Arsenic Toxicity

ARSENIC Toxicity

Arsenic is released into the air by volcanoes and is a natural contaminant of some deep-water wells.

Occupational exposure to arsenic is common:

In the smelting industry in which arsenic is a byproduct of ores containing lead, gold, zinc, cobalt, and nickel
In the microelectronics industry, in which gallium arsenide is responsible.
Commercial use of inorganic arsenic compounds in common products such as wood preservatives, pesticides, herbicides, fungicides, and paints.
Through the consumption of foods and the smoking of tobacco treated with arsenic-containing pesticides
Through the burning of fossil fuels in which arsenic is a contaminant.
Arsenic was also a major ingredient of Fowler’s solution and continues to be found in some folk remedies.

Fowler’s solution is a solution containing potassium arsenite that once was prescribed as a remedy or a tonic. A Dr. Fowler of Stafford, England proposed its use in 1786 as a substitute for a patented medicine, It was prescribed in the United States until the late 1950s for a range of ailments including malaria, chorea, and syphilis. In 2001 the U.S. FDA approved a proprietary formula of a solution of arsenic trioxide for acute promyelocytic leukaemia.Fowler’s solution, is a 1% solution of potassium arsenite, KH₂AsO₃.Because of the poisonous and carcinogenic nature of arsenic compounds, Fowler’s solution is dangerous. Documented side effects of treatment with Fowler’s solution include: cirrhosis of the liver, idiopathic portal hypertension, urinary bladder cancer, skin cancers.

Metabolism

The toxicity of an arsenic-containing compound depends on its valence state (zero-valent, trivalent, or pentavalent), its form (inorganic or organic), and the physical aspects governing its absorption and elimination. In general, inorganic arsenic is more toxic than organic arsenic, and trivalent arsenite is more toxic than pentavalent and zero-valent arsenic.

The normal intake of arsenic by adults occurs primarily through ingestion and averages around 50 ug/d (range, 8 to 104 ug/d). Most (around 64 percent) of this amount is accounted for by organic arsenic from fish, seafood, and algae; the specific arsenic compounds obtained from these sources are arsenobentaine and arsenocholine, which are relatively nontoxic and are rapidly excreted in unchanged form in the urine. After absorption, inorganic arsenic accumulates in the liver, spleen, kidneys, lungs, and gastrointestinal tract. It is then rapidly cleared from these sites but leaves a residue in keratin-rich tissues such as skin, hair, and nails. Arsenite (+5) undergoes biomethylation in the liver to the less toxic metabolites methylarsenic acid and dimethylarsenic acid; biomethylation can quickly become saturated, however, and the result is the deposition of increasing doses of inorganic arsenic in soft tissues. Arsenic, particularly in its trivalent form, inhibits critical sulfhydryl-containing enzymes. In the pentavalent form, the competitive substitution of arsenic for phosphate can lead to rapid hydrolysis of the high-energy bonds in compounds such as ATP.

CLINICAL FEATURESAcute arsenic poisoning from ingestion results in increased permeability of small blood vessels and

inflammation and necrosis of the intestinal mucosa; these changes manifest as hemorrhagic gastroenteritis, fluid loss, and hypotension. Delayed cardiomyopathy accompanied by electrocardiographic abnormalities may develop. Symptoms include nausea, vomiting, diarrhea, abdominal pain, delirium, coma, and seizures. A garlicky odor may be detectable on the breath. Acute tubular necrosis and hemolysis may develop. The reported lethal dose of arsenic ranges from 120 to 200 mg in adults and is 2 mg/kg in children. Arsine gas causes severe hemolysis within 3 to 4 h of exposure and can lead to acute tubular necrosis and renal failure.In chronic arsenic poisoning, the onset of symptoms comes at 2 to 8 weeks. Typical findings are skin and nail changes, such as hyperkeratosis, hyperpigmentation, exfoliative dermatitis, and Mees’ lines (transverse white striae of the fingernails); sensory and motor polyneuritis manifesting as numbness and tingling in a “stocking-glove” distribution, distal weakness, and quadriplegia; and inflammation of the respiratory mucosa.Epidemiologic evidence has linked chronic

consumption of water containing arsenic at concentrations in the range of 10 to 1820 ppb with vasospasm and peripheral vascular insufficiency culminating in “blackfoot disease – a gangrenous condition affecting the extremities.Chronic arsenic exposure has also been associated with a greatly elevated risk of skin cancer and possibly of cancers of the lung, liver (angiosarcoma), bladder, kidney, and colon.

LABORATORY FINDINGSWhen acute arsenic poisoning is suspected, an x-ray of the abdomen may reveal ingested arsenic, which is radiopaque. The serum arsenic level may exceed 0.9 umol/L (7 ug/dL); however, arsenic is rapidly cleared from the blood.Electrocardiographic findings may include QRS complex broadening, QT prolongation, ST-segment depression, T-wave flattening, and multifocal ventricular tachycardia. Urinary arsenic should be measured in 24-h specimens collected after 48 h of abstinence from seafood ingestion; normally, levels of total urinary arsenic excretion are less than 0.67 umol/d (50 ug/d).Arsenic may be detected in the hair and nails for months after exposure.Abnormal liver function, anemia, leukocytosis or leukopenia, proteinuria, and hematuria may be detected.Electromyography may reveal features similar to those of Guillain-Barre syndrome.

TREATMENT

	Vomiting should be induced in the alert patient with acute arsenic ingestion.
	Gastric lavage may be useful; activated charcoal with a cathartic (such as sorbitol) may be tried.
	Aggressive therapy with intravenous fluid and electrolyte replacement in an intensive-care setting may be life-saving.
	Dimercaprol is the chelating agent of choice and is administered intramuscularly at an initial dose of 3 to 5 mg/kg on the following schedule: every 4 hr for 2 days, every 6 hr on the third day, and every 12 hr thereafter for 10 days. (An oral chelating agent may be substituted.)Succimer is sometimes an effective alternative, particularly if adverse reactions to dimercaprol develop (such as nausea, vomiting, headache, increased blood pressure, and convulsions). In cases of renal failure, doses should be adjusted carefully, and hemodialysis may be needed to remove the chelating agent-arsenic complex. Arsine gas poisoning should be treated supportively with the goals of maintaining renal function and circulating red-cell mass.