Chemical Mutagens: Principles and Methods for Their Detection - Volume 8.

Volume 8 of Chemical Mutagens covers a wide range of topics in this continuously changing field. This volume includes chapters on the detection of genetic damage in mammalian sperm both at specific loci and over the entire genome. The discussion of in vitro techniques for working with mammalian cells covers not only specific locus assays but also cellular activation systems. Another chapter extensively discusses the need for a revised protocol for the micronucleus assay. Structure­ activity relationships are investigated in a chapter dealing with hair dye constituents. One of the most comprehensive chapters deals with problems associated with the detection of mutagenic effects in defined human populations. Finally, there is a detailed presentation of a comprehensive study tabulating the genetic bioassay data on some known or suspected human carcinogens. In keeping with our policy of publishing important legislation in the area of chemical mutagens, we have also included the Council of the European Communities Directive of 18 September 1979. Frederick J. de Serres Research Triangle Park, North Carolina vii Contents Chapter 1 Detection of Effects of Mutagens in Human Populations George R. Hoffmann 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Monitoring Progeny for Evidence of Germ-Cell Mutations. . . . . 3 2. 1. The Classical Approach: Phenotypic Monitoring . . . . . . . 3 2. 2. Monitoring for Changes in Gene Products . . . . . . . . . . . 7 3. Detection of Gene Mutations in Somatic Cells. . . . . . . . . . . . . 9 3. 1. Drug-Resistant Lymphocytes . . . . . . . . . . . . . . . . . . . . . . 9 3. 2. Hemoglobin Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 4. Nongenetic Indicators of Mutagen Exposure . . . . . . . . . . . . . 21 4. 1. Alkylation of Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4. 2. DNA Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1 Detection of Effects of Mutagens in Human Populations.- 1. Introduction.- 2. Monitoring Progeny for Evidence of Germ-Cell Mutations.- 2.1. The Classical Approach: Phenotypic Monitoring.- 2.2. Monitoring for Changes in Gene Products.- 3. Detection of Gene Mutations in Somatic Cells.- 3.1. Drug-Resistant Lymphocytes.- 3.2. Hemoglobin Variants.- 4. Nongenetic Indicators of Mutagen Exposure.- 4.1. Alkylation of Proteins.- 4.2. DNA Damage.- 5. Testing for Mutagenic Substances in Body Fluids.- 6. Detection of Altered Sperm.- 6.1. Morphological Sperm Abnormalities.- 6.2. Double Y Bodies in Sperm.- 6.3. Gene Mutations in Sperm.- 7. Summary.- 8. References.- 2 The Use of Intact Cellular Activation Systems in Genetic Toxicology Assays.- 1. Introduction.- 2. Mammalian Cell Mutagenesis.- 2.1. Fibroblast-Mediated Mutagenesis.- 2.2. Hepatocyte-Mediated Mutagenesis.- 2.3. Target Organ and Cell Type Specificities.- 2.4. Studies Using Human Cells.- 3. Bacterial Mutagenesis.- 4. Sister Chromatid Exchange and Chromosome Aberrations.- 5. Cell-Mediated Transformation.- 6. Cytotoxicity and Nucleic Acid Interactions.- 7. Discussion.- 8. Summary.- 9. References.- 3 The Mouse Spot Test As a Predictor of Heritable Genetic Damage and Other Endpoints.- 1. Introduction.- 2. Relation to Measures of Heritable Mutations.- 2.1. Genetic Comparisons.- 2.2. Calculation of “Unit” Mutation Rates.- 2.3. Quantitative Comparisons of SLT and MST Results.- 3. Relation to Other Endpoints.- 4. Summary.- 5. References.- 4 The Bone Marrow Micronucleus Assay: Rationale for a Revised Protocol.- 1. Introduction.- 2. Kinetics of Erythropoiesis.- 3. Rationale for the Basic Aspects of the Protocol.- 3.1. Treatment Regimen.- 3.2. Sample Intervals.- 4. Protocol.- 4.1. General Approach.- 4.2. Protocol Specifics.- 4.3. Spindle Poisons.- 5. Statistical Analysis.- 6. Conclusions.- 7. References.- 5 Relationships between the Chemical Structure and Mutagenic Activity of Monocyclic Aromatic Amines.- 1. Introduction.- 2. Bacterial Strains.- 3. Experimental Methods.- 4. Chemicals.- 5. Mutagenicity Data and Their Interpretation.- 5.1. The 2,4-Diaminoalkoxybenzenes.- 5.2. m-Diaminobenzene and Its 2,4-Diaminoalkylbenzene Derivatives.- 5.3. Nitro-p-phenylenediamine Derivatives.- 5.4. The 3-Amino-4-nitrophenols and the 4-Amino-3- nitrophenols.- 6. Possible Pitfalls in Studies of Structure-Activity Relationships.- 7. Conclusions.- 8. References.- 6 The Measurement of Recessive Lethal Mutations in the Mouse.- 1. Introduction.- 2. Haldane’s Method of Detecting Lethals.- 3. The Backcross Method of Detecting Lethals.- 3.1. Choice of Animals for Studies.- 3.2. Treatment and Breeding Schedule.- 3.3. Identification of Translocation Bearers.- 3.4. The Backcross Matings.- 3.5. Controls.- 4. Irradiation Treatment of Male Germ Cells.- 5. Irradiation Treatment of Female Germ Cells.- 6. Chemical Mutagen Induction of Recessive Lethal Mutations.- 7. Dominant Effects of Recessive Lethal Mutations.- 8. Conclusions.- 9. References.- 7 Chemically Induced Changes in Sperm in Animals and Humans.- 1. Introduction.- 2. The F0 Mouse Sperm Head Morphology Assay.- 2.1. Reproducibility between Laboratories.- 2.2. Results.- 2.3. Method Development.- 3. The F1 Sperm Head Morphology Assay.- 3.1. Genetic Basis of F1 Mouse Sperm Head Morphology Assay.- 3.2. Results.- 3.3. The Potential of the F1 Assay.- 4. Induced Sperm Abnormalities in Humans.- 4.1. Assays Used in the Evaluation of Human Sperm.- 4.2. Comparison of Human and Animal Semen Quality.- 4.3. The Uses of Semen Analysis in Humans.- 5. Implications of Alterations in Human Sperm Quality.- 5.1. Reproductive Implications.- 5.2. Mutagenic Implications.- 5.3. Carcinogenicity Implications.- 6. The Advantages of Sperm Assays.- 7. Recommendations for Future Research and Development.- 8. References.- 8 Mutational Analysis in Cultured Human-Hamster Hybrid Cells.- 1. Introduction.- 2. Origin of Specific Lethal Antisera and Human-Hamster Hybrid Cells.- 2.1. Demonstration of Antisera Specificity.- 2.2. Preparation of Human—Hamster Hybrid Cells Containing Specific Human Chromosomes.- 3. Characterization of the AL Hybrid.- 3.1. Origin of the AL Hybrid.- 3.2. Assignment of the AL Surface Antigens to Human Chromosome 11.- 3.3. Analysis of the AL Antigenic System: Demonstration That the AL Antigenic System Is Composed of a Subset of Activities a1, a2, and a3.- 3.4. Regional Gene Mapping of Markers on Human Chromosome 11.- 3.5. Complementation Analysis of the AL Markers.- 3.6. Biochemical Characterization of the a1 Surface Antigen.- 4. Mutation Studies.- 4.1. Source of Antisera and Complement.- 4.2. Treatment of AL Cells with Suspected Mutagens.- 4.3. Scoring Loss of the a1+ Surface Marker.- 4.4. Yield of a1? Mutants.- 4.5. Fluctuation Analysis for Spontaneous Loss of a1+.- 4.6. Analysis of Induced Loss of Other Markers from Chromosome 11.- 4.7. Production of Mutations by Colcemid.- 5. Conclusions.- 6. References.- 9 Genetic Toxicology of Some Known or Suspected Human Carcinogens.- 1. Introduction.- 2. Chemical Selection.- 3. Method of Literature Review.- 4. Results.- 5. Discussion.- 5.1. Human Respiratory Tract Carcinogens.- 5.2. Human Hematolymphopoietic System Carcinogens.- 5.3. Human Bladder Carcinogens.- 5.4. Human Liver Carcinogens.- 5.5. Other Human Carcinogens or Suspected Human Carcinogens.- 6. Summary and Conclusions.- 7. Appendix: Complete Data Base.- 8. References.- 10 Control of Commercial Chemicals: The Sixth Amendment to the Directive on Dangerous Chemical Substances (79/83 I/EEC) Adopted by the Council of the European Communities.- 1. Introduction.- 2. Text of the Sixth Amendment to the Directive on Dangerous Chemical Substances Adopted by the Council of the European Communities.- 3. References.