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PREFACE TO THE FOURTH EDITION xxi CONTRIBUTORS xxiii PART I INTRODUCTION 1 1. Introduction to Toxicology 3Ernest Hodgson 1.1 Definition and Scope 3 1.2 Relationship to Other Sciences 9 1.3 A Brief History of Toxicology 10 1.4 Dose–Response Relationships 11 1.5 Sources of Toxic Compounds 12 1.6 Movement of Toxicants in the Environment 12 Bibliography and Suggested Reading 13 Sample Questions 14 2. Introduction to Biochemical and Molecular Methods in Toxicology 15Ernest Hodgson, Gerald A. Leblanc, Sharon A. Meyer, and Robert C. Smart 2.1 Introduction 15 2.2 Cell Culture Techniques 15 2.3 Molecular Techniques 19 2.4 Immunochemical Techniques 23 2.5 Proteomics 26 2.6 Metabolomics 26 2.7 Bioinformatics 26 2.8 Summary and Conclusions 27 Bibliography and Suggested Reading 27 Sample Questions 27 PART II CLASSES OF TOXICANTS 29 3. Exposure Classes, Toxicants in Air, Water, Soil, Domestic, and Occupational Settings 31W. Gregory Cope 3.1 Air Pollutants 31 3.2 Water and Soil Pollutants 38 3.3 Occupational Toxicants 42 Bibliography and Suggested Reading 46 Air Pollutants 46 Water and Soil Pollutants 47 Occupational Toxicants 47 Sample Questions 47 4. Classes of Toxicants: Use Classes 49W. Gregory Cope and Ernest Hodgson 4.1 Introduction 49 4.2 Metals 49 4.3 Agricultural Chemicals (Pesticides) 55 4.4 Food Additives and Contaminants 65 4.5 Toxins 66 4.6 Solvents 71 4.7 Therapeutic Drugs 71 4.8 Drugs of Abuse 72 4.9 Combustion Products 72 4.10 Cosmetics 74 Bibliography and Suggested Reading 74 General 74 Metals 74 Pesticides 75 Toxins 75 Solvents 75 Therapeutic Drugs 75 Sample Questions 75 PART III TOXICANT PROCESSING IN VIVO 77 5. Absorption and Distribution of Toxicants 79Ronald E. Baynes and Ernest Hodgson 5.1 Introduction 79 5.2 Cell Membranes 80 5.3 Mechanisms of Transport 82 5.4 Physicochemical Properties Relevant to Diffusion 87 5.5 Routes of Absorption 90 5.6 Toxicant Distribution 99 5.7 Toxicokinetics 108 Bibliography and Suggested Reading 112 Sample Questions 113 6. Metabolism of Toxicants 115Ernest Hodgson and Randy L. Rose 6.1 Introduction 115 6.2 Phase I Reactions 116 6.3 Phase II Reactions 143 Bibliography and Suggested Reading 154 Sample Questions 155 7. Reactive Metabolites 157Ernest Hodgson and Randy L. Rose 7.1 Introduction 157 7.2 Activation Enzymes 158 7.3 Nature and Stability of Reactive Metabolites 160 7.4 Fate of Reactive Metabolites 161 7.5 Factors Affecting Toxicity of Reactive Metabolites 162 7.6 Reactive Oxygen Species 163 7.7 Examples of Activating Reactions 164 7.8 Summary and Conclusions 170 Bibliography and Suggested Reading 171 Sample Questions 171 8. Chemical and Physiological Effects on Xenobiotic Metabolism 173Andrew D. Wallace and Ernest Hodgson 8.1 Introduction 173 8.2 Nutritional Effects 173 8.3 Physiological Effects 176 8.4 Comparative and Genetic Effects 182 8.5 Chemical Effects 191 8.6 Environmental Effects 207 8.7 Summary and Conclusions 209 Bibliography and Suggested Reading 210 Sample Questions 211 9. Elimination of Toxicants 213Gerald A. Leblanc 9.1 Introduction 213 9.2 Transport 215 9.3 Renal Elimination 216 9.4 Hepatic Elimination 217 9.5 Respiratory Elimination 220 9.6 Conclusion 221 Bibliography and Suggested Reading 221 Sample Questions 222 PART IV TOXIC ACTION 223 10. Acute Toxicity 225Gerald A. Leblanc 10.1 Introduction 225 10.2 Acute Exposure and Effect 225 10.3 Dose–Response Relationships 227 10.4 Nonconventional Dose–Response Relationships 229 10.5 Alternative Methods 230 10.6 Mechanisms of Acute Toxicity 231 Bibliography and Suggested Reading 236 Sample Questions 236 11. Chemical Carcinogenesis and Mutagenesis 237Robert C. Smart 11.1 DNA Damage and Mutagenesis 237 11.2 General Aspects of Cancer 239 11.3 Human Cancer 242 11.4 Classes of Agents That Are Associated with Carcinogenesis 251 11.5 General Aspects of Chemical Carcinogenesis 254 11.6 Oncogenes 259 11.7 Tumor Suppressor Genes 262 Bibliography and Suggested Reading 264 Sample Questions 264 12. Teratogenesis 265Jill A. Barnes and Ida M. Washington 12.1 Introduction 265 12.2 Overview of Embryonic Development 266 12.3 Principles of Teratogenesis 268 12.4 Mechanisms of Teratogenesis 268 12.5 Future Considerations 272 Bibliography and Suggested Reading 272 Sample Questions 272 PART V ORGAN TOXICITY 275 13. Hepatotoxicity 277Andrew D. Wallace and Sharon A. Meyer 13.1 Introduction 277 13.2 Susceptibility of the Liver 279 13.3 Types of Liver Injury 279 13.4 Mechanisms of Hepatotoxicity 283 13.5 Examples of Hepatotoxicants 285 13.6 Metabolic Activation of Hepatotoxicants 288 Bibliography and Suggested Reading 289 Sample Questions 289 14. Nephrotoxicity 291Joan B. Tarloff and Andrew D. Wallace 14.1 Introduction 291 14.2 Factors Contributing to Nephrotoxicity 292 14.3 Examples of Nephrotoxicants 293 14.4 Summary 301 Bibliography and Suggested Reading 301 Sample Questions 302 15. Toxicology of the Nervous System 303Bonita L. Blake 15.1 Introduction 303 15.2 The Nervous System 303 15.3 Toxicant Effects on the Nervous System 312 15.4 Neurotoxicity Testing 317 15.5 Summary 321 Bibliography and Suggested Reading 322 Sample Questions 322 16. Reproductive System 323Heather Patisaul 16.1 Introduction 323 16.2 The Hypothalamic–Pituitary–Gonadal Axis 324 16.3 Male Reproductive Physiology 326 16.4 Disruption of Male Reproduction By Toxicants 330 16.5 Female Reproductive Physiology 332 16.6 Disruption of Female Reproduction by Toxicants 335 16.7 Summary 341 Bibliography and Suggested Reading 341 Sample Questions 343 17. Endocrine Toxicology 345Gerald A. Leblanc 17.1 Introduction 345 17.2 Endocrine System 345 17.3 Endocrine Disruption 352 17.4 Incidents of Endocrine Toxicity 358 17.5 Conclusion 361 Bibliography and Suggested Reading 362 Sample Questions 362 18. Respiratory Toxicology 363James C. Bonner 18.1 Introduction 363 18.2 Anatomy and Function of the Respiratory Tract 363 18.3 Toxicant–Induced Lung Injury, Remodeling, and Repair 373 18.4 Occupational and Environmental Lung Diseases 380 Bibliography and Suggested Reading 385 Sample Questions 385 19. Immune System 387MaryJane K. Selgrade 19.1 Introduction 387 19.2 The Immune System 388 19.3 Immune Suppression 391 19.4 Classification of Immune–Mediated Injury (Hypersensitivity) 396 19.5 Effects of Chemicals on Allergic Disease 398 19.6 Other Issues: Autoimmunity and the Developing Immune System 403 Bibliography and Suggested Reading 404 Sample Questions 404 PART VI APPLIED TOXICOLOGY 407 20. Toxicity Testing 409Ernest Hodgson and Helen Cunny 20.1 Introduction 409 20.2 Experimental Administration of Toxicants 412 20.3 Chemical and Physical Properties 414 20.4 Exposure and Environmental Fate 414 20.5 In Vivo Tests 415 20.6 In Vitro and Other Short–Term Tests 442 20.7 Ecological Effects 451 20.8 Risk Analysis 453 20.9 The Future of Toxicity Testing 453 Bibliography and Suggested Reading 454 Sample Questions 455 21. Forensic and Clinical Toxicology 457Sharon A. Meyer and Bonita L. Blake 21.1 Introduction 457 21.2 Forensic Toxicology 457 21.3 Clinical Toxicology 462 21.4 Analytical Methods in Forensic and Clinical Toxicology 469 Bibliography and Suggested Reading 472 Sample Questions 473 22. Prevention of Toxicity 475Ernest Hodgson 22.1 Introduction 475 22.2 Legislation and Regulation 475 22.3 Prevention in Different Environments 482 22.4 Education 485 Bibliography and Suggested Reading 486 Sample Questions 487 23. Human Health Risk Assessment 489Ronald E. Baynes 23.1 Introduction 489 23.2 Risk Assessment Methods 490 23.3 Noncancer Risk Assessment 493 23.4 Cancer Risk Assessment 500 23.5 PBPK Modeling 503 Bibliography and Suggested Reading 504 Sample Questions 505 PART VII ENVIRONMENTAL TOXICOLOGY 507 24. Toxicant Analysis: Analytical Methods and Quality Assurance 509Chris Hofelt 24.1 Introduction 509 24.2 Environmental Sample Collection Methods 510 24.3 Analytical Techniques 514 24.4 Quantifi cation, QA, and QC 525 24.5 Summary 528 Bibliography and Suggested Reading 528 Sample Questions 529 25. Basics of Environmental Toxicology 531Gerald A. Leblanc and David B. Buchwalter 25.1 Introduction 531 25.2 Environmental Persistence 532 25.3 Bioaccumulation 535 25.4 Toxicity 539 25.5 Conclusion 546 Bibliography and Suggested Reading 547 Sample Questions 547 26. Transport and Fate of Toxicants in the Environment 549Damian Shea 26.1 Introduction 549 26.2 Sources of Toxicants to the Environment 550 26.3 Transport Processes 553 26.4 Equilibrium Partitioning 557 26.5 Transformation Processes 560 26.6 Environmental Fate Models 567 Bibliography and Suggested Reading 569 Sample Questions 569 27. Environmental Risk Assessment 571Damian Shea 27.1 Introduction 571 27.2 Formulating the Problem 573 27.3 Analyzing Exposure and Effects Information 578 27.4 Characterizing Risk 582 27.5 Managing Risk 587 Bibliography and Suggested Reading 588 Sample Questions 589 PART VIII NEW APPROACHES IN TOXICOLOGY 591 28. Perspectives on Informatics in Toxicology 593Seth W. Kullman, Carolyn J. Mattingly, Joel N. Meyer, and Andrew Whitehead 28.1 Introduction 593 28.2 Transcriptomics 594 28.3 Annotation Resources 595 28.4 Genome Sequencing, Resequencing and Genotyping 597 28.5 Epigenomic Profi ling 598 28.6 Computational Toxicology 599 28.7 Informatics Tools in Toxicology 601 Bibliography and Suggested Reading 602 Sample Question 605 29. Future Considerations 607Ernest Hodgson 29.1 Introduction 607 29.2 Risk Assessment 609 29.3 Risk Management 613 29.4 Risk Communication 613 29.5 In Vivo Toxicity 614 29.6 In Vitro Toxicity 614 29.7 Molecular and Biochemical Toxicology 614 29.8 Development of Selective Toxicants 615 29.9 Summary and Conclusions 616 Bibliography and Suggested Reading 616 Sample Questions 617 GLOSSARY 619 INDEX 638