Toxicology of Industrial Compounds

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40 METABOLIC ACTIVATION OF INDUSTRIAL CHEMICALS avidly to thiol and amine groups in protein. In mice the kidney toxicity is much more pronounced in males than in females; this sex-difference is due to the much higher activity of the bioactivating cytochrome P450 species in male mouse kidney than in the females (Pohl et al., 1984). Chloroform also increased the tumor incidence in the liver and kidney in some experiments (Reitz et al., 1990), at dose levels which damaged these organs. However, there are no indications of mutagenicity or genotoxicity in in vitro or animal in vivo systems. Therefore, most likely the increased tumor frequency in animals is due to tissue toxicity, leading to increased cell turnover and a mitogenic stimulus. This is an important distinction, at least in some countries such as The Netherlands, because for such chemicals a threshold approach is allowed, whereas for initiating chemicals a linear extrapolation for carcinogenic risk is used. Benzene Benzene presents something of a mystery in the evaluation of its toxicity mechanism (Swaen et al., 1989). Exposure to high levels of benzene has been associated with leukaemia in man. However, in vitro it shows little genotoxicity, and it hardly generates DNA adducts when it is given even at high dose to animals. A candidate for DNA damage could have been the 1, 4-dihy-droxybenzene (hydroquinone) metabolite, which, however, does not form DNA adducts readily. Recently a ring-opened metabolite, the trans,trans-muconic dialdehyde has been proposed as a possible reactive metabolite of benzene (Figure 3.4). Whether it really plays a role in benzene toxicity is unclear as yet (Kline et al., 1993). Dichloromethane Dichloromethane can be metabolized by two pathways, an oxidative and a conjugative route. Oxidation catalyzed by P450 yields carbon monoxide (Figure 3.5). The glutathione pathway generates a reactive intermediate, which is mutagenic and has been implicated in the hepatocarcinogenic effect of dichloromethane in mice. It could be shown that the human liver has a negligible activity of the glutathione transferase involved, so that the risk for hepatocarcinogenesis in man is virtually non-existent (Green et al., 1988; Reitz et al., 1989; Dankovic and Bailer, 1994). This example illustrates how insight into the mechanism of bioactivation enables a more reliable species extrapolation in terms of hazard and risk. 1,2-Dibromoethane This compound can be conjugated with glutathione to form a reactive thiiranium ion which forms adducts with DNA. This is the reason for the
Figure 3.4 Possible route of bioactivation of benzene. Figure 3.5 Bioactivation of dichloromethane. carcinogenic and mutagenic effects of 1,2-dibromoethane (Inskeep et al., 1986). 2-Naphthylamine G.J.MULDER 41 2-Naphthylamine causes bladder tumors in the dog and man, but not in mice and rats. The most likely cause is a complicated interplay between glucuroni dation and urinary pH. In all four species 2-naphthylamine is Nhydroxylated and subsequently N-glucuronidated. The resulting metabolite
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Toxicology of Industrial Compounds
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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
Page 14 and 15: Richard A.Versen Schuller MTC, Heal
Page 16 and 17: 1 Biomonitoring and Absorption of I
Page 18 and 19: 4 BIOMONITORING AND ABSORPTION OF I
Page 24 and 25: 10 BIOMONITORING AND ABSORPTION OF
Page 26 and 27: 2 Toxicokinetics and Biodisposition
Page 28 and 29: 14 TOXICOKINETICS AND BIODISPOSITIO
Page 50 and 51: 3 Metabolic Activation of Industria
Page 52 and 53: 38 METABOLIC ACTIVATION OF INDUSTRI
Page 56 and 57: 42 METABOLIC ACTIVATION OF INDUSTRI
Page 58 and 59: 4 Sizing up the Problem of Exposure
Page 60 and 61: 46 SIZING UP THE PROBLEM OF EXPOSUR
Page 74 and 75: 5 Metabolism of Reactive Chemicals
Page 76 and 77: 62 METABOLISM OF REACTIVE CHEMICALS
Page 86 and 87: 6 Methods for the Determination of
Page 88 and 89: 74 METHODS FOR THE DETERMINATION OF
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PART THREE Pulmonary toxicology of
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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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