Introduction
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.
Arsenical pesticides are still used in some areas in agriculture. Chronic toxicity from ingestion or inhalation of arsenic may be occupational or environmental. Wells drawing from watersheds near old mines may be contaminated with dangerous amounts of arsenic. 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).
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
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.
Environmental exposure to well water containing inorganic arsenic can result in skin hyperpigmentation or an eczematous dermatitis. 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, 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.
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.
International
In 1955, in Japan, 12,000 people were poisoned after consumption of powdered milk contaminated with arsenic; 131 people died.
Mortality/Morbidity
Fortunately, the known mortality rate is low—4 reported in 1998 and only sporadic cases in prior years.
Race
No racial predilection is apparent.
Sex
Industrial exposures to arsenic are more likely to involve men. 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.
- Most occupational exposures are in males because of the predominance of males in the mining and smelting industries.
- Accidental and environmental exposures are equal in males and females.
Age
Most cases of exposure are in adults.
Clinical
History
Acute toxicity following ingestion, inhalation, or absorption of inorganic arsenic produces a burning sensation in the mouth and throat. This is followed, usually somewhat later, by severe gastrointestinal distress with copious and severe diarrhea and vomiting. Vertigo, delirium, coma, and often convulsions are seen as the toxicity is manifest. Circulatory collapse and renal and hepatic failure ensue, and hemolysis usually occurs 4-6 hours after onset of evidence of toxicity. Acute symptoms typically develop hours after exposure to inorganic arsenic. Inhalation of arsine gas produces headache, malaise, weakness, dizziness, dyspnea, and GI distress more rapidly.
The typical picture in subacute arsenic toxicity includes the onset of gastrointestinal symptoms—nausea, vomiting, and diarrhea—which may be intermittent but in retrospect are associated with ingestion of hot or cold beverages. For a layperson's account of an experience with arsenic poisoning, read "My Husband Poisoned Me" by Ellen Harris in the March 2000 issue of McCall's Magazine, pages 68-73.
Chronic exposure effects should be suspected when a patient presents with a distal sensorimotor neuropathy accompanied by skin hyperpigmentation. History of drinking well water is an additional clue. Bae et al have written on the role of a rice cooking technique associated with arsenic toxicity in Bangladesh.
Physical
Heavy metal poisonings have many similarities, making clinical distinctions between them difficult at times. Arsenic is more likely than other heavy metals to produce a dramatic gastroenteric picture when ingested. Inhalation of arsine gas produces clinical features whose onset is dependent on the degree of exposure. The initial complaints may be vague, with headache, malaise, weakness, dizziness, and dyspnea. Later, the features are the same as those seen in inorganic arsenic ingestion. The cutaneous manifestations are rather different depending on the heavy metal exposure.
- Cutaneous: Hyperpigmentation of the skin of the face or extremities is in a "raindrop" distribution. The skin has a peculiar bronze tint. A patient described by Kyle and Pease had pigmentation of the buccal mucosa resembling the hyperpigmentation of Addison disease. Oral herpetiform lesions or a diffuse macular rash may be present, as may brawny, nonpruritic desquamation and patchy alopecia as well as hyperkeratosis of the palms and soles. Mees lines are transverse, 1-2 mm white striations in the fingernails, which may be deformed or fall out within 2-3 weeks of exposure. The Mees lines are actual arsenic deposits. Because of the availability of sulfhydryl groups in keratin, arsenic can be measured in hair and fingernail samples. Arsenic can be detected in hair samples as early as 30 hours after ingestion and as late as 9 years after ingestion. Thallium toxicity can be suspected in case of hair loss and fingernail loss, but thallium is more likely to produce hyperglycemia.
- Neurological: Paresthesias and numbness, usually in a symmetric stocking-glove distribution, and muscle weakness are a result of peripheral neuropathy. The onset and progression may be mistaken for Guillain-Barré syndrome. This problem may persist long after arsenic exposure stops. Fatigue and weakness are major complaints. The neuropathy is not seen acutely but develops over the weeks subsequent to exposure in acute or subacute toxicity. In regular, long-term arsenic exposure, the presenting complaint is frequently a sensory neuropathy with features that resemble an alcoholic neuropathy. Burning paresthesias in glove and stocking distribution, early loss of stretch reflexes, and later weakness are seen. In severe toxicity, flaccid paralysis may appear in the lower extremities, then the upper extremities. This is maximal about 4 weeks after acute exposure. Again, the clinical picture resembles Guillain-Barré syndrome.
- Hematologic: Anemia with leukopenia is seen frequently; splenomegaly may be apparent. Granulocytopenia and an increase in the eosinophil count often occur.
- Systemic complaints of regional subcutaneous edema are present in arsenic intoxication. The eyelids in particular, and legs less frequently, become quite edematous.
More on Arsenic |
 Overview: Arsenic |
| Differential Diagnoses & Workup: Arsenic |
| Treatment & Medication: Arsenic |
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References
Axelson O, Dahlgren E, Jansson CD, Rehnlund SO. Arsenic exposure and mortality: a case-referent study from a Swedish copper smelter. Br J Ind Med. Feb 1978;35(1):8-15. [Medline].
Bae M, Watanabe C, Inaoka T, et al. Arsenic in cooked rice in Bangladesh. Lancet. Dec 7 2002;360(9348):1839-40. [Medline].
Ball P. Arsenic-free water still a pipedream. Nature. Jul 21 2005;436(7049):313. [Medline].
Bates MN, Smith AH, Hopenhayn-Rich C. Arsenic ingestion and internal cancers: a review. Am J Epidemiol. Mar 1 1992;135(5):462-76. [Medline].
Chen CJ, Wu MM, Lee SS, et al. Atherogenicity and carcinogenicity of high-arsenic artesian well water. Multiple risk factors and related malignant neoplasms of blackfoot disease. Arteriosclerosis. Sep-Oct 1988;8(5):452-60. [Medline].
Donofrio PD, Wilbourn AJ, Albers JW, et al. Acute arsenic intoxication presenting as Guillain-Barre-like syndrome. Muscle Nerve. Feb 1987;10(2):114-20. [Medline].
Enterline PE, Henderson VL, Marsh GM. Exposure to arsenic and respiratory cancer. A reanalysis. Am J Epidemiol. Jun 1987;125(6):929-38. [Medline].
Ford M. Arsenic. In: Goldfrank LR, Flomenbaum NE, et al, eds. Toxicologic Emergencies. 1994:1011-1029.
Fowler BA, Weissberg JB. Arsine poisoning. N Engl J Med. Nov 28 1974;291(22):1171-4. [Medline].
Franzblau A, Lilis R. Acute arsenic intoxication from environmental arsenic exposure. Arch Environ Health. Nov-Dec 1989;44(6):385-90. [Medline].
Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet. Dec 16 2006;368(9553):2167-78. [Medline].
Heinrich-Ramm R, Mindt-Prufert S, Szadkowski D. Arsenic species excretion in a group of persons in northern Germany-- contribution to the evaluation of reference values. Int J Hyg Environ Health. Jul 2001;203(5-6):475-7. [Medline].
Heyman A, Pfeiffer JB, Willett RW, Taylor HM. Peripheral neuropathy caused by arsenical intoxication; a study of 41 cases with observations on the effects of BAL (2, 3, dimercapto-propanol). N Engl J Med. Mar 1 1956;254(9):401-9. [Medline].
Karagas MR, Le CX, Morris S, et al. Markers of low level arsenic exposure for evaluating human cancer risks in a US population. Int J Occup Med Environ Health. 2001;14(2):171-5. [Medline].
Kyle RA, Pease GL. Hematologic aspects of arsenic intoxication. N Engl J Med. Jul 1 1965;273:18-23. [Medline].
Lee AM, Fraumeni JF Jr. Arsenic and respiratory cancer in man: an occupational study. J Natl Cancer Inst. Jun 1969;42(6):1045-52. [Medline].
Massey EW. Arsenic neuropathy. Neurology. Aug 1981;31(8):1057-8. [Medline].
Moyer TP. Testing for arsenic. Mayo Clin Proc. Dec 1993;68(12):1210-1. [Medline].
Neubauer O. Arsenical cancer. Br J Cancer. 1947;1:192-251.
Watanabe C, Kawata A, Sudo N, et al. Water intake in an Asian population living in arsenic-contaminated area. Toxicol Appl Pharmacol. Aug 1 2004;198(3):272-82. [Medline].
Further Reading
Keywords
arsine gas, heavy metal toxicity, arsenic ingestion, arsenic poisoning, arsenical pesticides, arsenic exposure
