Principles of Genetic Toxicology

Front Cover
Springer Science & Business Media, Nov 30, 1987 - Medical - 284 pages
The field of genetic toxicology has gone through remarkable development in the seven years since the appearance of the first edition of Principles of Genetic Toxicology. One branch of toxicology research, chemical mutagenesis, has been elucidated and expanded as a result of increased effort, testing, and the sharing of data. This expansion has occurred not only in the industrialized countries, but also in countries that are comparatively less advanced in scientific implementation. These developing countries have taken advan tage of the basic practical methods that were so well described in the first edition of this work. It is significant to note how many centers have been established throughout the world and are now studying the basic concepts and applying them to practical problems such as the detection of genetic effects caused by exposure to chemicals. In fact, there are now toxicology training centers in twelve countries. Genetic toxicology, in addition to being investigated as a science unto itself, has been taught to people in the applied fields so that these techniques may be put to use in solving other biological problems. For these reasons, it is most useful to have an update of the basic methods and their development. Dr. Brusick should be congratulated for doing such an excellent job of assembling a text that will be worthwhile to any researcher who is interested in the principles of genetic toxicology. Alexander Hollaender Council for Research Planning in Biological Sciences, Inc. Washington, D. C.

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Contents

Origins of Genetic Toxicology
xvii
THE ROLE OF GENETIC TOXICOLOGY IN HEALTH EFFECTS TESTING
1
HISTORY OF GENETIC TOXICOLOGY
2
TECHNOLOGY TRANSFER AND APPLIED GENETICS
3
THE COMPONENTS OF GENETIC TOXICOLOGY
4
REFERENCES
7
Fundamentals of Genetic Toxicity
11
Gene Function
14
Threshold
144
IS GENETIC RISK IMPORTANT TO SOCIETY?
146
REFERENCES
147
Applications of Genetic Toxicology to Human and Environmental Monitoring
153
OCCUPATIONAL MONITORING APPROACHES
158
Occupational Monitoring Objectives
159
Chromosome Damage and Cancer
160
INTERPRETATION OF HUMAN MONITORING RESULTS
162

THE CELL CYCLE AND CHROMOSOME MECHANICS IN SOMATIC AND GERM CELLS
20
The Chromosome
21
The Mitotic Cell Cycle
24
Meiosis and Chromosome Mechanics
27
MECHANISMS AND CATEGORIZATION
31
Significance of the Classes of Genotoxic Effects
42
REPAIR OF DNA DAMAGE
45
REFERENCES
48
The Consequences of Genotoxic Effects in Humans and Other Mammals
51
GENOMIC TARGET IN HUMANS CELLS
56
THE RELATIONSHIP OF GENOTOXIC EFFECTS TO OTHER TOXICOLOGIC PHENOMENA
65
FALSENEGATIVE AND POSITIVE RESPONSES
69
Promoting Agents as False Negatives
71
RELATIONSHIP OF POTENCY BETWEEN MUTAGENICITY ASSAYS AND IN VIVO ONCOGENICITY
73
REFERENCES
74
Screening Chemicals for Genotoxic Properties
77
DEFINITIONS OF TERMS
79
Screening Tests
80
Hazard Assessment Tests
81
The Metabolic Capability of the Test or Associated Activating System
83
Test ReliabilityReproducibility
87
Test Transferability
88
Specific Approaches
89
CONDUCTING THE TESTS
91
The Use of Controls in in Vitro and in Vivo Testing
97
Use of in Vivo Genetic Toxicology Assays
101
StandAlone Techniques
102
Expansion of Standard Toxicology Assays
103
Regulations Affecting Testing
105
Evaluation Approaches for Batteries
106
Interpretation of Results from Test Batteries
108
SUMMARY
113
REFERENCES
115
Genetic Risk Estimation INTRODUCTION
119
DEFINITION OF RISK ESTIMATION
120
Estimates of Current Genetic Burdens in Humans
121
SECONDARY FACTORS INFLUENCING RISK ANALYSES
122
Sex
123
Diet
124
Theoretical and Practical Considerations Important to Risk Analysis
125
RISK ESTIMATION METHOD FOR SOMATIC AND GERM CELLS Somatic Cell Risk
127
Germ Cell Risk
131
Direct Measurement Approach to Risk Estimation
132
Alternative Indirect Methods
133
DOSIMETRY ISSUES IN RISK ASSESSMENT
135
Relationship of the Route of Exposure to Metabolism
136
BloodGonadal Barriers
137
Molecular Dosimetry
138
GENE FUNCTION ISSUES IN RISK ASSESSMENT
140
DATA EXTRAPOLATION ISSUES IN RISK ANALYSIS
141
Extrapolation of in Vitro Potency to in Vivo Response
142
Extrapolation from Species to Species
143
APPLICATION OF BIOTECHNOLOGY TECHNIQUES TO HUMAN MONITORING
165
Immunoassays
166
32PPostlabeling
167
REFERENCES
168
The Genetic Toxicology Laboratory
171
REGULATORY REQUIREMENTS AFFECTING LABORATORY OPERATIONS
173
Guidelines
174
General Laboratory Ventilation
175
Handling and Storage of Chemicals
178
PERSONNEL PROTECTION
180
Protective Clothing
181
Respiratory Protection
182
WASTE DISPOSAL
184
GOOD LABORATORY PRACTICES REQUIREMENTS
185
REFERENCES
189
8 Descriptions and Evaluation of Genetic Toxicology Assays
191
Mammalian Cells in Vitro
194
Insects
197
Mammals
198
TESTS FOR CHROMOSOME ABERRATIONS
199
Insect Tests for Chromosome Effects
200
Mammals
201
Dominant Lethal Assays
202
Heritable Translocation Assay
204
SexChromosome Loss
207
TESTS FOR PRIMARY DNA DAMAGE
208
Yeast
209
SCE Analysis
212
In Vitro Cell Transformation
213
Transfection Assays
219
Applications from Biotechnology Research to Genetic Toxicology
225
Applications of DNA Probes in Genetic Toxicology
227
Gene Cloning
229
APPLICATION OF TECHNIQUES TO GENETIC TOXICOLOGY
235
Human Monitoring
237
SiteSpecific Mutagenesis
239
ASSOCIATED IMPLICATIONS OF BIOTECHNOLOGY Gene Therapy
240
Oncogenes
243
Types of Oncogenes
247
REFERENCES
252
10 Genetic Toxicology and Its Role in the Study of Congenital Malformations
255
Teratogenicity and the Male
259
SUMMARY
261
Appendixes
263
S9 Standardization
267
S9 Storage
269
REFERENCES
272
DOSE SELECTION FOR IN VIVO GENETIC ASSAYS
273
REFERENCES
274
SELECTED REFERENCES AND REVIEWS OF GENETICS AND GENETIC TOXICOLOGY
275
Index
277
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