Document QgJ1o9N84BGkxqM8ZqwREdv57

difrerenr.ative expression.... !M;veioid jeukemcgenesi' i? a muJtistep process during which a cions or cells acauites a succession of abnormalities cha; ultimate!-.' leads through subcior.aJ evolution to oven leukemia. PruLp ]. rlalkow, clonal revolution of Human Myeloid leukemias, GENES .AND CANCER 115 1984 i. With this language. Fialkow seems to recognize that AML has several forms and that otuv one form is like CML in developing donaliv ir stem celis. He also seems to suggest that mveioid. in contrast to lymphoid, leukemia undergoes a mulnstep process, thus recognizing several distinctions among various types of leukemia. We fail to read this passage as providing sufficient supporc for Ttitelbaum's contention that all types of leukemia are so closely related in terms of how and whs- thev develop that thev can be treated interchangeably. The Austins have not indicated whether i lectlbaum's theory can be or has been tested anc have not directed us to anv location in the record where other scientists espouse this theorv. '2C,I The Austins cue the testimony of KcrrMcGee's toxicology expert. Dr. Gary Kneger. who testified that benzene can affect the piunpotenual stem cell. However. Knrger testified rha: benzene can attack at a varietv of places and that benzene-related leukemias have been recognized at slightly more differentiated cell levels. He testified that while benzene affects the piunpotenual stem cell, it has never been shown to cause the lesion called the Philadelphia Chromosome, which he opined is wha: causes CML. Furthermore, to refute KerxMcGte's theorv that benzene does not cause the development of rht Philadelphia Chromosome, the Austins ti om: oniv- to Fialkow-'s o ant er. in which Fialkow- merely suggests that the initial hit or mutation occurs before the Phiiadeio4 hia Chromosome develops. The Austins give no further explanation regarding the -possibility that the Philadelphia Chromosome may cause CML independently of other possible causes. The Austins also contend that the epidemiological studies' authors' grouping May 23 2006 8:30AM choices demonstrate that in: different leukemia cell-types are so closely related m terms of f,cy and why they develop that thev car. be treated interchangeably. They rite D:. Ott: V.'cne epidemiological study. rFN9 jo which V.'cnr stated that based on the conclusion that transformation events occur at an eariv rnulapotent stem cell level, it was appropriate to combine lvmphoma and itukemi: in some of hi; analyses- But Wong"; opinion ;s not sc one sided- Despite the similanty between ivmohorra and leukemia that Wong recognized ;r. his study. Wong testified at the Robinson/Havner hearing that leukemia consists of different type; of diseases that have different patterns and different etiological agents. Simply because the author; group their findings under broad heading; like "lymphatic and hemacoooieti: cancer;" doe; not mean that the authors believe all leukemia; are denved from the same source. In one studv. the author, recognizing tha: verv few srudie; reviewed medical records or histoiogi: data to ensure correct categorization of diseases, expressed a need for more accurate categorization. Trains, supra, at 92. FN9. O- "Wong. An Industry-Wide Mortality Studv of Chemical Workers Occupationally Exposed to Benzene. 44 BRITISH' iOURNAL o? INDUSTRIAL MEDICINE 565 T98T- Addiuonallv. we find persuasive the ruimg; or. s similar issue in two cases tried in the federal courts. In the cases of Mitchell v. Gencorp int165 F.3d 778 10th Cir.1999";. and Chamber; v. Exxon Corp- 81 ?.Supp.2d 661 fM.D-La-2000 . the plaintiff; sough: to establish that the exposure of the deceased worker tc benzene or chemicals defined as benzene derivatives caused him tc contracr CML. In both casts the court; excluded the plaintiffs' scientific evidence because it w as not shown tc be rehabit. Although the scientific studies relied on in those casts are no: the same a; those rebec on in out case, tnev au suffer from the same defects, inadequacies, arm inconclusiveness. In those casts the court'- tount t.na: tnc experts' estimates and conclusions were mere that. guj<s-wCrk. and tha: th: expert:' assurance;- cna: the methodology and supporting data were reliable would no: suffice. In face, in Chamoe:.- eh: court pointed ou: tha: while no sruev rcur.o a staiisuraliv sigmncan: association between -ML anc exposure to benzene, to the contrar.'. there were several scientmcallvsigmtican: studies chat demonstrated no association between benzene exposure and the ceveiepmen: or CML. Chambers. 81 F.Sirpp.2d a: 664-cz. The Austins conceae that there is insufficient reliable daoa to establish an association between exposure to benzene and CML. In their bnef to this Court, thev state that CMC u a relatively rare disease and "mere simply arc not enough cases or the disease for epidemiologists cc generate a statistical!'.'- significant relative nsk...... N x benzene-exposed population is significantly iarg: tc generate the numbers -- required to create statistical significance." =292 A similar concession was made bv the plaintiffs in Chambers. 81 r-Suor.2d at 664 n. 3. The Austins aisc state. "Epidemiology as a science is ... handcufrec bv the persistent problem of rusciassificancr. of disease, and that problem is paruculariv relevant in the context of ClML." This lack o: scientific evidence is unfortunate, bu: as stated bv the Texas. Supreme Court in Hsvner. "Our legal svstem reouires that claimants prove their cases bv a preponderance of the evidence." Havhcr. 953 SAV.ld at 728. The lack or reliable scientific evidence cannot be an excuse for imposing liability without proof of causation. 21 22 23 Likewise, the Austins did not offer scientifically reliable evidence of specific causation, i.e.. that Austin was exposed to benzene at all. or if he was. to wha: degree orievei. Spccm: causation teauircs that a plaintiff she? that the imured person is similar tc those m tht eoiaemioiogica: studies, that he was exposed tc- tne same substance, and tha: the exposure or dosage ir-'cis were comparable tc or greater than tn ose :r. the studies. Havjier. 933 S.TTc a: ~2C- Tht Austin: concede tna: nenr of the actual mineral some: used b'- Austin was ever tested tor benzene The Austins' expert: oniv assumed tha: oecause met: solvents contain benzene, the solvents Austin used aiso contained benzene. Bu: this is inadequate tc show tha: there was anv exposure, and cerramiv i: is inadequate to show a level of exposure. It is fundamental tha: a plaintiff in a toxic tort case must prove the levels of exposure tha: art dangerous tc humans generally, and must aisc prove the actual level of exposure of the miurec party tc the defendant's toxic substances. See id.: Mitchell, 165 F.3d at 781. The Austins must show that benzene probably, or more likely than not. caused Austin's CML. See Hamer. 953 S.W.2d a: 720. In addition tc showing general anc specific causauor.. if mere axe other plausible alternative causes of CML that could be negated, the Austins mus: affirmatively exclude those cause? with reasonable certainty- See id.: Robinson. 923 S.V\*.2d a: 558. Before he worked a: Tuboscope and Surratt. Austin heic a job where he was a fcvstander tc pipe inspection activities involving radiographic techniques. Tne -job required that Austin wear a radiation badge that monitored the levels or radiation he received. Teitelbaum requested data regarding Austin's radiation exposure from his emoiovee badge. Teitelbaum suggested tha: carnation exposure could not have been ar. independent cause or Austin's CML. stating. "*Tlhe contributing cause [benzene exposure - stands whether we mode, it Eradiation" or non" However, he aisc suggested that radiation mav have been an alternative cause. He stated that he did not find any alternative cause, "other than the radiation issue." and he further testified. "Because radiation is always... o: potentially : 'one-nit' kind o: experience, single ionization could cause a genetic change anc remains a viable possibility....1 . citelbaum w-en: or. to come tha: radiation exposure was unlikin' or less iikeiv thar. benzene cc- have causec Austin's CML dccius: o: the size or" the dose of rcckiuor. that Austin received- However, like the Austins' treatment of the Philadelphia Chromosome as ar. alternative cause of Austin's CM-- the record does no: contain a nil! explanation o: the dosr-size or the duration of Austin's radiation exposure, or a ml] explanation of the reason tor * eitelbaum's decision to exclude radiation as a cause. Tcitelbaum stated that he received Austin's badge but did no: have data from which to model a radiation dose, suggesting a: best that the dose of radiation was insignificant. C-r We conclude that the Austins' scientific evidence does not adequately exclude exposure to radiation as a cause of CML. The Austins concede that exposure to radiation is a recognized cause o: leukemia generally. Yet. their evidence onlv assumes that Austin, who admittedly e295 worked m an atmosohere that exposed him to radiation, did not receive sufficient exposure to cause him to develop leukemia. These assumptions, in cum. are based or. "estimates" made bv the Austins' experts. These estimates, however, are not based on scientifically reliable data. As noced in Mitchell, 165 F.oc 778. absent supporting scientific data, estimates anc assumptions are "little more than guesswork. Guesses, even if educated- are insufficient tc- prove the level of exocsure in a toxic tor: case." Id. at 781- After thorough and careful review o: the Austins' contentions, as well as the record testimony and exhibits thev cite, we conclude tha: the Ausuns have railed to demonstrate the reliability of their scientific evidence as to either general or specific causation. They also have failed to exclude other plausible causes with reasonable certainty. We conclude that the cnal court acted within its discretion in excluding the Ausuns' causation evidence on the basis tha: i: faiiec to satisfy the requirements of Robinson and Havner. Accordingly, we affirm the ludgmenn ENT- OF EOCJMENT *** Pergamon / rrrvr Hrt vt>: Nc i {to W T W finuin Gceu^iuorul hy*icn: Soot-. Pubiitntd o Eitv*r Somcr Lie Al. nnu rorr*tc Primed ;n 6ru;r oar--tin*? si: oo-ooo Pfl: S0003--4878(97)00031 -5 CHRYSOTILE. TREMOLITE AND CARCINOGENICITY J. C. McDonald* and A. D. McDonald Department of Occupational and Environmental Medicine. National Heart and Lung Institute. Imperial College of Science. Technology and Medicine. Dovthouse Street. London SWJ 6LY. U.K. (Received 29 April 19971' Absmct--It has been suspected for many years that araphioote fibres m tbs tremolite series, a low eve! contaminant of chrysoiilc asbestos, may contribute disproportionately to the incidence of mesothelioma and perhaps other exposure-related cancers. A cohort of some 11000 Quebec enrysotile workers, 80% of whom have now died, provided the opportunity to examine this hypothesis further. An analysis was made of deaths from mesothelioma (21), cancers of the mne .'262). larynx (15). stomach (99). and coion and rectum (76). in men employed by the iarges; company ir, Tbetford Mines, with closely matched referents. Risks wen estimated by logistic regression for these five cancers m two groups of mines--five mines located centrally and ten mines located peripherally; tremolite contamination had been demonstrated to be some four umts higher in the former than m the latter. Odds ratios for work in the central mines were raised substanualiy and significantly for mesothelioma and lung cancer, but not for the gastric, intestinal or larynges! cancer sites. Jr. the peripheral mines, there was link or no evidence of increased risk for any of the five cancers. The hypothesis that, because of the difference in distribution of fibrous tremolite. cancer nsks in the central area would be greater than in the periphery was thus substantiated. That the explanation may tie in the greater' bioptTtisience of amphi'ook fibres than enrysotile is important :r. framing policies for the use and control of asbestos and is directly relevant to the selection of man-made mineral fibre suostitutes. . 199" British Occupational Hygiene Society. Puoiisheo by Elsevier Science Ltd. INTRODUCTION Since the observation by Dr Chris Wagner 40 yean ago of malignant mesotheiial tumouTS in crociooiite miners anc millers and their family contacts, but rarely in miners of chrysotile or amosite, the history of asbestos-related research has been dominated by efforts to assess the relative carcinogenicity of the main mineral fibre types isee McDonald and McDonald, 1996). While this aim was largely achieved for enrysotile in an extensive and continuing research program in the mines and mills of Quebec, and by numerous cohort studies of factory workers exposed to enrysotile only, until quite recently there had been no comparable data for crociooiite or amosite. Meanwhile, confusion was created by the inevitable difficulty of interpreting findings in workers usually exposed to amphibole-chrysotile mixtures in manufacturing and product use; this in mm gave rise to much bitter controversy. There were those investigators (the `chrysophiles') who believed the evidence to show a major difference between the relatively low carcinogenicity of enrysotile and the much higher nsk, particularly of mesothelioma, usually associated with amphibole exposure; others (the 'chrysophobes") concluded from much the same "Author to whom correspondence should be addressed 699 700 J C. McDonald and A. D McDonald evidence that all types of asbestos were equally dangerous. These arguments seem likeiy to continue (for exarapit see Smith and Wright, 1996). During the past 20 years the suspicion has grown, at least among the chrysophilcs, that the frequent contamination of chrysolite deposits by amphibole fibres ir, the tremolitr series may contribute disproportionately to the carcinogenic effects of occupational exposure. Beginning in the 1970s. newly applied techniques for lung burden analysis revealed the unexpected finding that despite the overwhelming exposure of Quebec miners and millers to chrysotile, tremolite was usually the predominating fibre present at death (Pooley. 1976; Rowlands ei al.. 1982). Wagner ei al. (1982) reported that the carcinogenicity of tremolite in experimental animals was similar to that of the other fibrous amphiboles and ir. a study by Churg et at. (1984) of six cases of mesothelioma in Quebec mine workers tremolite was reported as the predominating fibre type. The fibrogenic and carcinogenic potential of fibrous tremolite was confirmed a few years later by both mortality and radiographic studies of American vermiculite miners and millers exposed to tremolite, but to no other type of asbestos. The risk of mesothelioma, lung cancer and pulmonary fibrosis among these men was many times higher than that experienced by Quebec chrysotile workers (Amandus et a!., 1988; Armstrong e: al., 1988). Later, carefully controlled case-referent studies of deaths from mesothelioma across Canada, with detailed lung burden analyses, showed that whiie tTemolite was indeed the dominant fibre in cases from the Quebec mining area its aetiological contribution to cases elsewhere was probably fairly similar to that of amosue and of crocidolue (McDonald et al,, 1989). Given that chrysotile and tremolite tend to ^ccur together it has not been easy to assess separately their effects on mortality. Even in our Quebec mortality cohort, until recently the number of mesothelioma and lung cancer deaths was not large enough for a sufficiently detailed study. However, the most recent update of deaths in the cohort to the end of 1992 (see Liddell e: al., 1997) identified a much larger number of such cases among the 8000 deaths from all causes. From this total. 38 deaths were considered due to mesothelioma and it was estimated that some 65 deaths from lung cancer were in excess. Also important was the growing evidence that neither the risk of these two diseases nor the level of tremolite contamination was equally distributed across the Quebec mining region, both being higher at Thetford Mines than at Asbestos (McDonald et ai,, 1994). Of the 38 deaths from mesothelioma in the cohort, 33 were in miners and millers--25 from Thetford Mines and 8 from Asbestos, and the remaining 5 were in an associated asbestos products factory. Thetford Mines offered the best opportunity for study, partly because of the higher levels of tremolite thought to prevail there than at Asbestos but mainly because the industry at Tnetford originally comprised 21 mining companies, some located centrally and the others at varying distances peripherally. Six of the 21 companies were small and independent: the remaining 15 had been amalgamated many years ago into a large complex where 80 of the cohort in the Thetford area had been employed. . In a preliminary study, (see McDonald and McDonald, 1995), the work histones of the 22 cases of mesothelioma in men who had been employed -by the largest company at Thetford Mines were compared in detail with similar data Tot a large senes of comparable referents. The total number of years worked by the case senes Chrysoiii;, iremolhs and carcinogenicity 701 m the cleariy definable group of five centrally located mints Urea A) was six times greater than in 10 mines located peripherally (area B), whereas the ratio for the referent senes was 1.5. That this difference might be related to the distribution of fibrous tremoiitt in the ore body was supported by observations made by Sebastien e: a.'. (1989) of mineral fibres in lung tissue from 83 cohort members who had worked in the same mines and died from causes other than mesothelioma. In that investigation, the geometric mean concentration of mineral fibres 5 um or more ;n length was for tremolite four times higher in area A than in area B, a difference of very nigh statistical significance (p 0.0002), whereas for chrysotile it was lower in A than in B. Although this preliminary study thus provided evidence of a strong geographical correlation between the distribution of tremolite and the incidence of mesothelioma, the question of risk in relation to duration and intensity of exposure in the rwo areas was not addressed, and in retrospect it was felt that the referent series had not been matched sufficiently closely. The present paper describes a study designed to test the question of risk not oniv for mesothelioma but also foT lung cancer and other malignant diseases potentially associated with chrysotile exposure. MATERIALS AND METHODS Cases The cohort of 10918 men bom 1891-1920 who had worked for a month or more in the chrysotile mines and mills of Quebec, included over 4/'90 employed by the targes: company in the region of Thetford Mines (Liddell es ai,, 1997). Of these more than 80% had died by the end of 1992, giving the following numbers of cancer deaths for the current analysis: mesothelioma 22 (as before), lung 266. larynx 16. stomach 99. colon and rectum 79. Referents For each death in the five categories of malignant disease, referents were selected from men who had survived the case, closely matched individually for year of birth and age at first recorded employment in the industry. Ten referents were sought for each mesothelioma, four for each laryngeal cancer and one foT each cancer of lung, stomach, coion or rectum. In three cases of mesothelioma only six. five and three adequately matched referents could be found. A total of nine cases (mesothelioma, one; iung cancer, four; laryngeal cancer, one; colon and rectum cancer, three) had to be eliminated from the analysis, usually because tidier die cast himself or his only referent had had frequent changes of employment between areas A and B which had not been recorded. The number of cases analysed is shown in Table 1. Analysis From the detailed work histories for each subject, periods of employment in central (area A) or peripheral (area B) mines were calculated- Periods of service within 10 years of death of the case were excluded for all cases and referents: tKese exclusions were made to reduce dilution by periods of exposure generally believed to be actiologicaliy unimportant- For the mesothelioma cases and referents, the periods J C. McDonald and A. D. McDonald n t HI Z*! S .22P I *s>MN ^cs --r~ o?o -vc- 5t,i: -- o c> ; 2E g I'Cp.'^-WnPP/-rrcj*S5j: I1 rrwsI ia--(tscA--\* --. ' | I 5. =, 2, . ? ~i < a&_ pP*r Nr-->vi>px_i. --Je-K lI XI *: Ss v> w Si .< TV p*-. v, \ ^-. ; v% m . ec r> ~ - * O' s. c; l2??" U t s A*' N Ne-SOv f: c f*>l 2" - *Ss 1 i*5i S g ttf g ; 5 < --S"` --1 -V2;3 ipV Cfcrysoliie. trtmoln: and carcinogenicity JO!' were adjusted lor the length of the working week, as fully described by Lidaeli ti al. (1997). This was not done for the other cancers because the considerable amount of work required did not appear to be justified. Cases and referents were compared for years of employment m areas A and B by conditional logistic regression, anc odds ratios were calculated with 90% confidence intervals. The results are summarised m Table 1. from which it can be seen that the odds ratios for mesothelioma and lung cancer were raised quite substantially in relation to work in the central mines (area A) but not for work in the peripheral mints (area B). The differences in risks between the two areas are reflected in likelihood ratios, aiso in Table 1, which can be referred to the x* distribution with 1 degree of freedom, implying p-vaiues of approximately 0.03 for mesothelioma and 0.004 for iung cancer; that the latter is much the lower is probably a reflection of the larger number of subjects. Table 1 also shows there was little relationship between the other cancers (laryngeal, stomach or colo-rectal) and work in either area. That the main findings do not arise from greater intensity of exposure in area A than in area B is demonstrated by the time-weighted average levels of exposure of the referents during the same period, namely Tot mesothelioma referents 17.4 million particles per cubic foot (mpef) in area A and 16.3 mpef in area B, and for iung cancer referents '.5.1 and 20.7 mpef. respectively. As each average has a iarge standard error, all four can be considered quite similar. DISCUSSION Our studies of Quebec chrysotile miners and millers have consistently jhown iittic evidence of a cancer risk, except at very high levels of exposure and conclusively only for lung cancer and mesothelioma; it is important .to note that the evidence presented in this paper on the role of tremolue also applied only to these two diseases. With the exception of a cohort of asbestos textile workers in Charleston. South Carolina, where a high risk of lung cancer but not of mesothelioma was observed (McDonald er al, !983a; Dement et al., 1994), this has been the experience of the many other cohorts exposed to chrysotile only, in marked contrast to the far more serious effects of work with amphiboles (crocidolite and amosite) or chrysotile-amphibole mixtures (Hughes, 1991; McDonald and McDonald. 1996). Tremolite is also an amphibole and, although its fibres are seldom used commercially, it has been shown in the several studies mentioned earlier in this paper to share much the same carcinogenic potential for lung and pleura as CTocidolite. Our findings are thus plausible and consistent with tbt view that amphibole fibres are considerably more hazardous than chrysotile in man. If the incidence of mesothelioma and of lung cancer resulting from exposure to commercial chrysotile is mainly attributable to low but varying levels of tremolite fibres, effective steps are needed to minimise such contamination. In the meantime it must be accepted that for practical purposes chrysotile asbestos, as used commercially, may contain low but varying concentrations of fibrous tremolite. Tnt extent to which this increases the potential carcinogenicity of the coj^pyyrcial product must be kept in proportion. As stated earlier our most recent findings indicate that the excess mortality from malignant disease in our cohort, some 80% of whom had then died, amounted to 38 deaths from mesothelioma and some 65 "Oi J C McDonald and A. D. McDonald from lung cancer (Liddell e: ai. 1997). These men, born 1891-1920. had worked through years of very high dust exposure yet with no discernible effect on mortalnv from iunc cancer below an accumulated exposure of about 1000 (fibres/mDxyears and no case of mesothelioma among over 4000 men employed for less than 2 years. At present-day levels of exposure to commercial chrysotile, whether or not contaminated with tremoiite, the risk must be vanishingly small. Full reports on mortality from mesothelioma and from lung cancer in the cohort, with emphasis on the estimation of risk in relation to quantitative and qualitative aspects of exposure, will be published shortly. ^ The discrepant risks of lung cancer in textile workers are not explained by our findings but tend to suggest that the factors responsible were specific to asbestos textile processes, not only in Charleston. South Carolina, but also in Mannheim. Pennsylvania (McDonald ex a!., 1983b) and in Rochdale, England (Peto ex al.s 1985). where important amounts of crocidolite were incorporated in the process. All three textile plants showed a similar high level of lung cancer risk, with few cases of mesothelioma in Charleston but many in both Mannheim and Rochdale. The far greater durability in lung tissue of amp'niboie than chrysotile fibres underlines the importance of biopersistence ir. carcinogenicity and of avoiding this quality wher. selecting man-made fibres for industrial use. REFERENCES Amanaus. H. E-. Armstrong. B. G.. McDonald. A. D.. McDonald, i. C.. Sebastter.. P. and Wheels:. R. ('WES I Mortality of vemuculiie miners exposed to tremoiite. Annats of Occupational Hygiene 31 459 465. Armstrong. B. G., McDonald. J. C.. Sebistien. P.. Althoust. R.. Amandus. K. E. and Wheeler. P*. (19881 Racioiogicai changes in vermiculits workers exposed to tremoiite. Anrutis of Occupational Hygiene 32. 46V--4 .3. Churg. A.. Wjgp. B.. Depaoli. L.. Kamps. B. and Stevens. B. f 198-4) Lung asbestos content in chrysotile workers with mesothelioma. American Review oi Respiratory Diseases 130. 1042-1045 Dement. J. M.. Brown. D. P. and Okun. A. 0994} Follow-up study of chrysotiie asbestos textile workers: conor: mortality and case-reierem analyses. American Joumul of Industrial Mediant 26. 43:-^47. Hughes. J-. M. (19911 Epidemiology of lung cancer ;n relation io asbestos exposure. In Mineral Fibers arui Health, eds D. Liddell anc K. Miller, pp. 135-145. CRC Press. Boca Raton. FL. Liddell. F, D. K.. McDonald. A. D. and McDonald. J. C. (!???> Tnt 1891-1920 birth cohort of Quebec chrysolite miners and millers: development from 1904 and mortality to 1992. -4nnaAj of Occupational Hygiene 41, 13--36. ' McDonald. A. D.. Fry.-J-S. Woolley, A. J. and McDonald. J C. (1983a> Dust exposure and mortality in an American chrysotiie textile plant. British Journal of Industrial Medicine 40. 361-36?. McDonald. A. D,, Fry, J. S.. Wooliey. A. J. and McDonald, i C. (1983b) Dust exposure and mortality ir ar. American factory using chrysotiie, amostie and croddohte in mainly textile manufacture. British. Journal of Industrial Medicine 40. 368-374. McDonald. A. D.. LiddcD. F. D. K. and McDonald. J. C. (1994.) Malignant mesothelioma in Quebec chrvsotile miners and millers: a preliminary report. DHHS (NJOSH) publication No 94-112, pp. 22>- 228. McDonald.L C. and McDonald. A. D. (1995) Chrysotile. tremoiite and mesothelioma. Science 261,775 776. ' McDonald. J. C. and McDonald. A. D. (1996) The epidemiology of mesothelioma in historical context European Respiratory Journal 9, 1932-1942. McDonald. J C.. Armstrong. B., Case. B.. DoeJ). D.. McCaugney, W. T. E.. McDonald. A D- anc Seoastien. P (19891 Mesothelioma and asbestos fibre type: evidence from hmg tisru^imiysis. Cancer 63. 154i-'547. . . ~. . Pete. J.. Doll. R.. Hermon. C.. Bmns. W,, Clayton. R. and GofTc. 7. (19851 Relationship of mortality tc measures of environmental asbestos pollution in an asbestos textile factory. Armais of Occupational Hygiene 29. 305-355. Chrysolite. tremorne and carcinogenicity 705 Pooiev. F. D. (1976) An examination or the fibrous mineral content of asbestos in lung tissue from the Canadian chrysotile mining industry. nvjronmenio/ Research 12. 281-298. Rowlands. N.. Gibbs. G W. .and McDonald, A. D. (1982) Asbestos fibres in tbe lungs of chrysotile miners and millers. A preliminary report. Annals of Occupational Hygiene 26. 4| 1-415. Sebastier., P.. McDonald. J. C.. McDonald. A. D.. Case. B. and Harley. R. (1989) Respiratory cancer in chrysotile textile and mining industries: exposure inferences from lung analysis. British Journal of Industrial Mediant 46. 180-187. Smith. A. H. and Wright. C. C. M996) Chrysotile asbestos is the main cause of pleura! mesothelioma A mcricun Journal of Industrial Medicine 30, 252-266. Wagner. J. C. Chamberlain. M.. Brown. R. C., Berry. G.. Pooiey. r. D.. Davies. G. and Griffiths. D. M (19S2) Biological effects of tremohtc. British Journal of Cancer 45, 351-360. Pathology of Occupational Lung Disease *> Second Edition Andrew Churg, MD Professor of Pathology The University of British Columbia Pathologist Vancouver Hospital Vancouver, British Cofemfcic Francis H. Y. Green, MD Professor of Pathology The University of Calgary Calgary, Alberta Jfc zdttar Chares W. M;:cheii 'ianaring zz::or: Grar: Miiier Murvrnnj .VJjnaffr: ?;:;r Dare--' ?-Si2c::cn Caoremator: Raymond Z. Rr.s: ?'Oiee: Edits-: ui:u Lashr.vcicv Teat and Cote- Deiigner: Graphic Worid. inc.. Sc. Louis, Missouri iijjuiTCXion Planner; Lorraine Wntosek Tyoeierrer: Maryland Composition Cc.. inc.. C'.en ournir. Ma.-viani ,erm.*e' r~ Smder; R.R. Doruitliev h: Sons Cc., Ctawfords-.-iiit. inci-na Digitized illustrations: Marviar.d Composition Co., inc.. Gien Barr.u. Msr-uar.c Copyright O 1998 Williams Jc Wilkins 251 Test Camden Scree: Baltimore, Marviana 21201-2436 USA Rote Tree Corporate Center 1400 North Providence Roac Buiidine U. Suit: 5025 Mecja. Pennsylvania 29063-2043 USA a`oV*i'=. Ail rights reserved. This book is protected bv copyright. No part o: this boos rr.av be reoroaucsc in inv form or by anv means, including photocopying, or utilized by anv iniorinatior. storage ano rernsval system without written permission com me copyright owner. Accurate indications, adverse reactions, and dosage schedules for drugs art provided m this book, bit: it is possible that they mav change. The reader is urged to review- me packaet inrarrrur.on iata o; me manuracturers or the medications mentioned. filmed the United Suites of America Pint Edition. 1988. by 1GAJCU-SHOIN Medical Publishers, inc. . library of Congress Cauloguig-in-Publicauon Data Pathology or occupational lung disease! (edited by! Andrew Churg. Francis K.Y. Green. -- 2nd ed. . an. Includes bibliographical references and index. ISBN 0-683*30386-* 2. Lungs--Diseases. 2. Occupational diseases. 3. Lungs--Dus; diseases. I. Churg, Andrew, n. Green. Francis H. V. . (DNLM: 1. Lung Diseases--pathology. 2. Occupational Disease;-- chemicalVv induced. W? 600 P29~ 1??S] RCTJ6J3r 1998 616.2-4--dc2l DNLM/DLC :or Ubrarr of Congress 97-52344 ` OP The publishers hove mode every effort to trace the copyright holders for borrowed mstenai. Ifthey have madvertentty overlooked any, they will be pleased to make the necessary arrangements at the first opportunity. To purchase additional copies of this book, call our customer service department at (800) 636-0672 or fax orders to (800) 447-8438. For other book services, including chapter repnnrs and large quan tity sales, ask tot the Special Sales department. Canadian customers should call (800) 665-1148. or fax (800) 665-0103. For ail other calls origi nating outside of the United States, please call (410) J2W223 or fix us at (410) 528-8550. Visit TTJ/iami & XFtUcms on the iKsemet: bttpt//wvrw.wwSkins.com Or costae; our customer ser vice department at camerr^wwilkias.com. Williams 6 Wilkins customer service representatives art available from 6:30 am to 6:00 pm, 5T. Monday through Friday-ferr telephone access. 97 98 99 00 01 123456'S910 96 lnrrap*riton*ol and Intrapleural Inoculation Studies. Some :nvrsr;carors have aaopTeo the technique, originally usec v- Stanton e: ai. ;2., c: instilling fibers into the peritoneal or pieurai cavincs of experimental animals anc onserving tumor incidence. Tne most extensive studies were don; b1' Pen a;. 1 141 using mtraperitoneai instiliarion ot fibers in rats. The results of such studies are in a general sense similar to those seen \vjtn m vitro monolay-T cultures. Virtually all fibers oroduce mesothelioma. The effect depends on dose and to a certain ;xtent fiber icneth. Gnh fibers that are ex tremely soluble rail to produce rumors. Fibers that on the oasis of human epi demiologic studies are thought to produce quite different tumor incidences--for example, chrysotiie and amosite or crocidolite asbestos--produce essential^- the same tumor incidence by mtraptmontal inoculation. Although intrapleural and particularly intraperitoneal inocuiation tests form the basis ror the classification of giass fibers as possible human carcinogens '15. 16>. they are extremely controversial and have been the subject of considerable criticism f5-10. 17,1. The intraperitoneal test in particular appears to depend on a marked and very nonspecific sensitivity' of the rat peritoneum to foreign mate rials. This sensitivity is so extreme that even instillation of saline has been snown to produce a 6% incidence of mesotheliomas .5}. compared with iarae control series of untreated rats in which the incidence of peritoneal mesothelioma is iess than l/o Il8i. Other fibrous and nonfibrous particulates that have never beer, suggested to be mesothelial carcinogens in man. for example caiciuro-soaium metaphosphate, gypsum, sepioiite. basai:. silicon carbide, and even iron oxide, also produce increased incidences of mesothelioma in this svstem 114.. Use or inoculanon tests also bypasses normal fiber defense mechanisms, which prevtnr most fibers, particularly relatively soiuble fibers such as glass, from ever reaching the pleura. These tests aiso allow extremely long fibers, which may be highly carcinogenic, to reach the pleura by a totaljv nonchvsio* logic route, whereas such fibers could never reach the r?lcui2 or ever, the lung parenchyma by inhalation. Moreover, the doses used in inoculation tests often are massive. Last, inoculation tests by definition produce only mesotheliomas, and although some claim that this indicates the potential of the fibers to cause carcinomas ? 13.14;. carcinoma of the lung has numerous other well defined eti ologies. and probably is associated -at leas: in the rat; with parenchymal fibro sis. There is no rational mechanistic basis for using mesothelioma incidence by intraperitoneal inoculation to predict the parenchymal carcinogenicity of fibers. For these reasons most reviewers i'5-10. 1"- have concluded that inoculation tests are not suitable for predicting the carcinogenicity of fibers in man. Inhalation and Intratracheal Instillation Tests. There are numerous ir. vivo studies on MMVF, most using long-term inhalation and a few using intratra cheal instillation. Much of this material has been reviewed recently 8, IfU. The most extensive and carefully designed studies are those summarized by Bunn et al. '.IS - and described in more detail in Hesterberg et ai. :20! and others (21-23i. In these experiments rats were exposed by inhalation to glass fibers, slag wooi, rock wool, and refractory ceramic fibers at concentrations up to about 250 fibers per cubic centimeter for periods up to 24 months. Of note are the facts that the MMVF fiber sizes and exposure levels in these studies were roughly the same and that analysis of lung content revealed high burdens, indi cating piamly that the fibers were respirable. Table 11J summarizes fibrogcmcity and carcinogenicity of the various jvLMAT fiber types as determined from these and other published experiments.  roac. I 22$46 Federal Kegiiler / V01, 5;. No. mg / Friday. lunc 20. 1866 / Ruies and Regulations i 1 iow i 1? f-yicc (thii i*vl produced 1* prevalence of crepitations | and n exposure 10 hazardous workplace chemicals takes into consideration a OSHA has foliowed the** guioeiinet in making a determination tfia! the risk conatsteni wito live predictions made number oi iaciors that are conaiftmi of material health impairment resulting above. During the hearings. aeverti with recent eourt interpretations of the " from occvptnonai exposure to ttoestos i witnesses tirened the rang* of phyaicei and menial bn ability/impairment whicn may ocmf iong before even radiologic evidence of disease appear*. Typical of OSH Act and rational, obteettve policy formulation. As preaeribed by Section fbJ(J( of the Act. OSHA examiner (ha body of "best available evidence" on is aignificant. The eoidemtoiogicai and toxicological evidence and testimony pretented in the November nciiee and tr, Section IV (Health Eliecti) el this i then comments wen those made by Dr. Irvinf Selikoff of the Mount Sinai School of Madicine.He states; the ioxic affects of hazardous chemicals to determine the nature and extent of possible health consequences resulting preamble dtarry show mat exposure te asbestos is carcinogenic to humans snd additionally cause* disabling fibroiic , t. wkel yev re seem* an *-r*y u alwsyt from exposure to the hatardous agent in lung diaetat. Lung cancer commutes in. ! 'eery mock ieet than is realty present p%thvt*gtt*lty. Be that, when you ete a positive a-ray. there a a (air amount there in the rung .. . I've seen people with comparatively tittle on a-ray. who can t walk aeroaa a room. Bet by and large. aU II meant question. Quantitative risk aatestmenti art conducted, where possible, snd the results art considered along with other relevant information, each e the nature and aeverity of the health consequences, greatett health ruk to asbestos worktrs; in iota* occupational cohorts, this disease ha* been responaibla for more than half of the excess mortality from asbestos exposure- Malignant fr la that there a been scarring (TR. ?/2- p J70|. While several participants commented in general on the riek of asoestosts. there was littlt direct comment on OSHA t quantitative estimates of nsiu Hence, for these revised rules. OSHA has relied on the models developed for the proposal to predict the risk of tsbestoeis at the new to determine whether a hezardou* agent poses a significant riak to workers at th current permissible exposure level. The Agency also determines whether e reduction tn the permissible exposure level for the hazardous agent wj|] substantially reduce that riak. The Court gave tome general guidance 10 the Agency for arriving at findings of the significance of an cnsaothelioaea of the pleura and peritoneum, which are extremely rare among non-expossd persona, have been conclusively linked with asbestos exposure. Some studies of as bchosexposed workers have also mown increases in mortality from gastrointesuna! and other types o' cancer. It has been known (or yeare that PEL of 0-2 fi'cc. Using OSKA'a best estimate ef nek. that from the Fmkeistetn dm. OSHA predicted that exposure over working lifetime to the 2 f/sc levei w-H result in approxims'eiy a St incidents el aseettosis. Reducing occupational health riak. It recognised that the Agency's determination that a particular level of risk is "sirnifieafl!" will be baaed largely on policy consideration* [IUD v. API. 448 U-S- 6S5. 654. n. 82). To llluctrste how one may exposure to atbettot is the oniy known cause of asbestosis. a progressive, fibtoii: lung disease causing (fleet: ranging from inertness of breath curtr-r exertion to complete disability, respiratory and cardiae failure, and the exposure to 0.2 f/cS would result m a lifetime incidence of asbestosit of 0.5'.. While OSHA did not make predictions of risk at levels below 0.5 f/es in the make e determination from quantitative information that a health riak is significant, the Court stated aa follows; death. OSKA * determination that the health risks from tabeitos exposure is significant la baaed, in part, on the irreversible and ultimately fatal nature prepeeed rotes, testimony recetved curing the roiemaking increases OSHA's confidence that the Agency* estimates of risk at C.2 f/ccare valid and reasont'oie. This is due primarily to the It is the Agency's retoonalbiiity to determine tn the first utitsnce what It consider* to be a -significant" nsk. Same risks are plainly acceptable and others a r plainly vnaeceptabis. if. for example, the odds ate one in billion that a person wili c( these ditcam. particularly of lung cancer and mesothelioma. The finding (hat a significant risk exist* ia primarily supported by OSHA's quantitative risk assessment, which is comments noting the validity of the die from eaneer by taking a drink of bated on studies of tsbestos-exposed model In the io-w dose region- Given the difficulties in accurately diagnosing cases of asptsleaii and the fact that OSHA's estimates only take the risk of disabling asbestosia into account, OSHA believes thatlht Agency's estimates may be underestimate* of the true risk of ubestoait to exposed worker*. VI Sigoifiexact of Risk As discussed above in Section U1 (Pertinent legal Authority! the Supreme Court in the Benzene case [indusunJ Union Dtpcrvnenl AFl~CIO v. chlorinated **iier. the risk clearly eould net bs considered significant. On the other hand, if the odds are one in a thousand that regular bihslatioQ at gasoline vapors that an zk benzene will be fatal, a eaaaenabie person might <w!l eeniMer tbs riak significant and taka appropriate steps 10 decrease or eliminate It VUV x. API 444 US. at U5| Although the Court's example la baaed on a quantitative exprtetion of the risk, the Court indicated that the significant tick determination required of OSHA it noi "a raathtmtlical gtreitfoekei.** and that **OSHA la not required to support the finding that a significant riak exiau worker peculations. OSHA a risk assessment (discussed in Section V of this preamble) estimates that M excess cancer deaths (including those from lung and gastrointestinal cancer and mesothelioma! will occur among 2.000 worker* exposed at (he existing permissible exposure limit of 2 f/es lor 45 years, a working lifetime. Tne esumaits of mortality risk from mesothelioma. Vung cancer, and gastro intestinal eaneer are 14. M.. and excess deaths, respectively, per 1.000 workers exposed for 45 years at 2 f/cc- Amencon Peireieutn institute 441U.S. with anything approaching scientific OSHA also estimated the risk of lung T. (1MC11 ruled that, prior to the issuance of a new or revised algndard certainty " "A reviewing court (la) tc give OSKA eotne leeway where It* tance:. mesotheUomt- and gastrolntsalinal cancer for 2&-year and regulating occupational exposures to findings ptuat be made on the frontiers 1-year duration* of expoture to^asbeatoi toxic materials. OSHA must make a of aeieflbTts knowledge (and)... the at 2 f/ee. From thii analysis. OSHA determination that a "aignifieanr health Agency is free to use conservative estimates that die nsk from all tsbes'os- risk exist: and that the new standard will reduce or eliminate that risk. aifomption* in Interpreting the dale with respect to carcinogens, risking related canetrs among workers exposed from 20 years to 2 f/cs'* d4 exetsi OSHA s analytical approach to making error on the side of everprcieetior, deaths par 1.000 workers. The estimated a determination tost a significant risk of rathe: than anaerprotecticr" (448 U.S. at cancer riak from aU cancers among material impairment exists from 855. 856) worker* exposed to 2 ft sc for one yes: 1994 OSHA Standards. Preamble: There are at least three reasons for OSHA s decision not to separate fiber types. First. OSHA believes that the evidence in the record supports similar potency for chrysotile and amphiboles with regard to lung cancer and asbestosis. The evidence submitted in support of the claim that chrysotile asbestos is less toxic than other asbestos fiber types is related primarily to mesothelioma. This evidence is unpersuasive, and it provides an insufficient basis upon which to regulate that fiber type less stringently. As OSHA explained in the preamble to the 1986 standards. * * * to summarize the data on risk differential by asbestos fiber type, human epidemiological studies have suggested that occupadonal exposure to amphiboles is associated with a greater risk of mesothelioma than is exposure to chrysotile * * * No clear risk differential for lung cancer or other asbestos-related disease has been demonstrated by epidemiological studies. Animal experiments, however, have indicated that chrysotile is a more potent carcinogen than amphiboles when administered by inhalation or intrapleural injection * * * (51 FR at 22628). OSHA agreed with the testimony of Dr. Davis, who stated that "the evidence cannot answer ' * * with certainty * * * if "one fiber * * * of amphibole (is) more dangerous than one fiber * " * of chrysotile." (Ibid). Second, as stated in the 1986 asbestos standard, even if OSHA were to accept the premise (which it does not), that chrysotile may present a lower cancer risk than other asbestos fiber types, occupational exposure to chrysotile asbestos still presents a significant risk of disease at the revised PEL (See 51 FR 22649.22652). In particular, asbestosis. the disabling and often fatal fibrosis of the deep portions of the lung, is caused by exposure to all types of asbestos. The evidence on this is strong and no new information has been presented to contradict this. As stated above, OSHA estimated asbestosis risks at 0.2 f/cc exposures as an unacceptably high 5 cases per 1000 workers. Thus, asbestosis risks alone justify the regulation for chrysotile. Lung cancer risks associated with chrysotile exposures are also high -- 6.7 lung cancer deaths per 1000 workers exposed to 0.2 f/cc for a full working lifetime. OSHA notes that SB.Vs witness. Dr. K. Crump acknowledged that "(tihere s not a clear difference.v ** even in humans, for lung cancer * * * in terms of distinguishing the potency of amphiboles vs. chrysotile " (Tr. 4220). Third, the record show's that employees are likely to be exposed to mixed fiber types at most construction and shipyard industry worksites most of the time. Assigning a higher PEL to chrysotile would present the Agency and employers with analytical difficulties in separately monitoring exposures to different fiber types. Thus, regulating different fiber uEXHIBIT 1 types at differing levels, would require more monitoring all the time and would produce limned benefits (51 FR 22682). Consequently. OSHA believes that its conclusion to treat all asbestos fibers as bavins a similar potency in the occupational setting remains valid. Most of the evidence submitted to the remand Tulemakins duplicated evidence submitted to the 1986 standards' record, or was cumulative to tbe earlier body of evidence. For example AIANA appended its 1988 submission to the EPA. consisting of numerous studies and repons. Some of these documents were considered by OSHA in the prior rulemaking. There. OSHA had stated that the 1983 Bern1 and Newhouse study of friction materials manufacturing workers which found nonsignificant increases in lung cancer mortality, was inconsistent with other studies showing that low level asbestos exposure resulted in excess lung cancer mortality, because of the relatively shon follow up period used (51 FR 22618). Other studies involved lung burden analyses of mesothelioma victims, apparently showing that the pulmonary content of chrvsotile was within the range of the general population, whereas ampbibole content was significantly elevated compared to the general population (see e.g. Churg. Malignant Mesothelioma in British Columbia in 1982. Cancer, 2/85. 672). OSHA noted in the preamble to the 1986 rule, that there is a difference in tissue retention which would account for the autopsy results and cited a study by Glvseth et al. (Doc. 33-C. Ex. 312) which supported that explanation. OSHA also noted that "the differential lung retention of various fiber types has been demonstrated in animals." citing a study by Wagner which found that animals exposed to chrvsotile fibers developed lung cancer even though a smaller amount of chrvsotile was retained in the lung compared to similar tests with amphiboles. Dr. Weill believed that "these differences in tissue persistence may wholly or partially explain the observations (that exposure to amphiboles are associated with a higher prevalence of mesothelioma] in human * * * population * * *. Non-confirmation of fiber type differences in animal experiments may be related to the much shorter life span * * * (of experimental animals, which would not allow] the effects of varying tissue-persistence to be expressed" (Doc. 33-C. Ex. 99, p.3 8: 51 FR 22628). Therefore OSHA had reviewed and evaluated in the earlier rulemaking a portion of the evidence submitted by proponents of differential regulation of fiber types, and had rejected the claim that chrvsotile should be regulated less stringently. Some new- evidence on the issue of differential risks of asbestos fiber types was submitted by both supporters and detractors of that theory. In support of the position that chrvsotile asbestos exposure is equivalent in risk to amphibole asbestos exposure. BCTD submitted studies which indicated excess mesothelioma cases in workers exposed solely to chrvsorile asbestos (see x. 119 C. 1-136.125. Ait.6. 143 An C. 143 Att. Di. In support of the opposing claim that chrvsotile has reduced carcinogenic potential. AlANA and SBA submitted additional evidence. For example. ALAN A submined the World Health Organization's 1989 working report which'resgpunended that the exposure iimn for chrysotile should be reduced 10 1 f/cc or below (8 hourTWA>. where n was recommended that exposure to crocidobte and amosite asbestos be prohibited fEx. 21 A. p. 91. In particular, two papers by Mossman. ct. al. are cued as the basis for the claim that a scientific "consensus" believes that chrysotile carries a reduced carcinogenic risk fEx. 1-153. 151). Thus AJANA states that "since OSHA issued its 1984 asbestos risk assessment, the scientific consensus .that chrysotile asbestos poses lesser risks has solidified" (Ex. 142 at 3j. However. OSHA notes that various participants in this rulemaking, including N70SH and Dr. Nicholson, disputed the existence of such a consensus. Dr. Nicholson and others including Dr. Landrigan, in a letter to Science. (Ex. 1-155). dispute various interpretations of data in Mossman et al. s paper, and challenge the conclusion that chrysotile asbestos carries little cancer risk. Nicholson et al, point out that human studies show excess lung cancer risk that is proportionate to exposure across all fiber types, and that animal tests confirm these relationships. OSHA believes that the scientific community has not achieved "consensus" on these issues. Among the srudies submitted in support of the lowered risk of chrysotile asbestos, are those of Churg. and others show ing that the lung burden of mesothelioma victims is predominantly amphibole-. even though high chrysotile exposure levels were reported. As noted above, this line of argument was presented in the earlier asbestos rulemaking, and OSHA had concluded that lung burden studies are inconclusive. Additional response to this argument is provided by Dement who notes that "ulhe biological significance of post-mortem lung fiber burden data has yet to be established. These data are not useful as a predictor of disease for several reasons. Chrysotile is known to split longitudinally and partially dissolve in the lung whereas amphiboles remain in the lungs for ve^rs without significant dissolution * * w. Measurements of tissue fiber burdens many years afteT first exposure may bear no relationship to the carcinogenic events which likely have taken place many year? before clinical manifestation of cancer." (Ex. 1-2731BCTD pointed out in it? post-bearing brief, that "Dr. Landrigan testified, w'hile the observation that chrysotile does not last as long in the lungs as other forms of asbestos is not new knowledge (Tr. 1074 j. there is recent evidence that chrysotile is "the most effective of the three major fiber types at migrating to the pleura, that ins present in substantial amounts in pleural plaques and mesotheliomas, even in circumstances where it is not present or minimally present in the lungs themselves" (Tr. 1074k '` ~ Tne Agency also notes that the HEI report, in summing up its discussion of its literature search of studies examining the issue of the relative potency of chrysotile in inducing mesothelioma, stated: "(tlhe evidence that chrysotile rarely causes pleural mesothelioma is not conclusive * * and concluded that the absence of mesothelioma in one of the "two cohorts of heavily exposed asbestos workers who worked only with chrysotile * * * seem? likely to be due at least in pan to chance" (Ex. 1-344 p. 6-231. HEI concluded that "the mesothelioma risk for chrysotile was an issue of disagreement: some members of the Literature Review Panel held the view that a lower estimate should be recommended, as it would be more consistent with available data. The crucial issues, neither of which can be resolved unequivocally, are (1) what proportion of the mesotheliomas observed in groups such as the U.K. textile workers and the U.S. insulation workers were caused by their exposure to crocidolite or amosite: and (2) whether the best general estimate of the ratio of mesothelioma to excess lung cancer caused by chiysotile is provided by the Quebec miners and millers (about 1:4 or 1:5). or by the South Carolina textile workers handling Quebec fiber (zero')'' (Ex. 1-344 p. 6-32). Thus, although there is some evidence linking chrysotile to a lower mesothelioma rate than some amphibole fiber types. OSHA believes that there is insufficient evidence to show that chrysotile does not present a significant mesothelioma risk to exposed employees. Furthermore, the major disease linked to asbestos exposure, lung cancer, occurs at the same frequency among employees exposed to equivalent doses of chiysotile or to amphibole asbestos fiber types. Indeed, evaluation of all of the evidence indicates that chrysotile asbestos presents a similar significant risk of lung cancer and asbestosis as other forms of asbestos. Since these adverse health effects constitute the majority of diseases related to asbestos exposure. OSHA is still of the opinion that chrysotile exposure should be treated the same as other fonns of asbestos.  The New EngClland Journal of Medicine VOLUME 338 C CoD''Tiih:. 1901. n- tne Misutmutri; MaVIS. 1 99S aocitt- NUMBER 22 NON OCCUPATIONAL EXPOSURE TO CHRYSOTILE ASBESTOS AND THE RISK OF LUNG CANCER Michel Camus. Ph.D., Jack Siemiatycki. Pk.D.. anc Bette Meek. M.Sc. Abstract SBESTOS is a commercial group ot'strong. background Heavy industrial exposure to asbes tos causes lung cancer and mesothelioma, but it re mains unknown whether much iower environmental exposure to asbestos also causes these cancers. Nev ertheless, regulatory agencies, including the Envi ronmental Protection Agency (EPAl, have assessed tne risk of lung cancer by extrapolating known risks from past industrial exposure to asbestos to today's much lower environmental asbestos levels irougnlv 100.000 times lower!. We also tested the EPA's model for predicting the risk of asbestos-induced lung can cer in a population of women with relatively high Aductile, and fire-resistan: mineral fibers. These properties, which differ among different mineralogic types of asocstos. strongly affect its in vivo persistence and toxicity.Chrvsotile asbestos, which constitutes abou: 99 per cent of airborne asbestos fibers in the general envi ronment. is cleared much more rapidly from the June than arnphibole asbestos5` it has been recognized for several decades that ex posure to asbestos at high Ieveis. as was 'common among asbestos workers in the firs; hall* of this centu ieveis of nonoccupational exposure to asbestos. ry. can cause lung cancer and mesothelioma of the Methods Mortality among women in 2 chrysotiie- pleura and peritoneum.4 Among asbestos workers, asbestos-mining areas of the province of Quebec was compared with mortality amo 3 women in 6C control areas, and ape-standardizeo mortality ratios were derived. With the help of an expert panel, we estimated past exposure to asbestos among women in the mining areas and used these data with the EPA's mooel to predict the relative risk of iung can cer. We then compared this prediction with the ob served mortality ratios. Remits On the basis of the estimated exposure tn tne asoestos-rpining areas, a relative risk of death nearly all mesotheliomas are induced by exposure to asbestos, whereas most lung cancers are attributable tc smoking. Ye; because mesothelioma is so rare, asnestos-induced cases of lung cancer greatly outnumber cases of mesothelioma among asbestos workers/ " In the 1980s. after labor-union campaigns and eo' crnjnemal regulations had greath reduced occupa tional exposure to asbestos, public attention turned to environmental exposure.'^ Pressed to recommend : preventive regulations and remedial measures, public due to iung cancer of 2.1 was predicted by tne EPA's health authorities assessed the risks of asbestos- model, amounting to aoout 75 excess deaths from induced cancers in the general population on the lung cancer in this population. By contrast, we cal ; basis of occupational data.*"12 The validity of such es culated a standardized mortality ratio of 1.0 and timates of risk has-been questioned for several rea a standardized proportionate mortality ratio of 1.1 <P>0.05j, suggesting that there were between 0 and 5.5 excess oeaths from lung cancer among the wom ' sons.1422 Extrapolations were made to environmenxai exposure tc asbestos at levels thar were I . TOO.000 en with nonoccupational exposure to asbestos. Sev ; of those to which workers had been exposed in the en oeaths from pieural cancer were observed (rela - past. The arnphibole content of airborne dust cor. tive risk. 7.63; P<0.05). ' raining asbestos (aerosolsi is much lower in the gen Conclusions We found no measurable excess risk eral environment now than in historical occupation of death due to lung cancer among women in two al settings. In addition, pas; studies of occupational cnrvsotile-asbestos-mining regions. The EPA's mod- ei overestimated the risk of asbestos-induced lung cancer by at least a factor of 1C. (N Engl J Med 1998; 236:1565-71.1 "1898. Msucnuscru Medici! Soctetv Ttom tht L'nr ofEtnotmioioev and Swantatisi. insom: Armani-rrar Otct. Uiw-mirv or' Qiwbez. Ijvx. Qc IM.C . 1.S... tn? l/cD-iTnen- cf ec^ermotoP' and Bicmwo. KkGil! Lmnrmr-. Monttea' M C . '..5-- arci the Emirumnena! Healrr. Center. Haiti- Canada. Ortawj On: :M.C.. hi Adorer* nBrim nrquean to Dr Camus t tttt ininw: A' imnd-frappter- SSI Soul, do frame. Laval, QC H~V4Zi. Canatu Vnium: Nurr.rr- 22 1565 Tne Nt?- Enciand iou'nj1 of Medicine exposure to asbestos wcrt niethadoloeicalh limited, enure observation period. inun: wnmtr. 50 '-ears n; iee nr ho- dose-response estimates varied hv a factor of 1000 imonc studies, and estimates ot' the ask ol asbestosinduced cincer nave not been validated in nonoccupauonaliv exposed populations. c: there wer: 222.": rerson-vsars u; in: ascesn-s-mmin-.- .irejand S.62V.630 persnn-vears in trie retcrener areas The numerators n>r nur calculations cam: tr..m Que net's innulrr- regisrr . we notainez tnr oeath ccmhcarev nf women 30 in old nr nicer wim Dice irom .`9?0 to 1939 in Quthc.- fim Ue tested tie Environmental Protection Agency's .EPA's dose-response model tor asbestos-related lunc cancer in a population exposed to asbestos at Icvcis intermediate benveen those encountered by me: Tne mumcipafirv nere each wnman resided at tnr time fi ner deatn was used to amen tne Ocatn to ar. asoesms-minin-j are;, to an unespised reference area, n: in j ir.uniogaiir riciudcc from the anaivsis The conventional sunaardtted mnrtllir ratio and standard asbestos u-orkers and those encountered bv today's ized proportionate mortamv ratio were esnmared for tile two a>- urban populations. A smali region of the province of Quebec. Canada, produced most of the world's as bestos until 19->4 and remains the world's largest ex porter of asbestos. Between 1891 and 1980. asbes bcrtos-mirung areas senantei' and together, as comparcC 'vitr tht refertne: areas. Both measures are raous nf tne numren n-' nhserred Qcaths m (hr population unekT ttudv to the otrectec numbers, u-sh adiusoneni for ace and calendar rear For tnr srandardizeo mortality ratio, the expected number is bases on tnr tos-dust emissions and fallout were usually visible. Asbestos aerosols were similar truncralosically to those found in cities today; more than 98 percent were chrysouJe.2? Our study was restricted to wom ansoiuic mortality according m cause in the reference peipuiatmr. rev the standardized preaportumate nwinalitv ratio, the expected ' nomoer is eased im the proponion of all oeaths in tne reference population that are due tn each cause Tne confidence intervals lor tne standardized mortality ratio* were comruieu witti use of en in order to exclude most asbestos workers.2"' Bvax's ipprmitnaiior.: the confidence imeivai n.r each standard- in contrast to previous srudies of general popula j tzed proportionate mortality ratio was compered with use of jr tions.11-^ we estimated levels of exposure to asbestos approximation of the standard error of its natural logarithm ** in order to quantify the relation between asbestos xtimx* 1 Exposure to AsbMtos and lung cancer. We used data obtained from death certificates, which are adequate to study the risk of iunz cancer but not that of mesothelioma 2114 Ales- To predict the ns* of King cancer according to the nsk moas:. ws estimated the population's average cumulative itoosure in a-hestns. which u the product of the intensin- and me auntmn tv' otheiioma* are currently being investigated in a sep arate study. exposure. Tiles: two eiimnoncm* were estimated senareiei'- meach of three possible p-pcs of exposure; neighruirhood exposure, resulting from emissions fmm asbestos tninmc or milling in in: METHODS towns* outdoor air. housenoId emosurt. resulting fnnr. oust brought home b' asbestos workers, and occupatKinal exnosure The stucv comprised three dminci components. a moruiir We present here a brief sammarv of the rasner complex process rreo--- ii measure the actual relative nst nfoeath due to iung can- of assessing exposure, described in ottai* elsewhere 1 <e- and other caus.es. a historical aposure assessment. i"i a risk asicstmen: to predict the reJatnx risk of lung cancer on .k basis neighborhood xpo*we of the exposure assessment and tne EPA's mi. model. Wc as sumed. as ir. the EPA's risk-assessment modei. that the risk of eatr. oue to lung cancer -was ticariy identical to the ns*, of wnt cancer -- a commonh accepted appniximatmr. for diseases ir. vnich survival it snort Our nbiecttsT was to estimate historical isveis of asbestos in the mining towns and to dernt nme-weichted average exposure iveis for the 'arerag:' femai: resident, information on airborne esnesttts levels in the ashesios-mming towns was obuinee from connnuous mtasuremerrs nf dust made bv govemmen: acenc-- nr- Mortality Study ginning in 19"2i annual me.isurements of asnenot finer? sr. :r.r air. made m- the asbestos mdustrv since 3974. and r*t< recent sin- M:s determined rhr number of deaths that occurred oerweer. vcvs s'** To derrvt estimates of exposure tor earlier period. wr )9"0 and 2989 among women at leas: SO vun of age who itvee took the folknvinc steps to ootam evidence. :r. 2 cnn-sotiit-isbcsTo;--mining areas or 60 reference areas m the pmvincc of Quebec. An area was denned as a jtmuftof contigu Annual production volume- were computed for each asbestos ous municipalities with a total population of at itas: <500 The mining town from 2900 to 1964 areas where the population was exposed to asbestos were Thetford Mmes '.poputwwir.. 29.09s in 19S1 - and Asbestos ipopusjr ru>r.. U.22S . these rw areas comprised eight towns, of which Detailed insonr.ation about determinants of asbestos pollution cuing back tu 3900 was nbtamea -- specificaliy. tnr classes of fi three Tncriurd Mines. Black Lake, and Asbestos contained bers croduced. controls on emissions. locatKin nf mining m mill ncariv all tne asbestos mutes and mills. The residents of these ar ing sites and tailing piles in reuitnn to inhabited areas, urbaniza eas hvec within 10 krr of a mint nr mil1., and 80 percent mid tion, topographic maps, and the oirectnmai distnbutKtn nf wtnos within 4 km. .Among the other 65 areas in Quebec. 4 large urban centers and 1 shipbuilding area were excluded. The remaining 60 The relanor among levels of airborne dur.. annual asbestos pr'- reference area; were sprue across the province and had popuia- ductior.. and dost controls was tromarec iVir each mining tvt nuns ranging from 8000 n. 41.000 (total noDuunur, i.3T5.3?0 for the period mim 19~2 through 1984. and extrapolations were mJOSJ. ` ' made back to 1900. To compute the reiamre risk of oeath due n> specific causes in the asbestos-nnnim: areas, we compared the observed numbers of The frcpuenc-- and intensit' of past visible asnenos depositn-r cratn? tne numbers eipecteo on the basis oi the rates in the and the distance of residences fmm mines ana roiii' were estimat unexposef! area;. Since there was migraotm ir. and our of tne as- ed on tn: oasts of thr responses of 4 reprtscntaTi'e sampir o- Si" bettos-mining areas during the period of observation. tne stud' eideriv femaie residents to a survey. population actualr- consisted of different peonle each rear Tne annual noouiaitnr. numben. which wr used as denominators for Tnr vntum: and characteristics of asbestos ous: currer*:- retained mortaitn rates, were based on Canadian census Oau Over the re- tnr corns' dusi-emissmn filcranor jvnerm *r: cn::.-rc ir.n 1566 NONOCCUPATION AL EXPOSURE TO CHflYSOTILE ASBESTOS AND THE RISK Or LUNG CANCER j sunca-c atmsui-dispersion model to estimate jironrn; asr-esto: ;ere;S :r tn: tou-n m Asnestos. Queoec. benre tn; onset 01 Ous: controls ir. tne 1950:. ings ooliuitQ asnestos.-v in nnmes in naturahv enntarvim:: CQ areas of the world **l| ano in an experiment wuji emtnes c< tammated uitn asivestnj aus: Vi; jni'vieo th: relation i)trtcn the lunc huroen nr asbestos anc titr histories oi occuoatwnsi exposure among 89 Queoer miners an; tinkers sruaiec a? aucuosv hv Sebasiten et al 3' We men applied mat reijnon to in- iuns burdens nf 22 deceased resWcnts nf Inc mining area who ruo no uccuoational exposures to asoestns. as reported nv Case and Sebasnen.''- to estimate past cnposure lereis We ;ncr tsuil an imemaoonal panei nf fn-c experts or tn: measurement of exposure to asbestos to consider tne evidence Arte- evaluating the data critically, the panel estimated average eiciphbocfKKSQ exposure level* in the three mam mining towns list lour wv vears ,'JWS. 1960.1974. and 19B4), which cmxithe im portant phases in the implementation nf dust-emission control. The panci also provided guiaeiines for estimating rearlv average icreis front 1900 to 1989. based on the values for the key vears and on Town-specific asbestos-production revels (rig. 1.. Average annual ambient levels were estimated to hate Disced at 1 fiber per miiliiiter or more ;ihis value reflects the number of fitters longer than 5 rare, and visible on optical micniiajpv per milliliter of air between 1*M0 and 195-? and t<- hast been atxrve 0.2 liner per miliiiiter from about 1905 to about 2965, Tne panel thought that tne true vaiues were unlikslv to iie below- 33 percent or above 300 percent of their Dcst estimates. trterebv crovidi/ig subientYC niausibiitrv ranges, Furthermore. it was esnmated that the three mam Towns were * to 20 times more poliuted man me five other mu nicipalities tn tne two asotsun-tnining areas. ; i : I ' Household Exposure Sevtnrv percent of the women in the asbestos-mining areas rue: tad' itved in the same household as an asbestos worker.3' out mere were verview data regarding indoor exposure. VVe esnmated manor exposure on the basis of the results of autopsies nf 10 reswent? who nad irvec with asbestos workers. Using data on the relation between tns lung burden of asbestos and lifeume expo sure asbestos among workers, we calculated that the asbesios tuni burden of most JO residents had resulted from indoor as- . restos itveis tna: were rouphfv 0.5 fiber per miliiiner higher than th: outdoor reveis. This csrimatc was consistent with the meager Documentation or indoor asbestos ieveis <0.1 to 6.0 fibers be; rmiiiiitet in the nontes of asbestos miners in Quebec." in the nomes of cnrvsnnrc-asrcstcs miners elsewhere *'' ir. urban build Occupation*/ Exposure rmm out survev m the area, re estimates tns; .if>r>u: 5 fiercer.of local winner had worked ir. tn; ashcstni mausirs <.r na; mended bags used hr snipping asnestos. A large occuDanona smdv in the iocai asbestos industrv esnniatec tna: rne ie>v temair workers had worked tn less dusn ions uun mai: winters and nae accumuiared leas than. 50 fiber-tar$ per millmtrr ifiber-resrs are calculated by multtpivmg average annual exposure hv vears <v c posurc.35 We used this value to estimate cumulative exposure inthc proportion nf person-rears spent by the population ir won, in the atbestos indunn Duration of Exposure In 1989. hi interviewed Si" eldertvfemale residents of the a?bestos-mming areas about tiieir lifetitne residennai and etnpnment histones and those of the persons thev had lived with. Tr.:: inquiry gave us information about the numbers nf persnn-vr' nf residence tn the area, residence with an jsnestos worne:. j:ic ashesnis-reiated work for women of different birth inmin: each o: the asbestos-mining areas Cumuietive Lifetime Exposure ror each woman m the 1989 surety, th; lifetime cumuutn: neighborhood exposure was esttmaied by muiapivsnc rears m ;v posure bv the estimated asnestos levels tor each rear ana town tr which she had irvec. Cumulative household and occupatwmi! exposure wav computed ir. tne same wav but adtusted for discon tinuous exposure. W- extrapoutec vaiues for tne curr.uianv: posure of tn; women t survered to tn; entire exposed r-orup turn and tn; study period f 1970 through 19S9 i nv assuming ;r.j- the women interviewed m 1989 were represcntati'- m th; entire poputation with rtgarc to tn;ir histnrv of exposure Tabie 3 shows the estimated cumulative exposure for tn; pop- datKin tn the asbestos-mining areas according to th; ryp; of exposure. Neichborhood exposure represented about 65 percen: of th; studv population's average cumuiatne exposure, housin' iie exposure about 30 percent, anc occapationai exposure anou: ? percent. Th; esttmaaci astrag; cumubrne of exposure was 25 nner-vears per milliliter Considering the rang; of piaus-- bi; vaiues around th; expert panel's neighoarnooc-exrosure ; nmatCL the greater uncerumrv of the nmtsem.la-exrosare vO> < figure Mwn fcmoiant A*b**w* Lavis in Thre Atoeetat-Minins Towns in tr>* Pnavinet o< Oveoet. ^900 tnroupn 198, &asa on Esumattt dv an Exocn Panel. Asbestos levels are axoressad as the numoars of fibars tonga? tntn S <xm anc visibi* on ooticai m- croscoov per milliliter ol air. The vertical lines indicate the years lor wnicn the oana> astimataa irfies tos itveis 11945 1960.1974. and 1984;; other values were interpolated on tn oasis of local asbestos production volumes. * --w w Volume 535 Number 22 1567 ;n; Nr" eianc journa o' Median: Tabic 2 shows the standardized monalit'- rauos Twbu l..V-TA\r.- Cvw.cA't.'- L:?rnt ivw'.Utc r-ir ; T'-':. AX2L-'<'- .MlNI-' . A>-.'.`A- < --r.A'N.' 7- ~V5: '1- HemUi. !9"<l 7HH<ItT.ti 1 *>5^' ' and standatcuicd ptopOTOonatc moiuht' ratios ior death rrom selected causes tn the exposes ponuijlion. The standardized mortaiif. raao ua die two as- TTft or fcwwjW *TM*ne CuMuut-rwt fcXPOMM rib*yTfvol bestos-mininc areas combined was 0.9] for death from all causes {2242 deaths observed - and 0.92 for death due ro aU cancers (595 deaths observed There were T] deaths due to lunc .or broncruaj can NtuMjornoori {Tpomrt rtamsnoM nronr: 16 0 cer among the exposed women Th; standardized 7 S mortality ratio for lung cancer was 0.99 ?9> percent OcciiD3ttonji esomiirr ;.7 conhdencc interval. 0.78 to 1-25,, whereas the stand Tot.ii oimiiun>7 ucojurr >i*orrcti'7 DumiJirc nnsr o: iwoinir' Zj.O o-U? ' aidiicd proporuonate mortaiin ratio was 1.10 :9? percent confidence inters-ai, 0.88 to 1.38.. The con " VjI'.lC! iliOviK jit nvcntcs tc*f mmtii SO 'tin oi j*t Of okicr vi\o riT ; fidencc intervals barely twerlapped with the plausible ivint m in: rT3 iiiintoi mmmc rw dirnnc sn i6llo\v-up period, until range of the relative risk prediaed mom tht EPA's Miutcment ici the cuintton oi epoturt Mum jrr espmud in lioer-vcan per miiliirtci oi ji:. uiniuied t- mtitripwinB itin oi trpouirs trr the >' trjci oooiuft mil. inn reiteet cumuiatnc remndrnt-docl nvorofr '! tVws-itit Ac: tniSilw n tmit-iiti-.i i S.2 firrei-'-wn per tniilihtrr tn cntim model. The difference between the expeaed number of deaths, based on rates in the Ttrerence population, nnt tioowtc aicniiiec tc- wm ctpotcc sO noun per week and die observed number of deaths vidds an esti *Thf miitni't oumibi: nntt p-cr-idti tor erron m otimatmt pmi en ' irar.mcr.r.i. and nomtnoid ctposun if'Tii xnd lot efton tn lfimpiinc and muimne m cnif Moomrt-hntorv iiirve Tne iO-e: iunit of ? ricer-nrarj mate of the excess number of deaths in th; exposed population. Applying the relative risk predicted h\ rt: tmiiwtet corntoondi. t tsjrrolt. to (.< ot cvpotun to iidtstoi the EPA`s risk-assessment mood to the same expea x. j f'Ti f O.i hint tf milliliter tne .acm.ii mean ambient airborne -ntxi to; it' ci in the arti J974ms upper iimn :' !-> eonrtnondi. tor t: jmce. ic 56 vean oi tsocaurt re Z.r> fiixn cer miiithte: -- a rtatrvclv id" ed numbers, it is possible to derive the number of ex cess deaths that would be prediaed b; the mode!. nrreuutj ioti i:t icc.i: .libewoj-mitutic an.i ajiiestoi miTiine moiittnei o: rore ivec Table ? shows these computations. Depending on whether one bases the computation ot" expeaed num bers on the standardized mortality ratio or the stand maiei. and tns tincenainn- in hut eitrapoianon irxwn the samnit n: u-tirnsr, su.-ve'vd in '.9S9 n1 tns entire pKipuianun m the asneiV'f-rnir.irj ars.ii. "t oetrrmineo a suoicCTivr p'uujible ranui extsniiin; TTtrr. 20 percent t< 500 percent nr this estimate estimates of Risk ardized proportionate mortality ratio, the risk-assess ment mode! predicts between 68 and "o excess deaths trom lung cancer, whereas we observed C1 tc6.5. Th s. the EPA's risk-assessment model overesti mated the mortality attributable to asbestos bv a fac tor of at least 10 <68 4- 6.51. Tne dost-responst model used r> tnc SPA expresses tns rsb- There were, however, two significant eievauoni tn rnt risi of iunit cancer ir. a population as linear runaion of iu aseraite cumuiatne exposure t" ashestui ' as lolkrws. risks associated with residence ir the asbestos-mir ing areas. The standardized mortality ratio for pieu- K*i-V -51. ral cancer was 7.6? <9? percent confidence interval. vmttt N isthtti::orsr 'CTaa'.etv_ ti; the intrtis ir. the tc hits- tix>. of I'jr.a cancer tor racr. additiiina! fictr-vsir rer milliiicet nr curm:- 5.0o to 15"? - and the standardized mortaiin ratic for asbestosis was 23.49 '95 percent confidence in Lime esrisure. ia tits estirrtaie of mean cumuianvt iKCupitirinai txtMisurr nased "n a worewecu of 40 hours, and R ts trie rw nf terval. 2.o4 tc- 84.S?:. :icnc cancer ir r-n exposed cx'.huiatKC. as compared with that ir. cowrararie unexposea population ixnth similar jmoiunc fumts imc ustc ;.n: stanaarduec monaiin- mm ano the sundardoed nnipor- DISCUSSION Regulators politics regarding asbestos arc influ tionace mn^jiir' ra:u as estimates of thu reianve risk;. enced by estimates of the risk of lung cancer and Tn: EPA's estimate of K r 0.01 is tne jieumetnc mean of rtf _ mesothelioma attributable co environmental exposure acne-risk uradients estimated on the basis of data from 11 occuritiotia- studie: ' Tne model requires that tne exposed and refer- to asbestos. Such estimates axe controversial because encr popiciations ha't simiiar smokine habits, rspardiess of the they rely on unverified assumptions and imprecise da srr.okmc habits o: workers in tne ornnnai cohort studies. Accord- ta. In this study, the EPA`s model overestimated th; ire to the mooei. a continuous exoosur: of 16R hours c week is scur.-aien: ti 4.2 4G*nour woriwreeks o: exposure r< the same itve" o: airborne asotstos We app'ued thu model to the exposure ieve. estimates for the population? m tht asbestos-tninini: areas t>. nreaic: r.! rt:ati'T nsk of mnp cancer RESULTS risk of asbestos-induced iunc cancer among women who lived in chrysotilc-asbestos -mining areas be tween 1970 and 1989 by at least a raaor of 10. Such risk assessments may also overestimate the nsk of as bestos-induced lung cancer in other population:- with nonoccupadotul exposure. Gnxn the estimated average cumulative exposure Our units of observation were dusters of towns, o: the poouiatioo in the ashestos-mining areas Ta not individual residents, since it was dot feasible to ble 1 . the EPA model prediaed a rdatjve risk of identify' a large cohon of individual residents and as tunc cance: o: Z.Of ipiausibSe ranet. 1.21 tc- o.2r . certain their exposure" levels status. The ap- 1568 v..v :s '"os. NONOCCUPATIONAL EXPOSURE TO CHRYSOTtLE ASBESTOS AND THE RISK OP LUNG CANCER Table 2. Vr.AS-nAxniaiD Mohaltt KatuhSMRj and S'AMOAMnttn PuiroKnosikTi MORTALITY RATIO '5PM R.- FOR DEATH FROM SELECTED Ca'JLL' AMONG WOMEN in THE Asf.CTOvMlNIN; AAM.>, a< COMPARED 'VTT>: MORTAI.iT; AMONG WOMF.S is the Kinhence Porutxnos. from 19"0 through 1989 * Cauh o< Diaih Ali cjmr: Cnruuiwv ducua Respiratory oiteaia All'CKOtU aii eiKco Dieemve cancer Oral cincer Breast oncer GemrJ canee: Imnarv oncer Lrenpiunc or henuroooiutc cancer Reiptraton.- once' Laivn* Lone or wondm' Ftenre No. or DtATMt 224: 105" 1(H " 59? 205 4 130 64 JO 42 s: 7 7; BMR BSV C1I BRMR IKL a: 0.9) >0 5--0 95 0.89 '0.85-0 94 0.SI {0*5-0 95 23.49 .2.64-84 .83 0-92 <0.65-1.000 96 <0.85-1.10. 0 68 <0.16-1.74 0.88 <0.75-1 06; 0.55 <0.65-i.OS. 0.64 <0.31-1.52; 0.78 <0 56-1 051.06 <064-3.320 64 -0C--2.3: 0 99 rQ Tf-1.23 7.65 <306-15 73- 1 00 - 098 <0 94-1.02 0.60 0S 24 10 <6.0o-9s.5i 1.02 10.96-1.10j.(fe <0.95-1 Jl- 0."5 <0.38-2.00! 09" (0X2-1.15: 053 tO.73-1.16, 0.94 <0.60-1.46 0.15 10.65-1.13, l.!7 <0.95-1,45 0.72 10.15-2 83 1 10 <0.88- ; 3S sz\ u.r.-r,is Tnert *rt no nooceibrt dintrmco m momirr- bcmren the t-a-o Mbenoftnimnc areas ib: rirarh irorr. am- cans:, ocrr: tor rhe net that all *cvcn ricauts Tram eieurel cancer eccurrerf m ir.e Theitoni Mmo arcs Cl aenom cenndenct ntrenrai proach we used was nevertheless adequate, because Substantial bias due to confounding is unlike1.', in exposures to asbestos differed much more between this study. Both the exposed and the reference por- the exposed and reference populations than within illations were small-town homemakers of french- cither one. Furthermore, risk estimates such as these ; Canadian ancsstrv (93 percent who were born in are applicable to group averaees. the early part oi this century in a societ'- that was The study populations were dynamic; during the ; culturally and socioeconomically homogeneous un study period, peopie migrated between asbestos- ; til the 1960s. According to the 198' Quebec Health mining areas and reference or excluded areas. For ; Survey*4 and our local survey in 1989. the women in cultural and linguistic reasons, the population of the exposed and reference populations were similar Quebec was very stable until quite recently. The pros- , in ethnic background, lifestyle, and socioeconomic perity of the asbestos-mining areas attracted mi characteristics. However, the population in the as grants until 1980. Those who left this area most of- ; bestos-mining areas may have smoked slightly less ten moved to Urge dries that w-ere exduded from \ (25 percent were current smokers and 54 percent this study. Migration patterns would have been sim- ! had smoked at some rime > than the women in the alar in the reference areas, albeit with somewhat less reference areas (31 percent and 55 percent, respec in-migration. Migration from exposed to reference ! tively According to Axeison's method of correcting areas would not significantly have affected mortality risk ratios." differences in smoking status should not in the reference population, since it greatly.outnum have distorted the relative risk of lung cancer by bered the exposed population (by 40 to 1>. Migra- ( more than 7 percent. In view of possible confound tion from reference areas to asbestos-mining areas ing and bias due to migration, and given the low was not substantial, according to our survey of eld- mortality from all causes and from cancer in the as erh female residents of the asbestos-mining areas. - bestos-mining areas, we believe that the best esti Finally, exposed and reference areas had similar health j mate of the relative risk ofhong cancer fells between services, making it unlikely that out-migration from ; the standardized mortality ratio of 1.0 and the an asbestos-mining ares would have been more . standardized proportionate mortality ratio of 1.1. strongly related to lung cancer than out-migration - The results of the eclectic and varied methods from reference areas. For these reasons and because : used as the basis for the retrospective estimate of ex of the resuits of simulations with various plausible posure were sufficiently coherent that five expert? assumptions, we concluded that in- and out-migra- agreed easily on past levels of neighborhood expo rion could not have distorted the relative risk sub sure. Our assessment of exposure w-as similar to the stantially. ' assessment in historical eohotuwdies of asbestos Voiofn? S3? Nvrobrr 22 1569 The N?'- Erehnd o'' Mtoicm: Table 3. \r.tv> Death*. from Lvnp Cascsk tvomsv :\ ;'li- A<BE.rrm-M!*nNt. Aae.v. *< CuMrw' "Ttk '.`Hi f.E'" r-RJDlCTT.I' ON TH: OV TH?. ?.V' KjM.-A.sI!.\iev7 Mod?... Vaaasu S"*X 0* FoaMuu :oetren ncjm- Onttr>tri oeatns Obterixrl reiativ: rut? Ouaened caceu death' frediotcl reiam-r mkt rrerittd ricarn; I-reriicred eaceti deith' Rant- oi predined to ontenxh eactu aeatnr l 0 O/E O-E R fKR'E r-E rr-z:/iO-E Jl ro Ej-tbodho t*trees CHaina agu fUTta m Rnwiei Ama SMR spm:-. 71 4 ?: 10 -0 4J 2.1 146 4 ?3,0 Undcnncdr W> 71 U 6> 2.! 1*2.2 6" * 10.4 to asbestos mat be lower among nonsmoker than among smokers, contrar-- tr. die mood's assumption ot constant retain: risks"- And bnalh. tire EPA'*1- 2 3 * 5 * 7 * * 10 statistical anajvsis ma\ na-.-e overestimated the doserespons: gradient .a rcccr.: mcta-amivsis found tht EPA's esumate tci n: between 4 and 24 times too high: The results of this sruen are reassuring witii re spect to lung cancer, but there were significant e?.cess numbers of deaths due to pleural cancer 'seven deaths: and asbestosis (two deatns.. The instances o'pleural cancer suggest an excess risk of mesothelio ma. However, since historical death certificates re flect the incidence of mesothelioma pooriy.S5-u we have launched a separate study based on a province wide survey of hospital records. '3 otnoru the rzpccied number of oeatna m mu oopuutior,. nattrt on tht Ge.nth tries or proportion -of darns in tn? rritrenc? poouunor. O rh; oinerven number, and R th: relatni nsk trui a predicted m me population apphtny nit PAt modci to tht esomated etpotnre levei m mu poou unor iTnt cmnwr? ct tht numiteT or rtcers deaths m tht oonul.inon ncTTnch on tn: ntimr-tr tntl ""as eanecrrii on tn? cam oi tn: rare; of pmttr tn tnt rtterene? rconianor. Sint: w-c oertred r-o versions of eh? csoecrcr. nurr- ' -- on: uasert on tht awndaidized mor-uah- ratio >5MR and on: iuwr. on tn? jnmeurritaer. rropontonate morwiir. ratio 'SPMP- -- cn: tsett- nnmiitrs rorrapondmi: to ucn of thes? camiutioi't ir: thouti Oi'ico-c.- Otjtns ana prtoietcd rxjnmx nit art tn: onlv wnalncs in mis Table that tic no: oewnri on the tihecrcd number or" dams: tJiev art therefore neeei aani' entiai in toe n columns . iTnt neiatnx ranie tor O --I '*,as interpreted as an absfttc; of efieft C -5 & . leariins to an vndcrinee vatue for tn: ratio fT'-Xi/'O-E. 'mprontr'. m- contrac" urth Head* Carwr... .in,J. t", j tran: Tom tut N tion.l Heatu: Research and Df'-tiopmer.: iTCeranimj SHROf ci jr aa.: D: atenuarreii Mr ?nt reamer.: c .. s<noi.r A"-jr- torNHXDP anti i Vmnite Seiemvr Award iron m? inremaoorvi Acetic rcRcacarcn on Cancer Ur ar: indexed r< In: lucmcrr <:" in: arpr-T snn;. or, ixotuur: cjifsrmcn.- Dr.. J^rurr Cat: reCjmaa?.. ,\tmm Cimi r' u:: Ur.:::: iiair;. Gfi/ani Gtem nt CmuiAz. Hi.i:rt. S\tnuiir. >'-`rij.- Z.r.::tr. and Secnuier: n'pran::: ttu- c*uC0"r3i*~:. Mi".- tmnawma: rtrz :n: reiesrcr r.-airrr.-.? nir: i: e*r.- v:cr rnjTw.r Kjrr. inrar. Lt.iir^ Rtvisrxsvi. Man: Der. Louts: X*a<w;. Dent:: Beurnimnet:, aha Aisas /itn-v at to: inmru: -- mand-FmpvuT and znorr Leiotimeau a: m: Queer: Szisir.i:.' }> ran:; u ftifetsen Martere: BteiiaL'. jthr- Bauer. Anar: i>r-r,-/n. her. ArmstirnA. and Jtn: Hanirr a: .tfcGi.V L;"iscrnrvi Dtsa~- men: e^ipiermuiinjr.. Stasraim . am Oteuaatttna: Heaiti: rV- sitetr aatiee; anti sp Ai&enrrf Ledu: if Queer:: Er.r-.renmer,: Mr tirry. m- twin mm/ rn: campuirrtied &rrnui:-tvismtut r.rru:: non: workers. which also relied on incomplete data and on subieciiv: and imprecise retrospective estimates. REFERENCES These uncertainties and those resulting from the es timation of cumulative exposure on the basis of a survey conducted in 198*9 were accommodated by 1. McClelbn RC. Miller Ft. H?:r.*eri TV". ?: -- Apr-roJcn?' tn e\ait<.r me ihc ttiw *r<) OKinOKnicir- o: mcr..m.'flr fit-erj jimvn.t'- r: u-oresnof neW Kovxmotr ] 1 13. lOfli. bumJff.. Norm tbtoun. Kee:: Tostcol rrumuto! *09;.16.321 assigning a large plausible ranee to our best estimate of exposure levels. There are several possible reasons for the overcs- timation ofthe risk of lung cancer by the EPA mod el. First, the risk in the low-dcrse range may be less than would be predicted by a linear model. Second, cumulative exposure may be a poor measure of the biologically effective dose of asbestos (the actual 2. McOelbn RO. UtlterNer?: TSV Roir of tnonersurcncr in tit? pjtnctt niorv oi nun-made fiom and ittnhoos mt evsiuanne tnor-erunen;: atimman- ot tv o ronnd-ubic otacuuiom.. in'iron Ktalm Txraoee; !9-i lCC.Snppl 5 J-TT.S5 3. Vr'awne? 1C. Be n?' G- SkjaiTton Tttncrel' Tn? tireits of in? " haiation oi'atltenot m no 5r 1 Cancer -33.6 A. SeiMMKnr Pulmonar. beriotition ann citifanc: ot airnom: minemi ? ben. in Liddell 0. Militrr K. edj Mineral ai'en and health Boc.: Karor. Fb.- CRC Preat. ] 991 J2-4S 5. Upron AC.llatTCti 1C. teclUk.: Mt..?t 1 Aibesrot m nul'lic iru-tcor: ' metoal HiiMinjn a Itreraiuit review mri yvnthesn O' ctiftent know ic.-tc: dose that contributes to the risk of disease!. Third, exposure-risk gradients in occupational studies may have been overestimated because exposure was un derestimated, because of confounding by smoking, or because inappropriate reference populations were Camtmd*?. Mias Halrh iftten Inatitiiie-Atnatoi Reieart.. 1'. S. Achewn AD. Gardner Ml. Awotoj fh? controi iimi? ior aiireitcj ar upas?: of th: rtie\-am seaions oi tnt afenr ot uneatos upon nealtr. London' Health and Satcr*- Commaiioit. Her Matesn-1 Stationer? Orncr. 19S3 7. Nichouon Airborne uvettot heahn aaesamenr tipoar: t\a?hinc ron. D C Ofnee ofHalth anti eni-ironmertui .lautmen:. Em-nonntenta. used. Fourth, chrysotilc fibers may be less carcino genic than ampbiboie asbestos, which was proportionatelv more prevalent in the environment of the I-rotecnon Attne . 1966. -Rroor nt !>A-60<' 'S-W '003? I. Doll F.. Pcto 1. Aalrenos enecu on heairn otesroanre tc atheitc j-r oor.. Heahr. and Saaer- Commturor. He: .Matetr t itattonrr Oiht: 193:1 SJ _ occupational cohorts used to estimate the doseresponse gradient than in the general environment toda;.. Fifth, the relative nsk of lung cancer due I. Compmrnr on Ncmocoitntionil Health Rtua c: Aai'sswpnn nt-ett Aaoesnorm tibm nonoccupanonal heaim n**a Waihmcror.. DC S.;nona: Acaneim- T-reai. !9Rn 10. Repon o: tn: Rora! Comniaawn or. Martin-j:~Htani- and Sairr 157C Ma- !9o? NONOCDUPfiTlONAL EXPOSURE TO CHRYSOTILE ASBESTOS AND THE RISK OF LUNG CANCER Amin:: from rnr Uv o' Aii-w:sroi ir Gnraric. Vo. J Torouc- Onr/rtc Mmijrr c-i the '.nornrv Clcncrs: 193-5 1" Repot: it/ I1'* 2 Consume: I'tonnct Saten Commimcin i-- tot Cnr~n:.- Hxur' Anvijcrv J-anei on Aalcnos Hammeror.. D C Direcroi atr K hfJli"- iocnees Comi'mer f-roan;- Saterv Commotio1:. 19S2 12. Tonne. AI CoMiieri; A. Hemc"t D ; a. Ernes mr i.i same Of ;Otmf,-cic.U". uri 3 rioosinon .i (ami-ini: j-nj Let Editions 1NSEXM. 13 runcninnt.iD.ini. Wal! Sitcc* lonnui Seottmher IS. 1989 Alt 14 Ai'cnon TH Tne ooesios removal nasce Science 1990.24 7 1 01 " 15 licrr ` E?.\ and *su-esros rctnovj.' Science 1990.248 1595 IS Lance: AM. Noun P.!\ Ron M. Ausesros douo Science 1990:249 14 E - IT Hotsnun ET. Bienon Com M. Seaton A. Gee TBL. Ashesr-os sc- ; ennne developments and implications lor public polio . Science 1990.24" 294 SOI ' 18 Stone r. No meeonc ot the minds on aslieitoi Socnce 1991.2.-4 92S-31 ' 19 Nicltoison vr. lohnson M. Hampton IS. Meiius 1. Lafionean PI AwKfto*. arcmoeeiiiCiTv and ouhlic poiio- Science 1990,348 796 9 20. orofiv AR Asi-ewcs. carcinotcmeir-.. and otil'iic polio. Socnce 1990. 245 "9i '' 21. famueis .3V-' Aanesros. carcinoeenian. and public police Science ' 299C.24S ''93-6 ' 22 Mosman IT. Gee TUI Aoetos-reiated diseases N Enel: .Med 1989 52o:rc:-nC- 23 Seaasutti 7, Piourfie V.. Robb F.. Roes M. Nation 2. Wynnii T Am iuent a:r aioestcs surve-.- ir. Quenc; tmninc towns. 2. Main stud- tenon to Environmental Protection Service. Em-ironmem Canada Onatra. On: Environment Canaa.. 198t (Report nc. EPS 5/AP/XQ-2 24. Sicrr.iatveki ` Moruiirv m the tencrai population tn asbeetos mminc areas in Proceedings of the Woiid Symposium on Asbestos. Montreal. 19S2 Montreal Canadian Aabeetos information Centre. ' a. ; :.' -4l: 25. .\r,,-tenon HA ramiiv contact tooonirt. In Vrocecnir.cs oi the World s'-mnomirr. on .Asi-ejujs. Montreal. Mav 2S'27 ]9S2 Montreal' Canadian Afi-esicn jnronriition Center. 19S2.549-62 t= bc-r. ir.Mc CM. Srrenel VS'. Eace mortaiirv from stomaai can c:'. nine cancer, and asbestcsis and/or mesothelioma in crociooitte mminc . . 3^.:' . Attic.'. Am 1 Epidemiol 1986:122.30-40 22 Aa.nmonc EC. SelikoA I". Scidman H Aebesto* eirosurc. oearertr irokin: ann eeari: rates Ann N V Acad Sc: 19"9;330:4 7?-9C 2e 'a, ..ar C. Tertacivu t. Kalrii C. et a;. A Conor, sr.ifik on monaUv a;:.o-ic vivet :t n-orecn in tne asbestos cetneni indium in Cat.ii: Mon ip.'.n.. :ai- &r T ind Med 1993:50 **9-Re 7 1 nan*- 2 tr-nronnenicnT ei jiu-morni'iirc j Asbestos et Tnetiorti .e-C-ienec l9Sc.]S:9*-9 3. l a-no-./r StermaTvciu I. SHtnchet V. Pollution nsvironnemcnai: -ii ' jr.-ame same cubiinne an Qitebe; Union Med Can !9J2.Ui.4"r et 3' T\ Oncer m-miir. in reiauor. te asiaestci m mumopai note; scrr.ies .nr::: Emiror HeaWi 19":32:18r-9C 32 nis.K> !. Seinmau H. Seliod`]l. -Amoiit: mesotheiionia ui a cohcrr of twtswi .-otKets Stand 1 v.'otk Envuon ritaltr. 1989.13:100-10 33 Raw- ' Liiii Suzui-i V. Pennet L. Selieoffl!. Deatn cemncate cat- etor:carion cf rrantnant pienral and peritoneal mesothelioma in a conor c; asbestos insuuoor.Votacn 1 Soc Oceup Med !99i:4i,JJT.t. 34. aeliitr-fl'i;. ae:fmai- H Vt: of death etninenes tn eruoemioieieic.i! smdies. incmdine cca'Ostional hat-iros varuoons in ducoroance of dint; cw asneitet associated diseases on best evidcnc: ascenainmen: Am 1 lnb Med :9'2.2:4S: 92 33 arssic--' NE. Da- NE isaraticai metnods tn eantet ttstartr. Vo'.. Z Tr- ds$:sn and anairsis ot cohort tmdies Lvor.. France, international Attnc.- ;c- Rcseurci on Cancer. 19S" -1ARC soentm: pubiieatjons no 52 36 C.innis V. Lame cancer mortalrtv among lemales m Quecse: ! cnrvsc- nk asnestos-niinine areas cotnoaiei 'c Uim ortructed m il:e ! I p - exooi'in: tnec: mod:: .rub (heie Montreal MeCili U-nn-tnn , so<5~ 37 Cibm C1'.'. Rowlands N. bruiOtr: r. A ouoi tn.r.- on tn; me.iiurr ment oi airnome aioeiic*' note concentration! >" amincn: i- ' resmicc tne 'itfl Annual Mctnise of me hr i'ommon Conrrol .Assr>c:;nc<- Aici treal. njnc 22-2" 19SC: 38. Seuasuen 7. McuonaM 1C. McDonald AD. Cast l. Kafir F. Rest-, ratorv cancer in cntvtotue rexnie and muunt inrltisirics c-.Dosiir: inreten. es from nine anaivsi: h' ' inti Med .'989 4o )S(i " 39. Case B\V. Scnaitien 7. Fiore m nine ants corrciatron v tin an sart pies /r Bienon i. pete I. Saracci R. eoi Non-occtio.incru, ;imnu: ic mineral (lures, bvon. France lnttmanon.il Acenev tor Rtsea^n on Canes: 1989.107 IS ILAP.C KKCicitse owhiieations nc 9b 40. Nidiouon WJ. Rohl AN. v*'euman SclifoiT 1irssironnientaj isi-c ros concentrations m the United Stares in Warner 1C ec. Biological c recti or mineral Mam VoI 2 Lvofi. Prance intemanonal Atenc ic: R: search on Cancer, 1980 823 " lARC scientific P'liiiicanons nc 30 41. Gibin GW. bwchanc: M Dust exposure in the enrvsoti- ast-euc- mines and nulls of Queue;. Arch Environ Health 1972.24 IS0-?" 42. Carter Rr The maturetntnt of ailnsto* dust le'-eu in a oofunor er vitonment. Haruell, United Kmtdom Atomic Eneniv Wtaootis Kesjar; r. Escabnshtnen:. 1970 fRepon no. AEWJLE-O28/70 43. burniey KPS.Harries PC. O'Kellv FI Buikinns msniatcd u itn spraver asvcsrm a potenua! haiarrt. Ann Ocnip Hye 197:,14 44. S.iuVTt R.N. Asneiros cinosurt in a fair omlciine ananats ano rt'C.1' twtt. Environ Res 1977,13 146-69 45 CONS.O Researtn Corporaoor. EcOnomi; .man-sis c-f -nt rrsrosr.- revtiions to th: OSHA asossros srancjir.i ter constr.miC'i .mj esntr.:1 u- eusir. 'Vasfunetor..DC. beoarmtemofbanor, 1990 "Keuo-- n- 0:H; l-o-F-R-0933 ' 46. Rohl AN. Lanir-AM. Monmr: G. SeiicpF 17 Fuchneir: A Enosn- pkursl disease isiooitt.-i wnh tipesun to mistd aus: t; "ar*f Science 1982.216:518-20 47. Bans 1. Simonafo L. Arrvinii M e:Epinemioice:;ai .md environ mental evidence of Inc heattn stieos ot esoosnr: tc rnomt; ni'r:; .: ton- vest srudt m me Cappadocian rteion ofTurso int I Cjncc: !9S*,?9 ;v * 48. Coruramopouios SH. Condf-tno' . S.trjfii' N. Lint:: . 3r sieeeft* 12. Montsonoiiios HM Metso'd tunc- pieur.il ejion.jtioi: an,-, r: irricri'e mne mnciion m nprmwejtem Ciretce envi*onm:nrui ersccsure it mineral fiinr as etiolott- Environ Fes 19Si.iU.319-3: 49. Lancer AM. Noiait Rp. Consrantopouios SH. Moutioooniri H.V A- soeianon o.-'MeuovC lime and cietirai mesorneiiom vitn exi-osurr it rrementre-tonttiitiini -amttwasn. banet: 19S-;1-S>65 50. Luce D. Brocnard P. Qucne! ?. e: a.` Maiicuam pieural mesomthom. associated ivhh esposuri to rremoiite Lancer 1994.5+4.1"* 51 Goldnert Ti Luce D. pilion-Cialiand M.;.. *: a! Role potcntici dr I position cnuronnementai; et nomestuMi: a i.i rremoiite salts it ranee- o: b pieiTr en Noiivtli: Caledonre Rd Eeiaetmol same Puisucue 1995.43 444-5C- 52. Hum R. Differences bem-eer tne re-aerosobbiim- r:s(n:;.i aimcrnr chtviocue and atttpitinoie nusts C'tcij-.otor,. L'med Kinsnon-, .A'l-eno Research Ccnnc.-:. 19S2 53. Mcbsnald 1C. Lidoel' FDR. Gibus Gi''. Eraser Cl. McDonald AI- "utm ewosurt and mortaiirv in enrvsotiit ntmms. 19j0-"5 lir ) inr Med 1993.50.1058-"2 ` 54 Emonc A. Guvoi: L. Carmranri ?. Cncnar.4 L. P:ns.iult I-- Rcbicaili: V E: Li same, c.- tv Rapoon fie i ennucte iants Qniei'c.. !9S" Queue. Canada Mmistere ar u Sante et net aer ice; Sod-m:. 19Sf 55 Aieison O Aspects on contoundinc vtt occstpawr.iv e.islm eDinemvo e*v Roane. T Work Environ Kcultn 19*6.4 95-102 56. haracc; R. Asnesrot and ning cancer an anaivsit oftne ends nuOK>t:L- evioene; on the isltestos-smotinc meeracnor. In; 1 Cancer 19*",2C 2-12 3: 57. Lain TL. Ctoucn SAC. Green LC A meta arumit ct tne rtutiou ve rv+en ciimuatne eeoostir: to asiiciros ano reiatn-e nsa ot luitu cance- Occur Environ Men 19":54.254-62 VAium: ?35 Nuntre- 1571 N-JN* Home I Nearer: I Log to Full Texi ; abb o:' Contemn 1 Previous Article I Next Article The New England Journal of Medicine - May 28.1998 - Vol. 338. No. 22 Editorial Asbestos -- Still a Carcinogen Asbestos is an important cause of human illness. Clinical and epidemiologic studies have established incontxovertibly that asbestos causes cancer of the lung, malignant mesothelioma of the pleura and peritoneum, cancer of the larynx, and certain gastrointestinal cancers. (1) Asbestos also causes asbestosis, a progressive fibrotic disease of the lungs. The risk of these diseases increases with cumulative exposure and also with the length of time since the first exposure. Asbestos has been declared a proven human carcinogen by the Environmental Protection Agency (EPA) and by the International Agency for Research on Cancer of the World Health Organization. (2,31 The total number of deaths in the United States that will eventually be caused by exposure to asbestos is estimated to exceed 200.000. <4i . Asbestos is a generic term applied to a group of minerals, all of them fibrous. There are four commercially important forms: chrysotile, crocidolite. amosite. and anthophyllite. Chrysolite is the most important. It accounts for more than 95 percent of current world production. Nearly all asbestos used in North America has been chrysotile from die province of Quebec. Canada. (2i * .All forms of asbestos are carcinogenic. All have been shown in clinical, epidemiologic, and laboratory studies to be fully capable of causing lung cancer, mesothelioma, and the full range of asbestos-related diseases. (3) Although crocidolite appears to be two to four times more potent than chrysotile or amosite in its capacity to induce mesothelioma, all forms appear to be equally potent in their capacity to cause cancer of the lung. New use of asbestos has almost completely ended in the United States and in most other developed nations as the result of government bans and market pressures. Those forces were stimulated by the landmark epidemiologic studies of Selikoff and colleagues (61 and by the release of information on the carcinogenicity of asbestos that had previously been suppressed by the industry. Q) By contrast, extensive and aggressive marketing of asbestos by Canada and other exporting nations continues in the developing world, where sales remain strong. (S1 With the virtual cessation of high-dose occupational exposure to asbestos, medical and public health attention has turned to the risks of exposure at lower doses in the general environment. Particular concern focuses on the asbestos that remains as a legacy of past construction practices in many thousands of schools, homes, and commercial buildings. Qt Mistakes were made initially in dealing with asbestos in buildings. Pacpois in a few communities caused great harm by tearing out asbestos from schools with little regard for proper safety procedures. With the passage in 1986 of the federal Asbestos Hazard Emergency Response Act (AHERA). a rational set of legally enforceable control? was put in p\acs. The suidii. rnciple of AHERA is that asbestos ir. hiding is deemed to pose no hazard to health unless fibers become airborne and can be inhaled, (d i So long as asbestos remains in place and is protected from disturbance, it can safely be left alone. AHERA requires all school authorities to conduct visual inspections to identifv asbestos-containing materials: air sampling is inaccurate and is not required. The results of inspection and plans for dealing with any asbestos detected must be made public. Overall. AHERA has been a success. In the great majorin' of schools, it has been feasible to manaee asbestos in place. Removal <also referred to as abatement) is required on]}- when asbestos-containing materials are visibly deteriorating or when renovation is imminent. Yet debate continues about the risks of low-dose exposure to asbestos. - In a study reported in this issue of the Journal (10) Camus et a], used two epidemiologic approaches to assess the risks of nonoccupational exposure to asbestos. Both analyses were undertaken in a population of women in townships in the province of Quebec that have long been the major sites of asbestos mining in North America. Camus et al. first compared mortality among women in these communities with that among women in 60 other areas of Quebec (after excluding cities and shipbuilding areas). They then compared the number of deaths due to lung cancer among women in the mining areas with the number predicted by a risk-assessment model developed by the EPA. (3) Camus et al. found no excess mortality due to lung cancer among women in the mining communities. In addition, they found the number of excess deaths due to lung cancer among women in these areas to be smaller by at least a factor of 10 than the number predicted by the EPA model. Beyond lung cancer. Camus et al- observed that the rate of death due to "pleural cancer." presumably mesothelioma, was more than seven times the. rate in the nonmining areas. They also found substantial excess mortality due to asbesiosis. How can these findings be explained? Why does there appear to be no excess mortality from lung cancer among these women? One possibility', noted by Camus et al.. is that the dose-response relation between asbestos and lung cancer may be less steep at low doses than is assumed in the EPA model. Indeed, it has been suggested that there may exist a threshold level of exposure to asbestos below which no carcinogenicity is evident. 001 While interesting, this explanation is entirely speculative and not-based on data. Another possibility is that the past exposure of the Quebec women may have been overestimated; such overestimatipn would inflate their calculated risk. It seems most unlikely, though, that this factor could account for more than a small fraction of the difference observed in mortality due to lung cancer. A third possible explanation is based on the fact that the populations of workers on which the EPA model was based are known to have been exposed to the amphibole forms of asbestos: the women studied by Camus et al. were exposed only to chrysotile asbestos, however, and the model may therefore not apply to the study group. Although it is true that exposures differed there is no evidence that chrysodle is less potent in causing lung cancer than other types of asbestos. (LLi?l The most plausible explanation of the low mortality from lung cancer observed in this study is that women in the mining areas were exposed to an asbestos aerosoLifi-which many particles were too large to reach their lungs. Previous studies have established that the risk of canceT in the mining and milling industry is much lower than that in the industries that process and use asbestos, such as textile manufacture and insulation. In mining and*** *** milling, many , agglomerates and long curly fibers a. jspended in the air. These larse panicles are easily seen and counted under the light microscope, but they tend not to reach the pulmonary alveoli as efficiently as small particles. Thus, air sampling based on light microscopy in the mining environment produces a spuriously high estimate of true alveolar exposure. By contrast, in the asbestos-processing industries, large mineral bundles are broken up into shorter, thinner fibers. Many of those smaller fibers are invisible under the light microscope and can be seen only with an electron microscope. They are. however, readily inhaled and retained in the alveoli. It is this fundamental difference in accual pulmonary* exposure -- at the same level of exposure as measured with a light microscope -- that accounts for the profound difference in the risk of lung cancer observed between asbestos-mining workers and those in the industries that process and use asbestos; these risks differ by a factor of 10 to 50. (B) The EPA was fully aware of this difference when its model was constructed, and accordingly, the data from studies of workers in asbestos mining and milling were excluded. Qi Camus et al. (JO) go beyond their data when they- assert, without qualification, that the EPA's model overestimates the risk of lung cancer among persons with nonoccupational exposure to asbestos by at least a factor of 10. The EPA's current regulatory controls embody a level of caution commensurate with the hazard. The data of Camus et al. from their study of a population in rural Quebec with highly atypical exposure to asbestos would be an inappropriate basis for revamping regulatory standards foT asbestos in buildings throughout the United States. A final, take-home lesson from this report is that chrysotile asbestos is still indisputably a human carcinogen. The observation by Camus et al. of a more than sevenfold mortality rate (relative risk. 7.63) from pleural cancer in mining areas, as compared w th nonxnining areas, corroborates an enormous body of literature showing that Canadian chrysotile. like all forms of asbestos, is a potent carcinogen. (1,6) This finding is sufficient by itself to argue against any relaxation of public health controls on chrysotile asbestos. Moreover, it underscores the inaccuracy of recent efforts to portray chrysotile asbestos as safe. Q4> Assertions that chrysotile can be used without risk in developing nations are contrary to fact and extremely dangerous. (151 Philip J: Landrigan. M.D. Mount Sinai School of Medicine New VoTk. NY 10029 * 1 ahic o: Contents 1 Previous Article I Next Article Copyright 199S by the Massachusetts Medical Society. All rights reserved. To the Editor: Landrigan is wrong in concluding that "a more than sevenfold morality rate... from pleural cancer in mining areas, as compared with nonmining areas, corroborates an enormous body ol literature showing that Canadian chrysotile... is a potent carcinogen." This mortality rate (seven cases) is entirely explained by the few cases among women in the area who had occupational exposure to amphiboles in the manufacture of gas masks. CD repair of burlap bags that contained imported fibers. (2) and possibly, in one case, the tremolite brought home on miners' clothes. Q) Seven such women received workers' compensation in Quebec during the period of the study by Camus et al. Indeed, there is now a scientific consensus that chrysotile asbestos is not a cause of malignant mesothelioma, even among chrysotile-asbestos miners and millers. CD Reasonable caution should continue to be used in exposing workers or bystanders to chrysotile, but if the levels of exposure currently recommended by the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health can be maintained, public health workers can concentrate their work on lung cancer where it belongs: on smoking. With respect to women in the mining area, it has been established that the content of chrysotile and tremolite in the lungs is directly proportional to the number of years lived in the mining region and inversely proportional to the distance between the place of residence and the mining region. (2) In fact, these women were exposed to levels of chrysotile as high as 1 fiber per milliliter of air as recently as one month in 1984. Editor's note: ' Dr. Case has served as an expert witness in asbestos litigation during the past five years. Bruce W. Case, MX). McGill University Montreal, QC H3A 2B4. Canada References 1. McDonald AD, Case BW, Churg A, et al. Mesothelioma in Quebec chrysotile miners and millers: epidemiology and aetiology. Ann Occur* Hvs 1997:^1:707-19. Return to Text 2. Case BW. Biological indicators of chrysotile exposure. Ann Occur Hvc 1994:38:503-18. Return to Text To the Editor: Landrigan misleads readers with the statement. "Clinical and epidemiologic studies have established incontrovertibly that asbestos causes cancer of the lung, malignant mesothelioma of the pleura and peritoneum, cancer of the larynx, and certain gastrointestinal cancers." To prove his point, he cites only one report. The cohort cited by Landrigan is only one of many asbestos-exposed cohorts described in the medical literarure. That cohort has an atypical pattern of lung cancer, as compared with other cohorts. Our review of mortality from EXHIBIT Sn-.ah and Wright Stanton MF. Wrench C (1972): Mechanisms cf mesothelioma inoucuon '4rjgr.tr IC ; I'M'The aiscovtry of me aiiccuuon Oe:wee- >,,<. v.in ajocttos ana fibrous fiaii. t Natl Canes: Inst -;g;797-32:, and me>othe:iomas and me sttermaift- Sr 1 .no \Ui -8.299--C2, * Stanton MF. Layard M. Tegerts A. Miller . May M. Kent a :',(`77V. Ci-cmogtrucity of fibroua fiats: pleural responte :n me rat in relation :o Wagner JC. Berry G. Timers:! V (!9"2: Mesothelioma in -u sfur 'oer sirneniion. J Natl Cancer inst 38:387-603. inoculation w,m asoestoi and oiner msicnaU. 3r 1 Cancer 23:1 73-! 3" Stanton MF, Liysrd M. Tejem A. Miller E. May M. Morgan E. Smith A ;I98I>: Relation of panicle dimeruion to carcinogenicity in ampniboie atoev.coea and outer fibrous tmneraii. J Natl Cancer Ins; 67:963-973. Taicort JA. Thurber WA. Kantor AF. Gaenslcr EA. Oinihy JF. Amman KH. Li r? (19891: Asbestos-associated diseases in a cohort of sigsrauefitter corner*. N Eng) J Mefl 31i:)220-t223. Wagner JC. Berry C. Skidmore )W, Trrore:) V ;tr74': The effects af me inhalation of isoestes in rau. Sr 1 Cancer 29.252 -269 Wagner JC. Chamberlain M. Brown RC. Berry G. Pooley FT3, Davies R_ Griffiths DM (1982): S.'o.ojieai effects of urmoiite. 3r J Cancer ^15;.. 360. Thomas fir. Benjamin iT. Eiwood PC. Swetinam PM (1982): Further (oHow-cp study of workers from an asbestos cement factory. Br } ind Med 9:273-276, Viallat JR. Raybuad r. Passarel M. Boutin C (1986): Plecral migration of crvvsotiie Goers after intratracheal injection in rau. Arch environ Health 41:232-236. Weill H. Hughes J. Wajjtnspaclt C U979h Influence af dose and fiber type on respiratory malignancy ntk in asbestos cement manufacturing. Am Rev Respir Dis 120:345-33-1. ' WeU* 9/ (19773: Mortality of a cohort esposed ;o cnrysoiiie asoestos, J Oecup Med 19:737-740. . AMERICAN ,`CUR.NAi 0? INDUSTRIAL MEDlC'N- SC.2SI-HE - Chrysotile Asbestos is the Main Cause of Pleural Mesothelioma Allan H. Smith, md, pkd, and Catherine C Wright, mpm in contrast to omphiboie forms of asbestos, chrysotile asbestos is often claimed to be oniy a minor come of malignant pleural mesothelioma, a highly fatal cancer of the lining of the thoracic cavirv, In this article we examine the evidence from animal and human studies that relates to this issue. Reported data do not support widely quoted views regarding the relative inertness of chrysotilefibers in mesothelioma causation. Infact, examination ofall pertinent studies makes it clear that chrysotile asbestos is similar in potency to omphiboie asbestos. Since asbestos is the major cause of mesothelioma, and chrysotile constitutes 95% of all asbestos use world wide. it can be concluded that chrysotile asbestos is the main cause of pleural mesothelioma in humans. /Wrf wUry-Uij. Inc. KEY "WORDS: chrysotile, asbestos, mesothelioma, epidemiological studies, animal srjdies, amphibolt hypothesis, Stanton hypothesis INTRODUCTION Chrysotile asbestos is established to be a cause of as- bestosis and lung cancer. In fact, one of the highest nsks of .Asbestos inhalation is an established cause of cancer in asbestos-related lung cancer was observed in textile manu humans, particularly malignant mesothelioma and lung can facturing where 100% chrysotile was used (Dement et a1... cer. it is the main cause of cancer resulting from workplace 1994]. However, the opinion is held by some that chrysotile exposure to carcinogens. . asbestos is much less hazardous than crocidolite. amosite. Despite extensive cancer studies in humans, certain and tremolite. particularly where malignant rcesotr.eiioma is controversies remain about asbestos exposure and human concerned. McDonald et al. (1989] state: "Ampniboie as cancer. The primary controversy is the question of fiber type bestos fibers could explain most mesothelioma cases m in causation of mesothelioma. Commercial use of asbestos Canada and other inorganic fibers, including cr.rysotiie. mainly involves che'two amphibole fiber types, crocidolite very few." Wagner[199I] states: "There is overwhelming and amosite. and one serpentine fiber type, chrysotile. How evidence that crocidolite is the main fibre associated with ever. chrysotile asbestos is often contaminated with small mesotheliomas. There is no clear evidence that exposure amounts of uemolite. an omphiboie fiber. The key questions to uncontaminated chrysotile or amhophyilite is associated concern whether or not. and to what extern, exposure to -.with these tumors/* Two recent articles, however, have con chrysotile asbestos (including its natural contaminant trem- cluded dtat chrysotile is. in fact, an important cause or ma oiice) causes mesothelioma in humans. While there is evi lignant mesothelioma (Huncharek, 1994; Nicholson and dence that chrysotile asbestos is not a potent cause of ma Landriean. 1994). Nicholson and Landrigan conducted a lignant peritoneal mesothelioma fEPA. 1986: Doll and Peto. thorough review of the evidence concerning the carcinoge .1985}. the role of chrysotile in the causation of pleural nicity of chrysotile asbestos. In particular, they utilized the mesothelioma is still disputed. strong time dependence of mesothelioma risk to apportion the contribution of the different exposure periods, and thus of different fiber types, to the observed risk. Huncharek Senoei ot haM Nrim. univrs'fj' of Ca&foroa. Berkeley. CA. aceress r*pnni requests Allan h. Smith, M.Q.. ?a.G. htitsw tf toe*mio<ogy, Scrwoi oi hofe Kcaitn. Uwerwy or Cjiiioma. Serxeter. CA 94720. addresses some current controversufpfiffues surrounding as bestos health effects, and their relationship to cancer risk assessment and risk management. As these articles point Scctoitt for pwWiapcn January 26. '9=6. out. ihe question of the carcinogenic potential of cnrysotiis X 1996 Wiley-Uss. me. is nc\ cmy of scientific interest. but aiso has less!. expect ail the toe 10 nsk concra :o oc :::c:r.,r.;.-:.v ;-c-1c policy, and public heaUn importance. pmboit exposure cohorts. The purpose of this paper is to funher s.samrnt bom The hignest ratio of 88.1 preurat retscme-.-.c-r.aa z-z: umun ana animal evidence concerning the imccnanc: of l.000 deaths was for railroad macr.:r.;:ts :-ooseo re settle asoev.cs m causing malignant pleural mesoihc- chrysoiiie (Mancuso. 19881. This stucy r.aj ocen c.ni:z\nz ;z--z. Spec::.rally. we aav- identified the 25 tpioemioiogtc tor attributing the mesothelioma inc'.aenc: to enrysouie aohen stuoiss having the highest ratio of pleural mesothe- posure ratner than possible amombolc exposure '.Grilse:-.. .icrr.as per 1.000 deaths, and have assessed the rype(s) of 1989: McDonald and McDonald. 1989. Churg ar.d Greer, asbestos fiber exposure in the highest risk cohorts. V*e have i990J. Mancuso's responses to such cr,i;c:sn cemonstrate aiso review-p those lines of evidence often cited in support that the principal exposure of the milrcac machinists wzs ;0 of the theory that amphibole asbestos, not chrysotilc. is the lagging or removal of lagging, which was chrysotne. v/Vit pr.rr.ary. if not sole, cause of malignant mesothelioma. Such other joos may have used amphiboles. leading to the acs- lines of evidence include: results of certain epidemiological sibiiity pf secondary exposure to the railroad workers, re studies (such is the gas mask studies), and the "Stanton" made a strong case that chrysoiiie was the overwneirmr.s and "amphiboie" hypotheses. exposure to the machinists [Mancuso. I989a.b. '990]. A REVIEW OF THE EPIDEMIOLOGICAL DATA - A number of other epidemioiogicai studies nave beer, published but lack data that would allow caicuiation of pleu ral mesothelioma incidence. Begirt et al. [1992] described a series of mesothelioma cases in Canadian asbestos workers. A review of the literature was undenaken to identify All of these cases were seen and accepted by -.he Quebec available asbestos epidemiological studies. Cohort studies Workman's Compensation Board for work-reiated compen -.most recent follow-up available as of October 1994) were sation of industrial disease. There were 49 cases ir. miners reviewed for the following data: industry, primary asbestos and millers of the Quebec Eastern Township region. Twer.:- exposure (the fiber type to which the cohort or subcohort mesotheliomas occurred in miners and miners from Asots- had the greatest exposure), secondary asbestos exposure (fi tos. where trtmoiite contamination was similar :o back tter types to which ate cohort or subcohon had lesser expo ground urban levels. Twenty-nine mesotheliomas-occurred sure:. number of workers in the cohort, number of deaths, in workers from Thetfcrd Mints. wr,-re hnsr.er ieveis pf number of lung cancer deaths, excess lung cancer deaths. tremolite occur. Tne authors stated that. or. the basis ofur.e z~i numbers of mesotheliomas. Pleural mesothelioma inci number of workers exposed at each mine site, the inci dence within the cohort was determined in terms of the dences in Asbestos andTnerford Mines were similar cesrire -umber of pleural mesothelioma deaths per 1,000 deaths as the differing levels of tremolite contamination. McDor.aic well as the ratio of pleural mesotheliomas to excess lung et al. [1980. 1993] conducted a.cohort study of the miners ranctr deaths. When possible, the mortality data for subco and millers from TnetfonJ Mines and Asbestos. Oniy 23 . Z: horts with'greater than ot equal to 20 years since start of In the period 'S75-1988) mesotheliomas have beer, identi employment were used in determining mesothelioma inci- fied in the entire cohort of aoout l i.QOO men. 80% of when aence. Coheres were rank ordered from the highest to lowest had died as of 1992. According to. the authors, preliminary ra:io of pleural mesotheliomas per 1.000 deaths. analysis of mesotheliomas suggests that the risk of mesothe Table l summarizes the data for the 25 top-ranking lioma was higher in the mine and mills at Tnenoro Mines asbestos cohorts. Other'studies which were considered but (higher tremolite exposure) than in those at Asbestos (lower which ranked below the top 25 cohorts are listed in Table II. tremolite exposure). Their data, however, do not clearly Chrysoiiie was the primary exposure for at least two of the support this conclusion, especially in the high exposure 10 top-ranking cohorts [Mancuso. 1988: Pero et aL. 1985] groups where the rates of mesothelioma were 0.97 per 1.000 and was '-he secondary exposure or identified as part of a person-years for Asbestos and 0.92 per i.000 person-years mixed exposure in six of the 10 top-ranking cohorts. Cro- for Tnetford Mines. ctdolite was the primary exposure for three of the top 10 A number of other studies have demonstrated risks of cohorts {Jones et al.. 1980: Talcott et al.. 1989: McDonald mesothelioma due to chrysoiiie exposure. Borew : al. and McDonald. 1978] and was the secondary exposure or [1972] reported 72 cases of malignant mesothelioma in per identified as part of a mixed exposure in another five co sons exposed primarity to chrysorile in an asbestos mill. horts. Amosite was identified as pan of a mixed exposure in Fifty-three acceptable cases of chrysotile-induced mesotne- three, of the top IQ cohorts, but was not the pnmary expo liomas were identified by Churg et al. (:9881. Two mai;ssure in any of them. These findings suggest that chrysotilc nant mesotheliomas were reported in a small group of :s a major cause of pieurai mesothelioma. They are incon sistent with the claim that amphibole fibers are much more potent than chrysoiiie. If that were the case, one would former chrysoiiie miners and millers in Zimbabwe {Cullen and Baioyi. 19911. A case series of 80"mesotheliomas in railroad rolling-stock machinists and others in me Italian Snur. ana Wright TABLE I. Assesses Canon Studies iinn Pnturt SeeMeeir iunw utiim llUBiq tain MffMI > IIM OM> IllUt lure UKtil irn. r-Moi r,, rmw 1.U0 41MM 74wn (4en nUncute fI UnitM memra Cwi ^UllWf urn* wyiWi '.51 ffiwi'M !'S*M enn <1 L ilMOl Teccit m il !1W! uni me Simmon iitrn 1M vf JL Ctnun MMiee See eat MMMbm Seutni tar mwueon WaveMn iltnwft Cft/w crac Cm Cw UrWnewn Tcnta o*r> Cta MeQwuM m Zu *a. taOe--e Cm Om tw| us 1M t iW Ba !C in MS m ma r; li-HMSl - , ; f. ei. .-C, 7min' oreeuet U*n Se^tt* *i L. :st;4| Starve UilM imev WW vee Mine emev tfUYV sme Suvv 4IW n. Umeie m'V Mmon Mtnnrme M'*t *MwgeM 44 [IMS) aetemja me biien ;'C! *en* l taduojn Met me we tata Manw tamo S/oe Ttaw qmte nee 4teC im*V cwrv cot nmiiM Swan Utat *W tl*L Stamm tt *1. .U'l ** tin. <<MS( Stua<nmtr M IL pw*1 AeMm eentm Mnwaam Mtninen tan* Tmh tan; Usm m*n wrenewtg me SlMHm -1J4SI taeta M 41. '.'HSi Aetateetf. mMM H p * n :w fncaen UUIW Own Starvee >n MttMum Mm iiwm Ui mui KUMiewi A.` Clrn 700 1.400 30 14 CO LM * xooo i?joa 1B7S 1.4S4 CS Crae U11 PS 1ZS mh lltl 4.120 TJ7 tawe 7JM V* 1S7 rj 433 to GO 1 4t IMS SR m TV 1U f*3 W 3U It* 00s 11 HA a 21 < u S.7 11 ><U 24 tu 20 Mi ? e| 37 32.0 30 27 3 70 V 13J 27 1U 01 su ISO tea l.ttt MU 04 1S3 a lli n tu S3 UA U JJ <1 4} J7-t 13 II 1*2 721 , 1 4 3 s i i 11 1 3 2 7 1 a us 2 0 1 3 M 1 9 14 U_1 u tti 13 7IJ 2 n.e 4 U.I T Sil 3 Hi 14 S1.1 7 44J 3 41.1 17 401 ( 401' S a.a 31 3TJ m 141 a vi 13 si 0 111 to Ul 2 121 * H> < Ul 4 12J 2M 10 , 77 U Sit 211 Samoa *e up iinni -, ,s( mm. -t.-t-jiv? nm- WMI jiwir aim ;j ,,i,, vncj Vlt tmgiovmgm. Umc-.IS "5*1' <n*r*idn re: jnnc*iei naeivi <ru W v *>nvpr ei nee*?. _,t tvnoaa. wwi jen- i3t <n*, ue mmeew. m uesncuv % iMm SM Wl sen K', -eetspn inn MiWKi. 2& tun ran ami-, frmau 5n. 0.11 A 041 Oti 3*4 20> **n sen Oinsn manerei '; CMVin gr nncemenet nc: m wnefex. 5?i. u6i j 2? mi- 3 nau wn; anuri uv 3vi es-Nn. Snoot mm cm. rmsmrn 25- <un e> 10* W>vci egtwi 'ns. .fln mam grwa. ^aoeMm euai m !v. went ibm Mr*** U32 me :j>s. Uwi me HfMiri eam*Ae. 23-S <vi pe*4 MW ar uwun - t-aceemi. t>9pun a s>wm **. - * tccwrM txrvr n tntf Softer. ineneci nmnmtn W* M* Smvmuaei.n;r>n ?mf; austeu- n esc Sen ! i/*o ;e V* i gftr. ~Vi aoor *e svneiw wt '52! ir vw. g ;- mn^t. fier aie orf. -tom ixeritsi. iut9e in . :';i unite a -~x 'SiO-'S-*' mr Thu tntn -sic arm m eetfiGen w*a )>PC<u*{ swrMOM Su nua uurj* U pfRwmM i Crjw* in . * . i/i MMenv fte an 0 gwum mMMemi *m wenv pun- m eemtae Me 1 mil iwivu ecu r-r Tim 2 (imcOoaim me MeOaiue .;: mcemesr ^tuns we :i*ri mtienmcmu wenwa siw*. Iratt' nu iC Tti<e 01* um tar 2>nui ran `0 jn talk*.-.-: <e ampeti ssa :i.2J**af: lane* '; (taim. ou 124 0.0 StaW eiiBUK! imeri 7nt A*4t.3 29CM 9 Stw i.j'i -:-n Um s mwtn nw m rj t::Eeu: M uiemr, ssu ter 2S rtin .1; (AMl. 20* tan non 017 urn **7. meusei tmw tswft. Ueea* is MM* tt 41. >'M0i. 023 im m*r. **8 /tea 5*em-i. 030 -111 dnn wren, tawi rt ntem 3 swn run. 00 Oil 30-e emit run vr<t tm*> k s'* US SlKMIl 0 *1** *r "W'rC 1SJ3 *r <mi.20> 4n ime iwt IU UWI v nwi upon * ""* iw nMH4~. ww v >": MM sm. unoev 111 20> JM 9*B CL 10 wniMMlt Ql n ncta. US mi-- m Mttnn Htat. -wvmi m - w-- n* m onm i**n ait UMW1 on C/hmn nntn *M1 Semi i.-mon sithm tu .mm mn vu *' t* f'1 tav 0 14 U% 4U 'OratW.l 1U-,*4 Chrysoiiie Asces;.., arc --a i^2l; !1. AaomonjJ atuoies .onjiat.'tO* A:-.s;n *: ;i ?Si2;--:nrysa::ie cnnort u !:S32f fiiurstfn ;'?9f -sncsrjan ir>G E-iterline [19731 Hvpnes anc Weill [19601 Hu^nes et ji. (19871 McDonaiO si ai. (i960. 1SS3] WcOonWQ u. [\963i| McOonaicl et ai. [iSBObj McDoruid <i ai, [1984! Nicnoison ti ai. [i979j 3ioiana et it. (1S901 Puniom et ai. [1S79J RoQinson ei at [19791 Sluts-Cftmer ei al. 112S2]--amosile cohort Thomas a k. [19621 Weflletat (18791 Weiss [197T] `Siucia ween were rtviewM sur vrerc not m ctuaes m Taot i io rjjics ai aieut* meweiworau sc seal iw.M. 197S: Acnescn e: ai.. 19821. The expect-c r.ur-.cer - ,a-; ccr.crr chains for ihe McDonaia and M;Dcnaid study wai not given. but w: rtavc assumed :t *-as ;pa :;r:;[ makes very iniie differenc: to the c-t":i ra^daerattars the studies. The last row of Tabie III gives tr.e summed data tram me three gas mask studies.'There were 19 pleural mesothe lioma cases in the. crocidolite group with a lung cancer excess of about 13.5. There was only one case in me chrysotilt-only category, but the excess `.ung cancer nurr.oer was only 1.2. Since chrysoiile is a potent cause cf iur.s cancer, this low excess makes it clear that the enrysonie 2as mask workers had relatively low exp<osares. In fact, the xta: length of exposure to chrysotile in the Jones et a!, study was shorter than 5 months. In the Acheson study, the exposure to chrysotile was probably much lower than the exposure to crocidolite, since the crocidolite filters were made by hand while the manufacture of chrysotiit filters was mechanized. Thus these three studies provide no evidence whatsoever that crocidolite is more potent in causing mesotneiiema man chrysotile asbestos. Fiber Typ Risk Comparisons railroad industry, where chrysotile was the primary expo Hughes and Weill [1986] have suggested that crocido sure. has also been reported (Maltoni e: al.. 1991]. Fifty lite is about K times more potent than chrysotiie in causin' malignant mesothelioma cases have betn identified in the combined pleural and peritoneal mssotneiiomas. This find manufacturing, insulation, and shipbuilding trades, and 21 ing is based on combined data from selected cohorts *ur, cases in the construction and building maintenance trades chrysotile. amosice. Crocidoiite. or mixed exposures. The [Begin s: al.. i992|.'ffraiFof- these'trades, chrysotile con results indicated that the number of mesoiheiiomas was stituted the primary exposure and amphiboles the secondary 12% of the excess lung cancers among chrysotiie-exposed exposure. Sanden et si. (1992] conducted a cancer incidence populations, but 165% for crocidoiite exposure. 22.23: for study of shipyard workers exposed primarily to chrysotile. amosile exposure, and 65.93; for mixed fiber exposure. with i-sser exposure to amosile and crocidolite. Eleven of Table IV presents our reanalysts of the above findings. the 168 cancers were pleural mesothelioma. Including sight The same cohorts are included, but me most recent fol of the 70 cancers in persons with 20 or more yean latency. low-up data from these cottons were used m the analysis. In addition, sight cases of malignant mesothelioma were Where possible, data from subcohorts with 20m years since reported following household exposure to the dusty clothing first exposure were used. Furthermore, since it is generally of asbestos workers {McDonald and McDonald. 1980]. agreed that chrysotile asbestos is not a potent cause of peri Three of these eight cases were children of chrysotile mine toneal mesotheliomas, only pieural mesotheliomas are in employees. Tr.t above data demonstrate that chrysodie ex cluded in the tabie. Our analysis indicates very different posure. even a: the relatively low levels expected in house results from Hughes and Weill [1986]. The number of pleu hold exposures, can cause malignant mesothelioma. ral mesotheliomas is 209c of :he excess lung cancers among Cas Mask Studies chrysotiie-exposed populations. 723c for crocidolite expo sure. 13% for amosite exposure, and 27% for mixed expo sures. The longer foilow-up period makes a large differenc: Studies of workers who assembled gas masks during between the Hughes and'Weill [1986] analysis and that Worid War II have been widely quoted as indicating that presented here. Rather tnan appearing to be U times less crociucljts is much more potent than chrysotile asbestos in potent than crocidolite. based on this selection of studies causing mesothelioma [Doll and Peto. 1985: Haringcon. chrysotile may be oniy three or four times less potent in 1991). Tacle III presents data abstracted from the three gas causing malignant mesothelioma. This is in close agreement mask studies where workers nave been exposed to one fiber with the conclusions of Nicholson {fWlT*wno looked at type only [Jones es al.. 1980: McDonald and McDonald. comparative oose-response relationships of asbestos fiber Smitr. and Wr:cnt TABLE IU. Pleural Mt'.vV'.ti'GiT.ii ,'jng Cancer C/oocoiilt cr Onry C>.rystjoie -hstss Lung Careers ,n Css '/as* Ci" Cnv/ Crocidolite aniy Chrvjsiile only Pleural Lung Excess lung Pleural Lung Excess lung mesotheliomas sancer saneers mesotheliomas cancer cancers MtDonatO anO McOonaio [197B]* ,'cnes et si. (i93G| Acneson et /. [1507] Total IS 3 19 21 11 , 5.7 13 6.8 26 13.5 -- 0 01 E -.2 1 6 -4 `Onzm csngn tn tssojure 19 croasoica onry. types and included more studies chan Hushes and Weill Since only one inhalation experiment has seen done fc: .'1986U His conclusion was: that "'There appears 10 be no tremolite. it is not included in this comparison. difference in the potency of chrysotile and amosite in pro Intrapleural injection studies have also demonstrated ducing mesothelioma. However. exposures to pure crocido- that chrysotile is a potent cause of pieural mesotheiicmas ;r. iitt. which has been and is mreiy used in the U.5.. may carry rats [Reeves et al.. 1971: Wagner et al, [972]. in fee:.. a two- 10 three-fold greater risk" tNienolson. 199!]. Wagner et al. found that finely milled chrysotile was more To summarize the epidemiological findings as they re potent than the crocidolite and amosite -sampies tested. late to chrysotile and pleural mesothelioma, she following Surgical pleural implantation offine chrysotile. croci points can be made: (I) If crocidolite were much more dolite. amosite, or tremolite fibers also induced sizr.ificar.t potent, the highest mesothelioma risk cohorts should in numbers of pleural sarcomas in rats (Stanton e: si.. :9"2. volve predominantly exposure to crocidolite. In fact, the 1981]. The cumulative incidence of deaths with m.esctr.e- highest risk cohorts do not show this differtr.iiaiion. (2) iioma from chrysotile. amosite. and two types of crociccike Limited data concerning exposure of household members was similar at tht maximum dose level of iQ mg 'Stanton suggest chrysotile is a highly potent cause of mesothelioma. ai.. 1972]. ' ;31 The widely quoted gas mask workers studies do not In conclusion, there is clear evidence in animzi inhala provide evidence that crocidolite is more potent than chry tion and pieural injection/implamation studies that chrysc- solite. (A) Considered overall, the evidence suggests chryso- tiic asbestos causes pleural mesothelioma. Indeed, if ore tiie may be less potent than crocidolite by a factor in the considers the dose of asbestos in terms of mass, ahrysotiie range of 2-4. However, the epidemiological evidence does asbestos is generally the more potent fiber when comparts not support chrysotile beins less potent than amosite. to crocidolite and amosite. However, the data do not permit estimation of potency per fiber. The data for tremoiice is A REVIEW OF AVAILABLE ANIMAL DATA quite limited, but do not support the conclusion that oiite Is a more potent mesothelial carcinogen than :hry- soiite. Chrysotile, amosite, crocidolite. and tremolite can cause pleural mesotheliomas in experimental animals ex THE STANTON AND AMPH1BOLE posed by inhalaaon. intrapleural injection, or surgical im HYPOTHESES REVISITED plantation. Table V summarizes data from long-term studies cf experimental animals exposed via inhalation, the most Two lines of evidence have led some researchers to relevant route for human exposure. believe that chrysotile Is not an important cause of pleura: In order to get an overall incidence of pleural mesothe mesothelioma in asbestos workers, and that the risk is at liomas in rats following inhalation, incidence daa were tributable to amphibole exposure. The "Stanton Hypothe added together for each of the three asbestos types (i.e.. sis*' suggests that mesothelioma incidence is strongly chrysotile. amosite, and crocidolite). The overall incidence correlated with longer, thinner fibers. The "Amphiboie r.y- of pieural mesothelioma in rats exposed via inhalation is pothesis" states that amphibokr-ffcers are responsible :cr I-SSe (13/733) for chrysotile. 1,3*5- (5/377) for amosite. and causing mesothelioma, since these fibers are founo in me 1.2% (4/328) for crocidolite. Thus, inhalation studies in rats lungs of mesothelioma cases at autopsy, but or.rysoule do not support the argument that chrystotile is far less po bers are not. The evidence leading to these nypeweses s tent than imphibotes in pleural mesothelioma causation. summarized beiow. C'*-fVS0tre Asotstos no TA3L; :'J- ''ej;:fit::crr.j .n ?;;vijjors Hjscsso IQ C'lHertn; "set *<?esi: *;btr Tit Ohr/sctne* Arnosiu' Cfoaooute* Mixes Sider' OsseneC sums 10.3<5 7.153 1.042 9.532 Lung ::ar.cir Observe! Ltssts 725 133 no V722 186.3 50.2 66.8 *..106.: Pfeurit mesmfieiiomj Observes As * ol lung 2S 22.3 12 '2 2 46 n 3 301 27 2 `Biseci an Tei ; ai Hugnts n */vtif (I986i. , a:nc;uoM luacaftorrs *if. 20* run s<nee first emcigymern wntn jomSu. :MtOcr,i3i el a. (1943.19*4. ',993). UcDonw ino MtOonuiJ [I940|. *twu e it- 11S791. ?iw !t Ji. {3990). W*m (19771. AcT-ae . (1SI2]. T^errij t: au. (1942|. `Stiamwi ti U. (3979.1H|. itfttaon at (M|. hocm IL pS40l.-Armnrorvg ei if. [1944[. McOowtd and McOomid |19781. Jonu n jL (19401. 'McOcnua *t iL (19431 3erry iM Nevmcuse (3943|. *** wa SuH'w (19891. Sritefl ei ai-119731. Seidman jnd StOon pSSOl. Acnesgn : u (1542). NfrmouM ind Scrry |1979|. Njwncuji c 41 pWS|. finuuieifl [1383. ISWj. 3n irw SrfMson [3977]. Therms jt [19SZ1. Rosiner ing 3aies :i980i. Stanton and his colleagues conducted a series of exper tos from Stanton's data, there appears to be iicrle cr r,c iments :n which a number of durable minerals in the form of relationship between the probability of tumor and the num respiraiie particles were implanted in the pleura of rats for ber of particles measuring <0.25 pm diameter and >S urn periods of more than 1 year (Stanton and Wrench. 1972: length (Fig. !). Stanton. 1973: Stanton ecal- 1977. 1981). Significant num Other researchers have studied the cotreiaticn bevwier; bers of pieural sarcomas were induced in rats with a wide dimensional properties of fibers and mesothelioma." in ex variety of fine, duraoie fibers including chrysotile. croeido- periments similar to Stanton's. Jaurand (1991) aetermir.ee lite. amosite, and tremoiitt. The two earlier studies showed the percentage of mesotheliomas occurring after imrcDitu- r.o difference in potency between standard UICC samples of raJ inoculation of 20 mg asbestos sampies into rats. She chrysotile and crocidoiite (Scamon and Wrench. 1972: Stan found a fairly good correlation (r * 0.6J3. p <0.0!) between ton. I9"3j. The primary conclusion of these srudies was that the risk of mesothelioma and the number of "index" fibers tne ability of mineral particles to cause tumors is mostly a ti.e.. 5)25 um diameter and 2$ urn length; inoculated ac function of the dimensional properties of the panicles, cording to Stanton's criteria. However, there was oniy ; rather than physicochemical properties. 30% difference (20ft v$. 50ft) between the percentage at Tne later studies, which did not include chrysotile. at mesotheliomas produced by samples with the smallest num tempted to further cnaracterize the importance of dimen ber of index particies compared to samples with a higner sional aspects of fibers (Stanton et ai.. 1977. 1981). Accord-, number of index panicles, Furthermore. when Jaurand ing to the authors, the incidence of malignant mesenchymal (199J) combined all of her available data from previous neoplasms correlated well with the dimensional distribution studies of amosite. crocidoiite. and chrysotile (Monchaux et of the panicles. The probability of pleural sarcoma corre aL 1981). there was no correlation between the percentage lated best with the number of fibers that measured 0.25 tam of mesotheliomas and the number of index panicles tr = or less in diameter and more than 8 |wn in length. Relatively 0.164).. high correlations were also observed with fibers in other Despite Stanton's warning and the findings describee categories naving a diameter up to 1.5 pm and a length of above, many researchers have utilized the Stanton hypoth greater than * pm. esis to link mesothelioma casts to particular asbestos fiber This evidence led to the "Stanton Hypothesis.'* which types and sizes. Churg. for example, stated: "Given the staies that durable fibers (provided they subscribe to well very high exposures experienced by the Quebec workforce, oefined ranges of diameter and length;, of which asbestos is the short size and low aspect ratio of the tremolite fibers but one sampie. cause cancer irrespective of their physico found in the ore may be a fortunate accident which "pro chemical nature simply because they art fibers. Stanton also tects' these workers from mesothelioma" (Churg. 19381. stated, however, that direct application of the results of his experiments to the problems in humans would be unwise given the deficiencies in the method of application and the Churg's statement, however, also assumes that it is me tremolite. not the chrysotile. that is resgonsrtjie for those mesotheiiomas that did occur. This assumption is based on massive amounts of fibers used (standard dose. JO mg). In the finding that, although "tremolite comprises only a tmy fact, if one were to exclude alt fiber types other than asbes fraction or'-the asbestos dust in the Quebec mines ana mills. :ss Smith and Wj-.gnt TABLE Long-Term Asoestos innaiadon Stucies :n Ammais Reference Soetitj Pfter rype Dote1 * mg'r;J st;vts St ii. ' 1 S?tJ Wagner e: at. [1974] Retvts et al. [1974] Davis et al. [1S78] Davis it al. <1S*S) Davis et ai. [1986a] Davis et al. [18860] * Davis and Jones [19M] Total Rats Rattntt G. oigs Hamsters Rats Rats G trails Rats Rats Rats Rats Rats Raa Amos Croc Chrys Amos Croc Cliiys Amos Croc Chrys Amos Croc Chrys Amos Croc Chrys (Can.)* Chrys (Rh.)' Chrys Croc Amos Chrys Croc Amos * Chrys (Rh.) Chrys (Rh.) Amos Croc Croc Trtmolite <Kcr.) Short amos long amos WOC yam* factory WOC Chrys yam1 Exc WOC Exo WOC/RC Shan chrys Long chrys Chrys Amos Croc --ta -<B -Jg -<8 -48 , -<8 -4fl -48 ~4| -48 -48 11-14 1CM3 10-12 10-15 -50 -50 -50 -SO -50 -SO 2 10 10 t 10 ? 10 10 4 4 A 4 4 10 10 'No pitvnf mtsomtsomu we owerwc in iny tofttroi prove. Sirnuar ootti mg/ffH may M wy fliflirwi in terms of QtoorvM. 'WescfMfiema esuntd *rtn just t say creei (>t yarn tatowuei. 'One mnotfvtfioma ocsunw win pst 1 say maun W ytsn loOowvei. 'An. nmecMA. `Can. Canietan. Kor Keren. '"WOC" it wit ehMfMd ewysotrta. "Ouji Imm booty air. `Sanears enrywaw loxai* yvn. 'betnmenai WOC enem. j5tdfn*na/ WOC 'rmratfl Myfipm." Numcer tinea Ko. ol jltarai mt:;:.*|tj;5rr,j 53 5* 49 20 18 26 17 33 21 ' so <5 49 146 141 13? 144 34 43 43 40 31 45 ' 42 40 43 43 40 40 42 40 41 44 ' 42 43 37 40 40 733 377 328 ' 0 'j 2 : c i 0 0 ft s Jl 7 . ft 0 ft ri D C n* 2 0 2 0 3 1 4 1 0 2 13 (V8V.' (u%: 4{i.:%' Chryscute +r.z ''?srv.':cr; 3.3 0.3 0.7 0.6 -- 0.5 * ' 0.4 - i 0.3 r 02 i 0.7 - ii 0 0 .......... 1 4 234 5 FIGURE 1. Siar.ion et at. (isail sata icr asuestns fibers onry. i-axs: Lj numoer sirccies mtasur.n? sC.IS urn wen ay >fl urn per micrafom. T-axis: PronaDUiiy of tjmor. I. aemoiitt; O. amesue *. aoeisciils. high tremoiite lung burdens were associated with the pres Lung tissues of si* mesothelioma cases frem the Que ence of fnesotheiioma in miners and millers from Thetford bec chrysotile mining regions were examined ov Churs e: Mine; [Churg. 1994]. After adjustment for the presence of al. (1984). The five cases that had only chrysotile ore com tremome. no correlations between chrysotile concentration ponents in their lungs had larger amounts of tremciite ii.e.. and disease couid be found. tremolite/actinolite/anthopnyllite} than chrysotiie. The Tnis leads us tc the `'amphiboie hypothesis." which mean levels of chrysotile and tremoiitt in mesothelioma attributes the mesotr-iiomas observed in various groups of cases were higher than their respective mean levers ir. nine workers to the asaestos fibers present in their lungs at the chrysotile miners without mesocheiioma or the mean levels time of ceatn rather man to the fiber exposure eariier in life in nonexposed controls. Assuming that the fibers resent ir. [McDonald et ai.. !989t Mossman et a!.. 1990: Churg, lung tissue at autopsy are responsible for mesotneiioma. mis 198S]. The "amphiboie hypothesis" is based on the find study would support the conclusion that tremolite is respon ings mat workers exposed to asbestos have more amphi- sible for the mesotheliomas occuring in this cohort. boles in their lungs than chrysotile at autopsy. This occurs McDonald it al. [1989] examined lung tissue sampies because chrysotile fibers (but not amphiboies) break down from 78 mesothelioma cases in Canada and from matched and split apart 'longitudinally in tissue, leading to a loss of referents. Chrysotile fiber distributions in the two series fibers in lung tissues that are visible by electron microscopy were similar. Relative risk was related to the concentration [Nicholson and Landrigan. 1994], Sotne suggest that some of long amphibole fibers. The proportion of long amphiboie 'if not most) of the chrysotile fibers further fragment into and chrysotile fibers was higher in cases than referents. shoner fibers and are then cleared from the lunas (Churg, According to the authors, amphiboie asbestos fibers aouio 9941. ~ explain most mesothelioma cases in Canada, and other in A number of studies have examined fiber content in organic fibers, including chrysotile. very few. McDonald et lungs of mesoiheiioma cases. Those of Churg et al. (I9&4| al. (1989] concluded that fibrous tremolite probably ex ana McDonald et ai. (1S89J are often referenced in support of tne "emphihoie hypothesis." Other important studies induce Roggii et ai. (19931. Morinsga et al. (1989J, Rogers et al. (1991). and Sakai et ai. (1994]. In fact, the results of ;nese studies are inconsistent, as demonstrated in the fol plained most cases in the Quebec mining region. In a more recent study. Roggii et al. (1993] analyied the mineral fiber content of the lungs in 94 patients with malignant mesothelioma from the Uniud-.&ates, A large proportion of the cases were either insulators or shipyard lowing reviews. workers. Only fibers that were greater than or equal to 5 urn Smith and Wright In ler.g'.n were -.ncluced in the analysis. Arr.osite *03 iden the mesothelioma, ar.d (2) the finding that workers tified :n "6 cases (Sl^oj. the noncommercial ampnibcies to asbestos have more arr.pr.iboies :n me-.: lungs :ra.-. pr.mor.iy tremolite) were identified in 52 cases f35?b}. chrysotile at autopsy. Chrysolite fibers breax oowr ;nC rr.rysotiis "as detected :n 20 cases (2!%;. and crocidoiite apart longitudinally in tissue ana can be cleared from n \i cases (16~<0. Another five cases 15%) could not be lungs, while amphibole fibers are less attacxed ay -cc^ distinguished between amosite ana crocidoiite. According fluids and can be detected in the lungs of workers v-;rs to the authors, tremolite fibers are probably a marker for the after exposure [Nicholson and Landngan. 1594], in fa:-., much greater numbers of chrysotile fibers which were de complete fragmentation of a single chrysouie fiber mas posited but subsequently cleared. produce 1.000 fibrils [Wagner et ah, 1973), and these fibr.is The authors found that, assuming it is the fibers that mpy be so thin that they are ao longer visibie by electron accumulate within the lung that are responsible for the de microscopy in lung tissue. velopment of mesothelioma, the order of importance of fi Results of the lung content studies described above 2re bers is amosite > tremolite > chrysotile * crocidoiite. How inconsistent, and do not resolve the question of the irr.ocr- ever. they were unable to exclude a greater role for the long tance of fiber type in mesothelioma causation. Some studies chrysotile fibers found in their cases, especially since they report significant amounts of chrysotile fibers in iune tissue. probably constitute only a small fraction of the long fibers Furthermore, the results of Morinaga ah (1989) demon actually deposited. One issue raised was that the meods strate that mesothelioma can occur in the absence of am used might have underestimated the numbers of chrysotile phibole fibers, since six cases had only chrysciiie fibers m fibers 5 p.m or greater in length, because chrysotile tends to their lung tissues. undergo longitudinal splitting with many of the resulting The limitations of using lung content studies in deter fibers having diameters less than 0.1 um. The techniques mining the role of chrysotiie in mesothelioma causation are used :r. Roggii e: al. primarily detected fibers that are 0.2 as follows: (1) The methods used often exclude fibers less jam or greater in diameter. than 5 p.m in length. (2) The potential for carcinogenic A study of asbestos fiber content of lungs with me effects induced by large numbers of short fibers has not sothelioma in Osaka. Japan was conducted by Morinaga et been investigated. (3) The methods may have underesti ai. [ 1989]. Chrysotile was observed In 1,2 of the 23 mesothe mated the number of long thin chrysotiie fibers actually lioma cases, amosiie in 12. crocidoiite in three, and actin- present in the lungs due to an inability to detect very t.nn olitf-tremoiite in tnree-cases examined. Six of the mesothe fibers. (4) The number of chrysotile fibers counted ccns;;- lioma cases had only chrysotile fibers. This study provides tute only a minute proportion of the long fibers actually evidence that, if indeed it is the fibers present in the lung at deposited and subsequently cleared. (5) Finding a signifi death that are responsible for mesothelioma, then chrysotile cant number of tremolire fibers wouid indicate a major ex asoestos is a potent cause of this cancer. posure to chrysotiie. since tremolite is oniy a minor con Rogers e*. al. [1991) examined lung tissues from 221 taminant of chrysotile. definite and prooabie cases of malignant mesothelioma re Dement [1991] makes the obvious point that measure ported to the Australian Mesothelioma Surveillance Pro ments of lung fiber burdens made many years after first gram. and from an age-sex frequency-matched control se exposure may bear no relationship to the carcinogenic ries of 359 postmortem cases. A progressive increase in events that took place long before clinical manifestation of relative risk with increasing fiber content was observed for disease (lung cancer or mesothelioma). In addition, the fi all fiber content measures. The relative risks for chrysotile. ber levels of tremoiite measured in lung tissues of work crocidoiite. and total amphibole fibers which were 10 pm or ers exposed to chrysotile may be a surrogate measure of longer were greater than the corresponding risks for fibers cumulative dose of chrysotile. Case [1991). on the other iess than 50 um in length. When cases and controls were hand, states: "it is presumably necessary for fibers to be compared in relation to exposure to single-fiber types only presen! in order for them to e.xcn a c3rcino$er.tc ejjec:. [ail lengths), increased relative risks were observed for both This point is often missed by those who regard tremoiite-- chrysotile and crocidoiite. the mere potent carcinogen--simpiy as a `marker for Pulmonary fiber content was analyzed by Sakai et al. chrysotile." [199*5) in 16 patients with malignant mesothelioma and in However, we cannot presume that the fibers present :n 16 esse-matched controls. Amphibole. chrysotile. and nonas the lungs at death are responsible for mesothelioma, m view bestos fiber contents were significantly higher in patients of the long latency between asbestos exposure and mesothe than in the control subjects. lioma diagnosis (average of abouj.^2jy:ars in all studies).:: Summary of Lung Content Studies is more likely that ihe'effective target organ oose invokes fibers in contact with the pleura many yean before diagno The "amphibole hypothesis'* is based on (1) the as- sis. Data concerning fibers present in the oieurel space are sunciion mat the fibers present in the lungs at death caused considered below. Chrysctile Asoestas arc -.c~i Pleural Content Studies and could be retrieved from the pleura: fiy;c :? - - :rv.r. i month. A number of studies nav- addressed picura! Tiber con- in summary, pleural content studies demonstrate -a. rent. which is likely to be more biologically reievant [0 the chrysotile fibers preferentially reach tne oleum and :r: divtiopmem of asbestos-related pieurai mesothelioma than predominant fiber found at this target sue :n asbestos-ex lung tissue content. posed humans. These findings are ciearlv more per.mer.: One study comparing the retention of asbestos fibers in than lung content findings, and support chrysotile asetstes parenchyma! and pleural tissues found that lunc parenchy being a potent cause of pleural mesothelioma. mal retention is not a good indicator of pleural retention [Sebastien et al., 1$80|. Although amphibole-rype fibers longer than 8 um were present in lung parenchyma, in pa rietal pleura! tissues shon chrysotile fibers greatly outnum CONTRIBUTION OF CHRYSOTILE ASBESTOS TO PLEURAL MESOTHELIOMA INCIDENCE bered long fibers of the amphiooie type. The retention of asbestos dusts in the parietal pleura was related to type and ' In considering the contribuooivdLchrysociie to pleura! si2e: 84**! of the chrysotile fibers in the parietal pleura were mesothelioma incidence, three factor* will be addressed: r '. '1 from 0.4 to 4 4m in length and from 0.Q3 to Q.25 4m in the'relauve potency of the three commercial asbestos fiber diameter. If the fiber content of the pleura is responsible for types; (2) the proportion of pleural mesotheliomas due to pleural mesothelioma, then this study suggests that asbestos exposure: and (3) the extent of chrysotile produc chrysotile fibers would be more important than amphiboles tion and use. in causation of this cancer. Tissue samples from 13 North American insulators Potency of Chrysotile were examined in order to investigate translocation of as bestos fibers (Kohyama and Suiuki. 1991]. These cases To summariK the evidence presented concerning the included three of asbestosis. three lung cancers, two malig potency of chrysotile asbestos in causing pleural mesothe nant pleural mesotheliomas, and five malignant peritoneal lioma. the following points can be made: Studies cf mesotheliomas. The authors concluded that (l) transloca asbestos-exposed workers provide evidence that the chryso tion of inhaled asbestos fibers from the lung to other organs, tile and crocidolite forms of asbestos are major causes 0: such as the pleura and the peritoneum, seemed to occur pieural mesothelioma in humans. Crocidolite asbestos may frequently among asbestos insulation workers, although the be 2-4 times more potent than chrysotile and amosite. :2`- route of the translocation has not been completely investi In rodents, chrysotile, amosite. and crocidoiiie asbestos gated: (2) chrysotile seemed to be more actively cleared have similar potencies, both in inhalation studies and :rs from the lung and translocated into extra pulmonary tissues, pieural injection studies. (3) Reexamination of the dau on compared with amesite: (3) chrysotile fibers cleared from which the Stanton Hypothesis is based demonstrates mat the lung were not later eliminated from the host. Tne au data do not support the hypothesis that long thin amphibole thors suggested that biological effects of the translocated asbestos fibers are the most potent in causing mesothelio asbestos fibers may be significant, and translocated mas. (4) Studies of lung tissue on which the *'Amphi'ooie chrysotile fibers may play an important role in the induction Hypothesis" is based are inconsistent. In any case, findings of either malignant mesothelioma and/or hyaline plaques. in lung tissue at the time of diagnosis have no relevance to Asbestos fibers detected in both mesothelial tissue and hy causal events which take place decades earlier. 12) Pleura: aline plaques were mainly chrysotile. content studies demonstrate that chrysotile fibers preferen Data from a study of lungs and pleurae of shipyard tially reach the pleural space, which is important since the workers vert reported by Bignon et al. [19781. Larger fi pleura is the target site. bers. often amphiooie. were found in the lung tissue. In the Based on these points it can be concluded that pleura, the fibers were generally chrysotile. but shorter and chrysotile asbestos is a potent cause of pleural mesothe thinner. lioma. In light of the evidence regarding their relative po Le Bouffant [1980] observed a preferential migration of tencies, it is reasonable to make the same regulatory ooiicies chrysotile fibers to the pleura, with a significant increase for each of the three primary asbestos fiber types. and accumulation in the pleura in comparison with the lung parenchyma. The median percentage of chrysotile fibers was 3?e in the lung and 239c in the pleura. Similar results Proportion of Mesotheliomas Due to Asbestos have been demonstrated in rats [Viallat et a!.. 1936). Fol lowing intratracheal injection of rats with small amounts of UiCC enrysotile. the shortest fibrils (mean lengths 0.44i .32 um. diameter 0.03 ami reached the pleura very rapidly There has been wide variation m-earimates of the pro portions of mesotheliomas attributable to asbestos ex posurt. For example, Petenon et al. [1984] reviewed ;ne literature Lie Smun and Wnqnt zr.z noted ;r.ut the proportions linked to asbestos exposure accourued for only 5% of the asoestes usage m, 3 zr.tzz from :3% m two studies (Ratzer ;t al.. 196"; Bren over ;r.e years (Table VI) (Minerals Yecrcccx. r2- ' 9;>*- ner t; a;,. 1922] to 100% in one study at the other extreme For txampie. the percent ampmboie usage *ang;c from <; [Czzr.rzne and Webster. 19731- .They concluded that there in 1925 to a peak of <5.9% (<25.l2i tons amcnibc.sc. were large numbers of apparently nonasbestos-related ma- -L45.902 tons total asbestos consumed) in :9^3. zz- iigr.ar.t mesctr.eHomas. creased to less than 2% by 1950. During -.ms period the L'.a. Closer examination of the evidence does not supoort depended mainly on Canada for :ls suppiy of r0r.spinr.ir2 mis conclusion. The studies which find a low proportion of (short chrysotile') fiber and upon South Africa. Canada. ar.d coses unices to asbestos exposure tend to use poor exposure Russia for nearly all of its spinning (long chrysct:;; and ascertainment methods, such as reviewing medical records amppibole) asbestos. The U.S. preauesd or..v 'Rata:: :t al.. 1967; Brenner et al.. 1982). .Assessment of the amounts of both chrysociie and amphiboies. proportion of cases due to asbestos requires careful expo Chrysotile had a wide variety of uses in the V.S. dur.rs sure ascertainment methods. This point was made very the 1935-1945 period. The higher grade, lone fibers were clearly by Cochrane and Webster (1978), who noted that "a used in woven brake linings, textiles, and sheet cackme. history of exposure to asbestos can be established in a sig Lower grade, short fibers were used in asbestos snir.aies. nificant number of cases if histories are taken from the paper, molded brake linings, fireproofing, floor tries, etc. patient and recorded by a medical specialist with experience Rhodesian chrysotile was used for electric :nsu:a:icr. ezs- in the fteid of occupational medicine." In their own study, kets. and flameproof navy cable construction. Chrysotiie histories were taken from patients by one or other of the was also used extensively in heat insulation '.Minerals Year authors, usually by both. Where confirmation of exposure to book. 1936-1950]. ' cscccos was necessary, it was obtained from executive and During the war years, amphiboies had specialized uses government sources. Al! interviews -were repeated at least in the U.S. Amosite was used for insulation arour.c steam once. These authors reported asbestos exposure in all but machinery on warships, special pipe coverings, and blocs or.e of the 70 cases, and the one exception was a carpenter insulation. Crocidoiite was used for asbestos-cement era who ciaimed he had "worked with asbestos sheeting only sure pipes, chemical filters, arid-resistant packings. ar.d gas ery occasionally, and although he had always kept asbestos masks (Minerals Yearbook. 1936-1950). filling for screw hoies on his workbench, he did not feel that this, or any other exposure, had been meaningful" [Coch- *ar.e and Webster. 1978]. *" Another early study with carefully obtained work his tories found that 35% of 246 cases could be linked to a$- CONCLUSION CONCERNING THE CONTRIBUTION OF CHRYSOTILE ASBESTOS TO MESOTHELIOMA INCIDENCE . bts'.c: exposure (Greenberg and Davies. 1974], Living sub jects were interviewed where possible. Occupational Tne three points made above can be summarized as histories were also sought from coroners and from former follows: (l) chrysotile asbestos is a potent cause of pieural employers and workmates. Tne final classification was mesotheiicma; (2) the large majority of mesothelioma :s made by two medical advisors in consultation. If one fo attributable to asbestos exposure: and (3) chrysotile asbestos cuses attention solely on those epidemiological studies has been the major fiber type used. Based on this evidence, which have obtained careful work histories, then it is clear we conclude that chrysotile asbestos is by far the main that the large majoriry of mesotheliomas in adult males are contributor to pieural mesotheiioma causation ir. the U.S. attributable to asbestos exposure. Since additional cases and other countries in which it has been the predominant may occur from unknown occupational exposures, it is fiber type, `bcidolite may beTT^^Umes 'morTpctehL cut likely that at least 80% of pleural mesothelioma cases in ,the<ois^crvriiye^idericfe11nKamefne is Wore potent than adult males are attributable to asbestos exposure. That a .rirryfotilerEven considering an extreme that crocidoiite cr.d large proportion is due to asbestos is also consistent with the amosite were 10 times more potent than chrysotiie. the ex evidence that the rate of mesothelioma prior to die 1930s tent of use of chrysotiie means that it wouid still be the mam was extremely low in the United States and in Europe contributor to pieural mesotheiioma causation. (Mark and Yokio. 1991). Production and Use of Asbestos in the U.S. ACKNOWLEDGMENTS Support for this work was proviijjgi by the Heaitn E:* fecu component of the University of California Toxic Sub Chrysotile represents approximately 95% of the total stances Research and Teaching Program, and by grant ?; world production of all forms of asbestos, with Canada its 0023 from, the California Environmental Prcts'cucr. .aretsi producer (Mancuso. 1988). Amosite and crocidoiite Agency Interagency Agreement. Additional support zzrr.i Chrysaule Asststos ana r.euc~s TABLE /I. Estimjieo Quantities o( Asbestos (Short "ansi imoontd Of Consumes -.r. tht ur,ns; States' Year 1S25 1335 1927 1939 1940 ISO 1942 1943 1946 1945 1946 1*49 1950 Canadian chryiotile imooned' U.S. - chrysolite arsauced 154.200 226.060 27S.002 222.840 225.653 3B9.391 366.647 365.655 353.223 355.766 442.073 470.783 678.358 NA* 10.520 13.234 14.666 17.481 20.1*4 13.109 3.900 6.296 13340 4.438 NA NA African amooibaitt import* tf* 945 2.080 4.247 6.359 8.752 21.447 20.424 24.007 19.162 13J247 6.324 22.720 14.805 0.3. tmptiUiaks produced HA 404 612 450 1.693 2.252 Z.2QS 2114 317 250 *37 HA NA Tom consumed in U.5.* 174.555 250.922 316.260 MS .5*7 262.199 438.741 434.121 445.902 407.148 377.875 459.752 535.132 728.785 Percem :r.ai :.i Chryxolit* 29,5 99.0 98 .S 97.3 w.e Hi 9*. 94.! 95.2 96.4 98.5 95.8 58.0 "Oki ( years 193S-1S50 otnauMd tram m Mimas Yur kxx (1X36-1950). `inausts cru wa mtiM fiben. u ocs as 'stucco ins refuse.' sM*y *oue* jctut jcnai amount ot Alncan Otrysoae. 'inpuao a imoortM u *tfi u oomencoresucts amohibeies ms piryteai* consumes in mat year. *KA cast net available. from ihe Environmental Health Science Center Grant ES0139. and the University of California Center for Occu pational and Environmental Health. REFERENCES fect. In: Workshop on Asbestos: Definition and Measurement. Me'.rtecs. Gaithersburg. Maryland. NBS Special Publieation. pp 95-i 19. Bora* M. Ccnston A. Uvomese L Sehalet N (1973): Mesothelioma fol lowing exposure asbestos: A review of *2 eases. Chest 6-*:6-i 1-6*6. Brenner J. Sordillo ?P. .Viatill CB. Golbey RB (1982): Malignant me sothelioma of Ok pleura. Cancer A9:2J3l-t433. Acr.esen ED. Gardner >MJ. Pippard EC. Grime LP (1982U Mortality aT two croups of women *no manufactured gas masks from chryiwiie and ere.'iColite asoestes; A aO>year follow-up. Br j ind Meet 39-_)ia--J-iJ. Achcjori ED. Gartner Mi. Winter PD-. Bennett C (198*1: Cancer in a factory wing amosue asbestos. Inc J EpiOefflioi 13J-I0. Albin M. Jakobsson 1C. 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Setdman R Lilts R. rormby P (19791: Lon;i-rt. tnonaiity tr.ber-.er.es: of cr.r<soiii< mir.cn and millers in Thstford Mines. Quebec. Ann NY Acad 5c: 330:11-21. Chiton CC C1989'- Is ehfywtiie a sumficant risk factor (or mete*heuoma! Am J In: Med 13:331-336. Sar.den A. Jarrholnt B. Laraon S. Thirinjer G < 1992'.: The risk of '.urt cancer and mesothelioma after cessation of asbestos exposure: A prospec tive canon study of shipyard workers. Ear Respir J 2:231-225- Sebasuen P. Janion X. Guadicnet A. riirsch A. oilmen J : !.9S0>: Asbesios retention in human respiratory tissues: Comparative measurement! ir. i-ar.j parenchyma and in cariraal pleura. In Wjjner JC >'edl: "Bioioticai Effesa of Mineral ribros." Lyon. France: '.nteraationai Ajeney for Research cn Cancer. Scientific Publication No 30. pp 237- 246. Peterson JT. Greenber; SD. Buffler PA 11984): Non.asbestos-related maiijrsnt mesothelioma. Cancer 54931-960. 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Pool JL Melamed MR 119671: Pleural mesotheliomas: Clinical experiences with thmy->eeft paoemi Am J Radiol 99:163-380. Seioman K. Selikoif II (19901: Decline m death rates among asbestos insulation workers 1967-1916 associated with diminution of work expo sure to asbestos. Ann NY Acad Bet 609:300--317- Setdrtusi H. Selikoft U. Hammond EC tV9"9V. ShortAerm asbestos work expoture and lonj-tenn observation. Ann NY Acad Sei 330:61-19. Setdman R SelikolT U. Gelb SK (1986): Mortality experieae# of amosite asbestos factory workera: Dove-response relationships 5 to 40 years after onset of short-term work exposure. Am i Ind Med tO'.479-51*. Selikoft U. Lilis R. Nichdsott WJ tl979ar. Asbestos disease in United States shipyards. Ann NY Acad Sci 330:293-311. SelikofT U. Hammond EC. Seidman H 11979b): Monaliry experience of itaulsKofl worien in the United States and Canada. 1943-1976 Ann NY Acad So 3MWt-m. 5iui>-Crtmer GK. Liddell FDK. Logan 'YFO. Beiuidenhew BN (1992): The rwulitv of amphibole miners in South Africa. 19J6-3U. Sr J inti Med 49:566-373. --art *W*- Stanton MF H973r Some etiolopical L'cmiiderations of fibre carcmojen- Ckis. In: "Sioioj-.ua' Effects, of Awbrnct." Lyon. France: international Ajency for Research on Cancer. Scientific Publication No 8. pp 239-294 OccuDational t asure 10 Cnrvsouie Asbestos and Cancer Risk: A Review of the Amphibole Hypothesis Leslie T. Stayner, PhD, DavidA. Dankovic. PhD. and Richard A.. Lemen. PhD Introduction Lung Burden Studies Chrysotile is the predominant type of asbestos produced and consumed in the world today, and it accounted for over 9855b of US asbestos consumption in 1992.'* Although asbestos consumption has declined in North America and Europe, sales in other countries (e.g.. Southeast Asia. South America, and East ern Europe) have increased primarily due to the use of asbestos-based construction materials.1 Chrysotiit is a serpentine (curly) form of asbestos that is distinguished from other amphibole forms of asbestos (i.e., croddolite. amostte. tremolite). It has been hypothesized that 0) the mesothelioma risk observed among work ers exposed to chrysotile asbestos may be explained by the relatively low con centrations (<1%) of tremolite fibers in commercial chrysotile asbestos fibers and (2) that chrysotile asbestos may be less potent than amphiboies in the induction of asbestosis and lung cancel. This has been dubbed the amphi bole hypothesis - It has even been suggested that exposure to chrysotile asbestos in the absence of tremolite may present little or no carcinogenic hazard.4 The arguments advanced to support the amphibole hypothesis have been pri marily based on pathologic studies of burdens of asbestos fibers in human lungs and on toxicoiogic. mechanistic, and epide miologic studies. This article presents a critical review of these arguments and of the literature on the carcinogenic hazards associated with exposure to chTysotile asbestos and considers the implicauonsof these findings for the development of occupational health policies. Tne development of methods that involve electron diffraction and energy dispersive analysis of x-rays i'EDAXV' has made possible the measurement o: the amounts of different fiber types in the lung.' Tne results from iung burden studies have provided the tinman basts for the advancement of the amphiooie hypothesis. Case studies of individuals who have worked in industries using o: producing chrysolite asbestos revealed an unexpect edly..high proportion of ampniboit^primariiy tremolite i fibers, considering the relatively low percentage of amphiooie fibers in commercial chrysotile asbestos.' In one of the earliest swdies, Pooley observed a greater number of amphibole fibers than chiysotiie fiber? in ' of 21 patients with asbestosis who had worked in the Canadian chrysotile mining indus try." Rowlands et al. also reported a neariy equal concentrauon of tremolite fibers and chrysotile fibers in the lungs of 4" workers employed as miners or millers in Quebec.4 Similarly, in populationbased studies the percentage of enrysotile fibers found in the lungs has been surpris ingly iow considering the fact that chryso tile is the major source oi exposure for the general population.9 * Most case-control studies that evalu ated the potential reiauonshir netw-eer. The authors are with the Risk Assessment Program and Office of the Directo:. Nations. Institute tot Occupational Safer- and Health. Cincinnati. Omc. Requests for repneis should oe sent k LeslieT^StayneT. PhD. Nations: institute ie: Occupational Safety and Health. Rooen A Tah Laboratories. 4o"f Columbia Pan-way Mai! SiocClf.Cincinnati. OH ^S--c This paper was accented August It. !r Editor's Sou. See rciatec annotation b? Cullen tp '5S'i tn this issue ..me cnrvsoiiie exposure in these studies. TABLE '--Summary ol Epidemiological Cohort Studiaa ot Worker* Expowd to Predominantly Chryaotiw A*b*sto* As Cntirg et a:, suggested. "h may be true that ihs trcmoiut serves as- a better Stuoy industry Lung Cancer Deaths Mesothelioma Cases i Observed Expected Ooserved earns measure of past cnrvsoiiie than the crirvso- tiJc itself.* ' Finally, studies of fiber counts m extrapuimonary sues raise serious ques Acnsscn e: ar *' Gas masts Cneno arc KcncJt Textiles, friction mate rials. ana cement Dement et a! 24 Textiles Finneisteir30 Eiectncai conduit oipe FmKeistetr--1 ' Automotive Hupnes eta!Xcz Cemeni manufacturing Huilan and Zniming3-' 6 asoestos lactones McDonald et a!.34 friction products McDonald et a!.35-3* 0 Mining and miffing Piotano et a! r Mining Shiqu ei a*33 Mining Weiss38 facer and millboard Tens! 2i 126 6 11 70 65 73 516 22 6 4 92?* 4.e 6.7' 64,0* 3.7 7.9 53.2 15.6** 49.1* 389.7' 19.9 4.3 618.9 i 0.6 CC 2 1 1-21 1 2 0 26 2. 3 0 41.0 02 1.0 1.0-1.9 0.4 0 0.4 03 4.5 0 0.3 tions about the validity of using lung burden studies for assessing mesothe lioma risk. Several investigators reported cases in which short chrysotile fibers were the predominant fiber found in the pleura, pleural plaques, or pleural fibrotic tissue when amphibolts were the predominant fiber found in the lung.=2J<-j6 These results suggest that chrysotile may be ; preferentially translocated to the pleura and that the fiber counts found in the lung may sot accurately reflect the concentra tions found at the site for mesothelioma i Non. SMR * tne stancarooeo modality rtoo, which is the r*> between tne ooswveo arc l j exceaec. j *Th exoeaed numoer ts tor cancer ot the lung ana o*eun eombmad \ ; *One or rwo cases el mesotneiionu ware reooned. Only one was irtciuoed mth totals j ; `Resufts <e tor womers exxwseaortiytoetwyeoWe tnjm one olrwo Wants snxlteo. The total numoer j & J1 oteeatns was not reoonecrtnus. the oercanvage mesotneitoma oestnscouio not dc estimaieti. ! "Observes ana axDecteonumoet*extiuooe>seTVBbe>ns trom tne asbestos factory. j 'The ShiouetaJ. stuoy was not mctuoed in tne total number of lung ameer eases because expected { burners ware ncfl teeoned r ' 'SignificantlydfHerentfrom the ooserveo number.. < .05 frwotaited). i j induction. Epidemiologic Studies Lung Cancer There have been 12 retrospective cohort mortality studies of workers who were predominantly exposed to chrysolite asbestos fibers. Results ior mortality from iung cancer (and mesothelioma! from the inesotheiioma risk and lunc concentra received in early years would not be most recent updates of these cohorts are tions of the different fiber types of reflected in the lung burdens measured at summarized in Table 1. .Mortality from asbestos -demonstrated a dear relation the time of autopsy. This is of particular hing cancer wasgteater.than expected in. ship with amphiboie lung burdens but concern for mesothelioma, which Iras nearly all Of- the, studies. .Combining the ; failed to find a relationship with lung been estimated to have a latency period of results from these studies,1 there were 92 chrysotile concentrations.McDonald at least 20 years.21 For example, assuming observed and 618.9 expected lung cancer et al. reported an association between a 90-dav half-life and first-order kinetics, deaths, resulting in a pooled standardized mesothelioma and lung concentrations of only approximately 1/(8 x 10s) of the mortality ratio for lung cancer of 130 long (^ 8 u.ro> chiysotBt fibers in univari dose received 20 years earlier would be (95% confidence interval [Cl] *= 1.40, 4 ate analyses but not in multivariate analy predicted to be present in the iungs at the l.0). The observed excesses of lung sis. which controlled for the other fiber time of the autopsy. Hence, iung burdens cancer mortality did not appear to be types.15 Rogers et al. reported a significant Of chrysotile may be a poor measure ofthe explained by differences in cigarette smok- association between mesothelioma risk imepaicd exposures to chrysotile. ing habits in the studies that had mfonna- and lung concentrations of short chryso Tne high degree of correlation be tion on tobacco consumption.?*-53-35*1'*'^ lite fibers (< 10 pm) in multivariate tween the lung concentrations of the Collectively, these studies provide strong models and a significant trend ior lung different fiber types, which has been evidence that exposure to chrysotDe asbes concentrations among mesothelioma case and control subjects who had only chrvso- noted by several investigators, further complicates the interpretation of the lung tos is associated with an excess risk of iung cancer. tile detected in their lungs.16 burden analyses. r5-,t-D Cburg reported There is little, if any, evidence to Tne interpretation ol the results that the correlation coefficient between suggest that the excess in lung cancer from the studies of lung burden is compli the numbers of chrysotile and crocidoihe mortality observed in these cohorts may cated by differences in the respiratory fibers in lungs of -asbestosis patients was be attributable to tretuolite contamina clearance rates o; the different forms of .88 (P < .055--1 Rowlands e: al. reported tion. in fact this hypothesis b strongly asbestos. Experimental srudies demon a stronger correlation between cumula contradicted by the fact that the lung strated that ebrysotile fibers are cicartd tive asbestos exposure and iung fiber cancer response in the studies of popula far more rapidly from the lungs than art counts for tremolhe than between cumula tions with reiaux&lyjpurt chrysotile expo amphiboie fibers.1'-15' Tne retention half- tivt asbestos exposure and lung burdens sures is similar to that in studies ofcohorts iiie of chrysouie in human lungs is of chrvsotue in tbeir study of Quebec with amphiboie or mixed exposures. Esti unknown, but a half-liie of 90 days has miners and millers.1 Toe ruth deeret of mates of the increase ir. excess relative beer, reported in experimental studies of correlation mighi explain the negative nsk per unit of exposure ii.e.. potency ] for baboonsy If the half-liie for chrysotile is findings in some of the case-control lung cancer based on cohort studies by similar for humans anc baboons, iher. studies if amphiboie exposures are simply industry and fiber type are presented in cieariy tnt vast maionp of the dose acting as t surrogate for integrated hie- Tabic Z. Variations ir. ns,-. according to .-sjn;r::ar -muni, of f'ut'ii: Healu rernii- r. k x. - A5o<.i<.i ant _ani\ .ttidusm typ; appea: 10 b. mors remarkable than variations according to fiber type The potencies for lung cancer risk are similar among the cohorts with pure chrysoule and mixed exposures in the textile industry and are generally higher than the potencies observed among workers in the mining or asbestos prod ucts industries. The studies of asbestos products industry workers all show very low potencies, with the lowest unit risks observed among friction product workers. One study of cement workers, which provided separate analyses for workers exposed to chrysotile asbestos and work ers exposed to a mix of chrysotile and croridolits fibers, produced remarkably similar potency estimates for these two -`groups.31 Among the studies of miners, lung cancer potency was substantially lower among workers in the Quebec minmg industry who were exposed to chrysotile ores than among eroddolite or tremolite miners. It has been suggested that the high lung cancer mortality observed among : (South Carolina textile workers might be i^explained by exposure to mineral oils.47 c'ylX^4*-..^H' owever. Dement et al. demonstrated in r^i_-caso-comrol analyses that the risk ofiiung r^JV-^canccT observed in this cohort is unrelated -mineral oil exposure.29^ lo addition, .studies of workers exposed to mineral oils have generally not demonstrated an ex cess of lung cancer.49 There is evidence that asbestos fibers m the textije industry were considerably longer than the fibers measured in chrysotile mining and milling . and other industries.50 Thus, differences in fiber dimensions would appear to be a more likely explanation than mineral oil exposures for the higher lung cancer rates observed in textile workers. Mesothelioma A total of 45 cases of mesothelioma (primarily pleural) were reported in the epidemiologic studies of workers who were predominantly exposed to chrysotile asbestos (Table 1). Ahhough il has gener ally not been possible to estimate ex pected numbers of mesothelioma deaths, the percentage of deaths due to mesothe lioma may be estimated and compared with background percentages. Tnis per centage is CL?Cl for all studies combined. In contrast, tbs percentage of deaths due to pleuzal malignancies (most of which art mesotheliomas) was oniy 0.0255- in the United States in 19SS.51 .Although the evidence of excess mortality ef mesothelioma among work* TABLE 2--*tlmat* of Aabeatos Potency tor Lung Cancer from Studies with individual Exposure Estimate*, by Industry and Fiber Type Study Demerit et al.7* McDonald eta!.15 Pmoeial.45 Industry Textiles Mainiy textiles Textiles Fiber Type Cnrysotite Cnrysotiie. amosne. croadohte Chrysotile. crocidoWe Excess Relative Risk pe' Fipe'rec > v- 0.030.0V" 0.015* McDonald et al.43 de Klerfc eta!" McDonald et al.9* Mining Tremolite Mining and milling Croddolne Mining and milling Chrysotile 0.013 0.010 0.0006 Henderson and enterime45 Hugnes et a!.52 Asbestos products Dement products Berry and Newhouse Friction products et al.44 McDonald et al.34 Friction products Chrysotke, amosne. crooklohte Chrysotile, chrysotile.5 and croddolrte Chrysotile Chrysotile 0.002s 0.007* . 0.0076= 0.00C5E 0.00053' j *A convencn factor oi three fo*rs per cuo>c cermmeier oetng eauivaiem tc ` million oamcies pe* j ojoic loot was assumed. | "Data an based on results lor workers employed after 1951. ' cSooa was estimated by fitting a linev relative risk Poisson regression mooel to tne stancardizec J monaJnv ratio resuns reooned oy McDonalo et a!." ere exposed to commercial chrysotile is compelling, the critical issue is whether . this excess `may -be attributable lo -trace contamination by tremolite. All of-the asbestos workers studied (Table 1) are likely to have potential exposures to tremolite, although in minute concentra tions compared with their chrysotile expo sures. In a few studies the percentage of tremolite is known and varies. Contrasting the results from these studies provides some information os the plausibility of the amphibole hypothesis. Two cases of mesothelioma have been reported among chrysotile asbestos miners and mDlere in Zimbabwe, where the chrysotile ores ait believed tobe free of tremolite contamina tion.53 Begin et al. noted that although exposure to tremolite may be as much as IS times higher in Thetford than in Asbestos, the incidence of mesothelioma in these two Quebec mining towns was proportional to the size of their work forces.53 He suggested that this fact may indicate that tremolite contamination may' not be a determinant of mesothelioma risk in Quebec. In the most recent update ofthe study ofQuebec miners and millers. McDonald et al.* presented separate exposure-response analyses for workers at the Thetford and Asbestos mines and mills. There is no indication in their findingsThat these two iacuiries exhibit a different exposure-response relationship for mesothelioma. On the other hand. McDonald and McDonald54 recently re ported that the average concentration of tremolite fibers in the lungs of miners was higher in one area of the Tnetford mine, which also demonstrated a stronger asso ciation with mesothelioma risk than an other area of the mine. Informative comparisons may also be made between the proportion of deaths from mesothelioma observed in the South Carolina textile workers study and tha: observed in the Quebec miners and millers study. Based on lung burden studies, Sebastien et ai. estimated that the proportion of tremolite in dust was prob ably 2S times higher in the Thetford mines of Quebec than in the Charleston textile facility;47 The percentage of deaths due to mesothelioma in tbe most recent reports was one half as high in the South Carolina textile workers (G.2Cc) as it was among Quebec miners and millers (0.455- i (Table 1). However, in making this com parison one needs to consider the fact that the incidence o? mesothelioma is known,jfs*increase exponential^ with follow-up time.55 and 7255- of the Quebec minen and millers had died.* compared with <255 of the workers ir. the South Caroline study.39 m the roost recent updates of these cohorts, ir the previous rtruer !*,, \c-.. ^c.Nt 1 Ameneac jourr.ai cfHibii: Htaltr. IS: , Toxicologic Studies 100 60 9. c s 60 O) -5j sc 40 - * a Control ` i Amosite * Arrthopnyllne v - C. Chrysotile P.. Chrysotile c Crocidoliie - ! j- . v1 - i 20 _ J - 0 i{ * If `| 1 3 Months - -- *_ i -; T ,,, . i j!iJ -r* ! 1 * !1 , *! ; i |! : fM- i; fj j** * * 1 ; J '- J. 6 Months 12 Months Duration of Exposure 'i -! - -1 i. ' ~ ii * ~ :, i M1 'i r 1 ' j . 1 i ! ; i i 24 Months Nae Daia are from Wagner el a!.1'; aoDnuoTTUH* 95% corrfioenea enervate tor a Dtnomel outcome nave own aooec. C = Canadian; R * ftraoMten. ---------- --------- -------------------------------------------------- --------------------------------- FIGURE 1--Lung tumors In rata exposed to 10 mg itn3 concentrations of asbestos for 3. t, 12. or24 months. i 1 , ! , ; , : . i i i j I j I ii i i . Lung Cancer Toxicologic studies demonstrated that ah forms of asbestos can induce juog cancers m experimental animals. For example, the lung tumor response tc to 24-month exposures to Union Interna tional Centre ie Cancer reference amositc, amhophyUite. Canadian chrysotile. Rhodesian chrysotile, and CTocidoiuc is shown in Figure IT Toe overlapping 95% confidence intervals suggest that there is no significant difference in potency among the five types of asbestos (U- the am phiboies are not systematically more or Jess potent than the ebrysotiles). Darvu and co-workers also compared the carcmogenic potencies of chrysotile and amphibole asbestos by exposing rats to 20 mg of amosite, crociooliie. and Zimbabwe chrysotile per nv5 for 1 year. These investigators found that chrysotile actually produced more lung tumors than the other forms of asbestos.s These results obviously differ from those of Wagner el a!.r and may point to the need to consider differences in fiber length when comparing the potencies of differ update of the Quebec miners and millers sxuds. the percentage that had died was 41% and the percentage of deaths due to mesothelioma was 02%, which is nearly identical to the percentage of deaths from mesothelioma in the most recent update of the South Carolina textile workers.35 The fact that these percentages are so similar is even more remarkable when it is recognized that the fiber exposure levels were approximately ten times higher in the Quebec miners and millers than in the South Carolina textile 'workers.'*' Thus, comparison of the mesothelioma results from th: study of Quebec miners and millers with those from the study of South Carolina textile workers does not provide support for the hypothesis that tremolhe exposure explains the mesothelioma ex cess observed in these studies. In contrast to the evidence for lung cancer, there is epidemiologic evidence indicating that exposure to chrysotile may be less potent than exposure to some amphiboies with regards to the induction of mesothelioma. Hughes and Weill esti mated that the risk of mesothelioma was approximately five times tower among tos miners was recently reported to be 4.7% among those exposed to croddotiie, which is- substantial!)' greater' than <the percentage of deaths due to rhesothcBotna observed in either the Quebec miners (0.4%) err the South Carolina textile workers (02%) exposed to predonainanth' chrysotile fibers.57 The per centage of deaths due to mesothelioma was only slightly higher amoDg South African miners exposed to amosite (0.6%! than among the chrysotile-exposed co horts.57 McDonald et al/- reported that the percentage of deaths due to mesothe lioma was 2.4 % among venniculite miners who were predominantly exposed to tremolite fibers, which is approximately six times higher than the percentage (0.4%j reported in the study of Ouebec miners and millers.50 It must be recog nized that the usefulness of these compari sons is limited by our inability to control for potential differences tn exposure con centrations. fiber size distributions, and iength ofobservation and are thus difficult to interpret. Nonetheless, the differences in mesothelioma response observed among ent types of asbestos. Davis et al. noted that 5% of the chrysotile in their study consisted of fibers grcatd'than.20 *im in ? length vs 0J5% of the `fibers- for 'the amosite and croddobie exposures.56 Other studies by Davis et al. showed that long-fiber samples of arooshe55 and chrysotile-60 are considerably more active than short-fiber samples in inducing lung turnon. Davis et al. also snowed that tremclitc.t: crocidobtt,5* and long-fiber chryso lite*' produce similar numbers of lung tumors. Figure 2 represents lung tumors due to amosite. crocidoliie. chrvsotile. or tremolite from the 3-ycar inhalation stud ies of Davis et al. and Davis and Jones, plotted against the exposure concentra tion in units of fiber count.56"*'- Inspection of Figure 2 suggests that the tumor incidence is strongly related to the concen tration of fibers 5 p.m or greater in iength. regardless of which type of asbestos is involved. More recep^y. Coffin ti aI.4- re ported the results from studies o: rats exposed via intratracheal insulation of chrysotile or crocidolht. Although these workers exposed to chrysotile fibers than chrysotile- and amphibole (primarily cto investigators focused primarily on meso among workers with mixed fiber expo ridohie L-exposed workers are so striking theliomas. it is worth noting that <summed sure * The percentage of deaths due to that alternative explanations for these across all dose groups) intratracheal instil mesothelioma among South African asbes differences atrocar unlikely. lation of chrysotile asbestoi produced Ame:::ar. journal of.Public Htaltr rrrfua- to'. KcT5'*?'- sijl kjflc; iunc carcinomas m 18.3% of i.. .limais ^tested vs 4.69c for crociaobtt.6* Overall, the toxicologic data suggest 60 2; xhat. chrysotile asbestos is .at leas: as ng ^jpotcni, ifjioLJuore so..as the amphiboie -j- y, forms in the induction of lung rumors on a 50 J -jper-miUigram basis. The data shown in :o LtFjgure 2 further suggest that the carcino- ,:jgcnic potencies of the various types are V) -iis '.-.similar when the dosage is measured in 'terms of the number of fibers greater than 5 tiro in length, as is customary in o 3 fr 40 i iI epidemiologic studies. IS 3f Mesothelioma o> 5 30 -j or . Rats exposed to asbestos by inhala tion also develop mesotheliomas, albeit at c oWor 20 - :..a iow incidence. Wagner ei al.1' exposed <D id 4-ats to 10 mg/m3 of Union International CL /.Comre le Cancer reference asbestos65 for `15 /periods of 1 day to 2 years; the mesothe- id .'lioma yields were atnosite. 0.7%; anthoJ* v-phyllite. 1.4%; crocidolite, 2.8%: and 10 lift /.Canadian chrysotile. 2.9%.'No raesothelio- Control Amosite Chrysotile T Crocidolits Tremolits in as were observed in control animals or 0 se Is exposed to chrysotile from Zimof t.v Similarly, Davis ct al. and Davis 1000 2000 3000 4000 5000 6000 :d tfe :d Jones reported small numbers of theiiomas in -response -to 1-year Fibers per ml ;r- ilation exposures to amosite/crocidol- ! Note. Data are from Davis t al. and Dwrs and Jooes.*"*' Controts are tne nootofl control animal .d .^Canadian.-chiysotile, and-Zimbabwe i from all lour studies.- 3V ^hrysotilt.5^*1 The highest mesothelioma in inddenee in these studies, 7.5%. was I ------ ---------------- ------------------------------------------------------------- at tr jjroductd by exposure to long-fibeT chryso tile.*1 Although the low inddenee rates ' FIGURE 2--Lung tumor* In rata exposed to 10 mg/m3 concentrations oi j crocidolhe, amosite. chrysotile. or tremolhe tor 1 year. at and small numbers of animals make tv quantitative comparisons uncertain, it w cannot be said that these studies provide these studies do not resolve the question consisted primarily of shon fibers, with convincing support for the amphiboie of whether or not chrysotile is less potent median fiber lengths on the order of j iitr '^hypothesis. in this regard than the amphiboie forms. for both chrysotile and crocidolite. Ifshon * . The mesotheiioma-induring poten- Coffin et al. recently reported that fibers do in fact have some mesothelioma- o- ' ,.4ial of asbestos fibers that reach pleural both chrysotile and crocidolite produce inducing potential tire attribution of all ng -surfaces has also" been examined via w. implantation studies. Union International mesotheliomas when administered intratrachcalh'.62 No consistent dose-response mesotheliomas to the small fraction of the fibers that were greater than 5 u.rr. in or Comre ic Cancer reference amosite, aotbophvUitc. croddolite, Canadian relationship was observed in these experi ments. but (summing across all dose length may lead to ar. exaggerated esti mate of the difference in potency of chrysotile. and Zimbabwe chrysotile all groups) chrysotile asbestos produced me crocidolite vs chrysod/e. in addition, reli e* produced mesotheliomas in rats after intrapleural inoculation.1- Extensive stud sotheliomas in 93% of the animals vs S.1% for crocidolite. This suggests that ance on the quantitative responses in this study should probably be limited out to IT ies by Stanton and co-workers suggest that chrysotile may have greater mesothelioma- the lad; of dose-response. Nevertheless, all long. thin, durable fibers have the inducing potential than croddolite on a these data do provide some support ior potential to induce mesotheliomas after per-milligram basis. However, the chryso the hypothesis that chrysotile may have surgical implantation and that fiber dimen tile preparation used in this experiment tower mesothelioma-inducing potennal jc, sions have much more influence on contained more fibers per rafiligjam Chan than the amphiboie forms of asbestos. mesothelioma yield than any differences the croddolite preparation, as well as a that may exist between types of asbestos.65 However, it is certainly possible that larger proportion of long fibers. If the experimental exposures are expressed on Mechanistic Studies different types of asbestos fibers may have differing probabilities of reaching piturai suriaces-when inhaled into the lungs. the basis of the number of fibers greater than 5 tun in length, it appears that CToddolhe produced nearly 12 times mote l:~fcasbesr, hypothesized that tne cytotoxic, genotoioc. and proliferative ef fects of asbestos are in pan mediated fry CK-trall. the implantation studies suggest mesotheliomas per fiber than chrysotile. the production of reactive oxygen species that chrysotile asbestos does have the potential to induce mesothelioma, bu: It should be noted that the fiber prepara tions in the Coffin e: al. experiments released by alveolar macrophages ir. re sponse to enrollment of lone fibers and rt?ruan !oue. \c. ?> Nc.I Amenear. .iourr-r..aa:-tov: -fu r'll rsealt-' awvner et i- mat this process may be catalyzed ov iron on the finer surface. Furthermore, it has been suggested that the needle-like con figuration. durabilin. and increased iron content of CTOCidolne render it more pathogenic than either amosite or chryso tiie.* Evpenmenui suppon for this hy pothesis is primarily derived from in vitro studies, which suggest that iron could potenuaJly act as a source of free radicals, an inhibitor of uimoriridal defense mecha nisms. and a nutrient for unrestricted tumor cell replication.6' However, com panion of the carcinogenic potencies of fibers in the rat in vrvo does not suppon the hypothesis that carcinogenic potency is related to iron content. As discussed above. Wagner et aJ.r observed similar numbers of tumors in rats with crocidolite. amosite, and chrysotile. even though these fibers have an elemental iron con tent of 40%. 28%, and less than 1%, respectively.6' The nonasbestos mineral erionite does not include iron as a constituent** but is nonetheless a potent mesothelioma inducer in rats.** Silicon carbide `whiskers," with an iron content of essentially zero, induce pleural turnon in rats after intrapleural implantation.45 Therefore, no obvious correlation be tween iron content and carcinogenicity is apparent in the rat. from patboiorir Studies in which iung burdens were measured. However, inter pretation of these studies is hampered by tnc fact that cntysotiic lung burdens are a pooT refieciion of integrated exposures and the fact that chrysotile exposure is highly correlated with tune burden of the amphioolcs icx.. iremobte'.. In addition, the pattern of asbestos fiber deposition in the iung does not appear to be consistent with the pattern of deposition in the target tissue (i.e., pleura). The previously reviewed empirical data from toxicoiogic studies and comparisons of mesothelioma mortality and lung cancer mortality be tween epidemiologic studies with differ ing levels of iremobte contamination do not provide suppon for this hypothesis. Mechanistic arguments that have been made to support the amphiboie hypoth esis. which are based on in vitro studies of iron content, appeal to be contradicted by the lad: of correlation between iron content and carcinogenic potency ob served in experimental studies. -Whether chrysotile asbestos is less potent than the amphibole forms of asbestos is a question that has not yet been fully resolved. There is currently very little toxicologic evidence to suppon this hypothesis. There is evidence from epidemiologic studies that chrysotile may pact of associated errors on the assess ment of risk.'1 Tnc currctn Ocarpatxraal, Safety and Health Administration (OSHAj metnod counts asbmos fibers that are longer than 5 urn and that have a icngth-to-diamcter ratio of at least 3 to 1. This metnod tmpiicniy assumes tbai less than 5 um m length arc not carcino genic and that all fibers greater than 5 me in length arc of equal carcinogenic dotency. These assumptions arc dearh inconsistent with the experimental data and most likely result b substantial misclassificauon of exposure in the epide miologic studies. Policy Implications The American Conference of Gov ernmental industrial Hygienists and sev eral countries fe.g., the Unhed Kingdom) have adopted iess restrictive standards for chrysotile asbestos than fir the other forms of asbestos. in our view, the currently available scientificevirienrr. does not provide sufficient support for develop ing separate standards fur the different forms of asbestos. As tins article docu ments, th: scientific evidence for tht amphibole hypothesis is stffl tenuous. Furthermore, the fact remains that in' practice workers in this country and other . be less potent for mesolhelfdnu induction countries are not exposedto pure-dnysb-' Summary ' tharitroddoliie.' The proportion bf^eaths due to mesothelioma arc strikingly lower tile, but rather to a imxrnrc of chrysotUev tremoliie,-and'otheT fimarefasbestbii.- Our review of both the tendcologic in chrysotile-exposed miners and mOlers Thus, it is- highly impractical to and cpidcmioiogic literature strongly sup than in crodoolite miners. There is setting separate standard for the differ-' ports the view that occupational exposure absolutely no epidemiologic or toxicologic ent forms of asbestos. Fma&y, even if one to chiysotQe asbestos is associated with an evidence to support the argument that accepts the argument that chrysotile asbes increased risk of both lung cancer and chrysotile asbestos is any less potent than tos does not induce mesothelioma (which mesotheiioma. The hypothesis that these other fonns of asbestos for inducing lung we do not), the 'risk of lung cancer (and observations may be attributable to trace cancer. asbesiosis) can not be dismissed, and amounts (< 1%) of tremoliie contamina It should be recognized that compari chrysotile appears to be jus: as patent a tionmay seem to be primarily of academic sons of the potency of the different ioims lung carcinogen as the other fonns of interest because chrysotile exposures in of asbestos are severely limited by uncon asbestos. Iris noteworthy that therisk of workers and the public are also contami trolled differencesin the bivariate distribu iung cancer is of greater concern than the nated with trernolne. However, the per tion of fiber length and diameter (i.e_ risk of mesotheiioma became, in most centage of tremoliie has been reported to fiber dimensions). Experimental studies studies there are at least two excess lung range from 0.5% to 6.9% in one analysis clearly demonstrated that fiber dimen cancers fox every mesothelioma observed of eight commercial chrysotile asbestos sions arc a critical component of the (see Table 11. There is also the additional samples.1 and h has been suggested that carcinogenic potency of fibers.* This concern of asbesiosis risk, winch was not chrysotile from Zimbabwe'*' and other concern applies to roost of the toxicologic considered m this article but dearly adds countries maybe tree of contamination by studies is which exposure is determined to the risk associated with chrysotiie amphiboles. Hence, the amphibole hy on an equal mass basis and is particularly exposure. pothesis may be of some public health pertinent to the epidemiologic investiga Therefore, given the dear evidence Tcievance. tions. Historic exposures in most of the of a iung^wcer risk, the feat of compel in our view, the cunentiy available epidemiologic investigations were based ling evidence foT the amphibole hypoth scientific literature does not provide per on impinge? samples that assessed the esis. and the fact that workers arc gener suasive evidence for the hypothesis that number of fibers., and conversion factors ally exposed to mixture of fiber types, we tremoiite contamination explains tnc me were applied to estimate the number of believe that it is prudent policy to treat sothelioma excesses observed in the stud fibers longer than 5 jur*. Concerns have chrysotile asbestos with virtually the same ies of chrysotiie-exposed workers. The been raised about the accuracy of these level of concern as the ampbiboie fonns of primary evidence for this hypothesis comes conversion factors and the potential im asbestos. Tm? vie* is consistent with the t1- -cr.ercar >o`---.2 c ` f-uriv. Hear.i bcuar .N* -