Chemical Mutagens

1 Chemical Mutagens and Sister-Chromatid Exchange.- 1. Introduction.- 1.1. Advantages of Studying Sister-Chromatid Exchange.- 1.2. Development of Modern Techniques.- 2. Sister-Chromatid Exchange as a Measure of Chromosome Damage.- 2.1. Variation in the Baseline Frequency of Sister-Chromatid Exchange.- 2.2. Induction of Sister-Chromatid Exchanges by Ultraviolet Light, X Rays, and Viruses.- 2.3. What Are Sister-Chromatid Exchanges?.- 2.4. Factors That Affect the Frequency of Sister-Chromatid Exchanges Induced by Chemicals.- 3. Systems and Methods t2.- 4. Summary.- 5. References.- 2 Modification of Mutagenic Activity.- 1. Introduction. 41 2. Factors That Influence Metabolic Activation t2.- 3The Detection of Chemical Mutagens/Carcinogens by DNA Repair and Mutagenesis in Liver Cultures.- 1. Introduction.- 2. Types of Chemical Carcinogens.- 3. Metabolic Activation Capability of Liver.- 4. Liver Cultures.- 4.1. Hepatocyte Primary Cultures.- 4.2. Long-Term Epithelial Cultures.- 5. Carcinogen Metabolism in Liver Cultures.- 6. Hepatocyte Primary Culture/DNA Repair Assay.- 6.1. Autoradiographic Assay.- 6.2. Liquid Scintillation Counting Assay.- 7. Mutagenesis of Rat Liver Epithelial Lines.- 8. Hepatocyte-Mediated Mutagenesis of Rat Liver Epithelial Lines.- 9. Discussion.- 10. References.- 4 Commercial Screening of Environmental Chemicals.- 1. Introduction.- 2. Transfer of Technology.- 3. Goals of Genetic Toxicology in Chemical Safety Evaluation.- 3.1. Approaches for Assay System Deployment in the Identification of Genotoxic Substances.- 3.2. Application of Test Results to Health and Safety Considerations.- 3.3. Application of Test Results to Management Decisions Concerning Chemical Development.- 4. Technical Operation Requirements.- 4.1. Facilities.- 4.2. Data Management and Control.- 4.3. Chemical Storage and Waste Disposal.- 5. Legal Operation Requirements.- 5.1. Laboratory Safety and Employee Monitoring.- 5.2. Good Laboratory Practices and Guidelines.- 6. Summary.- 7. References.- 5 Determining the DNA-Modifying Activity of Chemicals Using DNA-Polymerase-Deficient Escherichia coli.- 1. Introduction.- 2. Materials and Methods.- 2.1. Media.- 2.2. Preservation of Tester Strains.- 3. Standard Assay.- 3.1. Preparation of Cultures for Testing.- 3.2. Important Precautions.- 3.3. Procedure for the Pol A Assay.- 3.4. Preparation of Test Agents.- 3.5. Standards.- 4. Modified Assay.- 4.1. Modification of the Pol A1-Assay (Liquid Suspension).- 4.2. Procedure.- 5. Microsomal Activation.- 5.1. Preparation of Rat Liver S-9 Fraction.- 5.2. Plate Assay.- 5.3. Liquid Assay Procedure.- 6. Results and Discussion.- 6.1. Standard Assay.- 6.2. Modified (Liquid) Assay.- 7. Comparison of the Pol A and Salmonella Assays.- 8. References.- 6 Screening of Environmental Chemical Mutagens by the Rec-Assay System with Bacillus subtilis.- 1. Introduction.- 2. Principles and Related Background of the Rec-Assay.- 3. Experimental Procedures.- 3.1. Rapid Streak Method (without Metabolic Activation).- 3.2. Quantitative Analysis by the Spore Rec-Assay (with and without Metabolic Activation).- 3.3. Quantitative Liquid Method (with and without Metabolic Activation).- 4. Examples of Detection of Chemical Mutagens by the Rec-Assay Procedures.- 4.1. Food Additives.- 4.2. Pesticides.- 4.3. Metals.- 4.4. Miscellaneous.- 5. Rec-Assays on Chemical Carcinogens.- 6. References.- 7 Transformation of Syrian Hamster Embryo Cells by Diverse Chemicals and Correlation with Their Reported Carcinogenic and Mutagenic Activities.- 1. Introduction.- 2. Mammalian Cell Transformation Systems as Prescreens for Identifying Carcinogens in the Environment.- 3. Hamster Embryo Cell in Vitro Carcinogenesis Bioassay.- 3.1. Standardization of the Bioassay Procedure by the Use of Cryopreserved Cells.- 3.2. Criteria for Positive Response.- 4. Correlation of Transformation Response with Reported Carcinogenicity and Mutagenicity.- 4.1. Direct-Acting Alkylating Agents.- 4.2. Polycyclic Aromatic Hydrocarbons.- 4.3. Nitrosamines and Nitrosamides.- 4.4. Aromatic Amines, Aminoazo Dyes, and Nitro Compounds.- 4.5. Carcinogenic Metallic Salts.- 4.6. Miscellaneous Compounds.- 5. Metabolic Activation.- 6. A Battery vs. a Tier of Short-Term Tests for Identifying Potentially Carcinogenic Chemicals.- 7. Conclusions.- 8. References.- 8 Chemical Mutagenesis in the Silkworm.- 1. Introduction.- 2. Methods for Mutation Detection in the Silkworm.- 2.1. Correlation between Developmental Stages of the Silkworm and the Stages of Spermatogenesis and Oogenesis.- 2.2. Specific Locus Method.- 2.3. Dominant Lethal Method.- 2.4. Detection of Nondisj unction and Polyploidy.- 3. Procedures for Administration of Chemicals.- 3.1. Oral Administration.- 3.2. Injection.- 3.3. Soaking of Eggs in Chemical Solution.- 3.4. Gas (Aerosol) Treatment.- 4. Sensitivity.- 4.1. Strain Difference.- 4.2. Variation with the Progress of Germ-Cell Development.- 5. Mosaics and Delayed Mutagenesis.- 5.1. Preponderance of Mosaics.- 5.2. Delayed Mutagenic Effect.- 6. Exploitation of a Sensitive Test System with Oocytes.- 6.1. Effective Stage of Injected Chemicals in the Oocyte System.- 7. Screening of Environmental Mutagenic Compounds.- 8. Modification of Mutagenicity by Metabolic Activation.- 9. Conclusion.- 10. References.- 9 The Use of Short-Term Tests in the Isolation and Identification of Chemical Mutagens in Complex Mixtures.- 1. Introduction.- 2. Extraction Methodology.- 2.1. Rapid, Simple Extraction Methods.- 2.2. Class Fractionation.- 3. Mutagenesis Assay Methodology.- 3.1. Microbial Mutagenesis Assays.- 3.2. Comparative Mutagenesis.- 3.3. Precautions for the Use of Short-Term Mutagenicity Assays.- 4. References.- 10 Mathematical Analysis of Mutation-Induction Kinetics.- 1. Introduction.- 2. Definitions.- 3. Stochastic Description of Mutagenesis and Killing.- 4. Formal Dose-Response Patterns.- 5. The Linear Response Pattern (Lk,Lm).- 6. Nonlinear Response Patterns.- 6.1. Initial Slope of Yield Curves.- 6.2. Positions of Yield Maxima.- 6.3. Magnitude of Yield Maxima.- 6.4. Lethal Hit Units for Nonlinear Cases.- 6.5. Integral Yields for Nonlinear Cases.- 7. Illustrative Calculations of Yield Curves.- 8. Relative Mutagenic Efficiency (RME).- 9. Stochastic Dependence of Mutation and Killing.- 10. Repair-Mediated Mutagenesis.- 11. Concluding Remarks.- 12. Summary.- 13. Appendix t2.- 11 Comparison of the Mutagenic Effect of Ultraviolet Radiation and Chemicals in Normal and DNA-RepairDeficient Human Cells in Culture.- 1. Introduction.- 1.1. Significance of Studies with Diploid Human Cells.- 1.2. Implications for Carcinogenesis.- 2. Procedures.- 2.1. Cell Strains and Media.- 2.2. Assay for Cytotoxicity.- 2.3. Quantitating the Frequency of Drug-Resistant Colonies in the Population.- 2.4. Characterization of Drug-Resistant Colonies.- 3. Evidence that Excision Repair Can Eliminate Potentially Cytotoxic and Mutagenic Lesions from DNA.- 3.1. Potentially Cytotoxic Lesions.- 3.2. Potentially Mutagenic Lesions.- 4. Conclusion.- 5. References.- 12 Gene-Locus Mutation Assays in Diploid Human Lymphoblast Lines.- 1. Introduction.- 1.1. Sources and Care of Starter Cultures.- 1.2. Mutation Assays.- 2. Exposure.- 2.1. Duration.- 2.2. Limits to Statistical Precision.- 2.3. Treatment with Metabolic Activation.- 2.4. Posttreatment Handling.- 3. Determination of Colony-Forming Ability.- 4. Selection Systems.- 4.1. General Considerations.- 4.2. Potential Cell-Density Artifacts.- 4.3. Useful Selective Systems.- 5. Experimental Observations.- 5.1. Mutation at the hgprt Locus.- 5.2. Comparison of Mutation at the hgprt Locus in Different Human Lymphoblast Lines.- 5.3. Mutation at Other Loci.- 6. Discussion.- 6.1. Further Developments in Lymphoblast Mutation Assays.- 6.2. Further Uses of Lymphoblast Assays.- 7. References.- 13 The Need for Both in Vitro and in Vivo Systems in Mutagenicity Screening.- 1. Introduction.- 2. General Considerations of Mutagenicity Screening of Chemicals.- 2.1. Use of in Vitro and in Vivo Systems in Qualitative Testing.- 2.2. Use of in Vitro Systems Only in Qualitative Testing.- 2.3. Inadequacies of in Vitro Testing.- 2.4. Necessity for Combined Testing.- 3. Correlations between Carcinogenicity and Mutagenicity in Salmonella.- 3.1. Background.- 3.2. Statistical Considerations of Correlating.- 4. Construction of a Table of 465 Compounds with Known or Suspected Carcinogenic Activity (Table 4).- 4.1. International Agency for Research on Cancer (IARC).- 4.2. Environmental Protection Agency (EPA).- 4.3. Department of Health, Education and Welfare (DREW).- 4.4. Correlation Studies.- 5. Discussion of False Negatives from Table 4.- 5.1. Azo Compounds.- 5.2. Carbamyls and Thiocarbamyls.- 5.3. Phenyls.- 5.4. Benzodioxoles.- 5.5. Bactericides.- 5.6. Halogenated Compounds.- 5.7. Steroids.- 5.8. Antimetabolites.- 5.9. Hydrazines and N-Alkyl Compounds.- 5.10. Intercalating Agents.- 5.11. Chloroethylenes.- 5.12. Membrane-Specific Agents.- 5.13. Pyrazolinone.- 5.14. Mitotic Poisons.- 5.15. Cross-Linking Agents.- 5.16. Summary.- 6. Validation of Salmonella Testing as a Predictor of Carcinogenicity.- 7. Concluding Comments on Mutagenicity Testing.- 8. References.