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Section XVI - Toxicology

The environmental metals of greatest concern are lead, mercury, arsenic, and cadmium. In the past, lead paint was available for use in homes, and lead pipes and/or lead solder delivered water to some homes. As a result, people can be exposed to lead on a daily basis; this exposure is a major pediatric concern. Mercury similarly is a contaminant of our environment; human beings are exposed to mercury in the fish they eat as well as in the amalgam fillings in their teeth. Section XVI. Toxicology C

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  1. Section XVI. Toxicology Chapter 67. Heavy Metals and Heavy-Metal Antagonists Overview The environmental metals of greatest concern are lead, mercury, arsenic, and cadmium. In the past, lead paint was available for use in homes, and lead pipes and/or lead solder delivered water to some homes. As a result, people can be exposed to lead on a daily basis; this exposure is a major pediatric concern. Mercury similarly is a contaminant of our environment; human beings are exposed to mercury in the fish they eat as well as in the amalgam fillings in their teeth. Arsenic is found naturally in high concentrations in drinking water in various parts of the world. Recently, cadmium has been classified as a known human carcinogen. This chapter deals primarily with the toxic effects of these four metals and the chelators that are used to treat metal intoxication. Heavy Metals and Heavy-Metal Antagonists: Introduction People always have been exposed to heavy metals in the environment. In areas with high concentrations, metallic contamination of food and water probably led to the first poisonings. Metals leached from eating utensils and cookware also have contributed to inadvertent poisonings. The emergence of the industrial age and large-scale mining brought occupational diseases caused by various toxic metals. Metallic constituents of pesticides and therapeutic agents (e.g., antimicrobials) were additional sources of hazardous exposure. The burning of fossil fuels containing heavy metals, the addition of tetraethyllead to gasoline, and the increase in industrial applications of metals have now made environmental pollution the major source of heavy-metal poisoning. Heavy metals exert their toxic effects by combining with one or more reactive groups (ligands) essential for normal physiological functions. Heavy-metal antagonists (chelating agents) are designed specifically to compete with these groups for the metals, and thereby prevent or reverse toxic effects and enhance the excretion of metals. Heavy metals, particularly those in the transition series, may react in the body with ligands containing oxygen (—OH, —COO–, —OPO3H–, >C O), sulfur (—SH,—S—S—), and nitrogen (—NH2 and >NH). The resultant metal complex (or coordination compound) is formed by a coordinate bond—one in which both electrons are contributed by the ligand. The heavy-metal antagonists discussed in this chapter possess the common ability to form complexes with heavy metals and thereby prevent or reverse the binding of metallic cations to body ligands. These drugs are referred to as chelating agents. A chelate is a complex formed between a metal and a compound that contains two or more potential ligands. The product of such a reaction is a heterocyclic ring. Five- and six-membered chelate rings are the most stable, and a polydentate (multiligand) chelator typically is designed to form such a highly stable complex, far more stable than when a metal is combined with only one ligand atom. The stability of chelates varies with the metal and the ligand atoms. For example, lead and mercury have greater affinities for sulfur and nitrogen than for oxygen ligands; calcium, however, has a greater affinity for oxygen than for sulfur and nitrogen. These differences in affinity serve as the basis of selectivity of action of a chelating agent in the body. The effectiveness of a chelating agent for the treatment of poisoning by a heavy metal depends on
  2. several factors. These include the relative affinity of the chelator for the heavy metal as compared to essential body metals, the distribution of the chelator in the body as compared with the distribution of the metal, and the ability of the chelator to mobilize the metal from the body once chelated. An ideal chelating agent would have the following properties: high solubility in water, resistance to biotransformation, ability to reach sites of metal storage, capacity to form nontoxic complexes with toxic metals, ability to retain chelating activity at the pH of body fluids, and ready excretion of the chelate. A low affinity for Ca2+ also is desirable, because Ca2+ in plasma is readily available for chelation, and a drug might produce hypocalcemia despite high affinity for heavy metals. The most important property of a therapeutic chelating agent is greater affinity for the metal than that of the endogenous ligands. The large number of ligands in the body is a formidable barrier to the effectiveness of a chelating agent. Observations in vitro on chelator–metal interactions provide only a rough guide to the treatment of heavy-metal poisoning. Empirical observations in vivo are necessary to determine the clinical utility of a chelating agent. The first part of this chapter covers the toxic properties of lead, mercury, arsenic, and cadmium as well as radioactive heavy metals and treatment of the consequences of toxic exposure to these metals. The second part of the chapter covers the chemical properties and therapeutic uses of several heavy-metal antagonists. Lead Lead is ubiquitous in the environment as a result of its natural occurrence and its industrial use. The decreased use of leaded gasoline over the past two decades has resulted in decreased concentrations of lead in blood in human beings. The primary sources of environmental exposure to lead are leaded paint and drinking water; most of the overt toxicity from lead results from environmental and industrial exposure. Acidic foods and beverages—including tomato juice, fruit juice, cola drinks, cider, and pickles— can dissolve the lead when packaged or stored in improperly glazed containers. Foods and beverages thus contaminated have caused fatal human lead poisoning. Lead poisoning in children is a fairly common result of their ingestion of paint chips from old buildings. Paints applied to dwellings before World War II, when lead carbonate (white) and lead oxide (red) were common constituents of both interior and exterior house paint, are primarily responsible. In such paint, lead may constitute 5% to 40% of dried solids. Young children are poisoned most often by nibbling sweet-tasting paint chips and dust from lead-painted windowsills and door frames. The American Standards Association specified in 1955 that paints for toys, furniture, and the interior of dwellings should not contain more than 1% lead in the final dried solids of fresh paint and, in 1978, the Consumer Product Safety Commission (CPSC) banned paint containing more than 0.06% lead for use in and around households. Renovation or demolition of older homes, using a physical process that would cause an airborne dispersion of lead dust or fumes, may cause substantial contamination and lead poisoning. Lead poisoning from the use of discarded automobile-battery casings made of wood and vulcanite and used as fuel during times of economic distress, such as during World Wars I and II, has been reported. Sporadic cases of lead poisoning have been traced to miscellaneous sources such as lead toys, retained bullets, drinking water that is conveyed through lead pipes, artists' paint pigments, ashes and fumes of painted wood, jewelers' wastes, home battery manufacture, and lead type. Finally, lead also is a common contaminant of illicitly distilled whiskey ("moonshine"), because automobile radiators frequently are used as condensers, and other components of the still are connected by lead solder.
  3. Occupational exposure to lead has decreased markedly over the past 50 to 60 years because of appropriate regulations and programs of medical surveillance. Workers in lead smelters have the highest potential for exposure, because fumes are generated and dust containing lead oxide is deposited in their environment. Workers in storage-battery factories face similar risks. Dietary intake of lead also has decreased since the 1940s, when the estimate of intake was about 500 g per day in the United States population, to less than 20 g per day in 2000. This decrease has been due largely to: (1) a decrease in the use of lead-soldered cans for food and beverages; (2) a decrease in the use of lead pipes and lead-soldered joints in water distribution systems; (3) the introduction of lead-free gasoline; and (4) public awareness of the hazards of indoor leaded paint (NRC, 1993). A decline in blood levels from 13 g/dl in the 1980s to
  4. concentration of lead in blood and the rate of its excretion in urine. In experimental animals, lead is excreted in bile, and much more lead is excreted in feces than in urine (Gregus and Klaassen, 1986). In human beings, urinary excretion is a more important route of excretion than in animals (Kehoe, 1987), and the concentration of lead in urine is directly proportional to that in plasma. However, because most lead in blood is in the erythrocytes, very little is filtered. Lead also is excreted in milk and sweat and is deposited in hair and nails. Placental transfer of lead also is known to occur. The half-life of lead in blood is 1 to 2 months, and a steady state is thus achieved in about 6 months. After establishment of a steady state early in human life, the daily intake of lead normally approximates the output, and concentrations of lead in soft tissues are relatively constant. However, the concentration of lead in bone appears to increase (Gross et al., 1975), and its half-life in bone has been estimated to be 20 to 30 years. Because the capacity for lead excretion is limited, even a slight increase in daily intake may produce a positive lead balance. The average daily intake of lead is approximately 0.2 mg, whereas positive lead balance begins at a daily intake of about 0.6 mg, an amount that will not ordinarily produce overt toxicity within a lifetime. However, the time to accumulate toxic amounts shortens disproportionately as the amount ingested increases. For example, a daily intake of 2.5 mg of lead requires nearly 4 years for the accumulation of a toxic burden, whereas a daily intake of 3.5 mg requires but a few months, because deposition in bone is too slow to protect the soft tissues during rapid accumulation. Acute Lead Poisoning Acute lead poisoning is relatively infrequent and occurs from ingestion of acid-soluble lead compounds or inhalation of lead vapors. Local actions in the mouth produce marked astringency, thirst, and a metallic taste. Nausea, abdominal pain, and vomiting ensue. The vomitus may be milky from the presence of lead chloride. Although the abdominal pain is severe, it is unlike that of chronic poisoning. Stools may be black from lead sulfide, and there may be diarrhea or constipation. If large amounts of lead are absorbed rapidly, a shock syndrome may develop as the result of massive gastrointestinal loss of fluid. Acute symptoms of the central nervous system (CNS) include paresthesias, pain, and muscle weakness. An acute hemolytic crisis sometimes occurs and causes severe anemia and hemoglobinuria. The kidneys are damaged, and oliguria and urinary changes are evident. Death may occur in 1 or 2 days. If the patient survives the acute episode, characteristic signs and symptoms of chronic lead poisoning are likely to appear. Chronic Lead Poisoning Signs and symptoms of chronic lead poisoning (plumbism) can be divided into six categories: gastrointestinal, neuromuscular, CNS, hematological, renal, and other. They may occur separately or in combination. The neuromuscular and CNS syndromes usually result from intense exposure, while the abdominal syndrome is a more common manifestation of a very slowly and insidiously developing intoxication. The CNS syndrome usually is more common among children, whereas the gastrointestinal syndrome is more prevalent in adults. Gastrointestinal Effects Lead affects the smooth muscle of the gut, producing intestinal symptoms that are an important early sign of exposure to the metal. The abdominal syndrome often begins with vague symptoms, such as anorexia, muscle discomfort, malaise, and headache. Constipation usually is an early sign,
  5. especially in adults, but diarrhea occasionally occurs. A persistent metallic taste appears early in the course of the syndrome. As intoxication advances, anorexia and constipation become more marked. Intestinal spasm, which causes severe abdominal pain, or lead colic, is the most distressing feature of the advanced abdominal syndrome. The attacks are paroxysmal and generally excruciating (Janin et al., 1985). The abdominal muscles become rigid, and tenderness is especially manifested in the region of the umbilicus. In cases where colic is not severe, removal of the patient from the environment of exposure may be sufficient for relief of symptoms. Calcium gluconate administered intravenously is recommended for relief of pain and usually is more effective than morphine. Neuromuscular Effects The neuromuscular syndrome, or lead palsy, that characterized the house painter and other workers with excessive occupational exposure to lead more than a half century ago, now is rare in the United States. It is a manifestation of advanced subacute poisoning. Muscle weakness and easy fatigue occur long before actual paralysis and may be the only symptoms. Weakness or palsy may not become evident until after extended muscle activity. The muscle groups involved usually are the most active ones (extensors of the forearm, wrist, and fingers and extraocular muscles). Wrist-drop and, to a lesser extent, foot-drop with the appropriate history of exposure have been considered almost pathognomonic for lead poisoning. There usually is no sensory involvement. Degenerative changes in the motoneurons and their axons have been described. CNS Effects The CNS syndrome has been termed lead encephalopathy. It is the most serious manifestation of lead poisoning and is much more common in children than in adults. The early signs of the syndrome may be clumsiness, vertigo, ataxia, falling, headache, insomnia, restlessness, and irritability. As the encephalopathy develops, the patient may first become excited and confused; delirium with repetitive tonic-clonic convulsions or lethargy and coma follow. Vomiting, a common sign, usually is projectile. Visual disturbances also are present. Although the signs and symptoms are characteristic of increased intracranial pressure, flap craniotomy to relieve intracranial pressure is not beneficial. However, treatment for cerebral edema may become necessary. There may be a proliferative meningitis, intense edema, punctate hemorrhages, gliosis, and areas of focal necrosis. Demyelination has been observed in nonhuman primates. The mortality rate among patients who develop cerebral involvement is about 25%. When chelation therapy is begun after the symptoms of acute encephalopathy appear, approximately 40% of survivors have neurological sequelae, such as mental retardation, electroencephalographic abnormalities or frank seizures, cerebral palsy, optic atrophy, or dystonia musculorum deformans (Chisolm and Barltrop, 1979). Exposure to lead occasionally produces clear-cut, progressive mental deterioration in children. The history of these children indicates normal development during the first 12 to 18 months of life or longer, followed by a steady loss of motor skills and speech. They may have severe hyperkinetic and aggressive behavior disorders and a poorly controllable convulsive disorder. The lack of sensory perception severely impairs learning. Concentrations of lead in blood exceed 60 g/dl (2.9 M) of whole blood, and x-rays may show heavy, multiple bands of increased density in the growing long bones (see above). Until recently it was thought that such exposure to lead was restricted largely to children in inner-city slums. However, all children are exposed chronically to low levels of lead in their diets, in the air they breathe, and in the dirt and dust in their play areas. This is reflected in elevated concentrations of lead in the blood of many children and may be a cause of subtle CNS toxicity, including learning disabilities, lowered IQ, and behavioral abnormalities. An increased incidence of hyperkinetic behavior and a statistically significant,
  6. although modest, decrease in IQ have been shown in children with lower blood lead concentrations (Needleman et al., 1990; Baghurst et al., 1992; Bellinger et al., 1992; Banks et al., 1997). Increased blood lead levels in infancy and early childhood may be manifested in older children and adolescents as decreased attention span, reading disabilities, and failure to graduate from high school. Most studies report a 2- to 4-point IQ deficit for each g/dl increase in blood lead within the range of 5 to 35 g/dl. As a result, the Centers for Disease Control and Prevention (CDC) considers a blood lead concentration of greater than or equal to 10 g/dl to be indicative of excessive absorption of lead in children and to constitute grounds for environmental assessment, cleanup, and/or intervention. Chelation therapy is recommended for consideration when blood lead concentrations are higher than 25 g/dl. Universal screening of children, beginning at 6 months of age, is recommended by the CDC. Hematological Effects When the blood lead concentration is near 80 g/dl or greater, basophilic stippling (the aggregation of ribonucleic acid) occurs in erythrocytes. This is thought to result from the inhibitory effect of lead on the enzyme pyrimidine-5'-nucleotidase. Basophilic stippling is not, however, pathognomonic of lead poisoning. A more common hematological result of chronic lead intoxication is a hypochromic microcytic anemia, which is more frequently observed in children and is morphologically similar to that resulting from iron deficiency. The anemia is thought to result from two factors: a decreased life span of the erythrocytes and an inhibition of heme synthesis. Very low concentrations of lead influence the synthesis of heme. The enzymes necessary for heme synthesis are widely distributed in mammalian tissues, and it is highly probable that each cell synthesizes its own heme for incorporation into such proteins as hemoglobin, myoglobin, cytochromes, and catalases. Lead inhibits heme formation at several points, as shown in Figure 67– 1. Inhibition of -aminolevulinate ( -ALA) dehydratase and ferrochelatase, which are sulfhydryl- dependent enzymes, is well documented. Ferrochelatase is the enzyme responsible for incorporating the ferrous ion into protoporphyrin, and thus forming heme. When ferrochelatase is inhibited by lead, excess protoporphyrin takes the place of heme in the hemoglobin molecule. Zinc is incorporated into the protoporphyrin molecule, resulting in the formation of zinc-protoporphyrin, which is intensely fluorescent and may be used to diagnose lead toxicity. Lead poisoning in both human beings and experimental animals is characterized by accumulation of protoporphyrin IX and nonheme iron in red blood cells, by accumulation of -ALA in plasma, and by increased urinary excretion of -ALA. There also is increased urinary excretion of coproporphyrin III (the oxidation product of coproporphyrinogen III), but it is not clear whether this is due to inhibition of enzymatic activity or to other factors. Increased excretion of porphobilinogen and uroporphyrin has been reported only in severe cases. The pattern of excretion of pyrroles found in lead poisoning differs from that characteristic of symptomatic episodes of acute intermittent porphyria and other hepatocellular disorders, as shown in Table 67–1. The increase in -ALA synthase activity is due to the reduction of the cellular concentration of heme, which regulates the synthesis of -ALA synthase by feedback inhibition. Figure 67–1. Lead Interferes with the Biosynthesis of Heme at Several Enzymatic Steps. Steps that are definitely inhibited by lead are indicated by blue blocks. Steps at which lead is thought to act but where evidence for this is inconclusive are indicated by gray blocks.
  7. Measurement of heme precursors provides a sensitive index of recent absorption of inorganic lead salts. -ALA dehydratase activity in hemolysates and -ALA in urine are sensitive indicators of exposure to lead but are not as sensitive as quantification of blood lead concentrations. Renal Effects Although the renal effects of lead are less dramatic than those in the CNS and gastrointestinal tract, nephropathy does occur. Renal toxicity occurs in two forms (Goyer and Clarkson, 2001): a reversible renal tubular disorder (usually seen after acute exposure of children to lead) and an irreversible interstitial nephropathy (more commonly observed in long-term industrial lead exposure). Clinically, a Fanconi-like syndrome is seen with proteinuria, hematuria, and casts in the urine (Craswell, 1987; Bernard and Becker, 1988). Hyperuricemia with gout occurs more frequently in the presence of chronic lead nephropathy than in any other type of chronic renal disease. Histologically, lead nephropathy is revealed by a characteristic nuclear inclusion body, composed of a lead–protein complex; this appears early and resolves after chelation therapy. Such inclusion bodies have been reported in the urine sediment of workers exposed to lead in an industrial setting (Schumann et al., 1980). Other Effects
  8. Other signs and symptoms of plumbism are an ashen color of the face and pallor of the lips; retinal stippling; appearance of "premature aging," with stooped posture, poor muscle tone, and emaciation; and a black, grayish, or blue-black so-called lead line along the gingival margin. The lead line, a result of periodontal deposition of lead sulfide, may be removed by good dental hygiene. Similar pigmentation may result from the absorption of mercury, bismuth, silver, thallium, or iron. There is a relationship between the concentration of lead in blood and blood pressure, and it has been suggested that this may be due to subtle changes in calcium metabolism or renal function (Staessen, 1995). Lead also interferes with vitamin D metabolism (Rosen et al., 1980; Mahaffey et al., 1982). A decreased sperm count in lead-exposed males has been described (Lerda, 1992). The human carcinogenicity of lead is not well established but it has been suggested (Cooper and Gaffey, 1975), and several case reports of renal adenocarcinoma in lead workers have been published (Baker et al., 1980; Kazantzis, 1986). Diagnosis of Lead Poisoning In the absence of a positive history of abnormal exposure to lead, the diagnosis of lead poisoning easily is missed. Furthermore, the signs and symptoms of lead poisoning are shared by other diseases. For example, the signs of encephalopathy may resemble those of various degenerative conditions. Physical examination does not easily distinguish lead colic from other abdominal disorders. Clinical suspicion should be confirmed by determinations of the concentration of lead in blood and protoporphyrin in erythrocytes. As noted earlier, lead, at low concentrations, decreases heme synthesis at several enzymatic steps. This leads to the buildup of the diagnostically important substrates -aminolevulinic acid, coproporphyrin (both measured in urine), and zinc protoporphyrin (measured in the red cell as erythrocyte protoporphyrin). Because the erythrocyte protoporphyrin level is not sensitive enough to identify children with elevated blood lead levels below about 25 g/dl, the screening test of choice is blood lead measurement. Since lead has been removed from paints and gasoline, the mean blood levels of lead in children in the United States have decreased from 17 g/dl in the 1970s to 6 g/dl in the 1990s (Schoen, 1993). The concentration of lead in blood is an indication of recent absorption of the metal (Figure 67–2). Children with concentrations of lead in blood above 10 g/dl are at risk of developmental disabilities. Adults with concentrations below 30 g/dl exhibit no known functional injury or symptoms; however, they will have a definite decrease in -ALA dehydratase activity, a slight increase in urinary excretion of -ALA, and an increase in erythrocyte protoporphyrin. Patients with a blood lead concentration of 30 to 75 g/dl have all of the above laboratory abnormalities and, usually, nonspecific, mild symptoms of lead poisoning. Clear symptoms of lead poisoning are associated with concentrations that exceed 75 g/dl of whole blood (Kehoe, 1961a,b), and lead encephalopathy is usually apparent when lead concentrations are greater than 100 g/dl. In persons with moderate-to-severe anemia, interpretation of the significance of concentrations of lead in blood is improved by correcting the observed value to approximate that which would be expected if the patient's hematocrit were within the normal range. Figure 67–2. Manifestations of Lead Toxicity Associated with Varying Concentrations of Lead in Blood of Children and Adults. -ALA = - aminolevulinate.
  9. The urinary concentration of lead in normal adults generally is less than 80 g/liter (0.4 M) (Kehoe, 1961a,b; Goldwater and Hoover, 1967). Most patients with lead poisoning show concentrations of lead in urine of 150 to 300 g/liter (0.7 to 1.4 M). However, in persons with chronic lead nephropathy or other forms of renal insufficiency, urinary excretion of lead may be within the normal range, even though blood lead concentrations are significantly elevated. Because the onset of lead poisoning usually is insidious, it often is desirable to estimate the body burden of lead in individuals who are exposed to an environment that is contaminated with the metal. In the past, the edetate calcium disodium (CaNa2EDTA) provocation test has been used to determine whether or not there is an increased body burden of lead in those for whom exposure occurred much earlier. The provocation test is performed by intravenous administration of a single dose of CaNa2EDTA (50 mg/kg), and urine is collected for 8 hours. The test is positive for children when the lead excretion ratio (micrograms of lead excreted in the urine per milligram of CaNa2EDTA administered) is greater than 0.6 and may be useful for therapeutic chelation in children with blood levels of 25 to 45 g/dl. This test is not used in symptomatic patients or in those whose concentration of lead in blood is greater than 45 g/dl, because these patients require the proper therapeutic regimen with chelating agents (see below). Neutron activation analysis or fluorometric assays, currently available only as research methods, may offer a unique in vivo approach to the diagnosis of lead burden in the future. Organic Lead Poisoning Tetraethyllead and tetramethyllead are lipid-soluble compounds and are readily absorbed from the skin, gastrointestinal tract, and lungs. The toxicity of tetraethyllead is believed to be due to its metabolic conversion to triethyllead and inorganic lead. The major symptoms of intoxication with tetraethyllead are referable to the CNS ( Seshia et al., 1978). The victim suffers from insomnia, nightmares, anorexia, nausea and vomiting, diarrhea, headache, muscular weakness, and emotional instability. Subjective CNS symptoms such as
  10. irritability, restlessness, and anxiety are next evident. At this time there is usually hypothermia, bradycardia, and hypotension. With continued exposure, or in the case of intense short-term exposure, CNS manifestations progress to delusions, ataxia, exaggerated muscular movements, and, finally, a maniacal state. The diagnosis of poisoning by tetraethyllead is established by relating these signs and symptoms to a history of exposure. The urinary excretion of lead may increase markedly, but the concentration of lead in blood remains nearly normal. Anemia and basophilic stippling of erythrocytes are uncommon in organic lead poisoning. There is little effect on the metabolism of porphyrins, and erythrocyte protoporphyrin concentrations are inconsistently elevated (Garrettson, 1983). In the case of severe exposure, death may occur within a few hours or may be delayed for several weeks. If the patient survives the acute phase of organic lead poisoning, recovery usually is complete; however, instances of residual CNS damage have been reported. Treatment of Lead Poisoning Initial treatment of the acute phase of lead intoxication involves supportive measures. Prevention of further exposure is important. Seizures are treated with diazepam (Chapters 17: Hypnotics and Sedatives and 21: Drugs Effective in the Therapy of the Epilepsies); fluid and electrolyte balances must be maintained; cerebral edema is treated with mannitol and dexamethasone. The concentration of lead in blood should be determined, or at least a blood sample for analysis obtained, prior to initiation of chelation therapy. Chelation therapy is indicated in symptomatic patients or in patients with a blood lead concentration in excess of 50 to 60 g/dl (about 2.5 M). Four chelators are employed: edetate calcium disodium (CaNa2EDTA), dimercaprol (British anti-Lewisite; BAL), D-penicillamine, and succimer (2,3– dimercaptosuccinic acid; DMSA; CHEMET). CaNa2EDTA and dimercaprol usually are used in combination for lead encephalopathy. CaNa2EDTA CaNa2EDTA is initiated at a dose of 30 to 50 mg/kg per day in two divided doses, either by deep intramuscular injection or slow intravenous infusion for up to 5 consecutive days. The first dose of CaNa2EDTA should be delayed until 4 hours after the first dose of dimercaprol. An additional course of CaNa2EDTA may be given after an interruption of 2 days. Each course of therapy with CaNa2EDTA should not exceed a total dose of 500 mg/kg. Urine output must be monitored, because the chelator–lead complex is believed to be nephrotoxic. Treatment with CaNa2EDTA can alleviate symptoms quickly. Colic may disappear within 2 hours; paresthesia and tremor cease after 4 or 5 days; coproporphyrinuria, stippled erythrocytes, and gingival lead lines tend to decrease in 4 to 9 days. Urinary elimination of lead is usually greatest during the initial infusion. Dimercaprol Dimercaprol is given intramuscularly at a dose of 4 mg/kg every 4 hours for 48 hours, then every 6 hours for 48 hours, and finally every 6 to 12 hours for an additional 7 days. The combination of dimercaprol and CaNa2EDTA is more effective than is either chelator alone (Chisolm, 1973). D-Penicillamine In contrast to CaNa2EDTA and dimercaprol, penicillamine is effective orally and may be included
  11. in the regimen at a dosage of 250 mg given four times daily for 5 days. During chronic therapy with penicillamine, the dose should not exceed 40 mg/kg per day. Succimer Succimer is the first orally active lead chelator available for children with a safety and efficacy profile that surpasses that of D-penicillamine. Succimer is usually given every 8 hours (10 mg/kg) for 5 days, and then every 12 hours for an additional 2 weeks. General Principles In any chelation regimen, 2 weeks after the regimen has been completed, the blood lead concentration should be reassessed; an additional course of therapy may be indicated if blood lead concentrations rebound. Treatment of organic lead poisoning is symptomatic. Chelation therapy will promote the excretion of the inorganic lead produced from the metabolism of organic lead, but the increase is not dramatic (Boyd et al., 1957). Mercury Mercury was an important constituent of drugs for centuries as an ingredient in many diuretics, antibacterials, antiseptics, skin ointments, and laxatives. More specific, effective, and safer modes of therapy have largely replaced the mercurials in recent decades, and drug-induced mercury poisoning has become rare. However, mercury has a number of important industrial uses (Table 67– 2), and poisoning from occupational exposure and environmental pollution continues to be an area of concern. There have been epidemics of mercury poisoning among wildlife and human populations in many countries. With very few exceptions and for numerous reasons, such outbreaks were misdiagnosed for months or even years. Reasons for these tragic delays included the insidious onset of the affliction, vagueness of early clinical signs, and the medical profession's unfamiliarity with the disease (Gerstner and Huff, 1977). Chemical Forms and Sources of Mercury With regard to the toxicity of mercury, three major chemical forms of the metal must be distinguished: mercury vapor (elemental mercury), salts of mercury, and organic mercurials. Table 67–3 indicates the estimated daily retention of various forms of mercury from various sources. Elemental mercury is the most volatile of the inorganic forms of the metal. Human exposure to mercury vapor is mainly occupational and has been known since antiquity. Extraction of gold with mercury and then heating the amalgam to drive off the mercury is a technique that has been extensively used by gold miners and is still used today in some developing countries. Chronic exposure to mercury in ambient air after inadvertent mercury spills in poorly ventilated rooms, often scientific laboratories, can produce toxic effects. Mercury vapor also can be released from silver-amalgam dental restorations. In fact, this is the main source of mercury exposure to the general population, but the amount of mercury released does not appear to be of significance for human health (Eley and Cox, 1993) except for allergic contact eczema seen in a few individuals. Salts of mercury exist in two states of oxidation—as monovalent mercurous salts or as divalent mercuric salts. Mercurous chloride, or calomel, the best-known mercurous compound, was used in
  12. some skin creams as an antiseptic and was employed as a diuretic and cathartic. Mercuric salts are the more irritating and acutely toxic form of the metal. Mercuric nitrate was a common industrial hazard in the felt-hat industry more than 400 years ago. Occupational exposure produced neurological and behavioral changes depicted by the Mad Hatter in Lewis Carroll's Alice's Adventures in Wonderland. Mercuric chloride, once a widely used antiseptic, also was commonly used for suicidal purposes. Mercuric salts still are widely employed in industry, and industrial discharge into rivers has introduced mercury into the environment in many parts of the world. The main industrial uses of inorganic mercury today are in chloralkali production and in electronics. Other uses of the metal include the manufacturing of plastics, fungicides, and germicides and the formulation of amalgams in dentistry. The organomercurials in use today contain mercury with one covalent bond to a carbon atom. This is a heterogeneous group of compounds, and its members have varying abilities to produce toxic effects. The alkylmercury salts are by far the most dangerous of these compounds; methylmercury is the most common. Alkylmercury salts have been used widely as fungicides and, as such, have produced toxic effects in human beings. Major incidents of human poisoning from the inadvertent consumption of mercury-treated seed grain have occurred in Iraq, Pakistan, Ghana, and Guatemala. The most catastrophic outbreak occurred in Iraq in 1972. During the fall of 1971, Iraq imported large quantities of seed (wheat and barley) treated with methylmercury and distributed the grain for spring planting. Despite official warnings, the grain was ground into flour and made into bread. As a result, 6530 victims were hospitalized and 500 died (Bakir et al., 1973, 1980). Minamata disease also was due to methylmercury. Minamata is a small town in Japan, and its major industry is a chemical plant that empties its effluent directly into Minamata Bay. The chemical plant used inorganic mercury as a catalyst, and some of it was methylated before it entered the bay. In addition, microorganisms can convert inorganic mercury to methylmercury; the compound is then taken up rapidly by plankton algae and is concentrated in fish via the food chain. Residents of Minamata who consumed fish as a large portion of their diet were the first to be poisoned. Eventually 121 persons were poisoned and 46 died (McAlpine and Araki, 1958; Smith and Smith, 1975; Tamashiro et al., 1985). In the United States, human poisonings have resulted from ingestion of meat from pigs fed grain treated with an organomercurial fungicide. Chemistry and Mechanism of Action Mercury readily forms covalent bonds with sulfur, and it is this property that accounts for most of the biological properties of the metal. When the sulfur is in the form of sulfhydryl groups, divalent mercury replaces the hydrogen atom to form mercaptides, X—Hg—SR and Hg(SR)2, where X is an electronegative radical and R is protein. Organic mercurials form mercaptides of the type RHg–SR'. Even in low concentrations, mercurials are capable of inactivating sulfhydryl enzymes and thus interfering with cellular metabolism and function. The affinity of mercury for thiols provides the basis for treatment of mercury poisoning with such agents as dimercaprol and penicillamine. Mercury also combines with other ligands of physiological importance, such as phosphoryl, carboxyl, amide, and amine groups. The various therapeutic and toxic actions of the mercurials are associated with chemical substituents that affect solubility, dissociation, relative affinity for various cellular receptors, distribution, and excretion. Absorption, Biotransformation, Distribution, and Excretion
  13. Elemental Mercury Elemental mercury is not particularly toxic when ingested because of very low absorption from the gastrointestinal tract; this is due to the formation of droplets and because the metal in this form cannot react with biologically important molecules. However, inhaled mercury vapor is completely absorbed by the lung and then is oxidized to the divalent mercuric cation by catalase in the erythrocytes (Magos et al., 1978). Within a few hours the deposition of inhaled mercury vapor resembles that after ingestion of mercuric salts, with one important difference. Because mercury vapor crosses membranes much more readily than does divalent mercury, a significant amount of the vapor enters the brain before it is oxidized. CNS toxicity is thus more prominent after exposure to mercury vapor than to divalent forms of the metal. Inorganic Salts of Mercury The soluble inorganic mercuric salts (Hg2+) gain access to the circulation when taken orally. Gastrointestinal absorption is approximately 10% to 15% of that ingested, and a considerable portion of the Hg2+ may remain bound to the alimentary mucosa and the intestinal contents. Insoluble inorganic mercurous compounds, such as calomel (Hg2Cl2), may undergo some oxidation to soluble compounds that are more readily absorbed. Inorganic mercury has a markedly nonuniform distribution after absorption. The highest concentration of Hg2+ is found in the kidneys, where the metal is retained longer than in other tissues. Concentrations of inorganic mercury are similar in whole blood and plasma. Inorganic mercurials do not readily pass the blood–brain barrier or the placenta. The metal is excreted in the urine and feces with a half-life of about 60 days (Friberg and Vostal, 1972); studies in laboratory animals indicate that fecal excretion is quantitatively more important (Klaassen, 1975). Organic Mercurials Organic mercurials are more completely absorbed from the gastrointestinal tract than are the inorganic salts because they are more lipid soluble and less corrosive to the intestinal mucosa. Their uptake and distribution are depicted in Figure 67–3A. Over 90% of methylmercury is absorbed from the human gastrointestinal tract. The organic mercurials cross the blood–brain barrier and the placenta and thus produce more neurological and teratogenic effects than do the inorganic salts. Methylmercury combines with cysteine to form a structure similar to methionine, and the complex is then accepted by the large neutral amino acid carrier present in capillary endothelial cells (Figure 67–3B; Clarkson, 1987). Organic mercurials are more uniformly distributed to the various tissues than are the inorganic salts (Klaassen, 1975). A significant portion of the body burden of organic mercurials is in the red blood cells. The ratio of the concentration of organomercurial in erythrocytes to that in plasma varies with the compound; for methylmercury, it approximates 20:1 (Kershaw et al., 1980). Mercury concentrates in hair because of its high sulfhydryl content. The carbon–mercury bond of some organic mercurials is cleaved after absorption; with methylmercury the cleavage is quite slow, and the inorganic mercury formed is not thought to play a major role in methylmercury toxicity. Aryl mercurials, like mercurophen, usually contain a labile mercury– carbon bond, and the toxicity of these compounds is similar to that of inorganic mercury. Excretion of methylmercury by human beings is mainly in the feces in the form of a conjugate with glutathione; less than 10% of a dose appears in urine (Bakir et al., 1980). The half-life of methylmercury in the blood of human beings is between 40 and 105 days (Bakir et al., 1973).
  14. Figure 67–3. Uptake and Relative Distribution of Organic Mercurials. A. The intestinal uptake and subsequent distribution of organic mercurials, such as methylmercury, throughout the body. a: conjugation with glutathione (GSH), shown as CH3—Hg—SG; b: secretion of conjugate into bile; c: reabsorption in gallbladder; d: remaining Hg enters intestinal tract. B. Uptake of the methylmercury complex by capillaries. The ability of organic mercurials to cross the blood–brain barrier and the placenta contributes to their greater neurological and teratogenic effects when compared to inorganic mercury salts. Note the structural similarity of the methylmercury complex to methionine, CH3SCH2CH2 —CH(NH3+)COO–. Toxicity Elemental Mercury Short-term exposure to vapor of elemental mercury may produce symptoms within several hours;
  15. these include weakness, chills, metallic taste, nausea, vomiting, diarrhea, dyspnea, cough, and a feeling of tightness in the chest. Pulmonary toxicity may progress to an interstitial pneumonitis with severe compromise of respiratory function. Recovery, although usually complete, may be complicated by residual interstitial fibrosis. Chronic exposure to mercury vapor produces a more insidious form of toxicity that is dominated by neurological effects (Friberg and Vostal, 1972). The syndrome is referred to as the asthenic vegetative syndrome and consists of neurasthenic symptoms in addition to three or more of the following findings (Goyer and Clarkson, 2001): goiter, increased uptake of radioiodine by the thyroid, tachycardia, labile pulse, gingivitis, dermographia, and increased mercury in the urine. With continued exposure to mercury vapor, tremor becomes noticeable, and psychological changes consist of depression, irritability, excessive shyness, insomnia, reduced self-confidence, emotional instability, forgetfulness, confusion, impatience, and vasomotor disturbances (such as excessive perspiration and uncontrolled blushing, which together are referred to as erethism). Common features of intoxication from mercury vapor are severe salivation and gingivitis. The triad of increased excitability, tremors, and gingivitis has been recognized historically as the major manifestation of exposure to mercury vapor when mercury nitrate was used in the fur, felt, and hat industries. Renal dysfunction also has been reported to result from long-term industrial exposure to mercury vapor. The concentrations of mercury vapor in the air and mercury in urine that are associated with the various effects are shown in Figure 67–4. Figure 67–4. The Concentration of Mercury Vapor in the Air and Related Concentrations of Mercury in Urine Associated with a Variety of Toxic Effects. Inorganic Salts of Mercury Inorganic, ionic mercury (e.g., mercuric chloride) can produce severe acute toxicity. Precipitation of mucous membrane proteins by mercuric salts results in an ashen-gray appearance of the mucosa of
  16. the mouth, pharynx, and intestine and also causes intense pain, which may be accompanied by vomiting. The vomiting is perceived to be protective, because it removes unabsorbed mercury from the stomach; assuming the patient is awake and alert, it should not be inhibited. The local, corrosive effect of ionic inorganic mercury on the gastrointestinal mucosa results in severe hematochezia with evidence of mucosal sloughing in the stool. Hypovolemic shock and death may occur in the absence of proper treatment. Prompt corrective treatment can overcome the local effects of inorganic mercury. Systemic toxicity may begin within a few hours after exposure to mercury and last for days. A strong metallic taste is followed by stomatitis with gingival irritation, foul breath, and loosening of the teeth. The most serious and frequently encountered systemic effect of inorganic mercury is renal toxicity. Renal tubular necrosis occurs after short-term exposure, leading to oliguria or anuria. Renal injury also follows long-term exposure to inorganic mercury; however, glomerular injury predominates. This is the result of both direct effects on the glomerular basement membrane and a later indirect effect mediated by immune complexes (Goyer and Clarkson, 2001). The symptom complex of acrodynia (pink disease) also commonly follows chronic exposure to inorganic mercury ions. Acrodynia is an erythema of the extremities, chest, and face with photophobia, diaphoresis, anorexia, tachycardia, and either constipation or diarrhea. Acrodynia was observed in 1980 in Argentina in infants exposed to a phenylmercuric fungicide used by a commercial diaper service (Gotelli et al., 1985). This symptom complex is seen almost exclusively after ingestion of mercury and is believed to be the result of a hypersensitivity reaction to mercury (Matheson et al., 1980). Organic Mercurials Most human toxicological data about organic mercury concern methylmercury and have been collected as the unfortunate result of several large-scale accidental exposures. Symptoms of exposure to methylmercury are mainly neurological in origin and consist of visual disturbance (scotoma and visual-field constriction), ataxia, paresthesias, neurasthenia, hearing loss, dysarthria, mental deterioration, muscle tremor, movement disorders, and, with severe exposure, paralysis and death (Table 67–4). Morphological changes are found in the calcarine area of occipital lobes, pre- and postcentral lobes, and temporal transverse gyri; diffuse lesions are found in the cerebrum; and a decrease in granular cells in the cerebellum (Eto, 1997). Effects of methylmercury on the fetus can occur even when the mother is asymptomatic; mental retardation and neuromuscular deficits have been observed. Diagnosis of Mercury Poisoning A history of exposure to mercury, either industrial or environmental, is obviously valuable in making the diagnosis of mercury poisoning. Without such a history, clinical suspicions can be confirmed by laboratory analysis. The upper limit of a nontoxic concentration of mercury in blood is generally considered to be 3 to 4 g/dl (0.15 to 0.20 M). A concentration of mercury in blood in excess of 4 g/dl (0.20 M) is unexpected in normal, healthy adults and suggests the need for environmental evaluation and medical examination to assess the possibility of adverse health effects. Because methylmercury is concentrated in erythrocytes and inorganic mercury is not, the distribution of total mercury between red blood cells and plasma may indicate whether the patient has been poisoned with inorganic or organic mercury. Measurement of total mercury in red blood cells gives a better estimate of the body burden of methylmercury than it does for inorganic mercury. The relationship between concentrations of mercury in blood and the frequency of
  17. symptoms that result from exposure to methylmercury is shown in Table 67–4; but this is only a rough guide. Concentrations of mercury in plasma provide a better index of the body burden of inorganic mercury; however, the relationship between body burden and the concentration of inorganic mercury in plasma is not well documented. This may relate to the importance of timing of measurement of the blood sample relative to the last exposure to mercury. The relationship between the concentration of inorganic mercury in blood and toxicity also depends on the form of exposure. For example, exposure to vapor results in concentrations in brain about 10 times higher than those that follow an equivalent dose of inorganic mercuric salts. The concentration of mercury in the urine also has been used as a measure of the body burden of the metal. The upper limit for excretion of mercury in urine in the normal population is 5 g/liter. There is a linear relationship between plasma concentration and urinary excretion of mercury after exposure to vapor; in contrast, the excretion of mercury in urine is a poor indicator of the amount of methylmercury in the blood, because it is eliminated mainly in feces (Bakir et al., 1980). Hair is rich in sulfhydryl groups, and the concentration of mercury in hair is about 300 times that in blood. Human hair grows about 20 cm a year, and a history of exposure may be obtained by analysis of different segments of hair. Treatment of Mercury Poisoning Measurement of the concentration of mercury in blood should be performed as soon as possible after poisoning with any form of the metal. Elemental Mercury Vapor Therapeutic measures include immediate termination of exposure and close monitoring of pulmonary status. Short-term respiratory support may be necessary. Chelation therapy, as described below for inorganic mercury, should be initiated immediately and continued as indicated by the clinical condition and the concentrations of mercury in blood and urine. Inorganic Mercury Prompt attention to fluid and electrolyte balance and hematological status is of critical importance in moderate-to-severe oral exposures. Emesis can be induced if the patient is awake and alert, although emesis should not be induced where there is corrosive injury. If ingestion of mercury is more than 30 to 60 minutes before treatment, emesis may have little efficacy. With corrosive agents, endoscopic evaluation may be warranted, and coagulation parameters are important. Activated charcoal is recommended by some, although there is a lack of proven efficacy of this treatment. Administration of charcoal may make endoscopy difficult or impossible. Chelation Therapy Chelation therapy with dimercaprol (for high-level exposures or symptomatic patients) or penicillamine (for low-level exposures or asymptomatic patients) is routinely used to treat poisoning with either inorganic or elemental mercury. Recommended treatment includes dimercaprol, 5 mg/kg intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12 to 24 hours for 10 days. Penicillamine (250 mg orally every 6 hours) may be used alone or following treatment with dimercaprol. The duration of chelation therapy will vary, and progress can be monitored by following concentrations of mercury in urine and blood. The new, orally effective
  18. chelator succimer appears to be an effective chelator for mercury (Campbell et al., 1986; Fournier et al., 1988; Bluhm et al., 1992), although it has not been approved by the United States Food and Drug Administration (FDA) for this purpose. The dimercaprol–mercury chelate is excreted into both bile and urine, whereas the penicillamine– mercury chelate is excreted only into urine. Thus, penicillamine should be used with extreme caution when renal function is impaired. In fact, hemodialysis may be necessary in the poisoned patient whose renal function declines. Chelators may still be used, because the dimercaprol– mercury complex is removed by dialysis (Giunta et al., 1983). Organic Mercury The short-chain organic mercurials, especially methylmercury, are the most difficult forms of mercury to mobilize from the body, presumably due to their poor reactivity with chelating agents. Dimercaprol is contraindicated in methylmercury poisoning because it increases brain concentrations of methylmercury in experimental animals. Although penicillamine facilitates the removal of methylmercury from the body, its clinical efficacy in the treatment of intoxication with methylmercury is not impressive (Bakir et al., 1980). The dose of penicillamine normally used in the treatment of poisoning with inorganic mercury (1 g per day) produces only a small reduction in the concentration of methylmercury in blood; larger doses (2 g per day) are needed. During the initial 1 to 3 days of administration of penicillamine, the concentration of mercury in the blood increases before it decreases. This probably is due to the mobilization of metal from tissues to blood at a rate more rapid than that for excretion of mercury into urine and feces. Methylmercury compounds undergo extensive enterohepatic recirculation in experimental animals. Therefore, introduction of a nonabsorbable mercury-binding substance into the intestinal tract should facilitate their removal from the body. A polythiol resin has been used for this purpose in human beings and appears to be effective (Bakir et al., 1973). The resin has certain advantages over penicillamine. It does not cause redistribution of mercury in the body with a subsequent increase in the concentration of mercury in blood, and it has fewer adverse effects than do sulfhydryl agents that are absorbed. Clinical experience with various treatments for methylmercury poisoning in Iraq indicates that penicillamine, N-acetylpenicillamine, and an oral nonabsorbable thiol resin all can reduce blood concentrations of mercury; however, clinical improvement was not clearly related to reduction of the body burden of methylmercury (Bakir et al., 1980). Conventional hemodialysis is of little value in the treatment of methylmercury poisoning because methylmercury concentrates in erythrocytes and little is contained in the plasma. However, it has been shown that L-cysteine can be infused into the arterial blood entering the dialyzer to convert methylmercury into a diffusible form. Both free cysteine and the methylmercury–cysteine complex formed in the blood then diffuse across the membrane into the dialysate. This method has been shown to be effective in human beings (Al-Abbasi et al., 1978). Studies in animals indicate that succimer may be more effective than cysteine in this regard (Kostyniak, 1982). Arsenic Arsenic was used more than 2400 years ago in Greece and Rome as a therapeutic agent and as a poison. The history and folklore of arsenic prompted intensive studies by early pharmacologists. Indeed, the foundations of many modern concepts of chemotherapy derive from Ehrlich's early work with organic arsenicals, and such drugs were once a mainstay of chemotherapy. In current therapeutics, arsenicals are important only in the treatment of certain tropical diseases, such as
  19. African trypanosomiasis (see Chapter 41: Drugs Used in the Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections). In the United States, the impact of arsenic on health is predominantly from industrial and environmental exposures. (For reviews, see Winship, 1984; Hindmarsh and McCurdy, 1986; NRC, 1999.) Arsenic is found in soil, water, and air as a common environmental toxicant. Well water in sections of Argentina, Chile, and Taiwan has especially high concentrations of arsenic, which results in widespread poisoning. Large numbers of people in West Bengal, India, also are being exposed to high concentrations of arsenic in their well water used for drinking. It also is in high concentrations in the water in many parts of the western United States. The element usually is not mined as such but is recovered as a by-product from the smelting of copper, lead, zinc, and other ores. This can result in the release of arsenic into the environment. Mineral-spring waters and the effluent from geothermal power plants leach arsenic from soils and rocks containing high concentrations of the metal. Arsenic also is present in coal at variable concentrations and is released into the environment during combustion. Application of pesticides and herbicides containing arsenic has increased its environmental dispersion. The major source of occupational exposure to arsenic-containing compounds is from the manufacture of arsenical herbicides and pesticides (Landrigan, 1981). Fruits and vegetables sprayed with arsenicals may be a source of this element, and it is concentrated in many species of fish and shellfish. Arsenicals sometimes are added to the feed of poultry and other livestock to promote growth. The average daily human intake of arsenic is about 10 g. Almost all of this is ingested with food and water. Arsenic is used as arsine and as arsenic trioxide in the manufacture of most computer chips using silicon-based technology. Gallium arsenide is used in the production of compound (types III–V) semiconductors that are used for making LEDs as well as laser and solar devices. In the manufacture of both computer chips and semiconductors, metallic arsenic also may be used or produced as a by-product of the reaction chambers. Chemical Forms of Arsenic The arsenic atom exists in the elemental form and in trivalent and pentavalent oxidation states. The toxicity of a given arsenical is related to the rate of its clearance from the body and therefore to its degree of accumulation in tissues. In general, toxicity increases in the sequence of organic arsenicals < As5+ < As3+ < arsine (AsH3). The organic arsenicals contain arsenic linked to a carbon atom by a covalent bond, where arsenic exists in the trivalent or pentavalent state. Arsphenamine contains trivalent arsenic; sodium arsanilate contains arsenic in the pentavalent form.
  20. The organic arsenicals usually are excreted more rapidly than are the inorganic forms. The pentavalent oxidation state is found in arsenates (such as lead arsenate, PbHAsO4), which are salts of arsenic acid, H3AsO4. The pentavalent arsenicals have very low affinity for thiol groups, in contrast to the trivalent compounds, and are much less toxic. The arsenites [for example, potassium arsenite (KAsO2)] and salts of arsenious acid contain trivalent arsenic. Arsine (AsH 3) is a gaseous hydride of trivalent arsenic; it produces toxic effects that are distinct from those of the other arsenic compounds. Mechanism of Action Arsenate (pentavalent) is a well-known uncoupler of mitochondrial oxidative phosphorylation. The mechanism is thought to be related to competitive substitution of arsenate for inorganic phosphate in the formation of adenosine triphosphate, with subsequent formation of an unstable arsenate ester that is rapidly hydrolyzed. This process is termed arsenolysis. Trivalent arsenicals, including inorganic arsenite, are regarded primarily as sulfhydryl reagents. As such, trivalent arsenicals inhibit many enzymes by reacting with biological ligands containing available —SH groups. The pyruvate dehydrogenase system is especially sensitive to trivalent arsenicals because of their interaction with two sulfhydryl groups of lipoic acid to form a stable six- membered ring, as shown below. Absorption, Distribution, and Excretion The absorption of poorly water-soluble arsenicals, such as As2O3, greatly depends on the physical state of the compound. Coarsely powdered material is less toxic because it can be eliminated in feces before it dissolves. The arsenite salts are more soluble in water and are better absorbed than the oxide. Experimental evidence has shown a high degree of gastrointestinal absorption, 80% to
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