Toxicology of Metals

1 Transplacental Transfer of Lead and Cadmium.- A. Introduction.- I. Comparison of Human and Rodent Fetal-Maternal Blood Barriers.- II. Methods for Sampling the Human Placenta.- B. Placental Transfer of Lead.- I. Mechanism of Placental Transfer of Lead.- II. Maternal Blood Lead Levels During Pregnancy.- III. Effect of Maternal Lead on Birth Outcomes.- IV. Effect of Lead on Neurobehavioral and Cognitive Development In Utero.- V. Mechanisms for the Neurotoxicity of Lead.- C. Placental Transfer of Cadmium.- I. Cadmium Levels in Human Placenta.- II. Cadmium Effects on Placenta and Fetus.- III. Interactions in Placenta Between Cadmium, Zinc and Copper, and Metallothionein.- D. Summary.- References.- 2 Porphyrin Metabolism as Indicator of Metal Exposure and Toxicity.- A. Introduction.- B. Heme Biosynthesis and Porphyrin Metabolism.- C. Mechanistic Basis of Metal-Induced Porphyria (Porphyrinuria).- I. Metal Effects on Specific Steps of the Heme Biosynthetic Pathway.- II. Metal-Induced Oxidation of Reduced Porphyrins.- D. Metal- and Metalloid-Induced Porphyrinopathies and Porphyrinurias.- I. Lead.- 1. Erythrocyte ALA Dehydratase.- 2. Erythrocyte Zinc-Protoporphyrin.- 3. Urinary Coproporphyrin.- II. Mercury.- 1. Mercury-Directed Alteration of Renal Coproporphyrinogen Metabolism.- 2. Mercury-Facilitated Porphyrinogen Oxidation.- III. Arsenic.- IV. Other Metals.- 1. Cadmium.- 2. Platinum.- 3. Aluminum.- 4. Metal Interactions.- E. Perspectives on the Use of Porphyrins as Biomarkers of Metal Exposure in Human Studies.- References.- 3 Membrane Transporters as Sites of Action and Routes of Entry for Toxic Metals.- A. Introduction: Metals and Membranes.- B. Chemical Properties of Metals in Solutions.- C. Model Systems.- D. Mercury Inhibition of NaCl Cotransport: An Example Problem witha Model System.- E. Metal Entry into Cells.- F. Permeation in a Lipid-Soluble Form.- G. Permeation as a Cation.- H. Permeation as an Anion.- I. Transport of Organic Complexes.- J. Physiological Significance of Metal Permeation Pathways.- References.- 4 Immunotoxicology of Metals.- A. Introduction.- B. Basis of the Immune Response.- C. Hypersensitivity Reactions.- D. Experimental Models of Metal-Induced Autoimmunity.- I. Description of the Models.- 1. HgCl2-Induced Autoimmunity in Rats.- 2. HgCl2-Induced Autoimmunity in Other Species.- 3. Gold-Induced Autoimmunity.- II. Mechanisms of Induction.- III. Autoregulation.- E. Nonantigen-Specific Immunosuppression Induced by HgCl2.- F. Conclusions.- References.- 5 Effects of Metals on Gene Expression.- A. Introduction.- B. Molecular Control of Gene Expression.- C. Eukaryotic Strategies of Signal Transfer.- I. Multiple Factor Signal Transduction Systems.- II. Single Factor Signal Transduction Systems.- D. Transduction of Metal Signals in Eukaryotes.- I. Entry, Binding, and Storage of Essential Metals.- 1. Iron.- 2. Copper.- II. Essential Metals as Regulators of Metabolism.- 1. Iron.- 2. Copper.- III. Metallothionein and Other Genes as Models for Metal Regulation.- 1. Metal Regulation in Yeast.- 2. Metal Regulation in Mammals.- IV. Metal Bioavailability and Sequestration.- E. Other Metal-Regulated Genes.- I. Plastocyanin and cyt c6.- II. Superoxide Dismutase.- III. Heat Shock Proteins.- IV. Acute Phase Proteins, Heme Oxygenase, and Oncogenes.- F. Metal-Induced Changes in Chromatin Structure.- G. Summary.- References.- 6 Metallothionein and Its Interaction with Metals.- A. Introduction.- B. Metal Binding and Dynamic Aspects of Metallothionein Structure.- C. Induction of Metallothionein and Excretion of Metals.- D. Detoxificationof Metals.- E. Regulation of Zinc and Copper Metabolism.- F. Lipid Peroxidation and Oxidative Stress.- G. Summary.- References.- 7 Biochemical Mechanisms of Aluminum Toxicity.- A. Introduction.- B. Aluminum Species in Biological Systems.- C. Bioavailability of Aluminum.- I. Exposure.- II. Gastrointestinal Absorption.- III. Transcellular Uptake.- IV. Paracellular Uptake.- V. Systemic Transport.- VI. Accumulation in Erythrocytes.- VII. Cellular Uptake.- VIII. Aluminum Interactions with Desferrioxamine.- D. Aluminum-Related Anemia.- E. Aluminum-Related Bone Disease.- F. Aluminum Neurotoxicity.- G. Aluminum and Second Messenger Systems.- I. Fluoroaluminate Stimulation of G-Protein Systems.- II. Fluoride Stimulation of Second Messenger Systems.- III. Aluminum Stimulation of Second Messenger Systems.- IV. GTP Interaction with Aluminum.- References.- 8 Mercury Toxicity.- A. Introduction.- B. Organic Mercury.- I. Methylmercury.- 1. Mechanism of Uptake and Excretion.- 2. Mechanism of Toxicity.- C. Inorganic Mercury.- I. Mercuric Mercury.- 1. Tissue Accumulation and Excretion.- 2. Toxicity.- 3. Mechanism of Renal Toxicity.- II. Elemental Mercury.- 1. Exposure to Elemental Mercury.- 2. Metabolism.- 3. Biotransformation.- 4. Toxicity.- 5. Mechanism of Toxicity.- References.- 9 Toxicology of Cadmium.- A. Introduction.- I. Production and Uses.- II. Exposure to Cadmium.- III. Metabolism.- B. Molecular and Cellular Effects.- I. Calmodulin-Calcium-Cadmium Interactions.- II. Other Effects.- C. Target Organ Toxicity.- I. Acute Toxicities.- II. Chronic Toxicities.- 1. Lung.- 2. Kidney.- 3. Liver.- 4. Developmental Effects.- 5. Reproductive Effects.- 6. Bone.- 7. Immune Effects.- D. Carcinogenesis.- I. Human Studies.- II. Animal Studies.- 1. Lung.- 2. Prostate.- 3. Testes.- 4. Injection Site.- 5. Hematopoietic.- 6. Metal-Metal Interactions.- 7. Synergism and Antagonism.- E. Roles of Metallothionein and Glutathione in Cadmium Toxicity.- I. Metallothionein.- II. Glutathione.- F. Conclusion.- References.- 10 Chromium Toxicokinetics.- A. Introduction.- B. Chromium Actions and Kinetics.- I. Local and Systemic Toxicity.- II. Essentiality of Cr(III).- III. Carcinogenicity of Cr(VI).- C. Key Features of Chromium Kinetics.- I. Solubility.- II. Membrane Permeability and Chromium Absorption.- 1. Gastrointestinal Absorption.- 2. Pulmonary Absorption.- III. Reduction of Cr(VI) to Cr(III).- IV. General Chromium Disposition.- V. Chromium in the Red Cell.- VI. Chromium in Bone.- VII. Chromium in Other Tissues.- VIII. Excretion.- D. Uncertainties and Research Needs.- References.- 11 Metals and Stress Proteins.- A. Introduction.- B. Stress Proteins and Their Functions.- C. Metals and Their Effects on Expression of Stress Proteins.- I. General.- II. Arsenic.- III. Cadmium.- IV. Mercury.- V. Copper.- VI. Zinc.- VII. Lead.- VIII. Iron.- IX. Gold.- D. Tolerance Induction and Stress Proteins.- E. Heme Oxygenase Is a Stress Protein.- F. Is Metallothionein a Stress Protein?.- I. Evolutionary Conservation.- II. Common Inducers.- III. Protective Roles and Cross-tolerance.- IV. Gene Regulation.- V. Increased Expression in Neoplasms and Other Diseases.- VI. Adjuncts to Chemotherapy.- G. Stress Proteins as Biomarkers of Metal Exposure and Toxicity.- I. Rationale and Criteria.- II. Exposure and Toxicity.- III. Toxicity Screening Assays.- IV. Environmental Monitoring.- V. Human Applications.- References.- 12 Metals and Anticancer Drug Resistance.- A. Introduction.- B. Metal-Binding and Metal-Based Anticancer Agents.- I. Bleomycin.- II. Doxorubicin.- III. Cisplatin and Carboplatin.- C. Metal-Induced Anticancer Drug Resistance in Cell Culture.- I. Cadmium.- II. Zinc.- D. Metallothionein and Anticancer Drug Resistance.- I. In Vitro Metallothionein-Drug Interactions.- II. Metallothionein in Drug-Resistant Cells.- III. Nonmetal Induction of Metallothionein.- IV. Metallothionein Gene Transfer.- V. Human Tumor Expression of Metallothionein and Drug Sensitivity.- E. Metal-Mediated Changes in Drug Sensitivity In Vivo.- I. Zinc.- II. Bismuth.- F. Summary.- References.- 13 Chemistry of Chelation: Chelating Agent Antagonists for Toxic Metals.- A. Chelation: Its Basic Chemistry and Advantages as a Metal Complexation Process.- B. Chemistry of Chelation in Biological Systems.- C. Toxic Metal Excretion and Its Acceleration.- I. Toxic Metal Half-Lives, Organ Distribution, and Normal Rates of Excretion.- II. Acceleration of Rates of Excretion of Toxic Metal Ions Subsequent to Chelation.- 1. Lead Intoxication.- D. Alteration of Metal Reactivity, Toxicity, and Distribution by Chelation.- E. Stability Constants of Clinical Chelating Agents with Toxic Metal Ions.- I. Conditional or Effective Stability Constants.- F. Development of Chelating Agents for Clinical Use.- I. BAL and Its Derivatives.- II. EDTA and Its Analogs.- III. D-Penicillamine and Triethylenetetramine Dihydrochloride.- IV. Deferoxamine and Hydroxypyrid inones.- V. Sodium Diethyldithiocarbamate.- G. Toxicity and Adverse Effects of Clinically Used Chelating Agents.- H. Current Clinical Treatments for Common Metal Intoxications and Their Underlying Chemistry.- I. Lead.- 1. D-Penicillamine.- II. Arsenic.- III. Mercury.- IV. Copper.- V. Other Toxic Metals.- I. Unsolved Problems and Future Prospects.- References.- 14 Therapeutic Use of Chelating Agents in Iron Overload.- A. Transport, Storage, and Toxicity of Iron.- B. Chronic Iron Overload and the Clinical Need for Iron Chelators.- I. Intake.- II. Absorption.- III. Transfusion.- C. Other Applications of Iron Chelation.- D. Structural Considerations for Iron-Specific Chelators.- E. Biological Considerations for Iron Removal.- F. Criteria for the Safe Chelation of Iron.- G. Clinically Useful Iron Chelators.- I. Natural Siderophores.- 1. Desferrioxamine B.- 2. Other Siderophores.- II. Synthetic Chelators.- 1. Deferiprone B.- 2. Other Synthetic Chelators.- H. Summary.- References.- 15 Zinc Fingers and Metallothionein in Gene Expression.- A. Introduction.- B. Zinc Finger Proteins in Gene Expression.- C. Modulation of Zinc Finger-Dependent Gene Expression by pZn.- D. Effects of Thionein on Zinc Finger-Dependent Gene Expression.- E. Implications and Speculation.- F. Summary.- References.- 16 Role of Active Oxygen Species in Metal-Induced DNA Damage.- A. Introduction.- B. Chromium.- C. Iron Complex.- D. Nickel.- E. Cobalt.- F. Copper.- G. Manganese.- H. Arsenic, Lead, and Cadmium.- I. Role of Active Oxygen Species in Carcinogenesis.- References.- 17 Metal Mutagenesis.- A. Introduction.- B. Mutagenesis by Oxidative Reactions.- C. Confounding Factors in Metal Mutagenesis.- D. Mutagenic Effects of Human Carcinogens.- I. Arsenic.- II. Beryllium.- III. Cadmium.- IV. Chromium.- V. Nickel.- E. Multagenic Effects of Other Metals.- I. Lead.- II. Mercury.- III. Other Metals.- References.- 18 Biological Mechanisms and Toxicological Consequences of the Methylation of Arsenic.- A. Introduction.- B. Biological Methylation of Arsenic.- I. Role of Methylation in Arsenic Metabolism.- II. Determinants of Interindividual Variation in Methylation Capacity.- 1. Saturable Capacity for Arsenic Methylation.- 2. Influence of Nutritional Status.- 3. GeneticallyDetermined Capacity for Arsenic Methylation.- III. Enzymology of Arsenic Methylation.- 1. Characteristics of Arsenic Methyltransferases.- 2. Role of GSH in Arsenic Reduction, Binding, and Methylation.- C. Comparative Metabolism, Kinetics, and Toxicity.- I. Methylation in Prokaryotes.- II. Methylation in Eukaryotes.- 1. Methylation in Nonhuman Species.- 2. Arsenic Methylation in Humans.- D. Conclusions and Future Research Directions.- References.- 19 Bacterial Plasmid-Mediated Resistances to Mercury, Cadmium, and Copper.- A. Introduction and Overview: Generalities.- B. Mercury and Organomercurial Resistance.- I. Introduction.- II. Genetic Organization and Molecular Biology.- 1. Operon Structure in Gram-Negative Bacteria.- 2. The Special Case of Thiobacillus.- 3. Operon Structure in Gram-Positive Bacteria.- C. Cadmium and Zinc Resistance.- I. CadA Cd2+ ATPase in Staphylococcus and Bacillus.- II. Czc (Cd2+, Zn2+, and Co2+) and Cnr (Co2+ and Ni2+) Resistance Systems of Alcaligenes.- D. Relationship Between Human Menkes' and Wilson's ATPases and Bacterial P-Type ATPases.- E. Copper Transport and Resistance in Bacteria.- F. Summary and Conclusions.- References.