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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