A Textbook of Modern Toxicology

ERNEST HODGSON, PhD, is Distinguished Professor Emeritus of Toxicology at North Carolina State University. In addition to the previous editions of A Textbook of Modern Toxicology, he coedited Molecular and Biochemical Toxicology, Fourth Edition (Wiley) and its prior editions. Dr. Hodgson is the Editor of the Journal of Biochemical and Molecular Toxicology.

PREFACE TO THE FOURTH EDITION xxi

CONTRIBUTORS xxiii

PART I INTRODUCTION 1

1. Introduction to Toxicology 3
Ernest 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 15
Ernest 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 31
W. 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 49
W. 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 79
Ronald 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 115
Ernest 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 157
Ernest 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 173
Andrew 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 213
Gerald 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 225
Gerald 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 237
Robert 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 265
Jill 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 277
Andrew 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 291
Joan 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 303
Bonita 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 323
Heather 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 345
Gerald 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 363
James 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 387
MaryJane 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 409
Ernest 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 457
Sharon 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 475
Ernest 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 489
Ronald 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 509
Chris 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 531
Gerald 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 549
Damian 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 571
Damian 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 593
Seth 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 607
Ernest 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