Mammalian Toxicology

Content: 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