Principles of Genetic ToxicologyThe 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. |
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 |
263 | |
S9 Standardization | 267 |
S9 Storage | 269 |
REFERENCES | 272 |
DOSE SELECTION FOR IN VIVO GENETIC ASSAYS | 273 |
274 | |
SELECTED REFERENCES AND REVIEWS OF GENETICS AND GENETIC TOXICOLOGY | 275 |
277 | |
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Common terms and phrases
acid activity alterations analysis animal antibodies application approach assay base bioassays biological Brusick cancer carcinogens cell transformation cellular Chemical Mutagens chromosome aberrations Class cloning Codon cytogenetic detection DNA adducts DNA damage DNA repair dominant lethal dose Drosophila effects endpoint environmental mutagens enzymes eukaryotic evaluation exposed exposure expression Figure gametes gene mutation genetic risk genetic toxicology genotoxic genotoxic agents germ cell hazard heritable translocation HGPRT human identified induced involves laboratory lesions lymphocytes male malformations mammalian cell mammals meiosis metabolic methods mice models molecule monitoring mouse mutagenesis mutagens mutation induction ND ND ND nondisjunction normal nucleotide oncogenes organism plasmid population potential produce prokaryotic protein rats recessive replication responses risk assessment risk estimates rodent sample screening selection sequences short-term tests Sister chromatid exchange somatic cell specific specific-locus sperm studies synthesis Table target cells techniques teratogenic test battery toxicity tumor vitro vivo