Toxicology (eBook)

Front Cover 1
Toxicology 4
Copyright Page 5
Contents 6
Contributors 16
Preface 20
Introduction 26
Paracelsus to Parascience: The Dose/Trace Makes the Poison 26
Even Rachel Carson Was Made of Chemicals: Natural versus Synthetic Chemicals 27
Errors of Omission: Toxicity of Insufficient Micronutrients 29
Damage by Distraction: Regulating Low Hypothetical Risks 31
PART I: FUNDAMENTALS 34
Chapter 1. History of Toxicology 36
Toxicology—The Science of Poison 36
Early Fundamental Developments 37
From Alchemy to the Development of a Pure Science 38
Academic Qualification and the Practical Application of Toxicological Knowledge at the Beginning of the Industrial Age 39
Chemistry and the Chemical Industry in the Nineteenth Century 41
Substance Effects—Uses and Limits 43
The Scope of Toxicology in Historic Terms 47
Chapter 2. Biostatistics in Toxicology 50
Principles 50
Acute Toxicity 54
Chronic Toxicity 55
Reproductive Toxicology 60
Mutagenicity Studies 61
Carcinogenicity Studies 63
Biostatistics in Regulatory Toxicology 65
Chapter 3. Principles of Toxicokinetics 68
Introductory Remarks 68
Principal Kinetic Parameters 69
Kinetic Models 83
Kinetic Principles of Drug Dosing 86
Nonlinear Kinetics 90
Stereoselective Kinetics 92
Variability of Kinetic Parameters 94
Species Differences in Kinetics 101
Chapter 4. Xenobiotic Metabolism 108
Introduction 108
Classification of Xenobiotic- Metabolizing Enzymes 109
Characterization of Individual Xenobiotic-Metabolizing Enzymes 111
Factors Influencing Xenobiotic Metabolism 129
Chapter 5. Free Radicals and Reactive Oxygen Species 136
Introduction 136
What are Free Radicals? 136
Oxygen Free Radicals and Nonradical Reactive Oxygen Species 136
Organic Free Radicals 139
Biological Effects of Free Radicals 142
Cellular Defence Mechanisms against Free Radicals 147
Conclusion 149
Chapter 6. Genetic Toxicology 152
Introduction 152
Basic Genetic Mechanisms 153
DNA Alterations Resulting in Genotoxic Effects in Cells 154
Relationship of Genotoxic Damage to Toxicity 160
Genetic Toxicology Testing Strategies and Data Evaluation 162
Considerations for Assay Selection 163
Data Analysis and Interpretation 165
Genetic Risk Assessments 166
Extrapolation of Somatic Cell Responses to Germ Cells 167
New Technology and its Place in Genetic Testing 167
Conclusion 172
Chapter 7. Chemical Carcinogenesis 176
Introduction 176
Historic Review 178
Chemical Carcinogens—Structure and Function 179
Metabolic Activation 191
Mechanisms of Action 192
Conclusion 203
Chapter 8. Tumor Promotion 204
Stages of Carcinogenesis 204
Relation Between Tumor Promoters and Nongenotoxic Carcinogens 208
Kinetic and Mechanistic Aspects 209
Tumor Promotion in Specific Organs 213
Testing and Risk Assessment of Tumor Promoters 238
Chapter 9. Transgenic Rodent Models 242
Introduction 242
General Methods for Development of Transgenic Model Systems 243
Transgenic Models for Mutagenesis 247
Transgenic Models in the Identification of Carcinogens 249
Transgenic Models to Address Other Issues in Toxicology 252
Future Directions 253
Chapter 10. Receptor Toxicology 256
Transcription Factors as the Cellular Targets of Toxins 256
Conditional Cellular Response to a Challenge by a Toxin 256
Consequences of Toxin-Induced Cellular Signaling 266
Chapter 11. Mechanisms of Toxicity Programmed Cell Death (Apoptosis) 270
Introduction 270
Discovery of Programmed Cell Death 270
Programmed Cell Death in Physiological and Pathological Processes 271
Morphology and Biochemistry of Programmed Cell Death 272
Intracellular Apoptosis Pathways 274
Concluding Remarks 280
Chapter 12. Mixtures 282
Basic Concepts of Combined Action of Chemicals 282
Experimental Approaches for Mixture Studies 284
Examples from the Environment 286
Risk Assessment of Chemical Mixtures 291
Conclusion 294
PART II: ORGAN TOXICITY 296
Chapter 13. The Liver 298
Morphology and Function of the Liver 298
Classification of Hepatotoxic Substances 301
Manifestations of Liver Injury 304
Chapter 14. The Kidney 322
Glomerular Structure 322
Renal Tubule Structure 325
Glomerular Function 326
Tubule Function 327
Pathophysiology 328
Biotransformation and Nephrotoxicity 330
Nephrotoxic Compounds 331
Chapter 15. Respiratory Tract 356
The Lung as a Target Organ for Inhaled Toxic Materials 356
Physical and Chemical Characterization of Airborne Materials 358
Anatomy of the Respiratory Tract 360
Lung Function Tests and Bronchoalveolar Lavage 363
Uptake and Elimination Of Xenobiotics 364
Pathobiology of the Respiratory Tract 367
Exposure Techniques 371
Summary 371
Chapter 16. Blood and Blood-Forming Organs 374
Introduction 374
Fundamentals of Hematopoiesis 374
Toxic Actions on the Bone Marrow 376
Toxic Actions on Granulocytes 378
Toxic Actions on Erythrocytes 379
Toxic Actions on Thrombocytes 392
Toxic Actions on Hemostasis 393
Chapter 17. Immune System 396
Introduction 396
Basic Functions of the Immune System 400
Examples of Alterations of Immunological Components and Functions 422
Methods for Assessing Effects on the Immune System 445
Predictive Power of Animal Data for Assessing Risk 458
Chapter 18. Skin 464
Introduction 464
Relevant Anatomy and Physiology 465
Adnexial Appendages 468
Percutaneous Absorption and Penetration 470
Experimental Techniques Used to Assess Absorption 475
Conclusion 480
Chapter 19. The Eye 484
Anatomy of the Eyeball 484
Acute Toxicity 484
Eye Irritants 486
Chapter 20. Nervous System 488
Functions of the Nervous System 488
The Nervous System as a Target for Toxic Chemicals 489
Acute and Chronic Neurotoxic Effects 492
Functional Effects 492
Structural Injuries 493
Mechanisms of Neurotoxicity 495
Assessment of Neurotoxicity 497
Neurotoxic Substances 504
Chapter 21. Reproduction and Development 516
Introduction 516
Reproductive Toxicity 528
Developmental Toxicity 536
Risk Assessment and Preventive Hazard Minimization 577
Chapter 22. Endocrine System—Adrenal Cortex, Thyroid, and Pancreas 584
Introduction 584
Endocrine Modulation 585
Adrenal Cortex 586
Thyroid Gland 589
Pancreas (Endocrine) 592
Chapter 23. Gastrointestinal Tract 598
Physiology 598
Pathophysiological Impacts on Gastrointestinal Functions 602
Selected Groups of Toxic Substances 604
Tumors in the Gastrointestinal Tract 605
Effects of Food and Luminal Factors 608
Chapter 24. Cardiovascular System 612
Introduction 612
Cardiac Toxins 612
Vascular Toxins 619
Treatment and Conclusions 622
PART III: TOXICOLOGY OF COMPOUNDS 626
Chapter 25. Hydrocarbons 628
Introduction 628
Aromatic Hydrocarbons 628
Aliphatic Hydrocarbons 649
Chapter 26. Halogenated Hydrocarbons 670
Introduction 670
Dichloromethane (Methylene Chloride) 671
Trichloroethene (Trichloroethylene) 672
Tetrachloroethene (Tetrachloroethylene/ Perchloroethylene) 675
1,1,1-Trichloroethane (Methyl Chloroform) and 1,1,2- Trichloroethane 676
Further Examples of Halogenated Solvents 677
Chlorofluorocarbons (CFC) 679
Miscellaneous Halogenated Substances 679
Chapter 27. Fluorocarbons 684
Introduction 684
Ozone Depletion and Chlorine 684
Physical and Chemical Properties 685
Absorption, Distribution, Metabolism, and Excretion 685
Acute and Subchronic- Chronic Toxicology 685
Developmental and Genetic Toxicology 687
Human Exposure 687
Chapter 28. Pesticides 688
Introduction 688
Fundamentals of Pesticide Toxicity 688
Reproductive and Developmental Effects 690
Carcinogenicity 691
Immunological Effects 691
Classification of Pesticides 691
Future Directions 721
Chapter 29. Dioxin and Dioxin-like Polychlorinated Hydrocarbons and Biphenyls 724
Introduction 724
Polychlorinated Dibenzo-p-Dioxins and Dibenzofurans 724
Polychlorinated Biphenyls (PCBs) 736
Chapter 30. Aromatic Amines, Nitroarenes, and Heterocyclic Aromatic Amines 754
Aromatic Amines 754
Nitroarenes 759
Heterocyclic Aromatic Amines 761
Chapter 31. N-Nitroso Compounds 768
Occurrence, Chemistry, and Exposure 768
Absorption, Distribution, Metabolism, and Excretion 771
Metabolism and Mechanisms of Toxicity 771
Nitrosamides 771
Nitrosamines 772
Formation of Adducts 773
Acute and Chronic Toxicity 777
Reproductive Toxicology 777
Mutagenicity 778
Carcinogenicity 778
Dosage in Long-Term Exposure 778
Chapter 32. Metals 780
Principles of Metal Kinetics 780
Aluminum 781
Arsenic 785
Cadmium 791
Copper 797
Lead 800
Nickel 812
Platinum Metals 815
Plutonium 818
Thallium 821
Tin 825
Chapter 33. Gases 830
Introduction 830
Carbon Monoxide 831
Carbon Dioxide 836
Cyanides 837
Hydrogen Sulfide 845
Hydrazoic Acid (Hydrogen Azide) 847
Nitrogen Oxides 848
Ozone 853
Chapter 34. Fibers 858
Introduction 858
Concepts in Fiber Toxicology 858
Studies of Synthetic Vitreous Fibers 861
Organic Fibers 869
Summary 873
Chapter 35. Chemical and Biological Agents 876
Chemical Agents 876
Biological Agents 894
Chapter 36. Active and Passive Smoking 904
Introduction 904
Consumption of Cigarettes 906
Physicochemistry of Tobacco Smoke 906
The Biochemistry of Tobacco Carcinogenesis 917
Aromatic Amines 919
Passive Smoking 919
Summary 920
Chapter 37. Cosmetic Toxicology 924
Introduction 924
Cosmetic Safety Regulation 924
Hair Cosmetics 926
Other Cosmetic Product Categories 935
Cosmetic Ingredients 937
Exposure and Risk Assessment Considerations for Cosmetic Products and Ingredients 940
Ingredient, Toxicology and Product Safety 941
Chapter 38. Polymers 944
Introduction 944
Monomers 944
Polymers 955
Additives and Modifiers 956
Special Aspects 959
Chapter 39. Radiation 962
Introduction 962
Ionizing Radiation 962
Nonionizing Radiation 980
Chapter 40. Natural Compounds 984
Introduction 984
Animal Venoms and Poisons 984
Toxins of Protozoa and Algae 996
Mycotoxins 998
Plant Toxins 1010
Chapter 41. Bacterial Toxins 1034
Introduction 1034
Classification of Bacterial Toxins 1034
Agents That Interact with the Plasma Membrane 1036
Intracellularly Acting Toxins 1037
PART IV: APPLICATIONS OF TOXICOLOGY 1050
Chapter 42. Biomonitoring in Occupational Medicine 1052
Introduction 1052
Sources of Biological Material 1052
Quality Assurance in the Analytical Laboratory 1053
Reference Values in the Biological Material 1054
Biological Effect Monitoring 1055
Determinants of Susceptibility to Toxic Influences 1061
Chapter 43. Water 1066
Introduction 1066
Pathways of Exposure Involving Water 1066
By-Products Associated with the Disinfection of Water 1067
Summary 1074
Chapter 44. Risk Assessment in Environmental Remediation 1076
Introduction 1076
History of Environmental Remediation 1076
Risk-Based Remedial Investigations 1077
Risk-Based Cleanup Criteria 1082
Using Risk Assessment to Optimize Remedy Evaluation and Selection 1086
Risk-Based Remediation in Brownfields Redevelopment 1089
Comparing the United States Approaches to those Used in Other Countries 1089
Conclusions 1090
Chapter 45. Ecotoxicology 1092
Introduction 1092
Specific Aspects of Environmental Toxicity 1092
Ecosystems 1096
Pollution of Ecosystem and Fate of Pollutants 1099
Effects of Pollutants—Selected Examples 1104
Methods of Recognizing Ecotoxicity by Pollutants 1108
Chapter 46. Food Toxicology: Legal Aspects 1112
Historical Perspective 1112
Current U.S. Food Law 1113
Conclusion 1124
Chapter 47. Food Compound Related Aspects 1128
Introduction 1128
Toxins Formed by Microbes 1128
Toxic Food Constituents 1129
Food Additives 1130
Food Contaminants 1132
Food-Contact Materials 1133
Treatment and Preparation of Food 1134
Confusion Of Food with Toxic Products and Adulterations 1135
Carcinogenic Substances in Food 1136
Chapter 48. Toxicological Evaluation of Methods for the Registration of Chemicals 1140
General Considerations 1141
Groups of Toxicological Studies 1144
Test Methods 1144
Extrapolation and Correlation of Animal Data 1153
Risk Assessment and Risk Management 1153
Product Safety and Product Stewardship 1154
Chapter 49. In Vitro Methods 1156
Introduction 1156
The Three Rs Concept of Russell and Burch 1156
Validation and Valid Methods 1158
Current Use of in Vitro Methods in Toxicology Testing 1158
Where Do in Vitro Methods Fit? 1159
An Integrated in Vitro and in Vivo Testing Strategy 1162
Chapter 50. Regulatory Toxicology 1164
Introduction 1164
The Scope of Regulatory Toxicology 1165
Procedural Frameworks of Regulation 1166
Regulatory Influences in Toxicology 1168
Risk Assessment, Characterization, and Management 1169
Conclusion 1172
PART V: RISK ASSESSMENT 1176
Chapter 51. Risk Assessment and Preventive Hazard Minimization 1178
Introduction 1178
Toxicological Risk by Human- Made versus Natural Chemicals 1180
Definition of Toxicity, Hazard, and Risk 1181
Toxicological Risk Assessment versus Preventive Hazard Minimization 1182
Pharmacological and Toxicological Principles Relevant to Risk Assessment 1186
Toxicological Risk Assessment from Human Data 1190
Preventive Hazard Minimization from Animal Data 1196
Types of Extrapolation 1202
Special Problems in Certain Fields of Toxicology 1205
Verification of Preclinical Data in Humans 1213
Chapter 52. Toxicity Equivalents and Their Use in Hazard and Risk Assessment 1216
Introduction 1216
Toxicology and Mechanism of Action 1216
Structure–Activity Relationships and Development of Toxic Equivalency Factors (TEFs) 1216
Use of Toxic Equivalency Factors 1217
Limitations of the Toxic Equivalency Factor Approach for Risk Assessment 1218
PART VI: APPENDIX 1224
Appendix: Threshold Values and Recommendations 1226
General Remarks 1226
Reference Doses 1226
Workplace 1231
Drinking Water 1231
Air 1247
Food 1253
Cosmetics 1254
Soil 1254
Index 1256