I have been privileged to witness and participate in the great growth of knowledge on chemical carcinogenesis and mutagenesis since 1939 when I entered graduate school in biochemistry at the University of Wisconsin­ Madison. I immediately started to work with the carcinogenic aminoazo dyes un­ der the direction of Professor CARL BAUMANN. In 1942 I joined a fellow graduate student, ELIZABE1H CAVERT, in marriage and we soon commenced a joyous part­ nership in research on chemical carcinogenesis at the McArdle Laboratory for Cancer Research in the University of Wisconsin Medical School in Madison. This collaboration lasted 45 years. I am very grateful that this volume is dedi­ cated to the memory of Elizabeth. The important and varied topics that are reviewed here attest to the continued growth of the fields of chemical car­ cinogenesis and mutagenesis, including their recent and fruitful union with viral oncology. I feel very optimistic about the application of knowledge in these fields to the eventual solution of numerous problems, including the detection and estimation of the risks to humans of environmental chemical carcinogens and re­ lated factors.

Inhalt

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…