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Toxicology an introduction to the science of toxicology

Transcript of Toxicology - introduction

Toxicology

3

ToxicologyWolfgang Dekant, Institute of Toxicology, University of Wuerzburg, Germany Spiridon Vamvakas, Institute of Toxicology, University of Wuerzburg, Germany

1. 1.1. 1.2. 1.3. 1.4. 1.5. 1.6. 1.7. 1.7.1. 1.8. 1.9. 1.9.1. 1.9.2. 1.9.3. 1.9.4. 1.10. 2.

2.1. 2.2. 2.2.1. 2.2.2. 2.2.3. 2.2.4. 2.2.4.1. 2.2.4.2. 2.2.4.3. 2.3. 2.4. 2.5. 2.5.1. 2.5.2.

Introduction . . . . . . . . . . . . . . Denition and Scope . . . . . . . . . Fields . . . . . . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . Information Resources . . . . . . . Terminology of Toxic Effects . . . Types of Toxic Effects . . . . . . . . DoseResponse: a Fundamental Issue in Toxicology . . . . . . . . . . Graphics and Calculations . . . . . . Dose-Response Relationships for Cumulative Effects . . . . . . . . . . Factors Inuencing DoseResponse . . . . . . . . . . . . Routes of Exposure . . . . . . . . . . Frequency of Exposure . . . . . . . . Species-Specic Differences in Toxicokinetics . . . . . . . . . . . . . Miscellaneous Factors Inuencing the Magnitude of Toxic Responses . Exposure to Mixtures . . . . . . . . Absorption, Distribution, Biotransformation and Elimination of Xenobiotics . . . . Disposition of Xenobiotics . . . . . Absorption . . . . . . . . . . . . . . . Membranes . . . . . . . . . . . . . . . Penetration of Membranes by Chemicals . . . . . . . . . . . . . . . . Mechanisms of Transport of Xenobiotics through Membranes . . Absorption . . . . . . . . . . . . . . . Dermal Absorption . . . . . . . . . . Gastrointestinal Absorption . . . . . Absorption of Xenobiotics by the Respiratory System . . . . . . . . . . Distribution of Xenobiotics by Body Fluids . . . . . . . . . . . . . . Storage of Xenobiotics in Organs and Tissues . . . . . . . . . . . . . . . Biotransformation . . . . . . . . . . Phase-I and Phase-II Reactions . . . Localization of the Biotransformation Enzymes . . . . .

6 6 6 8 9 11 13 13 15 18 19 19 20 21 22 23

2.5.3. 2.5.4. 2.5.4.1. 2.5.4.2. 2.5.4.3. 2.5.4.4. 2.5.4.5. 2.5.5. 2.5.5.1. 2.5.5.2. 2.5.5.3. 2.5.5.4. 2.5.5.5. 2.5.5.6.

23 23 24 24 25 26 27 27 30 31 33

2.5.6. 2.5.6.1. 2.5.6.2. 2.5.6.3. 2.5.6.4. 2.5.6.5.

2.5.6.6.

2.5.7. 36 37 37 38 2.5.7.1. 2.5.7.2.

Role of Biotransformation in Detoxication and Bioactivation . . . Phase-I Enzymes and their Reactions . . . . . . . . . . . . . . . . Microsomal Monooxygenases: Cytochrome P450 . . . . . . . . . . . Microsomal Monooxygenases: Flavin-Dependent Monooxygenases Peroxidative Biotransformation: Prostaglandin-synthase . . . . . . . . Nonmicrosomal Oxidations . . . . . Hydrolytic Enzymes in Phase-I Biotransformation Reactions . . . . Phase-II Biotransformation Enzymes and their Reactions . . . . UDP-Glucuronyl Transferases . . . Sulfate Conjugation . . . . . . . . . . Methyl Transferases . . . . . . . . . . N-Acetyl Transferases . . . . . . . . Amino Acid Conjugation . . . . . . Glutathione Conjugation of Xenobiotics and Mercapturic Acid Excretion . . . . . . . . . . . . . . . . Bioactivation of Xenobiotics . . . . Formation of Stable but Toxic Metabolites . . . . . . . . . . . . . . . Biotransformation to Reactive Electrophiles . . . . . . . . . . . . . . Biotransformation of Xenobiotics to Radicals . . . . . . . . . . . . . . . . . Formation of Reactive Oxygen Metabolites by Xenobiotics . . . . . Detoxication and Interactions of Reactive Metabolites with Cellular Macromolecules . . . . . . . . . . . . Interaction of Reactive Intermediates with Cellular Macromolecules . . . . . . . . . . . . Factors Modifying Biotransformation and Bioactivation Host Factors Affecting Biotransformation . . . . . . . . . . . Chemical-Related Factors that Inuence Biotransformation . . . . .

38 39 39 41 42 44 44 45 45 46 47 47 47

48 49 50 50 52 53

53

55 58 58 62

Ullmanns Industrial Toxicology Copyright c 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31247-1

42.5.8. 2.5.8.1. 2.5.8.2. 2.5.8.3. 2.6. 2.6.1. 2.6.1.1. 2.6.1.2. 2.6.2. 3.

ToxicologyElimination of Xenobiotics and their Metabolites . . . . . . . . . . . . . . . Renal Excretion . . . . . . . . . . . . Hepatic Excretion . . . . . . . . . . . Xenobiotic Elimination by the Lungs . . . . . . . . . . . . . . . . . . . Toxicokinetics . . . . . . . . . . . . . Pharmacokinetic Models . . . . . . . One-Compartment Model . . . . . . Two-Compartment Model . . . . . . Physiologically Based Pharmacokinetic Models . . . . . . . Mechanisms of Acute and Chronic Toxicity and Mechanisms of Chemical Carcinogenesis . . . . . . Biochemical Basis of Toxicology . Receptor-Ligand Interactions . . Basic Interactions . . . . . . . . . . . Interference with Excitable Membrane Functions . . . . . . . . . . . . Interference of Xenobiotics with Oxygen Transport, Cellular Oxygen Utilization, and Energy Production Binding of Xenobiotics to Biomolecules . . . . . . . . . . . . . . Binding of Xenobiotics or their Metabolites to Cellular Proteins . . Interaction of Xenobiotics or their Metabolites with Lipid Constituents Interactions of Xenobiotics or their Metabolites with nucleic Acids . . . Perturbation of Calcium Homeostasis by Xenobiotics or their Metabolites . . . . . . . . . Nonlethal Genetic Alterations in Somatic Cells and Carcinogenesis DNA Structure and Function . . . DNA Structure . . . . . . . . . . . . . Transcription . . . . . . . . . . . . . . Translation . . . . . . . . . . . . . . . Regulation of Gene Expression . . . DNA Repair . . . . . . . . . . . . . . . Molecular Mechanisms of Malignant Transformation and Tumor Formation . . . . . . . . . . Mutations . . . . . . . . . . . . . . . . Causal Link between Mutation and Cancer . . . . . . . . . . . . . . . Proto-Oncogenes and TumorSuppressor Genes as Genetic Targets Genotoxic versus Nongenotoxic Mechanisms of Carcinogenesis . . . 3.8. 62 63 64 65 65 66 66 67 68 Mechanisms of Chemically Induced Reproductive and Developmental Toxicity . . . . . . . Embryotoxicity, Teratogenesis, and Transplacental Carcinogenesis . . . Patterns of DoseResponse in Teratogenesis, Embryotoxicity, and Embryolethality . . . . . . . . . . . . Methods in Toxicology . . . . . . . Toxicological Studies: General Aspects . . . . . . . . . . . . . . . . . Acute Toxicity . . . . . . . . . . . . . Testing for Acute Toxicity by the Oral Route: LD50 Test and FixedDose Method . . . . . . . . . . . . . . Testing for Acute Skin Toxicity . . Testing for Acute Toxicity by Inhalation . . . . . . . . . . . . . . . . . . . . Repeated-Dose Toxicity Studies: Subacute, Subchronic and Chronic Studies . . . . . . . . . Ophtalmic Toxicity . . . . . . . . . . Sensitization Testing . . . . . . . . . Phototoxicity and Photosensitization Testing . . . . . Reproductive and Developmental Toxicity Tests . . . . . . . . . . . . . Fertility and General Reproductive Performance . . . . . . . . . . . . . . Embryotoxicity and Teratogenicity Peri- and Postnatal Toxicity . . . . . Multigeneration Studies . . . . . . . The Role of Maternal Toxicity in Teratogenesis . . . . . . . . . . . . . . In Vitro Tests for Developmental Toxicity . . . . . . . . . . . . . . . . . Bioassays to Determine the Carcinogenicity of Chemicals in Rodents . . . . . . . . . . . . . . . In Vitro and In Vivo Short-term Tests for Genotoxicity . . . . . . . . Microbial Tests for Mutagenicity . . The Ames Test for Bacterial Mutagenicity . . . . . . . . . . . . . . . . . Mutagenicity Tests in Escherichia coli . . . . . . . . . . . . . . . . . . . . Fungal Mutagenicity Tests . . . . . . Eukaryotic Tests for Mutagenicity . Mutation Tests in Drosophila melanogaster . . . . . . . . . . . . . . In Vitro Mutagenicity Tests in Mammalian Cells . . . . . . . . . . . In Vivo Mammalian Mutation Tests Mouse Somatic Spot Test . . . . . .

84 85

3.8.1. 3.8.2.

4. 4.1. 4.2. 4.2.1.

86 87 87 90

3.1. 3.2. 3.2.1. 3.2.2. 3.2.3.

69 69 70 70 72

4.2.2. 4.2.3. 4.3.

90 92 94

73 74 75 76 76

4.4. 4.5. 4.6. 4.7. 4.7.1. 4.7.2. 4.7.3. 4.7.4. 4.7.5. 4.7.6. 4.8.

95 96 97 99 99 100 100 101 101 102 102

3.3. 3.3.1. 3.3.2. 3.3.3. 3.4.

77 78 79 79 80 80 80 81

3.5. 3.6. 3.6.1. 3.6.2. 3.6.3. 3.6.4. 3.6.5. 3.7.

103 105 106 106 111 112 112 112 112 114 114

4.9. 4.9.1. 4.9.1.1. 4.9.1.2.

3.7.1. 3.7.2. 3.7.3. 3.7.4.

81 81 83

4.9.1.3. 4.9.2. 4.9.2.1. 4.9.2.2.

83 84 4.9.3. 4.9.3.1.

Toxicology4.9.3.2. 4.9.3.3. 4.9.4. 4.9.4.1. 4.9.4.2. 4.9.5. 4.9.5.1. 4.9.5.2. 4.9.5.3. 4.9.6. 4.9.7. 4.9.7.1. 4.9.7.2. 4.9.7.3. 4.9.8. 4.9.8.1. 4.9.8.2. 4.9.9. Mouse Specic Locus Test . . . . . Dominant Lethal Test . . . . . . . . . Test Systems Providing Indirect Evidence for DNA Damage . . . . . Unscheduled DNA Synthesis (UDS) Assays . . . . . . . . . . . . . . . . . . Sister-Chromatid Exchange Test . . Tests for Chromosome Aberrations (Cytogenetic Assays) . . . . . . . . . Cytogenetic Damage and its Consequences . . . . . . . . . . . . . In Vitro Cytogenetic Assays . . . . . In Vivo Cytogenetic Assays . . . . . Malignant Transformation of Mammalian Cells in Culture . . . . In Vivo Carcinogenicity Studies of Limited Duration . . . . . . . . . . . Induction of Altered Foci in the Rodent Liver . . . . . . . . . . . . . . Induction of Lung Tumors in Specic Sensitive Strains of Mice . Induction of Skin Tumors in Specic Sensitive Strains of Mice . . . . . . . Methods to Assess Primary DNA Damage . . . . . . . . . . . . . . . . . Alkaline Elution Techniques . . . . Methods to Detect and Quantify DNA Modications . . . . . . . . . . Interpretation of Results Obtained in Short-Term Tests . . . . . . . . . . . . 114 114 114 114 115 116 116 117 117 118 119 119 120 120 120 120 121 122 5.4. 6. 4.11.1. 4.11.2. 4.12. 5. 5.1. 4.10. 4.11. Evaluation of Toxic Effects on the Immune System . . . . . . . . . . . . Toxicological