Document Evw4EyEnqJq83xRZpen4MDeqj

Health Effects of Asbestos and IMonasbestos Fibers Omowunmi Y.O, Osinubi, Michael Gochfeld, and Howard M, Kipen UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA Exposures to asbestos and synthetic fibers remain areas of great concern in the field of occupational elsewhere in this monograph. Concluding lung disease. Despite extensive study, the health effects associated with fibers remains an area of remarks address current policy and research substantial controversy. In particular, effects of fibers at relatively low doses, particularly for mesothelioma, remain a matter of evolving opinion, especially when integrated with the divergence of opinion on relative pathogenicity of different fiber types. Mechanistic studies continue to provide a window into pathogenesis and some hope for understanding dose-response relationships at the implications of fiber health hazards. The focus of discussion is on information pub lished in the last decade of the 20th century. lower levels seen in contemporary Western workplaces and the general environment. Changes in clinical assessment based on use of new chest imaging techniques beyond the traditional plain film are also an area of evolution and begin to challenge B-reading as the definitive tool for nonmvasive Nomenclature, Sources, and Production of Fibers assessment of disease. Public health concerns have to a great extent been transported to the Asbestos developing world where there is a strong trend toward increased use of asbestos, although it has been virtually eliminated from commerce in most developed countries. For remasbestos fibers, the major unsettled issues are their relative potencies as carcinogens for the human Sung and mesotheiium and the need to sort out the relation between physical and chemical properties of these fibers and their pathogenicity. The recent discovery of "'flock worker's lung" due to synthetic fibers once again alerts us to emerging diseases associated with new technologies. Key words'. asbestos, ssbestosis, chrysotile, man-made mineral fibers, man-made vitreous fibers, mesothelioma, susceptibility. -- Environ Health Perspect 108(suppl 4):66B-674 (2000). Asbestos is a commercial term for six different types of naturally occurring fibrous crystals (crocidolite, amosite, chrysotile, anthophyllite, tremolire, and actinolite) composed of hydrated aluminum-magnesium silicates with varying metal composition. The two major classes are serpentine (limited to http://ehpn@thnmhs,nih,govfiiQCs/20Q(y$uppl-4A>&5-674Q$inubi/8b$tract,htmi chrysotile) and amphiboles, which include all the remaining asbestos fiber types, although only chtysotile, crocidolite, and amosite have In this article we examine the current state of levels (/), others suggest the presence of experienced widespread commercial exploita knowledge regarding the association of nat thresholds for at least asbestosis (2). Thus, tion. Chrysotile has long relatively flexible ural. and synthetic fibers with fibrotic and health research objectives have progressed to fibers, whereas amphiboles are characterized neoplastic lung disease. It is well established focus on the effects of much lower levels of by shorter, rigid fibers. Fiber types sometimes that inhalation by humans of all forms of asbestos fiber exposure, including ambient occur in combination, e.g., chrysotile from asbestos can cause pleural plaques, pleural exposure in the vicinity of operations that Quebec, Canada, typically contains approxi fibrosis, interstitial fibrosis (asbestosis) of the use or process asbestos. mately 1% of tremolite, an amphibole. lung parenchyma, carcinoma of the lung, and The major asbestos-exposed cohorts that Worldwide, about 95% of asbestos produced mesothelioma, but potency and risk vary with continue to be studied for health effects are continues to be chrysotile, and total contem fiber type and exposure history. Numerous construction insulation workers (studied by porary annual production of 2.9 million tons epidemiology studies of workers in produc Selikoff and colleagues), South Carolina tex is comparable to that of the early 1960s (3). tion, fabrication, and end use (largely con tile workers (studied by Dement and NIOSH) The former Soviet Union is the leading con struction) have been published, and asbestos and Quebec miners, millers, and factory temporary producer, followed by Quebec, is probably the best studied occupational and workers (studied by McDonald and others). China, and Brazil, environmental health hazard. However, The latter two chrysotile-exposed cohorts have important controversies persist, partly because undergone detailed exposure reconstructions. Man-Made Vitreous Fibers of gaps in science and partly because of differ Within limits, this has facilitated attempts to Man-made vitreous fibers, a large subset of ent interpretations of existing data. Currently, examine dose-response relationships and per man-made mineral fibers (MMMFs), are syn the most important controversies concern the form risk assessments (i). Although all these thetic, vitreous silicate fibers widely used in risks from low-level and ambient asbestos cohorts were originally reported on well before presenr-day insulation and construction indus exposure, as well as the magnitude of the 1990s, new information continues to tries in industrialized nations, following the mesothelioma risk from chrysotile inhalation. appear that refines or revises that originally decline of widespread use of asbestos materials. These issues are critical not only because of reported with respect to the associations MMVFs are broadly categorized into insula their inherent scientific importance but also between asbestos and disease. As asbestos uses tion wools (rock wool and slag wool), glass because of their profound implications for have been phased our of commerce, many fibers (glass wool, continuous glass filaments future asbestos use and use constraints, espe new fibrous materials have been used as sub and microfibers), and refracroiy ceramic fibers cially from an international perspective. stitutes, usually before the health hazard (kaolin-wool and other high-temperature insu Dust control regulations in developed potential has been adequately evaluated. lating fibers). There are over 70 varieties of nations have become progressively more In this article we discuss asbestos fibers, synthetic inorganic fibers (4). demanding compared with the 10-100 zeolites, man-made vitreous (mineral) fibers fiber/cc exposure concentrations of the mid- (MMVFs), as well as some newer nonvitreous 20th century. The current U,S. Occupational Safety and Health Administration permissi ble exposure limit (OSHA PEL) is 0.1 fibers/cc, rime-weighted average, for all six fiber types. Although some risk assessments still predict substantial morbidity at these (organic) synthetic fibers (nylon flock). We emphasize aspects of fibers and health such as fibrosis and mesothelioma not specifically addressed elsewhere in this monograph but cannot completely avoid discussion of lung cancer, which is addressed more specifically This article is part of the monograph on Environmental and Occupational Lung Diseases. Address correspondence to H.M. Kipen, EOHSi, 170 Frelinghuysen Rd,, Room 208, Piscataway, NJ 08854 USA. Telephone: (732) 445-0123, ext. 629. Tax: (732) 445-3644. E-mail: kipen@eohst.rutgers.edu Received 2 March 2000; accepted 5 June 2000 Environmental Health Perspectives * Vol 108, Supplement 4 * August 2000 665 OSIBUBIFTAL MMVFs arc produced from molten rock, recent exposures in rock wool and slag wool Mechanistic studies of fiber health effects slag, glass, and kaolin clay as well as from production are considered to be somewhat have recently proceeded along two major lines: combinations of silicon and aluminum oxide. Higher (8). Much higher exposures may occur those demonstrating biochemical mechanisms Processes used in manufacture include among end users such as construction workers by which fibers induce disease, and those mechanical drawing, blowing threads or when MMVFs are used in confined spaces, as investigating human susceptibility and other droplets through jets of steam, hot air, or during application of insulation. This parallels host factors that contribute to or mitigate toxi Same, as well as attenuation of droplets of the experience with asbestos in which early con city. New lines of investigation among the lat molten liquid by centrifugation. Several addi trols over exposure were applied solely in the ter with important clinical applications are a tives including fire retardants, binders, wet production facilities and exposures in the con- group of studies beginning to investigate the ting agents, and antifungal agents are often struccion/insulation setting were largely ignored role of certain enzyme polymorphisms in incorporated in the production processes (5). until the dramatic epidemiologic reports of the contributing to diseasesusoepribility. The common-purpose insulation wools, 1960s and 1970s (9/9). Fibrosis from asbestos and other fibers rock, glass, and slag constitute approximately 80% of MMVFs currently produced and are widely used for fire protection, acoustic and Mechanisms of Fiber-Induced Disease appears to arise from a process of chronic inflammation associated with the elaboration and release of mediators such as lysosomal thermal insulation, acoustic ceiling tiles and A detailed account of fiber pathogenesis at the enzymes, intermediates of arachidonic acid panels, air-conditioning and ventilation cellular, biochemical, and molecular levels is production, proteases, cytokines, growth fac ducts, and as growing media for horticulture. beyond the scope of this article. The study of tors, and reactive oxygen species (ROS) from Continuous filament glass fibers comprise the potential mechanisms of pulmonary health pulmonary macrophages, neutrophils, and about 10--15% of MMVF production and effects from fibers has been dominated by a other inflammatory cells. As the inflamma are used in reinforcement of cement, plastics, concern for asbestos because of its much better tion proceeds, fibroblast proliferation occurs resins, paper and rubber products, for textiles, demonstrated carcinogenic and fibrogenic and excess collagen is deposited in the lung and for electrical insulation. Refractory properties, but many of the observations about parenchyma in the area of the offending ceramic fibers (RCFs) constitute only 1-2% asbestos have direct relevance or give perspec fiber. Continued exposure and fibrosis results of MMVFs and are used in high-temperature tive to understanding the effects of MMVFs in asbescosis (2,14), The ROS, in particular, insulation offurnaces and kilns. Other special and other synthetic fibers. The capacity for hydrogen peroxide, superoxide anion, and purpose glass fibers comprise less than 1% of asbestos to induce pulmonary and pleural hydroxy! radical, can also be produced in production and are used for high-efficiency fibrosis in humans is indisputable, whereas the cell-free systems, and thus presumably by thermal insulation in aircraft and aerospace, evidence supporting this for MMVFs is lim direct chemical reactions between intrinsic high-performance acoustic insulation, and as ited. Although all forms of asbestos are well- metals on the fiber surface and extracellular battery separation media. They constitute less established animal and human carcinogens, the fluids (IS), Among the most prominent than 1% of MMVFs produced and are used International Agency for Research on Cancer mechanisms hypothesized to account for in aerospace, high-efficiency filtration, and (IARC) (8) categorized insulation wools as fiber carcinogenesis is DNA damage from the other ft^ft-perfbrmance applications (4). Class 2b (possibly carcinogenic to humans), ROS (15,16), Rock and slag wools were first introduced and glass fibers as Class 3 (indeterminate as to In recent years a number of investigators in the late 1800s. Fiberglass came into use in whether they are carcinogenic). Present-day have shown the susceptibility hypothesis to the 1930s and refractory ceramic fibers have concerns about the toxicity of all fibers are have some clinical relevance. For instance, it been produced since the 1950s (6). The based on principles derived from experience has been shown that the glutathione ikrans- industrial processes utilized in MMVF pro with the toxicity of asbestos fibers. In particu ferases (GSTs) conjugate a variety of reactive, duction facilities have changed over the years. lar, in vim and in vivo studies of MMVFs are electrophilic substrates. Deletion of the gene In the early years of production, batch often designed to replicate studies that have coding for the mu class of GSTs is associated processes involving labor-intensive and hand- been done with asbestos fibers (11). with increased risk for mesothelioma (17), operated production methods as well as Depositional characteristics, biopersis lung cancer (18), and asbescosis (19,20). poorly ventilated facilities were common tence, and the chemical composition are place. In addition, dust-suppressing agents among the most important determinants of Lung Burden Studies were not used. Hence, workers employed the intrinsic toxicity of any inhaled fiber. Fiber biopersistence is defined as the retention during this period had high levels of fiber Many studies have attempted to understand of fibers in the lung, over time, with regard to dust exposure. It is also noteworthy that in pathogenesis by microscopic detection and their number, dimensions, surface chemistry, the early technological phase, contaminants quantification of different fiber types in dif chemical composition, surface area, and other such as asbestos, bitumen, pitch, silica, and ferent areas of the lung (see section "Lung physical characteristics (21,22). Long fibers formaldehyde were present in many work Burden Studies"). Respirable fibers of con are generally believed to have more biologic places. The recent phase of MMVF produc cern have an aspect ratio of at least 3 and an activity and therefore greater pathogenicity tion is characterized by the use of more aerodynamic diameter <10 pm, correspond chan short fibers. Experimental studies have modern production methods as well as dust ing to a measured physical diameter of less shown that fibers that are most carcinogenic suppressing agents (mainly mineral oil) and than approximately 3--4 pm. However rela for the mesothelium have fiber lengths > 8 pm resin binders, with significant reductions in tionships between measured diameters, and diameters < 0.25 pm (23). Asbestos fibers levels ofrespirable fiber exposure (7). shape, length, and aerodynamic diamerer are chat tend to split longitudinally thereby pro The annual worldwide production of quite complex as determinants of pulmonary ducing thinner and longer respirable fibers are MMVFs as of 1985 was in excess of 6 million penetrance and deposition of fibers (12). more pathogenic according to this hypothesis, tons (8)- MMVF products release airborne res Beyond shape and size, increasing attention whereas MMVFs (because of their brittleness) pirable fibers during both their production and is being paid to particle (liber) chemistry as a tend to split transversely resulting in shorter use, and it is estimated that exposure levels of determinant of variables such as dissolution fibers of reduced aspect ratio (24). Long respirable fibers in glass wool production gener behavior, ion exchange, sorption properties, asbestos fibers are cleared less rapidly than ally have been in the region of 0.1 fibers/cm3; and surface reactivity (13). short fibers (23). However, this does not hold 666 Environmental Health Perspectives Vol 108, Supplement 4 August ZOOO ASBESTOS AND NONASBESTOS FIBERS true for all MMVFs, Although long RCFs cumulative exposure and the concentration of substantial long-term retention for MMVFs behave in a fashion similar to asbestos fibers asbestos fibers in the lung, although tremolite in the human lung. Roggii {24) examined (26), studies of glass wool fibers reveal that provided a better correlation with pathologic lung tissue from three ceramic fiber workers, long fibers actually are cleared more rapidly fibrosis. The authors concluded that a com one of whom had adenocarcinoma of the than shorter fibers, perhaps because of differ ponent of fibrosis in these asbestos workers lung and parietal pleural plaques. He identi ences between intracellular and extracellullar could be due to asbestos fibers that were sub fied substantial numbers of aluminum silicate pH. Thus, although the ability of fibers to sequently cleared (i.e., chtysotile}, which is fibers that were consistent with RCFs. In induce tumors in lung tissue or serosa is consistent with current mechanistic under addition, he observed a few ferruginous bod thought to be related to their biopersistence, standing of the largely irreversible effects of ies with RCF cores in one patient. These lim there are often conflicting data and no clear inflammation in producing fibrosis. The mnst ited findings suggest that the RCFs are thresholds (27). These mechanistic likely interpretation of these data is that deposited in the lung but that other types of approaches to differentiate fiber toxicity have tremolite concentrations in lung are a better MMVFs, including those more commonly parallels to more clinical investigations of metric of asbestos exposure than chrysotile used, are not persistent in lung tissue. fiber burden in exposed cohorts of asbestos concentrations but cannot necessarily be used and MMVF workers. to infer differential asbestos pathogenicity. We Clinical and Epidemiologic Data Lung burden studies involve the micro scopic examination of lung tissue to identify, localize, and estimate the concentration of agree with Stayner et al. (33) that, for both technical and biologic reasons, the lung bur den studies of differential fiber types do not on Asbestos Health Effects Nonmalignant Disease different fiber types in different parts of the clearly support a strong gradient in ability to Asbestosis (interstitial fibrosis of the lung lung. Light microscopy, electron microscopy, cause fibrosis and mesothelioma and offer parenchyma) typically has a slow subdinical and more recently, energy dispersive X-ray insufficient basis for discounting chrysotile as course for many years evolving to a sympto analysis have been used. Although tremolite is a cause of either condition. matic phase with the typical presentation of present at a low concentration of approxi Although previous work with asbestos interstitial fibrosis: dyspnea, inspiratory mately 1% in commercial chrysotile, lungs of indicates that long and relatively thick crackles, basilar interstitial opacities, and workers exposed to chrysotile have a dispro asbestos fibers have a tendency to become physiologic restriction. In the 1990s a num portionate amount of tremolite compared asbestos bodies, there are species-specific vari ber of studies of highly exposed workers with chrysotile present in the pulmonary ations in the ability of asbestos fibers to established that radiographic manifestations parenchyma ar autopsy (28). McDonald et al. become coated in the Jung (33). Studies of of interstitial fibrosis are more common (29) analyzed autopsy specimens from 78 MMVFs in animals indicate that the synthe among those who smoke (42). At the lower Canadian mesothelioma cases and matched sis of ferruginous bodies depends on fiber end of the exposure scale, non-occuparional controls and concluded that there were signif dimensions as well as on the animal model. environmental exposure to asbestos in prox icant differences in amosite, crocidolite, and Holmes et al. (36) instilled glass fibers into imity to a factory has been implicated in tremolite but not chrysotile between the two hamsters and demonstrated partially coated some cases of asbestosis (43). groups. The results of subsequent studies are glass fibers in lung tissue, with the frequency Over the past 10-15 years, considerable subject to conflicting interpretation, but most of the coated fibers varying according the attention has been focused on the clinical and report a better association of mesothelioma fiber dimensions. The proportion of coated physiologic effects of asbestos-related pleural risk with lung concentrations of tremolite fibers varied considerably in animals killed at disease (44,40). Substantial evidence has than chrysotile (30). Since chtysotile appears the same time. Although Davis et al. (371 accumulated that pleural fibrosis is associated to be cleared from the parenchyma more found ferruginous bodies in rats exposed to with measurable decrements In forced vital rapidly than tremolite or other amphiboles, RCFs, Smith et al. (30) did not find ferrugi capacity (FVC) and diffusing capacity inde the concentration of tremolite may actually nous bodies in rats exposed to fiberglass or pendent of detectable fibrosis (by high-resolu be a better exposure (dose) metric for RCFs; they did, however, find some ferrugi tion computed tomography fHRCT]) or chrysotile than the lung burden of chrysotile nous bodies in hamsters exposed to the same alveolitis (by btonchoalveolar lavage) (46). itself (31). The paradoxical observation that a MMVFs. Dufresne et al. {39) used a sheep Experience has accumulated with the use number of studies have found higher concen model of pneumoconiosis to evaluate the of computed tomography (CT) and HRCT trations of chrysotile than amphiboles in the long-term effeccs of glass wool, rock wool, for determination of asbestosis and asbestos- pleura, even when amphiboles were the pre and RCFs on lung tissue. Ferruginous bodies related pleural disease. HRCT is generally dominant exposure, limits the relevance of were not found for any of the MMVFs but regarded as more sensitive than chest radio these parenchymal measurements for delin were present in sheep exposed to crocidolite graphs and conventional CT, and HRCT eation of risk of mesothelioma (32,33). (the positive control group). Thus, evidence findings correlate with restriction, as Green et al. (39) examined lung tissue supporting MMVF ferruginous body produc described above. Pleural disease can be more from Charleston, South Carolina, chrysotile tion in animal models is limited, and it is readily distinguished from normal chest wall textile workers compared with a demographi- unlikely that formation of Ferruginous bodies structures, and underlying parenchyma can cally marched referent group of autopsy from MMVFs could be used as a marker of be imaged in the presence of extensive over deaths from the same hospitals and found that exposure to MMVFs. lying pleura (47,48). Newer investigations chrysotile levels were 5-fold higher and tremo- Human data from electron microscopic have begun to score HRCT readings quanti lite levels were 15-fold higher in the workers. fiber burden analysis of MMVFs suggest tatively, and it is noteworthy that in one This study estimated lifetime individual some differences in persistence according to study that had histopathologic comparisons, inhalation exposures. Significant positive fiber type. Lung tissue samples from 131 the HRCT was normal or near normal in 5 correlations were found between lifetime workers in a cohort of glass, rock, and slag of 25 asbestosis cases (49). cumulative exposure to asbestos and total lung wool production workers did not show a con The International Labor Office (ILO) burden of all asbestos fibers, as well as vincing excess of any one fiber type compared classification of chest radiographs for chrysotile and tremolite fibers individually. to unexposed controls (40). A study by pneumoconiosis is the established standard Pulmonary fibrosis was correlated with both Sebastien (41) did not yield any evidence for for epidemiologic study of the clinical effects Environmental Health Perspectives Vot 108, Supplement 4 * August 2000 66? OSINUBI T AL of dusts. Improved imaging techniques such controversy and disagreement. We now turn of mesothelioma at any exposure level, and a as HRCT may improve the sensitivity of to the epidemiologic studies. fairly low risk of lung cancer at environmen readings, particularly at the low end of the In the 1980s, various authors [e.g., tal, as opposed to textile-production, levels spectrum, although the reading of plain films (57,52)} began to suggest, primarily on the of exposure. . by two experienced B readers did comparably basis oflaboratory pathology observations, that However, additional data have emerged well in one controlled study (50) The chal amphiboles were far more carcinogenic than that challenge the conclusions of these studies lenge for the future is to integrate use of CT chrysotile, and in particular, that carcinogenic that chrysotile presents relatively little risk of or other advances for screening and diagnosis properties of chrysotile, particularly for mesothelioma. Recently Camus et al. (67) in a cost-effective manner among the lesser- mesothelioma, were due to its contamination demonstrated a relative risk of 7.6 for exposed cohorts of the future. by rremolite fibers. This led to the develop mesothelioma in women living (but report Mesothelioma ment of the "Amphiboie Hypothesis" (59), edly not working with asbestos) in asbestos enabling some to argue that chtysotile is rela mining towns in Canada compared to other Mesothelioma is a malignant disease of the tively innocuous with respect to its ability to Canadian communities. There was no com lining of the chest or peritoneal cavity. The cause mesothelioma. If this were true, it would parable excess of lung cancer in this non more common pleural.mesothelioma classi allow the global economy to safely focus on worker cohort. The considerable controversy cally presents with dyspnea, chest pain, and strict control of amphiboie exposure while engendered by this article in terms of its rela opacification of one or both lung fields; the expanding the use of duysotile to take advan tively low risk for lung cancer (when com case fatality rate is extremely high, with few tage of its many desirable commercial proper pared to an existing U.S. Environmental documented survivors and no effective stan ties, These arguments have been updated (2) Protection Agency [U.S. EPA] model for dard therapy (51). and reviewed in detail, with many authors environmental lung cancer risk from asbestos) In the first half of the 20th century finding them unpersuasive, largely from an and its relatively high risk for mesothelioma mesothelioma was an exceedingly rare disease, epidemiologic perspective (33,60-63). attributable to environmental exposure, with background rates in the United States Substantial new epidemiologic data have speaks to the continuing lack of consensus on and Canada for the 1960-1970 period esti emerged in just the past 5 years on the risk the two issues; the carcinogenic dose response mated at 2 per million, somewhat higher in for mesothelioma from chrysotile, with or for lung cancer from chrysotile exposure and males (52). Case reports in conjunction with without tremolite contamination, and the the presence of significant risk for mesothe asbestosls began to appear in the 1930s and nature of the dose response for causation of lioma following even nonoccupational 1940s, and by I960 data from South Africa lung cancer by chrysotile. These are addressed chrysotile exposure. showed a strong association with asbestos in detail below. Specifically, commentators argue that the exposure in miners, their family members, McDonald and McDonald (64) reported low risk of lung cancer in this non- and other local residents {see McDonald and a nested case-control study of miners and occupationally exposed group is most likely McDonald (52) for historical review]. millers within subregions of Thetford Mines, attributable to predominantly rsonrespirable Despite this, debates in the pathology com Quebec, Canada. They found odds ratios (too large) fibers characteristic of mining and munity questioned the existence of primary (ORs) of 2,55 for mesothelioma and 1.98 for milling (production) operations, as well as to malignant mesothelioma into the 1960s (55), lung cancer (compared to general population methodologic problems inherent in the use of suggesting the possibility of undercounting in controls) in the central mines area, which has the U.S. EPA model altogether (68,62). some retrospective epidemiology based on been reported (on the basis of limited mea Another criticism of the high risk of mesothe clinical or death certificate records from surements) to have 4-fold higher contamina lioma was that some of the women with before the 1970s. The existence of this devas tion of its commercial chrysotile with mesothelioma may actually have had occupa tating tumor, as well as its very strong rela tremolite than the peripheral area (65). They tional or household bystander exposures to tionship to asbestos exposure, is now reported no elevated ORs in the peripheral amphiboles (70,71). Unfortunately, it is true undisputed, although some question the (lower but nonzero tremolite) area relative to that explanations for these controversial lung extent to which chrysotile causes mesothe a general population comparison group. cancer and mesothelioma findings are specu lioma and the lower limits of the Liddell et al. (66) report for the same popula lative (67). A definitive process for resolution dose-response relationship (54). tions no increase in the standardrized mortal of such compering explanations from obser Hie Amphibolc Hypothesis of Differential Fiber Toxicity ity ratio (SMR) for lung cancer at < 300 mpcf-years (millions of particles per cubic foot-years)of cumulative exposure, which vational data has yet to be identified, and competing interpretations of data are likely to continue because such an observational study Over the last quarter century it has become they state is much lower than any currently cannot be repeated. widely acknowledged that crocidolite fiber is permitted occupational exposure, although In an important effort to address the the most potent fiber type for causing there are at least issues of noncomparability of amphiboie hypothesis. Smith and Wright mesothelioma, whereas chrysotile is the most the exposure metrics. They reported however, (56) selected for reanalysis or reassessment widely used fiber type. But the relative poten substantial numbers of mesotheliomas and published studies with the 25 highest cies are controversial, with some, at one pneumoconiosis deaths at this level, with data incidence rates of pleural mesotheliomas extreme, asserting that the potential for suggestive of a dose response. and examined the fiber-type exposure in chrysotile to cause mesothelioma is minimal McDonald (55} recently reexamined the each study. , (55). and others maintaining that chrysotile so-called asbestos textile mystery, in which he Of their top 10 studies, chrysotile was the because of its ubiquity and substantial estimates the risks of lung cancer in South primary exposure in 2 and was part of mixed although lesser toxicity is the predominant Carolina textile workers to be "perhaps 50 exposure in 6; crocidolite was the primary cause of mesothelioma cases (56). Although times higher" than in the Quebec miner exposure in 3 and was part of a mixed expo the evidence can be divided into toxicologic cohort, whereas the mesothelioma risk is sure in 5 others. Of their entire 25 studies, (laboratory) studies, human lung burden similar and relatively low (between 2 and 5 chrysotile was the main exposure in 8 and studies, and epidemiologic studies, it is the per 1,000). These data are interpreted by the crocidolite in 5 studies. Thus, no clear domi latter two that have engendered the greatest author to show that chrysotile poses little risk nance of amphiboles emeiged. 668 Environmental Health Perspectives * Vol 108, Supplement 4 August 2000 ASBESTOS AND NONASBESTOS FIBERS Smith and Wright (56) also reanalyzed at the current OSHA PEL of 0.1 fibers/mL- was necessary. Jones et al. (86) studied 271 data from studies of gas mask workers, often year would produce a 4-fold excess of lung cancer patients and 678 referents and cited as supporting the amphiboie hypothesis mesothelioma {74). reported an OR of 1.56 [95% confidence {72). Because the thrysotiie-exposed gas mask workers had only a 20% excess lung cancer Nonasbestos Causes ofMesothelioma interval (CI):1.02-2.39J even in workers with an ILO reading of 0/1. Case and Dufresne risk. Smith and Wright (56) concluded that Asbestos is clearly the main cause of mesothe (70) studied the autopsy records and work his they must have actually had overall low lioma and for a period of time was the only tories of 111 Quebec chrysotile miners and asbestos exposure and relied on excess lung known cause of this disease, A series of millers and concluded that the community cancers as a marker of substantial exposure to studies in the late 1970s and early 1980s pathologists' diagnoses of asbestosis seemed chrysotile. Others have used a similar argu demonstrated that certain villages in central arbitrary, and were not sensitive and effective ment to proportionately adjust expected Anatolian Turkey had elevated incidences of predictors of lung cancer. Egilman and mesothelioma risk to observed lung cancer mesothelioma (up to 50% of deaths) as well Reinert (87) reviewed 11 epidemiologic excess (61). Hence, they discount the rela as pleural and parenchymal chest film abnor studies as well as histologic studies and con tively low mesothelioma rates in gas mask malities characteristic of asbestosis (76-75). cluded that these are all consistent with the workers originally attributed to the lack of Natural exposure from home construction hypothesis thac asbestosis and lung cancer are potency of chrysotile and ascribe it to overall activities using soil containing a fibrous zeo two distinct pathologic processes with the low exposure. lite known as erionite has been implicated as same dose-related causative agent. Finally, Smith and Wright (56) added the causative agent. It is both fibrogenic and One interesting study of lung cancer has additional years of follow-up to a cohort of carcinogenic in animal models. Interestingly, shown that mutations of the k-zar gene at asbestos cement workers and found the excess small amounts of chrysotile and tremolite codon 12 in lung cancer of asbestos-exposed of mesotheliomas to be 20% for chrysotile were found in soil from the same region {79). individuals occurred independently of the versus 72% for crocidolite, which gave the Conversely, mesothelioma has not been radiographic presence of interstitial fibrosis, latter approximately a 4-fold greater potency observed around geologically similar deposits suggesting that the carcinogenic process, pre rather than the often-cited 14-fold greater in the Western United States, although zeo sumably dependent on some of the biochemi potency (75). They ultimately conclude that lites are not commercially mined in the cal genotoxic mechanisms explained above, chrysotile is a potent cause of mesothelioma United States, as nonfibrous synthetics are does not requite that the inflammatory with 25-50% of the potency of crocidolite. used instead for commercial purposes (86), process advance to the point of producing Because chrysotile accounts for 95-98% of Tremolite asbestos has been found in the soil visible scarring (85), global asbestos use, they argue that chrysotile of inhabited California communities, and Controversy remains about the extent to causes more actual mesothelioma cases world studies to examine relationships with which idiopathic pulmonary fibrosis is a risk wide than the amphiboles, mesothelioma are under way (8$. for lung cancer (89), and if so, whether the Low-Ix*vel Exposure Cohort studies of workers have amply Is Asbestosis Necessary for AsbestosInduced Lung Cancer? risk is due to radiographically evident lesions or to the underlying inflammatory process. Despite being cleared from parenchyma documented asbestos-related disease but pro A 1987 article {82) is frequently misinter sooner than amphiboles, chrysotile may well vide very limited dose-response information preted as strong support for the idea that persist long enough to influence a carcino at low exposure levels of ambient environmen asbestosis is necessary before there is a car genic process through generation of ROS or tal health concern. Of relevance, Iwatsubo et cinogenic risk from asbestos exposure. The other mechanisms previously discussed. al. (74) used a large-scale, population-based highly exposed insulation worker study from Many other human carcinogens, including sample to identify 405 hospital-based cases which our sample was drawn, with the ionizing radiation and benzene, do not and controls. Through individual interviews requirement that all in our subsample had to require years of residence time to exert their they generated an exposure metric for each have had a lung tissue sample available, neoplastic effects and are not identified in case and control on the basis ofthe probability makes it impossible to sustain such an necropsy tissue with the tumors they cause. of exposure, its intensity, and the frequency unhypothesized generalization about causal At this point there is insufficient evidence to and duration. This revealed a dose-response ity. Also, there are strong arguments against conclude that pulmonary fibrosis (asbestosis) relationship with an OR of 1.2 (0.8-1.8) for the hypothesis that fibrosis is a prerequisite is a necessary antecedent of carcinogenic risk the low-exposure category versus 8.7 for carcinogenicity. This ties in with some of from asbestos. (4.1-18.5) for the high-exposure category, the concerns about the amphiboie hypothesis. with the categories corresponding to estimated Early observations finding an excess of Health Effects of MMVFs cumulative exposures of 0.001-0.49 fibers/mL-year; 0.50-0,99 fibers/mL-year; 1-9.9 fibers/mL-year, and >10 fibers/mL-year. lung cancers in asbestosis cases (83,84) led some researchers to argue that lung cancer occurred only in persons with pulmonary Chronic Animal Bioassays ofMalignant and Nonmalignant Disease Although an accompanying commentary fibrosis. If this were true, it might reflect the Animal studies of the toxicity of asbestos raises some solid methodologic questions increased susceptibility of damaged lung tissue fibers indicate that there are several potential about inadequacies and potential biases in the to neoplasia. Alternatively, the fibrosis may mechanisms for fiber-induced carcinogenesis. retrospective dose--response estimate by a simply be a marker of high exposure or of the There is some evidence that asbestos fibers panel of expert industrial hygienists (75), this process of ROS generation, as described previ generate free radicals that cause DNA damage, study, with its derailed and individual expo ously. However, some recent studies have doc interfere with mitosis, stimulate proliferation sure reconstructions, represents a benchmark umented a significant excess of lung cancer of target celts, and provoke chronic inflamma for future investigations. It does not, however, incidence in workers who have no radio tory reaction, resulting in the release of ROS, attempt to distinguish exposures according to graphic evidence of fibrosis. Hughes and Weill cytokines, and growth factors (15,16). We did fiber type. They conclude that there is a signif (85) studied a group with asbestos exposure not consider bioassays with respect to asbestos icant excess of pleural mesothelioma at levels but no radiographic fibrosis and no significant because of the widely accepted status of below regulatory limits. For example, 5 years excess of lung cancer, reporting that asbestosis asbestos as a cause of fibrosis and cancer in Environment;*) Health Perspectives Vol 108, Supplement 4 August 2000 669 OSiNUBt ET AL humans; however animal bioassays remain wool, rock wool, and glass microfibers were years. The reduction in RCF exposure levels pertinent to consideration of the fibrogenicity largely negative. Although intrapleural RCF after the 1980s was postulated to be responsi and carcinogenicity ofMMVFs. injection studies for mesothelioma were ble for eliminating any further effect of RCFs The cytotoxicity of MMVFs has been largely negative, intraperitoneal inoculation on pulmonary function. Lemasters et al. examined in several studies. Luoto et al. (90) studies showed statistically significant {100) also observed a significant decrease in showed that MMVFs caused a modest but increases in tumors for glass wool, glass FVC in men who smoked and manufactured dose-dependent release of lactic dehydro microfibers, and RCFs (11). RCFs. However, in women a significant genase from alveolar macrophages, activated Inhaled RCFs induced lung tumors and decrease in FVC was found only in nonsmok the release of RGS, and caused hemolysis in mesotheliomas in both rats and hamsters, ers. The implications of this intriguing sex sheep erythrocytes. In vitro studies by although with some inconsistencies between difference in response to combined RCF Ruotsalainen et al. (90) examined the effects studies. In one study, inhalations of RCFs in exposure and smoking require replication and of glass wool, rock wool, and RCFs on rats and hamsters were negative for lung further investigation. human polymorphonuclear leukocytes fibrosis or tumor (94- Mesothelioma was Several studies examined chest radio (PMNLs) and erythrocytes. MMVFs did not observed in hamsters, but this did not achieve graphs of occupationally exposed individuals, affect the viability ofPMNLs (as measured by statistical significance. In a subsequent RCF and the results have been largely negative for the trypan blue exclusion test) or induce cell study, however, the results were positive for evidence of pneumoconiosis (97,98,101,102). hemolysis, unlike chrysorile and quam, lung fibrosis and mesotheliomas in both rats Weill et al. (103) reported radiographic find which caused dose-dependent increases in lac and hamsters as well as for lung cancer in rats ings of small irregular opacities (ILO grades tic dehydrogenase and induced hemolysis. (6). The latter study also demonstrated a 1/0 to 1/1) in 3% of glass, slag, and rock However, there is evidence that MMVFs dose-response relationship for lung fibrosis. wool production workers during an initial caused a dose-dependem activation of ROS The differences in the results of the two cross-sectional survey in 1983. This study was in human PMNLs, with RCFs being the studies have been attributed to the slightly not controlled and was subject to bias from a most active inducer of ROS production larger diameter RCFs (4> hence reduced fiber survivor effect. A follow-up survey of the among the MMVFs tested. Variation in fiber penetration and retention, in the initial study same workers in 1993 (97) did not find any length did not modify the ability of MMVFs by Smith et al. (94, significant effect of MMVF exposure com to induce ROS production. It is postulated Because continuous glass filament fibers pared to local blue-collar worker controls and that MMVFs activate ROS production, tend to have larger diameters, typically there was also no apparent progression of thereby causing DNA damage, cell injury, 4-7 pm, and were negative in injection radiographic opacities in the MMVF workers. and eventually cell death. studies, they are generally thought to have A study of fiberglass workers (end users) The ability of fibers to induce tumors in minimal potential to be carcinogenic. by Kilburn et al. (104 reported a 13% overall lung tissue or serosa is generally thought to be Sufficient animal bioassays for carcinogenicity prevalence of pleural abnormalities and small related to their biopersistcncc, although, as have not been conducted to completely irregular opacities, profusion 1/0 to 2/1, due we have discussed with chrysorile, this can be exclude this possibility, and 1ARC considers to fiberglass exposure. Possible limitations of complex. Solubility and clearance studies of these fibers unclassifiable with respect to the study were that there was insufficient MMVFs in animal lung tissue indicate that in carcinogenicity (8,11). information on individual historical asbestos general, glass fibers are more soluble than rock wool, whereas RCFs are the most durable ofMMVFs (92). However, studies of Clinical and Epidemiologic Studies ofNowmlignant Disease exposure, as asbestos fibers were reportedly present in the production facility (109), and most of the chest film readings were not even the most durable MMVFs such as Rock and slag wool have been produced since blinded to exposure. Using the ILO classifica alumino-silicate RCFs show surface morpho the 1800s and glass fibers since the 1930s, tion, Trethowan et al. (98) reviewed the chest logic alterations after in vivo residence of with remarkably few reports of pulmonary films of employees of seven European plants 6 months in rat lungs, suggesting that RCFs disease due to MMVF exposure. The preva that manufacture ceramic fibers. Small opaci show signs of dissolution and are physically lence of nonspecific respiratory diseases ties profusion of 0/1 or greater were found in cleared from the lung (93). (chronic obstructive pulmonary disease, 13% of the radiographs. Profusion scores of Animal experiments have been used in an emphysema, chronic bronchitis, and asthma) 1/1 or greater were found in 18 of 392 (about attempt to determine whether exposure to has been examined in a number of studies of 3%), 11 of whom had reportal confounding MMVFs has health effects similar to asbestos MMVF workers. Even though there are varia exposures to other dusts. The prevalence of exposure. Several studies have clearly demon tions in the study designs, the results have small opacities increased with age, smoking, strated that MMVFs are highly carcinogenic been largely negative (96,97). A study of and previous exposure to asbestos and impor when injected into the pleural and peritoneal ceramic fiber workers did not find any associ tantly was not related to cumulative exposure cavities (11), whereas long-term rodent ation between chronic bronchitis or wheezing to ceramic fibers. To date, the cumulative evi inhalation studies of MMVFs have yielded and cumulative exposure to respirable fibers. dence of radiographic changes indicative of conflicting findings with respect to produc However, there was a significant decrease in pulmonary interstitial fibrosis in MMVF tion oflung fibrosis and cancer (27,94). the forced expiratory volume and forced workers is inconsistent. Inhalation studies with glass wool, glass mid-expiratory flow related to cumulative Pleural plaques have been reported in a fiber, and slag wool are generally reported fiber exposure in smokers (98). This study cohort of RCF manufacturing workers in an negative for fibrosis. Minimal fibrosis was concluded that cumulative exposure to res ongoing respiratory morbidity and mortality observed in rock wool studies at the highest pirable ceramic fibers may contribute to air study in the United States, Twenty of 652 exposures, but no significant excess of lung ways obstruction by promoting the effects of (3.1%) workers were found to have pleural rumors was reported (95). Ellouk and cigarette smoke. A recent study by Lockey changes (pleural plaques and thickening) on Jaurand (11) pooled data on glass wool et al. (99) showed a significant decrease in chest films. The prevalence was highest inhalation studies and found a statistically FVC among workers employed in RCF (12.5%) in chose who began their production significant increase in lung tumor develop production jobs prior to 1980 that did not jobs more than 20 years ago, for an OR of ment in rodents, whereas studies with slag persist with analysis of subsequent production 9.5. Additionally, 5 of 19 workers (26.3%) 670 Environmental Health Perspectives Vol (08, Supplement 4 * August 2000 ASBESTOS AND NONASBESTOS FIBERS with more than 20 years total employment in other excess risks for cancer or mortality were RCF production jobs had pleural plaques on observed in this study. chest films, for an OR of 22. A dose-response A study of MMVF workers in Finland relationship with cumulative estimated expo did not show any any significant difference in sure was also demonstrated, A nested mortality or excess cancer risk (/if). Gardner case--control interview study showed that et al. {Ill) examined cancer mortality in a asbestos exposure did not account for the glass wool plant in the United Kingdom and observed association between plaques and observed a borderline increased risk of lung RCF exposure. There was no increase over cancer among the workers compared to historical control levels (0,5%) for small national cancer rates. However, the excess risk irregular opacities that would be indicative of had little relationship to the length and dura lung fibrosis {99}- It is noteworthy that tion of employment or to the level of expo pleural abnormalities were also observed in sure to MMVFs. Claude and Frentzei-Beyme 16 of 592 films of ceramic fiber workers (two (112) reported similar findings in a study of of whom had experienced previous exposure rock wool factory workers in Germany. to asbestos) in the European study by IARC conducted a historical cohort study Ttechowan al. (98), The pleural changes of mortality of approximately 25,000 MMVF were related to age but not independently to workers in seven European countries (7). This estimated ceramic fiber exposure. Thus, study found an increase in lung cancer mortal although the evidence to date does not clearly ity risk (SMR = 128) in rock/slag wool work indicate that radiographic changes of pul ers. The risk increased as the time since first monary interstitial fibrosis are clearly associ exposure to rack/slag wool production ated with MMVFs, there is substantial increased. Exposures such as smoking and pre evidence in at least one cohort that RCFs vious employment were considered unlikely caused pleural plaques. The fact that the explanations for the excess risk observed. The worst degree of fibrosis reported in any indi highest lung cancer mortality risk {SMR = vidual from a cohort is 2/1 provides substan 223) was observed in the early technological tial reassurance that MMVFs are not as likely phase of production during which worker as asbestos Of silica to'cause morbidity from exposure to high levels of respirable fibers as pulmonary fibrosis. well as arsenic (component of slag) and poly cyclic aromatic hydrocarbons from furnace Epidemiologic Evidence That MMVFs Cause Malignancy Human Studies fumes occurred in the production facilities. Excess mortality was not observed in workers employed in the late technological phase of mineral fiber production when production Several large population-based mortality changes reduced exposures. This study did not studies of MMVF workers have been pub find an increased risk of mortality from non- lished. Emerline and Marsh (106} conducted malignant respiratory disease or from pleural a study of 7,049 MMVF workers in the tumors. The findings in the IARC study (7) United States. Even though SMRs were ele are supported by Boffetta et al. (113), who vated for most major causes of death for also reported that workers employed in the workers with more than 20 years since expo early technologic phase of production, partic sure (4,120 workers), none of the observed ularly rock/slag woo! workers, were at higher excesses achieved statistical significance. In risk of lung cancer mortality than those in addition, there was no evidence of excess orher categories. malignant or nonmalignant respiratory dis More recently, Boffetta et al. (114) ease associated with fiberglass exposure. A reported follow-up data on the IARC cancer Canadian study by Shannon et ah {107} actu mortality study of European MMVF workers. ally found a reduced nsk (SMR = 78) in glass The SMR for lung cancer was significantly fiber workers. There was a statistically increased at 134 for rock/slag wool workers, insignificant increase in lung cancer deaths in although not elevated compared to local mor this cohorr. These results were supported by a tality rates. The associations between lung subsequent study of glass filament textile cancer risk and time since first exposure as well workers in Ontario, Canada U08). as duration of employment were maintained as Bertazzi et al. (109} found an increased in rhe earlier study, although the trend for risk of laryngeal cancer (based on four deaths) increased cancer risk according to rhe techno in a cohort of 1,098 glass wool and continu logical phase of production was less marked. ous filament fibers workers in Italy. The risk This study also reported five deaths from for laryngeal cancer was highest in persons mesothelioma, although the authors did not employed before 25 years of age, with at least feel that this represented a clear excess over 1 5 years of fiber exposure, and with onset of relevant national rates. exposure before I960. The authors could not Marsh et al. (115) conducted a follow-up attribute the excess risk observed to known study of over 16,000 mineral fiber workers in con founders for laryngeal cancer, and no the United States. They observed a small bur statistically significant excess of malignant neoplasms (SMR = 108.3) and respiratory tract cancer (SMR = 112.1) in the workers. Mineral wool fiber workers bad higher respi ratory tract cancer risks compared to glass wool/filament workers. This study reported 4 mesotheliomas. Wong et a!. (116) and Chiazze et al. (96) conducted case-control studies of lung cancer and MMVF exposure, and both studies reported no significant asso ciation with exposure, although, as expected, associations were found with smoking. In summary, MMVFs are a diverse group of synthetic fibers that have biologic activity in both animal and human lung tissue. MMVFs generally differ from asbestos fibers in that a lesser proportion of them are res pirable and the inhaled fibers are less durable than asbestos fibers. Nonetheless, there is convincing evidence that some of these fibers, in particular RCFs, are capable of inducing lung tumors in rats and mesotheliomas in hamsters. The data provided by mortality studies are not sufficient to conclude that rock/slag wool causes an excess in the risk of lung cancer, nor do they support compla cency with respect to carcinogenicity. Many mineral fibers are respirable and may have contributed to increased lung cancer risk, possibly in combination with other work exposures, particularly in the early technolog ical phases of mineral wool production. Recent convincing studies have demonstrated the occurrence of pleural plaques in RCF workers without concomitant interstitial fibrosis. It has yet to be determined if these pleural changes augur a risk for human mesothelioma. Long-term follow-up studies of the RCF worker cohorts may provide these answers over the next decade. At the present time, significant human carcinogenic risk from any inhaled MMVFs is neither clearly established nor refuted. Nylon Flock-Associated Interstitial Lung Disease In 1998, David Kern and colleagues from Brown University in Providence, Rhode Island, described an occurrence of radio graphically visible interstitial lung disease that occurred among workers at a Rhode Island nylon flocking plant (117), There was both radiographic and functional improvement, although not complete resolution, after cessa tion of work. A subsequent pathologic review concluded that the pathologic findings, a lymphocytic bronchiolitis and peribronchioli tis with lymphoid hyperplasia represented by lymphoid aggregates, were distinctive com pared with known lung conditions. Although not the only inhalation exposure in the plants investigated, the preliminary concern is that flock, from cut or pulverized fiber (synthetic or natural), used to produce a velvetlike coat- Invironmentai Health Perspectives Vol 108, Supplement 4 August 2QOQ 671 Hit Tljvuhvlfiiir OStNUBl ET At. ing on fabrics, is the causative agent. should be applied to better quantify the Preliminary reports of some toxicologic exposures in these settings (at least, where studies support that ultrafine respirable exposures are ongoing), particularly with fibrous fragments of nylon can cause acute regard to differential distributions of particle inflammatory lung injury in rodents (118). size and shape. This approach may also con The popularity of the processes used in this tribute to resolution ofcontroversy about rel plant suggests that more cases of "flock ative risks of different types of MMVFs. worker's lung" are likely to be identified. Discrepancies in the epidemiologic lirerature Additional organic fibers such as para-aramid must be examined more critically with fibrils, used in the manufacture of bulletproof respect to the type, intensity, constancy, and vests, are being studied in animal models for duration of exposure. toxicity. One study reported much less reten A systematic transnational study of the tion and inflammation than long chtysotile impact of these policies on the uses, exposure, fibers (119)', no human data are available. and health effect consequences of fibers appears overdue. Where policies change, uses Regulatory Policies for and exposures change, affording experimental Exposure to Fibers and Research Recommendations opportunities to study the impacts of expo sure on health consequences. In some ways we are at a crossroads with As of 1999, asbestos use was banned in respect to research into the health effects of Sweden, Norway, Denmark, the Netherlands, fibers. In the developed nations powerful new Finland, Germany, Italy, Belgium, France, advances are being made in exposure assess Austria, Poland, and Saudi Arabia. Groups of ment and in basic toxicology, especially as knowledgeable scientists have called for a applied to susceptibility. These advances, worldwide ban on asbestos mining and use coupled with coherent epidemiologic designs, (120,62), This effort is based on estimates of promise a more fundamental understanding, residual lifetime risk for lung cancer (5/1000) as well as a personalized risk assessment for and asbescosis (2/1000) {/) at the present U.$. fiber toxicity. Many inconsistencies in the standard of 0.1 fibers/mL and the fact that current epidemiologic database may be elimi few if any developing countries are expected nated if prospective studies of exposed indi to achieve such low levels of exposure (121). viduals can be mounted with the new and The LIS. OSHA PEL for asbestos is based developing tools to look at variations in indi on fibers > 5 mm long with a 3:1 aspect ratio, vidual responses to fibers and other toxicants. counted by phase-contrast light microscopy. With increasing use and new applications For many years the PEL was 5 fibers/cc, but it of asbestos in developing nations, there are has been progressively reduced to 2 fibers/cc ample opportunities to initiate new prospec in 1976, 0,2 fibers/cc in 1986, and 0.1 tive cohort studies taking advantage of new fibers/cc in 1994, The American Conference research technologies. However, ethical of Governmental Industrial Hygienists lists concerns of such investigations must be different threshold limit values for different addressed carefully because of the well- fiber types (2 fibers/cc for chrysotile vs 0.5 documented hazards of asbestos. Although fibers/cc for amosire and 0,2 fibers/cc for croci- some researchers feel that education and dolite). OSHA does not recognize this distinc interdiction are a higher priority than further tion. There are no U.S. standards for MMMFs investigation, the fact remains that exposures at this time. Sweden imposes an exposure limit are presently occurring. for glass fibers of 2 fibers/cc (6). Although new information about cell Different nations have developed various signaling involving free radicals, growth fac regulatory and economic policies for exposure tors, and cytokines may yet identify interven to asbestos and MMMFs. These range from tions that can abort or retard the fibrotic banning of the former and encouragement of process, the situation is more than comple the latter, to increased use of asbestos and mented by the molecular epidemiology only tentative use of MMMFs. Most devel approach toward differential human oped nations are at the former end of the responses to fibers. The latter seems a more spectrum and many developing nations are in direct approach, well-rooted in clinical expo the latter category, largely as a function of sure issues, toward identification of critical cost. Where asbestos is used, different coun pathways of disease and development of tries (and indeed different agencies within responses. This is a rapidly expanding countries) advocate different standards for research area throughout environmental med workplace and ambient exposure. Central to icine. Although in terms of fibers, research the controversy over asbestos-related disease has largely been limited to asbestos, it will are observations of very different rates of dis greatly augment our understanding of the ease In different parts of the world, related to variation in response to other mineral fibers different fiber types and industrial activities. as well. To an increasing extent, health effects Modern techniques of exposure assessment are dealt with through the surrogate of risk assessment. Changing mechanistic and expo sure models may alter how risk assessments for both asbestos and MMVFs should be done (122) as will the incorporation into risk assessments of susceptibility factors based on polymorphisms or other characteristics. Epidemiologic studies have provided much insight into the pathogenicity and carcinogeniciry of asbestos. Inconsistent results among studies, however, point to the omnipresent need to better characterize expo sures and vulnerability. Continued tracking of the few long-term cohorts and the study of additional cohorts of people exposed to asbestos under different scenarios will play important roles in further defining the risks from asbestos. 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