Basic & Clinical Pharmacology, 10th Edition

58. Heavy Metal Intoxication & Chelators - Michael J. Kosnett, MD, MPH

INTRODUCTION

Some metals such as iron are essential for life, while others such as lead are present in all organisms but serve no useful biologic purpose. Some of the oldest diseases of humans can be traced to heavy metal poisoning associated with metal mining, refining, and use. Even with the present recognition of the hazards of heavy metals, the incidence of intoxication remains significant and the need for preventive strategies and effective therapy remains high. When intoxication occurs, chelator molecules (from chela "claw"), or their in vivo biotransformation products, may be used to bind the metal and facilitate its excretion from the body. Chelator drugs are discussed in the second part of this chapter.

TOXICOLOGY OF HEAVY METALS

LEAD

Introduction

Lead poisoning is one of the oldest occupational and environmental diseases in the world. Despite its recognized hazards, lead continues to have widespread commercial application, including production of storage batteries, metal alloys, solder, glass, plastics and ceramics. Environmental lead exposure, ubiquitous by virtue of the anthropogenic distribution of lead to air, water, and food, has declined considerably in the past 3 decades as a result of diminished use of lead in gasoline and other applications. While these public health measures, together with improved workplace conditions, have decreased the incidence of serious overt lead poisoning, there remains considerable concern over the effects of low-level lead exposure. Extensive evidence indicates that lead may have subtle subclinical adverse effects on neurocognitive function and on blood pressure at blood lead concentrations once considered "normal" or "safe." Lead serves no useful purpose in the human body. In key target organs such as the developing central nervous system, no safe threshold of lead exposure has been established.

Pharmacokinetics

Inorganic lead is slowly but consistently absorbed via the respiratory and gastrointestinal tracts. Inorganic lead is poorly absorbed through the skin, but organic lead compounds, eg, leaded antiknock gasoline, are well absorbed by this route. Absorption of lead dust via the respiratory tract is the most common cause of industrial poisoning. The intestinal tract is the primary route of entry in nonindustrial exposure (Table 58-1). Absorption via the gastrointestinal tract varies with the nature of the lead compound, but in general, adults absorb about 10-15% of the ingested amount while young children absorb up to 50%. Low dietary calcium, iron deficiency, and ingestion on an empty stomach have all been associated with increased lead absorption.

Once absorbed from the respiratory or gastrointestinal tract, lead is bound to erythrocytes and widely distributed initially to soft tissues such as the bone marrow, brain, kidney, liver, muscle, and gonads; then to the subperiosteal surface of bone; and later to bone matrix. Lead also crosses the placenta and poses a potential hazard to the fetus. The kinetics of lead clearance from the body follows a multicompartment model, composed predominantly of the blood and soft tissues, with a half-life of 1-2 months; and the skeleton, with a half-life of years to decades. Approximately 70% of the lead that is eliminated appears in the urine, with lesser amounts excreted through the bile, skin, hair, nails, sweat, and breast milk. The fraction not undergoing prompt excretion, approximately half of the absorbed lead, may be incorporated into the skeleton, the repository of more than 90% of the body lead burden in most adults. In patients with high bone lead burdens, slow release from the skeleton may elevate blood lead concentrations for years after exposure ceases; and pathologic high bone turnover states such as hyperthyroidism or prolonged immobilization may result in frank lead intoxication. The lead burden in bone has been quantitated using noninvasive x-ray fluorescence, a technique that may provide the best measure of long-term, cumulative lead absorption.

Pharmacodynamics

Lead exerts multisystemic toxic effects that are mediated by multiple modes of action, including inhibition of enzymatic function; interference with the action of essential cations, particularly calcium, iron, and zinc; disturbance of cellular redox status; and alteration of the structure of cell membranes and receptors.

A. NERVOUS SYSTEM
The developing central nervous system of the fetus and young child is the most sensitive target organ for lead's toxic effect. Epidemiologic studies suggest that blood lead concentrations less than 5 mcg/dL may result in subclinical deficits in neurocognitive function in lead-exposed young children, with no demonstrable threshold for a "no effect" level. Hearing acuity may also be diminished. Adults are less sensitive to the central nervous system effects of lead, but at blood lead concentrations in excess of 30 mcg/dL, behavioral and neurocognitive effects may gradually emerge, producing signs and symptoms such as irritability, fatigue, decreased libido, anorexia, sleep disturbance, impaired visual-motor coordination, and slowed reaction time. Headache, arthralgias, and myalgias are also frequent complaints. Tremor occurs but is less common. Lead encephalopathy, usually occurring at blood lead concentrations in excess of 100 mcg/dL, is typically accompanied by increased intracranial pressure and may produce ataxia, stupor, coma, convulsions, and death. Recent studies suggest that lead may accentuate an age-related decline in cognitive function in older adults. There is wide interindividual variation in the magnitude of lead exposure required to cause overt lead-related signs and symptoms.

Peripheral neuropathy may appear after chronic high-dose lead exposure, usually following months to years of blood lead concentrations in excess of 100 mcg/dL. Predominantly motor in character, the neuropathy may present clinically with painless weakness of the extensors, particularly in the upper extremity, resulting in classic wrist-drop. Preclinical signs of lead-induced peripheral nerve dysfunction may be detectable by electrodiagnostic testing.

B. BLOOD
Lead can induce an anemia that may be either normocytic or microcytic and hypochromic. Lead interferes with heme synthesis by blocking the incorporation of iron into protoporphyrin IX and by inhibiting the function of enzymes in the heme synthesis pathway, including aminolevulinic acid dehydratase and ferrochelatase. Within 2-8 weeks after an elevation in blood lead concentration (generally to 30-50 mcg/dL or greater), increases in heme precursors, notably free erythrocyte protoporphyrin or its zinc chelate, zinc protoporphyrin, may be detectable in whole blood. Lead also contributes to anemia by increasing erythrocyte membrane fragility and decreasing red cell survival time. Frank hemolysis may occur with high exposure. The presence of basophilic stippling on the peripheral blood smear, thought to be a consequence of lead inhibition of the enzyme 3¢,5¢-pyrimidine nucleotidase, is sometimes a suggestive¾albeit insensitive and nonspecific¾diagnostic clue to the presence of lead intoxication.

C. KIDNEYS
Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations in excess of 80 mcg/dL, may result in renal interstitial fibrosis and nephrosclerosis. Lead nephropathy may have a latency period of years. Lead may alter uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis ("saturnine gout"). Acute high-dose lead exposure sometimes produces transient azotemia, possibly as a consequence of intrarenal vasoconstriction.

D. REPRODUCTIVE ORGANS
High-dose lead exposure is a recognized risk factor for stillbirth or spontaneous abortion. Epidemiologic studies of the impact of low-level lead exposure on reproductive outcome such as low birth weight, preterm delivery, or spontaneous abortion have yielded mixed results. However, a well-designed nested case-control study recently detected an odds ratio for spontaneous abortion of 1.8 (95% CI 1.1-3.1) for every 5 mcg/dL increase in maternal blood lead across an approximate range of 5-20 mcg/dL. In males, blood lead concentrations in excess of 40 mcg/dL have been associated with diminished or aberrant sperm production.

E. GASTROINTESTINAL TRACT
Moderate lead poisoning may cause loss of appetite, constipation, and, less commonly, diarrhea. At high dosage, intermittent bouts of severe colicky abdominal pain ("lead colic") may occur. The mechanism of lead colic is unclear but is believed to involve spasmodic contraction of the smooth muscles of the intestinal wall. In heavily exposed individuals with poor dental hygiene, the reaction of circulating lead with sulfur ions released by microbial action may produce dark deposits of lead sulfide at the gingival margin ("gingival lead lines"). Although frequently mentioned as a diagnostic clue in the past, in recent times this has been a relatively rare sign of lead exposure.

F. CARDIOVASCULAR SYSTEM
Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in susceptible individuals. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure. Studies of middle-aged and elderly men and women have identified relatively low levels of lead exposure sustained by the general population to be an independent risk factor for hypertension. Lead can also elevate blood pressure in experimental animals. The effect may be caused by an interaction with calcium-mediated contraction of vascular smooth muscle.

Major Forms of Lead Intoxication

A. INORGANIC LEAD POISONING (TABLE 58-1)

1. Acute¾ Acute inorganic lead poisoning is uncommon today. It usually results from industrial inhalation of large quantities of lead oxide fumes or, in small children, from ingestion of a large oral dose of lead in lead-based paints or contaminated food or drink. The onset of severe symptoms usually requires several days or weeks of recurrent exposure and presents with signs and symptoms of encephalopathy or colic. Evidence of hemolytic anemia (or anemia with basophilic stippling if exposure has been subacute) and elevated hepatic aminotransferases may be present. The diagnosis of acute inorganic lead poisoning may be difficult, and depending on the presenting symptoms, the condition has sometimes been mistaken for appendicitis, peptic ulcer, pancreatitis, or infectious meningitis. Subacute presentation, featuring headache, fatigue, intermittent abdominal cramps, myalgias, and arthralgias, has often been mistaken for a flu-like viral illness and may not come to medical attention. When there has been recent ingestion of lead-containing paint chips, glazes, or weights, radiopacities may be visible on abdominal radiographs.

2. Chronic¾ The patient with chronic lead intoxication usually presents with multisystemic findings, including constitutional complaints of anorexia, fatigue, and malaise; neurologic complaints, including headache, difficulty in concentrating, irritability or depressed mood; weakness, arthralgias or myalgias; and gastrointestinal symptoms. Lead poisoning should be strongly suspected in any patient presenting with headache, abdominal pain, and anemia; and less commonly with motor neuropathy, gout, and renal insufficiency. Chronic lead intoxication should be considered in any child with neurocognitive deficits, growth retardation, or developmental delay.

The diagnosis is best confirmed by measuring lead in whole blood. Although this test reflects lead currently circulating in blood and soft tissues and is not a reliable marker of either recent or cumulative lead exposure, most patients with lead-related disease will have blood lead concentrations above the normal range. Average background blood lead concentrations in North America and Europe have declined considerably in recent decades, and the geometric mean blood lead concentration in the United States in 2001-2002 was estimated to be 1.45 mcg/dL. Although predominantly a research tool, the concentration of lead in bone assessed by noninvasive K x-ray fluorescence measurement of lead in bone has been correlated with long-term cumulative lead exposure, and its relationship to numerous lead-related disorders is a subject of ongoing investigation. Measurement of lead excretion in the urine following a single dose of a chelating agent (sometimes called a "chelation challenge test") primarily reflects the lead content of soft tissues and may not be a reliable marker of long-term lead exposure, remote past exposure, or skeletal lead burden.

B. ORGANOLEAD POISONING
Poisoning from organolead compounds is now very rare, in large part due to the worldwide phase-out of tetraethyl and tetramethyl lead as antiknock additives in gasoline. However, organolead compounds such as lead stearate or lead naphthenate are still used in certain commercial processes. Because of their volatility or lipid solubility, organolead compounds tend to be well absorbed through either the respiratory tract or the skin. Organolead compounds predominantly target the central nervous system, producing dose-dependent effects that may include neurocognitive deficits, insomnia, delirium, hallucinations, tremor, convulsions, and death.

Treatment

A. INORGANIC LEAD POISONING
Treatment of inorganic lead poisoning involves immediate termination of exposure, supportive care, and the judicious use of chelation therapy. (Chelation is discussed later in this chapter.) Lead encephalopathy is a medical emergency that requires intensive supportive care. Cerebral edema may improve with corticosteroids and mannitol, and anticonvulsants may be required to treat seizures. Radiopacities on abdominal radiographs may suggest the presence of retained lead objects requiring gastrointestinal decontamination. Adequate urine flow should be maintained, but overhydration should be avoided. Intravenous edetate calcium disodium (CaNa₂EDTA) is administered at a dosage of 1000-1500 mg/m²/d (approximately 30-50 mg/kg/d) by continuous infusion for up to 5 days. Some clinicians advocate that chelation treatment for lead encephalopathy be initiated with an intramuscular injection of dimercaprol, followed in 4 hours by concurrent administration of dimercaprol and EDTA. Parenteral chelation is limited to 5 or fewer days, at which time oral treatment with another chelator, succimer, may be instituted. In symptomatic lead intoxication without encephalopathy, treatment may sometimes be initiated with succimer. The end point for chelation is usually resolution of symptoms or return of the blood lead concentration to the premorbid range. In patients with chronic exposure, cessation of chelation may be followed by an upward rebound in blood lead concentration as the lead reequilibrates from bone lead stores.

While most clinicians support chelation for symptomatic patients with elevated blood lead concentrations, the decision to chelate asymptomatic subjects is more controversial. Since 1991, the Centers for Disease Control and Prevention have recommended chelation for all children with blood lead concentrations of 45 mcg/dL or greater. However, a recent randomized, double-blind, placebo-controlled clinical trial of succimer in children with blood lead concentrations between 25 mcg/dL and 44 mcg/dL found no benefit on neurocognitive function or long-term blood lead reduction. Prophylactic use of chelating agents in the workplace should never be a substitute for reduction or prevention of excessive exposure.

B. ORGANIC LEAD POISONING
Initial treatment consists of decontaminating the skin and preventing further exposure. Treatment of seizures requires appropriate use of anticonvulsants. Empiric chelation may be attempted if high blood lead concentrations are present.

ARSENIC

Introduction

Arsenic is a naturally occurring element in the earth's crust with a long history of use as a constituent of commercial and industrial products, as a component in pharmaceuticals, and as an agent of deliberate poisoning. Recent commercial applications of arsenic include its use in the manufacture of semiconductors, wood preservatives for industrial applications (eg, marine timbers or utility poles), nonferrous alloys, glass, gel-based insecticidal ant baits, and veterinary pharmaceuticals. In some regions of the world, groundwater may contain high levels of arsenic that has leached from natural mineral deposits. Arsenic in drinking water in the Ganges delta of India and Bangladesh is now recognized as one of the world's most pressing environmental health problems. Arsine, a hydride gas with potent hemolytic effects, is manufactured predominantly for use in the semiconductor industry but may also be generated accidentally when arsenic-containing ores come in contact with acidic solutions.

It is of historical interest that Fowler's solution, which contains 1% potassium arsenite, was widely used as a medicine for many conditions from the eighteenth century through the mid-twentieth century. Organic arsenicals were the first pharmaceutical antibiotics* and were widely used for the first half of the twentieth century until supplanted by penicillin and other more effective and less toxic agents.

Other organoarsenicals, most notably lewisite (dichloro[2-chlorovinyl]arsine), were developed in the early twentieth century as chemical warfare agents. Arsenic trioxide was reintroduced into the United States Pharmacopeia in 2000 as an orphan drug for the treatment of relapsed acute promyelocytic leukemia and is finding expanded use in experimental cancer treatment protocols (see Chapter 55). Melarsoprol, another trivalent arsenical, is used in the treatment of advanced African trypanosomiasis (see Chapter 53).

*Paul Ehrlich's "magic bullet" for syphilis (arsphenamine; Salvarsan) was an arsenical.

Pharmacokinetics

Soluble arsenic compounds are well absorbed through the respiratory and gastrointestinal tracts (Table 58-1). Percutaneous absorption is limited but may be clinically significant after heavy exposure to concentrated arsenic reagents. Most of the absorbed inorganic arsenic undergoes methylation, mainly in the liver, to monomethylarsonic acid and dimethylarsinic acid, which are excreted, along with residual inorganic arsenic, in the urine. When chronic daily absorption is less than 1000 mcg of soluble inorganic arsenic, approximately two thirds of the absorbed dose is excreted in the urine. After massive ingestions, the elimination half-life is prolonged. Inhalation of arsenic compounds of low solubility may result in prolonged retention in the lung and may not be reflected by urinary arsenic excretion. Arsenic binds to sulfhydryl groups present in keratinized tissue, and following cessation of exposure, hair, nails, and skin may contain elevated levels after urine values have returned to normal. However, arsenic present in hair and nails as a result of external deposition may be indistinguishable from that incorporated after internal absorption.

Pharmacodynamics

Arsenic compounds are thought to exert their toxic effects by several modes of action. Interference with enzymatic function may result from sulfhydryl group binding by trivalent arsenic or by substitution for phosphate. Inorganic arsenic or its metabolites may induce oxidative stress, alter gene expression, and interfere with cell signal transduction. Although on a molar basis inorganic trivalent arsenic (As³⁺, arsenite) is generally two to ten times more acutely toxic than inorganic pentavalent arsenic (As⁵⁺, arsenate), in vivo interconversion is known to occur, and the full spectrum of arsenic toxicity has occurred after sufficient exposure to either form. Recent studies suggest that the trivalent form of the methylated metabolites (eg, monomethylarsonous acid [MMA^III]) may be more toxic than the inorganic parent compounds. Arsine gas is oxidized in vivo and exerts a potent hemolytic effect associated with alteration of ion flux across the erythrocyte membrane; however, it also disrupts cellular respiration in other tissues. Arsenic is a recognized human carcinogen and has been associated with cancer of the lung, skin, and bladder. Marine organisms may contain large amounts of a well-absorbed trimethylated organoarsenic, arsenobetaine, as well as a variety of arsenosugars. Arsenobetaine exerts no known toxic effects when ingested by mammals and is excreted in the urine unchanged; arsenosugars are partially metabolized to dimethylarsinic acid.

Major Forms of Arsenic Intoxication

A. ACUTE INORGANIC ARSENIC POISONING
Within minutes to hours after exposure to high doses (tens to hundreds of milligrams) of soluble inorganic arsenic compounds, many systems are affected. Initial gastrointestinal signs and symptoms include nausea, vomiting, diarrhea, and abdominal pain. Diffuse capillary leak, combined with gastrointestinal fluid loss, may result in hypotension, shock, and death. Cardiopulmonary toxicity, including congestive cardiomyopathy, cardiogenic or noncardiogenic pulmonary edema, and ventricular arrhythmias, may occur promptly or after a delay of several days. Pancytopenia usually develops within a week, and basophilic stippling of erythrocytes may be present soon after. Central nervous system effects, including delirium, encephalopathy, and coma, may occur within the first few days of intoxication. An ascending sensorimotor peripheral neuropathy may begin to develop after a delay of 2-6 weeks. This neuropathy may ultimately involve the proximal musculature and result in neuromuscular respiratory failure. Months after an episode of acute poisoning, transverse white striae (Aldrich-Mees lines) may be visible in the nails.

Acute inorganic arsenic poisoning should be considered in an individual presenting with abrupt onset of gastroenteritis in combination with hypotension and metabolic acidosis. Suspicion should be further heightened when these initial findings are followed by cardiac dysfunction, pancytopenia, and peripheral neuropathy. The diagnosis may be confirmed by demonstration of elevated amounts of inorganic arsenic and its metabolites in the urine (typically in the range of several thousand micrograms in the first 2-3 days following acute symptomatic poisoning). Arsenic disappears rapidly from the blood, and except in anuric patients, blood arsenic levels should not be used for diagnostic purposes. Treatment is based on appropriate gut decontamination, intensive supportive care, and prompt chelation with unithiol, 3-5 mg/kg intravenously every 4-6 hours, or dimercaprol, 3-5 mg/kg intramuscularly every 4-6 hours. In animal studies, the efficacy of chelation has been highest when it is administered within minutes to hours after arsenic exposure; therefore, if diagnostic suspicion is high, treatment should not be withheld for the several days to weeks often required to obtain laboratory confirmation. Succimer has also been effective in animal models and has a higher therapeutic index than dimercaprol. However, because it is available in the United States only for oral administration, its use may not be advisable in the initial treatment of acute arsenic poisoning, when severe gastroenteritis and splanchnic edema may limit absorption by this route.

B. CHRONIC INORGANIC ARSENIC POISONING
Chronic inorganic arsenic poisoning also results in multisystemic signs and symptoms. Overt noncarcinogenic effects may be evident after chronic absorption of more than 500-1000 mcg/d. The time to appearance of symptoms will vary with dose and interindividual tolerance. Constitutional symptoms of fatigue, weight loss, and weakness may be present, along with anemia, nonspecific gastrointestinal complaints, and a sensorimotor peripheral neuropathy, particularly featuring a stocking-glove pattern of dysesthesia. Skin changes¾among the most characteristic effects¾typically develop after years of exposure and include a "raindrop" pattern of hyperpigmentation, and hyperkeratoses involving the palms and soles. Peripheral vascular disease and noncirrhotic portal hypertension may also occur. Epidemiologic studies suggest a possible link to hypertension, diabetes, and chronic nonmalignant respiratory disease. Cancer of the lung, skin, bladder, and possibly other sites, may appear years after exposure to doses of arsenic that are not high enough to elicit other acute or chronic effects. Administration of arsenite in cancer chemotherapy regimens, often at a daily dose of 10-20 mg for weeks to a few months, has been associated with prolongation of the QT interval on the electrocardiogram and occasionally has resulted in malignant ventricular arrhythmias such as torsade de pointes.

The diagnosis of chronic arsenic poisoning involves integration of the clinical findings with confirmation of exposure. Urinary levels of total arsenic, usually less than 30 mcg/L or 50 mcg/24 h in the general population, may return to normal within days to weeks after exposure ceases. Because it may contain large amounts of nontoxic organoarsenic, all seafood should be avoided for at least 3 days prior to submission of a urine sample for diagnostic purposes. The arsenic content of hair and nails (normally less than 1 ppm) may sometimes reveal past elevated exposure, but results should be interpreted cautiously in view of the potential for external contamination.

C. ARSINE GAS POISONING
Arsine gas poisoning produces a distinctive pattern of intoxication dominated by profound hemolytic effects. After a latent period that may range from 2 hours to 24 hours postinhalation (depending on the magnitude of exposure), massive intravascular hemolysis may occur. Initial symptoms may include malaise, headache, dyspnea, weakness, nausea, vomiting, abdominal pain, jaundice, and hemoglobinuria. Oliguric renal failure, a consequence of hemoglobin deposition in the renal tubules, often appears within 1-3 days. In massive exposures, lethal effects on cellular respiration may occur before renal failure develops. Urinary arsenic levels are elevated but will seldom be available to confirm the diagnosis during the critical period of illness. Intensive supportive care¾including exchange transfusion, vigorous hydration, and, in the case of acute renal failure, hemodialysis¾is the mainstay of therapy. Currently available chelating agents have not been demonstrated to be of clinical value in arsine poisoning.

MERCURY

Introduction

Metallic mercury as "quicksilver"¾the only metal that is liquid under ordinary conditions¾has attracted scholarly and scientific interest from antiquity. In early times it was recognized that the mining of mercury was hazardous to health. As industrial use of mercury became common during the past 200 years, new forms of toxicity were recognized that were found to be associated with various transformations of the metal. In the early 1950s, a mysterious epidemic of birth defects and neurologic disease occurred in the Japanese fishing village of Minamata. The causative agent was determined to be methylmercury in contaminated seafood, traced to industrial discharges into the bay from a nearby factory. In addition to elemental mercury and alkylmercury (including methylmercury), other key mercurials include inorganic mercury salts and aryl mercury compounds, each of which exerts a relatively unique pattern of clinical toxicity.

Mercury is mined predominantly as HgS in cinnabar ore and is then converted commercially to a variety of chemical forms. Key industrial and commercial applications of mercury are found in the electrolytic production of chlorine and caustic soda; the manufacture of electrical equipment, thermometers, and other instruments; fluorescent lamps; dental amalgam; and artisanal gold production. Use in pharmaceuticals and in biocides has declined substantially in recent years, but occasional use in antiseptics and folk medicines is still encountered. Environmental exposure to mercury from the burning of fossil fuels¾or the bioaccumulation of methylmercury in fish¾remains a concern in some regions of the world. Low-level exposure to mercury released from dental amalgam fillings occurs, but systemic toxicity from this source has not been established.

Pharmacokinetics

The absorption of mercury varies considerably depending on the chemical form of the metal. Elemental mercury is quite volatile and can be absorbed from the lungs (Table 58-1). It is poorly absorbed from the intact gastrointestinal tract. Inhaled mercury is the primary source of occupational exposure. Organic short-chain alkylmercury compounds are volatile and potentially harmful by inhalation as well as by ingestion. Percutaneous absorption of metallic mercury and inorganic mercury can be of clinical concern following massive acute or long-term chronic exposure. Alkylmercury compounds appear to be well absorbed through the skin, and acute contact with a few drops of dimethylmercury has resulted in severe, delayed toxicity. After absorption, mercury is distributed to the tissues within a few hours, with the highest concentration occurring in the kidney. Inorganic mercury is excreted through the urine and the feces. Excretion of inorganic mercury follows a multicomponent model: most is excreted within weeks to months, but a fraction may be retained in the kidneys and brain for years. Following inhalation of elemental mercury vapor, urinary mercury levels decline with a half-life of approximately 1-3 months. Methylmercury, which has a blood and whole body half-life of approximately 50 days, undergoes biliary excretion and enterohepatic circulation, with more than two thirds eventually excreted in the feces. Mercury binds to sulfhydryl groups in keratinized tissue, and, as with lead and arsenic, traces appear in the hair and nails.

Major Forms of Mercury Intoxication

Mercury interacts with sulfhydryl groups in vivo, inhibiting enzymes and altering cell membranes. The pattern of clinical intoxication from mercury depends to a great extent on the chemical form of the metal and the route and severity of exposure.

A. ACUTE
Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (see below) may also ensue. Acute ingestion of inorganic mercury salts, such as mercuric chloride, can result in a corrosive, potentially life-threatening hemorrhagic gastroenteritis followed within hours to days by acute tubular necrosis and oliguric renal failure.

B. CHRONIC
Chronic poisoning from inhalation of mercury vapor results in a classic triad of tremor, neuropsychiatric disturbance, and gingivostomatitis. The tremor usually begins as a fine intention tremor of the hands, but the face may also be involved, and progression to choreiform movements of the limbs may occur. Neuropsychiatric manifestations, including memory loss, fatigue, insomnia, and anorexia, are common. There may be an insidious change in mood to shyness, withdrawal, and depression along with explosive anger or blushing (a behavioral pattern referred to as erethism). Recent studies suggest that low-dose exposure may produce subclinical neurologic effects. Gingivostomatitis, sometimes accompanied by loosening of the teeth, may be reported after high-dose exposure. Evidence of peripheral nerve damage may be detected on electrodiagnostic testing, but overt peripheral neuropathy is rare. Acrodynia is an uncommon idiosyncratic reaction to subacute or chronic mercury exposure and occurs mainly in children. It is characterized by painful erythema of the extremities and may be associated with hypertension, diaphoresis, anorexia, insomnia, irritability or apathy, and a miliarial rash.

Methylmercury intoxication affects mainly the central nervous system and results in paresthesias, ataxia, hearing impairment, dysarthria, and progressive constriction of the visual fields. Signs and symptoms may first appear several weeks or months after exposure begins. Methylmercury is a reproductive toxin. High-dose prenatal exposure to methylmercury may produce mental retardation and a cerebral palsy-like syndrome in the offspring. Low-level prenatal exposures have been associated with a risk of subclinical neurodevelopmental deficits. Dimethylmercury is a rarely encountered but extremely neurotoxic form of organomercury that may be lethal in small quantities.

The diagnosis of mercury intoxication involves integration of the history and physical findings with confirmatory laboratory testing or other evidence of exposure. In the absence of occupational exposure, the urine mercury concentration is usually less than 5 mcg/L, and whole blood mercury is less than 5 mcg/L. In 1990, the Biological Exposure Index (BEI) Committee of the American Conference of Governmental Industrial Hygienists (ACGIH) recommended that workplace exposures should result in urinary mercury concentrations less than 35 mcg per gram of creatinine and end-of-workweek whole blood mercury concentrations less than 15 mcg/L. To minimize the risk of developmental neurotoxicity from methylmercury, the US Environmental Protection Agency and Food and Drug Administration have advised pregnant women, women who might become pregnant, nursing mothers, and young children to avoid consumption of fish with high mercury levels (eg, swordfish), and to limit consumption of fish with lower levels of mercury to no more than 12 ounces (340 g, or two average meals) per week.

Treatment

A. ACUTE EXPOSURE
In addition to intensive supportive care, prompt chelation with oral or intravenous unithiol, intramuscular dimercaprol, or oral succimer may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. Vigorous hydration may help to maintain urine output, but if acute renal failure ensues, days to weeks of hemodialysis or hemodiafiltration in conjunction with chelation may be necessary. Because the efficacy of chelation declines with time since exposure, treatment should not be delayed until the onset of oliguria or other major systemic effects.

B. CHRONIC EXPOSURE
Unithiol and succimer increase urine mercury excretion following acute or chronic elemental mercury inhalation, but the impact of such treatment on clinical outcome is unknown. Dimercaprol has been shown to redistribute mercury to the central nervous system from other tissue sites, and since the brain is a key target organ, dimercaprol should not be used in treatment of exposure to elemental or organic mercury. Limited data suggest that succimer, unithiol, and N-acetyl-L-cysteine (NAC) may enhance body clearance of methylmercury.

PHARMACOLOGY OF CHELATORS

INTRODUCTION

Chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to accelerate the elimination of the metal from the body. Chelating agents are usually flexible molecules with two or more electronegative groups that form stable coordinate-covalent bonds with a cationic metal atom. In some cases, eg, succimer, the parent compound may require in vivo biotransformation to become an active complexing agent. The chelatormetal complexes formed are excreted by the body. Edetate (ethylenediaminetetraacetate, Figure 58-1) is an important example.

The efficiency of the chelator is partly determined by the number of ligand groups on the molecule available for metal binding. The greater the number of these ligand groups, the more stable the metal-chelator complex. Depending on the number of metal-ligand bonds, the complex may be referred to as mono-, bi-, or polydentate. The chelating ligand groups include functional groups such as -OH, -SH, and -NH, which can donate electrons for coordination with the metal. Such bonding effectively prevents interaction of the metal with similar functional groups of enzymes or other proteins, coenzymes, cellular nucleophiles, and membranes.

In addition to removing the target metal that is exerting toxic effects on the body, some chelating agents (such as calcium EDTA used for lead intoxication) may enhance the excretion of essential cations such as zinc or copper. However, this side effect is seldom of clinical significance during the limited time frame that characterizes most courses of therapeutic chelation.

In some cases, the metal-mobilizing effect of a therapeutic chelating agent may not only enhance that metal's excretion¾a desired effect¾but may also redistribute some of the metal to other vital organs. This has been demonstrated for dimercaprol, which redistributes mercury and arsenic to the brain while also enhancing urinary mercury and arsenic excretion. Although several chelating agents have the capacity to mobilize cadmium, their tendency to redistribute cadmium to the kidney and increase nephrotoxicity has negated their therapeutic value in cadmium intoxication.

In most cases, the capacity of chelating agents to prevent or reduce the adverse effects of toxic metals appears to be greatest when they are administered very soon after an acute metal exposure. Use of chelating agents days to weeks after an acute metal exposure ends¾or their use in the treatment of chronic metal intoxication¾may still be associated with increased metal excretion. However, at that point, the capacity of such enhanced excretion to mitigate the pathologic effect of the metal exposure may be reduced.

The most important chelating agents currently in use in the USA are described below.

DIMERCAPROL (2,3-DIMERCAPTOPROPANOL, BAL)

Introduction

Dimercaprol (Figure 58-2), an oily, colorless liquid with a strong mercaptan-like odor, was developed in Great Britain during World War II as a therapeutic antidote against poisoning by the arsenic-containing warfare agent lewisite. It thus became known as British anti-Lewisite, or BAL. Because aqueous solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in peanut oil and must be administered by intramuscular injection, which is often painful.

In animal models, dimercaprol prevents and reverses arsenic-induced inhibition of sulfhydryl-containing enzymes and, if given soon after exposure, may protect against the lethal effects of inorganic and organic arsenicals. Human data indicate that it can increase the rate of excretion of arsenic and lead and may offer therapeutic benefit in the treatment of acute intoxication by arsenic, lead, and mercury.

Indications & Toxicity

Dimercaprol is FDA-approved as single-agent treatment of acute poisoning by arsenic and inorganic mercury and for the treatment of severe lead poisoning when used in conjunction with edetate calcium disodium (EDTA; see below). Although studies of its metabolism in humans are limited, intramuscularly administered dimercaprol appears to be readily absorbed, metabolized, and excreted by the kidney within 4-8 hours. Animal models indicate that it may also undergo biliary excretion, but the role of this excretory route in humans and other details of its biotransformation are uncertain.

When used in therapeutic doses, dimercaprol is associated with a high incidence of adverse effects, including hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever (particularly in children), and pain at the injection site. Its use has also been associated with thrombocytopenia and increased prothrombin time¾factors that may limit intramuscular injection because of the risk of hematoma formation at the injection site. Despite its protective effects in acutely intoxicated animals, dimercaprol may redistribute arsenic and mercury to the central nervous system, and it is not advocated for treatment of chronic poisoning. Water-soluble analogs of dimercaprol¾unithiol and succimer¾have higher therapeutic indices and have replaced dimercaprol in many settings.

SUCCIMER (DIMERCAPTOSUCCINIC ACID, DMSA)

Introduction

Succimer is a water-soluble analog of dimercaprol, and like that agent it has been shown in animal studies to prevent and reverse metal-induced inhibition of sulfhydryl-containing enzymes and to protect against the acute lethal effects of arsenic. In humans, treatment with succimer is associated with an increase in urinary lead excretion and a decrease in blood lead concentration. It may also decrease the mercury content of the kidney, a key target organ of inorganic mercury salts. In the USA, succimer is formulated exclusively for oral use, but intravenous formulations have been used successfully elsewhere. It is absorbed rapidly but somewhat variably after oral administration. Peak blood levels occur at approximately 3 hours. The drug binds in vivo to the amino acid cysteine to form 1:1 and 1:2 mixed disulfides, possibly in the kidney, and it may be these complexes that are the active chelating moieties. The elimination half-time of transformed succimer is approximately 2-4 hours.

Indications & Toxicity

Succimer is currently FDA-approved for the treatment of children with blood lead concentrations greater than 45 mcg/dL, but it is also commonly used in adults. The usual dosage is 10 mg/kg orally three times a day. Oral administration of succimer is comparable to parenteral EDTA in reducing blood lead concentration and has supplanted EDTA in outpatient treatment of patients capable of absorbing the oral drug. However, despite the demonstrated capacity of both succimer and EDTA to enhance lead elimination, their value in reversing established lead toxicity or in otherwise improving therapeutic outcome has yet to be established by a placebo-controlled clinical trial. Based on its protective effects against arsenic in animals and its ability to mobilize mercury from the kidney, succimer has also been used in the treatment of arsenic and mercury poisoning. Succimer has been well tolerated in limited clinical trials. It has a negligible impact on body stores of calcium, iron, and magnesium. It induces a mild increase in urinary excretion of zinc that is of minor or no clinical significance. Gastrointestinal disturbances, including anorexia, nausea, vomiting, and diarrhea, are the most common side effects, occurring in less than 10% of patients. Rashes, sometimes requiring discontinuation of the medication, have been reported in less than 5% of patients. Mild, reversible increases in liver aminotransferases have been noted in 6-10% of patients, and isolated cases of mild to moderate neutropenia have been reported.

EDETATE CALCIUM DISODIUM (ETHYLENEDIAMINETETRAACETIC ACID [EDTA])

Introduction

Ethylenediaminetetraacetic acid (Figure 58-1) is an efficient chelator of many divalent and trivalent metals in vitro. To prevent potentially life-threatening depletion of calcium, the drug should only be administered as the calcium disodium salt.

EDTA penetrates cell membranes relatively poorly and therefore chelates extracellular metal ions much more effectively than intracellular ions.

The highly polar ionic character of EDTA limits its oral absorption. Moreover, oral administration may increase lead absorption from the gut. Consequently, EDTA should be administered by intravenous infusion. In patients with normal renal function, EDTA is rapidly excreted by glomerular filtration, with 50% of an injected dose appearing in the urine within 1 hour. EDTA mobilizes lead from soft tissues, causing a marked increase in urinary lead excretion and a corresponding decline in blood lead concentration. In patients with renal insufficiency, excretion of the drug¾and its metal-mobilizing effects¾may be delayed.

Indications & Toxicity

Edetate calcium disodium is indicated chiefly for the chelation of lead, but it may also have utility in poisoning by zinc, manganese, and certain heavy radionuclides. In spite of repeated claims in the alternative medicine literature, EDTA has no demonstrated utility in the treatment of atherosclerotic cardiovascular disease.

Because the drug and the mobilized metals are excreted via the urine, the drug is relatively contraindicated in anuric patients. In such instances, the use of low doses of EDTA in combination with hemodialysis or hemofiltration has been described. Nephrotoxicity from EDTA has been reported, but in most cases this can be prevented by maintenance of adequate urine flow, avoidance of excessive doses, and limitation of a treatment course to 5 or fewer consecutive days. EDTA may result in temporary zinc depletion that is of uncertain clinical significance. Analogs of EDTA, the calcium and zinc disodium salts of diethylenetriaminepentaacetic acid (DTPA), pentetate, have been used for removal ("decorporation") of uranium and certain transuranic radioisotopes, and in 2004 were approved by the FDA for treatment of contamination with plutonium, americium, and curium.

UNITHIOL (DIMERCAPTOPROPANESULFONIC ACID, DMPS)

Introduction

Unithiol, a dimercapto chelating agent that is a water-soluble analog of dimercaprol, has been available in the official formularies of Russia and other former Soviet countries since 1958 and in Germany since 1976. It has been legally available from compounding pharmacists in the USA since 1999. Unithiol can be administered orally and intravenously. Bioavailability by the oral route is approximately 50%, with peak blood levels occurring in approximately 3.7 hours. Over 80% of an intravenous dose is excreted in the urine, mainly as cyclic DMPS sulfides. The elimination half-time for total unithiol (parent drug and its transformation products) is approximately 20 hours. Unithiol exhibits protective effects against the toxic action of mercury and arsenic in animal models, and it increases the excretion of mercury, arsenic, and lead in humans.



Indications & Toxicity

Unithiol has no FDA-approved indications, but experimental studies and its pharmacologic and pharmacodynamic profile suggest that intravenous unithiol offers advantages over intramuscular dimercaprol or oral succimer in the initial treatment of severe acute poisoning by inorganic mercury or arsenic. Aqueous preparations of unithiol (usually 50 mg/mL in sterile water) can be administered at a dose of 3-5 mg/kg every 4 hours by slow intravenous infusion over 20 minutes. If a few days of treatment are accompanied by stabilization of the patient's cardiovascular and gastrointestinal status, it may be possible to change to oral administration at a dose of 4-8 mg/kg every 6-8 hours. Oral unithiol may also be considered as an alternative to oral succimer in the treatment of lead intoxication.

Unithiol has been reported to have a low overall incidence of adverse effects (< 4%). Self-limited dermatologic reactions (drug exanthems or urticaria) are the most commonly reported adverse effects, although isolated cases of major allergic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported. Because rapid intravenous infusion may cause vasodilation and hypotension, unithiol should be infused slowly over an interval of 15-20 minutes.

PENICILLAMINE (D-DIMETHYLCYSTEINE)

Introduction

Penicillamine (Figure 58-2) is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less toxic than the L isomer and consequently is the preferred therapeutic form. Penicillamine is readily absorbed from the gut and is resistant to metabolic degradation.

Indications & Toxicity

Penicillamine is used chiefly for treatment of poisoning with copper or to prevent copper accumulation, as in Wilson's disease (hepatolenticular degeneration). It is also used occasionally in the treatment of severe rheumatoid arthritis (see Chapter 36). Its ability to increase urinary excretion of lead and mercury had occasioned its use as outpatient treatment for intoxication with these metals, but succimer, with its stronger metal-mobilizing capacity and lower side effect profile, has generally replaced penicillamine for these purposes.

Adverse effects have been seen in up to one third of patients receiving penicillamine. Hypersensitivity reactions include rash, pruritus, and drug fever, and the drug should be used with extreme caution, if at all, in patients with a history of penicillin allergy. Nephrotoxicity with proteinuria has also been reported, and protracted use of the drug may result in renal insufficiency. Pancytopenia has been associated with prolonged drug intake. Pyridoxine deficiency is a frequent toxic effect of other forms of the drug but is rarely seen with the D form. An acetylated derivative, N-acetylpenicillamine, has been used experimentally in mercury poisoning and may have superior metal-mobilizing capacity, but it is not commercially available.

DEFEROXAMINE

Deferoxamine is isolated from Streptomyces pilosus. It binds iron avidly but essential trace metals poorly. Furthermore, while competing for loosely bound iron in iron-carrying proteins (hemosiderin and ferritin), it fails to compete for biologically chelated iron, as in microsomal and mitochondrial cytochromes and hemoproteins. Consequently, it is the parenteral chelator of choice for iron poisoning (see Chapters 33 and 59). Deferoxamine plus hemodialysis may also be useful in the treatment of aluminum toxicity in renal failure. Deferoxamine is poorly absorbed when administered orally and may increase iron absorption when given by this route. It should therefore be administered intramuscularly or, preferably, intravenously. It is believed to be metabolized, but the pathways are unknown. The iron-chelator complex is excreted in the urine, often turning the urine an orange-red color.

Rapid intravenous administration may result in hypotension. Adverse idiosyncratic responses such as flushing, abdominal discomfort, and rash have also been observed. Pulmonary complications (eg, acute respiratory distress syndrome) have been reported in some patients undergoing deferoxamine infusions lasting longer than 24 hours, and neurotoxicity and increased susceptibility to certain infections (eg, with Yersinia enterocolitica) have been described after long-term therapy of iron overload conditions (eg, thalassemia major).

DEFERASIROX

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome.

PRUSSIAN BLUE (FERRIC HEXACYANOFERRATE)

Introduction

Ferric hexacyanoferrate (insoluble Prussian blue) is a hydrated crystalline compound in which Fe^II and Fe^III atoms are coordinated with cyanide groups in a cubic lattice structure. Although used as a dark blue commercial pigment for nearly 300 years, it was only 3 decades ago that its potential utility as a pharmaceutical chelator was recognized. Primarily by ion-exchange, and secondarily by mechanical trapping or adsorption, the compound has high affinity for certain univalent cations, particularly cesium and thallium. Used as an oral drug, insoluble Prussian blue undergoes minimal gastrointestinal absorption (< 1%). Because the complexes it forms with cesium or thallium are nonabsorbable, oral administration of the chelator diminishes intestinal absorption or interrupts enterohepatic and enteroenteric circulation of these cations, thereby accelerating their elimination in the feces. In clinical case series, the use of Prussian blue has been associated with a decline in the biologic half-life (ie, in vivo retention) of radioactive cesium and thallium.

Indications & Toxicity

In 2003, the FDA approved Prussian blue for the treatment of contamination with radioactive cesium (¹³⁷Cs), and for intoxication with thallium salts. Approval was prompted by concern over potential widespread human contamination with radioactive cesium caused by terrorist use of a radioactive dispersal device ("dirty bomb"). The drug is part of the Strategic National Stockpile of pharmaceuticals and medical material maintained by the CDC (http://www.bt.cdc.gov/stockpile/#material) (Note: Although soluble forms of Prussian blue, such as potassium ferric hexacyanoferrate, may have better utility in thallium poisoning, only the insoluble form is currently available as a pharmaceutical.)

Following exposure to ¹³⁷Cs or thallium salts, the approved adult dosage is 3 g orally three times a day; the corresponding pediatric dosage (2-12 years of age) is 1 g orally three times a day. Serial monitoring of urine and fecal radioactivity (¹³⁷Cs) and urinary thallium concentrations can guide the recommended duration of therapy. Adjunctive supportive care for possible acute radiation illness (¹³⁷Cs) or systemic thallium toxicity should be instituted as needed.

Prussian blue has not been associated with significant adverse effects. Constipation, which may occur in some cases, should be treated with laxatives or increased dietary fiber.



PREPARATIONS AVAILABLE

Deferasirox (Exjade)
Oral: 125, 250, 500 mg tablets
Deferoxamine (Desferal)
Parenteral: Powder to reconstitute, 500 mg/vial
Dimercaprol (BAL in Oil)
Parenteral: 100 mg/mL for IM injection
Edetate calcium [calcium EDTA] (Calcium Disodium Versenate)
Parenteral: 200 mg/mL for injection
Penicillamine (Cuprimine, Depen)
Oral: 125, 250 mg capsules; 250 mg tablets
Pentetate Calcium Trisodium ([calcium DTPA] and Pentetate Zinc Trisodium [zinc DTPA])
Parenteral: 200 mg/mL for injection
Prussian Blue (Radiogardase)
Oral: 500 mg capsules
Succimer (Chemet)
Oral: 100 mg capsules
Unithiol (Dimaval)
Bulk powder available for compounding as oral capsules, or for infusion (50 mg/mL)



REFERENCES


Lead

Borja-Aburto VH et al: Blood lead levels measured prospectively and risk of spontaneous abortion. Am J Epidemiol 1999;150:590.

Canfield RL et al: Intellectual impairment in children with blood lead concentrations below 10 ug per deciliter. N Engl J Med 2003;348:1517.

Cheng Y et al: Bone lead and blood lead levels in relation to baseline blood pressure and the prospective development of hypertension. Am J Epidemiol 2001;153:164.

Nash D et al: Blood lead, blood pressure, and hypertension in perimenopausal and postmenopausal women. JAMA 2003;289:1523.

Rogan WJ et al: The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N Engl J Med 2001;344:1421.

Third National Report on Human Exposure to Environmental Chemicals. Lead. CDC, 2005. [http://www.cdc.gov/exposurereport/3rd/pdf/results_01.html]

Weisskopf MG et al: Cumulative lead exposure and prospective change in cognition among elderly men. Am J Epidemiol 2004;160:1184.

Arsenic

National Research Council. Arsenic in Drinking Water: 2001 Update. National Academy Press, 2001. [http://search.nap.edu/books/0309076293/html/]

Petrick JS et al: Monomethylarsonous acid (MMA^III) and arsenite: LD50 in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chem Res Toxicol 2001;14:651.

Unnikrishnan D et al: Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001;97:1514.

von Ehrenstein OS et al: Decrements in lung function related to arsenic in drinking water in West Bengal, India. Am J Epidemiol 2005;162:533.

Mercury

Clarkson TW: The three modern faces of mercury. Environ Health Perspect 2002;110(Suppl 1):11.

EPA web site: [http://www.epa.gov/waterscience/fishadvice/advice.html]

LSRO [Life Sciences Research Office]. Review and Analysis of the Literature on the Potential Adverse Health Effects of Dental Amalgam. LSRO: Bethesda, 2004. [http://www.lsro.org/amalgam/frames_amalgam_report.html]

Nierenberg DW et al: Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672.

Rice DC et al: Methods and rationale for derivation of a reference dose for methylmercury by the U.S. EPA. Risk Anal 2003;23:107.

Third National Report on Human Exposure to Environmental Chemicals. Mercury. CDC, 2005. [http://www.cdc.gov/exposurereport/3rd/pdf/results_01.html]

Chelating Agents

Cremin JD et al: Oral succimer decreases the gastrointestinal absorption of lead in juvenile monkeys. Environ Health Perspect 2001;109:613.

Dargan PI et al: Case report: Severe mercuric sulphate poisoning treated with 2,3-dimercaptopropane-1-sulphonate and haemodiafiltration. Crit Care 2003;7:R1.

Gong Z et al: Determination of arsenic metabolic complex excreted in human urine after administration of sodium 2,3-dimercapto-1-propane sulfonate. Chem Res Toxicol 2002;15:1318.

Thompson DF, Called ED: Soluble or insoluble prussian blue for radiocesium and thallium poisoning? Ann Pharmacother 2004;38:1509.

Yokel RA et al: Entry, half-life, and desferrioxamine-accelerated clearance of brain aluminum after a single 26Al exposure. Toxicol Sci 2001;64:77.