Chemical Carcinogenesis and Mutagenesis I

I. Theories of Carcinogenesis.- 1 Mechanisms of Chemical Carcinogenesis: Theoretical and Experimental Bases.- A. Introduction.- B. Historical Aspects.- C. Mechanistic Theories of Chemical Carcinogenesis.- I. Electrophilicity of Chemicals as a Determinant of Their Carcinogenicity.- II. Potential Role of Free Radicals as Ultimate Carcinogens.- III. Altered DNA Methylation as a Theoretical Mechanism of Chemical Carcinogenesis.- IV. Aberrations of DNA Repair as Theoretical Mechanisms of Chemical Carcinogenesis.- V. Other Theoretical Mechanisms of Chemical Carcinogenesis.- D. Pathogenesis of Malignancy: Natural History of Neoplastic Development.- I. Initiation.- II. Promotion.- III. Progression.- E. Reconciliation of the Theoretical Bases of Chemical Carcinogenesis with the Natural History of Neoplastic Development.- F. Conclusions.- References.- II. Exposure to Chemical Carcinogens.- 2 Environmental Carcinogens.- A. Introduction.- B. Fate of Chemicals in the Environment.- C. Classification of Environmental Carcinogens.- D. Exposed Populations.- E. Risk Assessment.- F. Examples of Important Environmental Carcinogens.- I. Arsenic.- II. Cadmium.- III. Chromium.- IV. Nickel.- V. Asbestos.- VI. Acrylonitrile.- VII. Benzene.- VIII. 1,2-Dichloroethane.- IX. Formaldehyde.- X. Methylene Chloride (Dichloromethane).- XI. Polycyclic Aromatic Hydrocarbons and Nitrated Forms.- XII. Polyhalogenated Aromatic Compounds.- 1. Polychlorinated Biphenyls.- 2. Chlorinated Phenols.- 3. Hexachlorobenzene.- 4. Dichlorodiphenyltrichloroethane, Toxaphene and Chlordane.- XIII. Radon.- XIV. Styrene.- XV. Tetrachloroethylene.- XVI. Trihalomethanes.- XVII. Vinyl Chloride.- G. Conclusions.- References.- 3 Advances in Tobacco Carcinogenesis.- A. Introduction.- B. Tobacco and Tobacco Smoke.- C. The Changing Cigarette.- D. Carcinogenic Compounds in Tobacco and Tobacco Smoke.- I. Polynuclear Aromatic Hydrocarbons (PAH).- II. N-Nitrosamines.- III. Aromatic Amines.- IV. Aldehydes.- V. Miscellaneous Organic Compounds.- VI. Inorganic Carcinogens.- E. Smokeless Tobacco.- I. Epidemiology.- II. Bioassays.- III. Carcinogens.- F. Environmental Tobacco Smoke.- G. Recent Studies on Mechanisms of Tobacco Carcinogenesis and Their Application to Dosimetry.- I. Polynuclear Aromatic Hydrocarbons.- II. Tobacco-Specific N-Nitrosamines.- III. Aromatic Amines.- IV. DNA Damage Induced by Unknown Constituents of Tobacco Smoke.- H. Perspectives.- I. Inhalation Bioassays.- II. Flavor Additives.- III. Bioassays with Smokeless Tobacco.- IV. Nutrition and Tobacco Carcinogenesis.- V. Tobacco Smoke and Indoor Radon Levels.- VI. Biochemistry of Tobacco Carcinogenesis.- References.- 4 Occupational Carcinogens.- A. Historical Introduction.- I. Early Occupational Cancer.- II. Prevention of Occupational Cancer.- III. Occupational Carcinogens.- B. Polycyclic Aromatic Hydrocarbons.- I. Occupational Skin and Scrotal Cancer.- II. Cancer at Other Sites.- III. Recognition and Occurrence of Polycyclic Hydrocarbons.- C. Aromatic Amines and Related Compounds.- I. Occupational Bladder Cancer.- II. Recognition of Human Bladder Carcinogens.- III. Control of Amine Carcinogen Hazards.- IV. Other 2-and 3-Ring Aromatic Amines.- 1. Substituted Benzidines and Other Industrial Compounds.- 2. 2-Fluorenylacetamide.- V. Single-Ring Aromatic Amines.- 1. Aniline and Derivatives.- 2. Phenylenediamines.- VI. Dyes.- 1. Magenta and Auramine.- 2. Azo Dyes.- VII. Nitro Compounds.- D. Alkylating Agents.- I. Mustard Gas; 2,2’-Bis(chloroethyl) Sulphide.- II. Chloromethyl Ethers.- III. Benzoyl Chloride Manufacture.- IV. Isopropanol Manufacture and Alkyl Sulphates.- V. Epoxides.- 1. Ethylene Oxide.- 2. Other Epoxides.- VI. ?-Propiolactone.- VII. Aziridines.- E. Halocarbons.- I. Vinyl Chloride.- II. Vinylidene Chloride and Chloroprene.- III. 1, 2-Dibromoethane and Related Compounds.- IV. Tetraehloromethane.- V. Other Chlorinated Solvents.- VI. Polychlorinated Pesticides.- VII. Polychlorinated and Polybrominated Biphenyls.- F. Nitrosamines.- I. Nitrosamines in Industry.- 1. Intentional Use.- 2. Inadvertent Formation.- G. Inorganic Carcinogens.- I. Arsenic.- II. Nickel.- III. Chromium.- IV. Beryllium.- V. Cadmium.- VI. Iron.- VII. Other Metals.- H. Asbestos and Other Mineral Fibres.- I. Introduction.- II. Asbestos and Lung Cancer.- 1. Synergism with Smoking.- III. Asbestos and Mesothelioma.- 1. Erionite and Mesothelioma.- IV. Asbestos and Other Cancers.- V. Asbestos Controls.- VI. Man-Made Mineral Fibres.- I. Wood and Leather Dust.- I. Nasal Cancer in Woodworkers.- II. Nasal Cancer in Leather Workers.- J. Benzene.- K. Formaldehyde and Other Aldehydees.- I. Animal Bioassays.- II. Epidemiological Studies.- III. Other Aldehydes.- L. Some Other Suspected Occupational Hazards.- I. Acrylonitrile.- II. Acrylamide.- III. Amitrole.- IV. 1,3-Butadiene.- V. Hydrazine.- VI. Di(2-ethylhexyl)/Phthalate and Related Compounds.- VII. Tobacco Smoke.- M. Continuing Problems and Prospects.- I. Proportion of Cancer Attributable to Occupation.- II. Identification of Carcinogenic Hazards.- 1. Identification Through Epidemiology.- 2. Experimental Identification of Carcinogens.- References.- 5 Therapeutic Agents as Potential Carcinogens.- A. Introduction.- B. Classification of Potentially Carcinogenic Therapeutic Agents.- C. Carcinogenicity of Antineoplastic Agents.- I. Nitrogen Mustards.- II. Myleran.- III. Therapeutic Nitrosoureas.- IV. Thiotepa.- V. Procarbazine and Dacarbazine.- VI. Summary.- D. Hormones as Carcinogenic Agents.- E. Other Therapeutic Agents as Potential Carcinogens.- F. Conclusions.- References.- III. In Vivo and In Vitro Carcinogenesis.- 6 In Vivo Testing for Carcinogenicity.- A. Introduction.- B. Development and Use of In Vivo Carcinogenesis Tests.- I. History of Carcinogenicity Testing.- II. The Bioassay Program (National Cancer Institute).- III. Mechanisms of Carcinogenesis.- IV. Carcinogenesis as a Toxicity Test.- V. Short-Term Assays as Substitutes for In Vivo Carcinogenesis.- VI. In Vivo Assays with N-Nitroso Compounds as Examples.- VII. Methods of In Vivo Carcinogenesis.- VIII. Routes of Administration.- IX. Assessment of Results.- C. Criteria for In Vivo Assays.- I. Group Size.- II. Species and Sex.- III. Route of Administration.- 1. Oral.- 2. Skin Painting.- 3. Inhalation.- 4. Conclusions.- IV. Size of Dose and Dose Selection.- 1. Studies in Adults.- 2. Multigeneration Studies.- V. Conduct of the Experiment.- VI. Examination of Animals and Evaluation of Results.- D. Conclusions.- References.- 7 Transformation of Cells in Culture.- A. Introduction.- B. Definition of Terms.- C. Transformation of Rodent Mesenchymal Cells.- I. Cells with a Limited Lifespan.- II. Established Cell Lines.- III. Oncogenes and the Transformation of Rodent Mesenchymal Cells.- 1. Introduction of Genetic Material into Mammalian Cells.- 2. Transformation of Immortal Fibroblasts by Oncogenes.- 3. Transformation of Primary Cells.- IV. Role of Immortalisation in Transformation.- D. Transformation of Rodent Epithelial Cells.- I. Submandibular Gland.- 1. Phenotypic Stages.- 2. Effect of a Tumor Promoter.- 3. Analysis of DNA Content and Karyotypic Markers.- II. Bladder.- 1. Phenotypic Stages.- 2. Effect of Promoting Agents.- 3. Properties of Immortal and Transformed Cell Lines.- 4. Role of Oncogenes and Suppressor Genes.- III. Trachea.- 1. Phenotypic Stages.- 2. Promotion and Inhibition.- 3. Role of Oncogenes.- IV. Epidermis.- 1. Induction of Foci Resistant to Calcium-Induced Differentiation.- 2. Effect of TPA.- 3. Role of ras Oncogenes.- V. Discussion.- E. Transformation of Human Cells.- I. Differences Between Human and Rodent Cells.- II. Transformation of Human Mesenchymal Cells.- III. Transformation of Human Epithelial Cells.- F. Conclusions.- References.- IV. Reactions of Carcinogens with DNA.- 8 Metabolic Activation and DNA Adducts of Aromatic Amines and Nitroaromatic Hydrocarbons.- A. Introduction.- I. 1-Naphthylamine and 1-Nitronaphthalene.- II. 2-Naphthylamine and 2-Nitronaphthalene.- III. 4-Aminobiphenyl and Derivatives.- IV. 2-Acetylaminofluorene, 2-Aminofluorene, and 2-Nitrofluorene.- IV. Benzidine.- VI.N,N-Dimethyl-4-aminoazobenzene and Its Demethylated Derivatives.- VII. 2-Acetylaminophenanthrene.- VIII. 4-Acetylaminostilbene.- IX. Nitropyrenes.- X. 6-Aminochrysene and 6-Nitrochrysene.- XI. Heterocyclic Aromatic Amines.- B. Conclusions and Comments.- References.- 9 Polycyclic Aromatic Hydrocarbons: Metabolism, Activation and Tumour Initiation.- A. Introduction.- B. Metabolism.- I. Diols.- II. Phenols.- III. Conjugation with Glutathione.- IV. Conjugation with Glucuronic and Sulphuric Acids.- V. Hydroxylated Products - Further Metabolism.- VI. Mechanisms Involved in Metabolic Activation.- C. Pathways of Activation.- I. 7,12-Dimethylbenz[a]antracene.- II. Benzo[a]pyrene.- III. Dibenzo[a,e]fluoranthene.- IV. Dibenz[a,h] anthracene.- V. Benz[c]aeridine.- VI. Benz[a]anthracene and Chrysene.- D. Stereochemistry of Activation Pathways.- I. Benzo[a]pyrene.- II. Primary Metabolism.- III. Secondary Metabolism.- E. Factors Governing Susceptibility to PAH-Induced Tumorigenesis.- I. Species and Strain Differences.- 1. Metabolism.- 2. Formation and Persistence of DNA Adducts.- II. Tissue Differences.- III. Influence of Sex and Age.- F. Concluding Remarks.- References.- 10 Interactions of Fungal and Plant Toxins with DNA: Aflatoxins, Sterigmatocystin, Safrole, Cycasin, and Pyrrolizidine Alkaloids.- A. Introduction.- B. Aflatoxins.- I. Occurrence.- II. Aflatoxin Chemistry, Metabolism, DNA and Protein Adduct Formation.- III. Experimental Animal Models for Aflatoxin Carcinogenesis.- 1. Animal Models, Dietary Antioxidants, and DNA Adduct Formation.- 2. Interactions with Cellular Oncogenes.- IV. Affinity Chromatography for Aflatoxin-DNA Adducts and Other Metabolite Isolation from Biological Samples.- V. Human Liver Cancer and Aflatoxin: Epidemiology and Exposure Monitoring.- C. Sterigmatocystin.- D. Safrole and Related Compounds.- I. Carcinogenicity.- II. DNA Adduct Formation and Oncogene Interactions.- E. Cycasin.- F. Pyrrolizidine Alkaloids.- G. Summary.- References.- 11 N-Nitroso Compounds.- A. Introduction: Development of the Importance of N-Nitroso Compounds for Carcinogenesis Studies.- I. Historical Origins.- II. Development of the Concept that N-Nitroso Compounds are Alkylating Carcinogens.- III. N-Nitroso Compounds as Mutagenic Carcinogens.- IV. N-Nitroso Compounds as Mutagenic Activators of Oncogenes.- B. Organotropism in Carcinogenesis by N-Nitroso Compounds.- I. Role of N-Nitroso Compounds in Multistage Carcinogenesis.- II. Structure-Activity Relationships for N-Nitroso Compounds.- III. Role of Metabolic Activation in Structure-Activity Relationships.- C. N-Nitroso Compounds and Human Cancer.- I. Introduction.- II. Environmental and Endogenous Formation of N-Nitroso Compounds.- III. In Vivo Alkylating as a Measure of Human Exposure.- IV. Activating Mutations in Human Tumour Oncogenes Possibly Consistent with Induction by N-Nitroso Compounds.- D. Epidemiology.- E. Conclusions.- References.- 12 Heterocyclic-Amine Mutagens/Carcinogens in Foods.- A. Introduction.- B. Chemical Analysis of Heterocyclic-Amine-Mutagens in Cooked Foods.- I. Food Mutagen Sources and Exposure.- II. Chemical Extraction and Purification.- 1. Extraction.- 2. Bioassay-Directed Purification.- III. Identification of Unknown Mutagens.- 1. General Approach.- 2. Characteristics of Food Mutagens.- C. Mutagen Formation from Modeling Reactions.- D. Heavy Isotope Labeling of Mutagens in Model Reactions.- E. Structure and Mutagenicity of the Aminoimidazoazaarene Compounds.- F. Genetic Toxicology.- I. Microbial.- II. Nonmicrobial Genotoxicity.- 1. Mutation.- 2. DNA Repair and Damage.- 3. Clastogenesis.- G. DNA Binding.- I. Guanine Adduets.- II. Adduet Analysis by 32P-Postlabelling.- H. Carcinogenesis.- J. Significance of Aminoimidazoazaarenes in the Diet.- References.- 13 Modem Methods of DNA Adduct Determination.- A. Introduction.- B. Postlabelling Methods.- I. Principles of 32P-Postlabelling.- II. Applications in Animal and Tissue Culture Studies.- III. Exposure to Environmental Carcinogens: Animal & Human Studies.- IV. Advantages and Limitations of 32P-Postlabelling.- V. 14C-Postlabelling.- VI. Fluorescent Postlabelling.- C. Immunochemical Methods.- I. Principles.- II. Applications in Animal and Tissue Culture Studies.- III. Human Studies.- IV. Advantages and Limitations of Immunochemical Methods.- D. Physicochemical Methods.- I. Fluorescence Spectroscopy.- II. Gas Chromatography and Mass Spectrometry.- E. Future Prospects.- References.- 14 Biological Consequences of Reactions with DNA: Role of Specific Lesions.- A. Introduction.- B. Biological Effects.- I. Effects on the Synthesis of Macromolecules.- II. Promutagenicity and Alkylation-Induced Mutagenesis.- III. Clastogenesis.- IV. Teratogenesis and Transplacental Effects.- V. Transformation in Cultured Mammalian Cells.- C. Correlation of Promutagenic Lesions with Carcinogenesis.- D. Role of Specific Lesions: Effects of E. coli Alkyltransferase Gene Expression in Mammalian Cells.- I. Mutagenesis.- II. Sister Chromatid Exchanges and Other Clastogenic Events.- III. Toxicity.- E. Conclusions.- References.