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Asbestiform Fibers: Nonoccupational Health Risks (1984)

Chapter: 5 Effects of Asbestiform Fibers on Human Health

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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Suggested Citation:"5 Effects of Asbestiform Fibers on Human Health." National Research Council. 1984. Asbestiform Fibers: Nonoccupational Health Risks. Washington, DC: The National Academies Press. doi: 10.17226/509.
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Effects of Asbestiform Fibers on Human Health This chapter begins with a discussion of the types of evidence that researchers generally use in determining causes of disease. It then pro~ldes information on biodispositlon of fibers and on diseases associated with exposure to asbestos. A discussion of health consequences that have been associated with nonoccupational exposure of humane to asbestos and other asbestiform fibers is followed by a description of occupational epidemiological studies. NATURE OF EVIDENCE Three lines of evidence--clinical, epidemiological, and laboratory- are considered when determining whether 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 was provided by clinical observations. Physicians observed that individual or clusters of cases of pneumoconiosis,} lung cancer, and finally mesothelioma were associated with exposure to asbestos. Paeumoconiosis was the first health effect to be associated with 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 where asbestos is manufactured have long suspected the dust to be the cause of chronic bronchitis and fibrosis....- (Cooke, 19241. Numerous other reports followed. Other types of paeumoconioses, such as silicosis, were also known at that time, so asbestosis, the fibrotic disease caused by asbestos, was not an entirely new type of disease. However, mesothelioma was sufficiently rare that its connection with asbestos was not accepted until 1960 (Wagner, 1960~. Clinical observations led to the hypothesis that asbestos caused the observed disease. Epidemlologists then conducted studies to ascertain whether the hypothesis was true. The association was eventually Pneumoconiosis is the pathological reaction of tissue to the inhalation and accumulation of dust in the lunge. 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 (Do1l, 1955; McDonald and McDor - ~d, 1981; Selikoff and Hammond, 1979~. In laboratory studies, asbestos was administered to avowals to determine whether pathological effects similar to those found in humans could be induced. These experiments followed the methodology established in the Scientific study of infectious agents as causes of disease--a methodology later extended to the investigation of noninfectious agenda. 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 rung cancer and mesotheliomas in animals. Fibrotic reactions, however, usually differed somewhat from the lesions observed in humans with asbestosis. This difference could be attributed to variation among species and in the nature and amount of fibers (Wagner, 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 entities 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 nonquantitative 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: (~) 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 being 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 noninfectious 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 renumber 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 [i.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 tat 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 Lit (1979) have updated Koch's postulates and applied them to environmental toxicology. ID 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 National Research Council (1983b), the authors noted that the steps of risk assessment involve (~) identification of a toxic agent and its effects, (2) determine Lion of dose-response relationships, (3) determiD.ation of the extent of exposure, and finally (4) determination of risk. . - ..

100 In 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. mus, 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 the existence and value of a 'background" rate for the disease. A background rate is the rate of occurrence of a disease with no association, or no known association, with the agents 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 to asbestos. In the 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 c igarettes 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 (Harmond et al., 1979~. Together, the cigarette smoking and asbestos exposure appear to produce a multiplicative effect, i.e., the lung cancer rate is inc reased up to 50-fold above background . Expressing the relationship as an absolute risk, rather than as a re let ive risk, may provide informal ion about the magnitude of the pub 1 ic 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, the risk for coronary heart disease among smokers is about 1.6 times greater than the risk for nonsmokers, as contracted with a lO-fold increase in risk for lung cancer among smokers compared with nonsmokers. However, cigarette smoking causes more deaths from coronary heart disease than it toes from lung cancer, because the base line "background" risk for heart disease is much higher than for lung cancer. BIODISPOSITION OF FIBERS - In this section the co~nmittee 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-l shows the anatomy of the respiratory tract ant the individual cell types ins olved in asbestos-associated diseased. The pathological effects of asbestos begin

Epiglottis Ail Visceral _ Pleura Parietal _ Pleura Alveol i- ~ Figure 5 101 ~ Esophagus Trachea- /~\\ \ Peritoneal Cavity ~ Diaphragm I Cavity Pharynx Main Bronchus See Figure 5-1B Pleural Cavity (the pleura consists of the membrane enveloping the lungs and lining e chest cavity) FIGURE 5-1A. Routes of inhalation and ingestion of asbeseifonm fibers are shown by small arrows. Mesothelial cells line the outside of the lungs ant the pleural and peritoneal cavities. Interaction of asbestos with these cells can result in either pleural or peritoneal me~othelioma. Adapted from Wagner, 1980.

102 niacin Granule Epi~elium Connemive Tissue so Tr;chea ~ #! ~ ~ . ~ ~' at , Macrophap~]'il~l' Ciiia~e~ Cell it} ., ~ ~ 4~/ I '~/)j?.2 torus ,~ ,,,.,~";'1.~}' ~ ".., FIGURE 5-1B. Cells of the bronchus, or large airways, leading from the trachea. The epithelial cell layer conalats of ciliated cells, mucin-secreting goblet cells, and basal cells. the interaction of asbestos with the epithelium and with macrophages is be' ieved 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. In'.rss't.~t Soace Alveo'at Ep''bel~um FlUed Layer ~ \ my, Surtactent I\ Layer ~\ ALVEOLUS D'ffuslon ~- ~ Cao~ll.rV Basement / l~kmDrane / ~CapellarY Entlot~l,um l.\ {~: of CAPILLARY} ~ FIGURE 5-1C. . _ . . i. Dittus~on'/ot ~ |Carbon Dioxide /f, L ~/~ 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.) r ..

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 Am 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, 1931; Timbrell 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/cm3 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 (Timbrell, 1965~. From his experiments in rats, Timbrell (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 Am 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 Am 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 ~m, the count median length fo''nd in lungs was 7 Am; for actual (as opposed to aerodynamic) diameters, the respective values were 1.2 Am and 0.5 ~m. They also found that length played some role. Timbrell (1982) compared the sizes of fibers found in the air of an anthophyllite 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 (Timbrell, 1965; Timbrell et al., 1970; Wagner et al., 1974~.

104 , _ ~ ._ , '1 1 ,1 1 E ._ C) - ~_ . I I I 1 1 - _ CD to (WH) NAZIS 8381d 14 - 1 l ] O tD ~O O O - o o Cut Cat _ - _ CO ~ (wow NAZIS H381d ~D o o o 1 . c LU o ~ as - UJ <: LO ~ Z I tn J z Ul _ I _ a _ 1 1 1 1 _ C ~° a, - l O CD ~ O o o C~ C~ (WH) ~ZIS B381d - LU o N ~ - C] UJ ~n Z cn ~n O L~ z UJ CC e C) 0 o x · - CO · - · - e E C' e Ct 5: o ·rl C' CL ~ E o o s" C~ 1 C,

105 In addition to diameter and shape, factors such as changes in breathing rate, individual anatomic variat ions , 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 en al., 1971). Studies in animals have demonstrated that most deposited fibers are removed from the respiratory tract within a few days. However, at least a quarter of the initial burden remains 1 month later (Evans et al., 1973; Muggenburg et al., 1981~. Since much of the 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 the mechanism of action of the fibers. In addition to pulmonary or other tissues, sputum and ravage samples have been stud fed ~ 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. Sebase fen et al. (1977) reported that the number of fibers/cm3 of lung sample, as seen by the light microscope, was approximately 106 for a heavily exposed group, 103 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 et al., 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, the term ferruginous body is now often used instead of asbestos body. There are many reports of ferruginous bodies counted under various circumstances (Sebastian et al., 1979), but the pathological significance of these bodies is unclear. Asbestos bodies form with greater efficiency on varieties of amphibole 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 (Lange r et al., 1973; Pooley, 1972~. Chrysotile seems to degrade or be removed In Vito more readily than the amphiboles (Lange r et al., 1972a, b; Wagner et al. , 1974, 1982 ; Rowlands, 1983) . Fibers found in tissue samples obtained from the general population tend to be shorter in length and diameter than those found in workers (Larger et al., 1971; Pooley en al., 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 the lung parenchyma ( the body of the lung) may be different from that in the parietal pleura (the pleura lining the chest cavity) as shown in a study of 29 persons, most of whom had pleural asbestosis (Sebastian et al., 1979~. The parenchymal samples had both amphibole and chrysotile fibers. Their average length was 4.9 ~m; 15% of them were longer than ~ Am. The pleural samples were predominantly chrysotile fiber, with an average length of 2.3 Am; 2X of these fibers were longer than 8 Am. 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 fibers2 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 attapulgite . More than 85: of the part ic les counted, and al 1 of the a~ctapulgite particles, were less than 5 Am long. Clearance and Transport Several mechanisms are involved in clearing fibrous materials from the lung. These include removal by the beating of ciliated cells and secretion of mucin (i.e., mucociliary clearance), transport by alveolar macrophages to regional lymph nodes and distal sites (Lippmann en al., 1980; Morgan et al., 1978, 1982), uptake by epithelial cells that line the airways and alveoli (Mossman et al., 1977; Suzuki, 1974), and direct translocation of fibers between ep~thelial 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 Am long) are not completely engulfed by macrophages and are cleared ineffectively (Morgan et al., 1978~. Incomplete mucociliary clearance might result from discont~nuities in the 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 ant secretory cells that line the airways (Sanchis _ al., 1971~. Clearance of asbestos from the gastrointestinal tract is less well understood, although it has been reported that fibers cross the mucosa of 2The materials detected did not necessarily have the characteristics of asbestiform fibers. -

107 the stomach and intestines (Cook, 1983; Westiake et al., 1965~. Fibers have been detected in urine and feces (Muggenburg et al., 1981~. When injected into the femoral vein of pregnant rats, chrysotile crosses the placenta and has been observed in fetal liver and lung (Cunningham and Pontefract, 19743. CLINICAL ASPECTS OF "BESTOS-"SOCIATED DISHES l m e four major asbestos-related diseases or changes are: (1) lung cancer; (2) mesothelioma; (3) pulmonary asbestosis; and (4) pleural plaques or diffuse thickening, calcifications, and effusion. Some other cancers may also be related to asbestos exposure (Selikoff et al.. 1979~. Lung cancer and mesothelioma are typically fatal cancers. Therefore, the degrees of severity are generally not relevant. Pulmonary asbestosis and the pleural changes noted above are nonmalignant 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, menothelioma and asbestonis 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. They 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; Selikoff and Lee, 1978~. _ ~ Necessary AsSumptioD8 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 litt le informal ion about the rate at which pulmonary asbestosis progresses following removal from exposure (Becklake, 1976), especially brief, low-le~rel exposure . Se idman et 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 et al., 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 occupat tonal exposures, are relevant in determining whether a disease may be related to asbestos exposure. Men diseases are observed in occupational groups exposed to asbestos, the exposure may be cons idered as a cause or contributing factor (Craighead et al., 1982; Goodman, 1983; Selikoff and Lee, 1978~. When such diseases occur among populat ions 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, nonoccupat tonal exposure to asbestos is likely to be light and may lead to some abnormalities, mainly pleural, but to no more than mild functional

109 impairment. Again, an association with asbestos exposure may never be established. General Diagnost ic Measures The following general discussion of diagnosis is followed by more specific information on each disease. Depending on the disease, to patient' s history often contains accounts of shortness of breath (dyspnea) upon exerc ise and, perhaps, at res t; 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 pathognomonic3 for any single illness (Becklake, 1976; Boahuys 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 et al., 1973~. An international classification for the radiological assessment of a~bestosis 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 auscultation4 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 expiatory volumes, to assess restrictions on lung movement (as in fibrosis or pleural thickening) or obstructions to air flow in the airways (as in bronchitis or emphysema), and to screen for 3Distinctively characteristic of a specific disease? i.e., the presence of the symptom uniquely determines the diagnosis. 4Auscultation is the act of listening to sounds made by body organs, such as lungs. .

- ~ 110 disease. Lung volumes may also be measured, but the necessary equipment is available only in well-equipped pulmonary function laboratories. Tests to measure diffusing capacity. In these teses, measurements are made. of the lung' ~ 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 uset extensively, in part because it is noninvasive. A reduced diffusing capacity results when a decreased amount of surface area in 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 the 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, ant 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 et al., 1975~. More refined measurements, such as progressive exercise teseing, are often helpful in assessing impairment. Asbestos bodies have been found in sputum and in bronchoalveolar ravage samples from persons occupationally exposed to asbestos (Di Menza et al., 1980; Fariey et al., 1977; McLarty et al., 1980; Smith ant Naylor, 1972~. Bronchoalveolar ravage has been used as a research tool to study asbestos is (Di Menza, 1980) . This technique al lows 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 diseased, come individuals deve lop asbestos-assoc fated 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. Pernis ( 1965 ~ fount an increase in rheumatoid factor titer in individuals with pulmonary asbestosi~. Turner-Warwick (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 thee the association is weak (Turner-Warwick, 1979) and not clinically relevant. At present there is no practical way to identify individuals immunologically or genetically susceptible to disease from asbestos exposure.

l 111 Lung Cancer. mi8 disease accounts for approximately 100, 000 deaths annual ly in the United States, predominant ly among smokers . Lung cancer is a malignant tumor of the epithelial covering of lung airways (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 airways, 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 asbesto~-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 tents often yie id findings consistent with chronic bronchitis, especially in smokers, perhaps with a localized wheeze , but as tumor invasion continuer, 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 the 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 40: to 50% survival after 5 years. In later stages of lung cancer of any cell type, the 5-year survival does not exceed 10% 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 d i ecus sed in th i s report . ~ Ma 1 ignant me sothe 1 ioma beg ins i t s deve 1 opment in the mesothelial cells of the pleura or peritoneum. During its early growth it causes few symptoms. By the 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 Varietal (lining the chest cavity), then visceral (covering the 1UDg8~. With time, the lung becomes encapsulated and restricted in its movements. The tumor may invade the lung tissue and may spread into adjacent structures, such as the chest wall (Suzuki, 1980~. Death often results from inadequate respiration or from hemorrhage (Becklake, 1976; Craighead et al., 1982; Selikoff and Lee, 1978~. Peritoneal mesothelioma may originate anywhere on the peritoneum and may initially grow without symptoms. Eventually the tumor 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 may be bowel obstruction or major hemorrhage. Early symptoms are either lacking or vague (Becklake, 1976; Selikoff 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 may 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 t''mor. It is more difficult to diagnose peritoneal mesothelioma than pleural mesothelioma. The diagnosis is confirmed only by microscopic examination, and even this may be difficult Or impossible if the tumor is sufficiently undifferentiated. Mesothelioma may be mistaken for both carcinoma and sarcoma. Identification of the cell type in which the tumor originated is difficult. This procedure may be facilitated in the future by new techniques using cytoakeletal or other cell markers defined by antibodies. The pathological diagnosis of mesothelioma in sufficiently difficult that special panels functioning under the auspices of the Union Inter~ationale 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 (Chahinian et al., 1982~, although surgery, chemotherapy, and/or radiotherapy may delay death for a few months. Fibrosis of Lung Parenchyma (Asbestosis). Asbesto~is belongs to the group of illnesses called the pneumoconiose~. This disease is characterized by a slowly progressing, diffuse interstitial fibrosis. The functional impairments from asbestosis fall into three groups:

113 (1) impaired ability to exchange gases between capillaries and alveolar air spaces ~ leading especially to inadequate oxygenat ion of blood (hypoxemia); (2) restricted breathing, 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 asbesto~i~ are considered in this section because the more severe forms would be unlikely to occur among those exposed to relatively low levels of particles (8ecklake, 1976; Craighead et al., 1982; Selikoff and Lee, 1978~. Animal experiments indicate that 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 et al., 1981, 1982, and in press). The fiber may be partially or completely surrounded or engu 1 fed by mac rophage s or giant cells. A small portion of fibers may be converted to asbestos bodies. Studies of biomineralizeeion may be able to offer additional insights into the interaction of asbestos and cells. Subsequently, fibroblasts lay down collagen, thereby initiating the fibrotic 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, asbeseosis 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 epitemiological 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 associa~ced 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 by auscultation. In addition, arterial oxygenation and diffusing capac ity may be decreased. Smoking may also affect the pulmonary function tests and radiological results, especially with respect to small airways disease (Buist, 1983~ . me 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, sepLal lines become more marked, and pleural involvement is often seen. At that stage, the radiological picture alone may strongly suggest asbestosis. The most effective prevention or treatment is early removal from exposure. Although asbesto~is often continues to progress (Becklake,

- 114 1976), the progression is not inevitable and often not rapid (Gregor et al., 1979; Jones et al., 1980a). Progressive hypoxia with car pulmonale are common causes of death among chose with advanced asbe~tosis, and many persons with advanced asbestosis die from lung cancer. Mild asbestosis is not necessarily associated with functional impairment. Pleural Changes. Diffuse pleural thickening, plaques, calcification, and effusion are nonmalignant changes in the pleura that have been associated with asbestos exposure (Albelda et al., 1982; Epler et al., 1982; Weiss et al., 1981~. mese changes, usually detected by . _ _ radiographic examination rather than 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 than the visceral pleura (Becklake, 1976; Selikoff and Lee, 1978~. There may be simple, benign pleural effusion, and the usually sterile f luid 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 those 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 NONOCCUPATIONAL INHALATION EXPOSURES TO . AS8ESTIFORM 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 that 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-asse ssment mode 1 s . 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~manufacturir~g facilities, and in areas with natural sources of asbestiform flbera. Mesothelioma provides a useful end point for studying effects of exposure. This fatal tumor is rare, except in certain groups exposed to asbestiform fibers. In some worker cohorts, as many as 10: of the deaths have been caused by mesothelioma (}lcl)onald 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 5% of all deaths in the United States (U.S. Department of Health and When Services, 1983~. Furthermore, unlike lung cancer, me8Othelioma is not associated with smoking (Hammond et al., 1979~. The best estimates of the n-tio=A1 incidence rate for mesothelioma have come from the National Cancer Institute' n Surveillance, Epidemiology and End Results (SEER) Program, which collects data on cancer incidence in about lob 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 mile cases and Il7 female cases (Connelly and Myers, 1982~. From theme 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 e~ctensi~re shipbuilding during World War II, the annual incidence race 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. Seesaw, National Center for Health Statistics, personal communication, 19133~. Because of the difficulties in diagnosing mesothelioma and determining exposure to asbestiform fibers, the background rate of mesothelioma is not knows. In one study of 4,539 canes from 22 countries between 1959 and 1976, there was no definite or probable history of exposure for 38: of the subjects (McDonald and McDonald, 1977~. In North America, it was estimated that from 50X to 75X of male cases, but only 10% 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 nicked workera5 and in persons with stinger et al. (1980) reported that they found asbestos fibers contaminating some nickel ores. 1

116 some other specific exposures (Peterson et al., in press). It is thus possible that not all cases of mesothelloma are associated with exposure to asbestifo~-- fibers. However, since the levels of general ambient exposures to asbestos were not known, the possibility that the residual cases might also be attributable to asbestos exposures cannot be discounted. Epidemiological data have led to questions about the characteristics of fibers that are associated with mesothelioma. Some investigators have interpreted the data as indicating that exposure to chrysotile is less likely to produce mesothelioma than is exposure to the other asbestos fibers (Craighead and Mossman, 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 from Household Contacts Anderson _ al. (1979) studied household cohabitants of 1,664 asbestos workers. The workers were employed in a factory that had produced amosite asbestos products from 1941 to 1954. Controls were urban New Jersey residents living in the same community who had routine chest e-rays between January 1975 and December 1976. Asbestos-associated x-ray abnormalities were found in 35: of the 678 household contacts examined and in 5: 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 clothes. 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 (Viable 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 occupatloDally exposed husbands or fathers. Neighborhood Exposure to Asbestos A cohort of 1,779 males living within 0.8 km 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 in the plant. No excess mortality or excess lung cancers were detected between 1962 and 1976 in the group li~rir~g near the plant. mus, in this study, males living in the factory neighborhood apparently were ie88 at risk (at least for mesothelio~) tin 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 Asbestiform Plbers Asbestos-related diseases have been associated with exposure to naturally occurring mineral fibers in Turkey, Finland, and Bulgaria (Bards et al., 1981; K1viluoto, 1960; 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 asbeston-associated lesions in some human populations and in animals not known to be esposed to asbestos. They and others (e.g., Glickman 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, 4: 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 asbestiform fibers (Burilkov and Hichai' ova, 1970) consisting of anthophyl' ice, tremolite, and sepiolite, the latter being a layered silicate with a triple subchain structure. No pleural plaques were found in a neighboring farming region that lacked asbestiform 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 (`Ar~cvi~i and Baris, 1982; Baris et al., 1981; Lilis, 1981; Rohl et al., 1982~. Dwellings are hollowed out of the rock. Studies of the population of these villager have revealed mortality and disease patterns that are similar to those usually seen among asbestos workers, with respect to occurrence of fibrosis, pleura' plaques, lung cancer, and mesothelioma (Artvinli and Baris, 1982~. In Karain, a village with a population of about 600, 36 cases of mesothelioma were reported between 1969 and 1974 (Bards et al., l9Bl). The median age of death in Karain was 54, whereas it was 68 in the nearby village of Karlik. In another nearby visage, Tuzkoy, malignancies accounted for 41 of 67 deaths that occurred from 1978 to 1980 among almost 2,000 residents older than 25 years (Arivin~i and Baris, 1982~. Of these deaths, 15 were due to pleural mesothelioma, 12 were attributed to peritoneal mesothelioma, and ~ were caused by lung cancer. lie mesothelioo~as were found equally among male and female residents, and the mean age of the

118 mesothelioma cases was about 50, which in 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. Dust and fiber levels were measured in Karain and in the "control" village lCarlik (Bards et al., 1981~. Dust levels in both villages were about 1 mg/m3. Levels of fibers were higher in Ka rain than in Karlik, but in both villages, most air samples had less than 0.01 fiber/cm3. Nonetheless, in 11 samples taken during the cleaning of the caves in which the Martin villagers Tiered, the concentrations ranged from less than 0.01 fiber/cm3 to 1.38 fibera/cm3. Although tremolite asbestos was apparently present in the area, the most prevalent fibers appeared to be erionite. Analysis of pleural and parenchymal tissues from mesotheliom~ patients from Karain indicated that 90% of the fibrous particles had a composition consistent with that of erionite (a fibrous zeolite), whereas from 1: to 5: were consistent with tremolite (Rohl 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 108 fibers per gram of dried lung tissue (Sebastian et al., 1981). Of the uncoated fibers, 93% were erionite with a mean length of about 3.7 ~m. Only 3% of the fibers were longer than ~ Am or thinner than 0.25 Am. The remaining fibers seem to have been either titanium oxide (rutile) or some material resembling amphibole. The data are consistent with the hypothesis that erionite may have a role in causing the high rate of mesothe~ioma 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 (Bards et _., 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 time-dose-response models for mesotheliom~ 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 fibera/cm3 accounts for a mesothelioma lifetime risk of 50:, based on the data presented in Table 7-3. Ram _ al. (1983) considered the possible health hazard posed by naturally occurring fibrous erionite 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 (2X) and pleural thickening (62) 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 (Wright et al., 1983~. Wagner (1982) has reported that erionite from Oregon is extremely potent in producing mesotheliomas in rata.

119 S''mma ry 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 WATIER ~- Epidemiologica' 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, 1983~. 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 ~ 106 fibers/liter. Except for Duluth, where taconite 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). lathe 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; Sigurdson et al., 1981~. In Quebec, cancer mortality was evaluated in relation to asbestos in municipal water supplies. In the first study (Wigle, 1977), 22 municipalities were grouped into three categories based on level of asbestos in water supplies. In a more extensive study (Taft et al.`, 1981), mortality rates for two cities with high exposure (~100 x 10 fibern/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 acicular cleavage fragments rather than asbes~ciform fibers (T. Zoltai, personal communication, 1983~. See alto Larger et al., 1979.

120 TABLE 5-1. Characteristics of Asbestos Exposures from Drinking Water in Different Study Populationsa Exposure Characteristics No. of Fibers Location of Type of per liter Study Asbestos (Range) , Size of Masi'iium Population Duration of Exposed E sposure (Years ) Duluth Amphiboleb 1-30 ~ 106 100,00015-20 Connecticut Chrysotile BDLC~ .7 s 106 576,80023~44 Quebec Chrysotile 1.1-1,300 s 106 420,00050 Bay Area, Chrysotile California 0.025-36 s 106 3,000,000 40 Utah Chrysotile NAG 24,000 20-30 Puget Sound Chrysotile 7.3-206.5 s lob 200,000 40 a From Marsh, 1983. boost of these particles were probably acicular crys tale rather than asbestlform fibers (T. Zoltai, University of Minnesota, personal communication, 1983~. Langer et al. (1979) referred to the particles as amphibole gangue minerals and discussed the uncertainties in determining whether they are asbestiform. CBDL ~ below detectable limit. dNA ~ not available. between asbestos risk scores and GI tumor incidence (Harrington et al., 1978; Meigs et al., 1980~. In San Francisco, there were inconsistent excesses of some cancers (Conforti et al., 1981; Ranarek et al., 1980; Tarter, 1981~. In Puget Sound, a proportional incidence analysis comparing length of residence suggested an excess for some GI cancers (Polissar et 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 may 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 lageation of drinking water containing asbestiform fibers might increase the risk of GI cancer. The NRC Safe Drinking Water

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123 Committee (1983a), U8i~g a variety of assumptions, estimated the excess risk of G! cancers that might be expected from ingestion of asbestos-containing drilling water and concluded that their risk estimates are consistent with the results of the epidemiological drinking water studies conaldered. OCCUPATIONAL EPIDEMIOLOGICAL STUDIES--METHODOLOGICAL CONSIDERATIONS Evaluation of potential health effects from nonoccupational exposure to asbestiform fibers depends primarily on results of epidemiological studies of occupational groups. Most of the analyses have involved cohort7 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 ~ to obtain a true count of fibers longer than 5 ~m. 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 7The two major types of epidemiologica' 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 within . cohort 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 occupatloDal 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. mese estlmaten 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 asbeatosls (Hammond et al., 1979). In morbidity studies, asbestosis, 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 asbestosi6, other diagnostic criteria have been suggested. Methodological differences are a mayor source of variation in comparing studies (Enterline, 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 (Weiss, 1983), 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 atatiseically significant, may indicate that excess deaths have occurred in the esposed 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 are confined to active workers, which is usually the case. A bins 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 et al., 1979; Rubino et al., 1979b). Numerous follow-up studies of asbestos-related mortality have been conducted on cohorts with varying intensity ant 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-1, 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-1. These studies indicate the variety of occupations and industries where asbestos exposure has occurred and the types of asbestos commerc ial ly used. The epidemiological study by Doll ( 1955) verified and quant if fed 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 o f 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 (Brealow et al., 1954; Mancuso and Coul~cer, 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 ~LE 50. Su~ry of Mortality Dets for Hesothello_, Lung Caccer, acd Gestrointestl"1 Cancer 1n "bestos-Esposed Occupatios~al Cohort~ RceDlratorY Cancerb Tot;~1 Size of Hesothello - / Ses and OccupationCohort Deathe in Cohort Pleural of Cohort CountryC Traced No. ~Perltoneal Obe ESP O/E M.4LES: l~g Chrysotlle C 9, B50 3, 291 33.4 10/10~0 230184.0 1. 3f C S44 178 32. 7 1/1-0 2811.0 2. 5f 1 933 332 35.6 0g/0-0 1010.4 1.0 "thophyllite ~ 1 ,045h 384 36. 7 0/0~0 4422.0 2. of Crocidolitc ~e ' ,960 526 10.6 26/26~0 6038.2 1.6f tSnufacturing Chrysotile US 1,261 308 23.6 1/0-1 3511.1 3.2f "osite US 820 528 64.4 14/7-7 8322.8 3. 6f Mised B 2, 88 7k S45 18.9 46/19-27 10343.2 2. 4f 7, 474 1 ~ 339 17.9 8/8-0 143139.5 1.0 B 1, 071h 317 29.6 10/10-0 5123.8 2. lf US 1, 075 781 72. 7 5/NA 6323.3 2. 7f US 5, 645 601 10.6 Og/O~O 4949.1 1. 0 C 241 72 22.0 11/6-5 203.3 6. lf D 5,686 e 3/NA 4727.8 1. If Insula tion ~- Mised US 632 478 75.6 38/11-27 9313.3 7. of US 17~800 2,271 12.8 175/63-112 429105.6 4.0f B 162 122 75.3 13/8-5 355.0 7.0f Shipyerds Mised B 6, 076 1, 043 17. 2 31/NA 88100. 7 0. 9 1 2,190 1,970 48.9 NA 12354.9 2.2f F~S: Manufacturing t:rocldolite B 578 166 28.7 17/13-4 126.3 1. gf Miset B 783 200 25.5 21/13-7 273. 2 8. 4f B 3, 708 299 8.1 2/2 - 611.3 0.5 B 1, 304 396 30.4 6/NA 2211. 0 2. of aAdapted fro~ McDonald and McDo~ald (1981) and fro. Consueer Product Safety Co~i~sion (1983, p. II-57). These studies are deacribet in ~ore detail in Table E-1 of Appendls E. bObe ~ obeerved; Exp - espected; O/E - obser~red/espected; LL - lower li~lt; UL - upper limit. CCountry of study: US - United States, B - Brltain, C - Ca~ada, ~ - Fi~nd, I ~ Italy, D - De~ark, Aus ~ Australla. dgs: confidence l~tenrals (two-sided) calculated assual~g nor~al dlatributlon for log SMR. eThe colu~e headed "power" above ludlcate the probability of detecti~g an effect, given the size of the population studied, assuming that exposure produced a eini~UD~ relative risk of 1.5. More precisely, statistical power 1s the probability that the oull hypothesis of no locreased relati~re risk (R ~ 1) trill be reJected by ~ one_ided test with ~ ~ (U.05 lf the tn~e relative rlelc (~) 1e actually 1.5 in a population of the size studied. The calculation (see 8esumont and Brealo~r, 1981) is "sea on the assumption chat, under the null hypothesis, the obeerved nua~r of deaths tree a Poisson distribution with expected ~ralue equal to E (the expected nuaber of deaths fcr persons of this age group) and that the square root transfor~ation stabilizes the ~rar"nce of the Poisson distribution. Power is calculated by coaputi~g ~ - 1.64S - 2^- 1)(~) and then detemining the area to the right of ~ froa a table of the standard nor~1 dlatrlbution.

127 U8 - 5~6 (CO8t. ) Resoirator~r Cancer (cont. ) 95% Conf idence Liaitad _ U G.8trolatesti"1 ~ncerb Power to Detece O/E >1..5 ~ ~ ().OSe Obs · _. _ Esp O/E 95: Conf ldence Lialt8d LL UL _ ~ Power to Detect O/E >1 5 ~ ~ 0~05e References · , 1.11.4 1.00 276272.4 1.0 0.9 1.1 1.00 McDonald et al., 1980 1.83. 7 0.44 109. 5 1. 1 0. 6 2.0 0.40 Nlcholson et ~., 1979 0.51.8 0.42 1919.3 1.0 0.6 1.5 0.63 Rubino et al., 1979a 1.52.7 0.68 78.0 o.gi 0.4 1.8 0.36 Meurman et al., 1979 1.22.2 0.87 NAiNA NA ~~ ~~ ~~ Hobba _ al., 1980 2.34.4 0.44 139.9 1.3 0.8 2.3 0.41 Deaent et al., 1983b 2.94.5 0.69 2822.7 1.2 0.9 1.8 0.69 Seld~an et al., 1979 2.02.9 0.90 4034.0 1.2 0.9 1.6 0.84 Newhouse and Berry, 1979 0.91.2 1.00 103107.2 1.0 0.8 1.2 1.00 Newhouse et a,., 1982 1.62.8 0.71 1615.7 1.0 0.6 1.7 0.56 Peto et al., 1977 2.13.5 0.70 5539.9 1.4f 1.1 1.8 0.88 Henterson and Ecterllne, 1979 0.8 1.3 0.93 25 50.1 0.5 0.3 0.7 0.94 Hughes and Weill, 1980 3.9 9.4 0.20 4 2. S 1.6 0.6 4.3 0.18 Finkelsteln, 1983 1.3 2.3 0.76 59 49.3 1.2 0.9 1.5 0.93 Cle~esen and H]algrie-Jenson, 1981 5. t 8.6 0.50 43 15.0 2. 9f 2.1 3.9 0.54 Selikoff et al., 1979 3.7 4.4 1.00 94 59.4 1.6f 1.3 1.9 0.97 Selikoff et al., 1979 5.0 9.7 0.26 13 2.2 5.9f 3.4 10.2 0.16 Elo~es and Simpson, 1977 0.7 1.1 1.00 73 83.3 0.9 0.7 1.1 0.99 Rosslter and Coles, 1980 1.9 2.7 0.95 74 58.6 1.3 1.0 1.6 0.96 Puntoni et al., 1979 1.1 3.4 0.30 10 20.3 0.5 0.3 0.9 0.65 Jones et al., 1980 5. 8 12.3 0. 20 20 10. 2 2. of 1. 3 3.0 0.42 Newhouse and Berry, l9t9 0.2 1.2 0.45 29 27.4 lel 0.7 1.5 0.76 Newhouse et al., 1982 1.3 3.0 0.44 NA NA NA -- -- -- Acheson et al., 1982 tStatistlcally signif icant increase ( p < . 05 ) . g One possible case (Rubloo e: al., 1979); two cases not aceting criteria (Hughes and Weill, 1980). hMales and feo~ales (Meur~an et ~., 1979; Peto et al., 1977). Based upon 1974 report (Meur~n et al., 1974). iNA ~ data not available. kBased on ~les, excludlag laggers (Newhouse and Berry, 1979). [Study of cancer incidence (Cle~esen and H]algrim-3cnson, 1981). .

128 Since 1964, a number of investigators have documented an excess occurrence of lung cancer and/or mesot2,elioma 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 other atudiea. (See Table 5-4 and Appendix E, Table E-1 for more details on the se stud ie ~ . ~ Mining and Mi 11 ing 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 the largest investigation, McDonald et al. (1980) studies 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 = 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 the 1,045 persons successfully traced. All lung cancer deaths occurred among the male employees, and the risk was associated with estimated intensity of exposure (SMR = 1.4 vs. 3.3 for low ant heavy exposures, respectively). Lung cancer risk among nonsmoking asbestos-exposed employees was 1.4 compared to ~ relative risk of 17.0 for the asbestos-expo~ed employees who smoked. Crocidolite. For exposure associated with crocidolite mining in Western Australia, there wee a similar increase in risk of lung cancer (SMR 5 1.6, 60 observed vs. 38.2 expected) and a strong association with mesothelioma (Hobba et al., 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. Manufactur~ng 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 observes/11.} expected), and the risk was strongly correlated with exposure level. There was also one peritoneal mesothelioma. Increased risks for botch lung cancer and nonmalignant respiratory disease were observed at exposure levels tower 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 a 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 obser~red/43.2 expected) and females (SMR = 8.4, 27 obser~red/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 10X 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 ll,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 1,34S 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, S5 observed/39.3 expected) (Henderson and Enterline, 1979~. Overall mortality among the 1,075 retirees successfully traced to 1973 was 73%. The lung 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 ret free 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 mesothelio~a, 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 crocidolite, and two aesothelioma deaths were reported. The low overall mortality, 10.6:, and the low tracing rate, approximately 75:, suggest that this study may have resulted in an underestimate of mortality risks. FiDkelatein (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 Hiaigrim-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 stomach cancers. Cancer incidence in the unexposed employees at the same factories was not increased. Jones_ al. (19BOb) studied a cohort of 578 females exposed to crocidolite from western Australia during the manufacture of gas masks. The 12 cases of lung cancer (SMR ~ I.9, 12 obeerved/6.3 expected) and the 17 mesothelioma cases (13 pleural and 4 peritoneal) were all exposed to crocidolite, whereas no cases of mesothelioma or lung cancer occurred among the 102 females exposed onto to chrysotile. Overall, 10: of deaths were due to mesothelioma. Risk of mestheliom~ was strongly associated with duration of exposure, although no dose-response relationship was observed for lung cancer. Similar results were 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 I''ng cancer (SMR - 2.0, 22 observe/ expected) and ovarian cancer (SMR ~ 2.2, 17 observed/7.8 expected) were increased. Lung cancer excess was higher for those exposed predominantly to crocidolite compared to those exposed predominantly to chrysotile. Five of the sis mesotheliomas occurred in those exposed predominantly to crocidolite. 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 (~.~) for gastrointestinal cancer were observed in sis of the nine cohorts reviewed (Clemmesen and H]algrim-Jenson, 1981; Dement et al., 1983b; F1Dkelatein, 1983; Henderson and Enterline, 1979; Newhouee and Berry, 1979; Seaman 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 al. (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 obeerved/105. 6 expected) and increased were observed for gastrointestinal cancer (SMR ~ 1. 6, 94 obeerved/59.4 expected), cancer of the larynx, pharynx, buccal cavity (SMR 2 1- 7, 25 observed/14.8 expected), and kidney (SMR a 2.2, 18 observed/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. 7X of the 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 asbestos- exposet ant unexposed groups. A five-fold increase in lung cancer risk was associated with asbestos exposure in both smokers and nonsmokers (Hammond et al., 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 75.3: by 1975; S4% of the deaths were due to cancer. Thirteen cases of mesothelioma (eight pleural and five peritoneal) were reported. 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. Ship _ _ 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.S, 63 observed/83.3 expected). Mesothelioma was reported for 31 (31) of the 1,043 deaths. However, since less than 20Z of this cohort have tied, excess cancers may not be fully apparent. In a study of 2,190 Italian dockworkers, Puntoni et al. (1979) observed increased risks for lung cancer (SMR a 2.2, 123 observed/54. 9 expected), gastrointestinal cancer (SMR ~ 1. 3, 74 observed/58. 6 expected), laryngeal cancer (SMR ~ I. 9, 15 observed/7. 7 expected), and kidney cancer (SMR ~ 2.0, 29 observed/14. 7 expected).

132 Relative Carcluogenicity of Different Types of Asbestos There has been much discussion about Whether certain asbestos varieties are more carcinogenic than others. The question is of practical importance, because the vast majority of asbestos used in the United States and the worId is chrysotile; however, it is difficult to answer, because studies of different types of asbestos are confounded by type of industry (mining and milling vet asbestos-cement vet asbestos insulation V8. asbestos testiies), 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 crocidolite, especially in regard to its association with mesothelioma. Some groups of workers exposed to crocidolite have had a relatively high rate of mesothelioma. Among those are black South African crocidolite miners (21 prevalence) (Talent et al., 1980) and gas-m~ak workers (up to 10% of deaths) (Acheson et al., 1980; Jones et al., 1980~. In a study of naval dockyard workers, Rossiter and Co1es (1980) reported 31 deaths from mesothelioma and only 13 other deaths from asbestos-related disease among 1,043 deaths ascertained (Rossiter and Coles, 1980~. McDonald (1980) suggested that use of crocidolite by the British nary could explain such a finding. Data on chrysotile exposures are mixed. Canadian studies of chrysotile miners and millers have suggested that the average incidence of mesothelloma is relatively low (0.5Z) (McDonald, 1980~. Dement et al. (1983b) reported that only one of 308 deaths in a chrysotile asbestos textile plant was attributable to mesothelioma. Peto (19SOb) reported a high risk from mesothelioma in an asbestos testile plant in which chrysotile predominated, although amall amounts of crocidolite were also processed. Similarly, Robinson et al. (1979) reported that mesothelio accounted for 4.3% of deaths among workers who processed predominantly chrysotile, and lesser amounts of crocidolite and amosite. The Connumer Product Safety Commission (1983) noted, "Epidemiological studies suggest that chrysotile has a rawer 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 pleura, menothelIoma and lung cancer." Acheson and Gardner (1983), in discussing mesothelioma in humans, have concluded that "exposure to chrysotile 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 any clearance of fibers in the lung. However, the possible role of other factors, including chemistry, has not 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 the studies on fiber type have been focussed on mesothelioma, which accounts for only some asbeatos-related disease. Experimental and animal studies, discussed in Chapter 6, have not detected systematic differences in carcinogenicity or fibrogenicity among 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 amok e on lung cancer. me 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. Among male asbestos workers who never smoked cigarettes regularly, eight mesotheliom~ deaths were observed, the same number as expected based on the age-specific death rates for all asbestos workers. Summary An increased risk of lung cancer is associated with exposure to all major types of commercial asbestos (chrysotile, amosite, crocidolite, 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 crocidolite, amosite, 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 chry~otile 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 I.1; but only two of these studies had sufficient power (0.80) to detect a 50% increase in relative risk (Table 5-4; Henderson and Enterline, 1979; Selikoff 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 esposed subgroups (ache son et al., 1982; Newhouse and Berry, 1979~. me association of asbestos with an increased risk of malignancies other than lung cancer and mesothe~ioma has not been confirmed in animal studies and has not been observed consistently in human studies.

134 The increased risk of lung cancer is aasociated with age, cumulative asbestos exposures 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 an 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 Jow) and cannot estimate cumulative fiber exposure levels for individuals. There is considerable variation in the risk estimates obtained in the studies reviewed by the coomittee. As noted earlier, this variation may result from many factors in the studies themselves, as well as from a true asbestos effect. Particularly 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; misclassification of cause of death; use of inappropriate comparison groups; and more aggressive efforts to ascertain disease (or deaths) 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 10: 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 the risk of lung cancer and mesothelioma or to attribute greater or lesser risk to Rome types of asbestos f ibere for lung cancer and me sothe 1 ioma . 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 en al. (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 inc. lude chronic bronchi" is , emphysema, influenza, and pneumonia in addition to pulmonary fibrosis or asbestosis. Mixed Fiber Ex osures. Most manufacturing plants have used a variety of f~hrysot lie and one or more amphiboles. Investigators studying exposures to mixed fibers have reported mortality rates attributable to asbestosis. For example, in a study of 17, 800 insulation workers, Selikoff en al. (1979) reported that approximately 8% 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 14% 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 (SMR = 1.4), among those employed after implementation of environmental controls in 1933. Newhouse (1969, 1973) and Newhouse et al. ( 1972) studied 4 , 600 male and 922 female workers in a plant initially producing asbestos textile and later asbestos insulation products. Among those in the highest exposure group (>10 fibers/cm3), mortality from chronic respiratory diseases was 1.8 times that expected. Exposure to Single Types of Asbestos. Hobbs et al . ( 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. 5% for pneumoconiosis along with evidence for increased incidence among those with heavy exposure and those with a longer duration of employment. Among those heavily exposed and employed at least 5 years, the incidence rate was 651. Mortality among workers manufacturing amosite asbestos insulation between 1941 and 1945 was reported by Selikoff et al. (1972) and Seidman

136 et Me (1977, 1979). Of 528 deaths observed over 35 years in a cohort of . _ _ 20 "en, approximately 5.6: were due to asbestosis. In the past, anthophyIlite asbestos was commercially mined and processed in arena of Fintand also known to contain same chrysoeile and tremolite asbestos. Meurman en al. (1974) reported that mortality from asbestosis was 5.2: 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 atudisa have been conducted on Quebec chrysotile miners and millers. The moat recent report on this cohort included observations of 10,939 men employed 9 or more months between 1926 and 1975 (Mcl)onald et al., 1980). They found 42 deaths, or 1.3: of total teatha, to be attributable to asbeatosia. Nicholson et al. (1979) studied a smaller cohort of 544 Quebec miners ant millers with a least 20 years of seniority ant followed them between 1962 ant 1977. Thirty noninfectious, nonmalignant respiratory disease deaths were observed, whereas 6.7 had been expec ted . Deaths from asbeatosia have been reported to occur in cohort a exposed to chrysotile in manufacturing plants. For example, Robinson et al. (1979), who Studier workers in a plant that uset 99% chrysotile and 1: crocitolite ant amosite, reported 76 teethe from noninfectious, nonmalignant respiratory diseases among males, whereas 16.4 had been expec ted . Dement en al. (1983b) reported mortality and assessed dose-reaponse for asbeatosia in a cohort of asbestos textile workers expo set only to chrysotile. They found that 17 (5.53) of 308 deaths were due to asbeatosia or pulmonary fibrosis. A linear relationship wee Remonstrated between cumulative fiber dose and the risk of mortality for noninfectious respiratory disease. Although Dement ant colleagues reported a much steeper slope, their findings are not inconsistent with those of McDonald en al. (1980), who reported a no threshold, linear dose-reaponae relationship between asbeatosia ant doses of Lust containing chrysotile. Morbidity Studies Morbidity studies have eatabliahet that 811 asbestos fiber types are asaociatet with asbeatosis, asbestoa-intucet plaques, diffuse pleural thickening, ant pleural calcification. Because of the methodological differences described above, it is difficult to compare these studies directly with each other or with mortality stutisa in regard to tose-reaponae. Nonethelesa, 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 prizes morbidity studies of asbestos~exposed populations. 1

137 Mixed Fiber Exposure. Early cross-sectional studies of asbestos works chest radiography, demonstrated a prevalence of pulmonary fibrosis as high as BOX 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 50% with Small irregular opacities and a 90% 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 chose examined 40 years after first exposure. Elapsed time from first exposure was similarly found to correlate with pleural calcification, which occurred in 50% of those examined 40 years or more after their first occupational exposure. Murphy et 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 studies by Lewinsohn et al. (1972), Berry et al. (1979), and Baselga-Monte and Segarra (1978~. Data from this type of plant formed the basis for the British Occupational Hygiene Society (BOBS) (1968) recommendation that was used to establish occupational exposure standards. The initial BOBS analysis revealed that there was radiographic evidence of asbesto~in~ for 2.7: of the 290 workers exposed to asbestos (chrysotile with some crocidolite) after 1933, when dust control had been implemented. A risk of 1: for a worker developing basal rales war 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 vary), or a cumulative exposure of approximately lO (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 populat ion. a later analysis of these data, Berry et al. (1979) estimated a prevalence of t: for crepitations at a cumulative dose of 43 (fibere/cm3)yr. For possible and certified asbestosis, 1% prevalences were estimated to occur at cumulative doses of 55 and 72 f ibere/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 this same textile factory for at lease 10 years. me most reliable data were judged to be those obtained for men employed after 1950; 6.6: of there were believed to have Impossible asbesto~is"9 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 capac ity. 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 that "possible asbestosis" would result in no more than 1: of men after 40 years of exposure to concentrations ranging from 0.3 to I.1 fibers/cm3. Furthermore, they noted that continued follow-up was indicated in order to refine the estimates. Baselga-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/cm3 for a 1X or 5: 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 an mppcf-yr. Both rounded and irregular opacities were observed, and there was a 4% prevalence of small opacities (reflecting a mixed dust exposure) at less than 50 mppcf-yr. Prevalence increased to 30X at exposures greater than 400 mppcf-yr. An 11% 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 et al., 1975~. Finkelstein (1982) recently reported asbestosis incidence rates in a cohort of 157 Canadian asbesto~-cement worker. exposed to both chrysotile and crocidolite. Criteria for certification of asbestosis were similar to those reported by Berry et al., (1979) ant were based on the findings of a pneumoconiosis medical panel. Finkelstein found an average overal 1 incidence rate of 0.1X, l. 6:, and 2.4: for 0-49, 50-99, and 100-149 cumulat ire (f ibers/cm3 lye, respect ive ly. Progression of radiographic abnormalities and lung function changes have been reported by Jones et al. ( 1980a) and Gregor et al. (1979~ . Jones and coworkers studied progression among 204 asbestos-cement workers 9The determination of "possible asbestosis" was baset on basal rates, radiological changes of varying degree, a falling gas transfer factor, and restric t ire 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 dec tine 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 al. ( 1979 ~ studied a variety of asbestos workers referred to the Brompton Hospital from the British Pneumoconio~is Panel. hey documented a progression in red iographic f ind ings wi thoue furthe r asbe s toe 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 chickening, somewhat less of a decrease when there were only plaques, and no difference if only pleural calcification was pre sent . Epidemiological and clinical evidence of asbestos-related 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 State., 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 1950 during the steam locomotive era (Lilts et al., 1980; Lorimer et al., 1976; Sepulveda and Me rchant, 1983 ~ . Anthophylliee and Tremolite. In several studies of Finnish anthophyllite miners, investigators have observed increased respiratory symptoms and increased prevalence of pleural plaques (6.51-9.0% vs. 0.1% for the Finnish population) (Kilviluoto, 1960; Mexican, 1968; Meurman et al., 1974~. In upper New York State, workers exposed to talc deposits containing both anthophyllite and tremoliee 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 operations ranged from 0.8 to 16.0 fibers/cm3, of which 12: to 19: was identified as tremolite and 30: to 45: as anthophyllite.l° Another tremolite exposure resulting in a relatively low prevalence of radiographic abnormalities was recently reported by Lackey et al. (1983~. Among factory workers processing tremolite-contaminated vermiculite mined in Montana, 4.4X were found to have some radiographic abnormality. 1ONot all of the fibers counted were necessarily asbestiform fibers.

140 Chrveoeile. The most extensive morbidity studies of chrysotile exposure beve been conducted in Quebec miners and millers (Becklake et al., 1972; McDonald en al., 1972, 1974) . In these studies, I, 015 current employees were studied radiographically, physiologically, and by British Medical Research Council standardized questionnaire. Respiratory symptoms were associated with dustll exposure, and the prevalence of bronchitis reached 50: in the highest dust exposure category. Dyspnea upon exertion was also found to be associated with dust exposure, but not with smoking, and the prevalence rose to 40: among those with a cumulative dust exposure of 800 mppcf-yr. The prevalence of those with small irregular opacities (~1/0 ILO/UC 1971 CIassification) differed between the two mines studied (1.~: at the Thetford mine and 6.4: at the Asbestos mine), but rose to 26.4X and 10. 9%, respectively, among those exposed to more than 800 mppef-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 39: of retired asbestos miners and millers wi th 1/0 profusion radiographs. Becklake _ al. (1979) made similar observations, but they also found that those who progressed were likely to have had higher exposures to asbestos. Summary 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 ant 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 I: risk of developing asbe~tosis (differing definitions) over a 40- to 50-year work exposure occurs when exposures are somewhere between 0.07 fiber/cm3 and 1.1 fiber/cm3. 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. 1lMiners and millers are exposed to dust other than just asbestos.

141 HEALTH EFFECTS OF OCCUPATIONAL EXPOSURE TO MAN-MADE MINERAL FIBERS12 Fibrous gla88 has some of the same physical properties as asbestos. For example, fine glass fibers are renpirable and exhibit flexibility and 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 Chent Physicians evaluated pulmonary response to fiberglass dust (Gross et al., 1976~. It concluded, "There is no evidence to indicate that inhaling fiberglass is associated with either permanent respiratory impairment or carcinogenesis; however, the final verdict as far as the latter is concerned must await the findings of long-term mortality studies." In a review article on the 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~ectional 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 rate 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 fount 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/cm3. In general, average exposure lies between O.1 and 1.0 respirable fibers/cm3. Another factor probably related to pathogenicity is fiber diameter, which is described as ordinary (~3 ~m), Man-made mineral fibers (MMMF) are sometimes called man-made vitreous fibers (MM9F).

142 TWLE 5-5. Su_ar, of Crose-"ctioas1 llorbidit~r Studies of Populetzone Exposed to - Mode ~cere1 Fi~re Top of fiber Study Population 8u~ry of Important Findin~e References Rock and stag 84 worlcere with 7-29 years "lb x-re, evidence of silicosis or Carpenter sad Spolyer, wool of exposure . f ibro. is of the lute . " 1945 Fibrous game 1,389 production workers. "No unucus1 pattern of rediologic Wright, 1968 1,176 bed 10 or more ycere densities was observed." in production. Fibrous ~1~e 232 production worl~ere. In "evidence that would support Utidji~ and deTresville, a hypothesis that those with 1970 dusty jobs were less healthy thee those with einias1 dust expocure." Fibrous Blase 2,028 production vorkere Prevalence of pulmonary aboor~ali- Nacr et al., 1971 who had worked an ties similar in office wordage average of 14 Scare. and production workers. Fibrous game 70 fibrous gums workers; "No evidence of any respiratory Bill et at., 1973 70 controls. hesert due to game fibre." Fibrous glass 467 production vorkere Based on una table cats, the pre- Ms us tori at al., 1980 who had worked an aver- valence of pheryugeal-laryn age of 13 years. gitis was higher in persons Who hat worked at least 5 years. Fibrous glass 340 production workers of Prevalcacc of aaa11 opacities Hill et al., 1982 whoa 81S had worked greater in hen who had worked more then 10 years. wore than 15 years in coeperi son to those who had worked leas (39S vet 9S). Rock wool 162 production workers Pulmonary function test values Skuric and Stahyljak with an average of 12 less than expected conceal Boritic, 1982 years of vorl`. values. clc wool 21 production workers who "llo evidence of pulao~ry Halaberg et al., 1982 had worked aore then 10 disease in the group of years and 43 controls. ~ workers studies." Fibrous glass 1,028 production worker Prevalence of s~11 opeci- Heill et al., 1982 who had worked an ties was related to Bile, average of 19 years. allowing, s~11 di~eter fiber exposure, and in Ricers, various quantitative measures of exposure dose. ,.

143 fine (1 to 3 ~m), or very fine (~1 ~m). Only in the study by Weill et _ . (1982) is there information on fiber diameter. Weil1 et al. (1982) reported that the prevalence of small opacities in exposes workers was low, increased with age and smoking, and was found predominantly in the ordinary/fine fiber (1 to 3 Am 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 manimade mineral fibers. Mortal ity Table 5-6 summarizes the results of seven retrospective mortality follow-up studies among worker e exposed to MMMF. In there studies, the mortality experience of persons exposed to MMMF was compared to that of a general population in the country where the study was done, usually the United States. In computing the expected numbers of deaths, the investigatory 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 (NMXD), 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 observet/expected numbers were: lung cancer, 14/11.8; nonmalignant respiratory disease, 5/~.~. Enterline ant Marsh (1982~. Among the fibrous glass workers, 129 deaths from W RD 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 was no clear relationship between the excess lung cancer or NERD and length of work or time since

144 TILE 5-6. Summary of ttortality Follow-Up Studies of Populations Exposed to tirade Hinera1 Fibers Type of Fiber Study Population Fibrous glass 416 U.S. Hen who retired between 1945 and 1972 from six plants that made f ibrous g las insulation. Fibrous glass 1,448 U. S. men who worded at less t 5 years in fibrous glass produc tion between 1949 and 1972. Sugary of "portent Findinge (OtE). References All causes j 111/131; all Enterline and Henderson, canecrs 20/24; lung cancer 1975 5/6; N - D 9/9. All causes 376/404; all Baylies et al, 1976 cancers 54/64; respiratory cancer 16/20 j NEED 25/20. Fibrous glass 4,399 U.S. Her who worked All causes 289/340; all tiorgan at al., 1982 reset 10 years in fibrous cancers 76/74; respiratory "less production ant who cancer 39/29; N. - D 14/19. were employed at some time between 1968 and 1977 Fibrous glass 2, 576 Canadian men who act rock wool worked at fess t 90 days in f ibrous glass produc tion between 1955 and 1977 woo 1 Fibrous glass, 16, 730 U S men who rock wool, worked at least 1 year and a lag in insulation produc t ion be tween 1945 and 1963. Fibrous glass and rock wool lock wool and ~ leg woo 1 All causes 88/113; all Shannon et al, 1982 cancers 20/20; lung cancer 9t5- NIXED: 415 .% Fibrous glass All causes 3,262/3,391; all cancers 612t635; respiratory cancer 202t203 j N. - D 186tl 76 17,083 European Men who ever worked in einere1 woo l produc t ion and who were followed at least 20 years. llinera1 wool Al 1 causes 499/468; al 1 cancers lO9t88; respiratory cancer 45t28; NMED 29/25. All causes 374t339; all cancers 109/88; respiratory cancer 33/27; NM8D 32/31. Enterline and Ilarch, 1982 Seracci et al 1982 _ _ . 596 U.S. aen who hat All caucce 184/205; all Robinson et al., 1982 worked at least 1 year cancers 36/36; lung cancer in einere1 wool protuc- 9/10; N - D 10/11. tion between 1940 and 1948. PO/E - obeer~red/espected destine. Expected deatbe based on age- ant tiee-epecific Mortality rates for the general population, usually that of the Visited States, for appropriate ses and ethnic groups. NERD - Non- ~li - ant respiratory diceasc. (N - D cats include deaths fro. influence and poe~onis.)

! 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 cleat ~ re 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), curren~c average exposure was approximately 0.04 fibers/cm3 for workers in fibrous glass plants and 0.4 fibers/cm3 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/cm3, in effect since 1976. Saracci and Simonato (1982) reviewed the papers presented at a 1982 conference on MMMF and other relevant literature. For chronic respiratory diseases, they reviewed 10 cro~-~ectional 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 showing no association between MMMF ant 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 March (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 court evaluate the association between MMMF ant respiratory cancer did not show such an Social ion. 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, mandate 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 name sothe l tomes among persons occupationally exposed to MMMF but not to asbestos. There in some evidence that a small excess of respiratory cancer has occurred among persons who produce MMMF-~either fibrous glass or mineral wool.

146 mid evidence derives from mortality 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 approximately 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 sub jects, 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 Attapulg~te A study of at tapulgite miners and mil lers in Georgia and in Florida has been performed by the National Institute for Occupational Safety and Health (R. Waxweiler, 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 is a hydrated magnesium silicate that is often contaminated with other minerals, including those that may occur as asbestiform fibers. In addition, talc can itself be fibrous, but this form is extremely rare. Materials often fount with talc include quartz, calcite, serpentine minerals , and amphiboles (both as c leavage fragments and asbestiform fibers). The fiber content of talc can vary from an undetectable level in some Montana mines to as high as 50% 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. 14 Many of these particles may not be asbestiform as defined by this committee (T. Zoltai, University of Minnesota; R. Clifton, Bureau of Mines, personal communication, 1983~. Various researchers have referred to talc that contains asbestiform fibers. Some of these fibers may be particles with 3:! aspect ratios but without the properties of asbestifonm fibers. To avoid confusion, the committee uses the more general terms "fiber" or "mineral fiber" in this section.

147 Workers from dif ferene geographic regions containing talc with or without fibers have been studied to determine if any adverse health effects are associated with the asbestiform fiber content of talc. Adverse effects have been found in some studies among workers exposed to talc both with and without fibers. These studies are discussed in the following paragraphs. Epitemiological studies on workers exposed to talc containing fibers have demonstrated ad~reree effects on pulmonary function. In a study of 121 New York miners and millers exposed to talc containing tremolite and anthophyllite fibers, pulmonary function was found to be significantly decreased (Gamble et al., 1979b). Reductions in forced vital capacity (EVC) and 1-second forced expiratory volume (FEV1) were associated with employment durat ion and the amount of fiber present. Increased pleural thickening and calcification were detected in talc workers with 15 or more years of employment (Gamble et al., 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 _ al., 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 (Stifle et al., 1982), whereas others have reported significant increases in lung cancer (Kleinfeld et al., 1967, 1974~. Morbidity and mortality studies have also been conducted on workers exposed to talc with low or undetectable levels of fibers. A study on the respiratory function of 103 Vermont talc 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/m3. Exposure to talc dust was also associated with small opacities seen on chest radiographs. Gamble _ al. (1982) conducted a cro~s-sectional study of 299 workers from Montana, Texas, and North Carolina who were exposes 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 mortality 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 (~l observed/~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 other fibrous materials, such as man-made mineral fibers, are needed. There studies should include reliable fiber exposure measurements and should have a high statistical power (ability to 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 des igned to facilitate evaluation of risk over several exposure levels. Continued fol low-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 autops fed 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 fees ibi ~ ity of conduc ~ ing pro-~pec t ive stud ie s in nonoccupat ions 1 ly exposed populations should be studied, ant 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.

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Much of the more than 30 million tons of asbestos used in the United States since 1900 is still present as insulation in offices and schools, as vinyl-asbestos flooring in homes, and in other common products. This volume presents a comprehensive evaluation of the relation of these fibers to specific diseases and the extent of nonoccupational risks associated with them. It covers sources of asbestiform fibers, properties of the fibers, and carcinogenic and fibrogenic risks they pose.

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