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Biologic Response to Kind and. Amount of Asbestos Morris Kleinfeld, M.D. Studies of the biologic response to different tvpes of asbestos dusts in dicate that their inhalation in adequate concentrations can produce pulmonary and pleural fibrosis and/or several types of malignancy, chiefly of the lung, pleura and peritoneum1. Associations between asbestos dust exposure and malignancy of the gastrointestinal tract have been reported* '*>. However, a general con sensus with regard to this association has not been evolved5. Most of the evidence of association between asbestos ex posure and human disease has been acquired from occupationally exposed groups. Effects of Exposure to Different Types of Inhaled Asbestos Dusts 1. Asbestotic Pneumoconiosis: Of the different pathogenic effects associated with asbestos dust exposure, the first clearly demonstrated adverse effect of asbestos in man was pulmonary fibrosis or asbestotic pneumoconiosis. There is general agreement that all forms of asbestos in commercial use can produce fibrotic effects in the lungs-*. Asbestotic pneumoconiosis is characterized roentgenographically by diffuse interstitial fibrosis ot variable degree, sometimes associated with pleural fibrosis and calcification. Clinical signs include lung crepitations, finger clubbing and dysp nea: physiological changes are con sistent with a restrictive lung disorder manifested by decreased forced vital capacity, diminished diffusion capacity. Qttecioc ot Division ot Indirtnal HvR*ene. New ^onc Stale Department 01 latsr. 60 Censte bueef. New York. N Y ttftl i and Cm- CJi PifK-v*x t n- .*:ocnenul Nxedj^.tne. New Yr* Mtntaai Center Reprint > 400 *kvvv. K'*>k!vn. N \ lliltj and decreased pulmonary, compliance. Asbestotic pulmonary fibrosis has been produced experimentally in various animal species. However, data on relative fibrogenicity of different asbestos dusts in animal work has not been con sistent5 A Human data on relative fibrogenicity of different asbestos dusts is still inconclusive. Murphy. Ferris and Burgess7 studied pipe coverers exposed mainly to chrysotile and amosite dust Asbestosis was first observed after 13 years of exposure to the dust or about 60 million particles per cubic foot (mpef) years. The prevalence was 38% after 20 years of exposure. In a recent un published study of talc workers exposed to a mixture of talc with tremolite and anthrophyllite as the predominant fibrous components. Kleinfeld, Messile and Unger* found only one case of pneumoconiosis among a group of 39 workers whose mean exposure was 16.2 years with a range of 11 to 22 years. The mean dust concentration to which the workers had been exposed over a 20 year period was 23 mppcf with an average minimum concentration of 6 and an average maximum of 68 mppcf. In both studies7 8 consideration was given only to time-weighted average ex posures. Peak concentrations were not mentioned. Lacking data on peak ex posures and since the operations differed significantly, one cannot trul/~compare the relative pathogenicity of the dusts referred to in the two studies. As in the case .of bronchogenic car cinoma. tire factor of smoking must be considered in relation to asbestos ex posure and development of pulmonary fibrosis. In a study of 100 asbestos textile workers, Weiss"* found that the prevalence of pulmonary fibrosis was 40% in smokers -^and--24% m non smokers. Age. sex and duration of ex posure to asbestos did not account for this difference. The prevalence of pulmonary fibrosis rose with increasing amount and duration of cigarette smoking and with increasing exposure to asbestos. 2. Bronchogenic Carcinoma: Available data confirm a relationship between past occupational exposure to asbestos dusts and higher than expected incidence of bronchogenic carcinoma10- '*. Some studies have demonstrated differences in degree of risk among different oc cupationally exposed groups, probably related to type and concentration of asbestos fiber, nature of work per formed. and other factors such as smoking cigarettes'* and presence of metals in the asbestos dust14. For exam ple, in a study of mortality in relation to occupational exposure in the asbestos industry. Enterline. DeCoufle and Hen derson1* observed differences in respiratory- cancer mortality between maintenance service workers and production workers. Two possible ex planations were offered for the dif ferences in respiratory cancer mortality between these two groups; one that the intermittent asbestos exposure of main tenance service workers probably at a very high level, produced excess respiratory cancer but no great excess in asbestosis; another explanation was based on types of asbestos to .which these two groups of workers were ex posed. Sixty-four percent of the main tenance service workers with high ex posures had been exposed to crocidolite asbestos whereas 8% of the production workers with high exposures'had been so exposed, indicating that crocidolite was more carcinogenic than the other "asbestos dusts-, namely, chrysotile and_ 296 *> i i 1 i i |i i r t ]> -\ \ it 5 s if \s e n 3* ris Df v to 3S nin *n id xitity he in*a in '3$ ich ex* iriexlite \on ;cn lit her and amosite. to which these workers were reported 33 cases of mesothelial tumors 'exposed. Cigarette smoking is an ad- in a part of South Africa- important for ditional factor of importance. In a study crocidolite mining, investigators in other of insulation workers. Selikoff, Ham- parts of the world** *r have examined the mond and Churgu reported a mortality distribution of mesotheliomas in the risk 92 times greater among insulators general population and among oc- who smoked cigarettes compared to cupationally exposed asbestos workers, men who neither smoked cigarettes nor The results indicate a fairlv good worked in the insulation industry. More relationship between exposure to dii- tecenfly. the role of trace metals has also ferent asbestos dusts, namelv. been considered a major factor in car- crocidolite. chrysolile and amosite or dnogenesis among asbestos insulators'4. mixtures thereof, and the occurrence of Wagner, Gilson, Berry et al* com- mesotheliomas. Wagner*4 pointed out mented that the risk of bronchogenic that amphibole fibers, which are straight, carcinoma is dearly related to the in- are more likely to reach the periphery' of tensity of past exposure and to the risk of the lung in contrast to chrysolite fibers, asbestosis. When the environmental which resemble stretched coils and are control is sufficient to eliminate readily intercepted by the bronchi, asbestosis. the excess risk of bran- especially at bifurcations. The lesser risk chogenic cancer, diminishes. Wagner of developing mesothelioma from ex- and associates also indicated that it is posure to chrysolite fibers may be due to not known whether the type of asbestos their curly nature, which prevents most inhaled influences the risk of bronchial of them from teaching the pleura, cancer in man. Experiments in animals Wagner has, therefore, emphasized that suggested to them that it should because quantitative studies of the distribution of chtvsolile produces less severe fibrosis different types of fiber within the lung than does amosite or crocidolite in equal following inhalation need lo be ex doses. tended. However, not all amphibole The question of whether the car- fibers show an increased prevalence for cinogenic rote of asbestos is related to mesothelioma production. Despite a the specific kind of fiber is more difficult thorough search, no mesotheliomas have to answer than the question of dose- been associated with anthrophyllite reiated response. For this purpose, asbestos production in Finland". Wright4 indicated that populations with Timbrell. Griffiths and Pooley20 em- long-term exposure to only one variety phasized the importance of fiber of fiber are needed. Virtually all diameter in addition to fiber shape in fabricating processes use more than one relation to development of variety within the same premises at any mesothelioma. They provided a one time or have used more than one plausible explanation for differences in variety at various times. Populations frequency of diffuse mesotheliomas in restricted to mining and milling the Northwestern Cape of South Africa operations in the production of asbestos where only crocidolite is mined corn- fiber tend themselves best to a study of pared to the Transvaal region where the effects of a single kind of asbestos both crocidolite and the closely related fiber: it is these populations which can amosite are mined. The occurrence of provide the answer to the influence of a mesothelioma in the Transvaal is rare, single variety of asbestos fiber in terms The mean fiber diameters of Transvaal of carcinogenesis. However, the rote of crocidolite and amosite were three times different types of asbestos in raising the those of Northwestern Cape crocidolite. incidence of bronchogenic cancer ap- Timbrell et al postulated That differences pears to be dose-related and may in diameter would influence the ability depend upon the specific category of of fibers to penetrate to the periphery of fiber, especially in regard to degree of ef- the lung and pleura where the tumors feet. develop. Because of their greater 3. Mesothelial Tumors: Primary aerodynamic size, a higher proportion by malignant tumors of the pleura and mass of Transvaal fibers will be peritoneum, formerly regarded as ex- deposited in the larger airways by ceedingly rare by most pathologists, are gravitational settling and hence will being reported more frequently, par- reach the periphery of the lungs with Jicularly among workers exposed to much less efficiency than the_shorter and asbestos dust*. Since Wagner1^ first smajlgsidiametg'r 'fibets of the NorfFi- western Cape. The greater penetration to the deeper alveoli adjacent to the pleura bv the smaller crocidolite fibers could account for differences in in cidence of mesothelioma among workers in the two areas. In addition to the biologic importance of fiber diameter and shape, other factors such as metallic cations and enzvmes present in asbestos dust remain to be evaluated, particularlv in view of the fact that not all mesotheliomas are related to asbestos dust exposure. There have been a varietv of animal studies in which experimentally induced mesothelioma has been reported in dif ferent animals.3' 33 Of particular interest is the study of Roe. Carter. Walters et al3; who produced pleural and peritoneal mesothelioma in mice subcutaneously injected with crocidolite. amosite and chrysolite and thus have shown evi dence of migration of fibers, a finding which helps explain peritoneal mesothelioma in workers exposed to dif ferent asbestos dusts. One noteworthy feature about the oc currence of asbestos mesotheliomas has been the long period, commonly over 30 years, between first exposure to asbestos and appearance of mesothelioma10 -Whitwell and Rawcliffe25 observed that the interval from first exposure to asbestos and appearance of meso theliomas ranged from 13 to hi years with a mean of 42 yeats. They ex pressed the opinion that the incidence of mesothelioma will continue to rise with increasing use of asbestos until about 40 years after adequate protective measures have been taken. Another important feature about mesothelioma in contrast to bronchogenic carcinoma is that cigarette smoking does not appear to be an important factor related to its development. 4. Pleural Calcification: Calcified pleural plaques have been reported among workers exposed to ar.- thophyllite. chrysotile. amosite and tremolite. or mixtures thereof-'*' ~ Multiple or bilaterai pleural piaques are regarded by some investigators as vir tually diagnostic ot asbesiO'-telated diseased however, other causes oi pleural calcification are wt~'< know n. Robinson" found oledrai piaques m 2.7% of 1.829 autopsies performed chiefly upon adult males, 'so relation ship to. typical asbestos _bodiesC degenerative Jlr neoplastic disease orf^ Jourrtal of Occupational Medicine/Vol. 15, No. 37March 1973  f. known infectious disease was discovered. Robinson indicated that pleural plaques should not be con sidered proof of asbestosis nor termed "benign fibrotic mesothelioma". With regard to those occupationally exposed, pleural calcification rarelv ap pears until 20 years after first exposure and does not necessarilv correlate with pulmonary fibrosis. Pleural calcification also aooears to differ in frequency in dif ferent occupationally exposed groups, but studies to date have not explained such differences. The finding of pleural calcification or pleural plaques has been reported as being common in large segments of populations not directly ex posed occupationally to asbestos but living in or near regions where asbestos fibers are being produced and used32 33. There is no evidence that presence of pleural plaques bears any relation to the development of mesothelioma. In Finland and Eastern 'Quebec where a greater frequency of pleural plaques has been reported, there has been no in creased frequency of mesothelioma4. Furthermore, one cannot conclude that presence of pleural calcification is an in dicator of previous asbestos ecposure since ether causes lead to this condition, nor can it be assumed that absence of plaques excludes a history of exposure to asbestos. Effects Related to Quantity of Inhaled Asbestos Ousts 1. Correlation of Environmental Ex posure and Biologic Response: Balzer and Cooper34 reported asbestosis among insulation workers.exposed to levels not exceeding the time-weighted average of 5 mppcf. Chrysotile and amosite were the principal types of asbestos minerals to which the group studied was ex posed. Murohy. Ferris and Burgess et a!7 reported that asbestosis was first ob served in the group thev studied after 13 years of exposure, or about 60 mppcfyears. The highest average concentration was 10.0 mppcf and lowest 0.8 mppef. with an overall average of 5.2 mppcf. Amosite and chrysotile were used but no crocidolite was present. No asbestosis was found in men exposed less than 60 mppef-years. Twenty percent of those exposed for 75 to 100 mppef-years were considered to have asbestosis. No at tempt was made to correlate workers who had asbestosis with the charac teristics of different jobs in the work place nor with time spent on the job. Peak concentrations were not given. In a recent unpublished paper. Williams. Baier and Thomas35 compiled data on exposure levels at various textile processing operations in two plants for 37 years and 20 years, respectively. Even though exposures were mainly below 5 mppcf and in many instances below 2 mppcf. 64 workers were reported to have asbestosis. In an unpublished study. Kteinfeld. Messite and langer* found only one case of pneumoconiosis in a group of 39 workers exposed to commercial talc containing tremolite and anthrophyllite as the major fibrous components, despite a mean exposure of 16.2 years with a range of 11 to 22 years and a time-weighted average of 23.0 mppcf. The mean fiber count, obtained only in 1970. was 34 ' fibers/ml with a fiber length greater than 5 microns/ml. The range varied from a low of 8 to a high of 160 fibers/ml. In a comparative study of talc workers employed in two different plants and exposed to the same minerals, these authors* observed a significantly increased prevalence of pneumoconiosis based on chest roent genograms and clinical findings in the workers who had four times the mean fiber count than the comparative group evert though mean age and average duration of exposure and range were similar for both groups, indicating a dose-response relationship. Enteriine. DeCaufle and Henderson34 recently demonstrated convincing evidence for an exposure-response relationship between chrysotile asbestos, measured in terms of million parts per cubic foot-years (mppef-years). and risk of malignant and non-malignant respiratory disease Specifically, the risk of respiratory cancer increased -frprh166.7 (Standardized Mortality Ratio) at minima) exposures to 555.6 at cumulative exposures in excess of 750 mppef-years. The percentage increase exceeded 300. With regard to nonmalignant respiratory disease, the in creased risk was not only to pneumoconiosis and pulmonary fibrosis but to other diseases of the respiratory system as well. McDonald, Rossiter. Eyssen et al37 reported on 129 primary thoracic neoplasms among 7354 former em ployees in a chrysotile asbestos mine and mill; five of the neoplasms were mesotheliomas. Although the authors concluded that even heavy asbestos ex posure earned only a modest risk of con- ' trading lung cancer and an even lesser risk of contracting mesothelioma, Selikoff3* in commenting on McDonald's "heavily exposed" group stated that these workers demonstrated five times as much lung cancer as the group of "lightly exposed" workers. Whereas bronchial cancer is more dearly related to intensity of exposure, data on mesothelioma are less certain with regard to the influence of quantity. There are many examples where ex posure has been short, though not necessarily slight10. As mentioned by Wagner, Gilson, Berry et al10, mesothelial tumors apparently occur more frequently in the peritoneum than In the pleura when the exposure has been extensive, but the route of entry of dusts into the abdomen is not known. Epidemiological studies show that there is much clearer evidence of risk of mesothelioma varying with type of asbestos than in the case of bronchial carcinoma. The study of Kiviluoto and Meurman19 provides evidence that exposure to anthophyllite very rarely causes mesothelioma. The very long period that elapses between first exposure and development of mesothelioma has prevented an estimate of what proportion of an exposed group develops mesothelial tumors. Wagner, Gilson, Berry et al10 believe that the proportion is likely to be fairly small, much less than that following exposure to bladder carcinogens for example. As true for pleural caldfication, not all pleural mesotheliomas are relatabie to exposure to asbestos; there are presumably other causative factors. This makes interpretation of the relationship between asbestos ecposure at a low level and mesothelioma difficult. There is need for more prospective studies on the quantity as well as type of asbestos bur den in the lung and occurrence of mesothelioma. 2. Mortality Experience From Lung Cancer, Asbestosis and Other NonMalignant Respiratory Diseases: Studies of the mortality of workers in different asbestos industries and trades and dif ferent asbestos dust exposures3 16 17 19 39 40 indicate that past exposure to different asbestos minerals Has contributed to an excess of mortality of-cancer of the lung, - 298 >e to Kind and Amount of Asbestos/KleinfelcT lii i l | \ i i i i i ii \ \ i 1 i it - pleura and peritoneum and its com plications. and non-malignant respiratory disease over the general population. In several studies an excess of deaths from gastrointestinal malignancy2 14 has been reported. Studies on mortality experience paint up the importance of etapsed time from initial exposure and duration and degree of exposure as factors which increase the risk of malignant and non-malignant respiratory disease In some instances where exposure was of short duration but degree was relatively high, there was an excess of observed deaths from can cer of the lung and pleura and cancer of other sites compared to the number ex pected. Knox. Holmes. Doll el al40 found, in a preliminary report, that after dust controls were introduced in a British asbestos textile plant during the 1930's, the incidence of respiratory can cer fell from a tenfold excess to a rate similar to that in the general population. Mancuso and El-Attar17 in their study of asbestos workers observed that the risk of pulmonary cancer varied with em ployment duration: in most instances as the level of employment experience in creased. mortality rate of pulmonary cancers increased. With regard to type of asbestos. Kleinfeld, Messite. Kooyman et alJ observed an excess of mortality from cancer of the lung and pleura among talc workers ex posed to a mixture of talc and tremolite. A significant increase in incidence ap peared in the oldest age group, 60 to "9 years rather than in the middle age group. 40 to 59 years. This was at variance with their findings among asbestos insulators exposed to chrysotile and amosite whose duration of exposure was similar to that of the talc workers. Among the asbestos insulators there was an increased incidence of lung and pleural cancers in both middle and oldest age groups. There was no excess of carcinoma of the gastrointestinal tract and peritoneum in talc workers whereas in asoestos workers, gastrointestinal and peritoneal malignancy v.as significantly increased compared to the general population, as also observed by Selikoff. Hammond and Churg.1'' Discussion and Conclusion Animal studies have been useful in ..illuminating certain factors that explain the biologic action of asbestos: howeve a precise animal mode* from which to derive a dose-response relationship for extrapolating risk factor? in producing disease is lacking. Unfortunately, the amount of asbestos dust required to produce pathologic effects in animals is unusually large in proportion to amounts to which man is exposed. Hence, animal data which have shown different respon ses to different'types of asbestos9 * can not be used as a basis for drawing firm conclusions as to the relative pathogenicity of different tvpes of asbestos in man. One major impediment in evaluating the relative pathogenicity in man is the fact that in most instances industrial exposures are not solelv to one type of asbestos mineral but rather to a mixture of several plus metals and oils and possibly other minerals. There are only a few studies which relate malignancy in exposed groups to a single type of asbestos1*-Most epidemiological studies that appear to indicate differences in pathogenicity among types of asbestos contain flaws in that they lack quantitative data on cumulative exposures, fiber charac teristics. and presence of cofactors. Therefore, it is difficult to grade different types of asbestos as to relative pathogenicity with regard to either asbestosis or neoplasia. Studies to date indicate that both shape and size of asbestos fibers are significant factors in determining respirability, deposition, retention, and clearance from the pulmonary tract and thus are important determinants of the site and nature of tissue response. The importance of fiber diameter and length in explaining the disparity in the pre valence of mesothelioma in the North western Cape and that of the Transvaal region of South Africa has been strengthened by the study of Timbrell. Griffiths and Pooley20. The curly'shape of the chrysotile fiber offers an explanation of its interception by the .bronchi especially at bifurcations in contrast to amphibole fibers which are needie-like and may, therefore, reach more deeply into the lung parenchyma and pleura. Since one of the amphiboles. namely, anthophyllite. has rarelv been associated with mesothelioma production, factors other than shape and size must be con sidered. Until recently_roost work and specu-" lation involved only fibers^dcrected by; Jhe *3fftrcaJ_ - or ligTtt microscope. . ` ~t---- S7Marcf * There is no gene'c!*v accepted basi- that permits assignme"* of relative risk factors to fibers in the electron microscope range compared :o fibers in the light microscope range. Suzuki and Churg41 contend that submicroscopic fibers are responsible for most of the biologic changes produced by asbestos. Other in vestigators have also pointed out that the fine dust particles below 1 micron in length mav be just as damaging as dust particles containing both large and small fibers.42 Gross45 informed us that inhalation of :he submicroscooic asbestos fibers experimentally produced only a phagocvtic response; he does not believe that submicroscopic fibers are responsible for the more extensive biologic changes produced bv asbestos. It is possible mat the relative risks associated with fibers of different sizes are different for maligna'nt and nonmalignant changes. Further studies bearing on this matter are necessary. Kleinfeld. Messite and Langer* found that the nature of the Gust samples analyzed indicated that fiber counts of aerosols did not provide a true picture of ex posure to asbestirorm minerals because they included taic fibers but excluded many small asbestos fibers and "aggregate fibers" which contained sub stantial amounts cf asbestiform minerals, namely, tremolite and anthophyllite. In light of recent observations, one cannot exclude :he influence of cofac tors on biologic effects as a major deter minant of pathogenicity. Dixon. Lowe. Richards et al14 postulated that asbestos fibers probablv serve as vectors in producing disease by carrying toxic or oncogenic substances to vulnerable sites. Relevant studies included analysis of various types c-: asbestos to determine components present in each with special emphasis on metals and polycvclic hydrocarbons44 4L The present con sensus is that contaminants are present but that identification of a specific pathogenetic roie tor them requires rurther study. If suosequent investigations verify that trace metals and other trac tions of the various types of asbestos dust do in fact piay a maior role in producing asbestosis or neoplastic diseases customar.n. associated with ex posure to asbestirorm ''mineral Cusk then existing standards governing ex posure to- asbes: rorm minerals in ;ne United .States, and Great .Britain--un-. doubted!y"wtll-be subiect to resision References I. Asbestos: The need for and feasibility of air pollution controls. Panel on Asbestos. Committee on Biologic Effects of Atmospheric Pollutants. Washington. DC. Division of Medical Sciences. National Research Council. 1971. X SHikoit II. Hammond EC. Qxng fc Mor tality experiences of asbestos insulation workers. 1943-1 %8. pp. 180-186. In H.A. Shapiro. Ed. Pneumoconiosis. Proceedings of the International Conference, lohannesbutg. 1969. Cape Town: Oxford University Press. 1970. 3. Kleinteld M. Messite I. Koovman O. et al: Mortality among talc miners and millers in New York State. Arch Environ Health 14:663667. 1967. 4. Wright GW: Asbestos and health in 1969. Am Rev Resp Dis 100:467-479. 1969. 5. Holt PF. Mills 1. Young DK: Experimental asbestosis in the guinea-pie. / Path Bact 92:185-195. 1966. 6. Morris TG. Roberts WH. Silverton RE. et al. pp. 2.205. In CN. Davies. Ed. Inhaled Par ticles and Vapours. Pergammon Press. London-Paris. 1969. 7. Murphy RIH. Ferris BG. Burgess WA. et al: Effects of low concentrations of asbestos. New Engl I Med 285:1271-1278. 1971. 8. Kleinteld M, Messite L Unger AM: A study of workers exposed to aSbestiform minerals in commercial talc manufacture. To be published. 9. Weiss W: Ggarette smoking, asbestos and pulmonary ftbrost- Am Rev Resp Dis 104:223-227. l`97l. 10. Wagner 1C. Gilson 1C Bern- G. et al: Epidemiology of asbestos cancers. Brit Med Bull. 27:71-76. 1971. II. Braun DC. Truan TD: An epidemiological study of lung cancer in asbestos miners. Arch Ind Health 17:634-653. ]958. 12. Enterline P. OeCoufle P. Henderson V: Mortality in relation to occupatronai exposure in the asbestos industry. Presented at the American Industrial Hygiene Conference. San Francisco. California. May 16. 1972. 13. Selikoff II. Hammond EC Churg J: Asbestos exposure, smoking and neoplasia. IAMA 204:106-112. 1968. 14. Dixon |R. Lowe DB. Richards OE. et al: The role of trace metals in chemical car cinogenesis: asbestos cancers Cancer Res 30:1068-1074. 1970. 15. Wagner !G Epidemiology of diffuse mesothelial tumors: evidence of an association from studies in South Africa and the United Kingdom Ann NY Acad Sci 132:575-578. 1965. 16. Selikoff II. Hammond EC Churg fc Mor tality experience of amosite asbestos factory workers. Presented at the [Vth International Pneumoconiosis Conference. Bucharest. Sep tember 29. 1971. 17. Mancuso TF. El-Attar AA: Mortality pat tern in a cohort of asbestos workers. / Occup Med 9:147-162. 1967. 18. Wagner IG Current opinions on the asbestos cancer problem. Ann Occup Hyg 15:61-65. 1972. 19. Kiviluoto R. Meurman L: Results of asbestos exposure in Finland, pp. 180-186. In H.A. Shapiro. Ed. Pneumoconiosis. Proceedings of the International Conference. Johannesburg. 1969. Cape Jown: Oxford University Press. 1970. < 20. Timbretl V. Griffiths DM. Poolev FD: Possible biological importance of fibre diameters of South African amphiboles. Nature 232:55-56. 1971. 21. Wagner 1C Experimental production of mesothelial tumors of the pleura by im plantation of dusts in laboratory animals. Nature 196:180-181. 1962. 22. Wagner 1C Berry G: Mesotheliomas in rats following innoculation with asbestos. 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Selikoff It The occurrence of pleural calcification among asbestos insulation workers. Ann NY Acad Sci 132:351-367.1965. 31. Robinson It Pleural plaques and splenic capsular sclerosis in adult male autopsies. Arch Path 93:118-122. 1972. 32. Kiviluoto R: Pleural calcification as a roentgenologic sign of non-occupational en demic anthophyllite-asbeslosts. Acta Radial Suppl 194:1-67. 1960. 33. Anspach M: Sind pleuraverkalkunsen pathognomonisch fur eine asbestosef Int Ar:h Cewerbepath Cewecbehyg 19:108-120. 1962. 34. Baker IL, Cooper WC The work en vironment of insulating workers. Am Industr Hyg Assn I 29:222-227. 1968. 35. Williams. Baier and Thomas: Un published data referred to in Occupational Ex posure to Asbestos. National Institute for Oc cupational Safety and Health. Health Services and Mental Health Administration. Public Health Service. US Department of Health Education and Weliare.'Publication HSM "210267. pp. 111-21.22. 1972. 36. Enteriine P, DeCoufle P. Henderson V: A study of the dose-response relationship be tween asbestos and lung cancer. Unpublished manuscript. 37. McDonald 1C Rossiler CE. Eys'sen C. et al: Mortality in the chrysolite producing in dustry of Quebec a progress report presented at IV International Conference on Pneumoconiosis (ILO| . Bucharest. 1971. 38. Selikoff If: Mount Sinai School of Medicine. Gty University of New York, per sonal communication. 1971. 39. Newhouse ML: A study of the mortality of workers in an asbestos factory. Brit I Industr Med 26:294-301. 1969. 40. Knox IF. Holmes S, Doll R. et al: Mor tality from lung cancer and other causes among workers in an asbestos textile factory. Brit I Industr Med 25:293-303. 1968. 41. Suzuki Y. Churg fc Structure and development of the asbestos body. Am / Pathol 55:79-91. 1969. 42. Davis IMG: Electron microscope studies of asbestosis in man and animais. Ann NY Acad Sci 132:98-111. 1965. 43. Gross P: Personal communication. 44. Galley- LI. Keenan RG. Kupel RE. et al: Characterization and solubility of metals associated with asbestos libets. Am Industr Hyg Assoc I 29:569-573. 1968. 45. Harington IS. Roe FIG Studies of car cinogenesis of asbestos fibers and their natural oils, Ann NY Acad Sci 132:439-450. 1965. 300 BiologifeJBjgSDfln.^eJg. Kind j^LAmount of'Asbestos/KTeinfeid