Toxicology (eBook)

Front Cover 1
Toxicology 4
Copyright Page 5
Table of Contents 6
Introduction 10
DEDICATION 14
PART I: REACTIVE METABOLITES AND THEIR IMPLICATIONS FOR TOXICOLOGY 16
Chapter 1. Metabolic Activation of Chemicals to Reactive Electrophiles: An Overview* 18
ABSTRACT 18
INTRODUCTION 18
CHEMICAL CARCINOGENS AND CARCINOGENESIS 19
CHEMICAL MUTAGENS 21
CHEMICAL ALLERGENS AND DRUGS 21
RECENT DATA ON SOME CHEMICAL CARCINOGENS 21
CONCLUSIONS 25
ACKNOWLEDGEMENTS 26
REFERENCES 26
Chapter 2. DNA Binding and Polycyclic Hydrocarbon Carcinogenesis 28
INTRODUCTION 28
REFERENCES 37
Chapter 3. Environmental Chemicals Causing Cancer and Genetic Birth Defects: Mutagenicity Testing for Reactive Metabolites* 44
Damage to DNA by Environmental Mutagens as a Cause of Cancer and Genetic Birth Defects 44
Identifying Mutagens and Carcinogens 44
New Chemicals in Our Environment 45
Animal Cancer Tests 47
The Salmonella/Mammalian Tissue Test 47
Other Short-Term Tests 50
Summary of Applications of the Salmonella Test and Other Short-Term Tests 51
Carcinogenic Potency and Human Risk Assessment 52
Potency in Short-Term Mutagenicity Tests 53
Dietary Carcinogens and Mutagens 53
Prevention of DNA Damage 54
REFERENCES 54
Chapter 4. Biological Activity of Polycyclic Hydrocarbon Metabolites and the Bay Region Theory 56
CARCINOGENICITY OF BENZO[a]PYRENE DERIVATIVES 56
THE BAY REGION THEORY OF POLY CYCLIC HYDROCARBON CARCINOGENESIS 59
ACKNOWLEDGEMENTS 63
REFERENCES, 63
Chapter 5. Stereoselective Metabolic Activation of Polycyclic Aromatic Hydrocarbons 68
RESOLUTION AND ASSIGNMENT OF ABSOLUTE STEREOCHEMISTRY TO BP METABOLITES 68
TUMORIGENICITY OF (+)– AND (–)-BP 7,8-DIHYDRODIOL 70
TUM0R1GENICITY OF THE (+)– AND (–)-ENANTIOMERS OF THE DIASTEREOMERIC BP 7,8-DIOL-9,10-EPOXIDES 72
TUMORIGENICITY OF THE (+)– AND (–)-ENANTIOMERS OF BENZO[a]ANTHRACENE 3,4-DIHYDRODIOL 74
CONCLUSIONS 74
REFERENCES 75
Chapter 6. Metabolic Inactivation of Reactive Metabolites 78
ABSTRACT 78
INTRODUCTION 78
PATHWAYS OF BIOTRANSFORMATION OF EPOXIDES 79
RELATIVE IMPORTANCE OF ENZYMES IN THE CONTROL OF MUTAGENICALLY REACTIVE EPOXIDES 79
DIHYDRODIOL DEHYDROGENASE, A PROTECTIVE ENZYME COMPLEMENTARY TO EPOXIDE HYDRATASE 81
CONCLUSION 82
REFERENCES 83
Chapter 7. Factors Influencing DNA Damage and its Repair with Cellular Implications for Toxicology* 86
Interactions with DNA 86
Preferential Interaction of Carcinogens with Different Regions of Chromatin-DNA 87
Factors which Influence the Expression of Chemical Damage in DNA in Terms of Cellular Damage 89
REFERENCES 91
Chapter 8. New Aspects of Nitrosamine-Induced Carcinogenesis 96
METABOLISM OF N-NITROSO COMPOUNDS 99
ORGAN SPECIFICITY 101
CONCLUSIONS 102
REFERENCES 102
ACKNOWLEDGEMENTS 106
Chapter 9. Tissue Specificity in Metabolic Activation 108
ABSTRACT 108
KEY WORDS 108
INTRODUCTION 108
METHODS 109
RESULTS AND DISCUSSION 110
ACKNOWLEDGEMENTS 116
REFERENCES 116
Chapter 10. Formation of Chemically Reactive Metabolites from Drugs 118
INTRODUCTION 118
FORMATION OF CHEMICALLY REACTIVE METABOLITES FROM DRUGS: SYNOPSIS OF RECENT WORK 118
STABILITY, REACTIVITY, METABOLISM AND HEPATOTQXICITY OF N-HYDROXYACETAMINOPHEN (12) 121
REFERENCES 126
Chapter 11. Metabolic Activation of Aminostilbene Derivatives and Diethylstilbestrol 128
Introduction 128
Metabolic activation of trans-4-dimethylaminostilbene 128
Dose-dependence of the metabolic activation of trans-4-dimethylaminostilbene 131
Metabolic activation of diethylstilbestrol 133
Acknowledgements 134
References 134
Chapter 12. Matabolic Activation of Chlorinated Ethylene Derivatives 138
ABSTRACT 138
INTRODUCTION 138
CHEMICAL REACTIVITY 139
METABOLIC CONVERSION 139
BIOLOGICAL REACTIVITY OF METABOLITES 143
REFERENCES 145
Chapter 13. Carbenes and Free Radicals of Haloalkanes as Toxic Intermediates 146
ABSTRACT 146
INTRODUCTION 146
RESULTS AND DISCUSSION 148
REFERENCES 152
Chapter 14. Concluding Remarks 154
REFERENCES 161
PART II: BEHAVIORAL TOXICOLOGY: EXPERIMENTAL AND CLINICAL CORRELATIONS 164
Chapter 15. The Agenda of Behavioral Toxicology 166
How Do We Recognize An Adverse Behavioral Effect? 167
How Can We Specify the Non-Specific? 168
Are Standardized Test Batteries Feasible? 168
Chronicity 169
Neurochemistry, Neuropathology, Neurophysiology 169
New Directions 169
Acknowledegements 169
REFERENCES 170
Chapter 16. Duration of Exposure: An Important Variable in Behavioural Toxicology* 172
ABSTRACT 172
WHAT IS THE IMPORTANCE OF CHRONIC EXPOSURE? 172
BEHAVIORAL CONSEQUENCES OF CHRONIC EXPOSURES 173
METHODOLOGICAL PROBLEMS POSED BY CHRONIC EXPOSURE 176
CONCLUSIONS 180
REFERENCES 180
Chapter 17. Changes in Performance, Personality and Subjective Well-being as Indicators of Long-term Exposure to Toxic Environments 184
EFFECTS OF EXPOSURE TO SOLVENT MIXTURES 185
EFFECTS OF LEAD EXPOSURE 187
DISCUSSION 191
REFERENCES 191
Chapter 18. Neurophysiological Characteristics of the Action of Toxic Substances on the Organism 194
Chapter 19. Neurochemical Changes Associated with the Behavioural Toxicity of Organophsophate Compounds 202
INTRODUCTION 202
METHODOLOGICAL ASPECTS OF STUDIES ON BEHAVIOURAL TOLERANCE 203
ALTERNATIVE PATHS TO ORGANOPHOSPHATE TOLERANCE 205
GENERAL DISCUSSION AND CONCLUSIONS 212
REFERENCES 214
Chapter 20. Approach to a Behavioural Screen in Toxicity Testing 218
ABSTRACT 218
INTRODUCTION 218
METHODS 219
RESULTS 221
DISCUSSION 223
ACKNOWLEDGEMENTS 225
REFERENCES 225
Chapter 21. Alertness Impairing Substances and Transport and Occupational Safety: Laboratory Assessment of Hazard 226
ABSTRACT 226
REFERENCES 234
PART III: TOXICOLOGY AND PHARMACOLOGY OF TOPICAL APPLICATIONS 236
Chapter 22. Principles of Percutaneous Absorption 238
ABSTRACT 238
INTRODUCTION 238
MATERIAL AND METHODS 239
RESULTS AND DISCUSSION 240
REFERENCES 250
Chapter 23. Epidermal Response to Antihyperkeratotic Agents 252
I.Salicylic acid 255
II. Retinoids 256
REFERENCES 259
Chapter 24. Toxicological and Pharmacological Aspects of Topical Agents in Relation to the Dermis 260
ABSTRACT 260
REFERENCES 262
Chapter 25. Toxicological and Pharmacological Aspects of Topical Agents in Relation to Specific Cutaneous Structures: The Melanocytes 266
Depigmenting Agents 267
Pigmenting Agents 270
REFERENCES 272
Acknowledgement 273
Chapter 26. The Pilosebaceous Unit: Toxicologicai and Pharmacological Aspects of Topical Agents 274
INTRODUCTION 274
METHODOLOGY FOR MEASURING HAIR GROWTH AND SEBACEOUS GLAND FUNCTION 274
PRINCIPLES OF ACTION OF TOPICAL AGENTS ON THE PILOSEBACEOUS UNIT 277
THE RESPONSE OF THE HAIR TO SPECIFIC TOPICAL AGENTS 278
THE RESPONSE OF THE SEBACEOUS GLANDS TO SPECIFIC TOPICAL AGENTS 278
REFERENCES 281
Chapter 27. Toxicology and Pharmacology of Topically-applied Agents on the Eccrine Sweat Gland 284
NORMAL STRUCTURE AND FUNCTION 284
EFFECT OF TOPICALLY APPLIED AGENTS 286
REFERENCES 288
Chapter 28. Carcinogenicity of Cosmetic Materials 292
CONTENT 292
I INTRODUCTION 292
II INITIATING POTENTIAL OF COSMETIC MATERIALS 293
III PROMOTING POTENTIAL OF COSMETIC MATERIALS 297
IV SAFETY REGULATION AND PUBLIC HEALTH 298
REFERENCES 300
PART IV: INVITED LECTURE 304
Chapter 29. Toxins Acting at the Presynaptic Part of the Neuromuscular Junction 306
PRESYNAPTIC SNAKE VENOM NEUROTOXINS 307
BOTULINUM TOXIN 309
LATRODECTUS SPIDER VENOM NEUROTOXINS 310
REFERENCES 311
Index 316