Chrysotile Asbestos As a Cause of Mesothelioma: Application of the Hill Causation Model

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Chrysotile Asbestos as a Cause of Mesothelioma: Application of the Hill Causation Model

RICHARD A. LEMEN, PHD

Chrysotile comprises over 95% of the asbestos used this method, researchers are asked to evaluate nine today. Some have contended that the majority of areas of consideration: strength of association, tempo- asbestos-related diseases have resulted from exposures rality, biologic gradient, consistency, specificity, bio- to the amphiboles. In fact, chrysotile is being touted as logic plausibility, coherence, experimental evidence, the form of asbestos which can be used safely. Causa- and analogy. None of these considerations, in and of tion is a controversial issue for the epidemiologist. How itself, is determinative for establishing a causal rela- much proof is needed before causation can be estab- tionship. As Hill himself noted, “[n]one of my nine lished? This paper examines one proposed model for establishing causation as presented by Sir Austin Brad- view points can bring indisputable evidence for or ford Hill in 1965. Many policymakers have relied upon against the cause and effect hypothesis, and none can this model in forming public health policy as well as be required as a sine qua non.” In the same vein, it is deciding litigation issues. Chrysotile asbestos meets not necessary for all nine considerations to be met Hill’s nine proposed criteria, establishing chrysotile before causation is established. Instead, Hill empha- asbestos as a cause of mesothelioma. Key words: sized that the responsibility for making causal judg- asbestos; chrysotile; amphiboles; causation; mesothe- ments rested with a scientific evaluation of the totality lioma; Hill model. of the data. He further acknowledged that decisions on causation must be made in the absence of perfect data. INT J OCCUP ENVIRON HEALTH 2004;10:233–239 As he stated,

All scientific work is incomplete—whether it be obser- n determining cause and effect, epidemiologists vational or experimental. All scientific work is liable are confronted with two distinct determinations, to be upset or modified by advancing knowledge. I general causation and specific causation. General That does not confer upon us a freedom to ignore the causation involves the determination of whether the knowledge we already have, or to postpone the action particular substance under consideration causes the that it appears to demand at a given time. effect being studied. Specific causation, on the other hand, focuses on whether a particular individual’s dis- With respect to the issue of whether chrysotile ease is attributable to exposure to that substance. In asbestos is capable of inducing or contributing to the determining general causation, a variety of data sets are development of mesothelioma, the body of scientific evaluated by researchers. The information that is evidence has long established a cause-and-effect rela- processed includes mechanistic processes, biological tionship. Throughout the last 30 years, many govern- principles, molecular studies, toxicologic studies, mental organizations have thoroughly and meticu- animal experimentation, and human epidemiologic lously reviewed reams of published data and have studies, including case reports, case–control studies, concluded that all fiber types are capable of causing cohort studies, and mortality and morbidity studies. It mesothelioma in American workers. Two publications is not surprising that consensus about basic definitions highlight the fact that the majority of the world med- and methods for causal inference is limited, even after ical community considers chrysotile to be a cause of three centuries of debate.1 mesothelioma. In 1997, a multidisciplinary gathering One of the most widely acclaimed methods for of 19 pathologists, radiologists, occupational and pul- determining cause and effect for general causation was monary physicians, epidemiologists, toxicologists, proposed by Sir Austin Bradford Hill in 1965.2 In using industrial hygienists, and clinical and laboratory scientists held a meeting in Helsinki, Finland, to agree upon criteria for attribution of disorders of the lung and pleura in association with asbestos. Collectively, the Dr. Lemen is retired Assistant Surgeon General, USPHS, and retired Deputy Director and Acting Director, NIOSH, and has group had published over 1,000 articles on asbestos testified as a plaintiff’s expert in asbestos-exposure cases. and asbestos-associated disorders. The consensus of the

233 group was that all types of malignant mesothelioma can ity of mesotheliomas are caused by exposure to be induced by asbestos, with the amphiboles showing asbestos.7,8 Moreover, it has been firmly established that greater carcinogenic potency than chrysotile.3 the level of exposure necessary to induce mesothe- The second publication was a monograph devoted lioma in certain individuals is well below the level nec- specifically to chrysotile asbestos that was prepared by essary to induce asbestosis or other asbestos-associated the International Programme on Chemical Safety diseases.4 Mesotheliomas have been documented not (IPCS) in conjunction with the World Health Organiza- only in occupational settings but also para-occupation. After an extensive review of the world’s literature, tional settings such as those occurring among family this body concluded that “commercial grades of members exposed to asbestos fibers introduced into chrysotile have been associated with an increased risk of the household through the clothes of the worker, and pneumonoconiosis, lung cancer and mesothelioma in in neighborhood settings where individuals are numerous epidemiological studies of exposed workers.”4 exposed to asbestos fibers introduced into the atmos- While these two publications represent the recent phere by manufacturing plants.9 The second important scientific consensus on the ability of chrysotile to cause feature of mesothelioma that needs to be highlighted is mesothelioma, the International Agency for Research its rarity among the population of people who have not on Cancer (IARC), a part of the World Health Organi- been exposed to asbestos. While a background inci- zation, came to similar conclusions in 1976. The IARC dence of mesothelioma has not been firmly estab- gathered a group of eminently qualified asbestos lished, it is estimated that it occurs probably on the experts to review and then develop a consensus report order of 1 case per million persons per year or less.10 on the carcinogenic effects of exposure to all forms of The rarity of the disease, coupled with the lack of mor- asbestos, including chrysotile. The group of scientists, tality rates in the populations used as controls and in addition to myself, included such noted researchers problems in diagnosis and reporting, make the assess- as Dr. J. C. Wagner (U.K.), Dr. I. J. Selikoff (U.S.), Pro- ment of the actual risk for mesothelioma through the fessor J. Bignon (France), Dr. P. Westerholm (Sweden), means of epidemiologic studies difficult.4 Dr. G. Berry (U.K.), Professor A.M. Langer (U.S.), Dr. Despite these difficulties, numerous scientific studies F. D. Pooley (U.K.), Dr. D. P. Rall (U.S.), Professor H. of workers exposed to chrysotile asbestos have demon- W. Schlipkoter (Germany), Dr. J. K. Wagoner (U.S.), strated that the risk of contracting mesothelioma after and Dr. J. A. H. Waterhouse (U.K.). The Monograph exposure to chrysotile asbestos is more than double that concluded, “All commercial forms of asbestos tested of individuals who have not had such exposure. While are carcinogenic in mice, rats, hamsters and rabbits.” most of these studies are of cohorts of workers who were And also “Many pleural and peritoneal mesotheliomas exposed to chrysotile contaminated with low levels of have been observed after occupational exposure to cro- tremolite, an amphibole form of asbestos, several stud- cidolite, amosite and chrysotile.” These conclusions, as ies revealed a substantially increased risk of contracting related to humans, were based on the epidemiologic mesothelioma from exposure to chrysotile that did not studies of various exposed cohorts.5 The conclusions of contain any tremolite contamination. In the first study, the IARC have been echoed by every regulatory agency Piolatto and his associates examined a cohort of 1,094 of the United States, including the EPA, OSHA, CDC, chrysotile production workers employed at the mine NIOSH, DHHS, PHS, and FDA. and mill in Balangero, Italy, a site where no tremolite The 1984 Report of the Royal Commission on Mat- was detected in any of the samples of chrysotile.11 ters of Health and Safety Arising from the Use of Among the 427 deaths, the authors discovered two Asbestos in Ontario concludes, “All fibre types can mesothelioma cases, one confirmed pathologically and cause all asbestos-related diseases. . . .”6 one based on radiographic findings and an examina- The substantial body of scientific evidence that tion of pleural fluid. While the authors report that the establishes that chrysotile asbestos, alone or in combi- fibrous silicate balangeroite was found, unlike the situa- nation with its naturally-occurring contaminant, tremo- tion for fibrous tremolite, no data exist on its toxicity or lite, an amphibole form of asbestos, is a cause of etiologic role in mesothelioma.* mesothelioma in human beings is revealed by the following analysis of the data according to the considerations for determining cause-and-effect relationships *Balangeroite was named after the Balangero serpentinite proposed by Hill: deposit at Piedmont, Italy. Balangeroite is a mineral fiber of the asbestiform variety, first discovered in 1983, with a mineral for-

mula Mg, Fe, Fe, Mn)42Si16O54(OH)40, brown in color, and is 1. Strength of association is a reflection of the found in schistose serpentinite in proximity to a large ultramafic strength of effect in a given study. At the outset of any massif associated with the Balangero serpentinite deposit. To evaluation of the issue of chrysotile asbestos and its risk date no data on its toxicity have been published, and definitely of inducing mesothelioma, it is important to note that no record of its role in the induction of mesothelioma (sources: ; Ministry of Energy & Mines, the medical and scientific community universally Government of British Columbia; ).

234 • Lemen www.ijoeh.com • INT J OCCUP ENVIRON HEALTH In a similar study, Cullen and Baloyi examined the anthophyllite, the later findings from Chinese mines records of Zimbabwean miners and millers who had can not be equated to those reported by the authors been certified as having an occupational lung dis- from their own analysis of the samples representing ease.12,13 As in the chrysotile ore mined in Balangero, those taken from their study. Italy, no tremolite or other amphibole mineral was In addition to the studies of exposures to unconta- detected in any of the samples, either bulk or through minated, “pure” chrysotile, there have been several electron microscopic analysis. While it is now claimed studies of populations who were exposed to chrysotile anthophyllite is a contaminate of the UICC samples ore and processed chrysotile products, which con- taken from Zimbabwe, there is no reason to doubt that tained trace amounts of the amphibole tremolite. In no contamination was found in the study by Cullen and the mining context, Camus et al.18 compared mortality Baloyi or to assume that the UICC sample is represen- among women in two chrysotile asbestos mining areas tative of the exposures of the miners and millers stud- in the province of Quebec with mortality among ied. Investigations of UICC samples have found the women in 60 control areas. While focusing on lung chrysotile taken from Zimbabwe contains 2% antho- cancer mortality, the authors discovered a statistically phyllite as an impurity.14 The authors estimated that significant increase in mesotheliomas, as evidenced by 6,647 Zimbabweans had been engaged in the mining an SMR of 7.63 with a 95% CI of 3.06–15.73. Camus et and milling operations at two mines: Shabani and al.19 in doing further analyses of women from both Goths. Among the chosen cohort of 27 miners with suf- Asbestos and Thetford Mines, identified one peritoneal ficient documentation, the authors discovered one mesothelioma from Asbestos and ten from the Thet- mesothelioma case proven by biopsy, one mesothelioma ford Mines area, again showing the ability of fibers proven by postmortem examinations, and one probable from both areas to produce mesothelioma. The mesothelioma based on radiographic findings. They authors explain the differences between the two areas also reported one case of asbestosis with probable ter- as due to the amounts of tremolite contamination, minal mesothelioma vs. lung cancer based on chest x- being less in Asbestos. ray only as having a pleural mass five years later. Given With regard to processed products composed of the size of the exposed population, and even though chrysotile asbestos, Nokso-Kollvisto and Pukkala20 the authors did not report a Standard Mortality Ratio examined a cohort of 8,391 members of the Finnish (SMR), it is most likely that it would have exceeded an Locomotive Drivers’ Association during the years 1953 SMR of 2 given the rarity of the disease in a comparison and 1991. They found a statistically significant fourfold population of non-exposed individuals. risk of mesothelioma [8 obs vs. 2 exp: standard inci- Rogers and his colleagues examined 221 cases of dence rate [SIR]: 4.05; 95% CI: 1.75–7.97] among men definite and probably mesothelioma obtained from the exposed to anthophyllite asbestos contaminated with Australian Mesothelioma Surveillance Program.15,16 tremolite and exposed to pipes, used in the locomo- Among these cases, Rogers tives, made of chrysotile. Chrysotile has been found most often together with anthophyllite.21 While antho- recorded a substantial number of mesothelioma phyllite is exceptionally common in the lungs of the patients in whom the only detectable type of asbestos Finnish population, when compared with people in was chrysotile (Table 9), with evidence of a dose– other countries, its potency in producing mesothe- response effect as reflected in a trend to an increasing odds ratio (OR) at relatively low fibre concentration lioma has been considered low, and mortality studies of 6 Finnish anthophyllite miners had historically not found of less than 10 fibers per gram dry lung tissue (log10 = 5.5–6; OR = 8.67). a causal relationship with mesothelioma22–25; however, Tuomi et al.26 did report anthophyllite fibers as the A 25-year longitudinal study of workers exposed to major fiber type in 70% of the mesothelioma patients amphibole-free chrysotile found two confirmed cases examined, but concluded that causality could not be of mesothelioma among the exposed workers.17 The established as no case was reported for anthophyllite relative risk for all cancers, adjusted for smoking and exposure only among the mesothelioma cases. Toumi age, was 4.29 (95% confidence interval [CI]: 2.17– et al.26 quoted Churg,27 noting that saying chrysotile 8.46). The authors reported that analysis of four com- content in the lung is low doesn’t mean that there has mercial samples of the asbestos used in the Chongqin been no past exposure to chrysotile asbestos that could chrysotile asbestos plant under study were shown to have been responsible for causing the disease. In 1994, contain less the 0.001% tremolite fiber, which is less the same year in which Nokso-Kollvisto and Pukkala than the detection limit for amphibole contamination reported their study results, the first epidemiologic using x-ray diffraction analysis and the analytical trans- study to suggest causation was published when Kar- mission electron microscopy method used in this study. jalainen et al.28 identified four cases of mesothelioma, It has been reported that samples of Chinese chrysotile one peritoneal and three pleural, among 999 Finnish are contaminated with tremolite; however, like the find- anthophyllite miners and millers, having latencies ings of the Zimbabwe UICC samples contaminated with between 39 and 58 years. All four had asbestosis with

VOL 10/NO 2, APR/JUN 2004 • www.ijoeh.com Commentary • 235 high lung fiber burdens of anthophyllite. However, the asbestos cement in Louisiana,36 textiles containing potency for anthophyllite in inducing mesothelioma is chrysotile asbestos in North Carolina31,37 and Somerset, lower that that of the other fiber types of asbestos.29 New Jersey38; workers manufacturing chrysotile Another study, of railroad workers predominantly asbestos friction products in Connecticut,39 England,40 exposed to chrysotile asbestos, by Dr. Thomas Man- and Germany41; wives of workers who manufactured cuso, arrived at a similar conclusion.30 Out of a cohort chrysotile textiles and friction products in New York of 181, there were 156 deaths, 14 of which were identi- State42; mechanics who installed chrysotile asbestos fied as mesotheliomas, constituting 34% of all cancer brake linings in Australia,43 Canada,44 the United deaths in the study, the incidence of mesothelioma far States,45–47 England,48 and Denmark49; railroad workers exceeding a doubling of the risk. using chrysotile insulation on locomotives in the In a study of workers employed between 1940 and United States,30 Italy,50 Finland,20 and Switzerland51; an 1967 in an asbestos textile, friction, and packing manu- Italian worker in the wine filter industry52; and individ- facturing facility that utilized 99% chrysotile asbestos, uals who simply lived in close proximity to a chrysotile Robinson et al.31 observed 17 mesotheliomas, repre- asbestos textile and friction products plant.53,54 senting 4.3% of the deaths. The authors concluded that the study demonstrated an excess risk of mesothe- 5. Specificity requires that each cause have a single lioma to the men and women studied. effect. This is rarely a useful criterion when dealing Finally, a review of 843 cases of mesothelioma with environmental carcinogens because most of them recorded in the German Federal State of Saxony– cause more than one type of cancer.55 Chrysotile, like Anhalt betweeen 1960 and 1990 found 67 cases, repre- the other forms of asbestos; amosite, anthophyllite, cro- senting 14% of the total, were directly attributable to a cidolite, and tremolite, causes asbestosis, lung cancer, sole exposure to chrysotile asbestos.32 and gastro-intestinal cancer in addition to pleural and peritoneal mesothelioma.4,5,23,24 2. Temporality requires that the cause precede the effect. This consideration is satisfied because in all of 6. Biologic plausibility seeks to determine whether the studies examining the carcinogenic potential of the theory of causation fits known mechanisms of chrysotile, the exposures to chrysotile preceded the injury causation. While it is impossible to have a com- development of mesothelioma. plete understanding of the mechanisms of cancer cau- 3. Biologic gradient is the existence of a dose– sation, the biologic facts known about the various response relationship for the proposed cause–effect asbestos fibers and how they cause disease are consis- combination. Research has shown that the association tent with the postulate that chrysotile asbestos fibers between exposure to chrysotile asbestos and the devel- are capable of producing mesotheliomas. First, it has opment of mesothelioma is a dose–response relation- long been known that it is not the chemical composi- ship. In their epidemiologic study, Rogers et al. found a tion alone of the various asbestos fibers that is impor- significant trend of an increasing risk of mesothelioma tant in their ability to produce disease, the health with increasing fiber concentrations, as shown by an effects of asbestos are related primarily to fiber mor- odds ratio of 15.7 for chrysotile fibers less than 10 µm phology and size. Many researchers contend that the 56,57 long.15 A similar dose–response relationship for all potency of crocidolite is related to its thin diameter. asbestos types was recently documented by Rodelsperger Similarly, inhaled chrysotile fibers have a tendency to et al.33 and Iwatsubo et al.34: “A significant excess of split longitudinally and partially dissolve, creating short mesothelioma was observed far below the limits adopted fibrils of the thin fibers in the lung. in most industrial countries during the 1980s.” Second, it is universally accepted that chrysotile Every United States government agency that has asbestos is carcinogenic and capable of causing or con- 55 dealt with this issue; the World Health Organization; tributing to the development of lung cancer. Third, and the World Trade Organization have all determined mesotheliomas develop in the pleura, peritoneum, and that this dose–response relationship has no threshold, other mesothelial cells that form a monolayer mesothe- that is, any exposure to chrysotile raises one’s risk of lium lining the serosal cavities and the organs contained 60 developing mesothelioma. within these cavities. Chrysotile is a cause of cancer in the lung and migrates to the mesothelial linings of the 4. Consistency requires that a proposed effect be body.61–64 Since chrysotile is carcinogenic and is present observed repeatedly under different circumstances. A in high concentrations in the mesothelial linings where review of the medical literature reveals that this consid- the mesothelioma is induced, it is biologically plausible eration has been amply demonstrated with regard to that it causes or contributes to causing mesothelioma. chrysotile exposure and mesothelioma. Cases of Fiber penetration can rearrange the cytoskeletal appara- mesothelioma have been observed in: chrysotile tus of the cell and this could indicate an interaction miners in Canada,35 Italy,11 and Zimbabwe, South between the chrysotile fibers and the normal mitotic Africa12,13; in workers manufacturing chrysotile process, since giant multinucleated cells are formed.

236 • Lemen www.ijoeh.com • INT J OCCUP ENVIRON HEALTH These studies indicate that chrysotile penetrates the cell, clusion that chrysotile per se can induce mesothelioma enters the nucleus, and induces abnormal chromosome even when tremolite or other amphiboles are not formations in dividing cells.65 Some of these abnormali- detected. These findings along with the results of the ties include the deletion of the P53 gene growth.66 experimental studies leave no doubt that the scientific evidence supports the carcinogenicity of chrysotile 7. Coherence asks whether the causal theory is not alone in the induction of mesothelioma.75,76 The inconsistent with what is already known of the injury or debate, as it applies to human exposure to pure- disease. There is no biologic argument that explains chrysotile-containing products, is academic, at best, as why chrysotile is incapable of causing mesothelioma. there appear to be few if any pure chrysotile deposits unequivocally identified or reported in the scientific lit- 8. Experimental evidence can consist of laboratory erature; nor has any product purported to contain only studies, animal studies, controlled clinical trials, or chrysotile been conclusively shown to contain unconta- observational pathology studies. The results from animal minated pure chrysotile. However, if and when such bioassays present a strong case that there is no safe form deposits or products are identified, the fact remains that of asbestos. Studies have shown that commercial-grade chrysotile alone can cause mesothelioma, as demon- Canadian chrysotile can induce mesotheliomas when strated in this paper, when fitting the existing scientific injected intrapleurally into rats, and induce primary knowledge into the parameters of the Hill causation lung neoplasms when the animals are exposed by inhala- model. The exact potency of chrysotile, per dose tion. The inhalation studies that produced mesothe- needed to cause mesothelioma, when compared with liomas among animals inhaling the superfine asbestos the amphiboles, remains controversial and has been dis- (SFA), where the majority particle size was less than 5 cussed elsewhere.4,77–79 However, even when potency, on µm, found the most mesotheliomas occurring after a dose-by-dose basis, is considered, the fact remains that injection of the SFA, which was found to be the most car- chrysotile is capable of causing mesothelioma and that cinogenic overall.67 It appears that chrysotile is not only no safe dose has been identified below which a risk of as potent as crocidolite and the other amphiboles in developing mesothelioma no longer exists. inducing mesotheliomas after intrapleural injections,68 While the Hill causation model has served a very but also equally potent in inducing pulmonary neo- useful purpose, its relevance to today’s multi-chemical plasms after inhalation exposures. In terms of degree of environment may have its limitations. Further, no epi- response related to the quantity of dust deposited and demiologic study has ever been done to validate such retained in the lungs of rats, chrysotile appears to be models for causation. In fact, the sum total of reliance much more fibrogenic and carcinogenic than the upon any causation model has been to resolve policy amphiboles.69 Another study found mesotheliomas decisions. Dr. Hill indicated he did not believe all nine developing in rats six to 23 months after peritoneal of his factors of causal evidence were clearly necessary introduction of chrysotile asbestos, and the tumors were to establish causation. Dr. Hill was concerned with strikingly similar to those occurring in man with regard “How do we determine what are physical, chemical and to both histologic features and growth patterns.70 Epi- psychological hazards of occupation, and in particular demiologic evidence and animal data support the role those that are rare and not easily recognized.” He was that all fiber types, including chrysotile, have in the cau- also concerned “However, before deducing ‘causation’ sation of lung cancer and mesothelioma as well as other and taking action we shall not invariably have to sit cancers. Several different animal species that have around awaiting the result of that research.” He further inhaled or been injected with pure chrysotile fibers have states that to determine causation “No formal tests of developed mesothelioma.71,72 significance can answer that question. Such tests can, and should, remind us of the effects that the play of 9. Analogy asks whether epidemiologic and other chance can create, and they will instruct us in the likely studies have established that an environmental exposure magnitude of those effects. Beyond that they con- analogous to the exposure being considered may cause tribute nothing to the ‘proof’ of our hypothesis.” diseases similar to those reported for the exposure being Finally, Hill states “The evidence is there to be judged considered. All other morphologically similar asbestos on its merits and the judgment (in that sense) should fibers cause mesothelioma in both the pleura and the be utterly independent of what hangs upon it—or who peritoneum.4,5 The presence of tremolite in chrysotile hangs because of it.” and the acceptance of the ability of tremolite alone to 73,74 cause mesothelioma satisfy this consideration. References

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