers and adverse health effects. These studies should include case-control studies for mesothelioma and lung cancer and prospective cohort studies among persons occupationally exposed to materials such as asbestos, actapulgite, and man-made mineral fibers. 7. To improve risk assessments, studies should be conducted Co elucidate the relationships between amount of exposure and time factors and the development of adverse health effects. SUMMARY OF THE STUDY Background Asbestos has been detected in both outdoor and indoor air, although almost always at concentrations far below the standard established by the Occupational Safety and Health Administration (OSHA) for Che workplace. Since 1976 the workplace standard has been 2 fibers/cm^ for fibers longer than 5 pm seen in a phase contrast light microscope under specified conditions. The general population is also exposed to other fibrous materials with some of the same physical properties as asbestos but whose effects on health are not well known. These materials include man-made mineral fibers such as fibrous glass and mineral wool, which are sometimes used as substitutes for asbestos, as well as certain natural asbestiform varieties of minerals not marketed as asbestos. Sources of exposure to asbestiform fibers may be roughly divided into three broad categories:  6 naturally occurring asbestiform fibers used commercially, such as asbestos; commercially used synthetic fibers with some properties similar to those of asbestos; and naturally occurring types of asbestiform fibers that are not used commercially. There is a substantial amount of data on exposures in the workplace, but very little information on nonoccupational exposures. In the occupational setting, four diseases have been clearly associated with exposures to asbestos. These are (1) lung cancer; (2) mesothelioma, a rare but almost invariably fatal cancer of the tissues that line the chest cavity (pleural mesothelioma) or the abdominal cavity (peritoneal mesothelioma); (3) asbestosis, a nonmalignant, progressive fibrosis of the lung that may result in severe disability and death; and (4) nonmalignant pleural disease, including diffuse pleural chickening and effusions and the formation of fibrous and calcified plaques. The occurrence of these four diseases in various occupational settings and the presence of asbestiform fibers in the general environment led to current concern about potential health effects from nonoccupational exposures. During the course of its study, the committee was confronted with several difficulties: Fibers in the general outdoor environment seem to differ in size and other physicochemical properties from chose in the workplace; however, it is not easy to characterize these materials. Different types and samples of fibrous materials vary greatly in their physical properties, even when they are composed of the same mineral. Therefore, it is difficult to develop a consistent methodology for determining and expressing the characteristics and concentrations of fibers found in different environments or used in laboratory studies. Because most health effects data are based on workplace exposures, it is necessary to extrapolate results from relatively high occupational concentrations to the much lower concentrations of fibers typically found outside the workplace. Although the health consequences are presumably similar among workers and nonworkers, incidence rates would be expected to be lower and the nonmalignant changes less severe among persons nonoccupationally exposed to lower levels of asbestos. Thus, the effects would be more difficult to detect. Other factors associated with the diseases must be considered. For example, cigarette smoking multiplies the effect of asbestos in causing lung cancer. The mechanisms by which the fibers produce disease are not well understood, nor is it clear how the fibers reach various parts of Che body. 7 The length of time from initial exposure to the expression of certain health consequences is often several decades. Thus, current disease is the result of past exposures, whereas present exposures will produce disease only many years in the future. Exposure in childhood may increase the possibility of ultimate damage to health, because disease can occur long after external exposure has ceased and more years of life remain for children. Thus, great uncertainty is likely to attend any conclusions drawn about the relevant fiber characteristics and the health risks that may accompany exposure. The committee agreed that Che major potential for future fiberassociated health problems is probably presented by inhalation exposures to airborne fibers rather than by the ingestion of these materials, for example, in water. Most of the committee's attention was therefore devoted to airborne fibers of respirable size, that is, to fibers less than approximately 3 pm in diameter. The committee made quantitative risk assessments for lung cancer and mesothelioma from inhaled asbestos, but it did not attempt quantitative risk assessments for other cancers, from inhalation of other asbestiform fibers, or from ingestion of asbestiform fibers in water or food. Materials of Concern For purposes of this report, the term "asbestiform fibers" is used broadly to include both naturally occurring and certain synthetic inorganic and carbon fibers chat share some specific physical properties with asbestos. Asbestos, the prime example of an asbestiform material, consists of the commercially marketed asbestiform varieties of several silicate minerals. They are primarily chrysotile, crocidolite, and the asbestiform variety of some amphibole minerals marketed as "amosite." Chrysotile accounts for approximately 95Z of the asbestos currently sold in the United States. Because of its great strength, flexibility, and heat resistance, asbestos came into extensive use during the 20th century for textiles, thermal and electrical insulation, and high strength reinforce ment in such products as vinyl-asbestos flooring and asbestos-cement sheet and pipe. In 1982, the United States used approximately 6Z of the world production of asbestos. Five basic physical properties distinguish asbestiform fibers from ocher materials. The presence of these properties generally depends on the physical and chemical conditions under which the fibers grow. Compared with a nonasbestiform variety of the same mineral, the properties are: * 8 microscopic, fiberlike dimensions and morphology, i.e., Che fibers are much longer Chan vide; enhanced screngch and flexibility; inverse relacionship between diameter and strength, i.e., Che smaller Che diameter, the greater Che strength per unit cross-sectional area; a enhanced physical and chemical durability; and a high quality, relatively defect-free surface structure. "High quality" fibers have all these properties to a great extent; "low quality" fibers possess them to a lesser extent. The presence of these properties does not necessarily indicate that a material is either carcinogenic or fibrogenic. Because these properties are interdependent and variable, naturally occurring asbesciform fibers, even those composed of the same mineral, have a range of physical characteristics. In contrast to fibers in the workplace, it is not currently possible to determine the sources of most fibers in the ambient environment or the extent to which these fibers have the above properties. Mineralogical terms pertaining to asbestiform fibers have sometimes been used inaccurately in scientific reports, including the literature on biological effects. As a result, it may be impossible to discern the composition of materials studied and extremely difficult to draw conclusions about their physical properties and biological effects. Relationship of Fiber Characteristics to Health Effects Various physical properties of asbestiform fibers appear to play a role in causing adverse health effects; however, the specific properties that are necessary and sufficient to produce such effects have not been postively identified. Furthermore, it is not known whether the properties associated with a given effect, for example, lung cancer, are the same or different from those associated with other effects, such as fibrosis or mesothelioma. Some characteristics that appear to be important are discussed below, in approximately descending order of the strength of the positive evidence. . Respirability. For significant health effects to result from inhalation of asbestiform fibers, the fibers must reach the lower portions of the respiratory tract where they cause the most damage. Although the limiting upper diameter appears to be about 3 pm, fibers that, are much longer than vide can penetrate deeply in the respiratory tract. Length, Diameter, and Aspect Ratio (i.e.. Ratio of Length to Diameter). Experiments inducing mesothelioma in rodents by injections of test material have indicated that long, thin fibers yield more tumors than do 9 short, thick fibers. Saaples with as overwhelming majority of fibers shorter than Sum yielded mesotheliomas In rats when Injected lntraperitoneally, but the pathogenic role of short fibers, especially those shorter than 3 ua, is unclear. Fibers longer than approximately 10 um csczot be completely engulfed and Inactivated by macrophages, and they have tended to produce more disease In animal tests than have the shorter fibers. Other Properties. The number of fibers, which Is also correlated with surface area, generally appears to be a more relevant measure than mass In determining pathogenicity. Durability also appears to be a factor. The more durable fibers appear to be more pathogenic in some studies than fibers that are less durable. The relevance of fiber surface charge to effects on human health remains to be demonstrated. Some experimental studies have Indicated that surface charge appears to be Involved in cytotoxicity. Although chemical composition 16 related to physical properties of asbestiform fibers, a direct role for chemical composition per se In biological activity has not been demonstrated. Measurement and Extent of Exposure Measurement. Information about asbestiform fibers In the ambient environment, although scanty, Indicates that they differ from those in the workplace. Different techniques for measuring the concentrations In the two environments have been used. The phase contrast light microscope has been adequate for counting fibers In the workplace. However, that technique has been less useful for the ambient environment, where fiber identity and character are usually unknown; almost all fibers are too small to be seen by light microscopy; and concentrations, expressed as mass, are usually hundreds or thousands of times lover than those in the workplace. Data on workplace fiber concentrations are generally given as numbers of fibers longer than 3 um, whereas data on ambient concentrations obtained with transmission electron microscope technlq< ?s have usually been expresseed as mass per unit volume. Substantial uncertainty may be Introduced in calculations that assume that ambient and workplace exposures differ only in fiber concentration. Furthermore, it is not usually possible to convert mass measurements to fiber concentrations accurately because the various conversion factors that are used assume particular fiber dimensions, and these vary greatly with different environments and sampling techniques. IXirlag the early 1970s, mass measurements of asbestos made in various U.S. cities ranged from 1 to 100 ng/m-3. If ve assume that 30 ug/m-3 is equivalent to 1 flber/cm^ (counting fibers longer than 5 ua through a light microscope), the mass measurements in those cities would lead to an expected concentration of 0.00003 to 0.003 asbestos fibers per cubic centimeter. Extent of Exposure. In assessing the likelihood that individuals would be exposed to various asbestiform fibers, the committee considered  10 patterns of use; production or consumption levels; fiber dimensions, i.e., whether the fibers are of respirable size; and potential for population exposure. In many situations, the fibers are tightly bound in a matrix during product manufacture and, therefore, might be expected to produce little subsequent exposure. In the United States, the annual use of asbestos peaked in 1973 at almost 800,000 metric tons, but decreased to approximately 250,000 metric tons, or about 62 of world production, in 1982. However, much of the more chan 30 million metric tons of asbestos used in the United States since 1900 is still present in its original application and provides a potential for exposure. Attapulgite (palygorskite) is the only natural asbestlform material used in the United States in amounts greater than those of asbestos. Of the more than 700,000 metric tons used annually, most appears to be classifiable as asbestlform. Most attapulgite fibers are less chan 5 um long and have diameters of approximately 0.03 urn. Some uses of this material could result in the release of fibers, but the committee found no reported measurements of attapulgite in ambient air. Synthetic fibers with some physical properties similar to those of asbestos Include man-made mineral fibers, of which more than 1 million metric tons are produced annually in the United States. Typical diameters of most of these fibers exceed the respirable 6lze range, although diameters of fine grades of fibrous glass and some rock wool and slag wool are mostly below 3 um. Some fibrous erionite found in deposits in the western United States falls into the respirable size range. Mining and natural weathering of this material could lead to significant local air concentrations, but the committee did not find any measurements of such concentrations. Moreover, the population exposed is probably small. Current U.S. consumption figures and use patterns indicate that future exposure of the general population to attapulgite and fibrous glass is likely to be somewhat greater than exposure to chrysotile, whereas exposure to mineral wool, ceramic fibers, other asbestos fibers, and carbon fibers would be less. - However, material already in place would also contribute to total exposure. Health Effects Methodology To develop an understanding of the health risks associated with exposure to environmental agents such as asbestlform fibers, investigators usually evaluate data from clinical, epidemiological, and laboratory studies. Clinical observations often provide the first suggestion that exposure to a particular substance may cause an adverse health effect. Epidemiological Btudles are then undertaken to attempt to confirm the hypothesized association and to quantify it. Laboratory studies of the 11 response in animals (in vivo) and in cells growing outside the body (in vitro) can provide further information. If a substance administered to animals produces pathological effects similar to those found in humans, the case for its being a causative agent in humans is strengthened. For asbestos, the major diseases observed in humans have been produced in animals by exposure to asbestos. In vitro and in vivo studies do not necessarily adequately reflect the amounts or routes of exposures experienced by humans, nor do they Cake into account individual susceptibilities or other substances to which people might be exposed. Thus, such studies should be extrapolated to humans only with great caution. Except for smoking, however, no environ mental or genetic factors have been unequivocally shown to influence the chance that a person will develop an asbestos-induced disease. Health Effects of Asbestos Appendix A of this report contains a chronological list of the major findings associating adverse health effects with exposure to asbestos. The first disease to be associated with asbestos exposure was asbestosis, which was first noted in the early 1900s. From 1938 to 1949, numerous autopsy reports indicated that a high proportion of persons dying of asbestosis also had lung cancer. In the 1950s, when the sharp increase in lung cancer attributable to smoking was occurring in the United States and ocher industrial nations, epidemiologists found that occupational exposure to asbestos also increased the risk of lung cancer, especially among cigarette smokers. In the early 1960s, che association with mesothelioma was established among asbestos miners in South Africa. Lung Cancer. Exposure to asbestos appears to increase a worker's underlying risk of getting lung cancer as much as fivefold. Since a smoker's risk of getting lung cancer is approximately 10 times greater chan that of a nonsmoker, an asbestos worker who smokes has up to a 50-fold greater chance of dying from lung cancer than does a nonsmoker who does not work with asbestos. An increase in exposure, expressed as con centration of asbestos and duration of exposure, appears to increase the lung cancer risk. Epidemiological data suggest that this relationship is linear; the data do not indicate the presence of an exposure threshold below which there is no increased risk. Mesothelioma. Approximately 1,600 cases of mesothelioma occurred in the United States during 1980, according to projections from cases reported in the 10Z of the U.S. population monitored by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Although exposure to asbestos has been strongly associated with most mesothelioma cases studied, some cases may occur without apparent asbestos exposure. The evidence does not exclude the possibility that ambient exposure to asbestiform fibers was associated with mesotheliomas for which exposure could not be documented. The percentage of workers 12 with mesothelioma has ranged from 0 Co 2Z among chrysotile miners and chrysotile textile workers, but has been as high as 10Z among workers who manufactured crocidolite-containing gas masks. The disease seems to be independent of smoking but related to dose and to time from first exposure. Asbestosis. All types of asbestos appear to be implicated in the development of asbestosis. Data indicate chat che incidence rate increases and the disease becomes more severe with increasing dust exposure, which is expressed as concentration of dust and duration of exposure. It is not clear whether an exposure threshold exists. Persons in Che early stages of this condition may be free of symptoms, but beyond a certain stage che disease seems able to progress even in the absence of further exposure. Pleural Thickening. Another nonmalignant pathological effect of asbestos exposure is che formation of fibrous'and sometimes calcified plaques and diffuse thickening of the pleural lining of the chest cavity. Effusion of fluid into the pleural cavity may also occur. Such pleural chickening is suggestive of asbestos exposure but is rarely a cause of significant, direct respiratory impairment. Gastrointestinal Cancer. Excess gastrointestinal (GI) cancers have been found among some cohorts of asbestos workers, but Che excesses were usually substantially less chan for lung cancer. Dose-response data are not available. Recent animal feeding studies have failed to demonstrate asbestos induction of GI cancers. Moreover, because of inherent limitations in the epidemiological studies, including the'limited sizes of che exposed populations and che lack of individual exposure data, it has not been possible to determine from these studies che extent to which there may be an association between GI cancers in humans and the presence of asbestiform fibers in drinking water. Health Effects of Nonasbestos Asbestiform Fibers Some natural asbestiform substances other than asbestos seem to have biological effects similar to chose of asbestos. For,example,\erionite, a fibrous zeolite, readily induces mesothelioma in animal tests, and populations living in central Turkey, where it is present in volcanic tuff, are reported to have an excess incidence of lung cancer, mesothelioma, and pulmonary fibrosis. As another example, epidemiological studies are being conducted on workers exposed to attapulgite, but as yet there are essentially no data on humans indicating whether it is toxic when inhaled. Exposure to man-made mineral fibers is relatively recent, and the occupational exposure levels apparently have not been as high as those for asbestos. Some epidemiological data do suggest, however, that diseases of the respiratory tract, such as pulmonary fibrosis and lung cancer, may result from long-term occupational exposure to these fibers. 13 Evidence Associating Fiber Properties with Adverse Health Effects Asbestos sod other asbestiform fibers appear to react with cells in a variety of ways. They nay alter normal cell function, they nay cause cell death, or they nay directly or indirectly alter the genetic information and the vay cells replicate. Studies of cells lining the respiratory passages suggest that asbestos may act as a promoter (in the initiacor/promoter model of carcinogenesis). The in vitro evidence that asbestos can damage DNA directly or be mutagenic to genes or chromosomes is weak and inconclusive. Laboratory studies have not identified one type of asbestos as being more potent than others. In animal inhalation experiments, however, asbestos generally appears to be more pathogenic than most other a8bestiform fibers that have been tested. At present, none of the available jin vitro models can be used to quantify the relative fibrogenic or carcinogenic potential of asbestiform fibers either in animals or in humans. Interpretation of results is hindered by the failure of most reported studies to define the test materials precisely, by the paucity of experiments showing dose-response information, and by the differences in response among species and cell types. Results of studies of various groups of workers indicate that it is extremely difficult to assess the role of fiber type (e.g., chrysotile or crocidolite) in determining the risk for developing either lung cancer or mesothelioma. Analysis of the epidemiological studies is complicated because of variations in type of industry, the diverse fiber characteristics within an industry, and the usual inadequacy of exposure data. Some of the apparent discrepancies may be explained by differences in physical properties of the fibers, their concentrations, and their characteristics in the different environments. These possibilities need further testing. Risk Assessments In general, three steps are necessary before one can assess health risk from environmental exposures: determination that a material is toxic and identification of adverse effects; determination of dose-response relationships; and determination of the extent of exposure. At least some types of asbestiform fibers are toxic and have identifiable adverse health effects. However, few occupational studies have demonstrated doseresponse relationships, and there is great variability among those few studies. . Estimates of exposure outside the workplace are particularly difficult to obtain, and it is the risk from such exposure that is the . focus of this report. Other factors that introduce uncertainty into risk assessments for nonoccupational exposures include assumptions about the magnitude of effects at low doses; differences in the characteristics of fibers in the 14 occupational and nonoccupational environments, especially regarding size and composition; and differences in the populations exposed, age at onset of exposure, and duration of exposure. In this report, risk assessments are limited primarily to mesothelioma and lung cancer as end points and to inhalation as the route of exposure. For asbestos, sufficient information was available for the committee to make quantitative estimates--albeit with great uncertainty--of the risk for lung cancer or mesothelioma after inhalation exposure. These risk assessments were conducted for a "generalized" asbestos exposure, rather than for exposure Co a specific type of asbestos. However, the committee assumed that the risk estimates would also apply if chrysotile were the primary agent of exposure. For the other types of fibers considered, the committee made comparative, i.e., qualitative, risk assessments that were subject to yet greater uncertainty. ' For the quantitative risk assessment, the committee concluded chat che epidemiological data supported che use of a linear, no-threshold model. Dose-response data from workplace studies were used in developing che equations. To estimate nonoccupational exposures, measurements of the mass of asbestos in the ambient environment were converted to the number of fibers longer than 5 ym that would have been found in the workplace at a similar mass concentration. These measured concentrations indicated to the committee that 0.0004 fibers/cm^ was a reasonable level to use in the risk assessment. However, there could be specific circumstances, such as schoolrooms with flaking asbestos, where persons are exposed to higher levels for limited periods. If a person were to inhale air containing asbestos at an average of 0.0004 fibers/cm^ throughout a 73-year lifetime, the committee's best estimate is that the lifetime risk of mesothelioma would be approximately nine in a million (range 0 to 330 per million, depending on assumptions regarding the relationship of dose to risk). The corresponding lifetime risk for lung cancer would be about 64 in a million for male smokers (range 0 to 290), 23 in a million for female smokers (range 0 to 110), and 6 and 3 in a million for male and female nonamokers, respectively. The risk for mesothelioma is greater than that for lung cancer among nonsmokers because of che strong dependence of mesothelioma risk on time since first exposure. Occupational studies indicate that mesothelioma usually first appears about 20 years after onset of workplace exposures and chat che incidence increases rapidly thereafter. The calculations suggest that a given exposure to asbestos in childhood markedly increases the lifetime risk of mesothelioma compared with an equivalent dose later. The risk estimates remain uncertain, especially because they are based on che assumption that Che data on occupational exposures are transferable to the nonoccupational situation. Smaller fiber size in the ambient environment would probably tend to lead to lower risk. The comparative or qualitative risk assessments for che other asbestiform fibers were based on chrysotile and lung cancer aa the baseline case. Population risk for particular fibers was compared with 15 Che population risk for lung cancer from ehrysotile. In making comparative risk assessments, the committee considered such factors as respirability, biodisposition, and intrinsic toxicity as they are related to population exposures and to individual risk. The materials considered were crocidolite, other asbestos fibers as a group, attapulgite, fibrous glass, mineral wool, ceramic fibers, and carbon fibers. (Appendix H of this report presents the qualitative assessments for each substance.) The risks for developing lung cancer or mesothelioma as a result of exposure to the other materials considered by the committee were usually much lower than those for ehrysocile, principally because of a lower potential for airborne exposure or because the fibers are less respirable--not because their intrinsic toxicity is necessarily less. For example, both ceramic and carbon fibers can be found in respirable size ranges and may have some biological properties similar co chose of asbestos, but production and opportunities for exposure are low, although increasing. The materials with potentially greatest impact are fibrous glass and attapulgite because of their current large production volume and extensive u6e. 1 Introduction Asbestos-associated diseases generally have been relaced to occupational exposures, such as those experienced by some miners, insulators, and factory workers (Doll, 1955; Gloyne, 1935, 1951; Merewether, 1930; Selikoff, 1979; Selikof f e_t al., 1964; Wagner et al., 1960). Recently, however, there has been concern that exposures to asbestos and related fibers may present a health hazard to the general public. Asbestos has been widely used in the United States for building materials and in other applications. Consequently, there is exposure to asbestos from many possible sources--in some schools and other public and private buildings, in ambient air,l and in drinking water (National Research Council, 1983; Sebastien et al_., 1982; U.S. Environmental Protection Agency, 1980). Because asbestos and other asbestiform fibers^ appear to be ubiquitous, virtually everybody is exposed to some extent. During autopsy, asbestos fibers have been detected in the lungs of most urban residents studied (Churg and Warnock, 1977; Langer et al., 1971; Pooley et al., 1970; Wagner e al_., 1982). However, reported concentrations of asbestos in urban air are usually considerably below the current U.S. occupational standard of 2 fibers/cm^. Exposure of the public is particularly worrisome because the populations involved are large and include unhealthy persons. Moreover, exposure may begin in childhood, leaving a longer time for development of adverse effects. Furthermore, asbestos may enhance the carcinogenic effects of other materials. There is little information about the health effects of most nonoccupational exposures to these fibers. Despite many epidemiological studies of workers and experimental studies on animals, questions remain about which properties of asbestos are responsible for the adverse health effects.and which conditions of ^Ambient air is outside air to which the public is exposed (U.S. Environmental Protection Agency, 1982b). ^These include asbestos and other fibers with some of the same physical properties as asbestos. 16 17 exposure are most likely to lead to such effects. Certain ocher natural mineral fibers, as well as man-made mineral fibers sometimes used as substitutes for asbestos and for other purposes, might have similar deleterious effects (Artvinli and Baris, 1983; Stanton, 1974; World Health Organization, 1983). The t*rm "asbestos" refers to the fibrous form of several specific silicate minerals that have been used commercially. Because of its high tensile strength, flexibility, and resistance to heat and chemical attack, asbestos is used in many products, including asbestos-cement pipes, insulation, friction materials, and flooring and roofing tiles (Suta and Levine, 1979). The consumption of asbestos in Che United States has greatly increased during this century (Seiikoff and Lee, 1978). Annual U.S. consumption peaked at about 800,000 metric tons in 1973 and 1974, but in 1982 it dropped to 250,000 metric tons, or about 62 of world production (U.S. Bureau of Mines, 1978, 1983). Figure 1-1 shows U.S. asbestos consumption by year since 1890 and cumulative consumption since 1905. The millions of tons of asbestos already in place provide an ongoing potential hazard to workers and Che public. The most serious health effects associated with exposure to asbestos are lung cancer, mesothelioma (an almost invariably fatal form of cancer), and asbestosis (a noncancerous but debilitating and sometimes fatal disease). In addition, other nonmalignant lung changes have been documented. Appendix A describes Che chronology of the major observa tions documenting the relationship between asbestos exposure and disease. Persons exposed Co asbestos nonoccupationally can be at increased risk of contracting these asbestos-associated diseases. In one of the first studies linking asbestos exposure and mesothelioma, the disease was found among residents of a raining area in South Africa. These subjects had presumably inhaled the material in the surrounding air (Wagner et al., 1960). In another study, persons living in households with asbestos factory workers in New Jersey were reported to be at increased risk of asbestos-associated disease (Anderson et al., 1979). The diseases usually become evident clinically 20 to 40 years after initial exposure, and may occur even in the absence of continued exposure. Thus, many current cases of diseases associated with asbestos exposure are primarily the result of occupational exposures that Che individuals experienced many years ago. It has been estimated that up to several hundred thousand excess deaths could result over the next few decades from such exposures already experienced (Hogan and Hoel, 1981; Nicholson et al., 1982; Walker t al^., 1983). Results of current exposures would be manifested as disease in the future. Because of the long latent period, it is difficult to reconstruct exposure histories. Moreover, variations in particle size and in other 18 FIGURE 1-1A. Annual U.S. consumption of asbestos from 1890 to 1982. FIGURE 1-1B. Cumulative U.S. consumption of asbestos from 1905 to 1982. Based on data from U.S. Bureau of Mines, 1973, 1978, 1983. \ 19 properties of asbestlform fibers aay lead to different degrees of health risk from apparently similar exposure. The effects of exposure to the fibers may also be modified by other factors, such as smoking. CONCURRENT NATIONAL RESEARCH COUNCIL AND GOVERNMENT ACTIVITIES RELATED TO ASBESTOS While this committee carried out its task, numerous other efforts were under way to coordinate government activities and to summarize and Interpret findings concerning the health effects of asbestos. The U.S. Environmental Protection Agency (1982a, 1983) Issued reporting require ments related to asbestos In schools and reaffirmed its interest in limiting the amount of asbestos used in certain applications. In 1983 the EPA, the Occupational Safety and Health Association (OSHA), and the Consumer Product Safety Commission (CPSC) formed an interagency task force on asbestos to coordinate information-gathering and regulatory efforts concerning asbestos among the three agencies. For example, OSHA has for several years considered revising the permissible exposure limit for asbestos in the workplace. In 1976 the standard became 2 flbers/cffl^. An asbestos fiber for counting purposes means a particulate that has a physical dimension longer than 5 um and a lengthto-dlameter ratio of 3:1 or greater (U.S. National Institute for Occupational Safety and Health, 1977, 1980). In early November 1983, OSHA issued an emergency temporary standard lowering the permissible exposure limit to 0.3 fibers/cm^ (U.S. Occupational Safety and Health Administration, 1983), but a stay on the temporary standard was granted later in the month. Asbestos as a health hazard was considered by the Chronic Hazard Advisory Panel (CHAP) on Asbestos, which was formed in January 1983 by the CPSC (Consumer Product Safety Act, 1981; U.S. Consumer Product Safety Commission, 1982, 1983). The panel was composed of persons nominated by the National Academy of Sciences. Its major purpose was to provide advice to CPSC on the risks of cancer associated with exposure to asbestos. The National Research Council (NRC) has also engaged in several activities related to asbestos. One was an analysis of data related to asbestos in drinking water, which was part of a study conducted by the NRC Safe Drinking Water Committee (National Research Council, 1983). The Committee on Nonoccupatlonal Health Risks of Asbestlform Fibers was able to draw upon the findings of the CHAP and NRC reports and on other draft documents. Another NRC activity is an ongoing study to identify and solve problems related to asbestos exposure in federal buildings. This report is being prepared by the Federal Construction Council Consulting Committee on Asbestos under the NRC Advisory Board on the Built Environment (National Research Council, in press). 20 THE COMMITTEE'S APPROACH To study the health effects of nonoccupatlonal exposure to asbestiform fibers, this committee took as Its overview a "chain of events" depicted in Figure 1-2. This figure shows that fibers nay occur naturally or be synthesized and that exposure of hunans nay result from either coaaerclal or envlronaental "flows." These human exposures may then lead to biological reactions and adverse health effects. While recognizing the difficulties Involved In interpreting data related to health effects of asbestlforn fibers, the committee considered the following questions: 1. What are the major sources of nonoccupatlonal exposure to asbestiform fibers, and how great are.such exposures ? .. 2. Which properties of the fibers seen to be most closely associated with adverse health outcomes? These properties may include length, diameter, chemistry, strength, durability, mass, and surface characteristics. 3. Is It possible to distinguish different levels of carcinogenicand fibrogenlc risks among the different types of asbestos fibers? The question is difficult to address by either epidemiological or laboratory studies, because virtually all samples of fibers contain a range of fiber sizes and other fiber characteristics may differ among the various studies. Thus, it is difficult to relate observed effects to specific types of particles. 4. To what extent can the data on occupational exposures be used to develop risk estimates for the general public? In order to respond to Its charge from EPA, the committee considered various routes of exposure, but placed emphasis on the inhalation route. To elucidate the relevant properties of the fibers responsible for the adverse health effects, it evaluated physical, epidemiological, and toxicological data related to asbestiform fibers.' It'also estimated the health risk for certain populations under various assumptions of exposure. Although many of the data reviewed in this study concern asbestos, the committee has drawn conclusions that encompass other fibrous materials as well. The committee has not carried out an exhaustive review of the literature, but has concentrated instead on those data that are most relevant to the charge. It found many excellent reviews and collections of articles related to asbestos and other fibrous materials that have appeared in recent years. Among the documents that were most useful during the course of this study were those prepared by Selikoff and Lee (1978), Wagner (1980), Craighead and Mosaman (1982), Walton (1982), and papers from a conference on biological effects of man-made mineral - I2)fc ! < uEo 21 > s5 u >s Vaa -M 44 B u* * a -a u aa a *< iwo u -* ao at u * *-* 0c V o OB o a a *4 <44 44 O (M 0 4 a e U4 a #4 *4 u y tw01 U4 u1* * a 5 *** a 44 u 0 4J 0 u *- <4* u a <a44 a e a a a a ai* u -* w x: 4-4 4 a 4) X44 a a u a X 0 4O4 a Hc -- aCD U a Ofl ^ > Ns U a v 4J a a a a a e a o a 9C e a 0 <9 V W 41 CV J4C-1 --> W3 g0e01 eoe4*w) OOK. JC 09 a. ik* vKO O 09 .Oe a 4> V C e3 C V XX -k 4U) -OO O .oe x u V V o*oi -aa CM ( uoe 3O b. 22 fibers, which was held in Copenhagen in April 1982. The proceedings of that conference have been summarized by the World Health Organization (1983). The succession of chapters in this report reflects a logical sequence for pursuing this study. First, the committee defined the kinds of materials it was considering and described some of their properties. It then assessed exposure to these materials. Its next step was to consider the various ways of determining the amounts of fibers both in the workplace and in the ambient environment and to evaluate epidemiological and laboratory data. Finally, it Integrated data from exposure, epidemiological and laboratory studies in order to make quantitative and comparative risk assessments. REFERENCES Anderson, H. A., R. Lilis, S. M. Daum, and I. J. Sellkoff. 1979. Asbestosis among household contacts of asbestos factory workers. Ann. N.Y. Acad. Sci. 330:387-399. Artvinli, M., and Y. I. Baris. 1982. Environmental fiber-induced pleuro-pulmonary diseases in an Anatolian village: An epidemiologic study. Arch. Environ. Health 37:177-181. Churg, A., and M. L. Wamock. 1977. Correlation of quantitative asbestos body counts and occupation in urban patients. Arch. Pathol. Lab. Med. 101:629-634. Consumer Product Safety Act. 1981. Section 1206 of the Omnibus Budget Reconciliation Act of 1981 (P.L. 97-35; 15 U.S.C. 2077, as amended). Craighead, J. E., and B. T. Mossman. 1982. The pathogenesis of asbestos-associated diseases. N. Engl. J. Med. 306:1446-1455. Doll, R. 1955. Mortality from lung cancer in asbestos workers. Br. J. Ind. Med. 12:81-86. Gloyne, S. R. 1935. Two cases of squamous carcinoma of the lung occurring in asbestosis. Tubercle 14:445-451. Gloyne, S. R. 1951. Pneumoconiosis. A historical survey of necropsy material in 1205 cases. Lancet 1:810-814. Hogan, M. D., and D. G. Hoel. 1981. Estimated cancer risk associated with occupational asbestos exposure. Risk Analysis 1: 67-79. Langer, A. M., V. Baden, E. C. Hammond, and I. J. Sellkoff. 1971. Inorganic fibers including chryaotile in lungs at autopsy: Preliminary report. Pp. 683-694 in W. H. Walton, ed. Inhaled Particles III. The Gresham Press, Surrey. Levine, R. J., ed. 1978. Asbestos: An Information Resource. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health. Herewether, E. R. A. 1930. The occurrence of pulmonary fibrosis and other pulmonary affections in asbestos workers. J. Ind. Hyg. 12:198-222, 239-257. 23 National Research Council. 1983. Drinking Water and Health. Vol. 5. A report of the Safe Drinking Water Committee, Commission on Life Sciences. National Academy Press, Washington, D.C. National Research Council. In press. Identifying and solving asbestos problems In existing federal buildings. Draft report of the Federal Construction Council Consulting Comalttee on Asbestos. National Academy Press, Washington, D.C. Nicholson, W. J., G. Ferkel, and I. J. Selikoff. 1982. Occupational exposure to asbestos: Population at risk and projected aw reality-- 1980-2030. Aa. J. Ind. Med. 3:259-311. Pooley, F. D., P. D. Oldham, (J. Chang-Hyun, and J. C. Wagner. 1970. The detection of asbestos In tissues. Pp. 108-116 in H. A. Shapiro, ed. Pneuaoconiosis. Proceedings of the International Conference In Johannesburg. Oxford University Press, Cape Town. Sebasclen, P., J. Bignon, and M. Martin. 1982. Indoor airborne asbestos pollution: Froa the celling and the floor. Science 216: 1410-1413. ... . . Selikoff, I. J. 1979. Mortality experience of insulation workers in the United States and Canada, 1943-1976. Ann. N.Y. Acad. Sd. 330: 91-116. Selikoff, I. J., and D. K. Lee. 1978. Asbestos and Disease. Academic Press, New York. 549 pp. Selikoff, I. J., J. Churg, and . C. Hammond. 1964. Asbestos exposure and neoplasia. J. Aa. Med. Assoc. 188:22-26. Stanton, M. F. 1974. Fiber carcinogenesis: Is asbestos the only hazard? J. Natl. Cancer Inst. 52:633-634. Suta, B. E., and R. J. Levine. 1979. Non-occupational asbestos emissions and exposures. Pp. 171-205 In L. Michaels and S. S. Chlssick, eds. Asbestos. Properties, Applications, and Hazards. Vol. 1. John Wiley & Sons, New York. U.S. Bureau of Mines. 1973. Minerals Yearbook 1972. Bureau of Mines, Department of the Interior, Washington, D.C. U.S. Bureau of Mines. 1978. Asbestos. Minerals Yearbook 1977. Bureau of Mines, Department of Interior, Washington, D.C. U.S. Bureau of Mines. 1983. Asbestos. Preprint from the 1982 Minerals Yearbook. Bureau of Mines, Department of the Interior, Washington, D.C. U.S. Consumer Product Safety Commission. 1982. Chronic hazard advisory panel on asbestos; Invitation to submit suggestions for scientists to serve as members. Fed. Regist. 47:17323-17324. U.S. Consumer Product Safety Commission. 1983. Report by-the Chronic Hazard Advisory Panel on Asbestos. Consumer Product Safety Commission, Washington, D.C. U.S. Environmental Protection Agency. 1980. Asbestos-Containing Materials in Schools. Health Effects and Magnitude of Exposure. Support document for proposed rule 6 on friable asbestos-containing materials in school buildings. Office of Pesticides and Toxic Substances, Environmental Protection Agency, Washington, D.C. 24 U.S. Environmental Protection Agency. 1982a. Asbestos; friable asbestos-containing materials In schools; Identification and notification. Fed. Reglst. 47:23360-23389. U.S. Environmental Protection Agency. 1982b. National primary and secondary ambient air quality standards. Definitions. Code of Federal Regulations, Title 21, Part 50.1. U.S. Environmental Protection Agency. 1983. Rules restricting the commercial and industrial use of asbestos fibers. Fed. Reglst. 43:47880. U.S. National Institute for Occupational Safety and Health. 1977. Asbestos Fibers in Air. NIOSH Manual of Analytical Methods. Second Edition. Vol. 1. National Institute for Occupational Safety and Health, Cincinnati. U.S. National Institute for Occupational Safety and Health. 1980. Workplace Exposure to Asbestos. NIOSH-OSHA Asbestos Work Group. NIOSH Pub. No. 81-103. National Institute for Occupational Safety and Health, Cincinnati. U.S. Occupational Safety and Health Administration, 1983. Occupational exposure to asbestos: Emergency temporary standard. Fed. Reglst. 48:51086-51140. Wagner, J. C., ed. 1980. Biological Effects of Mineral Fibres. Vols. 1 and 2. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. 1001 pp. Wagner, J. C., C. A. Sleggs, and P. Marchand. 1960. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br. J. Ind. Med. 17:260-271. Wagner, J. C., G. Berry, and F. D. Pooley. 1982. Mesothelioma and asbestos type in asbestos textile workers: A study of lung contents. Br. Med. J. 285:603-606. Walker, A. M., J. E. Loughlin, E. R. Friedlander, K. J. Rothman, and N. A. Dreyer. 1983. Projections of asbestos-related disease 1980-2009. J. Occup. Med. 25:409-425. Walton, W. H. 1982. Ihe nature, hazards and assessment of occupational exposure to airborne asbestos dust: A review. Ann. Occup. Hyg. 25:117-247. World Health Organization. 1983. Biological Effects of Man-Made Mineral Fibers. Report on a WHO/IARC Meeting, Copenhagen, April 20-22, 1982. EURO Reports and Studies No. 81. World Health Organization, Copenhagen. 2 Asbestiform Fibers: Historical Background, Terminology, and Physicochemical Properties Unlike many environmental substances that are discrete entitles definable by a fixed chemical structure, asbestiform fibers comprise a group of materials that are less easily defined. They have a broad range of chemical compositions and crystal structures, sizes, shapes, and properties, and have been described with diverse terminology. These factors have led to some difficulties in studying and classifying the effects of these materials over the years. This chapter provides a brief historical overview of asbestos use, defines Borne of the mlneraloglcal terms related to asbestos and other asbestiform fibers, describes the physical properties that characterize these fibers, and then discusses the biological relevance of the various physicochemical properties. As used In this report, the term asbestiform fibers includes fibers that possess great strength and flexibility, durability, a surface structure relatively free of defects, and several other properties described later. Commercial quality asbestos is an example of an asbestiform fiber. ASBESTOS IN HISTORY In some ways asbestos resembles organic material, such as hair or cotton, more than It resembles minerals. Some ancient philosophers apparently had difficulty deciding whether asbestos should be considered a plant or a stone. Pllnius (77 A.D.) compromised and referred to asbestos as "llnum vivum" (durable linen). He postulated that it was originally a plant that adopted partial mlneraloglcal properties to survive at high temperatures. . Asbestos has been used at least from the beginning of recorded history. The Egyptians used asbestos as embalming cloth; the Romans used It for cremation wrappings and for everlasting wicks In the lamps of the Vestal Virgins. Charlemagne is supposed to have had an asbestos table cloth that he cleaned after feasts by tossing it into the flames of a fireplace. Marco Polo reported that asbestos clothing was used In China. In 1647, de Boot gave a recipe for a "miraculous asbestos ointment" to cure various Infectious skin diseases (Figure 2-1). 25 4 26 Miracn- x Ainianro linimcnrmn ad rineam puerornm, UfumA. dead ulccri cibiaru miraculofum fit fcqucnri mo- Accipiuntur Amianri unc.quatuor, plumbi - unci* ii,rutix unci* dux,accalcinanrur, dcindc pulvcnfaram vitro maceranrur cum accro.ac quo* tidic per menfem mareria agicatur/emc^poft menfcm cbuilicndacftunius horx quadranre, ac quit /cere finitur, donee indarefcar: dcindc illius accti dariquanwaj, cum pan quantitate olci rofacci. mifccrur, donee bona fiarunio linimenri forma: eo imingirur caput pneri tot uni tit cito fanctur: ad fcabictn, Bculccratibiarum vefpcri partes ungnntur, Adult*. donee fmentur. Si lapis hie cum aqua vits, & fac- r4* charo folvarur.ac cxigtta porrio raanequoridiemulicri albo mcnftruo laboranti dctur,mox fanacur. mtjlru*. FIGURE 2-1. de Boot's recipe from 1647 for an asbestos ointment. Roughly translated, it states: Multiple application, miraculous asbestos ointment for juvenile "tinea" (head-fungus?) and shinbone (skin?) ulcer. Take 4 oz asbestos, 12 oz lead (oxide?), 2 oz zinc oxide, and calcinace. Thereupon pulverize into glass while adding vinegar, and agitate it daily for a month. After a month, boil it for a quarter hour and let it cure until it becomes clear. Thereafter, add some vinegar, mix it with rose-petal oil until it becomes a homogeneous ointment.... From Zoltai, 1978. Most of these and other early applications of asbestos were rela tively isolated examples. Asbestos was not available in large enough amounts for widespread use until the extensive Canadian deposits were discovered late in the 19th century. Subsequently, asbestos came into wide use for insulation, reinforcement of tiles and cements, and as an absorbent, thickener, and filler. MINERALOGICAL TERMINOLOGY Before discussing the properties associated with asbestiform fibers, a few definitions are provided. A MINERAL is usually defined as a 27 naturally occurring inorganic and crystalline substance having a definite chemical composition and crystal structure. A mineral name usually ends in "-ite." VARIETIES of minerals are distinguished when the physical appearance or properties of a mineral are modified by minor changes in chemical composition, crystal structure, and conditions of crystallization. The term ASBESTOS is a commercial-industrial term rather than a mineralogical term. It refers Co veil-developed and hairlike longfibered varieties of certain minerals that satisfy particular industrial needs. Table 2-1 lists Che names and chemical formulas of the minerals included in the Cerm asbestos. Other minerals used in industry, such as Commercial Name Chrysotile Crocidolite TABLE 2-1. Mineralogy of Commercial Asbestos Mineral Name Mineral Group Chemical Formula Chrysotile Riebeckite Serpentine Amphibole (Mg,Fe)6(OH)8Si40in Na2(Fe3+)2(Fe2+)3(0H)2Si8O22 Anthophyllite Anthophyllite Amphibole Amosite Cummingtonite- Amphibole grunerite3 Actinolitetremolite^ Amphibole (Mg,Fe)7(0H)2SigO22 Mg7(0H)2SigO22 Fe7(0H)2Sig022 Ca2Fe5(0H)2Si8O22 Ca2M85(0H)2Sig022 hyphenated mineral names, such as cummingtonite-grunerite, represent MINERAL SERIES. The minerals in the series are structurally identical but can contain variable proportions of two or more different cations in Che same structural site. Thus, these mineral series may be regarded as solid solution series. The variable cations in Che cummingtonitegrunerite series are magnesium and iron; most minerals in this series have both elements, totalling seven atoms per chemical formula. The end members are identified by the hyphenated names, e.g., cummingtonite, which contains seven atoms of magnesium per chemical formula, and grunerite, which contains.seven atoms of iron. ^Although asbestiform tremolite and actinolite occur in nature, large commercially mined deposits are rare. However, actinolite asbestos is found as a contaminant of amosite from South Africa, and tremolite asbestos is found as a contaminant of some talc and chrysotile deposits.  28 palygorskiteaay also crystallize as well-developed, thin halrllke fibers (l.e., in the asbestlform habit), but they are not called asbestos. The different kinds of asbestos belong to two groups of minerals: serpentine and aaphlbole. The most common asbestos, chrysotlle, is a aeaber of the serpentine group. Because of their layered silicate structure, serpentine minerals usually crystallize as thin platy crystals; however, some of them, e.g., chi^sotlle, occasionally crystallize as thin halrllke fibers. In chrysotlle, the structural layers are curled up to form scrolls or tubes (see Figure 2-2). All the other kinds of asbestos belong to the aaphlbole group. Their crystal structure is characterized by parallel chains of silica tetrahedra. Because of the strength of these chains, aaphlbole crystals are either prismatic or aclcular (needlelike).The asbestlforn varieties of aaphlboles have essentially the same crystal structure as the nonasbestlfora varieties. Figure 2-3 shows schematically the structure of aaphlbole crystals looking down the silica chains. Historically, mineralogists have had difficulty recognizing that "asbestos minerals" are actually varieties of several other minerals. Thus, Werner's recognition in the 18th century that amphlbole asbestos Is a variety of aaphlbole mineral was an important contribution to mineralogy (Frelesleben, 1817). Chrysotlle was not identified as a variety of serpentine until 1833. Aaoslte was not recognized as a mixture of asbestlforn actinolite and grunerlte until 1948,' and the term "aaoslte" is still used as a trade name for some asbestos. CRYSTAL refers to a solid with a highly ordered, periodic arrangement of atoms. The arrangement of atoms is called the CRYSTAL STRUCTURE. CRYSTALLIZATION HABIT refers to the distinct nature and shapes of Individual crystals or aggregations of several crystals. The crystalli zation habit of a mineral Is usually identified by terms describing its appearance, such as equant (equidimensional), filiform (halrllke), etc., according to the dominant geometric shape. The basic properties of minerals usually do not vary with different crystallizationjiabits, but a noteworthy exception is the asbestlform habit. - ASBESTIFORM HABIT refers to the unusual crystallization habit of a mineral when the crystals are thin, halrllke fibers. Historically, the definition of the asbestlform habit was based primarily on appearance, and the properties were only implied. At present, the definition of asbestlform habit is often augmented to Include a statement on the ^The term "attapulglte" Is a commercial designation for materials that consist of asbestlform and platy palygorBklte. Although the latter term Is more precise mineraloglcally. In this report the committee generally uses "attapulglte" for consistency. Not all palygorsklte (attapulglte) Is asbestlform. I 29 FIGURE 2*2. Electron microphotograph of a crosa section of chrysotile fibers displaying the scroll-like and tubular growth of the layered serpentine structure. From Yada, 1967. s,o4 mM*o6 c* *h FIGURE 2-3. Diagram of the structure and cleavage of amphibole crystals. Because of structural weakness, jche crystal preferentially breaks along the (110) and (110) planes, parallel with the e-axis, yielding acicular fragments. From Zoltai, 1979. 30 properties of asbestiform fibers, i.e., shape; enhanced strength, flexibility, and durability; diameter-dependent strength; and unique surfaces. The fibers of asbestos are good examples of the asbestiform habit. Asbestifora describes a special type of fibrosity. Fibrous is a broad tern that includes, for example, asbestos as well as pseudomorphic fibrous quartz. Asbestos is composed of distinct fibers with unique properties, whereas most fibrous quartz breaks into odd shaped fragments unrelated to its apparent fibrous appearance. The proper use of mineralogical nomenclature for fibrous materials, particularly asbestos, and problems that have arisen from improper usage have been discussed in several reports (Campbell et al., 1977; Langer et al., 1979; Zoltai, 1978). Thus, the term asbestiform has been used in a variety of ways in the past, sometimes applying only to asbestos or to fibers that look like asbestos. This committee has developed and used a definition that is more circumspect mineralogically. ACICULAR crystals are crystals chat are extremely long and thin and have a small diameter. (An acicular crystal is a special type of PRISMATIC crystal. A prismatic crystal has one elongated dimension and two other dimensions that are approximately equal.) As defined by Che American Geological Institute (1980), a mineral fragment must be at least three times as long as it is wide to be called acicular. Acicular crystals or fragments are not expected to have the strength, flexibility, or ocher properties of asbestiform fibers. However, small diameter acicular crystals with a high aspect ratio may be ASBESTIFORM if they are strong and flexible. Larger diameter crystals, even if stronger and more flexible than the parent mineral, are usually described as FILIFORM or HAIRLIKE. The limiting upper diameter of whiskers (see definition below) is usually considered to be 13 um; the same diameter may be used for the definition of asbestifora fibers. FIBROUS refers to (1) single crystals that resemble organic fibers such as hair or cotton and (2) large crystals or crystalline aggregates that look like they are composed of fibers (i.e., long. Chin, needlelike elements) (Dana and Ford, 1932). The apparent fibers do not need to be separable. If the fibers are separable and are strong and flexible, they are ASBESTIFORM. If they have the normal strength and brittleness of the mineral, they are ACICULAR. If the apparent fibers are not separable, the specimen may be a single crystal or a multiple (polycrystalline) aggregate displaying a fibrous pattern (resulting, for example, from striation or pseudomorphic replacement of an initially fibrous mineral). The term MINERAL FIBERS has traditionally referred to crystals whose appearance and properties resembled organic fibers, such as hair and cotton. In some recent literature, however, the term sometimes refers only to the appearance of Che material, and there can be confusion about whether particular properties are also implied. 31 CLEAVAGE refers Co Che preferential breakage of crystals along certain planes of structural weakness. Such planes of weakness are called cleavage planes. A mineral with two distinct cleavage planes will preferentially fracture along these planes and will produce ACICULAR fragments (Figure 2-3). Minerals with one cleavage plane produce PLATY fragments, and chose with three or more cleavage planes yield POLYHEDRAL fragments. Minerals without cleavage planes fracture into IRREGULAR, nongeometric fragments. The strength and flexibility of cleavage frag ments are approximately the same as Chose of single crystals. Cleavage cannot produce the high strength and flexibility of asbesciform fibers. COMMINUTION is the breaking down of material into smaller (more minute) particles. WHISKERS refer to synthetic crystals that share the properties of asbesciform fibers. . For more extensive definitions, see Campbell et al. (1977), Zoltai and Wylie (1979), and Walton (1982). SOURCES OF MINERAL PARTICLES Many types of mineral fragments are formed as the result of the constant weathering of rocks, as well as from various human activities. In general, the mineral composition of these particles approximately reflects che relative abundance of the minerals in Che earth's crust. These particles are transported by water and air before being eventually deposited in unconsolidated sedimentary rocks, and the very small particles may remain in the environment (i.e., air and water) for extended periods. A substantial proportion of these suspended particles have the apparent morphology of asbestiform fibers. However, most of these fiber-shaped particles are not asbestiform. For example, the suspended particles include elongated cleavage fragments of chain silicate and ocher minerals, such as the most common mineral, feldspar. PHYSICAL PROPERTIES OF ASBESTIFORM FIBERS A complete listing of the physical properties of asbestiform fibers would be very extensive. However, their common properties, as compared with nonasbestiform crystals of the same minerals, comprise a relatively short list: . fiberlike morphology and dimensions enhanced strength and flexibility diameter-dependent strength increased physical and chemical durability improved surface structure (i.e., relatively free of defects) 32 In addition, the presence and the quality of these properties depends on the conditions present during fiber growth. A conclnuua of these properties is possible. For example, "high quality" commercial asbestos has all these properties to a great extent, whereas other, more brittle fibers may have these properties to a lesser extent. Most whiskers and some amorphous materials, such as fibrous glass, may also have many of these properties, including fiber morphology, flexibility, and diameter-dependent strength. Therefore, in this report, some of the properties of asbestlform fibers are also assumed to apply to these other materials. Many natural minerals, such as palygorsklte (attapulglte), and some synthetic fibers have properties of asbestlform fibers to some extent. Appendix 3 lists many of these materials accompanied, in some instances, by brief comments related to human exposure or to health effects. The properties listed above are discussed in the following section, primarily as they apply to asbestos. Fiberlike Morphology The shape of these fibers is characterized by small crystal diameter, by extreme length to width ratio (aspect ratio), and by smooth and parallel longitudinal faces. The longitudinal faces may be: e rational crystallographic faces (Indexable by lattice parameters) chat are similar or identical to the prismatic faces of other crystals of the same materials; crystallographlcally irrational planes (not Indexable by lattice parameters--one of the mo6t unusual characteristics of high-quality amphlbole asbestos fibers); or curved, scroll-like or tubular structures, as in chrysotlle and carbon whiskers. . Although aclcular crystals and aclcular fragments may also display a high aspect ratio, that ratio is almost always small compared to that of asbestos, since nonasbestiform crystals are more brittle and break more readily across the longitudinal axis. Comminution of asbestos, especially the amphlbole varieties, may also produce some fragments with length-to-vidth ratios very similar to those observed for aclcular crystals and fragments, but these are usually only a small proportion of the total mineral mass and would still be expected to possess the properties of asbestlform fibers. At present, to determine whether a sample of particles seen in a microscope contains asbestlform fibers, it is generally necessary to know the origin of the sample. However, on average, aclcular fragments are shorter than asbestlform fibers (Campbell etal.,1979). i 33 Enhanced Strength and Flexibility Asbestos, whiskers, and fibrous glass with sufficiently small diameters have great strength and flexibility. The tensile strength of commercial quality asbestos fibers is 20 to SO times greater Chan Chat of the nonasbestiform crystals of the same minerals. For example, the strength of grunerite crystals is approximately 1,000 kg/cm?, whereas the strength of asbestiform grunerite (also called amosite) may reach 40,000 kg/cn>2. Whiskers and fine fibers of glass also possess extreme strength. Although the usual crystals of most minerals are brittle and cannot be bent more than a few degrees, asbestiform fibers are highly flexible and may also be somewhat elastic. In general, measurement of the bending strength of fibers is an acceptable approximation of tensile strength. Diameter-Dependent Strength One of the properties shared by high quality fibers of asbestos, whiskers, and glass is their diameter-dependent strength. That is, the strength of the fibers per unit of cross-section area increases as the diameter decreases. Thus, Che smaller the diameter of the fiber, the greater its strength. The diameter-dependent variation in the strength of fine wires was first observed by van Miisschenbroeck (1729). In Che ensuing centuries, similar observations were made by later investigators (e.g., Karmarsch, 1824; Gerstner, 1831), including famous bridge builders in Che early 19th century (Dufour, 1823; Seguin, 1824; Telford, 1814). An apparent strength-diameter effect was also observed in glass fibers by Threlfall (1890) and confirmed and quantitatively analyzed by Griffith (1921). The diameter-dependent strength of asbestos fibers was first studied by Nadgornyi et al. (1965). Later, the effect was observed in asbestiform varieties of other minerals by Maleev et el. (1972). Figure 2-4 illustrates the strength-diameter effect in f.crous glass and asbestos. Appendix C provides further discussion of the effect. Increased Physical and Chemical Durability Asbestos fibers are more resistant to physical stress chan are nonasbestos varieties of the same mineral. For example, asbestiform fibers are much more difficult to grind to a powder in a mortar than are the corresponding nonasbestiform crystals. Furthermore, high quality amphibole asbestos does not possess prismatic cleavage planes. Similarly, fibers of asbestos are more resistant to dissolution by acids Chan are other crystals of Che same minerals. Thus, Walker (1981)  34 OIAMETER (am) FIGURE 2-4. Illustration of the strength-diameter effect. Data from Griffith, 1921 (glass fibers) and Nadgornyi et al., 1963 (asbestos). noted that dissolution of grunerlte cleavage fragments was initiated on all surfaces, whereas dissolution of the asbestiform grunerlte fibers required stronger acid and began at the ends of the fibers--a process that resulted in the development of inverted cones at the end of the fibers. This observation suggests that the external structure of asbestiform fibers is more resistant to acids than is the internal structure, la many cases, the solid fibers became partially hollow cylinders before the surface dissolved. Glass and rock wool fibers also dissolve from the ends (Wojnarovits-Hrapka, 1977, 1978, 1979). (See Figure 2-5.) Defect-Free Surface Structure Many asbestos fibers have the shiny luster and high reflectivity indicative of a surface structure that is relatively free of defects. Investigators have noted the low density or the absence of surface defects in whiskers (Bokshtein et al., 1968; Brenner, 1956; Jones and Duncan, 1971; Mehan and Herzog, 1970; Webb et al., 1966) and in glass fibers (Bartenev and Izmailova, 1962; Griffith, 1921; Moorthy et al., 1956). 35 FIGURE 2-5. The dissolution pattern of a glass fiber (from WojnarovitsHrapka, 1977) and amosite fibers (from Walker, 1981). The lack of surface defects may be partly responsible for the high strength of the surface layer of asbestifora fibers. The strength may also be enhanced by the differences in bonding between the internal and surface structures of these fibers (Gerstner, 1831; Griffith, 1921; Joffe* et al., 1924; Orovan, 1933; Sella and Voigt, 1893; Weibull, 1939). Growth-Dependent Fiber Quality Although the conditions prevailing during crystallization can affect the physical and chemical properties of crystals, the effect is usually minor. However, the conditions of growth greatly influence the properties of asbestos, whisker, and glass fibers. A strong surface structure with relatively few defects can develop only when the crystal grows in only one direction. Such unidirectional growth can be achieved 36 if, for example, there is unidirectional tension or sudden release of stress. In major asbestos deposits, therefore, the fibers usually crystallize parallel vith tension and perpendicular to the vail of the fracture veins. In laboratories, whiskers are grown experimentally by creating various types of physical and chemical conditions that promote unidirectional growth (Wagner, 1970). Because the physical quality of the fibers depends on the growth conditions, fiber properties will vary as Che growth conditions vary. BIOLOGICALLY RELEVANT PHYSICOCHEMICAL PROPERTIES The various pathological effects associated with asbestiform fibers are discussed in detail in Chapters 5 and 6. However, the properties of Che fibers that may be relevant to Chose effects are introduced here, along with some of the evidence for'thexf~''ia^rtance.v'"-'"r^^'v''-*!^,-:<'^h"-- - Respirability Only fibers with mean aerodynamic diameters less than approximately 3 yin enter the small airways. This feature is discussed in greater detail in the section on biodisposition in Chapter 5. See also Leineweber (1980), Timbrell (1965), and Walton (1982). Size and Aspect Ratio (Length:Diameter) ............. , Dimensional characteristics of fibers determine not only where they will deposit in the respiratory tract but also how a cell will respond co them. In animals, shorter fibers and particles may be engulfed by scavenger cells and thereby may be substantially prevented from interaction vith ocher cell types. Thus, after being inhaled, these fibers may be present for extended periods in the cytoplasm of airway epithelial cells, in membrane-bound vesicles, or in macrophages (Mossman e jil., 1977; Suzuki and Churg, 1969). Longer fibers, which are incapable of undergoing phagocytosis (i.e., being engulfed by cells), are associated with marked cytotoxic alterations ^n vitro in animals, but toxicity is reduced substantially when larger fibers are milled to smaller sizes (Brown et al., 1978; Raw et al., 1982; Lipkin, 1980). Unfortunately, the reduction in toxicity cannot be attributed solely to the reduction in size, since milling also alters to some degree the crystallinity and surface features of the fibers, and these properties may also exert some effect (Langer et al., 1978). The greater toxicity of the longer fibers might be due to the inability of cells such as macrophages to engulf the fibers and/or inactivate the various sites on longer fibers. In animals, a direct relationship between dimension and development of mesothelioma has been suggested by results of studies in which intrapleural, intrathoracic, and intraperitonea 1 injections have been 37 administered. However, the appropriateness of extrapolating these data to humans Is questionable In view of the massive dosages, species** specific variability, and different pathological findings, e.g., sarcomas and histiocytomas, in these animal studies. Moreover, although most mesotheliomas in humans seem to be associated with exposure to asbestlform fibers, spontaneous mesotheliomas appear in the mouse (Shapiro and Warren, 1949), rat (Hueper and Bayne, 1962), and hamster (Fortner, 1961). Ihese observations suggest that different mechanisms of disease induction may occur in various species. Although data reported by most investigators show an increased risk of mesothelioma after exposure to long, thin fibers, in comparison to short, thick fibers, there does not appear to be a critical length below which fibers have no carcinogenic potential. For example, studies by Pott and colleagues (1974) show that fiber preparations containing an overwhelming majority of fibers shorter than 5 urn still possess measurable biological activity. Moreover, mesotheliomas have been induced by administering glass powder and other particulates, although the tumors occurred with less frequency than with long fibers (Wagner et al., 1973). Bertrand and Pezerat (1980) used a new statistical approach to analyze the information generated by Stanton and colleagues (1977) from experiments using fibrous glass of various sizes. Bertrand and Pezerat suggested that carcinogenesis is a continuous increasing function of aspect ratio, but concluded that it is not possible to separate the effects of the two variables, length and diameter. Durability Many asbestiform fibers survive in biological systems for long periods. However, the physicochemical properties of asbestos and other fibers may undergo alteration after inhalation (Spurny ej: al., 1983). For example, the surface characteristics of fibers are modified after adsorption of surfactant and mucin; this coating reduces the cytotoxic properties of fibers (Desal and Richards, 1978; Harlngton et al., 1975; Jaurand et al., 1979; Morgan, 1974). In addition, fibers in general appear to undergo comminution or breakdown in the lung. The number of fibers per unit mass of asbestos also Increases. Asbestos fibers tend to fragment longitudinally into thinner fibrils (Cook et al., 1982; Suzuki and Churg, 1969), whereas glass fibers cannot do so (Kllngholz, 1977). Chrysotlle also ia modified structurally after deposition in the lung, since magnesium, ions (Mg**), which contribute to both the structural Integrity and positive surface charge of the fiber, are leached from the fiber (Jaurand et el., 1979; Langer et al., 1972). This leaching process apparently causes fragmentation of chrysotlle and its faster disappearance from the lung in comparison to amphlbole types of asbestos (Morris et al., 1967). Depletion of Mg'H' decreases the 38 cytotoxicity of chrysotlle (Morgan et al., 1977) and the ability of this type of asbestos to cause mesothelioma in animals (Monchaux et al., 1981). The leaching of magnesium ions may alter the composition of chrysotlle, but it does not tend to dissolve in tissues as glass does (Leineweber, in press). Asbestos-related diseases, especially cancers, generally occur many years after first exposure. Autopsies and biopsies show that fibers are still present in the lungs and other tissues and often appear to be essentially Intact years after the last known exposure. It is possible, therefore, that the exceptional physicochemical durability of asbestiform fibers is one of the basic requirements for their biological effects. Flexibility and Tensile Strength The relatively high flexibility of the asbestiform fibers enables them to bend without breaking and may facilitate their passage through the respiratory tract. Like asbestos fibers, fine-diameter glass fibers do not tend to break across their axes and are often as strong as asbestos. However, relatively large-diameter glass fibers tend to break perpendicularly to the fiber axis into "blocky" fragments. The flexibility of fibers is directly related to tensile strength. Chemical Composition The possible significance of certain elements contained in the chemical formulas of fibers in relation to disease is under study. In Initial investigations of the health effects of asbestos, the chemical composition of the fibers was expected to be Important. The most obvious candidate for the common chemical component was silicon, since all commercial forms of asbestos are silicates. The likelihood that silicon plays a role in carcinogenesis is minimized, however, by the exceptionally strong and almost lndestructable bonding of silicon to oxygen in a tetrahedral structure. Furthermore, neither other silicates nor pure silica particles have carcinogenic properties similar to those of the asbestiform fibers (Churg, 1982). Magnesium was next considered, since it is present in most asbestos and on the chrysotlle surface. However, it was soon recognized that one of the major types of asbestos (asbestiform grunerlte) contained relatively little magnesium and that another type (croddollte) did not necessarily contain any magnesium in its chemical formula. Although it has not been shown that chemical composition has a direct role in the pathogenic properties of asbestiform fibers, the chemical composition and structure obviously underlie many of the other properties of the fibers. Thus, chemical composition may play an Important indirect role in determining which fibers exert pathological effects and what these effects are. 39 Some asbestifora fibers carry some foreign materiel on their surfaces and, in the case of chrysotile, in the centers of their fibrils. Zeolites also have large channels that may contain a variety of elements and compounds. These foreign materials could be carcinogenic, even if Che host crystal is not. Surface Area The surface area of asbestifora fibers per unit volume is very large because of the small diameter of the fibers. Most commercial asbestos occurs in bundles that are broken open as the size of the unit mass is reduced. An increase in surface area and particle number then occurs. Several biological effects studied in the laboratory are related directly to an increase in fiber surface area. These include hemolysis by chrysotile (Schnitzer and Pundsack, 1970) and by amphiboles (Morgan et al., 1977; Schnitzer and Pundsack, 1970); cytotoxicity of chrysotile when Tt is tested on alveolar macrophages from rabbits or humans (Yaeger et al., 1983); and general sorption of serum components (Desai et il., 1975). Presumably, an increase in surface area allows more cellular interaction, although the concomitant decrease in diameter may also play a role. Surface Charge Asbestos-induced cell damage appears to be initiated by a reaction of the plasma membrane that results either in cell lysis or in phagocytosis of the material (Mossman e al., 1983). The degree of cytolytic reactivity, as measured by a variety of techniques in vitro, including hemolysis and decrease in cell viability, is apparently dependent initially on the surface charge of the fiber (Light and Wei, 1977a,b; Reiss et al., 1980). Red blood cells lyse after exposure to asbestos, and the release of hemoglobin can be quantified. The surface charge on fibers, as measured by the zeta potential, is related directly to the fibers' hemolytic activity (Light and Wei, 1977a,b). When chrysotile fibers are treated with acid, both the zeta potential and Che hemolytic activity decrease. By contrast, Che hemolytic potential for crocidolite increases as the fibers become more negatively charged. Schiller and colleagues (1980) have shown regional differences in surface charge on omphibole fibers. The charge characteristics of fibers also vary according to their size. Standardized Asbestos Samples^ . . Samples of asbestos that come from different sources or have undergone modifications vary in many of the characteristics discussed. ^Much of this information was taken from an unpublished draft paper prepared by Paul W. Weiblen, University of Minnesota, 1983.  40 To facilitate comparisons of experiments and measurements among researchers throughout the world, five PICC standard reference samples for asbestos were prepared and partially characterized (Rendall, 1970, 1980; Tlmbrell, 1970; Tlabrell and Rendall, 1972). The fire half-con samples and the mines they came from are: amoslte (Penge, South Africa); anthophylllte CPaakktla, Finland); crocldollte (Koegas, Cape, South Africa); chrysotUe A (Shabanl, Rhodesia); chrysotUe B (various Canadian mines). The samples were prepared by a specific blending and milling procedure. As tested by elutrlator and cyclone, 67X to 87X of the fibers (by weight) have been reported as respirable (Rendall, 1970). For the four samples other than crocldollte, 8X to 15X of the fibers counted by electron microscope were reported to be longer than 10 mb; for crocldollte, 3Z of fibers were found to exceed 10 pm In length (Tlabrell, 1970). These samples do not completely satisfy sH the current requirements for comparing biological and health effects of different asbestos samples, and It would be useful if a new set of standards were prepared taking Into consideration all the fiber characterization criteria now considered important. The U.S. Bureau of Mines has prepared and characterized saaples of approximately one-half ton each of amoslte, chrysotUe, crocldollte, and nonfibrous treaollte for use In oral ingestion studies carried out by the National Institute of Environmental Health Sciences (Campbell et al., 1980). SUMMARY Asbestos Is a generic name for the asbestlform variety of certain minerals that are used commercially. The term commercial asbestos encompasses five minerals: chrysotile, anthophylllte, rlebecklte, cummingtonlte-grunerite, and actlnollte-tremollte. Many other minerals occasionally crystallize In the asbestlform habit and therefore may have the characteristic properties of asbestos. Asbestlform fibers. Including asbestos fibers, are mineral fibers that are characterized by a specific set of interdependent physical properties. Including fiberlike shape, enhanced strength and flexibility, Increased durability, strong and defect-free surface structure, and the dependence of these properties on conditions of growth. The fiber properties that have been considered for possible association with deleterious health effects are resplrabllity (l.e., fibers <3 m diameter), size and aspect ratio, durability, flexibility and tensile strength, chemical composition, surface area, and surface charge. Figure 2-6 and Table 2-2 Illustrate some of the characteristics described above for fibers with progressively smaller diameters. 41 m icroscopy. Adapted from A. Langer, personal com m unication, 1983. X>> Xa> 0u u at *u 00 XV 0 u*<' OCw a. <*-* U 2 at 5cOii <Ad 6 3. o ao x O Oc O <n g --04 P4 0 m-Sciuo *Of.sga^*> rwI 4 O ^ ij H SI *Pd *e3H x X^ O 0 xW fo V " " Oy - -o C* --V <M < 4>1 Uo U< eo ^4 e 0 0X 0 0) V . 00 u 0 u *sd u Ad sd 3 0 Ad k* o u 0 4) Ad 0 M X EC A 0 0 U V s 0 Ad *d 0 <*d 3 "3 0 Ud C dd d *sd X o o 6 U X c u ow M Ad 0 > u0 o d 0 Pd <Ad at g Q x 2 =4 X .d Id 06 00 3 hi w O e E0 W 0X 0U Ad Ud 0 00 *4 c *3 Ad 0 *d 0 0 W Ad sd 0 0 kd Id XX 0 w 0 sd Ad 0 < VAd 0 u vPOIvl u O=3S CM5 u. 42 TABLE 2-2. The Effects of Comminution on Properties of Polyfllamentous Asbestlform Fibers13 2* * * Fiber Diameter (um) Fiber Num ber/mg8 Relative Time of Fall (l/d2)c Aspect Ratio Relative (lens th/diameter) Surface Area<* 1.000 4 x 107 18 4 0.500 1.6 x 108 4 16 6 0.250 6.4 x 108 16 32 10 0.125 2.56 x 109 64 64 18 0.062 1.024 x 1010 256 128 34 0.031 4.096 x 1010 1,024 256 66 ^Adapted from A. Langer, personal communication, 1983. ^If mineral density is assumed to be about 2.80 g/cm8, 1 mg of dust would contain approximately the number of fibers shown In this column for the diameter shown. The increase in particle number is about three orders of magnitude when length is constant and the diameter of Individual particles is decreased to about 31 of initial value. cFalling speed of a fiber is approximately Inversely proportional to the square of the fiber diameter (1/d2). A chrysotile fiber with a 0.03 um diameter takes approximately 1,000 times longer to settle (neglecting other factors) out of an aerosol as compared to a 1-un diameter fiber. ^Change in surface area with comminution. Units are relative. Ends of fiber not considered In these calculations. Relative surface area * 2N-2. RECOMMENDATIONS 1. To facilitate communication among persons studying fibrous materials, mineralogical terminology should be used appropriately in all discussions and reports concerning fibrous materials. In particular, a distinction should be made between asbestlform fibers and elongated mineral particles that are not fibrous. When such a distinction cannot be made. It should be so stated. 2. Methods should be developed for both macroscopic and microscopic quantitative determination of the physical properties of fibers, such as their tensile strength. 3. In carrying out research to correlate the physical and chemical properties of fibers responsible for their pathological effects, the fibers should be characterized as completely as possible. Where studies are conducted to determine the effects of natural fibers, characterization should Include such parameters as surface and Internal fiber strength (discussed in Appendix C), surface charge, and density of surface defects. 43 REFERENCES American Geological Institute. 1980. Glossary of Geology. R. L. Bates and J. A. Jackson, eds. American Geological Institute, Washington, D.C. Bartenev, G. M., and L. K. Izmailova. 1962. Defect-free glass fibers. Dokl. Nauk. SSSR. Chem. Techn. Sect. 146:196-198. Bertrand, R., and H. Pezerat. 1980. Fibrous glass: Carcinogenicity and dimensional characteristics. Pp. 901-911 In J. C. Wagner, ed. Biological Effects of Mineral Fibers, Vol. 2. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. Bokshtein, S. Z., S. T. Kishkln, M. P. Nazarrova, and I. I. Svetlov. 1968. Size effect and anisotropy in the strength of sapphire whiskers at room temperature. Sov. Phys. Solid State 9:1488-1494. Brenner, S. S. 1956. Tensile strength of whiskers. J. Appl. Phys. 27:1481-1491. . Brown, R. C., M. Chamberlain, D. M. Griffiths, and V. Timbrell. 1978. The effect of fibre size on the in vitro biological activity of three types of amphibole asbestos. Int. J. Cancer 22:721-727. Campbell, W. J., R. L. Blake, L. L. Brown, E. E. Cather, and J. J. Sjoberg. 1977. Selected Silicate Minerals and their Asbestlform Varieties; Mineralogical Definition and Identification- Characterization. U.S. Bureau of Mines, Information Circular No. 8751. U.S. Bureau of Mines, Washington, D.C. Campbell, W. J., E. B. Steel, R. L. Virta, and M. H. Eisner. 1979. Relationship of Mineral Habit to Size Characteristics for Tremolite Cleavage Fragments and Fibers. Report of Investigations No. 8367. U.S. Bureau of Mines, Washington, D.C. Campbell, W. J., C. W. Huggins, and A. G. Wylie. 1980. Chemical and Physical Characterization of Amosite, Chrysotile, Crocidolite, and Nonflbrous Tremolite for Oral Ingestion Studies by the National Institute of Environmental Health Sciences. U.S. Bureau of Mines Report of Investigations No. 8452. U.S. Bureau of Mines, Washington, D.C. Churg, A. 1982. Reaction of the lung to silica, silicates, and asbestos. Pp. 201-228 in Environmental Pathology: An Evolving Field. A. R. Liss, Inc., New York. Cook, P. M., L. D. Palekar, and D. L. Coffin. 1982. Interpretation of the carcinogenicity of amosite asbestos and ferroactinolite on the basis of retained fiber dose and characteristics in vivo. Toxicol. Lett. 13:151-158. ' Dana, S. D., and W. E. Ford. 1932. A Textbook of Mineralogy. J. Wiley and Sons, New York. de Boot, A. B. 1647. Gemmarum et Lapidum Hlstoria. Lugdunid Bataborum, Amsterdam. 550 pp. Desal, R., and R. J. Richards. 1978. The adsorption of biological macromolecules by mineral dusts. Environ. Res. 16:449-464. Desal, R., P. Hext, and R. Richards. 1975. The prevention of asbestos-induced hemolysis. Life Scl. 16:1931-1938. Dufour, G. H. 1823. Description du pont suspendu en fll de fer constrult a Geneve. Bibl. Unlverselle 24:280-299; Fortner, J. C. 1961. The Influence of castration on spontaneous tumorlgenesls in the Syrian (golden) hamster. Cancer Res. 21:1491-1498. 44 Frelesleben, J. C. 1817. A. G. Werner's Letztes Mineral-System. Craz and Gerold, Freiburg and Vienna. Gerstner, F. G. R. von. 1831. Handbuch der Mechanlk. Vol. 1. J. Spumy, Prague. Griffith, A. A. 1921. The phenomena of rupture and flow in solids. Philos. Trans. R. Soc. London, Ser. A 221:163-198. Harington, J. S., A. C. Allison, and D.V. Badaml. 1975. Mineral fibers Chemical, physicochemical, and biologic properties. Adv. Pham. Chemother. 12:291-402. Mueper, W. C., and W. W. Payne. 1962. Experimental studies in metal carcinogenesis: Chromium, nickel, iron, arsenic. Arch. Environ. Health 5:445-462. Jaurand, M. C., J. Blgnon, P. Sebastlen, and J. Gonl. 1979. Leaching of chryaotlle asbestos in human lungs. Correlation with In vitro studies using rabbit alveolar macrophages.Environ. Jles.14:245-254. Joffe, A., M. W. Klrpitscheva, and M. A. Levitzky. 1924. Deformation und Festigkeit der Krlstalle. Z. Phys. 22:286-302. Jones, B. F., and R. G. Duncan. 1971. The effect of fiber diameter on the mechanical properties of graphite fibers manufactured from polyacrylonitrile and rayon. J. Mater. Sd. 6:1225-1227. Karmarach, L. 1824. Versuche iiber die Festigkeit der zu Draht gezogenen Metalle. Jhrb. Polytech. Inst. Vienna 18:54-115. Raw, J. L., F. Hikes, and E. G. Beck. 1982. Reaction of cells cultured in vitro to different asbestos dusts of equal surface area but different fibre length. Br. J. Exp. Pathol. 63:109-115. Klingholz, R. 1977. Technology and production of man-made mineral fibres. Ann. Occup. Hyg. 20:153-159. Langer, A. M., J. B. Rubin, I. J. Sellkoff, and F. D. Pooley. 1972. Chemical characterization of uncoated asbestos fibers from the lungs of asbestos workers by electron microprobe analysis. J. Histochem. Cytochem. 20:735-740. Langer, A. M., M. S. Wolff, A. N. Rohl, and I. J. Sellkoff. 1978. Variation of properties of chrysotlle asbestos subject to milling. J. Toxicol. Environ. Health 4:173-178. langer, A. M., A. N. Rohl, M. Wolff, and I. J. Sellkoff. ,1979. Asbestos, fibrous minerals and aclcular cleavage fragments: Nomenclature and biological properties. ?PpV'1-22 In R.'Lemen and J. M. Dement, eds. Dusts and Disease. Pathotox Publishers, Park Forest South, 111. . Lelneweber, J. P. 1980. Dust chemistry and physics: Mineral wool and vitreous fibers. Pp. 881-900 in J. C. Wagner, ed. Biological Effects of Mineral Fibres, Vol. 2. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. Lelneweber, J. P. In press. Solubility of fibers in vitro and in vivo. Presented at the Biological Effects of Man-Made Mineral Fibers, Occupational Health Conference, Copenhagen, April 20, 1982. World Health Organization. Light, W. G., and E. T. Wei. 1977a. Surface charge and hemolytic activity of asbestos. Environ. Res. 13:135-145. 45 Light, W. G., and E. T. Vel. 1977b. Surface charge and asbestos toxicity. Nature 265:537-539. Lipicin, L. E. 1980. Cellular effects of asbestos and other fibers: Correlations with in vivo Induction of pleural sarcoma. Environ. Health Perspect. 34:91-102. Maleev, M. N., A. P. Krusillna, and V. N. Rosanckij. 1972. Ultimate strength of naturally fibrous rutile, antimony and jamesonlte crystals. [In Russian] C. R. Acad. Bulg. Sci. 25:1085-1088. Mehan, R. L., and J. A. Herzog. 1970. Mechanical properties of whiskers. Chapter 6 in A. P. Levitt, ed. Whisker Technology. Wiley Interscience, New York. Monchaux, G., J. Bignon, M. C. Jaurand, J. Lafuma, P. Sebastlen, R. Masse, A. Hirsch, and J. Coni. 1981. Mesotheliomas in rats following inoculation with acld-leached chrysotlle asbestos and other mineral fibers. Carcinogenesis 2:229-236. . . ... Moorthy, V. K., F. V. Tooley, and G. F. Stockdale. 1956. Influence of water Immersion treatment on tensile strength of glass: Effect of temperature. J. Am. Ceram. Soc. 39:395-398. Morgan, A. 1974. Absorption of human serum albumin by asbestlform minerals and Its application to the measurement of surface areas of dispersed samples of chrysotlle. Environ. Res. 7:330-341. Morgan, A., P. Davies, J. C. Wagner, G. Berry, and A. Holmes. 1977. The biological effects of magnesium-leached chrysotlle asbestos. Br. J. Exp. Pathol. 58:465-473. Morris, T. G., W. H. Roberts, R. E. Sllverton, J. W. Skidmore, J. C. Wagner, and G. W. Cook. 1967. Comparison of dust retention In specific pathogen free and standard rats. Pp. 205-213 In C. N. Davies, ed. Inhaled Particles and Vapours, Vol. II. Pergamon Press, London. Mossman, B. T., B. Ley, J. B. Kessler, and J. E. Craighead. 1977. Interaction of crocidollte asbestos with hamster respiratory mucosa in organ culture. Lab. Invest. 36:131-139. Mossman, B., W. Light, and E. Wei. 1983. Asbestos: Mechanisms of toxicity and carcinogenicity in the respiratory tract. Ann. Rev. Pharmacol. Toxicol. 23:595-615. MUsschenbroeck, P. van. 1729. Physlcae experimentales et geometrlae. L. Batavorum and S. Lichtmans, Leiden. Nadgornyl, E. M., L. F. Grlgoreva, and A. P. Ivanov. 1965. The mechanical properties of synthetic fibrous fluoramphiboles and certain forms of natural asbestos. [In Russian] Izv. Akad. Nauk SSSR, Neoerg. Mater. 1:1117-1123. Orowan, E. 1933. Die erhShte Festigkelt dunner Faden, der Joffe-Effekt und verwandte Erscheinungen vom Standpunkt der Grlffltachen- Bruchtheorle. Z. Phys. 86:195-213. Pllnlus, Secundus, C. 77 A.D. Historla Naturalls. 27 books. Pott, F., F. Huth, and K. Friedrichs. 1974. Tumorlgenic effects of fibrous dusts In experimental animals. Environ. Health Perspect. 9:313-315. Rendall, R. E. G. 1970. The data sheets on the chemical and physical propetles of the UICC standard reference samples. Pp. 23-27 In H. A. Shapiro, ed. Pneumoconiosis. Proceedings of the International Conference In Johannesburg. Oxford University Press, Cape Town. 46 Randall, R. E. G. 1980. Physical and chemical characteristic* of UICC reference samples. Pp. 87-96 in J. C. Wagner, ed. Biological Effects of Mineral Fibres, Vol. 2. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. Reiss, B., S. Solomon, J. Weisburger, and G. M. Williams. 1980. Comparative toxicities of different forms of asbestos in a cell culture assay. Environ. Res. 22:109-129. Schiller, J. E., S. L. Payne, and S. E. Khalafalla. 1980. Surface charge heterogeneity in amphibole cleavage fragments and amphibole asbestos fibers. Science 209:1530-1532. Schnitzer, R. J., and F. L. Pundsack. 1970. Asbestos hemolysis. Environ. Res. 3:1-13. __ __ Seguin, M. 1824. D'Annonay: Sur la tenacite de fer. Ann. Chim. Phys. 25:109-111. Sella, A., and W. Voigt. 1893. Beobachtungen liber die Zerreissungsfestikeit von Steinsalz. (Wied.) Ann. Phys. Chem. 48:636-656. Shapiro, D. M., and S. Warren. 1949. Cancer innervation. Cancer Res. 9:707-711. Spumy, K. R., F. Pott, W. Stober, H. Opiela, J. Schormann, and G. Weiss. 1983. On the chemical changes of asbestos fibers and MMMFs in biologic residence and in the environment: Part 1. Am. Ind. Hyg. Assoc. J. 44:833-845. Stanton, M. F., M. Layard, A. Tegaris, E. Miller, M. May, and E. Rent. 1977. Carcingenicity of fibrous glass: Pleural response in the rat in relation to fiber dimension. J. Natl. Cancer Inst. 58:587-603. Suzuki, M. 0., and J. Churg. 1969. Structure and development of the asbestos body. Am. J. Pathol. 55:79-107. Telford, T. 1814. Experiments on the direct and transverse resistance of iron wire of different lengths and dimensions. Pp. 243-254 in Appendix to P. Barlow Essay on the Strength and Stress of Timber. Second Edition. Threlfall, R. 1890. The elastic constants of quartz threads. Phil. Mag. and J. of Sci. Fifth Ser. 30:99-116. Timbrell, V. 1965. The inhalation of fibrous dusts. Ann. N.Y. Acad. Sci. 133:255-273. ............. . - Timbrell, V. 1970. Characteristics of the International Union Against Cancer standard reference samples. In H. A. Shapiro, ed. Pneumoconiosis. Proceedings of the International Conference in Johannesburg. Oxford University Press, Cape Town. Timbrell, V., and R. E. G. Rendall. 1972. Preparation of the UICC standard reference samples of asbestos. Powder Technol. 5:279-287. Wagner, J. C. 1970. VLS mechanism of crystal growth. Chapter 3 in A. P. Levitt, ed. Whisker Technology, Wiley Interscience Publications, New York. Wagner, J. C., G. Berry, and V. Timbrell. 1973. Mesothelioma in rats after inoculation with asbestos and other materials. Br. J. Cancer 28:173-185. Walker, J. S. 1981. Asbestos and the asbestiform habit of minerals. M.S. Thesis, University of Minnesota, Minneapolis. 47 Walton, W. H. 1982. The nature, hazards and assessment of occupational exposure to airborne asbestos dust: A review. Ann. Occup. Hyg. 25:117-247. Webb, W. W., H. 0. Barths, and T. B. Shaffer. 1966. Strength characteristics of whisker crystals, microcrystals and macrocrystals. Chapter 14 in J. J. Burke, N. L. Reed, and V. Weiss, eds. Strengthening Mechanism. Syracuse University Press. Weibull, W. 1939. A statistical theory of the strength of materials. The Phenomenon of Rupture of Solids. Proc. No. 151 and 153. Ing. Vetensk. Akad., Stockholm. Wojnarovits-Hrapka, I. 1977. Structural examination of inorganic fibrous materials. Part I. [In Hungarian] Epitoanyag 29:498-503. Wojnarovits-Hrapka, I. 1978. Structural examination of inorganic fibrous materials. Part II. [In Hungarian] Epitoanyag 30:13-18. Wojnarovits-Hrapka, I. 1979. Crystallization of synthetic inorganic fibers used for thermal insulation. Epitoanyag 31:281-286, 361-366, 422-429. - Yada, K. 1967. Study of chrysotile asbestos by a high resolution electron microscope. Acta Crystallogr. 23:704-707. Yaeger, H., Jr., D. A. Russo, M. Yanez, D. Gerardi, R. p. Nolan, E. Kagan, and A. M. Langer. 1983. Cytotoxicity of a short-fiber chrysotile asbestos for human alveolar macrophages: Preliminary observations. Environ. Res. 30:224-232. Zoltai, T. 1978. History of asbestos-related mineralogical terminology. Pp. 1-18 in C. C. Gravatt, P. D. La Fleur, and K. F. J. Heinrich, eds. Proceedings of a Workshop on Asbestos: Definitions and Measurement Methods, July 18-20, 1977. NBS Spec. Pub. No. 506. National Bureau of Standards, Gaithersburg, Md. Zoltai, T. 1979. Asbestiform and acicular mineral fragments. Ann. N.Y. Acad. Sci. 330:621-643. Zoltai, T., and A. G. Wylie. 1979. Definitions of asbestos-related mineralogical terminology. Ann. N.Y. Acad. Sci. 330:101-109. 3 Assessing Nonoccupational Exposures to Asbestiform Fibers Lack of information about exposure is often the major impediment to assessing health risks associated vith environmental substances. In this chapter, the committee defines exposure and explores the sources of asbestiform fibers, both naturally occurring and man-made. It also describes the general movement of fibers in commerce and in the nonoccupational environment, notes the difficulties in determining amounts of fibers and in defining exposure, presents descriptive estimates of exposure levels and of the numbers of people exposed to various fiber types, and discusses the magnitude and significance of uncertainties about exposures to asbestiform fibers. In discussing the various types of fibers, asbestos is described first to provide perspective for the discussion of the other fibers. DEFINITIONS OF EXPOSURE To understand the extent of current and future health risks from exposures to substances of concern, it is necessary to characterize past, current, and projected future exposures. Information on past exposures serves as a guide for interpreting observed health impacts in epidemiological research and as a basis for estimating cumulative exposures. Information on current and projected future exposures provides information useful in making decisions about regulating exposure levels. The goal of exposure assessment is to estimate the distribution of various levels of exposure over a population or subpopulation so that the information can be integrated vith data on the substance's toxicity. Figure 3-1 provides one example of a distribution of asbestos exposure for some urban populations (Suta and Levine, 1979). In that example, exposure is expressed as units of mass per unit volume of air. Exposure information on asbestos is also often expressed by using the fiber con centration in air or water Cfibers/cm3 or fibers/liter, respectively) and the duration and pattern of exposure (e.g., 40 hours/week, 48 veeks/year, for 23 years). Attempts at exposure assessment involve many assumptions, complica tions, and difficulties. To characterize exposures completely, one would like to know: 48 U9 PERCENT OF POPULATION EXPOSED TO CONCENTRATIONS AT OR ABOVE THE INDICATED LEVEL FIGURE 3-1. Distribution of exposures to asbestos in ambient air of urban areas. From Suta and Levine, 1979. Who is exposed? - age - sex - race - health status - other exposures, e.g., tobacco smoke To which fibers are they exposed? - type of fiber - dimensions of fibers - other fiber characteristics How are they exposed? - occupational - community (near known sources of material of concern) - consumer use of manufactured products - general environmental 50 By vhae routes? - respiratory - oral - other . What pattern? - daily peak intake - annual fiber intake - cumulative fiber intake - cumulative exposure, e.g., fibers/cm^ times number of years - concentration of exposure, e.g., fibera/cm^ or fibers/liter a How frequently, and how long? - continuously - regular, periodic, e.g., 8 hours/vorkday; once per month - irregular, but repeated - single incidents - age during exposure Through what chain of events? - natural weathering - mining and milling - manufacturing processes - transportation - storage - use - industrial discharges - waste disposal - environmental transport How many people are exposed by various routes and under various conditions? - single routes of exposure - multiple routes and types of exposure, e.g., oral and respiratory, occupational and consumer In general, these questions are not easily answered, and fibrous materials such as asbestos pose some special difficulties. For example, fibers remain in the lungs after external exposure has ceased. In addition, there is no consensus on the best way to measure and express toxieologically significant doses, e.g., whether to use mass, fiber counts or fibers with particular characteristics. Measures of total mass are possibly not related to toxicity as reliably as appropriate fiber counts. Moreover, the various methods of collecting and counting fibers often do not correlate well with one another. However, to compare 51 dose-response relationships among studies and to predict health effects from exposure or dose measurements, data concerning exposure and dose oust be expressed in che same units, even though there is uncertainty about the appropriate conversion factors (see Chapter 4). Two major approaches are used for exposure assessment: one is based on measurements of exposure data and the other on calculations from more indirect indicators of exposure. In the first approach, exposure data are gathered as directly as possible. For example, a portable sampler worn by a person may provide good measurements of exposure. Most measurements are less direct, however, and che assessor must relate measured concentrations in air, water, or food to absorbed dose through some model of Che exposure, absorption, and elimination processes. The amount of material present in the body of the exposed person provides an additional way of assessing exposure. The measurement approach is founded on real exposure data rather than on a framework of assumptions; however, measurement procedures are expensive and many measurements are usually required if generalizations are to be made for a variety of situations. By contrast, calculation-based approaches begin with less direct measurements of exposure, e.g., measurements of production volumes or chemical and physical properties. Then, ultimate distributions of exposures are estimated through a series of calculations or mathematical models that attempt to represent the behavior of the substance. Although this second approach obviates che need for multiple measurements of fiber concentrations, it must depend on a series of assumptions and mathematical respresentations that may be exceedingly poor descriptions of real phenomena but that must be kept relatively simple to avoid excessive computational costs. The validity of Che input data--whether measured or simply estimated--may also be questionable. A conceptual model for determining fiber exposures is discussed in Appendix D. This model is useful for making rough exposure estimates when few or no measurements exist. It incorporates a scheme representing commercial and environmental flows of fibers, including such factors as natural occurrence, imports and exports, disposal, ambient concentrations, and biodisposition. The positive features of both approaches described above could be combined by calibrating the calculations against exposure measurements in known situations and then using the models to extrapolate or interpolate to unknown situations. Ideally, the actual amount of materials entering the human body would be measured for the most common conditions of exposure encountered by humans, taking into account differences in expo sure both over time and by location. 52 ASBESTIFORM FIBERS AMD THEIR SOURCES The major properties of the asbestiform fibers of concern to this committee are described in Chapter 2. Figure 3-2 shows a simple classification system for fibers with those properties. This classification is based on commercial use rather than on other distinctions among the fibers. Thus, commercially used asbestos and natural nonasbestos fibrous materials such as attapulgite are shown in che figure, whereas fibrous erionite, which is not used in commerce, is not specifically noted. Rather, such fibers are included in che general category "noncommercial natural mineral fibers." Asbestiform fibers probably account for che vast majority of the mass of most of these materials. Huggins e a_l. (1962) indicate that virtually all attapulgate consists of asbestiform fiberseven chough che fibers are short. The committee was unable to determine whether or not the material commercially exploited as attapulgite is all fibrous. By contrast, the fibrous form of erionite is rarer (T. Zoltai, University of Minnesota, personal comunication, 1983). There are many sources of exposure to asbestiform fibers. In addition to exposures from natural sources, humans are exposed during such activities as mining, milling, manufacturing, use, and disposal of fiber-containing products. Because the committee was asked to study nonoccupational exposures, this report is focussed on environmental discharges or releases, rather than on exposures in the workplace. Naturally occurring mineral fibers are a source of exposure through natural weathering or human disturbance of mineral deposits. Fibers measured in air far removed from known asbestos sources (Thompson and Morgan, 1971) or in drinking water are probably derived largely from such sources. Similarly, mining and milling of asbestos are direct sources of fiber release into air and, occasionally, into water. Manufacturing of synthetic fibers may be considered a processthatisparallel to the milling of asbestos. However, the fibers discharged during manufacturing probably represent a substantially smaller portion of the production output than would result from asbestos milling, because of differences in the processes and because cost considerations probably encourage greater efforts to minimize losses through discharge in the production of synthetic fibers. Manufactured fiber products can be divided into two major classes: primary products and secondary products. Primary products are those made directly from asbestiform fibers (see Table 3-1). The different fibers and their respective primary uses are not completely interchangeable. Secondary products are made from primary products. For example, asbestos paper and cord (primary products) may be used for making electric and 53 O9 A s b e itifo rm F ib e r* 00 9 CO 009 h* 0 bb S3 1 c !- --u *o <wm9aa ^--0>a0. o-- .5 8: w iO 9O O9 Mu UO --^ . u U E MO*4 -4O O Co 0 o CCI"M> sfaids o F ib ro u a P rim a ry P roduct in Which FibrouB M a te ria l is S u p p lie d B ulk F ric tio n Asbeatoa c 9 8 X XX wo uo u 4 .004*4 h 0o1 44 0 *4 u U4 04 .0 X u4 A u X u o c 04 W8 3 u Noe ^oi w8 a o o cu a9 V VA 9 H 4 0U V9 A Uu 00 u 4V ^g) 9 w M 4 3 Os 4 U AJ < 4U 3 4e u u .4o **01 w4 54 XxXxX 4O 4 00 43 ow X A m4 Oc * uo OS 4 ' 0* o0 u * 60 u CO U9 h 9 A M 8 4 W 4O 04 .coo u 4 04o> i g: U > eX <" a In t h ia And subsequent p re s e n ta tio n s , the m a te ria ls a re assumed to be la r g e ly a s b e a tifo rm . H ow ever,, the com m ittee does not know what p ro p o rtio n w ould be considered asbestiform , p a rtic u la rly fo r a tta p u lg ite . 55 thermal Insulation (secondary products). The major secondary uses of these fibers, based on total consumption, are shown In Tables 3-2 and 3-3. The United States Imports approximately 902 of the asbestos It uses, principally from Canada. On the other hand. It produces essentially all the attapulglte It uses and exports approximately 152 of Its total production (U.S. Bureau of Hines, 1982). The products that yield the greatest potential for exposure are not necessarily those produced in the greatest amounts. Conditions of use also influence exposure potential. For example, because the asbestos fibers in asbestos-cement pipe are relatively tightly bound In their cement matrix (as compared to other uses, such as in Insulation), they may present less potential for exposure than some other uses. These different exposure potentials are discussed in the following sections for the various classes of fibers: asbestos, attapulglte and other natural fibers, man-made mineral fibers, and other synthetic fibers. EXPOSURE POTENTIAL FOR ASBESTOS Types of Exposure Exposures to asbestos fall in the following four categories: occupational community (near known sources) consumer (use of manufactured products) general environmental Occupational Exposure. Because the heaviest exposures to asbestos occur in the workplace, they have received the most attention. There has been particular Interest in exposures associated with the following activities: asbestos mining and milling e asbestos product manufacturing shipyard activities Installation and removal of insulation in buildings brake lining manufacturing and replacement However, these occupational exposures are not of concern In this study except as they provide reference points and influence total exposure in conjunction with nonoccupatlonal exposures. Community Exposures. Closely related to occupational exposures are community exposures, which encompass exposures of residents in communities where there are significant industrial.sources of asbestos or other fibers. Such sources include mills, asbestos product manufacturing facilities, and brake manufacturing plants. These exposures can occur in 56 TABLE 3-2. O.S. Consumption of Asbestos Fibers in Secondary Products during 1982a Secondary Product Asbestos-cement pipe Asbestos-cement sheet Flooring products Roofing products Packing and gaskets Thermal insulation Electrical insulation Friction products Coatings and compounds All other Total Consumption (thousand of metric t"a) 37.6 10.8 49.0 7.0 13.6 0.2 0.7 52.9 25.0 49.7 246.5 Chrysotile (I) 57 100 99+ 100 99 0 100 100 100 99 93 aAdapted from U.S. Bureau of Mines, 1983 57 TABLE 3-3. Estimated D.S. Consumption and Production of Selected Nonasbestos Fiber Products Fiber and Use Attapulgite Drilling mud Fertilizers Filtering (oil grease) Oil and grease absorbents Pesticides and related products Pec waste absorbent Medical, pharmaceutical, cosmetic ingredient All other uses Total 1981 Consumption (thousands of metric tons) 173.5 50.2 18.7 178.2 106.5 105.8 0.06 79.5 712.46 References U.S. Bureau of Mines, 1982 Fibrous glass Wool Textile Fine fiber Total 1977 Production (thousands of metric tons) 1,100 340 5 1,445 Kirk-Othmer, 1980 Kirk-Othmer, 1980 J. Leineveber, Manville Corp., personal communication, 1983 Mineral vool Estimated Annual Production (thousands of metric tons) 200 Ceramic fiber ("current") High temperature insulation All others Total Carbon fiber (including uses in aerospace structures, automotive structures, and sporting goods) 20 1 21 0.56 J.D. Cornell,.0.S. Gypsum Co., personal communi cation, 1983 W.J. Breitsman, Carborundum Corp., personal communi cation, 1983 U.S. Bureau of Mines, 1982 58 a variety of ways. Fibers may be transported near the source via air and water or liberated from the clothes of a household member who works with the fibrous material. Community exposures are sometimes grouped with general environmental exposures. Suta and Levine (1979) have identified eight types of facilities that lead to community exposures to asbestos: mines and mills friction product plants gasket, packing, or insulation plants asbestos-textile plants asbestos-cement plants asbestos vinyl flooring plants roofing products plants asbestos paper plants Mines and millB are usually situated close to one another in rural communities. In the United States, all the mills are located within 100 km of the mine. According to the U.S. Bureau of Mines (1983), four active asbestos mining and milling operations existed In the United States In 1980, and there were three in 1982. The other facilities listed above can be located in either urban or rural settings. Those situated In or near urban areas have the greatest potential for exposing large numbers of people. Consumer Exposures. These exposures result from the use of specific products outside the workplace. For example, the wear of vinyl asbestos floor tile can liberate detectable levels of asbestos into room air, as can disturbance of old installed asbestos insulation (Sebastien e al., 1982). Other sources have Included hair dryers and other electrothermal appliances, which have been known to release asbestos In breathable form (Organization for Economic Cooperation and Development, 1982). Rice coated with talc has been reported to contain fibers that were apparently asbestos (Blejer and Arlon, 1973), presumably because the talc contained such filers. Asbestos fibers have also been reported in beer and wine (Cunningham and Pontefract, 1973) as well as in drinking water as a result of migration from asbestos-cement pipe (American Hater Works Association, 1974). Because both natural and waste asbestos can also reach drinking water through contamination of its source, drinking water Is usually classified as an exposure from the general environment. The Asbestos Information Association (1975) has reported more than 3,000 uses for asbestos. Many of these are probably hypothetical, many others entail very small quantities of asbestos and negligible potential for exposure, and yet other uses have disappeared over time. Nevertheless, there are scores and possibly hundreds of significant uses, most of which relate to the properties listed below: 59 thermal insulation electrical insulation chemical inertness tensile strength ability to act as a filter As shown in Table 3-2, the largest quantities of asbestos are used in the following products: . asbestos-cement sheet and pipe flooring products, e.g., vinyl asbestos tile friction products, e.g., brake and clutch linings packing and gaskets coatings, e.g., patching compounds e roofing products These products accounted for almost 90Z of U.S. consumption of asbestos in 1982. Some applications may have led to substantial earlier exposures through uses in filtration of parenteral drugs, filters for cigarettes, and insulation for home appliances such as hair dryers. Large amounts of asbestos were also formerly used in spray insulation for structural steel, especially in commercial and industrial buildings and in ships. Nonoccupational exposures attributable to the use of manufactured products have often been assumed to be relatively low, because almost all these products contain asbestos in a binding matrix, such as cement, plastic, rubber, or resin. However, exposures can occur if fibers are liberated from these matrices through such occurrences as traffic on asbestos flooring, wear of brake linings,! and abrasion or leaching from pipe or paper. The Consumer Product Safety Commission is undertaking studies to determine the amounts of asbestos that might be released during typical consumer use of some products (P. White, Consumer Product Safety Commission, personal communication, 1983). In addition, fibers are often released during the disposal of asbestos products. For example, demolition and renovation of asbestos-insulated buildings may result in elevated transient concentrations of fibers if proper precau tions are not taken. Exposures to asbestos may also result from the use of products made from asbestos-contaminated substances. . One example is talc, widely used as a pigment, extender, or processing aid in ceramic tile, paint, paper, plastics, and, in smaller quantities, as a component of cosmetic powders, foods, drugs, pesticides, and many other products. Although talcs can be virtually free of fibrous materials, they have also been reported to* *The material released from brake linings is in large part thermally altered (Harben, 1980). 60 contain asbestos fibers? in quantities sometimes constituting almost one-half the total product weight (Dement and Zumwalde, 1979). Talcum powders have also been reported to contain measurable amounts of asbestos (Rohl e a_l., 1976). Because more than 800 metric tons of talc are consumed annually in the United States (U.S. Bureau of Mines, 1982), exposures to asbestos may occur through these various uses. Another commercially important natural substance thac could be contaminated with asbestos is vermiculite (Bank, 1980). General Environmental Exposures. These exposures are usually attributable to fibers in ambient air and drinking water. To a lesser extent, they have resulted from ingestion of food and beverages. Asbestos fibers in air may result from human activities and from natural weathering of asbestos deposits. Drinking water may be contaminated by leaching from rocks, by deposition of^airborne asbestos,sor by runoff from dumps or ore deposits. Unlike community exposures, exposures to asbestos in the general environment cannot be clearly identified with a causative human activity. However, general environmental concentrations may come from natural sources or from the transport of fibers from human sources many kilometers away. The two principal routes of exposure to asbestos in the general environment are inhalation of ambient air and, in some areas, ingestion of drinking water. (After clearance from the lung, some of the inhaled asbestos is also swallowed with mucous secretions from the respiratory tract.) Exposures through the skin and possible ingestion of asbestos in foods are presumed to be much less important. Only the finer fibers remain suspended in ambient air for long times. Therefore, general environmental exposures to asbestos entail a larger proportion of fine fibers than do occupational or community exposures. Such exposures also occur 24 hours per day throughout the year--a total of 8,760 hours per year--in contrast to about 1,800 hours per year for occupational exposures and short, intermittent exposures from product use. The asbestos concent of drinking water is heavily influenced by the character of the rocks and soils present in the water supply basin. Another source is asbestos-cement water pipe. The release of fibers from that source appears to be relatively slow under some conditions (Hallenbeck, 1978), but may be considerable if the water is aggressive to asbestos-cement pipe (Buelow et al., 1980; Millette et *1., 1979a). Discharge of asbestos-containing wastes into water supplies could lead to ^Samples of talc mined in New York State contained tremolite and other particles with aspect ratios greater than 3:1. It is possible that most of these are not asbestiform fibers, as defined by this committee (T. Zoltai, University of Minnesota; R. Clifton, Bureau of Mines, personal communication, 1983). 61 high local concentrations, but such incidents have been infrequently reported. Croft (1982) has suggested that asbestos fibers in tap vater may enter ambient air in residences as the vater is sprayed or evaporates from the faucet. Asbestos appears to degrade in the environment exceedingly slowly. However, mechanical forces may break the fibers into successively smaller particles. Attack by acidic waters in the environment is possible, and some thermal decomposition may take place. Decomposition is likely when asbestos-containing wastes are incinerated (Cogley et al., 1982). The deposition and eventual burial of fibers in soils and sediments are probably the major natural processes by which asbestos leaves the ambient environment. Quantitative Exposure Estimates It is difficult to make quantitative estimates of exposure to asbestos. A common unit of cumulative dose for occupational exposures is obtained by multiplying the average concentration of fibers in workplace air by Che number of years that an individual worked there (full-time equivalent). The concentration of fibers in workplace air is expressed as fibers >5 um long/cm^, a* counted by the light microscope (LM) under specified conditions (U.5. National Institute for Occupational Safety and Health, 1977). A convenient way of abbreviating this expression of exposure is (fibers/cm3)yr. However, as discussed more extensively in Chapter 5, cumulative exposure measures do not take into account dose rate per unit time, duration of exposure, and ages at exposure. These three factors, particularly the third one, could be very important in determining effects on health. Another measure of exposure that allows comparison of different exposure situations is expressed as "lifetime fibers." This quantity is derived by integrating over time the product of fiber concentrations in media such as air and water (which are the sources of exposure) and the intake rates of those sources. Some of the fibers inhaled are soon exhaled and, thus, are not available for retention in the body. Because the exhaled portion has not been specifically determined and because that portion is presumed to be reasonably uniform over all inhalation exposure situations, the committee did not apply any adjustment factors in calculating lifetime fibers. Similarly, the majority of fibers in ingested water probably pass through the digestive tract without . penetrating its lining. The corresponding adjustment factor for determining lifetime fibers from this source also is not known, but would probably be different from that for inhalation. This difference should be remembered when interpreting the following calculations. When interpreting health effects information obtained from occupa tional studies, it may be necessary to convert nonoccupational exposures to equivalent occupational dose expressed in (fibers/cm3)yr. To do so, the number of lifetime fibers is divided by the volume of air inhaled at 62 work in 1 year. If one were Co assume an inhalation race of approxi mately 10 air per 8-hour workday (Incernacionai Commission on Radiological Protection, 1975) and 200 workdays per year, Che amount of air inhaled each work year would be approximately 2,000 m3, or 2 x 10^ cm3. Therefore, approximately 2 x 10^ lifetime fibers would be inhaled during an occupational exposure of 1 fiber/c3 for 1 year. To extend this calculation, as many as 4 x 10? fibers would be inhaled annually by a worker exposed to air containing the U.S. Occupational Safety and Health Administration (0SHA) standard of two LM fibers/cm3--a count based on fibers >5 um long counted with a light microscope.3 a working lifetime exposure to 2 fibers/cm3 could conceivably result in inhalation of 2 x 10H fibers; however, the number of people recently being exposed to such quantities is probably quite small--perhaps a few thousand. Occupational exposures of 10^0 co 1011 lifetime fibers may accrue to a few hundred thousand people, and perhaps a million or so others may be exposed to 10? lifetime fibers through peripheral sources (Daley et al., 1976). At the other end of the spectrum, Suta and Levine (1979), who sunsnarized a great deal of data related to asbestos exposure have estimated that the rural U.S. population (60 million people) might be exposed to concentrations ranging from 0.01 to 0.1 ng/m3. They estimate further that the urban U.S. population--perhaps 170 million people--is exposed to asbestos concentrations higher than 1 ng/m3 in ambient air. Spurny et al. (1979) also presented data showing fiber concentrations of approximately 1 ng/m3. If we choose a nominal conversion of 30 LM fibers per nanogram,^ an annual inhaled air volume of 7,300 m3 (20 m3/day x 365 days), and a 70-year lifespan, a lifetime exposure could reach 10^ to 10& fibers for rural dwellers and 10? fibers for the less exposed urban dwellers. Virtually none of the population would experience lifetime exposures as high as 10^ fibers. Most community exposures might average about 10 LM lifetime fibers for perhaps 15 million people, a figure consistent with the distribution of ambient air exposures (Suta and Levine, 1979). For example, people living near metal mines that contain asbestos-contaminated ores might experience such levels (Bank, 1980; Kuryvial et al., 1975), whereas people living very near asbestos mines and mills would probably experience considerably higher levels. Exposures in asbestos-insulated school buildings have caused considerable concern. Asbestos concentrations in schoolroom air have been estimated to range from approximately 10 to more than 1,000 ng/m3 3ln early November 1983, OSHA issued an emergency temporary standard (ETS) for workplace asbestos that lowered the permissible exposure to 0.5 fiber8/cm3 (U.S. Occupational Safety and Health Administration, 1983), but later in the month a stay was issued on the ETS. ^The committee used this conversion factor while recognizing its variability (Schneiderraan et al., 1981). 63 (Nicholson et *1., 1978; U.S. Environmental Protection Agency, 1980). Assuming that 1 ng/m^ contains 30 LM fibers, that exposure occurs during 1,000 hours of school yearly for 12 years of school, and that the breathing rate is approximately 0.75 m^/hr, one would estimate the exposures to range from approximately 3 x 106 to 3 x 10s lifetime fibers for the 2 to 6 million students attending such schools. The 100,000 to 300,000 teachers in those schools could accrue higher lifetime doses from these concentrations (U.S. Environmental Protection Agency, 1980). There are few measurements or calculations for estimating exposures from the use of manufactured products. In one study, Sebastian et al. (1982) reported concentrations of approximately 30 ng/m^ in the indoor air of buildings with vinyl asbestos flooring. This concentration is converted to a lifetime exposure of approximately 5 x 107 fibers, assuming 2,000 hours of exposure annually over 40 years. In another report, Le Guen and Burdett (1981) recorded concentrations as high as 10 ng/m-3 in public buildings with asbestos insulation. Most other product exposures would be much less frequent or prolonged, although possibly of higher intensity. Thus, although some uses of manufactured products may result in people being exposed to relatively high fiber concentrations, use of manufactured products probably does not contribute greatly to the lifetime exposure of the average urban dweller. Exposures to asbestos in drinking water may have an impact on human health. A committee of the National Research Council (1983) has summarized several studies on this subject. In Connecticut, exposures ranged from 104 to 7 x 10^ electron-microscope fibers per liter, or approximately 170 to 12,000 LM fibers per liter. In San Francisco, concentrations as high as 3 x 10^ LM fibers/liter have been reported, and in the Puget Sound area, levels ranging from about 10^ to 3 x 10^ LM fibers/liter were found. At an annual water consumption rate of 500 liters for 70 years, lifetime exposures could run from 6 x 10& to 10^ fibers. Suta and Levine (1979) reported that asbestos mass concentrations in drinking water ranged from a high of about 100 ug/liter to less than 0.01 ug/liter. Some of the data from which this distribution was calculated are suspect. If taken at face value, however, these data suggest a lifetime ingestion of 4 x 107 to 4 x 1011. LM fibers, assuming 30 fibers/ng and an annual water consumption of about 500 liters. Approximately 10Z of the population (23 million people) would receive lifetime exposures greater than 10? fibers, and not much more than 1Z (2 million) would receive lifetime exposures greater Chan 10^ fibers. Nevertheless, these exposures--in terms of fibers ingested--are greater than the lifetime exposures from inhalation of ambient air. As noted in Chapters 5 and 6, however, it has been difficult to document adverse health effects of ingested asbestos. 64 Ingestion of asbestos in foods probably does not constitute a large portion of total exposure. For example, Cunningham and Pontefract (1973) found 1 to 10 million electron microscope fibers per liter of various beverages. This is approximately 0.02 to 0.2 million IX fibers/liter, a range similar to that for drinking water. However, some of the fibers found in beverages probably originated from filters used in processing. Relative Contributions of Various Sources. Meylan e rl. (1979) presented data suggesting that asbestos production, use, and disposal could result in annual emissions of 100 to 300 metric tons into the air and 50 to 100 metric cons to surface water. The upper figures reported by these investigators are based on the assumption that the incineration of asbestos-containing wastes is a major source of emissions--an assumption that is probably not justified because some of the asbestos is likely to undergo thermal breakdown, which occurs as a function of temperature and type of fiber. Cogley et al. (1982) estimated chat manufacturing processes discharge approximately 100 metric tons of asbestos into Che air each year and about the same amount into water. They believe that emissions into air from disposal activities are minor. They also estimated that air emissions from mining and milling could reach 1,400 metric tons per year. Although none of these estimates have been reported to be very accurate, they can be used to check the reasonableness of ambient measured concentrations. A 1-ltm-thick layer of air over the 48 contiguous United States contains about 10^6 m-* of air, and all the rivers in the country discharge about 2 x 10^ liters of water per year (Brown e aJL., 1976). Assuming chat the air mass moves across the United States in about 5 or 6 days (1.5Z of a year), then about 1.5Z of the annual asbestos discharges from manufacturing and use would yield concentrations in this air layer of about 0.2 to 0.5 ng/m^ and mining and milling would yield up to 2 ng/m^. Assuming that wet and dry deposition would remove most of the asbestos on Che rest of its way around the world in approximately 1 month, the measured variation from 0.01 ng/m^ to 1.0 ng/m^ in air far from industrial sources could well be explained by the discharges estimated. Discharges from manufacture and use primarily involve paper or friction products such as brake linings. Additional discharges would result from the natural weathering of deposits or incidental uses of asbestos such as in road surfacing (Serra and Connor, 1981). The discharges from mines and mills, which consist of fibers and bundles larger than those from other sources, are presumably deposited relatively close to their sources and do not contribute as much to general ambient concentrations. If all discharges into water were confined to rivers, the average concentration would simply be the quotient of the discharge rate and the aggregate river flow rate, or approximately 0.02 to 0.05 pg/liter. The latter figure is close to the median value estimated oy Suta and Levine 65 (1979). However, sedimentation as well as discharges into lakes would reduce Che average concentration, suggesting that natural sources of fibers such as serpentine deposits may be responsible for a significant amount of Che waterborne asbestos. Of the sources attributable to human activity, asbestos paper manufacturing appears to account for Che largest amount (Meylan et , 1978). Asbestos-cement is also a large contributor (Cogley et_ a^.., 1982). Accuracy, Uncertainty, and Reliability of Estimates. The estimates of asbestos exposures discussed above are based on a series of data inputs, assumptions, models, and calculations that are individually and collectively rather tenuous. As noted in Chapter 4, many difficulties accompany attempts to measure levels of asbestos and to convert various measurements to comparable units. One analytical chemist (D. M. Coulson, personal communication, 1982) has stated chat a given laboratory report is at best a ballpark estimate and that inter laboratory variations of several hundred percent are not unusual. . ... A particularly critical assumption is that dose measured in either fibers/cm3 multiplied by years of exposure or in total lifetime fibers is the biologically significant exposure variable. Thus, the committee did not attempt to estimate details of the exposure pattern over time. In Chapter 7, it is shown chat this assumption provides a reasonably good fit to the data when assessing lung cancer risks, but that age at first exposure and duration of exposure may be more important for mesothelioma risks. The estimates are also based on the assumption that exposures are constant over periods as long as 20 to 70 years. Given the rise and fall of the asbestos industry, such an assumption is unlikely to be generally true. If most of the measurements were taken at times of high production and use rates, the lifetime exposure estimates could be grossly exaggerated. The estimates of populations at risk are also crude. For example, no details of living, shopping, and working patterns were included in estimates of exposures to airborne concentrations and no firm relationships were established between Che content of ster supplies, the content of delivered cap water, and Che actual populations consuming them. The inevitable conclusion is that errors in estimating the lifetime fiber exposures for the various exposed populations could be very large. Differences between the least exposed and most exposed persons in a given population could easily be several orders of magnitude, and even the average exposure of the population could be considerably in error. Although the size of. a specific population with known exposure conditions can be estimated with more certainty, it too can be substantially in error. The diversity of uncertainty factors and the lack of measurement of their variability make quantitative uncertainty estimates untenable, except in a very subjective way. Thus, the numbers cited in the previous 66 sections can be used only to suggest where attention should be focussed, not to guide firm decisions. They are useful, however, in indicating the current best estimates of the relative levels of exposure in different situations. Note that the deficiencies in estimating past exposures lead to uncertainties regarding the dose-response relationships for health effects. Trends. Little can be aaid about trends in exposures to asbestos. Occupational and related exposures increased rapidly after about 1940 and then decreased in the 1960s after risk factors associated with such exposures became known. Regulatory standards and a decline in the demand for asbestos products have led to lover occupational exposures and possibly to a reduction in comunity and general environmental exposures. (See Figure 1-1; (7.S. Environmental Protection Agency, 1982.) For manufactured products, the trends may be mixed. Spray asbestos insulation is no longer being installed, and many of the filtration and appliance insulation uses have diminished or stopped (Consumer Product Safety Conanission, 1983). Some uses have continued, partly because of assumed low emission potentials or lack of adequate substitute materials, for example, in vinyl tiles, brake linings, and asbestos-cement water pipe. After disposal of asbestos-containing products, especially old insulation and building materials, fibers formerly bound in a matrix may be liberated. This disposal-related exposure could continue to increase for many years if secure burial or decomposition techniques are not used. Overall, the distribution of lifetime exposures will probably shift toward lower levels, although the growth of the population will increase the number of people at risk for each class of exposure. Population Exposures. Societal risk depends both on the levels of risk corresponding to the individual exposure levels and on the number of people so exposed. If risks are proportional to lifetime fiber exposures, as the linear dose-response models assume, then relative societal risk can be modeled by multiplying the various exposure levels by the number of exposed persons. The same result can be obtained by adding the logarithms of the two variables--a natural procedure for numbers that range over many orders of magnitude. If the exposure levels and population exposed to each level are plotted on log-log graph paper (as in Pigure 3-3), then the diagonal lines are isopleths of equivalent total population exposure, measured as lifetime fibers for the particular population. The isopleths would also delimit regions of equivalent societal risk, with points near the vertical axis representing low exposures of large numbers of people and points near the horizontal axis indicating high exposures to few people. In general, the further away from the lower left-hand corner, the higher the societal risk. The horizontal axis indicates individual exposure. 67 ESTIMATED U S. POPULATION POTENTIALLY AT RISK (number o l people) INDIVIDUAL ASBESTOS EXPOSURE (lifetime fibtrsl FIGURE 3-3. Estimated lifetime exposures and numbers of people in various groups potentially exposed to asbestos. The points represent approximate estimates, and the lines indicate the ranges of uncertainty. As constructed, the uncertainty is about an order of magnitude for the population estimates and about two orders of magnitude for the exposure estimates. The conaittee was unable to make explicit estimates of the uncertainty limits, which would vary among the different populations. The points were derived from measurements or models for the groups represented; many of the points (e.g., the schoolchildren point) can be traced back to data provided in the section in this chapter entitled Quantitative Exposure Estimates. 68 Figure 3-3 also shows selected exposures^ estimated by the connittee as described in the section entitled "Qiantitation Exposure Estimates." Each source is represented by a point, and the horizontal and vertical lines extending from those points indicate the uncertainties in the variables. The population estimates are generally more accurate than the exposure estimates. If one accepts the estimates, the following conclusion can be drawn from this chart: assuming total population exposures and risks are the criteria governing the level of concern, then some of the nonoccupational exposure classes may rival some occupational exposures in overall population risk. For most of the populations noted in the figure, however, it would be very difficult to detect health effects attributable to ambient concentrations of asbestos because of the small relative excesses expected (Marsh, 1983; National Research Council, 1983). EXPOSURE TO OTHER NATURAL MINERAL FIBERS Some natural fibrous materials other than asbestos have the properties of asbestiform materials described in Chapter 2, but the only asbestiform variety of mineral with commercial importance comparable to that of asbestos is attapulgite. Although the common acicular crystals of wollastonite resemble fibers, none is known to possess the properties of asbestiform fibers as defined by the committee in Chapter 2. Of the remaining mineral fibers listed in Appendix B as possibly asbestiform, only meerschaum, a block fibrous sepiolite, is of some commercial importance. A few metric tons of meerschaum are -imported each year, and essentially all of it is carved into smoking pipes (U.S. Bureau of Mines, 1982). The committee did not consider meerschaum further because this material is used in such small amounts and because it remains intact in its natural form and does not readily release fibers. The exposure of humans to other known natural asbestiform fibers is associated with natural weathering, the incidental use of fibrous materials in road~surfacing operations and in similar applications, or the occurrence of fibers as impurities in other minerals of commercial importance. For example, asbestos may be found in deposits of talc and a few other materials. Of the natural asbestiformvmihe'rais not commercially exploited, the committee reviewed only the fibrous zeolite called erionite, primarily because of its possible association with . cancers in Turkish villages (Artvinli and Baris, 1982; Lilis, 1981). Figure 3-4 shows areas of the United States believed to be possible "incidental" sources of asbestiform fibers. These areas contain mineral deposits that could be, but are not necessarily, asbestiform (Kuryvial et al., 19.74). . . .. ^Estimated number of people in a group are shown versus the estimated exposure per individual. Individual exposures within the group can easily span four or five orders of magnitude, and even the best representative value can be in error by an order of magnitude. 69 FIGURE 3-4. Areas containing possible asbestiform phases of minerals. From Kuryvial et al., 1974. Attapulgite Atcapulgite belongs to a group of commercially defined clays known as fuller's earths. It is a nonplastic clay, usually with a high magnesium content and with decolorizing and purifying properties. The United States is a leading producer of attapulgite, essentially all of which is mined in the vicinity of Attapulgus, Georgia, and Quincy, Florida. Domestic consumption is currently greater than 700 thousand metric tons--almost triple that of asbestos. An additional 100 thousand metric tons is exported (U.S. Bureau of Mines, 1982). Attapulgite consists principally of short asbestiform fibers of the mineral palygorskite Gkiggins et al., 1962; Zoltai and Stout, 1984). As with other minerals, some material will exhibit asbestiform properties to a greater degree than will other material. Of the uses listed in Table 3-3, some are more likely to involve higher quality fibers (S. Ampien, U.S. Bureau of Mines, personal communication, 1983). Material of lower quality, that is, having the characteristics of asbestiform 70 fibers Co a lesser extent, is acceptable for use in oil and grease absorbents, pesticide fillers, and pec vaace absorbents. In France, attapulgite is used in drugs for the treatment of gastrointestinal diseases (Bignon e al., 1980); in Che United States, it is a component of nonprescription antidiarrheal drugs (Physicians' Desk Reference, 1983). Bignon e al_. (1980) reported Chat the French drugs contain fibers as long as 3.6 urn (median length, approximately 1 um) with typical diameters of approximately 0.03 um. Lengths of 0.5 um to 1 um appear to be typical in attapulgite from the Uhited States (Huggins et aK, 1962). The committee was unable to find data on airborne concentrations of attapulgite fibers. Because attapulgite is mined and processed in a region of relatively low population density, population exposures from these operations should be relatively low. Some uses, such as in pet waste absorbents, fertilizers, and pesticides, could release substantial amounts of attapulgite into the air. Attapulgite has also been found in water supplies (Hillette et al., 1979b). The levels of exposure to attapulgite and the numbers of people exposed could rival chose for asbestos, even when measured as mass rather than as number of fibers. Because of the smaller size of attapulgite fibers, both in length and diameter, the numbers of fibers and their respirability would probably exceed those for asbestos. Clearance mechanisms, such as phagocytosis, would probably also be more effective. Bignon et al. (1980) reported two case studies in which attapulgite fibers were found in human lungs and urine. Erionite Unlike the population in parts of Turkey, no one in the United States is likely to live in dwellings constructed of erionite-containing materials. However, there are several deposits of zeolites in Arizona, California, Nevada, and Oregon, and some of them have been reported to contain fibrous erionite (Rom et l., 1983; Wright et al., 1983). Some of this material has been mined, possibly for use in ion-exchange processes, for retention of nitrogen in fertilizers, and for use in concrete aggregate or road surfacing. Some of these applications could lead to significant local air concentrations, as would natural weathering. The natural processes could also be sources of concentrations in drinking water. However, because ambient erionite concentrations have not been reported and because the population densi ty in the intermountain western states is generally low, the committee believes there are few significant exposures to this substance. Erionite fibers are similar to asbestos fibers, although they are probably, on average, shorter. Their maximum length is about 50 um. Widths have been reported to range from 0.01 to 5.0 um, averaging 0.1 um in some samples (Suzuki, 1982) but most commonly ranging from 0.25 to 1.5 um in others (Wright et a_l., 1983). 71 EXPOSURE TO MAN-MADE FIBERS Man-Made Mineral Fiber* Man-made mineral fibers (MMMFs)--sometimes called man-made vitreous fibers--are glassy and amorphous rather than crystalline. The MMMFs include fibrous glass, mineral vool (i.e., rock wool and slag wool), and ceramic fibers. MMMFs compete with asbestos in some markets and have replaced it in others. Because they are amorphous, MMMFs do not split longitudinally; they do sometimes break transversely, yielding shorter, but not thinner, particles. Fibrous Glass. Fibrous glass consists of monofilaments of silicate or borosilicate glass usually produced by melting amorphous silicates and forcing the melt through an orifice, followed by air, steam, or flame attenuation. The current processes allow production of relatively narrow ranges of fiber sizes, depending on the commercial need. The three main classes are textile fiber, wool fiber, and fine fiber, and there are many subclassifications within these broad classes. Textile fiber is the coarsest, typically 10 to 15 urn in diameter,6 but may range from 6 to 20 ua (JRB Associates, Inc., 1981). Wool fiber usually ranges from about 3 to 10 urn in diameter (Konzen, 1982), but can be 1 to 25 um (JRB Associates, Inc., 1981). Pine fiber is usually considered to be 1 um nominal diameter or less.6 Fibrous glass accounts for approximately 802 of all MMMFs. At least 902 of the fibrous glass is produced as wool fibers, which are used primarily for thermal or acoustical insulation and for filtration. The largest category by far is thermal insulation, most of which is used to insulate buildings. These fibers are also used as duct linings, as insulation for pipes and appliances, and in ceiling tiles for acoustical insulation.^ Textile grades of fibers are used extensively in reinforcing resinous materials, e.g., in "fiber glass" automobile bodies or boat hulls (Watts, 1980). They are also used in various cloths (especially for draperies), papers, electrical insulation, and cording. Textile grades account for 52 to 102 of all fibrous glass.6 Approximately 0.52 by weight of fibrous glass produced falls within fine fiber size ranges. Because these fibers ate expensive to produce, they are found only in specialized markets. Their two major uses are thermal insulation for aerospace vehicles and filtration, mostly to reduce the particulate content of air going to sensitive areas, such as the clean rooms of semiconductor plants.6 The aerospace insulation is usually made as a fiber blanket sandwiched between metal or woven fiber cloth (Health and Safety Cosmission, 1979) and is installed between the inner and outer shells of the vehicle. The filter material is usually incorporated into a paperlike matrix with a small amount of binder.6 6j. Leineweber, Manville Corp., personal communication, 1983. 72 Less than 10Z of all glass fibers are smaller than 3 um in diameter. Fine fiber diameters are generally smaller than 3 um (Konzen, 1982) and cluster around 1 pm, but may range from 0.2 um to 5 um, with typical airborne fiber lengths ranging from 5 to 20 um (Esmen, 1982). Less than 2Z of all other fibrous glass categories are smaller than 3 Um in diameter. Very fine or superfine grades of fibrous glass have diameters predominantly less Chan 1 um. Thus the majority of the respirable fibers produced are probably in fine fiber grades; however, the uses for fine fibers do not appear to offer great opportunities for exposure. For example, the few measurements that have been made indicate that few fibers escape into che air during air filtration applications; otherwise, the utility of Che filters would be compromised.? Occupational exposures to fibrous glass have tended co be considerably lower than those to asbestos, mainly because of innate processing differences (JRB Associates, Inc., 1981) and the higher cost of producing fibrous glass. Typical levels in workplaces have been approximately 0.1 fiber/cn>3 as measured with a light microscope (Balzer, 1976; Corn, 1976; Esmen, 1982; Health and Safety Commission, 1979; Johnson et al., 1969; Shannon et al., 1982), although concentrations may exceed 10 fibers/cm3 in areas where fine fibers predominate (JRB Associates, Inc., 1981). Concentrations were probably higher before the use of oils and binders to suppress dust (Hartung, 1982), which were used relatively early in Che industry. The fact chat atmospheric concentrations of fibrous glass in Che workplace are lower than those for asbestos by about an order of magnitude suggests that plant emissions might be lower by about Che same factor on a pound-for-pound production basis. Although total production is currently greater for fibrous glass than for asbestos products, the portion of fibers in che respirable range is lower. Thus, tocal emis sions of fine glass fibers are probably considerably lower Chan asbestos emissions. Balzer (1976) reported that ambient concentrations of fibrous glass in California air were approximately 0.002 fibers/cm3 and chat che average diameter of che fibers was 4 um; 2/3 of the fibers were detectable by optical microscopy. Although Che significance of this isolated report is uncertain, Che reported concentration, which amounts to 2,000 fibers/m3, is much higher than any reported for asbestos in ambient air, even in urban areas. If manufacturing emissions are lower for fibrous glass chan for asbestos, as suggested earlier, some other explanation would be needed if the Balzer counts prove to be accurate and representative. For example, a point source might have been nearby. One possible nonmanufacturing source for glass fibers is in-place building insulation, which contains the fibrous material in relatively loose form (albeit with binders). In addition to being exposed from outside air, a majority of the U.S. population is probably exposed to some extent by living or working in ?J. Leineweber, Manville Corp., personal communication, 1983. 73 buildings with fibrous glass insulation. The exposures would probably be highest shortly after installation or disturbance of the insulation. The coassittee was unable to locate reports of measured concentrations of glass fibers in buildings. Many products contain fibrous glass. Smith (1976) has reported 35,000 individual product applications. Even if the vast majority of them are hypothetical or trivial, many possible sources of nonoccupational exposure still exist. However, fibrous glass production and its use in building insulation are likely to be the major sources. Mineral Wool. Two types of fibers fall under the general rubric of mineral wool. Rock wool is the term for glass fibers made by melting natural igneous rocks and then drawing, blowing, or centrifuging the melt into fibers. Slag wool is made by similar processes, except that the feedstock is the already-melted slag from iron blast furnaces or other metal-slagging processes. Total mineral wool production in the United States is estimated to be approximately 200,000 metric tons.8 Because of the generally less elaborate processes for manufacturing these two types of mineral wool, their diameter distribution tends to be broader chan that of fibrous glass, and Che product contains relatively large amounts of ''shot" or residual unfiberized droplets of the molten material (Pundsack, 1976). Rock wool and slag wool can serve many of the same purposes as fibrous glass. Most of it is used for either building insulation or specialty "technical" insulation for industrial processes. It is applied primarily as thermal insulation, but some is used for sound dampening.8 Applications include power plants, chemical processes, and ocher heavy induscrial manufacturing. Much smaller amounts are used in commercial buildings and even less in residences.8 in current practice, binders are added to the mineral wool so that it can be supplied in the form of blankets or other shaped forms, rather than as loose fiber. The reported measurements of slag and rock wool fiber concentrations in the workplace fall between those found for asbestos and those for fibrous glass, as one might expect from the processes involved and the relative costs of production. Most of the reported fiber concentrations range from 0.2 to 0.5 fibers/cm^, but concentrations as high as 2 fibers/cm^ have been observed (Esmen, 1982; Health and Safety Commission, 1979; Ottery et al., 1982). Per pound of throughput, fiber emissions could be expected to be intermediate between fibrous glass and asbestos. Because the production is lower than that for fibrous glass and the uses are somewhat more likely to be industrial than residential, it is likely that population 8j. 0. Cornell, U.S. Gypsum Corp., personal communication, 1983 74 exposures Co ainersl wools are generally lower Chan Chose for fibrous glass, alchough Che proporcion of fine fibers may be greacer. The aoainal diameter for aineral wools appears Co be siailar Co chac for glass wools--approximately 6 to 8 pa. However, Chere is a greater tendency for these wools Co contain fine fibers. In Che United States, as much as two-thirds of Che fiber counC may be less Chan 3 pm in diameter (Essen, 1982). In soae European roclt wool plants, however, Che portion of respirable fibers may be considerably lower (OtCery et al., 1982). Ceramic Fiber. Ceramic fibers are produced by aelcing kaolin clay or a combination of alumina and silica to fora aluminosilicate glasses and then blowing che melc to fora Che fibers. Mosc of Chese fibers are used for high ceaperacure insulation. Soae alumina and zireonia fibers are produced for even higher Ceaperacure applications; Chese are che fibers mosC ofcen referred to as refraccory (Health and Safety Commission, 1979). ToCal annual production is approximately 20,000 metric tons, but chere is a capacity Co manufacture at least double that figure.9 Ceramic fibers are used moady for high temperature insulation. Smaller quantities are used for expansion joint stuffing. Approximately 8SZ of the fibers produced are sold in the form of blankets or modular building blocks. Bulk fiber, paper, and textile forms are also marketed. The principal industrial purchasers of ceramic fibers are manufacturers of steel and other metals, ceramics, petrochemicals, and catalytic converters for automotive vehicles. Typical uses include insulation for kilns, furnaces, ovens, other types of heaters, and, to a lesser extent, consumer appliances. Virtually all the fibers produced are encapsulated or incorporated into structures. The target range of diameters is 2 to 3.5 pm, but the diameters can range from less than 1 pm to 12 pm. Fiber lengths are often several centimeters, but many fibers a few micrometers in length are also produced (JRB Associates, Inc., 1981).10 In general, occupational exposures to ceramic fibers seem to fall withic the same range as those for aineral wools, i.e., usually well under 1 fiber/cm^, but they occasionally exceed that figure (Esmen ejt al., 1979; Fowler, 1980; Health and Safety Conmission, 1979). Airborne fibers have a median diameter of about 1 pm and a median length of about 10 Pm. Thus, many of the airborne fibers appear to be respirable (Esmen, 1978). Given the relatively low production volume, the moderate workplace concentrations, and the specialized applications, however, ceramic fibers are probably responsible for rather low general population exposures. $W. J. Breitsaan, Carborundum Corp., personal communication, 1983. ^Information also received from W. J. Breitsman, Carborundum Corp., personal coBsminication, 1983. 75 Exposure to Other Man-Made Fibers In comparison Co Che MMMFs, ocher fibers chaC might be considered asbesciform sre produced in relatively small quantities. Among Chese are fibers of carbon, graphice, alumina, boron, pocassium cicanace, silicon carbide, and a variety of organic fibers such as Aramid or PTFE (polytecrafluoroechylene, or Teflon). The organic fibers usually enCer the same general markeCs as Che cexcile grade glass fibers and are correspondingly chick in diamecer. Because Chese fibers are noc of respirable size, exposures Co chem are noc examined in Chis report. Even if they were respirable, ic would be difficult Co classify chem as ssbestiform under chis committee's definition. Host of che inorganic man-made fibers are markeced principally as reinforcement for various kinds of composite materials used in fabricating structures or equipment Chat must be strong but lightweight. For example, alumina fibers can be incorporated in an aluminum melt Co produce fiber-reinforced metal (Chemical and Engineering News, 1980). Pocassium cicanace was markeced for reinforcing plascic friction materials in brakes, filters, and high temperature insulation, buc was withdrawn from the markec in Che mid-1970s (C. F. Reinhardt, E. I. duPont, personal communication, 1978). Such fibers are also generally coo large in diameter to be respirable, and they are presumed to have a very low exposure potential because they are sealed rather permanently in their matrix. Except for the carbon fibers, inorganic fibers are not discussed further in this report. At present, their production is limited, and their uses would not be expected to lead Co substantial exposure. In chis document, Che term carbon fiber is used Co describe both the carbon and graphite fiber classes, although such fibers may be manufactured by different processes (Beardmore et si., 1980; Zumwalde and Harmison, 1980). These fibers are typically of the same general sizes as man-made wools, i.e., approximately 7 ym nominal diameter, and at least in normal use, they fall mostly within a quite narrow range of diameters (Johnson, 1982). They may exceed 2 or 3 mm in length. Less Chan 25X of them are shorter Chan 80 yo and have diameters less than 3 ym (Delmonte, 1981; Zumwalde and Harmison, 1980). There is some evidence of longitudinal cleavage after these fibers have been burned or worked (e.g., after sawing a composite that contains them) (Wagman et a_i., 1979). Like the other mineral fibers mentioned in Chis section, most carbon fibers enter the reinforced materials market, e.g., in aerospace, automotive, and sports products such as golf club shafts. The matrices for the fibers are typically epoxy or polyimide resins (Kear and Thompson, 1980). The fibers are often Created first with another plascic product such as tetrafluoroetnylene to make Chem less brittle (Harben, 1980). The U.S. Bureau of Mines (1982) reported that only about 250 metric tons of high-modulus (i.e., with the high-strength properties most like an asbesciform fiber) carbon fibers were produced in the United  76 States in 1980, but the rate of production growth it high, having doubled almost every year for the past 5 years (U.S. Bureau of Mines, 1982). One unusual new use of these fibers is in surgical implants that are reported to improve the healing of torn ligaments and tendons (Arehart-Treichel, 1982). The committee found little information on exposures to carbon fibers. Both the small quantities produced and their applications primarily in composites suggest that little exposure occurs. The greatest opportunity for human exposure probably arises when the composite is accidentally or intentionally burned. Although the matrix is often decomposed under chose conditions, the fibers remain relatively intact (Wagman et al., 1979). In fact, the first concerns about carbon fibers involved their potential effects on electronic systems after a fire had released them as conducting IVires" ,.in semiconductor circuits. Overall, nonoccupational expoaurea to carbon fibers are probably extremely low in comparison with those to most of the other asbestiform fibers discussed in previous sections. The potential for such exposures could change, however, if the use of carbon fibers continues to grow and diversify. SUMMARY AND RECOMMENDATIONS In assessing exposures to asbestiform fibers that could cause adverse health effects, the committee considered (1) synthetic and natural fibers that are used extensively in commerce and (2) natural fibers that are widely distributed by natural processes. As examples of commercial fibers, the committee assessed exposure to chrysotile, crocidolite, and other asbestos fibers; attapulgite; fibrous glass, mineral wool, and ceramic fibers; and carbon fibers. Fibrous erionite was chosen as an example of a noncommercial, naturally produced and distributed asbestiform fiber. Asbestos and attapulgite fibers are also released by natural processes, as are other natural fibers found in ambient air. Many types of information would be helpful in assessing population exposures to various materials. However, because the most readily available information usually pertains to production or consumption levels, use patterns, fiber dimensions, and populations exposed, this type of information was used for the exposure assessment described in this chapter. Current chrysotile consumption in the United States is approximately 230,000 metric tons per year. Attapulgite production is greater, and fibrous glass production apparently greater still. Mineral wool, crocidolite, ceramic fibers, other types of asbestos, and carbon fibers are produced or used in smaller quantities, approximately in that descending order. 77 All types of asbestos have fibers within the respirable range, i.e., less than approximately 3 am In diameter, as do attapulglte and erlonlte. However, the nominal diaaeters of aost of the synthetic fibers exceed the respirable range. Exceptions are some types of ceramic fibers, which are near the upper Halt of the respirable range, and the fine grades of fibrous glass. Vlth the possible exception of carbon fibers, aost synthetic fiber products Include soae fibers of respirable sire. Carbon fibers nay split to finer, respirable fibers upon mechanical or thermal stress. Asbestos fibers can be hundreds of micrometers long, although aost of them detected In the aablent environment far from production sources are less than 3 urn long. Attapulglte fibers are generally less than 20 am long. Target lengths for synthetic fibers are often measured In centimeters rather than in micrometers, but many shorter fibers are also produced. . Many of the commercial fibers are used only In binding matrices such as In reinforced plastics or paper products. Fibrous glass, mineral wool, attapulglte, and to soae extent ceraalc fibers are sometimes used unbound as relatively loose fibers. Because of their limited applications and present low production volumes, ceraalc and carbon fibers probably have a relatively low exposure potential. Because of Its limited natural occurrence, the same Is true of fibrous erlonlte. Increased production and diversification of use is likely to be a significant factor for future exposures to carbon and ceraalc fibers. The use of asbestos In the United States has declined In recent years. As vlth most materials, lack of Information on exposures to the various fibers limits the ability of investigators to Identify the adverse health effects resulting from such exposure. Thus, there Is a need to Improve this Information base and to establish correlations between exposures and health effects. REFERENCES American Vater Works Association. 1974. A study of the problem of asbestos In water. J. Am. Water Works Assoc. 66:1-22. Arehart-Treichel, J. 1982. A healing scaffold. Sci. News 122: 219. Artvinll, M., and 7. I. Baris. 1982. Environmental fiber-induced pleuro-pulmonary diseases In an Anatolian village: An epidemio logic study. Arch. Environ. Health 37:177-181. 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Assessment of risks posed by exposure to low levels of asbestos in the general environment. Prepared for Instltut fur Wasser, Boden, und Lufthyglene des Bundesgesundheltsamtes. No. 4. Dietrich Relmer Verlag, Berlin. Sebastian, P., J. Blgnon, and M. Martin. 1982. Indoor airborne asbestos pollution: From the ceiling and the floor. Science 216:1410-1413. Serra, R. K., and M. A. Connor, Jr. 1981. Assessment and Control of Chrysotlle Asbestos Emissions from Unpaved Roads. EPA-450/3-61-006. Environmental Protection Agency, Washington, D.C. Shannon, H. S., M. V. Hayes, J. A. Julian, and D. C. F. Muir. 1982. Mortality experience of glass-fibre workers. Presented at the Bio logical Effects of Man-Made Mineral Fibres, Occupational Health Conference, Copenhagen, April 20-22. World Health Organization. Smith, H. V. 1976. History, processes, and operations In the manufac turing and uses of fibrous glass--one company's experience. Pp. 19-26 in Occupational Exposure to Fibrous Glass. Proceedings of a Symposium. Pub. No. 76-151. National Institute for Occupational Safety and Health, Cincinnati. i 81 Spumy, K. R., W. SCoeber, H. Opiela, and G. Weiss. 1979. On Che evaluation of fibrous parcicles in remote ambient air. Pp. 1-40 in The Science of the Total Environment. Elsevier, Amsterdam. Suta, B. E., and R. J. Levine. 1979. Nonoccupational asbestos emissions and exposures. Pp. 171-205 in L. Michaels and S. S. Chissick, eds. Asbestos: Properties, Applications, and Hazards. John Wiley & Sons, Nav York. Suzuki, Y. 1982. Carcinogenic and fibrogenic effects of zeolites: Pre liminary observations. Environ. Res. 27:433-445. Thompson, R. J. 1978. Ambient air monitoring for chrysotile in the United States. Pp. 355-363 in Proceedings of the Workshop on Asbestos: Definitions and Measurement Methods. Gaithersburg, July 18-20, 1977. NBS Spec. Pub. 506. National Bureau of Standards, Gaithersburg, Md. Thompson, R. J., and G. B. Morgan. 1971. Determination of asbestos in ambient air. Pp. 154-157 in Proceedings of the Symposium on Identi fication and Measurement of Environmental Pollutants, June 14-17, Ottawa, Ontario, Canada. U.S. Bureau of Mines. 1982. Minerals Yearbook 1981. Volume I. Depart ment of the Interior, Washington, D.C. U.S. Bureau of Mines. 1983. Asbestos. Preprint from Che 1982 Minerals Yearbook. Department of the Interior, Washington, D.C. U.S. Environmental Protection Agency. 1980. Asbestos-Containing Materials in Schools. Health Effects and Magnitude of Exposure. Support document for proposed rule on friable asbestos-containing materials in school buildings. Office of Pesticides and Toxic Substances, Environmental Protection Agency, Washington, D.C. U.S. Environmental Protection Agency. 1982. National Emission Standards for Asbestos. Section B. Code of Federal Regulations. Title 40, Parc 61.20-61.25. U.S. Occupational Safety and Health Administration, 1983. Occupational exposure to asbestos: Emergency temporary standard. Fed. Regist. 48:51086-51140. Wagman, J., H. R. Berger, J. L. Miller, and W. D. Conner. 1979. Dusts and Residues from Machining and Incinerating Graphite/Epoxy Composites: A Preliminary Study. Environmental Sciences Research Laboratory, Report No. EPA-600/2-79-196, Environmental Protection Agency, Research Triangle Park, N.C. 24 pp. Watts, A. A., ed. 1980. Commercial Opportunities for Advanced Compo. sites. ASTM Special Technical Publication 704. American Society for Testing and Materials, Philadelphia. Wright, W. W., W. N. Rom, and F. Moatmed. 1983. Characterization of zeolite fiber sizes using scanning electron microscopy. Arch. Environ. Health 38:99-103. Zoltai, T. 1979. Asbestiform and acicular mineral fragments. Ann. N.Y. Acad. Sci. 330:621-643. Zoltai, T., and J. H. Stout. 1984. Mineralogy: Concepts and Principles. Burgess Publishers, Minneapolis. Zumwalde, R. D., and L. T. Harmison. 1980. Carbon/Graphite Fibers: Environmental Exposures and Potential Health Implications. National Institute for Occupational Safety and Health, Cincinnati. 4 Measurement of Exposure to Asbestiform Fibers For nore chan 50 years, asbestos-containing dust in the workplace has been measured to characterize occupational exposure to these particles. These measurements were needed to correlate specific health effects in workers with their exposure to the dust, to ensure the proper functioning of dust control equipment, and to evaluate compliance with the fiber and/or dust standards or guidelines in effect at that time. In developing these measurement methods, attempts were made to balance and maximize specificity, sensitivity, and biological relevance for the different dust components. As measurement technology and knowledge of agents and disease mechanisms advanced, new sampling and analytical methods were developed with the goal of obtaining measurements that would be useful in protecting workers. (See reviews by Ayer and Lynch, 1961; Holt, 1957; Walton, 1982.) Attempts are now being made to determine the concentration of fibers in other environments, such as in buildings and in areas removed from known fiber sources. Techniques useful for the workplace are not always easily applied to other situations, where concentrations of materials are likely to be hundreds or thousands of times lower. In this chapter, the committee describes the measurement methods used to determine the concentration of asbestos in a given environment. Although the discussions are focussed on the specific methods used to measure asbestos, many of these methods may also be used to measure other asbestiform fibers. The development of the techniques is presented within a historical perspective. MEASUREMENT TECHNIQUES Table 4-1 summarizes the principal methods used in the quantification and identification of asbestiform fibers (Burdett et al., 1980). The earliest methods measured mass. In the gross mass methods, airborne dust was collected by filtration, precipitation, or impaction, and the total dust was determined by simple weighing on conventional balances. X-ray diffraction techniques were used to identify mineral phases present in the dust; magnesium analysis was used as an index of chrysotile asbestos 82 83 TABLE 4-1. Asbestifona Fiber Measurement Methods3 Measurement Collection Quantification Identification Mass, gross Filter Gravimetric Mineral identification by x-ray; chrysotile identification by magnesium analysis Electrostatic precipitator Craviaetric Not applicable (piezoelectric) Impaction Beta-absorption Not applicable Ki-vol/filter Microscopic Mineral identification by x-ray Mass, re spirable Horizontal elu- Cravisietric triator/filter Mineral identification by x-ray; chrysotile identification by magnesium analysis Cyclone/filter Gravimetric Mineral identification by x-ray; chrysotile identification by magnesium analysis Count Impingement Light microscope Identification by morphology Impaction Light microscope Identification by morphology Thermal precipitator Light microscope Identification by morphology Membrane filter Light microscope phase contrast Identification by morphology; mineral identification by dispersion staining Nuclepore filter TEM,b SEM,C image recog nition Mineral identification by SAED;^ chemical composition by EDXAe Nuclepore filter Light scattering Identification of fibers by magnetic alignment Adapted from Burdett e al., 1980. ^TEM - Transmission electron microscope. CSEM - Scanning electron microscope. ^SAED - Selected area electron diffraction. eEDXA - Energy-dispersive x-ray analysis. 84 concent. When chere was a need Co collect and measure samples over short times, such as in the evaluation of controls or brief exposure episodes, the mass of the small amount of material could be measured by very sensitive piezoelectric or beta-absorption instruments. Major drawbacks to these analytical methods were the insensitivity of the x-ray method in the detection of small particles, the nonspecificity in the resolution of chrysotile from the other serpentine minerals, and the similar nonspecificity of the magnesium assay. Because much of Che mass measured by gross methods consisted of particles coo large to penetrate into the lung, techniques were often used to remove the larger particles before assay. The horizontal, parallel plate elutriator was preferred in the United Kingdom, whereas industrial hygienists in the United States tended to use small cyclone devices. All the mass methods yield results stated in terms'of mass of dust per unit volume of air. In occupational environments, the units commonly used are milligrams of dust per cubic meter of air, whereas the much lower dust masses found in nonoccupational ambient environments are more conveniently expressed as nanograms of dust per cubic meter of air. Counting methods are far more sensitive Chan mass determinations, since samples with coo little mass Co be weighed are usually adequate for counting.! Furthermore, since small particles far outnumber large - particles, counting emphasizes the respirable dust. Lastly, fibers can be counted separately from other particles.2. Particles deposited directly on microscope slides by impaction or thermal precipitation can be counted by light microscopy. However, a more even dispersion can be obtained by impinging a jet of dust-ladened air on a surface submerged in a liquid. The liquid is then transferred from the impinger Co a counting cell where Che particles are allowed to settle so they can be seen and counted in the same focal plane. These methods have low and differing efficiency and resolving power. The membrane filter, however, is a very efficient dust collector. After being rendered transparent, thereby making the fibers visible, the filter can be examined by phase contrast microscopy,, The.^best ,resolution is ^For example, 1 ng of chrysotile dust would yield 400 fibers 5 urn in length and 0.5 um in diameter. A nanogram is about a thousand times lighter than most analytical balances can weigh with precision and accuracy. 2As noted in Chapter 2, shape alone does not determine whether a particle is asbestiform. In a workplace where asbestos fibers were the major dust present, the distinction was presumably not of major practical importance. For occupational environments, asbestos fibers are counted if they are more than 5 um long and at least three times longer than they are wide (National Institute for Occupational Safety and Health, 1977). 85 obtained by the transmission electron microscope, which can resolve particles made up of only a few hundred atoms. Somewhat larger particles may be identified by techniques that reveal their chemistry (a probe technique) or crystallographic characteristics (by electron diffraction). Results of impinger counts are usually expressed in millions of particles per cubic foot; dust concentrations measured by other methods are typically expressed as particles or fibers per cubic centimeter. In some electron microscope techniques, fibers or dispersed fibrils are counted, and the results are then converted to units of mass per volume. MEASURING ASBESTOS DUST IN THE WORKPLACE The Impinger Technique Early investigators of workplace exposures to asbestos fibers in the United States used the impinger technique, then conmonly used in mines. Dust was collected in an alcohol medium, usually over a short period (e.g., 20 to 30 minutes), and the suspension was examined by light microscopy at 100X total magnification. All particles in the dust were counted. Very few fibers were seen, partly because of the low resolving power of that optical system. The counting of large numbers of samples was tedious, and interobserver measurement differences led to systematic bias. The first asbestos dust "standard" in the United States was based on measurements made with impingers by Dreessen t al. (1938). These investigators correlated observed health effects with measured dust exposures in the asbestos textile industry and tentatively concluded, with reservations, that limiting exposure to 5 million particles per cubic foot (5 rappcf) of air may be effective in preventing asbestosis. No correlation with cancer of any type was attempted. They recognized, as did later investigators, that counts of all particles provided a very indirect index of disease potential. The Membrane Filter Technique In the membrane filter technique, efficient, convenient collection media are used for assaying the work environment (Edwards and Lynch, 1968; Holmes, 1965; Leidel et al.. 1979). A portion of the filter may be rendered transparent and then examined with a phase contrast light microscope. Fibers with an aspect ratio greater Chan 3 to 1 are counted on a prescribed, representative area of the filter^ (National Institute for Occupational Safety and Health, 1977). This technique is sufficiently sensitive to allow fibers in workplaces to be counted with measurable precision and accuracy. *See Chapter 2 for a discussion of mineralogical definitions. 86 Prior Co Che 1960s, fibers of several lengChs were counted separately and reported (Lynch, 1965). During the 1960s, the U.S. Public Health Service followed the counting strategy developed in Che British textile industry, and counted only fibers >5 pm in length--a length that was later incorporated into the U.S. occupational asbestos standard (U.S. Occupational Safety and Health Administration, 1971). The longer asbestos fibers were believed to be the agents responsible for asbestosis (Beattie and Knox, 1961). In addition, when only the "longer" fibers were counted, greater precision was attained from repetitive fiber counts on Che same specimen (Addingly, 1966). MEASURING ASBESTOS DUST IN THE AMBIENT ENVIRONMENT The number of fibers >5 pm in length counted on membrane filters by phase contrast light microscopy is used as an index for exposure in the industrial workplace. However, these fibers may constitute only a small portion of the total number of fibers present. When the fibers collected on membrane filters, which collect particles as small as 0.01 pm in diameter, are counted by transmission electron microscopy, up to 100 times more fibers may be detected than are visible by light microscopy. (See Lynch et ad., 1970, for accounts of studies in the textile industry, and Rohl et al., 1976, for measurements in the brake repair industry.) The ratio of transmission electron microscope fibers to fibers visible in the light microscope may be a function of fiber type, industry, degree of manipulation, distance from emission source, and other factors. Fibers in the ambient environment far from point sources of asbestos emissions are generally much shorter than 5 pm, thinner than 0.5 pm, and, thus, predominantly smaller than the resolution capacity of the light microscope (Spumy and Strober, 1981). In the ambient environment, electron beam instruments can be used to measure fiber concentration and to characterize single, isolated fibers (Langer and Pooley, 1973). Other mineral particulates may pose serious background problems. For example, in areas where rocks and minerals are crushed for processing, particles resembling asbestos may be emitted into the ambient environment (Langer et al., 1979). Because chrysotile accounts for more than 90Z of the asbestos used in the United States, the Environmental Protection Agency (EPA) has used it as an index of asbestos exposure. However, it was considered impractical to recover the fibers routinely vithout introducing artifacts or altering fiber size. Therefore, only the chrysotile mass, as determined with the electron microscope, has been monitored routinely (Thompson, 1978). In the standard technique, large volumes of air are pulled through membrane filters. Portions of the filters are ashed in nascent oxygen at low temperatures to remove interfering organic matter. This ash is then dispersed in water by ultrasound, and the residue is filtered onto another membrane filter. Then, either this filter is "rubbed out" in a 87 nitrocellulose medium end portions of the nitrocellulose film examined by electron beam instrumentation or it is directly transferred to an electron microscope grid for analysis. Both methods reduce the fibers to unit fibrils, thus enhancing homogenization of the specimen and reducing scan time, but information about the original nature of the fibers is lost. RELATIONSHIPS AMONG VARIOUS EXPOSURE MEASUREMENT METHODS Data on numbers of fibers in the workplace have been used in correlating exposure and health effects in various occupational studies (British Occupational Hygiene Society Committee on Asbestos, 1983; Dement et al., 1982; Liddell et al., 1982). In order to be able to compare diverse studies and to assess health risks from ambient exposures, it would be useful to establish a relationship among the various methods of determining exposure. Specifically, what are the relationships among the several methods used in estimating asbestos dust in the workplace and in the ambient environment? Consistent relationships among these methods do not exist. They are subject to analytical error and subjective bias (Thompson, 1978). As examples, the electron microscope technique and its associated sampling and analytical techniques have an experimental error of approximately 15Z to 30Z of the measurement value. Relative standard deviations of 45Z are not unusual in light microscope counts. In addition, measurements made in a particular environment at different times will vary because the actual concentrations vary. The different techniques measure a variety of indices, which often do not remain in constant proportion to each other from sample to sample. For example, with Che phase contrast light microscope, fibers longer than 5 um are counted as a single species, whereas shorter fibers are not counted at all. Therefore, a given fiber count obtained by this technique would undoubtedly represent very different numbers of fibers and mass concentrations than the same fiber count obcained by electron microscopy. In some cases, reproducible conversion factors may be determined when large numbers of paired samples are analyzed by the various methods. However, these conversion factors usually cannot then be applied to samples obtained under a different set of conditions. Table 4-2 summarizes some reported attempts to determine conversion factors among Che various methods. The ratios in that Cable are based on direct, independent estimates, except for Chose in parentheses, which were calculated from other ratios. Although the accuracy of these estimates is not known, an order of magnitude either way would probably embrace most situations. These ratios are equivalent only in the sense that they would be expected if aide-by-side measurements were made in an environment similar to that in which the data were originally obtained. 88 TABLE 4-2. Relationships Aaong Methods of Measuring Exposure to Asbestos in the Workplace3 Base Valued Equivalent Values Expected from Various Measurement Methods _________________ Phase Contrast Electron Light Microscope Microscope Impinger (mppcf) (PCLM) (>5-umlong fibers/cm^) (EM) (EM fibers/cm^) Mass (rag/m^) l mppcf (impinger)c 1 >5-um-long fibers/ cm3 (pcLM)e 1 0.17 6 1 1 EM fiber/cm3 (EM count) 1 mg/m3 (mass) (0.0028) 0.017 (5) 30f (360)d 60 1 2,0008 (0.2) 0.03 0.0005 l aRatios developed by Cook and Marklund, 1982; Davis e al., 1978; Dement e al., 1982; Lynch et al., 1970; Rohl ej: a_l., 1976, and the British Occupational Hygiene Society (Walton, 1982) were used to construct the table. Some adjustment was necessary to achieve consistency, bciven the base value indicated in column 1, the other columns show the equivalent value to be expected from the indicated method. Thus, 1 mppcf by impinger would be equivalent to 6 >5-urn-long fibers/cm^ measured by PCLM or 360 fibers/cm^ measured by the EM. Numbers have been rounded. cCollected in an impinger and counted at 100X light field, mppcf * millions of particles per cubic foot. ^Ratios in parentheses are calculated from other ratios. Collected on membrane filters and counted by PCLM at 430X. ^This ratio converts to 30 LM fibers/ng versus the nominal 20 fibers/ng sometimes used. . 8This ratio converts to 2,000 total EM fibers/ng. The data for this cable were obtained from workplace dust clouds or other environmental samples containing high concentrations of asbestos. . Fiber size/weight relationships are also presented (Table 4-3) to indicate the ratios that might be expected under various conditions. The electron microscope (EM) count/mass ratio (2,000 fibers/ca3 pr mg/m3) in Table 4-2 is equivalent to 2,000 Df fibers per nanogram, TABLE 4 -3 ' The Numbers o f F ib e rs p e r Nanogram fo r D iffe r e n t S ize C a te g o rie s ( C y lin d r ic a l F ib e r Shape, D e n s ity , 2 .5 ); D iam eter/Length R a tio in the Second L in e a 0 .2 5 0 .5 From P o tt, 1978 89 lA O NO lCAM sO 00 *" O MS CM oo ia oo CM Cl O CM MO3 -- oO 0o0 T oo ^o IA CM CM >o voO O 00 CM - OO oo o oCM lA IA CM IA o O VO CM --* o o vO 00 m CM J M3 oo O CM --o o A IA lA CM * CM oo O OO CO o CM Oo o OOOO C'* -- CM o A 00 -d O *A CM CM oo O <o 9O> oCM oCM ^o oo o IA Csl 6 o O CM CM oo o -1 oo* H.. .o* CM O *A 00 CM a 3. H 4) 1o m ao IA CM lA sO CM s oo c CM 90 which corresponds Co s distribution of fibers with a mean length of 3 um and diameter of 0.3 ym. Such a distribution suggests the presence of substantial numbers of fibers longer than 5 um, which would be visible under a light microscope. The ambient air in environments far from asbestos sources have few fibers longer than 5 um. In general, those remote ambient environments will contain many more, but smaller, fibers in a given mass Chan would the workplace clouds on which Table 4-2 was based (Spurny and Strober, 1981). For example, if Che fibers in the remote environment had average lengths of 1 um and diameters of 0.1 um, there would be 70,000 Di fibers/ng (instead of the 2,000 determined for the workplace) and the ratios would be altered accordingly. EXPOSURE TO CHRYSOTILE IN THE AMBIENT ENVIRONMENT Chrysotile has been detected in urban air (Selikoff e_al., 1972) and in lungs of urban dwellers (Langer et al., 1971; Pooley, 1972; Pooley e al., 1970). Ambient levels of chrysotile asbestos are usually expressed as mass concentrations (ng/m^). To estimate health risks from these ambient exposures, the mass measurements need to be converted to Che equivalent fiber concentrations Chat are used as dose measurements in workplaces, for which dose-response curves have been developed. There is no single way co do this conversion since, as explained earlier, the dust clouds are quite different, especially in regard to the sizes of fibers they contain. One approach is to convert the ambient mass data into numbers of fibers of the shortest length (5 um) generally counted in the workplace, with an assumed diameter of 0.5 um and aspect ratio 10:1. There are 400 fibers of this size in 1 ng. For a mass concentration of 20 ng/m^, which is typical of outdoor environments not near known sources, this conversion yields a concentration of 0.0080 fibers/cm^. Even in workplaces, however, most fibers are shorter than 5 um. Assuming chat workplace fibers average 3 um x 0.3 um (the assumption made in Table 4-2) and applying the equivalency factors in Table 4-2, a typical equivalent concentration for 20 ng/ra^ would be 0.040 fibers/cm^. However, if we were to assume an average remote ambient fiber size of 1 um x 0.1 ym, then a concentration of 1.4 fiber/cm^ would weigh 20 ng/m^. Measurements of ambient concentrations observed at single sampling locations may vary over several orders of magnitude. Seasonal changes in wind direction, especially near emission sources, account for much of this variability. For example, in studies reported by Thompson (1978), 20 specimens obtained downwind from an emission source had average asbestos fiber mass concentrations ranging from 0.03 to 8,200 ng/m3. However, for industrial cities in the continental United States from 1969 to 1970, average airborne asbestos mass concentrations ranged from 0.6 to 95.0 ng/m^, or two orders of magnitude. During 1971 and 1972, 91 44 sampie* similarly obtained contained concentrations ranging from 0.4 to 27.7 ng/s3. COMPLICATING FACTORS IN ENVIRONMENTAL ASSAYS In an asbestos workplace, all the fibers may be assumed to originate from the fiber being used. However, because remote ambient environments, by definition, are distant from known asbestos sources, the identity of fibers there can neither be assumed priori nor easily determined with any certainty, especially by light microscopy (Langer, 1979). The light microscope specified for analysis of membrane filter specimens (phase contrast microscopy) yields only size and shape information, which may allow the analyst to "identify" fibers by morphology alone. With Che increased resolution of the electron microscope, the internal structure of the elementary chrysotile fibril may be visualized (Langer and Pooley, 1973). For chrysotile asbestos, morphological information and the behavior of the fiber under the electron beam are usually sufficient information for identification (see discussion in Langer et aJL., 1974). However, other fibers require additional diagnostic procedures. Selected area electron diffraction (SAED) yields crystal data reflecting characteristic structural elements that may enable the microscopist to distinguish among types of fibers. Chemical information may also be obtained by means of either energy dispersive x-ray analysis or crystal spectrometry probe techniques. For fibers in remote ambient samples to be accepted as asbestiform, accurate fiber identification is needed. For example, Spurny and Strober (1981) have shown that more than 901 of "mineral fibers" in nonurban areas sampled in Europe were not asbestos, but, rather, were such materials as fibrous gypsum and even ammonium sulfate. In a study of the fibrous content of the lungs of the general population, Churg (1983) found approximately as many nonasbestos mineral fibers as asbestos fibers. Therefore, proper diagnostic tools are needed to characterize fibers in remote ambient samples as asbestiform. Furthermore, when extrapolating health risks from the workplace to such remote environ ments, it must be recognized not only that fiber concentrations and size distributions are different in the two environments but also that fiber types may include nonasbestiform varieties. The asbestiform properties enumerated in Chapter 2 cannot as yet be measured on microscopic samples. FUTURE MEASUREMENT OF EXPOSURE TO ASBESTIFORM FIBERS Walton (1982) has noted that "there is no practicable alternative to the membrane filter/phase contrast optical microscope for routine use in the occupational environment." Nonetheless, the method is too insensitive and nonspecific to yield the information needed to assess fiber exposure in the nonoccupational environment. 92 Several basic objectives should guide the development and eventual selection of a method for measuring fibers in nonoccupational or remote environments. First, the method should yield data that are useful in conducting epidemiological studies relating exposure and disease and in making decisions designed to reduce health risks. The ideal method should measure a characteristic, parameter, or index with biological relevance, i.e., the measurement should be related to the risk of the disease end point being studied. Possible types of measurement include fiber number, mass, length, diameter, and surface charge. Because of the great extent of environmental variability, developing accurate informa tion about the concentrations of fibers in the air will be more dependent on the number of samples collected than on limitations of analytical techniques. Current methods for determining .ambient concentrations of fibrous particles could benefit from substantial improvement. However, sufficient standardization is needed to allow comparisons of data from various laboratories so that a data bank of ambient concentrations can be established for use by epidemiologists and other researchers. Sensitivity and specificity improved as the light microscope was superceded by the electron microscope (EM) with its greater resolving power. One issue to be considered now concerns the relative merits of using the transmission electron microscope (TEM) and the scanning electron microscope (SEM). Other issues concern methods of preparing the fibers for the EM without disturbing them .and development^.of .improved identification techniques (Middleton and Jackson, 1982). The SEM has been used extensively to examine environmental fibers and has produced some dramatic photographs of fibers in situ. Although the SEM direct preparation method provides little opportunity for contamination, the image resolution, contrast, and x-ray resolution of the SEM have not been sufficient for precise mineralogical identification. With an energy-dispersive x-ray attachment, the SEM can now provide analytical information for identifying minerals, but it still does not provide structural data. Because of its high resolving power, the TEM has been more generally applied to studies*of'environmental fibers, especially when confidence in fiber identification is required (Chatfield, 1979, 1982; Chatfield and Dillon, 1978). Researchers do not agree on the best method of preparing representative and quantitative EM samples. The fibers in air or water must be deposited evenly and unaltered on the flat surface of an EM grid and spaced far enough apart to be readily counted and examined, yet not so far apart that there are too few to count. In most modern methods, the sample is collected either on mixed cellulose ester Millipore filters or on polycarbonate Nuclepore filters. To transfer the deposit directly onto an EM grid, the filter must be dissolved, usually by washing gently vith solvent. With uncoated Millipore filters, as much as 80Z of the fibers is lost. 93 The most setisfactory direct transfer preparation technique involves the carbon coating of particles on the surface of a Ifaclepore filter. This technique is part of the current EPA interim procedure (Samudra et al., 1977). Nuclepore filters are preferred because, unlike the Nillipore filters, they have a smooth, featureless surface. Because of this property, vacuum-coating with carbon produces a replicate that surrounds and traps the particles, holding them in their original position as the filter dissolves. The large amount of surface detail on Millipore filters makes them unsuitable for carbon coating. Rigorous fiber identification is not always necessary, especially in occupational or other defined environments. Morphology alone is often adequate, especially for chrysotile. For environmental samples, which may contain many fiber-shaped particles of different minerals, selected area electron diffraction (SAED) and energy dispersive x-ray analysis (EDXA) may be used to obtain crystallographic and chemical information for more precise identifications. < RECOMMENDATIONS Concentrations of asbestiform fibers in urban and rural locations, and at various distances from known sources, should be routinely monitored so that fiber levels and population exposures can be determined with respect to time and location. Fiber characterization is also needed. If feasible, these data should be used in conjunction with health studies to determine any effects on the exposed populations. Characterization of fihrous dusts should include to the extent possible the length, diameter, quality, and type of all fibers present and their concentrations, both as mass and number. Direct transfer techniques and TQi examination of the preparations, or other techniques chat allow examination of particles as they existed in the aerosol, should be used. Fiber monitoring techniques for use in nonoccupational environments should be standardized so that results from various studies are comparable. Automated instrument techniques are needed to permit analysis of the large number of samples required to monitor exposure of different segments of the U.S. population over time. . REFERENCES Addingly, C. G. 1966. Asbestos dust and its measurement. Ann. Occup. Hyg. 9:73-82. Ayer, H. E., and J. R. Lynch. 1961. 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Mass and number of fibres In the pathogenesis of asbestos-related lung disease in rats. Br. J. Cancer 37:673-688. Dement, J. M., R. L. Harris, Jr., M. J. Symons, and C. Shy. 1982. Estimates at dose response for respiratory cancer among chrysotile asbestos textile workers. Ann. Occup. Hyg. 26:869-882. Dreessen, V. C., J. M. Dalla Valle, T. I. Edwards, J. W. Miller, R. R. Sayers, H. F. Eason, and M. F. Trice. 1938. A study of asbestosls In the asbestos textile Industry. Public Health Bull. 241:217. Edwards, G. H., and J. R. Lynch. 1968. The method used by the U.S. Public Health Service for enumeration of asbestos dust on membrane filters. Ann. Occup. Hyg. 11:1-6. Holmes, S. 1965. Developments in dust sampling and counting techniques In the asbestos industry. Ann. N.Y. Acad. Scl. 132:288-297. Holt, P. F. 1957. Pneumoconiosis: Industrial Diseases of the Lung. E. Arnold & Co., London. 268 pp. Langer, A. M. 1979. Significance of aspect ratio In regulation of asbestos fiber exposure. Ann. N.Y. Acad. Scl. 330:601-604. Langer, A. M., and F. D. Pooley. 1973. Identification of single asbestos fibers in human tissues. Pp. 119-225 In P. Bogovskl, J. C. Gilson, V. Timbrell, and J. C. Vagner, eds. Biological Effects of Asbestos, IARC Scientific Publ. No. 8. International Agency for Research on Cancer, Lyon. 95 Laager, A. M., A. Sastre, and I. J. Sellkoff. 1971. Chrysocile asbestos In the lungs of persons In New York City. Arch. Environ. Health 22:348-361. Langer, A. M., A. D. Mackler, and F. D. Pooley. 1974. Electron micro scopical investigation of asbestos fibers. Environ. Health Ferspect. 9:63-60. Langer, A. M., C. M. Magglore, V. J. Nicholson, A. N. Rohl, I. B. Rubin, and I. J. Sellkoff. 1979. The contamination of Lake Superior with amphlbole gangue minerals. Ann. N. Y. Acad. Scl. 330:549-572. Leldel, N. A., S. G. Bayer, K. A. Busch, and R. D. Zumwalde. 1979. USPHS/NIOSH membrane filter method for evaluating airborne asbestos fibers. NIOSH Pub. No. 79-127. National Institute for Occupational Safety and Health, Cincinnati. Llddel, F. D. K., G. W. Gibbs, and J. C. McDonald. 1982. Radiological changes and fibre exposure In chrysotlle workers aged 60-69 years at Thetford mines. Ann. Occup. Hyg. 26:889-898. ......... Lynch, J. R. 1965. Asbestos study proceedings and findings. Trans actions of the American Conference on Governmental Industrial Hy gienists, May 1965. American Conference of Governmental Industrial Hygienists, Cincinnati. Lynch, J. R., and H. E. Ayer. 1966. Measurement of dust exposures in the asbestos textile Industry. Amer. Ind. Hyg. Assoc. J. 27:431-443. Lynch, J. R., H. E. Ayer, and D. L. Johnson. 1970. The interrelation ships of selected asbestos exposure indices. Amer. Ind. Hyg. Assoc. J. 31:598-604. Middleton, A. P., and E. A. Jackson. 1982. A procedure for the estima tion of asbestos collected on membrane filters using transmission electron microscopy (TEM). Ann. Occup. Hyg. 25:381-391. Pooley, F. D. 1972. Electron microscope characteristics of Inhaled chrysotlle asbestos fiber. Br. J. Ind. Med. 29:146-153. Pooley, F. D., P. D. Oldham, H. Um-Chang, and J. C. Wagner. 1970. The detection of asbestos in tissues: Pneumoconiosis. Pp. 108-116 In H. Shapiro, ed. Proceedings of the Ihlrd International Conference. Oxford University Press, Capetown. Pott, F. 1978. Some aspects on the dosimetry of the carcinogenic potency of asbestos and other fibrous dusts. Staub-Relnhalt Luft 38:486-490. Rohl, A. N., A. M. Langer, M. S. Wolff, and I. Weisman. .1976. Asbestos exposure during brake lining maintenance and repair. Environ. Res. 12:110-128. Samudra, A. U., C. F. Harwood, and J. D. Stockhalm. 1977. Electron microscope measurement of airborne asbestos concentration. EPA600/1-77-178. Environmental Protection Agency, Research Triangle. Park, N.C. Sellkoff, I. J., W. J. Nicholson, and A. M. Langer. 1972. Asbestos air pollution. Arch. Environ. Med. 25:1-13. Spurny, K. R., and W. Strober. 1981. Some aspects of analysis of single fibers In environmental and biological samples. Int. J. Environ. Anal. Chem. 9:265-281. 96 Thompson, R. J. 1978. Aabient air monitoring for chrysotile la the U.S. Pp. 355-363 In C. C. Gravatt, P. D. LaFleur, and K. F. J. Heinrich, eds. Proceedings of Workshop on Asbestos: Definitions and Measurement Methods. NBS Spec. Pub. No. 506. National Bureau of Standards, Gaithersburg, Md. U.S. Occupational Safety and Health Administration. 1971. Occupational Safety and Health Standards, Part 1910.93 Air Contaminants (Gases, Vapors, Fumes, Dusts, and Mists). Fed. Reglst. 36:10503-10506. Walton, W. H. 1962. The nature, hazards and assessment of occupational exposure to airborne asbestos dust: A review. Ann. Occup. Hyg. 25:115-247. 5 Effects of Asbestiform Fibers on Human Health This chapter begins with a discussion of the types of evidence that researchers generally UBe in determining causes of disease. It then provides Information on blodlsposltlon of fibers and on diseases associated with exposure to asbestos. A discussion of health consequences that have been associated with nonoccupatlonal exposure of humans to asbestos and other asbestiform fibers Is folloved by a description of occupational epidemiological studies. NATURE OF EVIDENCE Three lines of evidence--clinical, epidemiological, and laboratory--are considered when determining vhether a particular environmental agent may cause adverse effects on human health. For asbestos, as for most hazardous environmental agents, the first evidence of health effects vas provided by clinical observations. Physicians observed that Individual or clusters of cases of pneumoconiosis,1 lung cancer, and finally mesothelioma were associated with exposure to asbestos. Pneumoconiosis vas the first health effect to be associated vlth asbestos. In 1907 Dr. Montague Murray reported his observations of such disease in a man who had worked In a carding room at an asbestos plant In England (Murray, 1907). In 1924, Cooke wrote that "medical men In areas vhere asbestos Is manufactured have long suspected the dust to be the cause of chronic bronchitis and fibrosis...." (Cooke, 1924). Numerous other reports folloved. Other types of pneumoconioses, such as silicosis, vere also known at that time, so asbestosls, the flbrotic disease caused by asbestos, was not an entirely new type of disease. However, mesothelioma was sufficiently rare that its connection with asbestos vas not accepted until 1960 (Wagner, 1960). Clinical observations led to the hypothesis that asbestos caused the observed disease. Epidemiologists then conducted studies to ascertain vhether the hypothesis was true. The association vas eventually ^-Pneumoconiosis is the pathological reaction of tissue to the Inhalation and accumulation of dust In the lungs. 97 98 established primarily through cohort studies. In which the rate of disease occurrence In an exposed group Is compared with the rate In a group not exposed to the material of concern (Doll, 1955; McDonald and McDonald, 1981; Sellkoff and Hammond, 1979), In laboratory studies, asbestos was administered to animals to determine whether pathological effects similar to those found in humans could be Induced. Ihese experiments followed the methodology established in the scientific study of infectious agents as causes of disease--a methodology later extended to the investigation of noninfectlous agents. However, performing the experiments and interpreting the results are more complicated for diseases with long latency periods. The laboratory studies demonstrated that asbestos could cause lung cancer and mesotheliomas In animals. Flbrotlc reactions, however, usually differed somewhat from the lesions observed In humans with asbestosls. This difference could be attributed to variation among species and In the nature and amount of fibers (Vagner, 1960). Each of the three kinds of data have strengths and weaknesses. The clinician distinguishes the observed disease from similar conditions and considers the possible links to environmental and other factors. Thus the clinical contribution to understanding lies primarily in the definition of clinical entitles and In suggesting possible etiological factors. Erroneous conclusions may be drawn--or new insights gained--if an atypical group of cases comes to a particular clinician's attention. Difficulties may also arise if the observed effects are confused with other syndromes with similar signs and symptoms. Misinterpretation may also occur because of the usual reliance at this stage on nonquantltative methods of assessing the relationship to environmental circumstances. The epidemiological approach results in the quantification of risk for a defined health effect associated with exposure to particular environmental circumstances. During the application of this method, two types of errors are commonly made: (1) the findings are generalized too far beyond the population and circumstances studied and (2) there is a failure to adequately take Into account the presence of other factors that may be Involved In addition to, or Instead of, the major factor be'ng examined. In laboratory experiments In animals, the Investigator has the great advantage of being able to exercise control over the conditions of observation, rather than having to rely on observations of natural phenomena as in most nonintervention clinical and epidemiological studies. Also, the laboratory investigator can make more detailed observations over time, thereby increasing the potential for ascertaining the mechanism or steps by which the agent exerts its effect. On the other hand. Inference from one species to another carries some uncertainty. There is also uncertainty in extrapolating from laboratory observations to the exposures and resulting effects experienced by humans. Furthermore, laboratory animals are usually exposed to one agent, whereas humans are exposed to many. 99 Ultimately, the determination of a causal relationship between exposure to an environmental agent and a health effect is a judgment based on careful evaluation of evidence. Guidelines for making such causal inferences have been suggested and generally adopted. For example, Koch's postulates for infectious agents constituted a powerful and widely accepted framework for judging laboratory evidence to determine whether a particular microbiological agent is responsible for a certain disease. No such guidelines have been generally established for nonlnfectious agents. Perhaps the closest approximation is provided by the frequently cited criteria adopted by the Surgeon General's Advisory Committee on Smoking and Health (1964): The causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. To judge or evaluate the causal significance of the association between the attribute or agent and the disease, or effect upon health, a number of criteria must be utilized, no one of which is an all-sufficient basis for judgment. These criteria Include: (a) The consistency of the association [with diverse methods and among multiple studies] (b) The strength of the association [ratio of rates among those exposed to rates among those not exposed] (c) The specificity of the association [precision with which one component of the associated pair can be used to predict the other] (d) The temporal relationship of the association [l.e., which comes first, the agent or the disease] (e) The coherence of the association [with the natural history and biology of the disease] The more of these criteria that are met and the stronger the evidence related to them, the more likely it is that a causal relationship exists. As another example, Hackney and Linn (1979) have updated Koch's postulates and applied them to environmental toxicology. In evaluating relationships between exposure to hazardous environmental agents and adverse health effects, it is useful to proceed beyond identifying and confirming the hazard to quantifying the risks under various conditions. In a recent publication of the Natlotul Research Council (1983b), the authors noted that the steps of risk assessment Involve (1) identification of a toxic agent and its effects, (2) determination of dose-response relationships, (3) determination of the extent of exposure, and finally (4) determination of risk. 100 la some situations, it is difficult to identify the effects of an agent because a given disease, such as lung cancer, may be caused by a variety of agents. Thus, exposure to cigarette smoke, asbestos, certain chromates, ionizing radiation, some chemicals, and possibly other agents may all increase the chance that a person will develop lung cancer. By contrast, for infectious diseases such as typhoid fever or tuberculosis, the microorganism is the specific and only cause, although not everyone infected by the organism gets the disease. For most cancers, there is some chance that an individual will get the disease even with no known exposure to an identified cause. In comparing the risk of developing the disease in an exposed person to the risk for an unexposed person, it is often crucial and difficult to determine Che existence and value of a "background" rate for the disease. A background rate is Che rate of occurrence of a disease with no association, or no known association, with'the~agent(s) being considered. Exposure to an agent such as asbestos may then increase this background rate. For example, some lung cancer occurs in the absence of cigarette smoking or exposure Co asbestos. In Che absence of exposure to asbestos, cigarette smoking increases the chance of getting lung cancer (compared with nonsmokers) up to a factor of about 10, varying with the number of cigarettes smoked (U.S. Department of Health, Education, and Welfare, 1979). Asbestos exposure among insulation workers who do not smoke cigarettes increases the risk for lung cancer up to about 5 times (Hammond et jrl., 1979). Together, Che cigarette smoking and asbestos exposure appear to produce a multiplicative effect, i.e., the lung cancer rate is increased up to 50-fold above background. ` Expressing the relationship as an absolute risk, rather chan as a relative risk, may provide information about the magnitude of the public health problem. If a relatively small risk is increased 10-fold, the resulting public health problem may still be much smaller than would result from doubling a larger risk. For example, Che risk for coronary heart disease among smokers is about 1.6 times greater chan the risk for nonsmokers, as contrasted with a 10-fold increase in risk for lung cancer among smokers compared with nonsmokers. However, cigarette smoking causes more deaths from coronary heart disease, chan J.t does from lung cancer, because the baseline "background" risk for heart disease is much higher than for lung cancer. BIODISPOSITTON OF FIBERS In this section the committee briefly describes how asbestiform fibers enter the body, the properties of fibers that are important in cellular injury, and factors affecting durability of fibers after deposition and interaction with cells. Figure 5-1 shows the anatomy of the respiratory tract and the individual cell types involved in asbestos-associated diseases. The pathological effects of asbestos begin 101 FIGURE 5-1A. - Routes of inhalation and ingestion of asbestiform fibers are shown by small arrows. Mesothelial cells line the outside of -the lungs and the pleural and peritoneal . cavities. Interaction of asbestos with these cells can result in either pleural or peritoneal mesothelioma. Adapted from Vagner, 1980. 102 EprOwfigm FIGURE 5-1B. Cells of the bronchus, or large airways, leading from the trachea. The epithelial cell layer consists of ciliated cells, mucin-secreting goblet cells, and basal cells. The interaction of asbestos with the epithelium and with macrophages is believed to be related to the onset of asbestos-related diseases. Epithelial cells are the target for most lung cancer, whereas the macrophages serve as intermediary cells. Soscr FIGURE 5-1C. Cells of the alveoli, where gas exchange occurs. Interac tion of asbestos with fibroblasts within the Interstitial space can result in fibrosis, whereas interaction of asbestos with alveolar epithelial cells can give rise to lung cancer. (Drawing from Guyton, 1971.) 103 when fibers are Inhaled and ingested. Subsequently, they are deposited either in the respiratory tract or in the gastrointestinal tract. Fibers can then interact with resident cells and eventually move to the pleura and various organs. The mechanisms by which fibers reach the peritoneum are not known. Fiber Deposition Various factors influence the deposition of inhaled particles in the respiratory tract. When nonfibrous compact dust particles are inhaled, the ones greater than about 5 urn in diameter are generally trapped in the nasal passages before reaching the respiratory system (Walton, 1982). However, inhaled fibers align parallel to the airways and act as spheres of approximately ''equivalent" diameter (Gross, 1981; Tlmbrell et al., 1970), where the equivalent or aerodynamic diameter of a particle is defined as the diameter of a sphere with a density of 1 g/cnr* that has the same falling speed as the particle. There is no sharp cutoff of particle sizes determining their deposition site (Brain and Valberg, 1974). The aerodynamic diameter of fibers depends primarily on the diameter. For fibers with aspect ratios greater than about 10:1, it is only slightly affected by length (Tlmbrell, 1965). From his experiments in rats, Tlmbrell (1965) found that the aerodynamic diameter of fibers was about 3 times the actual diameter of the fibers. Fibers with diameters greater than about 3 urn would be very unlikely to reach the alveoli. The sizes of Inhaled and deposited fibers have been compared. Morgan et al. (1979) showed the relationship between median aerodynamic diameter and alveolar deposition in rats using a variety of fibers. Hammad et al. (1982) experimented with retention of sized glass fibers in lungs of rats and found that fibers less than 1 um in diameter accounted for most of the fibers retained (Figure 5-2). Although the count median length of fibers in the aerosol inhaled by the rats was 13 um, the count median length found in lungs was 7 pm; for actual (as opposed to aerodynamic) diameters, the respective values were 1.2 um and 0.5 um. They also found that length played some role. Tlmbrell (1982) compared the sizes of fibers found in the air of an anthophylllte mine and.mill with the sizes of fibers found in the lungs of three adult workers. Both the configuration and dimension of asbestiform fibers determine where they Impact after Inhalation. Because the curlier chrysotile fiber has a relatively large cross-sectional area, its chance for interception in the airways is greater. Hence, these fibers are more likely to deposit in larger bronchioles (Morgan et al., 1973), whereas thin, rodlike fibers are carried peripherally to the terminal airways and alveoli (Tlmbrell, 1965; Tlmbrell et al., 1970; Wagner et al., 1974). 104 From Itammad e t a l . , 1982. 105 In addition to diameter and shape, factors such aa changes in breathing rate, individual anatomic variations, smoking, and the presence of bronchitis or lung disease also influence both the extent and site of fiber deposition in humans (Brain and Valberg, 1979,* Sanchis et al., 1971). Studies in animals have demonstrated that most deposited fibers are removed from the respiratory tract vithin a few days. However, at least a quarter of the initial burden remains 1 month later (Evans et al., 1973; Muggenburg ,1** 1981). Since much of Che inhaled asbestos is not readily cleared, pulmonary tissue burden in humans may be a useful index of exposure. Attempts have been made to quantify the amount of fibers and ferruginous bodies in human and animal lungs in order to reach a better understanding of Che mechanism of action of Che fibers. In addition to pulmonary or other tissues, sputum and lavage samples have been studied (Di Menza, 1980). .................. Analyses of lung tissue samples from humans indicate that heavily exposed workers can be distinguished from those lightly exposed or from controls. Sebastien e_t al. (1977) reported that the number of fibers/cm^ of lung sample, as seen by Che light microscope, was approximately 10& for a heavily exposed group, 10-^ for lightly exposed workers, and 102 for controls. Early researchers discovered the presence of asbestos bodies as well as asbestos fibers in pulmonary tissues of exposed workers, especially in those with asbestosis (Cooke, 1927, 1929; Cooke and Hill, 1930; Gloyne, 1929; Sebastien e l., 1979). Asbestos bodies are asbestos fibers coated with an iron-protein material that is readily visible with a light micro scope. The coating, which is produced by macrophages (Suzuki and Churg, 1969), seems to prevent the fiber from interacting with cells as effectively as uncoated fibers. Because the coating may also be found on other types of fibers, Che term ferruginous body is now often used instead of asbestos body. There are many reports of ferruginous bodies counted under various circumstances (Sebastien et l., 1979), but the pathol igical significance of these bodies is unclear. Asbestos bodies form with greater efficiency on varieties of aaphibole asbestos than on chrysotile (Pooley, 1972). Because the vast majority of deposited fibers are not converted to ferruginous bodies, the presence of these bodies reflects past exposure in only a very limited way. Electron microscope observations have provided detailed information on the deposition of fibers in animal and human tissues (Langer et al., 1973; Pooley, 1972). Chrysotile seems to degrade or be removed in vivo more readily than the amphiboles (Langer et al., 1972a, b; Vagner et al. , 1974, 1982; Rowlands, 1983). Fibers found in tissue samples obtained from the general population tend to be shorter in length and diameter chan those found in workers (Langer et_ l., 1971; Pooley etal., 1970). Fibers have also been detected in extrapulmonary tissues from both humans and animals. (For reviews, see Sebastien et al., 1979 and Cook, 1983). 106 Fiber burden in Che lung parenchyma (the body of Che lung) may be different from chat in the parietal pleura (the pleura lining the chest cavity) as shown in a study of 29 persons, most of whoa had pleural asbestosis (Sebastien et al., 1979). The parenchymal samples had both amphibole and chrysotile fibers. Their average length was 4.9 pm; 15t of them were longer Chan 8 urn. The pleural samples were predominantly chrysotile fiber, with an average length of 2.3 um; 2Z of these fibers were longer than 8 pm. Thus, short chrysotile fibers tended to predominate in the parietal pleura. Most studies of fibers in human tissues have been conducted in workers known to have been exposed to asbestos (Churg, 1983a). However, there have been some studies of the amounts and types of fibers in the general population (Churg, 1983b; Churg and Warnock, 1980). Churg (1983b) examined mineral fibers^ in the pulmonary tissues of 20 patients with no known occupational exposure to asbestos. He reported 13 types or groups of minerals, other than asbestos, including silica, talc, and atcapulgite. More chan 85Z of the particles counted, and all of the attapulgite particles, were less chan 5 pm long. Clearance and Transport Several mechanisms are involved in clearing fibrous materials from the lung. These include removal by Che beati-ig of ciliated cells and secretion of mucin (i.e., mucociliary clearance), transport by alveolar macrophages to regional lymph nodes and distal sites (Lippmann et al., 1980; Morgan et ajL., 1978, 1982), uptake by epithelial cells that line Che airways and alveoli (Mossman et al., 1977; Suzuki, 1974), and direct translocation of fibers between epithelial cells to the interstitium and the pleura. The physical properties (i.e., length and cross-sectional dimensions) of fibers appear to determine the mechanisms of cellular interaction and transport. For example, short fibers with fine diameters can be translocated within cells, whereas longer fibers (approximately 20 um long) are not completely engulfed by macrophages and are cleared ineffectively (Morgan e al., 1978). Incomplete mucociliary clearance might result from discontinuities in Che mucus layer or hypersecretion, a situation observed in people who smoke or have infections. Alternatively, toxic irritants such as cigarette smoke cause dysfunction and loss of ciliated and secretory cells chat line the airways (Sanchis et al., 1971). Clearance of asbestos from the gastrointestinal tract is less well understood, although it has been reported that fibers cross the mucosa of ^The materials detected did not necessarily have the characteristics of asbestiform fibers. 107 Che stoaach and Intestines (Cook, 1983; Westlake et al., 1965). Fibers have been detected in urine and feces (Muggenburg et al., 1981). When Injected Into the fenoral vein of pregnant rats, chrysotlle crosses the placenta and has been observed In fetal liver and lung (Cunnlnghaa and Pontefract, 1974). CLINICAL ASPECTS OF ASBESTOS-ASSOCIATED DISEASES The four major asbestos-related diseases or changes are: (1) lung cancer; (2) mesothelioma; (3) pulmonary asbestosla; and (4) pleural plaques or diffuse thickening, calcifications, and effusion. Some other cancers may also be related to asbestos exposure (Sellkoff et al., 1979). Lung cancer and mesothelioma are typically fatal cancers. Therefore, the degrees of severity are generally not relevant. Pulmonary asbesto6is and the pleural changes not'ed above are nonmallgnant pathological conditions that may range from mild to severe. They are usually related to the amount (intensity and duration) of exposure that the Individual has experienced. Although lung cancer can usually be diagnosed with reasonable certainty, mesothelioma and asbestosis are often more difficult to Identify. For example, by the time a tumor is observed in a patient with mesothelioma, it may be difficult to ascertain both cell type and tissue of origin. For asbestosis, there is no complete agreement as to what constitutes a definitive diagnosis, especially for milder cases. These diagnostic uncertainties present difficulties to those analyzing results of epidemiological studies and determining incidence rates. Inhalation is the major route by which asbestiform fibers enter the body. Ihey may also enter the digestive tract via ingested material such as water or drugs or via asbestos-containing secretions from the lung airways that are brought up into the mouth and then swallowed (Bouhuys, 1974; Langer et al., 1979; Sellkoff and Lee, 1978). Necessary Assumptions Used in Determining Health Effects . In the absence of adequate data on the health effects of low-level and nonoccupational exposure, certain assumptions must be made in order to predict and Identify possible health effects. One assumption is that clinical manifestations in nonoccupational and occupational illness will be similar in kind but not necessarily in extent or degree. In cases of lung carcinoma and mesothelioma, malignancy is usually the cause of death. Both the time from exposure to onset of symptoms and the rate of progression from time of diagnosis are assumed to be similar in nonoccupational and occupational disease. 108 There is little information about the rate at which pulmonary asbestosis progresses following removal from exposure (Becklake, 1976), especially brief, low-level exposure. Seidman e al. (1977) showed that even exposure of a few months and no known subsequent external exposure can increase the risk of lung cancer. It would be important to know how removal from specific exposure to asbestos modifies the risk of getting lung cancer or severe asbestosis. Day and Brown (1980) have discussed this subject with regard to cancer and asbestos. Sensitivity and Specificity of Clinical Evidence It is difficult to show that a disease is associated with exposure to asbestiform fibers when the exposure is nonoccupational and had not previously been suspected. One reason is that clinical symptoms and signs and underlying tissue reactions are often general and nonspecific. Although certain clinical pictures, such as bilateral pleural thickening, are typically associated with asbestiform fiber-related disease, many causes can evoke the same or a very similar response. In addition, mesothelioma is rare, and most cases investigated seem to have been associated with asbestos exposure. The diagnostic process often begins with observations of respiratory symptoms that establish functional impairment. Then the possible morphological changes underlying the change in function are considered. Finally, the agent or factor that caused the tissue changes is sought. The response to an inhaled agent such as asbestos is likely to include airway reactions and tissue reactions (Becklake, 1976; Craighead ail., 1982; Selikoff and Lee, 1978) that affect breathing and ventilation in a manner similar to the effect of smoking (Niewoehner, 1974). Moreover, tobacco smoking is a confounding factor in the development of asbestos-related disease, except for mesotheliomas (Hammond et al., 1979). Thus, smoking history, as well as other environmental and occupational exposures, are relevant in determining whether a disease may be related to asbestos exposure. When diseases are observed in occupational groups exposed to asbestos, the exposure may be considered as a cause or contributing factor (Craighead et l., 1982; Goodman, 1983; Selikoff and Lee, 1978). When such diseases occur among populations not exposed in the workplace and exposure to asbestos is not suspected, the relationship may never be established. However, if mesothelioma is suspected in such nonoccupational groups, asbestos exposure will almost certainly be a diagnostic consideration. In contrast, patients believed to have lung cancer may be asked about smoking but not about asbestos exposure. For. nonmalignant diseases, such as pulmonary fibrosis, nonoccupational exposure to asbestos is likely to be light and may lead to some abnormalities, mainly pleural, but to no more chan mild functional 109 impairment. Again, an association with asbestos exposure may never be established. General Diagnostic Measures The following general discussion of diagnosis is followed by more specific information on each disease. Depending on the disease, the patient's history often contains accounts of shortness of breath (dyspnea) upon exercise and, perhaps, at rest; a dry cough or one that produces sputum; occasional coughing up of blood; and chest pain. Other symptoms may include generalized malaise, fatigue, and weight loss. None of these complaints are pathognomonic^ for any single illness (Becklake, 1976; Bouhuys and Gee, 1980). Chest radiographs are an important screening and diagnostic tool. For occupational diseases with well-established exposure, the radiographic appearance may be so characteristic that it provides a diagnosis with a high degree of likelihood. For nonoccupational diseases, a characteristic chest radiograph may suggest asbestos-related changes as a possibility (Goodman, 1983; Weill e aJL., 1973). An international classification for the radiological assessment of asbestosis and asbestos-induced pleural disease has been recommended to help standardize diagnoses (American College of Radiology, 1982; International Labour Office, 1980). Various abnormalities may be discovered by conducting a physical examination of a patient with an illness possibly related to exposure to asbestiform fibers. Chest auscultation^ is noninvasive, simple, and quick to perform, and therefore lends itself to screening. However, the procedure has limitations as a clinical tool because of variability in its application among clinicians and its lack of sensitivity and specificity for asbestosis. Lung function tests are often useful in diagnosing diseases that might be related to asbestos, although pulmonary tests alone do not lead to a definitive diagnosis. There are two basic groups of lung function tests: -.. ' - Spirometric tests. These tests are performed to measure vital capacity and timed expiratory volumes, to assess .restrictions on lung movement (as in fibrosis or pleural thickening) or obstructions to air flow in Che airways (as in bronchitis or emphysema), and to screen for ^Distinctively characteristic of a specific disease, i.e., the presence of the symptom uniquely determines the diagnosis. ^Auscultation is the act of listening to sounds made by body organs, such as lungs. . 110 disease. Lung volumes may also be measured, buC Che necessary equipment is available only in veil-equipped pulmonary funecion laboratories. Teats to measure diffusing capacity. In these tests, measurements are made-of the lung's ability to exchange oxygen and carbon dioxide (the "blood gases") between air spaces (alveoli) and small blood vessels (capillaries). This so-called diffusing capacity measurement has been used extensively, in part because it is noninvasive. A reduced diffusing capacity results vhen a decreased amount of surface area is available for gas exchange, which may occur in pulmonary emphysema or in pulmonary parenchymal asbestosis. The most accurate way of assessing blood gas exchange is to measure the partial pressures of oxygen and carbon dioxide in arterial blood, but Che use of this test in screening is limited because it requires sampling of arterial blood. These pulmonary function tests give reliable information on the degree of functional impairment, and most of them are relatively simple, inexpensive, and easy to perform. Furthermore, the necessary facilities for performing these tests are generally available (Becklake, 1976; Bouhuys and Gee, 1980; Selikoff and Lee, 1978; Weill e al., 1975). More refined measurements, such as progressive exercise testing, are often helpful in assessing impairment. Asbestos bodies have been found in sputum and in bronchoalveolar lavage samples from persons occupationally exposed to asbestos (Di Menza et al., 1980; Farley et al., 1977; McLarty et al., 1980; Smith and Naylor, 1972). Bronchoalveolar lavage has been used as a research tool to study asbestosis (Di Menza, 1980). Ihis technique allows recovery of substantial numbers of fibers and cells and may prove in the future to be a useful clinical tool for assessing progression and developing a prognosis for disease. As with many diseases, some individuals develop asbestos-associated diseases, whereas others, under similar or greater exposure conditions, do not. Why some individuals appear more susceptible to the effects of asbestos exposure than others is not understood. Immunological studies of persons with asbestosis were carried out to investigate possible differential susceptibility. Pernia (1965) found an increase in rheumatoid factor titer in individuals with pulmonary asbestosis. Turner-tfarvick (1973, 1979) described an ongoing survey of immunological factors (including rheumatoid factor) and antinuclear antibodies (ANA). In a preliminary study. Merchant and coworkers (1975) reported asbestosis to be somewhat more frequent and severe among those with the W27 antigen (HLA system) than among those without the antigen, but subsequent studies suggest that the association is weak (Turner-Warvick, 1979) and not clinically relevant. At present there is no practical way to identify individuals immunologically or genetically susceptible to disease from asbestos exposure. Ill Lung Cancer. This disease accounts for approximately 100,000 deaths annually in the United States, predominantly among smokers. Lung cancer is a malignant tumor of the epithelial covering of lung airvays (bronchi). Compared with lung cancers not associated with asbestos, asbestos-related cancers seem to arise more often from the lower and peripheral parts of the lung (Becklake, 1976; Craighead et al., 1982; Selikoff and Lee, 1978; Sluis-Cremer, 1980). The tumor grows invasively through surrounding tissue and often spreads to other tissues. Local invasion is likely to obstruct airvays, causing loss of ventilation, decrease in air volume, and subsequent infection behind the obstruction. Because local spread may affect blood vessels, hemorrhage is a frequent complication. Lung cancers of all the various cell types have been observed (e.g., adenocarcinoma and squamous cell carcinoma) (Kannerstein and Churg, 1972). The distribution of cell types in asbestos-exposed cases appears similar to that found in cases not associated with asbestos (Ives et al., 1983). The earliest symptom is often the development of a persistent cough, or change in a chronic cough. Chest pain or coughing up of blood may also occur. Physical examination and pulmonary function tests often yield findings consistent with chronic bronchitis, especially in smokers, perhaps with a localized wheeze, but as tumor invasion continues, the symptoms and signs of localized airway obstruction or metastases appear. Later symptoms can include loss of appetite, weight loss, pain, general malaise, and weakness. Chest x-ray may show shadows that are consistent with tumors and enlarged lymph nodes. Where tumors arise in a background of pulmonary fibrosis, tomograms and computed tomography may be helpful in detection. The definitive diagnosis of lung cancer is based on Che microscopic appearance of an appropriate tissue specimen (Adkins, 1976). For treatment, a primary lung cancer is usually removed surgically unless metastases have occurred (Tisi, 1980). The response of lung cancer to radiotherapy or chemotherapy varies with the cell type, but, except for oat cell carcinoma, results are generally not successful. Under the most favorable circumstances, a simple squamous cell carcinoma without evidence of spread to lymph nodes offers a 402 to 502 survival after 5 years. In later stages of lung cancer of any cell type, the 5-year survival does not exceed 102 in the general population (Tisi, 1980). Mesothelioma. Mesothelioma is also a tumor. It is of greatest concern when malignant. (There is a benign form of mesothelioma, not discussed in this report.) Malignant mesothelioma begins its development in Che mesothelial cells of the pleura or peritoneum. During its early growth it causes few symptoms. By Che time it is diagnosed, it is rapidly fatal, most deaths occurring in less than 2 years (Craighead et al., 1982). 112 Mesothelioma of the pleura often occurs first as a thickening of the pleura, first parietal (lining the chest cavity), then visceral (covering the lungs). With tine, the lung becomes encapsulated and restricted In Its movements. The tuaor may invade the lung tissue and aay spread Into adjacent structures, such as the chest vail (Suzuki, 1980). Death often results froa inadequate respiration or froa hemorrhage (Becklake, 1976; Craighead et al., 1982; Sellkoff and Lee, 1978). Peritoneal mesothelioma aay originate anywhere on the peritoneum and aay initially grow without symptoms. Eventually the tuaor is likely to restrict or constrict the bowel or interfere with other functions and to Invade structures of the gastrointestinal tract and the retroperitoneal space. Ascites Is common and recurs rapidly after tapping. The terminal event aay be bowel obstruction or major hemorrhage. Early symptoms are either lacking or vague (Becklake, 1976; Sellkoff and Lee, 1978). The two common complaints of pleural mesothelioma patients are shortness of breath and dull, aching, progressive chest pain that is often unresponsive to pain relievers. A common radiological finding Is a pleural effusion, which aay be extensive and which recurs rapidly after tapping. This finding or a chest radiography showing asymmetrical thickening, especially in the presence of pleuritic pain, should lead one to suspect mesothelioma. Occupational history Is also Important. Serological tests have not been shown to be useful diagnostic tools. Histologic diagnosis, even at autopsy, may be difficult because of the polymorphic nature of the tuaor. It Is more difficult to diagnose peritoneal mesothelioma than pleural mesothelioma. The diagnosis is confirmed only by microscopic examination, and even this aay be difficult or impossible if the tumor is sufficiently undifferentiated. Mesothelioma aay be mistaken for both carcinoma and sarcoma. Identification of the cell type in which the tumor originated is difficult. This procedure aay be facilitated in the future by new techniques using cytoskeletal or other cell markers defined by antibodies. The pathological diagnosis of mesothelioma is sufficiently difficult that special panels functioning under the auspices of the Union Internationale Contre Cancer (UICC) are often convened to assist In the diagnosis. Various studies have been conducted to assess differences in diagnosis among different pathologists or groups (Wright et al., In press). Effective therapy for mesothelioma does not exist (Chahlnlan et al., 1982), although surgery, chemotherapy, and/or radiotherapy aay delay death for a few months. Fibrosis of Lung Parenchyma (Asbestosls). Asbestosls belongs to the group cf illnesses called the pneumoconioses. This disease is characterized by a slowly progressing, diffuse interstitial fibrosis. The functional impairments from asbestosls fall into three groups: 113 (1) impaired ability Co exchange gases between capillaries and alveolar air spaces, leading especially to inadequate oxygenation of blood (hypoxemia); (2) restricted breaching, leading to decreased lung volume; and (3) increased resistance in the small airways. Both (2) and (3) make the physical act of breathing more difficult. Only the abnormalities seen in early and mild manifestations of asbestosis are considered in this section because the more severe forms would be unlikely to occur among those exposed to relatively low levels of particles (Becklake, 1976; Craighead et l., 1982; Selikoff and Lee, 1978). Animal experiments indicate Chat the earliest lesion is a local cellular reaction to the asbestos fiber lodged first in small airways and then in the alveoli (Brody and DeNee, 1981; Brody and Hill, 1982; Brody and Roe, in press; Brody a.1., 1981, 1982, and in press). The fiber may be partially or completely surrounded or engulfed by macrophages or giant cells. A small portion of fibers may be converted to asbestos bodies. Studies of biomineralization may be able to offer additional insights into the interaction of asbestos and cells. Subsequently, fibroblasts lay down collagen, thereby initiating the fibrocic process, which is both restrictive (preventing movement) and destructive (disrupting air spaces and their blood supply). The small airways show local fibrosis with distortion and narrowing. Classically, asbestosis has been regarded as a restrictive lung disease, but clinically one often finds evidence of obstructive lung disease, especially among smokers, or a mixed obstructive and restrictive physiological abnormality (Becklake, 1976). Results of well-designed epidemiological studies of the relative effects of smoking and asbestos exposure on small airways obstruction are not available. The earliest patient complaint is often coughing; dyspnea (breathlessness on exertion) is usually associated with more advanced illness. Radiological changes may precede, occur simultaneously with, or follow the changes in pulmonary function. The changes observed in the chest radiograph are typically located in the lower half of the lung. The early changes include ill-defined linear opacities. Before any patient complaints, fine crepitations or rales at the lung bases may be heard oy auscultation. In addition, arterial oxygenation and diffusing capacity may be decreased. Smoking may also affect the pulmonary function tests and radiological results, especially with respect to small airways disease (Buist, 1983). The early changes seen in the chest radiograph may not be immediately associated with pulmonary asbestosis, but as the opacities become more profuse,, more clearly defined.linear opacities appear, septal lines become more marked, and pleural involvement is often seen. At chat stage, the radiological picture alone may strongly suggest asbestosis. The most effective prevention or treatment is early removal from exposure. Although asbestosis often continues to progress (Becklake, 114 1976), the progression is not inevitable and often not rapid (Gregor e_t al., 1979; Jones et al., 1980a). Progressive hypoxia with cor pulmonale are common causes of death among those with advanced asbestosis, and many persons vith advanced asbestosis die from lung cancer. Mild asbestosis is not necessarily associated vith functional impairment. Pleural Changes. Diffuse pleural thickening, plaques, calcification, and effusions are nonmalignant changes in the pleura that have been associated with asbestos exposure (Albelda e _al., 1982; Epler et al., 1982; Weiss et si., 1981). These changes, usually detected by radiographic examination rather chan by patient symptoms, may indicate that asbestos exposure has occurred. They may develop after little apparent exposure and may result in few symptoms, or they may be associated with more extensive exposure and parenchymal asbestosis. The parietal pleura is usually more heavily involved chan the visceral pleura (Becklake, 1976; Selikoff and Lee, 1978). There may be simple, benign pleural effusion, and the usually sterile fluid may contain lymphocytes, possibly erythrocytes, and albumin. Asbestos bodies and fibers are rarely found in the fluid or the plaques. With extensive pleural involvement, the symptoms are similar to chose of restrictive pulmonary disease, and may include dyspnea, a feeling of tightness, and pulmonary restriction that may occasionally result in marked impairment. Complaints of pain are rare. Pleural changes progress slowly, and most patients experience little functional impairment. There are no well-designed studies to provide evidence on whether persons with these asbestos-induced pleural changes are at increased risk of lung cancer or mesothelioma beyond that attributable to asbestos exposure per se. DISEASE ASSOCIATED WITH NONOCCtiPATIONAL INHALATION EXPOSURES TO ASBESTIFORM FIBERS Having described clinical manifestations of the diseases associated with asbestos exposure, the committee now discusses some observations among populations exposed to asbestiform fibers outside the workplace. In general, data on nonoccupational exposures are sparse. However, the studies that have been conducted provide information about the variety of minerals in fibrous form chat may lead to asbestos-associated disease. If adequate population-based data were to become available, it might be possible in some situations to estimate exposure or to test . risk-assessment models. End points that have been used to detect health effects include overall mortality, mortality from lung cancer and mesothelioma, and nonmalignant respiratory changes such as the presence of asbestosis or 115 pleural plaques. Exposures have occurred in the households of asbestos workers. In neighborhoods near asbestos-manufacturing facilities, and In areas with natural sources of asbestlfora fibers. Mesothelioma provides a useful end point for studying effects of exposure. This fatal tumor Is rare, except in certain groups exposed to asbestlform fibers. In some worker cohorts, as many as 10Z of the deaths have been caused by mesothelioma (McDonald and McDonald, 1980, 1981; Sellkoff et al., 1979). Small numbers of mesotheliomas are more easily detected than small excess numbers of lung cancers, since lung cancers account for about 5X of all deaths In the United States (U.S. Department of Health and Human Services, 1983). Furthermore, unlike lung cancer, mesothelioma Is not associated with smoking (Hammond et al., 1979). The best estimates of.the nationa1,,Incidence ,rate for mesothelioma have come from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program, which collects data on cancer Incidence In about 10Z of the country. Approximately 1,600 mesothelioma cases were estimated to have occurred in 1980. For the period from 1977 to 1980, SEER reported 431 male cases and 117 female cases (Connelly and Myers, 1982). From these data, the annual Incidence rate for mesothelioma was calculated as 11.8 per million per year for males and 2.6 per million for females, age-adjusted to 1970. The Incidence rate apparently varies with opportunities for past exposure to asbestos. In the United States, the.lowest.rate, occurred in Iowa, where the Incidence rate for white males during 1977-1980 was 7.4 cases/million per year. In Seattle and San Francisco-Oakland, where there was extensive shipbuilding during World War II, the annual Incidence rate was about 20 cases/million, age-adjusted for 1970. National mortality statistics for mesothelioma are not available from the National Center for Health Statistics (NCHS) because cancers are classified by site rather than by type. For 1979, malignant neoplasms of the pleura (ICD Code 163, 9th Revision) were reported to be the cause of death for 257 males and 83 females (S. Seeman, National Center for Health Statistics, personal communication, 1983). Because of the difficulties In diagnosing mesothelioma and determining exposure to asbestlform fibers, the background rate of mesothelioma Is not known. In one study of 4,539 cases from 22 countries between 1959 and 1976, there was no definite or probable history of exposure for 38Z of the subjects (McDonald and McDonald, 1977). In North America, It was estimated that from 50X to 75X of male cases, but only 10Z of females, are likely to have been exposed to asbestos (McDonald and McDonald, 1981). A recent review Indicates that a few cases of mesothelioma have been reported in nickel workers^ and In persons with ^Danger et al. (1980) reported that they found asbestos fibers contaminating some nickel ores. 116 some ocher specific exposures (Peterson et el., in press). It is thus possible chat not all cases of mesothelioma are associated with exposure to asbestifora fibers. However, since the levels of general ambient exposures to asbestos were not known, the possibility that the residual cases night also be attributable to asbestos exposures cannot be discounted. Epldeoiologlcal data have led to questions about the characteristics of fibers that are associated with aesotheliona. Soae investigators have interpreted the data as indicating that exposure to chrysotlle is less likely to produce aesotheliona than is exposure to the other asbestos fibers (Craighead and Mossaan, 1982; McDonald and McDonald, 1981). However, because it is difficult to determine exposure and to characterize fibers adequately, it has not been possible to confirm or refute the argument. Asbestos Exposure froa Household Contacts Anderson et al. (1979) studied household cohabitants of 1,664 asbestos workers. The workers were employed in a factory that had produced aaoslte asbestos products froa 1941 to 1954. Controls were urban New Jersey residents living in the same community who had routine chest x-rays between January 1975 and December 1976. Asbestos-associated x-ray abnormalities were found in 35X of the 678 household contacts examined and in 5X of the controls. The abnormalities Included small, irregular parenchymal opacities as well as pleural thickening, calcifica tion, and plaques. Five of 550 deaths traced among the cohort of 3,100 household contacts were due to mesothelioma--a proportion much higher than that seen in the general population. No reliable estimates of dust levels in homes were available, but the authors assumed that asbestos was brought home on work cloches. Other data also indicate that household exposure can lead to health effects. In New York State, 52 females with malignant mesothelioma between 1967 and 1977 were investigated to determine their occupational histories and the occupations of their fathers and husbands (Vianna and Polan, 1978). Thirty-two of the cases were pleural mesothelioma and 20 were peritoneal. Six cases and two of the 52 controls had been exposed occupationally. Eight other cases had husbands or fathers who had been occupationally exposed, but none of the controls had occupationally exposed husbands or fathers. Neighborhood Exposure to Asbestos . A cohort of 1,779 males living within 0.8 La of a Unarco amosite factory in Paterson, New Jersey, was studied to determine if excess mortality had occurred (Hammond et al., 1979). Another neighborhood several kilometers away served as a control. None of the subjects had 117 worked la the plant. No excess aortallty or excess lung cancers were detected between 1962 and 1976 in the group living near the plant. Thus, In this study, males living In the factory neighborhood apparently were less at risk (at least for mesothelioma) than members of worker households. No estimates of neighborhood levels of asbestos fibers or other carcinogens were available for either area of study. Natural Sources of Asbestlform Fibers Asbestos-related diseases have been associated with exposure to naturally occurring mineral fibers In Turkey, Finland, and Bulgaria (Baris e al., 1981; Klviluoto, i960; Zolov et al., 1967). In most cases, quantitative exposure measurements have not been published. In the United States, no differences In mortality were found for specific cancers In counties with and without natural asbestos deposits (Fears, 1976), although the study design would not be likely to detect small effects. Coffin et al. (1983) have recently discussed the occurrence of mesothelioma and other asbestos-associated lesions In some human populations and In animals not known to be exposed to asbestos. Ihey and others (e.g., Gllckaan et al., 1983) suggest that further study of these situations, such as mesothelioma In pet dogs, might help people to discover sources of exposure to harmful fibers. Pleural plaques were found to be endemic among agricultural workers In an area of Southern Bulgaria (Zolov et al., 1967). Of 3,300 people examined, 4Z of those with no mining exposure to asbestos had pleural plaques. Most of those subjects were agricultural workers. Analysis of soil samples revealed the presence of asbestlform fibers (Burilkov and Michallova, 1970) consisting of anthophylllte, tremollte, and seplollte, the latter being a layered silicate with a triple subchain structure. No pleural plaques were found In a neighboring farming region that lacked asbestlform fibers In the soil. In south central Turkey, several villages are located on and In tuff, a rock composed of volcanic detritus that may contain a variety of fibrous minerals (Artvlnll and Baris, 1982; Baris et al., 1981; Lills, 1981; Rohl et al., 1982). Dwellings are hollowed out of the rock. Studies of the populations of these villages have revealed mortality and disease patterns that are similar to those usually seen among asbestos . workers, with respect to occurrence of fibrosis, pleural plaques, lung cancer, and mesothelioma (Artvlnll and Baris, 1982). In Karain, a village with a population of about 600, 36 cases of mesothelioma were reported between 1969 and 1974 (Baris et al., 1981). The median age of death in Karain was 54, whereas It was 68 In the nearby village of Karllk. In another nearby village, Tuzkoy, malignancies accounted for 41 of 67 deaths that occurred from 1978 to 1980 among almost 2,000 residents older than 25 years (Artvlnll and Baris, 1982). Of these deaths, 15 were due to pleural mesothelioma, 12 were attributed to peritoneal mesothelioma, and 8 were caused by lung cancer. The mesotheliomas were found equally among male and female residents, and the mean age of the 118 mesothelioma cases was about 50, which Is younger than that found among worker groups. These data suggest that an environmental exposure beginning at a young age might have been responsible for the diseases. Oust and fiber levels were measured In Karaln and in the "control" village Karlik (Baris et al., 1981). Dust levels in both villages were about 1 mg/m^. Levels of fibers were higher in Karaln than In Karlik, but In both villages, most air samples had less than 0.01 fiber/cm^. Nonetheless, in 11 samples taken during the cleaning of the caves in which the Karaln villagers lived, the concentrations ranged from less than 0.01 fiber/cm-* to 1.38 fibers/cm^. Although tremolite asbestos was apparently present in the area, the most prevalent fibers appeared to be erlonite. Analysis of pleural and parenchymal tissues from mesothelioma patients from Karaln indicated chat 90Z of the fibrous particles had a composition consistent with that of erlonite (a fibrous zeolite), whereas from 1Z to 5Z were consistent with tremolite (Roh1 et al., 1982). The use of an analytical transmission electron microscope to examine lung tissue from two mesothelioma cases from Tuzkoy revealed a concentration of 10 fibers per gram of dried lung tissue (Sehastlen et al., 1981). Of the uncoated fibers, 93Z were erlonite with a mean length of about 3.7 urn. Only 3Z of the fibers were longer than 8 um or thinner than 0.25 uo. The remaining fibers seem to have been either titanium oxide (rutile) or some material resembling amphibole. The data are consistent with the hypothesis that erlonite may have a role in causing the high rate of mesothelioma in these villages. It is not clear how to account for the higher mesothelioma and lung cancer rates in these villages if the diagnoses and measured environ mental exposures are correct. Possible explanations include enhanced ability of the fibers to cause cancer for reasons not yet known, the presence of other, undetected carcinogenic agents, or Increased susceptibility if inhalation of the fibers starts in infancy (Baris et al., 1981), since children are known to have Increased susceptibility to the effects of many environmental agents. It would be of interest to estimate the exposure necessary to account for the observed mesothelioma rates by using some of the tlme-dose-response models for mesothelioma that have been developed for worker populations. These models are discussed in Chapter 7 of this report. A rough calculation shows that a lifetime exposure to about 20 fibers/cm^ accounts for a mesothelioma lifetime risk of 50Z, based on the data presented in Table 7-3. Rom e al. (1983) considered the possible health hazard posed by naturally occurring fibrous erlonite in Arizona, Nevada, Oregon, and Utah. A review of 275 chest radiographs in one hospital near such an area in Nevada showed background levels of pleural plaques (2Z) and pleural thickening (6Z) and no pleural calcifications. Analysis of the fibrous materials in the various areas indicated the presence of materials of a size that would be respirable (Vright et al., 1983). Uagner (1982) has reported that erlonite from Oregon is extremely potent in producing mesotheliomas in rats. 119 Summary Persons residing in areas in Turkey where asbestiform fibers are present in the environment and persons living in the same household as workers exposed to asbestos develop mesothelioma at a rate In excess of that for the general population. The evidence is based primarily on clinical observations and on case-control studies that do not permit generalization. It seems likely that these mesotheliomas arise from respiratory exposure to asbestiform fibers. EPIDEMIOLOGICAL STUDIES OF EFFECTS RESULTING FROM THE INGESTION OF ASBESTOS IN DRINKING WATER Epidemiological studies of the effects of asbestos in drinking water in six geographical areas of the United States and Canada have been extensively reviewed and critiqued (Marsh, 1983; Workshop on Ingested Asbestos, 1963). In all these studies, a possible excess incidence of gastrointestinal (GI) cancers was evaluated as were morbidity or mortality rates for some other cancers. In addition, the National Research Council's Safe Drinking Water Committee addressed this problem and estimated the risk of excess GI cancers associated with ingesting asbestos in drinking water (National Research Council, 1983a). Tables 5-1, 5-2, and 5-3 summarize the characteristics and results of the various studies. Duration of exposure ranged from as little as 20 years (in Duluth6) to more than 50 years (in Quebec); asbestos concentrations ranged from less than detectable limits to 1,300 x 106 fibers/liter. Except for Duluth, where taconlte mine tailings were dumped into Lake Superior, the subjects were exposed to chrysotile from natural sources (in Quebec, the San Francisco Bay area, and Puget Sound) or from asbestos-cement pipes (in Utah and Connecticut). The studies did not Indicate consistent excesses of cancer. In Duluth, no consistent type of cancer occurred in excess among residents (Levy et al., 1976; Mason et al., 1974; Slgurdsoa et al., 1981). In Quebec, cancer mortality was evaluated in relation to asbestos in municipal water supplies. In the first study (Wlgle, 1977), 22 municipalities were grouped into three categories based on level of asbestos in water supplies. In a more extensive study (Toft et al., 1981), mortality rates for two cities with high exposure (>100 x 10 fibers/liter) were compared with 52 low exposure cities (<5 x 106 fibers/liter). Some excess cancers in males that were noted in the two studies were attributed to probable occupational exposure. In Connecticut, tumor registry data indicated that there was no association 6The particles in Lake Superior were mostly aclcular cleavage fragments rather than asbestiform fibers (T. Zoltai, personal communication, 1983). See also Langer et al., 1979. * 120 TABLE 5-1. Characteristics of Asbestos Exposures froa Drinking Hater In Different Study Populations3 Location of Study Duluth Connecticut Quebec Bay Area, California Utah Puget Sound Exposure Characteristics No. of Fibers Type of per Liter Asbestos (Range) Size of Maximum Population Duration of Exposed Exposure (Tears) Aaphlbole^ 1-30 x 106 100,000 15-20 Chrysotile BDLc-0.7 x 106 576,800 23-44 Chrysotlle 1.1-1,300 x 106 420,000 50 Chrysotile 0.025-36 x 106 3,000,000 40 Chrysotile NAd Chrysotile 7.3-206.5 x 106 24,000 20-30 200,000 40 8 From Marsh, 1983. bMost of these particles were probably adcular crystals rather than asbestlform fibers (T. Zoltai, University of Minnesota, personal coaaunlcation, 1983). Langer et al. (1979) referred to the particles as aaphlbole gangue minerals and discussed the uncertainties In determining whether they are asbestlforn. CBDL below detectable Halt. dNA * not available. between asbestos risk scores and GI tumor incidence (Harrington et al., 1978; Meigs et al., 1980). In San Francisco, there were ^consistent excesses of soae cancers (Conforti et al., 1981; Kanare* et al., 1980; Tarter, 1981). In Puget Sound, a proportional incidence analysis comparing length of residence suggested an excess for soae GI cancers (Polissar at al., 1982). All of the epidemiological studies had limitations. Perhaps the most serious were the substantial problems In classifying exposure because population data rather than Individual data were used* Errors In classification will tend to weaken any true associations that aay exist between asbestos in drinking water and health effects. Given the difficulty of determining Individual exposure, results of these epidemiological studies cannot be taken as strong evidence about the extent to which IngeBtion of drinking water containing asbestlform fibers sight Increase the risk of GI cancer. The NRC Safe Drinking Hater 121 --* O ^Ml sISSS 2.22532 0. C WI c 3j*SS-**2S 22x2xx22x222 III*x**2SSSxS 9 ^ t^l T|I!|||||s!s ?C i ceoScSo2s2^2s-x2 -- 2o 1=: sssssssslsssi U3 -- f XV 0 25 :|IH??: gill *> C ** x *e> xao o***il No o*Z^X^^o^^w*j*22*3 mi Mf9 --O= -i: *als S3* . . . 99 5n 5 X X X W SJ 229 23 C| C^-SX-SX .fcKZ.?i JJ*33iiS22 * O c -- XJ * *5 122 9 -- m m -- m9 9 e 0 K 0 Q mm am 9 | !-- - l , -- . --I -I m --j i ^ i . Ml l -- --I --I** m( !-- m| M*|l ml|c0 Mmo 9 l m*iix!.mrn - |Co bm Zs ^5M---aZS*t>^3--b.>roMs*Uo?Ht;*M*sfot-. M:* ai9 3 < J<w| co v)wv)woooeoccc M*ovi wZZZZwwwwZwZ O -N M *9 X P* e- cocococococococooccococo Z Z S S Z Z Z^wZ z z [U '' AX e u Z * 3* P ** 3 5 10 CzO 9-- c C I ecocococooococococo wZZZZ^wwwZZZw V "* co eeo o tOCOCOCOCOOOOCOttCOO ZZZZwwwvwZZZw e e coo IZAZIAZ(AZMwCwOwOCwOw0Z) ^^CwO 0 X > s0 o ^ Ar* fc. W c -- e -* K4 -- XC-- M XI wU3 > X*t* O -- A U A. mt; o o ooeoo o w o o * * o CO co co o w-Zn->*wwww^*ZZ^ cocnooecocoeotocaoo XXXvMUMUUMfci tVe cc 99 0P o 9 9 9 C CXX x o9o9o90ye 0u6 9oV c*9axoxoxom 'MC -- o >- M C M 0-- m u X M0 am W9 0 0 o> .CM tc a o -- mm J1 tl c M M ,i' X^ U Nx w 123 Committee (1983a), using a variety of assuaptlons, estimated the excess risk of GI cancers that night be expected from Ingestion of asbestos-containing drinking water and concluded that their risk eBtlaate8 are consistent vlth the results of the epidemiological drinking water studies considered. OCCUPATIONAL EPIDEMIOLOGICAL STUDIES--METHODOLOGICAL CONSIDERATIONS Evaluation of potential health effects from nonoccupational exposure to asbestlforn fibers depends primarily on results of epidemiological studies of occupational groups. Most of the analyses have Involved cohort? studies of workers exposed to asbestos of various types and in a variety of industries and occupations. Much Information has been obtained from these studies. However, they also suffer from limitations common to many epidemiological studies and from some additional problems related to determining dose (exposure) and'response'(health end point, such as death from a specific cause). Despite the limitations of individual studies, the committee finds that, when all the studies are considered, exposure to asbestos increases the risk of developing lung cancer, mesothelioma, asbestosis, and possibly other cancers. To quantify health risks from an exposure, It is necessary to obtain dose-response data, but exposure measurements are particularly difficult to obtain. Because of the long latency period for asbestos-associated diseases, investigators have found it necessary to try to reconstruct past exposures. Techniques of measurement vary from place to place and over time (Acheson and Gardner, 1980; Dement et al., 1983a). For example, fiber counts obtained by light microscope in various Industrial settings may need to be multiplied by a factor varying from 2 to 8 to obtain a true count of fibers longer than 5 urn. Typically, a cumulative dose measurement is used. This does not take into account the time lapsed since last exposure nor does it distinguish between short exposures of high intensity and long exposures to low dust concentrations. In addition, a cumulative dose measurement does not change when exposure ceases. Variability in these exposure-related ?The two major types of epidemiological studies are cohort studies and case-comparison studies. In a cohort study, a group with certain defined characteristics of exposure Is selected and followed to ` determine the number of members reaching a particular end point, such as death, by a specified time. The group Is called a cohort. In its purest form, the analysis of a cohort study depends entirely on withincohort comparisons, and the results may be presented as arrays of morbidity or mortality rates or by a large variety of other expressions of association or correlation. A cohort might comprise two major groups, differentiated by their exposure experience. However, in occupational studies, especially of cancer, the rate of occurrence of death or disease in the group is often compared with the rate In some (continued) 124 factors affect mortality responses in occupational cohorts. In some studies, exposure surrogates, such as type of job and duration of employment, are used to estimate exposure. These estimates may be less precise than actual measurements. (See Consumer Product Safety Commission, 1983, for a detailed assessment of exposure estimates among the various asbestos studies.) There may also be variability in reporting causes of death, ascertainment of deaths, and diagnostic accuracy of the reported cause of death. Inaccuracies are particularly likely for mesothelioma and asbestosls (Hammond at al., 1979). In morbidity studies, asbestosls, pleural thickening and calcification, and pulmonary dysfunction may be incompletely diagnosed. For example, although the American College of Radiology has stated that certain radiographic evidence [i.e., Category 1 profusion, as defined In the International labor Organization (ILO) 1980 Classification] together with a clear history of exposure to asbestos suffices to make a presumptive diagnosis of asbestosls, other diagnostic criteria have been suggested. Methodological differences are a major source of variation In comparing studies (Enterllne, 1976). For example, the results obtained will depend on the criteria for selecting the cohort, the choice of comparison groups, the Influence of other environmental factors that may Introduce competing disease risks, and the records available. In addition, heterogeneity In the time at which onset of exposure begins can Introduce additional distortion In the observed relative risks (Velss, 1963), especially because the types of exposure experienced by some workers in the distant past may differ from exposures experienced only more recently. Weiss also discussed how the results of lung cancer studies can be affected if persons who left a Job are not included in the study cohort. He found that the exclusion of these workers could affect the relative risk by a factor of 2 to 3. An additional difficulty is encountered when comparing dose-response results from mortality and morbidity studies, particularly if the (continued) other appropriate, external population, such as males of an appropriate age group, because the researchers did not have an appropriate internal comparison group. Results of mortality studies of cohorts are usually expressed as a standardized mortality ratio (SMR), which is defined as observed deaths In the cohort divided by expected deaths. An SMR of greater than 1, if statistically significant, may Indicate that excess deaths have occurred In the exposed cohort. The SMR is similar to the relative risk. In a case-comparison study, the epidemiologist starts with cases of the disease of interest, such as lung cancer or meso thelioma, and then compares exposure parameters and other risk factors between cases and appropriately selected persons without the disease to to determine whether certain exposures are seen more frequently among cases than among the noncases (sometimes called controls). 125 morbidity studies sre confined to sctive workers, which is usually the case. A bias is introduced in studies of active workers, since those with severe disease have probably already left employment. However, asbestosis generally progresses after cessation of dust exposures (Becklake e aK , 1979; Rubino e al, 1979b). Numerous follow-up studies of asbestos-related mortality have been conducted on cohorts with varying intensity and duration of exposure, type of exposure, type of work, time and duration of follow-up periods, and employment status at onset of study. There have also been differences in the completeness of the cohort, completeness of mortality ascertainment, availability of smoking histories, geographic area of study, selection of comparison populations, and methods of data analysis. Because of the variations noted, it is not surprising that the standardized mortality ratios (SMRs) and dose-response results differ greatly among studies (See Appendix E, Table E-l, and Consumer Product Safety Commission, 1983.),. In general, however, the same major diseases--lung cancer, mesothelioma, and asbestosis--have been observed, although not all investigators conducting these studies have reported or detected excesses of all three of those diseases. CANCER MORTALITY IN OCCUPATIONAL COHORTS EXPOSED TO ASBESTOS To evaluate variations in cancer mortality associated with occupational exposure to asbestos, the committee reviewed studies of 23 occupational cohorts. These are summarized in Table 5-4 and in Appendix E, Table E-l. These studies indicate the variety of occupations and industries where asbestos exposure has occurred and the types of asbestos commercially used. The epidemiological study by Doll (1955) verified and quantified the occurrence of excess lung cancer among persons who work with asbestos. His study population consisted of 113 men who had been exposed to high levels of chrysotile in an asbestos-processing plant in England before the effective implementation of regulations in 1933. During the follow-up through 1953, there were 11 deaths from lung cancer in comparison to an expected value of 0.8 based on national death rates. In 1980, Peto (1980a) reported on the mortality experience of 679 men who were initially employed after 1933 at the same plant studied by Doll. Among these workers, 40 deaths from lung cancer were observed compared to 23 expected. In addition, there were 10 pleural mesotheliomas. Furthermore, the risk of mesothelioma appeared to be associated with time elapsed since initial exposure. In the United States, excess lung cancers among persons who worked with asbestos were reported by epidemiologists in 1954, 1963, and 1964 (Breslow e al., 1954; Mancuso and Coulter, 1963; Selikoff et al., 1964). Among 632 insulation workers who had been followed for at least 20 years, there were 45 deaths from lung cancer in comparison to an expected number of 6.6, based on U.S. death rates (Selikoff et al., 1964). 126 TAM./ $-4. SuMary of Mortality Data for Mesothelioma, Lung Cancar, and Gastrointestinal Cancar la Asbestos-Exposed Occupational Cohorts* Sex and Occupation of Cohort Country*- MALES: Minina and Killing Chrysotlle Aathophylllte Croddollte C C I F Aus Size of Cohort Traced 9,850 544 9J3 1.045h 1,960 Deaths In Cohort No. 1-------------- " Total Mesotbelloaa/ PleuralPeritoneal 3.291 178 332 384 526 33.4 32.7 35.6 36.7 10.6 10/10-0 1/1-0 08/0-0 0/0-0 26/26-0 Respiratory Cancel Oba SEP... 0/E 230 184.0 1.3* 28 11.0 2.5* 10 10.4 1.0 44 22.0 2.0* 60 38.2 1.6* Manufacturing Chrysotlle Aaoslte Mixed US US B B B US 1.261 820 2,887k 7,474 l,071h 1,075 308 528 545 1.339 317 781 23.6 64.4 18.9 17.9 29.6 72.7 1/0-1 14/7-7 46/19-27 8/8-0 10/10-0 S/NA 35 11.1 3.2* 83 22.8 3.6* 103 43.2 2.4* 143 139.5 1.0 51 23.8 2.1* 63 23.3 2.7* US 5,645 601 10.6 0*/0-0 c 241 72 22.0 11/6-5 0 5,686 -- 3/NA 49 49.1 1.0 20 3.3 6.1* 47 27.8 1.7* Insulation Mixed Shipyards Mixed FEMALES: Manufacturing Croddollte Mixed US US 1 B I B B B B 632 17,800 162 478 2,271 122 75.6 12.8 75.3 6,076 2,190 1,043 1,970 17.2 48.9 38/11-27 175/63-112 13/8-5 31/XA SA 93 13.3 7.0* 429 105.6 4.0* 35 5.0 7.0* 88 100.7 0.9 123 54.9 2.2* 578 783 3.708 1.304 166 28.7 200 25.5 299 8.1 396 30.4 17/13-4 21/13-7 2/2-0 6/NA 12 6.3 1.9* 27 3.2 8.4* 6 11.3 0.5 22 11.0 2.0* Adapted froa McDonald and McDonald (1981) and froa Conauaer Product Safety Commission (1983, p, 11-57). These studies ere described In aore detail In Zsble -1 of Appendix E. ' hobs * observed; Exp * expected; 0/E * observed/expected; LI lower Halt; UL * upper Halt. c Country of study: US * United States, B - Britain, C " Canada, F * Finland, I - Italy, 0 - Denmark, Aus " Australia. ' - ^951 confidence intervals (two-sided) calculated assuming normal distribution for lo| SMR. The coluans handed "power* above Indicate the probability of detecting an effect, given the size of the population studied, assualng that exposure produced a alnlnua relative risk of l.S. More precisely, statistical power Is the probability chat the null hypothesis of no Increased relative rlak (R 1) will be rejected by a one-sided test with a " 0.05 If the true relative risk (R) Is actually 1.5 In a population of the size studied. The calculation (see Beauaont and Brealov, 1981) la baaed on the assuaptlon chat, under the null hypothesis, the observed nuabar of deaths has a Poisson distribution with expected value equal to (the expected nuabar of deaths for persons of this age group) and chat the square root transformation stabilises the variance of the Poisson distribution. Power la calculated by eoaputlng 2 * 1.645 - 2(/T - lK^E) and then determining the area to the right of 2 froa a cable of the standard normal distribution. 127 TABLE 5-4 (coat.) Respiratory Cancer (coat.) Gastrointestinal Csncerb 951 95Z Confidence Units* Power to Detect 0/E Confidence Halted LL UL_ >1.5. a 0-05e Ohs Exp 0/E LL UL Power to Detect 0/E >1.5. a ~ 0.05* References 1.1 1.4 1.00 1.8 3.7 0.44 0.5 1.8 0.42 1.5 2.7 0.68 1.2 2.2 0.87 2.3 2.9 2.0 0.9 1.6 2.1 0.8 3.9 1.3 4.4 4.5 2.9 1.2 2.8 3.5 1.3 9.4 2.3 0.44 0.69 0.90 1.00 0. 71 0.70 0.93 0.20 0.76 5.7 8.6 0.50 3.7 4.4 1.00 5.0 9.7 0.26 0.7 1.1 1.00 1.9 2.7 0.95 276 10 19 7 NAJ 272.4 9.5 19.3 8.0 NA 1.0 1.1 1.0 0.9* NA 0.9 0.6 0.6 0.4 -- 1.1 2.0 1.5 1.8 -- 1.00 0.40 0.63 0.36 -- 13 9.9 1.3 0.8 28 22.7 1.2 0.9 40 34.0 1.2 0.9 103 107.2 1.0 0.8 16 15.7 1.0 0.6 55 39.9 1.4* 1.1 25 50.1 0.5 0.3 4 2.5 1.6 0.6 59 49.3 1.2 0.9 2.3 1.8 1.6 1.2 1.7 1.8 0.41 0.69 0.84 1.00 0.56 0.88 0.7 0.94 4.3 0.18 1.5 0.93 43 15.0 2.9* 2.1 3.9 0.54 94 59.4 1.6* 1.3 1.9 0.97 13 2.2 5.9* 3.4 10.2 0.16 73 83.3 0.9 0.7 1.1 0.99 74 58.6 1.3 1.0 1.6 0.96 McDonald et al., 1980 Nicholson et al., 1979 Rublno et al., 1979a Meuraan et al., 1979 Hobbs et al., 1980 Deaent et al., 1983b Seldaan et al., 1979 Newhouse and Berry, 1979 Newhouse et aj.., 1982 Peto et al., 1977 Henderson and Eaterllne, 1979 Hughes and Weill, 1980 Finkelstein, 1983 Cleaaesen and HJalgrla-Jenson, 1981 Selikoff et al.. 1979 Selikoff et al., 1979 lines and Siapsoa, 1977 Rosaiter and Coles, 1980 Puntool et al., 1979 1.1 3.4 5.8 12.3 0.2 1.2 1.3 3.0 0.30 0.20 0.45 0.44 10 20.3 0.5 0.3 0.9 0.65 20 10.2 2.0* 1.3 3.0 0.42 29 27.4 1.1 0.7 1.5 0.76 NA NA NA -- ---- Jones e al., 1980 Newhouse and Berry, 1979 Newhouse e al., 1982 Acheson et al., 1982 *Statistlcally significant Increaaetp '.05). >Oae possible case (Rublno et ai., 1979); evo cases not seating criteria hMalea and feeslee (Meuraan t il., 1979; Peto et al., 1977). *Based upon 1974 report (Meuraan e al., 1974). Jna * data not available. *Baaed oa aales, excluding loggers (Newhouse and Berry, 1979). Study of cancer incidence (Cleaaesea and HJalgrla-Jenson, 1981). (Hughes and Weill, ' 1980). 128 Since 1964, a number of investigators have documented an excess occurrence of lung cancer and/or mesothelioma among persons occupationally exposed to asbestos. Several of these studies are briefly described below, by industry and fiber type. Criteria for selecting these studies included the availability of quantitative exposure data or a qualitative exposure assessment, size of the available occupational cohort, and any unusual exposure or disease observations not reported in ocher studies. (See Table 5-4 and Appendix E, Table E-l for more details on these studies.) Mining and Milling Chrysotile. Three cohorts occupationally exposed to chrysotile asbestos during mining and milling operations had a moderately increased risk for lung cancer (SMRs from 1.0 to 2.6). In Che largest investigation, McDonald ejt aJL. (1980) studied all employees who had worked for at least 1 month in Quebec mines. From 1950 to 1975, 3,291 deaths occurred among the 9,850 male employees successfully traced and followed for 20 years or more after initial employment. An increase in lung cancer mortality was observed (SMR 1.3, 230 observed vs. 184 expected), and the risk increased with duration of employment (SMR 3 1.0 for <1 year to 1.6 for >20 years) and level of exposure (SMR =0.9 for <30 mppcf(yr) to 2.3 for ^300 mppcf(yr). Eleven cases of mesothelioma were observed. Anthophyllite. Male and female employees of anthophyllite asbestos mines in Finland were studied by Meurman et al. (1974, 1979), who reported a twofold increase in lung cancer mortality (44 observed vs. 22.4 expected) and no mesotheliomas among Che 1,045 persons successfully traced. All lung cancer deaths occurred among the male employees, and Che risk was associated with estimated intensity of exposure (SMR =1.4 vs. 3.3 for low and heavy exposures, respectively). Lung cancer risk among nonsmoking asbestos-exposed employees was 1.4 compared to a relative risk of 17.0 for the asbestos-exposed employees who smoked. Crocidolite. For exposure associated with crocidolite mining in Western Australia, there was a similar increase in risk rt lung cancer (SMR * 1.6, 60 observed vs. 38.2 expected) and a strong association with mesothelioma (Hobbs ei aJL, 1980). Twenty-six cases of pleural mesothelioma were observed among the 526 deaths, and the mesothelioma risk increased with increased duration and intensity of exposure. Follow-up period was relatively short. No increases in gastrointestinal cancer were observed for any of the mining and milling cohorts reviewed. Manufacturing Chrysotile. Most asbestos exposures associated with manufacturing processes involve mixed fiber types, but Dement et al. (1982, 1983a,b) 129 examined the risks associated with exposure to chrysotile asbestos in textile factory workers. They observed a marked increase in lung cancer mortality (SMR 3.2, 35 observed/ll.1 expected), and the risk was strongly correlated with exposure level. There was also one peritoneal mesothelioma. Increased risks for both lung cancer and nonmalignant respiratory disease were observed at exposure levels lower than those reported in other studies. Amosite. Mortality due to lung cancer was increased three- to four-fold (83 observed /22.8 expected) for 820 factory workers exposed to amosite asbestos (Seidman et al., 1979). The higher risks were observed for the subgroup followed 20 years or longer after initial employment (SMR * 5.1, 52 observed/10.1 expected). This cohort is a somewhat unusual population because of its limited duration of intense work exposure (1941-1945) and long period of observation. Other excess cancers, including 14 mesotheliomas, were also reported. Mixed. Newhouse and Berry (1979) reported increased risks of lung cancer mortality for both males (SMR * 2.4, 103 observed/43.2 expected) and females (SMR * 8.4, 27 observed/3.2 expected) in a follow-up study of 4,600 male and 922 female employees of an East London asbestos factory in which crocidolite and amosite were used. Approximately 10Z of all deaths resulted either from pleural or peritoneal mesothelioma. Except for 10 cases of mesothelioma, no increased cancer mortality was observed among more than 11,000 males and females employed during 1941 or later at a British factory producing friction materials (Berry and Newhouse, 1983; Newhouse et al^., 1982). In a case-control study that corrected for total asbestos exposure, 5 of 6 cases had definitely worked with crocidolite, whereas 2 of 10 controls had. A cohort of 1,345 retired asbestos products workers employed from 1941 to 1967 had increased risks for lung cancer (SMR * 2.7, 63 observed/23.3 expected) and gastrointestinal cancer mortality (SMR = 1.4, 55 observed/39.3 expected) (Henderson and Enterline, 1979). Overall mortality among the 1,075 retirees successfully traced to 1973 was 73Z. The lur cancer risk was strongly associated with amount of exposure, expressed as million particles per cubic foot multiplied by number of years of exposure (mppcf-yr), ranging from an SMR of 2.0 up to 7.8. Lung cancer risk differed by type of asbestos exposure (SMR of 2.5 for chrysotile alone vs. 5.2 for mixed chrysotile and crocidolite exposures). Five mesothelioma deaths were observed. Study results suggest that effects of asbestos exposure on lung cancer risk may continue long after the termination of exposure. Studies of a retiree cohort may result in an underestimation of actual risks, since deaths among employees under age 65 would be omitted. The Consumer Product Safety Commission (1983) suggests that the risks may be understated by as much as two-fold. 130 No Increase In lung cancer mortality or cancer of any other site, except mesothelioma, was observed in the cohort of 5,645 employees of an asbestos-cement product manufacturing facility studied by Hughes and Weill (1980). In the high exposure subgroup, lung cancer risk was Increased for employees exposed to croddollte, and two mesothelioma deaths vere reported. The lov overall mortality, 10.61, and the low tracing rate, approximately 75Z, suggest that this study may have resulted in an underestimate of mortality risks. Flnkelstein (1983) studied 328 asbestos-cement workers hired before 1960 and employed for a minimum of 9 years. Mesothelioma was strongly associated with exposure level for production workers, whereas a dose-response relationship was not observed for lung cancer. Excess lung and gastrointestinal cancers were observed. Clemmesen and Hjalgrlm-Jenson (1981) studied cancer incidence among 6,372 Danish males who worked in asbestos-cement factories between 1944 and 1976. There were 55 cases of respiratory cancer compared to 33 expected, based on Danish Cancer Registry Incidence rates. Three mesotheliomas were observed in addition to excess prostate, laryngeal, and stomacn cancers. Cancer incidence in the unexposed employees at the same factories was not Increased. Jones et al. (1980b) studied a cohort of 578 females exposed to croddollte from western Australia during the manufacture of gas masks. The 12 cases of lung cancer (SMR * 1.9, 12 observed/6.3 expected) and the 17 mesothelioma cases (13 pleural and 4 peritoneal) were all exposed to croddollte, whereas no cases of mesothelioma or lung cancer occurred among the 102 females exposed only to chrysotile. Overall, 10Z of deaths vere due to mesothelioma. Risk of mesthelloma was strongly associated with duration of exposure, although no dose-response relationship was observed for lung cancer. Similar results vere reported among 1,304 females who manufactured gas masks at three locations followed from 1951 to June 30, 1980 (Acheson et al., 1980). Deaths from lung cancer (SMR 2.0, 22 observed/ll expected) and ovarian cancer (SMR " 2.2, 17 observed/7.8 expected) were increased. Lung cancer excess was higher for those exposed predominantly to croddollte compared to those exposed predominantly to chrysotile. Five of the six mesotheliomas occurred in those exposed predominantly to croddollte. All studies of occupational cohorts exposed to asbestos during manufacturing processes had an overall increased risk of lung cancer or a dose-response relationship In the exposure subgroups (Hughes and Weill, 1980; Peto et.al., 1977). Elevated risk ratios (1.1) for gastrointestinal cancer vere observed In six of the nine cohorts reviewed (Cleomesen and Hjalgrlm-Jenson, 1981; Dement at al., 1983b; Flnkelstein, 1983; Henderson and Enterline, 1979; Nevhouse and Berry, 1979; Seldman et al., 1979). 131 Insulation Mixed. All three of the cohorts involved in end product use of asbestos as insulators were exposed to mixed types of asbestos. One of the largest studies is that of Selikoff et l. (1979), who studied 17,800 members of an insulator's union. Overall mortality in this cohort was 12.82; 2,271 deaths were reported through 1976. Lung cancer risk was increased four-fold (429 observed/105.6 expected) and increases were observed for gastrointestinal cancer (SMR 1.6, 94 observed/59.4 expected), cancer of the larynx, pharynx, buccal cavity (SMR * 1.7, 25 observed/14.8 expected), and kidney (SMR * 2.2, 18 obaerved/8.1 expected). Dose-response relationships were not examined because of the lack of exposure data. Mesotheliomas (63 pleural and 112 peritoneal) accounted for 7.71 of Che deaths. Analysis of the relationship between smoking and lung cancer risk using data from the American Cancer Society indicated a consistent multiplicative effect, in that a 10-fold increase in risk of lung cancer was associated with-smoking-in both asbestosexposed and unexposed groups. A five-fold increase in lung cancer risk was associated with asbestos exposure in both smokers and nonsmokers (Hammond e l_., 1979). Elmes and Simpson (1977) reported an unusually high risk of lung cancer (SMR * 7.0, 35 observed/5 expected) and gastrointestinal cancer (SMR * 5.9, 13 observed/2.2 expected) for a cohort of 162 insulators and pipe coverers employed in Northern Ireland during 1940. Overall mortality in this cohort was 75.3Z by 1975; 54Z of the deaths were due to cancer. Thirteen cases of mesothelioma (eight pleural and five peritoneal) were reported.E No difference in cancer risk was apparent for workers first employed before or after 1933. Ascertainment bias is unlikely to explain the magnitude of the risks reported for this cohort. Shipyards Mixed exposures. Rossiter and Coles (1980) studied 6,076 dockyard workers employed before 1947. They reported no increase in lung cancer mortality (SMR * 0.7, 84 observed/119.7 expected) or gastrointestinal cancer (SMR * 0.8, 63 observed/83.3 expected). Mesothelioma was reported for 31 (3Z) of the 1,043 deaths. However, since less than 20Z of this cohort have died, excess cancers may not be fully apparent. In a study of 2,190 Italian dockworkers, Puntoni et l. (1979) ' observed increased risks for lung cancer (SMR * 2.2, 123 observed/54.9 expected), gastrointestinal cancer (SMR * 1.3, 74 observed/58.6 expected), laryngeal cancer (SMR * 1.9, 15 observed/7.7 expected), and kidney cancer (SMR 2.0, 29 observed/14.7 expected). 132 Relative Carcinogenicity of Different Types of Asbestos There has been much discussion about whether certain asbestos varieties are acre carcinogenic than others. The question Is of practical Importance, because the vast majority of asbestos used In the United States and the world Is chrysotlle; however, it Is difficult to answer, because studies of different types of asbestos are confounded by type of Industry (mining and milling vs. asbestos-cement vs. asbestos Insulation vs. asbestos textiles), by fiber size characteristics within an industry, by variations In fiber and dust particle concentration and their measurement, and by variations In study methods. Therefore, direct comparisons are not easily made among epidemiological studies. Special attention has been given to crocldollte, especially in regard to its association with mesothelioma. Some groups of workers exposed to crocldollte have had a relatively high rate of mesothelioma. Among those are black South African crocldollte miners (2Z prevalence) (Tolent et al., 1980) and gas-mask workers (up to 10Z of deaths) (Acheson et al., 1980; Jones et al., 1980). In a study of naval dockyard workers, Rosslter and Coles (1980) reported 31 deaths from mesothelioma and only 13 other deaths from asbestos-related disease among 1,043 deaths ascertained (Rosslter and Coles, 1980). McDonald (1980) suggested that use of crocldollte by the British navy could explain such a finding. Data on chrysotlle exposures are mixed. Canadian studies of chrysotlle miners and millers have suggested that the average incidence of mesothelioma Is relatively low (0.5Z) (McDonald, 1980). Dement et al. (1983b) reported that only one of 308 deathB in a chrysotlle asbestos textile plant was attributable to mesothelioma. Peto (1980b) reported a high risk from mesothelioma in an asbestos textile plant In which chrysotlle predominated, although small amounts of crocldollte were also processed. Similarly, Robinson et al. (1979) reported that mesothelioma accounted for 4.3Z of deaths among workers who processed predominantly chrysotlle, and lesser amounts of crocldollte and amoslte. The Consumer Product Safety Commission (1983) noted, "Epidemiological studies suggest that chrysotlle has a lower potential for producing peritoneal mesotheliomas than [do] other fiber types, but there Is less evidence of marked differences between fiber types in their potential to produce pleural mesothelioma and lung cancer." Acheson and Gardner (1963), In discussing mesothelioma in humans, have concluded that "exposure to chrysotlle alone so far has rarely been shown to cause mesothelioma." Many of these apparent differences may be explained by the differences in physical properties and concentrations of the fibers used by the various Industries. Both of these factors would affect deposition and clearance of fibers in the lung. However, the possible role of other factors, including chemistry, has cot been ruled out. Thus, the epidemiological literature on the relative ability of different fiber types to cause disease does not present a clear picture. 133 Most of Che studies os fiber type have bees focussed on mesothelioma, which accounts for only soae asbestos-related disease. Experimental and animal studies, discussed In Chapter 6, have not detected systeaatlc differences in carcinogenicity or fibrogenicity aaong different types of asbestos. Effects of Smoking Cigarette smoking is the single most important known cause of lung cancer in humans. Because most asbestos workers have also been cigarette smokers, it has been difficult to evaluate separately the effects of asbestos and of cigarette smoke on lung cancer. The most dependable data are those of Hammond et al. (1979), described earlier, in which a large number of workers were studied. These investigators also reported that mesothelioma risk does not appear to be affected.by cigarette smoking. Aaong male asbestos workers who never smoked cigarettes regularly, eight mesothelioma deaths were observed, the same number as expected based on the age-specific death rates for all asbestos workers. An Increased risk of lung cancer is associated with exposure to all major types of commercial asbestos (chrysotile, amoslte, croddollte, and anthophyllite), and this increase is observed for all occupational groups handling asbestos. Asbestos exposure is associated with an Increase In risk (1.5- to 5-fold) for both smokers and nonsmokers. An increased risk of mesothelioma in humans is associated with exposure to croddollte, amoslte, and chrysotile, but has not been reported for anthophyllite, possibly because anthophyllite is much less used than are the other types of asbestos. A lower risk of mesothelioma is observed for workers in chrysotile mining and milling operations as compared to chrysotile use in other industries. Mortality due to gastrointestinal cancer was increased in 11 of the studies reviewed, but the magnitude of the increased risk and the quality of available evidence were not as strong as they were for lung cancer and mesothelioma. The excess risk for gastrointestinal cancer was statistically significant In 5 of the 11 studies with relative risks greater than 1.1; but only two of these studies had sufficient power (0.80) to detect a 50X increase in relative risk (Table 5-4; Henderson and Enterline, 1979; Sellkoff et al., 1979). In addition, the increased risks for cancer of the larynx and kidney reported In some studies may, like risks for lung cancer, be partly a consequence of cigarette smoking and other environmental exposures. An Increase In ovarian cancer observed In two studies was concentrated among the heavily exposed subgroups (Acheson et al., 1982; Newhouse and Berry, 1979). The association of asbestos with an increased risk of malignancies other than lung cancer and mesothelioma has not been confirmed In animal studies and has not been observed consistently in human studies. 134 The Increased risk of lung cancer Is associated with age, cumulative asbestos exposure, and smoking. In many studies, a linear dose-response has been observed for lung cancer and asbestos exposure; however, there was a delay of approximately 10 to 20 years following exposure before the Increased risk became manifest. No association between mesothelioma and cigarette smoking has been observed. A delay of 20 to 40 years has been suggested as the latency period required for asbestos-induced mesothelioma. Measurements of exposure intensity are lacking In most studies. Where such measurements have been attempted, It Is still difficult to estimate earlier asbestos exposures when only dust measurements were obtained. Often one can only establish crude categories of exposure (high, moderate, and low) and cannot estimate cumulative fiber exposure levels for Individuals. There Is considerable variation In the rlBk estimates obtained in the studies reviewed by the committee. As noted earlier, this variation may result from many factors in the studies themselves, as well as from a true asbestos effect, ferticularly Important Is the use of different exposure-related criteria for selecting the study cohorts, such as selecting only Individuals exposed for a certain minimum period, who survived for a period after Initial exposure, who were employed before a specified date, or who were employed as of a specified date and had varying lengths of exposure and years since Initial exposure. Some cohorts are more heterogeneous than others with respect to exposure-related characteristics. Studies of these groups are likely to produce lower risk estimates. It Is increasingly difficult to identify a consistent gradient of risk across exposure subgroups (low, medium, high) if they are extremely heterogeneous with regard to date of hire, duration of employment, and time from initial employment. Comparisons of risk estimates from various studies are further limited by variations due to incomplete tracing of the cohort; mlsclasslflcatlon of cause of death; use of inappropriate comparison groups; and more aggressive efforts to ascertain disease (or deaths) In the cohort than in the comparison group. - Furthermore, In making comparisons among different cohorts, it Is important to consider the percentage of the cohort that has died, since It Is difficult to compare results from younger cohorts with 10Z mortality with results from older cohorts with much higher mortality. Some of the observed variation In risk may be due to differences in the effects of fibers of different types or dimensions and the use of these fibers In processes In which other contaminants are present. However, the magnitude of the difference in reported risks is not likely to be explained by fiber or process differences alone. Thus, on the basis of epidemiological data. It Is not possible to determine the role 135 of fiber type and fiber size in Che risk of lung cancer and mesothelioma or co accribute greater or lesser risk Co some types of asbestos fibers for lung cancer and mesothelioma. ASBESTOSIS AND ASBESTOS-ASSOCIATED PLEURAL DISEASE IN OCCUPATIONAL COHORTS This section reviews occupational mortality and morbidity studies of asbestosis and asbestos-associated pleural disease. For a more extensive review, see Dement et a_l. (in press). Mortality Studies Deaths attributable to asbestosis often are not reported as such. Instead, mortality rates are often.reported for nonmalignant or chronic respiratory diseases among workers exposed to asbestos. These may include chronic bronchitis, emphysema, influenza, and pneumonia in addition to pulmonary fibrosis or asbestosis. Mixed Fiber Exposures. Most manufacturing plants have used a variety of fiber types, usually chrysotile and one or more amphiboles. Investigators studying exposures co mixed fibers have reported mortality rates attributable to asbestosis. For example, in a study of 17,800 insulation workers, Selikoff t a_l. (1979) reported chat approximately 8Z of 2,271 deaths were due to asbestosis. Mortality studies of asbestos textile workers exposed to a variety of fiber types have had mixed results. Mancuso and Coulter (1963) observed 14X of 195 deaths from asbestosis among workers producing textile and friction products. In a cohort of British asbestos textile workers. Peto et al. (1977) observed 35 deaths due to nonmalignant respiratory disease, whereas 25 were expected (SMK * 1.4), among those employed after implementation of environmental controls in 1933. Newhouse (1969, 1973) and Newhouse e a_l. (1972) studied 4,600 male and 922 female workers in a plant initially producing asbestos textile and later asbestos insulation products. Among chose in the highest exposure group (>10 fibers/ca>3), mortality from chronic respiratory diseases was 1.8 times that expected. Exposure to Single Types of Asbestos. Hobbs t aJL. (1980) studied 7,000 employees exposed to crocidolite mined at Wittenoom Gorge in Western Australia between 1938 and 1966. Of 198 pneumoconiosis cases, 59 were asbestosis, 122 silicoasbestosis, and 17 were silicosis. They reported an overall incidence rate of 3.5Z for pneumoconiosis along with evidence for increased incidence among Chose with heavy exposure and Chose with a longer duration of employment. Among those heavily exposed and employed at least 5 years, the incidence rate was 65X. Mortality among workers manufacturing amosite asbestos insulation between 1941 and 1945 was reported by Selikoff et al. (1972) and Seidman 136 et *1. (1977, 1979). Of 528 deaths observed over 35 years in a cohort of 320 men, approximately 5.6Z were due to asbescosis. In the past, anthophyllite asbestos vas commercially mined and processed io areas of Finland also known to contain some chrysotile and tremolite asbestos. Meuraan e al. (1974) reported that mortality from asbestosis was 5.2Z in a group of 1,092 Finnish miners studied from 1936 to 1974 and that the mortality rate was similar between smokers and nonsmokers. Several studies have been conducted on Quebec chrysotile miners and millers. The most recent report on this cohort included observations of 10,939 men employed 9 or more months between 1926 and 1975 (McDonald e al., 1980). They found 42 deaths, or 1.3Z of total deaths, to be attributable to asbestosis. Nicholson et al. (1979) studied a smaller cohort of 544 Quebec miners and millers with a least 20 years of seniority and followed them between 1962 and 1977. Thirty noninfectious, nonmalignant respiratory disease deaths were observed, whereas 6.7 had been expected. Deaths from asbestosis have been reported to occur in cohorts exposed to chrysotile in manufacturing plants. For example, Robinson et al. (1979), who studied workers in a plant that used 99Z chrysotile and 1Z crocidolite and amosite, reported 76 deaths from noninfectious, nonmalignant respiratory diseases among males, whereas 16.4 had been expected. . Dement e al^. (1983b) reported mortality and assessed dose-response for asbestosis in a cohort of asbestos textile workers exposed only to chrysotile. They found that 17 (5.5Z) of 308 deaths were due to asbescosis or pulmonary fibrosis. A linear relationship was demonstrated between cumulative fiber dose and the risk of mortality for noninfectious respiratory disease. Although Dement and colleagues reported a much steeper slope, their findings are not inconsistent with those of McDonald et al. (1980), who reported a no threshold, linear dose-response relationship between asbescosis and doses of dust contain ig chrysotile. Morbidity Studies Morbidity studies have established that all asbestos fiber types are associated with asbestosis, asbestos-induced plaques, diffuse pleural thickening, and pleural calcification. Because of the methodological differences described above, it is difficult to compare these studies directly with each other or with mortality studies in regard to ' dose-response. Nonetheless, the various studies are quite consistent with regard to major health effects reported, whether ascertained by chest radiography, questionnaire on respiratory difficulties, or pulmonary function evaluation. Appendix E, Table E-2 suanarises morbidity studies of asbestos-exposed populations. I 137 Mixed Fiber Exposure. Early cross-sectional studies of asbestos workers, which relied on chest radiography, demonstrated a prevalence of pulmonary fibrosis as high as 80Z among those exposed for 20 years or longer (Donnelly, 1936; Dreessen et al.. 1938; Merewether and Price, 1930; Shull, 1936). More recent studies have confirmed the general observations of these early investigators, although disease prevalence has varied from industry to industry, Selikoff and his colleagues studied insulation workers exposed to chrysotile and amosite. They reported an overall prevalence of 50Z with small irregular opacities and a 90Z prevalence among those with more than 30 years of exposure (Selikoff, 1965; Selikoff et _al., 1965). Pleural fibrosis was observed in roughly two-thirds of those examined 40 years after first exposure. Elapsed time from first exposure was similarly found to correlate with pleural calcification, which occurred in 50Z of those examined 40 years or more after their first occupational exposure. Murphy e _al. (1971, 1978)studied insulation workers in shipyards and, using a more restrictive definition for asbestosis, reported an 11-fold prevalence compared to age-matched, unexposed controls. Asbestos textile plant exposures have been studied by Lewinsohn e_t al. (1972), Berry ejt al. (1979), and Baselga-Monte and Segarra (1978). Data from this type of plant formed the basis for the British Occupational Hygiene Society (B0HS) (1968) recommendation that was used to establish occupational exposure standards. The initial BOHS analysis revealed that there was radiographic evidence of asbestosis^ for 2.7Z of the 290 workers exposed to asbestos (chrysotile with some crocidolite) after 1933, when dust control had been implemented. A risk of 1Z for a worker developing basal rales was estimated to result from exposure for 50 years at an estimated average exposure of 2. fibers/cm3 as measured by a standard membrane filter method (fibers longer than 5 urn), or a cumulative expoaure of approximately 10 (fibers/cm3)yr. The BOHS estimate of risk is the basis for occupational standards for asbestos exposure in the United Kingdom, the United States, and several other countries. Precise criteria for radiographic assessment were not given, and subsequent studies have revealed more disease in this population. In a later analysis of these data. Berry et al. (1979) estimated a prevalenc * of 1Z for crepitations at a cumulative dose of 43 (fib;rs/cm3)yr. For possible and certified asbestosis, 1Z prevalences were estimated to occur at cumulative doses of 55 and 72 (fibers/cm3)yr, respectively. This same plant was later studied cross-sectionally by Lewinsohn (1972), who reported a much higher prevalence of "pulmonary fibrosis" and pleural thickening. Berry et al. (1979) subsequently restudied 379 men ^Radiological changes considered significant included increased general opacity of the lower lobes, blurring of the cardiac outline, pleural thickening, and adhesions (British Occupational Hygiene Society, 1968). 138 working at chia same textile factory for at least 10 years. The most reliable data were judged to be chose obtained for men employed after 1950; 6.6X of these were believed to have "possible asbestosis"? after an average follow-up of 16 years and an average exposure of 5 fiber/cm3 as assessed by static area dust samples. As exposure increased, there was a decline in pulmonary function, as measured by spirometric techniques such as forced expiratory volume and forced vital capacity. Nonsmokers and light smokers had less crepitations, asbestosis, and small opacities than did heavier smokers with similar exposure. On the basis of these data. Berry and colleagues estimated chat "possible asbestosis" would result in no more chan 1Z of men after 40 years of exposure to concentrations ranging from 0.3 to 1.1 fibers/cm'. Furthermore, they noted that continued follow-up was indicated in order to refine the estimates. Saselga-Monte and Segarra (1978) studied 1,262 Barcelona factory workers exposed to mixed-fiber asbestos and established a relationship between individual risk and cumulative dose (fibers/cm3)yr, based on radiographic findings only. They estimated a threshold limit value (TLV) of 0.07 or 0.10 fibers/cm^ for a 1Z or 5Z incidence of asbestosis for a 50-year work exposure. Weill and colleagues (1973, 1975) correlated radiographic changes and lung function with exposure among 859 U.S. asbestos-cement workers. Cumulative dust exposures were estimated but were expressed as mppcf-yr. Both rounded and irregular opacities were observed, and there was a 4Z prevalance of small opacities (reflecting a mixed dust exposure) at less than 50 mppcf-yr. Prevalence increased to 30Z at exposures greater than 400 mppcf-yr. An 11Z prevalence of pleural abnormalities was observed among those in the lowest exposure category. Lung volumes decreased in relation to increasing cumulative dust exposure, but pulmonary diffusing capacity was not related to dose (Weill e , 1975). Finkelstein (1982) recently reported asbestosis incidence rates in a cohort of 157 Canadian asbestos-cement workers exposed to both chrysotile and crocidolite. Criteria for certification of asbestosis were similar to those reported by Berry t _al., (1979) and were based on the findings of a pneumoconiosis medical panel. Finkelstein found an average overall incidence rate of 0.7Z, 1.6Z, and 2.4Z for 0-49, 50-99, and 100-149 cumulative (fibers/cm3)yr, respectively. Progression of radiographic abnormalities and lung function changes have been reported by Jones e al. (1980a) and Gregor et al. (1979). Jones and coworkers studied progression among 204 asbestos-cement workers ^The determination of "possible asbestosis" was based on basal rales, radiological changes of varying degree, a falling gas transfer factor, and restrictive lung function changes. 139 between 1970 and 1976. They concluded that progression (increased profusion of small opacities) depended on both average and cumulative exposure, that decline in lung function was related to both amount smoked and cumulative exposure, and that pleural changes progressed as a function of time from first exposure. Gregor et aU (1979) studied a variety of asbestos workers referred to the Brompton Hospital from the British Pneumoconiosis Panel. They documented a progression in radiographic findings without further asbestos exposure. - The relationship between lung function and radiographic findings associated with asbestos exposure was further studied by Lumley (1977), who reported highly significant decreases in lung function with pulmonary fibrosis and diffuse pleural thickening, somewhat less of a decrease when there were only plaques, and no difference if only pleural calcification was present. Epidemiological and clinicaT evidence^of asbestos-relaced disease has been found in studies of workers in some major industries not originally associated with asbestos exposure. For example, in recently reported studies of asbestos-related disease in the United States, investigators have documented that characteristic radiographic abnormalities have been found among chemical plant maintenance workers, oil refinery workers, brake workers, and railroad workers employed before 1930 during the steam locomotive era (Lilis e al., 1980; Lorimer e l^., 1976; Sepulveda and Merchant, 1983). Anthophyllite and Tremolite. In several studies of Finnish anthophyllite miners, investigators have observed increased respiratory symptoms and increased prevalence of pleural plaques (6.5Z-9.0Z vs. 0.1Z for the Finnish population) (Kilviluoto, 1960; Meurman, 1968; Meurman et_ al., 1974). In upper New York State, workers exposed to talc deposits containing both anthophyllite and tremolite asbestos have been studied by several investigators. Gamble et al. (1979a), reported increased respiratory symptoms, pulmonary fibrosis, and decreased lung function in exposed workers. They also noted a marked association between pleural thickening and decreased lung function, similar to that reported by Lumley (1977) among British shipyard workers. Dement and Zumwalde (1979) reported that fiber exposure in those mining and milling"operacions ranged from 0.8 to 16.0 fibers/cm^, of which 12Z to 19Z was identified as tremolite and 30Z to 43Z as anthophyllite.10 Another tremolite exposure resulting in a relatively low prevalence of radiographic abnormalities was recently reported by Lockey e al. (1983). Among factory workers processing tremolite-contaminated vermiculite mined in Montana, 4.4Z were found to have some radiographic abnormality. 7/.U>: -v/, l^Not all of the fibers counted were necessarily asbestiform fibers.  140 Chrysotile. The not extensive morbidity studies of chrysotile exposure have been conducted in Quebec miners and millers (Becklake e al., 1972; McDonald e al., 1972, 1974). In these studies, 1,015 current employees were studied radiographically, physiologically, and by British Medical Research Council standardized questionnaire. Respiratory symptoms were associated with dust*! exposure, and the prevalence of bronchitis reached 50X in the highest dust exposure category. Dyspnea upon exertion was also found to be associated with dust exposure, but not vith smoking, and the prevalence rose to 40X among those with a cumulative dust exposure of 800 mppcf-yr. The prevalence of those with small irregular opacities (>l/0 ILO/UC 1971 Classification) differed between the two mines studied (1.8Z at the Thetford mine and 6.4X at the Asbestos mine), but rose to 26.4Z and 10.9X, respectively, among those exposed to more than 800 mppcf-yr. Those with significant radiographic evidence of asbestosis (ILO category 2/1 or greater) had significantly lower values for all lung function parameters studied. Lung function also deteriorated more as cumulative dose increased (McDonald et al., 1972). Radiographic findings among chrysotile workers were also demonstrated to progress without further exposure. Rubino et al. (1979b) reported that there was progression without additional exposure among 39Z of retired asbestos miners and millers with 1/0 profusion radiographs. Becklake e al. (1979) made similar observations, but they also found chat chose who progressed were likely to have had higher exposures to asbestos. Morbidity studies of occupationally exposed asbestos workers have documented that asbestosis, diffuse pleural thickening, pleural plaques, dyspnea, and altered pulmonary function are associated with all types of exposure to asbestos. Generally, prevalence of these indices is lower among those who mine and mill asbestos-bearing ore than among those who subsequently produce or use asbestos products. Morbidity data support the concept of a linear cumulative dose-response relationship. Estimates based on mixed-fiber exposures suggest that a IX risk of developing asbestosis (differing definitions) over a 40- to 50*-year work exposure occurs when exposures are somewhere between 0.07 fiber/cm^ and 1.1 fiber/cm-3. Because of the nonspecificity in disease definition and the lack of data at very low doses, it is not clear whether there is a threshold of exposure for asbestosis. Data do suggest, however, that any incidence rate for asbestosis at the very low exposures normally found in the nonoccupational environment would be quite low. ^Miners and millers are exposed to dust other than just asbestos 141 HEALTH EFFECTS OF OCCUPATIOHAL EXPOSURE TO MAM-MADE MINERAL FIBERS12 Fibrous glass has some of cbe same physical properties as asbestos. For example, fine glass fibers are respirable and exhibit flexibility aad diameter-dependent strength. However, fibrous glass may be less durable than asbestos in biological tissues and apparently behaves differently in some biological test systems (see Chapter 6). Epidemiological studies have been conducted to determine if adverse health effects occur in workers exposed to man-made mineral fibers. The major studies are reviewed below. Morbidity In 1976, a committee of the American College of Chest Physicians evaluated pulmonary response to fiberglass dust (Gross et al., 1976). It concluded, "There is no evidence to indicate chat inhaling fiberglass is associated with either permanent respiratory impairment or carcinogenesis; however, Che final verdict as far as the latter is concerned must await the findings of long-term mortality studies." In a review article on Che health effects of man-made mineral fibers. Gross (1982) concluded that "exposure has not caused an increased risk of developing lung cancer or non-malignant respiratory disease." In Table 5-5, 10 cross-sectional studies of pulmonary function and disease among workers exposed.to fibrous glass or rock wool are summarized. In general, these studies were descriptive and did not permit a rigorous comparison of pulmonary status between exposed and nonexposed persons. Because only the prevalence of pulmonary disease in current workers could be assessed, it was not possible to measure the race of occurrence (incidence) of the development of pulmonary disease. Although no evidence of pulmonary abnormalities among workers exposed to MMMF was found in the early studies, several recent studies suggest an increased prevalence of minimal small lung opacities among workers exposed for longer periods. These studies provided only limited information on the level of exposure to man-made mineral fibers. In studies published before 1980, exposure was mainly categorized as light, medium, or heavy. The fact that no associations were found .between level of exposure and prevalence of disease could reflect imprecise measurements of exposure or could indicate that there is no effect from the exposure. In the studies published since 1980, exposure has generally been given as the number of fibers/cm^. In general, average exposure lies between 0.1 and 1.0 respirable fibers/cm^. Another factor probably related to pathogenicity is fiber diameter, which is described as ordinary (>3 um), ^Man-made mineral fibers (MMMF) are sometimes called man-made vitreous fibers (MMVF). 142 TABLE 5-5. Sunary of Cross-Sectional Morbidity Studied of Populations Exposed to Man-Made Mineral Fibers Type of Pibor Study Population Suaaarv of laportant Findings lock aad elag wool 1* workers with 7-29 years "Bo x-ray evidence of silicosis or of exposure. fibrosis of tbe lungs." Fibrous (lass 1.319 production workers. 1,176 bad 10 or wore years in production. "Bo unusual pattern of radiologic denaities was observed." Fibrous (lass 232 production worksrs. Mo "evidence that would support a hypothesis that those witb dusty jobs were less bealtby than those with ainiaal duac exposure." Fibrous glass 2,021 produccioo workers wbo had worked an average of 14 years. Prevalence of pulaonary abnormali ties similar in office workers and production workers. Fibrous glass 70 fibrous glass workers; 70 controls. "No evidence of any respiratory basard due to glass fibre." Fibrous glass 467 production worksrs who bad worked an aver age of 13 years. Based on unstable data, the pre valence of pharyngeal-laryn gitis was higher in persons wbo had worked at least 5 years. Fibrous glass 340 production workers of whoa BIZ bad worked aora than 10 years. : ' Prevalence of small opacities greater in nan who bad worked more than IS years in eomparison to those who bad worked less (39Z vs. 9Z). lock wool 162 production workers witb an average of 12 years of work. Pulmonary function test values less than expected normal values. lock wool 21 production worksrs wbo bad worked aore than 10 years and 43 controls. "Bo evidence of pulmonary disease...in the group of MMMF workers studied." Fibrous glass 1,028 production workers who bad worked an average of 19 years. Prevalence of small opaci ties was related to age, smoking, small diameter ... fiber exposure, and in smokers, various quantitative measures of exposure dose. ,, Inferences Carpencer aad Spolyar, 1945 Wright. 1968 Ocidjiaa and daTrsnville, 1970 Seer et sl_., 1971 Bill et al., 1973 Msggiori et sjl., 1980 Hill at si., 1982 Skuric and StehyljakBoritic, 1982 Malnbsrg et l., 2982 Weill et al., 1982 143 fine (1 to 3 um), or very fine (<1 ua)< Only in the study by Weill e al. (1982) is there information on fiber diameter. Weill et aK (1982) reported that the prevalence of small opacities in exposed workers vas low, increased with age and smoking, and was found predominantly in the ordinary/fine fiber (1 to 3 um in diameter) category. In addition, risk of small opacities was correlated with several quantitative exposure estimates among current smokers. However, respiratory symptoms and pulmonary function were not associated with exposure to man-made mineral fibers. Mortality Table 5-6 summarizes the results of seven retrospective mortality follow-up studies among workers exposed to MMMF. In these studies, the mortality experience of persons exposed to MMMF vas compared to that of a general population in the country where the study vas done, usually the United States. In computing the expected numbers of deaths, the investigators took into account age, sex, ethnic group, and calendar time. In general, no large excesses of respiratory cancer or nonmalignant respiratory disease were observed in the entire study group. However, some excesses were found upon examination of subgroups within each cohort. Because the subgroups were formed during the process of analyzing the data, the characteristics of the subgroups differ among the several studies. Also, the observed excesses were small, and the categories of causes of death were not consistent among the studies. These excesses are summarized below, by study. Bayliss et al. (1976). When follow-up started 10 years after onset of employment and influenza and pneumonia were not included in the mortality attributed to nonmalignant respiratory disease (NMRD), there were 19 deaths observed and 9.5 expected. Morgan et al. (1981). Among men who worked and were exposed at least 20 years and who were followed beginning at least 30 years after onset of employment, the observed/expected numbers were: lung cancer, 14/11.8; nonmalignant respiratory disease, 5/8.1. Enterline and Marsh (1982). Among the fibrous glass workers, 129 deaths from NMBD were observed and 99.5 deaths were expected; deaths from influenza and pneumonia were not included in these figures. There was no relationship between length of exposure to fibrous glass and excess mortality or between cumulative exposure and excess mortality. However, among those followed 30 or more years after onset of employment, there were 47 lung cancers observed and 36.0 expected. Among men exposed to mineral wool, there vas no clear relationship between Che excess lung cancer or NM&D and length of work or time since 144 TABLE 5-6. SuMery of Mortality Follow-Up Scudiss of Populscioas Exposed eo Man-Made Miaorsl Fibers Twos of Fiber Study Population S>Mry of Important Fiadiats (0/E)* Isfsrsacss Fibrous glass 416 U.S. oso who retired bstwssn 194J sad 1972 froa six plsacs chec Bade fibrous glsss iasulstioa. All causes; 111/131; all esacers: 20/24; lung cancer: 5/6; NMB0: 9/9. Encerlias sad Uaodersoo, 1975 Fibrous glass 1,448 U.S. woo who worked sc lease 5 years la fibrous glsss produc tion beewsea 1949 sad 1972. All causes: 376/404; all cancers: 54/64; respiratory cancer: 16/20; MMRD: 25/20. Beyliss e si., 1976 Fibrous glsss 4.J99 U.S. asa who worked All causes: 289/340; all lsssc 10 years ia fibrous esaesrs: 76/74; respiratory glsss production sad who csacer: 39/29; NHSD: 14/19. were employed at sobs tiae between 1968 sad 1977. Morgan e_C si., 1982 Fibrous glsss sod rock wool 2,576 Canadian as a who worked sc least 90 days ia fibrous glsss produc tion between 1955 sad 197 7. All causes: 88/113; all cancers: 20/20; lung csacer: 9/5; HMU: 4/5. Fibrous glMS. rock wool, sad slsg wool 16,730 U.S. aca who worked sc Isaac 1 year ia iasulstioa produccioa betweea 1945 sad 1963. Fibrous tlsss All causes: 3,262/3,391; all cancers: 612/635; respiratory cancer: 202/203; (USD: 186/176 Shannon et si., 1982 Interline sad Marsh, 1982 Mineral wool All causes: 499/468; all caocars: 109/88; respiratory cancer: 45/28; MMBS: 29/25. Fibrous glsss sod rock wool 17,083 European nea who ever worked ia ninaral wool production and who were followed at least 20 years. All causes: 374/339; all cancars: 109/88; respiratory cancer: 33/27; HUD: 32/31. Bock wool sad slsg wool. 596 U.S. Ben who had worked at least 1 year in ninaral wool produc tion betweea 1940 and 1948. All causes: 184/205; all . cancars: 36/36; lung cancer; 9/10; MMBS: 10/11. Saracci at al.. 1982 Bobiason at si., 1982 O/E obseread/sxpaccsd deaths. Expected deaths based an age- sad tias-epccific aortality ratsa for the general population-, usually chat of the United States, for appropriate sax and ethnic groups. MBfi Boaaaligaanc respiratory, disease. (MBS data include deaths .fron influence and pneiaoniq.) 145 first exposure. Furthermore, possible exposure to asbestos during the early years of the plant's operation could not be ruled out. Saracci et al. (1982). Among men followed at least 20 years, 33 deaths from lung cancer were observed and 27.3 were expected. Because all the mortality studies were retrospective, there was little information on exposure. Most of the workers had started work during the 1940s and 1950s, when, presumably, fiber concentrations in the air were higher than they are today. In the study by Enterline and Marsh (1982), current average exposure was approximately 0.04 fibers/cn3 for workers in fibrous glass plants and 0.4 fibers/ca>3 for workers in mineral wool plants. This range is similar to that reported in the morbidity studies and is below the U.S. workplace standard for asbestos of 2 fibers/cnP, in effect since 1976. Saracci and Sioonato (1982) reviewed the papers presented at a 1982 conference on MMMF and other relevant literature. For chronic respiratory diseases, they reviewed 10 cross-sectional studies, 7 mortality studies, and 2 other studies. The cross-sectional studies were limited because "no substantial follow-up data from the longitudinal observations of cohorts of workers are as yet available." The mortality studies were limited in that no control was possible for smoking habits, previous industrial exposures, including exposure to asbestos, or concurrent industrial exposures. Of the 19 studies, 11 were interpreted as shoving no association between MMMF and chronic respiratory disease. Although the remaining eight studies showed some association between MMMF and chronic respiratory disease, the associations were weak and not readily interpretable. Enterline and Marsh (1982) and McDonald (1982) concluded that, because of the low level of respirable fibers in the facilities, it was unlikely that health effects could have been detected, even if MMMF acted like asbestos. Four of nine studies that could evaluate the association between MMMF and respiratory cancer did not show such an association. In the five studies showing some association between MMMF and respiratory cancer in population subgroups, the excesses were small and had no association with intensity or duration of exposure to MMMF. The authors concluded that "the reality of the association of the respiratory cancer with work involving man-made vitreous fibers...remains dubious." Summary In the studies conducted to date, man-made mineral fibers have not presented the same magnitude of health hazard to humans as has asbestos. For example, the committee is not aware of any mesotheliomas among persons occupationally exposed to MMMF but not to asbestos. There is some evidence that a small excess of respiratory cancer has occurred among persons who produce MMMF--either fibrous glass or mineral wool. 146 Ihis evidence derives from aortality studies that could have detected a large excess if one were present. However, the level of exposure to MMMF has been much lower than that for asbestos. Also, exposure to MMMF was less common before approxiaately 1940, thereby providing only a limited period in which to assess excess risk from MMMF for effects with long latencies. With longer follow-up and greater numbers of subjects, it may be possible to detect an excess of some cancer that could reflect a causal association with MMMF. The evidence that MMMF causes nonmalignant respiratory disease is equivocal. Although some studies have reported an excess of nonmalignant respiratory disease among fibrous glass production workers, the excess was small and was found only in a subset of the nonmalignant respiratory diseases. Very little information is available from studies of morbidity among persons exposed to MMMF. ADDITIONAL OCCUPATIONAL EPIDEMIOLOGICAL STUDIES Attapulgite A study of attapulgite miners and millers in Georgia and in Florida has been performed by Che National Institute for Occupational Safety and Health (R. Waxveiler, personal communication, 1983). Consistent evidence of health effects was not found, although some excess lung cancers may have occurred. The report had not been released as of January 1983. Talc Talc is a hydrated magnesium silicate that is often contaminated with other minerals, including Chose that may occur as asbestiform fibers. In addition, talc can itself be fibrous, but this form is extremely rare. Materials often found with talc include quartz, calcite, serpentine minerals, and amphiboles (both as cleavage fragments and asbestiform fibers). The fiber content of talc can vary from an undetectable level in some Montana mines to as high as 50Z in some New York mines.13 Talc is used in the ceramic, rubber, and chemical industries as well as in cosmetic powders and pharmaceuticals. It is usually placed into one of two categories: talc that contains mineral fibers and talc that does not. l^Many of these particles may not be asbestiform as defined by this committee (T. Zoltai, University of Minnesota; R. Clifton, Bureau of Mines, personal cosmunieation, 1983). ^Various researchers have referred to Calc chat contains asbestiform fibers. Some of these fibers may be particles with 3:1 aspect ratios but without the properties of asbestiform fibers. To avoid confusion, the committee uses Che more general terms "fiber" or "mineral fiber" in this section. 147 Workers from different geographic regions containing talc vith or vichout fibers have been studied to determine if any adverse health effects are associated vith the asbestiform fiber content of talc. Adverse effects have been found in some studies among workers exposed to calc both vith and without fibers. These studies are discussed in the following paragraphs. Epidemiological studies on workers exposed to talc containing fibers have demonstrated adverse effects on pulmonary function. In a study of 121 New York miners and millers exposed to talc containing Cremolite and anthophyllite fibers, pulmonary function was found to be significantly decreased (Gamble ec al., 1979b). Reductions in forced vital capacity (FVC) and 1-second forced expiratory volume (FEY^) were associated with employment duration and the amount of fiber present. Increased pleural thickening and calcification were detected in talc workers with 15 or more years of employment (Gamble e l., 1979b). A mortality study of 398 New York miners exposed to talc containing fibers has demonstrated excess mortality from nonmalignant respiratory disease, excluding influenza, bronchitis, or pneumonia (5 observed/ 1.3 expected) (Brown e l., 1979). An excess in lung cancer with an average latency of 20 years was also observed (9 observed/3.3 expected). Additional studies have had conflicting results. Some investigators have found no significant increases in lung cancer and nonmalignant respiratory disease (Stille ejt l., 1982), whereas others have reported significant increases in lung cancer (Kleinfeld e l., 1967, 1974). Morbidity and mortality studies haveaiso been conducted on workers exposed to Calc with low or undetectable levels of fibers. A study on the respiratory function of 103 Vermont Calc workers indicated that there was a reduction in pulmonary function in smokers (Wegman et al., 1982). After adjusting for smoking, the effect of the exposure to talc was not statistically significant, although there was evidence of an exposure-related effect in workers with an annual dust exposure of approximately 1.5 mg/m^. Exposure to Calc dust was also associated with small opacities seen on chest radiographs. Gamble e i. (1982) conducted a cross-sectional iStudy of 299 workers from Montana, Texas, and North Carolina who were exposed to talc containing low levels of silica and fiber. There was no significant difference in lung function, respiratory symptoms, or pneumoconiosis . between workers and controls, although there was a significant increase in bilateral pleural thickening among the workers. Results of pulmonary pathology studies have also provided evidence of fibrosis in workers exposed to talc that does not contain fibers (Vallyathan et al., 1981). 148 A norcality study of 392 Vermont workers exposed to talc not containing fibers showed that there were excess deaths from nonmalignant respiratory disease, excluding influenza and pneumonia, among millers (11 observed/1.79 expected) (Selevan et. al^., 1979). This excess mortality was associated with small opacities seen on chest radiographs. An excess of respiratory cancer mortality among miners was also noted (5 observed/1.15 expected), but was attributed to exposures other than talc. RECOMMENDATIONS New detailed prospective epidemiological studies should be undertaken, and ongoing investigations continued, to examine cohorts exposed occupationally to fibrous materials. Despite the considerable number of studies reported, additional epidemiological studies of occupational groups exposed to asbestos and ocher fibrous materials, such as man-made mineral fibers, are needed. These studies should include reliable fiber exposure measurements and should have a high statistical power (ability Co detect a true effect of a specified magnitude) at relevant lengths of latency. They should also include adequate controls for confounding factors, such as smoking and exposures to other substances in the environment. The studies should be designed to facilitate evaluation of risk over several exposure levels. Continued follow-up of workers exposed to man-made mineral fibers is needed, especially to determine morbidity. Workers should be examined to determine current status of pulmonary function and pulmonary disease and followed for 5-20 years, with reexamination every few years to assess changes in pulmonary function. For epidemiological studies, efforts should be made to obtain detailed information about the characteristics of the respirable fibers in inhaled air. Every effort should be made to ensure that workers with long service in these industries are autopsied at death, especially for cases involving respiratory disease. Additional case-control studies of lung cancer and mesothelioma should be conducted among nonoccupationally exposed persons. Emphasis should be placed on assessment of previous exposure to asbestiform fibers and should include use of electron microscopy and other sensitive techniques to identify and quantify exposure and body burden. The feasibility of conducting prospective studies in nonoccupationally exposed populations should be studied, and the possibility of conducting more complete surveillance for mesothelioma in the United States should be considered. Clinical and epidemiological data indicate that a reduction in cigarette smoking should be encouraged, especially in view of its multiplicative effect in causing lung cancer in conjunction with asbestos exposure. Those in the medical profession and the general public should be informed about the possible exposures to asbestiform fibers and the health effects resulting therefrom. 149 REFERENCES Acheson, E. D., and M. J. Gardner. 1980. Asbestos: Scientific basis for environmental control of fibres. Pp. 737-754 In J. C. Vagner, ed. Biological Effects of Mineral Fibres. Vol. 2. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. Acheson, E. D., and M. J. Gardner. 1983. Asbestos: The Control Limit for Asbestos. An up-date of relevant sections of Asbestos: Vol. 2: Final Report of the Advisory Committee, Health and Safety Commission, 1979. Her Majesty's Stationery Office, London. Acheson, E. 0., M. J. Gardner, E. C. Plppard, and L. P. Grime. 1982. 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Characterization of zeolite fiber sizes using scanning electron microscopy. Arch. Environ. Health 38:99-103. Wright, W. E., R. P. Shervin, E. A. Dickson, L. Bernstein, J. B. Fromm, and B. E. Henderson. In press. Malignant mesothelioma: Incidence, asbestos exposure and reclassification of hlstopathology. Br. J. Ind. Med. Zolov, C., T. Bourllkov, and L. Babadjov. 1967. Pleural asbestosis in agricultural workers. Environ. Res. 1:287-292. 6 Laboratory Studies of the Effects of Asbestiform Fibers Ihls chapter describes experimental studies that have elucidated some biological effects of asbestlfom fibers and their interactions with cells. STUDIES IN ANIMALS In humans, inhalation of asbestos is associated with increased risks of lung tumors (bronchogenic carcinoma and peripheral adenocarcinoma), pleural and peritoneal mesothelioma, interstitial pulmonary fibrosis (asbestosls), pleural thickening, and possibly other tumors, including those of the gastrointestinal tract and kidney. Investigators have induced lung tumors, mesothelioma, and fibrosis after administration of asbestos to animals. This section summarizes the results of toxicological studies in an attempt to determine whether (1) certain physicochemical properties of asbestos are important in the induction of disease and whether (2) other asbestiform fibers exhibit pathogenic potential in animals. Lung Cancer In the lung, malignant tumors arise from the bronchial or alveolar epithelial cells and are classified according to their histological features (e.g., squamous cell carcinoma or adenocarcinoma; small or large cell carcinoma). Although small numbers of these types of tumors appear in rats after inhalation (Appendix F, Table F-l) or intratracheal instillation of asbestos and chemical carcinogens (Appendix F, Table F-2), benign (papilloma, adenoma) and malignant (fibrosarcoma) tumors uncommon to humans occur more frequently. In general, results are difficult to evaluate because of different experimental protocols (e.g., amounts of dusts, exposure regimens, different species or strains). For example, in inhalation studies conducted by Davis et al. (1978, 1982), Vagner et al. (1974, 1982a), and Bozelka et al. (1983) asbestos concentrations of approximately 10 mg/m^ of air were used, whereas Reeves and colleagues (1971, 1974, 1976) used concentrations approximately fivefold higher. 165 166 Another shortcoming Is the lack of dose-response Information at various concentrations of asbestos. With the exception of Davis et al. (1978) and Lee et al. (1981), all investigators have used only one concentration of dust, the different size distributions of fibers In these studies also present problems to those attempting to compare the pathogenic potential of different types of asbestos. For example, Inhalation Btudies by Davis et al. (1978) (Appendix F, Table F-l) demonstrated that clouds of cErysotlle contain many more fibers longer than 20 than are found In aerosolized amphlboles. This phenomenon could account for the greater tumor incidence observed after exposure to chrysotlle In these experiments. However, despite these general limitations In Interpretation, data in Appendix F, Tables F-l and F-2 support the following conclusions: 1. The development of lung cancers In rodents after inhalation of asbestos is specles-speclflc. For example, rats and mice develop both benign and malignant neoplasms, whereas hamsters, guinea pigs, and rabbits develop only benign neoplasms (Botham and Holt, 1972a,b; Gardner, 1942; Gross et al., 1967; Reeves et al., 1974; Vorwald et al., 1951; Vagner, 1963). In the few studies conducted in cats (Vorwald et al., 1951) and monkeys (Wagner, 1963; Webster, 1970), fibrosis but no tumors developed. Thus, cats and monkeys seem to be Inappropriate animal models for studies of asbestos-linked carcinogenesis. 2. Small numbers of benign and malignant lung tumors have been observed after inhalation of all types of asbestos (Appendix F, Table F-l). The short lifespan of rodents may not allow sufficient time for development of larger numbers of tumors. 3. A striking Increase In the number of neoplasms has been observed after rodents were exposed by instillation to a combination of asbestos and chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Thus, asbestos appears to act aynerglstically with PAH to Induce lung tumors (Appendix F, Table F-2). 4. For unexplained reasons, a synergistic effect has not been observed In rats exposed to both asbestos and cigarette smoke by inhalation (Shabad et al., 1974; Wehner et al., 1975); however, development of fibrosis In these animals leads to reduced lifespan. 5. When asbestos Is inhaled by rats simultaneously with the Intratracheal Instillation of sodium hydroxide, a caustic agent affecting mucociliary clearance, an increase In the number of tumors has been observed (Gross et al., 1967). The sodium hydroxide presumably leads to a greater retention of asbestos In the respiratory tract.6 6. Several types of man-made mineral fibers (MMMFs) have been evaluated In inhalation studies. Among the fibers studied are fibrous glass (Gross 1974; Gross et al., 1970; Lee et al., 1981; Moorman, in press; Schepers and Delahant, 1955; Schepers et al., 1958) and insulation (Morrison et al., 1981); alumina (Plggott et al., 1981); glass wool, rock 167 wool, and glass microfibers (Wagner e al., 1982a); ceramic aluminum silicate glass (CASG) (Davis et a_l., 1982); and potassium titanate, i.e., Fybex and pigmentary potassium titanate (PKT) (Lee e aK, 1981). In comparison to the various types of asbestos included as positive controls in many of these studies, these fibers are generally less carcinogenic. Tumors have been reported after exposure to CASG (Davis e al., 1982). Besults with fibrous glass vary (see footnote to Table F-l in Appendix F). Lee et al_. (1981) produced two malignant lung tumors in hamsters exposed to potassium octatitanate fibers and bronchogenic tumors in rats with use of fine fiber glass. No malignant tumors were produced in hamsters, rats, or guinea pigs inhaling ball-milled fiberglass. Wagner e aK (1982a) reported small numbers of lung cancers in rats exposed to glass wool, rock wool, and glass microfibers by inhalation and no cancers in control animals, whereas in comparable studies, McConnell et al. (1982) did not detect such an increase. 7. In comparison to amosite asbestos, more bronchogenic tumors developed in rats after intratracheal instillation of ferroactinolite--an unusual and impure asbestiform fiber (Coffin et l., 1982; Cook et al., 1982). Ferroactinolite appears to undergo longitudinal splitting as a result of dissolution in the respiratory tract, thereby producing an increased dose of extremely thin fibers. When the animals were exposed to nonfibrous grunerite, no carcinomas were observed. Mesothelioma Pleural and peritoneal mesotheliomas originate in the serosal cells lining the body cavities occupied by the lungs and digestive organs, respectively. They occur in small numbers after inhalation of asbestiform fibers by animals, but in larger numbers after intrapleural and intraperitoneal injection of Che fibers. Ibe injection technique has been used most frequently in reported studies because of its reproducibility. However, injection of fibers bypasses normal lung clearance mechanisms and is criticized as a nonpbysiological method of exposure. Table F-3 in Appendix F summarizes the results of experiments in animals injected with asbestiform fibers. From these data and the results of inhalation studies (Table F-l in Appendix F), the following observations can be made: 1. Mesotheliomas have been observed in rats after injection of all types of asbestos and a number of nonasbestos fibers, including fibrous glass, ceramic fibers, attapulgice (palygorskite) from the USSR, brucite, and erionite. Fewer mesotheliomas occurred in rats after inhalation of VICC chrysotile, amosite, and crocidolite, but none appeared after inhalation of respirable fibrous glass, alumina, and ceramic aluminum silicate glass fibers. 2. The incidence of fiber-induced mesothelioma in hamsters is lower than in rats and in mice, but tumors appear earlier, perhaps because of the shorter lifespan of the hamster. 168 3. Tumor response was related directly to the dosage of fiber administered in experiments by Smith and Hubert (1974) and by Wagner et al. (1973). Other investigators (e.g., Pott and Friedrichs, 1972; Stanton and Wrench, 1972) have not observed such dose-response relationships. 4. Exposure to either long (>10 um) or short (milled) fibers results in the appearance of mesotheliomas. Nonfibrous particles, including cleavage fragments, do not generally cause tumors (see Appendix F). 5. Alteration of crocidolite by leaching (a process that can cause fragmentation of fibers) reduces its ability to cause mesothelioma (Monchaux ejt a_l. , 1981; Morgan e a_l. , 1977), but removal of PAH or trace metals does not affect the development of tumors (Wagner e_t l., 1973). 6. In studies to evaluate various injected samples, no one type of asbestos has appeared to be more pathogenic than others (see Appendix F). Wagner (1982) has reported erionite from Oregon readily induces mesotheliomas in rats by inhalation or injection. 7. Inhalation of potassium octatitanate fibers (average size 6.7 x 0.2 um) produced three mesotheliomas in 59 hamsters surviving 21 months or more. No such tumors were produced in guinea pigs and rats exposed to these fibers, or in smaller numbers of rats, guinea pigs, and hamsters inhaling amosite asbestos or ball-milled fiberglass (Lee e al. , 1981). Fibrosis Asbestos-associated fibrosis is an irreversible disease characterized as an excessive deposition of fibrous tissue. Ibis cellular response is thought to occur as a reparative or reactive process. All types of asbestos cause pulmonary fibrosis of the lung (also called pulmonary interstitial fibrosis, or PIF) after relatively long periods of administration (Appendix F, Table F-4). A range of morphological alterations are observed after exposure to other fibers. Iti' important features of these experiments can be summarized as follows: 1. There are species and strain differences in fibrogenic response. After inhalation of chrysotile by rats, guinea pigs, and mice, granulomas (distinctive focal lesions formed as the result of an inflammatory reaction) and focal fibrosis have been observed in the rat and guinea pig but not in the mouse (Reeves et al^., 1974). Moreover, studies by Lee t al. (1981) show a direct relationship between dosage of fibers and development of fibrosis in the rat, whereas less prominent changes occur in the hamster and guinea pig. 2. Studies with fibrous glass in a diversity of size ranges suggest that responses are minimal in comparison to those induced by asbestos of comparable dimensions. Morphological changes in exposed animals include 169 mild macrophage infiltration without fibrosis (Gross et al, 1970; Moorman, in press), minimal peribronchiolar fibrosis (Kuschner and Wright, 1976), alveolitis (inflammation of the alveoli) (Begin et al., 1982), and alveolar proteinosis (alveolar accumulation of granular proteinaceous material) (Lee et_ al., 1979). No abnormal pathology has been observed with use of fibrous glass in inhalation experiments by Lee et al. (1981), Schepers (1959), and Schepers et al. (1958). 3. Inhalation and pleural injection studies implicate the increased fibrogenic potential of longer (>10 gm) fibers of both asbestos and fibrous glass. Minimal or no change has been observed after exposure of animals to smaller fibers or particles of chrysotile (Gardner, 1942), other types of UICC asbestos (Vorvald e al., 1951), fibrous glass, and a synthetic fluoro-smphibole (Kuschner and Wright, 1976). 4. Other fibers evaluated in rodents by inhalation Include alumina, which produced no fibrosis (Piggott et al., 1981); PKT and Fybex, which caused fibrosis, but to a lesser extent than amosite (Lee et al., 1981); and ceramic aluminum silicate glass, which induced alveolar proteinosis (Davis et al., 1982). These fibers tended to fall within the same size dimensions as asbestos. 5. Davis and Coniaml (1973) evaluated pleural fibrosis in mice after injection of the material resulting from heating chrysotile to temperatures exceeding 600C. Compared with control material, fiber length was reduced and the fibrotic changes in animals diminished. 6. Pleural plaques have not been observed in laboratory animals after exposure to asbestos (Craighead and Mossman, 1982). Events in the Gastrointestinal Tract After Exposure to Asbestos A number of investigators have attempted to Induce gastrointestinal tumors in animals by administering oral doses of asbestos (Gross et al., 1974; Smith et al., 1965, 1980a; Workshop on Ingested Asbestos, 1983). Thus far, these studies have yielded negative results, as have three National T^ Ecology Program bloassays (McConnell et al., 1983 a,b). Moreover, asbestos was not found to be cocarcinogenic when administered to rats with azoxymethane--a documented intestinal carcinogen (Ward e al., 1980). After being ingested by rodents, asbestos has been observed in mucosal cells of the gut (Westlake et al., 1965). In guinea pigs, epithelial injury has been observed (Jacobs et al., 1978) but erosion and degenerative changes regressed by 24 hours after administration of an oral 500-mg dose (Saxena et al., 1982). The acid environment of the stomach and the secretion of mucin by gastrointestinal cells could contribute to the modification of fibers as a result of the leaching or adsorbance of mucin. Moreover, the rat gut may be reslstent to asbestos. Studies by Reiss <st al. (1980b) ahow that asbestos is toxic to intestinal and colonic cells in culture. Leaching of chrysotile in 1 N hydrochloric acid ameliorates cytotoxicity. 170 IN VITRO STUDIES Investigators using suspensions of red blood cells (RBCs), monolayers of cells, and organ cultures have contributed to the understanding of the mechanisms by vhich cytotoxicity and carcinogenicity are induced by asbestiform fibers. Results of these studies have been discussed in various proceedings and reviews (e.g., Brown et si., 1980; Harington et al., 1975; Moasman and Craighead, 1981; Mossman et a^., 1983a). The types of studies and experimental information of most importance in elucidating the interactions of fibers with cells are summarized below. Hemolytic Assays The mechanisms of particle-induced cytotoxicity are complex. A critical part of this process appears to be the ability of particles and fibers to bind to and damage cellular membranes (Chamberlain et al., 1982; Craighead et al., 1980; Harington et jl, 1971, 1975; Jaurand ejc al., 1979a, 1980; Woodworth et al., 1982TT The disruption of the membranes can result in hemolysis, which is the leakage of hemoglobin from the RBCs. Hemolysis can be quantified apectrophotometrically and often is used to define: mechanisms of membrane damage by particles (Chamberlain e al_., 1982; Craighead et l., 1980; Desai e jrl., 1975; Jaurand et l., 1979a, 1980; Harington et al., 1971, 1975; Light and Wei, 1977a,b; Manyai e al., 1969; Zitting and Skytta, 1979) and the fibrogenic potential of particles (Hefner and Gehring, 1975). The degree of hemolysis by particles, however, does not correlate directly with their fibrogenic or carcinogenic effects. The hemolytic activity of fibers relates to physicochemical properties such as size (Schnitzer and Pundsack, 1970), magnesium content (Harington e a_l., 1971), crystallinity (Palekar et al., 1979; Zitting and Skytta, 1979), and surface charge (Harington et al., 1971, 1975; Light and Wei, 1977a,b). A large surface area also facilitates interactions with the RBC membrane. For example, hemolysis is enhanced as the number of fibers (Desai and Richards, 1978; Schnitzer and Pundsack, 1970) and the degree of their dispersion (Schnitzer and Pundsack, 1970) increase. Particle shape is not critical since certain fibers, such as crocidolite asbestos and fibrous glass, or particles with sharp edges, such as carborundum, are only marginally hemolytic (Harington et al., 1975). Moreover, some nonfibrous particles, such as montmorilIonite, are as hemolytic as chrysotile asbestos (Woodworth et_ al., 1982). The importance of surface charge in hemolysis by chrysotile and crocidolite has been suggested by Light and Wei (1977a,b). Other investigators have reported that chrysotile is both hemolytic and 171 cytotoxic in a variety of cell systems, whereas crocidolite is relatively inactive (Chamberlain and Brown, 1978; Miller and Harington, 1972; Mossman e a_l., 1980b; Woodworth e al., 1982). The magnitude of the surface charge on the fibers (e.g., chrysotile, +44.5 mV, and crocidolite, -43.5 mV, in distilled water, as measured by their zeta potential)! is directly related to their hemolytic potential. For example, when chrysotile fibers are leached in acid, their zeta potential decreases as does their hemolytic activity. In contrast, the hemolytic ability of crocidolite increases after leaching as the fibers become more negatively charged. Adsorption of components of surfactant or serum to fibers also renders them less hemolytic (Craighead e_t al., 1980; Desai and Richards, 1978; Jaurand el., 1979a; Light and Wei, 1977a). Harington et_ aK (1971, 1975) hypothesized that negatively charged residues of sialic acid from membrane glycoproteins bind to positively charged sites on minerals. This ionic interaction might result in the aggregation of integral membrane proteins and leakage of hemoglobin. To test this hypothesis, sialic acid was removed enzymatically from RBCs before hemolysis by chrysotile was measured. The treated RBCs were resistant to hemolysis, suggesting the importance of sialic acid in this process. Experiments with tracheobronchial epithelial cells have suggested that chrysotile also interacts with other carbohydrates on the cell surface (Mossman et al., 1983c). Cytotoxicity Studies Cytotoxicity is the ability of an agent to interfere with cellular function to the extent that the cell is either damaged or killed. Because asbestos and other particles are believed to play a role in the pathogenesis of respiratory tract diseases, the mechanisms whereby these substances induce cytotoxicity have been investigated in cell culture (Chamberlain et l., 1982; Harington et al., 1975; Mossman et al., 1983a). Although some researchers have attempted to correlate the cytotoxicity of fibers with their ability to cause pulmonary fibrosis and mesothelioma (Hefner and Gehring, 1975; Kaw et al., 1982; Wade et al., 1980), the validity of this correlation is not accepted in general, and one must conclude that cytotoxicity is not related directly to pathogenicity. For example, crocidolite is less damaging to red blood cells and less cytotoxic than chrysotile in macrophages and in cultures of tracheobronchial epithelia (Doll et al^., 1982a,b; Haugen e al.., 1982; Landesman and Mossman, 1982; Miller and Harington, 1972; Mossman et al., 1980b; Woodworth e al., 1982). Reiss and colleagues (1980a,b) and Wade et al. (1979) have suggested that sensitivity to asbestos differs among IZeta potential is a measure of surface charge. A zeta potential of zero indicates no measurable surface charge. 172 che various cell types (e.g., epithelial cells, fibroblasts, and macrophages). Cytotoxicity is dependenc on both Che geometry and the length of asbestos fibers. In macrophagelike cells, chrysotile is toxic, whereas its nonfibrous analog, platy serpentine, is not (Frank et al., 1979). Long fibers of various minerals are more cytotoxic than comparable amounts of short fibers (Beck^l., 1972; Brown et al., 1978; Chamberlain and Brown, 1978; Kaw et al., 1982). There is overwhelming evidence Chat short fibers are phagocytized completely, whereas long fibers are only partially enveloped by cells. Uptake of fibers by cells results in the release of lysosomal enzymes (Beck eaJL., 1972; Davies al., 1974) and oxygen free radicals (Mossman and Landesman, 1983), reactive species Chat cause peroxidation of membranes and damage to macromolecules (Freeman and Crapo, 1982). Cell injury in tracheal epithelial cell cultures can be prevented by Che addition of superoxide dismutase--a scavenger of superoxide (Mossman and Landesman, 1983). Cell death occurs rapidly when fibers are added to culture media without serum, but is inhibited or delayed when serum is present (Harington et al., 1975; Mossman et al., 1980b). Serum proteins adsorb to fibers (Desai and Richards, 1978), and this protective coating is believed to be removed by lysosomal hydrolases after phagocytosis of the particles (Allison, 1971; Heppleston, 1979). Alterations in Cells of the Immune System After Exposure to Asbestiform Fibers Aberrations of humoral and cellular immunity have been reported in individuals exposed to asbestos (Kagan j*l., 1977; Lange, 1980; Stansfield and Edge, 1974; Turner-Warwick and Parkes, 1973). These studies suggest activation and/or loss of normal immunoregulatory mechanisms in asbestos-associated diseases. Because macrophages may play a role as an intermediate in pulmonary defense, in vitro studies have been conducted to examine the responses of these cells to asbestos. After exposure Co asbestos, macrophages release potent inflasnnatory factors (Hamilton et al., 1976) and synthesize prostaglandins (Sirois t al., 1980), chemotactic factors for neutrophils (Schoenberger et al., 1982), and substances that increase replication of fibroblasts (Bitterman et al., 1981). Results of other in vitro experiments indicate that asbestos affects both cell-mediated (Barbers et al., 1982; Bozelka et al., in press) and antibody-mediated (Lawrence et al., 1982) immunity. In addition, both amphibole and serpentine types of asbestos depress viral induction of interferon--a glycoprotein that confers antiviral defense--thereby resulting in increased multiplication of che virus (Hahon and Eckert, 1976). Conversely, che mineral wollastonite enhances the induction of interferon by influenza virus in cultured cells, but the mineral per se ' 1 173 does not induce interferon (Hahon et al., 1980). Finally, in addition to obvious modulatory effects on cells of the immune system, asbestos can activate complement, a complex in serum chat is destructive to certain bacteria and cells chat have been sensitized with antibody (Hasselbacher, 1979; Saint-Remy and Cole, 1980; Wilson et l., 1977). Effects on Fibroblasts In Vitro Although the macrophage appears to be a key cell in Che induction of tissue injury by asbestos, the affected ceil in the fibrotic process is che fibroblast--a cell associated vith the production of collagen. It is not clear whether fibrosis results from increased production of collagen by individual cells, or from an increase in the proliferation of fibroblasts, or from both. Some investigators have suggested chat these synthetic responses are elicited by fibrogenic factors released by macrophages (reviewed in Vigliani, 1968). When noncytolytic amounts of asbestos are added to cultures of fibroblasts, abnormal and accelerated production of collagen and reticulin are observed (Hext and Richards, 1976; Richards and Jacoby, 1976). Fibroblasts undergo a maturation process leading Co rapid cellular aging. Surviving cells phagocytize fibers avidly and undergo morphological and biochemical changes such as alterations in secretion of proteoglycans (Richard and Morris, 1973), metabolism of RNA, and enhancement in cell mat collagen deposition (Hext and Richards, 1976). Fibrous glass is less cytotoxic, producing minimal but similar alterations. Long fibrous glass provides a substrate for the attachment of cultured fibroblasts and acts as a stimulus to promote cell division (Maroudas et al., 1973). INITIATION-PROMOTION MODEL OF CARCINOGENESIS This brief discussion of the initiation-promotion model of carcinogenesis is provided as a basis for subsequent sections describing possible carcinogenic properties of asbestiform fibers. It is possible t Chat cancers induced by asbestiform fibers result from the same | fundamental mechanisms as cancers induced by other physical and chemical agents. Carcinogenesis is a complex, multistep process that has been extensively reviewed by Becker (1981), Foulds (1969, 1975), Farber (1982), and Farber and Cameron (1980). Multiple focal proliferations of cells (hyperplasia) in target organs are common early features of carcinogenesis and serve as sices for > subsequent premalignant changes (Farber, 1982). Such focal alterations give cell populations selective growth and invasive properties (Cairns, i 1975; Fialkow, 1976; Foulds, 1954; Nowell, 1976). The concepts of initiation and promotion have been developed to explain this process in \ many experimental models and organ systems, including skin, liver, j I 174 nummary gland, colon, urinary bladder, and brain (Berenblum, 1941; Soutwell, 1974; Pitot and Sirica, 1980). Initiation is a change in the DNA of a cell induced by exposure to a carcinogen. This heritable alteration can be promoted ultimately to malignancy. Promotion is the process whereby an initiated cell develops focal proliferations, one or more of which may act as precursors for subsequent steps in the process of carcinogenesis. Promotion creates a mitogenic environment that differentially affects initiated cells. Some investigators suspect that many tissues or organs create a physiological promoting or selecting environment. In the early stages, promotion can be reversible, but it eventually brings about the phenotypic changes needed to stabilise the characteristics exhibited by cancer cells (Trosko and Chang, 1980). By stimulating a premalignant or initiated cell to proliferate, the process of promotion also enhances the probability that additional genetic errors will occur (Potter, 1981; Trosko and Chang, 1980). Promotion appears to occur after removal of cells, e.g., as the result of a surgical procedure or the infliction of a wound (Pound and McGuire, 1978); after physical irradiation (Argyris and Slaga, 1981); after cell death (Frei, 1976); or upon exposure to exogenous noncytotoxic chemicals (Trosko and Chang, 1980), endogenous chemicals, e.g., hormones (Yager and Yager, 1980), or solid objects, e.g., small plastic squares (Brand,1982). Some current views on promotion and promoters have been shaped by studies in which croton oil and its active agent, 12-0-cetradecanoylphorbol-13-acetate (TPA) were used in a mouse skin test system. Both chemical and physical tumor promoters have been shown to induce a constellation of biochemical and cellular responses (Diamond et al., 1978). Depending on the cell type, chemical tumor promoters can induce or inhibit normal differentiation (Diamond e l., 1978) or alter the proliferation of cells in a given tissue (Yuspa e al., 1982). One of the important biochemical markers of cell division is increased synthesis of polyamines, which is often detected as an increase in the activity of ornithine decarboxylase (ODC)--a rate-limiting enzyme in the biosynthesis of polyamines. The induction of ODC is related directly to tumor-promoting activity of a number of compounds in mouse skin (O'Brien, 1976). When applied to the skin of rodents, classical tumor promoters (e.g. , phorbol esters) also cause inflammatory changes and infiltration of polymorphonuclear leukocytes (PMNs) and macrophages. These cells release oxygen free radicals--reactive by-products of oxygen that cause peroxidation of membranes and other macromolecules (McCord and Wong, 1979) . 175 Detailed reviews of tumor promotion have been prepared by Becker e_t al. (1982) and by Slaga et al. (1978). Interaction of Aabestiform Fibers with DBA Mutagenicity is the ability of a chemical or physical agent to induce permanent, transmissible changes in the character of a gene by modifying the DMA. This event is believed by many to be an initiating step in the process of carcinogenesis. Daniel (in press) has prepared a review of ^n vitro tests that have been conducted with asbestiform fibers to determine their potential for mutagenicity and other types of interaction with DNA. In bacterial assays, such as the Ames Salmonella microsorae assay, UICC reference samples of asbestos, superfine Canadian fibers, and fibrous glass have not shown mutagenic activity (Chamberlain and Tarmy, 1977; Light and Wei, 1980). The investigators believe that these negative results may be attributable to the lack of fiber uptake by bacterial cells. Chromosome aberrations and chromatid breaks have been observed after chrysotile and crocidolite asbestos have been added to rodent cell lines (Lavappa e a_l., 1975), but not after the addition of fibrous or powdered glass (Sincock and Seabright, 1975). Huang (1979) demonstrated that chrysotile, crocidolite, and amosite are mutagenic to the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus of Chinese hamster lung fibroblasts. However, Che rates of induced mutation were low, and the conclusions drawn by Huang are strongly dependent on Che method of statistical analysis used in this study. Moreover, neither chrysotile, crocidolite, nor amosite was mutagenic in rodent liver epithelial cells (Reiss et al., 1982). Although amosite and crocidolite produced small increases in sister chromatid exchange (SCE) in Chinese hamster ovary cells (Livingston e , 1980), the V79-4 Chinese hamster lung cell line and cultured mesothelial cells did not exhibit altered SCE levels after exposure to crocidolite and chrysotile, respectively (Kaplan e l., 1980; Price-Jones ,el** 1980). Furthermore, in tracheal epithelial cells, chrysotile and crocidolite did not cause breakage of DNA, as measured by alkaline elution (Mossman et al., 1983b). Results of studies by Sincock (1977) and Lechner and colleagues (1983) suggest that human cells are relatively resistant to DNA damage by asbestos. Neither crocidolite, SFA chrysotile, nor glass fibers induces chromosome aberrations in human lymphocytes or fibroblasts (Sincock, 1977), although the number of chromatid and chromosome breaks increases in freshly isolated human lymphocytes exposed to Rhodesian chrysotile (Valerio e_t a_l., 1980). In another study, UICC chrysotile, amosite, and crocidolite did not appear to cause DNA strand breakage in human bronchial organ cultures (Lechner et al., 1983). 176 Tumor Promotion Properties of tumor promoters have been extensively reviewed and discussed (Farber, 1982; Hecker e , 1982; Slaga e al_., 1978). In studies of cultured tracheal epithelial cells from hamsters, Mossman e_t al. (1977, 1980a,b, 1983a,b), Mossman and Craighead (1981), and Woodworth et al. (1933a,b) have demonstrated chat several different types of asbestiform fibers exhibit the properties of tumor promoters. Both long (>10 ym) and short (<2 ym) chrysotile and crocidolite fibers interact with the membranes of differentiated superficial epithelial cells in organ culture. Short fibers are phagocytized successfully and are observed thereafter in basal epithelial cells (presumably the progenitors of carcinoma); longer asbestos fibers are enveloped by membranes, but appear incapable of being phagocytized (Mossman et al., 1977; Woodworth ec_ jrl., 1983). This latter phenomenon occurs concomitantly with release of the oxygen free radical, superoxide, into culture medium (Mossman and Landesman, 1983). After exposure to amosite or crocidolite asbestos, there are increases in the incorporation of ^H-thymidine (an indication of DNA synthesis) and basal cell hyperplasia in tracheal epithelial cells in vitro. The morphological changes were prevented by the addition of vitamin A, which has been associated with the reduction of cancer incidence in a number of studies in rodents (Mossman et. aK, 1980a). Enhanced uptake of ^H-thymidine and morphologic changes have also been observed in monolayers of tracheal epithelial cells exposed to either crocidolite or chrysotile (Landesman and Mossman, 1982). Some asbestiform fibers have been observed to alter normal epithelial cell function. For example, crocidolite, amosite, and fibrous glass facilitate the progression of basal cell hyperplasia to squamous metaplasia, i.e., the conversion of a differentiated epithelium to a squamous comified layer resembling akin (Mossman e _al., 1978, 1980b; Woodworth et al., 1983a,b). Chrysotile fibers induce significant increases in squamous metaplasia, but high concentrations of long fibers cause permanent destruction of the mucosa. Ground glass, attapulgite, and nonfibrous analogs of asbestos (e.g., riebeckite and mtigorite) neither cause squamous metaplasia nor stimulate DNA syr hesis (Woodworth et a_l., 1983a). Chrysotile, crocidolite, and fibrous glass induce ODC and stimulate cell division in tracheal epithelial cells in a dosage-dependent fashion (Landesman and Mossman, 1982), whereas these changes do not occur after exposure to nonfibrous crocidolite (e.g., riebeckite), chrysotile (e.g., antigorite), glass particles, or hematite (Mossman, personal cossnunication, 1983). These experiments suggest that fibrous glass exhibits some promoterlike features jin vitro, but experiments exploring this phenomenon in whole animals are lacking. 177 In Vitro Studies with Mcaothelial Cells The interaction of mesothelial cells and asbestos fibers has been studied ui vitro to investigate the genesis of mesothelioma (Allison, 2$73; Domagala and Koss, 1977; Jaurand et al., 1979c; Rajan and Evans, 1973; Rajan et al, 1972; reviewed in Whitaker e al., 1982). Chrysotile asbestos (1-2 yin length) is ingested by cultured mesothelial cells in both organ and monolayer cultures, whereas it is unclear whether larger fibers are phagocytized (Allison, 1973; Jaurand et al., 1979c). After introduction into cultures of pleura, crocidolite causes proliferation of cells in a manner similar to that observed in tracheal organ cultures (Rajan e j*l., 1972). Interactions Between Fibers and Polycyclic Aromatic Hydrocarbons (PAHs) Because PAHs are incomplete products of combustion, they are ubiquitous in the urban environment and are found in association with various types of atmospheric aerosols (Pierce and Katz, 1975). A number of investigators have explored the possibility that fibers and particles may act as "carriers" of these PAHs into the cells of the respiratory tract. Equal milligram amounts of crocidolite asbestos, carbon, hematite, and kaolin have been compared for their ability to bind and release the radiolabeled PAH, 3-methylcholanthrene (3MC), into culture medium (Mossman and Craighead, 1982). Asbestos neither adsorbed more 3MC nor eluted greater amounts of the hydrocarbon than did the other materials. However, when tested for release of PAH to artificial membranes or microsomes, asbestos fibers appear to be more effective than the nonfibrous materials tested (Lakowicz and Bevan, 1980; Lakowicz et al., 1978a,b). The association of PAH with the fiber surface before the fibers are added to tracheal epithelial cell culture appears to be critical to fiber-induced cellular uptake of the hydrocarbon. For example, increased uptake and retention of radiolabeled benzo(a)pyrene (BP) have not been observed with fibrous glass, a poorly adsorptive fiber, or when BP is added 1 hour after the addition of asbestos (Eastman et al., 1983; Mossman.et al., 1983b). CONCLUSIONS Asbestiform Fibers: Initiators and/or Promoters of Lung Tumors? Asbestiform fibers do not seem to damage DNA directly (Fornace, 1982; Hart ejt al., 1979; Haugen et si., 1982; Mossman et al., 1983b) or to act as mutagens (Chamberlain and Tarmy, 1977; Reiss e l., 1982). Thus, the role of asbestos in the initiation of lung tumors is questionable. Some 178 investigators have observed a weak mutagenic reaction (Huang, 1979; Huang e l., 1978) that could also be interpreted as indicating an epigenetic reaction (Isobe t l., 1982). The term epigenetic is used here to define the alteration of the expression, not the information, of genes. In other words, it is the repression or derepression of genetic information. One possible explanation of asbestos-facilitated carcinogenesis is that PAHs (known initiators of carcinogenesis) are more efficiently transferred to the target cells because they adhere to the asbestos fibers (Eastraan e aj.., 1983; Mossman et al., 1983b). Lung tumors generally do not appear after asbestos is intratracheally instilled into rodents, but they do appear when PAHs are adsorbed to fibers before instillation (Miller e aK, 1965; Shabad et al., 1974; Smith et al., 1968). However, small numbers of tumors of the respiratory tract have been observed after inhalation of UICC samples of asbestos by rats (Wagner e al.., 1974). The interpretation of these studies is complicated by the finding chat these reference standards of asbestos may be contaminated with PAH (Harington, 1962). The stimulation of cell proliferation by asbestiform fibers may result in Che promotion of initiated epithelial cells lining the airways. In support of the hypothesis that asbestos is a tumor promoter, Topping and Nettesheim (1980) have shown that asbestos has a promoting effect in rodent tracheal grafts exposed sequentially to an initiating PAH and then to chrysotile. In these studies, asbestos increased Che incidence of tumors obtained with small amounts of the PAH, although Che asbestos was not carcinogenic when administered by itself. However, when asbestos was applied to tracheal grafts in 10-fold higher amounts, a low incidence (5X) of squamous cell carcinoma was observed (Topping et al., 1980). Although this latter observation might be interpreted as indicating a weak initiating or carcinogenic potential of asbestos, it seems to be a common feature of many promoters (Iversen and Iversen, 1979). Additional evidence that asbestos acts as a promoter is provided by histological observations of hyperplasia and metaplasia in organ cultures of the respiratory tract after exposure Co asbestiform fibers (Landesman and Mossman, 1982; Mossman and Craighead, 1974; Mossman l., 1980b; Woodworth et al., 1983a,b,c). In addition, the dosage-dependent induction of ODC in tracheal epithelial cells has been seen after addition of chrysotile and crocidolite, but not after exposure to the nonasbesciforo particle hematite (Landesman and Mossman, 1982). The increase in enzyme induction occurs concomitantly with a mitogenic response as measured by uptake of ^H-thymidine. The accumulation of macrophages and inflammatory cells in the air spaces of rodents after inhalation of asbestos appears to be similar to 179 effects observed in the skin after application of phorbol esters (Gee, 1980; Hamilton, 1980). Isolated macrophages and polymorphonuclear leukocytes emit oxygen free radicals into medium and are chemiluminescent after exposure to asbestos in vitro (Caumer et aJL., 1979). One might assume that these reactive species are injurious to mucosal airvays. Again, the length of the fiber appears to be critical to the cellular response in that addition of superoxide dismutase (an enzyme converting the superoxide radical to H2O2 and O2) to tracheal epithelial cells prevents the membrane damage caused by long (>10 urn), but not short (<2 um), chrysotile fibers (Mossman and Landesman, 1983). Retinyl methyl ether, a synthetic vitamin A that blocks the action of at least some promoters (Verma e a_l., 1982), inhibits asbestos-induced epithelial changes in organ culture of hamster trachea (Mossman e aJL., 1980a). Taken together, these results are consistent with the hypothesis that certain asbestiform fibers may act in lung cancer in a manner similar to other knovn chemical and physical agents Chat have the properties of tumor promoters. Some experiments have suggested that promoters may exhibit a threshold concentration below which they do not exert their tumor-promoting effects (Peraino e l., 1980; Verma and Boutwell, 1980). However, there is no experimental evidence of a threshold for carcinogenic effects of asbestos. In Chapter 7, a linear nonthreshold model is used for risk assessment. Initiated cells in the lung could be stimulated to proliferate after exposure to asbestiform fibers either by a membrane-triggered response or by a cytotoxic response. Fibers lodged in cells might act as continuous promoting stimuli. Asbestiform Fibers: Initiators and/or Promoters of Malignant Mesothelioma? The pathogenesis and etiology of mesothelioma, a tumor arising from the membranes enclosing the body cavities, differ from those of lung cancer. There is no positive association between smoking and the development of mesothelioma in asbestos workers (Craighead and Mossman, 1982; Hammond et l., 1979), and prior extraction of PAH from asbestos does not appear to diminish tumor incidence after injection of fibers into the body cavities of rodents (Wagner et al... 1973). Studies by Brand and colleagues (Brand, 1982; Brand e al., 1975a,b) and by Davis (1971, 1974a,b) provide some insight into Che development of this lesion. After injection into the pleural or peritoneal cavity of rodents, longer fibers cause an immediate but chronic foreign body response, presumably because of their inability to be phagocytized by resident macrophages. Abnormal mesothelial cells with an increased mitotic index have been observed within a chickened fibrotic pleura (Jagatic et al., 1967). Studies by Davis (1974b) suggest Chat tumors arise from 180 undifferentiated mesenchymal cells just below the mesothelium. These cells retain their normal pleiomorphic appearance or differentiate into either epithelial-like (mesothelial) cells or spindle-shaped cells. This hypothesized origin could explain the histological variability of tumors in humans and animals, since mesotheliomas commonly contain cells of both epithelial and mesenchymal tissue origin. Other investigators have suggested that tumors arise from multipotential mesothelial cells that can express all Che variable structural patterns observed in these neoplasms (Maximov, 1927; Stout and Murray, 1942, Whitaker et aK, 1982). Asbestiform Fibers: Possible Mechanisms of Fibrosis During development of fibrosis (i.e., asbestosis), the normal architecture of Che terminal airways and air spaces is altered by excessive deposition of fibrous tissue. Fibrosis can also occur in the pleura. The sequence of cellular events that appear to trigger Che onset of fibrosis has been hypothesized on the basis of observations in animals after inhalation or intratracheal instillation of asbestos. Deposition of fibers in the terminal bronchioles and alveolar ducts--Che sites where fibrosis first appears in humans (Craighead and Mossman, 1982)--occurs with a rapid infiltration of macrophages and an acute inflammatory response (Gee, 1980). These observations suggest that asbestos and possibly other asbestiform fibers disrupt the normal proliferation and differentiation of lung fibroblasts either by direct interaction of the fibers with fibroblasts or via effects on an intermediary cell type, the macrophage (or by both mechanisms). Again, Che observations summarized above are similar to those reported for Che mouse skin after exposure Co chemical tumor promoters: infiltration of macrophages is observed, and hyperplasia and/or abnormal differentiation occurs in some cell types (Yuspa et al., 1982). SUMMARY Elucidation of the pathogenicity and mechanisms of asbestiform fiberinduced disease is complicated by the complexity, diversity of sizes, and variety of these materials. The experimental results described above . served as a basis for Table 6-1, which summarizes the relationships between properties of fibers, their effects on cells, and diseases associated with asbestos. Fibers greater than approximately 3 ym in diameter are not respirable; they do not gain access to Che respiratory tract but may be ingested. 181 TABLE 6-1* Possible Mechanisms of Disease Induction by Fibrous Materials at the Cellular Level Disease* Relevant Fiber Property1* Effect on Target Cells and/or Macrophages A 1. 2, 6 Adaorbance and transfer of polycyclic aromatic hydrocarbons (PAHs) to cell membranes A, C, D 1-7 Disruption of cell membranes (i.e., lysis and hemolysis) and release of cell enzymes A, C A, B, C, 0 1, 2, 5 1, 2, 3 Release of oxygen free radicals Induction of proliferative alterations (e.g., in DNA, RNA, or protein synthesis) A, B, C, D 1, 2, 3 Alterations in cell differentiation A, B, C, D 1. 3, 7 Interaction with DNA (e.g., chromosomal changes or alteration in normal DNA repair) B, C 1, 2, 5, 7 Effects on immune system (e.g., activation of complement or chemotactic factors) aThe Letters in this column represent diseases associated with exposure to fibrous materials: A * Lung cancer B * Mesothelioma C =* Fibrotic lung disease D * Gastrointestional tumors ^The numbers in this column represent the biologically relevant fiber properties: 1 * Respirability (<3 um diameter) 2 * Size and aspect ratio 3 Durability 4 Flexibility and tensile strength 5 * Chemical composition 6 " Surface area 7 = Surface charge 182 Although data from the aajority of investigators show an Increased risk of mesothelloaa with long, thin fibers in comparison to short, thick fibers, there does not appear to be a critical length below which fibers have no carcinogenic potential. For example, studies by Kolev (1982) and by Pott and colleagues (1972, 1976) suggest that amorphous asbestos and fibers shorter than 5 um are capable of inducing mesothelioma in rodents. The results of inhalation experiments to determine the Importance of aspect ratio in Inducing lung cancer are difficult to Interpret because the fibers in the aerosols are heterogeneous with regard to size. The specific effects of long versus short asbestos fibers of one type have not been evaluated in comparative experiments. Although studies by Gardner (1942), Vorwald et al. (1951), and Kuschner and Wright (1976) suggest Chat asbestlfora fibers longer than approximately 10 um are more active than shorter ones in inducing pulmonary fibrosis, not all long fibers (e.g., Saffll, fibrous glass) are flbrogenic. Moreover, some nonflbrous minerals (kaolin, silica) are flbrogenlc in humans (Heppleston, 1979). Asbestos fibers may fragment longitudinally during processing or within the lung and thus increase in both number and surface area. This property may enable more interaction of fibers with cells. Since direct cell contact appears essential to asbestiform fiber-induced diseases, the greater the surface area, the greater the likely pathogenic potential of a fiber. Furthermore, if polycyclic aromatic hydrocarbons (PAHs) adsorb to fibers as a function of surface area, fibers comprised of many fibrils (assuming all were accessible to the PAH) would present a greater surface for adsorption than would a single fiber. Under these circumstances, their (co)carcinogenic ability might be Increased. Longer fibers ( >ca 10 um), which tend to be more pathogenic, cannot be removed effectively by phagocytic macrophages. Thus, their time of residence in the respiratory tract might be greater than that of shorter fibers. Moreover, longer fibers appear to be more cytolytic than the shorter fibers, which can be phagocytlzed completely. Durability is another factor that could account for prolonged retention of asbestos within the lung and other tissues in comparison with a variety of other asbestiform materials. Although leaching may alter the composition of the fiber, asbestos does not tend to dissolve as does glass. It is unclear whether the chemistry of asbestos plays a direct role in pathogenicity. However, since chemistry determines both durability and surface charge, the latter a feature directly related to cytotoxicity, chemistry may play at least an indirect role. Both inhalation and in vitro studies indicate that asbestos is more pathogenic than a number of man-made mineral fibers (fibrous glass, glass wool, rock wool). However, they fail to identify one type of asbestos as more potent than others. Moreover, there have been few J 183 experiments Co Identify precise dose-response relationships. One obvious conclusion Is that there Is interspecies variability in response to asbestos. Thus, certain rodents, such as rats and alee, appear to be appropriate aodels for the study of carcinogenesis and fibrosis, whereas others (e.g., guinea pigs) have developed no obvious pathological effect froa exposures to asbestos. Different cultured cell types (e.g., epithelial, aesothellal, fibroblastic cells) also differ In their susceptibility to the toxic effects of asbestos. Unfortunately, no In vitro aodel studied to date has been predictive of the flbrogenlc or carcinogenic potential of fibers. However, in vitro systeas have been helpful in elucidating possible mechanisms of action of asbestos. The evidence that asbestos aay act as a gene or chromosomal autagen is weak and inconclusive, but Its ability to function as a tumor promoter at noncytolytlc amounts and as a cytotoxic agent at higher levels is well documented. RECOMMENDATIONS To increase our understanding of the health hazards of asbestlform fibers, a necessary first step is to study the common physical properties of these fibers in relation to their pathogenicity in animals and ability to injure cells. A number of experiments are needed to relate the physicochemical features to biological effects. In vitro and inhalation studies should be conducted to test whether the biological effects of asbestlform fibers are related to their size and shape. These studies should include as controls appropriate nonflbrous analogs of similar or identical chemical composition. "Positive" responses with nonflbrous analogs would be evidence to support the view that the chemical composition of asbestos is important in the development of disease. All preparations should contain fibers of comparable and respirable size. Investigators comparing the pathogenic potential of various fibers and particles should define completely the characteristics (i.e., chemical constitution, surface charge, crystallization habit, crystallography, and geometry) of their source materials. Different preparations of fibers should be sized to obtain comparable size distributions, thus controlling for this important variable. t Where possible, concentrations of particles should be documented in all experimental systems. There are also gaps In knowledge about such Important subjects as the basic molecular mechanisms by which asbestlform fibers Induce cell killing, alter differentiation, or cause gene and chromosomal mutations in various cells. The following experiments would be advantageous: 184 Dose-response curves for asbestiform fiber-induced cytotoxicicy, altered function, and possible mutagenicity in various human cell types in vitro. Experiments both in vivo and u* vitro to determine how various asbestiform fibers act synergistically with other environmental and host factors. Testing of various asbestiform fibers as initiators or promoters in lung tissue. Protocols might include: 1. Single inhalation exposure to asbestos at various doses, followed by administration of substances known to be physical or chemical promoters in lung tissue. These experiments could define fibers as "initiators" or as complete carcinogens (those not requiring exogenous promoters). 2. Investigations in animals to examine the effects of single and multiple inhalation exposures to fibers in air, water, and foods after treatment with initiators (e.g., documented chemical and physical carcinogens). These experiments would test the ability of asbestiform fibers to act as promoters, after single or multiple exposures. 3. 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Health 43:93-97. 7 Risk Assessment Exposure, laboratory, and epidemiological data provided earlier in this report are used in this chapter to make quantitative and qualitative (or comparative) assessments of risks from exposure to asbestiform fibers. To place Che discussion in context, the chapter begins with a brief general discussion of risk assessment and a few special considerations concerning asbestos and related fibrous materials. Various difficulties often limit the accuracy and precision with which risk to human health can be estimated. Nevertheless, when the data base is good, the risk estimates can be sufficiently informative to aid policy judgments. Some of the factors Chat enhance the usefulness of the data include dose-response information based on several accurately known exposure levels; knowledge of physiologic and metabolic factors that affect exposure of body tissues; an understanding of the mechanism by which the substance results in toxicity; knowledge of the extent to which experimental systems mimic the human response; and an understanding of the properties of a complex and variable substance that account for its toxicity. Many of these issues apply in the assessment of risk from asbestiform fibers, which have varying physical and chemical properties. Some members of the class, the commonly used naturally occurring forms of asbestos, have been clearly shown to cause fibrosis of Che lung and pleura as well as cancer of the lung, mesothelium, and possibly Che gastrointestinal tract in humans. Some oct '.national data on other fibers are also available, and considerable r jmbers of experimental studies have been conducted. It is reasonable from a biological viewpoint to use data from occupational studies to derive estimates of risk from nonoccupational exposure. However, differences in route of exposure, type and characteristics of fiber, exposure levels, and time patterns must be considered. Moreover, because working populations are generally healthier Chan Che public at large, the latter may contain a higher proportion of more susceptible individuals. THE PROCESS OF RISK ASSESSMENT The principles guiding the assessment of health risks from environmental substances were recently reviewed by a committee of the 200 201 National Research Council (1983). These principles are sunnarized here Co provide a framework for assessing Che healch risks from exposure Co asbescifotm fibers. The numerous cerms used Co describe differenc aspecCs of risk assessmenc include "hazard assessmenC," "hazard identification," "risk assessmenc," "qualicacive risk assessmenc," "dose-response assessmenc," "comparaCive risk assessmenc," "quancicacive risk assessmenc," and "risk characcerizacion." The use of Chese Cerms has noc been sCandardized. Three concepCs are generally incorporated into che risk assessmenc process. First is Che idencificaCion of Che kinds of harmful healch effecCs, e.g., anemia, birch defecCs, or cancer, ChaC can resulc from sufficient exposure to a substance. Second is Che dose-response curve for a particular effect, i.e., Che severicy of damage and/or che percentage of people or animals likely Co be aC various exposure levels. Third is Che number of people in a particular populaCion, e.g., residents of Che Uniced States or workers in a particular industry, likely Co be harmed under past, presenc, or projected levels and conditions of exposure. In this reporC, Che committee has used "risk assessmenc" as a broad term encompassing all three of Chese concepCs. "Hazard identification" refers Co che first concept, "dose-response" curves or relationships are used in discussions of parcicular secs of daca, and "quancicacive risk assessment" refers Co Che esCimaCes of risk Co humans derived by mathematical extrapolations from these daca. "Population risk escimaCes" describe che expected frequency or incidence of a harmful effecc in a specific group of humans under defined conditions of exposure. The amounC and complexity of information needed increase as we progress from hazard idencification Co dose-response assessmenc Co populacion risk estimation, although each seep builds on che preceding one. Hazard identification characterizes che nature of Coxic effects thac a sub cance is capable of causing in laboratory animals or humans. Dose-response curves based on experimental or epidemiological observations define Che frequency and sometimes Che severity of these coxic effeecs at several levels of exposure. The dose-response information is used in quantitative risk estimation. Through mathematical modeling and application of known biological principles, attempts are often made to estimate risk for dose levels, exposure conditions, or species other than those for which dose-response data have been obtained. For example, quantitative risk assessments often rely on dose-response data from studies of laboratory animals exposed to relatively high exposure levels in order to estimate che risk to humans exposed to lower levels. Assumptions and uncertainties involved in che application of quantitative risk assessmenc to cancer induction have been discussed extensively (Food  202 Safety Council, 1980; International Regulatory Liaison Group, 1979; Office of Technology Assessment, 1981). Population risk estimates bring together quantitative risk estimates and data on exposure of a specific group of humans to identify their risk under actual or anticipated exposure conditions. The most relevant information for categorizing the hazard or the dose-response for humans is derived from studies of exposed humans. Unfortunately, evidence from this source is often unavailable or inconclusive at times vhen decisions about acceptable exposure must be made. Humans are exposed to so many different substances through food, medicines, air, water, household materials, and occupational environments that sorting out the causes of harmful effects on health is often difficult. Perhaps of most importance is the fact that evidence of human health hazards from substances introduced into our environment cannot be obtained directly from observations in humans until people have been harmed. For these reasons, evidence from laboratory animals or from other biological test systems is often used as an alternative or as a supplement to data on humans. A substantial body of evidence has demonstrated the utility of these experimental systems (Doull et al., 1980; National Research Council, 1977; Richmond et al., 1981). A variety of mathematical models have been developed for using data at high doses, usually only available from studies in animals, to estimate risks for humans at low doses (Armitage, 1982; Cornfield et l., 1978; Crump et_ al_. , 1976; Fishbein, 1980; Food Safety Council, 1980; Krewski and Van Ryzin, 1981; Van Ryzin, 1980). Because there are extensive data on the effects of asbestos and some other fibers in humans, the quantitative risk assessments in this chapter are based exclusively on data from epidemiological studies in humans, whereas the comparative risk assessments also take into consideration data from laboratory studies. Every scientific study or technique has some lower limit to its sensitivity. A sensitive method in analytical chemistry may be capable of detecting a few molecules of a particular chemical among a billion other kinds of molecules but incapable of detecting a few among a . trillion. The sensitivity of an animal test for toxicity is limited by many factors, such as the number of animals chat it is practical to study, the subtlety of the effect of interest, the occurrence of similar effects in animals not exposed to the material under test, and limitations on the amounts of material that can be administered and on the methods used to administer them. Other difficulties limit the power of epidemiological studies. For example, it is often difficult to select appropriate control groups, estimate exposure, or detect health effects from the exposures of concern, especially if the exposures are much lower than those that occur among occupational groups. 203 Several kind* of information are uaeful for estimating riak* at low expoaure level* on the baaia of obaervationa at higher exposures. These include the ahape of the dose-response curve in Che range of expoaurea studied, knowledge of the mechanism by which the type of toxic effect occurs, and information on dose-related changes in Che uptake, distribution, chemical or physical modification, and excretion of the substance, i.e., pharmacokinetics. Substances vary markedly both in Che quantity required to produce a toxic effect and in the rapidity with which the incidence of toxic effects decreases with decreasing dose, i.e., the shape of the dose-response curve. In an experiment covering a sufficiently wide range of exposure levels, it is possible to find some levels chat are toxic and some lower levels at which no toxicity is observed. The highest dose at which no toxicity is seen is often called the "no-observed-effect level," or NOEL (Klaassen and Doull, 1980). However, any experiment will have some limit in its sensitivity to small effects, and the true no-effect-level, if any, may be below the NOEL in a particular experiment. The fundamental assumption underlying the NOEL safety factor approach is that some minimal level of a toxic substance is required to cause damage and chat the substance is not toxic below that level. The NOEL type of experiment is used to find that level. The maximum dose at which no toxicity would occur is called the "threshold" for that substance. However, several mathematical models for quantitative estimation of cancer risk assume that there is no threshold; risk diminishes with decreasing dose, but some risk is assumed to remain as long as there is any exposure. The determination of which of these two assumptions is correct will probably depend on the nature of Che toxic effect. Thus, understanding the mechanism of toxicity can provide guidance in setting acceptable exposure levels. For a substance that exerts its toxic effect by inactivating an enzyme present in abundance in each cell, it is reasonable to assume that a threshold would exist. Inactivation of a few molecules of Che enzyme is unlikely to damage the cell. On the ocher hand, a chemical that is mutagenic or carcinogenic because it damages some critical sice on a DNA molecule that starts the carcinogenic process can reasonably be assumed not to have a threshold. The likelihood that a critical site would be damaged would decrease with decreasing dose, but Che possibility that this damage could occur remains at any exposure above zero. For many effects, the severity of the toxic effect, as well as the probability that it will occur, also decreases with dose. For example, a dose that damages a high proportion of cells in the liver may be lethal; one that damages a moderate number may cause severe illness but not death; a small dose that causes damage to a few cells may not lead 204 to any clinical symptoms. The error in assuming a threshold if none truly existed vould generally not be expected to lead to serious cases of disease in this situation. By contrast, the severity of cancer and of mutationa is not related to the dose of the substance causing them. Low dose exposure to x-rays or cigarette smoke causes fewer cancers Chan does high dose exposure, but the resulting cancers are just as lethal. Thus, although there may be some substances that show a threshold for cancer induction (Hoel et_ al., 1983), an error in assuming a threshold when none really exists vould severely harm those persons who got Che disease despite a low exposure. Accurate documentation of exposure is important for determining Che dose-response curves for toxicity in animals or humans and also for estimating population risks. Errors in the estimation of exposure will lead to errors in defining the dose-response curve and in making quantitative risk estimates for individuals or specific populations. The amount of a toxic substance or its active metabolite Chat reaches the body site that is susceptible to its effect is the exposure that accounts for toxicity, but such measures are almost never available (Hoel e l., 1983). Other measurements, such as amounts in the blood, amounts entering Che body, or concentrations in Che air or water of a community, are often useful surrogates, but as noted earlier in this report, they are also often unavailable. The sensitivity of the exposed population is another consideration in the risk estimation process. Some individuals may be more sensitive than others to specific environmental insults because of nutritional deficiencies, genetic predisposition, and for children, small body size, developmental immaturity, and increased metabolic and respiratory rates (Calabrese, 1978, 1980). With their rapid metabolic rate, children consume proportionately more food and inhale greater volumes of air than an adult for a given body weight. Thus, they would also consume or inhale proportionately more of any contaminants that are present (Babich and Davis, 1981). Human infants do not have mature hepatic detoxification systems until they reach 2 to 3 months of age (Pelkonen ejt l., 1973; Rane and Ackerman, 1972). Serum immunoglobulin does not attain adult levels until children are 10 to 12 years old (Calabrese, 1978). Studies in animals have also demonstrated a greater sensitivity among the young after exposure to chemicals by a variety of routes (Goldenthal, 1971). Children's lungs, may also be especially sensitive to environmental pollutants. Tager et al. (1983) have observed measurable differences in lung function between children of smoking mothers and children whose mothers did not smoke. . 205 Population risk estimation is based on all the preceding steps. First, the exposure of the study population must be known. Heterogeneity of the population with respect to level of exposure or sensitivity to the toxic material should also be considered in the calculations. Exposure, dose-response curves, distribution of sensitivity factors, and the size of Che population are then used to estimate the number of people likely to suffer toxic effects from the substance of interest. If the material causes more than one type of toxic effect, each effect requires separate calculations. Ideally, calculation of risk is an objective, scientific activity devoid of policy judgments. The latter are made separately when deciding the acceptable level of exposure. However, policy decisions can seldom be divorced completely from the process of risk assessment. The reason for this lies in the uncertainty of many of the scientific judgments required. For example, if one experimental species is more susceptible to the toxicity of a material chan another and data on humans are unavailable, which species should be used for estimating human risk? Which mathematical model should be applied to the data? These and many other questions of judgment were discussed in Che recent National Research Council (1983) report. In the following sections, the committee has used epidemiological data, mostly from occupational settings, to develop a quantitative model of the relationship between fiber dose and carcinogenic response for a generalized "asbestos" exposure resulting in either lung cancer or mesothelioma. That dose-response relationship is Chen applied to a hypothetical, but reasonable, exposure level to show potential population risk levels in populations of arbitrary size. In the final section, Che committee assesses risks for other types of fibers and, in some cases, for other diseases by qualitative comparisons with the base case of a generalized asbestos exposure. QUANTITATIVE RISK ASSESSMENT In the previous chapters, the committee extensively reviewed information on the health effects of asbestos and other asbestiform fibers. In preparing this section, it also reviewed several risk assessments for asbestos in the open literature and in government documents. On the basis of its evaluation of the quality and coverage of the information and the assessment techniques, the committee decided chat a quantitative assessment of the risks for mesothelioma and lung cancer from nonoccupational exposures to asbestos would be meaningful. It also concluded Chat the information base was insufficient for useful quantitative assessments for other fiber types and diseases, but that in some cases a qualitative, comparative assessment was feasible and useful. These decisions do not mean that the asbestos assessment is without major uncertainties nor does it mean that Che comparative assessments are of poor quality. In both cases, the objective is to 206 present information useful for evaluating the health risks of asbestiform fibers in nonoccupational settings. First, an overview of mathematical models for carcinogenic risk assessment is presented to provide a context for the assessments for lung cancer and mesothelioma, which are of principal interest. Next, there is a review of several assessments for asbestos that were based on such models. Finally, these assessments and the committee's own analyses are applied to the information presented in earlier chapters to produce quantitative risk estimates for nonoccupational exposures to asbestos in ambient air. Mathematical Model for Carcinogenic Risk Estimate As explained earlier, it is not necessary to use data oq asbestos exposure from animal experiments to estimate risks for humans, but it is necessary to extrapolate from the health effects observed at high occupational levels of exposure to much lower nonoccupational exposures. Occupational epidemiology makes it possible to describe the probability of dying from a particular type of cancer as a function of age at first exposure, level and duration of exposure, and current age. Mathematical extrapolation models based on the multistage theory of carcinogenesis make it possible to estimate the probability of dying from that type of cancer for different ages at first exposure, different (lower) exposure levels, and different (often longer) duration of exposure, also as a function of current age. By considering the cumulative probability throughout a lifetime, the "lifetime risk" of cancer mortality can be computed. At any age, an individual faces some probability of reaching an end point that is related to cancer in the next year, for example, dying of lung cancer. Suppose that at a given age, a, the probability is given by p(a,d), where d is the dose of the carcinogen--in this case, asbestos. When d * 0, p(a,0) is the probability of the end point for unexposed people. If t is some age of interest, then the cumulative probability P(t,d) of reaching the end point before that age is given by the sum of the annual probabilities up to that age: P(t,d) * the sum of p(a,d) over all ages, a, t. (1) Reaching the end point by time t is analogous to the "failure time" for a generalized system that is no longer effective after time t. General mathematical analysis can be used to show that the probability of failure as a function of time can be written as follows: P(t,d) - 1 - e -Kt.d}^ (2) where l(t,d) represents the cumulative incidence function (or cumulative hazard function) of occurrence of the observable failure prior to time t. I 207 Armitage and Doll (1961), Peto et al. (1982), Kalbfleisch and Prentice (1980), Hartley and Sielken (1977), Hartley t al. (1981), and Kalbfleisch et al. (1983) have applied this model to carcinogenesis. If the cumulative incidence I(t,d) is small, then equation (2) may be simplified to P(t,d) i I(t,d), (3) where = means approximately. In carcinogenic risk assessment, attention ia usually focussed on the cumulative incidence function l(t,d) rather than on the probabi lity function P(t,d). The Armitage-Doll (1961) multistage theory of carcinogenesis suggests that l(t,d) can be written as a product of two terms--g(d), depending only on dose, and h(t), depending only on time. That is, I(c,d) * g(d) h(t). (4) If there are k dose-dependent stages in the process of carcinogenesis and the rate of transformation from one stage to the next is assumed to be a linear function of dose, the function g(d) would be a polynomial of degree k in the dose. The function h(t) depends only on time. This model and its generalization and justification have been discussed by Crump et al. (1976), Hartley e (1981), and Kalbfleisch et al. (1983). To determine the values of the constants in the polynomial g(d) and the functional form for h(t), the cumulative incidence function must be fitted to data--preferably to data based on observations in human populations. The multistage model described above has been fitted successfully to many sets of cancer data, including data on asbestos, and appears at present to be a generally adequate model for assessing cancer risk. Fitting equation (4) to data involves estimating the constants in the model for some suitably determined function h(t). This model has been applied to both mesothelioma and lung cancer data on asbestos-exposed workers. The form of h(t) and Che values of the constants from those studies will be discussed in the next section. The function g(d)--and thus the cumulative excess incidence function l(t;d)--can be approximated as a linear function of dose in the low-dose range that equals 0 when d 0. This relationship can be used for extrapolating from high to low doses and has Che following form: I(t,d) cdh(t). (5) This form assumes Chat there is at least one dose-dependent stage of cancer development. The argument for a linear (with respect to dose) approximation for low-dose exposures has been justified on the basis that the exposure dose d is added to a background level (Hoel, 1980; Peto, 1978). This assumption may not always be justified in application t 206 (see Cornfield t ^1., 1978 and Van Rytin, 1981), buC ic ahould lead Co an appropriate upper bound for Che committee's risk assessments for aabeatoa. Furthermore, and more importantly, ruling out a linear dose term for asbestoa exposure does not seem justified by the data now available (Nicholson, 1983; Peto, 1982; Schneideraan et al, 1981). Thus, Che model adopted for risk assessment in the next three sections of this chapter is based on the cancer mortality incidence calculated by equation (3). PUBLISHED RISK ASSESSMENTS This section reviews some published risk assessments for lung cancer and mesothelioma. These assessments helped the committee select a functional form for h(t) for the two diseases and to establish Che value of the constant c in equation (3). Lung Cancer Risk from Nonoccupational Environmental Exposures The following summary of risk assessments for lung cancer from asbestos exposures is based on data on exposure of worker populations. These data suggest that Che function l(c,d) in equation (3) becomes I(t,d) c*T0dI0(t), (6) where Tq is the duration of exposure to asbestos at dose d, Io(t) is the cumulative mortality incidence for lung cancer up Co age t for those who have not been exposed to asbestos, and c* is a constant that depends on the cohort under study, but not on dose or age. As used in equation (6) and in the remainder of this section, d is Che concentration of fibers in the workplace air, usually measured in fibers/cm^. Although d is referred to as dose, some authors would call it dose rate and would refer to the product Tgd as (cumulative) dose. Equation (6), derived by Peto (1982), is consistent with his earlier studies of chrysotile workers (Peto, 1978). This equation is also supported by four studies reviewed by Nicholson (1983), who noted that the relative risk of lung cancer deaths for asbestoa workers compared to a similar population was linearly related co Che accumulated dose years, i.e., fibers/cuP x years, or (fibers/cm3)yr. In equation (6), the underlying incidence rate lQ(t) is consider ably different for smokers and nonsmokers of each sex. Therefore, the risks for each of these groups must be assessed separately. Another consequence of equation (6) is Chat Che relative risk of lung cancer due Co asbestos exposure does not depend on age at first exposure. Thus, lifelong risk of lung cancer resulting from exposure to asbestos can be calculated quite simply by using equation (6). As an example, consider the following calculation given by Peto (1982). 209 Consider Che effect of 10 years of exposure at 1 fiber/cm3. if we assume chac Che relative risk for lung cancer among insulation workers increased approximately fourfold fHamaond et al. (1979) reported 4.2 for nonsmokers and 3.9 for smokers] and that this risk is based on a cumulative dose of 600 fibers/cm^ (20 years at 30 fibers/cm^), then 10 years of exposure to 1 fiber/cm^ will increase the relative riak by 4.0 x 10/600 * 0.067. Since approximately 15Z of lifelong smokers die of lung cancer, this mortality rate will increase to 0.15 x 1.067 x 100, or 16Z. Thus, the difference (1Z) is che excess due to asbestos as predicted by the equation. Since only 0.5Z of nonsmokers die of lung cancer, this would become 0.533Z (0.005 x 1.067 x 100) for an added risk of 0.033Z due to asbestos exposure. Mesothelioma Risk from Nonoccupational Environmental Exposures The committee reviewed two estimations of mesothelioma risk, one by Peto and his colleagues (Peto, 1982; Peto et. al^ , 1982) and che other by Nicholson (1983). These analyses and their consequences are summarized in this section. Using the data of Selikoff e_t al. (1979) on mortality among 17,800 members of the International Association of Heat and Frost Insulators and Asbestos Workers, Peto t^ a_l. (1982) showed that the mortality rate from mesothelioma in these workers was dependent on Che time since first exposure, but did not depend on the age at first exposure. From this finding, and the application of the multistage theory of carcinogenesis through equation (5), the cumulative incidence function becomes: I(t,d) = cd(t - t0)k, (7) where t - Cq represents time since first exposure at age to- For any group of workers exposed at the same dose level d, che product cd 3 b is a constant depending on che type of asbestos exposure. Equation (7) suggests that the risk for mesothelioma is primarily dependent on the time since first exposure (t - tg). This same phenomenon was noted by Schneiderman e l. (1981) and Nicholson (1983). Fitting equation (7) with b * :d to the data of Selikoff et l. (1979) for men up to age 80 by the method of maximum likelihood estimation resulted in an estimate of k * 3.2 with a standard error of * 0.36 and b * 4.37 x 10". Using this calculation, Peto et l. (1982) estimated che lifelong mesothelioma risk for this worker group to be 15Z, 7Z, and 3Z for age at first exposures of 20, 30, and 40 years, respectively. These figures have been adjusted for ocher competing causes of death. Using equation (7) with k * 3.2, Peto and colleagues determined that b x 10 ranges in value from 2.94 to 5.15 for four other sets of data (see Table 7-1). Using k * 3.5, Peto (1982) computed a lifetime mesothelioma rate of 1 in 100,000 children exposed from age 12 to age 18 210 TABLE 7-1. Mesothelioma Death Sates in Various Studies and Predictions of Rlska Study Population and Reference Relative Risk Cb x 108) North American insulation workers (mixed exposure) Selikoff et al., 1979 4.37 Factory workers (mixed exposure) Newhouse and Berry, 1976 4.95 Chrysotile textile factory workers Peto, 1980b 2.94 Australian crocldollte miners Hobbs e al., 1980 5.15 U.S. amoslte factory workers Seidman et al., 1979 4.91 Corresponding Lifetime Sisk (Z)b by Age at First Exposure (yrs) 20 30 40 15 7 3 17 8 3 10 5 2 17 8 3 17 8 3 aAdapted from Peto et al. (1982). The death rate at time t - tQ since first exposure at age tQ is proportional to b, obtained by fitting equation (7) with k 3.2. ^The calculation of "lifetime risk," i.e., the percentage of similarly exposed men who would die of mesothelioma before age 80, is based on an actuarial calculation using 1977 U.S. rates for white males for all causes of death other than mesothelioma Inflated by a factor of 1.26, the observed relative risk among insulation workers (Selikoff et al., 1979). (i.e., 6 years of school age), assuming the fiber level was 0.003 flber/cm^ (1/1,000 of the exposure of the insulation workers). A second risk assessment was done by Nicholson (1983), who criticized the Peto et al. (1982) analysis for fitting equation (7) to only those men who died of mesothelioma up to age 80. By including all insulation workers, he estimated k to be 5.0. 211 QUANTITATIVE RISK ASSESSMENT FOR NONOCCUPATIONAL ENVIRONMENTAL EXPOSURES As starting point for assessing the risk from nonoccupational environmental exposure to asbestiform fibers, the committee adopted equation (6) as representing the cumulative mortality up to age t, which is appropriate for lung cancer induced by a continuous exposure of Tq years at dose level d in fibers/cm^. This model implies that any given total dose before time t would have the same effect on the relative risk at time t, regardless of the time at which exposure started or its duration. The model thus ignores a minimum latency period, which might cause the model to overestimate effects, but also ignores the difference between exposures at earlier and later ages, which might cause the model to underestimate effects. Equation (7) was assumed to be a reasonable representation of the cumulative mortality from mesothelioma up to age t for continuous exposure to asbestos at dose level d in fibers/cm^ from age Cq until age t. In this case, latency is implicitly included in the dependence on (t-tg), because k is greater than 1, but no minimum latency is assumed. Ihese assumptions are supported by the work of Peto (1982), Peto e (1982), Nicholson (1983), and Schneiderman e al. (1981), who extensively reviewed the basis for these assumptions by examining the models and their consistency for several observed worker cohorts exposed to ambient concentrations of asbestos fibers. These authors have suggested that asbestos acts as a late-stage carcinogen in producing lung cancer but acts at earlier stages in the development of mesothelioma. Using these models, the committee developed lifetime estimates of risk for lung cancer and mesothelioma mortality from continuous nonoccupational exposures to 0.0004 fibers/cm^ and for 0.002 fibers/cm^. For lung cancer, the committee assessed the risk for four exposure subgroups: male smokers, female smokers, male nonsmokers, and female nonsmokers. For mesothelioma, only one calculation was made, since equation (7) and the supporting data in the papers cited above suggest that mesothelioma mortality does not depend on sex or smoking history, but does depend strongly on age at first exposure. Lifetime Risk Estimates for Lung Cancer and Mesothelioma Table 7*2 summarizes lifetime risk estimates for lung cancer and medothelioma for nonoccupational environmental exposures to 0.0004 fibers/cm^ (a median level) and 0.002 fibers/cm^ (a high level). It is assumed this exposure is continuous from birth through a lifetime of 73 years, an approximate average lifetime in the United States. Thus, in equations (6) and (7), t 73 years and d 0.0004 or 0.002. In equation (6), Tq 73 and in equation (7), tg 0 to account for continuous exposure. Because equations (6) and (7) are linear in the dose unit d, one can immediately obtain from Table 7-2 lifetime risks at other continuous (from birth) environmental exposures by multiplying by the appropriate dose factor. For example, lifetime risk estimates at 0.02 fibers/cm^ are 10 times higher than the estimates at 0.002 fibers/cm^. 212 TABLE 7-2. Estimated Individual Lifetime Risk** froa a Continuous Exposure Co Asbestos at 0.0004 Fibers/cm^ (a Median Dose) or 0.002 Fibera/csP (a High Dose)* Disease Lung cancer^ Lung cancer Lung cancer Lung cancer Mesothelioma Exposure Group Male saoker Female saoker Male nonsmoker Female nonsmoker All Estimated Individual Lifetime Risk x 108 Median Exposure (0.0004 fibera/cm^) High Exposure (0.002 fibers/cm3 64 (0 to 290)c 320 (0 to 1,500) 23 (0 to 110) 120 (0 to 530) 6 (0 to 22) 29 (0 to 130) 3 (0 to 13) 15 (0 to 66) 9 (0 to 350) 46 (0 to 1,700) aLifetime assumed to be 73 years; exposure occurs from birth. Lung cancer risks are calculated with c* * 1.02 or an excess risk of 22 per (fiber/cm^)yr, estimated from nine studies vith varied results. Mesothelioma risks are calculated vith c * 2.53 x 10~ and k - 3.2, estimated from five studies with varied results. See also explanations in text. 8Sex differences for lung cancer risk are due to differences in lung cancer background rates associated with smoking patterns, occupational exposures, and other factors. cSange of estimates. The lover limit of 0 is always possible if linear extrapolation overestimates risk. See also text below. The estimates in Table 7-2 were based on the following five considerations: Exposure levels. A mix of indoor and outdoor measured exposure levels was used to select the median value of 0.0004 fibers/cm^ and the high value of 0.002.fibers/cm8 as the reference levels. Use of the linear model. The models used by the committee all assume low-dose linearity and, as such, produce higher estimates of risk at low doses Chan would be obtained with ocher models. However, because the occupational data do not rule out lov-^iose linearity, the committee believes that these estimates do not unduly overstate the risks. Count-mass conversion. The conversion of ambient fiber mass measurements to an equivalent number of fibers was based on measurements I 213 of un and numbers of fibers in Che workplace. The coamittee realized, however, ChaC Che number of fibers in aabienC air would be much greater because these fibers Cend to be smaller chan those in Che workplace (see Chapcer 4). Depending on Che toxicity of small fibers, Cbe risks could be greaCer or less Chan Chose calculaCed in this chapCer. If Che presence of long fibers is necessary for a toxic response, risks would be lover. a Model dependence. The reaulcs of che mesothelioma model depend very heavily on che value of k. This accounts for cbe large range of estimates for mesothelioma. IC is assumed ChaC this dependence on k among workers holds for the encire population ChroughouC a lifetime. If che dependence is not as strong (i.e., a lover k value}, Che lower end of che range would apply. If this dependence is as strong (i.e., a higher k value), che upper bound may be more appropriate. Childhood exposure. The models used for extrapolation for boch lung cancer and mesochelioma are based on che assumption that a unit dose of exposure (measured as fibers/cm^ > 5 pa long) in early life is equivalent in its intrinsic carcinogenic potential to a unit dose in later life. If children are more biologically sensitive than the worker group, cbe risk per unit dose would be increased. Results from studies of exposure to other materials indicate that children are often more sensi tive than adults to a given dose, even when expressed as dose/body weight. The risk estimates and ranges shown in Table 7-2 are chose the committee considers most reasonable. Because of the uncertain value of k and the sensitivity of equation (7) to its value, the range of estimates is much larger for mesothelioma thao for lung cancer. TVo conclusions can be drawn from the estimates in Table 7-2: For nonsmokers, the lifetime risk for mesochelioma from nonoccupational environmental exposure to asbestos is higher than for lung cancer. For smokers, however, the risks of lung cancer are substantially higher Chan for mesothelioma, because of the multiplicative interaction of smoking and asbestos exposures. Individual lifetime risk estimates for lung cancer from nonoccupacional environmental exposures to 0.0004 fibers/cm^ are much lover than che risks observed for smoking. The basis for the calculations in Table 7-2 is discussed in detail in che following two subsections. Calculation of the Lung Cancer Risk Estimates in Table 7-2. Calcu lating lifetime risk estimates from equation (6) involves che notion of relative risk up to time t, designated here as RR. From equation (6), che RR for lung cancer by age c can be shown as follows:  214 I(t,d) io<c> (8) cumulative lung cancer mortality by age c at dose d baseline cumulative lung cancer mortality by age t * c*(T0d), where (Tod) * total dose-years for the exposed group and c* is a constant that depends on the cohort. For a given study showing an increased relative risk for lung cancer, c* - (1 P/100), (9) where P is the percentage increase in lung cancer risk per unit dose [Z per (fibers/cm^jyrj. Schneidennan et al. (1981) presented the values of P for nine different worker cohorts. Ihe results are summarised in Table 7-3. Values for P in Table 7-3 range from 0.06 (Study 8) to 9.1 (Study 1). The higher value establishes the upper end of the range given in Table 7-2. The zero value for the lower end of the range indicates that the low-dose linear approximation in equation (5) may overstate risk. The median value for P in the studies shown in Table 7-3 is P * 1.1 (Study 7). This value, rounded upward to 2, was used in obtaining the estimates for lifetime lung cancer risk in Table 7-2. To calculate these estimates, it was necessary to know only the baseline absolute risks for Che appropriate subpopulations. The baseline cumulative incidence rates of lung cancer for the four subgroups in Table 7-2 have been estimated by Schneidennan ad. (1981) as follows: male smokers * 0.11; female smokers * 0.04; male nonsmokers 0.01; and female nonsmokers * 0.005. Thus, using 2Z as a value for P, the lifetime risk of lung cancer for a male smoker is (O.ll)U P/100) (0.11)(1 + 0.02) - 0.1122. (10) The increased lifetime risk attributable to asbestos exposure at 1 fiber/cm^ for 1 year is 0.0022, i.e., 0.1122 - 0.1100. At the ambient exposure of 0.0004 fibers/cm^ assumed in Table 7-2 and for a 73-year lifetime exposure, the increased lifetime risk of lung cancer is 6.42 x 10*5, i.e., 0.0022 x 0.0004 x 73. Sounding to two significant figures gives the estimate in Table 7-2 for male smokers. The ocher calculations in that table were derived in a similar fashion. When describing the use of the percentages given in Table 7-3, Schneiderman et al. (1981) comnented that the low percentage increases in risk in Studies 3, 6, 8, and 9 probably resulted from several factors. In Study 3, for example, the subjects were retirees older than 65. I 215 TABLE 7-3. Estimated Increase in Lung Cancer Risk per Unit of Exposure to Asbestos* Study Occupation of No. Worker Cohort Asbestos Type Percent Increase in Lung Cancer Risk per (fibers/cm3)yr Reference 1 Insulation Amosite manufacturing 9.1 2 Asbestos Crocidolite, product manu chrysotile, 1.3 males 8.4 females facturing and amosite 3 Asbestos Amosite and 0.3 manufacturing chrysotile; some crocidolite 4 Asbestos Chrysotile; 1.1 product manu some amosite facturing and crocidolite 5 Textile Chrysotile production 5.3 6 Textile Chrysotile product ion 0.07 early employees*3 0.8 later employees*3 7 Insulation manufac turing Chrysotile and amosite 1.7 3 Mining Chrysotile and milling 0.06 9 Mining Chrysotile 0.15 and milling Seidman et al., 1979 Nevhouse and Berry, 1979 Henderson and Enterline, 1979 Nicholson et al., 1979 Dement et al. , 1982 Peto, 1980 Selikoff et al., 1979 McDonald and Liddell, 1979 Nicholson etal.,1979 aAdapted from Table 4 in Schneiderman e al_., 1981. ^Early employees began work before or during 1950. Later employees began work after 1950. 216 Schneideraan e al. stated that the investigators say thus have missed asbestos-related~7eaths occurring at earlier ages. In Study 6, the disease rates for workers employed earlier were lover than those employed later who were followed for shorter periods. The discrepancy has diminished as more data have accumulated. The subjects in Studies 8 and 9 were mining and milling workers whose exposure patterns were quite different from environmental ambient air exposures. There is also some evidence that many lung cancer cases were missed in Studies 8 and 9 because of competing causes of death at earlier ages. Thus, Schneideraan e l. (1981) concluded that the range from 1.1 (Study 4) to 9.1 (Study 1) is the most representative of true values. The value of P * 2 used in the calculations in Table 7-2 falls near the bottom of this range, but is within a factor of 5 of the top of the range. If we use P 5, which is the middle of the range, the lung cancer risk estimates in Table 7-2 would be multiplied by a factor of 2.5. Calculation of Mesothelioma Risk Estimates. To calculate the lifetime risk with equation (7), the numbers c and k must be deter mined. Then the lifetime risk L at d 0.0004 fibers/cm^, assuming t = 73 and tg * 0 (continuous exposure from birth to age 73), is L = c(0.0004)(73)*t. (11) To apply this equation, c and k must be estimated from epidemiological studies of occupational exposures to asbestos. Each study must be stratified by duration of exposure (t-tg) to estimate these parameters. Host of the following analysis is similar to that of Peto e al. (1982). First, let us consider Che choice of k. As noted earlier, when Peto et l. (1982) fitted equation (7) to the data of Selikoff e al. (1979), they obtained the equation l(t,d) b(t - tg)3.2> with b * 4.37 and k * 3.2 _ 0.36 (standard error). In equation (11), therefore, we initially use k * 3.2. Modifications using different values for k will give the range of estimates for d * 0.0004 fibers/cm3 in Table 7-2. For d 3 0.002 fibers/cm^, we replace 0.0004 with 0.002 in equation (11). With k * 3.2, Peto et. al. (1982) also fitted to' r other data sets to obtain four values of b in Che equation l(t,d) * b'c - Cg)3.2. The value of b is specific to each worker cohort and depends on three numbers: d (the average fiber/cm^ exposure), l (the average length of exposure), and t - tg (the average time since first exposure). These values are given in Table 7-4. In addition, Table 7-4 contains the estimates of c that are appropriate for equation (7), based on the corresponding estimate of b given by Peto e al. (1982). When exposure is not continuous from time of first exposure (tg) to the age of observation (t) for these studies, the relationship between b and c changes from c * b/d to 4.56 b/d 1 - [1 - l/(c-t0)]3.2 * (12) 217 TABLE 7-4. Estimated Constants for Equations (11) and (12) for Five Studies Study b x 108 d* fa ft 1 5 c x 10' Selikoff et al., 1979 Newhouse and Berry, 1976 Peto, 1980a,b Hobbs et al., 1980 Seldman et al., 1979 4.37 4.95 2.94 5.15 4.91 15 15 24 12.5 6 31.5 16.5 14 22.5 HAb NA NA 35 1 35 1.39 3.67 0.85 NA 7.22 ^Estimated from data given in Tables 4 and 10 of Schneiderman et al. (1981), using estimated median values. The product df from columns 3 and 4 above Is the estimated cumulative exposure in (fiber/cm3)yr of their Table 10. bNA not available. The factor 4.56 adjusts from occupational exposures at about 1,920 hours per year to environmental exposures at 8,760 hours per year. Appendix G provides the mathematical basis for equation (12). Table 7-4 gives the values of the constants for each study in which Peto et al. (1982) estimated b. To obtain the estimates for mesothelioma at the dose of 0.0004 fibers/^ in Table 7-2, equation (11) is used with values for c from Table 7-4 and k 3.2. In Table 7-2 the lifetime risk for mesothelioma at d * 0.0004 fibers/cm8 is 9 per million. This is calculated from equation (11) with c " 2.53 x 10"8, the median of the range of the c values In Table 7-4, and k 3.2. The highest value of the range In Table 7-2 at d * 0.0004 uses equation (11) with c 7.22 x 10" , the upper value of c in Table 7-4, and k * 3.8, obtained from 3.2 + 1.65 x 0.36. The selection of 3.8 as the value for k Is based on an approximate upper 95Z confidence limit for the estimate of k. The lower limit Is taken as 0, which is alvays a possible lower limit, especially If the low-dose linear assumption In equation (5) overestimates the individual lifetime risk. 218 Peco (1982) recommended using s k value of 3.5 for risk assessment purposes. As an example, he estimated that the risk of mesothelioma for children exposed for a 6-year period (ages 12 to 18) at 0.003 fibers/ca>3 would be one in 100,000. Nicholson reviewed additional data, including data on older workers up to age 80, and determined chat a k value would be 5. Schneiderman al. (1981) used k * 3.0. For Chis study, the committee used a value of 3.2. Although neither existing data nor biological theory can provide very much guidance on the value of k, its value is very important in projecting the lifetime risks of mesothelioma from asbestos exposures. Table 7-5 shows how lifetime risk varies from Che value of 9 per million for several values of k. Also shown are risk estimates for other values of c. The reader can easily calculate the results for other values of exposure. Ocher authors have also estimated the risks of mesotheliomas. Enterline (1983) derived a lifetime risk of 100 per million by using current reported rates of mesothelioma, an assumption about the relative contributions of nonoccupational and occupational asbestos exposures, and ocher factors. This estimate clearly relates to past exposure to varying levels of asbestos. Schneiderman e aK (1981) estimated lifetime risks for mesothelioma to be between 800 and 5,000 per million for a cumulative exposure of 1 (fiber/cm^Jyr. These estimates correspond to lifetime risks of 23 to 150 per million for 0.0004 fibers/cm3 for 73 years. As mentioned above, these investigators effectively assumed k * 3, but their equivalent c was higher than that used for the corresponding estimates in Tables 7-2 and 7-5. TABLE 7-5. Sensitivity of Eacimecea for Lifetime Risk** of Meaothelioma to Valuea of k and c \k cx 0.85 x 10-8 2.53 x 10'8 7.22 x 10-8 Lifetime Riak Eatimatea x 108, Using k Value* from Varioua Studiea Peto et Peto et Thia Study Schneiderman Thia Study al., 1982 Thia Study al., 1982 (low) et al.. 1981 (middle) 7middle) (hilh) (hilh) Nicholaon, 1983 2.6 0.2 3.0 1.3 3.2 3.5 3.8 4.0 5.0 3 11 41 97 7,000 0.7 4 9 34 120 290 21,000 2 11 26 96 350 820 60,000 All eatimatea are derived from equation (11), L " e(0.0004)(73)k, where L " lifetime riak at a eontinuoua expoaure Co 0.0004 fibera/cm^ for a lifetime of 73 yeara. Rote: Thia table deaonatraeea chat the riak eatimatea are extremely aenaitive to changea in the value of k. 219 The Use of 0.0004 Flbers/ca-3 and 0.002 Plbers/ca^ as the Median and High Nonoccupatlonal Environmental Exposure Levels. The lifetime risk estimates given In Table 7-2 are based on an assumed continuous environmental ambient exposure equivalent to either 0.0004 or 0.002 fibers longer than 5 urn per cm-3 of air breathed. The committee believes that 0.0004 flbers/cm-3 is a reasonable assumption for a median population exposure level and that 0.002 fibers/cm^ Is a reasonable high exposure level (considering only exposures from breathing ambient air continuously). These assumptions are discussed below. The effects of noncontlnuous high exposures are discussed later in this chapter. Table 7-6 summarizes some environmental asbestos sampling data provided by Nicholson (1983). To convert from mass measurements (ng/m^) of airborne exposures to fiber counts (fibers/cm^), the committee used the conversion factor of 30 ug/m-3 for 1 fiber/cm^. (See Chapter 4 of this report, Schneiderman et_ al., 1981, and Consumer Product Safety Commission, 1983 for further explanation.) The dose-response data used In the committee's risk estimate were taken from measurements of exposures In the workplace, where the fibers tend to be longer than those in ambient environments not close to major sources of asbestos. As discussed in Chapter 4, there would typically be approximately 2,000 fibers per nanogram In workplace air; in remote areas, however, there would be approximately 70,000 ambient fibers in a nanogram. To convert mass In the workplace to ambient air, the committee used the number of fibers longer than 5 ya that would be found In the workplace when the workplace mass equaled the remote ambient fiber mass. The dose estimate in numbers of fibers would be approximately 35 times greater (70,000/2,000) If the actual sizes of fibers in ambient air were considered. If we assume that all fibers are equally potent, then the risk estimates would be correspondingly higher. On the other hand, fiber size apparently affects fiber potency, but the appropriate adjustment factors for fiber size are not known. Table 7-6 Indicates that median concentrations In outdoor air have ranged from 0.00002 to 0.00075 fibers/ca^ in several studies (sample sets 1 to 8); their median is approximately 0.00007 fibers/cm^. The observed median Inside rooms without asbestos is 0.00054 (sample set 9). In rooms with asbestos surfaces, the median is 0.0006 flbers/cm^ (range of medians for sample sets 10 through 14, 0.00006 to 0.00405 fibera/cm-3). If these three medians are weighted by assuming persons . spend approximately one-fourth of their time outdoors, five-eighths of their time indoors in uncontaminated rooms, and one-eighth of their time In asbestos-contaminated rooms, a reasonable estimate for a median population exposure Is 0.0004 flbers/cm^. The committee also used 0.002 flbers/cm^ for a high value of continuous exposure In Its calculations for Table 7-2. This value was obtained by using the median of the 90th percentiles In Table 7-6 for each exposure subcategory. For outdoor air, the median is 0.0003 220 TABLE 7-6. Staaury of Environmental Aabeatoa Expoaure Saaplea* Sample Seta He. of Samplee Meaeured Concentra tion (ng/a3) 90th Per Median centile Equivalent Concentra tion (fibera/em3)* 90th ParMedian cencile la ferenee 1. Paria air 161 0.7 3.2 0.00002 0.00011 Snbuciea ec al. 1980 2. Paria (outdoor control) 19 0.7 5.2 0.00002 0.00017 Sebaatien ec al. 1980 3. Outdoor control aaaplta, for O.S. achoola 31 0.9 9.8 0.00003 0.00033 Conatant et al., 1982 4. Air of 48 0.5. citie* 187 1.6 6.8 0.00005 0.00023 Hicholaon, 1971 5. Air of U.S. cieiea 127 2.3 7.8 0.00008 0.00026 O.S. Environmenta Protection Agency, 1974 6. Air of five O.S. citiaa (outdoor control eample) 34 6.7 31.9 0.00022 0.00106 Hicholaon ec al., 1975, 1976 7. Rev York City air 22 13.7 42.9 0.0004 6 0.00143 Hicholaon et al., 1971 9. Air 0.3 nile (0.8 km) froa aabeatoa apraying 17 22.5 82.6 0.00075 0.00275 Hicholaon ec al., 1971 9. Air in O.S. achoolrooaa with out aabeatoa 31 16.3 72.7 0.00054 0.00242 Conatant et al., 1982 10. Air in Paria buildinga with aabeatoa aurfacea 135 1.8 32.2 0.00006 0.00107 Sebaatien ec al., 1980 11. Air in O.S. buildioja with ceaentitioua aabeatoa 28 7.9 19.1 0.00026 0.00064 Hicholaon et al., 1975, 1976 12. Air in O.S. buildinta with friable aabeatoa 54 19.2 96.2 0.00064 0.00321 Hicholaon et al., 1975, 1976 13. Air in O.S. 54 ' 62.5 achoolrooaa with aabeatoa aurfacea 550 0.00208 0.01833 Conetane et al., 1982 14. Air in O.S. achoola with damaged aabeatoa aurfacing meteriala 27 121.5 465 0.00405 0.01550 Hicholaon et al., 1978 Adapted from Hicholaon, 1983. bBaaed on eonveraion factor of 30 ug/*3 " 1 fiber/cm3 221 fibers/cm3; for indoor uncontaminated air, ic is 0.002 fibers/cm3; and for indoor asbestos-contaminated air, ic ia 0.003 fibers/cm3. The aaae diacribution of occupancy over tiae waa used to arrive aC the 0.002 fibers/cm3 figure for a high exposure level. Risk Assessments for Special Subpopulationa Table 7-2 shows lifeciae risk estimates for people who are exposed throughout cheir lives Co levels of eicher 0.0004 or 0.002 fibers/cm3 in ambienc air. The predominant risk ia from mesothelioma, buC lung cancers also contribute to the risk, especially for male smokers. For exposure patterns that are different from chose assumed, lifetime risks could be higher or lower. The following are three illustrations of how lifetime risks could be derived for such special populations. Children Exposed in Asbestos-Contaminated Schools. The committee estimated the risk for persons exposed from birth to age 73 years to environmental levels of 0.002 fibers/cm3 (as assumed in Table 7-2) plus an additional risk from a 10-year exposure (from ages 6 to 16) in an asbestos-contaainated schoolroom for 6 hours daily, 200 days per year, to 0.02 fibers/cm3 (550 ng/m3, the 90th percentile in Table 7-6). The equivalent continuous daily 10-year exposure is approximately 0.003 fibers/cm3, i.e., 0.02 x (200 x 6)/(365 x 24). Using equation (6), the lifetime risk of lung cancer for a male who eventually becomes a saoker is 0.003 x 10 x 0.0022, or 66 in a million. This risk represents an approximately 202 addition Co his ambient lifetime risk of 320 in a million (0.002 x 73 x 0.0022), for a total of about 390 in a million. For such an individual, the schoolroom exposure adds relatively more to the risk of mesothelioma, as shown below. Using equations (G4) and (G5) in Appendix C for the lifetime mesothelioma risk, L, at t * 73 for an exposure of * 10 years starting at age tg * 6 at the dose level d, this risk can be calculated from the formula: L - cd{1--[1 - /(t-tg)]k}(t-t0)k, with d - 0.003, 10, t - tg * 73 - 6 * 67, and k 3.2. This lifetime mesothelioma risk becomes L * c(0.003) {l-[l-(10/67)j3*2 }(67)3,2 - 845c. . If c is the median value of Table 7-4 (i.e., c 2.53 x 10"), the estimated lifetime mesothelioma risk, L, from the 10-year exposure is 21 X 10"*. Thi6 risk is then added to Che background risk of 46 x 10~ in Table 7-2, giving a lifetime mesothelioma risk for this subpopulation of 67 x 10"6. If a million people had received such a pattern of exposures, about 67 might be expected to die of mesothelioma. In this example, the contribution to total risk from Che schoolrooms is less than that of the lifetime exposure to the lower concentrations of asbestos estimated for Che ambient air. However, if the value for k in Equation (7) were higher than 3.2, the significance of the schoolroom exposures 222 would increase because of Che stronger dependence on time since first exposure. For example, if k 3.8, the highest value used in Table 7*2, the lifetime mesothelioma risk would be 910 x 10"^. If k were less than 3.2, the corresponding lifetime risk for mesothelioma would be less than 67 x 10~6. These calculations show that childhood exposures to asbestiform fibers might contribute noticeable lifetime mesothelioma risks to chose so exposed. A Female Nonsmoker in a Relatively Asbestos-Free Environment. An example of a person in a low-risk group is a female nonsmoker exposed to an average level of 0.0001 fibers/cm^. This exposure level would not be too unlikely for a person exposed primarily to rural indoor and outdoor air, since 0.00002 fibers/cm^ is the lowest median value for all the outdoor city readings in Table 7-6. Then, the calculations in Table 7-2 would lead to a mesothelioma lifetime risk of 2.25 x 10~^ (9 x 10-6 divided by 4) plus a lung cancer lifetime risk of 0.73 x 10-6. The lifetime individual risk for such a person would be 3 x lO'6 for both types of cancer. A Male Smoker Living in an Area Contaminated with High Levels of Asbestos Who is Also Exposed to High Indoor Concentrations. As an example of a high-risk person, consider an urban male smoker exposed to 0.003 fibers/cm^ for one-half the time and 0.018 fibers/cm^ for the ocher half. Ihis pattern is based on the assumption that the subject spends one-half of his time in indoor environments with a high asbestos concentration (see sample sets 13 and 14 of Table 7-6) and one-half either in highly contaminated outdoor environments (see sample sets 7 and 8 of Table 7-6) or in indoor environments at Che high end of Che distribution for rooms chat are normally not contaminated with asbestos (see sample set 9 of Table 7-6). Thus, his continuous average exposure would be approximately 0.01 fibers/cm^, i.e., 0.3(0.003) * 0.5(0.018). Therefore, multiplying che second column of Table 7-2 by a factor of 5 (0.01 * 5 x 0.002) would give Che individual lifetime risks for such a person as 1.8 x 10"^ for Che two forms of cancer taken together (230 x 10~^ for mesothelioma and 1,600 x 10~^ for lung cancer). This lifetime risk is the additional incurred risk attributable to the nonoccupational environmental exposure to asbestos and does not include che risk incurred by the smoking itself. The portion of the additional risk attributable to lung cancer is considerably higher than it would be for a nonsmoker experiencing identical asbestos exposures. COMPARATIVE RISK ASSESSMENT Methods The goal of comparative risk assessments is to determine whether the fiber exposure in question presents risks--in terms of total number and severity of effects per year in the United States--that are about the same, considerably more, or considerably less chan those assessed * 223 quantitatively above. The quantitative assessments made in the earlier part of this chapter were based on exposure to a generalized "asbestos" fiber. Because future exposures to asbestos in the United States will be dominated by chrysotile, risks of lung cancer and mesothelioma from chrysotile inhalation are assumed to be approximately the same as those attributed in the quantitative assessment to "asbestos." However, if at equal doses chrysotile is less hazardous than the other kinds of asbestos, the assumption of equal potency may lead to overstated risk estimates. These comparative risks are population risks, which combine information about the inherent risks that a given exposure to fibers could pose to an individual and information about the current and projected distribution of exposures over the U.S. population. Unlike the quantitative risk estimates for particular assumed exposure levels, the population risk estimates can easily change along with changing patterns of production and use. Even at a known population risk level, some individuals will receive higher than average exposures and stand at correspondingly greater individual risk, whereas the majority of the population will usually have lower risks. General Methodological Considerations The comparative risk assessments in this chapter are based on several factors, such as: fiber type - asbestos - other fibers with some similar properties type of effect^ - lung cancer - mesothelioma route of exposure - inhalation - ingestion source of exposure population at risk - smokers - other special groups (such as schoolchildren) ^The committee did not assess fibrosis or nonmalignant pleural disease because functional impairment resulting from such effects would occur much less often than would the cancers at nonoccupational levels of j exposures. i 1 i I 224 Taking Che firsc three of these factors as examples, risk assessment can be visualized as a three-dimensional matrix. As shown in Figure 7-1, the beat understood combinations (inhaled chrysotile and crocidolite asbestos for lung cancer and mesothelioma) are in the upper right "cells" of the matrix, and the less understood combinations are successively further from that position to emphasize their "distance" from the state of knowledge necessary for quantitative risk assessment. Additional cells could be added for other combinations. The following combinations of fiber type, effect, and route of exposure were considered for comparative risk assessments: chrysotile/gastrointestinal cancer/ingest ion chry8otile/mesothelioma/ingestion crocidolite/lung cancer/inhalation croc idolite/mesothelioma/inhalation other asbestos/all cancers/both routes fibrous glass/lung cancer/inhalation fibrous glass/mesothelioma/inhalation attapulgite/lung cancer/inhalation attapulgite/mesothelioma/inhalation mineral wool/lung cancer/inhalation mineral wool/mesothelioma/inhalation ceramic fiber/lung cancer/inhalation ceramic fiber/mesothelioma/inhalation carbon fiber/lung cancer/inhalation carbon fiber/mesothelioma/inhalation The committee's results are expressed in comparison with the chrysotile/lung cancer/inhalation cell, hereafter called the prime cell. Its designation as the prime cell does not imply that it is the cell corresponding to greatest population risk. According to the calculations in the preceding section, if environmental exposures to asbestos in early life are frequent, mesothelioma may prove to be the dominant effect. Both the comparative scores and the evaluation o "he uncertainty in them were made qualitatively rather than quantitatively, che entries are symbols (+, 0, -, a, b, c) rather than numeric. Appendix H describes how the conanittee went about assigning, combining, and assessing the symbolic codes. A score sheet for recording judgments about comparative risks is shown in Figure 7-2. Completed sheets for scored cells are included in Appendix H. These sheets are supplied to allow the reader to evaluate the individual judgments or the committee's subjective combination of them. 225 Other Fibers Fibrou* Other Glass Asbestos Crocidolite Chrysotile FIGURE 7-1. Three-dimensional matrix for conceptualizing the risk assessment problem. COMPARATIVE RISK ASSESSMENT SCORESHEET Cell Scored _______________ /___________ Fiber Effect /_________ Route Scores Comparative with Cell Exposure Score Score Production Use Pattern Geography Population Trends ______________ /_____________ Fiber Effect Biodisposition Effects /_________ Route Score Fiber Size Morphology Chemistry Penetration Stability Human Studies Animal Studies In-Vitro Studies Synergism Other Overall risk compared with cell above Overall risk compared with prime cell Quality of comparative risk assessment Remarks: FIGURE 7-2. Score sheet for recording judgments about comparative risks. 226 Scoring Considerations Production. If all other factors were equivalent, a greater production volume (or U.S. consumption level, if that Is significantly, different) would result In a greater level of exposure and a correspondingly greater population risk. If natural occurrence is Important, It can be used here as another surrogate for exposure. Use Pattern. Several concepts are embodied here. All have to do with the degree to which production, consumption, or natural occurrence will lead to actual human exposures. If the fibers are used only In products where they are tightly bound Into a matrix, relatively little exposure will occur at least until final disposal, whereas loose fiber use in consumer applications would lead to relatively heavy and Immediate exposures. Products such as talcum powder, which are Intended for direct human use, will lead to higher exposures per unit production than those that are not. Geography. This score applies to the spatial distribution of sources Including natural deposits, mills or production facilities, fiber product manufacturing sites, use sites, and disposal sites. Concentrated sources tend to Imply higher exposures of fewer people. This classification can also be used as a basis for evaluating such factors as the likelihood of fibers reaching drinking water. Population. The size of the population at risk determines the extent of the hazard for a given level of individual risk. A type of fiber that yields exposures to many people, such as a constituent of a common consumer product, has more potential for producing adverse health effects than one that affects only a few people, such as a naturally occurring but noncommercial fiber that Is present only in selected, sparsely populated regions. Trends. Exposure is a dynamic process that changes with changes in total production volume, production processes, use patterns, population distribution and habits, and many other factors that do not remain static. Thus, the risk that would apply to a steady state of exposure at current levels can be misleading both for currently observed effects or for future occurrence of effects. The sharp downtrend in asbestos exposures tends to ameliorate the population risks that might otherwise be assessed, whereas new fiber types may present enormously higher exposures in the future than they do at present. Fiber Size. Two counteracting influences are at work with fiber size. The clearest is their respirablllty, which declines markedly as fiber diameter Increases, becoming essentially zero above 3 or 4 pm. It Is likely that length also eventually affectB respirablllty and, especially, transport potential within the body. On the other hand, short fibers are probably more easily removed from the body by phagocytes; thinner ones may be more easily dissolved, coated, or gelled f 227 by body.fluids; and snail fibers In general nay not act biologically the sane as large fibers, which can disturb aany cells at once. Furthemore, snail fibers nay be sore likely to be exhaled with the tidal volume and, thus, not retained In the lung. The overall significance of fiber size nay therefore be represented as a potency that is greatest for fibers around 0.2 a> dlaneter and 20 an In length (Pott, 1978). Morphology. Whatever the response to fiber size, it seens likely that long, thin fibers that have strength, durability, flexibility, and a high aspect ratio are nore likely to cause adverse health effects than are fibers without these characteristics. The curliness of chrysotlle fiber bundles nay increase their effective aerodynamic dlaneter, thus decreasing their respirablllty below that expected on the basis of fiber dlaneter alone. Chemistry. Although little Is known about the influence of fiber chemistry on potential for health effects, It seems possible that the chemical properties of fibers play sone role, especially with respect to surface chemistry. Another feature of surface chemistry, l.e., the ability to adsorb carcinogenic substances, Is included under "synergism." Penetration. The ability of a fiber to penetrate to the site where effects are developed, for example, to the pleura or peritoneum in the development of mesothelioma, is clearly important to its potential for causing disease. This category includes all fiber properties that facilitate such penetration. It is closely related to fiber size, morphology, and stability. Stability. Some experimental evidence suggests that the longer a fiber remains in a tissue, the greater is its opportunity for inducing its biological effects, for example, stimulating cell hyperplasia when a transformed cell Is present. In this case, the Important factor Is not the resistance to translocation but the resistance to chemical or physical degradation such as dissolution or gelling. Human Studies. This category Includes both clinical and epidemiological observations In human populations. Animal Studies. The demonstration of significant biological effects in a well-designed animal experiment is considered evidence that the test substance has a potential for causing similar effects in humans. In Vitro Studies. Although the meaningfulness of ahort-term, in vitro experiments with respect to the effects of fibers is questionable, it is known that asbestos and some other fibers demonstrate some cellular-level effects such as hemolysis. The ability to cause such effects Is considered a weak, but not entirely worthless, argument for health effects potential. 228 Synergism. Information on aynergiatlc effects would markedly affect aaseasaent of comparative risk. The only such information available involves asbestos and cigarette smoking. Other. This catchall category could be applied to any influence on overall risk, Including exposure, biodisposition, and effects. For example, if a particular fiber is found to be more likely than the others to reach young children and if the effect in question is most prevalent in children or if it increases in incidence with time after first exposure as with mesothelioma, then the comparative risk estimate would be increased. Discussion of Comparative Risks Table 7-7 summarizes from a different perspective the information in Appendix H. No cell of the fiber/effect/route matrix approaches the population risk levels associated with the prime cell (chrysotlle/lung cancer/inhalation). As noted in the quantitative assessment, the mesothelioma risk from lifetime exposure to asbestos is potentially much greater than the lung cancer risk. Although some researchers question whether chrysotlle is as potent as other asbestos varieties in causing mesothelioma, the committee has assumed that even exposure only to chrysotlle continously since birth would cause more mesothelioma than lung cancer. Chrysotlle has been extensively used in the past and thus also provides a source of in-place exposure. Of the other combinations, the committee believes the ones most worth watching in the near term are fibrous glass and attapulglte for lung cancer by Inhalation. The risks for effects of croddollte and other asbestos varieties are reasonably well understood, and measures taken to reduce occupational exposures in the future may also keep the nonoccupatlonal exposures to a mlalnum. However, general population exposures to crocidollte already in place could be substantial, especially in connection with its disposal. The other cells seem to entail significantly less population risk (more than 10 times less) than the prime cell. In several cases, this judgment is based principally on current exposure or biodisposition rather than on definitive evidence that the fibers have low intrinsic health effects potential. For example, both ceramic and carbon fibers can be found in respirable size ranges and may well have biological properties similar to those of asbestos. However, they are produced in low volumes and are used in limited, generally contained applications. Population risks could become substantial if these facts changed. Most fibrous glass and mineral wool is produced in nonresplrable sizes, and some evidence from epidemiological and animal studies suggests that their biological toxicity is low. Thus, risk levels for these substances are rated low despite the substantial potential for exposure. 229 mi r 7-7. Sumary of Cooperative liak Asaeaaaent Factor______ Coopered with Chryaotile/tung Caneer/Inhalation, Data oa the Factor Suaaaat that Population liak Should ha Higher Sioilar Lowar Much Lower Production Fibroua glaa. Attapulgite KincraX wool Crocidolite Other aabeatoa Carbon fiber Ceraaic fiber Oaa pattern Fibroua glaaa Attapulgite Other aabeatoa Crocidolite Carbon fiber Mineral wool Chryaocile/ingeation Ceraaic fiber Geography Fibroua glaaa Other aabeatoa Mineral wool Carbon fiber Crocidolite Attapulgite Ceraaic fiber Chryaocile/ingeation Population Fibroua glaaa Attapulgite Crocidolite Other aabeatoa Mineral wool Carbon fiber Ceraaic fiber Trenda Fibroua glaaa Attapulgite Mineral wool Carbon fiber Cereaic fiber Other aabeatoa Crocidolite Fiber aire Crocidolite Other aabeatoa Carbon fiber Ceramic fiber Mineral wool Fibroua glaaa Attapulgite Morphology Crocidoliee All othcra Cheaiatry Mo clear effect of cheaiatry evident Penetration Crocidolite Other aebeatoe Attapulgite Carbon fiber Ceraaic fiber Mineral wool Chryaocile/ingeation Fibroua glaaa Stability Crocidoiiee Ocher aabeatoa All ochera Fibroua glaaa (continued on neat page) 230 IA1UE 7-7 (coot.) Coopered vieh Chryotlle/Lung Cancer/Inhalation, nets oo the Factor Suxaeat that Population Ltak Should bo_______________________________ Factor HI cher Similar Lover Much Lover Epidemiological studies Croeldollte/ aesoth*.'.loaa Croeldollte/ lung cancer Mineral wool Fibrous gUce Ceramic liber Mineral vool ialael itudies Croeldollte Other aebeetos all others la vitro studies* -- ---- -- Synerglsa All other* Fibrous glass Other5 Overall population risk -- ---- -- Qirytocile/ mesothelioma/ lngeetlon Croeldollte Attapulglt*/ lung cancer Fibrous glass Carbon fiber Ceramic fiber accepulglce/ aesochellome Other asbestos/ other cancer `Quantitative difference* i:i activity not apparent. ^Ko other factor vaa efficiently striking for Inclusion. 1 For any combination of fiber type, effect, and route of exposure not assessed, even for cooperative risk, the committee believes either chat risks are at most of marginal significance or that there is insufficient information on which tc base such a comparison. Most of the combinations fall into the former category. Carcinogenic effects other than lung cancer or mesothelioma constitute examples of the insufficient information category fer several fibers. SUMMARY ANDRECQMMENDAIIONS The committee has nade quantitative risk assessments for nonoccupational exposures to asbestos and qualitative (or comparative) risk assessments for a variety of asbestlform fibers. Lung cancer and mesothelioma from Inhaled materials received the greatest consideration. 231 For Che quantitative risk assessment, a linear model for low dose extrapolation was used. When quantifying risk from nonoccupational exposures, uncertainties are introduced not only by the selection of mathematical models but also because Che characteristics of fibrous materials in the ambient environment differ from those in the workplace. By converting mass concentrations measured in Che environment to equivalent numbers of fibers in the workplace, the committee assumed a median population exposure of 0.0004 fibers/cm^ air throughout a 73-year lifetime. Based on this and various other assumptions, the individual lifetime risk for lung cancer was estimated to be between 3 in a million for female nonsmokers and 64 in a million for male smokers, and for mesothelioma it was approximately nine in a million, regardless of smoking habits or sex. However, other assumptions could decrease the risks essentially to zero, or could increase them. The finding that the risk for mesothelioma is greater than chat for lung cancer among nonsmokers is due to the strong dependence of mesothelioma risk on time since first exposure. Thus, a given exposure in childhood markedly increases the lifetime risk of mesothelioma compared with an equivalent dose later. It should be remembered that these risk estimates were based on data obtained from worker cohorts. Smokers runs a substantially higher risk of malignant disease from asbestos than do nonsmokers; for smokers, lung cancer is a greater risk than mesothelioma. Studies should be conducted to learn more precisely the dependence of mesothelioma and lung cancer mortality on time since first exposure and on the characteristics of the exposure. Such efforts should include studies in animal models and follow-up studies of occupationally exposed cohorts. For the comparative risk assessment, population risks (as opposed to individual risks) were considered. The risks were based on three major factors: exposure levels, biodisposition, and evidence of adverse health effects. The potential for exposure was a dominant factor. Ihus, risk estimates for substances of equal biological potency may be widely divergent if the populations exposed to them differ greatly. Two points follow from this. First, some individuals may be exposed to high levels of a fiber for which the overall population exposure is low. Second, the overall population risk would change if use patterns change. Current population risk from exposures to the various substances considered, including fibrous glass, attapulgite, and carbon fibers, appears to be much less than for the risk from asbestos, especially chrysotile. However, further information is needed to evaluate the possible adverse effects of exposures to fine fibrous glass and attapulgite. 232 REFERENCES Armitage, P. 1982. The assessment of low-dose carcinogenicity. Biometrics 38(supplement):119-129. Armitage, P., and R. Doll. 1961. Stochastic models for carcinogenesis. Pp. 19-38 in Proceedings of the Fourth Berkeley Symposium on Statistics and Probability. Vol. 4. University of California Press, Berkeley. Babich, H., and D. L. Davis. 1981. Food tolerances and action levels: Do they adequately protect children? BioScience 31:429-438. Calabrese, E. J. 1978. Pollutants and High-Risk Groups. WileyInterscience , New York. Calabrese, E. J. 1980. Nutrition and Environmental Health. Vol. 1: The Vitamins. Wiley-Interscience, New York. Constant, Jr., P. C., F. J. Bergman, and G. R. Atkinson. 1982. Airborne asbestos levels in schools. Final Report, Environmental Protection Agency. Midwest Research Institute. Contract 68-01-3913. Consumer Product Safety Commission. 1983. Report by the Chronic Hazard Advisory Panel on Asbestos. Consumer Product Safety Commission, Washington, D.C. Cornfield, J., F. Carlborg, and J. Van Ryzin. 1978. Setting tolerances on the basis of mathematical treatment of dose-response data extrapolated to low doses. Pp. 143-164 in G. L. Plaa and W. A. M. Duncan, eds. Proceedings of the First International Congress on Toxicology. Academic Press, New York. Crump, K. S., D. G. Boel, C. H. Langley, and R. Peto. 1976. Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Res. 36:2973-2979. Dement, J. J., R. L. Harris, M. J. Symons, and C. Shy. 1982. Estimate of dose-response for respiratory cancer among chrysotile asbestos textile workers. Ann. Occup. Hyg. 26:869-887. Doull, J., C. D. Klaassen, and M. 0. Amdur, eds. 1980. Casarett and Doull's Toxicology: Ihe Basic Science of Poisons. Macmillan, New York. 778 pp. Enterline, P. E. 1983. Cancer produced by nonoccupational asbestos exposure in the Dbited States. J. Air Pollut. Control Assoc. 33:318-322. Fishbein, L. 1980. Overview of some aspects of quant tative risk assessment. J. Toxicol. Environ. Health 6:1273-1296. Food Safety Council. 1980. Proposed System for Food Safety Assessment. Food Safety Council, Washington, D.C. Goldenthal, E. I. 1971. A compilation of LD50 values in newborn and adult animals. Ibxicol. Appl. Pharmacol. 18:185-207. Hammond, E. C., I. J. Selikoff, and H. Seidaan. 1979. Asbestos exposure, cigarette smoking and death rates. Aon. N. Y. Acad. Sci. 330:473-490. Hartley, H. 0., and R. Sielken. 1977. Estimation of "safe doses" in carcinogenesis experiments. Biometrics 33:1-30. Hartley, H. 0., H. Tolley, and R. Sielken. 1981. The product form of the hazard rate model in carcinogenic testing. Pp. 185-200 in M. Csorgo, D. A. Dawson, J. N. K. Rao, and E. Saleh, eds. Statistics and Related Topics. North-Holland, Amsterdam. Henderson, V., and P. E. Enterline. 1979. Asbestos exposure: Factors associated with excess cancer and respiratory mortalilty. Ann. N.Y. Acad. Sci. 330:117-126. 233 Hobbs, M. S. T. , S. D. Woodward, B. Murphy, A. W. Musk, and J. E. Elder. 1930. The incidence of pneumoconiosis, mesothelioma and other respiratory cancer in men engaged in mining and milling crocidolite in Western Australia. Pp. 615-625 in J. C. Wagner, ed. Biological Effects of Mineral Fibres. IARC Scientific Publication No. 30. International Agency for Research on Cancer, Lyon. Hoel, D. C. 1980. Incorporation of background response in dose-response models. Fed. Proc. 39:73-75. Hoel, D. G., N. L. Kaplan, and M. W. Anderson. 1983. Implication of non-linear kinetics on risk estimation in carcinogenesis. Science 219:1037. Interagency Regulatory Liaison Group. 1979. Work Group on Risk Assessment. Scientific bases for identification of potential carcinogens and estimation of risks. J. Natl. Cancer Inst. 63:242. Kalbfleisch, J. D., and R. L. Prentice. 1980. The Statistical Analysis of Failure Time Data. John Wiley and Sons, New York. Kalbfleisch, J. D., D. Krewski, and J. Van Ryzin. 1983. Dose response models for time to response toxicity data. Can. J. Statist. 11:25-46. Klaassen, C. D. , and J. Doull. 1980. Evaluation of safety: Toxicologic evaluation. Chapter 2 in J. Doull, C. D. Klaassen, and M. 0. Amdur, eds. Casarett and Doull's Toxicology: The Basic Science of Poisons. Macmillan, New York. Krewski, D., and J. Van Ryzin. 1981. Dose response models for quantal response toxicity data. Pp. 201-231 in M. Csorgo, D. A. Dawson, J. N. K. Rao, and E. Saleh, eds. Statistics and Related Topics. North-Holland, Amsterdam. McDonald, J. C. , and F. D. K. Liddell. 1979. Mortality in Canadian miners and millers exposed to chrysotile. Ann. N. Y. Acad. Sci. 330:1-9. National Research Council. 1977. Principles and Procedures for Evaluating the Toxicity of Household Substances. A report of the Committee for the Revision of NAS Publication 1138, Assembly of Life Sciences. National Academy of Sciences, Washington, D.C. 130 pp. National Research Council. 1983. Risk Assessment in the Federal Gove-nment: Managing the Process. A report of the Committee on Che Institutional Means for Assessment of Risks to Public Health, Commission on Life Sciences. National Academy Press, Washington, D.C. 191 pp. . Nevhouse, M. L., and G. Berry. 1976. Predictions of mortality from mesothelial tumours in asbestos factory workers. Br. J. Indus. Med. 33:147-151. Newhouse, M. C., and G. Berry. 1979. Patterns of disease among long-term asbestos workers in che United Kingdom. Ann. N. Y. Acad. Sci. 330:53-60. Nicholson, W. J. 1971. Measurement of asbestos in ambient air. National Air Pollution Control Administration. Final Report, Contract CPA 70-92. 234 Nicholson, W. J. 1978. Control of sprayed asbestos surfaces in school buildings: A feasibility study. Final Report. Contract I-ES-2113. National Institute of Environmental Health Sciences, Research Triangle Park, N.C. Nicholson, W. J. 1983. Health Effects Update. June 1983. Unpublished draft prepared by W. J. Nicholson, Mt. Sinai School of Medicine, City University of New York. 148 pp. Nicholson, W. J., A. N. Rohl, and E. F. Ferrand. 1971. Asbestos air pollution in New York City. Pp. 136-139 in H. M. England and W. T. Barry, eds. Proceedings of the Second Clean Air Congress. Academic Press, New York. Nicholson, W. J., A. N. Rohl, and I. Weisman. 1975. Asbestos contamina tion of the air in public buildings. EPA-450/3-76-004. Environmental Protection Agency, Research Triangle Park, N.C. Nicholson, V. J., A. N. Rohl, and I. Weisman. 1976. Asbestos contamina tion of building air supply systems. Paper 29-6 in Proceedings of the International Conference on Environmental Sensing and Assessment. Institute of Electrical and Electronic Engineers, Vol. II. Institute of Electrical and Electronic Engineers, New York. Nicholson, W. J., I. J. Selikoff, H. Seidman, R. Lilis, and P. Formby. 1979. Long-term mortality experience of chrysotile miners and millers in Thetford mines, Quebec. Ann. N. Y. Acad. Sci. 330:11-21. Nicholson, W. J., A. N. Rohl, I. Weisman, and I. J. Selikoff. 1980. Environmental asbestos concentrations in the United States. Pp. 823-827 in J. E. Vagner, ed. Biological Effects of Mineral Fibres. Vol. 2. IARC Scientific Publication No. 30. International Agency for Research on Cancer, Lyon. Office of Technology Assessment. 1981. Assessment of Technologies for Determining Cancer Risks from the Environment. Office of Technology Assessment, Washington, D.C. 240 pp. Pelkonen, 0., E. H. Kaltiala, T. K. Karrai, and N. T. Karki. 1973. Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clin. Pharmacol. Ther. 14:840-846. Peto, R. 1978. Carcinogenic effects of chronic exposure to very low levels of toxic substances. Environ. Health Perspect. 22:155-159. Peto, J. 1980a. Lung cancer mortality in relation to measured dust levels in an asbestos textile factory. Pp. 829-836 in J. C. Wagner, ed. Biological Effects of Mineral Fibres. Vol. 2. I4RC Scientific Publication No. 30. International Agency for Research on Cancer, Lyon. Peto, J. 1980b. The incidence of pleural mesothelioma in chrysotile asbestos textile workers. Pp. 703-711 in J. C. Wagner, ed. Biological Effects of Mineral Fibres. Vol. 2. IARC Scientific Publication No. 30. International Agency for Research on Cancer, Lyon. Peto, J. 1982. Dose and time relationships for lung cancer and meso thelioma in relation to smoking and asbestos exposure. Presented at the Symposium on Asbestos Carcinogenesis. Feb. 17-19, 1982, in West Berlin. Organized by Bundesgesundheitsamt. 235 Peto, J., H. Seidman, and I. J. Sellkoff. 1982. Mesothelioma mortality la asbestos workers: Implications for models of carcinogenesis and risk assessment. Br. J. Cancer 45:124-135. Pott, F. 1978. Some aspects on the dosimetry of the carcinogenic potency of asbestos and other fibrous dusts. Staub Reinhalt. Luft 38:486-490. Rane, A., and E. Ackerman. 1972. Metabolism of ethylmorphlne and aniline in human fetal liver, din. Pharmacol. Ther. 13:663-670. Richmond, C. R., P. J. Walsh, and E. D. Copenhaver, eds. 1981. Proceedings of the Third Life Sciences Symposium, Health Risk Analysis, Gatllnburg, Tenn., Oct. 27-30, 1980. Franklin Institute Press, Philadelphia. 438 pp. Schneiderman, M. A., I. C. Nisbet, and S. M. Brett. 1981. Assessment of risks posed by exposure to low levels of asbestos in the general environment. Prepared for Instltut fur Vasser, Boden, und Lufthygiene des Bundesgesundheitsamtes. No. 4. Dietrich Relmer Verlag, Berlin. Sebastien, P., M. A. Billion-Galland, G. Dufour, and J. Blgnon. 1980. Measurement of asbestos air pollution inside buildings sprayed with asbestos. EPA 560/13-60-026. Environmental Protection Agency, Washington, D.C. Seidman, H., I. J. Sellkoff, and E. C. Hammond. 1979. Short-term asbestos work exposure and long-term observation. Ann. N.Y. Acad. Sci. 330:61-89. Sellkoff, I. J., E. C. Hammond, and H. Seidman. 1979. Mortality experience of Insulation workers in the U.S. and Canada, 1943-1976. Ann. N.Y. Acad. Sci. 330:91-116. Tager, I. B., S. T..Weiss, A. Munoz, B. Rosner, and F. . Spelzer. 1983. Longitudinal study of the effects of maternal smoking on pulmonary function in children. N. Engl. J. Med. 309:699-703. U.S. Environmental Protection Agency. 1974. A preliminary report on asbestos in the Duluth, Minnesota area. Office of Technical Analysis. Environmental Protection Agency, Washington, D.C. Van Ryzin, J. 1980. Quantitative risk assessment. J. Occup. Med. 22:321-326. Van Ryzin, J. 1981. Discussion: The assessment of low-dose carcinogenicity. Biometrics 38 (suppl. 2):130-139. Appendix A ASBESTOS EXPOSURE AND HUMAN DISEASE. HALLMARK OBSERVATIONS AND STUDIES FROM 1898 TO 1979 Disease or Benchmark Bronchids Phthisis Pulmonary fibrosis Asbestosls Asbestosls Asbestosls Asbestosls Contribution to the Field References "Asbestos fiber inhalation in the workplace injurious to the bronchial cubes and lungs." Clinical latency mitigates against establishing a stronger association between work with asbestos fiber and disease, because sick workers leave Industry. No mortality data. Anderson, 1898 (see Greenberg, 1982) Death due to pulmonary fibrosis (in an asbestos textile worker without tuberculosis). Autopsy showed fibrosed lungs and presence of "spicules of asbestos" in pulmonary tissues. When the worker was alive, this sputum contained what was thought to be "asbestos spicules." Fibrosis was believed to be induced by dust. Different work areas had a range of dust conditions. Murray, 1907 (see Greenberg, 1982) Complete histological and gross pathological description of asbestos. Author originated term asbestosls and cited experimental pathology studies indicating that asbestos dust causes fibrosis in the lungs of guinea pigs. Cooke, 1924 First major reviews of asbestosls. Detailed clinical, radiological, and pathological descriptions. Cooke noted the presence of "curious bodies" in pulmonary tissues of asbestotlcs. Asbestosls attack rate high for textile workers spinning Canadian chrysotlle. Cooke, 1927; McDonald, 1927; Oliver, 1927 "Curious bodies" probably some form of coated fiber. Author recommended the term "asbestosls body." Cooke, 1929 Review of asbestosls in Great Britain and ocher parts of the world. Relationship becveen asbestosls and tuberculosis discussed. Latency also discussed. Author suggested different forma of fiber may have different biological activities. Merewecher, 1930 237 238 Appendix A (coot.) Disease or Bench--rk Contribution to the Field References Asbestosis Authors suggested, on the basis of 57 cases they had seen, that tuberculosis increases severity of scarring in asbestotlcs. Wood and Gloyne, 1931 Asbestosis "Constitutional factors' My be important in determining who aaong the work force is "susceptible to asbescosis." Gerbis, 1932 Aabescosis German government issues dlctua forbidding all chose under the age of 18 from eaployoenc in the asbestos industry. Ger--ns followed British Hose Office. Gerbis, 1932 Asbescosis Pleural asbestosis Author discussed the different physical and cheaical properties of the various asbestos types used in coaaerce (e.g., size, shape, "others") and their possible role in determining the occurrence of disease and the types and patterns of lesions observed. Different kinds and intensities of exposures in industry also described. Geographic differences in occur rence of disease --y be related to fiber types and/or genetic factors. Role of alneral contaminants unknown. Gloyne, 1932 Asbestosis Mortality data suggested asbestos workers have shortened life expectancies. Greater attack rate in sills --y be related to the "ability of the fiber to split longitudinally into fibrils creating respirable dust." Merewecher, 1933, 1934 Asbestosis Lung cancer Pri--ry lung cancer found at autopsy la two fe--le textile workers with asbestosis. Gloyne, 1935 Asbestosillcoais Lung cancer Pri--ry lung cancer in sen eaployed in textile plants in South Carolina. Lungs fibrosed. Lynch and Smith, 1935 Lung cancer and latency Asbestosis Author found that the length of elapsed time from the start of asbestos work until the ti-- of death was 15 to 21 years in all six of the cases known to hia. In five of the six cases, the tumors developed in the lower lobes of the lung, whereas in the general population lung cancer was most common in the upper lobes. It was well recognized that the more extensive fibrosis in asbestosis was also found in the lower lobes of the lung. Nordaann, 1938 Asbestosis and Aaong 943 cases of fatal silicosis in Great lung cancer Britain in 1938, 23 lung cancers occurred attack rate (2.4ZJ. Aaong 103 cases of fatal asbestosis for all prior years, 12 lung cancers were found (11.6Z). Attack rates appeared to be different, although true incidence was unknown. Wilson, 1939 239 APPENDIX A (cone.) Disease or Benchmark_____ Contribution to the Field References Asbestoals Lung cancer .Mesothe lioma (?)* Other cancers (7) Comparison of autopsy series in general popula tion with 92 asbestocles. Fourteen malignancies in asbestotlcs (16Z), compared with approximately 2X in the "unexposed" general population. Metastasea to pleura, peritoneum, and pericardium. Histology much like 'sarcomas.'* Vedler, 1943 Asbestoals Lung cancer Prevalence of lung cancer among asbestotlcs Increases with age: 25-34, 4.8Z; 35-44, 5.6Z; 45-54, 18.9Z; 55-64, 25.6Z; 65 and older, 23.5Z. Latency, dose, and aging not separated as factors in this pattern. Barnett, 1948 Pneumoconiosis Compared mortality experience in different Lung cancer 'dusty trades' in Great Britain. Age at death Other cancers for seven silica-exposed groups ranged from 44 and ocher to 63 years (lowest in pottery industry), sites Asbestos trades averaged 36 years (39 for males, 34 for females. Approximately 14Z of asbestotlcs died with lung cancer. Author noted "strikingly' different attack rates in males and females: 19.6Z for males, 9.7Z for females. Neoplasms at other sites twice as high in asbestotlcs as compared to ocher pneumoconiosis groups (about 6Z, compared to 3Z). Gloyne, 1951 Lung cancer, occupation, and ciga rette smoking This study provided evidence linking certain occupations (including chose involving asbestos exposure) with lung cancer. The study also offered additional evidence associating cigarette smoking with lung cancer. Breslow et al., 1954 Asbestoals Lung cancer Mesothelioma Cohort study of textile workers at a plant in Great Britain. Incidence data indicated a standardised mortality ratio (SM&) of almost 14; 11 observed, 0.8 expected for lung cancer in workers employed before "protective standards" of the Asbestos Regulations Act of 1931. Author cautioned that smaller risk in workers employed after 1931 may be an artifact; they may have not yet reached "risk" period because of their short elapsed time after onset of exposure. Aa endothelioma waa observed in a worker. Doll, 1955 indicates the disease was not diagnosed by name. 240 APPENDIX A (cont.) Disease or Beach-- rk Contribution to the Field References Pleural --*oeheliosc Environ--a tal aeaotheiio-- Thirty-three caaea of pleural --sothello-- reported among ainera and alllera of crocidolite in the Northwest Cape Province, South Africa. Aaong the caaea were area residents wich no known occupational exposure. Histo logies1 evidence of asbestosls was not present in all caaea. Vagner et al., 1960 Pleural plaques Environ--ntal stig-- ta Pleural fibrosis and calcification--stig--ta nor--11y associated with fibrous dust insult-- were found in a population living in a region of Finland where anthophylllte aabeacoa was ained and allied. Aabient aabeacoa pollution was implicated. Kiviluoco, 1960 Aabescosis Abdominal tuaors found in asbestotlca during Abdominal autopsy. Ovarian cancers in woaen and general cunora carcino--tosis (no pri--ry) in aen. Mesothelio-- (?) Xeal, 1960 Asbestos bodies and exposure Asbestos bodies were found In pulmonary tissues in 26Z of 500 consecutive autopsies conducted in the general population of Capetown, South Africa. Use of asbestos by society was questioned in view of the known cancer hazard. Ihoason et al., 1963 Asbestosls Lung cancer Mesothelio-- (pleural and peritoneal) Gaatrointestlnal (Cl) cancer Morbidity and mortality data for insulation workers showed excess cancer and asbestosls accounting for aost deer--sed life expectancy. Malignancies Included lung cancer and pleural --sothelioaa. There was also peritoneal aesochelio-- and an excess of gastrointestinal cancer. Sellkoff et al., 1964 Peritoneal --scthelio-- Ocher cancer . (Cl) Peritoneal aesochelio-- seen in crocidoliteexposed workers. Other intraabdoainal turn rs --y have been present as well. Enclknap and Salther, 1964 Mesothelio-- Records in an east-end London hospital showed chat a large proportion of the --sothelio--s chat occurred were in nonoccupatlonally exposed persons: residents living within a half alle of an asbestos plant and families of workers. Newhouse and Thoapson, 1965 Mesothelio-- Byetender occupational expoaure Mesochelio-- observed in shipyard workers whose Jobs were not asbestos-related. Most --so thelio--s occurred in bystander populations. Iaportance of fugitive dust raised. Harries, 1968 241 APPENDIX A (cont.) Disease or Benchmark_______ Contribution to the Field Luag cancer and cigarette smoking Evidence suggested chat cigarette-smoking asbestos workers had a greatly Increased risk of developing lung cancer as coapared to nonsaoklng vorkaates. The risk appeared to be multiplicative--the product of both smoking and asbestos risks. Pleural asbestosls Pulmonary asbestosls Household exposures Radiographic and clinical survey of 678 individuals cohabiting with asbestos workers. Thirty-five percent (239) of them had pleural or pulmonary asbestosls. Questions raised concerning dust on clothing as the vector of the fiber. (In a follow up study published in 1979, the authors stated chat they were ascertaining causes of death among a larger population of house hold members. Of 550 decedents traced, five deaths were due to pleural mesothelioma.) xtrapulmonary cancers Multiple cancer in single h08t8 SMRs showed slight excesses of cancer of the larynx, buccal cavity, brain, skin, kidney, pancreas, and prostate among 2,271 deaths (168,000 man-years of observation) in a cohort of 17,800 insulation workers in the United States and Canada. Authors reported that 2.IX of the deaths involved multiple primary cancers and that occult malignancies were present at time of death. Fiber dose, latency, risk Short-term (1-monch) Intense exposure to amoslte fiber increased lung cancer risk. Latency period inversely related to dose. References Selikoff et al.. 1968 Anderson et al., 1976, 1979 Selikoff et al., 1979 Seidman et al., 1979 242 REFERENCES Anderson, A. M. 1898. Observations published in H.M. Chief Inspector of Factories and Workshops, Report for the year 1898. Anderson, H. A., R. Lilia, S. M. Daum, A. S. Fischbein, and I. J. Sellkoff. 1976. Household contact asbestos neoplastic risk. Ann. N.Y. Acad. Sci. 271:311. Anderson, H. A., R. Lilia, S. M. Daua, and I. J. Sellkoff. 1979. Asbestosls among household contacts of asbestos factory workers. Ann. N.Y. Acad. Sci. 330:387-400. Barnett, G. P. 1948. Annual Report of the Chief Inspector of Factories for the year 1946. CMD 7299, Her Majesty's Stationary Office, London. 132 pp. Breslow, L., L. Hoaglln, G. Rasmussen, and H. Abrams. 1954. Occupations and cigarette smoking as factors in lung cancer. Am. J. Pub. Health 44:171-181. Cooke, W. E. 1924. Fibrosis of the lungs due to the inhalation of asbestos dust. Br. Med. J. 2:147. Cooke, W. E. 1927. Pulmonary asbestosls. Br. Med. J. 2:1024-1025. Cooke, W. E. 1929. Asbestos dust and the curious bodies found in pulmonary asbestosls. Br. Med. J. 2:578-580. Doll, R. 1955. Mortality from lung cancer In asbestos workers. Br. J. Ind. Med. 12:81-86. Entlknap, J. B., and W. J. Smlther. 1964. Peritoneal tumors In asbestosls. Br. J. Ind. Med. 21:20-31. Gerbls, U. 1932. Ueber asbestosls der Lungen. Deut. Med. Woch. 58:285-287. Gloyne, S. R. 1932. The morbid anatomy and histology of asbestosls. Tubercle 14:445-451. Gloyne, S. R. 1935. Two cases of squamous carcinoma of the lung occurring in asbestosls. Tubercle 17:5-10. Gloyne, S. R. 1951. Pneumoconiosis. A histological survey of necropsy material in 1,205 cases. Lancet 1:810-814. Greenberg, M. 1983. Classical syndromes in occupational medicine: The Montague Murray Case. Am. J. Ind. Med. 3:351-356. Harris, P. G. 1968. Asbestos hazards in naval dockyards. Ann. Occup. Hyg. 11:136. Kiviluoto, R. 1960. Pleural calcification as a roentgenologic sign of non-occupatlonal endemic anthophylllte asbestos. Acta Radlologica (Supp.) 194:1-67. Real, E. E. 1960. Asbestos and abdominal neoplasms. Lancet 11:1211-1216. Lynch, K. M., and W. A. Smith. 1935. Pulmonary asbestosls III. Carcinoma of the lung in asbesto-slllcosls. Am. J. Cancer 24:56-64. McDonald, S. 1927. Histology of pulmonary asbestosls: A review. Br. Med. J. 2:1025-1026. Merewether, E. R. A. 1930. The occurrence of pulmonary fibrosis and other pulmonary affections in asbestos workers. J. Ind. Hyg. 12:198-222, 239-257. Merewether, E. R. A. 1933, 1934. A memorandum on asbestosls. Tubercle 15:69-81, 109-118. 243 Murray, J. M. 1907. Report of the Coanlttee on Compensation for Industrial Diseases. Minutes of Evidence. Newhouse, M. L., and H. Thompson. 1963. Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Br. J. Ind. Med. 22:261 . Nordmann, M. 1938. Der Berufskrebs der Asbesarbeiter. Zeltschrift fur Krebsforschung. Vol. 47. 288 pp. Oliver, X. 1927. Clinical aspects of pulmonary asbestosls. Br. Med. J. 2:1026-1027. Seidman, H., I. J. Sellkoff, and E. C. Hammond. 1979. Short-term asbestos work exposure and long-term observation. Ann. N.Y. Acad. Sci. 330:61-90. Sellkoff, I. J., J. Churg, and E. C. Hammond. 1964. Asbestos exposure and neoplasia. J. Am. Med. Assoc. 188:22-26. Sellkoff, I.J., E.C. Hammond, and J. Churg. 1968. Asbestos exposure, smoking and neoplasia. J. Am. Med. Assoc. 204:104-110. Sellkoff, I. J., E. C. Hammond, and H. Seidman. 1979. Mortality experience of Insulation workers in the U.S. and Canada, 1943-1976. Ann. N.Y. Acad. Scl. 330:91-116. Thomson, J. G., &. 0. Kaschula, and R. R. McDonald. 1963. Asbestos as a modem urban hazard. S. Afr. Med. J. 37:77-81. Vagner, J. C., C. A. Sleggs, and P. Marchand. 1960. Diffuse pleural mesothelioma and asbestos exposure In the Northwestern Cape Province. Br. J. Ind. Med. 17:260-271. Wedler, H. V. 1943. Asbestose und Lungenkrebs. Deut. Med. Voch. 69:575-576. Wilson, D. R. 1939. Annual Report of the Chief Inspector of Factories for the year 1938. CMD. 6081. Her Majesty's Stationary Office, London. 133 pp. Wood, W. B., and S. R. Gloyne. 1931. Pulmonary asbestosls complicated by pulmonary tuberculosis. lancet 11:954-956. Appendix B f9a ^M ^*c K* e fa c --al ofa X2 -O * f &O w -* U t Mue8 ftaf fe 5o fl fa Q S :;5ii 9 91 c eofa eo9 fa1k5X*"- fa 1 9 9&. ^6-- ^-- - x -- -o 90* 0-9 flU GVk v >b o wz *C2 X<J fa * u M9 <C --> ! fa 9 fa C 9 * * c - C e4) -- ~9 oO ^ -- * * 'O 9 -- rsk^9-si ~fa mc fa- 9e --9 -0Of-t 1 e3 > X & K fwa fa >9> C --0 -- xf0a 9l X 8 aC 9u 9a> uO e i 9 9 3 C 'O fa 4# Z2 S. u-- ee fa 9 O --e v -o CX 9 0fa e * 3 9- C X9 O 9 "O -- ^ 9 9 fa C ac fa : . l9 c o x 00 09 9 * 9 9 fa !fa oK 0fa. XO fa fa f0a.fa3. o S' 9 c SSS! 9 3 9 9 0 9 c ?- i -- X ^ fa - O to f9a 9e ofa 99 9 090 o C I 99 9 fa 9 o fa z * 9e 9 312 0 -- 9- C * fa a fa 9 a^fa -- e -"1f9a Rfa *fOa = ifa 9J fa 999 fCa a9 *fa ^-- O *- fa fa9 --C 9U 9 --C C X tX.w** 9s| Set s 3*i #>* o _e e-- 0< fa 1 *- fa f9a 9 9> Oe 9 g e *o e 0-- O M9 X fa 0 9** fa ^ ^ MG 9 -- O' < 9> fOa --o --9|| -- fa- o S9 -fa faf S*X 91 9 90 Z fa c 9 fa K 9 > -- 1-0 C " 9 -- 9 "fa : 9 fa a e jc 9 I -O 91 -- e 9o 9e ~ --e *2. 9 fa fa ^ 9 o w o * ^41 9 9 9 X fca 9--* c-- . Seo e9 3O *ofa fa 9 pi V X * u i l O 9e e0 9e > fa --9 c e -* 9w9 f--a r** 9 9o .fca uc fa 9 9 9U 1? o9 e x Oge fo9a Sfa o99-- 9e X O IC-.zv xfa 3 oC ii\ p a th o lo g tc a l e ffe c t hee been observed in e n ia a l* a n d /o r huana. p a th o lo g ic a l e ffe c t haa not been observed. ( M M o j u s a i s v ) s o t s a a s v i v i d k m o d o *fa ON e '' 2 ui --o Ofl e9 e-- 99 X V 244 fa 9 . o --C fa -5 ! i Xo fa 245 O -- u O 0 A >> AA *> U u b -JO <J I'*- 9 c- -- C 9 b -- 9 X x w _-- b b b u^ M e ( c 9 c o W -- e 9 t- =- *-9 bC b & x6 bJ 0 b >. *X e -- c -- > ~-- O Vbi --O Xb9Cub `0'->^-*9 X *9 X --' A. &0b m w e e -- ^> i * o -- c o 4* w9 < -- b b b - 0 c b m o b w e il X ^ ;. i U *--- *0** o- U -- -- b 0E X9 - 9 bb b OC --b b *3 -- ~ --b E --9 b so ex m -O X. X *9 b * u . bi --b C -- --o eu b - 9 41 wu e 9-- u C *c b 9 >A X 9* -- 9 X b * * U o > e Ub -Xw< M9 .90 !e --. b >* 1.1 *9 9 9 9 * b-- ' --0 -b b> IS --^ e - --1C wb O9 .? d { M O b * U bA --c *c99 --- ----bhxeu- . o (A w C bb 1 e )x t> o -- AC O wX b WX ' ott A 2 * f e i b 41 w e ^-- -- e o -j 4i| b ei a --s ** e C 9 9 O x e jc o C -9 c n a* X 9 'f S3 S b b-- ^ 9 m * u - I Vb --V oe --ws X -- B 49 C -- 9 -- w b ii > b0 * m T3 0 X X H -- C w E w " s2 *" -- C S -- -i ^>* a > ---* 2X A --X u Oft o x . .--4* --9^ Vb e- 4> -- 0 *-* * f* S -! c >^ 9 49 4 * bl *9 */ 9 > O b e 7 --0 --b 9A "O 9 X jr c 9 bx 9 wo --V 3c w4 vbj b----:----o-- 0x 9 0* -- b Z X --X b form s. page o f Appendix. in fib ro u s snd n o n fib ro u s v a r i a b l e q u a l i t y f i b e r s p r o b a b l y A S B E S T IF O K H )( P s th o lo g ic s l E ffe c ts O bserved in A n im a ls a n d /o r Humana* *M S2 -- b Xo o u b^ bX XX -I --b eb -- --3 -- 9 b bb --aw bx u9 bbbMb--9X --b XW -- b -- Aw C- bb9 - 9 b b --Xu u ^b --X xu b9 >s w -- X9 b& bb 9w X-- >>. b o( cI cr ui tr e y .e t *S 246 i <o* ft x O M ffat CO --3 e "ft ^* --> Ofa Oc M to. O cc !: ko* < fa. k. V ft * 3 Xk. V w 3ta *d XfVa 4CX)k ---- X> Xkft* ~ _ft eo Xfa Xo uI! wW3 --f>t 3 e* --i x* ^3 eo ** Oa..X< ** X .0 fa X3 o wft e X--fmt --O0 (A X faj o ffat ---- til xa --3 ?! ft s> el ft *K* e^ X3 10 U 3 tc ^ e xl w> K <faeat o ft 9 S a a p lc* o f fib ro u a a p p e a r Co be 247 E z ak. 3 : *. M "O -- m --9 M tCak b **o* >k >1 Xo b X& Eb -waO bOe8 rst m xie 3- er s -- -- b 41 b : (E; --S * -b2 E --^ ~ 3u -8 C a i: O 9 X O 3 t* O b > l b Jf X w -~ 0 b* Ob VV jt m x * MJVwM-- u3 : - co --: b -- I) E X W w*> X--e *'i Ve o a. w eoe vw --> '* >v .-- x 3 m* b 9b9 > X e if: 3 V wr e v oe b * X *- ** -V . w w3 & w>> b b0 V3bb ab < 9 ** 3 b 7 K X ' : X 8 o. i b *3 c --IX- *K XM b -- > 9X v c Oo 0 b u o &X V ---- c 9 X *- u -- a *-- u -- f * o*** . > 0-- uuo xC e3 ---- -- ' o - X a m w-- X 8e * mu 9 e u .Mb b & V t II X -- X J< > v o X <j -- * b P b* -- X b 0 --V -- o b0 w b b > ^ "fl . 9X 3 Vb XP w --* * c 9m --Cb --9 i -- X b - X M-- Kb Ve--X v X bM b V 9 --#e x e -9 b -- -- x wv V <"0 ibi aMM X3 -- Mb K 9 b X b o o a e M s b M ^3 ^ mVe --3 b3 --V 8 V b "O > --e C3l *-o c x9 0 & I9 4 f ). Co d a te (G runec, e x n in e d n o n a a b e a tifo rm . e e tt it a a t t io to mi innnnec V A E I/U H E Q U A LIT Y FIBERS (P O S S IB LY ASHESTI FORM) v Oe -oV :*3 s": rl o iw * Xo cj 8-S a oo ux -- 3 9 >% X X 03 8 --b --^ 248 e g r la ae and the o e t r ra ra u iv e ly expoa t m in e ra l! a rt not o f concern. e la io n r t a re al a h ey in Th ua, h . T t i b )a. nh *r uo Xto 3M * 3K *, b-. --' X X w-- * --tco tCo --to VC "!}!; k. 2 f x.a * e to O'-* ^to -- to T%CwJ --*to0--X*3 ^OC2OV I toi ~ -- to --'. --to to tcl <oNo -oa XP --f --^ 4w o to ** X COM Io to . --o -- || Cl N re E to O sil: c i s -i o o m\ uU , --tt -- > o > ** t> -- to V to 41 -- --to --4) aoto s*rto k* a V>to to > Jtof 3 X -- Oto tol to X3 x> * -- --Xu -- to X^ I s~ o X --- x --oe XE ? s-g =rs * CL -- 0 O O to y cX ---- u c c-- O L k. X - to -- to uXX 2-0. --i MOB M oxo --o too Xo 6 -- ~" * 2.2 - a -- s-- * I* to e -- V ^ ao u -- --ux O. . c o -- c to to 5 * * O hi uu to o --r O X *o o 0 hi --c -- x -t s eo x *- to -- 6 X 0 C O to -- a cO to U -- to o X S- X to *tCo - aO X- y- -- to to ItM 0 to 3-- o >-- to oX x e x o u -- -- <X -to oC e !!- "Io X_ o > 'to -- to to *0 to 0 -- to a to X Xc w to to ^ -- too e to t*o> > to X x O rx ---- e t^o to 3 to * X s i si'i -- ox to 3 It I ts tj -- C to Xo P^ c xe>v ---- -- V to o r O to -- to X -- Xc -- 3 to < to O' O to to e to to 2" as* aa Sox -- 3 " V to to I e ^ ou to ' . to X to *to ^ O to to X TJ c < * t3o e 1I Kc -V <3 .2 5 --a to* 2 -- 3 X0 O X e --t>o t0o *to0 X ou- Oe oM e -- c to u --a > MoO> w --to amto Xto 3-to to ^ -- ^X c CO V to P X to c m 3 o* . e. * . e au s o (to </9 M<l col CO I O' o CMMO ru I Oe o K oto X X V iof lr ifbi f( (e .f., tp h a le rite , a ilte rlte ) 249 V --a o A** m A. A o. ^o e a. om w --c o e 9~m e a o --Os6So0d> O ------ es . tl 0 --J -- c i -- l <j <J Q -* -- to V 0 JK f ! -ss ^ cO V to to 0> ~>6 O O to*. -( "O - 2 -V * -|| fl* - -i o COhi she 41 h- 4> C - t *0 - 4 3 -< o- u Cw-- >s 3 M Q *0 u :s r--m O' * --St'o --Oi' r m k* - t - .= xZw 6 w>A 3 >. A *0 --l b M M w| *0W 4> to "O fl --^o i- -9- V*0 j90 ii M ^ o U he 0 -- CO o a x w X 9C --to* o* o wa -- sf: . o - e 5 b I* o '? -Oh- -- *-- to* o 9 c to* ttoo *to U O >.0 b4 3 t0eo ^oto wc 0 >* o too Xo t9Uo* 5f>* h--* . eto ^a> ^a S^-S- e .2 ~ - o to C u 0 r3 ^-- J< -- --I > f o i -'i e s . m| -- oto ol-- t0too XCO A 0to Ao Cv0U -- wI f0t c "o t) w ^ wo 9f --> ac v ao u to Cl 9 *0 -'o' too ---- *t9o oe . go 0 o o e -- Xo B O 0 -- 9 -- ton X C C-- O O U "O W o0 o o X & to C 0 e ton 9 o e-- e e w * -- -> CW O ft> MM 41 M o nO ee o X eC 41 o 0 u e 9 e Q. c o O u u 0 c 0e 6 M ine - lo g ic * ! C a te g o ry 9 b E 9 nto E 0> O-- to too O oo to A --s.t0o 0V t4o1 *o S e e *`to O (J B - 3 , v a r ia b l e q u a l it y f ib e r s p o s s ib l y a s b e s t if o r m ) (( H i n e r e ______________l 4 POOR Q U A LIT Y FIB E R S (Q UESTIO NABLY A S B E S TIFO R M )0 i l __________________________ g sa m p te s and Comments e 2 Oa c e uio 13* X o 250 2 >s 2 X o - oe -- 0> nuo XX X JL 22 _fc --O *t9o S*03 X1CXO0 *- W * P u c These m in e ra ta a re o fte n fib r o u s and may o c c a s io n a lly be a s b e a tifo n n . Some a re a te r s o lu b le . ^S o lu b le fib e rs , e s p e c ia lly c a rb o n a te s , s u lfa te s , e tc ., m ight te n d not 0 251 REFERENCES Artvinli, M., and 7. I. Baris. 1979. Malignant mesotheliomas in a small village in the Anatolian region of Turkey: An epidemiological study. J. Natl. Cancer Inst. 63:17-22. Baris, Y. I., A. A. Sahin, and M. Ozesml. 1978. An outbreak of pleural mesothelioma and chronic fibrosing pleurisy in the village of Karain Urgup in Anatolia. Thorax 33:181-192. Blgnon, J., P. Sebastlen, A. Gaudichet, and M. C. Jaurand. 1980. Biological effects of attapulgite. Pp. 25-27 in J. C. Wagner, ed. Biological Effects of Mineral Fibres. IARC Scientific Pub. No. 30. International Agency for Research on Cancer, Lyon. Bowes, D. R., A. M. Langer, and A. N. Rohl. 1977. Nature and range of mineral dust in the environment. Trans. R. Soc. London, Ser. A 286:593-610. Burilkov, T., and L. Michailova. 1972. Uber den Sepiolitgehalt des Bodens in Gebleten mlt endemlschen Pleural-Verkalkungen. Int. Arch. Arbeltsmed. 29:95-101. Coffin, D. L., L. D. Palekar, and P. Cooke. 1982. Tumorigenesis by a ferroactinolite mineral. Toxicol. Lett. 13:143-150. Cook, P., L. D. Palekar, and 0. L. Coffin. 1982. Interpretation of the carcinogenicity of amoslte asbestos and ferroactinolite on the basis of retained fiber dose and characteristics in vivo. Toxicol. Lett. 13:151-158. Cummins, S. L. 1936. Serlclte and silica: Experimental dust lesions in rabbits. Br. J. Exp. Pathol. 18:395-401. Dietrich, V., F. de Quervain, and H. U. NIssen. 1966. Turoalin-Asbest aus den alplnen Mlneralkluften. Schweiz. Mineral. Petrogr. Mitt. 46:695-697. Gruner, J. W. 1946. The Mineralogy and Geology of the Taconites and Iron Ores of the Mesabl Range, Minnesota. Commission of Iron Range Research Rehabilitation, Minnesota Geological Survey, Minneapolis. Jiahon, N., J. A. Booth., B. A. Boehlecke, and J. A. Merchant. 1980. Enhanced viral interferon Induction by the mineral wollastonite. J. Interferon Res. 1:49-60. International Agency for Research on Cancer. 1973. Biological Effects of Asbestos. P. Bogovskl, V. Timbrell, J. C. Gilson, and J. C. Wagner, eds. IARC Scientific Pub. No. 8. International Agency for Research on Cancer, Lyon. 346 pp. Irwlg, L. M., R. S. J. DuToit, G. K. SlUis-Cremer, A. Solomon, R. G. Thomas, P. F H. Hamel, I. Webster, and T. Hastie. 1979. Risk of asbestosls in crocldollte and amoslte mines in South Africa. Ann. N. Y. Acad. Sci. 330:35-52. Kleinfeld, M., J. Mescite, 0. Kooyman, and M. H. Zaki. 1968. Mortality among talc miners and millers in New York State. Arch. Environ. Health 14:663-667. Koshi, R., H. Hayashl, and H. Sakabe. 1968. Cell toxicity and hemolytic action of asbestos dust. Ind. Health (Japan) 6:69-79. 252 Langer, A. M. 1978. Crystal faces and cleavage planes In quartz as teaplates In biological processes. Quart. Rev. Biophys. II, 4:543-575. Maleev, M. N., A. P. Krusillna, and V. N. Rozanckij. 1972. Ultimate strength of naturally fibrous rutile, antimony and jamesonite crystals. (In Russian) C. R. Acad. Bulg. Sci. 25:1085-1088. Pott, F., F. Huth, and K. H. Friedrichs. 1974. Tuaorigenlc effect of fibrous dust In experimental animals. Environ. Health Perspect. 9:313-314. Pott, F., K. H. Friedrichs, and F. Huth. 1976. Ergebnlsse aus Tlerversuchen zur kanzerogenen Wlrkung faserfb'rmiger Staube und ihre Deutung, I. Hlnblick auf die Tumor-Entstehung bela Menschen. Zbl. Bakt. Hyg. I. Abt. Orlg. B. 162:467-505. Sakabe, H., K. Koshi, and H. Hayashi. 1971. On the cell toxicity of mineral dust. Pp. 423-434 In W. H. Walton, ed. Inhaled Particles III, Vol. I. Unwin Brothers, Surrey, England. Schnltzer, R. J., and F. L. Pundsack. 1970. Asbestos hemolysis. Environ. Res. 3:1-13. Seidman, H., I. J. Selikoff, and E. C. Hammond. 1979. Short-term asbestos work exposure and long-term observation. Ann. N.Y. Acad. Sci. 330:61-90. Suzuki, Y. 1982. Carcinogenic and flbrogenlc effects of zeolites. Preliminary observations. Environ. Res. 27:433-445. Tarnovskll, G. N., G. M. Rashaeva, V. A. Shlrgaeva, and G. G. Afonina. 1976. First discovery of tourmaline asbestos In pegmatites of the USSR. (In Russian). Vopr. Mineral. Geokhlm. Pegmat. 7ost. Sib.: 54-64. Wagner, J. C. 1962. Experimental production of mesothellal tumors of the pleura by implantation of dusts In laboratory animals. Nature 196:567-581. Appendix C FIBER-QUALITY PARAMETERS OF SELECTED ASBESTOS, WHISKER, AND CLASS FIBERS The strength-diameter effect of fine wires and fibers has been discovered and rediscovered several times during the last 250 years. Each time it excited great interest within the scientific community but was soon doubted and finally ignored after a few years. It is difficult to explain the reasons for this cyclical interest in the strength-diameter effect. One reason could be that no satisfactory theory has been developed and experimentally proven. Today, it is possible to observe surface defects and other submicroscopic features, such as the dissolution pattern of fibers, but the surface structure of fine fibrous substances still cannot be determined. In the early 1800s, Karaarsch (1834) completed an extensive and systematic study on the strength-diameter effect of 18 different metal and alloy wires. In 1859, he derived an equation expressing the relationship between the increasing strength (F) and the decreasing diameter (D) of small-diameter wires. His equation (rephrased by Griffith, 1921) is: - F =* A B/D, (C-l) where A and B are constants. The constant A in the Karmarsch equation (C-l) was interpreted by Orovan (1933) as the strength of the internal structure and B as the strength of the surface structure. However, the Karmarsch equation did not satisfy all the more than 100 available strength-diameter measurements. This problem was recently resolved (Zoltai, 1981) by changing the surface area-to-voluae ratio (B/D in the Karmarsch equation) to incorporate other features of the surface structure, e.g., the depth of the surface layer, the presence of growth steps (Marsh, 1962), and the effect of longitudinal cleavages (Cook and Gordon, 1964). Thus, Of - Of (1 + 4K/D)1 * 4k/, (C-2) where Of is the strength of the fiber, of is its internal strength, and K and k are factors expressing the increased strength of the surface layer over that of the internal structure. 253 254 Table C-l shows che fiber characteristics (internal strength, X and k constants, etc.) of a selected group of natural and synthetic fibers. The values shown in the table illustrate the general characteristics of the examples and the relative magnitudes of the parameters given. Experimental data in reports by various researchers are difficult to compare because they often use different expressions of strength, different methods, and different units of measurement. Further limitations result from inaccurate readings of strength and diameter values from published small-scale graphs. SIGNIFICANCE OF THE FIBER-QUALITY PARAMETERS From the measurement of the tensile strength of sets of fibers and from subsequent calculations (using the above equations), one can calculate: (1) the internal strength of the fibers (ci) and (2) two constants (X and k), which express the relative increase in the strength of the surface structure. These parameters reflect the differences in the mechanical properties of fibers Chat grew under different conditions or that were modified by treatment and wear. The following conclusions about fiber-quality parameters may be relevant to the potential health effects of fibers: (1) The mechanical properties of fibers are directly related to the common properties of asbestiform fibers. Consequently, Che three parameters can be used as numerical indicators of the degree of asbestiform development of fibers. (2) - The two constants, X and k, must be positive for asbestiform fibers in order to account for their enhanced strength and flexibility. - The X and k constants must be equal to zero for crystals that have no enhanced strength despite a defect-free surface structure. - The X and k constants must be negative for cleavage fragments and other fragments whose surfaces are weaker than their internal structure because of the physical damage introduced by fracturing and subsequent processes. (3) Because of the interdependent nature of the common asbestiform fiber properties, these three parameters may include a direct or indirect measure of the critical physicochemical property or properties that may be primarily responsible for the adverse health effects of asbestiform fibers. However, the nature of relationship between the fiber quality and carcinogenic potential of asbestiform fibers is still unknown. u wI| i In te rn a l S trength S trength at Range o f 1 i" d ia m e te r C o r r e la t io n D ia m e te ra Number o f 255 Ue v e JC \ c E[ A II JC o c tr w~l *h* o oo oo * & uo 41 o 3to 1m eou CA c C hrom ium 1 0 ,0 0 0 *0.3 - 3 7 ,0 0 0 0 .7 4 0 .3 -1 .2 24 S a lk in d a t a l., 1970 1 256 R eference of iubmebre*r N F * r e t e am m) Range o f (Dui CC oo rerfef ilcaiteion tn I |ia d ia m e te r C b g /c m 2 )_______ S trength at xX 99 X X 9* X Xx 9 X ue 0) 9X el uo -i s\ e >Ve X^ *X- X* e n9 X, --O --V x tA ^ O " o f4 X *-\ X as. X <9 <N X o <9 9C** o P-d o oo oo *r*> XX X X "^9 oo o o o e cm r* 9 eoO o99 x99 9- XX 9 l --Ic I I X X9 9 99 9 0 O O XX X X 99 9 e --* e 9 o O 9 o o o O9 C 9 9F-l iCA o e !* X * O 9 ** 9 99 X c oTi X r*s .S -0 T5 o --*Ol wh* --^0b* 9 0 9 ^ c 09 ^1o0 V ^o CO 0 09 99 99 X9 9 9O 9 9 9 9 O 9 9 9X9 OK K O 0 mo mo m o 39 >ed e V9 e 8 9 9 i%\ 9 99 9 9 900 9 ?_______ b______ In te rn a l (S tbr le/nf *g t>h H a ta ria l or fib e r 257 R eference F ib e ra Number o f ( h g / c 2 )C o e f f i c i e n t (tn a )__________________ I ua d ia m e te r C o rre la tio n D iam etera Range o f S trength at ee 9u u ee e 9c iZ 55 gs 55 o 'e rO- *" Jf o 0 u oo I to aOOb aO c i ii* oas, o_* rot m b- an CD O O o n ao* o p* mo d dd o o oo o o oo o-- A o C e 40* a* o o c O O as0? O o o oo e c< Ob <0 <N '' o ii aO o oin .0 u c e *Oo etoo s o o oo o m o oo> Ob <r r V to CO BO CO 00 K_______ h______ In te rn a l S trength (h /c m 2 )- H a ta ria l or fib e r 1 J * <*o 258 e 9* -I I iciu e em oe -- ohO. oOi X oe *8o "r ei e fM <*4 *'G- >Nt? --N >o t --oO A *Or> * CD ed 9 o co ^ o <o7> BN rs 9* N 9* o do d o ao ooo XI I II I <9 sso -- o PHe. 9 * oO on o/> :l T *9 2 <m --o9 w o 4 *2 9* X9# 0oo 09 09 *1 X0 51 0ou 90 e 1-2 8 09 mi Ia A ib ltifo n i H liim l F ib e r*: 259 REFERENCES Anderegg, F. 0. 1939. Strength of glass fiber. Ind. Eng. Chea. 31: 290-298. Bartenev, G. M., and L. K. Izmailova. 1962. Defect-free glass fibers. (In Russian) Akad. Nauk. SSSR, Chen. Tech. Sect. 146:196-198. Bateson, S. 1958. Critical study of the optical properties of glass fibres. J. Appl. Phys. 29:13-21. Bayer, P. D., and R. E. Cooper. 1967. Size-strength effects In sapphire and silicon nitride whiskers at 20C. J. Mater. Scl. 2:233-237. Bokshceln, S. 2., S. T. Koshkin, and I. L. Svotkov. 1963. Tensile testing of filament crystals of copper, nickel and cobalt to failure. Sov. Phys. Solid State 4:1271-1277. Bokshteln, S. Z., S. T. Koshkin, M. P. Nazarrova, and I. I. Svetlov. 1968. Size effect and anisotropy In the strength of sapphire whiskers at room temperature. Sov. Phys. Solid State 9:1488-1494. Brenner, S. S. 1956. Tensile strength of whiskers. J. Appl. Phys. 27:1481-1491. Brenner, S. S. 1958. Growth and properties of whiskers. Science 128: 569-575. Cook, J. 1970. Mechanical testing of whiskers. Composites (March):176180. Cook, J., and J. J. Gordon. 1964. A mechanism for the control of crack propagation In all brittle systems. Proc. R. Soc. London, Ser. A 282:508-518. Evans, C. C., J. E. Gordon, and D. M. Marsh. 1964. The strength of whiskers of silicon, zinc oxide and phthalocyanine. Proc. R. Soc. London, Ser. A 282:218-220. Ewald, W., and M. Polanyl. 1925. PlastlzitSt und Festlgkelt von Steinsalz unter Vasser. Z. Phys. 31:29-50. Fridman, V. Y., and A. A. Shpunt. 1963. Investigation of the strength of lithium fluoride crystal fragments. Sov. PhyB. Solid State 5:575-579. Griffith, A. R. 1921. The phenomena of rupture and flow in solids. Phil. Trans. R. Soc. London, Ser. A 221:163-198. Gyulal, Z. 1954. Festlgkelt- und PlastlzitRtelgenschaften von NaCl Nadelkrlstallen. Z. Phys. 138:317-321. Gyulal, Z., E. Hartman, and B. Jeszenszky. 1961. Zerrelssfestlgkelt- Messungen an NaCl Nadelkrlstallen (whiskers). Phys. Satue Solidi 1:726-729. . Herzog, J. A. 1963. Strength Investigations with unidimensionally grown cyrstalline iron (whisker). Metallurgla 17:7-14. Herzog, J. A. 1967. Entwlcklung und Zukunft In der Whiskerforschung. Jahrb. Vissen. Gesellsch. Luftfahrt. (WGLR) Jones, B. F. 1971. Further observations concerning the effect of diameter on the fracture strength and Yung's Modulus of carbon and graphite fibers made from polyacrylonitrile. J. Mater. Scl. 6:1225-1227. Jones, B. F., and R. G. Duncan. 1971. The effect of fiber diameter on the mechanical properties of graphite fibers manufactured from polyacrylonitrile and rayon. J. Mater. Sci. 6:289-293. 260 Karmarsch, K. 1834. Versuche ffber die Festlgkelt der zu Draht gezogenen Metallen. Jhhrb. Polytech. Inst. Wien 18:57-115. Karmarsch, K. 1859. Uber die absolute Festlgkelt der MetalldrKhte. Hitt. Gew. Ver. Konlgr. Hannover, pp. 137-156. Kelsey, R. H., and R. H. Krock. 1967. Tension testing alualna whiskers. J. Mater. Sd. 2:146-159. Klrchner, H. P., and P. Knoll. 1963. Silicon carbide whiskers. J. As. Ceram. Soc. 46:299-300. Maleev, M. N., A. P. Krusillna, and V. N. Rosancklj. 1972. Ultimate strength of naturally fibrous rutile, antimony and jaaesoolce crystals. (In Russian) C. R. Acad. Bulg. Scl. 25:1085-1088. Marsh, D. M. 1963. Stress concentration at steps on crystal surfaces and their role in fracture. Fracture of Solids, Metal. Society Conference 20. Interscience Publishers, Mew York. Mehan, R. L., . Felngold, and E. Gatti. 1965. Technical Report AFML- TR 65 275, August. Mehan, R. L., W. H. Sutton, and J. A. Herzog. 1966. A review of measuring the strength of whiskers and their role in reinforcing ductile matrices. AIAA J. 4:1889-1898. Nadgornyl, E. M., L. F. Grlgoreva, and A. P. Ivanor. 1965. The mechanical properties of synthetic fibrous fluoramphlboles and certain forms of natural asbestos. Izv. Akad. Nauk. SSSR Neorg. Mater. 1:1117-1123. Noone, M. J. 1967. The preparation, structure and mechanical properties of filamentary forms of silicon carbide. Ph.D. Thesis. University of Leeds, United Kingdom. Orovan, E. 1933. Die erhohte Festlgkelt dilnner FSden, der Joffe-Effekt und verwandte Erschelnungen vom Standpunkt der Griffitschen- Bruchtheorie. Z. Phys. 86:195-213. . Perry, A. J., K. Phillips, and E. de lamotte. 1971. The mechanical properties of carbon fibres. Fibre Scl. Technol. 3:317-319. Relnkober, 0. 1931. Die Zerreissfestigkelt dtinner QuarzfSden. Phys. Zeitschr. 32:243-250. Salkind, M. J., F. D. Lemkey, and F. D. George. 1970. Whisker composites by eutectic solidification. Chapter 10 in A. P. Levitt, ed. Whisker Technology. Interscience Publishers, New York. Soltis, P. J. 1967. A new method and technique for tension testing whiskers. J. Mater. Scl. 2:300-324. Webb, W. W., R. D. Dragsdorff, and W. D. Forgeng. 1957. Dislocations of whiskers. Phys. Rev. 108:498-499. Webb, W. V., H. D. Bathand, and R. S. Shaffer. 1966. Strength characteristics of whisker crystals, microcrystals and aacrocrystals. Chapter 14 in J. J. Purke, M. L. Reed, and V. Weiss, eds. Strengthening Mechanisms. Syracuse University Press, Syracuse, M.Y. Weik, H. 1959. Whisker structure and tensile strength. J. Appl. Phys. 30:791-792. Wolff, E. G., and T. D. Coskren. 1965. Growth and morphology of magnesium oxide whiskers. J. Am. Ceram. Soc. 48:279-285. Zoltai, T. 1981. Amphlbole asbestos mineralogy. Pp. 237-278 In D. R. Veblen, ed. Amphlboles and Other Hydrous Pyrlboles. MSA Reviews In Mineralogy, 9A. Mlneralogical Society of America, Washington, D.C. Appendix D CONCEPTUAL MODEL OF FIBER EXPOSURE Because measurement of exposures to all potentially hazardous asbestiform fibers is technically infeasible in some cases and prohibitively expensive in others, indirect methods of estimating exposure must augment the direct measurements* Although the committee did not develop a comprehensive mathematical model of fiber exposure, it did develop a conceptual model of the computations that would be necessary for a full mathematical model of the exposure process. This conceptual model enabled the committee to identify the factors that could be important in determining exposure so that it could seek information in an organized way and attempt to relate the information about one fiber type to that for other fibers to facilitate an analysis of comparative exposure potentials. Figure D-l provides a conceptual overview of the calculations that would be necessary to estimate nonoccupational exposures of humans in the absence of direct measurements. The scheme shows four types of information: quantities, factors, units, and operators. A quantity is a calculated numeric value that represents some physical aspect of exposure to asbestiform fibers. A factor is an exogenous (external) input to the calculation, which can be measured or itself calculated outside the system. Without factor inputs, Che quantities cannot be calculated. Units are the physical units of measurement for the quantities and factors. An operator is a mathematical manipulation that derives a new quantity from one or more factors and other quantities. For example, the quantity "human intake rate (by inhalation)" is calculated by multiplying (using the multiplication operator on) the quantity "ambient concentration in air" by the factor "breathing rate." In each step, the input quantity is a result of all the previous steps; the factor represents a new, physically important parameter not a result of Che previous steps; and Che output quantity serves as the input quantity for the next step. In every case, the units of Che input quantities and factors must combine correctly under the operator to yield the units of the output quantity. In this conceptual-level scheme it is not necessary to be able to measure each factor physically, but each must describe a phenomenon of interest and be, at least in principle, estimatable from physically 261 Conwercial Floy 262 Environmental Flow Dcurrence_*f > (in million* of metric ton*, e.g., in U.S.) x |Exploication*~facTor *) (Z/year) x (Weachering_facor*H (Z/yr) I Environment*1 .fluxes ; (thousands of metric ton/year) ICross production"! (millions of metric ton*/year)--> *|FicJrge faccorTl (Z) (Environmental fluxes I (thousands of metric tons/year) [TmportTl (million* of metric tons/year) - iExportTl (millions of metric tons/year) * IReeycled_ material_sl (millions of metric tons/year) * |Chanje in_inve nt oryH (millions of metric tons/year) IConsumption ! (millions of metric ton/year)---------- ) x (Discharge aErTl (Z) ______ __ ____________________ x iPe_rcen4e_uci_l_iaionJ (Z) " I Environmental fluxes 1 (thousands of metric ton/year) [Use by category I (thousands of metric tons/year)-* x (Discharge faccorTl (Z) "[Environmental fluxes ! (thousands of metric cons/year) - iDijposal_bv *tejory3 (millions of metric tons/year) > -(Disappearance | (thousands of metric tons/year) [Set increase in ue I (million* of metric tons/year) |Wec increase of disposed material? (thousands of metric tons/year) / * 'Total in use! (thousands of metric tons/year) x IReTeTse faccorTl (Z/year) j't"(Total disposed [ (thousands ____ of met_ric_cons) x [Discharge faccorTl (Z/year) [Environmental fluxes"! (metric con*/year) ILocal fluxes I (metric tons/year) (Total fluxcsj (metric tons/yr) Natural materials only. FIGURE D-l. General flow of computational logic for estimating exposures to fibers. FIGURE D-l (Cont.) 263 Total fluxes I (metric tona/year) - Depo*icion~i (metric tona/yeer) i lj) i_lut in_feetoraj (o-Vyr; liters/year) lAnbient concentrations | (yg/m^; yg/liter) x (Coriverion_factorsJ (fibers/ca^ per Lg/n^; fiber*/ml per yg/liter) m Tiber concentration* | (fibers/caP; fibers/al) x !B re ahing,_drinking rate* I (mVday, iitera/day) " 'Human incake rates I (fibers/day) x ^8iod0ic.ion_fc_co_rjj (Z/organ) 'Ti**ue fluxe* I (fibera/day) - SiaappearancTl (fibera/day) * `Net cisnie increase ; (fibera/day) ftm Tissue burden I (fibers) x Tissue clearance rate I (Z/day) * Disappearance | Key: I I quantity . I______ " factor ( ) unit -------- * link from commercial to environmental flow t tine Metric ton 2,205 pounds. 264 amasurable quantities. Por example, the "deposition" of fibers on their way from source to exposed humans may not be directly measurable, but the principle can be demonstrated by measuring concentrations of fibers at various distances from known and quantified sources, and then describing the deposition as a function of distance through appropriate computations. The model sketched in Figure 0-1 is intended to apply to virtually any fiber type, but not all of the steps would apply to every type. For example, occurrence (millions of metric tons of fibrous material known or suspected) and weathering (relative rate of loss of such material) would not apply to man-made fibers. Moreover, the commercial flows on the left side of the scheme would be of dominant importance for some fibers, whereas the environmental flows on the right side would predominate for others. This commercial versus environmental flow distinction is important, as explained for Figure 1-2, because of potential need for controls of both types of flow. In brief, the factors shown in Figure D-l take into account the following phenomena: Occurrence: Geologic occurrence in the United States. In principle, this factor could be measured by the proven and indicated reserves of the mineral, if cotmaercially important, or by a relative abundance figure for others. It can be measured in millions of metric cons. Weathering: The amount of material in place that might be released into the environment (as either airborne or waterborne particulates) per year. The natural weathering processes may occasionally be enhanced through noncommercial disturbance by humans. Exploitation: The amount deliberately extracted for use. Should include amount used with and without further processing, for example, the asbestos content of road surfacing aggregates. Imports, exports: The flows of materials to and from foreign countries. For example, on the basis of relative sn<uuncs, asbestos flows from Canada are greater than those resulting from extraction in the United States. Recycled materials: Fibers suitable for recycling after disposal from first use. This practice does not seem to be very widespread in the industry because of the low cost of original production. Percentage utilization: Essentially synonymous with "use patterns." Considers percentage of the total consumption in the United States that goes into each use. There may be a chain of uses. For example, asbestos fiber may go into asbestos paper, which in turn is used in insulation for electric appliances. In principle, opportunities for release of asbestos occur both in the manufacture of the paper and in the manufacture of the appliance as well as during use of the appliance. 265 Disposal: Disposal of fiber products after use. Virtually every fiber product has a finite useful life. Aftervard, most of the fibers reach some fora of landfill, but some enter air, or possibly vater, during demolition. The fibers in landfill then pose a secondary source of potential exposure. Fibers lost from such sites ("disappearance") decrease the inventory there, thus decreasing the rate of accumulation. Discharge factors: The potential for release into environmental air or vater for each process through which the fibers pass. The factors can be expressed as a percentage of throughput (i.e., metric tons released per thousand metric tons processed, multiplied by 100) or as a percentage race of total inventory (i.e., metric tons discharged per year per metric too in place, multiplied by 100). Generally, the release is called a "discharge" when associated with a manufacturing process, but a "release" when associated with product use, e.g., when fibers are worn off vinyl asbestos tiles. Dilution factors: The net effect of all processes that disperse fibers in air or vater away from Che source. If fibers are released inside a building, the dilution factors are related to the number of air changes per hour and the volume of air in the enclosed space. In ambienc air, Che factors are used to convert the discharge rate to ambient concentration as a function of distance from the source, wind direction, and other influences. In water, they are used to convert the discharge rates Co the concentrations in water supplies. In tap water, the actual concentration may be lover than Che calculated concentration because of filtration and settling. In each case, the result of applying a dilution factor is to compute a concentration in a medium of exposure (generally air or water) at a location where people are exposed to these concentrations. Conversion factors: Factors used to convert measurements to number of fibers per unit volume. Concentration is often measured in terms of mass per unit volume. Conversion factors are used to change these measurements to fibers per unit volume to conform with the usual measurements of dose in dose-response relationships. They are functions ci fiber type, releasing activity, distance from point of release, and other considerations. Breaching and drinking rates: Factors used to convert the exposure doses into the intake doses or dose rates. For example, if a worker breathes air at a rate of 8 m3 per 8-hour day, then one can calculate the intakes of fibers per day, week, year, or working lifetime from the average concentration in the air of the workplace. For nonoccupational exposures, one must also account for such variations in rates as those occurring between working and other activities (including sleep), between ingestion of water or (in principle) food, between high and low exposure areas, and between adults and children. 266 Biodispoaition factors: Factors used to convert intake rates to dose rates for particular tissues. For example, if one estimates that 30% of Che inhaled dose is subsequently swallowed (National Research Council, 1983), Chen one can calculate che dose enCering Che gascroinCestinal (GI) Cract (fibers/unic time) from che inhalation race (fibers/unic time). Disappearance: Removal of fibers from cissues. Fibers may disappear from cissues through excretion or through various degradation processes. For example, fibrous glass appears co gel (Klingholz and SCeinkopf, 1981), whereas chrysocile separates into finer fibers and fibrils (jaurand et al., 1977) and shorter fibers may be removed from cissues by macrophages. These processes limit che buildup of fibers in tissue. Formation of ferruginous bodies also may "remove" the fibers making them less biologically active. The dose rate and disappearance race together determine Che buildup of tissue burden of fibers. SUMMARY Although the above list does not contain all the factors that define exposure at the tissue level, and although the conceptual model captures neither all their relationships nor the difficulty in measuring some of them, the model does give an idea of the complexity of the exposure of an individual to asbestiform fibers. A further difficulty for risk assessment is to estimate che number of people falling into each category of exposure so that che distribution of exposures over che entire U.S. population can be described. REFERENCES Jaurand, M.C., J. Bignon, P. Sebastien, and J. Goni. 1977. Leaching of chrysotile asbestos in human beings: Correlation with in vitro studies using rabbit alveolar macrophages. Environ. Res. 14:245-254. Klingholz, R., and B. Steinkopf. 1981. The Behavior of Synthetic Mineral Fibers in a Physiological Model Liquid and in Water. Report No. 81-0-08, ISOVER, Grunzweig und Hartman und Glasfaser AG, September 30 (Translated from German). National Research Council. 1983. Drinking Water and Health. Vol. 5. Report of Che Safe Drinking Water Committee, Commission on Life Sciences. National Academy Press, Washington, D.C. Appendix E EPIDEMIOLOGICAL studies among cohorts exposed to asbestos Contenta Table E-l: Studies of Cancer Mortality Among Asbestos-Exposed Occupational Cohorts Table E-2: Respiratory Morbidity Studies of Asbestos-Exposed Populations The references given In these tables can be found on the list for Chapter 5. 267 268 TABIC E - l. S tu 4 i < o f C<ncr M o r ta lity A a o n j A abaatoa-C apoacd O c c u p a tio n a l C o h o rt* *SM - ( U n d iN iie d a o r ta lity r a tio (0 /C ). ;i o V K szc * rO J> S s a a- ao m-- 3 >. ws o r^ o e-- wc c cr "i o -- to 9 ea aa a a to X l O -- o T> w c > c a a o-- a ^ WO--*. *to a to to --- a 9 a a -- jc O 0 x-- a &x -- > a a 9 -- jt --xx o a i a :I --a e i a*- o . [a*? ---- a , a * i * a -a > --u oa 1 a2= - iae: aI if- *- l-- -- la ^ | ftJaO* -- o -1 J r 9 N I to- C aaa sk X a wa o aaeue*w ---- 9 a-- a a a wow x w a e *- a o -- c v -- pa a X JV X t ---- 52 90 x a- to to 5 2 #9 * 6 a * -- o e o -- xx xa c s :i i oa s -- o -- ft. . a ^w< to M O . a-- I9 aa 5' e-- e w *? x : + 0 , - 8a 0 w g to i-- g 0---- 9 tao C e 25 -- a. a-- a a u %& ce cr 2f w 65 ^9 w a x r a-- -- C ato tao. 9 * o_ 9 9e a0ft *a aaw*--9 o a* a *9 a fl^_ a W a > a -a a -- a k I wt i o K a a -- ao e C -- m aa 9 faat**aCS -9a ---a *o 9a i--x ** ! 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O toiO 1x e . -- Cvto c--X a* to e to e w , -aif - .> -tJo W O :( --X -- o to X w to * to to X a* o to w ^ o* to vk I o ** c to X X e a* -1 iS -- a> > to o o-- o - a 0 -- to a to o o * b-,s.: IS act ^ o o oo> I oi - - - - * o ~ j ^ O -J ^ ^ 3 "" to to X e -- 0 at :3 to to - --e to --to c - v at w ----< ----< Jc3 O o> oto to t* t3o -- to ato *9e X0 at -- X0 9a --x Xto at > xao to^ > to e -- 9--X- ** o at I* to at 9 -- -- o 3 O'X X to. to. 9X X a^ ~ 2: -- ce a --X XCo9xI to e 9 I Si Xto OX ~> ttoo a (9 | . st 9 aI O~ ^X tOo** --D --to C* ^ to to B X a -- -- cX X to e to --a -- 0*9 0tIttooo --69*tteoo*xtt0oo u1 * 0 tao a ;i 9oe tCo 9to Vto* 0 w :5 i at B * c ;.to ^3 mallO >9 > O a 9 a at x a *0 t-l tao 23 . s9x X 3 *e vSo 9_3 K s r. 9 " * " 9 5 to ttoo 9 -- w 93 feg .o 2-- # ; 3- e x !to sto to* to XX 9t 8 271 !5 Lung cancer date suggest A n th o p h y Ilite i i b t i i o i m in in g . ?46 d e a th s re p o rte d in 19 ?< r e p o r t: -- JL * i; m* e --3 OC .5 uu SC --c e e M i* --j| X Ma. i** t ?to O s aC o. . O u 3 li SS t 0 to to -- to O to to w to to C I eto -tetoo ttoo *e fsf too d _> <J * 5 <3 to > I- lo c K io n ! P intn4 ttoo 6 -- tOo f0 *" 3X - 9 to > tot 1 -- to - -- ttoo tt*oo Xtfao --^o> -to -- : s: 8i. o 3 "to to c to v ;* ^tZo t2oTitzo9 ttoo eto ito -- O -- to to- to * to to oto'ttoo--* a toto 5to < taotoC--o t-o'OtoQ^'^ ai .at ^-- --* Cto M5 toeg to to ^ to ^ -- to to i^ > w -- C - ito to ?7 ae * 9 * e *>e w, _ -- -- - -3 C Z2 xWtOoC^0S ttttooto-----to--tJot'oTttoo**to ^ o -m -- a ~ - x tot<o> toto--to --^Ce----ctoo --^to ^oto ft--otkw.5to- 9* m& m a -- c - -- e . to^litole* -- " | xo o ec Jar ,j |o to | tqoe-- to^eoo it 03 ws * i 4 272 *1 S m'. x * . # o e 11 l l "e * i *eoo . -- to 0 -- --e toX " I to C - * Ic X,,I-_taoo.. 9 6* 2 uw X hi to "O -- 2 e *0 ---- I to . x 5 >A 9 ja w * r- <3 \.l i ' 9> <6 * c-- ' o H i ** +* <x _ aai rhC i *. f0 1 ' , t i e e 5 -s .:! wc --- 3 9 to to w X -- e . -- < 5 -i to r ooM V X e I O X 9 *" f ^ r. to 9 9 9 *C to o to* to e " " > o 0 > o --*" . m ^ B 5XPiv9 -. --to -* > 0 C 0 :1 i *Owtoo 5 e ttoo - 99 Xpt*o9i t9o -- to --to &9 O -tWo e c a w x to e u. & i s. 2 e e9 to to a. x o 9 to * - 5to I to w I3 ;* i*=^2ts?2; to. 9 a w to. 2> X>0 --* 2 V6 w9 oto -- oa KO 9to ^ ttoo> C *t9o --o& tSo ----to xth#o 9to to 1 C 9 0 tb> 9- Ke t--o _ttoco "to srs-Xi tIo ttoo to fto .<98fto lliilu Hi Hi2 a 0 VI S - O - *0 e1"* ttt9ooottttoooo^e-*--t*too. *to **#> *w'95o 5o*r 9 m 2 35 >a la ta n c a Si*maty o f C o n c lu s io n * S p a t ia l Co-- e n ta __________ 273 sis si = -0O*c3'0fft-t ft ft 6 ft a -- -- w^ a a >a *9. 0c ew c oa o ft* -6 c ft -a --u u au * a A ' -- "c e * I 0ft *C a . --a a-* -- u 91 a a--* -- c3a -- mo~a i xeai**C* i - s S3i'** w ft a a i> eaa a--o *a J o I--a au ft* a 0 ft e o o i: fta e3 <*k --a 0 --a-- a* -- ft* e a aa f^ta* T5 aca 0oa. a ae a < M o ** c r * - a c a rxZftaO.cfatO-- Caw9ul * i a 212; r .s ? sa - o a * a a#aa #&ox* i.i. a o ft a i!*cbi oc ma xa *c# 5 wa e * a 5 a c aaa o a/ v .S"fa a aue aaa--ea~e a * ^ 1 I <?x "ft 1 o x w aua * _ ea --aft a ** x u 9f3t* r^ at ese -- e -- -- a ft fxt* *3* a --a .a *- ft ao 3^ ao va aCafc --e o *0* Xa a a* -aft* a] * * -- 21 "- a3 eu *e --c aawO *> c << ^u Ca J? 0 > o ** a an aa eft fft * -1 * S. ea a * o aa ! a< 21 v a* I c a :;1 ii* | *X * 5o 0a a * a a Moultp a n < Q > it> c U ii at it a > ta p o a u t 2% -- Of*t* ft - ft w Xa o * 3a C3 0o a few! a -o z~i ae a -- -* o 6a a a9 3*g <7 x a ft w a > ~ ft *.* sa x* B a X O' a t* # * iZ ? ** *" * e . Wft # a ?o max u fc a - ** a * a w a f ft <w -- 3 o ft a a a ** _ a *5 ^ -- -- * ft 4* Q 3 ae x -* !*e>--*-*a g .2 .aaft a* * * H - ii" t~ c: ... sir ~2 :1 '-'fie-J - c *, iit^ia * j ft*!!2!aS*-^ aftjwa--*bg- 21 ZZZil82S *- j a si. --a -* v 2 ?: i* (x i e-- a X * k C ohort S tudy P o p u la tio n and H u d x t D aaian C h a ta tf r ia tic a 274 Si Si ss 2* x m i -: j H o X I ^ -*9 il 9 * M *. o e f > c -M Cto -j0 *to to ^ 0 i>0 sJH 11 c e o U 9 > *< -- - -- e jo: K M - re> o-- 9 to f ,ij2 i'to". e --iso i c x a . Stoti 8 I S *3 ^" ; is i to -J? "to i:si:: U a OI PU" u c* 9X o 1e "* a * f5 99 -<->' " . * ** ~ ' --~ I X - ^ j ^ X tom c J| o ^ uil sr ^ il i55 ~ 0 o-- t' >. X*t"o)> *to -*9 t0o Ic l*to ** S$ < me 11 i u e c -- : 1 W w*toO --S X0 .. ---- C9 toto to t0o --- Cw* ^c 9 *to .! " C" c --c w 0to to to e to e !3S 3u p = 1 _ i; *C to*-' =to --? & C Xto t * e X* 8 to to 0 to > c i to toJ ^ - 9 X f .hto e o <** sf to Xm t*o xto to e eo to to :: *s 1 i 1?XO ttoo Si > *3. 9e *O.--c o eto - II u 9 ~ Sil &4 S3 S' :7: s we i-SI s:; m to e 2! -i - c r^o^t tof to tXo- ttoo >' _ 1 tofw *0 9 O' tIo r* I 9 * toto Ja ::z*z~l8 x ?i: *S|- 5 ; < - to * w F - X 9 ^X 0 ttoo ^ C9 it'? *-- Cto eto 9 ttoo $ i :s X 0 Xto K Xto --W _ .e_ _ *. to to -- X 3totoF<Vto 1 2 , 2 *S ; 2 :i:5h>? w 0 < w 0 * >> O 9 90 X #* -8 9a -aO t9o ** --0 X0 **> : Ji M lrn n c t *v tn p a rito n a a l a cro th rIio a a a obaarved (ona o l unknown o rig in ) Suaaary o f C o n clu sio n * K aaulta________________ and S p a cla l C o u r n li 275 a e* i I i-- o i--X 9 a 'i to Xm -x > ** - -- v a o aw a a a i a * x o u 2 Jo to a "5 = "s - *a i,a&af tmo . oc iI mtooO oM .*b*8 ; o ia-e - - - a. * i Ma--*a-w g oa tao.* -- a --0 * ** a a a * m--m* M V * W< U w o*0 ouo^OckMeacu a<5f*f**J -- aa **O*a"O --c m m^ X* J** -9:sase M to to* --e oa* oa**<*o 8* t-o* *t >to to. m^V *e9 --to # two --to*. a .c a a* oe a- > a * -- a a a u wa a < *n- -e a 8 o ma9I --9 a afoe xaa aa ato I-- ^ C II -- ---ox* 0 a 9 6I a 1x a I x O C x * to. to. S -- fa a o* X * to a a -c to to a u a a a <o o fto e 9 tom a a> wv O aw ato io-t. a m * xa e ae ma o. o er C a x c -- -- _M oa I ma O-- ma mc ato i; * .s i aa o t0o X> --a ---- o> a 8 a <a ^a toa. x* | n r * 1*1 J l to* 2| *7 *a *to to* A e e to > a - a a* . Cr a x a w a r x o c1 -a* 2 * o ~ S7 9 * a w a i.c i s *r aa - oc ?I o- too t9oo .ma m 9o ---- a 3 * > > aa a a** to --*. e co ^^ 3 C to ^ 0 X a-- w9 s:; - M ~* ol - i~ <4 to> 1 - 2 S c ttootor a3 aw --o wi xa ---* c3 aa < -a " i -- a* . a 2C Srt 9o a, to ttoo. oIa* oto ~- aa :z -- C ^9-- *to'to .. teo --a. a- f- *a---- - ** o. 'o w o c a c -- 81 K. x a* a o *** o a* a i a ho % I < * e s layoaura C h a ra d e r i at ic a oO a sa 2 a-- a a aa a x oe to a :-- . 3al <a3 9-- oa to -- tOo . *w* Oa to C X M O 9 wa tz M9 %e .9 e o 8= 2!: o9 aa i e ld an la l r p u la tio n h a ra cla Po C Ito d y D # sl*n C o h o rt Wuabar 276 ii 2 2 2 -- eo-- 11 i " c~ ?? > o "a "a . e : . o u i"s Iw: - A u-- c w0 9u 8 5- ce -- i: - i x 9 0x9 O j( --C <9 9 I| r> b 4# x & A C MX O9 ,_ -- i -- i i|S!- Ox w I a 0* <- O 9 O u O e9 e --- *UW 9 -- 9> * . C ^V j: C It ff w * l .i C ~i . s .-- x c 9* .X w <Ju SO O 9* -- 4* w 0 wX y ----< -CaI xCNJ CM eZ* OxAv**OA*v>* A-- M "lie o e ~ok - -- c o I -- e '* 9 9 9 ?I > --> T<9y , 1I-- o C , i: &2 ; & *"X9 ->* xt0Vz--*** ie --I 0 I m0 xm X ee o9axwm - C -9 a -- 9 --0 - a3 i-- 9 J- I 9 VK 9 88 i--- u > i" . 8 "S ta C -- * 9" <1D ---9 e^ t*l J* f e e --c a ^-- Ua 9m 3*9-3-c ----pSU-*3e- Et i s n d uoamry of C onclusion* S p scisl C w w n ti O K*| -f * V * U 9> *1 " I? mv L ^ i U 55 0. u I , --O S S ii 9 i 0. V h. iI X9 i < 9. I' ^ o ft X ** U O oO u6 --tf --OO U9U M ^*" V M9 i: l v-- -o e ~ * O* f'*v'* - me -- <om w * w w 0 C r fi s O-- X - ea --o*j< *1 ;i jl 277 Eaposuts C h s rd c ts ris tic * ________ * i u > u --#o vc 'O ^ * e a W V X9 -- to o a UX-- > "o ^> Ve x-- m -mc & i o ea . u ^a iOs: o. --x cu --. % o S 9 9- kX I *- C wu> * e a x -- --oo *b -U * --9 o ^ca oa --a ou pF ^S ^ x a O -- to % o a-- - e ** 9 o9 e ** o-- tWb--muc o-- o # *: I -- x c to *o a -eo3-- oa i e9 S z9 i9z9 11 % --s ?0 , C o h o rt S tu d y P o p u la tio n ond| B uabsr 0 * o i rt C h s r s c ttr is t ic t M fsrsn cs Sunw ary o f C o n c lui ns iof n s snd S p e c ia l Co-- 278 r 11 oU t^ vo ,' Mc+mO+w---*--o0"Jo> _-C 9 w+* --v* -- ' * -' t M O -- *X * --O O9 -- Vc -a o "i M ' tOtm mO9 ' .00^1 !*** *o 5* c 9 : i t, o * o e ~ -- o --e > --c v --e W* o -- o-- il 8-2 .** o . w I t o c --o 8- If 9X o- C h; Oil -r ; il 5 N* -- < & E a o o su rs C h a r a c t e r is t ic s _______ S s s u lts oO a9 i om 2g I -- ""5 x 2i m 9o HI o 9 oe $ j: ow e o> O* --w 9o; :sl c: : o i 2r S 2 ? & oM e e --* -- --c X-- * * -- I * aUIaIOaI f 2 O rrrx' >* -- * & c - ** * oUO me 2 *n- o-- b o 3 l2u--CO<s?u9Ww-O9 iSbuai w m r-- O -- ----eO eooeMw*--ooO--o g - a9 0< _o X-> * *_ a_ * ^ * 11 *8""2S"2?_ O 9 *. m C c --:o ies ^ i= *2: = 1! C o h o rt Scurf? P o p u la tio n and Nunbor D oslan C h a rs c ts ris tic s 279 II M fo r*n cs ______________ Co-- m U S u w iry o l C onclusion* S p e cia l *n4 E apoaura C h < r< c t* r la t tea_______ M i u l U 51 ao m* ttuoo to9 9> --&mCOstoOe* e9 to ---- Afa 30to *O toO> 0 <J t0o Xto 0 '-*-o* o to ^ to "> O w to *e > --o0 " to ' * to0* to 3 < t 6^ . toa x0 w to 0--too-. t o a9. tOtoo Ooto tAo O e U t--"^o q.1J 0 to 51 2~ *"* - to- -- C t3uotCueo*Ctt0---oo>. totwe i ----X--tO0o ---- e9 to to < -)u r mi e ,i aj to- to* *- 3, s ~l to .* -- -to' SI =' 1 c- J ^ e> to** i -i ^ 6e ::: 50 to*!--iito 2 cal 0 tejl I 1 * o" to -r ^ ^l.---.5 -*a a2. a3. ~-o to. -- oc tOo toc * u eto *kt"o to * to Xto> -- kn*o"> e tco : ci: to w & I si< *Otot-ot-oIl teo t9o to to. . 2. S to ^ mes i e to - fa * -- to ll to* to- 0 sai :i-- -to to. to 3e teo toeo*. e to *to rtoi, o -- -- to -to Ho-- *to <- *to 3f I 9 I m n. a0 2c S4 0 ~O C-- c z c A Iv o O o e-to oto. oA* --I --e , A IAtA l A| : r x * to Xttoo ttoo S I * _** to 5 S2 H9 a98 8to t-oeMh> I6S I? 3 -- - iHto w* x tkt to- A. A 9 "0 oe tt*oo*i tto9o 0 s: tIOo\ t0o Ttwo * l tatnidc icofnr o p u l t C hara f n tu4y o a la S P C o h o rt W u nfc *r 280 z -I S r* mftli " w o * f22s c i! (OJ U 0 --ft til i: M .M O 9 Mt & o ft<* o A C -- * k -- *--" _c ^ C c-- * C ft* e9 oft - C- <ft* ft e. ftk ta ft--e --"> --44fty <c--oft ft* | J * o 0> cuw ^> **_ (M5>3wJ S* ft o o * -- x *7 ae ,,Sow B ** Ma * fft ftO i ii II fkt xf;t%X -- 8_ :e x .-o -- ew o cm --** --^ xxft Kj fot 1i^o f*t fot fat 8 -- fot x~ u Ja* 0 - ftte-f-t<*9ec^u* _ o -- ft X ** K Op*-* -- a--ftjftftt jr--2 j*;wJ CIfft*t-ftA fh.t--*^--*^X jI e -> si . -- -- fXt --c mm ii8 --o 2. fOffttt MCft ft _2. --Offtt** "--Xf"t ffott fOt -- ft ft c m ti a -- --fct -woft ft f8t ft ft b W a ft ft o i "if i < * 3 ** 4 51 IS -i i X 4 M' a d il a ^Xfffttt uft --*ff0fftttt* eff*9tt e Oft ex 35 C ft ft -- ft -- -ea ox** 2* . o ~l Mou Mc e fet b** i'ZZ :nz 2 - C fftt' ee h*i ft ft }e a --ai - S5 ft ft w Of*t' --kft, e ft ihN^^ uft ft ft -- O fot -C f--t* -ft 2 _x * --* ft ^cft faftt |j'. ;! efat oftft>o M O1ft 4TKJ ftO* f*^ft*I*t* I--*ft ^ir~ r1C 8ft -. fftt ft --ft U >XX f&ftt*ffttfftt "Oc> if1 ft* ^5 ft 4aI >fKt* f_ct S m-- *-J 0 K ft K-- X --x*- X"uo *4fI3ti S afaranca S u w ir f o f C onclusions fcapoauta C h a r a c te r l a t ic > ________ M a u l t o __________________________________________ and S p a c la l C o ^ a a n ta ______________ #--* w0 to --p_to el* M Ml & . sJ- il 8ft -1; i si o~ M M M O aa* a#a v0fe* 4* O M [a g -- -- n o yS -- M *O u .e Ioe i o* j toi e eto &a 1o a. - to M * r0-*^018 x -o .e oO 4^uOm ^C c 4" 281 - w" *! c * 13 5 ca oj ^x j* aI *to -[|'I i. si | 5<srr * Hs . ; o a * O oto 5a x oa9. a> aM ^ A m aa9o "ea to to OM O--k ttoo * I -- * K 9- "5 *X2- .'Sc e to a a o 12 5 *28. : 1|ir. y 5:]1I o .o a d ^ to * sa to K a 4 to to mao -to to4 3 e- C ohort Study p o p u la tio n and N usbcf D aalan C h a ra c ta c ia t U a 282 C-- I 5 ii -- to to -to mc e c1 w c $ ii om "to S3 to ewe . K . c a <- - 9 ft . 4 r* to O Xw ttoo ^ C M I ts e- *O to c 3 -- m ox ft -- .m ^ -- " -I . -- C ? to o -- S x O xOI --K& tofit t9ao >O- * to 'to X to O K 0 ittoo ^toto 9**^0toJ teo ^k3 i= C M to to -- o 3 ei to to --v 0o c K to tt9oo * tttooo to to to to to ft to X Ml Ns X " 4 teotoc to --to C O< -- -- to e to 3 to oto Xttoo kto xt<o < L. J W r < 0< ' XW 9C to C| to --to M --to-- -- to ----ttootCo ----ttoo--^e-tot0o*tfo-ot --e^-- toOtoOtototov -- to -- 0 X O ,,, sKtoKtotoU^ a $urru X r-i 9 9 " -- O' ii # ow --e t--too K3t9o cto -- to to 4- * 3to t>o o-- ft to to -- 11 o-- K I -- to to ft ft &2 X -to --Il - s9-e ek - ssW ^ to| ft 9 to O 2K9 ^^t-o 0- 9ttoo --* 'Xttoo45Of**t6to*to0 -- * -- *X 0w --to --^ M3 5 ft _,i ^ft oto eto 'to eC -- X <> to r.?ii2u**S!. * x 5* to o - -- to c to* o _ 0 *to C --* ft eO to. to --ft ft -- fftt ttoo --to ^ 9I :i l ft -- C e to 9 I to to 0sX?i r~rli< 9 e . e . 9 9 I o I-- Ctrotot|_o -----toft#t*--C J-Jtoe Oe- tW>ottoio --- o -o cto & *to . * ' 1 39 9ft o --o *" ^ x e 9 ft e o ft | i > a la *a c a Hugh** and Causa o l Death Ube. ta p . o / t M e k increased aora s te e p ly S u | o f C onclusion* and S pec1*1 toaa ________________________________________________o l *u 283 I to to :toewW3 e-- -- i^3d-o-- ft ft 9m c m 3Io hua e e uo in tAo sK M f9t to c - a':*! 31 a i *X w tVo e --u XUo* e |2"s* I ir -e ; ft X f| 9 OA s.r e39 --o --ft 9 - aft a9 i 2 i -- --ft ttoo ^ X t*oi 56b X O to* t g=, S3 |j to -- 9C ^ e9 -- O9 *a m o ( oo-- e ' to. m 9t O O O to N 99 9 P' 9 9 j| to ft 9 m -- 9 9 e a9rt 9 to* _-9 ato. ft --i tOo * O* _ x-- --ft eo to tco 9-- a S 9 ttoo to > S 6 *^ * e m-- 9 # --to wo to X9 -- X^ a 9 * - * JftStoSe---1toSo S59 J- 5> -o j- cto S' 82 : *2; to. to to - toI : sto ee tt9*oo gg oto Stog- -- o g A ue C--* to "2to ~-- 3 2to *" "2=5 22"* -W-VMCm u9 ftl *ft *to 9ft <^<i33 Xto 'Oto*t3o-99 _fta --v 9* 9909 ft -- pa 1. . ferss--S<A* *9> 9J tteoo 9--9 5122 * 2'1 2to 29 a* S O 9 to i* to V * ft ; -- * * i: 1 ;i !m i - ft --* 9h0 252 222 - 9 -- _ --c 9 w* - f * &SS 2 i e> 9- -- -- Id* e09 tgo* -9ft 9---- x. * irj-i*3 fBt e9g noto 9 to* *teo*ta*o --- IS 25S1J : *: y a'3 5 to to to -- - to jS to 0 to i -- -- -- to x? 2 i 2to 2 is *s:is i 9 ft O -- 9 i * T " -- i>X ft to -- !s s =-99* -- -- e* 9 to* e -- O -- to to . tt99oo _9tt0oo --Xef-t to to tottoo* 92 t99o --to ** *t9o _9to 9 to to Mw *Z U9 9 W ft -- 9 -- to ft to ---- - e 5 -- --to -- 9 >* aii:h 9 -- -- g to e o d -- to to 9 9 Xft --ttoo 9tgtoo gI g sal2oto sto :9 S ii 1" K a m ila ta p o a u r* C h a ta c ta c la tle a ________ fiadoalnaat lib e r c b ry a o llle , Slud fo p u la tlo n and Daalao C h a ra c ta t1*1 tea lo c a tio n ! U nited S tataa C o h o rt Huabat 12 to R 284 O #l !c 1 3" O --| x a # c -- e o* m e e a av 4M e w mjz i w --e c - - 0 I --E0mau x - o O'----** em l;*#- c CX 9 t - --9 9 u X - a_ * > " VW*5 x9 4 Oh _ M K 3 i U| * 4 ol - ' 4l +* a -e & c --- cCO- o * 5 c -- a -^ to to -- 31-- 5 - _ C 1 in j u XI X x to -- * * A X CO ac* Xt ?;-!; e Xto k. --> *0 - ---- *W J-- o X - * -- O *1 x to Oto' OO-S .8 i f <3 A to O ti s 3 u e ce w *o- v X e~ ---- c a < < -J o ^ - -- ~M 3 3M X KiH if l .H si to i 4w 1* --* --e C O to *0 3 C --^ mw O 1 13Z-- -v e3 -s L CI O * "*bo* 9 <0 a < -9 --tCo*o a-O* tt3ooo .A3. --tCCo U A 0 9 -- M 94 ?- o --X X0 g a g > e x a At -- & c0 --* to 9to --a X -x 5 6* V <S O k> a 0b. c 9 A-- --wcmO O3 !t>"> Sba". ;s:i ---g *o Is 5 * *-t; . Xto ito | 9V t2co-be S. * a ee a ma e I cue -- -0- a9. tCo XA-- 8 : 1. s i9 :I *s ;;to fto toto i a*b ato* a^ o to Xitoto IA to ^ x e 9 m9 ** -to 50 --: wg "ss.* ::toto to s ** *3 ^ i;ae jto au ^e Jo o too - e c x to w jx e a 3ea*a*2o A^ee?b2 z+~tzx~i to to ttoo A|B to % *# 9 *1 0#_tow* x: a',xx L4 2:s:;i:f:: 2i 285 *X aw to X 9 3a --e ue S3 : xX ** * 3x i u^ ve :> to. ~o3 9 aa to * to too to x m AS mMx *- -3 O-- | -4 OD ^ qJ Jit to 9 *1 r* -* Ml -- . p 9^ ^ to V ! e me 3o c !33 -- -- -4 ^ rs <s f* to ^ e ^x -1:1 kwO O U t e -* tco 3 * a9 wm0 .> *j -*-- -^ x v to to to t* -- o _ J- o d m* a vi ^ tXyo. to O W -ttoo X * .H to v - ^ " Oe 3tCo ta _o * - a. ^ m *0 u * e 9 t> ^ 9* " h v j Zto *to -* OCt 00. 9^ _ XtOtoo tOo t--*too* 9 m o 9J O to VI t3o tOo VV r i- JA2 i s e x *9 3-= 3 :3:` sttoo .t9o -*a* 3t*o 3oc to &to to -too tf > O ttoo to to X O 9 to x 23S XO ttoo to (OJ 'i iJ ji ^* O to > tttooo to ttoo oo Xttoo o -w * to ~9O x 9 i-f M t9o e xit2 k9 #to9&to X9^ Jatot0.oXtoOttoo X toi to 0 -- twtoo 9g ^?to , e * x * x X X to 9 to -- X 9 to to x to I I to oto * OO ttoo to w I .3 2 t-o -- t"t X ^< mto 0 u k* oo* <to . x: " * >m 9 to 9 X to to i, f H Z a e-_toto .*2 ( = siltSortoj i a x &9X to to >9 to 32ta - 2 I'J 2-8 2* lo * to S ao St 9 ^ to x <n to x ^ w m * | Ao S11 ~ " } J, S S 2 A " 2 5 2 8 u52 3 5 5 ototoXXOVX'Q"9toto & toOto9Hf93 C i o x' ak ^to e 3a ai o to*. 03 u 286 ii rl-s i lr 3C M- --C I ^ -- --ti 9 -- K V --f c -- e !-- -I c vy m --e ji o o o - c. ex ` -Cfl MJ >* ' X- *5 ** I W < 9 M <W a 9 X0 0 y V o9 x * ~ - "o s --> v i | > -* oj -- ^ t <-*' -- -- *> * * ve e T C-- y 0 v u M -u ---- ---- C9 y-- V ** W uX t C --O fc* U * X- 'f r V z ?9 Cy 0-- .r y i o X -- ` X4> c-* 9 ' ' Oy -- fc --r* >-*>>*r* IfS, [> o > ,e ^> --u > 9 w A> ' C c * --e --e x -* te <o y V * 5~~ x^ --o --e y teK C * S. i^lX Cfy * I--K* ~ ~ --w e%I xu e "i ** 9 o s"fs-E)y --K> O' 0--.> -- -- ey i: -- w -- o- o- - o mc --e x m * xy i * I -^3 O & <y * W 1: I r -f --i iI : t 1 " e M99 eO m-- --*"o* e ue --e y O " 9 iOk X 12 ij: eo u --9 u :s a"M C ~ 2 :i m oi X 3X * iiX* o e e !* rs 5* ----. _ xou --* y _ - - , m, -- x ztzta iXA X <B 9 -= e r *o-o - >-- --x "SI S2 x < y-- -- * ^ - X --X l, k. y -^ --* --y S J2.L 9 -- K o to o --"I al y ~0 > --XX --o -o f ---- --o xo y B> k u o-- -- oxl X X09}**1^ x w xi -- 287 Summary o f C o n c lu s io n * and S p e c ia l Cowm an!*__________ H e f r r e n c t i eo *^ f= wa a * 3 a 9 >. & SOX ---o 1.2 . a eu t| --X --v v a a < i - --a ,r m *s co aa* -- --- o^-- a. Zw coca3--f a -xa TW -- * U o o a e e o 5a -- a aa o3 ?u a h. ma> ao - ak. --yc *aw?o --o '> 4' *a*x*--cu> -u I a ue *C --C aw aw we m- ---- c a .i ^c ---- ae > aK* --to x 3 --^ w u X wa xo --a x-- -_ --e xc * og a3 as toa* oC to * S t j : --aaa a t a ax e o aa a XP e e o wa o aI a a 0 a" a3 O to . e r - a 9 -- 3 - --!>r* >a -- X O' I t o a V) ^ * 3 O ^ --a ou e a* o e ca o<a* .. o o -- e -- eO I to * aa KC m a c aa ua - e-- ma re 3 =* 1 5 Jxa aot -a a -a to a --Z aB Va ato W <J u cn*C<-- 9 to * * to > x f X ------a-. -a------ Hi H c *u lt* Ewpoaurc C h a ra c te ris tic * C ohort Study C o p u la tio n and Hubr D ca ltn C h a ra c te ris tic * 288 Z\ tm- ri o-- w Cl iA h ^ c-- " o *"* to to x -- m v " v em eo c w O-- e * e --l mm M 9 O -- to to * O. Ck. --m to x oe w X C to to C to X -- * o-?> ?--: o wc c * * *- .wCO3 ettoo* . *# to. C X --*t"o to _ttoo t_o a. + o a. -- -- $r w -ecw oi a O X . O Iy v 9 * X w C ---- X x * IS tSSre.S- v e C C - --O W Xto --3 * io -1 **t -- -- x 3 ^w ea. y . -- 09 -- &l e 3 o e < o to 0c : ! 15 S XX 0 i i5 f-- o -- * ** C ^ ^* ** ( "* < to ss <X iJJ w ee -- 9 e -- w w w m wb tfo xa; w-- ---- ea w to < < JO X --C wto I e-- e 3 *e I: -- 90 to t&o <I X ** 1 coo* --x * to to to > to o-- a to. 9 sir; a. I to ( *-.2 I ? c U W to C to 9 C to to -- to , -- e to e sS Si C0 ttoo wu mm to. 9 to e3 eto -e to otttooo ttotttooo ---OC w-*I - 2 to * oto 1 r* I 9-- l t --Ce w e I e M O 't 9 S6! 9 & toox-- e --m to x3 e 0 :sio? 22 i~ZZ to to It :i --to e toe x O0 9 9 21 ac ?9 ". 21 289 O ~m C, t 0 9to 9ttoo Kto K wO *N^rO t to * z% x o9 X** X to X . .S Off 3 to --?S --2 !:i :r. 9 V-- ~ X mm Ev zc o -~ O o aK. . (- <xT t*o* A V M ^ -- --4f# ^t"9 *< S'* 8 m O 9 *9 o c X *---- - O 9 to XfO v* * Xo ;""92 5 -o3 3c *9 a - oee 009 OC 9* X 1 si o o < ^ (T <% V* 4e >f-9 I *4 U se C uo c *- .-: -9e> o t. *9 JV1 *c ax 1; to o 9O -- ae to o \\ I t9o --:t>o 9 ee i r- rw C to * XMX99 t>o *9* e0 I O to 5 2 -- C to 9 5MS 9to M tfof -t9o ito fto *t!9o ; * 3 . * x e -- x :*sE"s =s2 # s ss *~ til 9U Si 9 .. --Co mu j 9*Xto 9 tof_'Wf toX* to ^to *---to ^ . e xu e9 e ou <hi*" m to <X* fc f* t:.-:-;115 its ttoo tXo to * 9X I0 I9 290 IS EI . u -- x o *o t II e OK -- c -:ii c 3U -- >. to Otol Vw to 0 ii --to. -- t9o C9 XX---- -- CX C to to to to o *- * M_ -ttoo to Oo to to Q T> -- 3 fc to O X s| i: ctuo -wto COOX *t1fo'--c:t,o -t'o*9' w ^_w"to 3 --9> to O . k. to o e o *. c X -J * O 0 - X-- ^to 1.0 *F * (0j -ttoo * x to--x**c* Z * to*' w '* -to to 0e --3 :* C -- C to O O O TJ Ito :9 I a. to ^to oto ;r i o & to W o c X O Xoto e --X O t0o o ~ . :* --' 9 fl ^r C3 2!! 3 . to O O ^ O "to to X X to X O. Mto --* 9 to > "* **-3-" s- fso Xi- -- 9c ^** Wn 2 e < ^3 -t>o tCo C "3 to eto 0to ht.o 0c 0a WK W to X0 Xto V to -- ^ u o _ --to o c0 < 9 *0e m to. -- IT , ^ttoo m9O oo iU JX 291 *U g5&c S^ u U i uaaarjr o f C o n c lu s io n s a n d S p e c ia l ____________________________________________________________C o w n t g .2 V 82 " J3 >. O u 3o *a --e &* t u : J m --a n2S & 0 M^ V II JJ I -# ~c3 T_VJ ,-- e a o c , b -*<* s9 !" UC * e a II 41 a a .03 w 3 * - a 3:25 > * Jt Ta9 3 a :s^ .*s t*-.1ostis M o ^ 33 ; 22 > e > + * m-o -*o *o -e -- i- *3 So 0 Si ^i- # ^--a eo -* o-- a-- J1 2:1 _ 31 :3 . -* t: Is I !2i<3 X i4 O 1 -* a u a * a * a a a a a ^ u ;2 1 oa ^ a e 19 -- 1 a a -o wo> a -- # a - o. a X ao w9 9w ^ Ww U9 < v a w 0 0a >- a c - - is u w * a . *a r* aa ai -ao>a-2e* a. a or 0 u --- o u a a * a ^ a a a as So t* e0oa o0 <--s_____ r> -* a -- ^ 5-:at0202-- i a > - ac ;|8 & a ma --Ca aaa. 'a * m ao sisr JC --a 3a s a a. a arf - - J^? Ba 0^ 1s : ,2s *# a w o !So3=.3-3- =? 5Co0 .2r, i: S2S3S 3 2.3 ft a aa- 6a au * _TJ, IS ae a ti a -o a .-3 . ei. ou 9 ;2 a a4 1*22 -.2.3 335 3 2 3!. 2&2 3 5o ao 25 E "2 is ^ ao ^a w0 o> * a a *-* a * 0 -> 2a 3= fxi 2 * ?3 *3 3 2 is; 2i 12 3 E ipoaura C h a c s c ts c ls tlc s i Uant ldc tc( oUn i uaktoi f oQp o S tud* P aala T ftblv t-1 (c o n i.) C o h o rt H uabtr 292 S r^a mo m d f i.*ika 0 O M 9 k- t9o XV 2 S f& 0* "0 M U M e -- . oa m.. t(0oJ e0tfto) -----a fM9l ------oi U -- X >> 0 U U to 3** * - ov* --mw^ OI 3S U --b0 t9oO'*** * - >O 9&m Ok0'-' m a u mmo o 'oQO--- S--m < m x -- -- *-* x i taSi)l 2, aJ ai 31 22 22 M 0 OV .3: is ^m 0 k. : i 0 0Ww00-k^a---* 09 00 0SO--U0X0 0W to 0 -- M- X 0 --0 0 3 0O -444--j9j0 10 k. z 0 0 0> k4 fc0 X0>6 ^0 33 - -3 >*5 0 4_ ,^_ 2 *2? - 0X ----X 09 0 0 0 k- -- to ka 0 0U a O0 0 a3 3 0 3 0 2 00 5 (to X 3 2: U 0 0 S * * * J- J2 M X-- 0 -Of 0o 0 *0-90 00 > 02 9f30 U kI 0 XO 1 s-:U 9U^< * l > fe J 1 s: x 0 2 XS IS r 22 iuo -- m m --* M to 0 O O 0 0 O O Xt--o pX ^00 f>. --9 0 0a -- kO- 0 d0 *9 *94 0 no. >X0( 0 5>s0X J Uo U' I-- ^ 9 |52 .k99 -00w-4V O ! --u ~u 90 3 2! 4. 0 -U0 0k0a --B0 0^0 5=1:=! J .5;! 1 9 0f-< O o C9 ^9 <M *? ka - * O a* ?M O W0 509 k0. 0 f 0 S 8 0 ^0 0a< I 0 V 8 35 a* O x 5 293 TABLE E -2 . R e s p ira to ry M o rb id ity S tu d ie s o f A s b e s to s -E x p o s e d P o p u la tio n s 8 o --0 --to _3d 2^ o* A <0 c> o it (/> f* xx G* * l 0 S o a y ? < i0d -d y i-- s O * Jw3 0 SO * <MM V -- --a0d 0M X -* W it u 3X c -- "O o O -^ N8 tl ta/ a 3W y 6 BX --a IM >Vd 0d (I o a ay >66 0 V06 Ob a X JfS 5 v ad tO >-- Os Vs id 0 V ** Om it atiO U G &* * Si - OkTt --_ y -- S3 0 00 <-- e e >VV O09 --O3^ -- --O -- .8 * 0*T5 O V-- 88 6 O-- ------VO0 M&8 --X W8e3 8 -- u oo W8 6 0 e 2, yoyX Ub ed 41 d 0 0 0 -' U wC --V3 -cXj --90 - ((WWOo o. i 40 ^-- f --c cit 0U --X 8 O3 * e41 *.*c xv oa-d * tf u ac 0-- 6d 6o C^ -- ^ BS 0u aB &rj it 3 -- 3--0 ^oa^. aow4>w0 8 IS. M -- 9 w"\ 0 -- _ 6 W0 O K w g (I -- C 0 08 ---- W 6 0 -- *3 V y y *d 0 -0 * ** -- 0 0 Id O d u U 3 --y - -- yy --o 0 0 0 O **> uy 6*8** sd (i b d ; g w 0 0 OO 03 y> > dUS ---- -ah* (W'kTs ---- 0 0 Se JS 3 --W --3 30 00 O-- 00&0 0---- 8 y -- id WOu yPed 3 *3 Oy 00 . > -- *d -- 8-- -- aa 80 --9 0 y * 8 0 * 0 -- 00 --0 W0 ---- O 8 aC a -i-y UO ---- -- 6O JZ 0 3 y yj 8 -o a s --^ eoo -- .8 -- 0 a0 0v i0 w0 u-- 00 3 3 0 _* 0 d 03 > > a o 0--3 8 0W OMs 8 5/1 -y 3 w 8> y0 0 --id 0 ---- -3 -- > 0 U U 6 <A 3 0 0u O jt i& is *e0 0> 0 80 8 0? 3-- 0 6 - G0 >--<aP --0 0 UJ -- 3 jG 3 fa. X -- U B -- > 3 o e s-- 2a-a & aI 0 -- 0 3 8o 0e y0 a- Z8 *d id 0 y 0-- a-- 0r 8 0 --i0- 00 0 oau w y s-- 5a mw a y 0-- a0I --m0 --y0 ae ao oa y 3 53 --U 0 y 0-- a0--m 0w aI 0 --O 80 0 ooy i --o a JK xaw < 6a --w ---- o x X-- xx Oa '' ---- ---- 99 0*0 0 xw Oa Ba 1 2^ -A V) x I 3 a 00U --0 -- dt f* -- id --a ---- 3 5-, a wa oa 000 --00 ----0 w0 y x O* ( 3. 00W --0 0 -- J* x-w 2JS S 5 Ou u 000 er5S g'-i a m-- -- ^0 0-0 O a x w id 00 0 X 0 * u---- 0 id-> -- *3 -o 00 wo ^y a 0a 0 0 O 0O -- 0 ^-- U0 <0 --0 O. id X-- 0 oM. 00 6 ^0 0y e -- ay 5- -3 Id -- --0 * *d --a -- 6 08 --o o 3 0-- --0 y 090 >-- 3 -- --> -0Be* 033 - 6-- a -- m -- 33 9 -- 0 IM00 8 JG W -9 - 0 *0 X 00 ;- 0 -- 0 SXo w `-- > a il y x -- Iid > 0 fa] ll - fas y a_ i w *3 iI -- 0 --o. o 0 !-- 0o 1 ^2 I^ 0 ^ > 0 y >s i y w-- I iod W a >x L--5 !^i ^y 294 X 31 ao 3a U (A U s e x ss- o 0 . M'A e b > o* o3 o a> x o X Xy -0 --e --. a O0 3 O "O - X b K ^ * -- to C x 4> b W> 0* e u^ *4 < a> 3 Oo um a be -- SOS 0 *b o bo b 41 > Xb 041 v a to X to e 0 o c b & X V >, X w -- 0--41 Mb W &x -3 o& .* -- o O 0 ## ** b - g ^ n b B-- V o X -* 4) b O C ib E 0 z *4 C oo e 0 O-- K0 1 w w --m *bv e -- w I - --0 uOw b 6 3M V W >H 41 & O X -- 41 K e g a 3 01 I/OS'c > b > wo 41 V W--^ X 0 -- 41 ". 0 e to 0 & o >-- 41 u 4i 41 41 & *9 >4 41 M I o<N -irf o to c-- tC bo a '- u C b0 41 JK *4 01 O g6 >ce X 4i ,, b-- s ft -- > M X *- M bO ftx 8 41 uxX U b *4 00 9 0e -- -- X -3 > 'Z 3 3 e o Q 0 #m C 4> K *tl e >X C oo o <n * C <N X4> --B bb 0 4) e to 41 c oE s. b00 b 0 b0 oX 0 IM 0 <w Xf 0N 0 0 0b 3 s0 0 Lr 0 0 0b 0 <0 00 ----o 0 b "* 0W-- x-- o 0 <b * b00 41 0 M be b mX 0 o b* 3X ft 3 0 b to b 3 I O' ft 3 o a 4> 1 0 00b 3 -- O b X ft 0. b- 3 X *- X W 00 m 0 we 3-- r e W 0 O' 0 3 0X X E 0 ft X 1 0 K *o 3 ft 0 -- X o. K 0 <b lb 0 O lb o0 0b g0 00 X 3b 0c u b 6bc 0 -X >*41 * -- V --o v0> > 9. O' I O>?^. b lO b B a q aa c e 3 b0 to o & 3 w3 --0 *1 o b *4 O s 0 ft >3 b l b3 u0 0-- ft <-- o 0 b- C-- o --c bb w0 b4i --0 0Kb 1 0b 00 o Co oeg c-- o --c b o 0-- 0b 0 Kb 1 0b 00 0 e0 o ew c-- o b 6 44 b 0 o 0-- 0b 0 0e 0o o ocg v X ft t s tf 6 ^3 3 hj O v> ft 0 e x .b b s Sx <b ^ *4 to C -b *b O E 31 b b 0--0 b--X 0 *b W eB b X c X *0 b -- C -- *b b* 0 3 b4 X 0 0 --0 0b 0X -b 0 bX 0 0< K b Ob J o 0 K 0 0b X -- 41 0 bX <Kb 0O b 3 0l X< bK0 b0b-03 295 T a b le E-2 (c o n t P a rt o f the c ta a a i f ic a t io n ay ite m d e v ite d by thn In te rn a tio n a l Labor O rg a n iz a tio n (11.0) fo r x -ra y changea aeen in p n e u a o co n io a e s. See S e lik o ff and Lee, 197H. p9->* O' 4u1 e 41 a v i 3 00 a O y c w c --X BO 461 f>a* o -co K9 5& E9 = --or6 V-- Q. fa 0B C- 3 c > E e wx -- -s* "3 41 ' --c oJ fa J co ^ 9 41 x u 9 19 w 9 s: o fa o ~ --X X-- B fa M ao. w*=c v 41 41 w u o *- 3 3 *J b E O& xO x41 ** X K 4; 4i V 41 9 4) 9 y-- fa 9 ^ a* 41 fa fa fa it 9 a* 99 9 ^a41fa fa V6 O 00 9 C *" * 3 fa 9 V o o oe x fa^ 4fka1* Ofa ---- --^. ^c Ea *---- 9 ' B >fas E >-- <M o 9 U1 O 00 X1 41 <-- 41 w O *9 O 41 C O 41 41 41 fa 9 -- C 'O m> J- --4i o4c> 41 ' ift ai 4fa1 o< e -- mm .mi ^ifS ' u un oo o ec x 9X or > 41 fa 41 5 *j a w O 6> O - 41 3 41 X X 9X - e oo -- o *** X C X -- y c C *9 M -- 41 -* fa a 3 k o -- o * Or 3 *s 41 uw --41 ^e g fa 9 41 ^ > e 4k*i X 41 9 00 9 o a o c 9 -- 41 9 fa 9 fa > 00 fa41 M 00 X 00 U) c (J X 9 fa --c 41 9 mm V 41 X fa -o fa 999 9e 9 00 B fa B C X > 41 9 3 9 9 fa fa fa41 fa X 41 X-- XU X> 1 bm -- V X if X X r--s* --4) w* -- m i --fao b JfOaO! *OO*- c u >* y m X X - mi W fa V M 1^ XC . -- c - 9 ^4 --X fa U 1 -- w- ^V c-- " xe 41* C9 X r. Bfiy 9 --g fa B fa 3 im J4C1 *fa 9c m - 4i yx 0 E 9 5 ^o u 41 fa O Jf a. y * 4H)^00 U M *1 o w 4i y 4) n *4 9 9 -- C 41 fa fa 01 ^ 3 41 0 x >4) C m9 &O C fa X 41 6 00 00 41 fa c 9 > 4fa1 X --e X --g 00 41 -- 41 fa 0 0C JC JC c o ex 41 ) W u fa4 3I O9 ? 4a1 ---- 0 9 O B- c-- .2 S X fa 41 fa S 90 eu c-- foa ac fa o X h* ** c oo eu <o c-- o --fa cfa u 4001 fa X tO U o1 41 fea BOO SCO 1 ^f3a ^o3. 41 -fa fa X -- 41 B fa jtf ^ x fa 9> f4a1 03 *9 41 X .mi X I x o X C 41 E fa 41 J4 < 4) 9 ao u 3 o ^3 41 K * X 41 fa fa X C 41 B V JO - E fa 41 O 9* U %r O ^ >fa 9c X u fa fa 9 C fa C 9 41 O m <r a. fa fa o^ f o 3 X) > 3 9 C fa 296 L e w in a o h n , 1972 a fte r 0-9 yeara o f expoaure, and up to C roaa-aec t io n a 1; P re va le n ce o f pulm onary fib r o a ia waa zero O' r. 3* o GO O' Si c o 9 e o *3 O <c V -- coh 3--0 O 9 X-- 0. 9 x9 3 --c 9 m UM o e --9 y o^ > s 99* X &* _& 9<n* o9 y .0 y --**d M >9* I L O9 9-- y 9 I 06 m yo 9y 9 9 9 O^ --4 Xm 9>s MM O Mm -- e A| ym 9 o - 0 c xe c y-- 9 O Sy 9 a o e-- X 9 9 9 ^O >. y 0 9 x </*> 'W y99 6o6 - 9 0C6 --0 C 9 X 9 V 9o X9 9 y S ygu -- -- 9c 9 9y> _^ 5e M 9 9 9 >* o -- y >s x 9. Q. O U 9 --C ucv M 9 aa9. 9y0 m oy & .0> --X9 9oyo y 9 OX a. 3 9 -- 9 C O 9a. ao c9 y -1 C C 9-- 9yi a3 0 9 "O 0 a0 y9 9K0 -- 99 9 -- 3 9 y9 --yU --0> 0& W0 O0 0 0 0-- aX0*60----y 0* 9-- y 0--9 ---06 u363 y9> 9>00 X93 y 0 y y y-- a --0 006 3 *0 3 -- 0 M *e90 --9c 3y0.60 -- O C -- 9a 00 9 w 0y c 9C mw-- 0 .y 9^ y Sy -- 0y -- 0 0 9 > C 0 ec --0 0C ^3 5 -- 0 yy aox u jt 0 u X y C o e ey y5 a. -o y* 60 X9--3 --3 03 0v --9 C CyX 0 9-- U .9**--00-- -- y>B ---- 9y oy >6 0 aex E xu ym 0 e ox 0 c -- y XX 0 0 9 y o. 03 * 0C 9 0--0 y y da X ty x -o m 0 y & yc 0 0& 03 --9 0e yo u o oc > --0CO- --o 5a9*. 0m y > O' y 9 9 aey y g*\ 0 O 0- fA u E e-- --O 0e 901 y0x yOy 0e 900 ocu 0 &X --> 3I ^ yu 0 --3o --1 0r*. 9 O O' 0---- c ^-- 900 xy i Uy 9y C 06 0 O no e x te rn a l H ille d >N y Xu ,287 A abeatoa 9) ^ ---- 0y 0o y3 C6 0 X 0y y X9 C0 X0 < 96 0y U3 O o 4 0o ^y --u y u 0y x0 y0 y0* x9 00 e0--J0; 3 (J 0 3 0 297 9 fx* 9 9 r*. 9 Si a0 X E 3 9 9 0 00 X9 fa O' oc p* Xa3s .Z -- -- e & E auc Oc 03 0 65K Ew >* u- <>J --oa. C ^ *a 4 0 EC --X ew c> * w e o u. -- o C 0 c *-* 0 cl e 0*a X md La ci x Vu s V 3 L w0 (I U ft) "w4 L) U O& K ft* --V . --4 -03 w e e o 0' XM S2 x -: 3 40 u0wm >b --a. -- 60 9.C ft* 00 mc c X0 M m fLt*. X b* o ' --O e3 E>s -- Xu 9 4c 4 ft* --A e 0 -t=j -->.LOa CK w* ` X 0 u 3 ft* ^ ** 0 V uS ft* --4> c* La ft. X*a --* u xVu o3 t* O *M Hi**> c* +* ft# ' <*> o m m Cft* E >S -0 a E 0 04- w m ft* > w o E w O CM c *3 e s o -- C -a -- O "** * e 0 xw 00 --0 4 -->o0% ft. 6 w O s 4v -->o E& 0 xL04 La 23 a. 0 La ft! >s 0 X X M** 04 4 La W --0 OC X0 v e* "i -- X L. >. 0 u <-- e^ --o , --00 24 f3t. --E - 0 3X s< 3 0a 0 -- 00 4 0 3*5 g 3O 0La X 00 --oc 3* -- A cr 0w0 a -- --C< o oo w * eo >. 4 C 3 L* 4 3 La O L0. *& 4) c CO --3 arf 0 0 ;E ^00 U 0 --0 0 4 -- La 0 o 4 4 & 3 0 4La 00 M0--3 o w d e y- & Q0**a 0 0 X L4 -- C* 'XA g3O 0 0 03 *3 O -- 0 44 -- 0 fiLba. --3 'Sol 0-- -- 3-- o * - - *4 O La X --o g00 La a < W -- La 3 3 W00 I ** ft* ^ C rv* o^ 4 g0 0a 00 c o o <0n 0b xX --ft J 3 -- <*- M 0-- O O 4O wa. oca . 0 --e 0g 0 L0a .a*ri 00 -- 00 0 La X-- c -- 00 0* O 00 -- X W MU 0-- EO C U 4 ---- o 0 CL. X xC O> l 5 - J 0 0 X 3 E La 0 O La 90 X -00 MW -- C-- M> <" --O X *43 0e ---0- oo --w3 U 4 O O4 0 9! X La 0 CL flta) >0 --* ft* La O Oa O X 0 --eO0 o A 0 3 "O ^( I 4S 3 c --0 o 0 a&9 Mu --4 e 0e oe 0| fLta* M0* --o ?* 0 M La M 3 c-- --O 4c M La 0 ^e oo CU 0 fib --> 3I M3 Oft* --0 ^00 -- O -- 0 Ck >3 aa I MCu0L ----3O 0O 0a I-- 0 O >x 4 M Xx c-- M CL 0 -- <e 4>* --3, VM35 fsOt.* 4e u 0 b. -a4 La 0 --0 H C-- --ee 4o ee 0 UM La ft* 0 IZ1 .0* -- U * eX --4 M o c - SO 4 3 o oI -- 0 m-- 4 o cu 4* 4 0 -- 0S0O4 0 La La 0 0 X 0 La 6 X -- 0X03 0 < 0La --0 0B --0 C4 9 } La ft. 0 ft. .I La 0 4c 3 0 n 4fUt* --MO 0 4La A 00 .a*rf >0s 0W --0 --6 4La 0 La C -- 3 4 ac xw --E --ft --> 0* xy*i Table E-2 (c o n t o 298 I X X '** a 9 bm 9 X m I o h 0 --> o-- 4i w w E - -- C-- w uO 3e --3 -- 30 - C 0 X w | bO Xb * boo.. ^ ^ a. X0 c8 0*V0 &-- X b. * > O 0 0 b o 4) C b---- c 0 O --0 b0 b0 3 >0v 0x bb 0* a. oo < v ao *o X 4) bN bc 0 X 43 O P ^ o -- -m --b x b x b g-ik x oo ai -3 -off# 0 b - 41 -J 03 x Xo wV* O rs -- , *3 AI ^ X ou e a, w b K JS OO_0 rx Q--` 3 0 41 b -- 0b 0 Xv Jt X O-- b u b O b 0 3 0a. b 3 >x o o bb3 0 b 3 * *3 -- 0 <* 3 0 O 0 0X b ( X-- U b ? b bC 0--000 O 3b4 g U 0 *3 "3 ^ C0 C Ob-- # . b .ri *-- x 0 -U50 -0X--X" "t3 fo*3 --"33 1 -o ft- -r ^ o 503 0-b0?----c?*0o- 0`bo- 0U 0fi o CO O' o o --c c VM -- ^o -- oe U W 4) 0b -- .-- c X0a. 0b3 o30c---0o bb> a*-- 00 C b or 0 ft -- --x --o *0 t -- 0 CO e o o O >X b be 8M >* r* M y *0 e -- ^ 41 X c-- 0^ >X ft X C 0 H0 X ao m nx bX b o a3 w --V b HH 0 O --0 b 3 bC X 4) 0 S 0b 0 tf b --S 000 e-- v^ 0 O *& 0 0 eb 0a -- o o y -- 3 -00 be0 0-- 0 b O 0 e x b O x e 0 Xo -- X b 0b o b 3 00 3X -- 00-- e b o * -- 30 00 X 0O mO U 0C -- Oft b --b b 0 0X0 b0 3X 0 00 *J K^ --C Ob 0O -- -- a3 M0 ObX c --0 o *b x C --b 0^0 0E ff y0 0 0b0 --3 --O 0 -- 3---oo a T3 b(fJf 0 b0 C 3 o 0b 0-- 00 b o *3 0 K X 0 h- 0 X-- o 3 3& w0 V) ft 0b w^t Ob 0Q. 0> -O *C --oc o CL U 0 O . &o b 0 *0 eo ao c -- 0W Xb 0 OX --' go J- 0 b# -- 0b ew ---- 3 -- 8 3 b b-- B b 00 ebye -- -- 0 0 *b bl O 0 b X8 c rffb00^ W 0 OX AC) b --^ ft -- 0 b a? b O 3 6 3 b o 0 b 3 S 0 X b 0 3 b 0 0 1 o o X 3 0 --0 b e o xi u a a s 0 299 0N0 o o c a; ac al >s t>o> ruau cnX41 U -O3 9 41 Q.Z a ag --v --o o >s e .ff a. x 4i a. k y b 1> C4i Xa ebo w uo. 4o*o3 --*oo a*I by b b 0 41 >X X b 9 eo ' 3 43 --4) -w9 43 X ax g.=43 N b fN O wb at m c -- *9 e X *9 9 43 M X 4* 43 ^ E O -- 9 e c 00 s e x c - 9-- C --3 co I_ 3 - s&43y 9e . oI s I e-- *9 *3 S 9 43 >s 4 T9 w9 4e0. c y a a *u* 0 b W* a ..* u no a9* ba b9- a >s--a >s ScP U Cc F -- y ca o e * a ab --^ oka3x u W>* x ^ a ab *O3 Ca 4b1 *o o X43*>- 6 aab ay o o x* 4e3 a. o bm aw ^ a oo a 43 O X >s -- 9a N N kN XaC ^X ^ca3 a 43 43 Ma a o* a* e a aa a ox ab aa -- a9 xa au 0a *9a K -- -- a o& I I *3 a --*o 4b3 b a i b a a o-- .i a u &o --b "9 iree **j w a 43 ac -* i o a >* c a x x a *9 9 >9 a b x --> 43 y CU I 43 9* : ar ^e bo --ooo----x ^a o b b o T able E -I (c o n t 9 3 9& MO V) ft* 4a3 4a3 >* a b I *# -- e 0 4y3 b aa a` u S b 43a xX XX 33 E b 43 X C 43 a 43 0 -- o >a o 1 * cl 43 ab ac " *a a 43 in boo-b ee ub9 x m -o ea --abb- xao* x-]*-->,Koati. n-oo-t oi--o/>t^a^a o(oj b^ X Appendix F EFFECTS OP ADMINISTERING ASBESTIFORM FIBERS TO ANIMALS Contents Table F-l: Respiratory Tract Tumors in Rodents after Inhalation of Asbestos and Other Asbestifora Fibers Table F-2: Tumors in Rodents After Inhalation or Intratracheal Instillation of Asbestos in Combination vith Other Chemicals Table F-3: Mesotheliomas in Rodents Appearing After Injection of Asbestiform Fibers Table F-4: Development of Fibrosis in Animals After Inhalation, Intratracheal Instillation, or Pleural Injection of Asbestos and other Asbestiform Fibers The references given on these cables can be found on the list for Chapter 6. 300 c e ll, a d e n o ca rcl- 1981 noss TABLE F - l. R e s p ira to ry T ra c t Tuaors In Rodents a fte r In h a la tio n o f A sbestos and O ther A s b e s tlfo rs F ib e rs 301 I I CCD* ->4 9-4 0 > 0 O> 90x. >0V 9r*4** h 0 r^#s <3 sis 0 9^ 0 X 0 JS o a 3ZU0 o *4 jC So O av 30 a S33 u oo wu ^ 3 3 -= O 0 *4 i-4 U O -4 J3 *4-4 0 c,m I 2 -i4 V OI -4c4 *4 O 00 4 0 a 3 23 mo 3 a 3Zbe O So o0 3 3 O e Zw 3o V --44 0 JZ S0 o0 00 0 <o O3 a0 39 U-- a a4 Aa4i ao j s\ 2 o O h0f3sl 0u H O .8 O 0 'O XN *-s 0 if>t*NC4. N0 O* l--/*45 W 0* *04 wI^ O <V zs u at >0 >r ^tn "4k W rn ~5 Z 000 9 r- a"x 0 9< 0U w0 A> 0o 0u u* a. 9t <"* *0 9^ Xu *n * QC 3 w* f3lC -4 22 x --- o0 0 ^ o s w ~5 vO n u lO *4 w 0o xw -4 0 s09f> fM o -4 o# 0 wA tfe fXl. 0M0 - s -4 ^ O Us 4N *" iPVnH\QvSp.40 w"V -4 W 4 .H 0XX a a< a* 4 --s- <--*. 4fl0 a2? <S) 9 9 <N x-4 Co-* 09 fl JM03 0 Oa Na O Op**tbx A. 0 44 O * 0fl 0 n -o 4 0- W0^ OU. UX* flX* 404 WH CM O0 0 1 a --4 3 3 0 ^ o^ Us H `O ^ 0 0 - *a4 CM. * ofl o 0Ms 0 ^00 <^o**\0P~s.. W * 04A04 4 w- 0 fl b H0 x ^ >s<n Ok <& A* 6u w <*> flWV sf4l 00 ^f- W 0 <"> 0 >* * a. As 0 > 04 3fl 0 3 CH " 5 /3 8 " 7,000 (a lu s ln s ); 1 4 ,0 0 0 (CH) le n g th , 35-62 us; d ie s . , 1 -5 Wb ) v s . CH (U IC C ) 55 se 55 g8 >-. I * 0 -- As S f 4 A 4 wM 'w> 0 M *4 0 fl. 0 0 X0 fib --4 0fl 3 3 2 302 Latency (a o n th e ) T u a o r T y p e s _______ R e fe re n c e e A nim al (No. o f Tuaora/N o. o f A n la a le ) o r X Tuaore 3l 4 vi u <3 aa00o0*4k 4 C* 9 o 2S I o a a0 1 Ia at ao ew aw e- oI * O0 *4 4* 4 Cl X W 33 .3 3 8-1 O'*** *3? 3 o a C4l u 3 el 3! *4 <33 ao 31 a o *4 Wu0 -o04k X -* aa oa o 4 4 ua wX e *4 uo oa e v aB 4 a 0U aa0-* xo 4e4 u o oa o H I <2 e to o <9 >y 00 U 3 >% J3 3 0O 01 92X O 4--I4 mw0 ebV u Og 4I4 000 4 4 -r to 0 mm XO 0 O Cl wO 44 oa ci 0 44 o_ ro >t aW v OM W 1*4 0 8 9O /-H * Si I>. . >* 3 e o<> o4 s. *o o ue x uCJ J 9 e 9 w9 X *4 'M I o(w a *4 3u W4*e44 XaM4 4eV4 owCl O - e e <9 o44 - Ob -o4 g iC>-wssOw *a4 ; 3' -4 O B 9*4 O 9e aw aw Q. a wa 09 nOo 4 -- 40o4 e>> X0a 0e o *0 4a>44 3S 0a e *4 *4 Ua aa a9 e aa eu *4 e e e 040 m ao e 44 ao 4 aW 99 00 eo 0 a. oe a CO w a 0k 44 e ^j*4 ei e e ai no o*4 t u w >s2O Xa 0k -4 2J 0a aa a> 4 w040*4 ae Cl "o *9 0 0k e w** e HX' 3-- *IOn i-4.1 *04k. 4e4l{. At *v4 44 el 44* 34 aw xaMa ewo e 44 a -4 o 0 e -o a -- e B *4 _ o 1 0 *- 0 -4 o e -- 5S-w -e .w i w*44 g|4 a a0 aW oa o e w to ^ & 14 ao i 0 g bo Agl a*4 *W4 44 io 0e w =u 3o x a ao .a u C oncentration a lr)^ F ib e r Type* 303 TABLE F-Z. Tunors la Rodents After lalialatloa or Intratracheal In s tilla tio n of Asbestos la Coablnatioa w ith Other Cheslcsls o 411 U 0a ^ IS 3 la x 21jT JAi*5-t a^ H>i iiU4); 0 idId !/> w-4 0 CO 3. 3 w00 0 5 <S 5 3wo 21 sn, 40O X*V4 *cgw4 o94a1 -o34 2 13o c 3ae 2wo o0 jrof 00 M0 O0 o'T' As i/l 0% O C4 4 MOs 13O -a 32 Ou 0<C 0a a a03O 2U*o < 5a 0U43 009- 3WfooUl <w30* 0O4 X-*04 00 w0 0a 3 2 s*M004 *4Io aOs w w 4 *a00 X ^*44Ca^4 0U O^^ o wa4s *rO>i a as 4 o 9 04 *0 a 53 0^ <n o "Ov 0*41 9p4 oo 0 00 W*4 O0 4 931 aO. 0U 0 *94 ^a0 XO>--. vS o w**44* wX*aMb00>0* >-**4w044a0404o va0UXa04W***9C0e>40040k * OS 5 B"2 ;f;c4**oo0 ^ax_i ii Uaa*<0a O c X u-- ew Of c 304 00 9* 00 9* X 0 J e 0 e 4o4 e 0 t/i 9* WCl e 00 icf 00 X CM ao 9" SI 00 0 TABLE F - ) . M e e o th e 1 loraaa in R g iie n ti A p p e a rin g A f t e r I n je c t io n o f A a b e s tifo rm F ib e ra co n tro l (0/55) w o ae vbe <e 9d o 0 uO*aj 9 X be 4 Ox H3 &S 0 Z0 53 wH 00 ee i* e a -- 4 a. 3E. -0 ~O 9 at i f"T "X U -4 i O O >0 x*9 s .-- y N V O t*. 00 -- yS --o W A"l sH ^ w 00 0 T3 AT W Cl - a: ^y -- at *1 r u o -o l/T -- ao gO 0 'M V *4 60 C ^ti *0o aS 44 --U BO Cl C A 44 -- y tk *44 Ohe Ua 3E 0* s *4 *4e -- T9 44 TJ f V E - v>a ag0, w00k ao .k4O01 --r`\ v X o E 3i Ca* b_n. e 3- - T5 ae y at" y 01 EX 830 4 i '* A O3 O* -w *44 00 . C g u -o 0 0-- 0 -- -- c> 3 V^5 oo a E-. --ba f"i *9 OA A 0*0 a 44 -- *EC| e 9 -- <o E * 0 (J 5 A C T3 - 7t o r s9 9* V3 --a 4U1 ba o Ea 3-- H3 U ^V u 9* XO o-- e 3 e 4 x 3 > E z I3 a* -3 --) *3 0X h0a 4040 ee ba < ba 0 Cl 0 ha U 44 -- X0 33 15 ^ *3 a E 3 C - W v Oa ba o E X y a*4O44 3V u -- 60 v 0 e E ba -5 os a, y II 0 0b0a -- 00 3 Ao yg (k 3 h 0> 400b1a X00w. E --*4e 03X0E O M-- he --a ^ -- y 00 w "0 2 - 1 C E a. 3---- ba 3 X 0 */* oe H OC y 00 --. 9 2 hy --0g* --. 0m 404 44 f --0300 --0 at c - - y o a. o c ao oo 9 Co --0 & o 9 o <9 o 9 -9 --* CL y o o e oS *eo r< L a te n c y 305 O0d flO O' >s 0 U m 9> c 00 c ac 9 3 c c o u ao X O Z E c < o m .v 00 e 00 0o rX v X 9 e x i CO *J 0 wCl * * ~ *5a 000 ^00 o ^><y --O ee :5 S w03 s*o ^ o*3 ^ X* yx= CO * oe a -- - r e E ci O ui mw mu k- o oE E3 w9 --v ^Cl aE, x -- x c ** <u *6 * ac *o u0 AwJ -- ^ c v oo m E - X .acrt u X X w 0X w <* y *-* u O'** > X > * X y wK -- --C 0v* | 'V iTv 0 v IX *--* V' T0J -- >< X-- U me*" i oe -- x X V X QC W *0 Cl ki y I X. o --e x9 *0o *-* K X U "* h* 0 & 0m 0 MV -- L5 b 0 be o y XV M ^ ^ kM IT* -- 0 V raj 00 yy 00 00 E e E^ *r* - SO .u v M w * *U 0" r s -- 00 X u I - o6e * *> -- e e 0 f^ ^ N ^ *A n iA y E ,ro--w^ 4 O o - w W u 5 00 E U 00 E 0 w ra^ m6* skO-< x w x< ^^ o wVe0b 0E0 kPA* ac d i*m ., 0 /1 5 0 ), fib ro u * nem alite a t 25 rag ( 0 /5 0 ) , c ilic o n d io x id e (N o. o f T um or*/N o. o f A n im a l*) o r X H p* CON m fW Mode o f A Os a a, a u e t\ au 1V44 0a6 a Vi 306 jtf u jg o e*4 Os 3 O a fM w a os O jtf ao 3 3 M 3 C/5 CD os 3 -4 2 aO. CM r* Os a aI o a. ! til ao. CM JuS bu* n9 a M Ob 3 e >. a U X! cw as jj w] a. o. 3A 3 0*0* (f Os O bS f s a a < B <M CU W H <n v pm I N-a3 wIm* --U as -* x a y u^ I A U I wV a6 5: 3 a a o3 r 5 i ! B t- <3 o 4 o J3 zt a u Jl o0 3 -* I tl H x; o au o ao z 3 H a en O CN I Q. =. i 3 ob N fM. /-* A ' A -4 0 w 3 ? *r U. CM --' Efc Il wAs 0 <-i 8 3. a <- A -4 Cb CM & 3 -C t 4b ^ 3 a O ** > oO ^ S0 o um u ao oo a V ~ O f>* Mab a - tow bM -w B * X a. 0 _ CLO 30 0a*tfc ^fS Mb ^a ^ B ^ A oa. a aa >s 44 w4 U o 2n fA <n V<i o a a^ o W U aa ^ fi ma 3 AW w-- 0 fl 0 >-o <*> 5- a S0 ^a wr o6 V 3 a ^Mb O <>A* 0 -- Sb ^ X* y <3 "o* *T PM Mb' a H &3 a < w -o y V a Bm Mqw X y a 3 aa Wu m* A 00 - gs Mb S*4 3B ao z a "O a3 0b "a A /-* e u M -* PM AW> MA vA y O 3ti > 0 0-4 U CM 3a 3 Oa >b a. -- a >> 3 KA h* n b 4ab mM 43 a B oO 3 a - 00 0 ^m0bH 3a a a fit B >* w g 00 a a 3a a *y y 000 _ A^ (V 4b "<mo a^ s * -0 o ^PMM. 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OU 10a j~ t0d 0 X * M 0 < P 0 X v^ 0>d X k* w00 *08 So y 1 2U *0- 1 0. *w-0*WU2< i' . 10 O 8 A X i C a rd n e r, 1942 0 0N e * ha e at m O. X V -- U 0> VJ Q 2 O 308 C8 m0 -- --> uoe al m\ >' > o o o-- la >>0 a >^ ai -- a tfi i , a wm u 0co0 co-- &V--*- sh0cc0--- O w -J t o 0 -- i 4J O W 0> *--X - Li 0 -b --<3J - 9S. - U0 w X -ma 3 x *o x e x r? oo -- 0b* - ow X la UDC XU XU C V 0c0 C f Mbo o x * i 5 ha ha ! c V X 00 oU X X' o 5O be W a. Vm 3o Sx --7 X o-- b9 -- a. ** O Ad O --C F ibroua re a c tio n (HD) more pronounced w ith long lib e r H .il, g u in e a NO p ig , r a b b it NO I n h a la t io n Long CH, b a l l - NDC n ille d Cll ai ** c- o a x 0c1 3e --6 o vi r: 5 , a- 8 00 2 0 CX --C0 A 9 -- I o 80 -- <N X e oC -- oe --o eearn 0 X s l x Q Z cV 3 co --g o9C " > <o X x e O CN o o ^.* A*Vad*00X 9v " *9 01 b h0 - X 00 W-- C c - 3 ^ b C w C 3-- < X f ia e12A0d CM C w I m ac u v-- -- C M --x Xc *c s X H-- -- X c e p* XX0* c9 0*- xe X** *3 0 .S m e Me -- --0U --3 *9 0oM TXJ ^41 e ----01 *0Co3b09l 3 O. Ea XoC a kn m vI g a uc41 W --o3 5c tbl wU- k X X *- 0 ob ea 0 x X41* --Oeouw M x*9>- II --e oe x*0c* - 41 OCb. 41 W0 4>1N vO> --0e0 309 3 aVt --aa* H0a. I. k IN 0e *0** s -3 x> ; i o e w 5m -*d5 --Z CII C e *4w*1 S *0i*Woi-0 *# O * xU : *9 g 3e --C* b .e* ab E -c 9 b2e In 41 C hC3. < < M30 lb 5A 56 o00 0O' -- 4O1 0 X* b *bX* Xh*9<* JM3*f 00^> 9 (A e --o --oe X OX CW w4n1 COE C r-> 4> 6 -e e j 6 O3 0b3 ^ b q W-v x X - Jt T3 X >* 41 O 4)1 O> 0 Ct 1 <** 0o3 ^** rO3 2 ^ Ci 41 4) 0*^ O >bbOX --*m> a5o x3o b* V 01 491 X lb o3 g U 4) . * O as x o X - *9 ci Xa. 41 3b E X eo tci 0c * 4 0 Ve H0 5 Xu z< *XV 5 e 63 -- wcn VC 0--c* 41 b 51 0zo 3<* 3C 41 M* XC XC X C &m 0e bO si n Xw C&O> Xs (0 2s oo Z 310 ;|: m Ok O - mo wV CVJ 9 E O ha X a ou be C a aX 3 X *3 O C X ue Xw e sv f*6 u -. eO a6O U b* LI x . a* h V JC c o z u ce o c C--D OB 30 Z 3 O9 b X o*e , M * X *9 9- 9X V* . ^ O --o ie -* aB ?i 32 W*S A 0S 1o fi B3 *0 a co e m ** tc e o * c a- - o V * C V 9 -- * A-- a5 aa i x j s x r> 8a oc* Ea in **- -- X A O ^ --* V QX. H X u 9 s 5 a X e Xc xOa. xaV *v b. 3 --W 3e be be Xv o C3 V) be < U X x0 vo | 5 --00 Xo&e><cs IXV .C.l * a_ bV .X 3 *- -->, x ea 9 Xa, ---- --" ^v 0 0x a xw 6tl aD Cb b K I HV Z< XH X* 4) c*i *a--I o0 -- -- c 0 a x-- --o----X- be >s 3 u a-- u xx a v a 0 V 0 b-- by. 63 O*. e~* *- L> V -- ** w 3 x coveab 0 x I -- >b &0 a xa --ceS il * * "5 * *x U U X -- b c-- 2 c<^ - 9 ti .2-si v -!?3 o a 1 o& x -- x Z K -fte _* 8- u h C ap m A X < X fc a. v X o ^ T able f-U (c e n t Appendix G DEVELOPMENT OF SOME EQUATIONS USED FOR QUANTITATIVE RISK ASSESSMENT This appendix develops Che equations necessary for arriving at the cohort-specific adjustment to calculate c in equation (12) of Chapter 7 from the values of the constant b in Table 7-1. The method of calculating the risk of mesothelioma mortality at age t for an exposure starting at age tQ is also given. In addition, justification is provided for the calculations in Chapter 7 that are used to determine the contribution to lifetime risk resulting from an exposure beginning at c0- To begin, the instantaneous mortality (or hazard) function at age u for an exposure of dose level D incurred at age v is defined as follows: i(u,v,D) = aD(u-v)R"2f u v> (Gl) where a >_ 0 and k > 2 are specified constants. D is the constant exposure level (concentration) over the period of exposure. By contrast, d in Chapter 7 and later in this appendix is the equivalent average continuous exposure level from time of first exposure until the time that all exposure ceases. It will become apparent from the following development that this equation for the instantaneous hazard from a brief constant exposure was selected to be consistent with equation 7 in Chapter 7. The hazard function i(u,v,D) means that the probability of death in the short time interval (u,u + Au) of length u from an exposure to dose D at prior time v is given by i(u,v,D)(Au). If this is the case, then the cumulative mortality (i.e., cumulative hazard) up to time t from the exposure D starting at time v is given by . t I(t,v,D) * / i(u,v,D)du v (G2) = sum of instantaneous hazards from time v to t. 311 312 Now consider the case of a continuous exposure of length l starting at tg, where exposure occurs during the time interval from tg to tg l. If one now calculates the cumulative mortality (hazard) at age t, it becomes IU,t0,Z,D) * /^0+l(c,v,D)dv C0 = /C0+* /Ci(u,v,D)dudv C0 v (G3) 3 sum of the instantaneous hazards of all u and v so Chat v u <_ t and tg <_ v _< tg + Z. Using i(u,v,D) as given in equation (Gl), one can calculate the integrals in equation (G3) as follows: with l(t,tg,i,D) * b(t-tg)k, (G4) b = cD{l-fl-/(t-C0))k}, (G5) where c * a/k(k-l). Note that equation (G4) is in the fora given by Peto et al. (1982), who estimated k as 3.2. The corresponding values of b for various worker cohorts are given in Table 7-1. Equation (G5) gives the correction term to obtain c in equation (12) with d (0.219)D * D/4.56. The choice of d = (0.219)D is justified as follows: equations (Gl), (G4), and (G5) all assume a continuous daily exposure to dose D. Assuming a worker is employed 240 days per year at 8 hours per day, a rough estimate of a continuous 24-hour exposure to dose d based on an 8-hour workday exposure D is given by d - (0.219)D, since 0.219 8 x 240 24 x 365 * Equation (12) in Chapter 7 is based on this adjustment to convert workday 8-hour exposures to daily 24-hour exposures along with the adjustment shown in equation (G5) for a partial exposure of length l from tg to tg + l , as compared to a continuous exposure tg to t, i.e., of duration (t - tg). If l * t - tg, equation (G4) can be simplified to equation (7) with D replacing d. Equations (G4) and (G5) also provide the framework for the risk assessments in Chapter 7, which are based on partial exposures at levels higher than the assumed environmental level d * 0.002 fibers/cm^. REFERENCE Peto, J., H. Seidman, and I. J. Selikoff. 1982. Mesothelioma mortality in asbestos workers: Implications for models of carcinogenesis and risk assessment. Br. J. Cancer 45:124-135. Appendix H COMPARATIVE RISK ASSESSMENT SCORE SHEETS The score sheets on the following pages contain the committee's assessments of the comparative risks posed by various combinations of fiber type, route of exposure, and health effects that were not tractable for quantitative risk assessment. Each assessment is made in comparison with Che "prime cell" for chrysotile inhalation leading to lung cancer. The comparisons are expressed in terms of population risk, which takes into account recent and projected exposure patterns for the U.S. population. Individual risks for persons with higher than average exposures could easily be as great or greater than those from moderate exposures 'to chrysotile. Comparative population risks would change if unanticipated changes in use levels or patterns affected exposure distributions. The results are expressed in a +/- system. The 0 means that the risks (number and severity of effects) are about the same as those for the prime cell, + and ++ mean that they are greater or substantially greater, - and -- mean that they are less and much less, and so on. A blank means that even comparative risk assessment was untenable given the data available. Thus, Che quantitative risk assessment suggested Chat for lifetime exposures to asbestos in ambient air, mesothelioma risks could easily exceed lung cancer risks by more than a factor of 10, which would result in a comparative risk score for mesothelioma of +. With respect to the prime cell, all comparative risks have been judged to be either - or --, meaning that they are less or much less important than for the prime cell, even though some of the indicators of risk are positive or more strongly negative. . To determine the comparative risks for each cell, the committee combined scores for several factors related to the potential for causing health effects; each was scored by the same +/- system for comparison with Che characteristics of the reference cell. The factors considered fell under three major categories: exposure, biodisposition, and effects. 314 315 EXPOSURE total production level (metric tons/yr) or surrogate measurement (e.g.a level of occurrence in nature) use pattern (e.g., dispersive or contained, matrix-bound or unbound, or accidental exposure of humans) geographic distribution of sources numbers of exposed people trends in production and use (e.g., increasing production or diversification of use) BIODISPOSITION . fiber size (e.g., length and diameter) fiber morphology (e.g., aspect ratio) fiber chemistry ' penetration characteristics (e.g., in lung or other target tissue) stability in tissue (e.g., solubility, gelling, and fibril formation) EFFECTS epidemiological observations observations in animals ill v**tro observations synergism (known or hypothesized) other considerations (e.g., susceptible populations or theory of action) The committee's evaluations were based on the following scoring conventions: 0: Within a factor of about 2 of the corresponding values for the prime cell (in the sense of its effect on the total number and severity of effects); for example, if production were between 0.5 and 2.0 times that of chrysotile, Che score would be 0. 316 + or Between 2 and 10 times the corresponding value or between 0.1 and 0.5 times that value, respectively. M- or --: Between 10 and 100 times the corresponding value or between 0.01 and 0.1 times chat value, respectively, and so on. Blank: A blank entry means that there is no basis for judgment; in further considerations, it is assumed to be equivalent to 0. The committee also attempted to provide a sense of the quality of these judgments. The following code was used for this purpose: a: reasonable assurance that comparative risk is in the direction indicated and approximately of the correct magnitude (e.g., if the risk compared with the prime cell was shown as "--", Chen it is probable, although not assured, that the effects are less than 0.1 times the effects for the prime cell) b: comparative risk is probably in the direction indicated, but the level is in great doubt c: comparative risk is highly uncertain due to paucity of information; this does not mean that the committee believes Chat the cell is very likely to provide as much risk as the prime cell, only that there is little information assuring a lower risk 317 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared wich Cell Chrysotile Fiber Chrysotile Fiber / GI Cancer Effect / Lung Cancer Effect / Ingestion Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score 0 Fiber Size -- Morphology -- Chemistry 0 Penetration 0 Stability 0 Human Studies - 0 Animal Studies - 0 In-Vitro Studies .. Synergism 0 Other Overall risk compared with cell above - Overall risk compared with prime cell - Quality of comparative risk assessment ____________ b Remarks: Even chough asbestos uses are more likely to result in air pollution than water pollution, chrysotile enters the water supply from natural as well as human sources (e.g., asbestos-cement water pipe) and the total number of fibers ingested could be greater than the number inhaled. Most is probably excreted rapidly, but the amount that moves into the body is not known. Both epidemiological and animal studies have generally yielded "negative" results, but the epidemiological studies have been too insensitive to detect relatively small effects. 318 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Chrysotile Fiber Chrysotile Fiber / Mesothelioma Effect / Mesothelioma Effect / Ingestion Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score 0 Fiber Size 0 Morphology 0 Chemistry 0 Penetration 0 Stability 0 Human Studies - 0 Animal Studies 0 0 In-Vitro Studies _ Synergism 0 Other Overall risk compared with cell above Overall risk compared with prime cell - Quality of comparative risk assessment ____________ a Remarks: It is not known whether peritoneal mesothelioma results from ingested asbestos, inhaled asbestos, or both. What little epidemiological information exists does not demonstrate an increased mesothelioma risk associated with ingested asbestos. Ingested asbestos is more likely to be excreted rapidly than is inhaled asbestos. 320 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Crocidolite Fiber Chrysotile Fiber / Mesothelioma Effect / Mesothelioma Effect / Inhalation Route / Inhalation Route Exposure Score Biodisposition Score Effects Score Production Use Pattern Geography Population Trends __ - ~ 0 - Fiber Size Morphology Chemistry Penetration Stability 0 0 __ _ Human Studies __ Animal Studies __ 0_ In-Vitro Studies 0 Synergism 0 Other ____ Overall risk compared with cell above ________ 2 Overall risk compared with prime cell ________ 2 Quality of comparative risk assessment ________ a Remarks: As with lung cancer, crocidolite appears to be more effective for the same exposures, but current lower exposures and decreasing trends significantly reduce the risk for crocidolite. 319 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Crocidolite Fiber / Lung Cancer Effect Chrysotile / Lung Cancer Fiber Effect / Inhalation Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score -- Fiber Size - Morphology - Chemistry 0 Penetration - Stability 0 Human Studies 0 + Animal Studies 0 0 In-Vitro Studies 0 + Synergism 0 Other Overall risk compared with cell above ____________ - Overall risk compared with prime cell ____________ - Quality of comparative risk assessment a Remarks: Crocidolite use has been on the decline and confined to wellcontained applications. In the United States, its '\se is already less than one-tenth that of chrysotile, and its occurrence is also low with respect to chrysotile. On the other hana, many investigators believe that equal exposures to crocidolite and chrysotile will result in more cancer from the former, possibly from crocidolite's greater ability to penetrate to the lung and its greater stability once there, rather than from a fundamental difference in potency at the site. Thus, the lower risk assessment is due almost entirely to much lower likelihood of significant nonoccupational exposures. 321 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Other Asbestos / Fiber All Effect Chrysotile / Lung Cancer Fiber Effect / Both Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score --- Fiber Sire 0 Morphology 0 Chemistry Penetration Stability 0 Human Studies + 0 Animal Studies 0 In-Vitro Studies 0 Synergism f Other Overall risk compared with cell above Overall risk compared with prime cell Quality of comparative risk assessment -- _________ b Remarks: Most other forms of asbestos have been shown to cause cancers if intr.duced into the lun^, in sufficient quantity. Like crocidolite, mo^'t amphiboles appear to penetrate to the lung and remain there more easily than ehrysotile. None of the other asbestos fibers are used to a great extent in commerce, so their exposure potential is associated with their natural occurrence or contamination of other products such as talc. 322 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Fibrous Class Fiber / Chrysotile Fiber / Lung Cancer Effect / Inhalation Route Lung Cancer Effect / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score Fiber Size Morphology Chemistry f Penetration Stability Human Studies - 0 Animal Studies - In-Vitro Studies - -- Synergism -- Other Overall risk compared with cell above Overall risk compared with prime cell Quality of comparative risk assessment b Remarks: Fibrous glass is produced in large quantities and is used widely, although much of it is in fibers larger than respirable size. Most of the population has opportunities for exposure, and the trends are toward increased production and at least level production of fine fiber. Most of the indicators for biological activity point toward lower risk. Evidence from human studies suggests lower, although not necessarily zero, risk of lung cancer. The latency period may not have fully elapsed, but considerations of fiber size distributions and the gelling of glass in tissue also suggest lower risk. Overall, the population risk appears lower despite higher exposure levels. 323 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Fibrous Class / Fiber Chrysotile Fiber / Mesothelioma Effect Mesothelioma Effect / Inhalation Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score 4- Fiber Size 4- Morphology Chemistry 4- Penetration + Stability -- 0 ______ -- - Human Studies Animal Studies In-Vitro Studies Synergism Other 0 ______ ______ Overall risk compared with cell above - Overall risk compared with prime cell ______ - Quality of comparative risk assessment b Remarks: Epidemiological studies suggest that Che association of a mesothelioma with fibrous glass is weaker than it is for lung cancer, but animal experiments have demonstrated the induction of mesothelioma with implanted material. 324 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Attapulgite/ Fiber Lung Cancer/ Inhalation Effect Route Scores Compared with Cell Chrysotile Fiber /Lung Cancer/ Effect Inhalation Route Exposure Score Biodisposition Score Effects Score Production Use Pattern Geography Population Trends + __ __ +_ __ + Fiber Size Morphology Chemistry Penetration Stability -- 0 ______ + ______ Human Studies _____ Animal Studies - Ia-Vitro Studies ______ Synergism ______ Other Overall risk compared with cell above - Overall risk compared with prime cell ________ " Quality of comparative risk assessment ________ c Remarks: Except for its extremely localized occurrence, attapulgite is more likely to lead to exposures Chan is chrysotile asbestos. The short, fine fibers are also likely to reach the lung but are cleared rapidly. Evidence is being collected on attapulgite miners, but no positive results have been obtained to date. Positive animal evidence suggesting biological activity is sparse. Overall, the risk is probably less than for chrysotile, but the support for that statement is weak. 325 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Mineral Wool / Fiber Lung Cancer/ Effect Inhalation Route Chrysotile Fiber /Lung Cancer/Inhalation Effect Route Exposure Production Use Pattern Geography Population Trends Score Biodiaposition Score Effects Score - Fiber Size - Morphology 0 Chemistry 0 Penetration + Stability 0 ______ ______ Human Studies 0 Animal Studies - In-Vitro Studies _____ Synergism Ocher _____ Overall risk compared with cell above ______ Overall risk compared with prime cell ______ Quality of comparative risk assessment ______ b Remarks: Mineral wools--both slag wool and rock wool--are not produced in as high a volume as asbestos, but neither is their production on the decline. They are used somewhat less widely than asbestos, but probably in forms that are more easily obtainable. Average fiber size is somewhat thicker. Scanty results from studies in occupational cohorts and animals suggest that mineral wool is no more potent than asbestos, and probably less. 326 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Mineral Wool / Mesothelioma Fiber Effect / Inhalation Route Scores Compared with Cell Chrysotile/Mesothelioma________________ /Inhalation Fiber Effect Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score - Fiber Size - Morphology 0 Chemistry 0 Penetration 4* Stability - 0 ______ - Human Studies Animal Studies In-Vitro Studies Synergism Other 0 0 ______ ______ Overall risk compared with cell above ~ Overall risk compared with prime cell ______ - Quality of comparative risk assessment ______b Remarks: See remarks for lung cancer on previous page. 327 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Attapulgite / Mesothelioma Fiber Effect / Inhalation Route Scorea Compared with Cell Chrvaotile Fiber / Mesothelioma Effect / Inhalation Route Exposure P roduc cion Use Pattern Geography Population Trends Score Biodisposition Score Effects Score * --I-- *...-- Fiber Size Morphology Chemistry Penetration Stability __ 2-- .--. * ______ Human Studies______ Animal Studies 0_ In-Vitro Studies _____ Synergism . Other -- Overall risk compared with cell above Overall risk compared with prime cell Quality of comparative risk assessment Remarks: See remarks for lung cancer on previous page. 328 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Ceramic Fiber / Fiber Chrysotile Fiber / Lung Cancer Effect Lung Cancer Effect / Inhalation Route / Inhalation Route Exposure Production Dse Pattern Geography Population Trends Score Biodisposition Score Effects Score -- Fiber Size -- Morphology - Chemistry - Penetration ++ Stability 0 Human Studies 0 Animal Studies - In-Vitro Studies 0 Synergism Other Overall risk compared with cell above Overall risk compared with prime cell Quality of comparative risk assessment -- _______ b Remarks: Most of the assessment is based on current production an. very limited uses. Fibers are respirable in size but are or:en well contained, and only a few major sources are likely to provide significant exposures. Little information is available on biological effects. . 329 COMPARATIVE RISK ASSESSMENT SCORE SHEET Call Scored Scores Compared with Cell Ceramic Fiber / Mesothelioma Fiber Effect Chrysotile / Mesothelioma/ Fiber Effect / Inhalation Route Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score -- Fiber Size -- Morphology - Chemistry - Penetration Stability 0 0 ______ 0 Human Studies - Animal Studies 0 In-Vitro Studies ______ Synergism ______ Other Overall risk compared with cell above - Overall risk compared with prime cell ______ - Quality of comparative risk assessment c Remarks: See remarks on previous page 330 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Carbon Fiber / Fiber Chrysotile Fiber / Lung Cancer Effect Lung Cancer Effect / Inhalation Route /______ Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score -- Fiber Size - Morphology Chemistry - Penetration Stability 0 0 ______ 0 Human Studies ______ Animal Studies _____ In-Vitro Studies ______ Synergism ______ Other ___ Overall risk compared with cell above ______Overall risk compared with prime cell ______ Quality of comparative risk assessment ______ c Remarks: Assessment is based almost entirely on consideration of the currently low exposure levels. 331 COMPARATIVE RISK ASSESSMENT SCORE SHEET Cell Scored Scores Compared with Cell Carbon Fiber Fiber / Mesothelioma Effect Chrysotile / Mesothelioma Fiber Effect / Inhalation Route / Inhalation Route Exposure Production Use Pattern Geography Population Trends Score Biodisposition Score Effects Score Fiber Size - Morphology Chemistry - Penetration +++ Stability 0 0 ______ 0 Human Studies ______ Animal Studies ______ In-Vitro Studies ______ Synergism ______ Other Overall risk compared with cell above _______ Overall risk compared with prime cell _______ Quality of comparative risk assessment _______ c Remarks: See remarks for lung cancer on previous page. / / / Appendix I BACKGROUND INFORMATION ON MEMBERS OF THE COMMITTEE ON NONOCCUPATIONAL HEALTH RISKS OF ASBESTIFORM FIBERS LESTER BRESLOW, committee chairman, is Dean Emeritus and Professor of Public Health, School of Public Health, University of California at Los Angeles. His work has been devoted mainly to the epidemiology of chronic disease. He is a member of the Institute of Medicine and has served as an adviser on health matters to the World Health Organization and to several federal agencies. ' RICHARD R. BATES is Senior Staff Scientist, Health Effects Institute, Cambridge, Massachusetts. Previously, he served as Associate Commissioner for Science of the Food and Drug Administration and Assistant to the Director for Risk Assessment at the National Institute of Environmental Health Sciences. He has extensive knowledge in the fields of risk assessment and experimental pathology and has concentrated his research on chemical carcinogenesis and toxicology. Dr. Bates is a member of the American Association of Pathologists, the American Association for Cancer Research, and the Society of Toxicology. HENRIK H. BENDIXEN is Professor of Anesthesiology and Chairman of the Department of Anesthesiology at Columbia University in New York City. His research interests include respiratory failure and other aspects of intensive care medicine. In addition to serving on National Research Council committees studying shock and the toxicity of anesthetic agents, he has been a member of various committees of the National Institutes of Health. He is a past president of the Society of Critical Care Medicine and a member of the Institute of Medicine. STEPHEN L. BROWN is an independent consultant specializing in chemical risk assessment and related problems. His contributions include the development of techniques for estimating human exposure to chemicals and other biologically significant agents, application of systems analysis techniques to chemical risk assessment, and priority setting for both testing and regulating hazardous substances. He was previously Director of the Center for Health and. Environmental Research at SRI International. PATRICIA A. BUFFLER is Professor of Epidemiology and Associate Dean for Research at the University of Texas Health Science Center at the 332