Toxicology of Industrial Compounds

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126 PULMONARY TOXICITY STUDIES WITH MAN-MADE ORGANIC FIBRES The BrdU pulmonary cell labeling results demonstrating sustained proliferative effects in chrysotile-exposed rats presented here are consistent with findings from several other investigators (Brody and Overby, 1989; McGavran et al., 1990; Coin et al., 1992a). In studies by Brody and Overby (1989), acute inhalation exposures to chrysotile asbestos fibres produced a biphasic cell labeling response in the lungs of exposed rats and mice. This was characterized by dramatic increases in epithelial cell DNA synthesis, followed several days later by enhanced labeling of interstitial cells. In follow-up studies, a 3 day exposure prolonged the duration of increased cell labeling (Coin et al., 1992b). In another study, Coin et al., (1991) reported that a 5-h exposure to chrysotile fibres in mice produced substantial increases in mesothelial and subpleural cell labeling indices at 2 and 8 days postexposure. The finding of sustained subpleural and mesothelial cell proliferation in chrysotile-exposed rats was unexpected and raises the issue regarding the association of chrysotile with the development of mesothelioma. In this regard, inhalation of chrysotile asbestos fibres produced mesotheliomas in exposed rats (Wagner et al., 1974; Davis and Jones, 1988). The biodurability data reported here demonstrating retention or reduced clearance of long chrysotile fibres are consistent with the results of previous studies by Roggli and Brody (1984) and Bellmann et al., (1986, 1987). In contrast to the enhanced biodurability of chrysotile asbestos fibres, the results with p-aramid fibres suggest that the fibrils undergo biodegradability in the lungs of exposed rats. These findings confirm our earlier studies (Warheit et al., 1992) and are in concordance with the results of Kelly et al. (1993) and the recent findings of the IOM. In conclusion, size separation techniques for chrysotile asbestos fibres were partially successful in increasing median lengths from 3 µm to 6 µm. Histopathological studies demonstrated that both p-aramid and chrysotile produced a minimal to mild inflammatory response which produced thickening of the alveolar duct bifurcations. These effects peaked at 1 month postexposure and were essentially reversible by 6 months postexposure. Pulmonary cell labeling studies demonstrated substantial increases in lung parenchymal, airway, pleural/subpleural, and mesothelial cell proliferation effects following chrysotile exposures, suggesting that chrysotile produces a potent proliferative response in the airways, lung parenchyma, and subpleural/ pleural regions. In contrast, p-aramid exposures produced only transient effects in airway and subpleural regions. Fibre biopersistence/durability results thus far indicate that the long chrysotile fibres are retained in the lung or cleared at a slow rate. In contrast, p-aramid fibres have low biodurability in the lungs of exposed animals. In this regard, median lengths of chrysotile fibres recovered from
exposed lung tissue were increased over time, while median lengths of paramid fibrils were decreased over time. It is concluded that the proliferative effects and enhanced biodurability of chrysotile that are associated with the induction of chronic disease do not occur with p-aramid fibrils. Therefore, inhalation of chrysotile asbestos fibres is likely to produce greater long-term pulmonary toxic effects in comparison to para-aramid fibrils. Acknowledgments This study was sponsored by the DuPont Co. and Akzo Nobel Corp. References D.B.WARHEIT ET AL. 127 BELLMANN, B., KONIG, H., MUHLE, H. and POTT, F., 1986, Chemical durability of asbestos and of man-made mineral fibres in vivo, J. Aerosol Sci., 17, 341–5. BELLMANN, B., MUHLE, H., POTT, F., KONIG, H., KLOPPEL, H. and SPURNY, K., 1987, Persistence of man-made mineral fibers (MMMF) and asbestos in rat lungs, Ann. Occup. Hyg., 31(4B), 693–709. BRODY, A.R. and OVERBY, L.H., 1989, Incorporation of tritiated thymidine by epithelial and interstitial cells in bronchiolar-alveolar regions of asbestosexposed rats, Am. J. Pathol., 134, 133–40. COIN, P.G., MOORE, L.B., ROGGLI, V. and BRODY, A.R., 1991, Pleural incorporation of 3 H-TdR after inhalation of chrysotile asbestos in the mouse, Am. Rev. Respir. Dis., 143, A604. COIN, P.G., ROGGLI, V.L. and BRODY, A.R., 1992a, Deposition, clearance and translocation of chrysotile asbestos from peripheral and central regions of the rat lung, Environ, Res., 58, 97–116. COIN, P.G., ROGGLI, V. and BRODY, A.R., 1992b, Pulmonary fibrogenesis and BRDU incorporation after three consecutive inhalation exposures to chrysotile asbestos, Am. Rev. Respir. Dis., 145, A328. DAVIS, J.M.G. and JONES, A.D., 1988, Comparisons of the pathogenicity of long and short fibres of chrysotile asbestos in rats, Br. J. Exp. Pathol., 69, 717–37. DAVIS, J.M.G., ADDISON, J., BOLTON, R.E., DONALDSON, K. et al., 1986, The pathogenicity of long versus short fibre samples of amosite asbestos administered to rats by inhalation or intraperitoneal injection, Br. J. Exp. Pathol, 67, 415–30. KELLY, D.P., MERRIMAN, E.A., KENNEDY, G.L.JR. and LEE, K.P., 1993, Deposition, clearance, and shortening of Kevlar para-aramid fibrils in acute, subchronic, and chronic inhalation studies in rats, Fundam. Appl. Toxicol, 21, 345–54. LEE, K.P., KELLY, D.P., O’NEAL, F.O., STADLER, J.C. and KENNEDY, G. L.JR, 1988, Lung response to ultrafine Kevlar aramid synthetic fibrils following 2-year inhalation exposure in rats, Fundam. Appl. Toxicol., 11, 1– 20.
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Toxicology of Industrial Compounds
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This edition published in the Taylo
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8. Pulmonary Toxicity Studies with
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Preface A large number of chemical
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Contributors May Akrawi Department
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Beverly M.Kulig TNO Toxicology, Dep
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Richard A.Versen Schuller MTC, Heal
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1 Biomonitoring and Absorption of I
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4 BIOMONITORING AND ABSORPTION OF I
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10 BIOMONITORING AND ABSORPTION OF
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2 Toxicokinetics and Biodisposition
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14 TOXICOKINETICS AND BIODISPOSITIO
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3 Metabolic Activation of Industria
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38 METABOLIC ACTIVATION OF INDUSTRI
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4 Sizing up the Problem of Exposure
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46 SIZING UP THE PROBLEM OF EXPOSUR
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5 Metabolism of Reactive Chemicals
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62 METABOLISM OF REACTIVE CHEMICALS
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6 Methods for the Determination of
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74 METHODS FOR THE DETERMINATION OF
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176 EXTRAPOLATION OF TOXICITY DATA
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178 EXTRAPOLATION OF TOXICITY DATA
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14 Molecular Approaches to Assess C
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182 MOLECULAR APPROACHES TO ASSESS
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198 EVALUATION OF TOXICITY TO THE I
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208 USE OF LONG-TERM CULTURES OF HE
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PART FIVE Mechanisms of toxicity of
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224 PEROXISOME PROLIFERATION normal
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226 PEROXISOME PROLIFERATION demons
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228 PEROXISOME PROLIFERATION Specie
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230 PEROXISOME PROLIFERATION intend
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232 PEROXISOME PROLIFERATION BENTLE
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234 PEROXISOME PROLIFERATION KRAUPP
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236 PEROXISOME PROLIFERATION POPP,
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18 Neurotoxicity Testing of Industr
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240 NEUROTOXICITY TESTING OF INDUST
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256 ENDOCRINE TOXICOLOGY OF THE THY
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20 Testing and Evaluation for Repro
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282 TESTING AND EVALUATION FOR REPR
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PART SIX Toxicity of selected class
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302 SPECIAL POINTS IN THE TOXICITY
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310 TOXICOLOGY OF TEXTILE CHEMICALS
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318 ANTIOXIDANTS AND LIGHT STABILIS
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340 TOXICOLOGY OF SURFACTANTS Inter
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342 TOXICOLOGY OF SURFACTANTS Figur
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344 TOXICOLOGY OF SURFACTANTS probl
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346 TOXICOLOGY OF SURFACTANTS nonio
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348 TOXICOLOGY OF SURFACTANTS and t
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350 TOXICOLOGY OF SURFACTANTS long-
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352 TOXICOLOGY OF SURFACTANTS COULS
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25 Low Dose of a Genotoxic Carcinog
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358 CARCINOGENESIS AT LOW DOSE Tabl
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360 CARCINOGENESIS AT LOW DOSE year
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26 Controversial Mechanistic and Re
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364 CONTROVERSIAL ISSUES IN SAFETY
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374 INDEX 2-bromo-glutathionyl 64 B
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376 INDEX Gas chromatography/mass s
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378 INDEX mRNA analysis 211 Mutagen
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380 INDEX Surfactants 338-55 acute
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