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CS National Bureau of Standards Special Publication 506. Proceedings of the Workshop on Asbestos: Definitions and Measurement Methods held at NBS, Gaithersburg, MD, July 18-20, 1977. (Issued November 1978) EPIDEMIOLOGICAL EVIDENCE ON ASBESTOS William J. Nicholson, Arthur M. Langer, Irving J. Selikoff Environmental Sciences Laboratory Mount Sinai School of Medicine of the City University of New York One Gustave L. Levy Place New York, New York 10029 Abstract Data on the human health effects from occupational and environmental exposure to asbestos will be presented with special emphasis on the role of different asbestos minerals. Further, human tissue burdens of fibers and their association with asbestos related diseases will be discussed. Experimental animal data from various species and utilizing different routes of administration will also be presented, again with emphasis on differing fiber types. Key Words: Asbestos; cancer; epidemiology; fibers; mesothelioma; occupational exposure. PART I. HUMAN HEALTH EFFECTS We have already heard in the session on mineralogical aspects of asbestos considerable comment and speculation about health effects. What I would like to do here is present some data on human health effects associated with different forms of asbestos, and to discuss briefly some of their meaning in terms of ambient air concentrations. The modern history of asbestos disease dates from the turn of the century, when two reports were published documenting the effects of uncontrolled conditions in asbestos textile factories. One, the testimony of Dr. H. Montague Murray at a compensation hearing, described severe pulmonary fibrosis found at autopsy, in 1900, in the last survivor of a group of ten workers first employed 14 years previously in a carding room [1]i. The second was the description by Auribault of deaths during the early years of operation of an asbestos weaving mill established at Conde-sur-Noireau, France, in 1890 [2]. During this period 50 men died, including 16 of 17 recruited from a cotton textile mill previously owned by the factory director. Subsequently, cases of pulmonary fibrosis following inhalation of asbestos were published in the medical literature, including one by Cooke, who gave the disease its cur- rent name, asbestosis [3]. A 1929 study of asbestos textile operations by the British Factory Inspectorate revealed the existence and extent of a continuing problem [4]. In a clinical survey of mill employees, 80 percent of those employed for 20 years or more had x-ray evidence of asbestos disease. This finding stimulated the Factory Inspectorate to require the introduction of extensive environmental control technology in the industry and the establishment of an ongoing medical surveillance program. Conditions in the United States were not improved significantly until the 1960's and in recent years the prevalence of abnormal x-rays among workers with 20 or more years of occupational exposure to asbestos has been high. Table 1 lists data of such abnormalities found among insulation workmen employed in the New York and New Jersey area prior to 1960 [5]. Most x-rays of the group were normal until 20 years, and if abnormal usually showed 1Figures in brackets indicate references at the end of each part of this paper. There is also a set of references following the discussion. 71 2063104871

Table 1. X-ray changes in asbestos insulation workers. Asbestosis (grade) Onset of Percent Percent exposure (yrs.) ~ No. normal abnormal 1 2 3 40+ 121 5.8 94.2 35 51 28 30-39 194 12.9 87.1 102 49 18 20-29 77 27.2 72.8 35 17 4 10-19 379 55.9 44.1 158 9 0 0-9 346 89.6 10.4 36 0 0 Total 1,117 366 126 50 changes only of minimal extent. However, after 20 years most had abnormal x-rays and, when abnormal, often of significant degree. Thus, long term observations are required to obtain a valid assessment of lung scarring associated with asbestos exposure. Analysis of short- term data can be highly misleading. Asbestosis was the only disease known to be present among occupationally exposed workers until 1935, when it was suggested that lung cancer might be associated with asbestos exposure. In that year and again in 1936 a clinical report was published of lung cancer in an asbestos worker who had died with evidence of pulmonary fibrosis [6,7]. While such reports were not sufficient to causally relate asbestos exposure to lung cancer, the pos- sibility was raised. In 1947 it was confirmed by substantial data, which showed that 13 percent of individuals who died with asbestosis in Great Britain also had bronchogenic carcinoma [8]. Mesothelioma, a rare tumor of the lining of the abdomen or chest, was described in an asbestos worker in 1953 [9], found frequently to have followed potential asbestos exposure in 1960 [10], and unequivocally related to such exposure in 1965 [11]. Gastronintestinal cancer also was found to be in excess among asbestos insulation workers in the United States [12]. In 1975, three-quarters of a century after the first identification of asbestos-related deaths, society continues to be plagued by their presence, unfortunately, in ever increasing numbers. Moreover, the population at risk from the several asbestos-related cancers has expanded from those directly handling the mineral to those working nearby the application or removal of asbestos materials, and, finally, to those who simply live in the vicinity of an asbestos operation or in the household of an asbestos worker. Hiah Exposure Effects The full spectrum of disease from asbestos exposure is best manifest in the data of Selikoff, Hammand, and Seidman on the mortality experience of 17,800 asbestos insuiation workmen [13]. Table 2 shows the expected and observed deaths among this group of workers from January 1, 1967, through December 31, 1976. Among those individuals who have died, one in five deaths was due to lung cancer, about 5 percent to gastrointestinal cancer, approxi- mately 7 percent to mesothelioma (a tumor so rare in the general population that it may account for only one in ten thousand deaths in the absence of exposure to asbestos), 10 percent to other cancers, and 7 percent to asbestosis, the disease first characterized seven decades earlier and wished away numerous times subsequently. The data on the mortality experience of this group of workmen are also sufficient to suggest that cancer at sites other than those mentioned above may also be increased from asbestos exposure. Here, however, the malignancies are less common. Overall, comparing the frequencies of deaths from the cancers and asbestosis with those among the general population, nearly 40 percent of the deaths in this group of workers can be attributed to their occupational exposure to. asbestos. N , W r ~ N 72

Table 2. Deaths among 17,800a asbestos insulation workers in the United States and Canada. January 1, 1967 - December 31, 1976 Number of men Man-years of observation Expected 17,800 166,855 Observed Ratio Total deaths, all causes 1,660.96 2,270 1.37 Total cancer, all sites 319.90 994 3.11 Lung cancer 105.97 485 4.58 Pleural mesothelioma b 66 -- Peritoneal mesothelioma b 109 -- Cancer of esophagus 7.01 18 2.57 Cancer of stomach 14.23 22 1.55 Cancer of colon, rectum 37.86 59 1.56 All other cancer 154.83 235 ' 1.52 Asbestosis b 162 -- A11 other causes 1,351.06 1,114 0.82 a Expected deaths are based upon white male age specific mortality data of the U. S. National Center for Health Statistics for 1967-1975 and extrapolation to 1976. b These are rare causes of death in the general population. From: Selikoff, I. J., Hanmond, E. C., and Seidman, H., Mortality experience of insulation workers in the United States and Canada, 1943-1977, to be published, Ann. N.Y. Acad. Sci. Asbestos related disease has also resulted from exposures in asbestos factories. A study of production employees of the largest asbestos products manufacturing facility in the United States again demonstrated the presence of significant excess disease [14]. In this study, the mortality experience of all 689 individuals who were working on January 1, 1959, and who were first employed prior to 1939, was analyzed. From 1959 to 1976, it was expected that 188 deaths would have occurred in this group. Instead, 274 died, 46 percent more than anticipated. About 40 cancers were expected; 99 were observed. As shown in Table 3, the anticipated asbestos-related tumors were found in excess - bronchogenic carcinoma, mesothelioma, and gastrointestinal cancer. 73 WY ~

Table 3. Expected and observed deaths among 689 factory workers, employed before January 1, 1939, during the seventeen years from January 1, 1959 through December 31, 1975. ~ -- -- Observed - 1959 - 1975 Expected -- - -- Obs. Ex . All causes 274 188.19 1.46 Cancer, all sites 99 39.93 2.47 Lung cancer 35 12.53 3.91a Pleural mesothelioma 14 n.a. -- Peritoneal mesothelioma 12 n.a. -- Cancer of esophagus, stomach, colon, and rectum 15 7.99 1.88 Cancer all other sites 23 19.40 1.19 All respiratory disease 42 12.16 3.45 Asbestosis 35 n.a. -- Other respiratory 7 b -- A11 other causes 133 136.11 0.98 Person-years of observation 9,646 a Pleural mesothelioma inctuded with cancer of bronchus in calculating ratio since expected rates are based upon "cancer of lung, pleura, bronchus, trachea." b This rate is virtually identical with that of "all respiratory disease." n.a. = not available. From: Nicholson, W. J., Case Study 1: Asbestos-the TLV approach, Ann. N.Y. Acad. Sci., 271, 152-169 (1976). Time Effects - Lapsed Period If one considers the time from onset of exposure to the clinical evidence of disease, one finds, just as with asbestosis, that there is a long-lapsed period from first exposure to appearance of asbestos related cancers. Data from the group of insulators illustrate this point in figure 1, where the excess cancer risk, calculated for equal but not aged standard- ized populations within each ten-year time interval, is plotted. A significant increase 9n risk is seen only after 25 years for lung cancer and after 30 years for mesothelioma. An increase in the ratio of observed to expected cases of the various asbestos cancers occurs prior to 20 years, but the total number of such cancers is small, as the population is relatively young. This long-lapsed period creates significant difficulties in attempting to establish dose-response relationships. The disease seen today is from exposures decades past when few .easurements were made of asbestos concentrations. Thus, we can only estimate past expo- sures, based on current knowledge. Further, such estimates can be unreliable, and the determination of the efficacy of standards based upon them cannot be made with certainty, until further decades have past. If we then find serious misjudgments have been made, asbestos disease will continue to plague us well into the twenty-first century.

TIME FROM ONSET OF EXPOSURE (YEARS) Figure 1. The excess, asbestos-related mortality rates for lung cancer and mesothelioma according to time from onset of asbestos disease. 75

Another aspect of time in the identification of carcinogens is seen in the data from the study of New York and New Jersey insulation workers over the period 1943 through 1973 [15]. Table 4 shows the mortality experience of 623 insulators, all with 20 years since first exposure in different time periods. One notable feature in these data is the deficit of deaths of all causes-in the first 10-year observation period; an excess of total mortal- ity appears only after several years from first observation (and 30 years from onset of exposure). It is common to observe such a deficit, often as great as 25 percent, in studies comparing the mortality experience of working groups with that of the general population the "healthy worker effect"). This results in part because identified groups of workmen are healthier than a corresponding age group in the general population, which would include terminally ill individuals and others unable to hold a job because of disability. However, even in these early years, the excess asbestos cancers can be seen, although they are not yet the dominant contribution to total mortality. Synergistic Effects A second important concern is increasing evidence that many cancers may have a multiple factor etiology. For example, lung cancer in asbestos workers is strongly associated with cigarette smoking. In the large cohort of 17,800 insulators observed by Selikoff and Hammond, the smoking habits were obtained on the majority of workers in 1967 [16]. Table 5 illustrates the effect of cigarette smoking on lungcancer mortality of these workers. Among 2,066 non-cigarette smokers, only eight lung cancers were seen in a ten-year period, where 1.82 were expected, based on American Cancer Society data on the risk of lung cancer death in non-smokers. Inhalation of asbestos by insulators appears to multiply the risk by four or five times. Considering the data for men with a history of smoking, among 9,591, 325 deaths were observed versus 66.78 expected, also a fivefold increase. However, since cigarette smokers already have a ten to twenty times greater risk of lung cancer deaths than non-smokers (depending on cigarette consumption), the multiplicative effect of the asbestos exposure increases the lung cancer risk up to 100 times for smoking asbestos workers compared to non-smokers unexposed to asbestos. This was also shown by the experiences of a cohort of New York and New Jersey insulators [17]. Hence, it was estimated that the risk of dying of lung cancer for cigarette smoking asbestos workers was more than 90 times that of individuals who neither smoked nor worked with asbestos. Indirect Asbestos Exposure In 1968 it was pointed out by Harries that shipyard workers other than insulators were at risk from asbestos disease [18]. Among Oevonport Dockyard employees, five cases of mesothelioma were found among men who had not been "asbestos workers" but had followed other trades in the yard. These men presumably had been inadvertently exposed to asbestos merely by working in the same shipyard areas where asbestos had been used. Continuing to follow this group, Harries later documented 55 cases of mesothelioma in this shipyard alone, only two of which occurred in asbestos workers [19], one, a man who had previously sprayed asbestos. A study of the distribution of all verified cases of mesothelioma found in Scotland between the years 1950 and 1967 is also revealing (20]. Of 89 cases available for study, 55 were in shipyard employees, dockers, or naval personnel. Of the 55, again only one was an asbestos insulation worker. A third important study of workers in British shipyards is that of John Edge, who reviewed x-rays of former shipyard workers in Barrow [21]. A prospective study was conducted of 235 men whose x-rays, taken between 1955 and 1969, showed abnormalities char- acteristic of asbestos exposure (pleural plaques, scarring of the covering of the lung or lining of the chest), but no parenchymal fibrosis (scarring of the lung tissue). Most of these x-rays were of individuals (riggers, welders, carpenters, electricians, machinists, steamfitters, etc.) who had not worked directly with asbestos, but who could have sometimes been nearby when asbestos was used. In tracing the individuals who had such x-ray changes, it was found that 70 had died froA 1970 to 1973_ Of these 70 deaths, 13 were of lung cancer, two and one-half times the number expected, and 17 were of mesothelioma (none, of_ course, were anticipated). N 9 h+ 76

Table 4. Expected and observed number of deaths among 623 New York-New Jersey asbestos insulation workers, i Janqary 1943 - 31 December 1973, twenty or more years after onset of first exposure to asbestos. Total 1943-1952 1953-1962 1963-1973 1943-1973 Exp. Obs. Ratio Exp. Obs. Ratio Exp. Ohs. Ratio Exp. Obs. Ratio Total deaths, all causes 88.22 82 0.94 111.05 170 1.53 101.38 191 1.88 300.65 444 1 48 . Cancer, all sites 13.02 30 2.30 18.75 65 3.47 19.49 103 5.28 51.26 198 3.86 Lung cancer 1.83 13 7.10 4.20 29 6.90 5.65 47 8.32 11.68 89 7.62 Pleural mesotheliona n.a.a 1 -- n.a. 2 -- n.a. 7 -- n.a. 10 -- Peritoneal mesothelioma n.a. 1 -- n.a. 3 -- n.a. 21 -- n.a. 25 -- Cancer of stomach 2.13 2 0.94 1.87 10 5.35 1.10 6 5.45 5.10 18 3.53 v Cancer of colon, rectum 2.22 7 3.15 2.74 9 3.28 2.54 6 2.36 7.50 22 2.93 Asbestosis n.a. 1 -- n.a. 11 -- n.a. 25 -- n.a. 37 All other causes 75.20 52 0.69 92.30 94 1.02 81.89 63 0.77 249.39 209 0.84 632 members were on the union's rolls on 1 January 1943. Nine died before reaching 20 years from first employment. All others entered these calculations upon reaching the 20-years-from-onset-of-first-exposure point. Expected deaths are based upon white male age-specific death rate data of the U.S. National Office of Vital Statistics from 1949 - 1971. Rates were extrapolated for 1943 - 1948 from rates for 1949 - 1955, and for 1972 - 1973 from rates for 1967 - 1971. a U. S. death rates not available, but these are rare causes of death in the general population. From: Reference [28]. LL,8b0i£9aZ

Table 5. Deaths of lung cancer among asbestos insulation workers in the United States and Canada, 1967-1976; influence of cigarette smoking. Expected deathsa Observed deaths U. S.b Smoking specificc 1. History of cigarette smoking 325 60.07 66.78 Current smokers 228 31.87 39.69 Ex smokers 97 23.29 13.34 2. No history of cigarette smoking 8 14.11 1.82 Never smoked 5 8.49 0.98 Pipe/Cigar 3 5.63 0.84 3. Unknown history of cigarette smoking 152 31.80 11.93 Total 485 105.97 66.78 a Age, year and sex specific. b Based upon age, specific data of the U. S. National Center for Health Statistics, cigarette smoking not considered. c Based upon American Cancer Society's Cancer Prevention Study, 1967-1972. From: Hammond, E. C., Selikoff, I. J., and Seidman, H., Cigarette smoking and mortality among U. S. asbestos insulation workers, to be published in Ann. N.Y. Acad. Sci. Environmental Asbestos Disease In 1960 Wagner reviewed 47 cases of mesothelioma found in the Northwest Cape Province, South Africa, in the previous five years [10]. Of this number, roughly half were in people who had worked with asbestos. Virtually all of the rest, however, were in individuals who had, decades before, simply lived or worked in an area of crocidolite asbestos mining (one lived along a roadway in which asbestos fibers were shipped). This germinal observation demonstrated that asbestos exposure of limited intensity, often intermittent, could cause mesothelioma. The hazard was further pointed by the findings of Newhouse[11], who showed that mesothelioma could occur among people whose potential asbestos exposure consisted of their having resided near an asbestos factory or in the households of asbestos workers. Twenty of 76 cases from the files of the London Hospital were the result of such exposure, 31 were occupational in origin, and asbestos exposure was not identified for 25. A recent extensive study of the effects of household exposure has been conducted by Dr. Henry Anderson and his colleagues of the Mount Sinai School of Medicine [22]. In a clinical survey of 489 family contacts of former factory workers, it was found that the x-rays of 36.2 percent of these individuals showed abnormalities characteristic of asbestos exposure. It did not matter greatly what the relationship to the worker was; the asbestos dust in the household could affect any resident - wife, sons, daughters, parents. While almost all were currently asymptomatic, and while most would perhaps suffer no impairment from their past exposure, others may be stricken with an asbestos-related cancer as a result of past household asbestos exposure. During the initial phase of the survey of deaths, mesothelioma had been identified in this group of family contacts. 78

Asbestos Fiber Types: Relation to Disease Canadian asbestos mine workers by the McGill group has already been mentioned earlier in these proceedings. In the initial publication of their mortality study [23], a favorable mortality experience was reported with lung cancer and gastrointestinal cancer being found in excess only in the higher exposure categories. While this study was comprised of 11,788 individuals, it should be noted that nearly half (4,818) were in the lowest dust category (virtually no exposure) or had been employed in the mines and mills for less than one year. Further, many others would have had relatively recent employment. Thus, the potential for dilution of asbestos-related health effects exists. A concomitant study of x-ray changes among mine and mill employees may suffer even more from the dis- advantage of short-term periods of observation [24]. Overall, 12.5 percent of 11,207 individuals were found to have abnormal x-rays. However, many of these had less than 10 years of employment and the x-ray that was read was the last maintained by the company of employment. We have also conducted studies of Canadian mine and mill employees, but of individuals who had been employed for at least 20 years [257. Table 6 lists the x-ray abnormalities found among 1,120 such individuals. As can be seen, extensive asbestos-related x-ray changes were present in this group of currently employed workers. Overall, 61 percent had abnormal x-rays. Table 7 presents the mortality experience of 535 men who were first employed in the mines and mills before 1941 and followed from 1961 [26]; 16 percent of the deaths were from asbestosis and 15 percent from lung cancer. One case of inesothelioma was found, considerably less than would have been expected on the experience of U. S. insulation workers or factory employees. The reason for this is unclear at this time. It may be related in part to the physical characteristics of the chrysotile fibers in the mine and mill environment, the fibers here being of a longer length than that encountered in manufacturing and end product use. Table 6. X-ray changes among 1,120 Quebec asbestos mine and mill employees by time from onset of exposure. Time from onset of Percent abnormal exposure (years) Normal x-ray Abnormal x-ray within category 20 - 24 83 46 35.7 25 - 29 99 104 51.2 30 - 34 122 182 57.6 35 - 39 76 170 69.1 40+ 58 180 75.3 Total 438 682 79

Table 7. Expected and observed deaths among 544a asbestos miners who were at least 20 years from onset of asbestos mining work at start of observation, 1961 through August 1977, by calendar years. - - - - - Total, 1961-77 Expected Observed Ratio 0 E Total deaths 159.92 178 1.11 Total cancer, all sites 36.73 49 1.33 Lung cancer 11.10 28 2.52 Pleural mesothelioma b I -- Peritoneal mesothelioma b -- -- Cancer of stomach 3.65 4 -- Cancer of colon, rectum 5.03 6 1.19 Cancer of esophagus All other cancers 0.87 16.08 -- 10 0.62 Asbestosis b 26 -- Other non-infectious respiratory 6.69 4 0.60 All other causes 116.50 99 0.85 Man years 7,408 a Expected deaths are based upon age-specific death rate data for Canadian white males. b Death rates not available but these have been rare causes of death in the general population. Data are also available on exposure to amosite asbestos. From 1941 to 1954 a factory producing amosite insulation materials operated in Paterson, New Jersey. The mortality experience of individuals employed at any time between 1941 and 1945 is shown in Table 8. The usual asbestos diseases are seen to be present. Lung cancer is six times expected and 10.of 298 deaths are from pleural or peritoneal mesothelioma. An important aspect of this study is that individuals with relatively short exposures are shown to have an increased risk of death from asbestos-related causes. Table 9 shows the expected and observed deaths from lung cancer, mesothelioma, gastrointestinal cancer, and asbestosis according to time of employment in the plant. All time categories less than one year are elevated, and while a single one-month category does not have statistical significance, the longer periods up to six months do. 80

Ca Table 8. Deaths among 933a workers employed in an amosite asbestos factory, starting five years from onset of work 1941-1945 to December 31, 1974. - - - - - Deaths 1946-1974 - - Cause of death Expected Observed Ratio All causes 285.62 483 1.69 Cancer, all sites 50.10 157 3.13 Lung cancer 12.45 83 6.67 G.I. cancer 12.05 24 1.99 Pleural mesothelioma b 5 -- Peritoneal mesothelioma b 5 -- "Asbestos" cancer 24.50 117 4.78 Other cancer 25.60 40 1.56 Asbestosis b 28 -- All other causes 235.52 298 1.27 a Expected deaths are based upon white male age-specific death rate data of the U. S. National Office of Vital Statistics, 1949-1972. Rates were extrapolated for 1946-1948 from rates for 1949-1955 and for 1973-1974 from rates for 1968-1972. 128 workers were omitted from these calculations: 33 had prior asbestos exposure; 38 died in the first five years after onset of employment. 49 were not completely traced; and eight had other asbestos employment after the five year from onset point. b U. S. death rates not available but these are rare causes of death in the general population. 81

Table 9. Deaths of all "asbestos disease" among 933a workers employed in an amosite asbestos factory, starting five years from onset of work 1941-1945 to December 31, 1974. Effect of duration of exposure. - Death of "asbestos disease" 1946-1974 Duration of employment No. Expected Observed Ratio <1 month 62 3.47 6 1.73 1 month 92 3.73 8 2.14 2 months 79 3.73 11 2.95 3-5 months 145 5.98 17 2.84 6-11 months 129 4.15 21 5.06 1 year 105 3.74 20 5.35 2 years 77 2.91 24 8.25 3-4 years 51 2.36 15 6.36 5+ years 65 2.88 34 11.81 Total 805 32.95 156 4.73 a "Asbestos disease": asbestosis and chronic pulmonary insufficiency, lung cancer, pleural, and peritoneal mesothelioma, cancer of esophagus, stomach, colon-rectum. 128 workers were omitted from these calculations: 33 had prior asbestos exposure; 38 died in the first five years after onset of employment. 49 were not completely traced; and eight had other asbestos employment after the five year from onset point. Finally, if one considers the fiber type that insulation workers were exposed to, data from manufacturers have indicated that it was only to chrysotile and amosite. No crocido- lite was ever used as thermal insulation materials [27]. Further amosite was used in significant quantities only from 1940 through the early 1960's. As neither the period of use nor the incidence of mesothelioma among amosite workers listed above can account for the high frequency of this cause of death among insulation workers, it is clear that exposure to chrysotile asbestos is of importance here as well. Summary Accumulated human health data indicate that all major commercial varieties of asbestos, chrysotile, amosite, and crocidolite, produce significant disease. Lung cancer, asbestosis, mesothelioma, and gastrointestinal cancer are in significant excess among factory workers and insulators, while lung cancer and asbestosis are dominant causes of death among mine and mill employees. Further, evidence exists that environmental exposures, such as in the homes of workers or in the vicinity of mines and factories, have been sufficient to produce mesothelioma. Workers indirectly exposed to asbestos in their work, as shipyard workers, can be at significant risk. Currently no data exist that would indicate a threshold for asbestos related cancers. Prudence would suggest that exposures to all asbestos fibers be reduced to the minimum commensurate with feasible environmental controls. Considerable data exist that most work environments can maintain concentrations well below the current asbestos standard. I believe the issue is not that reduction of standards will result in the closing down of the _ surface of the earth, as was suggested earlier in this symposium, but that reduction in standards, with feasible control measures, will allow us to use the surface of the earth safely. 82

CS References [1] Murray, H. M., Report of the Departmental Committee on Compensation for Industrial Disease, London, H. M. Stationary Office, p. 127 (1907). [2] Autibault, M., Bull. del'Inspect. du Travail, p. 126 (1906). [3] Cooke, W. E. , Pulmonary asbestosis, Br. Med. J. , 2, 1024-1025 (1927). [4] Merewether, E. R. A. and Price, C. V., Report on effects of asbestos dust suppression in the asbestos industry, Part I., London, H. M. Stationary Office (1907). [5] Selikoff, I. J., Personal communication. [6] Lynch, K. M. and Smith, W. A. , Pulmonary asbestosis III: Carcinoma of lung in asbesto- silicosis, Am. J. Cancer, 24, 56-64 (1935). [7] Gloyne, S. R., A case of oat cell carcinoma of the lung occurring in asbestosis, Tubercle, 18, 100-101 (1936). [8] Merewether, E. R. A., Annual Report of the Chief Inspector of Factories, London, H. M. Stationary Office (1907). [9] Weiss, A., Pleurakrebs bei lungenasbestose, in vivo morphologisch gesichert, Medi- zinische, 3, 93-94 (1953). [10] Wagner, J. C., Sleggs, C. A., and Marchand, P. , Diffuse pleural mesothelioma and asbestos exposure in the northwestern Cape Province, Br. J. Ind. Med. , 17, 260-271 (1960). [11] Newhouse, M. L. and Thompson, H., Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area, Sr. J. Ind. Med., 22, 261-269 (1965). [12] Selikoff, I. J., Churg, J., and Hammond, E. C., Asbestos exposure and neoplasia, JAMA, 188, 22-26 (1964). [13] Selikoff, I. J., Hammond, E. C., and Seidman, H., Mortality experience of insulation workers in the United States and Canada, 1943-1977, to be published, Ann. N.Y. Acad. Sci. [14] Nicholson, W. J., Selikoff, I. J., Seidman, H., and Hammond, E. C., Mortality experi- ence of asbestos factory workers: effect of differing intensities of asbestos exposure, Environ. Res. (in press). For earlier data, see: Nicholson, W. J., Case study 1: Asiesths - the TLV approach, Ann. N.Y. Acad. Sci., 271, 152-169 (1976). [15] Selikoff, I. J., Hammond, E. C., and Seidman, H., Cancer risk of insulation workers in the United States, In Biological Effects of Asbestos, Bogovski, Gilson, Timbrell, and Wagner (eds.), Lyon, IA ,RC pp. 209 2 97$f. [16] Hammond, E. C., Selikoff, I. J., and Seidman, H., Cigarette smoking and mortality among U. S. asbestos insulation workers, to be published in Ann. N.Y. Acad. Sci. For earlier data see: Hammond, E. C. and Selikoff, I. J., Relation of ciharette smoking to risk of death of asbestos-associated disease among insulation workers in the United States, in Biological Effects of Asbestos, Bogovski, Gilson, Timbrell, and Wagner (eds.), Lyon, IAFC31F3i7TM). [17] Selikoff, I. J., Hammond, E. C., and Churg, J., Asbestos exposure, smoking, and neoplasia, J. Am. Med. Assoc., 204, 106-112 (1968). [18] Harries, P. G., Asbestos hazards in naval dockyards, Ann. Occu .~., 11, 135 (1968). [19] Harries, P. G. et al., Radiological survey of men exposed to asbestos in naval dock- yards, Br. J. Ind. Med., 29, 274-279 (1972). 83 2063104883

[20] McEwen, J., Finlayson, A., Mair, A., and Gibson, A. A. M., Mesothelioma in Scotland, Br. Med. J., 4, 575-578 (1970). [21] Edge, J., Asbestos-related disease in Barrow-in-Furness, J. Environ. Res., 11, 244-247 (1976). [22] Anderson, H. A. et al., Household contact asbestos neoplastic risk, Ann. N.Y. Acad. Sci., 271, 311-323 (1976). [23] McDonald, J. C., McDonald, A. D., Gibbs, G. W., Siemiatycki, J., and Rossiter, C. E., Mortality in the chrysotile asbestos mines and mills of Quebec, Arch. Environ. Health, 22, 677-686 (1971). [24] Rossiter, C. E., Bristol, L. J., Cartier, P. H., Gilson, J. G., Grainger, T. R., Sluis-Cremer, G. K., and McDonald, J. C., Radiographic changes in chrysotile asbestos mine and mill workers of Quebec, Arch. Environ. Health, 24, 388-400 (1972). [25] Comite d'etude sur la salubrite dans 1'industrie de 1'amiante: rapport preliminaire, Beaudry, R. , Lagace, G. , and Juteau, L. (eds.) (1976). [26] Nicholson, W. J., Seidman, H., and Selikoff, I. J., (to be published) Ann. N.Y. Acad. Sci. (Proceedings of Science Week). [27] Selikoff, I. J., Hammond, E. C., and Churg, J., Mortality experiences of asbestos insulation workers, 1943-1968, in: Shapiro, H. A. (ed.), Pneumoconiosis, Proceedin s of the International Conference, Johannesburg 1969, Cape Town, x ord Un versity ress, PP._80-1 ~/d(1 T- PART II. EXTRAPOLATION TO OTHER INORGANIC FIBERS Current Status of the Asbestos Problem Part I of this contribution discusses essential elements and factors related to asbestos fiber exposure and associated human disease. The historical perspective presented, in conjunction with recent data, may help define the emerging problem area concerned with the biological potential of inorganic fibers as a class of compounds. These may be outlined as follows: The Time Required to Define the Asbestos Problem was Decades Long: Asbestosis, the disease characterized by scarred lungs due to the inhalation of asbestos fiber, was first described over 70 years ago [1]. It was not until the 1930's and 1940's that an accumulation of evidence suggested that asbestos fiber inhalation was also associated with increased neoplastic risk, specifically carcinoma of the lung [2-5]. This effect was not anticipated, and was overlooked for extraordinarily long time periods. Problems ~focussing on the ~acti~vity of mineral fibers, other than asbestos, ~ re u~ire _lenat~vt me ~e~riads to define. This ~ he or ung scarring, an obviou~fect associated with inha~a== tion, and esoecally so~'or neoplasms. The Different Asbestos Fiber Types Produce Similar Disease Patterns: The disease stigmata produced by asbestos fiber inhalation are similar for the different fiber species. Inhalation of all commercial asbestos, chrysotile [6], amosite [7], crocidolite [8], anthophyllite [9), and mixtures of these fibers [10] produce both scarring and various forms of malignant disease. A range of mineral species with different physical and chemical properties can produce disease patterns in humans which are similar and occasionally indistinguishable. It should be stressed that the major difference in biologi- cal effects noted are the relative risks associated with each fiber type for each disease entity. Because the ~man,y varietal forms of asbestos fibers Pro.d.uce- disease, and the non-asbestosbrous minerals are sim ar structural and chemicaliv, an eral entlLy which fi can be inhafed shou 3e studied for hea th effects. 84

C Extra-Pulmonary Organs in Humans are Involved in Asbestos Disease: The disease patterns associated with asbestos exposure are complex. Although inhala- tion is the primary route of exposure to the individual in the workplace, extra-pulmonary organs may be affected as well. For example, asbestos fiber exposure has been associated with the development of intra-abdominal and gastrointestinal tumors [11,12]; excess malignancies of the buccal cavity, pharynx, larynx, esophagus, and stomach have also been reported [13,22]. Therefore, multiple organs and cell types are targets of asbestos fiber action. Importantly, hundreds of thousands of man-years of observation were required to statistically verify that excesses of less common tumors occurred in these workers. Or9ans other than lungs should be considered targets for other mineral fibers as welt. Occasionally, Multiple Primary Tumors May Simultaneously Occur in the Same Host; Multiple primary tumors may occur in the same individual who had been occupationally exposed to asbestos fiber. Contributino causes of death, as well as the cause, are important in defining the extent of disease associatedwith miner f~er exposure. The Clinical Latency Period for Asbestos Disease is Extensive: There exists a long latency period between the onset of exposure to asbestos fiber and the first clinical appearance of neoplastic disease. These stigmata have different lapse time intervals for manifestation, e.g., mesothelioma is greater (30-40 years) than for lung cancer (20-30 years) [15,16]. This time lapse works against the establishment of an etiological link between the agent and the disease; it may confound exposure history by implicating several "agents." It therefore re ui~res ~many years of retros ective- ros ective stud to determine, gualitatively and guantitativety, the reTat onsh p betweem m nera exposure and disease. Fiber Exposure Continues Throughout the Life of the Exposed Individual: Although a long time period may elapse between the cessation of exposure to asbestos fiber and the appearance of disease, these materials tend to be retained in both lung parenchyma and extra-pulmonary tissues of exposed workmen [17-21]. Therefore, exposure in these individuals continues for their lifetime in that particles are often present, continuously interacting on the cellular level. Removal of an individual from immediate exposure to mineral fiber does not ~similarly remove him from o~ r a~n exposure This concept hd_Tds forwa 5 inorgamTitiers whdh are not readily solubfe in vivo. Fiber Dose-Response is a Function of both Duration and Intensity of Exposure: Both the duration and intensity of exposure to asbestos fiber appear to influence the relative risk of developing the different asbestos diseases, and markedly influence the length of the clinical latency period in which the disease becomes manifest [22]. For example, a study of workers employed in an asbestos factory utilizing amosite fiber demon- strated that exposure to high concentrations of amosite for as little as three months significantly increased the relative risk of developing lung cancer (3.87x=SMR) [13,22]. Exposures in this instance were extremely high. However, if one were to establish an average threshold limit value based on man-years of exposure (average fiber levels multiplied by number of years employed at such levels), such levels would be only 0.1 to 0.2 f/mL, generally considered to be a "safe" level for prevention of asbestosis by today's OSHA standard. This would essentially ignore short-term, high-level exposures which evidently carry significant disease potential. As counterpart, those workers employed for short time periods (less than one year) required longer clinical latency period before their diseases became manifest. This dose-response relationship is likely to hold for mineral fibers other than amosite. Peak exposures may be more importarnt than long-term ex osures and, on the other hand, low exposures m~ r uire~ger ep riods~observation to u y ~ine ne~asrisk. 85 N O ~ W H+ ~ w

Co-Factors Exist in Asbestos Oisease: Cocarcinogenic and other synergistic factors are important in the production of asbestos disease. The importance of cigarette smoking has been demonstrated by evidence that carcinoma of the lung synergistically increases in cigarette-smoking asbestos workers [23- 25]. However, present data indicate that cigarette smoking is important only for carcinoma of the lung, not for other malignancies. Lu~_n9 cancer, cigarette ~smokin and inhalation of other inorganic particles, e.., uranium min_ing__, has been shown to be interrelated in the past. 7herefore, such a synergism n~ exst for mineral- er than asbestos. The asbestos problem required decades of time to define through hundreds of thousands of man-years of observations. A range of materials produces similar disease patterns, acting singularly or in concert with other biologically active agents. The clinical latency period is long, target organs are many, and exposure related in part to fiber retention. No known safe level of exposure exists for the prevention of malignant disease. It may be logical to assume at present, that lessons learned from the study of the asbestos problem may be applied to other inorganic fibers as well; that these findings may be used as a model to guide and delineate in new and important areas. The Nature of Mineral Fibers Asbestos is the term which categorizes a specific group of natural silicate minerals which occur in fiber form. The term fiber indicates, by definition, that the mineral species grew with this morphology. It also indicates, by definition, that the plane surfaces which define the external symmetry of the mineral are crystal faces resulting from growth. Asbestos fiber consists of a polyfilamentous bundle of intergrown crystal units. The breaking open of such a fiber purportedly is brought about by separation along the juxtaposed crystal faces. The sane mechanical treatment, as during grinding, of a non- asbestos, single crystal fiber, produces acicular cleavage fragments. The surfaces so formed are cleavage planes rather than crystal faces. It is generally considered that the majority of cleavage surfaces normally follow crystal face morphological development, in that both tend to occur parallel to "low energy" planes within the mineral [28]. Some investi- gators, however, considered that there may be significant physical-chemical differences between crystal faces and cleavage planes (see T. Zoltai, this Conference). If so, such differences betweeo crystal faces and cleavage planes may result in different biological activities of these materials. This fundamental difference prevents direct extrapolation from asbestos fiber (bound by crystal faces) to fibrous rock-forming silicates (bound by cleavage planes). In addition to the differences in surface character, some difference in other proper- ties may exist as well. Asbestos minerals possess physical-chemical properties which are unique. Some of these properties, such as high fiber tensile strength and flexibility, are not observed in other mineral or synthetic fibers. These properties have been described in a number of recent documents [26,27]; their mineralogical character is detailed by others at this meeting (see, e.g., M. Ross, T. Zoltai, A. Goodwin). It is of very great importance to note that differences between asbestos fiber and other silicate fibers are based on mega- scopic properties, that is, those physical properties determined on bulk samples. The question arises as to whether or not these characteristics which distinguish asbestos from non-asbestos mineral fibers are derived from molecular properties (e.g., twinning). If they are, then these characteristics must also exist on the submicroscopic level as well. On the other hand, if these characteristics are determined by the physical nature of fiber bundles, that is, derived by properties related to the manner in which the units are inter- grown, then separation of these units upon comminution destroys the "unique characteristics." Single fibers on the submicroscopic level, of asbestos or other mineral fibers, are often indistinguishable on the basis of morphology, structural characterization (by selected area electron diffraction), and chemistry (as determined by an electron microprobe technique). Since mechanical properties cannot be measured on the microscopic or submicroscopic levels, it is unknown at the present time if the "asbestos properties" carry through to the sub- microscopic level. This focuses directly on the issue concerning the disease potential of fibrous silicates other than asbestos. If the "asbestos property" is only megascopic in nature, then size reduction of asbestos produces fibers essentially identical to acicular cleavage fragments of rock-forming silicates. The nature of the mineral fiber entity, on the submicroscopic level, prevents direct extrapolation concerning the biological activity 86

of other fibrous silicates. However, some extrapolation is currently possible on the basis of existing data. Data Which Suggest Inorganic Fibers Other than Asbestos are Biologically Active -Small fibers of various chemical compositions may form stable aerosols, persist in the work environment (with an accompanying increased inhalation potential), penetrate deep into the alveolar portions of the lung, and tend to be retained in tissues for long time periods. It has been suggested that such factors as fiber chemistry, trace metals, adsorbed hydro- carbons, etc. are not important in terms of carcinogenic potential. It has also been suggested that any fiber species in contact with the mesothelial lining of the chest, or lung, may produce mesothelioma, possibly by means of an "Oppenheimer" effect [297. Experi- mental work conducted with such materials as fibrous glass has demonstrated that even these man-made fibers may induce tumors when implanted at the mesotheliat surface [30,31]. Clinical human evidence suggests that all varieties of asbestos fibers can produce disease, and that any sub-species of a single variety can also produce disease. If certain forms of mineral species, commonly referred to as asbestos, are active biologically, what factors are responsible for this activity? Currently, only the size and shape of fiber are common to all mineral species which have been demonstrated to produce disease. It has been suggested that amphibole "fibers" observed in some industrial talcs are "acicular cleavage fragments" and therefore not asbestos per se.2 This argument carries with it the unsupported argument that since these particles are not asbestos, they are therefore not biologically active. However, a literature exists which implicates "fibers" in talc as a factor in human disease. These fibers are commonly asbestiform fibers (acicular cleavage fragments). Although these latter forms cannot be easily distinguished from each other, studies have indicated that these common contaminants of industrial grade talcs are the agents responsible for human disease. The disease stigmata are as follows: fibrosis, with patterns identical to asbestosis [34-38]; occurrence of uncoated fibers and asbestos bodies in lung tissues of workmen with interstitial lung scarring, and accompanied by other asbestosis stigmata (e.g., pleural plaques in workers with "talcosis") [37,39-41]; and excess malignancies, some of which are markers for asbestos exposure, e.g., mesothelioma [42]. One may cautiously accept that there are biologically active fibers contaminating industrial grade talcs. This might also carry with it, with some caution, that crystal faces and cleavage planes have the same biological potential in terms of producing human disease. Current Status It has taken 70 years to define the asbestos problem. The work of defining the human hazards associated with exposure to fibrous minerals, other than asbestos, will require at least as much effort and time. The varietal nature of asbestos, its broad range of mineralogical properties, suggests that other non-asbestos silicate fibers may be active as well. The argument centering on crystal face and cleavage plane difference extrapolated to biological potential requires study. The fact that a mineral fiber is non-asbestos does not extrapolate to its being non-active biologically. 2True asbestos, defined on the basis of mineral phase and its physical-chemical properties (flexibility and high tensile strength) does occur occasionally in talc deposits [32]. Asbestiform is defined as "formed-like or resembling asbestos...." This term refers to rock-forming fibrous silicates which are not flexible, do not have high tensile strength, yet when comminuted are identical to size-reduced asbestos. The term fiber in the present context is used to mean a morphological form, not necessarily the result of conditions of growth and therefore not necessarily bound by crystal faces. Since these characteristics cannot be easily measured on submicroscopic "fibers," the distinction if presently academic. 87 2063104887

References [1] Murray, H. M., In: Re ort of the Oepartmental Committee on Com ensation for Industrial Disease, Minutes of~ence ~ppendices and nd.d. 3495 - c.d. 349 , L~ ondon, Wyman and Sons (1907). [2] Lynch, K. M. and Smith, W. A., Pulmonary asbestosis. III. Carcinoma of lung in asbestos-silicosis. Amer. J. Cancer, 24, 56-64 (1935). [3] Gloyne, S. R., Two cases of squamous carcinoma of the lung occurring in asbestosis, Tubercle, 17, 5-10 (1935). [4] Wedler, H. W. , Asbestose und Lungenkrebs, Dtsch med. Wschr. , 69, 575-576 (1943a). [5] Wedler, H. W. , Uber den Lungenkrebs bei Asbestose, Dtsch. Arch. klin, Med. , 191, 189- 209 (1943b). [6] McDonald, J. C., Becklake, M. R., Gibbs, G. W., McDonald, A. D., and Rossiter, C. E., The health of chrysotile asbestos mine and mill workers of Quebec, Arch. environm. Hlth., 28, 61-68 (1974). [7] Selikoff, I. J., Hammond, E. C., and Churg, J., Carcinogenicity of amosite asbestos, Arch. environm. H1th., 25, 183-186 (1972b). [8] Wagner, J. C. and Berry, G., Mesotheliomas in rats following inoculation with asbestos, Brit. J. Cancer, 23, 567-581 (1969). [9] Meurman, L. 0., Koviluoto, R. , and Haka®a, M., Mortality and morbidity among the working population of anthophyllite asbestos miners in Finland, Brit. J. industr. Med., 31, 105-112 (1974). [10] SeliKoff, I. J., Hammond, E. C., and Seidman, H., Cancer risk of insulation workers in the United States, In: Bogovski, P., Gilson, J. C. Timbl, V., and Wagner, J. C., es.__o.~log~_ciTTffects of Asbestos, Lyon, International Agency for Research on Cancer (IARC Sc- ientiffc PuicatTone No. 8, pp. 209-216 (1973). [11] Keal, E. E. , Asbestosis and abdominal neoplasms, Lancet, pp. 1211 (1960). [12] Selikoff, I. J., Churg, J., and Hammond, E. C., Asbestos exposure and neoplasia, J. Amer. med. Assn., 188, 22-26 (1964). [13] Selikoff, I. J., Epidemiology of gastrointestinal cancer, Environm. Hlth. Perspect., 9, 299-305 (1974). [14] Dohner, V. A. , Beegle, R. G. , and Miller, W. T., Asbestos exposure and multiple primary tumors, Amer. Rev. resp. Ois., 112, 181-199 (1975). . [15] Selikoff, I. J., Hammond, E. C., and Churg, J., Mortality experiences of asbestos ~ insulation workers, 1943-1968, In: Shapiro, H. A., ed., Pneumoconiosis; Proceedings of the nternat~ Con erence, Johannesburg 1969, Cape Tawn, Oxford University Press, ( Pp. 1 -9 M [16] Selikoff, I. J., Lung cancer and mesothelioma during prospective surveillance of 1249 ~ asbestos insulation workers, 1963-1974, Ann. N.Y. Acad. Sci., 271, 448-456 (1975). ! [17] Pooley, F. 0., An examination of the fibrous mineral content of asbestos lung tissue from the Canadian chrysotile mining industry, Environm. Res., 12, 281-298 (1976). [18] Langer, A. M., Rubin, I. B., Selikoff, I. J., and Pooley, F. D., Chemical characteriza- • tion of uncoated asbestos fibers from the lungs of asbestos workers by electron micro- probe analysis, J. Histochem. Cytochem., 20, 735-740 (1972b). 88

[19] Fondimare, A. and Desbordes, J., Asbestos bodies and fibers in lung tissues, Environm. Hlth. Perspect. , 9, 147-148 (1974). [20] Sebastein, P., Fondimare, A., Bignon, J., Monchaux, G. , Desbordes, J., and Bonnaud, G., Topographic distribution of asbestos fibers in human lung in relation with occupational and non-occ_ - ex_ op ure, In: Wa~ton, T(.~., -,edIia eT d article and Vapours, ~, New York, ergamon (in press). [21] Langer, A. M., Inorganic particles in human tissues and their association with neoplastic disease, Environm, H1th. Perspect. , 9, 229-233 (1974). [22] Selikoff, I. J., Cancer risk of asbestos ex._ op sure, In: Hiatt, H. H., Watson, J. D., and Winsten, J. A., eds., ri 1784 (1977) gins of Human Cancer, Cold Spring Harbor, N.Y., pp. 1765- . [23] Selikoff, I. J., Hammond, E. C., and Churg, J., Asbestos exposure, smoking and neoplasia, J Amer. med Ass., 204, 106-112 (1968). [24] Doll, R., The age distribution of cancer: implications for models of carcinogenesis, J. ro- stat. Soc., 134, 133-166 (1971). [25] Berry, G. , Newhouse, M. L. , and Turok, M., Combined effect of asbestos exposure and smoking on mortality from lung cancer in factory workers, Lancet, ii, 476-479 (1972). [26] IARC Monograph Series: Evaluation of Carcinogenic Risk of Chemicals to Man, V. 14, Asbestos WH0-IARC Lyon, 1977, 106p. [27] Langer, A. M. and Wolff, M. S., Asbestos Carcino enesis, In: Schrauzer, G., ed., Inorganic and Nutritional Aspects of aer, P enum ress, N.Y., pp. 29-55 (1977). [28] Langer, A. M., Rohl, A. N., and Wolff, M. S., The nature of mineral surfaces and their role in biological interactions, Soc. Occup. and Environ. H1th., Wash., 1977 (in press). [29] Oppenheimer, B. S., Oppenheimer, E. T., Stout, A. R., Danishefsky, I., and Eirich, F. R., Malignant tumors and high polymers, Science, 118, 783-784 (1953). [30] Stanton, M. F. and Wrench, C., Mechanisms of mesothelioma induction with asbestos and fibrous glass, J. nat. Cancer Inst., 28, 797-821 (1972). [31] Stanton, M. F., Some etiolo ical considerations of fibre carcino enesis, In: Bogovski, P., Giison~ C., imbre ,., an~gner, S C. eds., ological ffects of Asbestos, Lyon, International Agency for Research on Cancer (IARC Scientifi~c PubT3ca- Lions No. 8, pp. 289-294 (1973). [32] Ford, W. E. , Dena's Textbook of Mineralogy, N.Y. Wiley, 4th Ed., 678p (1957). ' [33] Bureau of Mines, Dictionary of Mining, mineral and related terms, ed. P. W. Thrush, Washington, D. C. , U. S. Government Printing Office (1968). [34] Oreessen, W. C., Effects of certain silicate dusts in the lungs, J. Indust. Hyg., 15, 66-78 (1933). [35] Dreessen, W. C. and Dalla Valle, J. M., The effects of exposure to dust in two Georgia talc mi11s and mines, Publ Health REpts., 50, 1405-1415 (1935). [36] Siegal, W., Smith, A. R., and Greenburg, L., The dust hazard in tremolite talc mining, including roentgenological findings in talc workers, Am. J. Roentgenol., 4, 11-29 (1943). [37] Daymon, H., Latent silicosis and tuberculosis, Am. Rev. Tuberculosis, 53, 554-559 (1946). 89 2063104889

[38] Porro, F. W. and Levine, N. M., Pathology of talc pneumoconiosis with report of an autopsy, North. N.Y. State Med. J., 3, 23-25 (1946). [39] Hobbs, A. A., A type of pneumoconiosis, Am. J. Roentgenol. Radiol. Therap., 58, 488-497 (1950). - [40] McLaughlin, A., Rogers, E. , and Dunham, K. C., Talc pneumoconiosis, 8r. J. Indust. Med., 6, 184-194 (1949). [41] Porro, F. W. , Patton, J. R. , and Hobbs, A. A., Pneumoconiosis in the talc industry, Am. J. Roentgenol., 47, 507-524 (1942). [42] Kleinfeld, M., Messite, J., Kooyman, 0., and Zaki, M. H., Mortality among talc miners and millers in New York State, Arch, Environ. Health, 14, 663-667 (1967). Discussion M. SCHNEIDERMAN: You talked about short term exposures and problems of peak exposures. Then you divided an exposure by 20 years and that came out to some very small number, and you said that small number is substantially below the standards now set. Have you any information on the difference between biological results from peak exposures and long term exposures or should we consider only integrated exposures totaled over time and not consider problems of peak exposure? A. NICHOLSON: We don't have good data on the effects of peak exposures per se. They may in fact be proportionally greater than an amount averaged over a longer period of time. Insulation workers' exposures are very pealty-like. That is, they tend to spend most of their time working In conditions that would have very low ambient air concentra- tions. The material is wet or else they're not using asbestos, but at times when they were mixing cement, cutting block, or doing something like that they had very high concen- trations. This may be a factor. We just have no way of obtaining data on that particular item separately from the integrated exposures that we can make some estimate of. E. CDX: Dr. Nicholson, you mentioned an amosite exposure study of very short term nature and then went on to correlate that to the safe exposure over a long period of time. I believe your figures were three deaths, contrasted with an expected 1.34, from lung cancer for a person who was employed in that plant for one month or less. Was there any correlation with smoking done in that study? NICHOLSON: No, there was not, and the number of deaths in each single category were small. The consistency over each of those month by month categories, though, was strong. That is, if you looked at all months together over the period of time for less than one month through five months, the results are of statistical significance. In terms of cigarette smoking, we know it is strongly correlated with asbestos exposure. What asbestos does, in essence, is multiply whatever existing risk of death from lung cancer that is already present. If an individual has a high risk from cigarette smoking, then additional asbestos exposure can multiply that from five to ten times. If he has a very low risk of death from lung cancer because he's a non-smoker, it can be increased perhaps five times by the asbestos exposure. COX: Thus, there wasn't any correlation done. Now the other question would be with Dr. Langer's work, and perhaps you could answer it. It deals with the concentration of uranium involved in the mining danger. Langer had a chart, that went by rather rapidly, of the different things that are particularly dangerous and one was mining where uranium was involved. NICHOLSON: Uranium mining produces a very high risk of lung cancer. COX: Yes, I wonder if you could speak about the concentration of uranium? The amount of uranium in the are body is the thing of interest to me. 90

Ca NICHOLSON: Well, most ore bodies in the Southwest have two or three percent uranium oxide. COX: Well, let me be more specific. Phosphate mining in Florida where the yield is one pqund of uranium per ton of H3P04, would that be dangerous? NICHOLSON: It would depend on what the air concentration of the material is. I couldn't answer the question directly. COX: All right, thank you. L. SWINT: I'd like to clear up that question on uranium mining. Actually the cancer is caused by radon daughters which come from the radium, which is a decomposition product of uranium. The amount of uranium in the ore has nothing to do with the lung cancer. It's really a function of the exposure to radon daughters rather than the amount of uranium present. Although radon gas and radon daughters are decay products in the uranium decay series which, when in equilibrium, would be present in direct proportion to the amount of uranium present, for practical purposes they are independent because there are many events which occur that keep equilibrium of randon daughters and uranium from being established. Uranium and radium, the direct parent of radon, may be out of equilibrium due to differential leaching by groundwaters, since uranium is much more leachable than radium. The porosity and permeability of the rock affect the rate at which the rock will release radon gas into a mine atmosphere. Thus, the amounts of radon gas and radon daughters present in a mine atmosphere are not completely controlled by the amount of'radium or uranium in the rock. The grade of uranium ore mined in the U. S. through 1973 averaged between two and three tenths of one percent U308, but since 1973 this grade has steadily declined to fifteen hundredths of a percent in 1976. SCHNEIDERMAN: In fact, in some of those studies, the hard rock miners who would have similar exposures to the kinds of things that Dr. Nicholson was talking about were used as controls so that one might measure whether it was the radioactive material or the fibrous material that was of consequence. Those might have been inappropriate controls now that we know better, but hard rock miners were used as controls. NOTE: The following notes were sent following the meeting and were not part of the verbal discussion at the end of the session. P. GROSS: Dr. Langer's presentation suggested that fiberglass is carcinogenic to man. Epidemiologic studies as well as experimental studies in which animals inhaled fiberglass or were injected intratracheally with it have provided evidence that glass fibers were not carcinogenic. Only when glass fibers of a special thinness and length are placed in the chest cavity (not the lungs) or injected into the abdomen of rats do cancers develop. According to a recent publication (Money Causes Cancer: Ban It, by G. E. Moore and W. N. Palmer, JAMA 238, 397, August 17, 1977), sterilized dimes placed into the abdomen of rats caused more than'~5 percent of them to develop cancer within 14 months. The proclivity of certain rodents to develop cancers in response to various insoluble, solid materials embedded in their tissues is well recognized as "Solid-State Carcinogenesis" and should not be extrapolated to man. A. LANGER: During my presentation I voiced concern that among fibers other than asbestos, synthetic insulation fibers, e. g. , fibrous glass, when inhaled, may be biologi- cally active. This concern has been raised by a number of investigators, in different laboratories, based on observations made during more than 20 years of experimental work. As early as 1955, Schepers and Delahant [1], utilizing the inhalation route of administration, exposed guinea pigs and rats to 6-micron diameter fibrous glass. These animals were serially sacrificed for time periods up to two years, and progressive pulmonary changes followed. Guinea pigs were observed to develop pneumonia, lung abscesses, emphysema, and systemic neoplasms. Rats, in addition to these alterations, also formed pleural plaques, a stigma normally associated with asbestos fiber inhalation. "Severe parenchymal changes" were 91 2063104891

observed in both animal populations. In the same year, Schepers [2] published additional experimental data concerning the biological effects of intratracheally injected and inhaled glass wool. He observed persistence of glass in animal lung for up to 18 months after cessation of exposure. Glass wool fibers were observed in multinucleated giant cells and in areas of incipient atrophic emphysema. Epithelial hyperplasia was commonly observed. Inhalation experiments, cdnducted simultaneously with the same animals, produced epithelial hyperplasia and cellular desquamation; papillomas were observed in bronchioles. Focal cellular pneumonitis and other effects, such as alveolar wall thickening, were noted. Schepers considered some of these as "remarkable lesions" and suggested that ....... glass is not ~fibro9e~ni..c when retained in lu~g tissue. At the same time the gravity of the type a ronchiole lesion prov-oke~-necesitates caution in ~issTng qTas as tnnocuous. ndeed it shou~b ebe regarded as a ootential y harmf7 substance in circumstances leading to the inhalati- o of-lar e uan~ties of the t e of r~oducts studied in these experiments7 Yt shou d be strss-ed that t ~s ear~y study did not provide a contron group; however, one amy cautiously accept these findings considering the nature of the diseases and the extent to which the animal colony succumbed. In a number of animal studies which followed (e.g., Gross et al., 1959 [3]; Gross et al. , 1970 [4]), pulmonary changes from a variety of synthetic-7-i ers, in a number of an mi al models, appeared to occur. However, faced with some experimental caveats, these workers interpreted the results as not exclusivel indicative of biological activity of the fibers. It was not until 1972 that tanton an Wrench [5] demonstrated the ability of fibrous glass to induce malignant mesothelioma in experimental animals with appropriately vigorous control groups. This was substantiated further by Stanton in 1973 [6] and Pott et al. , 1974 [7]. Further work by Wright and Kuschner, in 1976 [8] unequivocally demon- stra ed the ability of fibrous glass to act in a manner similar to asbestos fibers in animal tissues (formation of scar tissue). Finally, Wagner et al., 1976 [9], were able to produce mesotheliomas in Wistar rats, after intrapleural inotuTation of glass fiber into chest cavities. The extent and even the histopathic nature of induced lesions may not be so marked as those from asbestos; nevertheless, many reports in the experimental pathology literature unequivocally demonstrate the potent activity of synthetic fibers in animal models [10]. Dr. Gross is correct in suggesting that the ability to induce tumors in the experimental model may well be related to the "Oppenheimer effect" (solid state carcinogenesis). Extrapolating to humans, this may indeed be the very same reactions which evokes mesothelial tumors. Hence, it has often been said that mesothelioma merely requires the hp ysical ,r~e_sence of a fiber at the pleural surface. If this is so, then the chemistry of the fiber, and its physical state, are secondary in terms of this particular biological response. Therefore, if inhalation of thin asbestos fibers (of any variety) produce mesotheliomas, the inhalation of thin glass fibers, which may also penetrate to the mesothelial lining of the lung, may produce the same response. The subject is still one which requires animal studies, and certainly human studies. It is an open issue. Discussion References [1] Schepers, G. W. H. and Delahant, A. B., An experimental study of the effects of glass wool on animal lungs, Arch. Ind. Health, 12, 276-279 (1955). [2] Schepers, G. W. H., The biological action of glass wool, Arch. Ind. Health, 12, 280- 287 (1955). [3] Gross, P., Westrick, M., and McNerney, J. M., Glass dust: a study of its biologic effect, Arch. Ind. Health, 16, 10-23 (1959). [4] Gross, P., Kaschak, M., Tolker, E., Bobyak, M., and deTreville, R. T. P., The pulmonary reaction to high concentrations of fibrous glass dust, Arch. Environ. Health, 20, 696-704 (1970). [5] Stanton, M. and Wrench, C., Mechanisms of mesothelioma induction with asbestos and fibrous glass, J. Nat. Cancer Inst., 48, 797-821 (1972). 92

Cs [6] Stanton, M., Some etiological considerations of fiber carcinogenesis, In: IARC Mono., Biolog. Effects of Asbestos, Bogovski, P., et al., Eds, Sci. Pub. No. 8, Lyon, pp 289-294 (1973). [7] Pott, F., Huth, F., and Friedrichs, K. H., Tumorigenic effect of fibrous dusts in -experimental animals, Env. Health Perspect., 9, 313-315 (1974). [8] Wright, G. and Kuschner, M., The influence of varying lengths of gtass and asbestos fibers on tissue response in guinea pigs, In: BOHS-Inhaled Particles and Vapours, IV, Edinburgh (1976), in press. [9] Wagner, J. C., Berry, G., and Skidmore, J. W., Studies of the carcinogenic effects of fiber glass of different diameters following intrapleural inoculation in experimental animals, In: Occupat. Exp. to Fibrous Glass, A Symposium - HEW - NIOSH, Univ. Maryland, June, 1974, U. S. Govt. Printing Office, Wash. p. 193-204 (with discussion). [10] Occu a~tional Ex to Fibrous Glass: A Sgposium, HEW - NIOSH, Univ. Maryland, June, 1974, U. Govt. Printing ffi'ce, Was6. 404 p. 93 ~ $ ~ w