Arsenic poisoning

Signs and symptoms

Ingesting large amounts of arsenic can cause symptoms similar to food poisoning, with abdominal pain, nausea, vomiting, and diarrhea starting within hours. Bloody diarrhea can cause severe fluid loss, resulting in hypovolemic shock. Inhaling arsine gas – the most toxic form of arsenic – causes a multisystem disease starting 2 to 24 hours after inhalation. Symptoms include gastrointestinal distress, headache, weakness, difficulty breathing, kidney and liver dysfunction, and the destruction of red blood cells.

Chronic ingestion of lower levels of arsenic causes visible changes in the skin, typically hyperpigmentation (dark areas), but sometimes hypopigmentation (light areas) or alternating areas of each. Some experience general thickening of the skin on the palms and soles of the feet, or small thickened areas. Around 5% of those affected develop light-colored bands across the fingernail, called Mees' lines. Chronic exposure eventually causes disease across multiple body systems, including peripheral neuropathy (numbness and tingling), enlargement of the liver and spleen, diabetes, heart disease, cognitive impairment, and damage to the portal vein (non-cirrhotic portal fibrosis and portal hypertension).

Repeated arsenic exposure also increases the risk for developing several cancers, particularly of the skin, lung, liver, bladder, prostate, and blood vessels.

Causes

Arsenic poisoning is caused by incidental ingestion or inhalation of arsenic, typically from drinking contaminated well water, eating food cooked in contaminated water, or being exposed to arsenic-containing pesticides, folk medicines, or industrial chemicals. The World Health Organization considers arsenic levels above 10 parts per billion (10 micrograms per liter) to be unsafe.

Sources

Because of its high toxicity, arsenic is seldom used in the Western world, although in Asia it is still a popular pesticide. Arsenic is mainly encountered occupationally in the smelting of zinc and copper ores.

Groundwater

Arsenic is a ubiquitous naturally occurring chemical element, and the 20th most common element on Earth. Arsenic levels in the groundwater vary from around 0.5 parts per billion to 5000 parts per billion, depending on an area's geologic features, and possible presence on industrial waste. The highest groundwater arsenic levels have been recorded in Brazil, Cambodia, Afghanistan, Australia, and Bangladesh.

Arsenic is a ubiquitous element present in American drinking water. In the US, the U.S. Geological Survey estimates that the median groundwater concentration is 1 μg/L or less, although some groundwater aquifers, particularly in the western United States, can contain much higher levels. For example, median levels in Nevada were about 8 μg/L but levels of naturally occurring arsenic as high as 1000 μg/L have been measured in the United States in drinking water. Groundwater associated with volcanics in California contains arsenic at concentrations ranging up to 48,000 μg/L, with arsenic-bearing sulfide minerals as the main source. Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of arsenic 50 μg/L. In Wisconsin, arsenic concentrations of water in sandstone and dolomite aquifers were as high as 100 μg/L. Oxidation of pyrite hosted by these formations was the likely source of the arsenic. In the Piedmont of Pennsylvania and New Jersey, groundwater in Mesozoic age aquifers contains elevated levels of arsenic—domestic well waters from Pennsylvania contained up to 65 μg/L, whereas in New Jersey the highest concentration measured recently was 215 μg/L.

Rice and seafood

Organic arsenic is less harmful than inorganic arsenic. Seafood is a common source of the less toxic organic arsenic in the form of arsenobetaine.

In the United States, Schoof et al. estimated an average adult intake of 3.2 μg/day, with a range of 1–20 μg/day. Estimates for children were similar. Food also contains many organic arsenic compounds. The key organic arsenic compounds that can be routinely found in food (depending on food type) include monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), arsenobetaine, arsenocholine, arsenosugars, and arsenolipids. DMAsV or MMAsV can be found in various types of fin fish, crabs, and mollusks, but often at very low levels.

Arsenobetaine is the major form of arsenic in marine animals and is considered nontoxic. Arsenocholine, which is mainly found in shrimp, is chemically similar to arsenobetaine, and is considered to be "essentially nontoxic". Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic. Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and their toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks. Studies addressing arsenosugar toxicity, however, have largely been limited to in vitro studies, which show that arsenosugars are significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites.

It has been found that rice is particularly susceptible to the accumulation of arsenic from soil. Rice grown in the United States has an average 260 ppb of arsenic, according to a study; but U.S. arsenic intake remains far below World Health Organization-recommended limits. China has set a standard for arsenic limits in food (150 ppb), as levels in rice exceed those in water.

Air

The European Commission (2000) reports that levels of arsenic in air range 0–1 ng/m3 in remote areas, 0.2–1.5 ng/m3 in rural areas, 0.5–3 ng/m3 in urban areas, and up to about 50 ng/m3 in the vicinity of industrial sites. Based on these data, the European Commission (2000) estimated that in relation to food, cigarette smoking, water, and soil, air contributes less than 1% of total arsenic exposure.

Pesticides

The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, due to the pesticide's environmental persistence, it is estimated that millions of acres of land remain contaminated with lead arsenate residues. This presents a potentially significant public health concern in some areas of the United States (e.g., New Jersey, Washington, and Wisconsin), where large areas of land used historically as orchards have been converted into residential developments.

Some modern uses of arsenic-based pesticides still exist. Chromated copper arsenate has been registered for use in the United States since the 1940s as a wood preservative, protecting wood from insects and microbial agents. In 2003, manufacturers of chromated copper arsenate initiated a voluntary recall of residential wood treated with the chemical. The Environmental Protection Agency Act 2008 final report stated that chromated copper arsenate is still approved for use in nonresidential applications, such as in marine facilities (pilings and structures), utility poles, and sand highway structures.

Copper smelting

Exposure studies in the copper smelting industry are much more extensive and have established definitive links between arsenic, a by-product of copper smelting, and lung cancer via inhalation. Dermal and neurological effects were also increased in some of these studies. Although as time went on, occupational controls became more stringent and workers were exposed to reduced arsenic concentrations, the arsenic exposures measured from these studies ranged from about 0.05 to 0.3 mg/m3 and are significantly higher than airborne environmental exposures to arsenic (which range from 0 to 0.000003 mg/m3).

Pathophysiology

Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenase complex, which catalyzes the oxidation of pyruvate to acetyl-CoA by NAD+. With the enzyme inhibited, the energy system of the cell is disrupted resulting in cellular apoptosis. Biochemically, arsenic prevents the use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic can raise lactate levels and lead to lactic acidosis. Low potassium levels in the cells increase the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. Arsenic in cells clearly stimulates the production of hydrogen peroxide (H2O2). When the H2O2 reacts with certain metals such as iron or manganese, it produces a highly reactive hydroxyl radical. Inorganic arsenic trioxide found in ground water particularly affects voltage-gated potassium channels, disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure, central nervous system dysfunction, anemia, and death.

Arsenic has also been shown to induce cardiac hypertrophy by activating certain transcription factors involved in pathologically remodeling the heart. Tissue culture studies have shown that arsenic compounds block both IKr and Iks channels and, at the same time, activate IK-ATP channels. Arsenic compounds also disrupt ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress. These metabolic interferences lead to death from multi-system organ failure, probably from necrotic cell death, not apoptosis. A post mortem reveals brick red colored mucosa, due to severe hemorrhage. Although arsenic causes toxicity, it can also play a protective role.

Mechanism

Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It can form Glc-6-arsenate in vitro; therefore, it has been argued that hexokinase could be inhibited. (Eventually this may be a mechanism leading to muscle weakness in chronic arsenic poisoning.) In the glyceraldehyde 3-phosphate dehydrogenase reaction arsenate attacks the enzyme-bound thioester. The formed 1-arseno-3-phosphoglycerate is unstable and hydrolyzes spontaneously. Thus, ATP formation in glycolysis is inhibited while bypassing the phosphoglycerate kinase reaction. (Moreover, the formation of 2,3-bisphosphoglycerate in erythrocytes might be affected, followed by a higher oxygen affinity of hemoglobin and subsequently enhanced cyanosis.) As shown by Gresser (1981), submitochondrial particles synthesize adenosine-5'-diphosphate-arsenate from ADP and arsenate in presence of succinate. Thus, by a variety of mechanisms, arsenate leads to an impairment of cell respiration and subsequently diminished ATP formation. This is consistent with observed ATP depletion of exposed cells and histopathological findings of mitochondrial and cell swelling, glycogen depletion in liver cells and fatty change in liver, heart and kidney.

Experiments demonstrated enhanced arterial thrombosis in a rat animal model, elevations of serotonin levels, thromboxane A[2], and adhesion proteins in platelets, while human platelets showed similar responses. The effect on vascular endothelium may eventually be mediated by the arsenic-induced formation of nitric oxide. It was demonstrated that +3 As concentrations substantially lower than concentrations required for inhibition of the lysosomal protease cathepsin L in the B cell line TA3 were sufficient to trigger apoptosis in the same B cell line, while the latter could be a mechanism mediating immunosuppressive effects.

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures. Dimethylarsinic acid, DMA(V), caused DNA single strand breaks resulting from inhibition of repair enzymes at levels of 5 to 100 mM in human epithelial type II cells.

MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA. Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations, micronuclei and sister-chromatid exchanges. An explanation for chromosomal aberrations is the sensitivity of the protein tubulin and the mitotic spindle to arsenic. Histological observations confirm effects on cellular integrity, shape and locomotion.

DMA(III) can form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical. Both DMA(III) and DMA(V) were shown to release iron from horse spleen as well as from human liver ferritin if ascorbic acid was administered simultaneously. Thus, the formation of reactive oxygen species can be promoted. Moreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially those containing thiol groups. The accumulation of reactive oxygen species like that cited above and hydroxyl radicals, superoxide radicals, and hydrogen peroxides causes aberrant gene expression at low concentrations and lesions of lipids, proteins, and DNA in higher concentrations, which eventually lead to cellular death. In a rat animal model, urine levels of 8-hydroxy-2'-deoxyguanosine (as a biomarker of DNA damage by reactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased. This theory is further supported by a cross-sectional study which found elevated mean serum lipid peroxides in the As exposed individuals which correlated with blood levels of inorganic arsenic and methylated metabolites and inversely correlated with nonprotein sulfhydryl (NPSH) levels in whole blood.

Another study found an association of As levels in whole blood with the level of reactive oxidants in plasma and an inverse relationship with plasma antioxidants. A finding of the latter study indicates that methylation might in fact be a detoxification pathway with regard to oxidative stress: the results showed that the lower the As methylation capacity was, the lower the level of plasma antioxidant capacity. As reviewed by Kitchin (2001), the oxidative stress theory explains the preferred tumor sites connected with arsenic exposure. Considering that a high partial pressure of oxygen is present in lungs and DMA(III) is excreted in gaseous state via the lungs, this seems to be a plausible mechanism for special vulnerability. The fact that DMA is produced by methylation in the liver, excreted via the kidneys, and later on stored in the bladder accounts for the other tumor localizations.

Regarding DNA methylation, some studies suggest interaction of As with methyltransferases, which leads to an inactivation of tumor suppressor genes through hypermethylation; others state that hypomethylation might occur due to a lack of SAM, resulting in aberrant gene activation. An experiment by Zhong et al. (2001) with arsenite-exposed human lung A549, kidney UOK123, UOK109 and UOK121 cells isolated eight different DNA fragments by methylation-sensitive arbitrarily primed polymerase chain reactions. It turned out that six of the fragments were hyper- and two of them were hypomethylated. Higher levels of DNA methyltransferase mRNA and enzyme activity were found.

Kitchin (2001) proposed a model of altered growth factors, which lead to cell proliferation and thus to carcinogenesis. MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1-dependent efflux. The efflux requires glutathione, but no arsenic-glutathione complex formation.

Although many mechanisms have been proposed, no definite model accounts for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. The current consensus on the mode of carcinogenesis is that it acts primarily as a tumor promoter. Its co-carcinogenicity has been demonstrated in several models. However, the finding of several studies that chronically arsenic-exposed Andean populations (as most extremely exposed to UV-light) do not develop skin cancer with chronic arsenic exposure, is puzzling.

Kinetics

The two forms of inorganic arsenic, reduced (trivalent As(III)) and oxidized (pentavalent As(V)), can be absorbed and accumulated in tissues and body fluids. In the liver, the metabolism of arsenic involves enzymatic and non-enzymatic methylation; the most frequently excreted metabolite (≥ 90%) in the urine of mammals is dimethylarsinic acid or cacodylic acid, DMA(V). Dimethylarsenic acid is also known as Agent Blue and was used as herbicide in the American war in Vietnam.

In humans, inorganic arsenic is reduced nonenzymatically from pentoxide to trioxide, using glutathione, or it is mediated by enzymes. Reduction of arsenic pentoxide to arsenic trioxide increases its toxicity and bioavailability. Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as a methyl donor. Various pathways are used, the principal route being dependent on the current cellular environment. Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).

Methylation had been regarded as a detoxification process, but reduction from +5 As to +3 As may be considered as a bioactivation instead. Another suggestion is that methylation might be a detoxification if "As[III] intermediates are not permitted to accumulate" because the pentavalent organoarsenics have a lower affinity to thiol groups than inorganic pentavalent arsenics. Gebel (2002) stated that methylation is a detoxification through accelerated excretion. With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.

Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacting with a variety of proteins and inhibiting their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification. Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase and thioredoxin reductase.

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers. Other forms of arsenic toxicity in humans have been observed in blood, bone marrow, cardiac, central nervous system, gastrointestinal, gonadal, kidney, liver, pancreatic, and skin tissues.

The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day.

Heat shock response

Another aspect is the similarity of arsenic effects to the heat shock response. Short-term arsenic exposure has effects on signal transduction inducing heat shock proteins with masses of 27, 60, 70, 72, 90, and 110 kDa as well as metallothionein, ubiquitin, mitogen-activated [MAP] kinases, extracellular regulated kinase [ERK], c-jun terminal kinases [JNK] and p38. Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines. The effects are largely dependent on the dosing regime and may be as well inversed.

As shown by some experiments reviewed by Del Razo (2001), reactive oxygen species induced by low levels of inorganic arsenic increase the transcription and the activity of the activator protein 1 (AP-1) and the nuclear factor-κB (NF-κB) (maybe enhanced by elevated MAPK levels), which results in c-fos/c-jun activation, over-secretion of pro-inflammatory and growth promoting cytokines stimulating cell proliferation. Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels. Thus, taking into account p53's function, a lack of it could cause a faster accumulation of mutations contributing to carcinogenesis. However, high levels of inorganic arsenic inhibit NF-κB activation and cell proliferation. An experiment of Hu et al. (2002) demonstrated increased binding activity of AP-1 and NF-κB after acute (24 h) exposure to +3 sodium arsenite, whereas long-term exposure (10–12 weeks) yielded the opposite result. The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis. As the contradicting findings and connected mechanistic hypotheses indicate, there is a difference in acute and chronic effects of arsenic on signal transduction, which is not clearly understood yet.

Oxidative stress

Studies have demonstrated that the oxidative stress generated by arsenic may disrupt the signal transduction pathways of the nuclear transcriptional factors PPARs, AP-1, and NF-κB, as well as the pro-inflammatory cytokines IL-8 and TNF-α. The interference of oxidative stress with signal transduction pathways may affect physiological processes associated with cell growth, metabolic syndrome X, glucose homeostasis, lipid metabolism, obesity, insulin resistance, inflammation, and diabetes-2. Recent scientific evidence has elucidated the physiological roles of the PPARs in the ω- hydroxylation of fatty acids and the inhibition of pro-inflammatory transcription factors (NF-κB and AP-1), pro-inflammatory cytokines (IL-1, −6, −8, −12, and TNF-α), cell4 adhesion molecules (ICAM-1 and VCAM-1), inducible nitric oxide synthase, proinflammatory nitric oxide (NO), and anti-apoptotic factors.

Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of type 2 diabetes. The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis. However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.

Diagnosis

Arsenic may be measured in blood or urine to monitor excessive environmental or occupational exposure, confirm a diagnosis of poisoning in hospitalized victims or to assist in the forensic investigation in a case of fatal overdose. Some analytical techniques are capable of distinguishing organic from inorganic forms of the element. Organic arsenic compounds tend to be eliminated in the urine in unchanged form, while inorganic forms are largely converted to organic arsenic compounds in the body before urinary excretion. The current biological exposure index for U.S. workers of 35 μg/L total urinary arsenic may easily be exceeded by a healthy person eating a seafood meal.

Tests are available to diagnose poisoning by measuring arsenic in blood, urine, hair, and fingernails. The urine test is the most reliable test for arsenic exposure within the last few days. Urine testing needs to be done within 24–48 hours for an accurate analysis of an acute exposure. Tests on hair and fingernails can measure exposure to high levels of arsenic over the past 6–12 months. These tests can determine if one has been exposed to above-average levels of arsenic. They cannot predict, however, whether the arsenic levels in the body will affect health. Chronic arsenic exposure can remain in the body systems for a longer period than a shorter term or more isolated exposure and can be detected in a longer time frame after the introduction of the arsenic, important in trying to determine the source of the exposure.

Hair is a potential bioindicator for arsenic exposure due to its ability to store trace elements from blood. Incorporated elements maintain their position during the growth of hair. Thus, for a temporal estimation of exposure, an assay of hair composition needs to be carried out with a single hair, which is not possible with older techniques requiring homogenization and dissolution of several strands of hair. This type of biomonitoring has been achieved with newer microanalytical techniques like synchrotron radiation-based X-ray fluorescence spectroscopy and microparticle-induced X-ray emission. The highly focused and intense beams study small spots on biological samples, allowing analysis at the micro level along with chemical speciation. In a study, this method has been used to follow arsenic levels before, during, and after treatment with arsenious oxide in patients with acute promyelocytic leukemia.

Treatment

Chelation

Dimercaprol and dimercaptosuccinic acid (succimer) are chelating agents that sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning. The most important side effect is hypertension. Dimercaprol is considerably more toxic than succimer. Dimercaptosuccinic acid monoesters, e.g., MiADMSA, are promising antidotes for arsenic poisoning.

History

Beginning in about 3000 BC, arsenic was mined and added to copper in the alloying of bronze, but the adverse health effects of working with arsenic led to it being abandoned when a viable alternative, tin, was discovered.

In addition to its presence as a poison, for centuries, arsenic was used medicinally. It has been used for over 2,400 years as a part of traditional Chinese medicine. In the western world, arsenic compounds, such as salvarsan, were used extensively to treat syphilis before penicillin was introduced. It was eventually replaced as a therapeutic agent by sulfa drugs and then by other antibiotics. Arsenic was also an ingredient in many tonics (or "patent medicines").

In addition, during the Elizabethan era, some women used a mixture of vinegar, chalk, and arsenic applied topically to whiten their skin. This use of arsenic was intended to prevent aging and creasing of the skin, but some arsenic was inevitably absorbed into the bloodstream.

During the Victorian era (late 19th century) in the United States, U.S. newspapers advertised "arsenic complexion wafers" that promised to remove facial blemishes such as moles and pimples.

Some pigments, most notably the popular Emerald Green (known also under several other names), were based on arsenic compounds. Overexposure to these pigments was a frequent cause of accidental poisoning of artists and craftsmen.

Arsenic became a favored method for murder of the Middle Ages and Renaissance, particularly among the ruling classes in Italy, allegedly. Because the symptoms are similar to those of cholera, which was common at the time, arsenic poisoning often went undetected. By the 19th century, it had acquired the nickname "inheritance powder", perhaps because impatient heirs were known or suspected to use it to ensure or accelerate their inheritances.

In post-WW1 Hungary, arsenic extracted by boiling fly paper was used in an estimated 300 murders by the Angel Makers of Nagyrév.

In imperial China, arsenic trioxide and sulfides were used in murder, as well as for capital punishment for members of the royal family or aristocracy. Forensic studies have determined that the Guangxu Emperor (d. 1908) was murdered by arsenic, most likely ordered by the Empress Dowager Cixi or Generalissimo Yuan Shikai. Likewise, in ancient Korea, and particularly in the Joseon Dynasty, arsenic-sulfur compounds had been used as a major ingredient of sayak (사약; 賜藥), which was a poison cocktail used in capital punishment of high-profile political figures and members of the royal family. Due to social and political prominence of the condemned, many of these events were well-documented, often in the Annals of Joseon Dynasty; they are sometimes portrayed in historical television miniseries because of their dramatic nature.

One of the worst incidents of arsenic poisoning via well water occurred in Bangladesh, which the World Health Organization called the "largest mass poisoning of a population in history" and was recognized as a major public health concern. The contamination in the Ganga-Brahmaputra fluvial plains in India and Padma-Meghna fluvial plains in Bangladesh demonstrated adverse impacts on human health.

Arsenic poisoning from exposure to groundwater is believed to be responsible for the illness experienced by those that witnessed the 2007 Carancas impact event in Peru, as local residents inhaled steam which was contaminated with arsenic, produced from groundwater which boiled from the intense heat and pressure produced by a chondrite meteorite impacting the ground.

Legislation

In the U.S. in 1975, under the authority of the Safe Drinking Water Act, the U.S. Environmental Protection Agency determined the National Interim Primary Drinking Water Regulation levels of arsenic (inorganic contaminant – IOCs) to be 0.05 mg/L (50 parts per billion – ppb).

Throughout the years, many studies have reported dose-dependent effects of arsenic in drinking water and skin cancer. In order to prevent new cases and deaths from cancerous and non-cancerous diseases, the Safe Drinking Water Act directed the Environmental Protection Agency to revise arsenic levels and specify the maximum contaminant level (MCL). MCLs are set as close to the health goals as possible, considering cost, benefits, and the ability of public water systems to detect and remove contaminants using suitable treatment technologies.

In 2001, the Environmental Protection Agency adopted a lower standard of MCL 0.01 mg/L (10 ppb) for arsenic in drinking water that applies to both community water systems and non-transient non-community water systems.

In some other countries, when developing national drinking water standards based on the guideline values, it is necessary to take account of a variety of geographical, socio-economic, dietary, and other conditions affecting potential exposure. These factors lead to national standards that differ appreciably from the guideline values. That is the case in countries such as India and Bangladesh, where the permissible limit of arsenic in absence of an alternative source of water is 0.05 mg/L.

Challenges to implementation

Arsenic removal technologies are traditional treatment processes that have been tailored to improve the removal of arsenic from drinking water. Although some of the removal processes, such as precipitative processes, adsorption processes, ion exchange processes, and separation (membrane) processes, may be technically feasible, their cost may be prohibitive.

For underdeveloped countries, the challenge is finding the means to fund such technologies. The Environmental Protection Agency, for example, has estimated the total national annualized cost of treatment, monitoring, reporting, record keeping, and administration to enforce the MCL rule to be approximately $181 million. Most of the cost is due to the installation and operation of the treatment technologies needed to reduce arsenic in public water systems.

Pregnancy

Arsenic exposure through groundwater is highly concerning throughout the perinatal period. Pregnant women are a high-risk population because not only are they at risk for adverse outcomes, but in-utero exposure also poses health risks to the fetus.

There is a dose-dependent relationship between perinatal exposure to arsenic and infant mortality, meaning that infants born to people exposed to higher concentrations, or exposed for longer periods, have a higher mortality rate.

Studies have shown that ingesting arsenic through groundwater during pregnancy poses dangers to the pregnant woman, including, but not limited to, abdominal pain, vomiting, diarrhea, skin pigmentation changes, and cancer. Research has also demonstrated that arsenic exposure causes low birth weight, low birth size, infant mortality, and a variety of other outcomes in infants. Some of these effects, like lower birth rate and size, may be due to the effects of arsenic on weight gain during pregnancy.

References

References

1. (October 2011). "Arsenic exposure and toxicology: a historical perspective.". Toxicological Sciences.
2. (1 July 2003). "Acute and chronic arsenic toxicity". Postgraduate Medical Journal.
3. (1 October 2007). "Arsenic neurotoxicity A review". Human & Experimental Toxicology.
4. (3 January 2013). "The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem". Environmental Health Perspectives.
5. (2013). "Care and Conservation of Geological Material". Routledge.
6. Mahajan PV. (2020). "Nelson Textbook of Pediatrics". Elsevier.
7. (7 December 2022). "Arsenic". World Health Organization.
8. (December 2021). "Arsenic exposure and non-carcinogenic health effects". Hum Exp Toxicol.
9. (2017). "Arsenic Contamination in the Environment: The Issues and Solutions". Springer.
10. (January 2021). "Arsenic: A Global Environmental Challenge". Annu Rev Pharmacol Toxicol.
11. "USGS NAWQA Arsenic in Groundwater".
12. "Arsenic in Ground-Water Resources of the United States: A New National-Scale Analysis".
13. (1999). "Drinking water arsenic in Utah: A cohort mortality study.". Environmental Health Perspectives.
14. (1 May 1988). "Arsenic in Ground Water of the Western United States". Ground Water.
15. (1 June 2013). "Arsenic in marine hydrothermal fluids". Chemical Geology.
16. (1 October 2004). "Arsenic occurrence, mobility, and retardation in sandstone and dolomite formations of the Fox River Valley, Eastern Wisconsin". Environmental Science & Technology.
17. (January 2008). "The occurrence and geochemistry of arsenic in groundwaters of the Newark basin of Pennsylvania". Applied Geochemistry.
18. (1 January 2010). "Sources, mobilization and transport of arsenic in groundwater in the Passaic and Lockatong Formations of the Newark Basin, New Jersey". N J Geol Soc Bull.
19. EFSA Panel on Contaminants in the Food Chain (CONTAM). (22 October 2009). "Scientific Opinion on Arsenic in Food". EFSA Journal.
20. (Aug 1999). "A market basket survey of inorganic arsenic in food". [[Food Chem. Toxicol.]].
21. (2004). "Estimation of dietary intake of inorganic arsenic in U.S. children". [[Hum. Ecol. Risk Assess.]].
22. (2007). "Seafood arsenic: implications for human risk assessment". [[Regulatory Toxicology and Pharmacology]].
23. (27 July 2021). "Toxicological Profile for Arsenic".
24. (2007). "Seafood arsenic: implications for human risk assessment". Regulatory Toxicology and Pharmacology.
25. CONTAM. (Oct 2009). "Scientific opinion on arsenic in food". EFSA J..
26. Fujiwara, S.. (Jan 2000). "Isolation and characterization of arsenate-sensitive and resistant mutants of Chlamydomonas reinhardtii". Plant Cell Physiol..
27. Kotz, Deborah. (December 8, 2011). "Do you need to worry about arsenic in rice?". Boston Globe.
28. "Surprisingly high concentrations of toxic arsenic species found in U.S. rice".
29. "Rice as a source of arsenic exposure".
30. "China: Inorganic Arsenic in Rice – An Underestimated Health Threat?".
31. (August 2006). "The apple bites back: claiming old orchards for residential development". Environmental Health Perspectives.
32. (1 January 1995). "Cancers related to exposure to arsenic at a copper smelter". Occupational and Environmental Medicine.
33. (1994). "Assessment of exposure to arsenic among smelter workers: a five-year follow-up". American Journal of Industrial Medicine.
34. (27 July 2021). "ATSDR – Toxicological Profile: Arsenic".
35. (July 2011). "Mechanisms Pertaining to Arsenic Toxicity". Toxicology International.
36. (2013). "Arsenic Exposure Induces the Warburg Effect In Cultured Human Cells". Toxicology and Applied Pharmacology.
37. (July 2007). "Effects of arsenic trioxide on voltage-dependent potassium channels and on cell proliferation of human multiple myeloma cells". Chin. Med. J..
38. (2009). "Impaired Voltage Gated Potassium Channel Responses in a Fetal Lamb Model of Persistent Pulmonary Hypertension of the Newborn". Pediatric Research.
39. (December 2009). "Arsenic Exposure and Cardiovascular Disorders: An Overview". Cardiovascular Toxicology.
40. (2021-04-01). "Inorganic arsenic induces sex-dependent pathological hypertrophy in the heart". American Journal of Physiology. Heart and Circulatory Physiology.
41. Klaassen. (2003). "Casarett and Doull's Essentials of Toxicology". McGraw-Hill.
42. Hughes MF. (July 2002). "Arsenic toxicity and potential mechanisms of action". [[Toxicology Letters]].
43. Gresser MJ. (June 1981). "ADP-arsenate. Formation by submitochondrial particles under phosphorylating conditions". The Journal of Biological Chemistry.
44. (March 2002). "Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease". Toxicology and Applied Pharmacology.
45. (February 1958). "Acute oral toxicity and chemical and physical properties of arsenic trioxides". AMA Archives of Industrial Health.
46. (February 2002). "Interactions by carcinogenic metal compounds with DNA repair processes: toxicological implications". Toxicology Letters.
47. (November 1997). "Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics". Mutation Research.
48. (October 2002). "Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite". Environmental Health Perspectives.
49. (April 2001). "Methylated trivalent arsenic species are genotoxic". [[Chemical Research in Toxicology]].
50. (1998). "Association between the clastogenic effect in peripheral lymphocytes and human exposure to arsenic through drinking water". Environmental and Molecular Mutagenesis.
51. (1994). "Increased micronuclei in exfoliated bladder cells of individuals who chronically ingest arsenic-contaminated water in Nevada". Cancer Epidemiology, Biomarkers & Prevention.
52. (June 1997). "Cytogenetic effects in human exposure to arsenic". Mutation Research.
53. (2000). "Molecular aspects of arsenic stress". Journal of Toxicology and Environmental Health, Part B.
54. (April 1990). "Induction of DNA damage by dimethylarsine, a metabolite of inorganic arsenics, is for the major part likely due to its peroxyl radical". Biochemical and Biophysical Research Communications.
55. (February 2000). "Antigen binding characteristics of antibodies against hydroxyl radical modified thymidine monophosphate". Immunology Letters.
56. (May 2001). "Oral administration of dimethylarsinic acid, a main metabolite of inorganic arsenic, in mice promotes skin tumorigenesis initiated by dimethylbenz(a)anthracene with or without ultraviolet B as a promoter". Biological & Pharmaceutical Bulletin.
57. (April 2002). "Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water". Environmental Health Perspectives.
58. (October 2001). "Association of blood arsenic levels with increased reactive oxidants and decreased antioxidant capacity in a human population of northeastern Taiwan". Environmental Health Perspectives.
59. (May 1999). "The enigma of arsenic carcinogenesis: role of metabolism". Toxicological Sciences.
60. (July 2001). "Both hypomethylation and hypermethylation of DNA associated with arsenite exposure in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR". Toxicology Letters.
61. Gebel TW. (March 2001). "Genotoxicity of arsenical compounds". International Journal of Hygiene and Environmental Health.
62. (September 2002). "Chronic arsenic-exposed human prostate epithelial cells exhibit stable arsenic tolerance: mechanistic implications of altered cellular glutathione and glutathione S-transferase". Toxicology and Applied Pharmacology.
63. (January 2000). "Differential sensitivities of MRP1-overexpressing lung tumor cells to cytotoxic metals". Toxicology.
64. (April 2002). "The MRP1-mediated effluxes of arsenic and antimony do not require arsenic-glutathione and antimony-glutathione complex formation". Journal of Bioenergetics and Biomembranes.
65. Gebel T. (April 2000). "Confounding variables in the environmental toxicology of arsenic". Toxicology.
66. (July 2004). "Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse". [[Proceedings of the National Academy of Sciences of the United States of America]].
67. Thompson DJ. (September 1993). "A chemical hypothesis for arsenic methylation in mammals". [[Chemico-Biological Interactions]].
68. (July 2001). "Role of metabolism in arsenic toxicity". [[Pharmacology & Toxicology]].
69. Gebel TW. (October 2002). "Arsenic methylation is a process of detoxification through accelerated excretion". International Journal of Hygiene and Environmental Health.
70. Kitchin KT. (May 2001). "Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites". [[Toxicology and Applied Pharmacology]].
71. (2001). "Application of modelling techniques to the planning of in vitro arsenic kinetic studies". Alternatives to Laboratory Animals.
72. (April 2001). "Selenium modifies the metabolism and toxicity of arsenic in primary rat hepatocytes". Toxicology and Applied Pharmacology.
73. (May 1989). "Urinary excretion of meso-2,3-dimercaptosuccinic acid in human subjects". Clinical Pharmacology and Therapeutics.
74. (March 2005). "Glutathione reductase inhibition and methylated arsenic distribution in Cd1 mice brain and liver". [[Toxicological Sciences]].
75. (2007). "Environmental and Occupational Medicine". Lippincott Williams & Wilkins.
76. (2006). "Effects of Arsenic Toxicity at the Cellular Level: A Review". Texas Journal of Microscopy.
77. {{cite Q. Q126687121
78. (December 2001). "Stress proteins induced by arsenic". Toxicology and Applied Pharmacology.
79. (January 1998). "The stress inducer arsenite activates mitogen-activated protein kinases extracellular signal-regulated kinases 1 and 2 via a MAPK kinase 6/p38-dependent pathway". The Journal of Biological Chemistry.
80. (2000). "Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms?". Journal of Environmental Pathology, Toxicology and Oncology.
81. (November 1996). "Arsenic induces overexpression of growth factors in human keratinocytes". Toxicology and Applied Pharmacology.
82. (September 1999). "Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis". Biochemical and Biophysical Research Communications.
83. (July 2002). "Effect of arsenic on transcription factor AP-1 and NF-κB DNA binding activity and related gene expression". Toxicology Letters.
84. (August 2004). "Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes". Toxicology and Applied Pharmacology.
85. Black PH. (October 2003). "The inflammatory response is an integral part of the stress response: Implications for atherosclerosis, insulin resistance, type II diabetes and metabolic syndrome X". Brain, Behavior, and Immunity.
86. (March 2003). "Interleukin-6 gene expression is increased in insulin-resistant rat skeletal muscle following insulin stimulation". Biochemical and Biophysical Research Communications.
87. (January 2004). "Inflammation: the link between insulin resistance, obesity and diabetes". Trends in Immunology.
88. (November 2005). "Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans". Clinical Immunology.
89. (January 2004). "Physiologically based pharmacokinetic modeling of arsenic in the mouse". Journal of Toxicology and Environmental Health, Part A.
90. (February 2001). "Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology". Molecular Carcinogenesis.
91. (February 2005). "An overview on biological mechanisms of PPARs". Pharmacological Research.
92. (May 2005). "Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
93. (June 2006). "Peroxisome proliferator-activated receptors and inflammation". Pharmacology & Therapeutics.
94. R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 106–110.
95. "ToxFAQs for Arsenic". Agency for Toxic Substances and Disease Registry.
96. (October 2009). "Arsenite medicinal use, metabolism, pharmacokinetics and monitoring in human hair". Biochimie.
97. "Dimercaprol medical facts from Drugs.com".
98. Kreppel H, Reichl FX, Kleine A, Szinicz L, Singh PK, Jones MM. Antidotal efficacy of newly synthesized dimercaptosuccinic acid (DMSA) monoesters in experimental arsenic poisoning in mice. Fundamentals of Applied Toxicology 26(2), 239–245 (1995).
99. (November 9, 2000). "A Woman's Face is Her Fortune (advertisement)". The Helena Independent.
100. (2016-09-22). "Arsenic Pills and Lead Foundation: The History of Toxic Makeup".
101. Harper, M.. (1987). "Possible toxic metal exposure of prehistoric bronze workers". British Journal of Industrial Medicine.
102. "Application of arsenic trioxide for the treatment of lupus nephritis". Chinese Medical Association.
103. (2025-05-06). "Arsenic Pills and Lead Foundation: The History of Toxic Makeup".
104. James G. Whorton. (2011). "The Arsenic Century". Oxford University Press.
105. Buckley, Thomas E.. (2002). "The great catastrophe of my life: divorce in the Old Dominion".
106. "MBC NEWS".
107. [https://web.archive.org/web/20080423171648/http://spn.chosun.com/site/data/html_dir/2008/02/18/2008021800711.html 구혜선, '왕과 나' 폐비윤씨 사약받는 장면 열연 화제]
108. "Contamination of drinking-water by arsenic in Bangladesh: a public health emergency". World Health Organisation.
109. "Arsenic".
110. (2007-09-25). "How did a meteor make hundreds of people sick?".
111. "United States Environmental Protection Agency. State Implementation Guidance for the Arsenic Rules".
112. (2015-10-13). "Chemical Contaminant Rules".
113. "Chapter 5: Drinking Water Guidelines and Standards". World Health Organization (WHO).
114. "Arsenic".
115. "United States Environment Protection Agency. Technical Fact Sheet: Final Rule for Arsenic in Drinking Water".
116. Rahman, Anisur et al. [https://pdfs.semanticscholar.org/c73c/d69071183b6038f7ebebbda160d565364dc3.pdf"Arsenic Exposure and Risk of Spontaneous Abortion, Stillbirth and Infant Mortality"] {{Webarchive. link. (2019-03-04 . ''Epidemiology'', 21(6), 797–804. Accessed on 24 May 2019.)
117. Bloom, M. S., Surdu, S., Neamtiu, I. A., & Gurzau, E. S. (2014). Maternal arsenic exposure and birth outcomes: a comprehensive review of the epidemiologic literature focused on drinking water. International journal of hygiene and environmental health, 217(7), 709–719. doi:10.1016/j.ijheh.2014.03.004
118. Kile, M. L., Cardenas, A., Rodrigues, E., Mazumdar, M., Dobson, C., Golam, M., ... & Christiani, D. C. (2016). Estimating effects of arsenic exposure during pregnancy on perinatal outcomes in a Bangladeshi cohort. Epidemiology, 27(2), 173. doi:10.1097/EDE.0000000000000416.