Arsenic poisoning

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Arsenic poisoning (or arsenicosis) is a medical condition that occurs due to elevated levels of arsenic in the body.<ref name=Va2007/> If arsenic poisoning occurs over a brief period of time, symptoms may include vomiting, abdominal pain, encephalopathy, and watery diarrhea that contains blood.<ref name=Rat2003/> Long-term exposure can result in thickening of the skin, darker skin, abdominal pain, diarrhea, heart disease, numbness, and cancer.<ref name=Rat2003/>

The most common reason for long-term exposure is contaminated drinking water.<ref name=EH2013/> Groundwater most often becomes contaminated naturally; however, contamination may also occur from mining or agriculture.<ref name=Rat2003/> It may also be found in the soil and air.<ref name=Hug2011>Template:Cite journal</ref> Recommended levels in water are less than 10–50 μg/L (10–50 parts per billion).<ref name=Rat2003/> Other routes of exposure include toxic waste sites and pseudo-medicine.<ref name=Rat2003>Template:Cite journal</ref><ref name=EH2013/> Most cases of poisoning are accidental.<ref name=Rat2003/> Arsenic acts by changing the functioning of around 200 enzymes.<ref name=Rat2003/> Diagnosis is by testing the urine, blood, or hair.<ref name=Rat2003/>

Prevention is by using water that does not contain high levels of arsenic.<ref name=Rat2003/> This may be achieved by the use of special filters or using rainwater.<ref name=Rat2003/> There is not good evidence to support specific treatments for long-term poisoning.<ref name=Rat2003/> For acute poisonings treating dehydration is important.<ref name=Va2007/> Dimercaptosuccinic acid or dimercaptopropane sulfonate may be used while dimercaprol (BAL) is not recommended.<ref name=An2016>Template:Cite journal</ref> Hemodialysis may also be used.<ref name=Va2007>Template:Cite journal</ref>

Through drinking water, more than 200 million people globally are exposed to higher-than-safe levels of arsenic.<ref name=EH2013/> The areas most affected are Bangladesh and West Bengal.<ref name=EH2013/> Exposure is also more common in people of low income and minorities.<ref>Template:Cite journal</ref> Acute poisoning is uncommon.<ref name=EH2013>Template:Cite journal</ref> The toxicity of arsenic has been described as far back as 1500 BC in the Ebers papyrus.<ref>Template:Cite book</ref> Template:TOC limit

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.<ref name=Mahajan2020>Template:Cite book</ref> Bloody diarrhea can cause severe fluid loss, resulting in hypovolemic shock.<ref name=Mahajan2020/> The heart and nervous system can also be affected, causing disruption to heart rhythms (QT interval prolongation or tachycardia), heart failure, confusion, seizures, brain swelling, coma, and death.<ref name=Mahajan2020/><ref name=WHO>Template:Cite web</ref> 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.<ref name=Mahajan2020/>

Chronic ingestion of lower levels of arsenic causes visible changes in the skin, typically hyperpigmentation (dark areas), but sometimes hypopigmentation (light areas) or an alternating areas of each.<ref name=Martinez2021>Template:Cite journal</ref> Some experience general thickening of the skin on the palms and soles of the feet, or small thickened areas.<ref name=Martinez2021/> Around 5% of those affected develop light-colored bands across the fingernail, called Mees' lines.<ref name=Mahajan2020/> 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).<ref name=Mahajan2020/><ref name=Chen2021/>

Repeated arsenic exposure also increases the risk for developing several cancers, particularly of the skin, lung, liver, bladder, prostate, and blood vessels.<ref name=Mahajan2020/><ref name=Chen2021/> The most common arsenic-induced skin cancer is squamous cell carcinoma in situ which typically occurs 2 to 20 years after arsenic exposure.<ref>Template:Cite book</ref>

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.<ref name=Mahajan2020/> The World Health Organization considers arsenic levels above 10 parts per billion (10 micrograms per liter) to be unsafe.<ref name=Martinez2021/>

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

Template:See also Arsenic is a ubiquitous naturally occurring chemical element, and the 20th most common element on Earth.<ref name=Gupta2017>Template:Cite book</ref> 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.<ref name=Gupta2017/><ref name=Chen2021>Template:Cite journal</ref> The highest groundwater arsenic levels have been recorded in Brazil, Cambodia, Afghanistan, Australia, and Bangladesh.<ref name=Chen2021/>

Arsenic is a ubiquitous element present in American drinking water.<ref>Template:Cite web</ref> 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<ref>Template:Cite web</ref> but levels of naturally occurring arsenic as high as 1000 μg/L have been measured in the United States in drinking water.<ref>Template:Cite journal</ref> Groundwater associated with volcanics in California contain As at concentrations ranging up to 48,000 μg/L, with As-bearing sulfide minerals as the main source.<ref>Template:Cite journal</ref> Geothermal waters on Dominica in the Lesser Antilles also contain concentrations of As >50 μg/L.<ref>Template:Cite journal</ref> In Wisconsin, As 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 As.<ref>Template:Cite journal</ref> In the Piedmont of Pennsylvania and New Jersey, groundwater in Mesozoic age aquifers contains elevated levels of As—domestic well waters from Pennsylvania contained up to 65 μg/L,<ref>Template:Cite journal</ref> whereas in New Jersey the highest concentration measured recently was 215 μg/L.<ref>Template:Cite journal</ref>

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.<ref name=EFSA2009>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> Estimates for children were similar.<ref name="YostTao2004">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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".<ref>Template:Cite web</ref> Although arsenobetaine is little studied, available information indicates it is not mutagenic, immunotoxic, or embryotoxic.<ref>Template:Cite journal</ref> Arsenosugars and arsenolipids have recently been identified. Exposure to these compounds and toxicological implications are currently being studied. Arsenosugars are detected mainly in seaweed but are also found to a lesser extent in marine mollusks.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

It has been found that rice is particularly susceptible to accumulation of arsenic from soil.<ref>Template:Cite news</ref> 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.<ref>Template:Cite web</ref> China has set a standard for arsenic limits in food (150 ppb),<ref>Template:Cite web</ref> as levels in rice exceed those in water.<ref>Template:Cite web</ref>

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.Template:Better source needed

Pesticides

The use of lead arsenate pesticides has been effectively eliminated for over 50 years. However, because of the pesticide's environmental persistence, it is estimated that millions of acres of land are still 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.<ref>Template:Cite journal</ref>

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 instituted a voluntary recall of residential uses of 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.<ref>Template:Cite journal</ref> Dermal and neurological effects were also increased in some of these studies.<ref>Template:Cite journal</ref> 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).<ref>Template:Cite web</ref>

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 use of thiamine resulting in a clinical picture resembling thiamine deficiency. <ref>Template:Cite journal</ref> Poisoning with arsenic can raise lactate levels and lead to lactic acidosis.<ref>Template:Cite journal</ref> Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.Template:Citation needed 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,<ref>Template:Cite journal</ref> disrupting cellular electrolytic function resulting in neurological disturbances, cardiovascular episodes such as prolonged QT interval, neutropenia, high blood pressure,<ref>Template:Cite journal</ref> central nervous system dysfunction, anemia, and death.

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Arsenic has also been shown to induce cardiac hypertrophy by activating certain transcription factors involved in pathologically remodeling the heart.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite book</ref>

Mechanism

Arsenite inhibits not only the formation of acetyl-CoA but also the enzyme succinic dehydrogenase. Arsenate can replace phosphate in many reactions. It is able to form Glc-6-arsenate in vitro; therefore it has been argued that hexokinase could be inhibited.<ref name=Hughes2002>Template:Cite journal</ref> (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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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 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.<ref>Template:Cite journal</ref>

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures.<ref>Template:Cite journal</ref> 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 Template:Nowrap cells.<ref name=Yamanaka1997>Template:Cite journal</ref><ref name=Bau2002>Template:Cite journal</ref>

MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA.<ref name=Mass2001>Template:Cite journal</ref> Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations,<ref name="Maki-Paakkanen1998">Template:Cite journal</ref> micronuclei<ref name=Warner1994>Template:Cite journal</ref><ref name=Gonsebatt1997>Template:Cite journal</ref> 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.<ref name=Bernstam2000>Template:Cite journal</ref>

DMA(III) is able to form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.<ref name=Yamanaka1990>Template:Cite journal</ref> 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, formation of reactive oxygen species can be promoted.<ref name=Ahmad2000>Template:Cite journal</ref> Moreover, arsenic could cause oxidative stress by depleting the cell's antioxidants, especially the ones 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 byreactive oxygen species) were measured after treatment with DMA(V). In comparison to control levels, they turned out to be significantly increased.<ref name=Yamanaka2001>Template:Cite journal</ref> 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.<ref name=Pi2002>Template:Cite journal</ref>

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.<ref name=Wu2001>Template:Cite journal</ref> 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 provides an explanation for the preferred tumor sites connected with arsenic exposure.<ref name=Kitchin2001/> 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.<ref name=Goering1999>Template:Cite journal</ref> 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.<ref name=Zhong2001>Template:Cite journal</ref> It turned out that six of the fragments were hyper- and two of them were hypomethylated.<ref name=Zhong2001/> Higher levels of DNA methyltransferase mRNA and enzyme activity were found.<ref name=Zhong2001/>

Kitchin (2001) proposed a model of altered growth factors which lead to cell proliferation and thus to carcinogenesis.<ref name=Kitchin2001/> From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity.<ref name=Gebel2001>Template:Cite journal</ref><ref name=Brambila2002>Template:Cite journal</ref> MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1 dependent efflux.<ref name=Vernhet2000>Template:Cite journal</ref> The efflux requires glutathione, but no arsenic-glutathione complex formation.<ref name=Salerno2002>Template:Cite journal</ref>

Although many mechanisms have been proposed, no definite model can be given for the mechanisms of chronic arsenic poisoning. The prevailing events of toxicity and carcinogenicity might be quite tissue-specific. 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.<ref name=Gebel2000>Template:Cite journal</ref>

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.<ref name="Ueki">Template:Cite journal</ref> 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).<ref name="Vigo"/> 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 bio availability, Methylation occurs through methyltransferase enzymes. S-adenosylmethionine (SAM) may serve as methyl donor. Various pathways are used, the principal route being dependent on the current environment of the cell.<ref name="thom">Template:Cite journal</ref> Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).

Methylation had been regarded as a detoxification process, Template:By whom but reduction from +5 As to +3 As may be considered as a bioactivation Template:Clarify instead.<ref name="vaht">Template:Cite journal</ref> 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.<ref name="thom"/> Gebel (2002) stated that methylation is a detoxification through accelerated excretion.<ref name=Gebel2002>Template:Cite journal</ref> With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.<ref name=Kitchin2001>Template:Cite journal</ref><ref name=Kenyon2001>Template:Cite journal</ref><ref name=Styblo2002>Template:Cite journal</ref>

Arsenic, especially +3 As, binds to single, but with higher affinity to vicinal sulfhydryl groups, thus reacts with a variety of proteins and inhibits their activity. It was also proposed that binding of arsenite at nonessential sites might contribute to detoxification.<ref name=Aposhian1989>Template:Cite journal</ref> Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase<ref name=Rodriguez2005>Template:Cite journal</ref> and thioredoxin reductase.<ref name="willi">Template:Cite book</ref>

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers.<ref name="Vigo">Template:Cite journal</ref> 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.<ref name="Vigo"/>

The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day.<ref name="dart">Template:Cite Q</ref>

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.<ref name=Bernstam2000/><ref name=DelRazo2001>Template:Cite journal</ref> Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines.<ref name=Bernstam2000/><ref name=Cavigelli1996>Template:Cite journal</ref><ref name=Ludwig1998>Template:Cite journal</ref> 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.<ref name=DelRazo2001/><ref name=Simeonova2000>Template:Cite journal</ref> Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.<ref>Template:Cite journal</ref>

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.<ref name=Hamadeh1999>Template:Cite journal</ref> 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.<ref name=hu2002/> The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis.<ref name=hu2002/> 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.Template:Citation needed

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,<ref name = Vigo/><ref name=hu2002>Template:Cite journal</ref><ref name = walton>Template:Cite journal</ref> as well as the pro-inflammatory cytokines IL-8 and TNF-α.<ref name="Vigo"/><ref name=hu2002/><ref name = walton/><ref name = black>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name = kota>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name = moraes>Template:Cite journal</ref> 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.<ref name = Vigo/><ref name= black/><ref name = kota/><ref name = moraes/><ref>Template:Cite journal</ref>

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

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 over dosage. 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 prior to 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.<ref>R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 106–110.</ref>

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.<ref>Template:Cite web</ref> Chronic arsenic exposure can remain in the body systems for a longer period of time 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 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 to micro level along with the chemical speciation. In a study, this method has been used to follow arsenic level before, during and after treatment with arsenious oxide in patients with acute promyelocytic leukemia.<ref>Template:Cite journal</ref>

Treatment

Chelation

Dimercaprol and dimercaptosuccinic acid 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.Template:Citation needed<ref>Template:Cite web</ref> Dimercaptosuccinic acid monoesters, e.g. MiADMSA, are promising antidotes for arsenic poisoning.<ref>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).</ref>

Nutrition

Supplemental potassium decreases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.<ref>Arsenic Trioxide (Trisenox). The Abramson Cancer Center of the University of Pennsylvania. Last modified: December 25, 2005</ref>

History

File:18891109 Arsenic complexion wafers - Helena Independent.png

An 1889 newspaper advertisement for "arsenic complexion wafers".<ref name=HelenaIndependent_18891109>Template:Cite news</ref> Arsenic was known to be poisonous during the Victorian era.<ref name=NatGeo_20160922>Template:Cite magazine</ref>

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.<ref name="Harper, 1987" >Template:Cite journal</ref>

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.<ref>Template:Cite web</ref> 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 blood stream.<ref>Template:Cite web</ref>

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.<ref name=NatGeo_20160922/>

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 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.<ref name=Whorton>Template:Cite book</ref>Template:Rp 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.<ref name=Whorton/>Template:Rp It was also a common murder technique in the 19th century in domestic violence situations, such as the case of Rebecca Copin, who attempted to poison her husband by "putting arsenic in his coffee".<ref>Template:Cite book</ref>

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.<ref>Template:Cite web</ref> 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.<ref>구혜선, '왕과 나' 폐비윤씨 사약받는 장면 열연 화제</ref>

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"<ref>Template:Cite web</ref> 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.<ref>Template:Cite web</ref>

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.<ref>Template:Cite web</ref>

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).<ref name=":2">Template:Cite web</ref>

Throughout the years, many studies reported dose-dependent effects of arsenic in drinking water and skin cancer. In order to prevent new cases and death from cancerous and non-cancerous diseases, the Safe Drinking Water Act directed the Environmental Protection Agency to revise arsenic's levels and specified 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.<ref name=":2" /><ref>Template:Cite web</ref>

In 2001, 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.<ref name=":2" />

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.<ref name=":0">Template:Cite web</ref><ref>Template:Cite web</ref>

Challenges to implementation

Arsenic removal technologies are traditional treatment processes which have been tailored to improve 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.<ref name=":2" />

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.<ref>Template:Cite web</ref>

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 foetus.

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 of time, have a higher mortality rate.<ref>Rahman, Anisur et al. "Arsenic Exposure and Risk of Spontaneous Abortion, Stillbirth and Infant Mortality" Template:Webarchive. Epidemiology, 21(6), 797–804. Accessed on 24 May 2019.</ref>

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.<ref name="Bloom, M. S. 2014">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</ref> Research has also demonstrated that arsenic exposure also causes low birth weight, low birth size, infant mortality, and a variety of other outcomes in infants.<ref name="Bloom, M. S. 2014"/><ref name=":1">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.</ref> Some of these effects, like lower birth-rate and size may be due to the effects of arsenic on weight gain during pregnancy.<ref name=":1" />

References

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