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List of Contributors xxiii
Acknowledgments xxvii
Introduction xxix
1 General Principles 1Mohamed 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 15Shayne 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 49Scott 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 75Joshua 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 85Hisham 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 101Mohamed 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 131Mohamed 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 171Ebany 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 187James 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 219Mohamed 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 233David 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 a-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 245Martha 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 269Mohamed 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 289Gwendolyn 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 309Heather 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 323Robert 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 341Shayne 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 395Mohamed 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 425Shayne 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 453Mitchell 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 473Gary 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 493Jerome 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 519Aimen 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 539Shayne 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 569Gregg 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 579Mohamed 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, Ha
Toxicology is the discipline that is concerned with investigating the adverse effects of chemicals and radiation. Mammalian Toxicology was tailored after the course that the Editor has been teaching at Duke University since 1980, during which time he has been assisted by a team of toxicologists who are experts in the their fields, from Duke University, the Durham Veteran's Administration Medical Center, the U.S. Environmental Protection Agency (US EPA), the National Institute of Environmental Protection Agency (NIEHS), and the National Toxicology Program (NTP). Many of these toxicologists have contributed chapters in this book.
Chronic diseases and disabilities have become a global problem. In the United States, in particular, chronic diseases have reached epidemic proportions, affecting more than 100 million men, women and children, which is more than one-third of the population. Asthma, autism, birth defects, cancers, developmental disabilities, diabetes, endometriosis, infertility, Parkinson's disease, Alzheimer's disease and other diseases and disabilities that cause increased suffering and concern. The human cost for families and communities is immeasurable, particularly those who are already disadvantaged by persistent economic disparities. The economic cost of these diseases exceeds US$325 billion yearly in health care and lost productivity.
Scientific evidence increasingly indicates a relationship between a range of environmental factors and these diseases and conditions. One important contributor may be an increased exposure to the wide array of chemical substances that are used in modern industrial society, including diverse synthetic chemicals, compounds, metals and related elements such as lead, mercury and arsenic, as well as other pollutants in food, water and air. There are three toxic entities: chemical, biological, and physical:
While the industrial revolution took place during the nineteenth century, the twentieth witnessed tremendous advances in the chemical industry. In 1900, US minerals consumption was less than100 million metric tons, but by 2000 this had increased to more than 3.3 billion metric tons. Humans are exposed to thousands of chemicals, either naturally occurring or man-made. The known number of chemicals has been estimated to be over five million man-made chemicals, of which only 70 000 are in commercial use today. In addition, it has been reported that there are more than 100 000 naturally occurring substances of known structure. Chemicals have impacted many aspects of life, such as the development of mechanistically based new drugs, pesticides against agricultural pest and health-borne diseases, fertilizers, and industrial chemicals. Advances in chemical industry during the second half of the past century, such as developments in synthetic chemistry, have resulted in an expansion in the number of products that are used in everyday life, including industrial chemicals, drugs and household products. Many of these chemicals are persistent in the environment and some have long-term adverse effects.Other chemicals, such as those contained in tobacco and also alcohol, which are consumed socially are often abused and result in many human illnesses.
Between 1930 and 2000, the global production of man-made chemicals increased from one million to 400 million tons each year. Although some of these chemicals benefit society (e.g., therapeutic drugs), many are damaging to people, wildlife and cause widespread contamination. Chemicals are released into the environment during their manufacture and use, they can travel long distances by air or water, and they can be absorbed through the skin or ingested via food and water.
The spread of legal use of medical marihuana by 18 states and Washington DC, including legalizing its recreational use in the States of Colorado and Washington as well as Washington DC by the end of 2013, represents another challenge regarding chemical-induced short and long-term adverse health effects of drugs of abuse. The regulation of drugs of abuse has always been influenced not only by their known health effects, but also by other social and political issues that include overwhelming considerations, leading to differences in the legal or illegal use of drugs not just between different countries but among various states within a country. A State's regulations allowing the legal use of marihuana must be accompanied by a complete outreach program including medical, social and legal measures to guide the public and warn people against the dangerous adverse effects of occasional and long-term use of this drug.
There is particular concern about three types of chemicals in use today:
Some reports have indicated that hazardous chemicals are present in the tissues of essentially every person on Earth, and exposure to them has been linked to chemicals which cause cancer and reproductive problems, including birth defects. Recent studies have detected DDT and polychlorinated biphenyls (PCBs) in 99% of 150 people tested, despite such materials being banned many years ago.
Human health effects that have been associated with exposure to man-made chemicals include the following:
Today, many children suffer from reduced attention spans, delayed development and poor school performance, and industrial chemicals are emerging as likely causes. Neurobehavioral problems such as autism, ADHD and dyslexia affect about 10-15% of children born today. Although genes play a major role in some of these disorders, only about 30-40% of the disorders can be accounted for by genetic effects alone, with the remainder being related to environmental factors.
Chemicals that contribute neurodevelopmental disorders in children include:
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