Arsenic poisoning

Rice and seafood

It's estimated that an average adult in the United States consumes 3.2 μg/day of arsenic, with a range of 1–20 μg/day.^[14] Estimates for children were similar.^[15]

Food also contains many organic arsenic compounds. A wide range of arsenic containing compounds have been found in food,^[16]although arsenic compounds may range significantly in toxicity. Seafood is a common source of organic arsenic in the form of arsenobetaine.^[17] There is evidence indicating that Arsenocholine, which can be found in some food sources, is non-toxic. ^[18][19] Arsenosugars are present in some forms of seafood and been shown through in vitro studies to be significantly less toxic than both inorganic arsenic and trivalent methylated arsenic metabolites.^[20]

It has been found that rice is particularly susceptible to the accumulation of arsenic from soil.^[21] Rice grown in the United States has an average 260 ppb of arsenic, but U.S. arsenic intake remains far below World Health Organization-recommended limits.^[22] China has set a standard for arsenic limits in food (150 ppb),^[23] as levels in rice exceed those in water.^[24]

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.^{[better source needed]}

Pesticides

Although the of lead arsenic-containing pesticides has long been stopped, large areas land remain contaminated.^[25]

Some 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.^[26] Dermal and neurological effects were also increased in some of these studies.^[27] Although further occupational controls were introduced and workers were exposed to lower arsenic concentrations, the arsenic exposures measured in these studies range from about 0.05 to 0.3 mg/m³, significantly higher than usual airborne levels, ranging from 0 to 0.000003 mg/m³).^[28]

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.^[36] (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.^[37] 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.^[38] 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.^[39]

Its comutagenic effects may be explained by interference with base and nucleotide excision repair, eventually through interaction with zinc finger structures.^[40] 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.^[41][42]

MMA(III) and DMA(III) were also shown to be directly genotoxic by effectuating scissions in supercoiled ΦX174 DNA.^[43] Increased arsenic exposure is associated with an increased frequency of chromosomal aberrations,^[44] micronuclei^[45][46] 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.^[47]

DMA(III) can form reactive oxygen species by reaction with molecular oxygen. Resulting metabolites are the dimethylarsenic radical and the dimethylarsenic peroxyl radical.^[48] 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.^[49] 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.^[50] 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.^[51]

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.^[52] 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.^[53] 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.^[54] 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.^[55] It turned out that six of the fragments were hyper- and two of them were hypomethylated.^[55] Higher levels of DNA methyltransferase mRNA and enzyme activity were found.^[55]

Kitchin (2001) proposed a model of altered growth factors, which lead to cell proliferation and thus to carcinogenesis.^[53] From observations, it is known that chronic low-dose arsenic poisoning can lead to increased tolerance to its acute toxicity.^[56][57] MRP1-overexpressing lung tumor GLC4/Sb30 cells poorly accumulate arsenite and arsenate. This is mediated through MRP-1-dependent efflux.^[58] The efflux requires glutathione, but no arsenic-glutathione complex formation.^[59]

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.^[60]

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.^[61] 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).^[62] 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.^[63] Resulting metabolites are monomethylarsonous acid, MMA(III), and dimethylarsinous acid, DMA(III).

Methylation had been regarded as a detoxification process, ^{[by whom?]} but reduction from +5 As to +3 As may be considered as a bioactivation ^{[clarification needed]} instead.^[64] 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.^[63] Gebel (2002) stated that methylation is a detoxification through accelerated excretion.^[65] With regard to carcinogenicity it has been suggested that methylation should be regarded as a toxification.^[53][66][67]

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.^[68] Arsenite inhibits members of the disulfide oxidoreductase family like glutathione reductase^[69] and thioredoxin reductase.^[70]

The remaining unbound arsenic (≤ 10%) accumulates in cells, which over time may lead to skin, bladder, kidney, liver, lung, and prostate cancers.^[62] 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.^[62]

The acute minimal lethal dose of arsenic in adults is estimated to be 70 to 200 mg or 1 mg/kg/day.^[71]

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.^[47][72] Via JNK and p38 it activates c-fos, c-jun and egr-1 which are usually activated by growth factors and cytokines.^[47][73][74] 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.^[72][75] Germolec et al. (1996) found an increased cytokine expression and cell proliferation in skin biopsies from individuals chronically exposed to arsenic-contaminated drinking water.^[76]

Increased AP-1 and NF-κB obviously also result in an up-regulation of mdm2 protein, which decreases p53 protein levels.^[77] 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.^[78] The authors conclude that the former may be interpreted as a defense response while the latter could lead to carcinogenesis.^[78] 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.^{[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,^[62][78][79] as well as the pro-inflammatory cytokines IL-8 and TNF-α.^{[62][78][79][80][81][82][83][84]} 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.^[85][86][87] 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.^{[62][80][85][87][88]}

Epidemiological studies have suggested a correlation between chronic consumption of drinking water contaminated with arsenic and the incidence of type 2 diabetes.^[62] The human liver after exposure to therapeutic drugs may exhibit hepatic non-cirrhotic portal hypertension, fibrosis, and cirrhosis.^[62] However, the literature provides insufficient scientific evidence to show cause and effect between arsenic and the onset of diabetes mellitus Type 2.^[62]

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.^{[citation needed][92]} Dimercaptosuccinic acid monoesters, e.g., MiADMSA, are promising antidotes for arsenic poisoning.^[93]

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.^[107]

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.^[111]