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6 Laboratory Studies of the Effects of Asbestiform Fibers .! This chapter describes experimental studies that have elucidated some biological effects of asbestiform fibers and their interactions with cells. STUDIES IN ANIMALS In humans, inhalation of asbestos is associated with increased risks of lung tumors (bronchogenic carcinoma and peripheral adenocarcinoma), pleural and peritoneal mesotnelloma, 1ncers~al pulmonary fibrosis (asbestosis), pleural thickening, and possibly other tumors, including those of the gastrointestinal tract and kidney. Investigators have induced lung tumors, mesothelioma, and fibrosis after administration of asbestos to animals. This section a''mmarizes the results of toxicological studies in an attempt to determine whether (1) certain physicochemical properties of asbestos are important in the induction of disease and whether (2) other asbestiform fibers exhibit pathogenic potential in animals. Lung Cancer ~. ~_ ~ ~ ~ In the lung, malignant tumors arise from the bronchial or alveolar epithelial Celia and are classified according to their histological features (e.g., squamous cell carcinoma or adenocarcinoma; Small or large cell carcinoma). Although small numbers of these types of tumors appear in rats after inhalation (Appendix F. Table F-1) or intratracheal instillation of asbestos and chemical carcinogens (Appendix F. Table F-2), benign (papilloma, adenoma) and malignant (fibrosarcoma) tumors uncommon to humans occur more frequently. In general, results are difficult to evaluate because of different experimental protocols (e.g., Amounts of dusts, exposure regimens, different species or strains). For example, in inhalation studies conducted by Davis et al. (1978, 1982), Wagner et al. (1974, 1982a), and Bozelka et al. (1983) asbestos concentrations of approximately lO mg/m3 of air were used, whereas Reeves and colleagues (1971, 1974, 1976) used concentrations approximately fivefold higher. 165

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166 Another shortcoming is the lack.of dose-response information at various concentrations of asbestos. With the exception of Davis et al. (1978) and Lee et al. (1981), all in~restigators have used orgy one concentration of dust. The different size distributions of fibers in these studies also present problems to those attempting to compare the pathogenic potential of different types of asbestos. For example, inhalation studies by DaVi8 et al. (1978) (Appendix , Table Fit) demonstrated that clouds of ZErysotile contain many more fibers longer than 20 Am than are found in aerosolized amphiboles. This phenomenon could account for the greater tumor incidence observed after exposure to chrysotile in these experiments. However, despite these general limitations in interpretation, data in Appendix F. Tables F-l and F-2 support the for owing conclusions: I. The development of lung cancers in rodents after inhalation of asbestos is specie~-specific. For example, rats and mice develop both benign and malignant neoplasms, whereas hamsters, guinea pigs, and rabbits develop only benign neoplasms (Botham and Holt, 1972a,b; Gardner, 1942; Gross et al., 1967; Reeves et al., 1974; Vorwald et al., 1951; Wagner, 1963~. In the few studies conducted in cats (Vorwald et al., 1951) and monkeys (Wagaer, 1963; Webster, 1970), fibrosis but no tumors developed. Thus, cats and monkeys seem to be inappropriate animal models for studies of asbestos-liDked carcinogenesis. 2. Small numbers of benign and malignant lung tumors have been observed after inhalation of all types of asbestos (Appendix F. Table F-1). The short lifespan of rodents may not allow sufficient time for development of larger numbers of tumors. 3. A striking increase in the number of neoplasm has been observed after rodents were exposed by instillation to a combination of asbestos and chemical carcinogens such as polycyclic aromatic hydrocarbons (PAHs). Thus, asbestos appears to act synergistically with PAN to induce lung tumors (Appendix F. Table F-2~. 4. For unexplained reasons, a synergistic effect has not been observed in rats exposed to both asbestos and cigarette smoke by inhalation (Shabad et al., 1974; Wehner et al., 1975~; however, development of fibrosis in these ~nima\B leads to reduced lifespan. 5. When asbestos is inhaled by rats simultaneously with the intratracheal instillation of sodium hydroxide, a caustic agent affecting mucociliary clearance, an increase in the number of tumors has been observed (Gross et al., 1967~. The sodium hydroslde pres''-=bly leads to a greater retention of asbestos in the respiratory tract. 6. Several types of man-made mineral fibers (MMMFa) have been evaluated in inhalation studies. Among the fibers studied are fibrous glass (Gross 1974; Gross et al., 1970; Lee et al., 1981; Moorman, in press; Schepers and Delahant, 1955; Schepers et al., 1958) and insulation (Morrison et al., 1981~; alumina (Piggott et al., 1981~; glass wool, rock

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167 wool, and glass microfibers (Wagner et al., 1982a); ceramic aluminum silicate glass (CASG) (Davis et al., 1982~; and potassium titanate, i.e., Fybex and pigmentary potassium t~tanate (PKT) (Lee et al., l9Bl). In comparison to the various types of asbestos included as positive controls in many of these studies, these fibers are generally less carcinogenic. Tumors have been reported after exposure to CASG (Davis et al., 1982~. Results with fibrous glass vary (see footnote to Table F-1 in Appendix F.). Lee et al. (1981) produced two malignant lung tumors in hamsters exposed to potassium octatitanate fibers and bronchogenic tumors in rats with use of fine fiber glass. No malignant tumors were produced in hamsters, rats, or guinea pigs inhaling ball-milled fiberglass. Wagner et _ . (1982a) reported Small numbers of lung cancers in rats exposed to glass wool, rock wool, and glass microfibers by inhalation and no cancers in control animals, whereas in comparable studies, McConnell _ al. (1982) did not detect such an increase. 7. In comparison to amosite asbestos, more bronchogenic tumors developed in rats after intratracheal instillation of ferroactinolite--an unusual and impure asbestiform fiber (Coffin et al., 1982; Cook et al., 1982~. Ferroactinolite appears to undergo longitudinal splitting as a result of dissolution in the respiratory tract, thereby producing an increased dose of extremely thin fibers. When the animals were exposed to nonfibrous grunerite, no carcinomas were observed. Mesothelioma Pleural and peritoneal mesotheliomas originate in the serosal cells lining the body cavities occupied by the lungs and digestive organs, respectively. They occur in small numbers after inhalation of asbestifo~m fibers by animals, but in larger numbers after intrapleural and intraperitoneal injection of the fibers. The injection technique has been used most frequently in reported studies because of its reproducibility. However, injection of fibers bypasses normal lung clearance mechanisms and is criticized as a nonphysiological method of exposure. Table F-3 in Appendix F summarizes the results of experiments in animals injected with asbestiform fibers. From these data and the results of inhalation studies (Table F-1 in Appendix F), the following observations can be made: 1. Mesotheliomas have been observed in rats after injection of all types of asbestos and a number of nonasbestos fibers, including fibrous glass, ceramic fibers, attapulgite (palygorskite) from the USSR, brucite, and erionite. Fewer mesotheliomas occurred in rats after inhalation of UICC chrysotile, amosite, and crocidolite, but none appeared after inhalation of respirable fibrous glass, alumina, and ceramic aluminum - silicate glass fibers. 2. The incidence of fiber-induced mesothelioma in hamsters is lower than in rats and in mice, but tumors appear earlier, perhaps because of the shorter lifespan of the hamster.

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168 3. Tumor response was related directly to the dosage of fiber administered in experiments by Smith and Hubert (1974) and by Wagner et al. (1973~. Other investigators (e.g., Pott and Friedrichs, 1972; Stanton and Wrench, 1972) have not observed such dose-response relationships. 4. Exposure to either long (>10 ~m) or short (milled) fibers results in the appearance of mesotheliomas. Nonfibrous particles, including cleavage fragments, do not generally cause tumors (see Appendix F.). 5. Alteration of crocidolite by leaching (a process that can cause fragmentation of fibers) reduces its ability to cause mesothelioma (Monchaux et al., 1981; Morgan et al., 1977), but removal of PAR or trace metals toes not affect the deve Shipment of tumors (Wagner et al., 1973~. 6. In studies to evaluate various injected samples, no one type of asbestos has appeared to be more pathogenic than others (see Appendix F). Wagner (1982) has reported erionite from Oregon readily induces mesotheliomas in rats by inhalation or injection. 7. Inhalation of potassium octatitanate fibers (average size 6.7 x 0.2 ~m) produced three mesotheliomas in 59 hamsters surviving 21 months or more. No such tumors were produced in guinea pigs and rats exposed to these fibers, or in smaller numbers of rats, guinea pigs, and hamsters inhaling amosite asbestos or ballimilled fiberglass (Lee et al., 1981~. Fibrosis _ Asbestos-associated fibrosis is an irreversible disease characterized as an excessive deposition of fibrous tissue. Thin cellular response is thought to occur as a reparative or reactive process. All types of asbestos cause pulmonary fibrosis of the lung (also called pulmonary interstitial fibrosis, or PIF) after relatively long periods of administration (Appendix F. Table F-4~. A range of morphological alterations are observed after exposure to other fibers. The important features of these experiments can be summarized as follows: 1. There are species and strain differences in fibrogenic response. After inhalation of chrysotile by rats, guinea pigs, and mice, granulomas (distinctive focal lesions formed as the result of an inflammatory reaction) and focal fibrosis have been observed in the rat and guinea pig but not in the mouse (Reeves et al., 1974~. Moreover, studies by Lee et _. (1981) show a direct relationship between tosage of fibers and development of fibrosis in the rat, whereas less prominent changes occur in the hamster and guinea pig. 2. Studies with fibrous glass in a diversity of size ranges suggest that responses are minimal in comparison to those induces by asbestos of comparable dimensions. Morphological changes in exposed animals include

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169 At, . . 3` mild microphage infiltration without fibrosis (Gross et al., 1970; Moorman, in press), minimal peribronchiolar fibrosis (Kuschner and Wright, 1976), alveolitis (inflammation of the alveoli) (Begin et al., 1982), and alveolar proteinosis (alveolar accumulation of granular proteinaceous material) fine et al., 1979~. No abnormal pathology has been observed with use of fibrous glass in inhalation experiments by Lee _ al. (1981), Schepers (1959), and Schepers et al. (1958~. 3. Inhalation and pleural injection studies implicate the increased fibrogenic potential of longer (~10 ~m) fibers of both asbestos and fibrous glass. Hinimal or no change has been observed after exposure of animals to smaller fibers or particles of chrynotile (Gardner, 1942), other types of UICC asbestos (Vorwald et al., 1951), fibrous glass, arid a Pathetic fluoro~amphibole (Kirchner and Wright, 1976~. 4. Other fibers evaluated in rodents by inhalation include alumina, which produced no fibrosis (Piggott et al., 1981~; PKT and Eybes, which caused fibrosis, but to a lesser extent than amosite (Lee et al., 1981~; and ceramic aluminum silicate glass, which induced alveolar proteinosis (Davis _ al., 1982~. These fibers tended to fall within the same size dimensions as asbestos. 5.^ Davis and Coniami (1973) evaluated pleural fibrosis in mice after injection of the material resulting from heating chrysotile to temperatures exceeding 600C. Compared with control material, fiber length was reduced and the fibrotic changes in animals diminished. 6. Pleural plaques have not been observed in laboratory animals after exposure to asbestos (Craighead and Mosaman, 1982~. A number of investigators have attempted to induce gastrointestinal tumors in animals by administering oral dosen of asbestos (Gross et al., 1974; Smith et al., 1965, 1980a; Workshop on Ingested Asbestos, 1983~. Thus far, these studies have yielded negative results, as have three National Toxicology Program bioassays (McConnell en al., 1983 a,b). Moreover, asbestos was not found to be cocarcinogenic when administered to rats with azoxymethane-~a documented intestinal carcinogen (Ward et al., 1980~. After being ingested by rodents, asbestos has been observed in mucosal cells of the gut (Westlake et al., 1965~. In guinea pigs, epithelial injury has been observed (Jacobs et al., 1978) but erosion and degenerative changes regressed by 24 hours after administration of an oral 500-mg dose (Sasena et al., 1982~. The acid environment of the stomach and the secretion of mucin by gastrointestinal cells could contribute to the modification of fibers as a result of the leaching or adeorbance of mucin. Moreover, the rat gut may be resistent to asbestos. Studies by Reiss et hi. (1980b) show that asbestos is toxic to intestinal and colonic cells in culture. Lea chiming of chrysotile in ~ N hydrochloric acid ameliorates cytotosicity.

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170 IN VITRO SAVVIES Investigators using suspensions of red blood cells (RBCs), monolayers of cells, and organ cultures have contributed to the understanding of the mechaniams by which cytotoxicity and carcinogenicity are induced by asbestiform fibers. Results of these studies have been discussed in various proceedings and reviews (e.g. , Brown et al. , 1980; Harington et al., 1975; Mossman and Craighead, 1981; Mossman et al., 1983a). The types of studies and experimental information of most importance In elucidating the interactions of fibers with cells are summarized below. Hemolytic Assays The mechanisms of particle-induced cytotoxicity are complex. A critical part of this process appears to be the ability of particles and fibers to bind to ant damage cellular membranes (Chamberlain et al., 1982; Craighead et al., 1980; Harington et al., 1971, 1975; Jaurand et al., 1979a, 1980; Woodworth et al., 1982~ The disruption of the membranes can result in hemolysza, which is the leakage of hemoglobin from the RBCs. Hemolysis can be quantified spectrophotometrically and often is used to define: mechanisms of membrane damage by particles (Chamberlain et al., 1982; Craighead et al., 1980; Desai et al., 1975; Jaurand et al., 1979a, 1980; Harington et al., 1971, 1975; Light and Wei, 1977a,b; Manyai et al., 1969; Zitting and Skytta, 1979) and the fibrogenic potential of particles (Hefner and Gehring, 1915~. The degree of hemolysis by particles, however, does not correlate directly with their fibrogenic or carcinogenic effects. The hemolytic activity of fibers relates to physicochemical properties such as size (Schnitzer and Pundsack, 1970), magnesium content (Harington et al., 1971), crystallinity (Palekar et al., 1979; Zitting and skyeta, 1979), and surface charge (Harington et al., 1971, 1975; Light and Wei, 1977a,b?. A large surface area also facilitates interactions with the RBC membrane. For example, hemolysi~ is enhanced as the number of fibers (Desai and Richards, 1978; Schnitzer and Pundeack, 1970) and the degree of their dispersion (Schnitzer and Pundsack, 1970) increase. Particle shape is not critical since certain fibers, such as crocidolite asbestos and fibrous glass, or particles with sharp edges, such as Carborundum, are only marginally hemolyeic (Harington et al., 1975~. Moreover, some nonfibrous particles, such as montmorillonite, are as hemolytic as chrysotite asbestos (Woodworth et _., 1982). The importance of surface charge in hemolysis by chrysotile and crocidolite has been suggested by Light and Wei (1977a,b). Other investigators have reported that chrysotile is both hemoly~cic and

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4 I 171 cytotoxic in a variety of cell systems, whereas crocidolite is relatively inactive (Chamberlain and Brown, 1978; Miller and Harington, 1972; Mossman et al., 1980b; Woodworth et al., 1982~. The magnitude of the surface charge on the fibers (e.g., chrysotile, +44.5 mV, and crocidolite, -43. 5 my, in distilled water, as measured by their zeta potential) 1 is directly related to their hemolytic potential. For example, when chrysotile fibers are leached in acid, their zeta potential decreases as does their hemolytic activity. In contrast, the hemolytic ability of crocidolite increases after leaching as the fibers become more negatively charged. Adsorption of components of surfactant or serum to fibers also renders them less hemolytic (Craighead et al., 1980; Desai and Richards, 1978; Jaurand et al., 1979a; Light and Wei, 1977a). Harington et al. (1971, 1975) hypothesized that negatively charged residues of 8 ialic acid from membrane glycoproteins bind to Poe it ively charged sites on minerals. This ionic interaction might result in the aggregation of integral membrane proteins and leakage of hemoglobin. To test this hypothesis, sialic acid was removed enzymatically from RBCs before hemolysis by chrysotile was measured. The treated RBCs were resistant to hemolysis, suggesting the importance of sialic acid in this process. Experiments with tracheobronchial epithelial cells have suggested that chrysotile also interacts with other carbohydrates on the cell surface (Mossman et al., 1983c). Cytotoxic ity Studies Cytotoxicity is the ability of an agent to interfere with cellular function to the extent that the cell is either damaged or killed. Because asbestos and other particles are believed to play a role in the pathogenesis of respiratory tract diseases, the mechanisms whereby these substances induce cytotoxicity have been investigated in cell culture (Chamberlain et al., 1982; Harington et al., 1975; Mossman et al., 1983a). Although some researchers have attempted to correlate the cy~cotoxicity of fibers with their ability to cause pulmonary fibrosis and mesothelioma (Hefner and Gehring, 1975; Kaw et al., 1982; Wade en al., 1980), the validity of this correlation is not accepted in general, and one must conclude that cytotoxicity is not related directly to pathogenici~cy. For example, crocidolite is less damaging to red blood cells and lees cytotoxic than chrysotile in macrophages and in cultures of tracheobronchial epithelia (Doll et al., 1982a,b; Haugen et al., 1982; Landesman and Mossman, 1982; Miller and Harington, 1972; Mossman et al., 1980b; Woodworth et al., 1982~. Reiss and colleagues (1980a,b) and Wade et al. (1979) have suggested that sensitivity to asbestos differs among Zeta potential in a measure of surface charge. A zeta potential of zero indicates no measurable surface charge.

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172 the various cell types (e.g., epithelial cells, fibroblasts, anal mac rophage ~ ~ . Cytotoxicity in dependent on both the geometry and the length of asbestos fibers. In macrophagelike cells, chrysotile is toxic, whereas its nonfibrous analog, piety serpentine, is not (Frank et al., 1979~. Long fibers of various minerals are more cytotoxic than comparable amounts of short fibers (Beck et al., 1972; Brown et al., 1978; Chamberlain and Brown, 1978; Kaw et al., 1982~. There is overwhelming evidence that short fibers are phagocytized completely, whereas long fibers are only partially enveloped by cells. Uptake of fibers by cells results in the release of lysosomal enzymes (Beck ee al., 1972; Davies et al., 1974) and oxygen free radicals (Mossman and Landesman, 1983), reactive species that cause peroxidation of membranes and damage to macromolecules (Freeman and Crapo, 1982~. Cell injury in tracheal epithelial cell cultures can be prevented by the addition of superoxide dismutase--a scavenger of superoxide (Mossman and Landesman, 1983~. Cell death occurs rapidly when fibers are added to culture media without serum, hut is inhibited or delayed when serum is present (Harington et al., 1975; Mossman et al., 1980b). Serum proteins adsorb to fibers (Desat and Richards, 1978), and this protective coating is believed to be reproved by lysosomal hydrolases after phagocytosis of the particles (Allison, 1971; Heppleston, 1979~. Alterations in Cells of the It ne System After Exposure to Asbestiform Fibers Aberrations of humoral and cellular immunity have been reported in individuals exposed to asbestos (Kagan et al., 1977; Lange, 1980; - Stansfield and Edge, 1974; Turner-Warwick and Parkes, 1973~. These studies suggest activation indoor loss of normal immunoregulatory mechanisms in asbestos-associated diseases. Because macrophages may play a role as an intermediate in pulmonary defense, In vitro studies have been conducted to examine the responses of these cells to asbestos. After exposure to asbestos, macrophages release potent inflammatory factors (Hamilton et 81., 1976) and synthesize prostaglandins (Sirois et al., 1980), chemotact~c factors for neutrophils (Schoenberger et al., 1982), and substances that increase replication of fibroblasts (B~tterman et al., 1981~. Results of other in vitro experiments indicate that asbestos affects both cell mediated (Barbers et al., 1982; Bozelka et al., in press) and antibody-mediated (Lawrence et al., 1982) immunity. In addition, both amphibole and serpentine types of asbestos depress viral induction of inte rfe roe--a g lycoprote in that con fe rs ant ivira 1 de f ense--the reby resulting in increased multiplication of the virus (Hahon and Eckert, 1976) . Conversely, the mineral wollastonite enhances the induct ion of interferon by influenza virus in cultured cells, but the mineral per se

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173 toes not induce interferon (Hahon et al., 1980~. Finally, in addition to obvious modulatory effects on ce lle of the immune system, asbestos can activate complement, a complex in serum that is destructive to certain bacteria and cells that have been sensitized with antibody (Hasselbacher, 1979; Saint-Remy and Cole, 1980; Wilson et al., 1977~. Effects on Fibrobla~ts In Vitro Although the microphage appears to be a key cell in the induction of tissue injury by asbestos, the affected cell in the fibrotic process is the fibroblast--a cell associated with the production of collagen. It is not clear whether fibrosis results from increased production of collagen by individual cells, or from an increase in the proliferation of fibroblasts, or from both. Some investigators have suggested that these synthetic responses are elicited by fibrogenic factors released by macrophages (reviewed in Vigliani, 1968~. When noncytolyt ic amounts of asbestos are added to cultures of fibroblasts, abnormal and accelerated production of collagen and ret iculin are observed (Hext and Richards , 1976 ; Richards and Jacoby, 1976~. Fibroblasts undergo a maturation process leading to rapid cellular aging. Surviving cells phagocytize fibers avidly and undergo morphological and biochemical changes such as alterations in secretion of proteoglyeans (Richard and Morris, 1973), metabolism of RNA, and enhancement in cell mat collagen deposition (Hext and Richards, 1976~. Fibrous glass is lens cytotoxic, producing minimal but similar alterations. Long fibrous glans provides a substrate for the attachment of cultured fibroblasts and acts as a stimulus to promote cell division (Maroudas _ al., 1973~. I INITIATION-PROMOTION MODEL OF CMCINOGENESIS . This brief discussion of the initial ion-promotion model of carcinogenesis is provided as a basis for subsequent sections describing possible carcinogenic properties of asbe~tiform fibers. It is possible that cancers induced by asbestiform fibers result from the same fundamental mechanisms as cancers induces by other physical and chemical agents. Carcinogenesis is a complex, multistep process that has been extensively reviewed by Becker (1981), Foults (1969, 1975), Farber (1982), and Farber and Cameron (1980~. Multiple focal proliferations of cells (hyperplasia) in target organs are common early features of carcinogenesi~ and serve as sites for subsequent premalignant changes (Farber, 1982~. Such focal alterations give cell populations selective growth and invasive properties (Cairns, 1975; Fialkow, 1976; Foulds, l9S4; Nowell, 1976~. The concepts of initiation and promotion have been developed to explain this process in ~many experimental models and organ systems, including skin, liver, ; i

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174 mammary gland, colon, urinary bladder, and brain (Berenblum, 1941; Boutwell, 1974; Pitot and Sirica, 1980~. Initiation is a change in ache DNA of a cell induced by exposure to a carcinogen. This heritable alteration can be promoted ultimately to mal ignancy . Promotion is the process whereby an initiated cell develops focal proliferations, one or more of which may act as precursors for subsequent steps in the process of carcinogenesis. Promotion creates a mitogenic environment that differentially affects initiated cells. Some investigators suspect that many tissues or organs create a physiological promoting or selecting environment. In the early stages, promotion can be reversible, but it eventually brings about the phenotypic changes needed to stabilize the characteristics exhibited by cancer cells (Trosko and Chang, 1980~. By stimulating a premalignant or initiated cell to proliferate, the process of promotion also enhances the probability that additional genetic errors will occur (Potter, 1981; Trosko and Cnang, 1980). Promotion appears to occur after removal of cells, e.g., as the result of a surgical procedure or the infliction of a wound (Pound and McGuire, 1978~; after physical irradiation (Argyris and Slaga, 1981~; after cell death (Erei, 1976~; or upon exposure to exogenous noncytotoxic chemicals (Trosko and Chang, 1980), endogenou~ chemicals, e.g., hormones (Yager and Yager, 1980), or solid ob Sects, e.g., small plastic squares (Brand, 1982~. Some current views on promotion and promoters have been shaped by studies in which croton oil and its active agent, 12-0-tetradecanoylphorbol-13-acetate (TPA) were used in a mouse skin test sys tem. Both chemical and phys ical tumor promoters have been shown to induce a constellation of biochemical and cellular responses (Diamond et al., 1918) . Depending on the cell type, chemical tumor promoters can induce or inhibit normal differentiation (Diamond et al., 1978) or alter ache proliferation of cells in a given tissue (Yu~pa et al., 1982~. One of the important biochemical markers of cell division is increased synthesis of polyamides, which is often detected as an increase in the activity of ornithine decarboxylase (ODC)--a rate-limiting enzyme in the biosynthesis of polyamides. The induction of ODC is relates directly to tumor-promoting activity of a number of compounds in mouse skin (O' Brien, 1976) . When applied to the skin of rodents, classical tumor promoters (e.g., phorbol esters) also cause inflammatory changes and infil~cra~ ion of polymorphonuclear leukocytes (PMNs) and macrophages. These cells release oxygen free radicals--reactive by-products of oxygen that cause peroxidation of membranes and other macromolecules (McCord and Wang, 1979).

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s 175 Detailed reviews of tumor promotion have been prepared by Hecker et _. (1982) and by Slaga et al. (1978~._ Interaction of Asbestiform Fibers with DNA Mutagenicity is the ability of a chemical or physical agent to induce permanent, transmissible changes in the character of a gene by modifying the DNA. This event is believed by many to be an initiating step in the proce s ~ of care inogene si s . Daniel (in press) has prepared a review of In vitro tests that have been conducted with asbestiform fibers to determine their potential for mutagenicity and other types of interaction with DNA. In bacterial assays, such as the Ames Salmonella micro~ome assay, UICC reference samples of asbestos, superfine Canadian fibers, and fibrous glass have not shown mutagenic activity (Chamberlain and Tarmy, 1977; Light and Wei, 1980~. The investigators believe that these negative results may be attributable to the lack of fiber uptake by bacterial cells. Chromosome aberrations and chromatic breaks have been observed after chrysotile and crocidolite asbestos have been addled to rodent cell lines (Lavappa _ al., 1975), but not after the addition of fibrous or powdered glass (Sincock ant Seabright, 1975). Huang (1979) demonstrated that chrysotile, crocidolite, ant amosite are mutagenic to the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus of Chinese hamster lung fibroblasts. However, the rates of induced mutation were low, and the conclusions drawn by Huang are strongly dependent on the method of statistical analysis used in this study. Moreover, neither chrysotile, crocidolite, nor amosite was mutagenic in rodent liver epithelial cells (Reins et al., 1982~. Although amosite and crocidolite produced small increases in sister chromatic exchange (SCE) in Chinese hamster ovary cells (Livingston et al., 1980), the V79-4 Chinese hamster lung cell line and cultured mesothelial cells did not exhibit altered SCE levels after exposure to crocidolite and chrysotile, respectively (Kaplan et al., 1980; Price-Jones et al., 1980~. Furthermore, in tracheal epithelial cells, chrysotile and crocidolite did not cause breakage of DNA, as measured by alkaline elusion (Mossman et al., 19836~. Results of studies by Sincock (1977) and Lechner and colleagues ( 1983) suggest that human cells are relatively resistant to DNA damage by asbestos. Neither crocidolite, SEA chrysotile, nor glass fibers induces chromosome aberrations in human lymphocytes or fibroblasts (Sincock, 1977), although the number of chromatic and chromosome breaks increases in freshly isolated human lymphocytes exposed to Rhodesian chrysot ile (Valerio _ al., 1980~. In another study, UICC chrysoeile, amosite, and crocidol ite Lid not appear to cause DNA strand breakage in human bronchial organ cultures (Lechner et al., 1983~.

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