Toxicology and Experimental Models (eBook)

Front Cover 1
Toxicology and Experimental Models 4
Copyright Page 5
Table of Contents 6
Introduction 10
Part I: SYMPOSIUM The Rational Interpretation of Species and Strain Differences in Toxicity for the 
12 
Chapter 1. The Rational Interpretation of Species and Strain Differences for the Prediction o fRisk to Man 
14 
INTRODUCTION 14
REFERENCES 17
Chapter 2. The Potential Value of Immunopathology 
18 
ABSTRACT 18
KEYWORDS 18
PRESENT POSITION 18
POSSIBLE STRATEGIES 19
TOXICITY STUDIES IN RATS AND DOGS 20
MINIMAL REQUIREMENTS FOR IMMUNO-TOXICOLOGY 26
SPECIFIC IMMUNOPATHOLOGICAL INVESTIGATIONS 26
CONCLUSION 27
REFERENCES 27
Chapter 3. Lessons from Studies in Animals for the Evaluation of Human Risk from 
28 
ABSTRACT 28
KEYWORDS 28
INTRODUCTION 28
EMBRYONIC NUTRITION 30
IN VITRO TERATOGENESIS 36
CONCLUSION 37
REFERENCES 37
ACKNOWLEDGEMENTS 39
Chapter 4. Genetic Variability in Man as a Complicating Factor in the Extrapolation 
40 
ABSTRACT 40
KEYWORDS 40
INTRODUCTION 40
INTER-SUBJECT VARIABILITY IN DRUG METABOLISM 41
PHARMACOGENETICS - RECENT FINDINGS 42
IN VITRO STUDIES OF HUMAN DRUG METABOLISM 45
ACKNOWLEDGEMENTS 48
REFERENCES 48
Chapter 5. The Rational Interpretation of Species and Strain Differences in Toxicity for the Prediction of Risk to Man: Review and 
52 
ABSTRACT 52
KEYWORDS 52
REFERENCES 60
Part II: SYMPOSIUM Chemical Interactions Resulting in Liver 
64 
Chapter 6. Ethanol Potentiation of Liver Injury 66
ABSTRACT 66
KEYWORDS 66
INTRODUCTION 66
MECHANISM(S) OF ACTION 68
CLINICAL IMPLICATIONS 72
ACKNOWLEDGEMENTS 73
REFERENCES 73
Chapter 7. Potentiation of Liver and Kidney Injury 
76 
ABSTRACT 76
KEYWORDS 76
INTRODUCTION 76
DOSE-RESPONSE CONSIDERATIONS 77
TIME INTERVAL AND POTENTIATION 80
CHAIN-LENGTH AND POTENTIATION 80
HEPATOTOXICITY INDUCED BY OTHER HALOALKANES 80
POTENTIATION OF CHOLESTATIC REACTIONS 82
POTENTIATION OF NEPHROTOXICITY 82
MECHANISMS INVOLVED 83
ACKNOWLEDGEMENT 84
REFERENCES 84
Chapter 8. Biochemical Mechanisms of Acetaminophen (Paracetamol) Induced 
88 
ABSTRACT 88
KEY WORDS 88
FACTORS INTERACTING TO ENHANCE OR DECREASE ACUTE ACETAMINOPHEN 
89 
FACTORS INTERACTING TO ENHANCE OR 
91 
REFERENCES 95
Chapter 9. The Hepatotoxicity and Nephrotoxicity of 
98 
ABSTRACT 98
KEYWORDS 98
INTRODUCTION 98
RESULTS AND DISCUSSION 99
Acknowledgements 106
References 106
Chapter 10. Modulation of Nephrotoxicity by 
108 
ABSTRACT 108
KEY WORDS 108
INTRODUCTION 108
ENVIRONMENTAL CONTAMINANTS 109
SUMMARY 113
ACKNOWLEDGEMENTS 113
REFERENCES 113
Part III: SYMPOSIUM Heme Synthesis and Degradation: 
116 
Chapter 11. Heme Synthesis and Degradation: Its Role in Predicting Drug Toxicity — 
118 
INTRODUCTORY REMARKS 118
REFERENCES 121
Chapter 12. Effect of Drugs and Chemicals on d-Aminolevulinic Acid Synthase, the Ratelimiting 
122 
ABSTRACT 122
KEYWORDS 122
INTRODUCTION 123
REGULATION OF ALA SYNTHASE ACTIVITY 124
MECHANISMS BY WHICH DRUGS AND CHEMICALS 
125 
INDUCTION OF HEPATIC ALA SYNTHASE 
128 
ACKNOWLEDGMENT 129
REFERENCES 129
Chapter 13. Effects of Drugs and Metals on Heme 
132 
ABSTRACT 132
KEYWORDS 132
INTRODUCTION 132
EXPERIMENTAL OBSERVATIONS 134
COMMENTS 139
ACKNOWLEDGMENT 140
REFERENCES 140
Chapter 14. Liver Haem as a Target for Drug Toxicity 142
ABSTRACT 142
KEYWORDS 142
INTRODUCTION 142
EFFECT OF UNSATURATED DRUGS ON LIVER CYTOCHROME P-450 143
LIVER ACCUMULATION OF N-METHYL PROTOPORPHYRIN AFTER 
144 
MECHANISM OF PRODUCTION OF N-METHYL PROTOPORPHYRIN BY DDC 146
REFERENCES 148
Chapter 15. Toxic Effects of Metals on the Synthesis 
150 
ABSTRACT 150
KEY WORDS 150
INTRODUCTION 150
THE EFFECT OF METALS ON HEME BIOSYNTHESIS 151
THE EFFECT OF FASTING ON CARDIAC ALA SYNTHETASE 
154 
EFFECT OF COBALT ON ALA SYNTHETASE ACTIVITY IN FRIEND ERYTHROLEUKEMIC CELLS 155
ACKNOWLEDGMENT 156
REFERENCES 156
Chapter 16. The Heme Biosynthetic Pathway in the Prediction of Haloaromatic Hydrocarbon 
158 
ABSTRACT 158
KEYWORDS 158
INTRODUCTION 158
THE TURKISH EPIDEMIC AND HEXACHLOROBENZENE PORPHYRIA 160
PORPHYRIA DUE TO TCDD 161
STUDIES ON THE MECHANISMS OF PORPHYRIA DUE TO TCDD 162
STUDIES OF PORPHYRIN METABOLISM: PREDICTION OF HEPATOTOXICITY 165
POPULATION SCREENING 166
ACKNOWLEDGEMENT 167
REFERENCES 167
Part IV: SYMPOSIUM Delayed Toxic Effects of Pre- and Perinatal 
172 
Chapter 17. An Overview on Delayed Toxic Effects of 
174 
ABSTRACT 174
KEYWORDS 174
INTRODUCTION 174
REFERENCES 185
Chapter 18. Improvements in the Postnatal Detection 
188 
1 · Prenatal 
189 
2.The newborn Period 190
3 · Methodology 190
4. Results 191
SUMARY AND CONCLUSIONS 203
BIBLIOGRAPHIE 205
Chapter 19. Maldevelopment of CNS Induced by Perinatal Metabolic Insults and Possibilities of Its 
210 
ABSTRACT 210
KEYWORDS 210
INTRODUCTION 210
BEHAVIORAL TERATOLOGY MODELS 213
PERINATAL DISTRESS IN HIGH-RISK NEWBORNS 217
CONCLUSION 219
REFERENCES 219
Chapter 20. Altered Postnatal Development Following Intrauterine Exposure to Hormonally Active Chemicals 222
ABSTRACT 222
KEY WORDS 222
INTRODUCTION 222
TRANSPLACENTAL TOXICOLOGY 223
TRANSPLACENTAL TOXICOLOGY: INFERTILITY IN OFFSPRING 223
TRANSPLACENTAL TOXICOLOGY OF DIETHYLSTILBESTROL (DES) 226
ACKNOWLEDGEMENT 229
REFERENCES 229
Chapter 21. WORKSHOP 
232 
Chapter 22. Alcohol Intoxication and Withdrawal: 
234 
HISTORICAL COMMENTS 234
BACKGROUND ON ALCOHOL RESEARCH 234
ETHANOL METABOLISM 234
METABOLIC CHANGES INDUCED BY ETHANOL: METABOLIC TOLERANCE 235
CELLULAR BASIS OF THE ACTION OF ETHANOL ON THE NERVOUS 
236 
CONCLUSION 236
REFERENCES 237
KEYWORDS 237
Chapter 23. The Role of Mitochondrial NADH Reoxidation in the Hepatic Metabolism of Ethanol: Studies with Perfused Livers from Ethanol and CCl4-Treated 
238 
ABSTRACT 238
INTRODUCTION 238
MATERIALS AND METHODS 239
RESULTS & DISCUSSION
KEY WORDS 242
REFERENCES 242
Chapter 24. Ethanol and Membrane Cholesterol 244
ABSTRACT 244
KEYWORDS 244
ACKNOWLEDGEMENT 247
REFERENCES 247
Chapter 25. Susceptibility to Ethanol of Neurons in Lateral Vestibular, Spinal Trigeminal and 
250 
ABSTRACT 250
KEYWORDS 250
INTRODUCTION 250
METHODS 251
RESULTS 251
DISCUSSION 253
REFERENCES 255
Chapter 26. Dissociation of Components of Ethanol 
256 
ABSTRACT 256
KEYWORDS 256
INTRODUCTION 256
PROCEDURES AND RESULTS 257
DISCUSSION 260
ACKNOWLEDGEMENTS 261
REFERENCES 261
Part V: WORKSHOP Models of Experimental Peptic Ulcers 
264 
Chapter 27. Models of Experimental Peptic Ulcers and 
266 
KEYWORDS 266
Chapter 28. Possible Roles of Central Gatecholamines 
268 
ABSTRACT 268
KEY WORDS 268
INTRODUCTION 268
CENTRAL NA ON STRESS-INDUCED GASTRIC ULCER 269
CENTRAL MONOAMINES IN REGULATION OF GASTRIC ACID 
269 
RELATION OF MUCOSAL BLOOD FLOW TO GASTRIC ACID 
271 
REFERENCES 271
Chapter 29. Duodenal Ulcer and Dopamine: 
274 
ABSTRACT 274
KEYWORDS 274
INTRODUCTION 274
MATERIALS AND METHODS 275
RESULTS AND DISCUSSION 275
ACKNOWLEDGEMENTS 279
REFERENCES 279
Chapter 30. Defensive Mechanism in Peptic Ulcer and 
280 
ABSTRACT 280
KEYWARDS 280
INTRODUCTION 280
INCREASE IN THE HYDROGEN ION PERMEABILITY OF THE GASTRIC MUCOSA AS 
280 
INCREASE IN HYDROGEN ION PER- MEABILITY OF GASTRIC MUCOSA IN ASPIRIN-INDUCED ULCERATION IN 
281 
CONCLUSIONS 285
REFERENCES 285
Chapter 31. Differential Role of Histamine in Duodenal 
286 
ABSTRACT 286
KEYWORDS 286
INTRODUCTION 286
EXOGENOUS HISTAMINE AND ULCER INDUCTION 287
INDUGENOUS HISTAMINE AND ULCER INDUCTION 287
MECHANISMS OF ACTION OF HISTAMINE IN ULCER PATHOGENESIS 288
ACKNOWLEDGMENT 291
REFERENCES 291
Chapter 32. Can the Mechanisms of 
292 
ABSTRACT 292
KEYWORDS 292
INTRODUCTION 293
MUCOSAL INJURY INDUCED BY ASPIRIN 293
EFFECT OF ASPIRIN ON MUCOSAL PROSTAGLANDIN FORMATION 293
EFFECT OF ASPIRIN ON GASTRIC MUCOSAL BLOOD FLOW 293
EFFECT OF ASPIRIN ON THE "GASTRIC MUCOSAL BARRIER 294
EFFECT OF ASPIRIN ON GASTRIC ACID SECRETION 294
EFFECT OF ASPIRIN ON GASTRIC MUCUS AND BICARBONATE SECRETION 294
CONCLUSION 295
ACKNOWLEDGEMENT 295
REFERENCES 295
Chapter 33. Screening of Anti-Ulcer Agents Using 
298 
ABSTRACT 298
KEYWORDS 298
INTRODUCTION 298
SCREENING METHODS 298
EFFECTS OF ANTI-ULCER AGENTS ON EXPERIMENTAL ULCERS 301
PREVENTION OF RECURRENCE 301
ULCER MODELS IN LARGE ANIMALS 302
SUMMARY 303
REFERENCES 303
Part VI: SYMPOSIUM Models and Quality Control of Laboratory 
304 
Chapter 34. Introduction to Models and Quality Control of Laboratory Animals 306
REFERENCES 309
Chapter 35. Consideration of Provision and Characterization of Animal Models 310
ABSTRACT 310
KEYWORDS 310
INTRODUCTION 310
PRINCIPLES OF EXTRAPOLATION 311
DEVELOPMENT OF NEW ANIMAL MODELS 314
CONCLUSION 317
ACKNOWLEDGEMENT 318
REFERENCES 318
Chapter 36. 
320 
ABSTRACT 320
KEYWORDS 320
INTRODUCTION 320
REFERENCES 329
Chapter 37. Species Variation in Evaluation of Safety of Drugs in the Developing Animal 330
ABSTRACT 330
KEYWORDS 330
INTRODUCTION 330
MOTHER 331
PLACENTA 332
EMBRYO 333
REFERENCES 333
Chapter 38. Defined Laboratory Animals 336
ABSTRACT 336
KEYWORDS 336
INTRODUCTION 336
CLASSIFICATION OF EXPERIMENTAL ANIMALS 337
SITE OF THE RESPONSE TO THE EXPERIMENT- 
338 
CONTROL AND TESTING OF LABORATORY ANIMALS AND DEFINITION 
339 
GENETICAL AND MICROBIOLOGICAL MONITORING AS A PERFORMANCE 
340 
CONCLUSION 343
REFERENCES 343
Chapter 39. Quality Control in Diets — the Attainable 346
ABSTRACT 346
KEYWORDS 346
INTRODUCTION 346
DIET MANUFACTURE 347
DIET INGREDIENTS 348
CONTAMINATION IN DIETS 351
MICROBIOLOGICAL CONTROL AND DIET STABILITY 353
COST 355
NUTRIENT VARIATIONS IN FIXED FORMULA DIETS 357
CONCLUSION 357
Chapter 40. Problems and Improvements 
358 
ABSTRACT 358
KEYWORDS 358
INTRODUCTION 358
PROGRAM MILESTONES 359
SCIENCE AND PROCESS 360
GLP CONCEPTS 360
THE PRINCIPAL GLP PROVISIONS 361
FDA"S LABORATORY INSPECTION PROGRAM 362
SUMMARY 363
REFERENCES 363
Index 364