Arsenic
By Grace R. Williams, PhD, DABCC (CC, TC), FADLM
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Published in the March 2025 issue of Clinical & Forensic Toxicology News
The chemical element arsenic is one of the most notorious poisons known and its use as a homicidal agent during the European Renaissance is widely reported. While the modern individual in economically advantaged countries is relatively safe from acute arsenic poisoning (aside from occupational exposures), chronic exposures still occur frequently and carry significant health risks. In the United States, arsenic is the number 1 substance on the priority list from the Agency for Toxic Substances and Disease Registry (ATSDR), followed directly by lead and mercury (1). As a metalloid, arsenic cannot be destroyed in the environment. It can only change its form or become attached to or separated from particles. Thus, awareness and sequestration are the best strategies to avoid toxic exposures.
Given the nickname “inheritance powder” in the 19th century, the metallic element arsenic is infamous for its use in murder by poisoning. Arsenic is odorless, tasteless, and dissolves readily in many foods and beverages intended for consumption. Acute poisoning is characterized by gastrointestinal symptoms and can be mistaken for another illness like cholera or pneumonia, which were historically common. In 1840, James Marsh used a new version of a test he developed for arsenic detection as evidence in a murder trial, and the defendant was convicted of poisoning her husband (2). This is reportedly the first use of a forensic toxicology test for a murder conviction and the test remained in use, with modifications, until the 1970s. The scientific community embraced the new test and James Marsh was awarded the Large Gold Medal from the Royal Society of Arts, its highest accolade. Since a reliable test for arsenic existed, poisoners were more likely to be discovered and convicted, so the prevalence of arsenic poisoning declined. However, arsenic-containing compounds were still readily available for purchase in the form of rat poison and consumer products. It is thought that many unintentional arsenic poisonings resulted from the use of arsenic in pigments such as Paris Green, a popular paint color containing copper acetoarsenite that was used in a variety of consumer products, most notably wallpaper and insecticides (2). Arsenic was used in purportedly medicinal products for treating a variety of illnesses. Some evidence-based use of arsenicals included that of arsenic trioxide (Fowler’s Solution, 1878) for leukemia treatment and arsphenamine (Salvarsan, 1910) for syphilis. While arsenic is no longer utilized for syphilis treatment, arsenic trioxide (sold as Trisenox®) has been FDA-approved for the treatment of acute promyelocytic leukemia since 2000.
For most toxic exposures, the frequency of poisoning is dependent on the availability of the substance. Increasing regulation of arsenic-containing compounds has decreased availability and, thus, sinister exposures have dropped off precipitously. Although used as a homicidal agent since the time of antiquity, it wasn’t until 1851 that there were legal restrictions on the sale of arsenic. Public outcry led to an act of Parliament whereupon the Sale of Arsenic Regulation Act went into effect in England (3). This act required arsenic purveyors to maintain records of sales, including the purchaser’s name, the quantity sold, and its intended purpose. It did not restrict who could sell the poison, only that the purchaser be documented. In 1868 the English Pharmacy and Poisons Act defined who could call themselves a pharmacist and, thus, sales of arsenic-containing compounds were restricted to individuals who met certain criteria (4). In the United States, the American Pharmaceutical Association proposed similar legislation using England’s Pharmacy and Poisons Act as a template for the regulation of poison sales in the U.S., and by 1890, 33 states had adopted some version of this law (5).
Overall, arsenic abundance is relatively low in the earth’s crust but it is a major constituent of greater than 100 mineral species, the most common of which is arsenopyrite (6). The compounds are dissolved or distributed by natural environmental activities such as rain or volcanic eruptions and, thus, are widely distributed in soil and water. Additional distribution has resulted from the discharge of industrial wastes. Many common arsenic compounds readily dissolve and have contaminated sources of drinking water. As the results of chronic arsenic exposure became more well-known, standards were adopted for the maximum content of arsenic in drinking water. In 1942, the United States Public Health Service established a maximum arsenic content of 50 mcg/L for interstate drinking water carriers. In 2001, the Environmental Protection Agency lowered the standard to 10 mcg/ L which is still in place today (7).
The toxicity of arsenic greatly depends on the chemical species involved in the exposure. Arsenic occurs as organic or inorganic forms in a pentavalent or trivalent state. Research indicates that the trivalent arsenic (arsenite) is more toxic than the pentavalent form (arsenate), and both are orders of magnitude more toxic than organic species such as arsenobetain or arsenocholine which are created through biotransformation of arsenic in seafood (8). It is generally accepted that the decreased toxicity of the organic species may be attributed to the strength of the arsenic-carbon bond, which prevents the arsenic from detaching and interacting with cellular systems. Most mammalian species do not have the capacity to break this bond and so inorganic arsenic may not be formed by human consumption of organic arsenic compounds (9).
One of the most toxic forms of the element is arsine gas (hydrogen arsenide, AsH3), which is formed when arsenic comes into contact with an acid. Arsine is a colorless, flammable, non-irritating toxic gas with a mild garlic odor. It is an extremely potent hemolytic agent. Arsine gas may be encountered in metal industries such as the manufacture of semiconductors or in the refining of ores since it is present as an impurity in many mineral deposits. Death from arsine toxicity usually results from renal failure caused by blockages of the tubules by hemoglobin casts and this effect may be ameliorated by hemodialysis. As the toxicology profile of arsine is quite different from other forms of arsenic, it will not be discussed in further detail in this article.
It is known that arsenical compounds interfere with cellular respiration leading to tissue death (9, 10). The mechanism of this disruption is through several pathways. The first is the binding of arsenic to the sulfhydryl groups of enzymes and the prevention of their function. Arsenite is typically involved in this function and this enzyme inhibition has been demonstrated to inhibit the pyruvate oxidation pathway, tricarboxylic acid cycle, gluconeogenesis, and reduce oxidative phosphorylation in the electron transport chain (11). Another mechanism is the substitution of arsenate for phosphorous. Pentavalent arsenate is a phosphate analog and this homology may lead to the replacement of phosphate with arsenate resulting in disruption of essential mechanisms of homeostasis. Arsenate has been shown to replace phosphate in several essential biological reactions, including the synthesis of adenosine triphosphate and glucose-6-phosphate which may be used in either the glycolysis or pentose phosphate pathways. Replacement of the stable phosphorus ion in phosphate with the less stable arsenic leads to an increased rate of adenosine triphosphate hydrolysis, leading to the loss of high-energy phosphate bonds and a depletion of energy that decreases the effectiveness of cellular respiration. As a phosphate analog, arsenate could also exert toxic effects by interfering with bone metabolism and DNA synthesis. Competition between arsenate and phosphate has been proposed for many other enzymatic reactions, and there is an abundance of publications on the topic (6).
Human and animal data indicate that greater than 90% of an ingested dose of inorganic arsenic (arsenite or arsenate) is absorbed from the gastrointestinal tract. Organic arsenic compounds such as arsenobetain or arsenocholine found in seafood are ~80% absorbed. Less soluble compounds are absorbed to a smaller extent and absorption depends on the pH of the stomach and the size of the arsenic particle (10).
After absorption, organic forms of arsenic such as arsenobetain or arsenocholine appear to be excreted largely unchanged within 40-60 hours (8). The metabolism of inorganic arsenic is more complex as it is transported by the blood to other areas of the body with tissue partitioning being dependent on the oxidation state and hepatic biotransformation of the compounds. The metabolism of arsenic is accomplished by the reduction of arsenate to arsenite which is required before methylation can occur. While arsenite is regarded as the more toxic form of inorganic arsenic, this required reduction may be related to the undissociated form of arsenite predominating at physiological pH (the pKa is 9.23) (12). This unionized form of arsenite would enable transfer of the compound across cellular membranes and this property likely contributes to its enhanced distribution and toxicity. In vitro studies have shown that the cellular uptake of arsenite is greater than that of arsenate (10). The reduction reaction requires glutathione and is followed by methylation of arsenite to monomethylarsonic acid and dimethylarsinic acid in the liver by methyltransferases that use S-adeno-methionine as a co-substrate.
In humans, clearance of arsenic appears relatively rapid, with half-lives of 40-60 hours in blood although there is considerable variation in the published literature. In cancer patients treated with intravenous infusions of arsenic trioxide, the elimination half-lives for arsenate and arsenite were 17 and 18 hours, respectively. While the arsenic half-life in blood is short, an initial accumulation may be observed in the liver, kidneys, and lungs, although it is rapidly cleared. More persistent accumulations are observed in cysteine or phosphaterich tissues such as hair, nails, and skeleton. Elimination is primarily renal, with only a very low percentage excreted in the feces and urinary half-lives around 8-20 hours depending on the arsenic species. However, some studies have shown that small amounts of arsenicals may be detected for longer periods, with a triphasic elimination pattern and the last phase having a half-life of 8 days (10). While the published elimination half-lives in blood and urine vary, they are predominantly short and less than 2 days. Given the ethical considerations of in vivo arsenic research it is not possible to obtain detailed, concentration-dependent elimination profiles of arsenic pharmacokinetics in humans.
The signs and symptoms of acute and chronic inorganic arsenic poisoning are significantly different and thus the toxicology profile of arsenic will be sub-divided into acute and chronic exposures. No reports of deaths attributed to organic arsenic were located.
The estimated acute lethal dose of inorganic arsenic is 1-3 mg/kg per day. Classic acute poisoning is defined by hemorrhagic gastritis, hypotension due to volume loss, and cardiac abnormalities (6, 13). Acute poisonings most frequently present with gastrointestinal syndrome abdominal pain, nausea, vomiting, and diarrhea. Gastrointestinal syndrome is caused by the action of arsenic on the digestive tract and leads to paralysis of capillary control, general vasodilation, and transudation of plasma. There may also be sloughing off of intestinal mucosal tissue due to damage by arsenic. Symptom onset is rapid and may appear as early as eight minutes after ingestion although the formulation of the arsenic-containing substance will affect the timing of the poison’s release into the digestive tract. Acute cardiac effects of inorganic arsenic are extensive and include altered myocardial depolarization, arrhythmias, and ischemia. Specific EKG abnormalities that have been reported include torsades de points, QTc elongation, QRS lengthening, non-specific ST changes, and T wave flattening. Gastrointestinal syndrome and cardiomyopathy predispose the patient to hypotensive shock. Published reports of acute inorganic arsenic poisoning include damage to many organ systems (9). Some patients present with non-cardiogenic pulmonary edema related to the increased capillary permeability. A small fraction of patients will present with acute neurologic symptoms such as altered mental status, encephalopathy, seizures, and paresthesia, although these are more typically seen days to weeks after the exposure. The majority of acute and chronic arsenic exposure case studies do not report significant renal injury. However, some reports do include clinical signs of kidney damage from arsenic ingestion. These effects include proteinuria, hematuria, and acute renal failure (9). Given the close relationship between the renal and cardiovascular systems, the cause of renal injury may be a hypotensive shock, tubular injury, or direct effects of arsenic on tubule cells (11). In large acute ingestions, death often results from fluid loss and circulatory collapse. If the poisoned individual does survive the initial acute symptoms, sub-acute symptoms often develop days to weeks later such as hair loss and Guillain- Barré syndrome-like neuropathies.
Due to increased regulations of toxic substances, the modern individual is more likely exposed to inorganic arsenic through contaminated groundwater or occupational means rather than household products. The Department of Health and Human Services (DHHS), International Agency for Research on Cancer (IARC), Environmental Protection Agency (EPA), and the World Health Organization have all classified inorganic arsenic as a known human carcinogen. The association between chronic arsenic exposure and cancer is strongest for skin, lung, and bladder cancer. There is no scientific consensus on the mode of arsenic carcinogenesis.
The most common method for chronic arsenic exposure is drinking contaminated groundwater. The United States has several regions with greater than 0.5 probability that the groundwater contains greater than 10 mcg/L arsenic as determined by a U. S. Geological Survey (USGS) (14), these regions include much of Maine, Nevada, and several isolated areas around the great lakes. It is strongly advisable for individuals obtaining their drinking water from a well to get it tested for heavy metals prior to ingestion. Additional sources of exposure include occupational settings such as smelting factories or plants focused on the production of semiconductor chips.
Dermal symptoms predominate for chronic arsenic exposure. Commonly seen symptoms are keratinoses on the palms or soles of the feet, hyper- and/or hypopigmentation spots that tend to aggregate. The common appearance of the dark brown patches with scattered pale spots is sometimes described as “raindrops on a dusty road.” These symptoms have been consistently observed in humans with occupational, environmental, and medical exposures to arsenic via inhalation or ingestion. Patients with long-term arsenic exposure may also present with skin lesions or Mees’ lines. Arsenic exposure has links to basal cell carcinoma, as well as squamous cell carcinoma secondary to hyperkeratosis (15). Neurological symptoms of chronic arsenic exposure include a “stocking-glove” type distribution of dyskinesia, and patients often describe a painful tingling effect. In some chronic cases, physicians have reported loss of deep tendon reflexes and gait disturbances. Additional reported effects of oral exposure to inorganic arsenic include increased incidences of high blood pressure and circulatory problems. General depression of the hematopoietic system is also a sign of chronic arsenic exposure, including effects such as various anemias, granulocytopenia, thrombocytopenia, and myelodysplasia. These effects vary according to the population studies and in some populations have been absent (10). Lastly, there is a significant body of evidence that chronic arsenic exposure increases the risk of diabetes mellitus. This effect has been observed in populations from multiple countries including the United States, Bangladesh, and Taiwan.
Arsenic toxicity is a life-threatening condition and mandates aggressive treatment. Volume repletion, cardiac monitoring, and blood pressure support should be initiated. Chelation therapy should not be delayed in severely ill patients. The affinity of arsenic for thiol groups is exploited in chelation therapy for the treatment of arsenic poisoning. British anti-Lewisite was historically the chelator of choice, however; the significant adverse effects of this compound have led to a decline in its popularity, and more tolerable chelators such as succimer (2,3-dimercaptosuccinic acid) or dimercaptopropanesulfonic acid are often used in its place. Additionally, British anti-Lewisite is often difficult for clinicians to obtain even when it is indicated.
The most specific and reliable indicator of arsenic exposure is an elevated arsenic concentration in a 24-hour urine collection. Random or spot urine collection may also be used in an emergency. Arsenic clearance from blood is rapid and blood testing is often not the matrix of choice as it is prone to false negatives. Blood arsenic testing may be useful in cases of large exposures and those less than 24 hours prior. A typical modern arsenic test is performed via inductively-coupled plasma mass spectrometry and will include a reflex speciation assay if the total arsenic is elevated (greater than 10 mcg/ L) to determine the type of arsenic compounds present. The most common method for performing arsenic speciation analysis is high-performance liquid chromatography separation coupled to an inductively- coupled plasma mass spectrometry detector. The high-performance liquid chromatography portion of the instrument allows for species identification by matching the retention times of unknown substances to that of known standards. Method challenges include long analysis times, poor/inconsistent chromatographic separation, post-column carry over, and high analysis cost. It is also generally observed that arsenite will convert to arsenate over time which can be problematic for the stability of stored standards. A recent publication from the Mayo Clinic offers a new method utilizing ion chromatography in lieu of high-performance liquid chromatography coupled to an inductively-coupled plasma mass spectrometry system which appears to ameliorate these issues (8).
An unspeciated “total” urine arsenic is of virtually no utility in diagnosing toxic arsenic exposure unless the sample was obtained at least 5–7 days after any seafood ingestion, or there was some clear evidence of exposure to inorganic arsenic. An elevated total arsenic is not reflective of acute or chronic poisoning per se. Appropriate interpretation of urine or blood arsenic values must be accompanied by speciation to determine if inorganic arsenic and/or its metabolites are present. A speciation test will frequently report the concentration of organic arsenic, inorganic arsenic, and the two metabolites of inorganic arsenic—monomethylarsonic acid and dimethylarsinic acid. These compounds combined will constitute the total arsenic value reported. Due to the significant clinical and legal implications of arsenic testing results, interpretation assistance by the laboratory director is advisable in cases of elevated arsenic of any kind. If possible, a medical toxicology consult should be obtained prior to collecting the sample and this may be accomplished by contacting the local poison control center. Poisoning is a rare event in a patient’s life and many providers would benefit from assistance regarding arsenic testing. An expertly guided and informed process may prevent unnecessary confusion and anxiety on the part of the patient.
Grace R. Williams, PhD, DABCC is toxicology director and clinical chemistry associate director for Virginia Commonwealth University Health and assistant professor at the Virginia Commonwealth University School of Medicine, department of pathology, Richmond, Va.
The author has nothing to disclose.
From the humble tuna casserole to artistic displays of sushi, seafood is an integral component of the cuisine of most cultures. As a rich source of the omega-3 fatty acids thought to aid neurological development and cardiovascular health, seafood consumption is recommended by several health organizations, including the American Heart Association. However, reports of toxic chemicals and heavy metals in seafood have led many to question what’s really going in their mouths alongside that wasabi. This article will discuss two well-known toxic metals, mercury (Hg) and arsenic (As), and address common concerns related to their presence in seafood.
Both of these metals are found in multiple forms, with varying degrees of toxicological relevance. Mercury is released from soil, water, volcanic activity, and industrial sources as unionized vapor (Hg0) into the atmosphere. There, it can be converted to the water-soluble ion, Hg2+, and fall back to earth with rainwater. Hg2+, which is also released from industrial sediment, is methylated by aquatic microbes to form methylmercury (MeHg), the primary mercury-containing species in seafood. MeHg and similar compounds (e.g., ethylmercury, dimethylmercury) are referred to as “organic mercury”, while elemental Hg0 or compounds containing ionized Hg2+ (e.g., HgCl2) are referred to as “inorganic mercury”.
All forms of mercury pose risk of toxicity to humans, but MeHg is by far the most concerning when the route of exposure is ingestion. Unlike inorganic mercury, MeHg is well-absorbed (~95%) from the gastrointestinal tract; once absorbed, MeHg distributes extensively to tissues such as kidney, liver, and brain, with a systemic half-life of 6-8 weeks. Inorganic mercury is poorly absorbed and is not methylated by human metabolic enzymes, thus MeHg must be consumed to occur in humans. MeHg can be measured in blood samples, where it accumulates in erythrocytes to roughly 20 times the plasma concentration. However, a preferable analytical matrix may be hair, where MeHg accumulates to over 200 times the level in blood.
Although more toxic mercury species (e.g., dimethylmercury) are present in trace levels in seafood, the primary risk of toxicity arises from MeHg. MeHg is the predominant form of mercury in seafood, is readily absorbed from the digestive tract, and can rapidly cross the blood-brain barrier to exert its neurological effects. Long-lived and predatory fish (e.g., sharks) absorb MeHg from their diets, leading to higher MeHg levels than those present in species lower on the food chain. However, the risk of mercury toxicity from seafood consumption is low for most individuals, with the exception of acute poisonings (e.g., Iraq in 1971, Japan in the 1950’s).
The greatest danger of seafood-derived mercury is posed to the developing fetus: MeHg readily crosses the placenta and blood-brain barrier, thus it can accumulate in fetal tissues to concentrations significantly higher than maternal blood. Sufficient MeHg exposure in utero can lead to neurological deficits and developmental delays, even in infants whose mothers exhibit no mercury toxicity or only mild effects. For this reason, in March 2004, the Food and Drug Administration (FDA) released a safety warning intended to limit mercury exposure in pregnant and nursing mothers, women who may become pregnant, and young children.
The FDA alert recommends those individuals to avoid high-mercury fish (e.g., shark, king mackerel) entirely, and to limit consumption of lower-mercury fish (e.g., shrimp, canned tuna, salmon) to 1-2 meals per week. Fish consumption is still recommended because of the recognized benefits of specific omega-3 fatty acids for fetal neurodevelopment. A 2006 review published in JAMA concurred with these guidelines, finding that the benefits of fish consumption outweigh the risks of mercury and other food-borne toxins, and supporting the recommendation for consumption of two seafood meals per week for women of childbearing age. In May 2014, the FDA released a Quantitative Assessment of the Net Effects on Fetal Neurodevelopment from Eating Commercial Fish (pdf).
In contrast to mercury, the arsenic found in seafood presents minimal risk to humans. Inorganic arsenic (trivalent As[III] or pentavalent As[V]) is ubiquitous in groundwater and seawater; the predominant route of arsenic exposure in humans is through drinking water. Microbial and marine life transforms inorganic arsenic into a variety of organic species. The best-characterized organic forms include monomethylarsenate (MMA), dimethylarsenate (DMA), and arsenobetaine. Arsenic species are readily absorbed, with rapid elimination typically leading to complete clearance within a few days of a single ingestion.
Inorganic arsenic is highly toxic: high levels can cause neurological damage, anemia, leucopenia, and vascular disease, while low-level chronic exposure increases an individual’s risk of developing cancer. MMA and DMA were previously believed to be non-toxic, but have recently been linked to arsenic-induced toxicity. Humans can metabolize inorganic arsenic to MMA and DMA, and it is believed that these metabolites contribute significantly to carcinogenicity and overall toxicity, particularly in their trivalent (As[III]) forms.
However, inorganic arsenic, MMA, and DMA comprise only a very small amount (typically <5% combined) of the total arsenic-containing species in seafood, and generally fall well short of the toxic threshold in humans. The majority of arsenic in marine life takes the form of substituted macromolecules such as sugars. In fish, most arsenic is found as arsenobetaine (an analog of trimethylglycine), whereas other edible sea life, e.g., seaweed, has substantial quantities of arsenosugars. Arsenobetaine, arsenosugars, and their metabolites have shown little to no toxic potential in laboratory studies, suggesting that their consumption by humans is of minimal concern.
Analytical speciation is therefore essential to determine the clinical significance of arsenic levels. Methods coupling high-performance liquid chromatography to various detectors (e.g., atomic absorption spectroscopy, inductively-coupled plasma mass spectrometry) allow separation of highly-toxic inorganic and organic species from non-toxic arsenicals. Arsenobetaine is the major arsenic-containing compound found in human urine when the origin is dietary, whereas DMA and other toxic species can be detected after consumption of arsenic-contaminated water.
In conclusion, the major heavy metal risk posed by seafood consumption is exposure of a developing fetus to MeHg, thus women and children should limit intake of certain fish to minimize MeHg toxicity. Arsenic concentrations in seafood are notable, but the metal is present in the form of non-toxic arsenobetaine and arsenosugars. Laboratory analysis should include speciation to ascertain the source and clinical importance of urinary arsenic.
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