Toxicology of Industrial Compounds

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6 Methods for the Determination of Reactive Compounds PETER SAGELSDORFF CIBA-GEIGY Ltd, Basel Introduction It has well been recognised for a long time that adverse effects of chemicals are associated with their reactivity whereby many unreactive chemicals are metabolised in the cell to a reactive intermediate. Reactive intermediates are generally electrophiles which undergo reactions with cellular nucleophiles and the toxicological response is often the consequence of the covalent binding of a chemical to cellular macromolecules. This chapter will provide a brief survey of current methods for the determination of protein and DNA adducts generated by reactive compounds, and will discuss some useful applications of these technologies. Source of reactive metabolites Reactive chemicals are generally strong electrophilic agents. These compounds can be reactive per se (direct electrophiles), such as methylmethanesulphonate, epoxides or strained lactones. On the other hand, unreactive chemicals can be enzymatically converted to electrophilic agents (indirect electrophiles), such as aromatic amines and nitroarenes to the corresponding nitrenium ions, polycyclic aromatic hydrocarbons to diol epoxides or N-nitroso compounds to carbenium ions (Figure 6.1; Magee et al., 1975; Weissburger and Williams, 1975; Lutz, 1979). Interaction of reactive compounds with cellular constituents As electrophiles, these reactive compounds undergo reactions with nucleophiles. The nature of the toxicological response is dependent on the biological macromolecule affected. Reactions with water or glutathione, two of the most abundant cellular nucleophiles, in most cases, lead to an inactivation of the respective reactive compound.
P.SAGELSDORFF 73 Figure 6.1 Examples of electrophilic compounds. The arrows indicate the suspected electrophilic centres (from Lutz, 1979).
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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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Page 36 and 37: 22 TOXICOKINETICS AND BIODISPOSITIO
Page 50 and 51: 3 Metabolic Activation of Industria
Page 52 and 53: 38 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
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Page 76 and 77: 62 METABOLISM OF REACTIVE CHEMICALS
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Page 104 and 105: PART THREE Pulmonary toxicology of
Page 106 and 107: 92 CARCINOGENIC POTENTIAL OF MAN-MA
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122 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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354
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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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Toxicology of Industrial Compounds

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