Mechanisms and Concepts in Toxicology

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Contents......Page 5
Preface......Page 10
Acknowledgements......Page 12
1.1  Toxicology and Mechanisms of Toxicity......Page 13
1.2.1  Organisms......Page 15
1.2.2  Responses......Page 16
1.2.3  Toxic Chemicals......Page 17
1.3.2  Exposure at Work......Page 19
1.4  Discussion......Page 20
1.5  Summary......Page 21
2.1  Introduction......Page 22
2.3  Exposure and Entry of Chemicals......Page 23
2.4  Delivery of Intoxicant......Page 24
2.6  Early Changes and Clinical Consequences......Page 25
2.7  Discussion......Page 26
2.8  Summary......Page 27
3.1  Introduction......Page 28
3.2  Reversible Interactions......Page 29
3.3  Covalent Interactions......Page 31
3.4  Michaelis Constants......Page 34
3.5  Criteria to Distinguish Reversible from Covalent Interactions......Page 35
3.6  In vivo Kinetics......Page 36
3.7  Discussion......Page 37
3.8  Summary......Page 38
4.2  Single Exposure, Rapid Biological Effect, Rapid Recovery......Page 40
4.4  Single Exposure, Rapid Biological Effect, Slow but Complete Recovery......Page 42
4.5  Single Exposure, Latent Intoxication, Little or No Recovery......Page 43
4.7  Single Exposure, Latent Intoxication, No Recovery......Page 44
4.8  Discussion......Page 45
4.9  Summary......Page 46
5.1  Introduction......Page 47
5.1.2  Methyl Isocyanate......Page 49
5.2  Delivery (Entry and Distribution)......Page 50
5.3.1  Passive Diffusion......Page 51
5.3.2  Filtration......Page 54
5.3.4  Endocytosis: Pinocytosis and Phagocytosis......Page 55
5.3.5  Absorption from the Castro-intestinal Tract......Page 56
5.5  Factors which Reduce the Concentration of Free Intoxicant......Page 57
5.5.2  Haemoglobin......Page 58
5.5.3  Ligandin (Glutathione S-transferase)......Page 59
5.5.4  Metallothionein......Page 60
5.5.6  Excretion......Page 61
5.5.7  The Enzymes and Chemistry of Detoxification......Page 62
5.5.8  The Detoxification of Electrophiles, Oxidants and Active Oxygen Metabolites......Page 64
5.6  Discussion......Page 65
5.7  Summary......Page 66
6.1  Introduction......Page 68
6.3.1  Dimethylnitrosamine......Page 70
6.3.3  Tri 2-tolyl phosphate......Page 71
6.3.4  Tetraethyllead......Page 73
6.3.5  Hexachloro- 1,3-butadiene......Page 74
6.4  Cytochrome P450s......Page 75
6.5.1  Paraquat......Page 77
6.5.2  Beryllium......Page 79
6.7  Methods to Establish if In Vivo Bioactivation Occurs......Page 81
6.8  Discussion......Page 83
6.9  Summary......Page 84
7.1  Introduction......Page 86
7.2  Intoxicants which Affect Oxidative Energy Conservation (Many Tissues)......Page 88
7.3  Pyrethroids (Nervous System)......Page 90
7.4  Paraquat (Lung)......Page 92
7.5  Organophosphorus Compounds and Carbamates (Nervous System)......Page 93
7.6  Organophosphorus Compounds (Delayed Neuropathy; Axonopathy)......Page 98
7.7  Acrylamide (Nervous System; Axonopathy)......Page 100
7.8  2,5-Hexanedione (Nervous System; Peripheral and Central Axonopathy)......Page 103
7.9  Trichlorethylene (Liver Peroxisome Proliferation)......Page 106
7.10  Glycol Ethers (Testis, Embryonic and Foetal Development)......Page 107
7.11  Beryllium and the Rare Earths (Liver, Reticulo-endothelial System)......Page 110
7.12  Triorganotins (Nervous System; Intramyelinic Vacuoles and Neuronal Necrosis)......Page 111
7.13  Cell Death (Necrosis and Apoptosis)......Page 113
7.14  Mutation and Carcinogenesis......Page 114
7.15  Immunotoxicity......Page 117
7.16  Discussion......Page 120
7.17  Summary......Page 122
8.1  Introduction......Page 123
8.2  Functional without Morphological Change: Perturbation of the Cellular Utilisation of Oxygen......Page 124
8.3  Functional without Morphological Change: Perturbation of the Cholinergic Transmitter System......Page 125
8.4  Functional without Morphological Change: Perturbation of the Voltage-dependent Sodium Channels......Page 127
8.5  Cell Death: Liver and Lung Damage and Fibrosis......Page 129
8.6  Cell Death: Neuronal Necrosis in Specific Areas of the Brain......Page 130
8.7  Cell Death: External Stimuli and Neuronal Cell Necrosis......Page 131
8.8  Axonopathy: Primary Effects on the Nerve Axon......Page 132
8.9  Chemical Carcinogenesis: DNA Adduct to Tumour......Page 135
8.10  Inflammatory Response: Toxic Oil Syndrome......Page 137
8.11  Discussion......Page 140
8.12  Summary......Page 142
9.1  Introduction......Page 143
9.2  Essential and Toxic Compounds......Page 144
9.3  Exposure-response for Bioassay: The Maiathion Episode in Pakistan......Page 145
9.4  Exposure-Response: Chemical Carcinogens......Page 146
9.5  Structure- and Dose-Response Relationships: γ-Diketones and Acrylamide.......Page 148
9.6  Structure-Response: Triorganotins, Phenols and Phenylimino Compounds......Page 151
9.7  Thresholds......Page 154
9.8  Discussion......Page 157
9.9  Summary......Page 158
10.1  Introduction......Page 160
10.2  Differences in Metabolism: Methanol......Page 163
10.3  Differences in Detoxification and Reaction with Target: Chlorfenvinphos......Page 165
10.5  Human Chemical-induced Diseases with No Animal Model......Page 167
10.6  The Ames Test......Page 168
10.7  In vitro Techniques and the Use of Animals......Page 169
10.8......Page 170
10.9  Summary......Page 172
11.1  Introduction......Page 173
11.3  Succinyldicholine......Page 175
11.4  Exposure, Dose and Effect Monitoring in Humans......Page 176
11.5  Dose Monitoring in Humans: Methylmercury (Epidemic in Iraq)......Page 177
11.6  Dose Monitoring in Humans: Ethylene Oxide......Page 179
11.7  Dose and Effect Monitoring in Humans: Anticholinesterases......Page 181
11.8  Dose and Effect Monitoring in Humans: Dichlorvos......Page 182
11.10  Effect Monitoring......Page 183
11.11  Discussion......Page 184
11.12  Summary......Page 185
12.1  Introduction......Page 186
12.2  General Methodological Approaches......Page 188
12.3  Epidemiological Methods used in Occupational Exposures......Page 190
12.4  Smoking and Lung Cancer......Page 191
12.5  Toxic Oil Syndrome in Spain......Page 193
12.6  Health Effects of Environmental Exposure to Cadmium......Page 196
12.7  Discussion......Page 199
12.8  Summary......Page 200
13.1  Introduction......Page 201
13.2  Polychlorinated Biphenyls......Page 202
13.3  Toxic Chemicals produced by Cyanobacteria (Algae)......Page 205
13.4  Methylmercury: Minamata and Niigata Episodes......Page 206
13.5  Chlorinated Mutagenic Agents in Drinking Water......Page 208
13.6  Discussion......Page 211
13.7  Summary......Page 212
14.1  Reflections......Page 213
14.2  Research......Page 214
14.3  Risk......Page 217
14.4  Summary......Page 220
References......Page 221
Index......Page 249