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Ann. occup. Hyg., Vol. 26, Nos. 1-4, pp. 417-422, 1982. Printed in Great Britain. Inhaled Particles V 0003-4878.82/010417-06S03.0C/Q Pergamon Press Ltd. i' 1982 British Occupanonal Hygiene Society. MINERAL FIBRE CONTENT OF LUNG IN MESOTHELIAL TUMOURS IN NORTH AMERICA A. D. McDonald*, J. C. McDonald! and F. D. PooleyJ *St. Mary's Hospital Medical School, London +TUC Centenary Institute of Occupational Health, London School of Hygiene & Tropical Medicine, London, England ^University of Cardiff, Cardiff, Wales Abstract--In a survey through pathologists of all fatal malignant mesothelial tumours in North America in 1972,274 cases were ascertained and case-control studies were carried out. Specimens of lung tissue were obtained for 99 (76 male and 23 female) of the 172 autopsied case-control pairs and were analysed for asbestos fibres by electron microscopy and X-ray energy-dispersive analysis. Equal quantities ofchrysotile fibres were found in cases and controls. An amosiie fibre content of more than 1 x It1' per g dried lung was found in 2ft male cases and 8 controls and of crocidolite in 15 cases and 5 controls. The two men who had ever worked in an asbestos factory, 6 of the 8 who had worked as insulators and 9ofthe 14who had worked inashipyard had morethan 1 x 106 fibres of one or both of these amphiboles. In the 23 female pairs studied, there was a small excess of amphiboles (3 cases and 1 control) and of chrysotile (23 cases and 17 controls) in cases compared with controls. , INTRODUCTION An association between malignant mesothelial tumours and exposure to asbestos was first recognized in about 1960. With the aim of studying the incidence of these tumours in Canada and their association with occupational exposure to asbestos and other possible agents, we began in 1966 to ascertain and register all cases in Canada. We communicated with all pathologists who were members of the main Canadian pathological societies asking for information about all cases diagnosed since 1959. By further letters and telephone calls we obtained a reply from every pathologist. This procedure was repeated in 1970, and in 1973, using the same methods, we surveyed the entire U.S.A. and Canada; this involved communicating with over 7000 pathologists. We carried out case-control studies of the cases registered by methods which have bHf described (McDonald et al., 1970) and with results recently summarized (McDonald and McDonald, 1980). In brief, for each case a control was selected with pulmonary metastases from a primary tumour other than lung cancer and matched for sex and age. Relatives and friends of the deceased patients were interviewed by field investigators who were ignorant of whether they were cases or controls. They completed a standard questionnaire which included a full occupational history. This was coded `blind" hv clerks, using a classification described elsewhere (McDonald, 1979). In ail. 274 mesothelial tumours were ascertained in North America in 1972. 102 diagnosed at biopsy and 172 at autopsy. These 172 autopsied mesothelial tumours (129 in males and 43 in females) and their matched controls are the subjects of this study. NOTICE: THIS MATERIAL MAY BE protected by COPYRIGHT {TITLE 17 U.3. CODE) 417 HWBUI0002094 METHODS Specimens oflung were sought from pathologists for all 172 cases and their matched controls. Pieces of lung tissue (in paraffin or formalin) were obtained for 99 case-control pairs (76 male and 23 female). For the remaining 73 pairs, no lung tissue was available for the case or the control or both. However, the cases studied resembled the whole series in terms of asbestos-related occupations except for relatively fewer asbestos factory workers because ofa lack ofmaterial from New Jersey. Before analysis, cases and controls were assembled in random order in one series and renumbered; the analyses were thus carried out `blind'. They were analysed in five batches, constituted in the order in which specimens were received, the two members of a case-control pair being included in the same batch. The lung tissue specimens were prepared and examined by the methods described by Pooley and Clark (1979, 1980) using an electron microscope and X-ray energy-dispersive analyser. For each specimen, an estimate was made of the numbers of different types of mineral fibres per g dried lung. Fibres were defined as having a length/breadth ratio of 3 or more. A preliminary report on the asbestos content of the first 37 case-control pairs that were analysed has been published (McDonald, 1980a). We now report the analyses of all 99 case-control pairs. FINDINGS Five mineral types of asbestos were found in the lung specimens. The distributions of the counts are shown in Table 1. In the 76 pairs of males. 86% of both cases and controls had more than 1 x 106 fibres per g dried lung and there was no difference in chrysotile fibre content between cases and controls. For amosite, 26 cases had more than 1 x 106 fibres compared with 8 controls, and for crocidolite, 15 cases and 5 controls. Six cases and 3 controls had more than 1 x 106 fibres of anthophyllite and there was also a small excess of cases with more than 10 x 106 fibres of tremolite. In the males 21 (35%) of the 60 lung specimens from pleural mesothelial tumours contained more 1 x 106 fibres of amosite or crocidolite and 8 (50%) of the 16 peritoneal tumours. Table 1. Number (x 106) of asbestos fibres per g dried lung tissue in 76 male and 23 female CASES OF MESOTHELIOMA IN NORTH AMERICA AND MATCHED CONTROLS No. of fibres Chrysotile Amosite Crocidolite Anthophyllite Tremolite Cases Controls Cases Controls Cases Controls Gases Controls Cases Controls Males None <i 3 1 37 47 47 60 58 61 - 31 8 11 13 21 14 11 1! 12 33 28 1 < to 10<100 38 38 14 7 6 5 4 3 10 16 25 >22 8 1 8 -- 2 31 100 <1000 22 3-- 1 -- -- __ -- -- 1000 and over -- 2 i ---- ---- 1-- Females None <i 1<10 > 17 15 IS 16 IS 17 - 9 --547 6 6 2 s 8 12 11 2 1 2 i 3 1 7 6 10< 100 10 7 -- -- -- -- ------ 100 and over 1 -- .-- -- -- -- -- ------ 1 ` f, %0 StJl* ' * *.i rip* < ,, <: :. v F; ifc*> * iilf HWBUI0002095 Hatched for 99 ig tissue sembled :y fewer - ualysis, . ..'d; the `.uted in rol pair red and cng'an ..lien, an id lung. report as been control hutions es and ence in ,1 more and 5 nite and In the 'Uained umours. iolite ontrols 31 28 16 1 9 6 Mineral fibre content of lung in mesothelial tumours ' 419 Occupational histories were known in 70 (92%) of the 76 male cases studied. Table 2 shows the numbers of men with mesothelial tumours who were ever employed in certain occupations for which an association with mesothelioma has been reported. These groups are not mutually exclusive. More than 1 x 10fi fibres of either amosite or crocidolite or both were found in the two employees of factories which had manufactured or used asbestos, 6 of the 8 insulators, 9 ofthe 14 men who had worked in construction and 6 of the 21 who had worked in heating trades. In many instances both amphiboles were present; when only one mineral type was found, it was generally amosite and in only 1 case (an electrician who had worked in the naval shipyard at Charleston, SC) was it crocidolite. Table 3 shows the chrysotile content of the lung specimens according to whether more than 1 x 106 fibres of amphibole were present in the cases. The 29 mesothelial tumours with an amphibole content of 1 x 106 fibres or more had a similar quantity of chrysotile to their matched controls. The chrysotile content of cases with less than 1 x 10s fibres of amphibole was a little lower, but again the cases closely resembled the matched controls. All 23 female cases had more than 1 x 106 chrysotile fibres per g lung compared with 18 controls; 3 cases and 1 control had this quantity of amosite or crocidolite. There was also a small excess of anthophyllite (3 cases to 1 control) but 2 of these cases also contained amosite or crocidolite. Table 2. Amphibole fibres in lung tissue of men with mesothelioma evfr employed in CERTAIN OCCUPATIONS Ever employed More than 1 x 106 fibres per g of dried lung Either amosite Amosite Crocidolite or crocidolite only only Heating trades Shipyards Construction Insulation Factory (asbestos) 21 14 15 8 2 6 41 931 6 3-- 6 1-- 2 2-- Table 3. Chrysotile fibrf. content of lung in cases and matched controls according to jhe AMPHIBOLE (AMOSITE OR CROCIDOLITE) CONTENT OF THE CASES Chrysotile fibres 1 x 106 per g lung Nil <1 1 < 10 10 <100 100 and over Amphibole > l x 106 fibres per g lung Cases Controls 1_ 34 12 14 11 10 21 29 29 Amphibole < 1 x 106 fibres per g lung Cases Controls 21 57 26 24 14 3 3 47 47 HWBUI0002096 420 A. D. McDonald, J. C. McDonald and F. D. Pooley DISCUSSION An association between malignant mesothelial tumours and exposure to crocidolite is well documented for both mining and milling (Wagner et al, 1960; Talent et al., 1980; Hobbs et al, 1980) and manufacture (Jones et al, 1980b; McDonald, 1978a). In this series there was evidence that amosite was associated with mesothelial tumours, but not evidence that crocidolite was independently associated with them. A large excess of mesotheliomas has been reported in amosite factory workers (Seidman ef al., 1979), but only a few cases have been observed in amosite miners and millers (Webster, 1973), although no cohort study has yet been undertaken. Amosite has been extensively used for insulation in the United States (Selikoff et al, 1970; Cooper and Balzer, 1968). It has been suggested from the epidemiological evidence that the high incidence of mesothelial tumours in North American insulators might be due to their exposure to amosite (McDonald, 1978b); the present findings are consistent with this explanation. The equal quantities ofchrysotile fibres found in lung tissue from cases and controls fail to support any association between this mineral type of asbestos and mesothelial tumours. However, the lung chrysotile fibre content at death must be interpreted cautiously, as these fibres probably disappear in the course of time (Rowlands et al, 1982). In a British study Jones et al (1980a) also found that lung tissue from cases of mesothelioma contained no more chrysotile than controls. If chrysotile were responsible for a proportion of the mesothelial tumours in the present study, higher counts of chrysotile fibres might be expected among cases without an excess of amphibole fibres, but this was not found. The failure to find an association with chrysotile in the present study is consistent with the very low incidence of mesothelioma reported in a large cohort study of workers exposed only to chrysotile in mining and milling (McDonald et al,-1980) and its virtual absence in factories (Elwood and Cochrane, 1964; Weiss, 1977; Dement et al, 1982; Newhouse et al, 1982). The epidemiological findings for cases in 1972 showed a 36% excess of occupations entailing exposure to asbestos in cases compared with controls. The 26% excess found in the present study of mesothelial tumours with more than 1 x 106 fibres of amosite or crocidolite is of the same order. In females the possible small association between amphibole content and mesothelial tumours is consistent with the epidemiological finding that only about 2% of these tumours in females were attributable to an occupational exposure to asbestos. On the other hand, female cases were rather more frequently employed in industry (although not working with asbestos) than controls, which could account for the slightly higher chrysotile content of their lungs, r--. Differences of opinion occur among pathologists over the diagnosis of mesothelial tumours. A pathological review of these 99 cases will shortly be completed by the UICC mesothelioma panel in tlie U.S.A. The series will then be re-analysed in the light of their findings. Acknowledgement---This work was undertaken with the assistance of a grant from the Institute of Occupational and Environmental Health of the Quebec Asbestos Mining: Association. REFERENCES Cooprr, W. C. and Balzhr, J. L-R. (1968) Evaluation and control of asbestos exposures in the insulating trade. In Proc. of hit. Conf on Biological Effects of Asbestos, pp. 151-160. Dresden. 22-25 April 1968. >dolite "t al., sa). In nours, large ' el al., .'.TER, : sivelv LZER, clence ure to union. tirols itelial preted e> al., ss of were tgher ss of with v.e of die in lories <.- al., '.lions mnd t'eor and 2 % ..`StOS. ' ustry r the :e!ia! . ICC ! i heir . `e of Mineral fibre content of lung in mesothelial tumours 421 Dement, J. M., Harris, R. L-, Symons, M. J. and Shy, C. (1982) Estimates of dose-response for respiratory cancer among chrysotile asbestos textile workers. Inhaled Particles V (Edited by Walton, W. H.), pp. 869-887. Pergamon Press, Oxford. Elwood, P. C. and Cochrane, A. L. (1964) A follow-up study of workers from an asbestos factory. Br. J. ind. Med. 21, 304-307. Hobbs, M. S. T., Woodward, S., Murphy, B., Musk, A. W. and Elder, J. E. (1980) The incidence of pneumoconiosis, mesothelioma and other respiratory cancer in men engaged in mining and milling crocidolite in Western Australia. IARC Symposium on the Biological Effects of Mineral Fibres, Lyon. 25-27 September 1979, INSERM. pp. 615--625. Jones, J. S. P,, Poolf.y, F. D., Clark, N. J., Owen, W. G., Pollock, D. J., Roberts, G. H., Smith, P. G., Wagner, J. C. and Berry, G. (1980a) The pathology and mineral content of lungs in cases of mesothelioma in the United Kingdom in 1976. I ARC Symposium on the Biological Effects of Mineral Fibres, Lyon. 25-27 September 1979, INSERM. pp. 187-199. Jones, J. S. P., Smith, P. G., Pooley, F. D., Berry, G. and Sawle, G. V. (1980b) The consequences of asbestos dust exposure in a wartime gas mask factory. IARC Svmposium on the Biological Effects ofMineral Fibres, Lyon. 25-27 September 1979, INSERM. pp. 637-653. McDonald, A. D,, Harper, A., El Attar, O. A. and McDonald, J. C. (1970) Epidemiology of primary malignant mesothelial tumours in Canada. Cancer 26, 914-919. McDonald, A. D. (1978a) Mesothelioma after crocidolite exposure during gasmask manufacture. Environ. Res. 17, 340-346. McDonald, A. D. (1978b) Contribution to discussion. Proceedings of Asbestos Symposium, Johannesburg. 3-7 October 1977 (Edited by Glenn, H. W.), p. 82. National Institute for Metallurgy, Ranclbiirg. McDonald, A. D. (1979 (Mesothelioma registries in identifying asbestos hazards. Ann. New York Acad. Set. 330, 441-454. McDonald, A. D. and McDonald, J. C. (1980) Malignant mesothelioma in North America. Cancer 46, 148-154. McDonald, A. D. (1980a) Mineral fibre content of lung in mesothelial tumours--preliminary report. IARC Symposium on Biological Effects ofMineral Fibres, Lyon. 25-27 September 1979, INSERM. pp. 681-685. McDonald, J. C. and McDonald, A. D. (1977) Epidemiology of mesothelioma from estimated incidence. Prev. Med. 6, 426-446. McDonald, J. C. (1980b) Asbestos-related disease: an epidemiological review. IARC Symposium on &. Biological Effects of Mineral Fibres, Lyon. 25-27 September 1979. INSERM. pp. 587-601. McDonald, J. C., Liddell, F. D. K., Gibbs, G. W., Eyssen, G. E. and McDonald, A. D. (1980) Dust exposure and mortality in chrysotile mining, 1910-75. Br. J. ind. Med. 37, 11-24. Newhouse, M. L,, Berry, G. and Skidmore, J. W. (1982) A mortality study of workers manufacturing friction materials with chrysotile asbestos. Inhaled Particles V (Edited by Walton, W. H.), pp. 889-909. Pergamon Press, Oxford. Pooley, F. D. and Clark, N. J. (1979) Quantitative assessment of inorganic fibrous particulates in dust samples with an analytical transmission electron microscope. Ann. occup. Hyg. 22, 253-271. Pooley, F. D. and Clark, N. J. (1980) The chemical and physical characteristics of fibrous particles detected in human post-mortem lung tissue. IARC Symposium on the Biological Effects of Mineral Fibres. Lyon, 25-27 September 1979, INSERM. pp. 79-86. Rowlands, N., Gibbs, G. W. and McDonald, A. D. (1982) Asbestos fibres in the lungs of chrysotile miners and millers. Inhaled Particles V (Edited by Walton, W. H.), pp. 411-415. Pergamon Press, Oxford. Seidman, H., Selikoff, I. J. and Hammond, E. C. (1979) Short-term asbestos work exposure and long-term observation. Ann. New York Acad. $ci. 330, 61-89. Selikoff, 1. J., Hammond, E. C. and Chukg, J. (1970) Mortality experiences of asbestos insulation workers. In Proceedings of the International Conference on Pneuntoconiosis, pp. 180-186. Johannesburg, 1969. (Edited by Shapiro, H. A.). Oxford University Press, Cape Town. Talent, J. M., Harrison, W. O., Solomon, A. and Webster, I. (1980) A survey of black mineworkers of the Cape Crocidolite Mines: IARC Symposium on Biological Effects of Mineral Fibres, Lyon. 25-27 September 1979, INSERM. pp. 723-729. Wagner,J. C,, Sleggs, C. A. and Marchand, P. (1960) Diffuse pleural mesothelioma and asbestos exposure in the North-Western Cape Province. Br. J. ind. Med. 17, 260-271. Webster, I. (1973) Malignancy in relation to crocidolite and amosite. In Biological Effects ofAsbestos. Lyon. IARC pp. 195-198. Weiss, W. (1977) Mortality of a cohort exposed to chrysotile asbestos. J. Occur. ,\hd. 19, 731 " : 422 A. D. McDonald, J. C. McDonald and F. D. Pooley DISCUSSION G. Berry : In your concluding remarks, you quoted a paper presented at the IARC Symposium on Biological Effects of Mineral Fibres, Lyon, 1979, by Jones el ai, as saying that dust studies in the U.K.. had demonstrated an association between mesothelioma and crocidolite rather than amosite. As one of the authors ofthat paper I would like to correct your quotation; what was actually said was: This study provides no evidence on the relative hazards of amosite and crocidolite in producing mesotheliomas'. Professor A. D. McDonald: I stand corrected. What I should have said was that in Britain crocidolite and amosite appeared to be equally present in the lungs ofcases of mesothelioma, but in North America amosite was far commoner than crocidolite and where only one ofthese amphibole types was present, it was amosite. H. Weill: While your conclusions are, in general, suitably cautious, you may be over cautious on the disappearance of chrysotile from tissue. Your data show that chrysotile fibres are present in the tissue; it does not disappear completely. If there has been some loss of chrysotile, there seems no reason to believe that this would be different between cases and controls, your conclusions concerning the pathogenicity of amphibole should not therefore be affected. Professor A. D. McDonald: There is substantial evidence that chrysotile fibres disappear from lung tissue in the course of time. Exposure at different intervals before death could have resulted in equal quantities of crysotile in the lungs of cases and controls. It seems unlikely, as you point out, that differential removal of chrysotile occurred in cases compared with controls. M. Lippmann: I would like clarification on how you selected your controls: did they have known exposures to asbestos? Professor A. D. McDonald: The controls were cases of metastatic carcinoma of the lung arising from primary tumours other than those oflung or pleura; they were matched for hospital and for age and sex. They w-re also selected so that their mode of death might not have been very different from that of the mesothelioma cases. The interviewers were given cases and controls `blind', so that they interviewed without knowing w hether they were interviewing relatives of cases or controls. Prior to the interview they knew nothing about the occupational histories. The occupations recorded were then coded by clerks who did not know which were cases and which controls. F. H. Y. Green: What was the rationale for choosing cases with metastatic carcinoma of the lung as your control group? How did you ensure that the control tissues were free of tumour? Professor A. D. McDonald: These were specimens that had been taken at autopsy; pathologists generally keep one or more pieces oflung tissue. Before incineration for fibre analysis, sections were cut from the blocks end any tumour present was removed from the blocks. G. Major: More detailed classification of occupations than demonstrated in Table 1 is desirable. As a practising occupational hygienist, I know that insulators are employed in shipyards and that the broad term `construction' is too wide to be helpful. Professor A. D. McDonald: The method of classification and coding of occupations was described in a paper 2 yr ago at the American Academy of Science. I agree that this is a great problem and, to make it as objective as possible, we asked Prof. Selikoff for a classification which he had used in a studyf#aepsies in New York. We took his series of questions regarding different occupations and got the clerk to apply them to cases and controls in a blind fashion so that each successive question was answered. We have previously examined shipyard and construction workers without insulation and heating trades and found that there was still an association with mesothelioma. In Table 2 the shipyard and construction workers included insulation and heating trades (as stated in the text). W. H. Walton ; Almost half the male and nearly all the female cases had no amphibole in their lungs and yet alt had chrysotile. How can you deduce from that, that the cause is the amphibole and not the chrysotile? Professor A. D. McDonald: Mesiheliomas have been reported well before the industrial exp', n .'ion of asbestos and they are by no means all caused by asbestos. Most cases did have chrysotile fibres mi-....lu"t tissue, but so did most controls, and in similar quantities. Taken at face value this finding suggests that .be- c ts no association between chrysotile and mesothelioma. The substantially larger number of eases than controls with more than 1 x 10*' fibres of amosite and crocidolite indicate an association between these mineral types o' asbestos and mesothelioma. Amu occur, a > Primed in On Inhaled Punk 'ftP t',, r' ASBL t.sb ^ ' ; i '* . Detaf . and c~ 1977 i Kingd - of corv : tissue , contrp .we cc ', proYit . Their signif Later contr .. 'Seqiu . 'and . It first | ' \ I| HWBUI0002099