Epidemiology

Arsenic is a metalloid that exists in four forms: elemental arsenic, arsine gas, inorganic arsenic salts (pentavalent arsenate form or trivalent arsenite form), and organic arsenic compounds. Toxic manifestations are higher in the more soluble and higher-valence compounds. Arsine gas is the most toxic form of arsenic. Mass poisonings due to exposure to arsenic have occurred throughout history, including one in 1998 in Wakayama, Japan, in which 70 people were poisoned. Children may be poisoned after exposure to inorganic arsenic found in pesticides, herbicides, dyes, homeopathic medicines, and certain intentionally or accidentally contaminated folk remedies from China, India, and Southeast Asia (Chapter 59). Soil deposits contaminate artesian well water. Groundwater contamination is a common problem in developing countries. Food products (e.g., rice) cooked in contaminated water may actually absorb arsenic, thus concentrating it in the food. The World Health Organization (WHO) has set 10 µg/L as the upper limit of safety. In many parts of Asia and South America, this limit is frequently exceeded. Arsenic concentrations in one quarter of the wells in Bangladesh exceed 50 µg/L and 35-77 million of the 125 million inhabitants of Bangladesh regularly consume arsenic-contaminated water. Occupational exposure may occur in industries such as glass manufacturing, pottery, electronic component, semiconductor and laser, manufacturing, mining, smelting, and refining. Although arsenic is no longer produced in the USA, it is produced in many countries and is imported into the USA for industrial use. Organic arsenic compounds may be found in seafood, pesticides, and some veterinary pharmaceuticals. In contrast to mercury, the organic forms of arsenic found in seafood are nontoxic.

Pharmacokinetics

Elemental arsenic is insoluble in water and bodily fluids and, therefore, is insignificantly absorbed and nontoxic. Inhaled arsine gas is rapidly absorbed through the lungs. The inorganic arsenic salts are well absorbed through the gastrointestinal tract, lungs, and skin. The organic arsenic compounds are well absorbed through the gastrointestinal tract. After acute exposure, arsenic initially is bound to the protein portion of hemoglobin in the red blood cells (RBCs) and rapidly distributed to all tissues. Inorganic arsenic is methylated and is eliminated predominantly by the kidneys, with about 95% excreted in the urine and 5% excreted in the bile. Most of the arsenic is eliminated in the first few days, with the remainder slowly excreted over a period of several weeks. Arsenic concentrates in hair, nails, and skin. Measurement of the distance of Mee lines (transverse white striae on the nail) from the nail bed can provide an estimate of time of exposure (nails grow at the rate of 0.4 mm per day).

Pathophysiology

After exposure to arsine gas, absorbed arsine enters RBCs and is oxidized to arsenic dihydride and elemental arsenic. Complexing of these derivatives with red cell sulfhydryl groups results in cell membrane instability and massive hemolysis. The inorganic arsenic salts poison enzymatic processes vital to cellular metabolism. Trivalent arsenic binds to sulfhydryl groups, resulting in decreased production of adenosine triphosphate through the inhibition of enzyme systems such as the pyruvate dehydrogenase and α-ketoglutarate complexes. Pentavalent arsenic may be biotransformed to trivalent arsenic or substituted for phosphate in the glycolytic pathway, resulting in uncoupling of oxidative phosphorylation.

Clinical Manifestations

Arsine gas is colorless, odorless, nonirritating, and highly toxic. Inhalation causes no immediate symptoms. After a latent period of 2-24 hr, massive hemolysis occurs, along with malaise, headache, weakness, dyspnea, nausea, vomiting, abdominal pain, hepatomegaly, pallor, jaundice, hemoglobinuria, and renal failure (Table 701-1). Acute ingestion of arsenic produces gastrointestinal toxicity within minutes to hours and manifested as nausea, vomiting, abdominal pain, and diarrhea. Hemorrhagic gastroenteritis with extensive fluid loss and third spacing may result in hypovolemic shock. Cardiovascular toxicity includes QT interval prolongation, polymorphous ventricular tachycardia, congestive cardiomyopathy, pulmonary edema, and cardiogenic shock. Acute neurologic toxicity includes delirium, seizures, cerebral edema, encephalopathy, and coma. Lethal doses of arsenates are 5-50 mg/kg; lethal doses of arsenites are less than 5 mg/kg.

Table 701-1 EFFECTS OF ARSENIC ON ORGAN SYSTEMS

Late sequelae include hematuria, proteinuria, and acute tubular necrosis. A delayed sensorimotor peripheral neuropathy may appear days to weeks after acute exposure, secondary to axonal degeneration. Neuropathy manifests as painful dysesthesias followed by diminished vibratory, pain, touch, and temperature sensation; decreased deep tendon reflexes; and, in the most severe cases, an ascending paralysis with respiratory failure mimicking Guillain-Barré syndrome (Chapter 608). Adult survivors of infant arsenic poisoning experience higher mortality from disorders of the nervous system compared to adults without such exposure.

Subacute toxicity is characterized by prolonged fatigue, malaise, weight loss, headache, chronic encephalopathy, peripheral sensorimotor neuropathy, leukopenia, anemia, thrombocytopenia, chronic cough, and gastroenteritis. Mee lines in the nails become apparent 1-2 mo after exposure in about 5% of patients. Dermatologic findings include alopecia, oral ulceration, peripheral edema, a pruritic macular rash, and desquamation.

Chronic exposure to low levels of arsenic is from usually environmental or occupational sources. Over the course of years, dermatologic lesions develop, including hyperpigmentation, hypopigmentation, hyperkeratoses (especially on the palms and soles), squamous and basal cell carcinomas, and Bowen’s disease (cutaneous squamous cell carcinoma in situ). Encephalopathy and peripheral neuropathy may be present. Hepatomegaly, hypersplenism, noncirrhotic portal fibrosis, and portal hypertension occur. Blackfoot disease is an obliterative arterial disease of the lower extremities associated with chronic arsenic exposure that has been described in Taiwan. Carcinogenicity of chronic arsenic exposure is reflected in increased rates of cancers of the skin, lung, liver, bladder, and kidney as well as of angiosarcomas. The effects of prenatal exposure to arsenic are uncertain but may include low birthweight.

Laboratory Findings

The diagnosis of arsenic intoxication is based on characteristic clinical findings, a history of exposure, and elevated urinary arsenic values, the last of which confirm the exposure. A spot urine arsenic level should be determined for symptomatic patients before chelation, although initially the result may be negative. Because urinary excretion of arsenic is intermittent, definitive diagnosis depends on a 24-h urine collection. Concentrations greater than 50 µg/L in a 24-h urine specimen are consistent with arsenic intoxication (Table 701-2). Urine specimens must be collected in metal-free containers. Ingestion of seafood containing nontoxic arsenobetaine and arsenocholine can cause elevations of urinary arsenic. Blood arsenic levels rarely are helpful because of their high variability and the rapid clearance of arsenic from the blood in acute poisonings. Elevated arsenic values in the hair or nails must be interpreted cautiously because of the possibility of external contamination. Abdominal radiographs may demonstrate ingested radiopaque arsenic.

Table 701-2 NORMAL AND TOXIC LEVELS OF ARSENIC AND MERCURY

Later in the course of illness, a complete blood cell count may show anemia, thrombocytopenia, and leukocytosis, followed by leukopenia, karyorrhexis, and basophilic stippling of RBCs. The serum concentrations of creatinine, bilirubin, and transaminases may be elevated; urinalysis may show proteinuria, pyuria, and hematuria; and examination of the cerebrospinal fluid may show protein elevations.

Epidemiology

Mercury exists in three forms: elemental mercury, inorganic mercury salts, and organic mercury (Table 701-3). Elemental mercury is present in thermometers, sphygmomanometers, barometers, batteries, and some latex paints produced before 1991. Workers in industries producing these products may expose their children to the toxin when mercury is brought home on contaminated clothing. Vacuuming of carpets contaminated with mercury and breaking of mercury fluorescent light bulbs may result in elemental mercury vapor exposure. Severe inhalation poisonings have resulted from attempts to separate gold from gold ore by heating mercury and forming a gold-mercury amalgam. Elemental mercury has been used in folk remedies by Asian and Mexican populations for chronic stomach pain and by Latin Americans and Caribbean natives in occult practices. Dental amalgams containing elemental mercury release trace amounts of mercury that do not pose a credible risk to health. An expert panel for the National Institutes of Health concluded that existing scientific evidence does not indicate that dental amalgams pose a health risk; they should not be replaced merely to decrease mercury exposure.

Inorganic mercury salts are found in pesticides, disinfectants, antiseptics, pigments, dry batteries, and explosives and as preservatives in some medicinal preparations. Organic mercury in the diet, especially fish containing methyl mercury, is a major source of mercury exposure among the general population. Industries that may produce mercury-containing effluents include chlorine and caustic soda production, mining and metallurgy, electroplating, chemical and textile manufacturing, paper and pharmaceutical manufacturing, and leather tanning. Mercury compounds in the environment are methylated to methyl mercury by soil and water microorganisms. Methyl mercury in the water rapidly accumulates in fish (swordfish, king mackerel, fresh tuna, tile fish, shark) and other aquatic organisms, which are in turn consumed by humans. To address concerns that maternal consumption of large quantities of fish during pregnancy may expose the fetus to concentrations of mercury with adverse consequences, the longitudinal Seychelles Child Development Study has been ongoing since the late 1980s. The first cohort of the study involved nearly 800 mother-child pairs, with subsequent cohorts enrolled. Despite a high maternal fish intake (mean of 12 fish meals per week), follow-up of children at least through 9 years yr of age has revealed no consistent adverse developmental effects. Well-known large outbreaks of methyl mercury intoxication include the incidents in Japan in the 1950s (Minamata disease, from consumption of contaminated seafood) and in Iraq in 1971 (from consumption of grain treated with a methyl mercury fungicide).

Thimerosal is a mercury-containing preservative used in some vaccines. Thimerosal contains 49.6% mercury by weight and is metabolized to ethyl mercury and thiosalicylate. During an ongoing review of biologic products in response to the U.S. Food and Drug Administration (FDA) Modernization Act of 1997, the FDA determined that infants who received thimerosal-containing vaccines at multiple visits might have been exposed to more mercury than recommended by federal guidelines. As a precautionary measure, the American Academy of Pediatrics, American Academy of Family Physicians, Advisory Committee on Immunization Practices, and U.S. Public Health Service issued a joint recommendation in 1999 that thimerosal be removed from vaccines as quickly as possible. In the USA, thimerosal has been removed from all vaccines in the recommended childhood immunization schedule. Infants and children who have received thimerosal-containing vaccines do not need to undergo blood, urine, or hair testing for mercury because the concentrations of mercury would be quite low and would not require treatment. The benefits and risks of vaccines containing thimerosal should be discussed with parents (as with all vaccines). The larger risks of not vaccinating children far outweigh any known risk of exposure to thimerosal-containing vaccines. Studies do not demonstrate a link between thimerosal-containing vaccines and autistic spectrum disorders (Chapter 28.1), and no evidence supports a change in the standard of practice with regard to administration of thimerosal-containing vaccines in areas of the world where they are used. A rise in blood mercury levels following a single dose of hepatitis vaccine was seen in preterm infants, but the clinical significance is unknown. The American Academy of Pediatrics recommends that the initiation of hepatitis vaccine series be deferred until 2-6 mo of age in children who are born to hepatitis B surface antigen–negative mothers.

Pharmacokinetics

Inhaled elemental mercury vapor is 80% absorbed by the lungs and is distributed rapidly to the central nervous system (CNS) because of its high lipid solubility. The elemental mercury is oxidized by catalase to the mercuric ion, which is the reactive form that causes cellular toxicity. Elemental mercury liquid is poorly absorbed from the gastrointestinal tract, with less than 0.1% being absorbed. The half-life of elemental mercury in the tissues is about 60 days, most of the excretion occurring in the urine.

Inorganic mercury salts are about 10% absorbed from the gastrointestinal tract and cross the blood-brain barrier to a lesser extent than elemental mercury. Mercuric salts are more soluble than mercurous salts and, therefore, produce greater toxicity. Elimination occurs primarily in the urine, with a half-life of about 40 days.

Methyl mercury is the most avidly absorbed of the organic mercury compounds, with about 90% absorbed from the gastrointestinal tract. The lipophilic, short-chain alkyl structure of methyl mercury allows it to distribute rapidly across the blood-brain barrier and placenta. Methyl mercury is about 90% excreted in the bile, with the remainder being excreted in the urine. The half-life is 70 days.

Pathophysiology

After absorption, mercury is distributed to all tissues, particularly the CNS and kidneys. Mercury reacts with sulfhydryl, phosphoryl, carboxyl, and amide groups, resulting in disruption of enzymes, transport mechanisms, membranes, and structural proteins. Widespread cellular dysfunction or necrosis results in the multiorgan toxicity characteristic of mercury poisoning.

Clinical Manifestations

Five syndromes describe the clinical presentation of mercury poisoning. Acute inhalation of elemental mercury vapor results in rapid onset of cough, dyspnea, chest pain, fever, chills, headaches, and visual disturbances. Gastrointestinal findings include metallic taste, salivation, nausea, vomiting, and diarrhea. Depending on the severity of the exposure, the illness may be self-limited or may progress to necrotizing bronchiolitis, interstitial pneumonitis, pulmonary edema, and death from respiratory failure. Younger children are more susceptible to pulmonary toxicity. Survivors may demonstrate restrictive lung disease. Renal dysfunction and neurologic disturbances (ataxia, persistent weakness, emotional lability) may develop subacutely. Chronic exposure to volatilized elemental mercury in dental amalgams has not been found to be of any clinical significance.

Acute ingestion of inorganic mercury salts (typically secondary to ingestion of a button battery) can manifest in a few hours as corrosive gastroenteritis, signified by metallic taste, oropharyngeal burns, nausea, hematemesis, severe abdominal pain, hematochezia, acute tubular necrosis, cardiovascular collapse, and death.

Chronic inorganic mercury intoxication produces the classic triad consisting of tremor, neuropsychiatric disturbances, and gingivostomatitis. The syndrome may result from long-term exposure to elemental mercury, inorganic mercury salts, or certain organic mercury compounds, all of which may be metabolized to mercuric ions. The tremor starts as a fine intention tremor of the fingers that is abolished during sleep but that may later involve the face and progress to choreoathetosis and spasmodic ballismus. Mixed sensorimotor neuropathy and visual disturbances may also be present. The neuropsychiatric disturbances include emotional lability, delirium, headaches, memory loss, insomnia, anorexia, and fatigue. Renal dysfunction ranges from asymptomatic proteinuria to nephrotic syndrome.

Acrodynia, or pink disease, is a rare idiosyncratic hypersensitivity reaction to mercury that occurs predominantly in children exposed to mercurous powders. The symptom complex includes generalized pain, paresthesias, and an acral (hands, feet) rash that may spread to involve the face. The rash typically is red-pink, papular, pruritic, and painful; it may progress to desquamation and ulceration. Morbilliform, vesicular, and hemorrhagic variants have been described. Other important features include anorexia, apathy, photophobia, and hypotonia, especially of the pectoral and pelvic girdles. Irritability, tremors, diaphoresis, insomnia, hypertension, and tachycardia may be present. Some cases initially were diagnosed as pheochromocytoma. The outcome is good after removal of the source of mercury exposure.

Methyl mercury intoxication also is referred to as Minamata disease after the widespread mercury poisoning that occurred at Minamata Bay in Japan in people who had ingested contaminated fish. Methyl mercury poisoning manifests as delayed neurotoxicity that appears after a latent period of weeks to months and is characterized by ataxia; dysarthria; paresthesias; tremors; movement disorders; impairment of vision, hearing, smell, and taste; memory loss; progressive dementia; and death. Infants exposed in utero are the most severely affected, with low birthweight, microcephaly, profound developmental delay, cerebral palsy, deafness, blindness, and seizures. Although there is significant residual morbidity from methyl mercury neurotoxicity, observations on long-term follow up of children exposed in Iraq reveal complete or partial resolution in most cases.

Laboratory Findings

The diagnosis of mercury intoxication is based on characteristic clinical findings, a history of exposure, and elevation of whole blood or urine mercury values, the last of which confirms the exposure. Thin-layer and gas chromatographic techniques can be used to distinguish organic from inorganic mercury. Blood should be collected in special tubes for trace elements from laboratories that are capable of performing those tests. Levels less than 10 µg/L in whole blood and less than 20 µg/L in a 24-h urine specimen are considered normal (see (Table 701-2). Although blood mercury levels may reflect acute exposure, they decrease as mercury redistributes into the tissues. Urine mercury levels are most useful for identifying long-term exposures, except in the case of methyl mercury, which undergoes minimal urinary excretion. Urinary mercury levels are used in monitoring efficacy of chelation therapy, whereas blood levels are used primarily in monitoring organic mercury poisonings. Hair analysis for mercury is not reliable because hair reflects endogenous as well as exogenous mercury exposure (hair avidly binds mercury from the environment). Abdominal radiographs may demonstrate ingested radiopaque mercury.

Urinary markers of early nephrotoxicity include microalbuminuria, retinol-binding protein, β₂-microglobulin, and N-acetyl-β-D-glucosaminidase. Early neurotoxicity may be detected with neuropsychiatric testing and nerve conduction studies, whereas severe CNS toxicity is apparent on CT or MRI.