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 (nearly 90% of US consumption), ammunition, metal alloys, solder, glass, plastics, pigments, and ceramics. Corrosion of lead plumbing in older buildings or supply lines may increase the lead concentration of tap water. Environmental lead exposure, ubiquitous by virtue of the anthropogenic distribution of lead to air, water, and food, has declined considerably in the last three decades as a result of the elimination of lead as an additive in gasoline, as well as diminished contact with lead-based paint and other lead-containing consumer products, such as lead solder in cans used as food containers. Legislation in the United States in 2011 further reduced the maximum permissible lead content of children’s products to 100 ppm. Lead continues to be used in some formulations of aviation gasoline for piston-engine aircraft. The presence of lead in certain folk medicines (eg, the Mexican remedies azarcon and greta, and certain Ayurvedic preparations) and in cosmetics (eg, kohl utilized around the eyes in certain African and Asian communities) has contributed to lead exposure to children and adults. Although 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 low levels of lead exposure may have subtle subclinical adverse effects on neurocognitive function in children and may contribute to hypertension and cardiovascular disease in adults. Lead serves no useful purpose in the human body. In key target organs such as the developing central nervous system, no level of lead exposure has been shown to be without deleterious effects.
Inorganic lead is slowly but consistently absorbed via the respiratory and gastrointestinal tracts. It is poorly absorbed through the skin. 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 57–1). 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, whereas young children absorb up to 50%. Low dietary calcium, iron deficiency, and ingestion on an empty stomach all have been associated with increased lead absorption.
TABLE 57–1Toxicology of selected arsenic, lead, and mercury compounds. ||Download (.pdf) TABLE 57–1 Toxicology of selected arsenic, lead, and mercury compounds.
| ||Form Entering Body ||Major Route of Absorption ||Distribution ||Major Clinical Effects ||Key Aspects of Mechanism ||Metabolism and Elimination |
|Arsenic ||Inorganic arsenic salts ||Gastrointestinal, respiratory (all mucosal surfaces) ||Predominantly soft tissues (highest in liver, kidney). Avidly bound in skin, hair, nails ||Cardiovascular: shock, arrhythmias. CNS: encephalopathy, peripheral neuropathy. Gastroenteritis; pancytopenia; cancer (many sites) ||Inhibits enzymes; interferes with oxidative phosphorylation; alters cell signaling, gene expression ||Methylation. Renal (major); sweat and feces (minor) |
|Lead ||Inorganic lead oxides and salts ||Gastrointestinal, respiratory ||Soft tissues; redistributed to skeleton (>90% of adult body burden) ||CNS deficits; peripheral neuropathy; anemia; nephropathy; hypertension; reproductive toxicity ||Inhibits enzymes; interferes with essential cations; alters membrane structure ||Renal (major); feces and breast milk (minor) |
| ||Organic (tetraethyl lead) ||Skin, gastrointestinal, respiratory ||Soft tissues, especially liver, CNS ||Encephalopathy ||Hepatic dealkylation (fast) → trialkyl metabolites (slow) → dissociation to lead ||Urine and feces (major); sweat (minor) |
|Mercury ||Elemental mercury ||Respiratory tract ||Soft tissues, especially kidney, CNS ||CNS: tremor, behavioral (erethism); gingivo-stomatitis, peripheral neuropathy; acrodynia; pneumonitis (high-dose) ||Inhibits enzymes; alters membranes ||Elemental Hg converted to Hg2+. Urine (major); feces (minor) |
| ||Inorganic: Hg+ (less toxic); Hg2+ (more toxic) ||Gastrointestinal, skin (minor) ||Soft tissues, especially kidney ||Acute renal tubular necrosis; gastroenteritis; CNS effects (rare) ||Inhibits enzymes; alters membranes ||Urine |
| ||Organic: alkyl, aryl ||Gastrointestinal, skin, respiratory (minor) ||Soft tissues ||CNS effects, birth defects ||Inhibits enzymes; alters microtubules, neuronal structure ||Deacylation. Fecal (alkyl, major); urine (Hg2+ after deacylation, minor) |
Once absorbed from the respiratory or gastrointestinal tract, lead enters the bloodstream, where approximately 99% is bound to erythrocytes and 1% is present in the plasma. Lead is subsequently distributed 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. Migration of retained lead bullet fragments into a joint space or adjacent to bone has been associated with the development of lead poisoning signs and symptoms years or decades after an initial gunshot injury.
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; generation of oxidative stress; changes in gene expression; alterations in cell signaling; and disruption of the integrity of membranes in cells and intracellular organelles.
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 <5 mcg/dL may result in subclinical deficits in neurocognitive function in lead-exposed young children, with no demonstrable threshold or “no effect” level. The dose response between low blood lead concentrations and cognitive function in young children is nonlinear, such that the decrement in intelligence associated with an increase in blood lead from <1–10 mcg/dL (6.2 IQ points) exceeds that associated with a change from 10 to 30 mcg/dL (3.0 IQ points).
Adults are less sensitive to the central nervous system (CNS) effects of lead, but long-term exposure to blood lead concentrations in the range of 10–30 mcg/dL may be associated with subclinical effects on neurocognitive function. At blood lead concentrations higher than 30 mcg/dL, behavioral and neurocognitive signs or symptoms may gradually emerge, including irritability, fatigue, decreased libido, anorexia, sleep disturbance, impaired visual-motor coordination, and slowed reaction time. Headache, arthralgias, and myalgias are also common complaints. Tremor occurs but is less common. Lead encephalopathy, usually occurring at blood lead concentrations higher than 100 mcg/dL, is typically accompanied by increased intracranial pressure and may cause ataxia, stupor, coma, convulsions, and death. Recent epidemiological studies suggest that lead may accentuate an age-related decline in cognitive function in older adults. In experimental animals, developmental lead exposure, possibly acting through epigenetic mechanisms, has been associated with increased expression of beta-amyloid, increased phosphorylated tau protein, oxidative DNA damage, and Alzheimer’s-type pathology in the aging brain. There is wide interindividual variation in the magnitude of lead exposure required to cause overt lead-related signs and symptoms.
Overt peripheral neuropathy may appear after chronic high-dose lead exposure, usually following months to years of blood lead concentrations higher than 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.
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. 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 suggestive—albeit insensitive and nonspecific—diagnostic clue to the presence of lead intoxication.
Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations >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. Studies conducted in general population samples have documented an association between blood lead concentration and measures of renal function, including serum creatinine and creatinine clearance. The presence of other risk factors for renal insufficiency, including hypertension and diabetes, may increase susceptibility to lead-induced renal dysfunction.
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 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. Recent studies have linked prenatal exposure to low levels of lead (eg, maternal blood lead concentrations of 5–15 mcg/dL) to decrements in physical and cognitive development assessed during the neonatal period and early childhood. In males, blood lead concentrations higher than 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, mediated by alteration in synaptic transmission at the smooth muscle-neuromuscular junction. 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.
Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in experimental animals and in susceptible humans. The pressor effect of lead may be mediated by an interaction with calcium-mediated contraction of vascular smooth muscle, as well as generation of oxidative stress and an associated interference in nitric oxide signaling pathways. 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 exposure has also been associated with prolongation of the QTc interval on the electrocardiogram. Epidemiologic studies have linked chronic environmental lead exposure associated with population blood lead concentrations in the range of 10–25 mcg/dL to a significantly increased risk of cardiovascular mortality. This is of considerable public health concern because these concentrations were prevalent in the USA prior to the 1980s. Although general population blood lead concentrations have since fallen considerably (see below), exposure associated with blood lead in this range persists in occupational settings worldwide.
Major Forms of Lead Intoxication
A. Inorganic Lead Poisoning
1. Acute—Acute inorganic lead poisoning is uncommon today (Table 57–1). 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 the form of lead-based paint chips; small objects, eg, toys coated or fabricated from lead; or contaminated food or drink. The onset of severe symptoms usually requires several days or weeks of recurrent exposure and manifests as 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, biliary colic, 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. When there has been recent ingestion of lead-containing paint chips, glazes, pellets, or weights, radiopacities may be visible on abdominal radiographs.
2. Chronic—The patient with symptomatic chronic lead intoxication typically presents with multisystemic findings, including complaints of anorexia, fatigue, and malaise; neurologic complaints, including headache, difficulty in concentrating, and 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. It is important to recognize that adverse effects of lead that are of considerable public health significance, such as subclinical decrements in neurodevelopment in children and hypertension in adults, are usually nonspecific and may not come to medical attention.
The diagnosis of lead intoxication 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 have blood lead concentrations higher than the normal range. Average background blood lead concentrations in North America and Europe have declined by 90% in recent decades, and the geometric mean blood lead concentration in the United States in 2011–2012 was estimated to be 0.973 mcg/dL. Though predominantly a research tool, the concentration of lead in bone assessed by noninvasive K X-ray fluorescence measurement of lead has been correlated with long-term cumulative lead exposure, and its relationship to numerous lead-related disorders is the subject of ongoing investigation. Measurement of lead excretion in the urine after 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. Accordingly, this test is rarely indicated in clinical practice. Because of the lag time associated with lead-induced elevations in circulating heme precursors, the finding of a blood lead concentration of 30 mcg/dL or more with no concurrent increase in zinc protoporphyrin suggests that the lead exposure was of recent onset.
Poisoning from organolead compounds is now very rare, in large part because of the worldwide phase-out of tetraethyl and tetra-methyl 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 CNS, producing dose-dependent effects that may include neurocognitive deficits, insomnia, delirium, hallucinations, tremor, convulsions, and death.
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 or hypertonic saline, 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 (DMSA), 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 re-equilibrates from bone lead stores.
Although 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 (CDC) has recommended chelation for all children with blood lead concentrations of 45 mcg/dL or greater. However, a randomized, double-blind, placebo-controlled clinical trial of succimer in children with blood lead concentrations between 25 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.
Management of elevated blood lead levels in children and adults should include a conscientious effort to identify and reduce all potential sources of future lead exposure. Many local, state, or national governmental agencies maintain lead poisoning prevention programs that can assist in case management. Blood lead screening of family members or coworkers of a lead poisoning patient is often indicated to assess the scope of the exposure. In 2012, the CDC adopted a new policy that defined as elevated any childhood blood lead concentrations at or exceeding a reference value corresponding to the 97.5th percentile of quadrennial reports of the National Health and Nutrition Examination Survey (NHANES). The blood lead reference value established in 2012 was 5 mcg/dL, and it is projected to decline in the future. Because there is no blood lead concentration known to be devoid of deleterious effects, the finding of a blood lead concentration exceeding the reference value (ie, elevated in relation to the general population) should prompt clinical and environmental investigation (https://www.cdc.gov/nceh/lead/acclpp/final_document_030712.pdf). Although the US Occupational Safety and Health Administration (OSHA) lead regulations introduced in the late 1970s mandate that workers be removed from lead exposure for blood lead levels higher than 50–60 mcg/dL, an expert panel in 2007 recommended that removal be initiated for a single blood lead level >30 mcg/dL or when two successive blood lead levels measured over a 4-week interval are 20 mcg/dL or greater (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849937/pdf/ehp0115-000463.pdf). The longer-term goal should be for workers to maintain blood lead levels <10 mcg/dL, and for pregnant women to avoid occupational or avocational exposure that would result in blood lead levels higher than 5 mcg/dL. Environmental Protection Agency (EPA) regulations effective since 2010 require that contractors who perform renovation, repair, and painting projects that disturb lead-based paint in pre-1978 residences and child-occupied facilities must be certified and must follow specific work practices to prevent lead contamination (see Box: Prevention of Lead Poisoning: An Ongoing Effort).
Prevention of Lead Poisoning: An Ongoing Effort
|Exposure: Sources ||Examples of Preventive Measures |
|Home exposure: The US Consumer Product Safety Commission adopted major restrictions on the use of lead in residential house paint in 1977. Prior to then, thousands of tons of lead pigments were applied in millions of homes. The American Healthy Homes Survey (2005–2006) estimated that 35% of homes had some lead-based paint and 22% had one or more lead-based paint hazards. || |
The US Environmental Protection Agency’s (EPA) Lead Renovation, Repair, and Painting Rule requires that companies performing renovation, repair, and painting projects that disturb lead-based paint in homes, child care facilities, and preschools built before 1978 have their firm certified by EPA (or an EPA-authorized state), use certified renovators who are trained by EPA-approved training providers, and follow lead-safe work practices.
|Workplace exposure: The US Occupational Health and Safety Administration (OSHA) estimates that more than 1.6 million workers are potentially exposed to lead. State and federal OSHA programs have established permissible exposure levels for lead in workplace air, as well as medical surveillance requirements for workers that may mandate periodic blood lead monitoring. || |
Present OSHA rules regarding workplace lead exposure and medical removal protection date from the late 1970s and no longer offer adequate protection. The Occupational Lead Poisoning Prevention Program of the California Department of Public Health offers up-to-date, health protective guidance.
|Water: Lead may enter drinking water when service pipes contain lead, especially when the water has high acidity or low mineral content that corrodes pipes and plumbing fixtures. || |
Under EPA’s Lead and Copper Rule [https://www.epa.gov/dwreginfo/lead-and-copper-rule], if more than 10% of tap water samples at sites likely to have lead plumbing exceed the lead action level of 15 parts per billion, water systems are required to institute corrosion control and other measures. The Safe Drinking Water Act, amended by the Reduction of Lead in Drinking Water Act of 2011, sets limits on the lead content of new plumbing materials for potable water.
|Children: Because of normal mouthing behavior, children are at special risk of exposure to lead present in toys, jewelry, printed material, and other consumer products. || |
The US Consumer Product Safety Commission has promulgated rules that limit the amount of lead that can be present in children’s products.
Production of lead began 6000 years ago, and lead poisoning is one of the oldest known occupational illnesses. Worldwide, lead production has doubled over the past two decades in part because of the growing demand for lead acid storage batteries. Efforts to prevent lead poisoning from multiple industrial, commercial, and environmental sources remain an active focus of public health in the USA.
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 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, and the turf herbicide monosodium methane arsonate (MSMA). The use of phenylarsenic compounds as feed additives for poultry and swine was terminated in the United States in 2015. 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. Environmental risk assessments have suggested that arsenic migrating from coal combustion wastes (eg, coal ash) deposited in unlined landfills may contaminate underlying groundwater. Arsine, an arsenous hydride (AsH3) gas with potent hemolytic effects, is manufactured predominantly for use in the semiconductor industry but may also be generated accidentally when arsenic-containing ores or scrap gallium arsenide semiconductors 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 antimicrobials* and were widely used for the first half of the twentieth century until supplanted by sulfonamides and other more effective and less toxic agents.
Other organoarsenicals, most notably lewisite (dichloro-[2-chlorovinyl]arsine), were developed in the early 20th 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. Melarsoprol, another trivalent arsenical, is used in the treatment of advanced African trypanosomiasis (see Chapter 52).
Soluble arsenic compounds are well absorbed through the respiratory and gastrointestinal tracts (Table 57–1). 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 monomethyl-arsonic acid and dimethylarsinic acid, which are excreted, along with residual inorganic arsenic, in the urine. When chronic daily absorption is <1000 mcg of soluble inorganic arsenic, approximately two thirds of the absorbed dose is excreted in the urine within 2–3 days. 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 in hair and nails as a result of external deposition may be indistinguishable from that incorporated after internal absorption.
Arsenic compounds are thought to exert their toxic effects by several modes of action. Interference with enzyme 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 [MMAIII]) may be more toxic than the inorganic parent compounds. Reduced efficiency in the methylation of MMA to dimethylarsonous acid (DMA), resulting in an elevated percentage of MMA in the urine, has been associated with an increased risk of chronic adverse effects. Arsenic methylation requires S-adenosylmethionine, a universal methyl donor in the body, and arsenic-associated perturbations in one-carbon metabolism may underlie some arsenic-induced epigenetic effects such as altered gene expression.
Arsine gas is oxidized in vivo and exerts a potent hemolytic effect associated with alteration of ion flux across the erythrocyte membrane; 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 and arsenolipids. Arsenobetaine exerts no known toxic effects when ingested by mammals and is excreted in the urine unchanged; arsenosugars are partially metabolized to dimethylarsinic acid. Thioarsenite compounds that occur as minor metabolites of inorganic arsenic and methylated arsenic compounds in vivo may contribute to toxicity.
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 (particularly in association with QTc prolongation on the electrocardiogram) may occur promptly or after a delay of several days. Pancytopenia usually develops within 1 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 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 after 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 0.01 mg/kg/d (~500–1000 mcg/d in adults). The time to appearance of symptoms varies 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 changes—among the most characteristic effects—typically develop after years of exposure and include a “raindrop” pattern of hyperpigmentation, and hyperkeratoses involving the hands and feet (Figure 57–1). Peripheral vascular disease and noncirrhotic portal hypertension may also occur. Epidemiologic studies suggest a possible link to hypertension, cardiovascular disease mortality, diabetes, chronic nonmalignant respiratory disease, and adverse reproductive outcomes. Cancer of the lung, skin, bladder, and possibly other sites, including the kidney and liver, may appear years after exposure to doses of arsenic that are not high enough to elicit other acute or chronic effects. Some studies suggest that tobacco smoking may interact synergistically with arsenic in increasing the risk of certain adverse health outcomes.
Dermatologic lesions associated with chronic ingestion of arsenic in drinking water. (Photo courtesy of Dipankar Chakraborti, PhD.)
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 torsades de pointes.
The diagnosis of chronic arsenic poisoning involves integration of the clinical findings with confirmation of exposure. The urine concentration of the sum of inorganic arsenic and its primary metabolites MMA and DMA is <20 mcg/L in the general population. High urine levels associated with overt adverse effects may return to normal within days to weeks after exposure ceases. Because it may contain large amounts of nontoxic organoarsenic such as arsenobetaine, or arsenosugars that are metabolized to DMA, all seafood should be avoided for at least 3 days before submission of a urine sample for diagnostic purposes. The arsenic content of hair and nails (normally <1 ppm) may sometimes reveal past elevated exposure, but results should be interpreted cautiously in view of the potential for external contamination. Segmental analysis of hair or nails using sensitive methods such as neutron activation analysis or synchrotron radiation sources may sometimes have forensic value for investigation of the temporal pattern of arsenic poisoning.
Management of chronic arsenic poisoning consists primarily of termination of exposure and nonspecific supportive care. Although empiric short-term oral chelation with unithiol or succimer for symptomatic individuals with elevated urine arsenic concentrations may be considered, it has no proven benefit beyond removal from exposure alone. Preliminary studies suggest that dietary supplementation of folate—thought to be a cofactor in arsenic methylation—might be of value in arsenic-exposed individuals, particularly men, who are also deficient in folate.
Arsine gas poisoning produces a distinctive pattern of intoxication dominated by profound hemolytic effects. After a latent period that may range from 2 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 are seldom available to confirm the diagnosis during the critical period of illness. Intensive supportive care—including exchange transfusion, vigorous hydration, and, in the case of acute renal failure, hemodialysis—is the mainstay of therapy. Currently available chelating agents have not been demonstrated to be of clinical value in arsine poisoning.
Metallic mercury as “quicksilver”—the only metal that is liquid under ordinary conditions—has attracted scholarly and scientific interest from antiquity. The mining of mercury was early recognized as being hazardous to health. As industrial use of mercury became common during the last 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; and dental amalgam. The widespread use of elemental mercury in artisanal gold production is a growing problem in many developing countries. Mercury use in pharmaceuticals and in biocides has declined substantially in recent years, but occasional use in antiseptics, folk medicines, and cosmetic skin-lightening creams is still encountered. Thimerosal, an organomercurial preservative that is metabolized in part to ethylmercury, has been removed from almost all the vaccines in which it was formerly present. Environmental releases of mercury from the burning of fossil fuels, which contributes to the bioaccumulation of methylmercury in fish, remains 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.
The United States banned the export of elemental mercury in 2013. Once fully implemented, the international Minamata Convention on Mercury, signed by 128 countries since 2013, will result in a worldwide phase-out by 2020 of mercury in numerous products including batteries, switches and relays, fluorescent lamps, pesticides, biocides and antiseptics, measuring instruments (eg, thermometers, sphygmomanometers), and manufacturing processes such as chloralkali production (by 2025)
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 57–1). 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 feces. Excretion of inorganic mercury follows a multicompartment model: most is excreted within weeks to months, but a fraction may be retained in the kidneys and brain for years. After inhalation of elemental mercury vapor, urinary mercury levels decline with a half-life of approximately 1–3 months. Urine mercury concentration is <3 mcg/L in most individuals without occupational exposure, and the median general population urine mercury concentration in the 2011–2012 NHANES was 0.324 mcg/L. 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. The geometric mean total blood mercury concentration in the US population in the 2011–2012 NHANES was 0.703 mcg/L; the 95th percentile was 4.40 mcg/L (~90% present as methylmercury). Mercury binds to sulfhydryl groups in keratinized tissue, and as with lead and arsenic, traces appear in the hair and nails. Mercury in hair has served as a valid biomarker of methylmercury exposure over an interval of weeks to months in epidemiologic studies.
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.
Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (see following text) 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.
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 miliary rash. Chronic exposure to inorganic mercury salts, sometimes via topical application in cosmetic skin-lightening creams, has been associated with neurological symptoms and renal toxicity in case reports and case series.
Methylmercury intoxication affects mainly the CNS and results in paresthesias, ataxia, hearing impairment, dysarthria, and progressive constriction of the visual fields. Signs and symptoms of methylmercury intoxication 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 to methylmercury have been associated with a risk of subclinical neurodevelopmental deficits.
A 2004 report by the Institute of Medicine’s Immunization Safety Review Committee concluded that available evidence favored rejection of a causal relation between thimerosal-containing vaccines and autism. In like manner, a recent retrospective cohort study conducted by the CDC did not support a causal association between early prenatal or postnatal exposure to mercury from thimerosal-containing vaccines and neuropsychological functioning later in childhood.
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 <5 mcg/L, and whole blood mercury is <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 <35 mcg per gram of creatinine and end-of-work-week whole blood mercury concentrations <15 mcg/L. To minimize the risk of developmental neurotoxicity from methylmercury, the EPA and the US Food and Drug Administration (FDA) 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 albacore tuna to 6 ounces a week, but to otherwise consume 8–12 ounces of fish per week (see http://www.fda.gov/Food/FoodborneIllnessContaminants/Metals/ucm393070.htm).
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.
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.