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ass--;ona: atior. VOCTi avt i to 1 leers :mo' um poeaiiy data filial aide- 40Rtom) 3 for tber th; does ioprent KU* th; otc. . - ifi flier vsouie re d;r fSTone tw itch inc aid r. a o: ' of the ost rat TC aa! tot ids ii; J:- .a; nt vSlKVt . pas. National insttnn; ior national Safety and Health Administration recom mendation and the recently revised OSHA standard to limit occupational exposures for ai) forms of asbestos to 0.1 fiber/co. Zj References 1. Pigs BJ. The uses of cnrvsotiie. Ann Occur Hyp. 19^4 ;36:453--456. ' 2. Lemtn RA, Bingham H. A case study in . avoiding a deadly legacy -in developing countries. Taacotind Health. 1994:10(1/21: 59-87. 3. Mossman BT, Btenon J. Corn M, Seaton A, Gee JBL. Asbestos: scientific develop ments and inn)l>Q lions for public poliev. Saencc. 199t24:29<-301. ' 4. Dunnigan. J. Linking eotysotile asbestos with m csoiheiioma.Am J ind Med. 1988:14: 205-209. 5. Pooley FD. Oark NJ. Ouantitatrve assess ment of inorganic fibrous particulates in dust samples with an analytical transmis sion electron microscope, Ann Occup Hyp 19?9^2^53-;71. 6. Addison J. Davies LST. Analysis of am- phibole asbestos in cnrysotil: and other minerals. Ann Occur Hyp. 199034:359 175. ' ' .7. Pooley FD, An examination of the fibrous , , minerai content of asbestos lung tissue form the Canadian chrvsodle mining ttidtis- ____ try. Environ fiei 1976:12381-298. ^`8'.. Rowlands 39. Gibbs Gy, McDonald AD ;ik/ . Asbestos fibres m the lungs of chrysotiie hep-,miners and mflien--a preliniinaiv reoart r r" Ann Occup Hyp. 1982:26:411--415. ' 2. Churj. A. Wiroock MU Asbestos fibers in me general Donuiatiot.Am Rev four Du 1980:122:669-676. ' 10. Jones ISP. Roberts GS. Pooley FD. et ai. The pathology and mineral content of iunes ir cases of mesothelioma in the Untied Kmcdom tr. 1976. It: Wagne: JC. V ed. Btoiopcal Effects of Mineral Fibers. . Lyon. France: International Agency for Researen on Cancer: 1980:185-199. Scien tific Publication No. 30. 11 Wagner JC. Fooiey FD. Berry G. et al. A patboiopcai and rruncraiocical study of asbestos-Teiased deaths m the United King dom in 1977, Ann Occur Hyp 198236:423- 531. ' 12. McDonald AD. McDonald JC Fooiey FD. Minerai fibre content of lung in mesothe- hal rumours in North Am;nci.Artn Occup ' fifty, 198236:4] "-422. 12, Gauoicnet A Jansor. >2 Memchain G, c: ai. Assessment by analytical microscopy of toe iota." iung fibre burden m mesothe lioma pausots maiched witr four other palnoiopcai series. Ann Occur Hyp 1966: 32(suppl 1:33-222. ' 14. Wagner JC. Berry G.PooievFD. Mesothe liomas ami asbestos type in asbestos textile workers: a stubv of June contents. BrMedJ. ]923Ec:607-6(>c " 25 McDonald JC, Armstrong B. Case B. etai. Mtsotneiioma and asbestos fiber type: evidence from lung ussue anaivses. Cancer !989:65;154r-154" ' it Rogen A2. Leigh 7. Berry G. Fergusor. DA Muider HE. Ackad M. Relationship petwetr. iting asbesios fiber rvpe and concemrauon ana relative risk or m harm. Cancer. 1991:67:1911-1921 17. Wagner JC Berry G, Skidmore JW. Tim- brell V. The effects of the mnalantm of asbestos in rats. Brj Cancer. 1914.29352 May/22 2006 269 ' 8:30AM 18. Middleton AF. Beckett ST, Davis JMG. A 32. Hutlan 2. Zhitntng W, Stuov oi oceuoi:. study of the short-term mention anc oonai iung cancer in asbestos factories ir clearance of inhaled asbestos by rats, using UJ.CC. standard reference sampies. In: China. BrJind Med. 1992^0: lOr^iful 34. McDonald AD. Fry J6. Woolitv *A ' W'altoo WH- ed inheied Pamae.I fil " McDonald JC. Dust exposure and mona- . Edinburgh, Scotland: Institute of Occupa in in an American chrvsoiut ascestos tional Medicine; 1975347-256. fnctiqr, produas plan:. B' inc Mec 19 Cnuig A WngbiTL Vedd S. Fiber mrrdcr, 7984:41:151-157. and patients of asbestos-related disease in 25. McDonald JC. Liddell FDA Gibes GW. chrvsotile miners and millers. Am Ret Evssen GE. McDonald AD. Dust exposure RapirDts. 1993:4835-31. 20. Rendall RE- Retention and Clearance o' and mortalitv m chrvsouie mimnt 'cltl975.Brfiirtd3fiec. 19SC;2":n-:4. ' Ckas Fibers and Different Vanener of 36. McDonald JC, Liddell FDA Dunesne A. Asbestos by the Dung. Johannesburg. South McDonald AD. Tne 1691-1920 birih cr Africa; University of Witwatersrand: 1986. oon of Oueoec chrysotiie mintrs and Dtfsenauoo21. Selikoff U, Hammond EC Seidman H mtllen: monaim 1976--86. fir 5 ind Med 1993:50:1073-103;. Monabty experience of insulation workers 37. Prolatto'G. Negri E. LaVecc'nia C. Fuu E.' in the United States and Canada, 1943 DecatrL A. Pete j. An update ot cance: 1976.Ann N YAcad Sd. 1979330.-91-116. roorulrty among chrysotiie asbestos miners 22. Sebasden F. Janson X. Gaudichet A in Balangero. Northern lean, brj ind Med. Htrscb A Bigon J. Asbestos mention in 1990A"-:31&~SK human respiratory tissues: comparative 36. Shiqu 2. Yongxtan W'. rusheng M. Hong- measurements in lung parenchyma and in shuen M. Wcnzh: S, Zhennuac 3. Retro parietal pleura. In: Wagner JC ed. Bioiopi- spective mortality study of asbestos wom cal Effects ofMineral Fibers Lyon, France: en th Latyuan. is: Fwceedinps of the 17/ international Agency for Research on fmensaaona;' Pneumoconioses Conference Cancer. 1980337-246. Part II: August 23-26.1986: Pittsburgh. Fa 23. Cburg A Asbestos fiber content of th* National Institute for Occupational Safer lungs in patients with and without asbestos and Health; 1990:1242-1244: DHHSpubh- airwave diaeaxe. Am Rev RespoZns. .1983; cation 90-109,-pan II. : 127:470-473. . 39. Weiss W. Mortality of a cohort exposed to 24. lxBouffant J- Martin JC Duytf S. Daniel chtvsotile asbestos- J Occur Mei 1977:19: H. Structure and composition of pleura: 737-740. '. plaou*. In: Bogovski P. Giison JC.TimbreU 40. Dement JM, Harris RE Symons Mi. Shy 3'. Wagner JC. edt Btobjtica! Effects o' CM. Exposures and mortality among Asbestos- Lyot. France: International chrysotiie aisoesio; workers, par. 1: extx- Agency For Research On Cancer, 1972:240 sure estimates. Am J ind Med. 19634:399 257. Scientific Publication No. S. 419. 25 Dodson RF. Williams MG. Com Cl. 42 Dement JM. Harris RE Symons MJ. Shy Brolic A Bianchi C. Asbesios content of CM. Exposures anc mortality among lung tissue, lymph nodes, and pieural chrysotiie asotstos workers, par. 11: morta!- plaoues from former shipyard workers.An: tTy.Am.iind Med. 1983;4:421-435. Rev Respir Dis. 1990:142:843-84-. 42. Fete Doll R. Herman C. Bmns W. 26. Kohyama N. Suzuki V. Anaiysis of asbestos Ciayron R. Gofie T. Riianonship oi mortal fibers in lung parenchyma, pieurai plaques, ity to measures of environmental asbesios and mesothelioma tissues of North Ameri pollution tr. an asbestos textile factor. .Ann can insulation workers. Ann V Y Acad Sc- Occup Hyp. 1985;29:305-355. 1991:64337-52. ' 27, Acheson ED. Gardner Mi, Pippard EC. Grime LP. Mortality of two pouns of women who manufactured pas masks from 43. McDonald JC. McDonald AD. Armstrong E, Seoastten P. Cohort study of mortality ot vermteulite miner, exposed to licmohtr. B * .: ind Med 1980:43:436--444 cnrysotilr and croridoln* asbestos: a 4Tvtar fobcw-uc. BrJ ini Mei- 1932539:344 44 ot Kierk NH. Armstrong BA Musk AW. Hobos MST. Cancer mortality in reiauor 348. ' to measures of occupational exposure tc 26. Cbertg W. Kong J- A rttrospeoive monai m cohort study of chrysoult asDcstos croDoohte at Wittenootn Gorge in West ern Australia Rrjjrtc Med ;989:46p29- products workers m Tianiin 1972-196*. Environ Res. 1992^9371-278. 53c 45. Hendersor. VE Enteriine PE. Asbtsto: 29. Demeni JM. Brown DP. Okur. A Mom!- exposure: Factors assoaated with excess fry among cnrysotile asbestos textile work cancer and respirator disease mortality ers: Conor mortality and case-controS Ann,Vy'Aced Ssl analyses. Ann Occup Hyp !95436:525--532. 30. rtruceIsieir. MM. Mortality among empio'- ees of an Ontario factor' tha: manutac- 46. Bern G. Newhouse ML. Mortaiiq o: workers manufaeturmg inetior ntatenai.uSmMVaestOofi' J ind Med J9B.-:40:;- turtd constructior. materials using enrysctiie asbestos and coal ta* pitcc. Am J inc 4' Stoasuer. F. M4Donald JC, McDcnaic AD. Case E. Kattsy R Respiratory 4ance- Med. !9e9--]t3:-26" 32 rinkeistcii. MM. Mortality rates among in ehrysotiit textile and mining Industrie;, exposure tniertnees rrotr. tunganatysir o' employee; potentially exposed to chrysrtile asnestos a: rwo automottvt pans J Inc Med. 19gv.4c; J 6f-16 . 4t Demen: JM. Caremofeni-r, of cnrvsouit rerruar !t,9t \ o. 8c. Nc. 2 .-smencat. journal cf runtii!cHeal'-' M*v*r t: a. asbestos 2 case conrroi study of ; sorters. Cell 6*0/ Toxicol 199.1 49 Tolocn P. Eisen , Pothier'LF Monton RR. Haltock MF. Smith T3 Mortality studies of machimflg-fiuid exposure in the auiotnobiie industry. fl nits associated wnh specific fluid tvpes. Scand J Work Envrpr, Heath. 1992:18351-360 5C Dement JM and W'ajiingford KM. Com parison o: phase contrast and electron microscopic method! for evaluation of occupational asbestos exposures. Appl Oc- cupEmvon H>f 399Ch5;242-247. * 51. VualStaasacsofthe Untied States. 1989. Vol H---Mortality. Part B. HyattsviDt. Md: Natjoiial Center for Health Statistics; 1992 DHHS publication PHS 92-1302 52 Cuflcn MR and Baioyi RS. Chrysolile asbestos and health is Zimbabwe, If analy sis of miners and millers compensated for asbestos-related diseases since indepen dence (1980\.Am}lndMed. 199139:163 169. 53. Bepin R, Gauthier J. Desmetiles M. Os- uguv G. Work-related mesothelioma Ouebec. 1967-1990,AW /nd Med. 199222 531-542. 54. McDonald JC, McDonald AD. Chrysotile. rrtrnobis and mesothelioma. Science Feb ruary 10.1995267:775-776. 55. Feio 3. Seidroan H. Selikofi 13. Mesothe lioma mortality m asbestos workers: Hnpii- calions for models of carcinogenesis and risk assessment. BrJ Cancer. 1982:45:12*- 335. 56. Hughes JM. Weill H. Asbestos Exposure- Ouamnative Assessment of Risk. Am Ret ReeveDa. 1986:133^-13. 57. Shnsr-Cremer GK. Liddeli FDI2 Logar, WPT>. Beztuoenhout BN. Tt monabty of amohibol: miners in South Africa. 1946tti.BrJjnJMtd. 1992*9-366-575 56. Davis JMG. Bedten ST, Bolton RE. Collins T\ Middleton A?. Mass and num ber offibres hi the pathogeoesa of asbestosreiattd lung disease in rats. Br J Cancer 197837:673-588. 59. Daws JMG. AddisonJ, Bolton RE. Donald son K. Jones AD. Smith T. The pathogenic ity of long versus short fibre samples of arooote asbestos administered 10 rats by inhalation and intraperitoneal injection- Br JExpPaihoL 1986;67:415-430. 60. Davts JMG. Jones AD. Comparisons of the pathogenicity of long and shon fibres of chpesotile asbestos in rau. BrJ Ejp PalhoL 1988-.69-.717-737. 61. Davis JMG. Addison J, Bolton RE Docaldson K. Jones AD. MSter BG. Inbaiatioo studies on tbe effects of tremolm and bruche dust in ms. Cardnageneas. 1985:6. 667-674. 62 Coffin DL Cook PM. Creason J?. Relative mesothelioma induction in rats by mineral flben: comparison with residual pulmo nary mineral fiber number and epidemiol ogy.Inhal 7<irieol 1992427>-300. 63. Timbrel! V. Gibson JC, Webster 1. U1CC standard reference samples of asbestos.Jni J Cancer. 1963:40M06. 64. WagnerJC,BenyG.Ttmbrel3\'.Mesoihe- Uotnata in rats after inocuiation with asbestos and other materials. BrJ Cancer. 1972;28:17>-185. 65. Stanton MF. Layard M. Tegrris A. ei a1. Relation of panicle dimension to carcino genicity m arnpruooie isbesioees and fibrous minerals.J Hail Cancer ins: 1 965-975. 66 Mosstnu FT. Mechanisms of carcinogenesis and ferocity: the amp hypothesis remntd. Gr J Ind Med 1 673-676. Lener. 67. Weinberg ED. Association of iron rcsptraiorv tract neoplasia. J Jrau Exp Med. 1993:6:117-125. 6S. fjrk-Oihmcr Encyclopedia cfChemicalT noio& 3rd ed. Vol 15. New York. John Wiley A Sons; 1981:639. 69. Davis JMG. Mineral fibre carcinogen experimental data relating to tbe unce offibre type. size, deposition, d bon, and migration. In: Bignon 3. Saracri R, eds. Hon-occupadanal to Miners! Fiber: Lyon, Trance: In tkmal Agmc- for Research on 1969-33-45. 70. Baioyi R. Exposure to Asbatoe __ ChysotSe Miners. Millers and Mrruc't dens andAsbeaasa in Zimbabwe. H Finland: University ofKuopio; 1989.T1 taaon 71. Pmo J. Fibre earemogenesb and _ mental hazards. In: Bignon 3,'Re. Stracei R, eds. hioo-occupadonal to Mineral Fiord- Lyon. Trance: tional Agtncv for Research on 1989:457-470* . 72 Threshold terns: Values for Chemical stance and Pnyjicai Agents and Biolc Exposure Indices Cincinnati. Ohio: can Conference of Governmental 7d trial Hygienists: 199*-1995. n:S& Si 15v American .'oumai o'Rubii: nealtf :cruar099c Vo>*t-fcc Pergamon >nn. orr>. Hy; . Vcl 4;. So #. po T0"*"!S |05" C- IW7 Brrujh Occupouoaal Kyntnt Soocts PubJiwd by Eatwr Soract U. All ncnu r*rv Printed in Omi bnmr. 000*-4J7S^7 117.00- 0.00 PIl: S0003--4S78(97)00020-3 MESOTHELIOMA IN QUEBEC CHRYSOTILE MINERS AND MILLERS: EPIDEMIOLOGY AND AETIOLOGY A. D. McDonald,**! B. W. Cass,"!1 A. Churg.t A. Dufrcsne,* G- W. Gibbs, P. Sebastienj) and J. C. McDonald* * Departments of Epidemiology, Biostatistics and Occupational Health, and of tPatbology. McGill University. Montreal, Canada; IDcparxment of Pathology. University of British Columbia. Vancouver. Canada. SSafety Health Environment International Consultants. Alberta. Canada; and ||lnstnut de recherche en same el en securile du travail. Montreal. Canada (Heurivtd 7 March 1997) Abstract~ln a cohort of some 11 000 men bom 1891-1920 and employed in the Quebec chrysotilt production industry, including a small asbestos products factory, of 9780 men who survived into 1936. 8009 are known to have died before 1993.38 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 me of 33.7 per 100 000 subiect-years; the corresponding figures for the 4031 men at Asbestos were eight out of 3331 (0.24%. or 13.2 per 100 000 suoiect-years). At the factory in Asbestos, where all 708 employees were potenUally exposed to crocidolite and.'or amostte, 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 umes 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 havr 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. Withtn 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 .ndicauon that risks were affected by the level of dust exposure. A similar pattern tn the prevalence of pieural calcification had been observed at Thetford Mines .in the 1970s. Tnese geographical differences, both within the Thetford region and between it and Asbestos, suggest that the explanation is mineralogicai. Lung tissue analyses showed that the concentration of trermohte fibres was much higher in Area A than in Area B. a finding compatible with geological knowledge of the Tegior.. These findings, probably related to toe far greater biopersisience of amphibole fibres than chrysoute, have important implications in the control of asbestos related disease and tor wider aspects of fibre toxicology. < 1997 British Occupational Hygiene Society. Published by Elsevier Science Ltd. INTRODUCTION In 1966. a cohort of some 11 000 men. bom 1891 through 1920 and employed for one month or more in the mining and milling of cbrysotile 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, che cohort consisted of 9780 men: 4175 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. Technolog)' and Medicine. Dovchouse Street, London SW3 6LY. U.K.. .. . 707 708 A. D. McDonald et aI mills, under one ownership for many years, in the area of Thetford Mines, wheTt production started in 1878; 866 in six smaller mines in the same region, the iarzrst with 35S men in the cohort) set up a few years later, but the rest much more recently, the iatest in 1965, 4031 men in the mine and mill opened in 1882 tn 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 al, 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 bncf 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 interpretabie pattern has emerged. The body of this paper is arranged in three mam 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 towii, 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 al. (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 JJ cases without autopsy, the diagnosis was based on clinical evidence plus biopsy taken at open surgery, except one (TM1) 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 m 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 Reviaon. Mcjotheiioma m chrysouis 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 (TM11) the peritoneum was also invaded. Electron microscopic analyses of dried lung tissue have been made m 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 drains Mesothelioma Proportional mortality Before 1950 85" 0 o 1950-1974 3405 6 0.18 V. 1975-1984 2208 15 0.68V. 1985-1993 1539 17 uov. This trend undoubtedly reflects the long latent period for this tumour--and possibly also some increase in diapostic awareness. Latency The time from first employment to death foT the 38 cases ranged from 21 to 60 years (mean 47 years). Employment After 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. It can be seen in Table 1 that of the 38 cases, eight were employed foT only 2-5 years, whereas duration of employment in the remaining 30 cases ranged from 20 to 49 years, with very similar average periods in the three groups (Thetford Mints 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 perMg, and the other was in a man (F3) who worked over the same period, but without autopsy ot 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 ME- * 710 D. McDonald e. a'. sss 00s sss SO -- SOo V l _>% -- c 1 . *s s. i SSS sdin ^S = PS S f" > P-i in *r c o 2ff.. CO O O' -- SOS V S wi --o cs K/-i i--i "B- VI o -- O -- 0fNTS>MnNm0rMrfS6T".f*N SPl^'SNVliPNvcism->-*-"-MirH s 1-- -- X-* c -sO _ *2 >s 1c= ic. S IS k_ -- SVi&eOf'MpipP>'OrlI>'P9H\fNfe`rONi'riJ'fef.>rnifrrst0V9\f'ttPpei>Hl'0IPw'Oiwi'PO(i'e'OOw'l0sR'tS.Ks,jBHcvCOeO'\f0f>--'9^O--'C'--C<' 'r' i'e'i'(CO'''e'^*'iPiff>-N'p-ONp'r'eeo"!r^ip\j; --O' O' 60 O' ^ Oj O' 09 O' O' --O' O' O' O' '''O-- '--O'S5O2'S2- modcmtc Yes 13 .5s>-3o O c. ft o If <> ? v C bo "Si.- bo *S> S S "Sb 5 "Si S {5 T5) ? "Sj *Jj> if qo 5 "ai "S> ^1g1l2' S2' 2f|2t'-S-t2^22-S2*e"0^0"=-- - oCCCC2oeSCCctJ5oSBoC5CS5 2Z>>>>>,Z2>.>>.Z).>ZZ>>.2>.> ~*n(S(Ni--^O<N"'wrsOivciOf^' 9--6'.O'p''0Oir'^,i"N''nOe;reoisf"r--ei'<bv>"o<'<ei OPN' Ofi' --p. --p. ,2 -*c*~'3c-u',>sep-co'*-'"'< *'* iSSSS2S2S2SS2S55*K22Z<22 hHHhl-HhHHrri-HI-l-rHi-rHI-rr'i-- IM 2 5 16.VV Mesothelioma in chrysouis miners and millers 71 Q fN o so o C* Cv O >o r so -3 'O'tC*BDKOC"CtveX"O< C oooooooo rr---\ w t--o-> veooi eocc B----OO'O'O'nO"Ci Om'SOrVrO'we'hO"-i so 9\ e<OvNi' ~GtN %rOso oo O O'OOO'OOOO. VV Z *Mi*ab Z 'nfi'ab'ob'ee -g22^S2 212 =E -- *- o-- o-- * O O' O' O' O' ^f -Wtoo s>,,g; vW*o--St c c-- 55 C WWWUWUVMVMOMOMVn >>>->.>>>> >2 2o Zo 2t >,, s o o O' <**1 <o *>4 v& <\--D> v> VC c <<<<< -- O 2uO1mtr oi SO (M r-1 *VnO L. u U. L. U. L. A. D. McDonald tt ol TM9 ' TM21 TM25 Al A4 AT baker (16--38). noieiier 08-70.) watchman (27-70) welcer 122-27;; salesman (2S-65) carder (20-60; army (25-29;; truck mechanic (29-611 mining engineer (20-27); professor of engineering (30-65) chrvsotiie 1.6: tremoiite 0.6 chrysotile U.l. tremoiite 8.9 crocidolite 0.? Ths concentration of tremoiite fibres in the lungs of the barber (Al) 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 tn some 4000 men employed less than 2 years (McDonald et al.t 1994) and it is possible that the six cases tn men employed from 2 to 5 years were attributable to some other source of asbestos exposure. Tne 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, nvt had been employed mainly as tradesmen, for example, as mechanics, electricians, or carpenters. Limg 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 al1993; Case et a!.. 1997); detailed results are in Table l. 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, the findings, summarised in Table 2, are informative. It is fairly clear that tremoiuc 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 geometric means') Place of employment No. of cases Chrysotile Tremoiite Crocidolite Amosite Mines and mills Thetford Mines >4 12.8 104.1 t> t* Asbestos 5 4J 7.5 1.7 0-3 Factory Asbestos 2 2.1 0.5 6.4 0.3 "In calculating geometric means, a zero count his been replaced by half the detectable limit, *Al) counts were zero, that is below the detectable limit '~ ' '' Mesothelioma in chrysouie ramcn and miliers 15 employment and according to exposure accumulated by age 55. There was littie 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 deeree of exposure; after exclusion of the one death at age 40 (TM1). they were as follows: Number of mesothelioma deaths Thetford Mines: main compicx and the oldest of the smaller mines 23 the five smallest mints 1 Asoestos mine and mill factory S 5 Suoiect-vtars (000s) 65.14 6.01 60.64 10.84 Rate tpc: 100 0( subject years) 35.3 16.6 132 46.2 There are two main reasons lor the low Tate 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 Tnetford Mines (excluding the smallest mines) than at Asbestos (PscO.015), and the Tate for the factory was 3.5 times that for mine and mill in Asbestos (J*0.02). EXPOSURE-RESPONSE To examine exposure-response relationships within place of employment, we sought 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 in the factory them, 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 sendee (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 (mpef); and accumulated dust exposure (mpef x years). For a case, the calculations were carried out up to 10 yean 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, provided likelihood ratio (LR) statistics which are given in Table 3; those in the last line of this table were obtained after pooling years in *Tne working week had been of 60-72 h before 1938,48 h 1938-1949, and 40 h thesaalter, see Liddell et al. (1997) for details of adjustments. ' ' (Definitions are not given because of the completely negative findings;'see Tsbk 3. A. D. McDonald rt ai Tabie 2 Likelihood rano fLR) statistics, with degrees of freedom in brackets Theu'ord Mines Asbestos Nci service (adjusted years) Accumulated dust exposure fmpcfx years) 'fears (adjusted) worked in different dust categories Main complex 7 94 (1) /* = 0.005 o.i3 o> p~ o.7: 0.79 (2) .D-0.6S Mine and mill o 04 n i P - 0.85 0.30 Oj P 0.58 0.54 (3) P * 0.91 Factory o.oo n) P~ 0,99 0.16 (I) P * 0.69 Did noi convene adjacent dust categories, to avoid purported protective effects, and thus reducing the degrees of freedom. The LR statistics can be referred to the 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 compart risks among cases and referents at the mam 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 (P=s0.91), about as dose as it is possible to get to `provin a negative'. THE TREMOLJTE HYPOTHESIS Background 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 crocidoiite in the small products factory in Asbestos was of any scientific importance, even given the possibility or 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 (Rossitei ei al. 19721. Parenchymal changes were more frequent and more systematically related to 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)j>upported 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 M=soiheiionu m chrysouic miners and militrs mints located peripherally. Gibbs concluded that the cause might be related, to some mineral cioseiv associated with ebrysotile, possibly mica, talc or brunneme. A few years later studies of lung tissue at autopsy from miners and miliers in the Thetford area revealed the unexpected finding that, despite overwhelming exposure ic chrysotiie, amphi'oole fibres in the tremoliie senes were present in similar or greater concentration (Pooley, 1976; Rowlands et al., 1982; Churg et al., 1984). This ied to speculation as to the relative importance of chrysotiie and tremolite fibres in the causation of human disease. Indications that this was no academic question were shown by cohort mortality and radiographic studies of vermiculite miners and millers in Montana exposed to contaminauon by amphibole fibres in the tremolite series but to no other type of asbestos (Amandus et al., 1988; Armstrong et al., 1988). In terms of radiographic changes and mortality from iung cancer and mesothelioma the results of fibrous rremolitt exposure were on a par with crocidolite and thus might explain much of the disease observed in chrysotiie miners and millers. Geographical distributions By the end of 1988, 33 deaths from mesothelioma had been identified in the cohort, sufficient to show that the risk of this disease was two to three times higher in miners and millers from Thetford Mines than from Asbestos and perhaps higher still in factory workers (McDonald et al., 1994). A small number of lung tissue samples taken at autopsy from ex-employees in the 1980s showed that fibrous tremolite was present in both regions but that the level of exposure may have been about three times higher in Thetford. By the end of 1992, the total number of cases had grown to 38, all but five in miners, and millers, 25 from Thetford Mines and eight from Asbestos. A detailed analysis of work histories showed that the cases from Thetford were predominantly .n t.-so who had been employed in a localised area of five central mines (Area A) rnthcr than in ten mines located peripherally (Area B) (McDonald and McDonald, 1995;. Lung burden analyses made some years earlier by Sebastien et al. (1989) subsequently indicated that concentrations of tremolite fibres, but not of chrysotiie. were some four times higher in Area A than Area B. Moreover, the mines in Area A were the same as those identified by Gibbs (1979) as carrying the highest risk of pleural calcification. A recent re-analysis of representative samples of fibres from the study by Sebastien et al. (1989) showed no important difference in dimensions or elemental composition of either chrysotiie or tremolite between the two areas. Geological evidence The potential importance of geographical differences in the distribution of tremolite warrants some consideration of the geology of the region, well described by Riordon (1957). Among the amphiboies, tiemolite was rarely mentioned nor its form, whether fibrous or not. The chrysotiie in Aica A tends to be less harsh than in Area B. Differences between mines were examined in a starch for the aetiology of pleural calcification by Gibbs (1972). He noted that the distribution by mine of more than 150 mineral/rock types, indicated that rarely did a specific minejjd occur in Area A which was not also found in Area B. ' ' ~ l r A. D. McDonald et ai A key factor m tremolite occurrcncr may be the frequency and nature of wha; nave been termed 'acid/sycnitic/aplinc/fclspathic' dykes. In Area A, these numerous acid dykes occur as irregular shapes, often at shear zones m ine serpenunised roc/;. According to Cooke (1937) the freshest dykes consisted mainly of oiigoclase feldspar altered through kaolimsauon to 'needles of tremolite, actmolite and colourless pyroxene'. Later. Riordon (1957) noted that serpenunised peridoute near contact points with add dykes was converted to talc and tremolite. While tremolite had been noted to occur at the margins of dykes in Area B, the pattern m 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 aciotc dykes being the main factor in the higher exposure of workers in Area A to tremolite. 77ic hypothesis tested Following the preliminary- report by McDonald and McDonald (1995), a formal test of the hypothesis that the risk of mesothelioma was higher in the mines with substantial tremolite contamination was mad: 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 m 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 (PwO.Ol). 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 ihe main complex in Thetford Mines Net service (20 adjusted yean) Accumulated dust exposure (300 mpcfxyears) Some or all yean in central area* 2.50 (1.4SM.20) 1.28 (0.44-1.75) All yean in peripheral area* 0.80 (0.27-2.38) 0.32 (0.06-1.76) "Classes C and M. "Class P. Mesolheboma in chrvioliic miners and millers ?r the very wide confidence intervals, and as the point estimate is well below unity it is quite unrealistic. The siight 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 bemc associated with a 'significant* LR statistic). One of the reasons that the estimates for ciass P are so unreliable is that it contained only three cases (TM1, 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 1.11 (with very wide confidence interval, 0.47-2.62, and hence negligible significance: Pw0.84) in the peripheral area; see also McDonald and McDonald (1997). Tnese 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 35 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 contrast for only 2-4 years, and causation is more doubtful. This does not, however, affect 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- 42 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 amositt, 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 Tnetford Mines, there is clear 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 m 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 to offer the best explanation. The only candidate capable of filling the role is fibrous tremolite, and there is considerable supporting evidence. Its pathogenicity and carcinogenicity have been amply demonstrated^ j.nd lung burden analyses suggest that its geographical distribution in the mining region is closely related to the pattern of mesothelioma risk. Geological knowledge, so fai as TIF A. D. McDonald et at i: goss. is also compatible with this hypothesis. It does not follow that pieural calcification and mesothelioma have the same mincralogical 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 (set McDonald, 1997). The fact that the risk of mesothelioma was strongly related to years of service m the central area at Thetford, but hardly at all to accumulated dust exDosure. suggests that employees were exposed to ircmolite intermittently, probablv 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 substantia] 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. Tne 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 unconiaminated chrysotile carries very little risk of mesothelioma. In Asbestos, exposures were not to unconiaminated chrysotile. 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. Even so, it remains desirable to minimise, perhaps by screening, the contamination of commercial chrysotile by amphibole fibres, however difficult this may be. Acknnwledgemems--This paper has depended on work on the cohort earned out continuously sines 1965 and made possible by the help of people and agencies too numerous to mention. 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