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5 Biological Aspects of Asbestos-Related Diseases ASBESTOS-RELATED PULMONARY DISEASES AND THEIR MECHANISMS The causal association between asbestos exposure and nonmalignant and malignant diseases of the lungs and mesothelial linings is well estab- lished and supported by epidemiologic, animal, and mechanistic toxico- logic studies (IARC 1987). The biologic mechanisms responsible for asbestos-related disease are complex and reflect a chronic, multistep pro- cess involving interactions between genetic predisposition and possibly other exposures, including exposure to viruses. Those mechanisms will be discussed in detail after a brief summary of the clinical features and risk factors of lung cancer and malignant mesothelioma. Asbestos-Related Diseases The International Agency for Research on Cancer (IARC 1987) has classified various types of asbestos fibers—specifically chrysotile, actinolite, anthophyllite, tremolite, and crocidolite—as known human carcinogens (Group I). Inhalation of asbestos fibers is associated with parenchymal and pleural lung diseases (Table 5.1), all of which have been reproduced in rodent models (reviewed in Bernstein et al. 2005). In chronic rodent inhala- tion assays, fiber biopersistence and carcinogenicity are associated with per- sistent inflammation, epithelial cell proliferation, and fibrosis in the lungs (Hesterberg et al. 1993, 1994, 1998). Chronic inflammation and fibrosis are also produced in the lungs and pleural linings of humans exposed to asbestos fibers; these responses are clinically described as asbestosis (or dif- 81

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82 ASBESTOS TABLE 5.1 Pulmonary Diseases Associated with Exposure to Asbestos Fibers Disease Humans Animal Models Asbestosis (diffuse interstitial fibrosis) + + Carcinoma of the lung + + Nonneoplastic pleural disease: Pleural effusion + + Visceral pleural fibrosis + + Parietal pleural plaques + + Malignant mesothelioma of the pleura and peritoneum + + SOURCE: Adapted from Bernstein et al. (2005). fuse interstitial fibrosis) of the lungs and visceral pleural fibrosis and pari- etal pleural plaques of the pleural linings (Table 5.1). In the pleura, bilateral and symmetric fibrotic plaques usually reflect environmental or occupa- tional exposure to asbestos fibers, and consequently pleural plaques are considered to be markers of asbestos exposure (Travis et al. 2002). These fibrous scars are not precursors of malignant mesothelioma or lung cancer. Risk Factors for Lung Cancer and Malignant Mesothelioma Tobacco-smoking is a major causal risk factor for lung cancer (Ta- ble 5.2) and risk of developing lung cancer in current or former smokers is greatly increased by exposure to asbestos fibers. Development of malignant mesothelioma of the pleura or peritoneum has not been found to be associ- ated with tobacco-smoking (Battifora and McCaughey 1995). Exposure to TABLE 5.2 Risk Factors for Development of Lung Cancer Certainty Agent Established Cigarette, pipe, or cigar-smoking Exposure to environmental tobacco smoke Exposure to asbestos fibers Exposure to radon Occupational exposures (metals and chemicals) Hypothesized Air pollution Outdoor Indoor (cooking fumes) HPV (human papilloma virus)

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83 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE TABLE 5.3 Risk Factors for Development of Malignant Mesothelioma Certainty Agent Established Exposure to asbestos fibers Exposure to erionite fibers Exposure to talc or vermiculite contaminated with asbestos fibers Hypothesized Radiation therapy Chronic inflammation SV40 virus SOURCE: Sporn and Roggli (2004). environmental erionite fibers has been found to be associated with malig- nant pleural mesothelioma (Baris et al. 1987, Roushdy-Hammady et al. 2001), while radiation, chronic inflammation, and SV40 virus are also pos- tulated as etiologic factors (Table 5.3). Genetic Predisposition to Malignant Mesothelioma Case reports of familial clusters of malignant mesothelioma resulting from occupational or household exposure have been published (Table 5.4). In some of these families, the histological subtype and location were identi- cal, for example, tubulopapillary malignant mesothelioma arising in the peritoneum (Lynch et al. 1994). Recent evidence of an inherited predisposi- tion to malignant mesothelioma after exposure to erionite in two villages in Turkey was published by Roushdy-Hammady et al. (2001). Malignant mesotheliomas have also been reported in people with in- herited cancer-susceptibility syndromes following exposure to asbestos fi- bers or radiation therapy (Table 5.4). Somatic mutations in the neurofibro- matosis type 2 (Nf2) gene have been detected in 50% of human malignant TABLE 5.4 Genetic Predisposition to Malignant Mesothelioma • Case reports of familial clusters: Genetic predisposition (Roushdy-Hammady et al. 2001) Household exposure (reviewed in Lynch et al. 1994) • Case report of 40-year-old mechanic with neurofibromatosis type 2 who developed peritoneal malignant mesothelioma (Baser et al. 2002) • Reports of patients with familial cancer syndromes (Wilms tumor, Li-Fraumeni syndrome) who developed malignant mesothelioma after radiation therapy for primary tumors (Antman 1986, Hisada et al. 1998) • Report of slightly increased risk of mesothelioma in people exposed to asbestos who have first-degree relatives with Li-Fraumeni syndrome (Heineman et al. 1996)

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84 ASBESTOS mesotheliomas (Sekido et al. 1995). Heterozygous Nf2-deficient mice show increased susceptibility to induction of peritoneal malignant mesotheliomas after intraperitoneal injection of asbestos fibers (Fleury-Feith et al. 2003), and these mice recapitulate the molecular alterations characteristic of hu- man malignant mesotheliomas (Altomare et al. 2005). Li-Fraumeni syn- drome is a rare heritable cancer-susceptibility disorder characterized by car- rying a mutant allele of the p53 gene. Although mutations in the p53 tumor-suppressor gene are generally rare in human malignant mesothelio- mas (Metcalf et al. 1992), individuals with Li-Fraumeni syndrome show increased susceptibility for malignant mesothelioma (Table 5.4). Heterozy- gous p53-deficient mice also show increased susceptibility to and acceler- ated progression of asbestos-induced mesotheliomas (Marsella et al. 1997, Vaslet et al. 2002). Those murine transgenic models support a role of inac- tivation of the Nf2 and p53 tumor-suppressor gene pathways in the patho- genesis of asbestos-induced malignant mesothelioma. Properties of Fibers Relevant to Biological Activity The physical and chemical characteristics related to the carcinogenicity of asbestos fibers include fiber dimensions, chemical composition, bio- durability, and surface reactivity (reviewed by Fubini and Oter-Areán 1999). The availability of transition metals, especially iron, to participate in free radical generation (Weitzman and Graceffa 1984) has been hypothesized as playing an important role in asbestos-induced lung diseases (reviewed in Kane 1996). Iron-catalyzed generation of free radicals can cause cell injury, genetic damage, and inflammation in the lungs and pleura (reviewed in Kamp and Weitzman 1999 and in Manning et al. 2002). Fiber dimensions and biopersistence have been linked mechanistically with persistent inflammation in a variety of toxicologic studies (reviewed in Bernstein et al. 2005). Fiber dimensions influence the extent and rate of fiber deposition and persistence in the lungs, and movement to the pleura (Oberdörster 1996). Long, thin asbestos fibers are trapped at the level of the terminal respiratory bronchioles or deposited in the alveolar spaces. Long fibers are less efficiently phagocytized by alveolar macrophages and stimulate persistent production of proinflammatory mediators, cytokines, and growth factors. Partial phagocytosis impairs macrophage motility and retards fiber clearance. In the absence of effective fiber clearance by the mucociliary escalator, fibers can move to the interstitium of the lung, mi- grate to the pleura and peritoneum, or even to more distant sites through lymphatics. Fibers that are retained in the walls of the terminal respiratory bronchioles, in the lung interstitium, or on the pleural lining can cause per- sistent epithelial or mesothelial cell injury, whose repair is accompanied by proliferation. Persistent or chronic macrophage activation can lead to

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85 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE chronic inflammation and fibrosis in the lungs or pleura (summarized in Bernstein et al. 2005). Mechanisms of Asbestos Carcinogenicity On the basis of extensive work with in vitro model systems and animal models of asbestosis, lung cancer, and mesothelioma, direct and indirect mechanisms for fiber carcinogenicity have been proposed. The mechanisms may or may not be applicable to tumors that develop at the other sites considered in this report. Direct mechanisms of asbestos fiber carcinogenesis include genotoxic and nongenotoxic pathways (Table 5.5). It has been hypothesized that long asbestos fibers that are partially phagocytized by macrophages trigger per- sistent production of reactive oxygen species by the respiratory-burst mecha- nism. Asbestos fibers contain a high surface content of redox-active iron and generate additional radicals, including the highly reactive hydoxyl radi- cal by Fenton chemistry (Fubini and Oter-Areán 1999, Hardy and Aust 1995). More stable lipid radicals and reactive nitrogen species can be gener- ated secondarily (Goodglick et al. 1989, Park and Aust 1998). Theoreti- cally, those free radicals could be generated in the vicinity of any target cells that are in contact with asbestos fibers. The reactive radicals could damage TABLE 5.5 Direct Mechanisms of Asbestos-Fiber Carcinogenesis Mechanism Experimental Endpoints References Genotoxic Oxidized bases Chao et al. (1996), Fung et al. (1997) DNA breaks Reviewed in Jaurand (1996) Aneuploidy Reviewed in Jaurand (1996), Jensen et al. (1996) Mutations Park and Aust (1998) Deletions Reviewed in Hei et al. (2000) Nongenotoxic Mitogenic Target cell proliferation BéruBé et al. (1996), Goldberg et al. (1997) Binding to or activation Boylan et al. (1995), Pache et al. (1998) of surface receptors Growth factor expression Liu et al. (1996), Brody et al. (1997) Activation of signaling Reviewed in Mossman et al. (1997), Manning pathways et al. (2002) Cytotoxic Apoptosis Broaddus et al. (1996), Goldberg et al. (1997), Levresse et al. (1997) Necrosis Reviewed in Kane (1996) SOURCE: Bernstein et al. (2005).

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86 ASBESTOS DNA or form adducts, such as 8-hydroxydeoxyguanosine (8-OHdG). If the DNA damage is not accurately repaired, mutations or deletions could result (reviewed in Hei et al. 2000). Long asbestos fibers have also been shown to interfere with the mitotic spindle, chromosomal segregation, and cytokine- sis in cells in culture (Ault et al. 1995, Hesterberg and Barrett 1985, Jaurand 1996, Jensen et al. 1996). Direct interference with the mitotic apparatus could lead to aneuploidy or polyploidy; these chromosomal alterations have been found in human mesotheliomas (reviewed in Kane 1996, Murthy and Testa 1997). Several in vivo studies have confirmed the results of these in vitro genotoxicity assays. In the 4 weeks after rats were gavaged with 100 mg/kg chrysotile, Amacher et al. (1974, 1975) found transient increases in DNA synthesis in tissues from the stomachs, small intestines, and colons (but not livers or pancreases), which occurred sooner after treatment in the stom- achs than colons. After intratracheal instillation of asbestos fibers in rats, hydroxyl radicals (Schapira et al. 1994) and lipid radicals (Ghio et al. 1997) have been detected. Increased mutation frequencies at the reporter gene locus have been discovered in lacI transgenic rats, after inhalation (Rihn et al. 2000) or intraperitoneal injection (Unfried et al. 2002) of crocidolite asbestos fibers. Both chronic and acute exposure to asbestos fibers increases the prolif- eration of epithelial and mesothelial cells. Nongenotoxic mechanisms lead- ing to increased cell proliferation include activation of growth factor recep- tors and intracellular signaling pathways (reviewed in Albrecht et al. 2004). Human and rodent mesotheliomas frequently show constitutive expression and activation of growth-factor pathways, including those of IGF, PDGF, VEGF, and TGF-β (Cacciotti et al. 2005). Alternatively, direct physical dam- age or free-radical-mediated injury could induce apoptosis or necrosis of target cells that is repaired by compensatory cell proliferation. Repeated episodes of target-cell injury and repair could expand a preneoplastic pro- liferating cell population during the early stages in the development of lung cancer or malignant mesothelioma (reviewed in Kane 1996). Epidemiologic studies have established that exposure to asbestos fibers increases the risk of lung cancer, particularly in cigarette smokers (reviewed by Churg 1998). Multiple indirect mechanisms may contribute to a syner- gistic interaction between smoking and asbestos (IARC 2004). Tobacco- smoking alters mucociliary functions and so may impair clearance of fibers from the bronchi and alveoli (McFadden et al. 1986). In rat tracheal ex- plants and guinea pigs, cigarette smoke enhanced penetration of asbestos fibers into airway epithelium and exacerbated epithelial hyperplasia and small-airway disease (Hobson et al. 1988, Tron et al. 1987). Oxidants in tobacco smoke combined with asbestos-catalyzed generation of reactive oxygen species have been proposed to mediate fiber penetration of airway

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87 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE epithelium (Churg et al. 1989). Inhalation of ozone was also shown to im- pair clearance and increase retention of asbestos fibers in the lungs of rats (Pinkerton et al. 1989). Because of their large surface area, asbestos fibers may adsorb polycyclic aromatic hydrocarbons (PAHs), transport them into the lungs, and facilitate metabolic activation (Kandaswami and O’Brien 1983, Lakowicz and Bevan 1979). The extent of PAH adsorption on the fiber surface depends on several factors including humidity, phospholipids content of the lung lining fluid, and extent of fiber leaching in the lung. These factors may also influence the kinetics and extent of desorption of PAHs deposited in the tracheobronchial epithelium (Fubini 1993, 1997). PAHs and asbestos fibers were found to be synergistic in inducing squa- mous metaplasia in tracheal explant cultures (Mossman et al. 1984). Simi- larly, intratracheal instillation of amosite asbestos fibers plus benzo[a]- pyrene induced a synergistic increase in mutations at the lacI reporter gene locus in a rat transgenic model (Loli et al. 2004). The combined effects of asbestos fibers and tobacco smoke on develop- ment of lung cancer may be explained at a molecular level (Table 5.6). K-ras and p53 gene mutations and FHIT tumor-suppressor gene deletions have been proposed to be increased by asbestos exposure and related to enhanced chromosomal instability (reviewed in Nelson and Kelsey 2002). Some smokers may be genetically predisposed to lung cancer as a result of mutations in DNA repair pathways (Hartwig 2002, Hu et al. 2002). Alter- natively, acquired mutations or deletions in key genes involved in DNA repair may facilitate accumulation of additional genetic mutations induced by tobacco-smoke carcinogens during early stages of development of lung cancer (Hollander et al. 2005). Epigenetic silencing of tumor suppressor genes has been described in human lung cancers (Dammann et al. 2001, Kim et al. 2001) and in human malignant mesotheliomas (Hirao et al. 2002, Toyooka et al. 2001, Wong et al. 2002). TABLE 5.6 Indirect Mechanisms of Asbestos-Fiber Carcinogenesis Mechanisms References Cofactor with tobacco smoke Reviewed in Kane (1996), Lee et al. (1998), Nelson and Kelsey (2002) Epigenetic gene silencing Reviewed in Esteller (2005) Persistent inflammation with secondary Vallyathan and Shi (1997) genotoxicity Persistent inflammation with release of Reviewed in Brody et al. (1997) cytokines and growth factors Cofactor with SV40 virus Reviewed in Gazdar et al. (2002) SOURCE: Bernstein et al. (2005).

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88 ASBESTOS Persistent inflammation in response to biopersistent asbestos fibers may lead to secondary genotoxicity caused by release of reactive oxygen and nitrogen metabolites from activated macrophages (Vallyathan and Shi 1997). Reactive oxygen metabolites have also been proposed to contribute to altered DNA methylation (Cerda and Weitzman 1997, Govindarajan et al. 2002). Activated macrophages also produce chemokines, cytokines, pro- teases, and growth factors that perpetuate tissue injury, inflammation, and target-cell proliferation (Robledo et al. 2000). Ultimately, the persistent in- jury and inflammation can culminate in progressive fibrosis or asbestosis of the lungs. Repair of epithelial injury is achieved by proliferation of type II alveolar cells, which are a potential target for accumulation of additional mutations and development of cancer (reviewed in Brody et al. 1997). A mechanistic link between chronic inflammation, fibrosis, and cancer has been proposed on the basis of animal models (Coussens and Werb 2002). Although a causal relationship between asbestosis and lung cancer based on epidemiologic studies is controversial, there are plausible biologi- cal mechanisms by which fibrosis could mediate an effect. In the lung, chronic inflammation is associated with epithelial cell proliferation and type II hyperplasia (Travis et al. 2002). Mediators derived from activated mac- rophages or other inflammatory cells may stimulate proliferation of pre- neoplastic cells. The proliferating population is a target for additional ge- netic mutations produced by oxidants, viruses, or chemical carcinogens. Activated macrophages and inflammatory cells also release proteases and fibrogenic factors that may increase extracellular matrix turnover and fi- brosis. And proteases, in combination with proangiogenic factors, may fa- cilitate invasion and metastasis during later stages of tumor progression (Tlsty 2001). Polyomaviruses as Possible Cofactors for Cancer The role of SV40, a polyomavirus, as a cofactor with asbestos fibers in the induction of malignant mesothelioma is controversial (Table 5.7). SV40 viral DNA sequences and oncoproteins have been detected in human pleu- ral malignant mesotheliomas by some investigators (reviewed by Gazdar et al. 2002) but there are technical concerns about these findings (López-Ríos et al. 2004). However, a role for SV40 as a carcinogen or cocarcinogen is biologically plausible on the basis of cellular and animal models (Carbone et al. 2003, Cicala et al. 1993) and the molecular mechanisms of action of these viral oncoproteins (reviewed in Gazdar et al. 2002). Human JC virus is a member of the polyomavirus family that is closely related to BK virus and SV40 virus. Like SV40 virus, JC virus encodes T and t antigens that function in cell transformation and induction of tumors in experimental animals (reviewed in White et al. 2005). Although JC virus

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89 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE TABLE 5.7 SV40 Virus and Malignant Mesothelioma Evidence for a Causal Relationship 1. SV40 viral DNA sequences have been detected in up to 80% of human malignant mesotheliomas in the United States (reviewed in Gazdar et al. 2002). 2. SV40 viral DNA has been detected in tumor cells, not in adjacent stroma or nonneo- plastic mesothelial cells (Carbone et al. 1994, 1997; Ranel et al. 1999; Shivapurkar et al. 1999). 3. SV40 T antigen binds to and inactivates p53 and pRb proteins (Carbone et al. 1997, De Luca et al. 1997). 4. SV40 virus preferentially infects and transforms human mesothelial cells (Carbone et al. 2003). 5. Antisense constructs directed against SV40 T antigen induce growth arrest and apoptosis in human mesothelioma cells in vitro (Waheed et al. 1999). 6. SV40 virus induces malignant mesothelioma in hamsters (Cicala et al. 1993). Evidence Against a Causal Relationship 1. Several studies have failed to detect SV40 viral DNA sequences in human malignant mesotheliomas (López-Ríos et al. 2004, Manfredi et al. 2005). 2. Epidemiologic studies fail to show an increased risk of cancer in individuals likely exposed to SV40 virus in contaminated vaccines (reviewed in IOM 2002). 3. SV40 T antigen is highly immunogenic (reviewed in Butel and Lednicky 1999). 4. Serologic tests for SV40 virus are cross-reactive with JC virus and BK virus which are nearly ubiquitous in humans but do not cause disease in immunocompetent individuals (reviewed in Shah 2004). 5. Distribution of potentially contaminated vaccines coincided with a period of increasing use of asbestos products (reviewed in Gazdar et al. 2002). is trophic for glial cells of the central nervous system, it can infect tonsillar tissue and is thought to replicate and spread in circulating lymphoid cells. More than 80% of adults have serologic evidence of exposure to JC virus, most likely due to subclinical infection in childhood. JC viral DNA se- quences have been detected in the urine, kidney, and gastrointestinal tract of normal people (Bofill-Mas and Girones 2001, Laghi et al. 1999, Ricciardiello et al. 2000). In immunocompromised patients, JC virus can produce a fatal demyelinating disease, progressive multifocal leukoencepha- lopathy (PML). JC virus has been detected in brain tumors in patients with or without PML (White et al. 2005). It has also been detected in esophageal and colonic tumors (Del Valle et al. 2005, Enam et al. 2002, Laghi et al. 1999). Like the association between SV40 virus and human malignant me- sotheliomas, the causal relationship between JC virus and gastrointestinal cancer is disputed (Boland et al. 2004, Newcomb et al. 2004). SV40 and JC viral T antigens perturb several key cell-signaling and growth-regulatory pathways, both directly by binding to and inactivating pRb and p53 and indirectly by binding to insulin receptor substrate 1 (Fei et al. 1995) and β-catenin (Enam et al. 2002), inducing expression of autocrine

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90 ASBESTOS and paracrine growth factors (Cacciotti et al. 2001), and altering patterns of gene methylation (Suzuki et al. 2005). In addition, T antigen and agnoprotein encoded by late viral genes may inhibit DNA repair (Digweed et al. 2002) and prevent the cell cycle arrest induced by DNA damage, thereby inducing genetic and karyotypic instability (White et al. 2005). SV40 virus also induces telomerase activity and immortalization of human me- sothelial cells (Foddis et al. 2002, Ke et al. 1989). Human mesotheliomas containing SV40 viral sequences show a significantly higher index of gene methylation (Toyooka et al. 2001). One of the most frequently methylated genes, RASSF1A, was shown to be progressively methylated during passage of SV40-infected mesothelial cells in vitro (Toyooka et al. 2002). Thus, SV40 virus may contribute to epigenetic gene silencing during tumor growth and progression. There is experimental evidence to support the hypothesis that SV40 virus and asbestos fibers can act as cofactors in inducing transformation of human mesothelial cells in culture (Bocchetta et al. 2000) and in hamsters (Krocynska et al. 2005). There are no studies reported on whether asbestos fibers act as a potential cofactor with JC virus in cell transformation in vitro or in tumorigenicity in animal models. INFORMATION FROM ANIMAL STUDIES Dosimetry Information A major consideration in assessing the risk of cancer in the oral cavity, pharynx, larynx, and gut after inhalation exposure to asbestos is the pro- portion of inhaled fibers that enters those regions and how long the fibers stay there. There is an extensive literature on the deposition and clearance of inhaled particles in animals and humans. Research on the dosimetry of inhaled radionuclides led to the development of extensive models of the deposition and clearance of such inhaled particles because of the ease of detecting the particles in the body. As noted in Chapter 4, the International Commission on Radiological Protection (ICRP 1994) has published its models. A recent dosimetry model for inhaled poorly soluble particles has been published by the Environmental Protection Agency (Jarabek et al. 2005), which allows extrapolation of dosimetry between species. It is known that poorly soluble particles that deposit in the oropharyn- geal, laryngeal, and tracheobronchial region are cleared mainly by cough- ing or movement up the mucociliary escalator followed by swallowing and passage through the gut. There are fewer studies on deposition and clear- ance of inhaled fibers. A multiple-path model of fiber deposition in the rat lung developed by Asgharian and Anjilvel (1998) indicated that in oral air- ways, where deposition is mainly by impaction, the larger the fiber aspect

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91 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE ratio, the lower the deposition by impaction. Modeling by Quinn et al. (1997), however, suggested that greater length would cause fibers to de- posit disproportionately higher in the tracheobronchial tree than aerody- namically equivalent spheres. More recently, deposition of fibers in the hu- man respiratory tract was studied by using a cast replica of the tract from the nose to the oral cavity to the fourth bifurcation (Su and Cheng 2005, Zhou and Cheng 2005); the oropharynx was found to be a preferred depo- sition site, but apparently there was less oral deposition of fibers than of spherical particles. Thus, one might use deposition data for spherical par- ticles as an approximation for fibers. On the basis of current knowledge, inhalation of asbestos would result in deposition in the oral cavity, pharynx, larynx, and tracheobronchial re- gion—all sites that lead to clearance of fibers through the gut. The toxicol- ogy data summarized below suggest that fibers do not persist at the site of deposition or in the gut long enough to induce toxicity in animal models at the cancer sites of concern in this review. Inhalation Toxicity Studies The carcinogenicity of asbestos was first noted in humans. Thus, inha- lation studies of the toxicity of asbestos in animals have not been directed toward the carcinogenicity of asbestos, but toward more specific issues: mechanisms of fiber-induced toxicity, including neoplasia; deposition and fate of inhaled fibers; and comparison of the toxicity of other fibers with that of asbestos. In that rodents are obligatory nose-breathers, inhalation exposure will not expose the pharynx in a fashion that precisely replicates human exposure. One would, however, expect a large portion of the inhaled fibers ultimately to be ingested because of removal of the fibers from the upper respiratory tract by the mucociliary escalator followed by swallowing. Inhalation studies have been conducted in F344 rats (Hesterberg et al. 1993, 1994; McConnell et al. 1994a) and Syrian hamsters (McConnell et al. 1994b, 1999) with exposures for 6 hr/day, 5 days/week for up to 24 months. Hesterberg et al. (1993, 1994) exposed F344 rats to chrysotile asbestos fibers at 10 mg/m3 as a positive control for comparison with re- sponses to glass fibers. At the end of the 2 years of exposure to asbestos, the rats had pulmonary fibrosis, one of 69 rats (1.4%) had mesothelioma, and 13 (19%) had lung tumors (adenomas and carcinomas). No lesions were found in the oropharyngeal region, the gut, or the larynx (McConnell 2005). Using the same species as an animal model, McConnell et al. (1994a) ex- posed F344 rats to crocidolite asbestos at 10 mg/m3 in a chronic study to compare the response to asbestos with that to slag wool insulation fibers. The exposure to asbestos fibers was terminated after 10 months because of increased morbidity and mortality, and both mesotheliomas (1%) and lung

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93 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE (HHS 1983, 1985, 1988, 1990a, 1990b). Nonfibrous tremolite was also tested in rats according to the same protocol (NTP Technical Report 277, HHS 1990c). Animals were exposed to asbestos 1% of the diet, which was estimated by the investigators to be about 70,000 times the greatest pos- sible human exposure in drinking water. The concern at the time of the studies was the potential toxicity of drinking water delivered through as- bestos cement pipes, because slightly acidic water was known to leach the cement and release asbestos fibers. Exposure of dams was followed by ex- posure of the pups by gavage while they were nursing and then in the diet for the remainder of their lives. Examination of the gut was extensive (McConnell 2005). The entire intestinal tract was opened and examined by running it over an “x-ray” view box. Even the smallest inflammatory lesion would have been identified and saved for histopathologic examination. In the gastronintestinal tract, sections of the esophagus, the entire stomach, three levels of small intestine, and the cecum were examined. In addition, the entire colorectum was fixed and then carpet-rolled and sectioned. That allowed histopathologically examination of the entire colorectum (the sus- pect target tissue). Any crypt lesion should have been identified, if present. The only finding of note in the gastrointestinal tract was a slight increase in the incidence of adenomatous polyps in the large intestine after exposure to the intermediate-length chrysotile (from Quebec) in rats, but preneoplastic changes in the epithelium were not found. No gastrointestinal lesions (in- flammatory, preneoplastic, or neoplastic) were found after exposure to the same sample of chrysotile in hamsters, to short chrysotile (from New Idria) in hamsters or rats, to amosite in rats or hamsters, to crocidolite in rats, or to nonfibrous tremolite in rats. The mesentery was examined in detail, as well as mesenteric lymph nodes and sections of the larynx, trachea, and lungs from every animal. No lesions were found in any of those tissues. Asbestos fibers, particularly the amphibole types, are highly tissue-reactive if of the appropriate length and would be hypothesized to produce lesions throughout the gastrointestinal tract if they persisted in sufficient numbers. Those studies involved extremely high exposures to asbestos in the gut over the lifetime of the animals beginning with nursing pups. The examina- tion of the gut and related tissues was thorough. The studies do not indicate an association between ingested asbestos and neoplasia. Summary On the basis of animal studies of asbestos exposure in rats and Syrian hamsters, one would not expect exposure to asbestos fibers at environmen- tal or even occupational concentrations to increase the incidence of tumors in the oropharyngeal region, the larynx, or the gut. Our knowledge of do- simetry suggests that inhalation exposure to asbestos would result in clear-

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94 ASBESTOS ance of a large amount of asbestos through the gut, but that the fibers would quickly pass through the gut and be eliminated from the body. The type of lesions observed after chronic exposures to asbestos fibers suggests that the fibers were not retained at any site in amounts needed to cause neoplastic change, although they did produce an increased incidence of (be- nign) adenomatous polyps in the large intestine of rats at very high expo- sure levels. Although correspondence of tumor sites in humans and experimental animals would constitute intuitively appealing evidence and would likely be mechanistically consistent, it should be noted, however, that empirical con- sideration of epidemiologic and experimental findings for known carcino- gens has demonstrated that site-specificity is not necessarily the rule across species (Maronpot et al. 2004). Most of the non-epidemiologic data consid- ered in this chapter do not lend particular credence toward a given extra- pulmonary site being the target of carcinogenic action in humans, but serve to establish the precept that asbestos is a human carcinogen. BIOMARKERS Role of Biomarkers in Detection of Asbestos-Related Cancer Biomarkers have not yet been used extensively in the early detection or treatment of cancer. One of the more established biomarkers is the presence of pleural plaques as a marker of pulmonary asbestosis and therefore in- creased risk of development of pleural mesothelioma. In our review of biomarkers for prediction of the development of laryngeal, pharyngeal, or gastrointestinal tumors, we surveyed the literature for evidence of changes in biomarker expression in animals (primarily rodents) and for serum and radiographic biomarkers in humans. There seems to be no evidence that definitively identifies a biomarker of asbestos exposure that predicts can- cers of the larynx, pharynx, esophagus, stomach, colon, or rectum. Animal Studies Human malignant mesotheliomas are induced by fibrous dusts, but the nature of the interactions between fibers and target cells, including the mo- lecular mechanisms leading to tumorigenesis, are not fully understood. Sev- eral studies in rats monitored mRNA expression patterns at different stages of asbestos-induced carcinogenesis and demonstrated the up-regulation of some proto-oncogenes—including c-myc, fra-1, and EGFR in fiber-induced disease. Several papers point to the possible role of fra-1 as one of the dimeric proteins generating the immediate early gene (AP-1 transcription factor) family of proteins, and there is some evidence of a dose-dependent

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95 BIOLOGICAL ASPECTS OF ASBESTOS-RELATED DISEASE increase in expression in mesothelial cells. There is also evidence that asbes- tos induces mitochondrial DNA damage and dysfunction with dose-related decreases in steady-state mRNA concentrations of cytochrome C oxidases. That result of asbestos exposure led to mRNA expression of pro- and anti- apoptotic genes and increased the numbers of apoptotic cells observed in asbestos-exposed mesothelial cells in murine models. The possible contri- bution of mitochondrial-derived pathways to asbestos-induced apoptosis was confirmed by its reduction in apoptosis when the cells were pretreated with a caspase-9 inhibitor. Genotoxicity and alterations in DNA synthesis were observed in the livers, and somewhat less consistently in the serum, of rats treated with asbestos. Human Biomarkers of Asbestos Exposure Several human studies have attempted to assay biomarkers of asbestos exposure in human serum. Asbestos exposure can lead to early inflamma- tory responses, such as the release of inflammatory cells that can be col- lected by non-invasive methods; and several free radicals are involved in the progression of asbestos-related diseases, ultimately leading to cytogenetic changes. Therefore, extensive evaluations have been carried out of antioxi- dant states and reducing equivalents such as reactive oxygen species. Marczynski et al. (2000a) showed that concentrations of 8-OHdG in DNA of white blood cells of workers highly exposed to asbestos in Germany were significantly increased over those in the control group (p < 0.001). The mean concentration for the 496 asbestos-exposed people was 2.61 ± 0.91 8-OHdG/105 dG compared to 1.52 ± 0.39 8-OHdG/105 dG for the 214 control subjects. Those results indicate that DNA samples from exposed people contain 1.7-2 times the amount of oxidative damage found in con- trols. The mechanism of action of fiber-induced oxidative damage has been studied with common assays and other procedures. The association between 8-OHdG in the DNA of workers highly exposed to asbestos correlated with a significantly increased risk of cancer compared with non-asbestos-exposed controls, but the risk was not significantly higher (p > 0.05) than that in asbestos-exposed patients without tumors of the respiratory tract, gas- trointestinal tract, mouth-pharynx-larynx, or urogenital tract. These intrigu- ing data suggest that there is a gradient in the concentrations of 8-OHdG in white blood cells between asbestos-exposed patients with and without can- cer and non-asbestos-exposed controls. There has been extensive work on several DNA-inducible genes as biomarkers of exposure to these agents, including p53 induction of DNA strand breaks, p53 expression, and apoptosis in cell lines, particularly in cultured mesothelial cells. In vitro data show significant biologic effects of asbestos fibers in human blood cells, particularly lymphocytes and neutro-

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96 ASBESTOS phils. There is little evidence to date with regard to asbestos-related bio- markers obtained from human serial sampling other than the aforemen- tioned compelling data in patterns of 8-OHdG descriptions of changes in low-molecular-weight DNA fragmentation in the white cells of workers highly exposed to asbestos (Marczynski et al. 2000b). Summary There is evidence of a difference between asbestos-exposed people and non-asbestos-exposed people in modulation of DNA-adduct formation, as demonstrated by a significant elevation in the concentration of 8-OHdG in DNA of white blood cells from asbestos-exposed people. There are no com- pelling data, however, that can differentiate between the concentrations of these DNA adducts in the lymphocytes of cancer patients exposed to asbes- tos and of other people exposed to asbestos. REFERENCES Albrecht C, Borm PJ, Unfried K. 2004. Signal transduction pathways relevant for neoplastic effects of fibrous and non-fibrous particles. Mutation Research 553(1-2): 23-35. Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K, Jhanwar SC, McClatchey AI, Kane AB, Testa JR. 2005. A mouse model recapitulating molecular features of human mesothelioma. Cancer Research 65(18): 8090-8095. Amacher DE, Alarif A, Epstein SS. 1974. Effects of ingested chrysotile on DNA synthesis in the gastrointestinal tract and liver of the rat. Environmental Health Perspectives 9: 319-324. Amacher DE, Alarif A, Epstein SS. 1975. The dose-dependent effects of ingested chrysotile on DNA synthesis in the gastrointestinal tract, liver, and pancreas of the rat. Environmental Research 10(2): 208-216. Antman KH. 1986. Asbestos-related malignancy. Critical Reviews in Oncology-Hematology 6(3): 287-309. Asgharian B, Anjilvel S. 1998. A multiple path model of fiber disposition in the rat lung. Toxicological Sciences 44(1): 80-86. Ault JG, Cole RW, Jensen CG, Jensen LC, Bachert LA, Rieder CL. 1995. Behavior of crocido- lite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer Research 55(4): 792-798. Baris I, Simonato L, Artvinli M, Pooley F, Saracci R, Skidmore J, Wagner C. 1987. Epidemio- logical and environmental evidence of the health effects of exposure to erionite fibres: A four-year study in the Cappadocian region of Turkey. International Journal of Cancer 39(1): 10-17. Baser ME, De Rienzo A, Altomare D, Balsara BR, Hedrick NM, Gutmann DH, Pitts LH, Jackler RK, Testa JR. 2002. Neurofibromatosis 2 and malignant mesothelioma. Neurol- ogy 59(2): 290-291. Battifora H, McCaughey WT. 1995. Tumors of the serosal membranes. In: Roasi J, ed. Atlas of Tumor Pathology. Third Series. Washington, DC: Armed Forces Institute of Pathol- ogy. Pp. 17-27. Bernstein D, Castranova V, Donaldson K, Fubini B, Hadley J, Hesterberg T, Kane A, Lai D, McConnell EE, Muhle H, Oberdorster G, Olin S, Warheit DB. 2005. Testing of fibrous particles: Short-term assays and strategies. Inhalation Toxicology 17(10): 497-537.

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