Toxicology of Industrial Compounds

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42 METABOLIC ACTIVATION OF INDUSTRIAL CHEMICALS is excreted in urine. In man and dog the urine is slightly acidic, while in rat and mouse it is slightly alkaline. Under acidic conditions the glucuronide is hydrolyzed to generate the hydroxylamine in the bladder. In this case glucuronidation is not a bioactivation, but rather a targeting biotransformation: in man and dog the carcinogenic metabolite is targeted to the bladder, due to the (necessary!) acidic local pH (Kadlubar et al., 1981). Conclusions The above illustrates the importance of bioactivation in toxicity of industrial chemicals. Is it possible to predict bioactivation from the structure? As outlined above, in some cases the compound contains structural elements which make bioactivation to a reactive intermediate quite likely. Whether it does play a role in toxicity then is still uncertain. Test systems to detect reactive intermediates depend on, for example, the availability of the radiolabeled compound; in fact, a very high specific radioactivity is required to detect low levels of binding. Alternatively, radiolabelled glutathione can be used for those reactive intermediates that readily bind to the thiol group of glutathione (Mulder and Le, 1988). Whether such systems can pick up every relevant toxic reactive intermediate remains to be seen. For extrapolation of one species to the other it is important to have insight into the metabolite that is responsible for the toxicity. Therefore, it is more than just of academic interest to know the mechanism of toxicity in safety assessment of industrial chemicals. Unfortunately, it is often not easy to establish such a mechanism beyond reasonable doubt: it may require too many rats to feel comfortable about it if we would have to do this for every chemical used industrially! References ANDERS, M.W. (Ed.), 1985, Bioactivation of Foreign Compounds, Orlando, FL: Academic Press. ANDERS, M.W. and DEKANT, W., 1994, Conjugation-dependent Carcinogenicity and Toxicity of Foreign Compounds, Orlando, FL: Academic Press. BOND, J.A., 1989, Review of the toxicology of styrene, CRC Crit. Rev. Toxicol 19, 227–49. DANKOVIC, D.A. and BAILER, A.J., 1994, The impact of exercise and intersubject variability on dose estimates for dichloromethane derived from a physiologically based pharmacokinetic model, Fund. Appl. Toxicol, 22, 20–5. ECETOC, 1992, Technical report No. 52, Styrene toxicology. Investigations on the potential for carcinogenicity, Brussels: Ecetoc.
G.J.MULDER 43 GREEN, T., PROVAN, W.M., COLLINGE, D.C. and GUEST, A.E., 1988, Macro molecular interactions of inhaled methylene chloride in rats and mice, Toxicol. Appl. Pharmacol, 93, 1–10. GUENGERICH, F.R., 1992, Roles of the vinylchloride oxidation products 1chlorooxirane and 2-chloroacetaldehyde in the in vitro formation of etheno adducts of nucleic acid bases, Chem. Res. Toxicol, 5, 2–5. INSKEEP, P.B., KOGA, N.K., CMARIK, J.L. and GUENGERICH, F.P., 1986, Covalent binding of 1,2-dihaloalkanes to DNA, Cancer Res., 46, 2839–44. KADLUBAR, F.F., UNRUH, L.E., FLAMMANG, T.J., SPARKS, D., MITCHUM, R.K. and MULDER, G.J., 1981, Alteration of urinary levels of the carcinogen, N-hydroxy-2-naphthylamine, and its N-glucuronide in the rat by control of urinary pH, inhibition of metabolic sulfation, and changes in biliary excretion, Chem.-Biol. Interact. 33, 129–47. KLINE, S.A., ROBERTSON, J.F., GROTZ, V.L., GOLDSTEIN, B.D. and WITZ, G., 1993, Identification of 6-hydroxy-trans,trans-2,4-hexadienoic acid, a novel ring-opened urinary metabolite of benzene, Environm. Hlth Perspect., 101, 310–12. MULDER, G.J., 1992, Pharmacological effects of drug conjugates: is morphine 6glucuronide an exception? Trends Pharmacol. Sci., 13, 302–4. MULDER, G.J. and LE, C.T., 1988, A rapid simple in vitro screening test to detect reactive intermediates of xenobiotics. Toxicol. In Vitro, 2, 225–30. POHL, L.R., GEORGE, J.W. and SATOH, H., 1984, Strain and sex differences in chloroform-induced nephrotoxicity. Drug Metab. Disposit., 12, 304–7. REITZ, R.H., MENDRALA, A.L. and GUENGERICH, F.P., 1989, In vitro metabo-lism of methylene chloride in human and animal tissues, Toxicol. Appl. Pharmacol, 97, 230–46. REITZ, R.H., MENDRALA, A.L. and CONOLLY, R.B., 1990, Estimating the risk of liver cancer associated with human exposures to chloroform using PbPK modeling, Toxicol. Appl. Pharmacol., 105, 443–59. SWAEN, G.M.H. et al., 1987, A scientific basis for the risk assessment of vinyl chloride, Regul. Toxicol. Pharmacol, 7, 120–7. SWAEN, G.M.H. et al., 1989, Carcinogenic risk assessment of benzene in outdoor air, Regul. Toxicol. Pharmacol., 9, 175–85. WACHSMAN, J.T., BRISTOL, D.W., SPALDING, J., SHELBY, M. and TENNANT, R.W., 1993, Predicting chemical carcinogenesis in rodents, Environm. Hlth Perspect., 101, 444–5. WANG, X.P., CHAN, H.M., GOYER, R.A. and CHERIAN, M.G., 1993, Nephrotoxicity of repeated injections of cadmium-metallothionein in rats, Toxicol. Appl. Pharmacol., 119, 11–16.
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Toxicology of Industrial Compounds
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This edition published in the Taylo
Page 6 and 7: 8. Pulmonary Toxicity Studies with
Page 8 and 9: Preface A large number of chemical
Page 10 and 11: Contributors May Akrawi Department
Page 12 and 13: Beverly M.Kulig TNO Toxicology, Dep
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Page 16 and 17: 1 Biomonitoring and Absorption of I
Page 18 and 19: 4 BIOMONITORING AND ABSORPTION OF I
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Page 26 and 27: 2 Toxicokinetics and Biodisposition
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Page 50 and 51: 3 Metabolic Activation of Industria
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Page 58 and 59: 4 Sizing up the Problem of Exposure
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92 CARCINOGENIC POTENTIAL OF MAN-MA
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100 CARCINOGENIC POTENTIAL OF MAN-M
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118 PULMONARY TOXICITY STUDIES WITH
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130 PULMONARY HYPERREACTIVITY TO IN
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10 Mechanisms of Pulmonary Sensitiz
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140 MECHANISMS OF PULMONARY SENSITI
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150 OCCUPATIONAL ASTHMA INDUCED BY
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12 Biomarkers and Risk Assessment K
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160 BIOMARKERS AND RISK ASSESSMENT
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168 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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