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-% C 3 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) EPIDEMIOLOGIC EVIDENCE OF THE EFFECT OF TYPE OF ASBESTOS AND FIBER DIMENSIONS ON THE PRODUCTION OF DISEASE IN MAN W. Clark Cooper Equitable Environmental Health, Inc. Berkeley, California 94704 Abstract There is epidemiologic evidence to indicate that all types of commercial asbestos, i.e., chrysotile, crocidolite, amosite, tremolite asbestos, and anthophyllite asbestos, when inhaled, can cause pulmonary fibrosis and increase the risk of 1ung cancer. All but anthophyllite asbestos have been associated with malignant mesothelial tumors. There is also strong evidence to support a decreasing gradient of pathogenicity as one proceeds from crocidolite to amosite to chrysotile, but this evidence does not clearly rule out the interrelated influence of fiber dimension, shape, and co-factors. Clear-cut epidemiologic evidence related to differing fiber dimensions is scanty. Such information is critically needed. The most pressing need is to determine the pathogenicity of ultrafine fibers in the electron-microscope size range, and for fibers shorter than 5 micrometers, whether inhaled or ingested. It is suggested that there be expanded epidemiologic studies of populations which have been exposed to such fibers, without the presence of long fibers. This will probably occur where the exposures are incidental to operations other than commercial asbestos production. It is also recommended that there be systematic study of the fiber content of human lungs and other tissues, as related to causes of death. Key Words: Asbestos; asbestosis; carcinoma; epidemiology; fine particles; mesothelioma. When the seriousness of the problem of asbestos-related disease became generally recognized 15 to 20 years ago, it was regarded as arising solely from commercially-produced asbestos. Most evidence had been obtained from workers exposed during the mining, process- ing, or use of commercial chrysotile, amosite, crocidolite, anthophyilite asbestos, or tremolite asbestos, so studies logically focused on these types. The scientific and practical importance of determining whether all these types of asbestos were equally hazardous became apparent. One of the first recommendations made by the Working Group on Asbestos and Cancer, under the auspices of the International Union against Cancer, meeting in New York City in October, 1964, was "that the importance of fiber type on the risk of developing asbestosis, carcinoma of the lung, and mesothelial and other tumors be investigated" [1]1. Eight years later, meeting in Lyon, the Advisory Committee on Asbestos Cancers to the International Agency for Research on Cancer [2], the successor to the subcommittee that arose out of the 1964 Working Group, answered its own question: "Are all commercial types of asbestos able to cause lung carcinoma?" as follows: 'Figures in brackets indicate the literature references at the end of this paper. Preceding page blank - N

"Yes. Since 1964 the evidence of a causal relationship has been increased by epidemiological studies showing exposure-response relations for the incidence of lung carcinomas. The production of lung carcinomas in certain animals by all types of asbestos supports this conclusion. The epidemiological evidence in man, however, shows that there are clear differences in risk, with type of fibre and nature of exposure." With respect to mesothelioma, the Committee's report stated that, "There is evidence that all commercial types of asbestos except anthophyllite may be responsible. Evidence for an important difference in risk in different occupations and with the type of asbestos has increased. The risk is greatest with crocidolite, less with amosite, and apparently less with chrysotile. With amosite and chrysotile there appears to be a higher risk in manufacturing than in mining and milling." The Committee then made specific recommendations for projects assessing excess cancer risks following exposure to only one type of fiber, mentioning chrysotile, amosite, and chrysotile, with special emphasis on differences between those engaged in mining and milling and those engaged in the manufacture and use of these types of commercial asbestos. It was further recommended that there be investigation of "talc-exposed groups in mining and manufacturing to establish any differences in morbidity or mortality which might be related to the amount and shape of the fine respirable particles." In a related recommendation pertaining to experimental work, recognition was given to the need for more information about the role of fine particles, especially the influence of fiber size in the induction of tumors: "These studies should be extended to include fibres other than asbestos. A subcommittee should be established to review the need for, and arrange the distribution of, standard samples of asbestos and other fibres in addition to the UICC reference samples." Another pertinent recommendation was: "There is an urgent need for the quantitative assessment, size analysis, and characterization of particles and fibres in the lungs and other organs." Participants in the present workshop are engaged in the continuing search for answers to the foregoing questions, and it is apparent definitive answers are not easy to obtain. There is an expanded appreciation of the ubiquity of mineral fibers with shapes resembling those of commercial asbestos, with diameters extending into a range below detectability by light microscopy, and with lengths below 5 micrometers (pm), now arbitrarily used as the lower limit for occupational standards. Decisions on pathogenicity for man are urgently needed with respect to these, the asbestiform varieties of many minerals, and for all durable fibers in the range below light microscopic detection, i.e., below 0.4 or 0.5 pm in diameter, and which are very short, i.e., less than 5 pm in length. How can epidemiologic evidence contribute to these decisions? Epidemiologic studies cannot stand alone. They fit into a network of observations from many sources, including theoretical and observed information on the aerodynamic properties of particles, in vitro tests, studies in experimental animals, and isolated clinical observations. They are nevertheless, by definition, the final source for quantita- tive information in man, and ultimately must be the basis for establishing and evaluating environmental controls. Some of the effects in man which lend themselves to quantitative study and correlation with occupational or non-occupational exposures include: (1) Evidence of asbestosis, such as fibrosis of the lung parenchyma, fibrosis or thickening of the pleura, calcification of the pleura, and other non- malignant reactions as demonstrated by radiography, functional tests, physical examination, or study of tissues. 122

(2) Evidence of malignancy, notably carcinoma of the lung, mesothelioma of the pleura or peritoneum, or cancer of the gastro-intestinal tract, larynx, or other sites. (3) Evidence of past exposures, as demonstrated by fibers in various tissues, sputum, or urine. It is generally accepted that fiber characteristics probably operate differently with respect to different pathologic effects, so that asbestosis, lung cancer, mesothelioma, and other malignancies will follow differing dose-response curves as we consider different types and dimensions of fibers. Hopefully, we can obtain useful epidemiologic evidence by considering the patterns of disease, as related to different types and dimensions of mineral fiber, in groups identified as follows: (1) Populations whose preponderant exposure has been to one type of asbestos or the asbestiform variety of a mineral, whether by inhalation, ingestion, or both, which can be observed for periods of at least 30 years and preferably 50 years after exposures began, and which can be compared with groups having little or no exposure to the same or related fibers; (2) Populations with suspect diseases, whose past exposures can be reconstructed by history, records, place of residence, or body burdens of fibrous particles, and which can be compared with a matched series having some disease unlikely to be asbestos-related. This case-study method is most useful in relatively rare diseases, such as mesothelioma. (3) Populations having differing concentrations, types, and sizes of mineral fibers demonstrated at autopsy, to determine whether or not the patterns of pathology and causes of death correlate with differing tissue burdens of fibers. What evidence have we gathered to date, using the foregoing approaches? Types of Asbestos Used Commercially There is unequivocal evidence that chrysotile, amosite, crocidolite, tremolite asbes- tos, and anthophyllite asbestos can produce asbestosis and increase the risk of lung cancer. All but anthophyllite have been associated with an increased risk of mesothe- lioma. Grading the relative biologic activity of these several types of asbestos, in terms of the production of each type of asbestos-related disease, is more difficult. As Margaret Becklake [3] pointed out in her excellent review, it is not easy to control precisely for dosage and cofactors. Fiber diameter, length, and shape are highly interrelated with asbestos type and may be more important than chemical and crystal structure. The consensus that crocidolite is the most hazardous commercial asbestos has been derived from a number of studies, but these do not all rule out an influence of shape and size. Emphasis on crocidolite as being particularly hazardous arose from its early associa- tion with mesothelioma in the Northwestern Cape Province of South Africa, as first described by Wagner et al. [4]. Although the relative absence of mesothelioma in the crocidolite areas of the Transvaal reported by Sluis-Cremer [5] was at first questioned because of the exclusion of black and colored miners, Webster [6] has confirmed that there is a much lower incidence of mesothelioma in the Transvaal. Timbrell [7,8] has offered as an explana- tion the fact that crocidolite in the Northwest Cape is of smaller diameter (therefore more respirable) and shorter (therefore more likely to avoid interception in the airways) than the crocidolite of the Transvaal. It should be emphasized that although the Transvaal fibers averaged three times as long as the Northwest Cape fibers, both samples had many fibers above 5 pm in length. Webster [6] on the basis of pathologic observations of the distribution of fibers in the lungs has questioned the foregoing explanation. He has suggested that possibly concurrent exposures to iron and manganese in the Northwest Cape may have an influence. 123 2063104921

C With respect to lung cancer, Enterline and Henderson [9] compared the experience of workers making asbestos cement pipe, where both crocidolite and chrysotile were used, with that of others exposed only to chrysotile. Those whose exposures included crocidolite had 6.1 times the expected number of deaths due to lung cancer, while those exposed only to chrysotile had 1.4 times the number expected. Weill et al. [10] carried out comparative studies of two populations of workers, one making asbestos shingles containing chrysotile, and the other making shingles, flooring, and asbestos-cement pipe and exposed to both chrysotile and crocidolite. Those exposed to crocidolite had more small irregular opacities by x-ray, more pleural thickening, and significantly greater reduction in pulmonary function. Despite the consensus that crocidolite is probably the most hazardous type of commercial asbestos, the evidence does not appear strong enough to support a 10-fold stricter standard for a time-weighted average, or a 60-fold stricter standard for 10- minute exposures, as applied in the United Kingdom [11]. Amosite has been positively identified as responsible for pulmonary fibrosis, lung cancer, anTmesothelioma. Selikoff et al. [12] found a 10-fold excess of lung cancer, as well as 5 deaths from mesothelioma, in a population of 230 men who had been previously employed in an amosite-using plant, during the period 1960 to 1971. This has been one of the few opportunities in the United States to study workers without mixed exposures. The high rates of asbestosis, lung cancer, and mesothelioma in asbestos insulation workers have been in men with mixed exposures, to both amosite and chrysotile. The foregoing experience in an amosite-using industry is in striking contrast to that reported in the amosite mines in South Africa. Webster [6] states that of 232 confirmed cases of mesothelioma diagnosed in South Africa between 1956 and 1972, 78 had been in miners, but practically all had been exposed to Cape Blue crocidolite, with only two having had exposures only to amosite. As pointed out earlier, the fact that Transvaal amosite shared with Transvaal crocidolite the property of being thicker and longer than Northwest Cape crocidolite makes it impossible to ascribe the difference to type alone. Men exposed to crocidolite in the Transvaal also had relatively few mesotheliomas. Chrysotile has been rated the least pathogenic type of the three major forms of commercially-produced asbestos on the basis of relatively few studies in which exposures were limited to this type. Most such studies have been in workers engaged in the mining and milling of chrysotile, in Canada, Italy, Russia, and Cyprus. A report by Braun and Truan [13] indicated that the incidence of lung cancer in chrysotile miners and millers in Quebec, while slightly elevated, was not nearly as great as had been described in asbestos workers in the United Kingdom or in U.S. Insulators. These studies have been criticized for methodologic flaws, but it would now appear that they reflected a lower risk in chrysotile miners. More recent studies of Quebec miners and millers by McDonald et al. [14] show an excess of lung cancer, 5 times expected, only in the highest exposure group. Only 5 deaths from mesothelioma were found among 3,270 deaths. A more recent estimate by McDonald [15] gives the proportion of mesothelioma deaths as 8 out of 4,000 deaths. This is far less than the proportion found in U.S. insulation workers, where, for example, Selikoff found 77 of 1,092 deaths due to mesothelioma. Weiss [16] has recently studied the mortality in a group of 264 employees hired during the period 1935-1944 in a plant manufacturing chrysotile products, and who worked one year or more. The Standard Mortality Ratio (5MR) for lung cancer was only 0.93. Although the design of the overall study did not permit strict comparison with the study by Selikoff et al. (17] in an asbestos insulation material producing plant, comparison of groups with similar intervals from first exposure to end of operation indicated a significantly lower lung cancer risk in the Weiss study. These reports, combined with those of Weill et al. [10] and Enterline and Henderson [9] previously reported, suggest that chrysotile is less pathogenic than crocidolite or amosite. But, as Timbrell [8] has pointed out, the curliness of chrysotile fibers influences their deposition and transmigration, so shape and size may be more important than chemical composition per se. The evidence on anthophyllite asbestos comes almost entirely from Finland, where this form of asbestos was commercially developed until recently, and where there have been widespread non-occupational exposures. The extraordinary incidence of pleural calcification associated with low level exposures is well-documented (Kiviluoto) [18]. Kiviluoto and Meurman [19] and Nurminen [20] have shown in studies of workers exposed to 124

C anthophyllite asbestos that they have an increased risk of asbestosis and lung cancer, but. mesotheliomas have not been reported. Meurman et al. (21] analyzed 248 deaths in 1,092 anthophyllite miners and millers. There were 21 deaths from lung cancer, where 12.6 were expected; no mesotheliomas were reported. Studies of workers exposed to tremolite asbestos without associated exposures to other fibers are not sufficiently well documented to permit placing them in a gradient of response with other commercial types of asbestos. The same is true for actinolite asbestos. ' . Other Asbestiform Minerals What is the evidence for the pathogenicity of mineral fibers other than the types of asbestos commercially exploited? It is almost non-existent because, in the absence of commercial development and occupational exposures, contacts have been incidental to other operations and have been poorly documented and usually of less magnitude. The best of such studies have been associated with commercial talc operations. The presence of tremolite asbestos, anthophyllite asbestos, and chrysotile in many talc deposits has confirmed the potential of these types to produce fibrosis, pleural plaques, and to increase the incidence of lung cancer. There are no studies to indicate that (ibrous talc, In the absence of asbestos of the types mentioned, can produce disease in man, but one would predict that such fibers in the right size ranges would be pathogenic. Non- fibrous talc is apparently hazardous only if there is concurrent silica exposure. Rubino et a1. [22] reported on the mortality pattern in 1,346 talc miners and 438 talc millers, in which there were 931 deaths. Although there was an'increased incidence of si]icosis and silico-tuberculosis, they reported no excess in cancer. • They did nqt indicate any fibrous talc being present. . A promising source of information on a non-commercial asbestiform variety of mineral has been the population of the Homestake gold mine in South Oakota, where there have been exposures to amphibole fibers, described as predominantly in the grunerite series similar to those found in the Mesabi range of Minnesota, extending back for over 100 years. Unfortunately, results to date are far from conclusive, despite a published mortality analysis by Gillam et al. [23] and an environmental report by Dement et al. [24]. Gillam et al. reported a statistically significant excess of iung cancer deaths (10 contrasted with 2.7 expected) in 440 gold miners identified by the Public Health Service in a 1960 silicosis study. However, a more recent report by McDonald et al. (1977) covering deaths between 1937 and 1973 in 1,321 employees of the same mine who were members of the Homestake Veterans Club, and had worked 21 years or more, showed no excess lung cancer deaths. There were 660 deaths for analysis. There was an excess of deaths from pneumoconiosis and pulmonary tuberculosis. This, and the excess of non-malignant respiratory disease deaths reported by Gillam et al. is not surprising, since 39 percent quartz had been demonstrated in settled dust. Records kept by the mines since 1937 showed dust concentrations ranging from 11 to 25.5 million particles per cubic foot (mppcf) before 1952, greatly exceeding standards for free silica. The miners who died of non- malignant respiratory disease had begun work as early as 1916. Even if an excess of lung cancer were proven in the Homestake mine, attributing it to low concentrations of mineral fibers would not be justified without careful consideration of what is known of smoking histories and concurrent exposures to arsenic and radon daughters. Asbestiform minerals almost certainly cannot be held responsible for the excess deaths from non-malignant respiratory disease, in view of quartz exposures and death certificates which in most cases had diagnoses of silicosis. It is absurd to attribute fatal pneumoconiosis in such a situation to grunerite fibers at levels approximating one-tenth the current standard for asbestos. Swent [25] has critically reviewed the Gillam study and documented ventilation back to 1916 and dust counts to 1937 which show that the assumption that past exposures to silica, arsenic, radon daughters, and fibers were the same as those found in a 1972 survey is untenable. As matters now stand, the Homestake study cannot be regarded as supporting the pathogenicity of grunerite fibers. One awaits the results of new studies being supported 125 2063104923

s by NIDSN, which may establish the mortality patterns with more certainty and hopefully will permit more accurate estimates of past exposures. Influence of Fiber Dimensions Throughout consideration of types of asbestos, it is apparent that type cannot be separated from shape and size. This is true even when exposures are characterized solely on the basis of fibers in the light microscopic range (i.e., with diameters greater than 0.4-0.5 pm) and those greater than 5 pm in length. It has been demonstrated in recent years, however, that neither in standard reference samples of commercial asbestos (Langer) [26], nor in air and water samples, nor in lung tissue, are fibers mainly in the light microscopic size range. Furthermore, as Pooley [27] has shown, even chrysotile miners and millers contain large numbers of amphibole fibers, most of them in the microfiber range, in their lung tissues, so their exposures are mixed. When we turn to consideration of epidemialogic evidence on fiber dimensions, either within a given species of commercially used asbestos, or in the asbestiform varieties of minerals not used commercially, there is relatively little to report. There is suggestive but not conclusive evidence from South Africa (7] that relatively short and fine fibers are more likely to produce mesotheliomas than longer and thicker fibers, but these are within the range of light microscopy and longer than 5 micrometers. There are no conclusive studies in man to support the strong evidence from animal studies that very short fibers (under 5 pm) are non-pathogenic. In considering the influence of fiber size, the question of the ultrafine fiber must be separated from the question of the very short fiber. The ultrafine fiber is defined as one below the level of resolution by the light microscope, i.e., less than about 0.4 pm in diameter, down. to the size of the smallest chrysotile fibril, of the order of 0.025 pm or 250 Angstrom units. Evaluation of such ultrafine fibers is of great importance because: 1) diameter has a strong inverse relationship to falling speed, so such fibers remain airborne for long periods and are highly respirable, although their capture and retention will vary not only with diameter, but also with length; 2) they are found in large numbers in lung tissues, both in individuals occupationally exposed and those without such exposures, but seldom to the exclusion of large fibers [28]; 3) they have been found to be widespread in coamunity air [29] and in association with the quarrying and use of serpentinite rock [30]; 4) they are not included in fibers counted by the methods currently recommended for monitoring work environments, and are not covered by current standards; 5) data are not being systematically collected on the numbers of ultrafine fibers in the air nor how their concentrations relate to the concentrations of larger fibers found in various occupational and environmental situations. There are no epidemiologic studies in which ultrafine fibers are an isolated variable. All studies of populations exposed to commercial asbestos have involved heavy exposures within the light microscope range, i.e., to fibers larger than 0.5 um in diameter, so the contribution of ultrafine fibers cannot be determined. On the evidence from studies in animals, it is likely that such fibers, when longer than 5 or 10 pm, would be pathogenic. 126

The problem of the very short fiber is more critical: `1) studies in animals strongly suggest a decreasing gradient of fibrogenic risk and carcinogenic potential (at least for mesothelioma) for fibers shorter than 5 to 10 micrometers; 2) samples of naturally occurring chrysotile, amosite, and crocidolite have been shown to contain a majority of fibers shorter than 5 Ym in length (28); 3) lung tissue contains a high proportion of short fibers; 4) samples of ambient air in many areas, such as those collected near taconite mining operations in Minnesota, and associated with crushed rock in Montgomery County, Maryland, are predominantly short fibers (303; 5) since current monitoring methods for the occupational environment exclude fibers shorter than 5 pm, data are not being systematically collected. The biologic activity of short fibers in man is not known. By analogy with studies in animals one would not expect fibers shorter than 5 pm or 10 pm in length to produce asbestosis or mesothelioma. The only epidemiologic study in which fibrosis and excess lung cancer has been attributed to exposures which were predominantly too short, ultrafine fibers is that of Gillam et al. (23] in the Homestake mine. Here 94 percent of fibers were less than 5 pm in length, the median diameter was 0.13 pm, and the median length was 1.1 Nm. For reasons pointed out earlier, these exposures, which were described as' consisting largely of grunerite with some fibrous cummingtonite and hornblende, are inconclusive. Neither the actual mortality experience nor the past exposures a'r,e well enough defined to be used as scientific evidence. ' The. case report by Miller et al. [31] in which a 53-year old man who died with extensive interstitial pulmonary fibrosis was found to have had large numbers of ultrafine, short fibers in his lungs cannot in itself establish a causal relationship, nor does it indicate how often such an association might occur. It is analogous to an earlier report by Miller et al. [32] who made a somewhat similar finding in a man who had been exposed for many years to talc in a rubber products plant and whose lungs showed enormous numbers of submicroscopic talc particles (non-fibrous). Both reports suggest that overwhelming concentrations of a reactive dust may in some individuals produce generalized interstitial fibrosis. It does not tell us how often such might occur, nor provide any information on relationships with malignancy. The essentially negative evidence as to health effects from the airborne fibers associated with taconite mining operations in Minnesota, and the negative evidence from Duluth (Masson et al.) [33] with respect to the ingestion of ultrafine, short fibers in Lake Superior water are reassuring, but it is too soon to rule out effects with long latent periods, i. e. , 25 years or more. In summary, no populations whose exposures have been confined to ultrafine fibers, short fibers, or fibers which are both ultrafine and short, have been defined or studied long enough to permit epidemiologic evaluation. There have been several studies in recent years in which the concentrations of fibers in lung tissue have been quantitated and described, with some attempt at correlation with pathologic changes. That of Ashcroft and Hepplestone (1973) [34] was limited to 35 individuals with asbestos bodies detected in histological sections, and all but one had definite or probable histories of occupational exposure. The authors found that from 12 to 30 percent of the fibers were optically visible, the rest being detectable only by electron microscopy. (They did not describe fiber lengths.) There was a general correlation between fiber concentration and asbestosis, up to the level of moderate asbestosis. Another study, by Doniach et al. [35], was limited to optically visible asbestos bodies in a London necropsy series. The study by Pooley [27] of the lungs of 127 2063104925

individuals with asbestosis who had been employed in the chrysotile mining industry in Canada, and in 30 individuals who died with mesothelioma, provided valuable information on the relative proportions of chrysotile and amphibole fibers and on the large numbers of EM-sized fiber present, but no detailed data on lengths and diameters of fibers were presented. Its most interesting feature was the large number of amphibole fibers that were found in chrysotile miners. In short, we know of no large series of cases in which the numbers and sizes of fibers in tissues have been correlated with causes of death. Studies Which Are Needed How can the necessary epidemiologic evidence be obtained? It can be accepted without reemphasis that infection and inhalation studies in animals, testing various types of asbestos and asbestiform varieties of other minerals in appropriate size ranges, must be done. It is not likely that further study of individuals who mine, mill, process, or use commercial asbestos will do more than tune more finely what we already know. Even though this is desirable and necessary, it is not likely to answer questions about very fine or very short fibers, since the nature of commercial asbestos is such that long fibers are always present. Only if dust control measures preferentially increase very greatly the proportion of short fibers in the electron microscope range would studies in commercial asbestos operations provide useful information regarding fiber size. We must turn to other populations, where exposures have been incidental to non- asbestos industrial operations but which liberate or disperse asbestiform varieties of minerals in the electron microscope range below 5 pm in length. The Homestake mine has had this type of population, but here a positive finding would lead to a need to consider several confounding variables. On the other hand, an absence of serious risk would be . highly reassuring, if past exposures were found to have been high. Other populations which might be studied are those in association with taconite mining and milling operations, where, in some areas, the airborne mineral fibers are predominantly less than 3 pm in length and do not represent any form of commercial asbestos. There are many sections of the United States where chrysotile and amphibole fibers are present in the natural rock and have been present in air or drinking water for long periods of time. Careful search should be made for areas which might permit comparisons of malignancy patterns as related to such exposures. The work of Fears (1976) [36], who found no excess of cancer in U.S. counties with known asbestos deposits, needs to be refined to concentrate on census tracts contiguous to operations which actually increase fiber concentrations in the air or water. A second approach which should be expanded is the large scale study of the fiber content of human lungs and other tissues, with determination of fiber concentrations and fiber dimensions, for comparison with causes of death. This has been periodically suggested but never actively pursued. Stanton (1974) [37] stated, "There is perhaps one way to determine the hazards of fibers without waiting the many years necessary for the effects of even massive exposure to become evident. Unlike most carcinogens, fibers that are a threat are sufficiently durable to remain in the tissues from which cancers are derived. Since carcinogenic response can be related to doses of sized fibers in experimental animals, it may be possible to equate the number and size distribution of fibers in human tissues to cancer in man. Although much has been accomplished in assessing large, protein-coated fibers in human lungs, surprisingly little has been done in assessing the size distribution and total quantity of all fibers in human tissues. This would be a tedious job, but it might determine the true significance of fibers as carcinogens in man." It is believed that the design and organization of such a major study is long overdue. Without the information it might provide, environmental decisions involving ultrafine and ultrashort asbestos fibers or the asbestiform varieties of other minerals will continue on a very uncertain and often emotional basis. When one considers the tremendous outlays involved in containing or capturing such fibers in mining and quarrying operations, as well as in asbestos-using industries and in waste disposal, the cost of such studies would 128

appear a prudent investment. As Rohl, Langer, and Selikoff observed in their recent report [30] providing data on fibers found near Montgomery County roads where serpentinite rock had been used, "The evaluation of the possible health hazard that may be associated with this exposure requires information that is not yet known in the scientific community: (i) the biological activity of short chrysotile fiber, (ii) the level of exposure to asbestos which is safe insofar as human cancers are concerned, if a safe level exists, and (iii) the biological activity of asbestiform silicates, not necessarily asbestos." The same comment applies to numerous other environmental situations currently under scrutiny. We do not know what fiber concentrations expressed in nanograms per cubic meter or in total fibers per unit volume, when detected by electron microscopy, mean in terms of human health. Unfortunately, epidemiology does not yet provide the answers. Summary and Conclusion There is epidemiologic evidence to indicate that all types of commercial asbestos, i.e., chrysotile, crocidolite, amosite, tremolite asbestos, and anthophyllite asbestos, when inhaled, can cause pulmonary fibrosis and increase the risk of lung cancer. All but anthophyllite asbestos have been associated with malignant mesothelial tumors. There is also strong evidence to support a decreasing gradient of pathogenicity as one proceeds from crocidolite to amosite to chrysotile, but this evidence does not clearly rule out the interrelated influence of fiber dimension, shape, and co-factors. Clear-cut epidemiologic evidence related to differing fiber dimensions is scanty. Such information is critically needed. The most pressing need is to determine the pathogenicity of ultrafine fibers in the electron-microscope size range, and for:fibers shorter than 5 micrometers, whether inhaled or ingested. It is suggested that there be expanded epidemiologic studies of populations which have been exposed to such fibers, without the presence of long fibers. This will probably occur where the exposures are incidental to operations other than commercial asbestos production. It is also recommended that there be systematic study of the fiber content of human lungs and other tissues, as related to causes of death. References [1] Report and Recommendations of the Working Group on Asbestos and Cancer, Ann. N. Y. Acad. Sci., 132, 706-721 (1965). - - - [2] Report of the Advisory Committee on Asbestos Cancers to the Director of the Interna- tional Agency for Research on Cancer, in Biological Effects of Asbestos, Proceedings of a Workin Conference, Lyon, 1972, P. Bogovski, V. mbrell,ll, J. C. Gilson, and .7. C. Wagner, eds. , IARC Scientific ublications No. 8 Lyon, pp. 341-346 (International Agency for Research on Cancer, 1973). j3] Becklake, M. R., Asbestos-related diseases of the lung and other organs: their epidemiology and implications for clinical practice, Amer. Rev. Resp. Dis., 114, 187- 227 (1976). [4] Wagner, J. C., Sleggs, C. A., and Marchand, P., Diffuse pleural mesothelioma and asbestos exposure in North Western Cape Province, Brit. J. Ind. Med., 17, 260-271 (1960). [5] 3lu3}oC319me~1,97G0) K., Asbestosis in South African asbestos miners, Environ. Res., [6] Webster, I., Malignancy in relation to crocidolite and amosite, in Biological Effects of Asbestos, Proceedings of a Workina Conference, L jyon, 1972, P. Bogovski, V. TimbreTS, J. 77-GiTs-on, and J. C. Wagner, eds., I~enti ic -hublications No. 8, Lyon, pp. 195-198 (International Agency for Research on Cancer, 1973). 129 2063104927

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