NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Institute of Medicine (US) Committee on Asbestos: Selected Health Effects. Asbestos: Selected Cancers. Washington (DC): National Academies Press (US); 2006.

Cover of Asbestos

Asbestos: Selected Cancers.

Show details

5Biological 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 established and supported by epidemiologic, animal, and mechanistic toxicologic studies (IARC 1987). The biologic mechanisms responsible for asbestos-related disease are complex and reflect a chronic, multistep process 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 inhalation assays, fiber biopersistence and carcinogenicity are associated with persistent 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 fuse interstitial fibrosis) of the lungs and visceral pleural fibrosis and parietal pleural plaques of the pleural linings (Table 5.1). In the pleura, bilateral and symmetric fibrotic plaques usually reflect environmental or occupational 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.

TABLE 5.1. Pulmonary Diseases Associated with Exposure to Asbestos Fibers.

TABLE 5.1

Pulmonary Diseases Associated with Exposure to Asbestos Fibers.

Risk Factors for Lung Cancer and Malignant Mesothelioma

Tobacco-smoking is a major causal risk factor for lung cancer (Table 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 associated with tobacco-smoking (Battifora and McCaughey 1995). Exposure to environmental erionite fibers has been found to be associated with malignant pleural mesothelioma (Baris et al. 1987, Roushdy-Hammady et al. 2001), while radiation, chronic inflammation, and SV40 virus are also postulated as etiologic factors (Table 5.3).

TABLE 5.2. Risk Factors for Development of Lung Cancer.

TABLE 5.2

Risk Factors for Development of Lung Cancer.

TABLE 5.3. Risk Factors for Development of Malignant Mesothelioma.

TABLE 5.3

Risk Factors for Development of Malignant Mesothelioma.

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 identical, for example, tubulopapillary malignant mesothelioma arising in the peritoneum (Lynch et al. 1994). Recent evidence of an inherited predisposition to malignant mesothelioma after exposure to erionite in two villages in Turkey was published by Roushdy-Hammady et al. (2001).

TABLE 5.4. Genetic Predisposition to Malignant Mesothelioma.

TABLE 5.4

Genetic Predisposition to Malignant Mesothelioma.

Malignant mesotheliomas have also been reported in people with inherited cancer-susceptibility syndromes following exposure to asbestos fibers or radiation therapy (Table 5.4). Somatic mutations in the neurofibromatosis type 2 (Nf2) gene have been detected in 50% of human malignant 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 human malignant mesotheliomas (Altomare et al. 2005). Li-Fraumeni syndrome is a rare heritable cancer-susceptibility disorder characterized by carrying a mutant allele of the p53 gene. Although mutations in the p53 tumor-suppressor gene are generally rare in human malignant mesotheliomas (Metcalf et al. 1992), individuals with Li-Fraumeni syndrome show increased susceptibility for malignant mesothelioma (Table 5.4). Heterozygous p53-deficient mice also show increased susceptibility to and accelerated progression of asbestos-induced mesotheliomas (Marsella et al. 1997, Vaslet et al. 2002). Those murine transgenic models support a role of inactivation of the Nf2 and p53 tumor-suppressor gene pathways in the pathogenesis 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, biodurability, 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, migrate 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 persistent epithelial or mesothelial cell injury, whose repair is accompanied by proliferation. Persistent or chronic macrophage activation can lead to 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 persistent production of reactive oxygen species by the respiratory-burst mechanism. Asbestos fibers contain a high surface content of redox-active iron and generate additional radicals, including the highly reactive hydoxyl radical by Fenton chemistry (Fubini and Oter-Areán 1999, Hardy and Aust 1995). More stable lipid radicals and reactive nitrogen species can be generated secondarily (Goodglick et al. 1989, Park and Aust 1998). Theoretically, 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 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 cytokinesis 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).

TABLE 5.5. Direct Mechanisms of Asbestos-Fiber Carcinogenesis.

TABLE 5.5

Direct Mechanisms of Asbestos-Fiber Carcinogenesis.

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 stomachs 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 proliferation of epithelial and mesothelial cells. Nongenotoxic mechanisms leading to increased cell proliferation include activation of growth factor receptors 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 damage 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 proliferating 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 synergistic 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 explants 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 epithelium (Churg et al. 1989). Inhalation of ozone was also shown to impair 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 squamous metaplasia in tracheal explant cultures (Mossman et al. 1984). Similarly, 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 development 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). Alternatively, 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.

TABLE 5.6

Indirect Mechanisms of Asbestos-Fiber Carcinogenesis.

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, proteases, and growth factors that perpetuate tissue injury, inflammation, and target-cell proliferation (Robledo et al. 2000). Ultimately, the persistent injury 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 biological 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 macrophages or other inflammatory cells may stimulate proliferation of preneoplastic cells. The proliferating population is a target for additional genetic 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 fibrosis. And proteases, in combination with proangiogenic factors, may facilitate 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 pleural 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).

TABLE 5.7. SV40 Virus and Malignant Mesothelioma.

TABLE 5.7

SV40 Virus and Malignant Mesothelioma.

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 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 sequences 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 leukoencephalopathy (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 mesotheliomas, 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 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 mesothelial 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 proportion 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 oropharyngeal, laryngeal, and tracheobronchial region are cleared mainly by coughing or movement up the mucociliary escalator followed by swallowing and passage through the gut. There are fewer studies on deposition and clearance of inhaled fibers. A multiple-path model of fiber deposition in the rat lung developed by Asgharian and Anjilvel (1998) indicated that in oral airways, where deposition is mainly by impaction, the larger the fiber aspect ratio, the lower the deposition by impaction. Modeling by Quinn et al. (1997), however, suggested that greater length would cause fibers to deposit disproportionately higher in the tracheobronchial tree than aerodynamically equivalent spheres. More recently, deposition of fibers in the human 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 deposition site, but apparently there was less oral deposition of fibers than of spherical particles. Thus, one might use deposition data for spherical particles 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 region—all sites that lead to clearance of fibers through the gut. The toxicology 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, inhalation 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 responses 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) exposed 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 neoplasms (14%) were observed. No tumors were found in the oropharyngeal region, the gut, or the larynx.

When the Syrian hamster was used as an animal model, mesotheliomas were observed but not lung tumors. In a chronic (24-month) inhalation study of Syrian hamsters exposed to amosite for comparison with glass fibers (McConnell et al. 1999), exposure at 250 fibers/cm3 for 78 weeks resulted in a mesothelioma incidence of 20%. Again, no lesions of the oropharyngeal region, the gut, or the larynx were observed (McConnell 2005). In another study by McConnell et al. (1994b), Syrian hamsters were exposed to chrysotile asbestos at 10 mg/m3 for 18 months as a positive control for comparison of responses with those to refractory ceramic fibers. In this case, only pulmonary fibrosis was observed in the exposed hamsters, and there were no neoplasms in the oropharyngeal region, the gut, or the larynx (McConnell 2005).

The above studies indicate that rats are more sensitive to development of pulmonary tumors following asbestos exposure than are Syrian hamsters and that chrysotile is somewhat less potent than the amphiboles. In neither species did chronic asbestos exposures by inhalation lead to tumors in the oropharyngeal region, the gut, or the larynx.

Ingestion Toxicity Studies

One report of the toxicity of ingested asbestos involved F344 rats exposed to asbestos in combination with subcutaneous administration of a known intestinal carcinogen, azoxymethane (AOM) (Ward et al. 1980). The asbestos was administered three times a week for 10 weeks by intragastric bolus dosing (1 mg in 1 ml saline). The first iteration of this experiment included a full complement of control groups and scheduled sacrifice at 34 weeks; neither amosite nor chrysotile appeared to increase the incidence of intestinal tumors above that produced by AOM alone, but they both produced four-to-five-fold increases in metastatic intestinal tumors. A life-span experiment with larger groups, but a more limited design, tested only amosite vs AOM. The lack of untreated vehicle controls made interpretation of the results difficult. Compared to historical controls, there was a nonsignificant increase in neoplastic lesions in the gut of the rats exposed only to asbestos; strictly speaking, one cannot know whether the results observed were associated with the asbestos or with irritation from the procedure, although one would not anticipate that gavage itself would impact the lower portion of the gastrointestinal tract.

The most definitive animal studies of oral exposure to asbestos were a series of studies conducted by the National Toxicology Program (Technical Reports 246, 249, 279, 280, and 295), in which asbestos (chrysotile, crocidolite, and amosite) was administered in the feed of rats and hamsters (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 possible human exposure in drinking water. The concern at the time of the studies was the potential toxicity of drinking water delivered through asbestos cement pipes, because slightly acidic water was known to leach the cement and release asbestos fibers. Exposure of dams was followed by exposure 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 suspect 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 (inflammatory, 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 examination 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 environmental or even occupational concentrations to increase the incidence of tumors in the oropharyngeal region, the larynx, or the gut. Our knowledge of dosimetry suggests that inhalation exposure to asbestos would result in clear 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 (benign) adenomatous polyps in the large intestine of rats at very high exposure 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 consideration of epidemiologic and experimental findings for known carcinogens has demonstrated that site-specificity is not necessarily the rule across species (Maronpot et al. 2004). Most of the non-epidemiologic data considered 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 increased 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 cancers 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 molecular mechanisms leading to tumorigenesis, are not fully understood. Several 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 increase in expression in mesothelial cells. There is also evidence that asbestos 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 contribution 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 inflammatory responses, such as the release of inflammatory cells that can be collected 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 antioxidant 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 controls. 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, gastrointestinal tract, mouth-pharynx-larynx, or urogenital tract. These intriguing data suggest that there is a gradient in the concentrations of 8-OHdG in white blood cells between asbestos-exposed patients with and without cancer 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 phils. There is little evidence to date with regard to asbestos-related biomarkers obtained from human serial sampling other than the aforementioned 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 compelling data, however, that can differentiate between the concentrations of these DNA adducts in the lymphocytes of cancer patients exposed to asbestos and of other people exposed to asbestos.

REFERENCES

  1. Albrecht C, Borm PJ, Unfried K. Signal transduction pathways relevant for neoplastic effects of fibrous and non-fibrous particles. Mutation Research. 2004;553(1-2):23–35. [PubMed: 15288530]
  2. Altomare DA, Vaslet CA, Skele KL, De Rienzo A, Devarajan K, Jhanwar SC, McClatchey AI, Kane AB, Testa JR. A mouse model recapitulating molecular features of human mesothelioma. Cancer Research. 2005;65(18):8090–8095. [PubMed: 16166281]
  3. Amacher DE, Alarif A, Epstein SS. Effects of ingested chrysotile on DNA synthesis in the gastrointestinal tract and liver of the rat. Environmental Health Perspectives. 1974;9:319–324. [PMC free article: PMC1475382] [PubMed: 4470950]
  4. Amacher DE, Alarif A, Epstein SS. The dose-dependent effects of ingested chrysotile on DNA synthesis in the gastrointestinal tract, liver, and pancreas of the rat. Environmental Research. 1975;10(2):208–216. [PubMed: 1193033]
  5. Antman KH. Asbestos-related malignancy. Critical Reviews in Oncology-Hematology. 1986;6(3):287–309. [PubMed: 3542255]
  6. Asgharian B, Anjilvel S. A multiple path model of fiber disposition in the rat lung. Toxicological Sciences. 1998;44(1):80–86. [PubMed: 9720144]
  7. Ault JG, Cole RW, Jensen CG, Jensen LC, Bachert LA, Rieder CL. Behavior of crocidolite asbestos during mitosis in living vertebrate lung epithelial cells. Cancer Research. 1995;55(4):792–798. [PubMed: 7850791]
  8. Baris I, Simonato L, Artvinli M, Pooley F, Saracci R, Skidmore J, Wagner C. Epidemiological 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. 1987;39(1):10–17. [PubMed: 3025107]
  9. Baser ME, De Rienzo A, Altomare D, Balsara BR, Hedrick NM, Gutmann DH, Pitts LH, Jackler RK, Testa JR. Neurofibromatosis 2 and malignant mesothelioma. Neurology. 2002;59(2):290–291. [PubMed: 12136076]
  10. Battifora H, McCaughey WT. Tumors of the serosal membranes. In: Roasi J, editor. Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology; 1995. pp. 17–27. Third Series.
  11. 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. Testing of fibrous particles: Short-term assays and strategies. Inhalation Toxicology. 2005;17(10):497–537. [PubMed: 16040559]
  12. BéruBé KA, Quinlan TR, Moulton G, Hemenway D, O'Shaughnessy P, Vacek P, Mossman BT. Comparative proliferative and histopathologic changes in rat lungs after inhalation of chrysotile or crocidolite asbestos. Toxicology and Applied Pharmacology. 1996;137(1):67–74. [PubMed: 8607143]
  13. Bocchetta M, Di Resta I, Powers A, Fresco R, Tosolini A, Testa JR, Pass HI, Rizzo P, Carbone M. Human mesothelial cells are unusually susceptible to simian virus 40-mediated transformation and asbestos cocarcinogenicity. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(18):10214–10219. [PMC free article: PMC27818] [PubMed: 10954737]
  14. Bofill-Mas S, Girones R. Excretion and transmission of JCV in human populations. Journal of Neurovirology. 2001;7(4):345–349. [PubMed: 11517414]
  15. Boland CR, Bigler J, Newcomb PA, Lampe JW, Potter JD. Evidence for an association between JC virus and colorectal neoplasia. Cancer Epidemiology, Biomarkers and Prevention. 2004;13(12):2285–2286. [PubMed: 15598796]
  16. Boylan AM, Sanan DA, Sheppard D, Broaddus VC. Vitronectin enhances internalization of crocidolite asbestos by rabbit pleural mesothelial cells via the integrin alpha v beta 5. Journal of Clinical Investigation. 1995;96(4):1987–2001. [PMC free article: PMC185837] [PubMed: 7560092]
  17. Broaddus VC, Yang L, Scavo LM, Ernst JD, Boylan AM. Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species. Journal of Clinical Investigation. 1996;98(9):2050–2059. [PMC free article: PMC507649] [PubMed: 8903324]
  18. Brody AR, Liu JY, Brass D, Corti M. Analyzing the genes and peptide growth factors expressed in lung cells in vivo consequent to asbestos exposure and in vitro. Environmental Health Perspectives. 1997;105 (Supplement 5):1165–1171. [PMC free article: PMC1470171] [PubMed: 9400718]
  19. Butel JS, Lednicky JA. Cell and molecular biology of simian virus 40: Implications for human infections and disease. Journal of National Cancer Institute. 1999;91(2):119–134. [PubMed: 9923853]
  20. Cacciotti P, Libener R, Betta P, Martini F, Porta C, Procopio A, Strizzi L, Penengo L, Tognon M, Mutti L, Gaudino G. SV40 replication in human mesothelial cells induces HGF/Met receptor activation: A model for viral-related carcinogenesis of human malignant mesothelioma. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(21):12032–12037. [PMC free article: PMC59762] [PubMed: 11572935]
  21. Cacciotti P, Mutti L, Gaudino G. Growth factors and malignant mesothelioma. In: Pass HI, Vogelzang NJ, Carbone M, editors. Malignant Mesothelioma: Advances in Pathogenesis, Diagnosis, and Translational Therapies. New York: Springer Science and Business Media; 2005. pp. 112–123.
  22. Carbone M, Pass HI, Rizzo P, Marinetti M, Di Muzio M, Mew DJ, Levine AS, Procopio A. Simian virus 40-like DNA sequences in human pleural mesothelioma. Oncogene. 1994;9(6):1781–1790. [PubMed: 8183577]
  23. Carbone M, Rizzo P, Grimley PM, Procopio A, Mew DJ, Shridhar V, de Bartolomeis A, Esposito V, Giuliano MT, Steinberg SM, Levine AS, Giordano A, Pass HI. Simian virus-40 large-T antigen binds p53 in human mesotheliomas. Nature Medicine. 1997;3(8):908–912. [PubMed: 9256284]
  24. Carbone M, Burck C, Rdzanek M, Rudzinski J, Cutrone R, Bocchetta M. Different susceptibility of human mesothelial cells to polyomavirus infection and malignant transformation. Cancer Research. 2003;63(19):6125–6129. [PubMed: 14559789]
  25. Cerda S, Weitzman SA. Influence of oxygen radical injury on DNA methylation. Mutation Research. 1997;386(2):141–152. [PubMed: 9113115]
  26. Chao CC, Park SH, Aust AE. Participation of nitric oxide and iron in the oxidation of DNA in asbestos-treated human lung epithelial cells. Archives of Biochemistry and Biophysics. 1996;326(1):152–157. [PubMed: 8579364]
  27. Churg A. Pathology of Occupational Disease. Baltimore: Williams and Wilkins; 1998. Neoplastic asbestos-induced disease; pp. 339–392.
  28. Churg A, Hobson J, Berean K, Wright J. Scavengers of active oxygen species prevent cigarette smoke-induced asbestos fiber penetration in rat tracheal explants. American Journal of Pathology. 1989;135(4):599–603. [PMC free article: PMC1880018] [PubMed: 2801882]
  29. Cicala C, Pompetti F, Carbone M. SV40 induces mesotheliomas in hamsters. American Journal of Pathology. 1993;142(5):1524–1533. [PMC free article: PMC1886912] [PubMed: 8388174]
  30. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867. [PMC free article: PMC2803035] [PubMed: 12490959]
  31. Dammann R, Takahashi T, Pfeifer GP. The CpG island of the novel tumor suppressor gene RASSF1A is intensely methylated in primary small cell lung carcinomas. Oncogene. 2001;20(27):3563–3567. [PubMed: 11429703]
  32. De Luca A, Baldi A, Esposito V, Howard CM, Bagella L, Rizzo P, Caputi M, Pass HI, Giordano GG, Baldi F, Carbone M, Giordano A. The retinoblastoma gene family pRb/p105, p107, pRb2/p130 and simian virus-40 large T-antigen in human mesotheliomas. Nature Medicine. 1997;3(8):913–916. [PubMed: 9256285]
  33. Del Valle L, White MK, Enam S, Oviedo SP, Bromer MQ, Thomas RM, Parkman HP, Khalili K. Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. Cancer. 2005;103(3):516–527. [PubMed: 15630684]
  34. Digweed M, Demuth I, Rothe S, Scholz R, Jordan A, Grotzinger C, Schindler D, Grompe M, Sperling K. SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11. Oncogene. 2002;21(32):4873–4878. [PubMed: 12118365]
  35. Enam S, Del Valle L, Lara C, Gan DD, Ortiz-Hidalgo C, Palazzo JP, Khalili K. Association of human polyomavirus JCV with colon cancer: Evidence for interaction of viral T-antigen and beta-catenin. Cancer Research. 2002;62(23):7093–7101. [PubMed: 12460931]
  36. Esteller M. Dormant hypermethylated tumour suppressor genes: Questions and answers. Journal of Pathology. 2005;205(2):172–180. [PubMed: 15643671]
  37. Fei ZL, D'Ambrosio C, Li S, Surmacz E, Baserga R. Association of insulin receptor substrate 1 with simian virus 40 large T antigen. Molcular and Cellular Biology. 1995;15(8):4232–4239. [PMC free article: PMC230662] [PubMed: 7542742]
  38. Fleury-Feith J, Lecomte C, Renier A, Matrat M, Kheuang L, Abramowski V, Levy F, Janin A, Giovannini M, Jaurand MC. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene. 2003;22(24):3799–3805. [PubMed: 12802287]
  39. Foddis R, De Rienzo A, Broccoli D, Bocchetta M, Stekala E, Rizzo P, Tosolini A, Grobelny JV, Jhanwar SC, Pass HI, Testa JR, Carbone M. SV40 infection induces telomerase activity in human mesothelial cells. Oncogene. 2002;21(9):1434–1442. [PubMed: 11857086]
  40. Fubini B. The possible role of surface chemistry in the toxicity of inhaled fibers. In: Warheit D, editor. Fiber Toxicology. Newark, DE: Academic Press; 1993. pp. 229–257.
  41. Fubini B. Surface reactivity in the pathogenic response to particulates. Environmental Health Perspectives. 1997;105 (Supplement 5):1013–1020. [PMC free article: PMC1470126] [PubMed: 9400693]
  42. Fubini B, Oter-Areán C. Chemical aspects of the toxicity of inhaled mineral dust. Chemical Society Review. 1999;28:373–381.
  43. Fung H, Kow YW, Van Houten B, Mossman BT. Patterns of 8-hydroxydeoxyguanosine formation in DNA and indications of oxidative stress in rat and human pleural mesothelial cells after exposure to crocidolite asbestos. Carcinogenesis. 1997;18(4):825–832. [PubMed: 9111221]
  44. Gazdar AF, Butel JS, Carbone M. SV40 and human tumours: Myth, association or causality? National Reviews of Cancer. 2002;2(12):957–964. [PubMed: 12459734]
  45. Ghio AJ, LeFurgey A, Roggli VL. In vivo accumulation of iron on crocidolite is associated with decrements in oxidant generation by the fiber. Journal of Toxicology and Environmental Health. 1997;50(2):125–142. [PubMed: 9048957]
  46. Goldberg JL, Zanella CL, Janssen YM, Timblin CR, Jimenez LA, Vacek P, Taatjes DJ, Mossman BT. Novel cell imaging techniques show induction of apoptosis and proliferation in mesothelial cells by asbestos. American Journal of Respiratory Cellular and Molecular Biology. 1997;17(3):265–271. [PubMed: 9308911]
  47. Goodglick LA, Pietras LA, Kane AB. Evaluation of the causal relationship between crocidolite asbestos-induced lipid peroxidation and toxicity to macrophages. American Reviews of Respiratory Diseases. 1989;139(5):1265–1273. [PubMed: 2540689]
  48. Govindarajan B, Klafter R, Miller MS, Mansur C, Mizesko M, Bai X, LaMontagne K Jr, Arbiser JL. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase. Molecular Medicine. 2002;8(1):1–8. [PMC free article: PMC2039931] [PubMed: 11984000]
  49. Hardy JA, Aust AE. The effect of iron binding on the ability of crocidolite asbestos to catalyze DNA single-strand breaks. Carcinogenesis. 1995;16(2):319–325. [PubMed: 7859364]
  50. Hartwig A. Role of DNA repair in particle- and fiber-induced lung injury. Inhalation Toxicology. 2002;14(1):91–100. [PubMed: 12122562]
  51. Hei TK, Xu A, Louie D, Zhou YL. Genotoxocity versus carcinogenicity: Implications from fiber toxicity studies. Inhalation Toxicology. 2000;12(Supplement 3):141–147. [PubMed: 26368610]
  52. Heineman EF, Bernstein L, Stark AD, Spirtas R. Mesothelioma, asbestos, and reported history of cancer in first-degree relatives. Cancer. 1996;77(3):549–554. [PubMed: 8630964]
  53. Hesterberg TW, Barrett JC. Induction by asbestos fibers of anaphase abnormalities: Mechanism for aneuploidy induction and possibly carcinogenesis. Carcinogenesis. 1985;6(3):473–475. [PubMed: 3978760]
  54. Hesterberg TW, Miller WC, McConnell EE, Chevalier J, Hadley JG, Bernstein DM, Thevenaz P, Anderson R. Chronic inhalation toxicity of size-separated glass fibers in Fischer 344 rats. Fundamental and Applied Toxicology. 1993;20(4):464–476. [PubMed: 8390950]
  55. Hesterberg TW, Miller WC, Mast R, McConnell EE, Bernstein DM, Anderson R. Relationship between lung biopersistence and biological effects of man-made vitreous fibers after chronic inhalation in rats. Environmental Health Perspectives. 1994;102 (Supplement 5):133–137. [PMC free article: PMC1567307] [PubMed: 7882917]
  56. Hesterberg TW, Chase G, Axten C, Miller WC, Musselman RP, Kamstrup O, Hadley J, Morscheidt C, Bernstein DM, Thevenaz P. Biopersistence of synthetic vitreous fibers and amosite asbestos in the rat lung following inhalation. Toxicology and Applied Pharmacology. 1998;151(2):262–275. [PubMed: 9707503]
  57. HHS (US Department of Health and Human Services) Lifetime Carcinogenesis Studies of Amosite Asbestos (CAS NO. 12172-73-5) in Syrian Golden Hamsters (Feed Studies). Research Triangle Park, NC: National Toxicology Program; 1983. NTP TR 249. [PubMed: 12748679]
  58. HHS. Toxicology and Carcinogenesis Studies of Chrysotile Asbestos (CAS No. 12001-29-5) in F344/N Rats (Feed Studies). Research Triangle Park, NC: National Toxicology Program; 1985. NTP TR 295. [PubMed: 12748710]
  59. HHS. Toxicology and Carcinogenesis Studies of Crocidolite Asbestos (CAS No. 12001-28-4) in F344/N Rats (Feed Studies). Research Triangle Park, NC: National Toxicology Program; 1988. NTP TR 280. [PubMed: 12748699]
  60. HHS. Lifetime Carcinogenesis Studies of Chrysotile Asbestos (CAS No. 12001-29-5) in Syrian Golden Hamsters (Feed Studies). Research Triangle Park, North Carolina: National Toxicology Program; 1990a. NTP TR 246. [PubMed: 12750747]
  61. HHS. Toxicology and Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in F344/N Rats (Feed Studies). Research Triangle Park, NC: National Toxicology Program; 1990b. NTP TR 279. [PubMed: 12748700]
  62. HHS. Toxicology and Carcinogenesis Studies of Tremolite (CAS No. 14567-73-8) in F344/N Rats (Feed Studies). Research Triangle Park, NC: National Toxicology Program; 1990c. NTP TR 277. [PubMed: 12748702]
  63. Hirao T, Bueno R, Chen CJ, Gordon GJ, Heilig E, Kelsey KT. Alterations of the p16(INK4) locus in human malignant mesothelial tumors. Carcinogenesis. 2002;23(7):1127–1130. [PubMed: 12117769]
  64. Hisada M, Garber JE, Fung CY, Fraumeni JF Jr, Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. Journal of National Cancer Institute. 1998;90(8):606–611. [PubMed: 9554443]
  65. Hobson J, Gilks B, Wright J, Churg A. Direct enhancement by cigarette smoke of asbestos fiber penetration and asbestos-induced epithelial proliferation in rat tracheal explants. Journal of National Cancer Instiute. 1988;80(7):518–521. [PubMed: 3367389]
  66. Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI, Fornace AJ Jr. Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(37):13200–13205. [PMC free article: PMC1201581] [PubMed: 16141330]
  67. Hu YC, Sidransky D, Ahrendt SA. Molecular detection approaches for smoking associated tumors. Oncogene. 2002;21(48):7289–7297. [PubMed: 12379873]
  68. IARC (International Agency for Research on Cancer) Overall Evaluations of Carcinogenity: An Updating of IARC Monographs Volumes 1 to 42. Supplement 7. Lyon, France: World Health Organization; 1987. IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Man.
  69. IARC. Tobacco Smoke and Involuntary Smoking. Vol. 83. Lyon, France: World Health Organization, IARC; 2004. IARC Monographs on the Evaluation of Carcinogenic Risks to Human. [PMC free article: PMC4781536] [PubMed: 15285078]
  70. ICRP (International Commission on Radiological Protection) Human Respiratory Tract Model for Radiological Protection. Oxford: Elsevier; 1994.
  71. IOM (Institute of Medicine) Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer. Washington, DC: National Academy Press; 2002.
  72. Jarabek AM, Asgharian B, Miller FJ. Dosimetric adjustments for interspecies extrapolation of inhaled poorly soluble particles (PSP) Inhalation Toxicology. 2005;17:317–334. [PubMed: 16020031]
  73. Jaurand MC. Use of in-vitro genotoxicity and cell transformation assays to evaluate the potential carcinogenicity of fibres. IARC Scientific Publications. 1996;140:55–72. [PubMed: 9101317]
  74. Jensen CG, Jensen LCW, Reider CL, Cole RW, Ault JG. Long crocidolite fibers cause polyploidy by sterically blocking cytokines. Carcinogenesis. 1996;17:2013–2021. [PubMed: 8824529]
  75. Kamp DW, Weitzman SA. The molecular basis of asbestos induced lung injury. Thorax. 1999;54(7):638–652. [PMC free article: PMC1745526] [PubMed: 10377212]
  76. Kandaswami C, O'Brien PJ. Effect of chrysotile asbestos and silica on the microsomal metabolism of benzo(a)pyrene. Environmental Health Perspectives. 1983;51:311–314. [PMC free article: PMC1569290] [PubMed: 6315372]
  77. Kane AB. Mechanisms of mineral fibre carcinogenesis. IARC Scientific Publications. 1996;140:11–34. [PubMed: 9101315]
  78. Ke Y, Reddel RR, Gerwin BI, Reddel HK, Somers AN, McMenamin MG, LaVeck MA, Stahel RA, Lechner JF, Harris CC. Establishment of a human in vitro mesothelial cell model system for investigating mechanisms of asbestos-induced mesothelioma. American Journal of Pathology. 1989;134(5):979–991. [PMC free article: PMC1879894] [PubMed: 2541616]
  79. Kim DH, Nelson HH, Wiencke JK, Zheng S, Christiani DC, Wain JC, Mark EJ, Kelsey KT. p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer. Cancer Research. 2001;61(8):3419–3424. [PubMed: 11309302]
  80. Krocynska B, Cutrone R, Bocchetta M, Yang H, Pass HI, Carbone M. Asbestos and SV40 are co-carcinogens. Proceedings of American Association of Cancer Research. 2005;46:56.
  81. Laghi L, Randolph AE, Chauhan DP, Marra G, Major EO, Neel JV, Boland CR. JC virus DNA is present in the mucosa of the human colon and in colorectal cancers. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(13):7484–7489. [PMC free article: PMC22112] [PubMed: 10377441]
  82. Lakowicz JR, Bevan DR. Effects of asbetos, iron oxide, silica, and carbon black on the microsomal availability of benzo[a]pyrene. Biochemistry. 1979;18(23):5170–5176. [PubMed: 227449]
  83. Lee BW, Wain JC, Kelsey KT, Wiencke JK, Christiani DC. Association between diet and lung cancer location. American Journal Respiratory and Critical Care Medicine. 1998;158(4):1197–1203. [PubMed: 9769282]
  84. Levresse V, Renier A, Fleury-Feith J, Levy F, Moritz S, Vivo C, Pilatte Y, Jaurand MC. Analysis of cell cycle disruptions in cultures of rat pleural mesothelial cells exposed to asbestos fibers. American Journal of Respiratory Cell and Molecular Biology. 1997;17(6):660–671. [PubMed: 9409553]
  85. Liu JY, Morris GF, Lei WH, Corti M, Brody AR. Up-regulated expression of transforming growth factor-alpha in the bronchiolar-alveolar duct regions of asbestos-exposed rats. American Journal of Pathology. 1996;149(1):205–217. [PMC free article: PMC1865228] [PubMed: 8686744]
  86. Loli P, Topinka J, Georgiadis P, Dusinska M, Hurbankova M, Kovacikova Z, Volkovova K, Wolff T, Oesterle D, Kyrtopoulos SA. Benzo[a]pyrene-enhanced mutagenesis by asbestos in the lung of lambda-lacI transgenic rats. Mutation Research. 2004;553(1-2):79–90. [PubMed: 15288535]
  87. López-Ríos F, Illei PB, Rusch V, Ladanyi M. Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids. Lancet. 2004;364(9440):1157–1166. [PubMed: 15451223]
  88. Lynch HT, Anton-Culver H, Kurosaki T. Is there a genetic predisposition to malignant mesothelioma? In: Jaurand M, Bignon J, editors. Mesothelial Cell and Mesothelioma. New York: Marcel Dekker, Inc; 1994. pp. 47–70.
  89. Manfredi JJ, Dong J, Liu WJ, Resnick-Silverman L, Qiao R, Chahinian P, Saric M, Gibbs AR, Phillips JI, Murray J, Axten CW, Nolan RP, Aaronson SA. Evidence against a role for SV40 in human mesothelioma. Cancer Research. 2005;65(7):2602–2609. [PubMed: 15805256]
  90. Manning CB, Vallyathan V, Mossman BT. Diseases caused by asbestos: Mechanisms of injury and disease development. International Immunopharmacology. 2002;2(2-3):191–200. [PubMed: 11811924]
  91. Marczynski B, Kraus T, Rozynek P, Raithel HJ, Baur X. Association between 8-hydroxy-2'-deoxyguanosine levels in DNA of workers highly exposed to asbestos and their clinical data, occupational and non-occupational confounding factors, and cancer. Mutation Research. 2000a;468(2):203–212. [PubMed: 10882897]
  92. Marczynski B, Rozynek P, Kraus T, Schlosser S, Raithel HJ, Baur X. Levels of 8-hydroxy-2'-deoxyguanosine in DNA of white blood cells from workers highly exposed to asbestos in Germany. Mutation Research. 2000b;468(2):195–202. [PubMed: 10882896]
  93. Maronpot RR, Flake G, Huff J. Relevance of animal carcinogenesis findings to human cancer predictions and prevention. Toxicologic Pathology. 2004;32 (Supplement 1):40–48. [PubMed: 15209402]
  94. Marsella JM, Liu BL, Vaslet CA, Kane AB. Susceptibility of p53-deficient mice to induction of mesothelioma by crocidolite asbestos fibers. Environmental Health Perspectives. 1997;105 (Supplement 5):1069–1072. [PMC free article: PMC1470134] [PubMed: 9400702]
  95. McConnell EE. Personal Communication to Mary Paxton for the Committee on Asbestos: Selected Health Effects. 2005 October 27 Available in IOM Public Access Files.
  96. McConnell E, Kamstrup O, Musselman R, Hesterberg T, Chevalier J, Miller W, Thevenaz P. Chronic inhalation study of size-separated rock and slag wool insulation fibers in Fischer 344/N rats. Inhalation Toxicology. 1994a;6(6):571–614.
  97. McConnell E, Mast R, Hesterberg T, Chevalier J, Kotin P, Bernstein D, Thevenaz P, Glass L, Anderson R. Chronic inhalation toxicity of a kaolin-based refactory ceramic fiber in Syrian golden hamsters. Inhalation Toxicology. 1994b;6(6):503–532.
  98. McConnell EE, Axten C, Hesterberg TW, Chevalier J, Miller WC, Everitt J, Oberdörster G, Chase GR, Thevenaz P, Kotin P. Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the Syrian golden hamster: Part II. Results of chronic exposure. Inhalation Toxicology. 1999;11(9):785–835. [PubMed: 10477659]
  99. McFadden D, Wright JL, Wiggs B, Churg A. Smoking inhibits asbestos clearance. American Reviews of Respiratory Diseases. 1986;133(3):372–374. [PubMed: 2869726]
  100. Metcalf RA, Welsh JA, Bennett WP, Seddon MB, Lehman TA, Pelin K, Linnainmaa K, Tammilehto L, Mattson K, Gerwin BI. p53 and Kirsten-ras mutations in human mesothelioma cell lines. Cancer Research. 1992;52(9):2610–2615. [PubMed: 1568228]
  101. Mossman BT, Eastman A, Bresnick E. Asbestos and benzo[a]pyrene act synergistically to induce squamous metaplasia and incorporation of [3H]thymidine in hamster tracheal epithelium. Carcinogenesis. 1984;5(11):1401–1404. [PubMed: 6488462]
  102. Mossman BT, Faux S, Janssen Y, Jimenez LA, Timblin C, Zanella C, Goldberg J, Walsh E, Barchowsky A, Driscoll K. Cell signaling pathways elicited by asbestos. Environmental Health Perspectives. 1997;105 (Supplement 5):1121–1125. [PMC free article: PMC1470124] [PubMed: 9400710]
  103. Murthy SS, Testa JR. Asbestos, chromosomal deletions, and tumor suppressor gene alterations in human malignant mesothelioma. Journal of Cellular Physiology. 1997;180(2):150–157. [PubMed: 10395284]
  104. Nelson HH, Kelsey KT. The molecular epidemiology of asbestos and tobacco in lung cancer. Oncogene. 2002;21(48):7284–7288. [PubMed: 12379872]
  105. Newcomb PA, Bush AC, Stoner GL, Lampe JW, Potter JD, Bigler J. No evidence of an association of JC virus and colon neoplasia. Cancer Epidemiology, Biomarkers and Prevention. 2004;13(4):662–666. [PubMed: 15066935]
  106. Oberdörster G. Evaluation and use of animal models to assess mechanisms of fibre carcinogenicity. IARC Scientific Publications. 1996;140:107–125. [PubMed: 9101320]
  107. Pache JC, Janssen YM, Walsh ES, Quinlan TR, Zanella CL, Low RB, Taatjes DJ, Mossman BT. Increased epidermal growth factor-receptor protein in a human mesothelial cell line in response to long asbestos fibers. American Journal of Pathology. 1998;152(2):333–340. [PMC free article: PMC1857975] [PubMed: 9466557]
  108. Park SH, Aust AE. Participation of iron and nitric oxide in the mutagenicity of asbestos in hgprt-, gpt+ Chinese hamster V79 cells. Cancer Research. 1998;58(6):1144–1148. [PubMed: 9515798]
  109. Pinkerton KE, Brody AR, Miller FJ, Crapo JD. Exposure to low levels of ozone results in enhanced pulmonary retention of inhaled asbestos fibers. American Review of Respiratory Diseases. 1989;140(4):1075–1081. [PubMed: 2529800]
  110. Quinn MM, Ellenbecker MJ, Smith TJ, Wegman DH, Eisen EA. A model to predict deposition of man-made vitreous fibres in the human tracheobronchial region. Annals of Occupational Hygiene. 1997;41 (Supplement 1):197–202.
  111. Ranel M, Nagels J, Heylen H, De Schepper S, Paulussen J, De Maeyer M, Van Haesendonck C. Detection of SV40 like viral DNA and viral antigens in malignant pleural mesothelioma. European Respiratory Journal. 1999;14(6):1381–1386. [PubMed: 10624771]
  112. Ricciardiello L, Laghi L, Ramamirtham P, Chang CL, Chang DK, Randolph AE, Boland CR. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology. 2000;119(5):1228–1235. [PubMed: 11054380]
  113. Rihn B, Coulais C, Kauffer E, Bottin MC, Martin P, Yvon F, Vigneron JC, Binet S, Monhoven N, Steiblen G, Keith G. Inhaled crocidolite mutagenicity in lung DNA. Environmental Health Perspectives. 2000;108(4):341–346. [PMC free article: PMC1638032] [PubMed: 10753093]
  114. Robledo RF, Buder-Hoffmann SA, Cummins AB, Walsh ES, Taatjes DJ, Mossman BT. Increased phosphorylated extracellular signal-regulated kinase immunoreactivity associated with proliferative and morphologic lung alterations after chrysotile asbestos inhalation in mice. American Journal of Pathology. 2000;156(4):1307–1316. [PMC free article: PMC1876879] [PubMed: 10751356]
  115. Roushdy-Hammady I, Siegel J, Emri S, Testa JR, Carbone M. Genetic-susceptibility factor and malignant mesothelioma in the Cappadocian region of Turkey. Lancet. 2001;357(9254):444–445. [PubMed: 11273069]
  116. Schapira RM, Ghio AJ, Effros RM, Morrisey J, Dawson CA, Hacker AD. Hydroxyl radicals are formed in the rat lung after asbestos instillation in vivo. American Journal of Respiratory Cell and Molecular Biology. 1994;10(5):573–579. [PubMed: 8179922]
  117. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, Minna JD. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Research. 1995;55(6):1227–1231. [PubMed: 7882313]
  118. Shah KV. Simian virus 40 and human disease. Journal of Infectious Diseases. 2004;190(12): 2061–2064. [PubMed: 15551202]
  119. Shivapurkar N, Wiethege T, Wistuba II, Salomon E, Milchgrub S, Muller KM, Churg A, Pass H, Gazdar AF. Presence of simian virus 40 sequences in malignant mesotheliomas and mesothelial cell proliferations. Journal of Cellular Biochemistry. 1999;76(2):181–188. [PubMed: 10618635]
  120. Sporn T, Roggli V. Mesothelioma. In: Roggli V, Oury T, Sporn T, editors. Pathology of Asbestos-Associated Diseases. New York: Springer; 2004. pp. 104–168.
  121. Su WC, Cheng YS. Deposition of fiber in the human nasal airways. Aerosol Science and Technology. 2005;39(9):888–901.
  122. Suzuki M, Toyooka S, Shivapurkar N, Shigematsu H, Miyajima K, Takahashi T, Stastny V, Zern AL, Fujisawa T, Pass HI, Carbone M, Gazdar AF. Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection. Oncogene. 2005;24(7):1302–1308. [PubMed: 15592515]
  123. Tlsty TD. Stromal cells can contribute oncogenic signals. Seminars in Cancer Biology. 2001;11(2):97–104. [PubMed: 11322829]
  124. Toyooka S, Pass HI, Shivapurkar N, Fukuyama Y, Maruyama R, Toyooka KO, Gilcrease M, Farinas A, Minna JD, Gazdar AF. Aberrant methylation and simian virus 40 tag sequences in malignant mesothelioma. Cancer Research. 2001;61(15):5727–5730. [PubMed: 11479207]
  125. Toyooka S, Carbone M, Toyooka KO, Bocchetta M, Shivapurkar N, Minna JD, Gazdar AF. Progressive aberrant methylation of the RASSF1A gene in simian virus 40 infected human mesothelial cells. Oncogene. 2002;21(27):4340–4344. [PubMed: 12082623]
  126. Travis WD, Colby JV, Koss MN, Rosado-de-Christenson ML, Muller NL, King TE. Non-neoplastic disorders of the lower respiratory tract. In: Roasi J, editor. Atlas of Nontumor Pathology. Washington DC: American Registry of Pathologists, Armed Forces Institute Pathologists; 2002. pp. 814–846.
  127. Tron V, Wright JL, Harrison N, Wiggs B, Churg A. Cigarette smoke makes airway and early parenchymal asbestos-induced lung disease worse in the guinea pig. American Review of Respiratory Disease. 1987;136(2):271–275. [PubMed: 2887135]
  128. Unfried K, Schurkes C, Abel J. Distinct spectrum of mutations induced by crocidolite asbestos: Clue for 8-hydroxydeoxyguanosine-dependent mutagenesis in vivo. Cancer Research. 2002;62(1):99–104. [PubMed: 11782365]
  129. Vallyathan V, Shi X. The role of oxygen free radicals in occupational and environmental lung diseases. Environmental Health Perspectives. 1997;105 (Supplement 1):165–177. [PMC free article: PMC1470247] [PubMed: 9114285]
  130. Vaslet CA, Messier NJ, Kane AB. Accelerated progression of asbestos-induced mesotheliomas in heterozygous p53+/- mice. Toxicological Sciences. 2002;68(2):331–338. [PubMed: 12151629]
  131. Waheed I, Guo ZS, Chen GA, Weiser TS, Nguyen DM, Schrump DS. Antisense to SV40 early gene region induces growth arrest and apoptosis in T-antigen-positive human pleural mesothelioma cells. Cancer Research. 1999;59(24):6068–6073. [PubMed: 10626792]
  132. Ward JM, Frank AL, Wenk M, Devor D, Tarone RE. Ingested asbestos and intestinal carcinogenesis in F344 rats. Journal of Environmental Pathology and Toxicology. 1980;3(5-6):301–312. [PubMed: 7441086]
  133. Weitzman SA, Graceffa P. Asbestos catalyzes hydroxyl and superoxide radical generation from hydrogen peroxide. Archives of Biochemistry and Biophysics. 1984;228(1):373–376. [PubMed: 6320737]
  134. White MK, Gordon J, Reiss K, Del Valle L, Croul S, Giordano A, Darbinyan A, Khalili K. Human polyomaviruses and brain tumors. Brain Research Reviews. 2005;50(1):69–85. [PubMed: 15982744]
  135. Wong L, Zhou J, Anderson D, Kratzke RA. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer. 2002;38(2):131–136. [PubMed: 12399123]
  136. Zhou Y, Cheng YS. Particle deposition in a cast of human tracheobronchial airways. Aerosol Science and Technology. 2005;39(6):492–500.
Copyright © 2006, National Academy of Sciences.
Bookshelf ID: NBK20336

Views

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...