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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