Arsenic Toxicity

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, Ayurvedic medications, 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).

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 exposure has also been associated with incident type 2 diabetes.[12]  

In the Strong Heart Family Study, arsenic exposure was measured in urine samples from 1,337 American Indian adults (average age 30.7 years, 61% female) and echocardiographic assessment was performed. With a two-fold increase in urinary arsenic, the researchers found a 47% greater chance of left ventricular hypertrophy in the group as a whole, and a 58% greater chance in participants with increased or high blood pressure (blood pressure at least 120/80 mm Hg or using pressure-lowering medication). The participants drank water from private wells in areas where groundwater is contaminated with arsenic. None of the participants had diabetes or heart disease at the start of the 5-year study.[13]

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).

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), in 2020, there were 528 single exposures related to arsenic (excluding pesticides) and 14 exposures related to arsenic-containing pesticides.[14]

Ayotte et al mapped out the probability of high (> 10 μg/L) arsenic levels in domestic wells in the coterminous United States. These authors estimated that of the approximately 44.1 million people in the US who use water from domestic wells, 2.1 million are exposed to water with high arsenic levels.[15]

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.[16, 17]  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.[18]

Men are more likely to experience industrial arsenic exposure than women. 

According to the American Association of Poison Control Centers' (AAPCC) National Poisoning Data System (NPDS), two patients suffered major effects but no deaths were reported from exposure to nonpesticide arsenic exposure in 2020.[14]

An association between exposure to arsenic and the development of Alzheimer disease has been proposed.[19]  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.[20, 21]

Arsenic exposure is usually suicidal, malicious, homicidal, or occupational. To reveal the exposure, record a careful work history on individuals with symptoms of a painful peripheral neuropathy. If the setting is not occupational, a careful epidemiologic history of those affected and those unaffected must be undertaken.

Exposure to arsine gas is usually the result of an occupational accident; in most cases, the worker presents promptly and ideally is brought in with the material safety data sheet (MSDS). One case report indicates that the presentation may be more insidious: In this report, a man in his 20s presented to an emergency department complaining of bloody urine and vomiting 34 hours after an apparent exposure to arsine in the workplace. Laboratory evaluation revealed arsenic in his blood and urine, and an industrial hygiene evaluation of his worksite was able to reproduce his exposure.[22]

Identifying unusual cases requires a careful history regarding dietary and nutritional habits, particularly the use of nutritional supplements and ayurvedic medicines, hobbies, and alcohol abuse.[23]

Often, patients with neurologic symptoms are subjected to  so-called heavy metal screens by their primary care practitioners or even neurologists. Often, the laboratories used are not the standard medical reference laboratories, and the results are of questionable reliability. In other cases, the results are reported as concentration of total arsenic in urine or blood, which is not generally accepted as valuable in the determination of possible exposure or toxicity.

In inorganic arsenic poisoning, clinical effects depend on the chronicity of exposure, as follows:

• Acute exposures generally feature the choleralike gastrointestinal symptoms of vomiting (often bloody) and severe diarrhea (which may be rice-watery in character and is often bloody). Dehydration and shock may result. Mees lines (white bands across the fingernails and toenails) and alopecia may occur after several weeks.

• Individuals exposed to arsenic may have abnormalities in keratin-containing tissues such as hair and fingernails. Fingernails may display Mees lines, which are opaque horizontal lines that correlate with a period of increased arsenic exposure (see the image below); however, note that Mees lines may also result from Hodgkin lymphoma, carcinoid tumors, and chemotherapy (eg, cyclophosphamide, vincristine, doxorubicin).[24]  Skin may have hypertrophic regions known as arsenical keratosis, which may be precancerous. 

  Mees lines, or leukonychia, are transverse white bands with no palpable ridges that appear on the fingernails as a result of arsenic poisoning, certain cancers, and treatment with certain chemotherapy agents. Courtesy of Wikimedia Commons (Author Yannick Trottier) (https://commons.wikimedia.org/wiki/File:Mees%27_lines.jpg).

• Chronic toxicity is more insidious and may manifest as a classic dermatitis (hyperkeratosis with a classic "dew drops on a dusty road" appearance)[25] or peripheral neuropathy (usually a painful paresthesia that is symmetrical and stocking-glove in distribution). Motor weakness and ascending paralysis similar to Guillain-Barré syndrome may develop.

• Multiple reports of cardiac arrhythmias exist in the literature, with abnormalities including prolongation of the QT interval, torsade de pointes, and ventricular fibrillation after acute arsenic intoxication.

• Chronic hepatic and renal damage is common with chronic exposure.

Toxicity from arsine gas exposure manifests as headache, abdominal pain, nausea vomiting, acute hemolysis, hemoglobinuric renal injury, and death. Hemoglobinuria causes the urine to appear black (see the image below), and the patient becomes rapidly obtunded and shocky. Shaking chills are often described in these patients.

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

Children may encounter arsenic trioxide as a rodenticide or herbicide. Examine for both arsenic and cholinesterase-inhibitor exposure. Possible transdermal absorption from exposure to pressure-treated wood, now banned for use by the US Environmental Protection Agency, has been reported.

Adults may be exposed through work in a metal foundry, mining, glass production, or the semiconductor industry.

Arsenic has been found to contaminate such common items as wine, glues, and pigments. Arsenic is commonly found in many foods both in its apparently nontoxic organic form and also in the more toxic inorganic form. Such arsenic has been reported in milk and dairy products, beef, pork, poultry, and cereal. Arsenic is also often found in rice, representing a potentially serious source of exposure in certain at-risk populations.

Arsenic exists in significant concentrations in some shallow wells dug for provision of clean water in some underdeveloped countries.

Arsenic screening prior to fractionation

Retrospective data analysis of urine arsenic results from previously tested samples concluded that performing a total arsenic screen before fractionation reduces the number of samples requiring fractionation by more than 91%.[26] A reflex approach of either testing for total arsenic or a heavy metal panel that includes total arsenic can function as a screening test to determine which samples need further evaluation for potential arsenic toxicity.[26]

Obtain a complete blood cell count (CBC) with indices and a reticulocyte count. Microcytic hypochromic anemia is common. Acute hemolytic anemia is characteristic of arsine exposure. Measure serum electrolytes, including calcium and magnesium, particularly in patients with severe vomiting and diarrhea. Type and screen or crossmatch blood for the transfusion in patients exposed to arsine gas.

A test for plasma arsenic concentrations is helpful but rarely available until after the decision to treat is made. Blood arsenic concentrations should not exceed 50 mcg/L. In patients with arsenic poisoning, blood arsenic concentrations commonly range from several hundred to several thousand micrograms per liter. The reported half-life of arsenic in blood immediately following ingestion is in hours, while whole-body clearance may be in days or months and is apparently dose-related.

Urine studies

A 24-hour urine collection for total arsenic excretion can be diagnostic and useful following therapy. A 24-hour clearance of more than 50 mcg is unusual (be sure the patient has not consumed seafood for at least 3 days prior to urine collection). Because nutritional sources of arsenic are not unusual, the laboratory must "speciate" the arsenic into organic and inorganic moieties. The inorganic arsenic is responsible for symptoms and signs of arsenic toxicity. This point is extremely important, since using just the total arsenic level may lead to unnecessary treatment for many patients.

Prior to urine colletion, patients should be instructed to avoid consuming any seafood for at least 7 days. Seafood contains a high concentration of protein-bound arsenic, which is not considered harmful but may lead to an elevated total arsenic level in urine. Elevated urine total arsenic in the setting of recent seafood consumption is unlikely to be clinically meaningful and may lead clinicians down the path of inappropriate treatment.

Various species of arsenic may be recovered in a urine specimen. The human body begins to metabolize inorganic arsenic into various organic forms after a short period of time. Metabolites include methylarsonic acid (MMA) and dimethylarsenic acid (DMA). It should be possible for the laboratory to separate these species from the usual dietary organic forms.

Non-targetted testing, such as urine assays for multiple heavy metals should rarely (if ever) be performed and should be interpreted with caution. Slight elevations above the reference range of urine arsenic are unlikely to represent arsenic poisoningin the absence of clinical signs and symptoms of arsenic toxicity.  

Additional urine studies may include the following:

• Obtain a urine pregnancy test in women of childbearing age.
• Obtain a serum acetaminophen level in cases of intentional ingestion.

An abdominal radiograph may reveal the presence of radio-opaque densities and may resemble an upper GI series.[27]

Nerve conduction studies may confirm the peripheral neuropathy. This may be particularly important because the classic stocking-glove distribution suggests another etiology.

Cardiac arrhythmias and, in rare cases, cardiac failure have been reported as resulting from arsenic toxicity. Electrocardiography is therefore indicated.

Treatment of acute inorganic arsenic toxicity is supportive. Chelation therapy should be considered in symptomatic patients. The efficacy of chelation therapy in providing either laboratory or clinical improvement in intoxicated patients is lacking. Chelation is not indicated for arsine gas exposure. 

Generally, organic arsenical compounds found in the urine are not an indication of arsenic toxicity and do not warrant therapeutical intervention.

Arsenic clearance by dialysis is substantial, and hemodialysis may be indicated if available within a short time after exposure. However, hemodialysis, in the absence of renal failure, has not been shown to alter medical outcome. 

Once arsenic distributes into the tissues, treatment may be unsuccessful. Clinical trials are not available, but attempting to remove arsenic from the plasma before it reaches the tissues makes sense.

In arsine exposure, hemolysis may be severe and life threatening, and no data suggest that chelation therapy can alter this. Arsine appears to rapidly bind to the erythrocytes, making them likely to lyse and release more toxin to contaminate other cells. The use of multiple transfusions and perhaps exchange transfusion may be necessary.

Many patients will develop profound peripheral neuropathy requiring extensive rehabilitation. Rehabilitation should be started as promptly as the clinical picture allows.

Hemodynamic stabilization is of primary importance, and large amounts of crystalloid solutions may be required because of significant gastrointestinal (GI) losses (ie, vomiting, diarrhea). In the face of acute blood loss, the use of blood products may be critical in sustaining the life of the victim.

The use of GI decontamination is controversial and may confuse the clinical picture. For acute arsenic ingestions, orogastric lavage is recommended if the patient presents rapidly or plain radiography indicates that arsenic is present in the stomach. Activated charcoal does not adsorb arsenic appreciably and is not recommended for patients in whom co-ingestants are not suspected. Whole bowel irrigation with polyethylene glycol may be effective to prevent GI tract absorption of arsenic. The use of invasive gastric-emptying procedures has been reported in dire cases, but these attempts do not seem to be fruitful.

Do not delay provision of definitive chelation therapy and hemodialysis.

Chelation should be performed in patients with symptomatic arsenic toxicity, although the evidence of therapeutic benefit from chelation derives largely from animal studies. Chelation is principally useful for acute toxicity. In such cases, chelation should be started as soon as possible, because its efficacy declines rapidly with increasing time after exposure.[28]  Chelation should be performed in consultation with a medical toxicologist, since it carries risks and not all cases of arsenic toxicity require chelation.

The following agents are used for chelation of arsenic[29] :

• Dimercaprol (British anti-lewisite [BAL]
• Succimer (dimercaptosuccinic acid [DMSA])
• Dimerval (dimercaptopropane sulfonate [DMPS])

In the United States, dimercaprol is the first-line agent for treating arsenic poisoning, but it is often in short supply. In animal experiments, repeated administration of dimercaprol has increased the brain uptake of arsenic.[30] Succimer and dimerval, which are water-soluble analogs of dimercaprol, have a higher therapeutic index than dimercaprol, but succimer is licensed in the United States only for use in childhood lead poisoning, and dimerval is not licensed for use in the US, although it is the international drug of choice for this indication.[29]

Sterile abscesses after the use of dimercaprol (BAL in oil) are not unusual. They initially may appear like erythematous macules, which spread or coalesce, and may continue to drain for some time.

Consultations may include the following:

• Consult a hematologist and nephrologist in cases of arsine exposure.
• Neurology and physiatry consultations are appropriate in cases of arsenic-induced neuropathy.
• Consultation with a medical toxicologist conversant with the use of chelation therapy may be very useful.
• Psychiatric consultation is necessary before discharge if the arsenic ingestion was intentional.

Perform a careful neurological evaluation in follow-up of all patients because the peripheral neuropathy, which may develop after an acute exposure, may not appear for 2-3 weeks.

Chelation should be performed in patients with symptomatic arsenic toxicity, although the evidence of therapeutic benefit from chelation derives largely from animal studies. Chelation is principally useful for acute toxicity. In such cases, chelation should be started as soon as possible, because its efficacy declines rapidly with increasing time after exposure.[28]

Class Summary

Bind heavy metals and to hasten excretion. By binding in plasma, they render heavy metals nontoxic.

Dimercaprol (BAL in Oil)

First-line agent available in the US for treating arsenic poisoning. Often in short supply, is one of the antidotes considered essential to be stocked by every ED.

Administered IM q4h, mixed in a peanut oil base. Excreted in urine and bile. May be administered to patients with renal failure.

Succimer (DMSA)

Licensed by the FDA for use only in childhood lead poisoning. Has been used worldwide as a heavy metal chelator and has been efficacious in treating arsenic intoxications. In the US, is only available in a bead-filled oral capsule of 100 mg.

Dimerval (DMPS)

Internationally accepted DOC for treating most heavy metal poisonings. Not licensed for use in the US and must be obtained from Helytex in Houston. Available as either a parenteral or oral form.