The toxicology of metals has been concerned in the past with effects that produced clinical signs and symptoms. However, this view of metal toxicology has expanded in recent years due principally to two advances. There has been a considerable increase in our knowledge of the biochemical effects of metals. In addition, biomarkers of toxicity can now be recognized that identify toxicity at levels of exposure that do not produce overt clinical effects. Thus, the toxicology of metals is now focused on nonclinical events that reflect adverse health effects. This new awareness has produced the challenge of determining the lowest adverse level of exposure. With increasing analytical sensitivity and methodologies to detect small changes at the molecular level, the lowest level of exposure of some toxic metals, like lead, is very small. Indeed, for metals in which there is no biologic requirement, it may be questioned whether there is a level of exposure that does not produce some degree of toxicity. For essential metals, the question is being asked as to the levels at which exposure exceeds biologic require­ ments and excess exposure becomes toxic. The appropriateness of health decisions and the formation of public policy are dependent on the availability of current scientific information that addresses these questions. The information in this volume is intended to be a resource for this purpose as well as a reference for students of toxicology and other health professionals.

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.