Chemical Induction of Cancer

Prefatory Chapter Multifactor Interaction Network of Carcinogenesis— A “Tour Guide”.- I. Introduction. The Interaction Network as a Graph.- II. Review of Elements of the Network-An Analysis of Their Interrelationships.- A. Varieties of Initiation Processes.- B. Beyond Initiation.- C. Repositories of Inheritable Epigenetic Information.- D. Role and Control of Mixed-Function Oxidases.- E. Promoters versus Epigenetic Carcinogens.- F. Promoters, Inhibitors, Calorie Intake versus Rate of Cell Proliferation.- G. The Neuroendocrine Interface. Factors Affecting Hormonal Regulatory Pathways.- H. Factors Affecting the Systemic Immune Network. The Neuroimmunoendocrine Interface.- I. Central Role of the Effect of Aging.- J. Generation of Reactive Radical Species and Damage to Membranes.- K. Aging, Cancer, and Loss of Homeostatic Functions.- III. Closing Note.- References.- 1 Cross-Reactions between Carcinogens. Modification of Chemical Carcinogenesis by Noncarcinogenic Agents.- 2 Synergism and Antagonism between Chemical Carcinogens.- I. Introduction.- II. Sources and Selection of Data for Analysis.- III. Overview of Carcinogenic Effects of Selected Binary Combinations.- IV. Overview of Carcinogenic Effects of Selected Multiple (Nonbinary) Combinations of Structurally-Defined Chemical Compounds and Complex Mixtures.- V. Considerations on the Mechanisms Involved in the Synergistic and Antagonistic Interactions of Chemical Carcinogens.- References.- 3 Synergism in Carcinogenesis: Mathematical Approaches to Its Evaluation.- I. Theoretical Background.- A. Conditions for Substantiation of Synergism.- B. Classes of Synergism.- 1. Suggestion of Synergism.- 2. Apparent Synergism.- 3. Probable Synergism.- 4. Strict Synergism.- 5. Absolute Synergism.- C. Significance of Linearity of Dose-Response Curves.- D. Significance of Nonlinearity of Dose-Response Curves.- E. Multiplicative Synergism.- II. Examples of Substantiation of Classes of Synergism.- A. Suggestion of Synergism (Class 1 Synergism).- B. Apparent Synergism (Class 2 Synergism).- C. Probable Synergism (Class 3 Synergism).- D. Strict Synergism (Class 4 Synergism).- E. Absolute Synergism (Class 5 Synergism).- III. Discussion.- A. Definition and Statistical Considerations.- B. On Interaction between Initiation and Promotion in Epidemiological Data.- C. Some Principles of Testing for Synergism in Animals.- D. Comments on Experimental Design of Testing for Synergism.- E. Speculative Considerations on the Mechanism of Synergism.- Appendix I: Statistical Significance.- A. Significance of Linearity of Dose-Response Curves.- B. Significance of Nonlinearity of Dose-Response Curves; Substantiation of Strict Synergism.- C. If Tumor Incidence in the Control Group Is Unknown.- References.- 4 Inhibition of Chemical Carcinogenesis.- I. Introduction.- II. Experimental Systems.- III. Mechanisms of Inhibition.- A. Blocking Activities.- 1. Inhibition of Carcinogen Uptake.- 2. Inhibition of the Formation or Activation of Carcinogens.- 3. Deactivation of Carcinogens.- 4. Increase of Detoxification by Enzymatic Reaction.- 5. Prevention of Carcinogen Binding to DNA.- 6. Increase of the Level or Fidelity of DNA Repair.- B. Antioxidant Activities.- 1. Scavenging of Reactive Electrophiles.- 2. Scavenging of Oxygen Radicals.- 3. Inhibition of Arachidonic Acid (AA) Metabolism.- C. Antiproliferative/Antiprogression Activities.- 1. Modulation of Signal Transduction.- 2. Modulation of Hormonal/Growth Factor Activity.- 3. Inhibition of Oncogene Activity.- 4. Inhibition of Polyamine Metabolism.- 5. Induction of Terminal Differentiation.- 6. Restoration of Immune Response.- 7. Increasing Intercellular Communication.- 8. Restoration of Tumor-Suppressor Function.- 9. Induction of Programmed Cell Death (Apoptosis).- 10. Correction of DNA Methylation Imbalance.- 11. Inhibition of Angiogenesis.- 12. Inhibition of Basement Membrane Degradation.- 13. Activation of Antimetastasis Genes.- IV. Chemical Agents Classified by Structure or Biological Activity that Have Displayed Inhibition of Chemical Carcinogenesis.- A. Antihormones.- B. Anti-inflammatory Agents.- C. Antioxidants.- D. Arachidonic Acid (AA) Metabolism Inhibitors.- E. GSH Enhancers.- F. Ornithine Decarboxylase (ODC) Inhibitors.- G. Protein Kinase C (PKC) Inhibitors.- H. Retinoids/Carotenoids.- I. Thiols/Dithiolthiones/Sulfides.- J. Other Chemical Classes Associated with Inhibition of Carcinogenesis.- 1. Arylalkyl Isothiocyanates.- 2. Calcium Compounds.- 3. DHEA/DHEA Analogs.- 4. Disulfiram/Disulfiram Analogs.- 5. Glucarates.- 6. Indoles.- 7. Molybdenum Compounds.- 8. Monocyclic Terpenes/Isoprenylation Inhibiting Compounds.- 9. Protease Inhibitors.- 10. Selenium Compounds.- 11. Vitamin D3/Vitamin D3 Analogs.- V. Cancer Chemoprevention: The Applied Science of the Inhibition of Carcinogenesis.- References.- 5 Promotion and Cocarcinogenesis.- Section I Tumor Promotion in Skin.- I. Multistage Carcinogenesis in Skin: Historical Background and Basic Conceptual Developments.- A. From Coal Tar Painting to the Initiation-Promotion Experiment.- B. Initiation-Promotion in Mouse Skin: An Experimental Model.- C. Conversion and Promotion (“Two-Stage Tumor Promotion”).- II. Skin Tumor Promoters.- A. Tumor Promotion by Specific Interactions With Intracellular Signalling.- B. Tumor Promotion via Nonspecific Tissue Damage.- C. Skin Tumor Promoters Involved in the Etiology of Human Cancer.- III. The Response of the Skin to Tumor Promoters.- A. Tumor Development.- 1. Papillomas and Carcinomas.- 2. Species and Strain Differences.- 3. Tissue Specificity.- B. Morphological and Cytological Responses.- C. Biochemical Responses.- 1. Activation of Protein Kinase C.- 2. Effect on the Biosynthesis of Eicosanoids.- 3. Effect on the Generation of Reactive Oxygen Species.- 4. Induction of Ornithine Decarboxylase.- IV. The Biological Nature of Skin Tumor Promotion and Conversion.- A. Skin Tumor Promotion as the Consequence of a Chronic Regenerative Reaction.- B. Conversion and Wound Response.- V. Concluding Remarks.- References.- Section II Tumor Promotion in Liver.- I. Stages in Hepatocarcinogenesis.- II. Liver Tumor Promoters.- III. Specificity of Liver Tumor Promoters.- IV. Effectiveness of Promoter as Carcinogen Without Initiator; Effect of Reversion of the Initiation-Promotion Sequence.- V. Mechanisms of Tumor Promotion in Liver.- A. Role of Liver Growth, Cell Proliferation, and Cell Death.- B. Changes in Gap-Junction-Mediated Intercellular Communication.- C. Role of Reactive Oxygen Species.- VI. Quantitative Aspects of Tumor Promotion in Liver.- VII. Relevance of Liver Tumor Promoters to Humans.- References.- Section IIIA Note on Multistage Carcinogenesis in Other Organs and In Vitro.- References.- Section IIIB Note on Tumor Promoters, Cocarcinogens, and Nongenotoxic Carcinogens.- References.- 6 Computerized Data Management as a Tool to Study Combination Effects in Carcinogenesis.- I. Introduction.- II. Combination Effects Categories: Definitions.- III. Conceptual Principles Involved in the Development of ISS.- A. The “Inherent Cancer Hazard” Component.- B. The “Hazard Modification” Component.- IV. System Overview and Application to Sample Mixtures.- V. Closing Note.- Appendix A: List of Structural and Functional Classes of Chemicals in ISS.- Appendix B: Derivation of Class Hit Values (HB) as Inferences from Class Interactions.- 1. General Principles.- 2. The Class Pair Interaction Matrix.- 3. Absolute Cell Frequencies and Expected Cell Values.- 4. Representativeness of Classes in the Database.- 5. Calculation of HB Values.- 6. Preparing an Inferred HB Values Class Matrix; the Use of These Values in the Weighting Ratio.- References.- 7 Intercellular Communication: A Paradigm for the Interpretation of the Initiation/Promotion/Progression Model of Carcinogenesis.- I. Introduction: Cancer as a Problem of Homeostatic Dysfunction.- II. The Natural History of Carcinogenesis.- III. Intercellular Communication: a Process to Ensure Homeostasis.- IV. Dysfunctional Gap-Junctional Communication During Carcinogenesis.- V. Chemical Inhibition During Tumor Promotion.- VI. Oncogenes/Anti-Oncogenes or Tumor-Suppressor Genes and Intercellular Communication.- VII. Modulation of Gap-Junctional Intercellular Communication by Growth Factors.- VIII. Altered Gap Junction Function and “Partially Blocked Ontogeny” During Carcinogenesis.- IX. The Integration of Extracellular-Intracellular-Intercellular Communication Mechanisms for Maintaining Homeostasis.- X. Modulation of Gap-Junctional Communication and Its Implications for the Prevention and Treatment of Cancer.- References.- Appendix to Part 1 Chemical Cancerogenesis: Definitions of Frequently Used Terms.- I. Introduction.- II. Definitions.- A. Chemical Cancerogenesis.- B. Chemical Risk Factors of Cancer.- C. Solitary Cancerogens (Synonyms: Cancerogens, Complete Cancerogens).- D. Conditional Cancerogens (Conditionally Cancer-Generating Factors).- E. Multistage Model of Cancerogenesis (Initiation, Promotion).- F. Progression.- G. Cocancerogenesis.- H. Syncancerogenesis.- I. Anticancerogenesis.- J. Synpromotion.- K. Antipromotion.- L. Genotoxicity.- M. Threshold Values for Chemical Risk Factors of Cancer (Non-Observed Effect Level, No-Effect Level, Threshold Value).- 2 Exogenous Factors and Endogenous Biological Parameters That Modulate Chemical Carcinogenesis.- 8 Immunotoxicology of Chemical Carcinogens.- I. Introduction.- II. The Immune System.- A. T Cells.- B. B Cells.- C. Natural Killer Cells (NK Cells).- D. Monocytes and Antigen Processing.- E. Lymphocyte Activation.- 1. Role of the T Cell Receptor (TCR).- 2. Cytokines/Lymphokines/Monokines.- 3. Interleukins.- 4. B Cell Activation.- F. Regulation of Immune Response.- III. Immune Surveillance and Carcinogenesis.- IV. Immunotoxicology.- V. Chemical Carcinogens and Other Immunesuppressants: Effects on the Immune System.- A. Polycyclic Aromatic Hydrocarbons.- B. Asbestos.- C. Therapeutic Drugs.- D. “Immunotoxic” Polyclonal and Monoclonal Antibodies.- E. Halogenated Aromatic Hydrocarbons.- F. Pesticides.- G. Metals and Metalloids.- References.- 9 The Effect of Diet on Tumor Induction.- Section I. Effect of Caloric (Energy) Restriction.- I. Caloric Restriction Effects on Tumorigenesis: Historical Beginnings.- II. Modalities of Caloric Restriction.- III. The Early Work of Albert Tannenbaum.- IV. Caloric Restriction versus Dietary Fat Content.- V. Influence of the Timing of Caloric Restriction.- VI. Caloric Intake versus Caloric Expenditure.- VII. Mechanism of Action of Caloric Restriction.- VIII. Overnutrition-Related Factors and Lack of Muscular Activity versus Cancer Risk.- References.- Section II. Modulation by Protein and Individual Amino Acids.- I. Introduction.- II. Some Background Concepts.- A. Dietary Protein Requirement.- B. Tumor Protein Requirement.- III. Epidemiology.- A. Breast Cancer.- B. Colon Cancer.- C. Other Cancers.- IV. Animal Studies with Whole Proteins.- A. Mammary Tumors.- B. Colon Tumors.- C. Liver Tumors.- D. Pancreatic Tumors.- E. Kidney Tumors.- F. Pituitary Tumors.- G. Tumors in Other Organs.- V. Effect of Individual Dietary Amino Acids on Carcinogenesis.- A. Methionine.- B. Tryptophan.- C. Tyrosine and Phenylalanine.- D. Leucine and Isoleucine.- VI. Closing Note.- References.- Section III. Modulation by Vitamins.- I. Introduction.- II. Physiological and Biochemical Roles of Vitamins with Special Emphasis on Relationship to Carcinogenesis.- III. Vitamin Deficiency and Carcinogenesis.- A. Vitamin A Deficiency and Carcinogenesis.- B. Deficiency in B Vitamins and Related Compounds.- C. Vitamin C Deficiency and Carcinogenesis.- D. Vitamin D Deficiency and Carcinogenesis.- E. Vitamin E Deficiency and Carcinogenesis.- F. Lipotrope Deficiency and Carcinogenesis.- IV. Modulation of Carcinogenesis by Vitamin Supplementation.- A. Influence of Vitamin A on Chemical Carcinogenesis.- B. Influence of Vitamin B on Chemical Carcinogenesis.- C. Influence of Vitamin C on Chemical Carcinogenesis.- D. Influence of Vitamin D on Chemical Carcinogenesis.- E. Influence of Vitamin E on Chemical Carcinogenesis.- F. Influence of Other Vitamins, Lipotropes and Other Quasi-Vitamins on Chemical Carcinogenesis.- V. Closing Note.- References.- Section IV. Modulation by Minerals.- I. Introduction.- II. Selenium Modulation of Chemical Carcinogenesis.- A. Selenium Modulation of Colon Carcinogenesis.- B. Selenium Modulation of Liver Carcinogenesis.- C. Selenium Modulation of Mammary Gland Carcinogenesis.- D. Selenium Modulation of Carcinogenesis at Other Sites.- E. Modulation of Carcinogenesis by Selenium Restriction/Deficiency.- III. Copper Modulation of Chemical Carcinogenesis.- IV. Zinc Modulation of Chemical Carcinogenesis.- V. Modulation of Chemical Carcinogenesis by Other Minerals.- A. Magnesium.- B. Calcium.- C. Lead.- D. Iron.- E. Potassium.- F. Sodium.- G. Arsenic.- H. Iodine.- I. Germanium and Other Minerals.- References.- Section V. Dietary Fiber and Its Effect on Cancer Incidence.- I. Dietary Fibers: Sources, Classification, Definitions.- II. Methodological Concepts and Limitations of the Assessment of Fiber Effects.- III. Protection by Dietary Fiber Against Colorectal Cancer.- IV. Mechanism of Fiber Protection Against Colorectal Cancer.- V. Dietary Fiber Effect on Cancer of the Breast and Pancreas: Epidemiological Studies.- References.- Editors’ Note I to Chapter 9: Indirect Modification of Chemical Carcinogenesis by Nutritional Factors Through Regulation of the Mixed-Function Oxidase System.- References.- Editors’ Note II to Chapter 9: On Evidence for Preventive Significance of Dietary Supplementation.- References.- 10 The Effect of Animal Age on Tumor Induction.- I. Introduction.- II. Background.- A. The Aging Process.- B. Relationship Between Aging and Cancer.- C. Research Approaches.- III. Studies on Chemical Carcinogenesis in Aging Animals.- A. Polycyclic Aromatic Hydrocarbons.- 1. In Skin.- 2. In Cell Culture.- B. Aromatic Amines.- C. Nitrosamines Requiring Activation.- D. Direct-Acting Nitrosamines.- E. Halogenated Hydrocarbons.- IV. Studies on Chemical Carcinogenesis in Aging Humans.- V. Studies on Chemical Carcinogenesis During Other Phases of the Life Span.- VI. Host Factors Affecting Chemical Carcinogenesis in Aging.- A. Metabolism and Disposition of Carcinogens.- 1. Carcinogen Activation.- 2. Carcinogen Detoxification.- B. DNA Susceptibility to Chemical Damage.- C. DNA Repair.- D. Cell Proliferation.- E. Immune Competence.- VII. Closing Note.- References.- 11 The Effect of Hormones on Tumor Induction.- Section I. Brief Overview of the Endocrine System.- I. Mechanisms of Hormone Action: Interaction with Receptors.- A. Steroid Receptors: Structure and Function.- B. Amine and Peptide Hormone Receptors: Structure and Function.- II. Classification, Biosynthesis, Release, and Disposition of Hormones.- A. Classification of Hormones Based on Chemical Structure and Mechanism of Action.- B. Biosynthesis and Release of Hormones.- C. Patterns of Hormone Secretion.- D. Transport and Metabolism of Hormones.- III. Principal Component Segments of the Endocrine System.- A. The Hypothalamic-Pituitary Axis and Its Peripheral Gland Targets.- 1. Hypophysis.- 2. Adrenal Glands.- 3. Thyroid Gland.- 4. Gonads.- B. Hormonal Regulation of Calcium Homeostasis.- C. Hormonal Control of Energy Utilization and Storage.- IV. Feedback Control in the Endocrine System: A Synoptic Overview.- Reference Sources.- Section II. Hormonal Carcinogenesis.- I. Kidney.- II. Liver.- III. Prostate.- IV. Testes.- V. Mammary Gland.- VI. Uterus.- VII. Note on the Mechanisms of Hormonal Carcinogenesis.- References.- Section III. Effect of Hormones on Carcinogenesis by Nonhormone Chemical Agents.- I. Enhancement of Chemical Carcinogenesis by Hormones.- A. Mammary Gland.- B. Liver.- C. Ovary.- D. Epidermis.- E. Bladder.- F. Prostate.- G. Other Organ Sites.- II. Inhibition of Chemical Carcinogenesis by Hormones.- III. Some Mechanisms of Hormonal Effects in Chemical Carcinogenesis.- References.- Editors’ Note Added in Proof: On the Significance of Environmental Xenoestrogens.- 12 Effect of Genetic Susceptibility on Tumor Induction.- I. Introduction.- II. Genetic Approaches to Studying Mechanisms of Carcinogenesis.- A. Mutant and Congenic Strains.- B. Variation Among Inbred Strains.- III. Genetic Control of Carcinogenesis in Inbred Strains.- A. Lung Tumor Induction in Mice.- B. Liver Tumor Induction in Mice.- C. Skin Tumor Induction in Mice.- D. Colon Carcinogenesis in Mice.- E. Rat Mammary Carcinogenesis.- IV. Effects of Specific Loci on Carcinogenesis.- A. A (Agouti).- B. Ah (Aromatic Hydrocarbon Responsiveness).- C. ApcMin (Adenomatous Polyposis Coli).- D. bg (Beige).- E. bm (Brachymorphic).- F. H-2 (Histocompatibility Complex-2).- G. K-ras-2.- H. Tfm (Testicular Feminization).- V. Concluding Remarks.- References.- 13 Radiation Injury and Radiation Carcinogenesis with Special Reference to Combination Effects with Chemical Agents.- I. Introduction.- II. Mechanism of Radiation Injury.- A. Radiation Interactions with Matter.- 1. Subatomic Nature of Interactions.- 2. Linear Energy Transfer.- 3. Units of Dose and Activity.- B. Chemical Nature of Interactions.- 1. Direct and Indirect Effects.- 2. Interaction with Biological Targets.- C. Radiation Effects on DNA.- 1. Induction of DNA Damage and Its Repair.- 2. Effect on DNA Function.- D. Induction of Chromosome Damage and Its Repair.- E. Cell Response to Ionizing Radiation.- 1. Cell Cycle Effects.- 2. Cell Toxicity.- 3. Induction of Mutation.- 4. Cell Transformation.- F. Radiation Carcinogenesis.- 1. General Considerations.- 2. Initiation, Promotion, and Progression.- 3. Molecular Aspects.- III. Modification of Response.- A. Physical Modifiers.- 1. LET Effects and Relative Biological Effectiveness.- 2. Oxygen Effects and the Oxygen Enhancement Ratio.- 3. Dose-Rate.- B. Biological Modifiers.- 1. Tissue Origin.- 2. Ploidy.- 3. DNA Repair.- 4. Cell Cycle.- 5. Chromosome Structure.- C. Chemical Modifiers.- 1. Mechanisms of Action.- 2. Examples of Radioprotectors and Anticarcinogens.- 3. Examples of Radiosensitizers and Cocarcinogens.- References.- 14 Mechanisms of Viral Tumorigenesis and the Combination Effects of Viruses and Chemical Carcinogens.- Section I. General Characteristics of Tumor Viruses. Viral and Cellular Oncogenes. Nonviral Oncogene Activators..- I. RNA Tumor Viruses.- II. DNA Tumor Viruses.- III. Varieties of Nonviral Oncogene Activators.- A. Chemical Carcinogens.- 1. Activation of ras.- 2. Augmentation of ras.- 3. Augmentation and activation of myc.- 4. Collaboration between ras and myc.- 5. Activation/enhancement of other oncogenes.- B. Radiations.- 1. Ionizing radiations.- a. Activation of ras genes.- b. Augmentation of myc genes.- 2. Nonionizing radiations.- C. Chromosome Translocations: Spontaneous and Induced; Intrinsically Fragile Sites. Excess Chromosomes Acquired in Meiosis.- 1. Summary clinical picture of chromosome instability syndromes.- 2. Excess chromosome syndromes.- 3. Chromosome translocation in chronic myelogenous leukemia.- D. Conditions of Sustained Cellular Stress.- 1 Deprivation from extracellular signals.- 2. Osmolarity crisis.- References.- Section II. Molecular Biology of Virally-Induced Cell Transformation and Tumorigenesis.- I. Assays for Cell Transformation and Oncogenesis; Properties of the Transformed Cell.- A. In vitro Assays for Cell Transformation.- 1. Properties of cultured cells: cell strains, established cell lines, and transformed cells.- 2. Basic methodology of in vitro cell transformation assays.- 3. Study of tumor viruses using cell transformation assays.- 4. Cell transformation in DNA transfection assays.- 5. Use of the cell transformation assay for screening potentially carcinogenic agents.- B. Specialized in vivo Assays for Oncogenesis.- 1. The “nude mice” assay.- 2. The transgenic mice assay.- a. Basic principles/methodology in making transgenic mice.- b. Transgenic models of tumor development.- c. Transgenic mice in tests of potential carcinogens, for exploring therapeutic strategies, and risk assessment.- II. Signal Transduction Cascades: Non-DNA Targets of Viral Effectors.- A. Transmembrane Receptors and Protein Tyrosine Kinase Activity.- B. “Signalling Motifs”: The Functional Domains in Proteins That Enact Signal Transduction.- C. Phosphatidylinositol-Associated Intracellular Signalling Pathways.- D. Grb2 and Sos: The Link Between the Activated Receptor and Ras.- E. Ras: The Molecular Switch of Cellular Signalling.- F. Raf and the 14-3-3 Family Proteins.- G. The MAP Kinase Cascade.- H. The Src Family Tyrosine Kinases.- I. JAKs and the STAT Family: Ras-Independent Signalling.- J. Transcription Factors Associated with Signal Transduction.- K. Closing Note: A Perspective on the Requirement for Complexity in the Signal Transduction Network.- III. Tumor-Suppressor Genes: Targets of Viral Effectors.- A. The p53 Tumor-Suppressor Gene.- B. The Retinoblastoma Tumor-Suppressor Gene.- C. The Wilms’-Tumor-Suppressor Gene.- IV. Retroviral Oncogenes-An Illustrative Sampling: Effectors of Oncogenic Transformation.- A. sis: Homology to Human PDGF B, a Mutated Growth Factor Analog.- B. fms: Mutated Analog of CSF-1 Receptor.- C. ras: Mutated Analog of GTP-Binding GTPase.- D. src: Membrane-Bound Mutated Nonreceptor Tyrosine Protein Kinase.- E. mos: Unscheduled Expression of Cytoplasmic Serine/Threonine Protein Kinase.- F. myc: Codes for Mutated and/or Excessive Nuclear Regulatory Protein.- G. Cis-Activation of c-onc Genes: MuLV and MMTV.- H. Trans-Activation of c-onc Genes: HTLV-I.- V. DNA Tumor Viruses: Effectors of Oncogenic Transformation.- A. Adenoviridae Family.- 1. General Features.- 2. Cell Transformation.- 3. Transforming Proteins.- a. E1A.- b. E1B.- 4. A Dual Link to Tumor-Suppressor Genes.- B. Papovaviridae Family.- 1. Polyomaviruses.- a. General features.- b. Cell Transformation.- c. Transforming proteins: T antigens.- 2. Papillomaviruses.- a. General features.- b. Animal papillomaviruses.- c. Human papillomaviruses.- d. Transformation of cells in culture by papillomaviruses.- e. Transforming proteins of papillomavirus.- C. Hepatitis Viruses.- 1. Hepatitis B Virus.- a. Internal organization and replication features.- b. Epidemiological linkage to HCC.- c. Viral mechanisms of neoplastic conversion.- 2. Hepatitis C Virus.- D. Herpesviridae Family.- 1. The Epstein-Barr Virus.- a. General features.- b. Burkitt’s lymphoma.- c. Nasopharyngeal carcinoma.- d. Immunodeficiency-associated lymphomas.- e. Transforming proteins.- 2. Marek’s Disease Virus.- a. General features.- b. Transforming genes.- E. Poxviridae Family.- 1. General Features.- 2. Virally-Encoded Growth Factors.- References.- Section III. Viral-Chemical Combination Effects in Tumorigenesis.- I. Epidemiologic Evidence of Possible Synergistic Interactions Between Tumor Viruses and Chemical Carcinogens/Promoters in Human.- II. Combination Effects Between Tumor Viruses and Chemical Carcinogens/Promoters in Animals.- III. Potentiation of Chemical Carcinogens by Viruses Not Known to Be Oncogenic.- IV. Combined Effects of Viruses and Chemical Carcinogens/Promoters in Cell Cultures.- V. Concluding Note.- References.- Speculative Closing Note.- 15 Effect of Stress on Tumor Induction.- I. Introduction.- II. Stressor, Stress, and Health Consequences.- III. Homeostatic Changes During Stress.- IV. Specific Homeostatic Changes Possibly Affecting Carcinogenesis.- V. Stress and Carcinogenesis in Animals.- VI. Effect of Stress on Virally-Induced Tumors and on Tumor Cell Growth.- VII. Stress and Spontaneous Tumors.- VIII. Trauma.- IX. Stress, Immunity, and Carcinogenesis in Humans.- X. Closing Note.- References.- Editors’ Note Added in Proof: Stress Proteins: Heat-Shock Proteins/Molecular Chaperones.- 16 Extremely Low Frequency Electromagnetic Fields and Cancer.- I. Introduction.- II. Physical Properties of Electromagnetic Fields.- A. Properties of ELF Electromagnetic Fields.- III. Epidemiologic Studies.- A. Epidemiologic Studies on Electric Blanket Use.- B. Occupational Epidemiologic Studies.- C. Brain Cancer.- D. Leukemia and Lymphoma.- E. Male Breast Cancer.- F. Melanoma.- IV. Overview of In Vitro Studies.- A. ELF Magnetic Fields Are Not Directly Genotoxic.- B. Altered Cell Proliferation.- C. Altered DNA Synthesis.- V. Effects of EMF on Gene Expression.- A. General Changes in RNA.- B. Altered Expression of Specific RNA.- C. Summary of Transcription Effects.- D. ELF Field Effects on Specific Proteins.- VI. Mechanisms for EMF-Induced Cellular Changes.- A. Modulation of Intracellular Calcium Concentration.- B. Possible Direct Effects of ELF Fields on Cell-Surface Receptors.- VII. In Vivo Studies.- A. Cancer Co-Promotion Potential of EMF.- B. Pineal Function and Cancer Risk.- C. Melatonin As a Tumor Suppressor.- D. EMF Effects on Melatonin Production.- E. Neuroendocrine Effects of EMF and the Melatonin Hypothesis.- VIII. Evidence for EMF Effects in Humans.- IX. Physiological Mechanisms of EMF Effects in Biological Systems.- X. Physical Mechanisms for EMF Effects on Biological Systems.- A. Other Possible Physical Bases for EMF Detection.- B. Free Radical Mechanisms.- XI. Concluding Note.- References.- Postscriptum: An Editor’s Musings.