INTRODUCTION — Arsenic is a metalloid element. Acute high-dose exposure to arsenic can cause severe systemic toxicity and death. Lower-dose chronic arsenic exposure can result in subacute toxicity that can include skin changes and skin cancer, peripheral sensorimotor neuropathy, diabetes mellitus, cardiovascular effects, peripheral vascular disease, hepatotoxicity, and other conditions [1-3]. Latent or long-term effects of arsenic exposure include an increased risk of cancers, even after exposure has ceased.
Clinicians may need to consider arsenic exposure in the emergency care setting when treating those suspected of acute poisoning or those who present with prolonged or intermittent gastrointestinal symptoms that are atypical for most viral and bacterial enteric illnesses [4]. In the office setting, clinicians may need to consider questions concerning chronic arsenic exposure in patients whose source of water is well water, exposure from food (particularly rice products), and exposure in other environmental or occupational settings.
SOURCES OF EXPOSURE
Overview — Arsenic is a naturally occurring element found in the earth's crust and within numerous ores. It is classed as a metalloid because it complexes with metals; it also reacts with other elements such as oxygen, hydrogen, chlorine, carbon, and sulfur. Elemental arsenic is rare, and the element exists more commonly as organic or inorganic compounds [2-4].
Arsenical compounds can be grouped as inorganic, organic, and arsine gas (AsH3). They are further classified according to their valence states: elemental (0), arsenite (trivalent, +3), and arsenate (pentavalent, +5). Trivalent arsenic or arsenite compounds, both inorganic and organic, are considered the most toxic. However, other organic forms of arsenic, found in some fish and crustaceans, as well as other foods, consisting mostly of arsenobetaine (a trimethylated arsenic compound sometime called "fish arsenic"), arsenocholine, and arsenosugars, are excreted rapidly and are thought to be of negligible toxicity [2-6].
Human exposures can occur from natural sources, such as volcanic eruptions, and arsenic leaching from soil and rocks into drinking water. Exposure can also through inhalation, usually when workers are exposed to arsenic dusts as in smelting and refining [2,3,5].
Inorganic arsenic levels in food are generally low and, when present, usually occur from contaminated soil-derived foods such as rice [7-9]. Certain foods may contain potentially toxic levels of arsenic. As an example, some analyses have found high levels of inorganic arsenic in hijiki (hiziki) seaweed [10,11].
Of note, arsenic is no longer produced in the United States; all of the arsenic used in the United States is imported [5]. Human-made exposures derive from various sources including [3-5]:
●Use and manufacture of arsenic-containing pesticides – Although regulations ban their use in the United States, some products are still used in other countries and/or found in older stored supplies (eg, arsenic trioxide, sodium arsenite, calcium arsenite, arsenic acid), ant poisons, and herbicides (cacodylic acid) [12]
●Semiconductors (gallium arsenide)
●Fossil fuel combustion
●Smelting/refining
●Mining [13]
●Metallurgy
●Decorative glass-making
●Use of medicines/contaminated drugs, as found in some Asian folk remedies, homeopathic remedies, and herbal preparations [14,15]
●Some "moonshine" (illegally distilled alcohol) products [16]
●Contact with pressure-treated wood (eg, treated with wood preservatives containing chromium-copper-arsenate [CCA] or other arsenic preservatives)
●Contaminated well water from industrial or other sources [2]
●Contaminated soil and water from hazardous waste or superfund sites
●Ingestion of chicken that has been given feed supplements with arsenical compounds (used to control intestinal parasites) [17,18]
●Arsenicals have been used in medications [3] in the past to treat syphilis (arsphenamine) and skin conditions (Fowler's solution) and presently to treat trypanosomiasis (melarsoprol) and acute promyelocytic leukemia (arsenic trioxide) [19-21]
Drinking water — Chronic exposures to arsenic can occur from drinking water [2,22-24]. In some locations, this contamination presents an enormous health hazard, as in the case of the ongoing epidemic of arsenic poisoning in West Bengal, India, and Bangladesh. High levels of arsenic leaching from natural underground sources have contaminated newly drilled wells, leading to more than one million people drinking arsenic-contaminated water (above 50 mcg/L) [2,25-29]. Thousands of people living there have been found to have arsenic-related skin lesions, liver problems, decreased motor function, and neuropathy [30].
Although less common, there have also been case reports of arsenic poisoning in the United States due to contaminated well water, and in rural Australia, from stream water thought to be contaminated from a nearby mine [31,32].
The greater focus of the United States and other countries has been on the potential long-term adverse health outcomes from chronic exposures to much lower doses of arsenic in drinking water (below a level that causes acute clinical manifestations) that could lead to future increased risk of cancer (see 'Cancer' below) and other health problems. Age at first exposure to high levels of arsenic in drinking water has also been related to increase risks of various cancers decades later [33]. To reduce the risk of cancer and other chronic effects, the US Environmental Protection Agency (EPA) lowered the arsenic standard for drinking water from 50 parts per billion (ppb) to 10 ppb, and the US Food and Drug Administration (FDA) has set 10 ppb for bottled water [23,34]. In the United States, drinking water generally contains an average of 2 mcg/L (2 ppb) of arsenic, although 12 percent of water supplies from surface water sources in the North Central region of the country and 12 percent of supplies from ground water sources in the Western region have levels exceeding 20 mcg/L (20 ppb) [5].
Dietary ingestion — Small amounts of inorganic arsenic is also consumed in the diet. United States dietary intake of inorganic arsenic has been estimated to range from 1 to 20 mcg/day [5]. There have also been concerns about elevated arsenic levels detected in some samples of apple and grape juice [35]. The FDA performed testing from 2005 to 2011 in 160 apple juice samples from several countries, noting mild elevation of the toxic arsenic species in some samples, but has not yet set a reference range for juices [34,36]. Specific source of the arsenic contamination is unclear, but concerns have been raised about arsenic residues from arsenic-containing pesticides, particularly from imported juices (banned in the United States, but still used in other countries), or contaminated water used in the preparation process. The FDA has proposed an "action level" of 10 ppb for inorganic arsenic in apple juice (same as bottled water) [37].
In addition, arsenic contamination has been found in rice products [7,8,38]. This has raised particular concerns since rice cereal has been one of the first foods given to children. This has lead to updated recommendations for how to reduce arsenic exposure in a baby’s diet [39]. In one study, a toddler milk formula containing organic brown rice syrup as a sweetener had total arsenic concentrations of up to six times the EPA safe drinking water limit. In 2016,the FDA proposed a limit or "action level" of 100 ppb of inorganic arsenic found in infant rice cereal, which parallels guidance from the European Commission for rice foods for infants and young children [40]. These interventions to reduce early exposure to arsenic are particularly important as more information is emerging about the potential for latent effects from early-life arsenic exposure [40,41].
There is also evidence that inorganic arsenic may accumulate in the meat of chickens treated with a growth-promoting arsenical drug, "roxarsone" [42].
Pressure-treated wood — Pressure-treated wood has been preserved by pressure treatment with pesticides including chromate copper arsenate (CCA), ammoniacal copper arsenate (ACA), and ammoniacal copper zinc arsenate (ACZA) in order to protect it from insect infestation, decay, and marine environments. In 2003, United States manufacturers began a voluntary phase-out of arsenic-containing wood preservatives for wood used in some residential uses such as play structures, picnic tables, decks, and fencing [5,43]. However, there are still existing wood structures that have CCA-treated elements.
Episodes of arsenic poisoning have been described in workers sawing the wood who were exposed to arsenic through inhalation or skin contact and in people burning arsenical-treated wood who were exposed to the arsenic-contaminated smoke [5].
BIOLOGICAL BASIS OF DISEASE — Tasteless and odorless in soluble form, arsenic compounds are well absorbed after ingestion or inhalation. For most trivalent and pentavalent arsenical compounds dissolved in water, gastrointestinal absorption exceeds 90 percent, whereas poorly soluble compounds such as arsenic trioxide are less well absorbed [4]. Skin absorption is minimal acutely but could result in low-level absorption from chronic application of arsenic-containing products. Arsenic can cross the placenta and accumulate in the fetus [4].
Arsenic is readily taken up by red blood cells and then quickly distributed to other tissues. Peak serum levels are reached approximately 30 to 60 minutes after a single oral dose. A study of humans receiving one intravenous radioisotope of arsenic found that arsenic was cleared in three phases [4,44,45]:
●Phase I – Very rapid, in which more than 90 percent is cleared from the blood in the first two to three hours through redistribution and renal excretion
●Phase II – Three hours to seven days
●Phase III – 10 or more days
The majority of trivalent arsenic is metabolized via methylation to form monomethylarsonic acid (MMA) followed by dimethylarsinic acid (DMA) and excreted through the urine [4,46].
The rapid elimination from the blood explains why blood testing is less reliable, and there is more reliance on urine testing to measure arsenic, except in cases of the earliest acute poisoning. Arsenic is initially distributed to the liver, kidney, muscle and skin, and ultimately to all tissues including the brain [4]. Arsenic also crosses the placenta and can accumulate in the fetus.
Primary target organs for toxicity are the gastrointestinal tract, skin, bone marrow, kidneys, and peripheral nervous system. Chronic ingestion of small amounts of inorganic arsenic results in the highest concentration in hair, nails, skin, and tissues rich in cysteine-containing proteins [4,47].
Trivalent arsenic (+3), the most toxic form, avidly binds to sulfhydryl groups (proteins, glutathione, cysteine) and interferes with numerous enzyme systems, such as those involving cellular respiration (inhibiting pyruvate dehydrogenase [PDH]), gluconeogenesis and glucose uptake, and glutathione metabolism [4]. Pentavalent arsenic (+5) and arsine gas are converted to trivalent arsenic in vivo, but they may also have some direct effect on uncoupling oxidative phosphorylation [4].
Other mechanisms of actions are being studied to explain underlying latent disease risks (such as increased risk of cancer, disturbances of immune function) associated with early-life arsenic exposure, even at lower levels of arsenic exposure [41]. A major focus of this research is on "epigenetic reprogramming," or changes to gene expression (as from DNA methylation) that ultimately lead to future increased susceptibility to develop cancer [41].
CLINICAL TOXICITY AND PRESENTATION
Acute poisoning — Acute arsenic poisoning can occur after ingestions or, in workers, from acute inhalation exposure to high levels of arsenic dusts or fumes. Symptoms following acute, large exposures to inorganic arsenic may develop within minutes or hours.
Acute toxicity typically starts in the gastrointestinal system and includes nausea, vomiting, abdominal pain, and severe watery diarrhea [4]. There may be a garlic odor of the breath and stool in severely poisoned patients [12]. These symptoms are soon followed by dehydration, hypotension.
Acute arsenic poisoning can also result in QTc prolongation with subsequent torsades de pointes [48]. In severe cases, patients may experience cardiac arrhythmias, shock, and acute respiratory distress syndrome, and sometimes death [4,5,12]. In some cases, acute encephalopathy can develop and progress over several days, with delirium, coma, and seizures [4,49]. There have also been reports of more persistent central nervous system symptoms such as headache, confusion, and memory problems [4]. Renal injury can lead to proteinuria, hematuria, acute tubular necrosis, and anuria [12,50].
The severity of the toxicity and symptom presentation depends upon the form and dose of the arsenic compounds. Acute oral exposure to inorganic arsenic at doses of 600 mcg per kg body weight per day or higher has resulted in death [50].
If severely poisoned individuals survive the initial illness, they usually develop hepatitis and pancytopenia within a week and then may experience a painful sensorimotor peripheral neuropathy one to three weeks after the exposure. This has been described as beginning with distal paresthesias, followed rapidly by an ascending sensory loss and weakness, which can sometimes mimic Guillain-Barré syndrome [4,44,51-54].
The blood changes are usually reversible once exposure ceases. Partial recovery from peripheral neuropathy can occur in some cases, especially in the more mild cases of poisoning [52,55].
Other symptoms that can develop after severe acute poisoning include dermatologic lesions (patchy alopecia, diffuse pruritic macular rash, herpetic-like ulcers in the mouth), respiratory symptoms (dry, hacking cough), and/or Mees lines (horizontal 1 to 2 mm white lines on the nails, also called transverse leukonychia), which occur from a disturbance in the nail matrix keratinization [4,53,56,57]. It usually takes at least 30 days for the Mees lines to become visible.
Less severely acutely poisoned patients may experience persistent gastroenteritis and mild hypotension necessitating intravenous fluids, along with a metallic taste and irritated mucous membranes that can mimic pharyngitis [4].
Chronic and latent toxicity — Chronic effects can occur as the sequelae of acute poisoning (as discussed above) or as the result of chronic longer-term exposure to lower levels of arsenic. Latent toxicity (such as cancer) can occur after exposure has ceased.
Chronic exposure to arsenical compounds have occurred at work [3], usually through inhalation of arsenic-containing vapors or dusts, or through non-work environmental exposures, such as drinking arsenic-contaminated water. The clinical effects of chronic toxicity can have an insidious onset and thus be more difficult to diagnose. In chronic exposure, the skin manifestations and peripheral neurologic complaints are usually more prominent than the gastrointestinal symptoms; there is also an increased future risk of cancer [1].
Skin lesions — Different types of arsenic-related skin lesions have been described in the West Bengal and Bangladesh chronic poisonings [22,26,27,58]. Hyperpigmentation or hypopigmentation can be an early manifestation (picture 1). Hyperkeratoses and scaling, particularly diffusely on the palms and soles, also are quite characteristic (picture 2). Eczematous lesions have also been described. Skin manifestations, particular maculopapular eruptions, have been described following an acute curry-poisoning incident, and included maculopapular eruptions (sometimes in intertriginous areas), nail changes (Mee's or Beau's lines), and periungual pigmentation [59].
Skin carcinomas and Bowen's disease (squamous cell carcinoma in situ) (picture 1) are associated with latent effects of arsenic poisoning (see 'Cancer' below). A cohort study from Bangladesh found a dose-response relationship between exposure to arsenic in drinking water and the risk of premalignant lesions; compared with exposure to well water with a concentration of arsenic below 8.1 mcg/L, the adjusted odds ratio for premalignant skin lesions was 5.4 in people exposed to water with a concentration between 175.1 and 864 mcg/L [60]. In the United States, private well water is not regulated and so may have elevated levels of arsenic, placing exposed individuals at an increased risk for developing skin cancers [61].
Peripheral vascular disease with associated gangrene, called "Blackfoot" disease, has been described in relationship to chronic arsenic poisoning [62-64].
Neurologic manifestations — A symmetrical sensorimotor polyneuropathy is one of the most prominent symptoms of arsenic poisoning and can develop one to three weeks after acute poisoning or insidiously from chronic exposures.
Sensory symptoms tend to present first and to predominate, starting with numbness and tingling particularly in the soles of the feet and then later in the hands as well [44,51,54]. These may be the only symptoms in milder forms of arsenic polyneuropathy.
In more severe forms, the pain is more intense, particularly with even light touch, so that affected persons are unable to walk because of intense burning pain in the soles [54]. Cramping in the calves is another common symptom. An early sign on physical examination is diminished vibratory sense.
Progressive symptoms may then develop in a stocking/glove distribution with decreased pain, decreased sensation of touch and temperature, and symmetrical weakness, along with decreased deep tendon reflexes. Electrophysiological findings of arsenic neuropathy typically suggest a distal motor and sensory axonopathy [44].
Neurologic findings may also occur with chronic exposure. A study of 43 smelter workers exposed to inorganic arsenic dust for 13 to 45 years found moderate clinical symptoms and nerve conduction velocities that were significantly lower in two peripheral nerves as compared with matching referents [65]. There was a significant negative correlation between cumulative absorption of arsenic and nerve conduction velocities.
In a case series examining the health consequences of drinking arsenic-contaminated water in India, a sample of 21 of 40 individuals with skin lesions and elevated arsenic in biological samples were diagnosed with clinical neuropathy [26]. Most of the cases presented with distal paresthesias and distal hypesthesias in stocking and glove distribution, followed by limb pains and diminished or absent deep tendon reflexes in those most affected.
In chronic arsenic exposure, peripheral nerve manifestations may also be subclinical. A blinded study of copper smelting factory workers exposed to arsenic trioxide found that the incidence of both subclinical (reduced conduction velocity and amplitude measurements on nerve conduction studies without signs or symptoms of clinical neuropathy) and clinical neuropathy was greater in arsenic-exposed workers than in controls [66].
Although peripheral neuropathy has been the predominant neurologic manifestation of chronic arsenic poisoning, there have also been case reports of encephalopathy, described as cognitive impairment, disorientation, hallucinations, agitations, and memory problems [67-69]. It is not clear from these case reports, however, how much of the symptoms can be attributed to arsenic and how much to other potential work exposures or psychiatric problems [70].
Cancer — There are many epidemiological studies demonstrating an association between arsenic exposure and various types of malignancies, including cancers of the skin, bladder, kidney, lung, liver, and prostate [5,22,33,71-77]. This association has been the basis for regulatory actions setting limits for exposure, both environmental and occupational. (See 'Prevention' below.)
●Skin cancer – Ingestion of inorganic arsenic increases the risk of developing skin cancers (picture 1) [26,61]. Lesions commonly described are multiple squamous cell carcinomas, arising from the arsenic hyperkeratotic warts, as well as basal cell carcinomas arising from cells not associated with hyperkeratinization.
●Bladder cancer – There is an association between exposure to inorganic arsenic and bladder cancer [74,78]. In a cohort study from Taiwan comparing those exposed to water with an arsenic concentration of ≤10 mcg/L, the adjusted relative risks of bladder cancer in people consuming water containing arsenic in concentrations of 10.1 to 50, 50.1 to 100, and >100 mcg/L were 1.9, 8.2, and 15.3, respectively [78]. Age at exposure is an additional contributor to risk, with younger age at exposure associated with increasing bladder cancer mortality rates in adulthood [33]. (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Drinking water'.)
●Kidney – Arsenic in drinking water may be associated with transitional cell cancers of the renal pelvis and ureter [79]. In one case-control study, the odds ratios for transitional cell cancer were 1.0, 5.7, and 11.1 for median arsenic water concentrations of 60, 300, and 860 mcg/L, respectively. (See "Malignancies of the renal pelvis and ureter", section on 'Environmental causes'.)
●Lung cancer – There is evidence to support an association between arsenic exposure and lung cancer [33,74,80-82]. Observational studies from Chile have found a dose-response relationship, with evidence that the risk for lung cancer may begin to increase when arsenic concentrations in drinking water reach approximately 60 mcg/L [80,81]. The adjusted relative risk for lung cancer was 8.9 for drinking water with arsenic concentrations of 200 to 400 mcg/L [81]. In another study, mortality rates from lung cancer declined following the elimination of arsenic from drinking water [83]. There is also evidence of synergy between arsenic and smoking on the risk of lung cancer [81,82]. (See "Cigarette smoking and other possible risk factors for lung cancer", section on 'Occupational and environmental carcinogens'.)
●Liver – Arsenic exposure is believed to increase the risk of hepatic angiosarcomas, but it does not appear to be associated with hepatocellular carcinoma [84].
●Prostate – A number of studies have shown an association between arsenic exposure and prostate cancer incidence and mortality [75,85,86].
Cardiovascular — Some patients with acute promyelocytic leukemia treated with arsenic trioxide have been found to develop QTc prolongation and ventricular arrhythmias [87,88].
Chronic exposure to high levels of arsenic in drinking water have been associated with hypertension [89-91] and prolongation of the QTc interval [92].
A study in Bangladesh found a dose-response relationship between levels of arsenic in drinking water and the prevalence of hypertension [91]. Another large cohort study in Bangladesh found that blood pressure increased to a greater degree among individuals in the highest compared with lowest quartile of arsenic exposure (median follow-up 6.7 years) [93]. This relationship is similar to that seen with exposure to lead, which is also associated with the development of hypertension. (See "Lead exposure, toxicity, and poisoning in adults".)
In older observational studies, associations were noted between chronic exposure to high levels of arsenic in drinking water (>500 mcg/L) and adverse cardiovascular outcomes (including death). Subsequent studies have found cardiovascular-related deaths associated with lower levels of arsenic exposure as well. In a prospective study of 11,746 men and women in Bangladesh with mean follow-up of 6.6 years, there were 198 cardiovascular deaths of which 29 percent were estimated to be attributable to arsenic levels greater than 12 mcg/L in well water [94]. There was a dose-response relationship between increasing levels of arsenic in the well water and cardiovascular deaths, as well as a synergistic effect with cigarette smoking. A study from the United States also found associations between even low to moderate baseline urine arsenic levels and cardiovascular disease incidence and mortality [95]. In a subsequent study including Colorado residents, lifetime exposure to low-level inorganic arsenic in drinking water was associated with an increased risk of coronary heart disease [96].
Some studies have described the effect of arsenic on the vascular endothelial cells and proposed an association between arsenic exposure and the risk of cardiovascular outcomes such as coronary heart disease and stroke [97]; however, other epidemiologic studies have not found such an association [98].
Liver — Arsenic exposure has been associated with hepatic angiosarcoma (see 'Cancer' above). A study in Mexico found evidence of increased bilirubin and alkaline phosphatase concentrations in people exposed to arsenic in drinking water [99]. A study of 248 people in India with evidence of chronic arsenic toxicity found that hepatomegaly was present in 77 percent; among a subset who underwent liver biopsy, noncirrhotic portal fibrosis (now referred to as idiopathic noncirrhotic portal hypertension) was the predominant lesion [100].
Endocrine — Some studies have demonstrated an association between arsenic exposure and the development of type II diabetes mellitus [101,102]. Some incidence and prevalence studies have found a dose-response relationship between exposure to arsenic in drinking water and the risk of diabetes [101,103], whereas a large population-based cross-sectional study did not demonstrate an association between low levels of arsenic levels and prevalence of diabetes [104].
Respiratory — Arsenic exposure increases the risk of respiratory symptoms (cough, dyspnea, hemoptysis) and decreased lung function in a dose-response fashion [33,105,106]. The risk of lung disease is also higher among those exposed at a younger age. As an example, in one study from northern Chile where the water supply was contaminated by high levels of arsenic for over a decade, children born during the period of contamination had a 12-fold increase in mortality from bronchiectasis, and those exposed under the age of 10 years had a fivefold increase in risk [33].
Mortality — The Health Effects of Arsenic Exposure Longitudinal Study (HEALS) cohort found that chronic arsenic exposure through drinking water (>150 mcg/L) was associated with increased all-cause mortality (hazard ratio [HR] 1.68, 95% CI 1.26-2.23) and increased cardiovascular mortality (HR 1.92, 95% 1.07-3.43) over seven-year follow-up [28,94]. Another important finding was that decreasing arsenic exposure after chronic exposure did not reduce an individual's risk of mortality [28]. This implies that, in addition to removing exposure, other strategies are needed to prevent mortality from chronic exposure to arsenic.
Other
Reproductive and developmental — Since inorganic arsenic has been found to cross the placenta, there is a potential for adverse reproductive and developmental outcomes. There is evidence of increased infant mortality, spontaneous abortions, stillbirths, and preterm births associated with maternal arsenic exposure [107-110]. (See "Occupational and environmental risks to reproduction in females: Specific exposures and impact", section on 'Reproductive health impact'.)
Nursing — Limited data suggest that arsenic levels in breast milk are low even in women exposed to high levels of environmental arsenic [111,112]. This has potentially important implications for protecting infants from arsenic toxicity in regions where there are high concentrations of arsenic in the drinking water.
Childhood exposure — Children, in general, are more susceptible to toxicants, such as arsenic, for a variety of reasons including: more opportunities for exposure from increased hand-to-mouth behavior and breathing closer to the ground, differences in metabolism, and greater sensitivity of the developing nervous system to toxic insults [113]. Children are less able than adults to internally detoxify inorganic arsenic through methylation [113].
Children can become poisoned with arsenic through accidental ingestion, as in the case of two siblings who drank outdated arsenic-containing pesticide stored in a water bottle [50]. Children can also develop arsenic poisoning from playing on soil contaminated with arsenic from nearby mining or smelting or in hazardous waste sites. Another potential source of exposure is through contact with pressure-treated wood through playing on it, chewing it, or being in the vicinity when it is burned. (See 'Pressure-treated wood' above.)
DIAGNOSTIC EVALUATION — The evaluation of an individual with potential arsenic toxicity involves taking a medical/environmental history. (See "Overview of occupational and environmental health", section on 'Occupational and environmental history'.)
History and physical examination — The history should identify potential sources of exposures and symptoms consistent with arsenic poisoning.
The physical examination should include examination for skin changes, including areas of hyper and hypo pigmentation and hyperkeratotic lesions, Mee's lines in the nails, and peripheral neuropathy.
Potential environmental/occupational exposures should be documented and measured. Soil, air, and water can be sampled, if indicated, and arsenic levels determined through reliable laboratories or government agencies. Biological monitoring evidence can also be obtained to confirm excessive arsenic exposure. (See 'Biologic monitoring' below.)
Biologic monitoring — It is important to understand the limitations of all of the tests in order to be able to interpret the result of biologic monitoring.
●Urine tests – Urine tends to be the best measure for recent exposure because arsenic is rapidly cleared from the blood. Inorganic arsenic (III or V) will be metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), all of which are excreted predominately in the urine [6,114]. Unless otherwise requested, laboratories will usually report "total arsenic." In adults, a spot sample can be taken and measured for arsenic (mcg/L) and corrected for concentration by also ordering a urine creatinine (result becomes mcg As/g creatinine). If there has been fish, shellfish, seaweed, or sushi intake within the last 48 to 72 hours, the relatively nontoxic "fish arsenic" may lead to increased urine levels of total arsenic. A single meal of fish can increase total urine arsenic to more than 1000 mcg/L [6,46]. In general, it is important to request that the patient refrain from ingesting any fish, shellfish, or seaweed prior to ordering a urine specimen for arsenic. However, we have found elevated total arsenic levels (in absence of any inorganic species) even in individuals who deny any fish or sea food intake. This can happen because there are other foods, such as wild mushrooms, that contain minimally to nontoxic forms of arsenic, such as arsenobetaine [6].
Because a diet history is frequently uncertain, it is best to obtain speciation of elevated urine arsenic levels in order to avoid mislabeling a person with arsenic poisoning and to obtain an accurate assessment of inorganic (toxic) arsenic levels and toxic metabolites [115]. For speciation, the laboratory may report individual levels of inorganic arsenic, metabolites MMA and DMA, as well as the total arsenic. At the time of ordering a total urine arsenic test, we specifically request that speciation be performed if total levels are elevated, as some laboratories do not automatically speciate the urine when levels are elevated.
The measurement of arsenic in the urine is a good measure of current or very recent exposure, but not for more distant exposure, because arsenic is rapidly metabolized and excreted, with half of measurable oral dose (given to volunteers) excreted within the first 28 hours, and the rest tapered off over the next three days [6].
●Hair and fingernail testing – Since inorganic arsenic (to a much greater extent than organic arsenic) is taken up and bound in hair and fingernails, hair and nails may be good indicators for recent past exposures for the amount of inorganic arsenic absorbed during the growth period (hair grows at 0.4 mm per day, while nails grow at a rate of 0.1 mm per day). However, in a setting in which arsenic is present in air or dust that comes into contact with hair, it is very difficult to remove exogenous arsenic from hair and therefore to get a reliable reading [6,46]. Also contributing to the variability of results from hair and nail testing is lack of standardization for analyses. Commercial laboratory hair analyses for multiple elements including arsenic have been found to be highly inaccurate [116,117]. Determination of arsenic in hair and nails has been most useful in epidemiologic studies performed to evaluate environmental exposures of populations to inorganic arsenic. For individual patients with other signs or symptoms of arsenic poisoning thought due to past exposures, careful collection of appropriate hair samples (ideally from areas of slow growth such as pubic hair) or nails can be sent and analyzed for arsenic. Nail analysis usually requires clipping as much as possible from all 10 digits, either fingernails or toenails.
Acute exposure — In the case of an acute ingestion, abdominal radiographs may demonstrate gastrointestinal radiopaque material soon after ingestion, although the absence of opaque material does not rule out exposure. An electrocardiogram (ECG) should be obtained to assess the QTc interval as well as cardiac monitoring for tachyarrhythmias. In general, measurement of arsenic levels in urine is preferable to blood, since blood arsenic is cleared rapidly. In an emergency situation, a spot urine arsenic can be obtained prior to beginning chelation therapy. The urine creatinine in the spot sample should also be obtained to correct for urine concentration. During treatment, 24-hour urine arsenic monitoring is usually performed to follow the levels of arsenic excretion over time [4]. If the clinical presentation and history are highly suspicious for acute arsenic poisoning, treatment would need to be started urgently, prior to the return of the test results, which could take days. (See 'Biologic monitoring' above.)
In acutely symptomatic patients, urine arsenic levels are usually in the thousands of micrograms per liter. Because urine arsenic excretion can be intermittent, a definitive diagnosis usually is supported by finding a concentration greater than or equal to 50 mcg/L, or 100 mcg As/g creatinine in the absence of recent fish or shellfish intake, ideally with inorganic arsenic found in the urine [4].
Chronic exposure — In evaluating a patient for chronic arsenic exposure, either a 24-hour urine arsenic or spot urine arsenic and creatinine can be obtained after advising the patient to eat no fish, seaweed, or shellfish for 48 to 72 hours. The 24-hour urine determination is more accurate but less convenient. Regular surveillance for arsenic exposure in workers (for instance, after shifts) is done with measurements of spot urine arsenic and creatinine. (See "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
Because avoiding fish may not always eliminate non-inorganic species from the total arsenic result, the lab should be instructed to speciate or fractionate the specimen if the total arsenic is elevated, as noted above (see 'Biologic monitoring' above). If the total arsenic is elevated, but there are little to no inorganic species detected, one can usually assume that the urine arsenic has derived from the non-toxic arsenic species.
There have been varying results from studies reporting the relationship between work-related air exposures and urinary arsenic measurements, but based upon studies from copper smelters, 30 to 35 mcg As/g creatinine would be expected from exposure to air levels of arsenic averaging 10 mcg/m3 [46].
There have been studies that measure urinary arsenic levels to determine what are background exposure levels. Urinary levels reflect recent exposures that tend to correlate with arsenic ingestion form drinking water and dietary sources [114]. The Centers for Disease Control and Prevention (CDC) measures a random sample of participants in the National Health and Nutrition Examination Survey (NHANES) and tests their blood and urine for various chemicals or metabolites, such as arsenic. Results from the 2015 to 2016 survey found that the mean urine total arsenic was 4.41 mcg/L and (creatinine corrected) was 6.69 mcg As/g creatinine; the mean urinary inorganic-related species was 4.94 mcg As/g [118].
Laboratory testing to assess chronic toxicity, including laboratory parameters that could become abnormal days to weeks after an acute overexposure, should include a complete blood count, renal and liver function tests, ECG (looking for persistent QTc prolongation), and a urinalysis. If there are signs or symptoms of peripheral neuropathy, nerve conduction/electromyogram (EMG) testing should be obtained.
TREATMENT — The first step in treatment is the elimination of further exposure. In cases of acute exposure, care should be taken to avoid contamination of medical personnel during the decontamination process.
Acute poisoning — Initial therapy of severe arsenic poisoning relies on the provision of basic and advanced life support. Patients may be acutely ill and require aggressive critical care to preserve organ function [4]. Extracorporeal membrane oxygenation (ECMO), hemodialysis, and exchange transfusion may be helpful, although there are few data supporting their use [50]. Subsequent therapy usually involves chelation [4,119]. Consultation with a regional poison center and/or clinical toxicologist is recommended to assist with the management of the severely poisoned patient (see 'Additional resources' below). For pediatric poisonings in the United States, it is also possible to contact one of the regional Pediatric Environmental Health Specialty Units.
Careful attention must be paid to fluid and electrolyte balance.
The approach to the patient with acute arsenic poisoning includes:
●Decontamination – Skin decontamination is particularly important in cases of poisoning from arsenical pesticides. Remove contaminated clothing and wash the pesticide from the skin and hair taking care to avoid contaminating providers [12].
Gastrointestinal decontamination is controversial since arsenic poorly adsorbs to activated charcoal, cholestyramine, and bentonite. Use of activate charcoal in conjunction with airway protection is performed when even a small amount of absorption might be helpful [4]. Do not administer cathartics since arsenic typically causes diarrhea. Use nasogastric suction and administer activated charcoal [4,12].
●Fluids – Administer intravenous fluids to maintain adequate urine flow.
●Monitoring – Patients should have continuous cardiac monitoring. Additionally, fluid and electrolyte balance should be monitored.
●Chelation – Chelation therapy is usually indicated in patients with symptomatic arsenic poisoning. In a severely ill patient with known, or highly suspected, acute arsenic poisoning, chelation may need to be started before laboratory confirmation of arsenic levels is available [4,119]. Delaying administration of the chelator decreases the efficacy of chelation [119].
●Activated charcoal – The role of activated charcoal, other than in patients who have had recent oral ingestion, is uncertain, since arsenic is poorly adsorbed to activated charcoal. Nevertheless, some sources still recommend its use (administered with airway protection, if necessary, if the patient has a decreased level of alertness) [4].
●Whole-bowel irrigation – If radiopaque material is visualized in the gastrointestinal tract, it is reasonable to institute whole-bowel irrigation until the material is no longer seen on the repeat radiograph.
Chelation for acute poisoning — Two chelating agents are available in the United States: dimercaprol (British Anti-Lewisite [BAL]) and meso-2,3-dimercaptosuccinic acid (DMSA, succimer). A third drug, unithiol (sodium 2,3-dimercapto-1-propane sulfonate [DMPS]), may have the most favorable profile for the treatment of acute poisoning by inorganic arsenic. It can be given intravenously but has not been approved by the US Food and Drug Administration (FDA) for that use in the United States [4,119,120].
Both DMPS and DMSA are water-soluble analogs of BAL, have a higher therapeutic index than BAL, and, unlike BAL, do not redistribute arsenic to the brain [119]. In the United States, BAL tends to remain the initial chelating drug for severe, acute arsenic toxicity [4], particularly if the patient cannot take DMSA (oral) and because DMPS may not be available. The precise dosing for BAL for severe inorganic arsenic exposure poisoning has not been specifically established. Most of the regimens for arsenic treatment, particularly with BAL, rely on studies that are more than 20 years old, but are still recommended by respected toxicological experts [4,121]. A regimen for adults is 3 to 5 mg/kg of deep intramuscular BAL administered every four to six hours [4,121]. The endpoint for chelation is a 24-hour urinary arsenic concentration of <50 mcg/L.
Since BAL is administered intramuscularly, it can be used in patients with reduced consciousness or decreased gastrointestinal motility. BAL is associated with significant side effects (table 1) and has a narrow therapeutic:toxic ratio [4]. BAL is formulated in peanut oil, and patients must be carefully questioned about presence of known peanut allergy. It should also be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. BAL may not be very effective in the presence of arsenic-induced hepatotoxicity [121]. Although BAL helps to speed excretion of arsenic and may help to inhibit some of the toxic effects, it is not clear that administration will prevent the development of the peripheral neuropathy.
Chronic or subacute poisoning — There are few data to support the use of chelation in subacute or chronic arsenic poisoning, particularly since arsenic is so quickly excreted. The first order of treatment is identification of the source of exposure and removal from exposure. Therapy for subacute or chronic poisoning in the setting of ongoing or recent arsenic exposure may be reasonable, after all measures to stop exposure have been made and as an effort to more quickly enhance excretion of arsenic.
Chelation for chronic poisoning — There are few studies, with significant limitations, regarding the efficacy of chelation therapy (using DMPS or DMSA) in the setting of chronic intoxication [119]. Although chelation therapy may increase arsenic excretion and possibly lower arsenic concentration in some tissues, it is unclear whether or not this results in less morbidity or mortality related to chronic arsenic intoxication [119]. However, if one decides to proceed with chelation therapy for subacute or chronic severe toxicity, DMSA (an oral hydrophilic analogue of BAL) is the chelator of choice [4]. The dosing of DMSA is based on testing in children being treated for lead poisoning. The recommended dose from the manufacturer is 10 mg/kg per dose three times per day for five days, followed by 10 mg/kg per dose twice per day for two weeks. Although we have found this dosing to be acceptable in treating some adults for lead poisoning, the dose can become quite high, especially in heavier adults. Given fewer adult treatment data with DMSA, we have also used an adult dosing level of 500 mg twice per day for two weeks as a sensible maximum limit for treating adults with mild symptomatic lead poisoning, and similar dosing may be appropriate for treating arsenic poisoning until there are additional clinical data available for adults.
Adverse effects of chelating agents are listed in a table (table 1).
DMPS can be administered by oral, intravenous (IV), or intramuscular (IM) routes and one study reported its value in treating chronic arsenic toxicity [122]; it is not approved in the United States for this use but has been used in other countries [119,120]. When given IM, it is administered at 5 mg/kg per dose as a 5 percent solution; a typical regimen would be dosing every 6 to 8 hours on the first day, every 8 to 12 hours on the second day, and every 12 to 24 hours thereafter [4].
PREVENTION
General issues — Efforts should be taken to reduce exposures to inorganic arsenic, a recognized carcinogen, to the extent feasible, from both naturally occurring and man-made sources [3]. In the United States, the Occupational Safety and Health Administration (OSHA) regulates inorganic arsenic exposure in air in the workplace through a "permissible exposure limit" (PEL) of 10 mcg/m3 as a time-weighted average over an eight-hour work day [123]. The National Institute of Occupational Safety and Health (NIOSH) is more conservative and advises minimizing exposures to a recommended exposure limit (REL) of 2 mcg/m3 (15-minute exposure) [124].
The World Health Organization (WHO), in its 1993 guidelines for drinking water quality, reported that based on health criteria the guideline value for arsenic in drinking water should ideally be less than 10 mcg/L, but given measurement limitations the WHO recommended a provisional guideline value of 10 mcg/L [2,125].
In 2002, the US Environmental Protection Agency (EPA) lowered the maximum contaminant level for the amount of arsenic allowed in drinking water from 50 to 10 ppb (10 mcg/L) based upon review of carcinogenic risks [126]. Although this represented an improvement, and lowering of risks, there were still estimates of excess cancer risk (at 10 mcg/L) among 70 kg resident drinking 1 L of water of day for a lifetime, with estimated lifetime risk, per 10,000: for bladder cancer 12 and 23 (women and men, respectively), lung cancer 18 and 24 (women and men, respectively). At lower levels of arsenic, the estimate lifetime excess risk is lower. Some advocate for lower maximum containment level (MCL).
To reduce the exposure to potential arsenic-contaminated rice products, the 2012 American Academy of Pediatrics guidelines advised giving children more foods made from wheat and oats [127], and there are additional strategies for reducing exposure of arsenic in rice. The US Pediatric Environmental Health Specialty Units advised limiting consumption of foods higher in arsenic content, rinsing rice, limiting rice milk in children younger than 54 months of age, and reducing intake of foods containing high amounts of brown rice syrup [128]. (See "Overview of acquired peripheral neuropathies in children".)
Most of the arsenical pesticides (including the common sodium arsenate ant killer, "Terro") were banned for use in the United States in 1991, but they may still be found in use in other countries. Copper chromium arsenate (CCA), used as a wood preservative, was not included in that ban. The use of CCA in pressure-treated wood for residential uses in the United States was supposed to voluntarily cease by December 31, 2003. However, existing structures remain as potential sources of concern. Care should be taken never to burn pressure-treated wood in fireplaces or campfires [129].
Referral — Practitioners involved in the care of patients with arsenic poisoning, or patients who have questions about arsenic exposures, may find it helpful to consult with occupational/environmental medicine clinicians who can assist in the diagnosis of arsenic poisoning, in the arrangement for environmental/work site evaluations and interventions, and in evaluations for worker compensation. Occupational/environmental medicine clinicians can also help with the decision for chelation therapy and administration of appropriate therapy.
Clinicians specializing in Occupational and Environmental Medicine can be located by contacting the Association of Occupational and Environmental Clinics (AOEC), a group of occupational medicine clinics (frequently academically affiliated) with board-certified occupational medicine physicians (phone: 202-347-4976; website: www.aoec.org), or the American College of Occupational and Environmental Medicine Physicians (www.acoem.org).
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lead and other heavy metal poisoning".)
SUMMARY AND RECOMMENDATIONS
●The primary target organs for arsenic toxicity are the gastrointestinal tract, heart, skin, bone marrow, kidneys, and peripheral nervous system. (See 'Biological basis of disease' above.)
●Acute toxicity typically starts in the gastrointestinal system and includes nausea, vomiting, abdominal pain, and diarrhea. These symptoms are soon followed by dehydration, hypotension, and QTc prolongation. In severe cases, patients may experience cardiac arrhythmias, shock, acute respiratory distress syndrome, and sometimes death. (See 'Acute poisoning' above.)
●In chronic poisoning, the peripheral neurologic complaints and skin manifestations are usually more prominent than the gastrointestinal symptoms. Chronic arsenic exposure is associated with the later development of a variety of malignancies, respiratory disease, cardiovascular disease, and an increase in all-cause mortality. (See 'Chronic and latent toxicity' above.)
●Arsenic is rapidly cleared from the blood, so measurement of urinary arsenic either on a 24-hour urine collection or in a spot urine (along with a creatinine to correct for the concentration of the spot urine) is generally preferable. Although concentrations greater than or equal to 50 mcg/L or 100 mcg As/g creatinine in the absence of recent fish, seaweed, or shellfish intake strongly suggests arsenic exposure/poisoning, no conclusion can be drawn until fractionated testing confirms the presence of inorganic-related arsenic species. For more accurate assessment, at the time of ordering, clinicians should request specific measurement of inorganic arsenic species if the total level is elevated. (See 'Biologic monitoring' above.)
●Treatment of acute poisoning involves decontamination of the skin and gastrointestinal tract as appropriate for the exposure, administration of fluids, cardiac monitoring, and usually chelation. For serious poisoning, in which the patient cannot take oral medications, treatment can be with dimercaprol (British Anti-Lewisite [BAL]) or, preferably, with sodium 2,3-dimercapto-1-propane sulfonate (DMPS) in countries where the latter is available. For less severe poisoning, and where the individual can take oral medication, treatment can be with meso-2,3-dimercaptosuccinic acid (DMSA, succimer). (See 'Acute poisoning' above.)
