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.