Document KGOdmMyZ09vyJvbL6pnzOOpqQ

VDI-n*'ichte Nr. 475, 1983 INFORMATION EXCHANGE CENTER PRICE GILBERT MEMORIAL LIBRARY GEORGIA INSTITUTE OF TECHNOLOGY ATLANTA. GEORGIA 30332-0900 241 Notice. Tkls Material May be Protected by Copyrig;' law (Title 17 U. S. Cod.) Carcinogenic effect of mineral fibres in inhalation studies By J. M.G. Davis* Since the discovery by Lynch & Smith ( 1 ) end dose resulting from variations in the period of Wagner et al ( 2 ) that asbestos fibres cause both exposure. For these experiments exposure periods bronchial carcinomas and mesotheliomas in asbestos of one day, three months, six months, twelve months workers, many animal experimental studies have been and twenty four months had been used. If the total undertaken in order to determine how these dusts number of lung tumours was considered, it was found exert their carcinogenic effects. Although Wagner that for all the asbestos types, there was a moder in I960 ( 3 ) showed that mesotheliomas could be ately good dose response effect. An occasional produced in experimental animals by intrapleural tumour was produced after only one day's dusting injection, early attempts at producing tumours by but from three months onwards tumour numbers in inhalation techniques were unsuccessful, probably creased with dose. However, a breakdown of the because they were not continued far a sufficiently tumour types produced revealed an interesting long time. However, in 1967 Gross et al ( 4 ) finding. The maximum number of benign adenomas had exposed rats to very high levels of chrysotile dust been produced for all dust types by only three months and produced large numbers of tumourb, mostly adeno of dusting and in some cases increasing the dose carcinomas. Similar results were reported by beyond this point greatly reduced the number of Reeves et al in 1971 and 1974 ( 9 & 6 ) and Wagner adenomas. For adenocarcinomas, .however, the number et al in 1974 ( 7 ) Wagner's study used the UICC of tumours increased up to twelve months of dusting reference samples of chrysotile, crocidolite, amosite but there was little difference between twelve and and anthophyllite was large enough for detailed com twenty four months. For squamous carcinomas on the parisons to be made between the carcinogenic effects other hand, by far the majority of these tumours of the different dust types. It was found that developed from animals dusted for twenty four months. Rhodesian chrysotile produced the most bronchial From this it is possible to conclude that while a carcinomas and amosite the least. Canadian chryso moderate dose of asbestos is sufficient to produce tile, crocidolite and anthophyllite all showed simi adenomas, larger doses produce carcinomas with lar levels of carcinogenicity. Only a few meso squamous carcinomas in particular being the response theliomas were produced with Canadian chrysotile and crocidolite producing slightly mare than amosite and anthophyllite idiile Rhodesian chrysotile, which pro duces the most carcinomas, produced none at all. to excessive dust. At present there is no evidence as to whether all rat lung tumours start as benign adenomas which only progress if the carcinogenic stimulus is maintained or whether prolonged dusting The surprising factor in these results was that causes tumours that are malignant from the start. crocidolite had been assumed from human studies to be the most carcinogenic type of asbestos, especially in relation to mesothelioma production, and this was not confirmed. The results from these inhalation studies did, however, agree with previous work by Wagner et al in 1973 ( 8 ) using injection techniques where crocidolite had again appeared to be no more carcinogenic than chrysotile. From '.'agner's inhalation studies seme interesting data were produced regarding the effects of dust While Wagner had studied the effects of dust doses graded by time, Davis et al in 1978 ( 9 ) used con stant exposure periods to explore the effects of mass versus fibre number for the UICC samples of crocido lite, amosite and Rhodesian chrysotile. At both equal mass, which at 10 mg/m^ was the same as the dose used by Wagner, and at equal fibre number where the mass doses of chrysotile, crocidolite and amosite were respectively, 2 mg, 5 g and 10 mg/a^, it was found that chrysotile was the most carcinogenic J.M.G. Davis, M.fl., Ph.D., Institute of Occupational duat. Both the chrysotile dust clouds had produced Medicine, 8 Roxburgh Piece, Edinburgh EHB 9SU/U.K. significai,tly more pulmonary adenomas and chrysotile 10002973 242 VDIBerichte Nr. 475. 1 as the only dust to produce carcinomas. (The more carcinogenic than amosite considering the numbers of tumours produced in this and subsequent different mass doses. Further inhalation studie inhalation studies by this group are listed in were reported by Davis et al in 1980 ( 11 ) in TABLE 1). As with Wagner's work, there was - which samples of ehrysotile and amosite dust less mass dose effect for adenoma production, where collected from the factory environment were admin, the 10 mg and 2 mg ehrysotile clouds had produced stered to rats. Unfortunately each sample was c seven and six tumours respectively than for carcino taminated by non-asbes ton material, especially the mas where the equivalent figures were eight and two. ehrysotile, so that while the respirable mass of t While dust clouds of equal fibre number had been pro dust clouds was the standard 10 mg/m^ of air, the duced by counting all fibres > 5 m in length, it was asbestos mass was only 8 mg and 9 mg for the chryt found that the ehrysotile cloud had the highest tile and amosite respectively. The factory chrys number of fibres over 20 urn in length and it was tile fibres were fewer in number but thicker than suggested that this was probably the reason for the VICC ehrysotile #iile the factory amosite fibres increased carcinogenicity of this material* tended to be both longer and thicker than VICC amo In 1980 Davis et al ( 10 ) further explored the effects of asbestos dose on tumour production using the VICC reference samples of both amosite and Rhodesian ehrysotile. In this study the same mass of each dust was administered for a year either at an even dose level over a five day week or as a peak dose all administered on one day during the week. Since there is a limit to the respirable mass that can be produced with a ehrysotile cloud before dust site. With the ehrysotile once again, the lower dose of factory dust ( 6 mg ) had produced as many benign adenomas as previously found with a higher dose ( 10 mg ) of UICC ehrysotile while the number of carcinomas was reduced in the experiment using factory dust. The amosite studies confirmed the . carcinogenicity of this material in rats since no tumours at all were produced by the factory amositi dust. flocculation begins to produce non-respirable In injection studies Wagner et al ( 8 ) had found particles, the ehrysotile study had to be undertaken that a specially well separated 'superfine' sample 4 at a baseline dose of 2 mg/m^ while the amosite base of ehrysotile was the most carcinogenic of a numbe: line used was 10 mg/m^ to give a better comparison or asbestos samples examined. In i960 ( 12 ), the with previous studies. Little or no difference in tumour production was seen between the peak and even dosing regimes but once again ehrysotile appeared same authors reported Inhalation studies in which the effects of this 'superfine' material had been compared with UICC Canadian ehrysotile and a fine ' commercial grade of Canadian ehrysotile which most Table 1. Ti/nour production during long-term inhalation studies in which rats were treated with a lumber of samples of asbestos and other mineral fibres. Davis et al. t978-82 closely compared to the 'superfine' specimen. . In this study the UICC ehrysotile sample produced the V- 10002974 VDI-Berichte Nr. 475, 1983 243 most adenomas and toy far the most carcinomas, a either by chemical dissolution or mechanical clear finding which appeared to toe related to a much ance. Chrysotile may survive long enough in rat higher number of fibres greater than 5 M in length lungs to produce tumours but be removed from human in this sample. These results suggest that Pereas lungs during the very much longer period required the number of long fibres may toe very important in for tumour induction in this long lived species. producing pulmonary tumours, they are less so in injection studies. However, since the dust samples in this study were sized only after collection from the dust clouds on nuclepore filters it is possible that the fibres in the material used for injection were different. In recent years there have been suggestions that some of the harmful effects of asbestos and especially chrysotile might be due not to the main commercially exploited mineral but to relatively small amounts of mineralogical impurities. Two such impurities frequently found are tremolite and brucite and In 1981 Davis et al ( 13 ) reported the results of studies using these materials have been undertaken inhalation studies with chrysotile prepared by the wet dispersion process. This material produces in Edinburgh toy Davis et al ( 14 ) Rats were treated with the standard 10 mg/m^ dose and pulmonary very little dust when handled in industrial pro cesses and the maximum respirable dust cloud that tumours were produced in tooth studies. However, while the number of tumours in the Brucite study was could be generated from it in experimental conditions low, tremolite produced more than previously reported was 4 mg/m^ of air. This dust was administered to from any similar study. This may indicate that two groups of rats with one group dusted using a chrysotile samples containing significant amounts of reversed dayli^it regime so that the animals were in tremolite should toe treated wit), caution. their most active phase while inhaling dust. This procedure was adopted because it was believed it would lead to a higher level of pulmonary dust de position. In practice this did not occur tout it was found that in both groups of rats the 4 mg dose of wet dispersed chrysotile had produced as many pulmonary tumours as previously found with UICC chrysotile at a dose level of 10 mg/a} of air. Electron microscope studies of lung tissue from seme of the animals treated with wet dispersed chrysotile indicated a possible reason for this high level of carcinogenicity. It was found that all the chryso tile fibres had separated into individual fibrils, many of which retained a length of more than 10 pm. Thus the number of fib*c units within the tissue was for hijjier th^n in the du:t cloud. Because of the accepted hazards of asbestos usage, industry has, riiere possible, substituted alternative fibrous materials especially man-made fibres and a number of animal inhalation studies have been under taken in order to determine if these materials are completely safe. Early studies by Cross in 1978 ( 15 ) end lee in 1969 ( 18 ) showed no carcinogenic effects in rats following prolonged inhalation of glass fibre. However, recently a number of reports were presented at the same scientific meeting where the results were more positive. Vagner ( 17 ), McConnell ( 18 ), Smith et al ( 19 ), lee and Reinhardt ( 20 ) and Davis et al ( 21 ) between them examined the effects on experimental animals ( mainly rats ) of a number of glass fibre samples, slag wool, rock wool and ceramic fibre. Small numbers of These results raised the interesting possibility that the high carcinogenicity of chrysotile in almost all published animal experiments might be due to some degree of fibril separation within the tissues, a phenomenon which may be more complete with wet dis persed chrysotile but not unique to this material. If this is sc then the tissue dose of chrysotile fibre units would always be higher than indicated by examination of the dust cloud. If this occurs in rats it must also occur in humans and yet here the epidemiological evidence suggests that chrysotile may actually be less carcinogenic than the amphiboles. pulmonary tumours were produced by most materials. The numbers were too low in most cases for detailed statistical comparisons tout since spontaneous pul monary tumours are extremely rare in rats the finding of even a few suggests the possibility of some hazard to workers if factory dust levels are uncontrolled. It was reported, however, that standard boron sili cate glass fibres at least showed considerable evidence of solubility in tissue fluids and this phenomenon, as with chrysotile asbestos,may limit the hazard to humans where the tumour induction period is so much longer than in rats. It may be that while chrysotile is potentially the most carcinogenic asbestos type, the fact that it To summarise the results of animal inhalation studies with mineral fibres to date it may be said tends to separate into individual fibrils in tissues that while there has not been complete agreement a also makes it the most easily removed from the lungs number of trends have emerged. Thus all the main 029p5 244 VDI-Berichte Nr. 475. 1 asbestos types show a dose response effect when Where the same dust has been used more than once l different mass dose levels have been used. However, similar studies in the same laboratory, agreement there appears to be a plateau effect above which appears to be much closer. Thus Wagner et al ( 7 further increases in dose do not increase tumour and ( 12 ) used UICC Canadian chrysoti le^ at the. sa numbers. Die plateau for benign pulmonary tumours dose level and produced closely comparable numbers appears to be lower than for carcinotsas. In general of pulmonary tumours (TABLE 3). Only the dust clouds containing very large numbers of fibres number of pleural oesotheliotaas differed noticeabl greater than 5 urn in length appear to be the most in the two studies, with three occurring in the carcinogenic but there are exceptions especially with first and none in the second. In their studies chrysotile materials. With these there is evidence with wet dispersed chrysotile, Davis et al ( 13 ) to suggest that fibril separation in the lungs treated two groups of rats with the same dust dose. produces a far higher number of fibres in the tissues Although one group waa dusted using a reversed day than would be expected from the original dust clouds. light regime the lung dust burden was not signifi Where similar dusts have been used at the same dose in different laboratories, the results have sometimes been different. lhus Wagner et al ( 7 ) and cantly changed by this approach and the number of both benign and malignant pulmonary tumours was almost identical (TABLE 3). Davis et al ( 9 ) both used UICC crocidolite, amosite It would appear, therefore, that the rat at least and Rhodesian chrysotile at dose levels of 10 mg/m^ provides a useful model far examining the carcino of air for a one year exposure period. from all genic potential of dusts administered by inhalation these dusts Wagner produced noticeably more tumours and indeed Davis et al failed to produce any malig and that the same exposure conditions will produce consistent results when the same material is tested nant tumours with the UICC amphibole samples. an more than one occasion. This model will Similar dust generators were used by both groups but obviously be useful in the future for screening new data was not available for the fibre length distribu mineral fibres that come into industrial use, but i tions of all the dust clouds (TABLE 2). It should also prove useful in studies of the tumour may be that subtle changes in dust generation pro induction process itself. In this field, perhaps cedures had resulted^in dust clouds with a substanti the most important area where new studies should be ally different fibre length. It is also possible undertaken concerns the importance of fibre length. that the strain of rats used by Wagner was more sus While Stanton et al ( 22 - 24 ) determined that ceptible to carcinogenesis than the one used in following intrapleural implantation, the most car- Edinburgh. Table 2. Tumour production in long-term inhalation studies under taken in two different laboratories. The UICC samples of Rhodesian Chrysotile, Amosite and Crocidolite were used at the same dote level on both occasions Watmer et al 1974 Davis et al 1978 Dust type and mass dose UICC Rhodesian Chrysoti le 1C sg/a>3 UICC Amosite 1C ag/m^ UICC Crocidolite 10 mg/m^ vice Rhodesian ChryLOtile 10 ag/o3 rice Amosite 10 mg/m$ UICC Crocidolite 10 ag/m^ Fibre number/nl of air > 5 MR Adenomas Total carcinomas Adenocarcinomas not quoted 2 13 7 Squamous carcinosis Mesotheliomas 6 0 not quoted 5 I 1 0 o not quoted 5 9 3 6 2 1950 7 8 6 2 0 550 860 21 c0 00 00 0 0 10< ________________ 1  VDI-Berichte Nr. 475, 1983 Table 3. Tiiaour production In long-term Inhalation studies where the sane dust type was tested on two occasions Dust type and mass dote Vagner et al 1974 U1CC Chrysotile B 10 mg/m' Wagner et al 1980 DICC Chrysotile B 10 mg/i3 Davia et al 1980 Wet dispersed Chrysotile 4 mg/m3 Wet dispersed Chrysoti le 4 (reversed daylight) Fibre nuaber/ml of air >5 Adenonas Total carcinomas not quoted 1 7 3750 0 5 111 7 10 117 5 12 Adenoearcinomas Squamous careinoaas Kesothelloaas 6 1 3 25 35 04 5 7 1 245 cinogenic fibres were those > 8 pm in length and < 1.5 |>a in diameter, this finding has not really been confirmed in Inhalation studies. In addition, while Stanton showed that long fibres were more car cinogenic than short, he was unable to prove that short ones were either completely safe or only rela tively so. Delay in settling these points has resulted entirely from the difficulty in producing mineral fibre samples in uniformly short lengths, especially in the large quantities needed for inhala tion studies. However, to some extent at least, these problems are being overcome and future studies should settle the points in question. References Asbestosis. The development of lung cancer in rats with pulmonary deposits of chrysctjle asbestos dust. Archives of Envircnmental Health 15 (1967), p. 343/355- ( 5 ) REEVES, A.L., fl.E. FURO., R.C. SMITH., and A.J. VCRYALD: Experimental asbestos carcinogenesis. Environmental Research 4 (1971), p. 496/511- ( 6 ) REEVES, A.L., H.E. FURO., and R.C. SMITH: Inhalation Carcinogenesis from various forms of asbestos. Environmental Research 8 (1974), P* 178/202. ( 7 ) WAGNER, J.C., G. BERRY., J.W. SXIIKORE., and V. TIKBRELL: The effects of the .nhalation of asbestos in rats. British Journal of Cancer 29 (1974), P. 252/269. ( 1 ) LYNCH, K.K., and V.A. SMITH: Pulmonary asbestosis III. Carcinoma of lung in asbestossilicosis. American Journal of Cancer 24 (1935)t P. 56/64. ( 6 ) WAGNER, J.C., C. BERRY., and V. TIMBRELL: Mesotheliomata in rats after inoculation with asbestos and other minerals. British Journal of Cancer 28 (1973), P- 173-165- ( 2 ) WAGNER, C.J., C.A. SLEGGS., and P. MARCHACT: Diffuse pleural mesotheliomata and asbestos exposure in the North Western Cape Province. British Journal of Industrial Medicine 17 (i960), p. 260/271. ( 3 ) WAGNER, J.C.: Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals. Nature, London 196 (i960), p. ieo/iei. ( 4 ) CRCSS, P..R.T.P. D TREVILLE., E.B. TOUCH., H. XASCKAX., and M.A. BABYAX: Experimental ( 9 ) DAVIS, J.M.C., S.T. BECKETT., R.E. BC1TCN., P. COLUNCS., and A.P. MIDDLETON: Mass and Number of Fibres in the Pathogenesis of Asbestos Related Lung Disease in Rats. British Journal of Cancer 37 (1978), p. 673/687. ( 10 ) DAVIS, J.I.C., S.T. BECKETT., R.E. BCLTON., and K. DONALDSON: The effects of Intermittent High Asbestos Exposure (Peak Dose Levels) on the Lungs of Rats. British Journal of Experimental Pathology 61 oseo). p. mm3. 10002977 * .r* -V` ;* :* --t 1r .1. .v- A.V . *i *sX> 246 VDI-Berichte Nr. 475. 1 ( 11 ) DAVIS, S.T. BECK2T7., H.E. BCITCN., and K. DcriLDSOI.': A comparison o' the Pathological Effects in Rats of the UICC Reference Samples of Amcslte ar.i Chrysotile with those of Amosite and Chrysotile collected from the Factory Environment. In: Biological Effects of Mineral Fibres (Ed. J.C. Wagner) IARC Scientific Publication No.30 (1980), 0. 285/292. ( 12 ) WACHER, J.C., C. BERRY., and J.W. SKIDUORE: The Comparative Effects of Three Chrysotiles by Injection and Inhalation in Rats. In: Biological Effects of Mineral Fibres (Ed. J.C. Wagner) IARC Scientific Publication No.30 (19C0), P* 285/292. { 13 ) DAVIS, J.M.C., R.E.BOLTON., X. DONALDSON., A. WRICKT., and A.D. JONES: Inhalation studies in rats using dust samples from chrysotile asbestos prepared by a wet dispersion process. Paper presented at XX International Conference on Occupa tional Medicine, Cairo. Conference report in press (1981). ( 14 ) davis, j.k.g., j. adetson., r.e. bolton., K. DONALDSON., A.D. JONES., and A. WRIGHT: The effects of long term Inhalation of Treraolite and Brucite on the lungs of rats (1982). To be published. ( 15 ) CROSS, P: The effects -of fibrous glass dust on the lungs of animals. In: Occupational Exposure to Fibrous Class. Proceedings of a Symposium Sponsored by NICSK. (DREW Publication No.NIOSH 76-151), (1??6;,P. 169/178. ( 16 ) LEE, X.P., C.E. BAWAS., F.D. GRIFFITH., and R.S. NARIT2: Pulmonary response to glass fiber by inhalation exposure. Laboratory Investigation 40 (1979), p. 123/133- ( 17 ) WAGNER, J.C: Effects of Inhalation and Intra pleural Inoculation of Man Made Mineral Fibres in Rats. Paper presented at WHO Conference on the Biological Effects of Man Made Mineral Fibres, Copenhagen (1982). Conference report in press. ( 18 ) McCONNELL, E.E: Comparable Effects of Inhe tion of Man Made Mineral Fibres in the USA and IT:. Paper presented at WHO Conference on the Biologies Effects of Man Made Mineral Fibres, Copenhagen (15Conference report in press. ( 19 ) SMITH, D.M., L.W. ORITZ., and R.F. ARCHUIZT Chronic Exposure of Laboratory Animals to Inhaled Small Diameter Class Fibres. Paper presented at Conference on the Biological Effects of Man Made V_ eral Fibres, Copenhagen (1982). Conference repor in press. ( 20 ) LEE, K.P., and C.F. REINHARDT: Biological Studies on Other Man Made Mineral Fibres. Paper presented at WHO Conference on the Biological Effec of Man Made Mineral Fibres, Copenhagen (1962). Conference report in press. ( 21 ) DAVIS, J.M.C., R.E. BOLTON., K. DONALDSON., A.D. JONES., and A. WRIGHT: The effects of inhala tion of ceramic Aluminium Silicate Fibres in Rats. Paper presented at WHO Conference on the Biological Effects of Man Made Mineral Fibres, Copenhagen (196 Conference report in press. ( 22 ) STANTON, M.F., and C. 7r3ICK: Mechanisms of mesothelioma induction with asbestos and fibrous glass. Journal of the National Cancer Institute 48 (1972), p. 797/821. ( 23 ) STANTON, M.F., M. LAYARD., A. TECSRIS., E. KILLER., M. KAY., and E. KEXT: Carcinogenicity of fibrous glass: pleural response in the rat in relation to fiber dimension. Journal of the National Cancer Institute 58 (1977), p. 567/6C3. ( 24 ) STANTON, M.F., and K. LAYARD: The Carcino genicity of Fibrous Minerals. Definitions and Measurement Methods. (Ed. Gravatt CC et al) National Bureau of Standards Special Publication 5C (1978), P. 143/151- 10002978