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Arsenic is the 20th most abundant element in the earths crust and 12th most abundant element in the human body. It has been used as a homicide since the middle Ages. However, As is also known as a therapeutic agent as early as 400 BC. For example, Fowler solution (arsenite solution containing 7.6 * 106 μg As/l) has been used since the 19th century for the treatment of leukemia, psoriasis, chronic bronchial asthma and also as a tonic. The daily dosage was often as high as 3000 μg. As has also extensively been used as pesticides, herbicides, wood preservatives, manufacture of dyestuffs, chemical warfare gases, glass industry, electronics, and growth promoting agent(3). The discovery of adverse health effects due to As exposure led to decreased usage of As. For example, the use of As salts in the agriculture went down drastically since 1970's with 70% of the worldwide production As trioxide applied in the agriculture in 1970 to only 45% in 1980 (4). The usage of As in the glass manufacturing industry is also reduced(5). The current uses of As compounds are as clarifier in the glass industry, as wood preservative, in semiconductors, as a desiccant and defoliant in agriculture (6, 7). One of the present usages of As as therapeutic agent is in Cancer treatment. Recently in 2000 randomized clinical trials in the US led the Food and Drug Administration (FDA) to approve As trioxide for treatment against leukemia (8).
Arsenic Chemistry of relevance
As in the environment can occur in several oxidation states (-3, 0, +3, +5) and as both organic and inorganic As. However, in natural waters inorganic As is predominant and is found as oxyanions of trivalent arsenite (H3As (III) O3) or pentavalent arsenate (e.g. (H2As (V) O4 -). In surface waters organic As compounds may be produced by biological activity, but are rarely important quantitatively. Figure 1 shows structures of some of the As compounds referred in the text. Redox potential and pH are the most important controlling factors in As speciation. As (V) is more predominant under oxidizing conditions and As (III) is more predominant under reducing conditions. The rate of oxidation of As(III) to As(V) or reduction of As(V) to As(III) depends on many factors like pH, Eh, the presence of micro-organisms, the presence of other oxidizing agents like manganese, Fe, etc., exposure to light and temperature(9,10,11,12,13,14). Generally the rate of oxidation of As (III) to As (V) is very low (15) in natural waters, but can proceed measurably in several days in strongly alkaline or acid solutions. The speciation of As is important in controlling the mobility, bioavailability and toxicity. As (V) with pK1 and pK2 values of 2.2 and 7.1 is present in the anionic form, whereas As (III) with pK1 value of 9.2 is present in neutral form in natural waters. The mobility of As is mainly controlled by the presence of metal (hydr)oxides and since at the pH of natural water As(III) is present as a neutral species and As(V) is present in anionic form the sorption of As(V) is strongly favored. Therefore As (III) is more mobile compared to As (V) in neutral to slightly acidic pH range. The presence of other competing ions also have an effect on the mobility of As (16, 17). For example high concentrations of P can desorb both As (V) and As (III). Similarly in the absence of other ions and abundance of available surface sites sorption of As (III) can also take place (18, 19). Under extremely reducing conditions and acidic pH with high concentration of reduced S precipitation of orpiment 4 (As2S3), realgar (AsS), FeAsS or other sulphide minerals is favored leading to lower As concentrations (14, 20).
Arsenic is readily absorbed when ingested in dissolved form (80-90%) or inhaled (30-85%). As (V), whether organic or inorganic, is better absorbed from the gastrointestinal tract compared to As (III). In contrast to inorganic arsenic, neither mono- methyl arsenic nor di-methyl arsenic binds strongly to biological molecules in humans (22).
Figures: Structures of some of the As compounds referred in the text (after (89)
Health effects and risk Assessment
As toxicity depends on many factors like species, amount of exposure, duration of exposure, nutritional status, methylation capacity, genetic conditions, bioavailability, selenium intake and presence of co-carcinogenic factors like exposure to sunlight, cigarette smoking (24,23,25,26,27,28,29,49). As methylation is considered to be a detoxification path, because the pentavalent organic As metabolites (DMA and MMA) were the most common forms found in urine samples of exposed humans. These forms are readily excreted and less toxic than inorganic As. However, some recent studies identified trivalent metabolites of organic As, DMA(As(III)) and MMA (As(III)), in urine samples of human exposed to As (sited in(30)). Laboratory studies have shown that these organic As(III) metabolites are more toxic than inorganic As(III)(31,32,33). Some of the early clinical symptoms of acute effects include abdominal pain, vomiting, diarrhoea, muscular pain, and weakness(34). Organic As is considered to be less toxic than inorganic As and the toxicity decreases in the order of AsH3 > As(III) > As(V) > organic arsenic compounds. The lethal dosage of As range from 1.5 mg/kg body weight for As2O3 to 500 mg/kg of body weight for DMA(1). Chronic exposure to low concentrations of As can cause dermal changes like skin pigmentation, hyperkeratosis and ulceration. Other chronic non dermal effects of As are diabetes(35), effects on cardiovascular system(36), hypertension(37), respiratory effects(38), adverse pregnancy outcomes etc(22). Chronic exposure to As is also documented to be carcinogenic in humans (1) at high exposures. However, discussion is still going on about the threshold limit for carcinogenic action of As, since both US and non-US-based studies showed only positive correlation between exposure to As and occurrence of cancer at As concentrations above 100 μg/l (39,40,41,42,23) Exposure to As can occur through food, water and air and table 1 shows general exposure level through these various routes(51). According to the values in table 1, the major route of exposure to total As is through food. However, the exposure through food did not receive much attention, since more than 90% of As in food is in the form of organic As. Water is the second major route of exposure to total As, and As is mainly present as inorganic As in natural waters. However, in areas with elevated As concentrations exposure of As through water becomes the major route. The first study related to exposure to As through drinking water and prevalence of skin cancer was reported from Taiwan(52). Based on this study WHO lowered the maximum permissible level from 50 μg/l to 10 μg/l(1). Table 2 depicts the acknowledgement of As in drinking water as a cause for adverse health effects in the form of lowered guideline values through years(53). In later years more studies also reported prevalence of internal cancers like bladder, liver, kidney and lung due to As exposure through drinking water (49,42,21,50,44,45). The latency period for development of skin and internal cancers are reported to be 6->40 years and depends on many factors like exposure level, duration of exposure, smoking habits, nutritional status, gender, sunlight and genetic conditions (46, 1, 47). The estimated life time excess risk of getting skin cancer in the US population at 50 μg/l is 3/1000 (22) and for the sum of internal cancers it is 1/100(48). This risk estimate would be even higher for general population in Bengal delta with a body weight of 50 kg, consuming 4-6 litres of water and nutrient deficient food. For more information see (IV).