Arsenic Toxicity

Updated: May 30, 2017
  • Author: Adam Blumenberg, MD, MA; Chief Editor: David Vearrier, MD, MPH  more...
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Overview

Practice Essentials

Arsenic toxicity can occur through industrial exposure (see the image below), from contaminated wine or moonshine, or due to malicious intent. It may also occur through heavy metal contamination of herbal preparations and so-called nutritional supplements. A resurgence of interest in arsenic as a medicinal agent for the treatment of acute promyelocytic leukemias, multiple myeloma, myelodysplastic syndromes, and assorted resistant solid tumors may potentially contribute to increases in arsenic exposure. [1, 2]

"Blackwater" urine due to massive hemolysis, from "Blackwater" urine due to massive hemolysis, from a patient exposed to arsine at a gas tank cleaning operation.

See Clues on the Skin: Acute Poisonings, a Critical Images slideshow, to help diagnose patients based on their dermatologic presentations.

Signs and symptoms

Arsenic exposure is usually associated with suicide, malicious intent, homicide, or occupational exposure. A detailed history to determine the exposure includes the following:

  • Careful work history on individuals with a painful peripheral neuropathy
  • Careful history regarding dietary and nutritional habits (eg, use of nutritional supplements and ayurvedic medicines, alcohol abuse) and hobbies

Clinical effects of arsenic toxicity depend on the chronicity of exposure(eg, acute, chronic) and chemical form (eg, arsenic, trivalent arsenic, arsine gas). Frequently, patients exposed to arsenic have a garlic smell to their breath and tissue fluids.

Acute severe arsenic poisoning manifests with the following signs and symptoms:

  • Tachycardia, hypotension, and even shock
  • Altered mental status, delirium, coma, seizures (acute encephalopathy)

Acute trivalent arsenic poisoning manifests as follows:

  • Prominent gastrointestinal (GI) signs – Vomiting (often bloody) and severe cholera-like diarrhea (may be rice-watery, often bloody); these patients may experience dehydration and hypovolemic shock
  • Cardiovascular effects – Myocardial dysfunction, capillary leakage, diminished systemic vascular resistance, ventricular dysrhythmias
  • Central nervous system (CNS) manifestations – Seizures, coma, encephalopathy, and cerebral edema

Chronic trivalent arsenic poisoning has an insidious presentation, as follows:

  • May manifest as a classic dermatitis (hyperkeratosis with a  "dew drops on a dusty road" appearance) or peripheral neuropathy (usually a painful, symmetrical paresthesia with stocking-glove distribution);
  • Hepatic and renal damage are commonly present (multiorgan involvement)
  • Fingernails: Whitish lines (Mees lines) that look like those from traumatic injuries

Arsine gas exposure manifests with an acute hemolytic anemia and shaking chills.

See Presentation for more detail.

Diagnosis

Laboratory testing

  • Complete blood count: Microcytic hypochromic anemia is common; with arsine exposure, acute hemolytic anemia is common
  • Serum electrolyte levels, including calcium and magnesium
  • Type and screen or cross-match blood for possible transfusion in patients exposed to arsine gas
  • Plasma arsenic concentrations are potentially helpful, but results are usually not available until hours to days after treatment decisions have been made
  • Urinalysis: Urine spot test for arsenic and 24-hour urine collection for total arsenic excretion; patient must not have consumed seafood for at least 3 days prior to urine collection; laboratory must “speciate” the arsenic into organic and inorganic moieties, because the inorganic form is responsible for symptoms and signs of arsenic toxicity
  • Urine pregnancy test
  • Serum acetaminophen levels

Other studies

  • Abdominal x-ray: May reveal radio-opaque densities; may resemble an upper GI series
  • Nerve conduction studies: May confirm peripheral neuropathy
  • Electrocardiography: May reveal cardiac arrhythmias/failure from arsenic toxicity

See Workup for more detail.

Management

Treatment of acute arsenic toxicity is supportive. Chelation therapy may be necessary in symptomatic patients; however, the use of chelators in patients exposed to arsine gas is controversial.

  • Support airway, breathing, and circulation
  • Hemodynamic stabilization: May include infusing large amounts of crystalloid solutions and the use of blood products
  • Acute arsenic ingestions: Orogastric lavage if the patient presents rapidly or plain radiography indicates that arsenic is present in the stomach; whole bowel irrigation with polyethylene glycol may be effective to prevent GI tract absorption of arsenic
  • Definitive chelation therapy; may be controversial for argine gas toxicity
  • Hemodialysis

Pharmacotherapy

The following chelating agents are used in the management of arsenic toxicity:

  • Dimercaprol
  • Succimer
  • Dimerval

See Treatment and Medication for more detail.

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Background

Arsenic, element 33, has a long and nefarious history; its very name has become synonymous with poison. In the 15th and 16th centuries, the Italian family of Borgias used arsenic as their favorite poison for political assassinations. Some even have suggested that Napoleon was poisoned by arsenic-tainted wine served to him while in exile.

The metal was reported as the causative agent in an outbreak of food-borne illness after a church gathering in which the coffee urn was apparently criminally contaminated with arsenic. This highlights the need for an index of suspicion when multiple individuals present to an emergency department temporally related and with similar symptoms and circumstances. [3]

Arsenic is typically considered a heavy metal and shares many toxic characteristics with the other heavy metals (eg, lead, mercury). Arsenic is ubiquitous in the environment. It ranks 20th in abundance in the earth's crust, 14th in seawater, and 12th in the human body. [4] In nature, arsenic exists in the metallic state in 3 allotropic forms (alpha or yellow, beta or black, gamma or grey) and several ionic forms.

Arsenic has been used as a medicinal agent, a pigment, a pesticide, and an agent of criminal intent. In the form of chromated copper arsenate (CCA), it was once used as part of the treatment to render architectural wood immune to pest infestation.

CCA was banned for use in the United States by the Environmental Protection Agency (EPA) in 2003, but a great deal of the treated wood continues to exist in the form of decks and other structures exposed to the elements. Data suggest that a significant quantity of arsenic may leach out from such wood into landfills and into the interiors of homes with existing CCA-treated decks. [5, 6, 7] Given the durability of the CCA-treated wood, such exposures may continue for decades. In the rodent model, exposure to CCA may produce significant renal pathology.

Arsenic may be found as a water or food contaminant, particularly in shellfish and other seafood, and often contaminates fruits and vegetables, particularly rice.

Currently, arsenic poisoning occurs through industrial exposure, from contaminated wine or moonshine, or because of malicious intent. In industry, arsenic is primarily used in the production of glass and semiconductors.The possibility of heavy metal contamination of herbal preparations and so-called nutritional supplements must also be considered. There has been a resurgence of interest in arsenic as a medicinal agent for treatment of acute promyelocytic leukemias, multiple myeloma, myelodysplastic syndromes, and assorted resistant solid tumors. [1, 2]

Aresenic can contaminate well water or ground water. Contamination may occur from natural sources, or from hazardous waste (eg, mine tailings).

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Pathophysiology

Inorganic forms of arsenic are more toxic than organic forms. The trivalent forms are more toxic and react with thiol groups, while the pentavalent forms are less toxic but uncouple oxidative phosphorylation. Very few organ systems escape the toxic effects of arsenic.

Trivalent inorganic arsenic inhibits pyruvate dehydrogenase by binding to the sulfhydryl groups of dihydrolipoamide. Consequently, conversion of pyruvate to acetyl coenzyme A (CoA) is decreased, citric acid cycle activity is decreased, and production of cellular ATP is decreased. Trivalent arsenic inhibits numerous other cellular enzymes through sulfhydryl group binding. Trivalent arsenic inhibits cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and further production of acetyl CoA; it also blocks the production of glutathione, which prevents cellular oxidative damage.

Effects of pentavalent inorganic arsenic occur partially because of its transformation to trivalent arsenic; toxicity proceeds as outlined above. More importantly, pentavalent arsenic resembles inorganic phosphate and substitutes for phosphate in glycolytic and cellular respiration pathways. Consequently, high-energy phosphate bonds are not made, and uncoupling of oxidative phosphorylation occurs. For example, in the presence of pentavalent arsenic, adenosine diphosphate (ADP) forms ADP-arsenate instead of ATP; the high-energy phosphate bonds of ATP are lost.

Arsenic has been shown to produce oxidative stress. In a small pilot study of environmentally exposed children, arsenic altered monocyte superoxide anion production and inhibited nitric oxide production. [8]

Arsenic trioxide has been shown to cause a significant prolongation of cardiac action potential duration at many levels of repolarization producing conduction delay and increased triangulation. Electrolyte imbalance appears to enhance this toxicity. [9]

Arsenic appears to inactivate endothelial nitric oxide synthase, leading to a reduction in production and bioavailability of nitric oxide. Chronic arsenic exposure also has been associated with inducing/accelerating atherosclerosis, increasing platelet aggregation and reducing fibrinolysis. [10]  Long-term exposure to low to moderate arsenic levels has been associated with increased cardiovascular disease incidence and mortality. [11]

Arsenic is listed as a presumed carcinogenic substance based on the increased prevalence of lung and skin cancer observed in human populations with multiple exposures (primarily through industrial inhalation).

 

 

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Frequency

United States

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), in 2015, there were 667 human exposures related to arsenic (excluding pesticides) and 31 exposures related to arsenic-containing pesticides. The majority of the pesticide exposures occurred in children younger than 6 years (16 [52%] of 31), whereas almost 64% of the nonpesticide exposures occurred in adults (426 of 667). [12]

International

Worldwide, up to 100 million people are at risk of exposure to unacceptable arsenic levels in either well water or ground water. Numerous "outbreaks" of excessive arsenic in water and food from an assortment of natural and anthropological causes have occurred.

In Bangladesh, more than 95% of the water supply to over 138 million people is potentially arsenic contaminated at levels exceeding the US EPA and WHO action limits. [13, 14] If international efforts at elimination of the risk are unsuccessful, it is estimated that a substantial proportion of the Bangladesh population will develop arsenic-related diseases such as pulmonary and skin cancers as well as cardiovascular and renal disease.

In addition to the concentration of arsenic in the water, the prevailing diet existing in the affected areas may place the citizens at increased risk for toxicity from the arsenic. A population survey found that individuals who had diets deficient in certain B vitamins and antioxidants appeared to have greater risk of arsenic dermatoses. An inverse correlation was found between consumption of vitamins A, C, and E, riboflavin and folic acid, and the existence of dermatological manifestations or chronic arsenic exposure. [15]

 

 

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Mortality/Morbidity

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), 3 patients suffered major effects and 1 died from exposure to nonpesticide arsenic exposure in 2015. [12]

An association between exposure to arsenic and the development of Alzheimer disease has been proposed. [16] In addition, an apparent link exists between arsenic exposure and gestational diabetes and potential long-term effects on the infants born to mothers consuming arsenic-contaminated water (among other sources) during pregnancy. [17, 18]

Sex- and Age-related Demographics

Men are more likely to experience industrial arsenic exposure than women. As in many reported cases of poisoning, the majority of reports of exposure to arsenic-containing pesticides occur with children younger than 6 years as the victim (16 of 31), whereas, when nonpesticide arsenic exposure is involved, the majority are in adults older than 20 years (426 of 667). [12]

 

 

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