Mammalian Toxicology

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 -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 -Oxalyl-L- , -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