A Textbook of modern toxicology

Preface xix Contributors xxi I Introduction 1 1 Introduction to Toxicology 3 Ernest Hodgson 1.1 Definition and Scope, Relationship to Other Sciences, and History 3 1.1.1 Definition and Scope 3 1.1.2 Relationship to Other Sciences 8 1.1.3 A Brief History of Toxicology 8 1.2 Dose-Response Relationships 10 1.3 Sources of Toxic Compounds 10 1.3.1 Exposure Classes 11 1.3.2 Use Classes 11 1.4 Movement of Toxicants in the Environment 11 Suggested Reading 12 2 Introduction to Biochemical and Molecular Methods in Toxicology 13 Ernest Hodgson, Gerald A. LeBlanc, Sharon A. Meyer, and Robert C. Smart 2.1 Introduction 13 2.2 Cell Culture Techniques 13 2.2.1 Suspension Cell Culture 14 2.2.2 Monolayer Cell Culture 14 2.2.3 Indicators of Toxicity in Cultured Cells 14 2.3 Molecular Techniques 16 2.3.1 Molecular Cloning 17 2.3.2 cDNA and Genomic Libraries 17 2.3.3 Northern and Southern Blot Analyses 18 2.3.4 Polymerase Chain Reaction (PCR) 18 2.3.5 Evaluation of Gene Expression, Regulation, and Function 19 2.4 Immunochemical Techniques 19 Suggested Reading 22 3 Toxicant Analysis and Quality Assurance Principles 23 Ross B. Leidy 3.1 Introduction 23 3.2 General Policies Related to Analytical Laboratories 23 v vi CONTENTS 3.2.1 Standard Operating Procedures (SOPs) 24 3.2.2 QA/QC Manuals 24 3.2.3 Procedural Manuals 24 3.2.4 Analytical Methods Files 25 3.2.5 Laboratory Information Management System (LIMS) 25 3.3 Analytical Measurement System 26 3.3.1 Analytical Instrument Calibration 26 3.3.2 Quantitation Approaches and Techniques 26 3.4 Quality Assurance (QA) Procedures 27 3.5 Quality Control (QC) Procedures 27 3.6 Summary 28 Suggested Reading 28 II Classes of Toxicants 31 4 Exposure Classes, Toxicants in Air, Water, Soil, Domestic and Occupational Settings 33 W. Gregory Cope 4.1 Air Pollutants 33 4.1.1 History 33 4.1.2 Types of Air Pollutants 34 4.1.3 Sources of Air Pollutants 35 4.1.4 Examples of Air Pollutants 36 4.1.5 Environmental Effects 38 4.2 Water and Soil Pollutants 40 4.2.1 Sources of Water and Soil Pollutants 40 4.2.2 Examples of Pollutants 41 4.3 Occupational Toxicants 44 4.3.1 Regulation of Exposure Levels 44 4.3.2 Routes of Exposure 45 4.3.3 Examples of Industrial Toxicants 46 Suggested Reading 48 5 Classes of Toxicants: Use Classes 49 W. Gregory Cope, Ross B. Leidy, and Ernest Hodgson 5.1 Introduction 49 5.2 Metals 49 5.2.1 History 49 5.2.2 Common Toxic Mechanisms and Sites of Action 50 5.2.3 Lead 51 5.2.4 Mercury 52 5.2.5 Cadmium 52 5.2.6 Chromium 53 5.2.7 Arsenic 53 5.2.8 Treatment of Metal Poisoning 54 CONTENTS vii 5.3 Agricultural Chemicals (Pesticides) 54 5.3.1 Introduction 54 5.3.2 Definitions and Terms 55 5.3.3 Organochlorine Insecticides 57 5.3.4 Organophosphorus Insecticides 58 5.3.5 Carbamate Insecticides 60 5.3.6 Botanical Insecticides 60 5.3.7 Pyrethroid Insecticides 61 5.3.8 New Insecticide Classes 61 5.3.9 Herbicides 62 5.3.10 Fungicides 63 5.3.11 Rodenticides 63 5.3.12 Fumigants 64 5.3.13 Conclusions 64 5.4 Food Additives and Contaminants 64 5.5 Toxins 65 5.5.1 History 65 5.5.2 Microbial Toxins 66 5.5.3 Mycotoxins 66 5.5.4 Algal Toxins 67 5.5.5 Plant Toxins 68 5.5.6 Animal Toxins 68 5.6 Solvents 70 5.7 Therapeutic Drugs 70 5.8 Drugs of Abuse 71 5.9 Combustion Products 71 5.10 Cosmetics 71 Suggested Reading 73 III Toxicant Processing In vivo 75 6 Absorption and Distribution of Toxicants 77 Ronald E. Baynes and Ernest Hodgson 6.1 Introduction 77 6.2 Cell Membranes 78 6.3 Mechanisms of Transport 80 6.3.1 Passive Diffusion 80 6.3.2 Carrier-Mediated Membrane Transport 83 6.4 Physicochemical Properties Relevant to Diffusion 85 6.4.1 Ionization 86 6.4.2 Partition Coefficients 87 6.5 Routes of Absorption 88 6.5.1 Extent of Absorption 88 6.5.2 Gastrointestinal Absorption 89 6.5.3 Dermal Absorption 91 6.5.4 Respiratory Penetration 94 viii CONTENTS 6.6 Toxicant Distribution 97 6.6.1 Physicochemical Properties and Protein Binding 97 6.6.2 Volume of Distribution (Vd ) 103 6.7 Toxicokinetics 105 Suggested Reading 109 7 Metabolism of Toxicants 111 Randy L. Rose and Ernest Hodgson 7.1 Introduction 111 7.2 Phase I Reactions 112 7.2.1 The Endoplasmic Reticulum, Microsomal Preparation, and Monooxygenations 112 7.2.2 The Cytochrome P450-Dependent Monooxygenase System 113 7.2.3 The Flavin-Containing Monooxygenase (FMO) 128 7.2.4 Nonmicrosomal Oxidations 130 7.2.5 Cooxidation by Cyclooxygenases 132 7.2.6 Reduction Reactions 133 7.2.7 Hydrolysis 135 7.2.8 Epoxide Hydration 135 7.2.9 DDT Dehydrochlorinase 136 7.3 Phase II Reactions 137 7.3.1 Glucuronide Conjugation 138 7.3.2 Glucoside Conjugation 139 7.3.3 Sulfate Conjugation 139 7.3.4 Methyltransferases 141 7.3.5 Glutathione S-Transferases (GSTs) and Mercapturic Acid Formation 143 7.3.6 Cysteine Conjugate β-Lyase 145 7.3.7 Acylation 145 7.3.8 Phosphate Conjugation 148 Suggested Reading 148 8 Reactive Metabolites 149 Randy L. Rose and Patricia E. Levi 8.1 Introduction 149 8.2 Activation Enzymes 150 8.3 Nature and Stability of Reactive Metabolites 151 8.3.1 Ultra-short-lived Metabolites 151 8.3.2 Short-lived Metabolites 152 8.3.3 Longer-lived Metabolites 152 8.4 Fate of Reactive Metabolites 153 8.4.1 Binding to Cellular Macromolecules 153 8.4.2 Lipid Peroxidation 153 8.4.3 Trapping and Removal: Role of Glutathione 153 8.5 Factors Affecting Toxicity of Reactive Metabolites 154 8.5.1 Levels of Activating Enzymes 154 CONTENTS ix 8.5.2 Levels of Conjugating Enzymes 154 8.5.3 Levels of Cofactors or Conjugating Chemicals 154 8.6 Examples of Activating Reactions 154 8.6.1 Parathion 155 8.6.2 Vinyl Chloride 155 8.6.3 Methanol 155 8.6.4 Aflatoxin B1 156 8.6.5 Carbon Tetrachloride 156 8.6.6 Acetylaminofluorene 157 8.6.7 Benzo(a)pyrene 158 8.6.8 Acetaminophen 158 8.6.9 Cycasin 159 8.7 Future Developments 160 Suggested Reading 161 9 Chemical and Physiological Influences on Xenobiotic Metabolism 163 Randy L. Rose and Ernest Hodgson 9.1 Introduction 163 9.2 Nutritional Effects 163 9.2.1 Protein 163 9.2.2 Carbohydrates 164 9.2.3 Lipids 164 9.2.4 Micronutrients 164 9.2.5 Starvation and Dehydration 165 9.2.6 Nutritional Requirements in Xenobiotic Metabolism 165 9.3 Physiological Effects 166 9.3.1 Development 166 9.3.2 Gender Differences 168 9.3.3 Hormones 169 9.3.4 Pregnancy 171 9.3.5 Disease 171 9.3.6 Diurnal Rhythms 172 9.4 Comparative and Genetic Effects 172 9.4.1 Variations Among Taxonomic Groups 173 9.4.2 Selectivity 181 9.4.3 Genetic Differences 181 9.5 Chemical Effects 184 9.5.1 Inhibition 185 9.5.2 Induction 190 9.5.3 Biphasic Effects: Inhibition and Induction 199 9.6 Environmental Effects 199 9.7 General Summary and Conclusions 201 Suggested Reading 201 10 Elimination of Toxicants 203 Gerald A. LeBlanc 10.1 Introduction 203 x CONTENTS 10.2 Transport 205 10.3 Renal Elimination 205 10.4 Hepatic Elimination 207 10.4.1 Entero-hepatic Circulation 208 10.4.2 Active Transporters of the Bile Canaliculus 209 10.5 Respiratory Elimination 210 10.6 Conclusion 210 Suggested Reading 211 IV Toxic Action 213 11 Acute Toxicity 215 Gerald A. LeBlanc 11.1 Introduction 215 11.2 Acute Exposure and Effect 215 11.3 Dose-response Relationships 217 11.4 Nonconventional Dose-response Relationships 219 11.5 Mechanisms of Acute Toxicity 220 11.5.1 Narcosis 220 11.5.2 Acetylcholinesterase Inhibition 220 11.5.3 Ion Channel Modulators 222 11.5.4 Inhibitors of Cellular Respiration 223 Suggested Reading 224 12 Chemical Carcinogenesis 225 Robert C. Smart 12.1 General Aspects of Cancer 225 12.2 Human Cancer 228 12.2.1 Causes, Incidence, and Mortality Rates of Human Cancer 228 12.2.2 Known Human Carcinogens 231 12.2.3 Classification of Human Carcinogens 233 12.3 Classes of Agents Associated with Carcinogenesis 236 12.3.1 DNA-Damaging Agents 237 12.3.2 Epigenetic Agents 239 12.4 General Aspects of Chemical Carcinogenesis 240 12.5 Initiation-Promotion Model for Chemical Carcinogenesis 241 12.6 Metabolic Activation of Chemical Carcinogens and DNA Adduct Formation 243 12.7 Oncogenes 245 12.7.1 Mutational Activation of Proto-oncogenes 245 12.7.2 Ras Oncogene 246 12.8 Tumor Suppressor Genes 247 12.8.1 Inactivation of Tumor Suppressor Genes 247 12.8.2 p53 Tumor Suppressor Gene 247 12.9 General Aspects of Mutagenicity 248 CONTENTS xi 12.10 Usefulness and Limitations of Mutagenicity Assays for the Identification of Carcinogens 249 Suggested Reading 250 13 Teratogenesis 251 Stacy Branch 13.1 Introduction 251 13.2 Principles of Teratology 251 13.3 Mammalian Embryology Overview 252 13.4 Critical Periods 255 13.5 Historical Teratogens 256 13.5.1 Thalidomide 256 13.5.2 Accutane (Isotetrinoin) 256 13.5.3 Diethylstilbestrol (DES) 256 13.5.4 Alcohol 257 13.5.5 “Non Chemical” Teratogens 257 13.6 Testing Protocols 257 13.6.1 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use 258 13.6.2 International Conference of Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)—US FDA, 1994 258 13.6.3 Alternative Test Methods 259 13.7 Conclusions 259 Suggested Reading 259 V Organ Toxicity 261 14 Hepatotoxicity 263 Ernest Hodgson and Patricia E. Levi 14.1 Introduction 263 14.1.1 Liver Structure 263 14.1.2 Liver Function 263 14.2 Susceptibility of the Liver 264 14.3 Types of Liver Injury 264 14.3.1 Fatty Liver 264 14.3.2 Necrosis 266 14.3.3 Apoptosis 266 14.3.4 Cholestasis 266 14.3.5 Cirrhosis 266 14.3.6 Hepatitis 267 14.3.7 Oxidative Stress 267 14.3.8 Carcinogenesis 267 14.4 Mechanisms of Hepatotoxicity 268 14.5 Examples of Hepatotoxicants 269 14.5.1 Carbon Tetrachloride 269 14.5.2 Ethanol 270 xii CONTENTS 14.5.3 Bromobenzene 270 14.5.4 Acetaminophen 271 14.6 Metabolic Activation of Hepatotoxicants 272 Suggested Reading 272 15 Nephrotoxicity 273 Ernest Hodgson and Patricia E. Levi 15.1 Introduction 273 15.1.1 Structure of the Renal System 273 15.1.2 Function of the Renal System 273 15.2 Susceptibility of the Renal System 274 15.3 Examples of Nephrotoxicants 275 15.3.1 Metals 275 15.3.2 Aminoglycosides 276 15.3.3 Amphotericin B 276 15.3.4 Chloroform 277 15.3.5 Hexachlorobutadiene 277 15.3.6 Tetrafluoroethylene 278 Suggested Reading 278 16 Toxicology of the Nervous System 279 Bonita L. Blake 16.1 Introduction 279 16.2 The Nervous system 279 16.2.1 The Neuron 280 16.2.2 Neurotransmitters and their Receptors 282 16.2.3 Glial Cells 283 16.2.4 The Blood-Brain Barrier 284 16.2.5 The Energy-Dependent Nervous System 285 16.3 Toxicant Effects on the Nervous System 286 16.3.1 Structural Effects of Toxicants on Neurons 287 16.3.2 Effects of Toxicants on Other Cells 289 16.3.3 Toxicant-Mediated Alterations in Synaptic Function 290 16.4 Neurotoxicity Testing 293 16.4.1 In vivo Tests of Human Exposure 293 16.4.2 In vivo Tests of Animal Exposure 295 16.4.3 In vitro Neurochemical and Histopathological End Points 296 16.5 Summary 297 Suggested Reading 297 17 Endocrine System 299 Gerald A. LeBlanc 17.1 Introduction 299 17.2 Endocrine System 299 17.2.1 Nuclear Receptors 302 17.2.2 Membrane-Bound Steroid Hormone Receptors 304 CONTENTS xiii 17.3 Endocrine Disruption 306 17.3.1 Hormone Receptor Agonists 306 17.3.2 Hormone Receptor Antagonists 308 17.3.3 Organizational versus Activational Effects of Endocrine Toxicants 309 17.3.4 Inhibitors of Hormone Synthesis 310 17.3.5 Inducers of Hormone Clearance 310 17.3.6 Hormone Displacement from Binding Proteins 311 17.4 Incidents of Endocrine Toxicity 311 17.4.1 Organizational Toxicity 311 17.4.2 Activational Toxicity 312 17.4.3 Hypothyroidism 313 17.5 Conclusion 314 Suggested Reading 315 18 Respiratory Toxicity 317 Ernest Hodgson, Patricia E. Levi, and James C. Bonner 18.1 Introduction 317 18.1.1 Anatomy 317 18.1.2 Cell Types 317 18.1.3 Function 317 18.2 Susceptibility of the Respiratory System 320 18.2.1 Nasal 320 18.2.2 Lung 320 18.3 Types of Toxic Response 320 18.3.1 Irritation 320 18.3.2 Cell Necrosis 321 18.3.3 Fibrosis 321 18.3.4 Emphysema 321 18.3.5 Allergic Responses 321 18.3.6 Cancer 321 18.3.7 Mediators of Toxic Responses 322 18.4 Examples of Lung Toxicants Requiring Activation 322 18.4.1 Introduction 322 18.4.2 Monocrotaline 322 18.4.3 Ipomeanol 323 18.4.4 Paraquat 324 18.5 Defense Mechanisms 324 Suggested Reading 325 19 Immunotoxicity 327 MaryJane K. Selgrade 19.1 Introduction 327 19.2 The Immune System 327 xiv CONTENTS 19.3 Immune Suppression 330 19.4 Classification of Immune-Mediated Injury (Hypersensitivity) 335 19.5 Effects of Chemicals on Allergic Disease 336 19.5.1 Allergic Contact Dermatitis 337 19.5.2 Respiratory Allergens 338 19.5.3 Adjuvants 340 19.6 Emerging Issues: Food Allergies, Autoimmunity, and the Developing Immune System 341 Suggested Reading 342 20 Reproductive System 343 Stacy Branch 20.1 Introduction 343 20.2 Male Reproductive Physiology 343 20.3 Mechanisms and Targets of Male Reproductive Toxicants 344 20.3.1 General Mechanisms 344 20.3.2 Effects on Germ Cells 345 20.3.3 Effects on Spermatogenesis and Sperm Quality 345 20.3.4 Effects on Sexual Behavior 345 20.3.5 Effects on Endocrine Function 345 20.4 Female Reproductive Physiology 346 20.5 Mechanisms and Targets of Female Reproductive Toxicants 347 20.5.1 Tranquilizers, Narcotics, and Social Drugs 347 20.5.2 Endocrine Disruptors (EDs) 348 20.5.3 Effects on Germ Cells 348 20.5.4 Effects on the Ovaries and Uterus 348 20.5.5 Effects on Sexual Behavior 348 Suggested Reading 349 VI Applied Toxicology 351 21 Toxicity Testing 353 Helen Cunny and Ernest Hodgson 21.1 Introduction 353 21.2 Experimental Administration of Toxicants 355 21.2.1 Introduction 355 21.2.2 Routes of Administration 356 21.3 Chemical and Physical Properties 358 21.4 Exposure and Environmental Fate 358 21.5 In vivo Tests 358 21.5.1 Acute and Subchronic Toxicity Tests 359 21.5.2 Chronic Tests 370 21.5.3 Reproductive Toxicity and Teratogenicity 371 21.5.4 Special Tests 378 21.6 In vitro and Other Short-Term Tests 385 21.6.1 Introduction 385 21.6.2 Prokaryote Mutagenicity 385 CONTENTS xv 21.6.3 Eukaryote Mutagenicity 387 21.6.4 DNA Damage and Repair 389 21.6.5 Chromosome Aberrations 390 21.6.6 Mammalian Cell Transformation 392 21.6.7 General Considerations and Testing Sequences 393 21.7 Ecological Effects 393 21.7.1 Laboratory Tests 394 21.7.2 Simulated Field Tests 394 21.7.3 Field Tests 395 21.8 Risk Analysis 395 21.9 The Future of Toxicity Testing 395 Suggested Reading 396 22 Forensic and Clinical Toxicology 399 Stacy Branch 22.1 Introduction 399 22.2 Foundations of Forensic Toxicology 399 22.3 Courtroom Testimony 400 22.4 Investigation of Toxicity-Related Death/Injury 400 22.4.1 Documentation Practices 401 22.4.2 Considerations for Forensic Toxicological Analysis 401 22.4.3 Drug Concentrations and Distribution 402 22.5 Laboratory Analyses 403 22.5.1 Colorimetric Screening Tests 403 22.5.2 Thermal Desorption 403 22.5.3 Thin-Layer Chromatography (TLC) 403 22.5.4 Gas Chromatography (GC) 404 22.5.5 High-Performance Liquid Chromatography (HPLC) 404 22.5.6 Enzymatic Immunoassay 404 22.6 Analytical Schemes for Toxicant Detection 404 22.7 Clinical Toxicology 405 22.7.1 History Taking 406 22.7.2 Basic Operating Rules in the Treatment of Toxicosis 406 22.7.3 Approaches to Selected Toxicoses 407 Suggested Reading 409 23 Prevention of Toxicity 411 Ernest Hodgson 23.1 Introduction 411 23.2 Legislation and Regulation 411 23.2.1 Federal Government 412 23.2.2 State Governments 416 23.2.3 Legislation and Regulation in Other Countries 416 23.3 Prevention in Different Environments 417 23.3.1 Home 417 23.3.2 Workplace 418 23.3.3 Pollution of Air, Water, and Land 419 xvi CONTENTS 23.4 Education 420 Suggested Reading 421 24 Human Health Risk Assessment 423 Ronald E. Baynes 24.1 Introduction 423 24.2 Risk Assessment Methods 424 24.2.1 Hazard Identification 424 24.2.2 Exposure Assessment 425 24.2.3 Dose Response and Risk Characterization 426 24.3 Noncancer Risk Assessment 427 24.3.1 Default Uncertainty and Modifying Factors 428 24.3.2 Derivation of Developmental Toxicant RfD 429 24.3.3 Determination of RfD and RfC of Naphthalene with the NOAEL Approach 430 24.3.4 Benchmark Dose Approach 430 24.3.5 Determination of BMD and BMDL for ETU 431 24.3.6 Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient 432 24.3.7 Chemical Mixtures 432 24.4 Cancer Risk Assessment 433 24.5 PBPK Modeling 436 Suggested Reading 437 VII Environmental Toxicology 439 25 Analytical Methods in Toxicology 441 Ross B. Leidy 25.1 Introduction 441 25.2 Chemical and Physical Methods 442 25.2.1 Sampling 442 25.2.2 Experimental Studies 446 25.2.3 Forensic Studies 446 25.2.4 Sample Preparation 447 25.2.5 Separation and Identification 448 25.2.6 Spectroscopy 455 25.2.7 Other Analytical Methods 460 Suggested Reading 461 26 Basics of Environmental Toxicology 463 Gerald A. LeBlanc 26.1 Introduction 463 26.2 Environmental Persistence 464 26.2.1 Abiotic Degradation 465 CONTENTS xvii 26.2.2 Biotic Degradation 465 26.2.3 Nondegradative Elimination Processes 466 26.3 Bioaccumulation 467 26.3.1 Factors That Influence Bioaccumulation 469 26.4 Toxicity 470 26.4.1 Acute Toxicity 470 26.4.2 Mechanisms of Acute Toxicity 471 26.4.3 Chronic Toxicity 472 26.4.4 Species-Specific Chronic Toxicity 473 26.4.5 Abiotic and Biotic Interactions 474 26.5 Conclusion 477 Suggested Reading 477 27 Transport and Fate of Toxicants in the Environment 479 Damian Shea 27.1 Introduction 479 27.2 Sources of Toxicants to the Environment 480 27.3 Transport Processes 483 27.3.1 Advection 483 27.3.2 Diffusion 485 27.4 Equilibrium Partitioning 487 27.4.1 Air–Water Partitioning 487 27.4.2 Octanol–Water Partitioning 488 27.4.3 Lipid–Water Partitioning 488 27.4.4 Particle–Water Partitioning 489 27.5 Transformation Processes 490 27.5.1 Reversible Reactions 490 27.5.2 Irreversible Reactions 493 27.6 Environmental Fate Models 497 Suggested Reading 498 28 Environmental Risk Assessment 501 Damian Shea 28.1 Introduction 501 28.2 Formulating the Problem 503 28.2.1 Selecting Assessment End Points 503 28.2.2 Developing Conceptual Models 506 28.2.3 Selecting Measures 506 28.3 Analyzing Exposure and Effects Information 507 28.3.1 Characterizing Exposure 508 28.3.2 Characterizing Ecological Effects 510 28.4 Characterizing Risk 512 28.4.1 Estimating Risk 512 28.4.2 Describing Risk 512 xviii CONTENTS 28.5 Managing Risk 516 Suggested Reading 517 VIII Summary 519 29 Future Considerations for Environmental and Human Health 521 Ernest Hodgson 29.1 Introduction 521 29.2 Risk Management 522 29.3 Risk Assessment 523 29.4 Hazard and Exposure Assessment 523 29.5 In vivo Toxicity 523 29.6 In vitro Toxicity 524 29.7 Biochemical and Molecular Toxicology 524 29.8 Development of Selective Toxicants 524 Glossary 525 Index 543