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Toxicology in Occupational and Environmental Setting

0,78

stron

2316

University Wuerzburg

2005

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1. Introduction 6

1.1. De.nition and Scope . 6

1.2. Fields . 6

1.3. History . 8

1.4. Information Resources . 9

1.5. Terminology of Toxic Effects . 11

1.6. Types of Toxic Effects 13

1.7. Dose–Response: a Fundamental Issue in Toxicology 13

1.7.1. Graphics and Calculations 15

1.8. Dose-Response Relationships for Cumulative Effects 18

1.9. Factors In.uencing Dose–Response 19

1.9.1. Routes of Exposure 19

1.9.2. Frequency of Exposure 20

1.9.3. Species-Speci.c Differences in Toxicokinetics . 21

1.9.4. Miscellaneous Factors In.uencing the Magnitude of Toxic Responses . 22

1.10. Exposure to Mixtures 23

2. Absorption, Distribution, Biotransformation and Elimination of Xenobiotics 23

2.1. Disposition of Xenobiotics . 23

2.2. Absorption . 24

2.2.1. Membranes . 24

2.2.2. Penetration of Membranes by Chemicals 25

2.2.3. Mechanisms of Transport of Xenobiotics through Membranes 26

2.2.4. Absorption . 27

2.2.4.1. Dermal Absorption 27

2.2.4.2. Gastrointestinal Absorption . 30

2.2.4.3. Absorption of Xenobiotics by the Respiratory System 31

2.3. Distribution of Xenobiotics by Body Fluids 33

2.4. Storage of Xenobiotics in Organs and Tissues . 36

2.5. Biotransformation 37

2.5.1. Phase-I and Phase-II Reactions . 37

2.5.2. Localization of the Biotransformation Enzymes . 38

2.5.3. Role of Biotransformation in Detoxication and Bioactivation . 38

2.5.4. Phase-I Enzymes and their Reactions 39

2.5.4.1. Microsomal Monooxygenases: Cytochrome P450 . 39

2.5.4.2. Microsomal Monooxygenases: Flavin-Dependent Monooxygenases 41

2.5.4.3. Peroxidative Biotransformation: Prostaglandin-synthase 42

2.5.4.4. Nonmicrosomal Oxidations . 44

2.5.4.5. Hydrolytic Enzymes in Phase-I Biotransformation Reactions 44

2.5.5. Phase-II Biotransformation Enzymes and their Reactions 45

2.5.5.1. UDP-Glucuronyl Transferases . 45

2.5.5.2. Sulfate Conjugation 46

2.5.5.3. Methyl Transferases 47

2.5.5.4. N-Acetyl Transferases 47

2.5.5.5. Amino Acid Conjugation 47

2.5.5.6. Glutathione Conjugation of Xenobiotics and Mercapturic Acid

Excretion 48

2.5.6. Bioactivation of Xenobiotics 49

2.5.6.1. Formation of Stable but Toxic Metabolites . 50

2.5.6.2. Biotransformation to Reactive Electrophiles 50

2.5.6.3. Biotransformation of Xenobiotics to Radicals . 52

2.5.6.4. Formation of Reactive Oxygen Metabolites by Xenobiotics . 53

2.5.6.5. Detoxication and Interactions of Reactive Metabolites with Cellular Macromolecules 53

2.5.6.6. Interaction of Reactive Intermediates with Cellular Macromolecules 55

2.5.7. Factors Modifying Biotransformation and Bioactivation 58

2.5.7.1. Host Factors Affecting Biotransformation . 58

2.5.7.2. Chemical-Related Factors that Influence Biotransformation . 62

2.5.8. Elimination of Xenobiotics and their Metabolites . 62

2.5.8.1. Renal Excretion 63

2.5.8.2. Hepatic Excretion . 64

2.5.8.3. Xenobiotic Elimination by the Lungs . 65

2.6. Toxicokinetics . 65

2.6.1. Pharmacokinetic Models . 66

2.6.1.1. One-Compartment Model 66

2.6.1.2. Two-Compartment Model 67

2.6.2. Physiologically Based Pharmacokinetic Models . 68

3. Mechanisms of Acute and Chronic Toxicity and Mechanisms of

Chemical Carcinogenesis 69

3.1. Biochemical Basis of Toxicology . 69

3.2. Receptor-Ligand Interactions 70

3.2.1. Basic Interactions . 70

3.2.2. Interference with Excitable Membrane Functions 72

3.2.3. Interference of Xenobiotics with Oxygen Transport, Cellular Oxygen Utilization, and Energy

Production 73

3.3. Binding of Xenobiotics to Biomolecules 74

3.3.1. Binding of Xenobiotics or their Metabolites to Cellular Proteins 75

3.3.2. Interaction of Xenobiotics or their Metabolites with Lipid Constituents 76

3.3.3. Interactions of Xenobiotics or their Metabolites with nucleic Acids . 76

3.4. Perturbation of Calcium Homeostasis by Xenobiotics or their Metabolites . 77

3.5. Nonlethal Genetic Alterations in Somatic Cells and Carcinogenesis 78

3.6. DNA Structure and Function . 79

3.6.1. DNA Structure . 79

3.6.2. Transcription 80

3.6.3. Translation . 80

3.6.4. Regulation of Gene Expression . 80

3.6.5. DNA Repair . 81

3.7. Molecular Mechanisms of Malignant Transformation and Tumor Formation 81

3.7.1. Mutations 81

3.7.2. Causal Link between Mutation and Cancer . 83

3.7.3. Proto-Oncogenes and Tumor-Suppressor Genes as Genetic Targets 83

3.7.4. Genotoxic versus Nongenotoxic Mechanisms of Carcinogenesis . 84

3.8. Mechanisms of Chemically Induced Reproductive and Developmental Toxicity . 84

3.8.1. Embryotoxicity, Teratogenesis, and Transplacental Carcinogenesis . 85

3.8.2. Patterns of Dose–Response in Teratogenesis, Embryotoxicity, and Embryolethality 86

4. Methods in Toxicology . 87

4.1. Toxicological Studies: General Aspects . 87

4.2. Acute Toxicity . 90

4.2.1. Testing for Acute Toxicity by the Oral Route: LD50 Test and Fixed-Dose Method 90

4.2.2. Testing for Acute Skin Toxicity 92

4.2.3. Testing for Acute Toxicity by Inhalation 94

4.3. Repeated-Dose Toxicity Studies: Subacute, Subchronic and Chronic Studies . 95

4.4. Ophtalmic Toxicity 96

4.5. Sensitization Testing . 97

4.6. Phototoxicity and Photosensitization Testing . 99

4.7. Reproductive and Developmental Toxicity Tests . 99

4.7.1. Fertility and General Reproductive Performance 100

4.7.2. Embryotoxicity and Teratogenicity 100

4.7.3. Peri- and Postnatal Toxicity . 101

4.7.4. Multigeneration Studies . 101

4.7.5. The Role of Maternal Toxicity in Teratogenesis 102

4.7.6. In Vitro Tests for Developmental Toxicity . 102

4.8. Bioassays to Determine the Carcinogenicity of Chemicals in Rodents . 103

4.9. In Vitro and In Vivo Short-term Tests for Genotoxicity 105

4.9.1. Microbial Tests for Mutagenicity 106

4.9.1.1. The Ames Test for Bacterial Mutagenicity . 106

4.9.1.2. Mutagenicity Tests in Escherichia coli 111

4.9.1.3. Fungal Mutagenicity Tests 112

4.9.2. Eukaryotic Tests for Mutagenicity . 112

4.9.2.1. Mutation Tests in Drosophila melanogaster 112

4.9.2.2. In Vitro Mutagenicity Tests in Mammalian Cells . 112

4.9.3. In Vivo Mammalian Mutation Tests 114

4.9.3.1. Mouse Somatic Spot Test 114

4.9.3.2. Mouse Speci.c Locus Test . 114

4.9.3.3. Dominant Lethal Test . 114

4.9.4. Test Systems Providing Indirect Evidence for DNA Damage . 114

4.9.4.1. Unscheduled DNA Synthesis (UDS) Assays 114

4.9.4.2. Sister-Chromatid Exchange Test 115

4.9.5. Tests for Chromosome Aberrations (Cytogenetic Assays) . 116

4.9.5.1. Cytogenetic Damage and its Consequences . 116

4.9.5.2. In Vitro Cytogenetic Assays . 117

4.9.5.3. In Vivo Cytogenetic Assays . 117

4.9.6. Malignant Transformation of Mammalian Cells in Culture 118

4.9.7. In Vivo Carcinogenicity Studies of Limited Duration . 119

4.9.7.1. Induction of Altered Foci in the Rodent Liver 119

4.9.7.2. Induction of Lung Tumors in Specific Sensitive Strains of Mice . 120

4.9.7.3. Induction of Skin Tumors in Specific Sensitive Strains of Mice . 120

4.9.8. Methods to Assess Primary DNA Damage . 120

4.9.8.1. Alkaline Elution Techniques 120

4.9.8.2. Methods to Detect and Quantify DNA Modi.cations 121

4.9.9. Interpretation of Results Obtained in Short-Term Tests 122

4.10. Evaluation of Toxic Effects on the Immune System 123

4.11. Toxicological Evaluation of the Nervous System 124

4.11.1. Functional Observational Battery . 124

4.11.2. Locomotor Activity 125

4.12. Effects on the Endocrine System . 126

5. Evaluation of Toxic Effects 126

5.1. Acceptable risk, Comparison of Risks, and Establishing Acceptable Levels of Risk . 127