Arsenic compounds are found in a select group of industrial, commercial, and pharmaceutical products. Use of arsenic as a wood preservative in industrial applications (eg, copper chromated arsenate for marine timbers and utility poles) accounts for two-thirds of domestic consumption, but former widespread use in new lumber sold for residential purposes (eg, decks, fencing, play structures) ended with a voluntary ban effective at the end of 2003. Arsenic-treated lumber used in residential structures and objects created before 2004 has not been officially recalled or removed. Virtually all arsenic in pesticides and herbicides in the United States have been withdrawn or subject to phaseout with the exception of the limited use of monosodium methane arsonate (MSMA) as an herbicide. Phenylarsenic compounds were formerly used as feed additives for poultry and swine, and poultry litter used as a soil amendment sometimes contained low levels of soluble arsenic. Intravenous arsenic trioxide, reintroduced to the US Pharmacopoeia in 2000, is used as a drug for cancer chemotherapy. Inorganic arsenic is used in the production of nonferrous alloys, semiconductors (eg, gallium arsenide), and certain types of glass. Inorganic arsenic is sometimes found in folk remedies and tonics, particularly from Asian sources. Artesian well water can be contaminated by inorganic arsenic from natural geologic deposits, and elevated levels of arsenic may be encountered in mine tailings and sediments and coal fly ash. Arsine, a hydride gas of arsenic, is discussed.

Arsenic compounds may be organic or inorganic and may contain arsenic in either a pentavalent (arsenate) or a trivalent (arsenite) form. Once absorbed, arsenicals exert their toxic effects through multiple mechanisms, including inhibition of enzymatic reactions vital to cellular metabolism, induction of oxidative stress, and alteration in gene expression and cell signal transduction. Although arsenite and arsenate undergo in vivo biotransformation to less toxic pentavalent monomethyl and dimethyl forms (monomethylarsonic acid [MMA] and dimethylarsinic acid [DMA]), there is evidence that the process also forms more toxic trivalent methylated compounds. Thioarsenite compounds, which occur in vivo as minor metabolites, may also contribute to toxicity.

1. Soluble arsenic compounds, which are well absorbed after ingestion or inhalation, pose the greatest risk for acute human intoxication.
2. Inorganic arsenic dusts (eg, arsenic trioxide) may exert irritant effects on the skin and mucous membranes. Contact dermatitis has also been reported. Although the skin is a minor route of absorption for most arsenic compounds, systemic toxicity has resulted from industrial accidents involving percutaneous exposure to highly concentrated liquid formulations.
3. The chemical warfare agent lewisite (dichloro [2-chlorovinyl] arsine) is a volatile vesicant liquid that causes immediate severe irritation and necrosis to the eyes, skin, and airways.
4. Arsenate and arsenite are known human carcinogens by both ingestion and inhalation.

The toxicity of arsenic compounds varies considerably with the valence state, chemical composition, and solubility. Humans are generally more sensitive than other animals to the acute and chronic effects of arsenicals.

1. Inorganic arsenic compounds. In general, trivalent arsenic (As³⁺) is 2-10 times more acutely toxic than pentavalent arsenic (As⁵⁺). However, overexposure to either form produces a similar pattern of effects, requiring the same clinical approach and management.
   1. Acute ingestion of as little as 100-300 mg of a soluble trivalent arsenic compound (eg, sodium arsenite) can be fatal.
   2. The lowest observed acute effect level (LOAEL) for acute human toxicity is approximately 0.05 mg/kg, a dose associated with GI distress in some individuals.
   3. Death attributable to malignant arrhythmias has been reported after days to weeks of cancer chemotherapy regimens in which arsenic trioxide at a dosage of 0.15 mg/kg/d was administered IV.
   4. Repeated ingestion of approximately 0.04 mg/kg/d can result in GI distress and hematologic effects after weeks to months and peripheral neuropathy after 6 months to several years. Lower chronic exposures, approximately 0.01 mg/kg/d, can result in characteristic skin changes (initially spotted pigmentation, followed within years by palmar-plantar hyperkeratosis) after intervals of 5-15 years.
   5. The US National Research Council (2001) estimated that chronic ingestion of drinking water containing arsenic at a concentration of 10 mcg/L can be associated with an excess lifetime cancer risk greater than 1 in 1,000. The latency period for development of arsenic-induced cancer is probably a decade or longer.
2. Organic arsenic. In general, pentavalent organoarsenic compounds are less toxic than either trivalent organoarsenic compounds or inorganic arsenic compounds. Marine organisms may contain large quantities of arsenobetaine, an organic trimethylated compound that is excreted unchanged in the urine and produces no known toxic effects. Arsenosugars (dimethylarsinoyl riboside derivatives) and arsenolipids are present in some marine and freshwater animals (eg, bivalve mollusks) and marine algae (eg, seaweeds, often used in Asian foods).

1. Acute exposure most commonly occurs after accidental, suicidal, or deliberate poisoning by ingestion. A single massive dose produces a constellation of multisystemic signs and symptoms that emerge over the course of hours to weeks.
   1. Gastrointestinal effects. After a delay of minutes to hours, diffuse capillary damage results in hemorrhagic gastroenteritis. Nausea, vomiting, abdominal pain, and watery diarrhea are common. Although prominent GI symptoms may subside within 24-48 hours, severe multisystemic effects may still ensue.
   2. Cardiovascular effects. In severe cases, extensive tissue third spacing of fluids combined with fluid loss from gastroenteritis may lead to hypotension, tachycardia, shock, and death. Metabolic acidosis and rhabdomyolysis may be present. After a delay of 1-6 days, there may be a second phase of congestive cardiomyopathy, cardiogenic or noncardiogenic pulmonary edema, and isolated or recurrent cardiac arrhythmias. Prolongation of the QT interval may be associated with torsade de pointes ventricular arrhythmia.
   3. Neurologic effects. Mental status may be normal, or there may be lethargy, agitation, or delirium. Delirium or obtundation may be delayed by 2-6 days. Generalized seizures may occur but are rare. Symmetric sensorimotor axonal peripheral neuropathy may evolve 1-5 weeks after acute ingestion, beginning with painful distal dysesthesias, particularly in the feet. Ascending weakness and paralysis may ensue, leading in severe cases to quadriplegia and neuromuscular respiratory failure.
   4. Hematologic effects. Pancytopenia, particularly leukopenia and anemia, characteristically develops within 1-2 weeks after acute ingestion. A relative eosinophilia may be present, and there may be basophilic stippling of red blood cells.
   5. Dermatologic effects. Findings that occasionally appear after a delay of 1-6 weeks include desquamation (particularly involving the palms and soles), a diffuse maculopapular rash, periorbital edema, and herpes zoster or herpes simplex. Transverse white striae in the nails (Aldrich-Mees lines) may become apparent months after an acute intoxication.
2. Chronic intoxication is also associated with multisystemic effects, which may include fatigue and malaise, gastroenteritis, leukopenia and anemia (occasionally megaloblastic), sensory-predominant peripheral neuropathy, hepatic transaminase elevation, noncirrhotic portal hypertension, and peripheral vascular insufficiency. Skin disorders and cancer may occur (see below), and a growing body of epidemiologic evidence links chronic arsenic ingestion with an increased risk for hypertension, cardiovascular mortality, diabetes mellitus, and chronic nonmalignant respiratory disease. Genetic factors affecting the methylation of arsenic, particularly those associated with an elevated percentage of urinary monomethylarsonic acid (MMA), may increase the risk for arsenic-related cancers and exhibit a variable association with nonmalignant arsenic-related chronic diseases.
   1. Skin lesions, which emerge gradually over a period of 1-10 years, typically begin with a characteristic pattern of spotted (“raindrop”) pigmentation on the torso and extremities, followed after several years by the development of hyperkeratotic changes on the palms and soles. Skin lesions may occur after lower doses than those causing neuropathy or anemia. Arsenic-related skin cancer, which includes squamous cell carcinoma, Bowen disease, and basal cell carcinoma, is characteristically multicentric and occurs in non-sun-exposed areas.
   2. Cancer. Chronic inhalation increases the risk for lung cancer. Chronic ingestion is an established cause of cancer of the lung, bladder, and skin, and epidemiological studies have increasingly linked arsenic to certain types of renal cancer and liver cancer.

Usually is based on a history of exposure combined with a typical pattern of multisystemic signs and symptoms. Suspect acute arsenic poisoning in a patient with an abrupt onset of abdominal pain, nausea, vomiting, watery diarrhea, and hypotension, particularly when followed by an evolving pattern of delayed cardiac dysfunction, pancytopenia, and peripheral neuropathy. Metabolic acidosis and elevated creatine kinase (CK) may occur early in the course of severe cases. Some arsenic compounds, particularly those of lower solubility, are radiopaque and may be visible on a plain abdominal radiograph.

1. Specific levels. In the first 2-3 days after acute symptomatic poisoning, total 24-hour urinary arsenic excretion is typically in excess of several thousand micrograms (spot urine >1,000 mcg/L) and, depending on the severity of poisoning, may not return to background levels (<70 mcg in a 24-hour specimen or <50 mcg/L in a spot urine) for several weeks. Spot urine analyses are usually sufficient for diagnostic purposes.
   1. Ingestion of seafood (eg, fin fish, shellfish and marine plants such as seaweed), which may contain very large amounts of nontoxic organoarsenicals such as arsenobetaine and arsenosugars, can “falsely” elevate measurements of total urinary arsenic for up to 3 days. Speciation of urinary arsenic by a laboratory capable of reporting the concentration of inorganic arsenic and its primary human metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), may sometimes be helpful; background urine concentration of the sum of urinary inorganic arsenic, MMA, and DMA is usually less than 20 mcg/L in the absence of recent seafood ingestion. (In the 2015-2016 National Health and Nutrition Examination Survey [NHANES] of the US general population, the median and 95% percentile values were 4.08 and 14.5 mcg/L, respectively.) It should be noted that although arsenobetaine is excreted unchanged in the urine, arsenosugars, which are abundant in bivalve mollusks and seaweed, are metabolized in part to DMA as well as recently recognized methylated thioarsenic species. Among terrestrial foods, rice naturally contains relatively high concentrations of arsenic (albeit at concentrations usually <1 ppm).
   2. Blood levels are highly variable and are rarely of value in the diagnosis of arsenic poisoning or management of patients capable of producing urine. Although whole-blood arsenic, normally less than 5 mcg/L, may be elevated early in acute intoxication, it may decline rapidly to the normal range despite persistent elevated urinary arsenic excretion and continuing symptoms.
   3. Elevated concentrations of arsenic in nails or hair (normally <1 ppm) may be detectable in certain segmental samples for months after urine levels normalize but should be interpreted cautiously owing to the possibility of external contamination.
2. Other useful laboratory studies include CBC with differential and smear for basophilic stippling, electrolytes, glucose, BUN and creatinine, liver enzymes, creatine kinase (CK), urinalysis, cardiac troponin, ECG and ECG monitoring (with particular attention to the QT interval), and abdominal and chest radiography.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary.
   2. Treat coma, shock, and arrhythmias if they occur. Because of the association of arsenic with prolonged QT intervals, avoid drugs (eg, antiarrhythmic, antiemetic) that can contribute to QT prolongation.
   3. Treat hypotension and fluid loss with aggressive use of IV crystalloid solutions, along with vasopressor agents if needed, to support blood pressure and optimize urine output.
   4. Prolonged in-patient support and observation are indicated for patients with significant acute intoxication because cardiopulmonary and neurologic complications may be delayed for several days. Continuous cardiac monitoring beyond 48 hours is warranted in patients with persistent symptoms or evidence of toxin-related cardiovascular disturbance, including ECG abnormalities, or any degree of congestive heart failure.
2. Specific drugs and antidotes. Treat seriously symptomatic patients with chelating agents, which have shown therapeutic benefit in animal models of acute arsenic intoxication when administered promptly (ie, minutes to hours) after exposure. Treatment should not be delayed during the several days often required to obtain specific laboratory confirmation.
   1. Unithiol (2,3-dimercaptopropanesulfonic acid, DMPS), a water-soluble analog of dimercaprol (BAL) that can be administered IV, has the most favorable pharmacologic profile for the treatment of acute arsenic intoxication. Although published experience is sparse, 3-5 mg/kg every 4 hours by slow IV infusion over 20 minutes is a suggested starting dose. In the United States, the drug is available through compounding pharmacies.
   2. Dimercaprol (BAL, British anti-lewisite, 2,3-dimercaptopropanol) is the chelating agent of second choice if unithiol is not immediately available. The starting dose is 3-5 mg/kg by deep IM injection every 4-6 hours. Lewisite burns to the skin and eyes can be treated with topical inunctions of dimercaprol.
   3. Once patients are hemodynamically stable and GI symptoms have subsided, parenteral chelation may be changed to oral chelation with either oral unithiol or oral succimer (DMSA, 2,3-dimercaptosuccinic acid). A suggested dose of unithiol is 4-8 mg/kg orally every 6 hours. Alternatively, give succimer, 7.5 mg/kg orally every 6 hours or 10 mg/kg orally every 8 hours.
   4. The therapeutic end points of chelation are poorly defined. For chelation instituted to treat symptomatic acute intoxication, one empiric approach would be to continue treatment (initially parenterally, then orally) until total urinary arsenic levels are less than 500 mcg/24 h (or spot urine <300 mcg/L), levels below those associated with overt symptoms in acutely poisoned adults. Alternatively, oral chelation could be continued until total urinary arsenic levels reach background levels (<70 mcg/24 h or spot urine <50 mcg/L). The value of chelation for the treatment of an established neuropathy (or prevention of an incipient neuropathy) is unproven.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). However, note that animal and in vitro studies suggest that activated charcoal has a relatively poor affinity for inorganic arsenic salts. Consider gastric lavage or whole-bowel irrigation for large ingestions.
4. Enhanced elimination. Hemodialysis may be of possible benefit in patients with concomitant renal failure but otherwise contributes minimally to arsenic clearance. There is no known role for diuresis, hemoperfusion, or repeat-dose charcoal.