1 Measuring Toxicity and Assessing Risk 1
Introduction 1
Chemistry of Toxicants 1
Toxicity Testing Methods 2
Factors to Be Considered in Planning Toxicity Testing 2
Routes of Exposure 3
Determining the Responses to Varying Doses of a Substance 3
Timing of Exposure 4
The LD50 Experiment 5
Testing 5
Analysis 6
Alternative Tests 7
Categories of Toxicity 9
Mixtures 9
Toxicity，Hazard，and Risk 10
Toxicity and Hazard 10
The Role of Laboratory Testing in Estimation of Hazard 10
Epidemiological Data 11
Risk Assessment and Risk Management 12
References 13
2 Toxicokinetics 15
Introduction 15
Pharmacokinetics and Toxicokinetics 15
Absorption 16
The Oral Route of Absorption 17
Respiratory Route of Absorption 18
Dermal Route of Absorption 18
Distribution 18
Elimination 19
Toxicokinetic Models 20
Mathematical Models of Elimination 20
Absorption and Bioavailability 23
Contrasting Kinetics of Lipophilic Substances 24
References 26
3 Biotransformation 27
Introduction 27
Primary Biotransformation（Phase Ⅰ Reactions）：Hydrolysis 28
Serine Hydrolases 29
Primary Biotransformation（Phase Ⅰ Reactions）：Oxidation 33
The Role of Cytochrome P450 33
Other Enzymes Carrying Out Oxidation 40
Primary Biotransformation（Phase Ⅰ Reactions）：Reduction 41
Secondary Metabolism（Phase Ⅱ Reactions） 41
Glucuronidation 42
Glutathione Conjugation 44
Acetylation and Other Phase Ⅱ Reactions 46
Factors That Influence Metabolism 47
References 47
4 Cellular Sites of Action 49
Introduction 49
Interaction of Toxicants with Proteins 49
Effects of Toxicants on Enzymes 51
Effects of Toxicants on Receptors and Ion Channels 57
Effects of Toxicants on Voltage-Activated Ion Channels 62
Effects of Toxicants on Transport Proteins 63
Effects of Toxicants on Lipids 64
Effects of Toxicants on Nucleic Acids 66
Mechanisms of Cell Death 67
Apoptosis 67
Necrosis 68
Stress，Repair，and Recovery 69
Case Study：Cyclooxygenase Inhibitors 70
References 72
5 Genomics and New Genetics in Toxicology 75
Introduction 75
The Human Genome Project 75
Model Organisms and Comparative Genomics 76
Toxicogenomics 79
Monitoring Transcription：Gene Expression and Microarrays 79
Other Roles for RNA 83
SNPs 84
Metabolomics 86
Personalized Susceptibility and Tailored Therapeutics 87
Race，Ethics，and Genomics 90
Systems Toxicology 92
Case Study：Using GenBank and Online Tools in Genomics 92
References 95
6 Carcinogenesis 97
Cancer 97
The Epidemiology of Cancer 97
Environmental Factors in Cancer 98
Genetic Factors in Cancer 99
Carcinogenesis 99
The Mutational Theory of Carcinogenesis 99
Competing Theories 100
Chemical Carcinogens 100
Genetic Carcinogens 101
Consequences of Mutagenesis 103
Epigenetic Carcinogens and Promotion 103
Oncogenes and Tumor Suppressor Genes 105
The Discovery of Oncogenes 105
An Example of an Oncogene：The Philadelphia Chromosome 106
The Role of Protooncogenes in Cell Function 106
Examples of Protooncogenes 107
Tumor Suppressor Genes 108
Protection against the Development of Cancer 110
Testing Compounds for Carcinogenicity 110
Critiques of Strategies in Cancer Research 112
Carcinogenesis：A Complex Process 112
Case Study：Predicting Carcinogenesis Based upon Chemistry（QSAR） 113
References 115
7 Reproductive Toxicology and Teratology 117
Introduction 117
Basic Processes in Reproduction and Development：Cell Division 117
The Cell Cycle and Mitosis 117
Meiosis 120
Cloning 122
The Male Reproductive System 123
The Female Reproductive System 124
The Effects of Toxicants on the Male and Female Reproductive Systems 125
Protective Mechanisms：The Blood-Testis Barrier 125
Interference with Cell Division 126
Cytotoxicity and Infertility 126
Interference with Hormonal Controls 127
The Process of Development 129
Embryogenesis and Developmental Genetics 131
Effects of Toxicants on Development：Teratogens and Teratogenesis 133
Effects of Dose or Exposure Level on Teratogenicity 133
Effects of Timing of Exposure on Teratogenicity 134
Examples of Teratogens 134
Mechanisms of Teratogenicity 136
Testing for Reproductive and Developmental Toxicity 137
Human Assessment 137
Testing of Laboratory Animals：General Principles 137
In Vitro Testing 138
Established Procedures for Testing 138
Case Study：Thalidomide 139
References 141
8 Respiratory Toxicology 143
Function of the Respiratory System 143
Anatomy and Physiology of the Respiratory System 143
Respiratory Anatomy 143
Pulmonary Ventilation 146
Gas Exchange 147
Control of Respiration 149
Effects of Toxicants on the Respiratory System：General Principles 150
Defense Mechanisms of the Respiratory System 150
Exposure to Respiratory Toxicants 151
Measuring Exposure Levels 151
Deposition of Gases 152
Deposition of Particulates 152
Immediate Responses to Respiratory Toxicants 153
Free Radical-Induced Damage 153
The Irritant Response 154
Involvement of the Immune System 154
Immediate Responses：Upper Airway Effects 154
Immediate Responses：Lower Airway Effects 155
Delayed and Cumulative Responses to Respiratory Toxicants 155
Asthma and Immune-Related Chronic Conditions 156
Chronic Obstructive Pulmonary Disease：Bronchitis and Emphysema 156
Fibrosis and Pneumoconioses 157
Lung Cancer 158
Inhalation Studies 160
References 160
9 Cardiovascular Toxicology 163
Function of the Cardiovascular System 163
Anatomy and Physiology of the Heart 163
Effects of Toxicants on the Heart 166
Arrhythmias 166
Cardiomyopathies and Other Effects on Cardiac Muscle 168
Myocardial Infarctions 169
The Vascular System 170
Effects of Toxicants on the Vascular System 172
Atherosclerosis 172
Vascular Spasms and Blood Pressure 173
The Blood 174
Effects of Toxicants on the Blood 175
Anemias，Hemolysis，and Related Disorders 175
Effects of Toxicants on Hemoglobin 177
References 178
10 Neurotoxicology 181
Function of the Nervous System 181
Anatomy and Physiology of the Nervous System 181
Effects of Toxicants on the Nervous System：General Principles 183
The Blood-Brain Barrier 184
Effects of Toxicants on the Nervous System：General Categories 185
Effects of Toxicants on Electrical Conduction 186
Effects of Toxicants on Synaptic Function 190
Acetylcholine 192
Biogenic Amines 196
Amino Acid Neurotransmitters 199
Neuroactive Peptides 200
Axonopathies 201
Axon Transport Systems 201
Proximal Axonopathies 203
Distal Axonopathies 203
Myelinopathies 205
Effects of Toxicants Directly on Neurons 207
Excitotoxicity 208
Other Cytotoxic Compounds 210
Other Neurotoxicants 211
Effects on Special Sensory Organs 212
Developmental Effects 212
Methods in Neurotoxicology 213
Case Study：Botulinum Toxin 215
References 217
11 Hepatic Toxicology 219
Anatomy and Physiology of the Liver 219
Liver Structure 219
Function of the Liver 221
Types of Toxicant-Induced Liver Injury 223
Fatty Liver 223
Liver Cell Death：Necrosis and Apoptosis 225
Cirrhosis 228
Carcinogenesis 228
Miscellaneous Effects 228
Response to Liver Injury 229
Evaluating Liver Injury and Treating Disease 229
Case Study：Reye’s Syndrome 230
References 231
12 Renal Toxicology 233
Function of the Kidneys 233
Anatomy and Physiology of the Kidneys 233
Effects of Toxicants on the Kidney：General Principles 235
Damage to the Glomerulus 235
Damage to the Proximal Tubule 237
The Remainder of the Tubule 242
Measurement of Kidney Function In Vivo 242
Measurement of Kidney Function In Vitro 244
References 245
13 Immunotoxicology 247
Function of the Immune System 247
Nonspecific Defense Mechanisms 247
The Skin and Mucus Membranes 247
Phagocytosis 248
The Complement System and Interferons 248
Fever 248
The Inflammatory Response 249
Specific Defense Mechanisms 250
Cellular Immunity 251
Humoral Immunity 252
Development of Immunity 253
Effects of Toxicants on the Immune System 254
Toxicant-Induced Allergies 254
Toxicant-Induced Autoimmunity 255
Toxicant-Induced Immunosuppression 256
AIDS and Antiviral Drugs 258
Methods for Studying Immunotoxicity 259
References 260
14 Ecological Toxicology 261
Introduction 261
Effects of Toxicants at the Population Level 261
Population Genetics 261
Natural Selection 262
Natural Selection，Toxicants，and Resistance 263
Recombinant Organisms 264
Population Growth and Dynamics 265
Effects of Toxicants at the Community Level 266
Effects of Toxicants at the Ecosystem Level 268
Energy Flow in Ecosystems 268
Material Cycling in Ecosystems 269
Examples of Ecosystems and Vulnerability to Impact by Toxicants 271
Marine Ecosystems 271
Freshwater Ecosystems 273
Terrestrial Ecosystems 275
Ecotoxicological Testing Methods 276
Single Species Testing 276
Microcosms 277
Field Studies 278
Mathematical Modeling 278
Molecular and Cellular Ecotoxicology：A New Direction 279
References 279
15 Applications：Pharmacology and Toxicology 281
Basic Principles of Pharmacology 281
Pharmacokinetics and Drug Delivery 281
The Magic Bullet：Mechanisms of Action and Side Effects 283
Drug Development and the Role of Toxicology 284
Preclinical Studies 285
Clinical Studies 286
Toxicogenomics and Drug Safety 287
The Return of Natural Products：Regulatory Issues 288
References 288
16 Applications：Forensic Toxicology 291
Analytical Toxicology 291
Thin-Layer Chromatography 292
Gas Chromatography-Mass Spectrometry 293
High-Performance Liquid Chromatography 294
Immunoassays 296
Forensic Toxicology and Alcohol Use 297
Forensic Toxicology and Illegal Drug Use 298
The Controlled Substances Act 298
Drug Identification 299
Major Categories of Illegal Drugs：Neuroactive Drugs 299
Anabolic Steroids 300
Criminal Poisonings 301
References 303
17 Applications：Environmental Toxicology and Pollution 305
Air Pollution 305
Types and Sources of Air Pollutants 305
General Effects of Air Pollutants 305
Carbon Oxides 306
Sulfur Oxides and Nitrogen Oxides 308
Hydrocarbons and the Formation of Secondary Pollutants（Including Ozone） 310
Chlorofluorocarbons 310
Particulates 311
Airborne Toxicants 312
Indoor Air Pollution 312
Control of Air Pollution 313
Water Pollution 313
Water in the Ecosystem 314
Organic Wastes as Water Pollutants 315
Petroleum Products as Water Pollutants 316
Pesticides 318
Other Organic Compounds 322
Phosphorus and Nitrogen 323
Metals 324
Other Pollutants 326
Regulation and Control of Water Pollution 326
Toxic Wastes 327
Sources of Toxic Wastes 327
Categories of Waste 328
Love Canal and Hazardous Waste Legislation 328
Waste Management：Reduce，Recycle，Treat，Store 330
References 332
Appendix List of Selected Toxicants 335
References 351
Index 353