9781119940418

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Mammalian Toxicology surveys chemical agents and examines how such chemicals impact on human health, emphasizing the importance in minimizing environmental exposure to chemical and physical hazards in our homes, communities and workplaces through such media as contaminated water, soil and air.

Starting with the basic principles on a wide range of toxic agents, this textbook describes how they enter the body, their mechanisms of action once inside, and strategies for diagnosis, prevention and treatment.

Topics covered include:

General principles of toxicology: pharmacological and toxicological principles underpinning the study of toxicology, risk assessments and mechanisms of cell death
Disposition: routes of chemical exposures, entry into the body and various tissues, storage, metabolic biotransformation and elimination, with examples from various toxicants.
Toxic agents: the occurrences, disposition in the body, health effects, toxic mechanisms, antidotes and treatments of a range of agents including pesticides, metals, solvents, gases, nanomaterials, food components and additives, pharmaceuticals, drugs of abuse, natural toxins, endocrine disruptors, radiation, and warfare weapons.
Toxic effects: including neurotoxicity, developmental toxicity, immunotoxicity, teratogenecity, male and female reproductive toxicity, mutagenecity, carcinogenicity, pulmonary toxicity, cardiovascular toxicity, hepatotoxicity, gastrointestinal toxicity and cardiovascular toxicity
Toxicology and society: epidemiological studies of chemical-induced diseases in human populations, and a vision for toxicology in the 21^st century.

Mammalian Toxicology is an essential primer for students of toxicology, biochemistry, biology, medicine and chemistry. It is also appropriate for professional toxicologists in research or regulatory affairs, and anyone who needs to understand the adverse effects of toxic agents on the human body.

Edited by

Mohamed B. Abou-Donia
Duke University Medical Center, USA

About the Editor vii

List of Contributors xxiii

Acknowledgments xxvii

Introduction xxix

1 General Principles 1
Mohamed B. Abou-Donia

1.1 Introduction 1

1.1.1 Definition of Toxicology 1

1.1.2 Toxicological Studies 1

1.1.3 Accreditation in Toxicology 1

1.1.4 Societies of Toxicology 1

1.2 Toxic Responses to Xenobiotics 2

1.2.1 Molecular Changes 2

1.2.2 Subcellular Changes 2

1.2.3 Cellular Changes 2

1.2.4 Allergic or Sensitization Reactions 2

1.2.5 Idiosyncrasy 2

1.3 Evaluation of Chemical-Induced Diseases 3

1.3.1 Strength 3

1.3.2 Consistency 4

1.3.3 Specificity 4

1.3.4 Temporality 4

1.3.5 Biological Gradient 4

1.3.6 Plausibility 4

1.3.7 Coherence 4

1.3.8 Experiment 5

1.3.9 Analogy 5

1.3.10 Differential Diagnosis 5

1.4 Toxicological Studies 5

1.4.1 Definitions 5

1.4.2 Evaluation of Toxicity 5

1.4.3 Therapeutic Index (IT) 6

1.5 Toxicological Studies 7

1.5.1 Test Compound 7

1.5.2 Impurities 7

1.5.3 Dose 7

1.5.4 Animals 7

1.5.5 Temperature 8

1.5.6 Diet 8

1.5.7 Controls 8

1.5.8 Parameters Recorded in Acute Toxicity Studies 8

1.6 Acute Toxicity 9

1.6.1 Methods for Evaluating Acute Toxicity 9

References 14

2 Alternatives to In-Vivo Studies in Toxicology 15
Shayne C. Gad

2.1 Introduction 15

2.2 Test Systems: Characteristics, Development, and Selection 18

2.3 In-Vitro Models 19

2.3.1 Tissue Culture 21

2.4 Lethality Testing 22

2.4.1 Lethality Testing in Lower-Species Animals 23

2.4.2 Ocular Irritation 24

2.4.3 Dermal Irritation 27

2.4.4 Irritation of Parenterally Administered Pharmaceuticals 27

2.4.5 Sensitization and Photosensitization 28

2.4.6 Phototoxicity and Photosensitization 29

2.4.7 Developmental Toxicity 30

2.4.8 Target Organ Toxicity Models 30

2.5 In-Silico Methods 34

2.6 The Final Frontier and Barrier: Regulatory Acceptance 36

2.7 Conclusions 36

References 40

Further Reading 46

3 The Application of Omics Technologies to the Study of Mammalian Toxicology 49
Scott S. Auerbach and B. Alex Merrick

3.1 Introduction 49

3.2 Genomics 50

3.2.1 Technologies Used in Genomics 50

3.2.2 Approaches in Genomics 51

3.2.3 Applications of Genomics 51

3.3 Epigenomics 53

3.3.1 Technologies Used in Epigenomics 54

3.3.2 Approaches in Epigenomics 54

3.3.3 Applications of Epigenomics 55

3.4 Transcriptomics 56

3.4.1 Technologies Used in Transcriptomics 57

3.4.2 Approaches to Transcriptomics 57

3.4.3 Applications of Transcriptomics 57

3.5 Proteomics 59

3.5.1 Technologies Used in Proteomics 59

3.5.2 Approaches to Proteomics 61

3.5.3 Applications of Proteomics 61

3.6 Metabolomics 62

3.6.1 Technologies Used in Metabolomics 62

3.6.2 Approaches to Metabolomics 63

3.6.3 Applications of Metabolomics 63

3.7 Systems Toxicology 65

3.7.1 Applications of Systems Toxicology 65

3.8 Analysis of Omics Data 66

3.9 Conclusion 68

References 68

4 Cell Death Pathways in Toxicological Response 75
Joshua L. Andersen and Jeffrey C. Rathmell

4.1 Tissue Homeostasis 75

4.2 Death Is the Default 75

4.3 Forms of Cell Death 76

4.4 The Key Constituents of Apoptosis 77

4.4.1 Caspases 77

4.5 Mitochondria and Bcl-2 Family Proteins 77

4.6 The Apoptosome 78

4.7 Extrinsic and Intrinsic Apoptosis 78

4.8 Toxins Kill Cells by Activating Apoptotic Pathways 79

4.9 Toxins Can Also Trigger a Cell’s Survival Response 80

4.10 Outcomes of Cell Death on Tissues 81

4.11 Toxicological Regulation of Cell Death: An Overview 82

References 82

5 Principles of Toxicokinetics and Predictive Toxicokinetics Modeling 85
Hisham El-Masri, Eva McLanahan, and Sheppard Martin

5.1 Introduction 85

5.2 Absorption 85

5.2.1 Oral Absorption 85

5.2.2 Inhalational Absorption 87

5.2.3 Dermal Absorption 89

5.3 Distribution 90

5.3.1 Oral Dosing 90

5.3.2 Inhalation Dosing 90

5.3.3 Dermal Dosing 90

5.3.4 Distribution within Tissues 90

5.3.5 Perfusion- and Diffusion-Limitation 91

5.4 Metabolism 91

5.5 Excretion 92

5.5.1 Urinary Excretion 92

5.5.2 Fecal Excretion 92

5.5.3 Exhalation 92

5.5.4 Sweat 93

5.5.5 Lactation 94

5.6 Pharmacokinetic Predictive Modeling 94

5.6.1 One-Compartment Models 94

5.6.2 Multi-Compartment Models 95

5.6.3 Physiologically Based Pharmacokinetic (PBPK) Models 96

5.7 Toxicokinetics: Applications to Human Health Risk Assessment 98

References 98

6 Metabolic Biotransformation of Xenobiotics 101
Mohamed B. Abou-Donia

6.1 Introduction 101

6.1.1 Tissue Localization of Xenobiotic-Metabolizing Enzymes 101

6.1.2 Reactions of Metabolic Biotransformation 101

6.2 Xenobiotic-Metabolizing Reactions: Phase I 102

6.2.1 Cytochrome P450 (Microsomal Mixed-Function Oxidase, MFO) 102

6.2.2 Cytochrome P450-Mediated Reactions 106

6.2.3 Reactions Other Than Microsomal Mixed-Function Oxidase 112

6.3 Xenobiotic-Metabolizing Reactions: Phase II 118

6.3.1 Conjugation with Sugars 119

6.3.2 Sulfation 122

6.3.3 Glutathione Conjugation 125

6.3.4 Other Conjugation Reactions 127

6.3.5 Phase II Metabolism of Endogenous Compounds 128

References 128

7 Pesticides 131
Mohamed B. Abou-Donia

7.1 Introduction 131

7.2 Insecticides 141

7.2.1 Axonal Transmission as an Insecticidal Target 141

7.2.2 The Synapse as an Insecticidal Target 145

7.3 Mitochondrial Injury 155

7.3.1 Organophosphorus Ester-Induced Chronic Neurotoxicity (OPICN) 155

7.4 Herbicides 158

7.4.1 Health Effects of Herbicides 158

7.4.2 Chlorophenoxy Acetic Acid Herbicides 158

7.4.3 Nitrophenolic and Chlorophenolic Herbicides 159

7.4.4 Dipyridyl Herbicides 159

7.4.5 Chlorate Salts 160

7.4.6 Atrazine 161

7.4.7 Organophosphate Herbicides 161

7.5 Fungicides 161

7.5.1 Thiocarbamates and Dithiocarbamates 161

7.5.2 Phthalimides 162

7.5.3 Hexachlorophene 162

7.6 Rodenticides 162

7.6.1 Anticoagulants 162

7.6.2 Sodium Monofluoroacetate (1080) 163

7.6.3 Zinc Phosphide 163

7.6.4 Strychnine 164

7.7 Insect Repellents 164

7.7.1 DEET 164

7.8 Combined Pesticide Exposure 165

7.9 Stress and Pesticide Toxicity 165

7.10 Pesticide Formulations and Inert Ingredients 166

7.10.1 Dusts 166

7.10.2 Wettable Powders (WPs) 166

7.10.3 Emulsifiable Concentrates (ECs) 166

7.10.4 Suspendable Concentrates (CSs) or Flowables 166

7.10.5 Water-Soluble Powders (SPs) 166

7.10.6 Solutions 166

7.10.7 Granules 166

7.10.8 Water-Dispersible Granules (WGs) 166

7.10.9 Ultra-Low-Volume (ULV) 166

7.10.10 Aerosols 167

7.10.11 Controlled Release (CR) Formulations 167

7.10.12 Baits 167

References 167

8 Metal Toxicology 171
Ebany J. Martinez-Finley, Sam Caito, Stephanie Fretham, Pan Chen, and Michael Aschner

8.1 Introduction 171

8.2 Human Health Effects 173

8.2.1 Types of Health Effect 173

8.2.2 Trace Metals 174

8.2.3 Administration: Routes of Exposure 174

8.2.4 Transport and Distribution: The Systemic Toxicity of Metals 174

8.2.5 Biotransformation (Metabolism) 177

8.2.6 Elimination 177

8.3 Properties of Metals 177

8.3.1 Determinants of Reactivity 177

8.3.2 Mechanisms of Action 179

8.4 Methodologies 180

8.4.1 Administration of Metals in Mammalian Systems 180

8.4.2 Detection of Metals 181

8.5 Conclusions 183

Acknowledgments 183

References 183

9 Organic Solvents 187
James V. Bruckner

9.1 Introduction 187

9.2 Occupational Exposures 188

9.3 Environmental Exposures 189

9.4 Toxicokinetics 190

9.4.1 Absorption 190

9.4.2 Transport and Distribution 192

9.4.3 Metabolism 192

9.4.4 Elimination 193

9.5 Aromatic Hydrocarbons 194

9.5.1 Benzene 194

9.5.2 Toluene 195

9.5.3 Styrene 196

9.6 Aliphatic Hydrocarbons 197

9.6.1 The Chemical Class 197

9.6.2 n-Hexane 198

9.7 Halogenated Aliphatic Hydrocarbons 200

9.7.1 Methylene Chloride 200

9.7.2 Chloroform 201

9.7.3 Carbon Tetrachloride 202

9.7.4 Trichloroethylene 204

9.7.5 Tetrachloroethylene 207

References 209

10 Gases 219
Mohamed B. Abou-Donia

10.1 Introduction 219

10.1.1 Threshold Limit Value (TLV) 219

10.2 Action of Gases 220

10.3 Simple Asphyxiants 220

10.3.1 Carbon Dioxide (CO2) 220

10.4 Toxic Asphyxiants 221

10.4.1 Carbon Monoxide (CO) 221

10.4.2 Cyanide 222

10.4.3 Hydrogen Sulfide 224

10.4.4 Other Methemoglobinemia-Producing Chemicals 225

10.5 Gases Affecting the CNS and PNS 226

10.5.1 Carbon Disulfide 226

10.6 Irritants 227

10.6.1 Ammonia 227

10.6.2 Chlorine 228

10.6.3 Air Pollutants 228

10.6.4 Oxides of Sulfur (SOx) 228

10.6.5 Oxides of Nitrogen 229

10.6.6 Ozone 230

10.6.7 Formaldehyde 230

10.7 Sensitizers 231

10.7.1 Methyl Isocyanate 231

10.7.2 Toluene 2,4-Diisocyanate 231

References 231

11 Nanotoxicology: Environmental, Health and Safety (EHS) Considerations for Assessing Hazards and Risks Following Nanoparticle Exposures 233
David B. Warheit and Kenneth L. Reed

11.1 Introduction 233

11.2 Importance of Physico-Chemical Characterization Studies on Nanoparticle-Types 234

11.3 Species Differences in Lung Responses to Inhaled Fine and/or Ultrafine TiO2 Particles 235

11.4 Strategies for Assessing Pulmonary Hazards to Nanomaterials 236

11.4.1 Pulmonary Bioassay Studies of Fine and Nanoscale TiO2 Particle-types 237

11.4.2 Pulmonary Bioassay Studies of Fine and Nanoscale α-Quartz Particle-Types 238

11.5 Evaluating the Risks Associated with Nanomaterial Exposures: The NanoRisk Framework 238

11.6 Safe Handling of Nanomaterials in the Laboratory 242

11.7 Conclusions 242

References 243

12 Pharmaceutical Toxicity In Humans 245
Martha M. Abou-Donia

12.1 Introduction 245

12.1.1 Evolution of the Study and Understanding of Pharmaceutical Toxicity 246

12.1.2 Regulatory Overview of Pharmaceutical Safety 246

12.1.3 Pharmaceutical Decision-Making in Drug Development 247

12.1.4 History of Drug Regulation in the US 247

12.1.5 Definitions of Toxicity 248

12.1.6 Preclinical Testing 249

12.1.7 Clinical Studies and Toxicity 250

12.1.8 Adverse Events 250

12.1.9 Serious Adverse Events 250

12.1.10 Risk : Benefit Analysis 250

12.2 Development of Pharmaceuticals to Ensure their Safe Use 252

12.2.1 Preclinical Testing 253

12.2.2 Clinical Testing 254

12.2.3 Types of Study 255

12.2.4 Types of Test Undertaken 258

12.2.5 Numbers of Patients Tested 258

12.2.6 Data Analyses 258

12.2.7 Potential Toxicity Signs 260

12.2.8 Approval Process, Including Labeling and Post-Approval Use 260

12.2.9 Post-Approval Phase IV Studies 260

12.2.10 Analyses of Data Overall: From Phase I to Phase II to Phase III 261

12.2.11 Drugs with Known Toxicity at Approval 262

12.2.12 Boxed Warnings 262

12.2.13 Risk : Benefit Analysis 262

12.3 Drugs Withdrawn or with Restricted Use or Dosage due to Toxicity Issues 263

12.3.1 Sulfa Drugs 263

12.3.2 Dinitrophenol 263

12.3.3 Acetaminophen (Paracetamol) 264

12.3.4 Thalidomide 264

12.3.5 Alfaxolone 264

12.3.6 Fen-Phen 264

12.3.7 Romozin 264

12.3.8 Vioxx 265

12.3.9 LotronexTM 265

12.3.10 Statins 265

12.4 Summary 266

References 266

13 Food Additives 269
Mohamed B. Abou-Donia and Mohamed Salama

13.1 Introduction 269

13.1.1 Definition of Food Additives 269

13.2 Regulation of Food Additives 269

13.2.1 Testing for Safety of Food Additives 270

13.2.2 Toxicological Testing 270

13.2.3 The Level of Concerns 270

13.2.4 Generally Recognized as Safe (GRAS) 270

13.2.5 Tolerance, Estimated Daily Intake (EDI) and Acceptable Daily Intake (ADI) 271

13.2.6 The Delaney Clause 271

13.2.7 Sources of Nitrates and Nitrites in Food 271

13.2.8 Negligible Risk 272

13.3 Intentional Food Additives 272

13.3.1 To Maintain and/or Improve Food Quality 273

13.3.2 To Make Food Make more Appealing 273

13.3.3 Processing Aids 278

13.4 Intentional Food Additives 279

13.5 Nonintentional Food Additives 279

13.5.1 Unintentional Food Additives 279

13.5.2 Incidental Additives 279

13.6 Toxicological Action of Food Additives 279

13.6.1 Foods in the US Market That May Be Harmful 281

13.7 Adverse Reactions to Food 282

13.7.1 Definition 282

13.7.2 Food Allergy 282

13.7.3 Food Allergens 283

13.7.4 Food Idiosyncrasies 283

13.7.5 Food Allergic Reactions 283

13.7.6 Pharmacological Food Reactions 284

13.7.7 Metabolic Food Reactions 284

13.8 Nutraceuticals 284

13.8.1 Definition 284

13.8.2 Classification of Nutraceuticals 285

13.8.3 Market Potential 285

13.9 Health Foods 285

13.10 Conclusions 285

References 286

14 Endocrine Disruptors 289
Gwendolyn Louis and Tammy Stoker

14.1 Introduction 289

14.2 Targets of EDC Interference 290

14.2.1 Effects on Intracellular Signaling 290

14.2.2 Effects on Steroidogenesis 292

14.2.3 Effects on Hormone Metabolism 294

14.2.4 EDC Effects on the HPG Axis 294

14.2.5 EDC Effects on Thyroid Function 296

14.2.6 EDC Effects on Pregnancy and Lactation 297

14.2.7 Summary 297

14.3 Endocrine Disruptor Screening Programs 297

14.3.1 In-Vitro Assays for the Detection of EDCs 298

14.3.2 Mammalian In-Vivo Assays for the Detection of EDCs 300

14.3.3 Summary of EDSP 301

14.4 Overall Conclusions 303

References 303

15 Ionizing Radiation: Toxicologic Action 309
Heather A. Himburg and John P. Chute

15.1 Introduction 309

15.1.1 Basics of Radiation Physics 309

15.2 Cellular Effects of Ionizing Radiation 309

15.2.1 DNA Damage and Repair 309

15.2.2 Intrinsic Pathway of Apoptosis 310

15.2.3 Extrinsic Pathway of Apoptosis 311

15.2.4 Senescence and Mitotic Catastrophe 311

15.2.5 Reactive Oxygen Species 312

15.3 Long-Term Effects of Ionizing Radiation 312

15.3.1 Carcinogenesis 312

15.3.2 Developmental Defects 313

15.3.3 Ocular Defects 314

15.4 Normal Tissue Injury from Ionizing Radiation in Adults 314

15.4.1 Hematopoietic System 314

15.4.2 Acute Radiation Sickness and the Hematopoietic Syndrome 316

References 318

16 Immune System Toxicity and Immunotoxicity Hazard Identification 323
Robert W. Luebke

16.1 Introduction 323

16.2 Overview of the Immune System 323

16.2.1 Organization 323

16.2.2 Innate Immunity 324

16.2.3 Adaptive (Antigen-Specific) Immunity 324

16.2.4 Host Factors Affecting Immunocompetence and Immunotoxicity 326

16.3 Immunotoxicology: The Immune System as a Target of Environmental Chemicals 327

16.3.1 Immunosuppression and Stimulation 328

16.3.2 Allergic Hypersensitivity 332

16.3.3 Autoimmunity 334

16.4 Immunotoxicity Risk Assessment 336

16.5 New Developments in Immunotoxicity Hazard Identification 336

References 337

17 Carcinogenicity and Genotoxicity 341
Shayne C. Gad, Charles B. Spainhour, and Samantha E. Gad

17.1 Introduction 341

17.1.1 History of Xenobiotic Carcinogenesis 341

17.2 Mechanisms and Classes of Carcinogens 342

17.2.1 Genotoxic Carcinogens 342

17.2.2 Epigenetic Carcinogens 345

17.3 Oncogenes 347

17.4 Metals and Carcinogens 349

17.5 The Two-Step Theory of Carcinogenesis 349

17.6 Multiple-Hit Theory of Carcinogenesis 350

17.6.1 Initiation, Promotion, and Progression 350

17.7 Solid-State Tumorigenesis 352

17.8 Traditional Carcinogenicity Bioassays of Xenobiotics 353

17.8.1 Regulatory Requirements and Timing 355

17.8.2 Species and Strain 355

17.8.3 Animal Husbandry 357

17.8.4 Dose Selection 357

17.8.5 Group Size 359

17.8.6 Route of Administration 360

17.8.7 Study Duration 360

17.8.8 Survival 360

17.8.9 Endpoints Measured 361

17.8.10 Statistical Analysis 363

17.8.11 Interpretation of Results 365

17.8.12 Relevance to Humans 369

17.8.13 Conclusions 370

17.9 Carcinogenicity Testing for Medical Devices 371

17.9.1 Dose Selection 373

17.10 Interpretation of Results 376

17.10.1 Criteria for a Positive Result 376

17.10.2 Use of Historic Controls 376

17.11 Transgenic Models 376

17.11.1 The Tg.AC Mouse Model 377

17.11.2 The Tg.rasH2 Mouse Model 377

17.11.3 The p53+/− Mouse Model 378

17.11.4 The XPA−/− Mouse Model 378

17.12 Genotoxicity (Predictive In-Vitro) 379

17.12.1 The Link between Mutation and Cancer 379

17.12.2 Cytogenetics 380

17.12.3 In-Vitro Cytogenetic Assays 382

17.12.4 In-Vivo Cytogenetics Assays 383

17.12.5 Sister Chromatid Exchange Assays 383

17.12.6 Predictive Models: QSAR 384

References 384

18 Neurotoxicity 395
Mohamed B. Abou-Donia

18.1 Introduction 395

18.2 The Nervous System 395

18.2.1 Nerve Fibers 395

18.2.2 The Brain 397

18.2.3 Spinal Cord 402

18.2.4 Peripheral Nervous System 402

18.2.5 Nerve Conduction 403

18.2.6 The Synapse and Neurotransmitters 404

18.2.7 Second Messengers 405

18.2.8 Cytoskeletal Proteins 405

18.2.9 Axonal Transport 407

18.2.10 Nervous System Diseases 407

18.3 Classification of Neurotoxic Action 408

18.3.1 Non-Selective Neurotoxic Action 408

18.3.2 Selective Neurotoxic Action 410

References 419

19 Cardiovascular Toxicology and Its Evaluation 425
Shayne C. Gad

19.1 Introduction 425

19.1.1 Cardiotoxins 425

19.2 Pharmacologic Profiling 427

19.2.1 In-Vitro Evaluation of Cardiovascular Toxicity 429

19.3 In-Vivo Parameter Evaluations in Standard Studies 432

19.3.1 Electrocardiograms 433

19.3.2 Blood Pressure and Heart Rate 434

19.3.3 Flow Measurement Techniques 434

19.3.4 Imaging Technologies: Magnetic Resonance Imaging and Echocardiography 436

19.4 Clinical Signs and Observations 437

19.5 Clinical Pathology 438

19.5.1 Electrolytes 438

19.5.2 Osmolality and Acid–Base Balance 438

19.5.3 Enzymes 439

19.5.4 Creatine Phosphokinase 439

19.5.5 Myoglobin 439

19.5.6 Lactate Dehydrogenase 440

19.5.7 Serum Glutamic-Oxaloacetic Transaminase and Serum Glutamic-Pyruvic Transaminase 440

19.5.8 Heart Fatty Acid Binding Protein 440

19.5.9 Troponins 441

19.5.10 Other Proteins 442

19.5.11 Lipids 443

19.6 Pathology 443

19.6.1 Cardiomyopathy 444

19.6.2 Cardiac Hypertrophy 444

19.6.3 Vasculature 445

19.6.4 Hemorrhage 447

19.6.5 Mitochondrial Damage 447

19.7 Medical Devices 448

19.8 Animal Models 448

19.9 Summary 449

References 449

20 Liver Toxicology 453
Mitchell R. McGill, C. David Williams, and Hartmut Jaeschke

20.1 Introduction 453

20.2 Liver Anatomy and Physiology 453

20.2.1 Liver Anatomy 453

20.2.2 Liver Cells and Function 456

20.2.3 Bile Formation and Flow 456

20.3 Mechanisms of Hepatotoxicity 457

20.3.1 Intracellular Mechanisms of Hepatocyte Injury 457

20.3.2 Injury of Non-Parenchymal Cells 462

20.3.3 Extracellular Mechanisms of Hepatocyte Injury 463

20.3.4 Survival Mechanisms 464

20.4 Liver Diseases and the Consequences of Liver Failure 465

20.4.1 Steatosis and Steatohepatitis 465

20.4.2 Cholestasis 465

20.4.3 Circulatory Disturbances 465

20.4.4 Fibrosis and Cirrhosis 466

20.4.5 Hepatic Encephalopathy 466

20.5 Conclusions 466

References 467

21 Male Reproductive Toxicology: Environmental Exposures versus Reproductive Competence 473
Gary R. Klinefelter

21.1 Introduction 473

21.2 Overview of Male Reproductive Biology 474

21.2.1 The Testis 474

21.2.2 The Epididymis 476

21.2.3 Reproductive Development 478

21.3 Why the Human Male is Vulnerable to Toxic Insult 481

21.4 Fertility Assessments 481

21.5 Assessing Toxicity in the Testis 484

21.6 Assessing Toxicity in the Epididymis 486

21.7 Assessing Toxicity during Reproductive Development 488

21.8 Epidemiological and Toxicological Needs 489

References 491

22 Female Reproductive Toxicology 493
Jerome M. Goldman and Ralph L. Cooper

22.1 Introduction 493

22.2 Development of the Reproductive System 494

22.2.1 Sexual Differentiation of the Brain 495

22.2.2 Puberty 496

22.3 The Adult Female Reproductive System 498

22.3.1 The Ovarian Cycle 498

22.3.2 Hypothalamic–Pituitary–Ovarian (HPO) Axis 503

22.3.3 Ovulation 508

22.4 Pregnancy 509

22.4.1 Toxicant Effects on Implantation, Pregnancy Maintenance, and Parturition 510

22.5 Reproductive Risk, Animal Models, and the Use of In-Vitro Assays 511

Acknowledgments 511

References 512

23 Pulmonary Toxicology 519
Aimen K. Farraj, Mehdi S. Hazari, and Daniel L. Costa

23.1 Pulmonary Disease Epidemiology 519

23.2 Comparative Functional Anatomy of the Lung 520

23.2.1 Ventilation and Perfusion 520

23.2.2 Nasal Passages, Pharynx, Trachea, and Main Bronchi 520

23.2.3 Conducting Airways of the Lung 520

23.2.4 Gas Exchange Region of the Lung 522

23.2.5 Vasculature of the Lung 522

23.2.6 Lymphatics, Innervation, and Connective Tissue 523

23.2.7 Exocrine and Metabolic Functions of the Lung 523

23.3 Principles of Gas and Particle Entry into the Lung, and Clearance 523

23.3.1 Gases and Vapors 523

23.3.2 Particle Deposition 524

23.3.3 Clearance 525

23.4 Susceptibility 525

23.4.1 Pre-Existing Lung Disease and Infection 525

23.4.2 Genetics 526

23.4.3 Age 526

23.5 Key Responses Triggered by Inhaled Agents 527

23.5.1 Spectrum of Responses 527

23.5.2 Oxidant Injury and Ozone 527

23.5.3 Fibrotic Pneuomoconiosis and Dust Inhalation 528

23.5.4 Occupational Asthma and Low-Molecular-Weight Chemicals 530

23.5.5 Metal Fume Fever 531

23.5.6 Respiratory Dysfunction and Particulate Matter 531

23.6 Spotlight on Nanomaterials 531

23.7 Lung Injury from Systemic Agents 532

23.7.1 Monocrotaline and Pulmonary Endothelial Injury 532

23.7.2 Paraquat and Alveolar Epithelial Injury 532

23.7.3 Other Systemic Agents 533

23.8 Lung Responses that Trigger Extrapulmonary Effects 533

23.9 Approaches in Pulmonary Toxicology 533

23.9.1 In-Vivo Toxicology 533

23.9.2 Pulmonary Function Assessment 534

23.9.3 In-Vitro and Ex-Vivo Toxicology 534

23.9.4 Modeling 535

23.10 The Future of Pulmonary Toxicology 535

Acknowledgments 535

References 536

24 Gastrointestinal Toxicology 539
Shayne C. Gad

24.1 Introduction 539

24.2 Structure of the GI Tract 539

24.2.1 Mucosa 541

24.2.2 Submucosa 541

24.2.3 Muscularis 541

24.2.4 Serosa 541

24.2.5 The Mouth 542

24.2.6 Tongue 543

24.2.7 Pharynx 544

24.2.8 Esophagus 544

24.2.9 Stomach 545

24.2.10 Small Intestine 547

24.2.11 Large Intestine 547

24.3 Function of the GI Tract 548

24.3.1 Mechanical and Chemical Digestion in the Mouth 548

24.3.2 Regulation of Gastric Secretion and Motility 550

24.3.3 Regulation of Gastric Emptying 551

24.3.4 Role and Composition of Bile 552

24.3.5 Role of Intestinal Juice and Brush-Border Enzymes 553

24.3.6 Digestion of Carbohydrates 554

24.3.7 Digestion of Proteins 555

24.3.8 Digestion of Lipids 555

24.3.9 Digestion of Nucleic Acids 555

24.3.10 Regulation of Intestinal Secretion and Motility 555

24.3.11 Absorption in the Small Intestine 555

24.3.12 The Large Intestine 558

24.4 Evaluating Effects of Xenobiotic Exposure on GI Tract Function 559

24.5 Nature of Xenobiotic Exposures 559

24.6 Nature of Intestinal Function 560

24.6.1 Chemical-Induced Alterations of Intestinal Function; Study Approaches 560

24.6.2 GI Functions Affected by Xenobiotic Exposure 561

24.7 Intestinal Transit 564

24.7.1 Ulcerogenic activity 564

24.8 Conclusions 565

References 566

25 Epidemiology 569
Gregg M. Stave

25.1 Introduction 569

25.2 Epidemics 569

25.3 Beyond Epidemics 569

25.4 Selection of Study Design 570

25.4.1 Cohort Studies 570

25.4.2 Case-Control Studies 570

25.4.3 Randomized Controlled Trials 570

25.4.4 Probability and Statistics 571

25.5 Bias and Confounding 572

25.6 Counteracting Problems 572

25.7 Correlation is NOT Causation! 572

25.7.1 The Bradford-Hill Criteria 573

25.8 Testing 573

25.9 Screening 575

25.9.1 Cancer Biology 575

25.9.2 Misperception 575

25.9.3 Cancer Screening 576

25.10 Conclusions 576

References 576

26 Drugs of Abuse 579
Mohamed B. Abou-Donia

26.1 Introduction 579

26.1.1 Definitions 579

26.1.2 Drug Addiction 581

26.1.3 Management of Drug Abuse 582

26.2 Drug Tolerance 582

26.3 Withdrawal Symptoms 582

26.4 Controlled Substances Act 583

26.5 CNS Stimulants 583

26.5.1 Amphetamines 583

26.5.2 MDMA (‘Ecstasy’) 584

26.5.3 ‘Club Drugs’ 584

26.5.4 Cocaine 585

26.5.5 Khat 586

26.5.6 Nicotine 587

26.6 CNS Sedatives and Hypnotics 588

26.6.1 Alcohol 589

26.6.2 Barbiturates 590

26.6.3 Benzodiazepines 591

26.7 Opiates 592

26.7.1 Naturally Occurring Opiates 592

26.7.2 Oxycodone 593

26.8 Neither CNS Depressant nor Stimulant Drugs 594

26.8.1 Cannabis (Marihuana, Hashish) 594

26.9 Hallucinogens (Psychedelics) 596

26.9.1 Lysergic Acid Diethylamide (LSD) 596

26.9.2 Phencyclidine (PCP) 597

26.10 Miscellaneous Drugs 597

26.10.1 Inhalants 597

26.10.2 Steroids (Anabolic) 599

26.10.3 Prescription Medications 600

26.11 Drug Testing 601

26.11.1 Interferences with Urine Drug Testing 601

References 602

27 Naturally Occurring Toxins 605
Eman M. El-Masry and Mohamed B. Abou-Donia

27.1 Introduction 605

27.2 Bacterial Toxins 605

27.2.1 Clostridial Neurotoxins 607

27.2.2 Cholera Toxins 610

27.2.3 Heat-Labile (LT) and Heat-Stable (LS) Enterotoxins from Enterotoxigenic Escherichia coli 611

27.2.4 Shiga and Shiga-Like Toxins 611

27.2.5 Anthrax Toxin 612

27.2.6 Staphylococcus Enterotoxins and Toxic Shock Syndrome Toxin 613

27.2.7 Bacillus cereus Cereulide 613

27.2.8 Diphtheria Toxin 614

27.2.9 Pneumolysin (Ply) 614

27.3 Mycotoxins 615

27.3.1 Aflatoxin 615

27.3.2 Sterigmatocystin 616

27.3.3 Ergot Alkaloids 617

27.3.4 Ochratoxins 618

27.3.5 Citrinin 618

27.3.6 Trichothecenes 618

27.3.7 Fumonisins 619

27.3.8 Patulin 619

27.4 Phytotoxins 620

27.4.1 Mushroom Poisoning 620

27.4.2 Atropine Toxicity 622

27.4.3 Nicotine Poisoning 623

27.4.4 Curare Poisoning 623

27.4.5 β-Oxalyl-L-α,β-Diaminopropionic Acid Toxicity 624

27.4.6 Castor Oil Plant Poisoning 624

27.4.7 Colchicine Poisoning 625

27.4.8 Paclitaxel (TaxolTM) 626

27.4.9 Cycad Toxicity 626

27.4.10 Oxalate and Oxalic Acid Poisoning 627

27.4.11 Cyanogenic Glycosides Poisoning 627

27.4.12 Nutmeg Poisoning 627

27.4.13 Caffeine Toxicity 628

27.4.14 Chocolate Poisoning 629

27.4.15 Digitalis Glycosides Toxicity 630

27.4.16 Glycyrrhizin 631

27.4.17 Goitrin Toxicity 631

27.4.18 Gossypol Poisoning 632

27.4.19 Urushiol Poisoning 633

27.5 Reptile Toxins 633

27.5.1 Snake Venom Toxins 633

27.6 Insects (Bees) 635

27.7 Marine Toxins 635

27.8 Amphibian Toxins 635

27.8.1 Batrachotoxins 635

References 636

28 Toxicology in the 21st Century 641
Mohamed B. Abou-Donia

28.1 Introduction 641

28.2 Toxicology in the 20th Century 641

28.2.1 Major Accidents of Human Exposure to Toxic Agents 641

28.3 Toxicology in the 21st Century 644

28.3.1 Toxicity Testing in the 21st Century 645

28.4 Future Studies in the 21st Century 647

28.5 Concluding Remarks 648

References 648

Index 651

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Mammalian Toxicology

Mammalian Toxicology

1119940419

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