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