4
Exposure and Disposition

EXPOSURE

Introduction

Briefly this section reviews the uses of asbestos, how people may be exposed to it, the magnitude of exposure, and how it is measured. For detailed information, the reader is directed to the more comprehensive reviews conducted by the Agency for Toxic Substances and Disease Registry (ATSDR 2001), the International Agency for Research on Cancer (IARC 1977), and the International Program on Chemical Safety (IPCS 1986).

Asbestos has had a very wide array of uses. It has been used extensively for insulation and in textiles and has been mixed and bonded with cement, plastics, and resins. Production of asbestos products in the United States, Canada, and most other industrialized countries increased rapidly in the 20th century, particularly during World War II, and peaked in the early to mid 1970s. In 1973, the US Environmental Protection Agency (EPA) prohibited spraying of asbestos insulation, and further restrictions were later applied. Many other industrialized countries enacted similar regulations or outright bans, and the use and production of asbestos dropped rapidly.

Although many uses have been discontinued, asbestos is still used in some limited applications. In 2003, asbestos was not produced in the United States, although 6,000 metric tons were consumed—80% for specialized roofing products; 8% for gaskets; 4% for friction products, such as vehicles brake pads, clutches, and transmissions; and 8% for other uses (USGS 2004). Some European countries have banned all uses of asbestos. How-



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4 Exposure and Disposition EXPOSURE Introduction Briefly this section reviews the uses of asbestos, how people may be exposed to it, the magnitude of exposure, and how it is measured. For detailed information, the reader is directed to the more comprehensive re- views conducted by the Agency for Toxic Substances and Disease Registry (ATSDR 2001), the International Agency for Research on Cancer (IARC 1977), and the International Program on Chemical Safety (IPCS 1986). Asbestos has had a very wide array of uses. It has been used extensively for insulation and in textiles and has been mixed and bonded with cement, plastics, and resins. Production of asbestos products in the United States, Canada, and most other industrialized countries increased rapidly in the 20th century, particularly during World War II, and peaked in the early to mid 1970s. In 1973, the US Environmental Protection Agency (EPA) pro- hibited spraying of asbestos insulation, and further restrictions were later applied. Many other industrialized countries enacted similar regulations or outright bans, and the use and production of asbestos dropped rapidly. Although many uses have been discontinued, asbestos is still used in some limited applications. In 2003, asbestos was not produced in the United States, although 6,000 metric tons were consumed—80% for specialized roofing products; 8% for gaskets; 4% for friction products, such as vehicles brake pads, clutches, and transmissions; and 8% for other uses (USGS 2004). Some European countries have banned all uses of asbestos. How- 63

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64 ASBESTOS ever, exposure occurs in all countries when buildings, ships, and other struc- tures insulated with asbestos are demolished, when asbestos is removed, or during maintenance and repair of asbestos-containing materials. Consideration needs to be given to the different measurement methods used when interpreting and comparing the reported levels of airborne expo- sure in various settings. Historically, airborne asbestos in workplaces was measured with a midget impinger to collect the fibers, a standard occupa- tional hygiene method, and concentrations were expressed as millions of particles per cubic foot (mppcf). More recently, airborne fibers have been collected on membrane filters, and concentration has been reported in terms of either mass (such as nanograms per cubic meter, ng/m3) or number of fibers (such as fibers per milliliter, f/ml). The latter measure is most com- monly used. In water, concentrations may be expressed in terms of fibers per liter. In a given measurement system, fibers may qualify for counting on the basis of criteria such as length (for instance, over 5 µm) or aspect (length:diameter) ratio (for instance, over 3:1), characteristics also relevant to their potential to cause health effects. Fibers may be counted with either phase-contrast microscopy (PCM) or transmission electron microscopy (TEM). Of the two, TEM is the more sensitive and may measure higher concentrations in the same environment than PCM, because PCM may miss very thin fibers. In addition, PCM may fail to distinguish asbestos from other types of fibers. However, workplace exposures are generally measured with PCM, which is less expensive and considered adequate by regulatory agencies. Conversion between different measures of airborne units is problematic because conversion factors vary with the distribution of fiber thickness and length in the environment of interest. The most valid approach to conversion involves obtaining mea- surements simultaneously under the same conditions using the different methods for which conversion factors are needed. Using that approach, Dement et al. (1983) found factors for converting PCM to TPM data within the same facilities in the textile industry that ranged from 2.5 to 7.5 f/ml :: 1 mppcf. Occupational Exposure Asbestos concentrations observed in occupational settings have been orders of magnitude higher than the highest concentrations observed in residential settings, but some in-home activities, such as shaking out work clothes, can produce levels that may rival those found in the workplace. The highest well-documented exposures have been among workers manu- facturing asbestos products or employed in mining and milling opera- tions. Table 4.1 provides selected summary statistics for some asbestos- product manufacturing facilities in the United States based on samples

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65 EXPOSURE AND DISPOSITION TABLE 4.1 Concentrations of Fibers in Various US Asbestos-Using Industries Range of Means Within Departments Industry Plants Years (# fibers >5 µm)/ml, PCM Insulation plants 5 plants 1966-1971 0.01-74.4 Textile plants 8 plants 1964-1971 0.1-29.9 Friction products plants 5 plants 1968-1971 0.1-14.4 Paper, packing, asphalt products not reported 1966-1970 0.2-13.6 Cement pipe 7 plants 1969-1970 0.2-6.3 Cement shingle, millboard, gasket 3 plants 1966-1970 0.1-4.4 SOURCE: NIOSH (1972). collected in 1964-1971 (NIOSH 1972). The table indicates that the highest concentrations were observed in the textile and insulation industries but also that levels of exposure varied considerably between and within indus- tries. Thus, exposure cannot be estimated with any certainty on the basis of descriptions of exposure situations. The report by Dement et al. (1983) provides a useful example of vari- ability of exposures within an industry. In a large US textile-manufacturing facility, exposures were highest in the 1930s and 1940s and generally, al- though not uniformly, decreased through the 1970s with the introduction of technologic changes. Concentrations varied among departments by as much as an order of magnitude. In the 1930s, mean concentrations in some areas of fiber preparation were up to 78 f/ml and other areas, such as spin- ning, had means below 10 f/ml. A similar range of exposures has been reported for the textile industry in Italy (Pira et al. 2005) and in England (Peto et al. 1985). Concentrations in the mining and milling industries have been similiar to those in manufacturing. For example, in the mid 1960s, mean exposures of 20-100 f/ml were reported at the Wittenoom crocidolite mines and mills in Western Australia; they may have been higher in earlier decades (Armstrong et al. 1988, Reid et al. 2004). Exposures in a similar range have been reported in Quebec (Gibbs and LaChance 1974); Libby, Mon- tana (Amandus et al. 1987); and South Africa (Sluis-Cremer et al. 1992). Exposure levels of end-users of asbestos are less well documented, at least historically, but appear to be lower when considered as time-weighted averages. Insulation workers constitute a group with potentially high expo- sures. Although Selikoff et al. (1979) anecdotally reported exposures of 4- 12 f/ml, the National Institute of Occupational Safety and Health (NIOSH 1972) reported individual exposures of 0 up to 100 f/ml when shorter-term

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66 ASBESTOS exposures were considered. Insulation workers engaged in ship building and repair, in which mean exposures may have been as high as 30 f/ml (NIOSH 1972), are of particular concern. Other end-users may have had lower exposures. For example, Corn et al. (1994) reported means during various maintenance activities of 0.008-0.061 f/ml, and other studies have observed similar, highly variable levels of exposure (ATSDR 2001). Mean levels of exposure during asbestos abatement have been measured at 0.006 to 0.76 f/ml (TEM) depending on the material being removed (ATSDR 2001). However, it is important to note that short-term exposures could be quite high. Limits considered acceptable for occupational exposure have dropped over time. The American Conference of Governmental Industrial Hygien- ists first proposed a Threshold Limit Value (TLV) of 5 mppcf in 1946 (ACGIH 1998). However, historical sampling data show that many indus- tries did not adhere to that guideline (for example, see Amandus et al. 1987, Dement et al. 1983, Hughes et al. 1987). With the wider recognition of the hazards of asbestos and the regulatory response, exposures rapidly de- creased in the industrialized countries. Reductions in exposure due to im- proved technology have been well documented. An example from the US textile industry is presented in Table 4.2; Dement et al. (1983) converted older measures in mppcf to f/ml using paired samples collected at the same facilities. NIOSH (1972) documented decreasing exposure in many indus- tries. Others noted further dramatic reductions of workplace concentra- tions in the early and mid 1970s in North America and Europe. For example, mean exposures in the Quebec mining industry declined from 16 f/ml in 1973 to less than 2 f/ml by the late 1970s (LeBel 1995). TABLE 4.2 Estimated Mean Concentrations (# fibers over 5 mm per ml, PCM) in a Chrysotile Textile Plant (1930-1975) Operation Before Controls After Controls Fiber preparation 26.2-78.0 5.8-17.2 Carding 10.8-22.1 4.3-9.0 Twisting 24.6-36.0 5.4-7.9 Winding 4.1-20.9 4.1-8.4 Spinning 4.8-8.2 4.8-6.7 Weaving 5.3-30.6 1.4-8.2 SOURCE: Dement et al. (1983).

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67 EXPOSURE AND DISPOSITION General Population Exposure Earlier National Academies committees have considered non- occupational exposure to asbestos (NRC 1984, 1993). Airborne asbestos fibers can be detected and measured in the general, ambient environment even far from industrial sources. The sources include disturbed natural deposits, improper disposal or transportation of asbestos- containing wastes, and uses that result in friable asbestos, such as motor- vehicle brake pads. Although exposure from undisturbed natural sources is possible, it has not been documented. Concentrations measured in outdoor air are highly variable, ranging from below the limit of detection (0.1 ng/ m3, and estimated to be equivalent to about 0.000003 f/ml as measured with PCM) in rural areas to over 100 ng/m3 (about 0.003 f/ml, PCM) near industrial sources. In rural areas, typical concentrations are about 0.00001 f/ml (PCM), while urban measurements are typically higher (up to about 0.0001 f/ml, PCM) (ATSDR 2001). Higher concentrations have been documented in communities near asbestos-related industries. Table 4.3 presents concentrations measured near asbestos manufacturing facilities in Taiwan (Chang et al. 1999). Although concentration appears to drop off with distance, the decreases are not dra- TABLE 4.3 Asbestos Concentrations in Ambient Air Around Taiwanese Factories GM (GSD) Asbestos Concentration (f/ml) Distance from Factoryb Factory No. of Methoda Type Factories 200 m 400 m 600 m Cement 5 TEM 0.006 (1.230) 0.007 (1.487) 0.006 (1.301) PCM 0.01 (3.49) 0.01 (2.91) <0.01 Friction 3 TEM 0.008 (2.441) 0.008 (1.978) 0.002 (2.221) PCM 0.01 (3.22) 0.02 (2.88) <0.01 Textile 2 TEM 0.012 (2.221) 0.020 (1.432) 0.006 (1.765) PCM 0.02 (3.21) 0.02 (3.33) <0.01 Ground tile 2 TEM 0.033 (1.412) 0.021 (1.421) 0.025 (2.321) PCM 0.4 (3.21) <0.01 0.01 (2.21) Insulation 1 TEM 0.012 (2.321) 0.020 (2.210) 0.006 (2.773) PCM <0.01 <0.01 <0.01 Refractory 1 TEM <0.0001<0.0001 <0.0001 PCM <0.01 <0.01 <0.01 aTEM = transmission electron microscopy; PCM = phase contrast microscopy. bGM = geometric mean; GSD = geometric standard deviation. SOURCE: Chang et al. (1999).

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68 ASBESTOS matic out to at least 600 m, indicating that the fibers remain airborne. Higher concentrations have been measured historically near asbestos- related open-pit mining and milling operations. For example, in towns near open-pit chrysotile mines in the Canadian province of Quebec, concentra- tions as high as 0.08 f/ml were measured in the early 1970s, although cur- rent concentrations are much lower (Case and Sebastien 1987, ICPS 1998). Residential exposure may also occur in communities with asbestos indus- tries from fibers carried home on the clothing or hair of asbestos workers (Anderson et al. 1979, Case and Sebastien 1989). Asbestos has been measured in the air inside many public and noncom- mercial buildings (HEI 1991). Sources of fibers released into the indoor air of non-industrial buildings include asbestos insulation, dry wall, ceiling and floor tiles, and materials used primarily for fireproofing. Exposures may occur by disturbance of asbestos-containing materials that are not well en- capsulated (HEI 1991). Nicholson (1987) reported concentrations in build- ings from about 0.00003 to 0.006 f/ml (PCM). In a survey of 94 public buildings, EPA (1988) reported concentrations ranging from below the limit of detection to about 0.003 f/ml (PCM), with a mean of 0.0004 f/ml (PCM). Population exposure may also occur through the consumption of as- bestos in drinking water. Asbestos may enter drinking water from erosion of natural deposits, mining operations, or asbestos-containing cement pipes (ATSDR 2001). Although most areas have concentrations less than 103 f/ml (PCM), much higher concentrations have been observed, some over 105 f/ ml (EPA 1976, Kanarek et al. 1980, Sigurdson et al. 1981). DOSIMETRY Introduction For inhaled contaminants, such as asbestos fibers, concepts of exposure and dose have been developed for the respiratory system. Asbestos fibers are particulate matter that is distinguished from other particles present in air by having a length substantially greater than their width. Aspect ratio is the term used for the ratio of length to width. The Occupational Safety and Health Administration defines a fiber as having a length of at least 5 mm and an aspect ratio of 3:1, whereas EPA defines a fiber as having an aspect ratio of over 5:1 (ATSDR 2003). Airborne particles are generally character- ized by their aerodynamic diameter, which is determined in reference to the behavior of a sphere of unit density; the aerodynamic diameter corresponds to the size of a unit-density sphere with the same aerodynamic characteris- tics as the particle of interest. Much has been learned about particle size and the handling of particles by the respiratory system from experimental findings and the use of phys-

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69 EXPOSURE AND DISPOSITION ical models of the lung. The mechanisms responsible for particle and fiber deposition are impaction, sedimentation, interception, and diffusion (Asgharian and Yu 1988). Aerodynamic diameter is a key determinant of the likelihood of deposition in the respiratory tract and the site of deposi- tion (see Figure 4.1). Particles greater than 10 µm in aerodynamic diameter are generally captured in the upper respiratory tract, the nose and upper airway, whereas smaller particles can penetrate more deeply and reach the airways and alveoli of the lungs. Particles smaller than about 2.5 µm have a greater likelihood of reaching the alveoli and depositing in this region. Ultrafine particles (less than 0.1 µm) also deposit heavily in the nose. These same considerations apply to inhaled fibers, which can have a range of aerodynamic diameters, depending on size and physical characteristics. In considering the potential risk posed by inhaled pollutants, including fibers, the critical determinant of injury is the amount of material that reaches the target site—a measure generally referred to as the biologically effective dose. As depicted in Figure 4.2, dose, without qualification, gener- FIGURE 4.1 Effect of aerodynamic diameter on deposition of particles in the respiratory tract. SOURCE: ICRP (1994).

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70 ASBESTOS Exposure Initial Cumulative Development Adverse Internal Biologic of Structural Health Effects Effective Dose Dose and Functional Changes FIGURE 4.2 Exposure and dose-response paradigm in toxicology. SOURCE: Modified from Lippmann (1992). ally refers to the amount of material that enters the body; exposure refers to the amount of contact with material, with units expressed as concentration multiplied by time. For the respiratory system, models have been developed that relate dose to exposure for inhaled particles (Jarabek et al. 2005); the models are useful in characterizing the chain that begins with the source of an inhaled pollutant and terminates with injury to target tissues. Various processes remove particles that are deposited in the lung in ways that depend on their size, physicochemical characteristics, and site of deposition (Table 4.4). Particles that reach the upper airways will generally be removed as mucus is swept toward the nostrils or into the pharynx for passage through the esophagus and the gastrointestinal tract. Particles reach- ing the bronchi are cleared by the mucociliary apparatus, which moves mucus toward the trachea, where it exits and is swallowed. Particles that reach the smaller airways are gradually scavenged by the lung’s macro- phages; their fate depends on their toxicity to the macrophages. Particles may also penetrate the respiratory epithelium and remain in the airways or migrate to bronchopulmonary lymph nodes. Experimental studies show that particles in the ultrafine fraction (less than 0.1 µm in aerodynamic diam- eter) may be moved across the barriers posed by the respiratory epithelium and the alveolar-capillary membrane and be disseminated systemically (Oberdörster et al. 1983). TABLE 4.4 Mechanisms of Fiber Clearance from the Lungs Physiological clearance processes of deposited fibers • Mucociliary movement • Scavenging by alveolar macrophages • Interstitial translocation • Lymphatic clearance Physicochemical processes reducing fiber burden • Leaching • Dissolution • Breakage SOURCE: Modified from Bernstein et al. (2005).

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71 EXPOSURE AND DISPOSITION Fiber dimensions are thought to be important in the pathogenesis of asbestos-related lung diseases (reviewed in Bernstein et al. 2005). Long as- bestos fibers are deposited by interception primarily at sites of bifurcations in the conducting airways of the lower respiratory tract (Asgharian and Yu 1988). It is postulated that long asbestos fibers (greater than the diameter of alveolar macrophages about 10-15 µm in rodents and about 14-21 mm in humans) are less likely to be completely phagocytized and are cleared more slowly (reviewed in Bernstein et al. 2005). Fibers that are not removed rap- idly by the mucociliary escalator may penetrate into the interstitium of the alveolar walls, be cleared by lymphatic channels, or migrate to the pleura and other extra pulmonary sites. Fibers that are not effectively cleared from the lung may be removed by physicochemical processes, including leaching of ions, dissolution, and breakage (see Chapter 3). Those processes could occur extracellularly in the lung-lining fluid or intracellularly in the phago- lysosomal compartment of alveolar and interstitial macrophages. In gen- eral, fibers that are long and persistent in the lungs have been shown to be associated with fiber-induced lung disease in animal models (Hesterberg et al. 1996, 1998). The physicochemical properties of asbestos fibers described in Chapter 3 influence the susceptibility of different fiber types to leaching, dissolution, and breakage in the extracellular compartment at neutral pH or in the phagolysosome at acidic pH. In general, amphibole asbestos fibers are more persistent than chrysotile asbestos fibers. In contrast with studies of fiber deposition in the lower respiratory tract, little is known about fiber deposition and clearance from the upper respiratory tract, particularly the larynx. A recent study by Zhou and Cheng (2005) modeled deposition of carbon fibers with laryngeal casts and pre- dicted that a fraction of inhaled fibers would be deposited in the larynx, especially at the higher ventilation rates associated with moderately heavy work. Gemci et al. (2001) modeled airflow in the larynx by using drug sprays and predicted turbulent flow at the laryngeal constriction. As is seen in the lower airways of cigarette smokers, tobacco-smoking and other causes of chronic laryngeal irritation might impair clearance of fibers from the laryngeal mucosal surfaces. Considerations for Inhaled Asbestos Fibers Extension of the general models and definitions to inhaled asbestos fibers provides a framework for considering exposure and the dosimetry of asbestos fibers in the respiratory tract. The exposure measures used in the epidemiologic studies can be considered in the context set by this frame- work. In the committee’s judgment, the most relevant dose measure for cancer is probably the cumulative number of fibers that reach and persist in the target organ, and the biologically effective dose would be related to

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72 ASBESTOS fibers that interact with target cells. Such measurements are not available, but the epidemiologic studies have not incorporated any attempt to esti- mate dose, for example, by considering the size distribution of the fibers or the activity of the workers. Instead, a variety of indexes of exposure have been used, ranging from crude indicators of potential for contact to more refined, semi-quantitative measures. Dose refers to the amount of material potentially available for deposi- tion in the respiratory tract—in this instance, the number of fibers in the air inhaled by the exposed person. Only some fraction of that dose is depos- ited, and much will be exhaled or cleared. However, studies of lung tissues of asbestos-exposed people show that fibers are retained in the lung and that long, thick fibers are coated with iron, protein, and mucopolysaccha- rides to form asbestos bodies (ABs) visible with light microscopy (Roggli 2004). ABs have also been documented in other tissues, although their pres- ence may reflect contamination occurring during handling and processing of specimens. For nonrespiratory organs, concepts of dose are not well developed and related experimental and observational data are limited. For the organs of the gastrointestinal tract (esophagus, stomach, and intestines), fibers cleared from the respiratory tract will move through, with the potential for interac- tion with target cells in the epithelium. For other abdominal organs (includ- ing the liver, pancreas, and kidneys), the routes of movement are uncertain, although fibers have been found in those organs on occasion (Borow et al. 1973, Pooley 1974). Translocation to the Pleura After inhalation, asbestos fibers that deposit in the alveolar region of the respiratory tract may be cleared or retained (Figure 4.3). Fibers that persist in the alveolar region may be directly toxic to alveolar epithelial cells or incite a chronic inflammatory response that perpetuates tissue injury followed by episodes of epithelial cell proliferation and fibrosis (Oberdörster 1996). It has been proposed that fibers that penetrate the alveolar lining and enter the interstitium may move to lymphatics and regional lymph nodes. Asbestos fibers that accumulate in subpleural lymphatics may pro- duce diffuse visceral pleural fibrosis and pleural effusions, directly and indi- rectly (Churg 1988). Asbestos-induced pleural effusions are hypothesized to be caused by cytokines (such as interleukin-8) released from mesothelial cells that trigger inflammation and fluid accumulation in the pleural space (Boylan et al. 1992). Inhaled particles could reach the pleural space after direct transpleural penetration, lymphatic translocation, or indirect trans- port by the blood (Holt 1981, Lee et al. 1981, Oberdörster et al. 1983). Recent studies in hamsters of inhaled refractory ceramic fibers (mean

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73 EXPOSURE AND DISPOSITION Exposure to airborne fibers Deposition in respiratory tract Alveolar region Tracheobronchial region effective Mucociliary clearance AM mediated clearance impaired impaired AM activation: release of mediators Cytotoxicity oxidants, growth chemotactic Gastrointestinal proteases factors factors tract ? Carcinoma Epithelial damage, proliferation Lymph clearance, Interstitial access Inflammatory tissue migration to fibers cell recruitment Interaction with Interaction with epithelial cells pleural cells IM uptake and Stimulation of inflammation activation fibroblasts Bronchogenic carcinoma Pleural fibrosis and plaques Pleural mesothelioma Lung fibrosis FIGURE 4.3 Translocation of inhaled asbestos fibers and adverse health effects. AM = alveolar macrophage, IM = interstitial macrophage. SOURCE: Modified from Oberdörster (1996). length, 20 µm; mean diameter, 1 µm) confirmed rapid translocation of short fibers to the pleural space, followed by inflammation and mesothelial cell proliferation (Gelzleichter et al. 1996a,b). Few investigators have quantified the mineral-fiber burden in human pleura, but several investigators have found asbestos fibers in the pleural lining of people exposed to asbestos fibers (Dodson et al. 1990, Gibbs et al. 1991, Sebastien et al. 1977, Suzuki and Yuen 2001). Boutin et al. (1996) obtained samples of parietal pleura and lung from workers exposed to as- bestos and counted asbestos fibers in dried tissue samples. Anthracotic par- ticles, as well as asbestos fibers, were detected near lymphatic openings on the surface of the parietal pleura. Scanning electron microscopy of these “black spots” revealed focal accumulation of inflammatory cells. The in- vestigators directly visualized black spots with video-assisted fiber-optic thoracoscopy; previous investigators had not been able to identify asbestos fibers in pleural samples, because they sampled tissues at random (Boutin et al. 1996). Identification of particles and fibers at sites of lymphatic drainage on the parietal pleura suggests that local transpleural or lymphatic translo-

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74 ASBESTOS cation is likely. Boutin and Rey (1993) have also diagnosed early cases of malignant mesothelioma arising on the parietal pleura; they speculated that focal trapping of long asbestos fibers at sites of lymphatic drainage from the pleura may provoke the development of mesothelioma. The potential rel- evance of fiber dimensions in induction of cancer at the sites under consid- eration is unknown. Extrapulmonary Translocation It has long been postulated that systemic dissemination of fibers occurs after retrograde transport via lymphatics and the bloodstream (Holt 1981, Lee et al. 1981, Taskinen et al. 1973). In addition, particle movement from the lungs to tracheobronchial lymph nodes by pulmonary alveolar mac- rophages has been documented in a canine model (Harmsen et al. 1985). Asbestos fibers that are cleared from the lower respiratory tract by the mucociliary escalator can be swallowed from the pharynx and gain access to the upper and lower gastrointestinal tract. It has also been proposed that fibers could penetrate the gastrointestinal mucosa, submucosa, and muscle layers and reach the peritoneal cavity (Selikoff et al. 1979). Cunningham and Pontefract (1973) analyzed samples of drinking wa- ter and various beverages with electron microscopy and detected chrysotile asbestos fibers. To determine whether ingested asbestos fibers could dis- seminate systemically, they instilled a preparation of short chrysotile asbes- tos (0.5-2 µm long) in the stomach of rats and sacrificed them after 2-4 days. Using precautions to prevent contamination during necropsy, they sampled blood from the retroorbital plexus, spleen, omentum, heart, brain, and lungs and detected a substantial number of asbestos fibers; the highest concentration was in the omentum (Cunningham and Pontefract 1973). More recent chronic feeding studies conducted by the National Toxicology Program (HHS 1983, 1985, 1988, 1990a, 1990b, 1990c) did not identify any asbestos bodies using light microscopy at the following sites: larynx, lymph nodes, esophagus, stomach, small intestine, colon, cecum, and mesentery (McConnell 2005). Lee et al. (1981) conducted a subchronic inhalation study with inor- ganic titanate fibers in hamsters, guinea pigs, and rats and reported fibers and multinucleated giant cells widely disseminated throughout the body, including mediastinal lymph nodes, adipose tissue, spleen, liver, Peyer’s patches in the intestine, and the mucosal, submucosal, and muscular layers of the gastrointestinal tract. Tissue responses were minimal except for mild inflammation and fibrosis in the epicardium. Cook and Olson’s (1979) demonstration of asbestos in human urine, which abated when drinking water was filtered, provides substantial evi- dence that fibers enter into systemic circulation.

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75 EXPOSURE AND DISPOSITION Case reports based on human autopsies have noted the presence of asbestos fibers or ABs in abdominal organs, including the spleen, abdomi- nal lymph nodes, liver, omentum, and mesentery (Borow et al. 1973, Dodson et al. 2000, Pooley 1974, Suzuki and Yuen 2001). ABs have also been recovered from sites under consideration by this committee: larynx, esophagus, stomach, and small and large intestines (Roggli 2004). Several caveats must be considered, however, in evaluating reports of asbestos fiber translocation to extrapulmonary sites. A taskforce of the European Respi- ratory Society (De Vuyst et al. 1998) prepared guidelines for mineral-fiber analyses in biologic samples focusing on the tissues involved in asbestosis, lung cancer, and mesothelioma, but the principles are in large part appli- cable to techniques that would be used to determine fiber presence in the selected sites considered in this review. First, electron microscopy (EM) is necessary to detect most asbestos fibers, with transmission EM being pref- erable to scanning EM, but light microscopy is adequate for visualizing ABs; limits of detection should be reported. Second, asbestos fibers and ABs can be identified in lung tissue in most people in the general population, even people who have with no occupational history of asbestos exposure and in the absence of clinical or pathologic evidence of lung disease, mean- ing that comparison with appropriate controls is essential (De Vuyst et al. 1998). Third, cross-contamination of tissue samples with fibers or particles from surgical gloves, specimen containers, fixatives, scalpel blades, and other organs collected in the surgical or autopsy suite is a serious concern (Cook 1983, De Vuyst et al. 1998; Roggli 2004). Those caveats should be considered in evaluation of the published papers. In two of five cases, Roggli et al. (1980) found ABs in laryngeal tissues gathered at autopsy from asbestos workers with known pulmonary disease. ABs were not recovered, however, from laryngeal tissue from ten autopsies controls. Auerbach et al. (1980) used light microscopy to detect ABs in paraffin- embedded tissue samples obtained at autopsy from the lungs and kidneys of a series of 37 cases recorded as having asbestosis, mesothelioma, or pleural plaques. ABs were observed in the lung sections of all but one of these cases and in 38% of the kidney samples. Other organs were available from a subset of these cases. Of the organs for which at least 30 samples were available (heart, liver, spleen, adrenal glands, and pancreas), ABs were de- tected in 32-62% of cases. Of organs with fewer samples available, stom- ach, duodenum, and colon were among those in which ABs were found; the others with positive findings were brain, prostate, thyroid, mediastinal lymph nodes, bone, omentum, and spinal cord. The prevalence of ABs in other organs reflected the number of asbestos fibers found in a case’s lung sample. Kobayashi et al. (1987) performed a similar analysis on formalin-fixed

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76 ASBESTOS tissues from 26 subjects. Esophagus, stomach, and both large and small intestine were among the 13 extrapulmonary organs from which tissues were examined. ABs were detected in some samples from all these organs, and the pattern corresponded with the degree of a given subject’s pulmo- nary burden. The number observed was high for the esophagus. Roggli (2004) noted that the reported results would be consistent with contamina- tion by pulmonary ABs via formalin. Kambic et al. (1989) examined a cohort of 195 asbestos-cement factory workers and controls in Yugoslavia. Chronic laryngitis was found more frequently in workers than in controls; in 10 workers, biopsies showed changes consistent with hyperplastic chronic laryngitis. Chronic laryngitis was diagnosed clinically in asbestos workers who were nonsmokers or former smokers, as well as in current smokers. Four of the biopsies were examined with scanning EM, and asbestos fibers were observed on the epi- thelial lining in three. Ehrlich et al. (1991) determined colonic asbestos burdens with light and electron microscopy in 44 asbestos workers with colon cancer. Chryso- tile fibers, amosite fibers, or ABs were identified in the colonic wall in 32% of workers. In contrast, no asbestos fibers or ABs were found in 20 patients who had colon cancer but no history of asbestos exposure. In addition to technical concerns about reported findings of fibers or ABs in extrapulmonary tissues, there are uncertainties that should be borne in mind when interpreting their biologic meaning. The fact that fibers found in tissues are predominantly amphibole, even when the individual’s expo- sure is documented to have been exclusively to chrysotile with a slight tremolite component, is fully in accord with what is understood about the relative biopersistence of those fiber types (Churg 1994). In the upper respi- ratory or gastrointestinal tract, are epithelial injury and chronic inflamma- tion (for example, secondary to tobacco-smoking, alcohol use, or persistent bacterial or viral infections) a prerequisite of accumulation of fibers and development of cancer at these sites? Finally, the finding of asbestos fibers or ABs in tissue samples obtained from gastrointestinal tract tumors raises the question of the causal significance of this observation: do the fibers accumulate secondarily at sites of mucosal damage or ulceration associated with a growing tumor? Few studies have systematically sought evidence of asbestos fibers in the particular extrapulmonary sites of interest in this review, and such in- vestigations are subject to technical difficulties. Nonetheless, there is some documentation that asbestos fibers may disseminate and persist at these selected tissue sites, although not with the regularity that has been estab- lished for the lungs, pleura, and lymph nodes.

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