2996R_ch23_811 5/21/01 3:39 PM Page 811 CHAPTER 23 TOXIC EFFECTS OF METALS Robert A. Goyer and Thomas W. Clarkson INTRODUCTION Essentiality Toxicity DOSE–EFFECT RELATIONSHIPS Carcinogenicity HOST FACTORS INFLUENCING THE TOXICITY OF Lead(Pb) METALS Exposure Toxicokinetics METAL-BINDING PROTEINS Toxicity Specific Metal-Binding Proteins Neurologic, Neurobehavioral, and Developmental Membrane Carrier Proteins Effects in Children COMPLEXATION AND CHELATION THERAPY Mechanisms of Effects on the Developing Nervous System BAL (British Anti-Lewisite) Peripheral Neuropathy DMPS Hematologic Effects DMSA Renal Toxicity EDTA Lead and Gout DTPA Effects on Cardiovascular System Desferrioxamine Immunotoxicity Dithiocarbamate (DTC) Bone Effects Penicillamine and N-Acetylcysteine Reproductive Effects Hemodialysis with Chelation Birth Outcomes MAJOR TOXIC METALS WITH MULTIPLE EFFECTS Carcinogenicity Arsenic (As) Other Effects Toxicokinetics Dose Response Biotransformation Treatment Mechanisms of Toxicity Organic Lead Compounds Toxicology Mercury (Hg) Reproductive Effects and Teratogenicity Exposure Carcinogenicity Disposition and Toxicokinetics Arsine Metabolic Transformation Biomarkers Cellular Metabolism Treatment Toxicology Beryllium (Be) Biological Indicators Toxicokinetics Treatment Skin Effects Nickel (Ni) Pulmonary Effects Exposure Carcinogenicity Toxicokinetics Cadmium (Cd) Essentiality Exposure Toxicity Toxicokinetics Nickel Carbonyl Poisoning Acute Toxicity Dermatitis Chronic ToxicityCopyrighted MaterialIndicators of Nickel Toxicity Carcinogenicity ESSENTIAL METALS WITH POTENTIAL FOR Biomarkers of Cadmium Effects TOXICITY Biomarkers of Cadmium Exposure Cobalt (Co) Reversibility of Renal Effects Trivalent Chromium, Cr(III) Treatment Essentiality Chromium (Cr) Copper (Cu) Human Body Burden Toxicokinetics 811 Copyright © 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com 2996R_ch23_811-868 4/27/01 3:32 PM Page 812 812 UNIT 5 TOXIC AGENTS Essentiality METALS RELATED TO MEDICAL THERAPY Deficiency Aluminum (Al) Toxicity Toxicokinetics Iron (Fe) Toxicity Toxicokinetics Human Dementia Syndromes Iron Deficiency Bismuth (Bi) Iron Overload Toxicokinetics Toxicity Toxicity Magnesium (Mg) Gallium (Ga) Toxicokinetics Toxicokinetics Deficiency Toxicity Toxicity Gold (Au) Manganese (Mn) Toxicokinetics Toxicokinetics Toxicity Deficiency Lithium (Li) Toxicity Toxicokinetics Molybdenum (Mo) Toxicity Toxicokinetics Platinum (Pt) and Related Metals Deficiency Allergenic Effects of Platinum Salts Toxicity Antitumor Effects of Platinum Complexes Selenium (Se) Nephrotoxicity Toxicokinetics Essentiality MINOR TOXIC METALS Selenium Deficiency Antimony (Sb) Toxicity Barium (Ba) Biological Interactions Germanium (Ge) Anticarcinogenicity Indium (In) Dose Effect in Humans Silver (Ag) Zinc (Zn) Tellurium (Te) Essentiality and Metabolism Thallium (Tl) Toxicokinetics Tin (Sn) Assessment of Zinc Status Titanium (Ti) Deficiency Uranium (U) Zinc in Neurologic Disorders Vanadium (V) Toxicity Carcinogenicity INTRODUCTION 80 of the 105 elements in the periodic table are regarded as metals, but less than 30 have been reported to produce toxicity in hu- Metals differ from other toxic substances in that they are neither mans. The importance of some of the rarer or lesser known met- created nor destroyed by humans. Nevertheless, their utilization by als such as indium or gallium might increase with new applica- humans influences the potential for health effects in at least two tions in microelectronics, antitumor therapy, or other new major ways: first, by environmental transport, that is, by human or technologies. anthropogenic contributions to air, water, soil, and food, and sec- Metals are redistributed naturally in the environment by both ond, by altering the speciation or biochemical form of the element geologic and biological cycles (Fig. 23-1). Rainwater dissolves (Beijer and Jernelov, 1986). rocks and ores and physically transports material to streams and Metals are probably theCopyrighted oldest toxins known to humans. Lead rivers, depositingMaterial and stripping materials from adjacent soil and usage may have begun prior to 2000 B.C., when abundant sup- eventually transporting these substances to the ocean to be pre- plies were obtained from ores as a by-product of smelting silver. cipitated as sediment or taken up in rainwater to be relocated else- Hippocrates is credited in 370 B.C. with the first description of where on earth. The biological cycles include bioconcentration by abdominal colic in a man who extracted metals. Arsenic and plants and animals and incorporation into food cycles. These nat- mercury are cited by Theophrastus of Erebus (370–287 B.C.) and ural cycles may exceed the anthropogenic cycle, as is the case for Pliny the Elder (A.D. 23–79). Arsenic was obtained during the mercury. Human industrial activity, however, may greatly shorten melting of copper and tin, and an early use was for decoration in the residence time of metals in ore, may form new compounds, Egyptian tombs. In contrast, many of the metals of toxicologic and may greatly enhance worldwide distribution not only by dis- concern today are only recently known to humans. Cadmium was charge to land and water but also to the atmosphere. When dis- first recognized in ores containing zinc carbonate in 1817. About charged in gaseous or fine particulate forms, metal may be trans- Copyright © 2001 by The McGraw-Hill Companies Retrieved from: www.knovel.com 2996R_ch23_811-868 4/27/01 3:32 PM Page 813 CHAPTER 23 TOXIC EFFECTS OF METALS 813 promise as markers of both effect and susceptiblity. The use of such biomarkers provides guidelines for preventive measures or therapeutic intervention. DOSE–EFFECT RELATIONSHIPS Estimates of the relationship of dose or level of exposure to toxic effects for a particular metal are in many ways a measure of the dose–response relationships discussed in greater detail in Chap. 2. Relationships between sources of exposure, transport, and distri- bution to various organs and excretory pathways are shown in Fig. 23-2. The dose or estimate of exposure to a metal may be a multidimensional concept and is a function of time as well as the concentration of metal. The most precise definition of dose is the Figure 23-1. Routes for transport of trace elements in the environment. amount of metal within cells of organs manifesting a toxicologic [From Beijer and Jernelõv (1986).] effect. Results from single measurements may reflect recent expo- sure or longer-term or past exposure, depending on retention time in the particular tissue. ported in the atmosphere over global distances. The role of hu- A critical determinant of retention of a metal is its biological man activity in the redistribution of metals is demonstrated by the half-life, that is, the time it takes for the body or organ to excrete 200-fold increase in lead content of Greenland ice, beginning with half of an accumulated amount. The biological half-life varies ac- a natural low level (about 800 B.C.) and continuing with a grad- cording to the metal as well as the organ or tissue; in the case of ual rise in lead content of ice through the evolution of the indus- many metals, more than one half-life is needed to fully describe trial age and finally a nearly precipitous rise in lead correspon- the retention time. For example, the biological half-lives of cad- ding to the period when lead was added to gasoline in the 1920s mium in kidney and lead in bone are 20 to 30 years, whereas for (Ng and Patterson, 1981). Metal contamination of the environment some metals, such as arsenic or lithium, they are only a few hours therefore reflects both natural sources and a contribution from in- or days. The half-life of lead in blood is only a few weeks, as com- dustrial activity. pared to the much longer half-time in bone. After inhalation of The conceptual boundaries of what is regarded as the toxi- mercury vapor, at least two half-lives describe the retention in cology of metals continue to broaden. Historically, metal toxicol- brain—one of the order of a few weeks and the other measured in ogy largely concerned acute or overt effects, such as abdominal years. colic from lead toxicity or the bloody diarrhea and suppression of Blood, urine, and hair are the most accessible tissues in which urine formation from ingestion of corrosive (mercury) sublimate. to measure an exposure or dose; they are sometimes referred to There must continue to be knowledge and understanding of such as indicator tissues. In vivo, the quantitation of metals within or- effects, but they are uncommon with present-day occupational and gans is not yet possible, although techniques such as neutron ac- environmental standards. There is, however, growing interest in, tivation and x-ray fluorescence spectroscopy are emerging tech- and inquiry into, subtle, chronic, or long-term effects in which nologies. Indirect estimates of quantities of toxic metals in specific cause-and-effect relationships are not obvious or may be subclin- organs may be calculated from metabolic models derived from au- ical. These might include a level of effect that causes a change in topsy data. Blood and urine concentrations usually reflect recent an important index of affected individuals’ performance—that is, exposure and correlate best with acute effects. An exception is uri- lower than expected IQs due to childhood lead exposure. Assign- nary cadmium, which may reflect renal damage related to an ac- ing responsibility for such toxicologic effects is extremely