CAS No. 7440-38-2
Arsenic is an element that is widely distributed in the earth's surface in small amounts. In nature, it is found in over 200 crystalline or mineral forms, such as arsenopyrite (FeAsS) and realgar (As4S4), or rarely as elemental metalloids (yellow, black, and gray forms). Arsenic can combine with such non-carbon chemicals as sulfur and oxygen to form arsenides, arsenites, and arsenates (oxidation states of -3, +3 and +5), referred to as inorganic arsenic compounds. Arsenic trioxide (As2O3, a trivalent compound known as white arsenic) is a common natural and commercial form that can be released into the air during volcanic action; the smelting of copper, lead, and other metals; and, to a lesser extent, from coal burning. The United States no longer produces arsenic from mining but imports about 22,000 metric tons annually, mostly for use in wood preservation (ATSDR, 2005). Various forms of inorganic arsenic can occur in groundwater from natural sources or as a result of soil application or industrial waste. Arsenic can also combine with organic substances in nature to form such organic arsenic compounds as arsenobetaine, arsenocholine, trimethylarsine oxide, and arsenosugars. Arsine (AsH3) is a reactive, gaseous hydride manufactured in small quantities for use in the semiconductor industry.
Arsenic and its compounds have had many uses in the past and present as medicines, pesticides, alloys, semiconductors, and as homicidal poisons. Before the 20th century, arsenic compounds, particularly arsenic trioxide, were used as treatments for syphilis, psoriasis, cancers, mental disorders, and as a cosmetic to lighten complexion. Various arsenic compounds were used in paint pigments and for tanning animal hides. In the last century, lead hydrogen arsenate, copper arsenates, sodium arsenite, cacodylic acid, and monosodium methyl arsenate were used as pesticides but contemporary uses are restricted. Roxarsone and other organic arsenicals are anticoccidial agents added to poultry feed. Since the 1940s, chromated copper arsenate (CCA) has been used to treat outdoor timbers and pressure-treated woods to prevent wood rot. Although it is still widely used in the United States, CCA-treated wood has been restricted since 2003 and no longer can be used in residential applications such as decks, retaining walls, and play sets. Arsenic trioxide is approved to treat acute promyelocytic leukemia. Gallium, aluminum, and indium arsenides are used in the semiconductor industry. Also, arsenic as elemental metalloids may be used in some ammunition, solders, as alloy in metal bearings, and in lead-acid storage battery grids.
General population exposure to inorganic arsenic can occur through consumption of drinking water and, to a lesser extent, meats, grain, and produce. Arsenic is measurable in most soils, ocean and fresh waters, and foods. Water sources contain mostly inorganic arsenate, though in some locations arsenite may be prevalent (WHO, 2001). Groundwater sources of drinking water often have measurable arsenic and several regions of the United States have naturally higher arsenic levels than the U.S. EPA's maximum contaminant level (Hughes, 2006; U.S. EPA, 2001). Extremely high groundwater arsenic levels, as observed in Bangladesh where millions of people have been exposed, have caused clinical arsenic poisoning. Though modest bioconcentration occurs in some aquatic life, arsenic does not show biomagnification in the food chain (WHO, 2001). Children may have additional exposures from ingestion of contaminated soils (e.g., mine tailings), dust, and contact with CCA-preserved wood structures. Smelter workers can have significant inhalational exposures to airborne arsenic trioxide for which air standards have been established. Smoking tobacco is also a source of inorganic arsenic. The semiconductor dopants, gallium arsenide and indium arsenide, are used in enclosed ultraclean operations within the semiconductor industry, so exposure to the general population is extremely limited.
Inorganic arsenic is well absorbed from the gastrointestinal tract and absorbed to a lesser degree through inhalation, but is poorly absorbed dermally (WHO, 2001). After absorption, inorganic arsenic is widely distributed within the body. Arsenate is reduced in the body to arsenite (oxidation state +3), though some reduction may occur in the gut prior to absorption. Arsenite is then oxidatively methylated to the monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) with subsequent excretion primarily in the urine (NRC, 2001). Inorganic arsenic and its metabolites have elimination half-lives of approximately 2–4 days (Lauwerys and Hoet, 2001; NRC, 2001). Some studies suggest that variation in the degree of methylation among persons is related to the susceptibility of arsenic-induced disease and may involve consideration of genetic polymorphisms, dose level, age, selenium, and folate status (Chen et al., 2007; Chowdhury et al., 2003; Gamble et al., 2006; Steinmaus et al., 2007; Tseng, 2007; WHO, 2001). Direct exposure to DMA and MMA may result from use of the two pesticides, cacodylic acid and monosodium methyl arsenate.
Fish, shellfish, kelp, and some other seafood can contain organic forms of arsenic including arsenobetaine, arsenocholine, trimethylarsine oxide (TMAO), and arsenosugars. In aquatic organisms, arsenocholine is converted to arsenobetaine and also to small amounts of TMAO (Christakopoulos et al., 1988). TMAO is also formed in the environment from microbiological action and is a metabolite of arsenic in certain mammals. In aquatic sediments, organic arsenic can be converted back to methylated and inorganic arsenic. Ingestion of arsenosugars in kelp and algae can also lead to the excretion of DMA. These organic forms of arsenic from seafood are absorbed and quickly excreted in the urine (WHO, 2001).
Inorganic forms of arsenic demonstrate high acute toxicity, with trivalent inorganic arsenic (arsenite) being more toxic than pentavalent inorganic arsenic (arsenate) (NRC, 2001, WHO, 2001). The reduced form of MMA (oxidation state +3) shows greater toxicity than arsenite itself (Aposhian et al., 2000; Bredfeldt et al., 2006; Cohen et al., 2006) and newly discovered thioarsenic metabolites may also be as toxic (Naranmandura et al., 2007; Raml et al., 2007). Arsenic has many actions demonstrated in cellular studies, including inhibition of numerous enzymes, substitution in phosphate metabolism, interference in signal transduction pathways, and altered gene expression. Such actions may lead to decreased energy production, increased oxidative stress, apoptosis, cytotoxicity, and endothelial injury (Kumagai and Sumi, 2007; NRC; 2001). Acutely, arsenite will inhibit cellular pyruvate dehydrogenase by binding to the sulfhydryl groups of dihydrolipoamide, and it also will inhibit succinate dehydrogenase, leading to a decrease in adenosine triphosphate energy production. Cellular glucose uptake, gluconeogenesis, fatty acid oxidation, and production of glutathione may be affected as well. Although arsenate is reduced in the body to arsenite, it may have its own separate toxic action by substituting for phosphate in glycolysis and other pathways, and by uncoupling oxidative phosphorylation (NRC, 2001; WHO, 2001).
Acute toxicity resulting from the ingestion of large amounts of trivalent arsenic (e.g., arsenic trioxide) includes hemorrhagic gastritis with nausea, vomiting, and diarrhea, which can lead to dehydration and shock. Cardiac arrhythmias, hepatotoxicity, renal failure, and peripheral neuropathy may also occur with large doses or after surviving an acute overdose. Chronic human intake of arsenic at less than acutely toxic doses, including drinking water sources with elevated arsenic levels (e.g., Bangladesh, Taiwan, Chile), can cause peripheral sensorimotor neuropathies, peripheral vascular disease, noncirrhotic portal hypertension, hematocytopenias, hyperkeratosis, and hyperpigmentation of the skin (NRC, 2001; WHO, 2001). With chronic exposure, some of these effects may take years to develop. Chronic elevated arsenic intakes have been associated with diabetes, hypertension, and childhood neurodevelopmental effects in observational human studies, but additional or confirmatory research is needed (Kapaj et al., 2006; WHO, 2001). The organic forms of arsenic occurring in seafood have little known toxicity. Acute unintentional inhalation of arsine gas can produce hemolysis of red blood cells.
Chronic arsenic exposure in humans is considered to be a cause of skin, lung, and bladder cancer (IARC, 2004; NRC, 2001). The risk of lung cancer appears more pronounced when large environmental exposures start in childhood (Smith et al., 2006) or when exposure occurs in smokers (Chen et al., 2004). Studies of arsenic at levels typical of U.S. drinking water have not been associated with increased cancer rates (Schoen et al., 2004). Laboratory studies using inorganic arsenic have shown chromosomal aberrations, cell transformations, and DNA repair inhibition (Cohen et al., 2006; U.S.EPA, 1998; WHO, 2001). OSHA and ACGIH have established workplace standards and guidelines for arsenic exposure and monitoring, respectively. The U.S.EPA has established drinking water, food residue, and environmental standards for arsenic and arsenic compounds, and the FDA has established a bottled drinking water standard. IARC and NTP recognize inorganic arsenic and arsenic compounds as human carcinogens. DMA produced bladder cancer in some chronic rat studies (Cohen et al., 2006). In animal studies, arsenic has been fetotoxic and teratogenic, but generally only at maternally toxic doses (WHO, 2001). Additional information about external exposure (i.e., environmental levels) and health effects is available from ATSDR at http://www.atsdr.cdc.gov/toxprofiles/index.asp.
Urinary arsenic levels reflect recent exposures and are moderately to highly correlated with arsenic intakes from drinking water and dietary sources (Ahsan et al., 2000; Calderon et al., 1999; Pellizzari and Clayton, 2006; WHO, 2001). Daily variation in creatinine-corrected urinary arsenic is relatively small when intake is constant (Calderon et al., 1999). Urinary arsenic levels were a better predictor for risk of arsenical skin lesions than were arsenic levels in drinking water in Bangladesh (Ahsan et al., 2000). Consequently, urinary arsenic levels have been accepted as a good biomarker of dose (WHO, 2001). Several studies have shown that urinary arsenic levels are not correlated with low levels of arsenic measured in house dust or in washings taken from hands (Hysong et al., 2003; Pellizzari and Clayton, 2006; Shalat et al., 2006), though air levels of arsenic fume and dust are correlated with urinary arsenic levels at higher occupational inhalational exposures (Jakubowski et al., 1998; Offergelt et al., 1992; Vahter et al., 1986). Though CCA-treated wood contains several thousand times more arsenic than untreated wood, hand washings from children playing on CCA-treated wood compared to children playing on non-CCA-treated wood playground equipment were slightly to fivefold higher (Kwon et al., 2004; Shalat et al., 2006), although urinary arsenic levels were not associated with CCA contact (Shalat et al., 2006).
Levels of total urinary arsenic in the U.S. population in the National Health and Nutrition Examination Survey (NHANES) 2003–2004 were similar to levels reported in the National Human Exposure Assessment Survey (NHEXAS) 1995–1996 for about 80 children residing in the Great Lakes region (Caldwell et al., 2009; Pellizzari and Clayton 2006). In the German Environmental Survey III of 1998, median urinary total arsenic levels in 4052 adults varied with seafood intake, had decreased since the prior1990–1992 survey, and were about two-fold lower than those for the U.S. population in NHANES 2003–2004 (Schulz et al., 2007; Caldwell et al., 2009). In a Nevada town where groundwater levels were naturally elevated, the median total urinary arsenic in about 200 people was approximately four times higher than that of the U.S. population (Rubin et al., 2007; Caldwell et al., 2009). Compared to the National Report on Human Exposure to Environmental Chemicals (CDC, 2012), higher mean or median total urinary arsenic levels have been reported among people living in specific western areas of North America (Calderon et al., 1999; Josyula et al., 2006; Meza et al., 2004; Valenzuela et al., 2005) and other areas of the world (Ahsan et al., 2000; Aposhian et al., 2000; Caceres et al., 2005; Sun et al., 2007) with higher levels of arsenic in the drinking water. Median and mean total urinary arsenic levels for residents in some districts in Bangladesh were reported to be about 50-fold higher than respective levels in the U.S. population (Ahsan et al., 2000; Caldwell et al., 2009; Chowdhury et al., 2003). For residents of Inner Mongolia, China, geometric mean levels were about 70-fold higher than for the U.S. population (Sun et al., 2007). Some noncancer effects of arsenic (e.g., dermal keratosis, vasospasm, and peripheral neuropathy) have been associated with urinary levels as low as 50–100 µg/L in chronically exposed populations (ACGIH, 2001; Blom et al., 1985; Tseng et al., 2005; Valenzuela et al., 2005; WHO, 2001). These associations are stronger at higher urinary levels, and other factors such as nutrition, methylation capacity, and duration of exposure are also considered important.
Total arsenic measured in the urine includes all species of inorganic and organic arsenic. Individually measurable species resulting from inorganic arsenic exposure are arsenate, arsenite, and two methylated metabolic products, DMA and MMA. Measurable organic arsenic species in the National Report on Human Exposure to Environmental Chemicals are three biologically generated environmental forms, arsenobetaine, arsenocholine, and TMAO (CDC, 2012). Arsenate, arsenite, arsenocholine, and TMAO were detected in only 7.6, 4.6, 1.8, and 0.3% of a representative sample of the U.S. population in the NHANES 2003–2004 subsample, respectively, with DMA, MMA, and arsenobetaine being the main contributors to the total urinary arsenic levels (Caldwell et al., 2009). When seafood intake is avoided, as evidenced by trace or nondetectable levels of arsenobetaine and arsenocholine in the urine, DMA and MMA compose most (about 75%) of the total arsenic species measured in urine. After recent seafood ingestion, arsenobetaine and arsenocholine will greatly increase the level of total urinary arsenic and comprise the highest percentage of the total urinary arsenic level. The higher percentiles of total urinary arsenic levels in the U.S. population showed a higher contribution of arsenobetaine (Caldwell et al., 2009). In most human studies, DMA has been the predominant metabolite composing the majority of measurable inorganic-related arsenic in the urine (i.e., when seafood organic arsenic is subtracted). Levels of DMA and MMA increase in approximate proportion to the intake of inorganic arsenic. In the late 1980s, a control population of 696 Tacoma residents had median urinary DMA levels similar to those for NHANES 2003–2004 (Kalman et al., 1990; Caldwell et al., 2009). Also, in NHEXAS 1995–1996, Great Lakes region residents had median urinary DMA levels that were slightly less than median levels in NHANES 2003-2004 (Caldwell et al., 2009; Pellizzari and Clayton, 2006). In the residents of a Chilean town who consumed water with high levels of arsenic, median levels of urinary DMA were about 40-fold higher than the adult median reported in NHANES 2003–2004, and urinary DMA represented about 67% of the total urinary arsenic (Hopenhayn-Rich et al., 1996; Caldwell et al., 2009). Detectable levels of MMA reported in NHANES 2003–2010 were characterized only at the 75th, 90th , and 95th percentiles and, as with DMA, these levels were much lower than those found in other studies where environmental exposures were highly elevated (Chowdhury et al., 2003; Sun et al., 2007).
In recent years, occupational monitoring and research studies have focused on the sum of inorganic-related species (arsenate + arsenite + DMA + MMA) as a measure of inorganic arsenic intake. Studies of small groups of metal and sulfuric acid smelter workers with varying industrial hygiene conditions have reported urinary inorganic arsenic levels (arsenate + arsenite + DMA + MMA) ranging as high as several hundreds of µg/L during or after work exposure (Jakubowski et al., 1998; Offergelt et al., 1992; Vahter et al., 1986; WHO, 2001). Timber treatment workers had median urinary DMA levels that were about 15-fold higher than the general adult median levels reported in NHANES 2003–2004 (Morton et al., 2006; Caldwell et al., 2009). The American Conference of Governmental Industrial Hygienists (ACGIH) provides an occupational biologic effect index (BEI) for urinary inorganic arsenic plus metabolites equal to 35 µg/L (ACGIH, 2001). The 95th percentile of the U.S. population for the sum of inorganic related species was 18.9 µg/L, which is below the ACGIH BEI (Caldwell et al., 2009). Information about the biological exposure indices is provided here for comparison, not to imply a safety level for general population exposure
Finding a measurable amount of arsenic in urine does not imply that the level of arsenic causes an adverse health effect. Biomonitoring studies of urinary arsenic can provide physicians and public health officials with reference values so that they can determine whether people have been exposed to higher levels of arsenic than are found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.
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