Document QXQ8nbZGJvb769Go7vNMLjkm4

Pergamon Am mp Hit . Vol 41. Nt* *. PP TO? "I*. |W C |M? British Oocupatnirui Hygiene Society Published by Elsevier Science Ltd All rights reserved Pnnied in Great Bnuin G0GT4g7g 97 SP.W0.00 PH; 80003-4878(97)00020-3 MESOTHELIOMA IN QUEBEC CHRYSOTILE MINERS AND MILLERS: EPIDEMIOLOGY AND AETIOLOGY A. D. McDonald,*^ B. W. Case.t A. Churg.f A. Dufresne,* G. W. Gibbs. P. Sebastien|| and J. C. McDonald* Departments of Epidemiology. Biostatistics and Occupational Health, and of tPathology. McGill University. Montreal. Canada; ^Department of Pathology, University of British Columbia, Vancouver, Canada; ^Safety Health Environment International Consultants, Alberta, Canada; and ]|lnstitui de recherche en sante et en securite du travail, Montreal, Canada (Received 1 March 1997) Abstract--In a cohort of some 11 000 men born 1891-1920 and employed in the Quebec chrysotile production industry, including a small asbestos products factory, of 9780 men who survived into 1936, 8009 are known to have died before 1991,18 probably from mesothelioma--33 in miners and millers and five in factory workers. Among the 5041 miners and millers at Thetford Mines, there had been 4125 deaths from all causes, including 25 (0.61%) from mesothelioma, a rate of 33.7 per 100 000 subject-years; the corresponding figures for the 4031 men at Asbestos were eight out of 3331 (0.24%, or 13.2 per 100 000 subject-years). At the factory in Asbestos, where all 708 employees were potentially exposed us crocidoiite and/or amosite, there were 553 deaths, of which five (0.90%) were due to mesothelioma; the rate of 46.2 per 100 000 subject-years was 3.5 times higher than among the local miners and millers. Six of the 33 cases in miners and millers were in men employed from 2 to 5 years and who might have been exposed to asbestos elsewhere; otherwise, the 22 cases at Thetford were in men employed 20 years or more and the five at Asbestos * for at least 30 years. The cases at Thetford were more common in miners than in millers, whereas those at Asbestos were all in millers. Within Thetford Mines, case-referent analyses showed a substantially increased risk associated with years of employment in a circumscribed group of five mines (Area A), but not in a peripherally distributed group of ten mines (Area B); nor was the risk related to years employed at Asbestos, either at the mine and mill or at the factory. There was no indication that risks were affected by the level of dust exposure. A similar pattern in the prevalence of pleural calcification had been observed at Thetford Mines in the 1970s. These geographical differences, both within the Thetford region and between it and Asbestos, suggest that the explanation is mineralogies!. Lung tissue analyses showed that the concentration of tremolite fibres was much higher in Area A than in Area B, a finding compatible with geological knowledge of the region. These findings, probably related to the far greater biopersistence of amphibole fibres than chrysotile. have important implications in the control of asbestos related disease and for wider aspects of fibre toxicology. " 1997 British Occupational Hygiene Society. Published by Elsevier1 Science Ltd. INTRODUCTION In 1966, a cohort of some 11 000 men, born 1891 through 1920 and employed for one month or more in the mining and milling of chrysotile in the Eastern Townships of Quebec, or in a small asbestos products factory, was registered for study. After exclusion of men lost to view, almost all after very short employment before 1935, the cohort consisted of 9780 menf4I75 registered in the main complex of mines and ^Author to whom correspondence should be addressed at Department of Occupational and Environmental Medicine, National Heart and Lung Institute, Imperial College of Science, Technology .i.'d Medicine. Dovehouse Street, London SW3 6LY, U.K. 707 , DEFENDANT'S EXHIBIT HWBUI0007903 708 A, D. McDonald et al. mills, under one ownership for many years, in the area of Thetford Mines, where production started in 1878; 866 in sis smaller mines in the same region, the largest (with 358 men in the cohort) set up a Few years later, but the rest much more recently, the latest in 1965; 4031 men in the mine and mill opened in 1882 in a town called Asbestos; and 708 in the asbestos products factory there, which was owned by the same mining company. Analyses of mortality have been published at intervals since 1971, the most recent on deaths to 1992 (Liddell et at., 1997). At this point, a total of 8009 men were known to have died, including 38 probably from mesothelioma. With three quarters of the cohort dead and the youngest survivor aged 72, an almost complete picture of mortality from this disease can now be seen. Although brief references have been made to the occurrence of mesothelioma in all our reports on the cohort since the first (McDonald et al, 1971), no previous attempt has been made at a comprehensive description. Initially there were very few cases; later, when the number had grown to a dozen or so their classification by place of employment and exposure remained difficult to explain. Now, with more knowledge of the widely differing opportunities for exposure of the cohort to amphibole fibres--commercial and naturally occurring--a clearer and more interpretable pattern has emerged. The body of this paper is arranged in three main sections, first a full description of the cases, second an analysis of exposureresponse and third an examination of the question of fibrous tremolite in the aetiology of mesothelioma. The rate of mortality from this disease was much higher for the factory in Asbestos than for the other employees in that town, but our main objective relates to miners and millers there and at Thetford Mines. THE CASES Ascertainment The total of 38 cases was arrived at by investigating: all deaths in which the term mesothelioma was mentioned on the death certificate; deaths coded since 1978 to ICD* 163; and by ongoing ascertainment of malignant mesothelioma through all Canadian pathologists, 1966-1984. In addition, data from recent studies by Quebec investigators with special interest in mesothelioma, notably Begin et al. (1992) and Case et at. (1997), were used. Included are deaths where in our opinion, after review of all accessible clinical and pathological sources of information, the cause was a primary malignant mesothelial tumour, more likely than not. The diagnosis was confirmed by full autopsy in 27 cases, but in eight of these the pathologist expressed an element of doubt. In the 11 cases without autopsy, the diagnosis was based on clinical evidence plus biopsy taken at open surgery, except one (TMl) diagnosed in 1956 by a needle biopsy only. After review of all the available evidence, an admittedly subjective assessment of the diagnosis being correct was high in 19, moderate in 14, and low (though more likely than not) in five. Of the 38 cases, only 18 had been coded on the death international Classification of Diseases. Ninth Revision. cert: the i f of th whu Trei 1 ascr: pror seen Tr M Pr q poss La 11 year Emf of n whic 4031 figui this 1 year 49 > year eigh Hov wor filtc: 3.96 sam min< with one outs coni scar sum resu HWBUI0007904 Mesothelioma in chrvsotile miners and millers 709 certificate to ICD 163 and the rest to a variety of other diagnostic codes. In all cases the disease was pleural but in one (TMI1) the peritoneum was also invaded. Electron microscopic analyses of dried lung tissue have been made in all but six of the 27 cases of mesothelioma for which there was an autopsy. All the information which we have on the 38 cases is summarised in Table 1, Trends In the first report on mortality, to November 1966, there were three deaths ascribed to mesothelioma in a total of 2413 (0.12%) and in the last, to 1992, the proportion had become 38 in 8009 (0.47%). The pattern of increasing mortality is seen below: Total deaths Mesothelioma Proportional mortality Before 1950 857 0 0 1950-1974 3405 0.18% 1975-1984 2208 15 0.68% 1985-1992 1539 17 1.10% This trend undoubtedly reflects the long latent period for this tumour--and possibly also some increase in diagnostic awareness. Latency The time from first employment to death for the 38 cases ranged from 21 to 60 years (mean 47 years). 11tnent rtfter exclusion of men lost, almost all before 1935, the net entry and total deaths of men first employed in the mines and mills of Thetford were 5041 and 4125, of which 25 (0.61%) were from mesothelioma, and for the mine and mill at Asbestos 4031 and 3331 of which eight (0.24%) were due to mesothelioma; the corresponding figures for the factory in Asbestos were 708 and 553 of which five (0.90%) were from this cause. h can be seen in Table 1 that of the 38 cases, eight were employed for only 2-5 years, whereas duration of employment m the remaining 30 cases ranged from 20 to 49 years, with very similar average periods in the three groups (Thetford Mines 35 years. Asbestos 36 years, factory 33 years). This raises the question of whether the eight cases with short employment were caused by exposure to asbestos elsewhere. However, of the two cases in the factory, one was in a man (FI) known to have worked for 3 years during the carding of pure crocidolite for military gas mask filters (McDonald and McDonald, 1978) and whose dried lung at autopsy contained 3.96 crocidolite fibres per fig, and the other was in a man (F3) who worked over the same period, but without autopsy or lung burden analysis. Of the six cases among miners and millers, the diagnostic probability was high in one (A7), moderate but with autopsy in four (TM21, TM25, A1 and A4) and moderate without autopsy in one (TM9). These six cases were in men'who had spent almost all their working lives outside the Quebec mining industry, and in four (TM21, TM25, A4 and A7) it is conceivable that their other known employment entailed asbestos exposure. The scanty information which we have about their work outside the mining industry is summarised below, with ages in parenthesis; also shown are the three available results of lung burden analysis in fibres per fig. e sRif E a2 Oi <n| fS> fM" *-- QO O rH ^b IS t S""ee " * h r\N0 _"gr> mrn r- mnMOOi? ^tv,1tei}o^ee'e(NMiwg*vCKNaoi#TnrH v ^ n rt n i*1! rt m ^("j '5- 5 =ra s SsO S " -g ito- w 4s5 >n'i!'ir'P*r'r^p*r*'005R}}ge!e$g9es h" > o -Sa S'* O' S' S' 0\ S' V S' s S' S' S' S' S' S' S' S' S' O' S' *,,*>1* 3 E.2 w>ie'h39^'eee^f'A^Mi>-QP>jr>'iH!so r, m w m n m w r n w m ? ''n 9 sr n p-i r-i tJ> O' i?1 I?1 fl1' CTs ? S' O' (S' ^ S' S' S' S' O' S' S' S' ''rOi^^fNSOS'^f^h-'t'e r*- ^ e t^- S' ^r;9vO->>-TM 3C S' S' S' S' 9>i S' O' S' S' S' S' s S' S' S' S' 1s .P2 O a , i>-Juca 'va:,, ^_:wJsuS>noa s te-Sfc I-g^I S E EE E 8 Q DO 0 S g O S g g g C g g 6 g g 6 ^ s55 i S' PH S' S1' W" S' S' a u jNNNifiSPtn(aPifn&lwn>=n`iS>^fnF. ^ fN N (N ^ ` Nl^iA'eP'!fflO'1 I ^ Vn@ N B .. s z rsiiisiiiisiiiisisiss -'^UMi TM 2I 162.9 Yes moderate 1917 1939 1988 49 55 TM22 163.9 No moderate 1912 1954 1990 36 23 16 TM 2J 199.1 Yes high 1904 1935 1991 56 31 31 TM 24 199.1 Yes high 1918 1935 1991 56 31 7 18" 56.4 2.5 i.6 10516 12 6 06 TM25 163.9 Yes moderate 1918 1938 1991 53 2 2 *I HWBUI0007906 =- ('I I--, vg K K <<<<<<<<< 712 A. D. McDonald ei at. TM9 TM2I TM25 Al A4 A7 baker (16-38); hotelier (38-70) watchman (27-70) welder (22-27); salesman (28-65) barber (20-60) army (25-29); truck mechanic (29-61) mining engineer (20-27); professor of engineering (30-65) chrysotile 1.6; tremolite 0.6 chrysotile 11.1, tremolite 8.9 crocidolite 0.7 The concentration of tremolite fibres in the lungs of the barber (A!) was perhaps related to the quality of talc used in his work. Excluding the factory workers, 9072 miners and millers of chrysotile at Thetford Mines and Asbestos were traced of whom 7456 (82%) have died, 33 from suspected mesothelioma (PMR 0.44%). No case was identified in some 4000 men employed less than 2 years (McDonald ex ai, 1994) and it is possible that the six cases in men employed from 2 to 5 years were attributable to some other source of asbestos exposure. The 27 remaining cases were in men employed in the mines or mills for between 20 and 48 years; whereas all but three of the 22 from Thetford Mines had worked at some time as miners, none of the five at Asbestos had done so. Of the eight cases of men at Thetford or Asbestos who had never worked in mining, five had been employed mainly as tradesmen, for example, as mechanics, electricians, or carpenters. Lung tissue analyses Of the 27 cases of mesothelioma for which there was an autopsy, electron microscopic analyses of dried lung tissue have been made in 19 miners and millers, including five from Asbestos, and two factory workers (Churg et al., 1993; Case et al,, 1997); detailed results are in Table 1. Given the possible effects of selection, small numbers, the inevitable uncertainty of diagnosis and the absence of controls or denominators, questions of risk and causation cannot be addressed; nevertheless, 1 the findings, summarised in Table 2, are informative. It is fairly clear that tremolite fibres predominated in the lungs of miners and millers who died of mesothelioma, especially in Thetford Mines, although these men were exposed overwhelmingly to chrysotile; however, in the two factory workers and in three of the five miners and millers from Asbestos there were substantial concentrations of crocidolite. Mortality rates Liddell et al. (1997), presented in their table 9 mesothelioma death rates per 100 000 subject-years. 1945-1992, for miners and millers, after age 55, by place of Table 2, Asbestos fibre concentrations in lungs at autopsy from 21 mesothelioma cases (fibres per jig: geometric means*) Place of employment Mines and mills Thetford Mines Asbestos Factory Asbestos No. of cases 14 5 2 Chrysotile 12.8 4,3 2.1 Tremolite 104.1 7,5 0.5 Crocidolite h 1.7 6.4 Amosite b 0.3 0.3 *! calculating geometric means, a zero count has been replaced by half the detectable limit. "All counts were zero, that is below the detectable limit. HWBUI0007908 Mesothelioma in chrysotile miners and millers 713 employment and according to exposure accumulated by age 55, There was little evidence that risk was related to cumulative exposure, and so it is not unreasonable to quote rates on the same bases but regardless of the degree of exposure; after exclusion of the one death at age 40 (TM1), they were as follows: Humber of mesothelioma deaths Thetford Mines; main complex and the oldest of the smaller mines 23 the five smallest mines 1 Asbestos mine and mil! 8 factory 5 Subject-years (000s) 65.14 6.01 60.64 10.84 Rate (per 100 000 subject years) 35.3 16.6 0.2 46.2 There are two main reasons for the low rate for the five smallest mines; the employees within the cohort were considerably younger than elsewhere, that is, few of them had been born before 1900; and the mines had started so recently that there were inadequate periods of latency. The other rates are reasonably comparable. It can be seen that the rate for miners and millers was over 2.5 times higher at Thetford Mines (excluding the smallest mines) than at Asbestos (/'ssO.015), and the rate for the factory was 3,5 times that for mine and mill in Asbestos (F0.02). EXPOS URE RESPONS To examine exposure-response relationships within place of employment, we .ought ten referents for each case except the three from the smaller mines in the Thetford region (TM12, TM21 and TM22). The selection criteria were that, relative to the case, the referent must have had a similar date of birth and survived to a greater age, and must have started work at the same place of employment, that is either at the main complex in Thetford Mines or at the mine and mill in Asbestos or m the factory there, and at a similar age. For most of the cases, more than ten men met these criteria, and a random selection was made. However, for four cases (TM3, TM23, TM6 and F4), we could find only six. five, three and two referents, respectively. There were thus 326 referents in all for the 35 cases. For these 361 subjects we calculated eight measures of exposure as follows: net service (years, adjusted for work-week*, and excluding gaps in employment); years (adjusted) worked in each of six dust categories definedt in terms of million particles per cubic foot (mpcf); and accumulated dust exposure (mpcf x years). For a case, the calculations were carried out up to 10 years before death; for a referent, they were carried out up to 10 years before he reached the age at which the relevant case died. Conditional logistic regression analysis by means of the EGRET package (Statistics and Epidemiology Research Corporation, 1989), and assuming multi plicative relative risks, providedjikelihood ratio (LR) statistics which are given in Table 3: those in the last line of this table were obtained after pooling years in `The working week had been of 60-72 h before 1938, 48 h 1938-1949, and 40 h thereafter; see Liddell <( at. (1997) for details of adjustments. tDefinitions are not given because of the completely negative findings; see Table 3. 714 A. D, McDonald et ul. Table 3. Likelihood ratio (LR) statistics, with degrees of freedom in brackets Thetford Mines Asbestos Net service (adjusted years) Accumulated dust exposure (mpcfxyears) Years (adjusted) worked in different dust categories Main complex 7.94(1) P = 0.005 0.13(1) f = 0.72 0.79 (2) P = QM Mine and mill 0.04 (1) P~ o.ss 0.30(1) P = 0.5S 0.54 (3) P = 0.91 Factory 0.00 (1) P-0.99 0.16 (1) P = 0.69 Did not converge adjacent dust categories, to avoid purported protective effects, and thus reducing the degrees of freedom. The LR statistics can be referred to the x2 distribution with the stated degrees of freedom and the corresponding approximate P values are included in the table; all but one lie between 0.58 and 0,99, implying minuscule effects. However, that for net service at the main Thetford complex is of undoubted statistical significance: the corresponding odds ratio relating to 20 years service is 2,31, with 90% confidence limits of 1.35 and 3.93, The opportunity was taken to compare risks among cases and referents at the main complex in Thetford Mines in non- and ex-smokers with those of cigarette smokers: the LR statistic with 1 degree of freedom was only 0.13 (/,0.9I). about as close as it is possible to get to `proving a negative'. Background THE TREMOLITE HYPOTHESIS When this cohort was set up in response to international requests for study of the effects on human health of exposure to pure chrysotile and other asbestos fibre types, no serious thought was given to the possibility that the Quebec ore body might contain mineral fibres other than chrysotile. Nor was it thought that the known use of crocidolite in the small products factory in Asbestos was of any scientific importance, even given the possibility of unrecorded movement of workers between it and the mines and mills. Soon, however, evidence that the situation was not so simple began to unfold. First, it was found that in our initial large scale morbidity surveys of current and past workers, there were qualitative and quantitative differences in exposureresponse between Thetford Mines and Asbestos, assessed radiographically (Rossiter ei a!,, 1972). Parenchymal changes were more frequent and more systematically related no estimates of cumulative dust exposure in Thetford Mines than in Asbestos. Pleural changes showed even bigger differences in that calcification was common in Thetford, but very seldom seen in Asbestos. As the chrysotile seemed reasonably similar in the two areas, some other geological explanation seemed probable, at least for the pleural changes. The results of a special study of pleural calcification among workers in Thetford Mines by Gibbs (1979) supported this view. These changes were more common among miners than millers and much more common in men who had worked in a localised central group of mines than in other ,, Mesothelioma sn chrysolite miners and millers 715 unes located peripherally, Gibbs concluded that the cause might be related to some .ineral closely associated with chrysotile, possibly mica, talc or briinnerite. A few years later studies of lung tissue at autopsy from miners and millers in the hetford area revealed the unexpected finding that, despite overwhelming exposure chrysotile, amphibole fibres in the tremolite series were present in similar or eater concentration (Pooley, 1976; Rowlands et al., 1982; Churg et al., 1984), This d to speculation as to the relative importance of chrysotile and tremolite fibres in e causation of human disease. Indications that this was no academic question were own by cohort mortality and radiographic studies of vermiculite miners and filers in Montana exposed to contamination by amphibole fibres in the tremolite ries but to no other type of asbestos (Amandus et al1988; Armstrong et al., *88), In terms of radiographic changes and mortality from lung cancer and esothelioma the results of fibrous tremolite exposure were on a par with crocidolite id thus might explain much of the disease observed in chrysotile miners and filers. : -ographical distributions : By the end of 1988, 33 deaths from mesothelioma had been identified in the I hort, sufficient to show that the risk of this disease was two to three times higher miners and millers from Thetford Mines than from Asbestos and perhaps higher 11 in factory workers (McDonald et al1994), A small number of lung tissue mples taken at autopsy from ex-employees in the 1980s showed that fibrous i.s present in both regions but that the level of exposure may have been out _...ee times higher in Thetford, By the end of 1992, the total number of cases had grown to 38, all but five in ners and millers, 25 from Thetford Mines and eight from Asbestos. A detailed lalysis of work histories showed that the cases from Thetford were predominantly men who had been employed in a localised area of five centra! mines (Area A) ;her than in ten mines located peripherally (Area B) (McDonald and McDonald, 95). Lung burden analyses made some years earlier by Sebastien et al. (1989) fbsequently indicated that concentrations of tremolite fibres, but not of chrysotile, 4 re some four times higher in Area A than Area B. Moreover, the mines in Area A Ire the same as those identified by Gibbs (1979) as carrying the highest risk of -sural calcification. A recent re-analysis of representative samples of fibres from the |idy bv-Sebastien et al. (1989) showed no important difference in dimensions or |mental composition of either chrysotile or tremolite between the two areas. |ological evidence The potential importance of geographical differences in the distribution of fmolite warrants some consideration of the geology of the region, well described jRiordon (1957). Among the amphiboles,,tremolite was rarely mentioned nor its m. whether fibrous-or not. The chrysotile in Area A tends to be less harsh than in ea B. Differences between mines were examined in a search for the aetiology of ;ural calcification by Gibbs (1972). He noted that the distribution by mine of more m 150 mineral/rock types, indicated that rarely did a specific mineral occur in ::a A which was not also found in Area B. 716 A. D. McDonald ei at. A key factor in tremolite occurrence may be the frequency and nature of what have been termed `acid/syenitic/aplitic/felspathic' dykes. In Area A. these numerous acid dykes occur as irregular shapes, often at shear zones in the serpentinised rock. According to Cooke (1937) the freshest dykes consisted mainly of oiigoclase feldspar altered through kaolinisation to `needles of tremolite, actinolite and colourless pyroxene'. Later, Riordon (1957) noted that serpentinised peridotite near contact points with acid dykes was converted to talc and tremolite. While tremolite had been noted to occur at the margins of dykes in Area B, the pattern in Area A would probably result in tremolite, some in fibrous form, being mined with the ore. The mineral assemblages associated with tremolite in commercial chrysotile samples (Addison and Davies, 1990) are not dissimilar from those predicted for Area A if tremolite were derived from `acid* intrusive alteration. This adds credence to acidic dykes being the main factor in the higher exposure of workers in Area A to tremolite. The hypothesis tested Following the preliminary report by McDonald and McDonald (1995), a formal J test of the hypothesis that the risk of mesothelioma was higher in the mines with i substantial tremolite contamination was made as follows. The detailed work histories of all cases and referents at the main complex in Thetford Mines were re examined and for every man each period of employment was classified as in the central or the peripheral area. One case (TM15) and six referents had to be eliminated because of frequent unrecorded moves between Areas A and B; also eliminated were the 10 referents of case TM15 and another because his work record could not be found. For the remaining 21 cases and 187 referents, periods of service (calendar years, without adjustment for work week) were calculated: for cases, up to 10 years before death; for referents, to the corresponding age of the relevant case. Of the 208 subjects, 104 (class C) had been employed only in the central mines and a further 69 (class P) only in peripheral mines, while 35 (class M) had had jobs in both areas. The EGRET package was again used to carry out conditional logistic regression analysis. The analyses reported in the first column of Table 3 were repeated: the results were almost identical, indicating that the exclusions had had virtually no effect. The introduction of class (C, M or P) as a factor into the analyses indicated lower risks for men in class P than for the other men. After pooling classes C and M, the LR statistic for the improvement in the fit of net service, with a single degree of freedom, was 6.33 (/'asO.OI). From the corresponding odds ratios in Table 4, it is clear that service in the central area led to definite risks of mesothelioma. However, the odds ratio for class P is rather unstable, as shown by .Table 4, Odds ratios (with 90% confidence limits) at the main complex in Thetford Mines Net service (20 adjusted years) Accumulated dust exposure (300 mpcfx years) JClasses C and M. "Class P. Some or all years in central area8 2.50 (1.49-4.20) 1.28(0.94-1.75) All years in peripheral area" 0.80 (0.27-2.38) 0.32 (0.06-1.76) HWBUI0007912 Mesothelioma in chrysolite miners and millers 717 the very wide confidence intervals, and as the point estimate is well below unity it is quite unrealistic. The slight indication that the risk in the central area was related to cumulative exposure is almost certainly a statistical artefact arising out of the negative tendency in the peripheral area (the difference between areas being associated with a 'significant' LR statistic). One of the reasons that the estimates for class P are so unreliable is that it contained only three cases (TM l, TM3 and TM14). A further analysis was carried out of net service in the two areas: it showed the odds ratio in relation to 20 years work in the central area to be 2.55 (90% confidence interval 1.52-4.27), a finding of high statistical significance compared to an odds ratio of 1.1! (with very wide confidence interval, 0.47-2.62, and hence negligible significance: P ssOJ4) in the peripheral area; see also McDonald and McDonald (1997). These odds ratios and those in Table 4 in relation to net service are entirely compatible with that of 2.31 quoted above under Exposure-Response, particularly in the light of methodological differences. CONCLUSION Of the 38 deaths from mesothelioma in this cohort, 27 were in miners and millers with employment ranging from 20 to 48 years, and we conclude from the evidence presented that these 27 deaths can be attributed with reasonable certainty to occupational exposure in the Quebec chrysotile production industry. For the six further cases of men who worked in the mines and mills, employment was by e -,st for only 2-4 years, and causation is more doubtful. This does not, however, a, our main conclusions; in particular, these cases were included in the analyses. In the factory, where the mesothelioma mortality rate was over three times higher than in miners and millers at Asbestos, two of the five cases were also in men employed for less than 6 years, but they were present in the plant in the years 1940-- 1942 when crocidolite was being used in the manufacture of military gas mask filters and were known to have worked near the carding operation. We believe therefore that all five cases in Factory workers should probably be attributed to work in the plant, where all employees were potentially exposed at some time to crocidolite and/ or amosite, which could reasonably account for the greater risk. This finding, although undoubtedly important, is not relevant to the main concern of this report. That concern is with the aetiology of the 33 cases in miners and millers, 25 at Thetford Mines in a total of 4125 deaths from all causes (PMR 0.61%), and eight at Asbestos among 3331 deaths (0.24%). Within Thetford Mines, there is dear evidence from case-referent analyses that the risk arising from employment in the localised area of central mines in the main complex (Area A) was much higher than in the peripherally located mines (Area B), where it was minuscule. A similar pattern of risk was documented for pleural calcification in the 1970s. As we have no reason to suspect that geographical variation in the character of chrysotile per se could account for these differences, the presence of other minerals in or near the ore body would appear ttroffer the best explanation. The only candidate capable of filling the role is fibrous iremolite, and there is considerable supporting evidence. Its pathogenicity and carcinogenicity have been amply demonstrated and lung burden analyses suggest that its geographical distribution in the mining region is closely related to the pattern of mesothelioma risk. Geological knowledge, so far as 718 A. D. McDonald et al. it goes, is also compatible with this hypothesis. It does not follow that pleural calcification and mesothelioma have the same mineralogieal cause, although the agents must be closely linked geologically. Indeed, there is no consistent correlation between the prevalence of pleural calcification and mesothelioma incidence in general populations or occupational groups (see McDonald, 1997), The fact that the risk of mesothelioma was strongly related to years of service in the central area at Thetford, but hardly at all to accumulated dust exposure, suggests that employees were exposed to tremolite intermittently, probably at different intensities for periods of variable lengths and at irregular and fairly infrequent intervals, and that the concentrations of tremolite fibres in the working environment were only poorly--if at all--related to prevailing dust levels. This is entirely reasonable having regard for the local geology and the nature of the mining operations. In Asbestos, Quebec, where amphiboles were used in the factory from time to time, there was not inconsiderable movement of labour between the factory and the mill, and, perhaps, mine, so that a substantial proportion of those registered as miners or millers will have worked in the factory, and of course vice versa. Further, some crocidolite was processed in the mill. It is not therefore surprising that crocidolite and to a lesser extent amosite fibres were found in the lungs of cases from both the factory and the mill; no such fibres were found in the lungs of the 14 autopsied cases at Thetford Mines. There must also have been some exposure to tremolite, although to nothing like the same extent as in the central area of Thetford Mines, The tremolite hypothesis, if correct, has several important implications. First, it supports the widely but not universally held view that most, if not all, asbestosrelated mesotheliomas are caused by amphibole fibres. This in turn points to fibre durability and biopersistence as critical factors in aetiology (McDonald. 1994), a point of even greater relevance in assessing the safety of man-made mineral fibres. Second, it implies that uncontaminated chrysolite carries very little risk of mesothelioma. In Asbestos, exposures were not to uncontaminated chrysolite, but also to some tremolite and crocidolite, yet among the miners and millers only five deaths from a total of over 3300 can be confidently attributed to their work. At present day levels of dust control the mesothelioma risk must be vanishingly small. Each so, it remains desirable to minimise, perhaps by screening, the contamination of commercial chrysolite by amphibole fibres, however difficult this may be. Acknmvlcdgemems--This paper has depended on work on the cohort carried out continuously since 1965 and made possible by the help of people and agencies too numerous to mention. 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