Background
The atomic number of arsenic, an element, is 33, and its atomic weight is 74.91. A commonly found form of arsenic is gray with a metallic appearance. Yellow, brown, and black forms are also known. When arsenic is heated, it sublimes, that is, it changes directly into the gaseous form, arsine. Arsenic is considered a transitional element intermediate between metals and nonmetals, but it classically is considered a heavy metal. It has been known since ancient times and has been and continues to be used medicinally. [1]
Arsenical pesticides are still used in some areas in agriculture. Chronic toxicity from ingestion or inhalation of arsenic may be occupational or environmental. [2, 3, 4, 5] Wells drawing from watersheds near old mines may be contaminated with dangerous amounts of arsenic. [6] Accidental ingestion, ingestion with suicidal intent, and intentional poisoning most commonly are associated with acute toxicity. With regular and long-term exposure, some tolerance may develop. At one time, people in southern Austria reportedly found that eating arsenic had a "tonic" effect and were able to ingest without toxicity what would usually be a fatal dose.
Documented cases of arsenic poisoning have been associated with ingestion of traditional Chinese herbal balls, Korean herbal preparations used to treat hemorrhoids, and kelp supplements. Arsenic is sometimes found in homeopathic preparations containing sulphur. Arsenic is used to treat and preserve lumber. As early as the 1890s, arsenical pigments were used in wallpaper both for coloring and for its antifungal properties. The action of the fungus Penicillium brevicaule releases arsine. Arsenic was used to strengthen lead and, in the glassmaking industry, to reduce discoloration caused by trace amounts of iron. All of these applications add to the hazards of old house restorations. Arsenic was used as a poison gas called lewisite in World War I; hence, the name of the agent used to treat arsenic intoxication is British antilewisite (BAL). [7, 8]
Pathophysiology
Acute exposure
Inorganic arsenicals, such as the trioxide, a by-product of smelting of ore containing copper, lead, and zinc, are more toxic than the organic. Arsenic may be inhaled in particulate form, ingested, or absorbed through skin and mucous membranes. The minimum lethal dose is 100–200 mg of arsenic trioxide.
Exposure to a toxic dose initially produces a dry burning sensation in the mouth and throat and a constricted feeling in the throat. This is followed by severe abdominal pain, cramping, diarrhea, and vomiting. The diarrhea begins with "rice water" stools progressing to a bloody discharge. Stools and breath may have a garlicky odor. Vertigo develops, followed by delirium, coma, and often convulsions. Circulatory collapse with hepatic and renal failure ensues. Myocardial toxicity involves broadening of the QRS, flattening of the T waves, and ST depression. In acute exposure to the gaseous form, inhalation of toxic amounts of arsine gas results in headache, malaise, weakness, dizziness, and dyspnea accompanied by gastrointestinal distress.
The effect is not immediate but typically is delayed by 2–24 hours. Usually, hemolysis occurs 4–6 hours after the onset of symptoms and dark red urine is noticed. Jaundice develops 24–48 hours later. Patients present to the emergency department with severe jaundice, anemia, and hemoglobinuria (ie, blackwater urine). On admission, the patient may have fever, tachycardia, and tachypnea. Acute oliguric renal failure occurs because concentration of arsenic in the proximal tubules and binding to proteins of tubular epithelium damages the tubules. Treatment involves hemodialysis and the use of BAL (Dimercaprol).
Subacute and chronic exposure
Chronic exposure, as in well water, has been associated with bladder cancer and risk of diabetes with neuropathy. In children, there have been reports of decreased intelligence quotients.
Arsine was identified in 1775. The first reported fatality from arsine inhalation was in 1815 when a German chemist died after inhaling the gas in his laboratory. Workers in the metallurgy industry are at a risk of repeated exposure to arsine gas. The action of acid on metal ore contaminated with arsenic causes release of arsine gas. Arsenic-containing dust emitted from smelters is another source. [2]
Environmental exposure to well water containing inorganic arsenic can result in skin hyperpigmentation or an eczematous dermatitis. [9, 10] Peripheral vascular involvement may occur, with acrocyanosis and the appearance of a Raynaud-like picture. In addition, a sensorimotor distal neuropathy may occur that presents like Guillain-Barré syndrome, [11] and sideroblastic anemia—a state of ineffective erythropoiesis characterized by a significant number of erythroid precursors containing mitochondria with stainable iron granules—also may be noted. Although a similar hematopoietic picture is seen in lead toxicity, the mechanism producing the anemia is not believed to be the same. Leukopenia is a common finding.
Biochemistry of arsenicals
Many enzyme systems are vulnerable to the tendency for arsenicals to react with sulfhydryl groups. The pyruvate and succinate oxidation pathways may be disrupted. The sulfhydryl cofactor dihydrolipoate appears to be the principal site of inhibition. The converting enzyme dihydrolipoate dehydrogenase is also susceptible. This inhibition effectively blocks the Krebs cycle, interrupting oxidative phosphorylation, which results in marked depletion of ATP stores. Arsenic also produces a picture of thiamine deficiency by preventing transformation of thiamine into acetyl-coenzyme A (CoA) and succinyl-CoA. Since alcohol affects the same cycle, arsenic toxicity is accentuated by alcohol ingestion. A number of other enzyme systems are susceptible, but they are of minor clinical significance.
Arsenolysis, another mechanism of toxicity, results when arsenic anions disrupt oxidative phosphorylation by replacing stable phosphoryl with less stable compounds. Unstable arsenic compounds irreversibly decompose, resulting in loss of high-energy phosphate bonds. The cell then self-destructs in an attempt to restore lost energy.
Medicinal uses of arsenicals
Inorganic arsenic has been used in medicine for over 2500 years. The most widely used form was Fowler solution containing 1% potassium arsenite, which was used for treatment of psoriasis. Arsphenamine was for many years the standard treatment for syphilis. Melarsoprol is an organoarsenic compound used to treat infections caused by Trypanosoma brucei or Trypanosoma gambiense. Retrospective studies have suggested an increase in the incidence of hepatic angiosarcoma in people previously treated with Fowler solution, but evidence is tentative. Regular, long-term arsenic exposure has been associated with various cutaneous carcinomas as well as internal malignancies including bronchogenic carcinoma and hepatocellular carcinoma. [12, 13]
Epidemiology
Frequency
United States
In 1998, American Association of Poison Control Centers (APCC) reported 956 cases that were not related to pesticides. Ninety-nine cases involved exposure to arsenic-containing pesticides; 4 of the nonpesticide cases died, while no death was reported from the pesticide-related cases. Estimating the number of unreported cases is difficult. One estimate is that 900,000 people a day are exposed to arsenic particularly in areas where well water is extensively used. [14] An arsenic level of greater than 10 micrograms/liter is considered excessive by most state authorities. According to the US Geological Survey, arsenic levels in bedrock well water have been found at a rate greater than 3x the national average along a corridor stretching from eastern Maine to northern Massachusetts. [15] The US Geological Survey found that within a belt of mata sedementary bedrock in a corrridor from eastern Maine through northern New Jersey and southern New York, significant levels of arsenic have been found in up to 23% of wells. In Maine, 10% of all wells have been found to have elevated levels.
International
In 1955, in Japan, 12,000 people were poisoned after consumption of powdered milk contaminated with arsenic; 131 people died. Arsenic exposure from drinking water is a worldwide problem, especially in Bangladesh, where beginning in the 1970s, 10 million hand-pumped wells were installed to prevent water-borne diseases. It was not appreciated that the water was contaminated with arsenic until 20 years later. Four hundred and seven deaths were attributed to arsenic between October 2000 and February 2009. [16] Similarly, arsenic is a known public health problem in India, Chile, Taiwan, Argentina, and Mongolia. Clusters of cases of bladder cancer in residents of the north coast of Chile were found to be 4-5 times the rate in other regions in Chile. [17]
Mortality/Morbidity
Fortunately, the known mortality rate is low—4 reported in 1998 and only sporadic cases in prior years.
Race-, sex-, and age-related demographics
No racial predilection is apparent.
Industrial exposures to arsenic are more likely to involve men. [18] The same may be said for exposure to arsenical preparations used in agriculture, construction, and forestry. Intentional poisonings involve both sexes. No hormone-related difference in the metabolism of arsenic is known.
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Most occupational exposures are in males because of the predominance of males in the mining and smelting industries.
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Accidental and environmental exposures are equal in males and females.
Most cases of exposure are in adults.
Prognosis
After removal from exposure, patients generally improve over the course of time. The neuropathy and accompanying weakness may take months or years to resolve. Little is known about the effect on cognition in regularly exposed children. Lead in relatively low levels is known to sometimes produce learning delays and cognitive problems in children. Evaluation of the Japanese children exposed in 1955 found a 10-fold incidence of intellectual disability in babies exposed to arsenic contamination of powdered milk.
Inorganic arsenic has been suspected as a carcinogen since 1879 when the high rates of lung cancer in German miners were thought to be caused by exposure to inhaled arsenic. Careful surveillance of patients exposed to occupational arsenic on a regular, long-term basis should include screening for cancers of the lung, liver, GI tract, kidney, and hematopoietic system. [22, 23]
Arsenic exposure and smoking appear to have synergism; therefore, smoking cessation should be advised strongly.
Regular and long-term alcohol intake also appears to contribute to the development and severity of peripheral neuropathy associated with arsenic exposure. This is another factor that can be modified and should be discussed at follow-up visits.
The keratotic skin lesions of arsenic toxicity are considered premalignant and must be monitored. OSHA requires periodic chest x-rays and regular skin examinations in workers exposed to arsenic in a work setting.
Patient Education
Public awareness of dangerous arsenic levels has somewhat improved in the United States because of the vigilance of State Housing Authorities and the US Geological Survey. A number of companies, especially in the northeast are able to treat the water to reduce arsenic levels in wells. Anyone planning to purchase property in areas where the water supply is a private well must have the water tested for arsenic levels in addition to other contaminents.
