Toxicology of Industrial Compounds

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330 ANTIOXIDANTS AND LIGHT STABILISERS: TOXIC EFFECT Table 23.8 Morphological changes of dam and foetal hepatocyte organelles after treatment with Compound F from day 6 through days 14, 17 and 20 of gestation
iochemical investigations which revealed a moderate four-fold induction of peroxisomal β-oxidation in dams and an up to 15-fold induction of this activity at day 21 of gestation in foetal livers, respectively, with the final foetal activity exceeding dam activity by 40 per cent. Strong increases in lauric acid 11- and 12-hydroxylation, which are known to be associated with isoenzymes of the cytochrome P450 CYP4A gene family and the phenomenon of peroxisome proliferation in rodents, of up to 2.6- and 10. 5-fold in dams and 11.5- and 23.2-fold in foetuses, respectively, at day 21 of gestation were recorded as well, indicating again a slightly higher final activity in foetal than in dam liver. By contrast, catalase, known as a detoxifying enzyme for hydrogen peroxide generated particularly in the course of increased peroxisomal activity, was shown to be induced up to 5. 6-fold in dam and 8.2-fold in foetal liver at day 21 of gestation, leaving foetal liver, however, with only about 30 per cent of the final activity seen in dams (Table 23.9). This discrepancy between the strong induction of hydrogen peroxide generating peroxisomal β-oxidation and the considerably less potent induction of the hydrogen peroxide destroying catalase activity appears to be reflected in the 1.7-fold increase in the lipid peroxidation product malondialdehyde in foetal livers as well as in the decrease of total and reduced hepatic glutathione levels at day 21 of gestation (Tables 23.9 and 23.10). Surprisingly, foetal defense systems against oxidative stress such as selenium-dependent and seleniumindependent glutathione peroxidase were found poorly developed throughout the investigated periods of gestation and barely inducible by the test article leaving the pups with little protection against any kind of oxidative insult (Table 23.10). Consequently, Compound F was clearly identified as a peroxisome proliferator in pregnant rat as well as foetal liver with high potential for the initiation of oxidative damage in foetal tissues. Implications for human safety assessment H.THOMAS ET AL. 331 The understanding of the mechanisms by which benzotriazole-based UV light stabilisers exert their hepatotrophic effects in rodents is of crucial importance for the assessment of safety aspects in humans. The presented rat studies have shown that the liver effects exerted by Compound C and its ester derivatives Compounds D, E and F are clearly related to the induction of peroxisome proliferation. The identical nature of the observed effects regardless of the alcohol component in the investigated esters suggests that the toxic potential resides solely with the 3-[3-(2Hbenzotriazole-2-yl)-5-tert-butyl-4-hydroxy-phenyl] propionic acid whereby the individual potency appears to be mainly determined by the different bioavailablity of the respective ester compound and the extent and velocity of its hydrolysis in vivo. Also, it appears, that in vitro hydrolysis studies do
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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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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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Page 294 and 295: 20 Testing and Evaluation for Repro
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Page 314 and 315: PART SIX Toxicity of selected class
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Page 370 and 371: 25 Low Dose of a Genotoxic Carcinog
Page 372 and 373: 358 CARCINOGENESIS AT LOW DOSE Tabl
Page 374 and 375: 360 CARCINOGENESIS AT LOW DOSE year
Page 376 and 377: 26 Controversial Mechanistic and Re
Page 378 and 379: 364 CONTROVERSIAL ISSUES IN SAFETY
Page 388 and 389: 374 INDEX 2-bromo-glutathionyl 64 B
Page 390 and 391: 376 INDEX Gas chromatography/mass s
Page 392 and 393: 378 INDEX mRNA analysis 211 Mutagen
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380 INDEX Surfactants 338-55 acute
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