Principles of Toxicology Second EditionPDF电子书下载

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