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5
Disposition of Inorganic Arsenic

This chapter reviews the data regarding the absorption, biotransformation, distribution, and elimination of arsenic in animals and humans. Physiologically based pharmacokinetic (PB-PK) models that incorporate that information are described in the section Kinetic Model. The implications of the subcommittee's conclusions for a risk assessment for arsenic in drinking water are presented in the section Summary and Conclusions.

Absorption

When ingested in dissolved form, inorganic arsenic is readily absorbed. About 80-90% of a single dose of arsenite As(III) or arsenate As(V) was absorbed from the gastrointestinal tract of humans and experimental animals (Pomroy et al. 1980; Vahter and Norin 1980; Freeman et al. 1995). A much lower degree of gastrointestinal absorption was reported for arsenic-contaminated soil (Freeman et al. 1995), although the form of arsenic in the soil, as well as the type of soil, can be assumed to influence the degree of arsenic absorption. Also, arsenic compounds of low solubility (e.g., arsenic selenide) (Mappes 1977), arsenic trisulfide and lead arsenate (Marafante et al. 1987), and gallium arsenide (Webb et al. 1984; Yamauchi et al. 1986) are absorbed much less efficiently than is dissolved arsenic. There is a lack of data on the bioavailability of inorganic arsenic in various types of foods.

No controlled studies have been conducted on the rate of absorption of inorganic arsenic through intact human skin. However, reported systemic toxicity in persons having extensive acute dermal contact with solutions of inorganic arsenic indicates that skin can be a route of exposure (Hostynek et al. 1993). In vitro studies in which water solutions of radiolabeled arsenate



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Page 150 5 Disposition of Inorganic Arsenic This chapter reviews the data regarding the absorption, biotransformation, distribution, and elimination of arsenic in animals and humans. Physiologically based pharmacokinetic (PB-PK) models that incorporate that information are described in the section Kinetic Model. The implications of the subcommittee's conclusions for a risk assessment for arsenic in drinking water are presented in the section Summary and Conclusions. Absorption When ingested in dissolved form, inorganic arsenic is readily absorbed. About 80-90% of a single dose of arsenite As(III) or arsenate As(V) was absorbed from the gastrointestinal tract of humans and experimental animals (Pomroy et al. 1980; Vahter and Norin 1980; Freeman et al. 1995). A much lower degree of gastrointestinal absorption was reported for arsenic-contaminated soil (Freeman et al. 1995), although the form of arsenic in the soil, as well as the type of soil, can be assumed to influence the degree of arsenic absorption. Also, arsenic compounds of low solubility (e.g., arsenic selenide) (Mappes 1977), arsenic trisulfide and lead arsenate (Marafante et al. 1987), and gallium arsenide (Webb et al. 1984; Yamauchi et al. 1986) are absorbed much less efficiently than is dissolved arsenic. There is a lack of data on the bioavailability of inorganic arsenic in various types of foods. No controlled studies have been conducted on the rate of absorption of inorganic arsenic through intact human skin. However, reported systemic toxicity in persons having extensive acute dermal contact with solutions of inorganic arsenic indicates that skin can be a route of exposure (Hostynek et al. 1993). In vitro studies in which water solutions of radiolabeled arsenate

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Page 151 were topically applied to human skin or the skin of rhesus monkeys showed that about 2-6% of the applied arsenic was absorbed in 24 hr (Wester et al. 1993). Similar in vitro studies using dorsal skin of mice showed a much higher absorption; 30% of the applied dose of radiolabeled arsenate in aqueous solution (100-200 ng/L) was absorbed in 24 hr (Rahman et al. 1994). A large percentage, on average 60-90 %, of the absorbed arsenic was retained in the skin. That result indicates that inorganic arsenic can bind externally to skin and hair. Rapid binding of 74 As to the skin and epithelium of the upper gastrointestinal tract in the marmoset fetus has also been observed 8 hr after maternal exposure to 74As-arsenite (Lindgren et al. 1984). Taken together, those results indicate a low degree of systemic absorption of arsenic via the skin. Some further information on the skin absorption of arsenic in humans may be obtained from a study in Fairbanks, Alaska, where arsenic was found in home water at 345 µg/L (Harrington et al. 1978). One group of people who drank bottled water only but used the arsenic-rich water for other purposes had about the same low concentrations of the sum of arsenic metabolites in urine (average 43 µg/L) as people with less than 50 µg/L in their home water (average 38 µg/L in urine), indicating a low degree of skin absorption. However, the hair arsenic concentrations were clearly elevated in the group drinking bottled water (5.7 µg/g compared with 0.43 µg/g in the low-arsenic-water group), suggesting that arsenic is bound externally to hair and probably also to skin during washing with arsenic-rich water. Biotransformation In this section, arsenate reduction and arsenite methylation are described. Species differences are reviewed, as are other factors influencing the metabolism of arsenic. Variations in arsenic methylation in humans are reviewed in more detail in Chapter 7. Arsenate Reduction and Arsenite Methylation In humans and in most experimental animals, inorganic arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Compared with inorganic arsenic, the methylated metabolites are less reactive with tissue constituents, less acutely toxic, less cytotoxic, and more readily excreted in the urine (Buchet et al. 198 1a; Vahter and Marafante 1983; Vahter et al. 1984; Yamauchi and Yamamura 1984; Marafante et al. 1987; Moore et al. 1997; Rasmussen and Menzel, 1997; Concha et al. 1998a; Hughes and

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Page 152 Kenyon 1998; Sakurai et al. 1998). In addition, experimental studies showed that inhibition of the methylation reactions results in increased tissue concentrations of arsenic (Marafante and Vahter 1984; Marafante et al. 1985). In the 1930s, Challenger found that microorganisms grown in the presence of arsenite, MMA, or DMA released trimethylarsine (Challenger 1945). Essentially the same sequence of alternating reduction and methylation reactions was postulated for various mammals exposed to inorganic arsenic (Challenger 1945). However, considerable variation in methylation products is found among species. For example, DMA is the major end point of arsenic biomethylation in most mammals, while in many microorganisms, trimethylarsine is the end product. In mice, hamsters, and humans exposed to DMA, a small fraction was further methylated and excreted in the urine as trimethylarsine oxide (Marafante et al. 1987). However, the formation of trimethylarsine or its oxide has not been demonstrated following exposure to inorganic arsenic. As noted in Chapter 3, methylation of inorganic arsenate to DMA involves alternating reduction of pentavalent arsenic to trivalent arsenic and addition of methyl groups (Vahter and Envall 1983; Cullen et al. 1984; Marafante et al. 1985; Vahter and Marafante 1988; Buchet and Lauwerys 1988; Hirata et al. 1990; Thompson 1993). Although all the steps and mechanisms in the arsenic biotransformation have not been elucidated, experimental animal studies performed in vivo or with animal tissue preparations in vitro indicate that the methylation takes place by transfer of methyl groups from S-adenosylmethionine (SAM) to arsenic in its trivalent oxidation state (Marafante and Vahter 1984; Buchet and Lauwerys 1985; Marafante et al. 1985; Styblo et al. 1995, 1996; Zakharyan et al. 1995). Probably, glutathione (GSH) plays an important role in the reduction of As(V) to As(III). The produced As(III) can form a complex with GSH (Delnomdedieu et al. 1994a,b). Also, cysteine or dithiothreitol (DTT) can reduce pentavalent arsenic, as shown in studies with purified rabbit-liver enzyme preparations (Zakharyan et al. 1995) or rat-liver cytosols (Buchet and Lauwerys 1985; Styblo et al. 1996). Studies with mice, rabbits, and marmoset monkeys showed that a substantial fraction of absorbed As(V) is rapidly reduced, probably mainly in the blood, to As(III) (Vahter and Envall 1983; Vahter and Marafante 1985; Marafante et al. 1985), most of which is then methylated to MMA and DMA (Marafante et al. 1985). As(V) might also be reduced in the stomach or intestine, but quantitative experimental data are not available. Because of the rapid reduction, chronic exposure to arsenite and arsenate will result in fairly similar metabolite distribution in the body. However, the distribution pattern will differ for the two forms if the reducing capacity is exceeded by acute high-dose exposure (Vahter 1981; Lindgren et al. 1982). If the newly formed

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Page 153 trivalent arsenic is not completely methylated, the reduction of As(V) to As(III) results in enhanced retention in most tissues, because trivalent arsenic is more reactive with tissue constituents than is pentavalent arsenic (Vahter and Marafante 1983; Bogdan et al. 1994; Styblo et al. 1995). Following ingestion of MMA(V) by humans, only about 10% is further methylated and excreted as DMA in the urine (Buchet et al. 1981a). Similar results were obtained in vitro with rat-liver cytosols, while more than 90 % of added MMA in reduced form, MMA(III), was further methylated to DMA (Styblo et al. 1995). That result indicates that MMA is not reduced as easily as arsenate or that there is a slow  cellular uptake of MMA  in vivo (Delnomdedieu et al. 1995; Mann et al. 1996a). The kinetics of arsenic methylation in vivo has not been completely elucidated. In rabbits exposed to inorganic arsenic, DMA appeared in the liver before appearing in other tissues (Marafante et al. 1985). Further support for the finding that the liver is an important initial site of arsenic methylation is obtained in studies conducted in experimental animals and humans. Orally administered inorganic arsenic, most of which initially passes through the liver following absorption, was found to be methylated more efficiently than inorganic arsenic administered subcutaneously or intravenously (Charbonneau et al. 1979; Vahter 1981; Buchet et al. 1984). Also the fact that the methylation of arsenic injected in patients with end-stage liver disease improved markedly with liver transplantation suggests that the liver plays an important role in arsenic metabolism (Geubel et al. 1988). The site of methylation might also depend on the rate of reduction of As(V) to As(III). Studies on isolated rat hepatocytes showed that arsenite, but not arsenate, is readily taken up and methylated by the liver cells (Lerman et al. 1983). That might occur because the trivalent inorganic arsenic is in non-ionized form (arsenous acid) at physiological pH, and the pentavalent form is ionized (see Chapter 3). On the other hand, studies with kidney slices showed that about five times more DMA is produced from arsenate than from arsenite (Lerman and Clarkson 1983), indicating that the arsenate that is not initially reduced to arsenite can be taken up by the kidney cells, reduced and methylated to DMA intracellularly, and then excreted in the urine. Reabsorption and reduction of arsenate in the kidney tubule were demonstrated in dogs (Ginsburg 1965). In vitro studies investigating the methylation capacity of different tissues had varying results.  Buchet and Lauwerys (1985) reported that the methylating capacity of red blood cells, brain, lung, intestine, and kidneys of rats was insignificant compared with that of the liver. In vitro studies using arsenite methyltransferases from mouse tissues showed that the highest amount of methylating activity is in the testes, followed by kidney, liver, and lung (Healy et al. 1998). The amounts of methyltransferases vary in different

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Page 154 tissues and animal species (Aposhian 1997). Although the methylating capacity of tissues in vitro does not reflect in vivo methylation, when the kinetics of the arsenic species plays an important role, the results indicate that arsenite initially bound to tissue constituents can be methylated and released. That could explain the observed slow elimination phase that follows the initial rapid phase; the slow elimination phase might involve the continuous release of arsenic from most binding sites (Marafante et al. 1981; Vahter and Marafante 1983). In vitro studies using rat-liver preparations showed that the methylating activity is localized in the cytosol and that SAM is the main methyl donor (Buchet and Lauwerys, 1985; Zakharyan et al. 1995; Styblo and Thomas 1997). Added vitamin B12, coenzyme B12, and methylcobolamin could also act as methyl donors, and the latter could produce MMA even in the absence of enzymatic activity. Research on the purification and characterization of arsenic methyltransferases (Zakharyan et al. 1995, 1996) indicated that the rabbit arsenite and MMA methyltransferase activities are in the same protein. Using the 2,000-fold purified protein, the investigators found no evidence that the activities were on different proteins (Zakharyan et al. 1995). SAM was used as the methyl source, as previously shown by in vivo studies and in vitro studies using tissue cytosol. The arsenite and the MMA methyltransferase had a molecular mass of 60 kDa, as determined by gel-size-exclusion chromatography but had different pH optima and different saturation concentrations for their substrates. Neither arsenate nor selenate, selenite, or selenide was methylated by the purified enzyme preparations. Species Differences There are major species differences in the biotransformation of inorganic arsenic (Vahter 1994). A number of studies, in which the metabolites of inorganic arsenic in human urine have been speciated, consistently show average values of 10-30%  inorganic arsenic, 10-20% MMA, and 55-75% DMA (for a review, see Hopenhayn-Rich et al. 1993). Those results were found in human subjects exposed to inorganic arsenic in the general environment and in those exposed at work. However, in recent studies of people exposed to arsenic via drinking water in northern Argentina, urinary arsenic consisted of only 2% MMA on average (Vahter et al. 1995a; Concha et al. 1998a). Variations in arsenic methylation in humans is reviewed in more detail in Chapter 7. Many experimental animals excrete less MMA and more DMA in the urine than do humans. Mice and dogs methylate inorganic arsenic efficiently,

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Page 155 and in general, more than 80% of the administered dose is excreted, mainly as DMA, in the urine within a few days (Charbonneau et al. 1979; Vahter 1981). The rat also methylates inorganic arsenic efficiently, but a major portion of the DMA produced is retained in the erythrocytes (Odanaka et al. 1980; Lerman et al. 1983), giving rise to a slow urinary excretion of DMA and a tissue-distribution pattern that is different from that in most other species (Vahter et al. 1984). In addition, the rat shows an extensive biliary excretion of arsenic, about 800 and 37 times more than the dog and rabbit, respectively (Klaassen 1974). With respect to arsenic methylation, the rabbit (Marafante et al. 1981; Vahter and Marafante 1983; Maiorino and Aposhian 1985) and the hamster (Charbonneau et al. 1980; Yamauchi and Yamamura 1984, 1985; Marafante and Vahter 1987) are more similar than other investigated animal species to humans, although more DMA and less MMA is excreted by rabbits and hamsters than by humans. The Flemish giant rabbit (De Kimpe et al. 1996) and a New Zealand rabbit (Bogdan et al. 1994) were found to excrete MMA in amounts similar to those in humans. The two animal species that were first shown not to methylate inorganic arsenic, the marmoset monkey (Vahter et al. 1982; Vahter and Marafante 1985) and the chimpanzee (Vahter et al. 1995b), in general have a metabolism most similar to that of humans. The cynomolgus monkey, on the other hand, seems to methylate inorganic arsenic well (S.M. Charbonneau, Health and Welfare Canada, Ottawa, Ont., personal commun., 1983; cf. Vahter 1983). Another unique feature of the marmoset monkey is that it accumulates arsenic in the liver, apparently firmly bound to the rough microsomal fraction (Vahter et al. 1982). The first phase of elimination has a fairly short half-time. In the second phase, as much as 70% of the administered dose is eliminated at a very slow rate. In the chimpanzee, excretion also seems to be biphasic, and the half-time of the second phase is similar to that observed in the marmoset; however, much less of the total administered dose is eliminated. In spite of the lack of methylation of arsenic in the chimpanzee, about 50% of an intravenous dose was excreted within 2 to 4 days in the urine (Vahter et al. 1995b). That is similar to that in humans, who excrete about half of a low dose of arsenite or arsenate in the urine within about 4 days (Tam et al. 1979; Pomroy et al. 1980; Buchet et al. 1981b), indicating that other factors influence the tissue retention and excretion of arsenic. Arsenite methyltransferase activity, tested by incubation of liver preparations with arsenite in vitro, has been detected in the liver of the rabbit, rat, mouse, hamster, pigeon, and rhesus monkey but not in the liver of the marmoset monkey, tamarin monkey, squirrel monkey, chimpanzee, and guinea pig

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Page 156 (Zakharyan et al. 1995, 1996; Healy et al. 1997). With human liver preparations, no methylated arsenic metabolites were detected.  As humans do methylate inorganic arsenic in vivo, the reason for the negative in vitro test is not known. In the case with marmoset monkeys and chimpanzees the negative in vitro test is in concordance with in vivo studies showing no methylation of inorganic arsenic in those animals (Vahter et al. 1982; Vahter et al. 1995b). The rhesus monkey, hamster, rat, mouse, and pigeon, have ample amounts of such methyltransferase activity. In decreasing order, the species with liver arsenite methyltransferase activity are the pigeon, rhesus monkey, mouse, hamster, rabbit, marmoset monkey, squirrel monkey, and tamarin monkey. In addition, when guinea pigs were injected intraperitoneally with radioactive arsenate, five of six guinea pigs did not have methylated arsenic species in their urine (Healy et al. 1997). The sixth animal had minimal but measurable amounts of DMA in its urine. Analysis of liver cytosol showed that the guinea pigs were deficient in liver arsenic methyltransferase activities (Healy et al. 1997). All the species had ample arsenate reductase activity, however. Factors Influencing the Metabolism of Arsenic It is likely that factors influencing the methylation of arsenic can modify the tissue retention and toxicity of arsenic, because the biomethylation of inorganic As(III) produces metabolites that have low reactivity toward most tissues and that are readily excreted in the urine. This section describes the experimental evidence for effects on the methylation of arsenic by such factors as the chemical form and dose of arsenic absorbed protein binding, nutrition, and genetic polymorphism. The observed variation in human methylation of arsenic in relationship to dose, sex, ethnicity, and recreational habits is discussed in Chapter 7. In some experimental animal studies, exposure to arsenite resulted in a higher degree of methylation and more DMA in the urine than did exposure to arsenate (Vahter 1981; Vahter and Marafante 1983). However, in spite of the fact that the reduction of arsenate is not complete, the total amount of arsenic excreted in the urine is slightly higher following arsenate exposure than following arsenite exposure, as shown by experimental studies on human volunteers (Pomroy et al. 1980; Buchet et al. 1981a). Most likely, the reason for this is that As(V) is less reactive with tissue constituents and more readily excreted in the urine than is As(III) (Vahter and Marafante 1983). The differences in retention of arsenic following exposure to arsenate and arsenite decrease with decreasing dose (Vahter 1981), because a large part of the arsenate is reduced rapidly following absorption.

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Page 157 Studies on mice showed that as the dose of inorganic arsenic increases substantially, the methylation rate decreases and the tissue concentrations of arsenic increase (Vahter 1981; Hughes et al. 1994). Also, in humans acutely intoxicated by very high doses of inorganic arsenic, there is a marked delay in the urinary excretion of DMA (Mahieu et al. 1981; Foà et al. 1984). In one case of attempted suicide, a person ingested about 3 g of As2O3 in water and was admitted to the hospital 2 hr later (Foà et al. 1984). The relative percentage of urinary DMA increased from about 30% on the 8th day to 78 % on the 13th day after ingestion. In three persons who ingested 100-500 mg of arsenic in the form of As2O3, which was mistakenly used instead of sugar, urinary DMA increased from about 10% the first days after ingestion (blood arsenic concentrations of 190-800 µg/L) to about 75% after a week (Mahieu et al. 1981). However, in the case of exposure to arsenic via drinking water, even at very high arsenic concentrations, the methylation of arsenic seems to be relatively unaffected by the concentration of the dose. According to an abstract of a study by Kosnett and Becker (1988), following subacute exposure to drinking water containing arsenic at a concentration of 25,000 µg/L, a 36-year-old man yielded a urinary arsenic collection containing 6,025 µg per 24 hr, 26% as inorganic arsenic and 74% as methylated metabolites. A further discussion of the dose-dependence of arsenic methylation in humans exposed via drinking water is presented in Chapter 8. Results from in vitro studies suggested that the delay in urinary excretion of DMA might occur because of the high tissue concentrations of arsenite inhibit the methyltransferase catalyzing the second methylation step (Buchet and Lauwerys 1985). Methylation capacity might also have been overloaded by the high tissue concentrations of As(III). However, in both human studies, BAL was administered for several days, which might have influenced the methylation of arsenic (see below). Protein binding is another factor in arsenic mechanism. Bogdan et al. (1994) found three arsenite-binding proteins in rabbit liver. They were 450 kilodaltons (kDa), 100 kDa, and less than 2,000 kDa in size. Inorganic arsenite was firmly bound to them. The affinity of arsenite for those proteins was 20 times greater than that for arsenate. Experimental studies on mice and rabbits showed that inhibition of SAMdependent methylation reactions by treatment with periodate-oxidized adenosine, which inhibits the metabolism of S-adenosylhomocysteine, results in decreased methylation and increased tissue concentrations of arsenic (Marafante and Vahter 1984; Marafante et al. 1985). That finding indicates that a low tissue concentration of SAM (e.g., as a result of low intake of precursors to SAM) might give rise to a low rate of methylation of arsenic. In fact, studies on rabbits fed diets with low amounts of methionine, choline,

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Page 158 or proteins showed a marked decrease in urinary excretion of DMA, accompanied by a 2-3 times increase in tissue concentrations of arsenic, especially in the liver (Vahter and Marafante 1987). A decrease in urinary excretion of arsenic was also observed in mice fed a choline-deficient diet (Tice et al. 1997). In particular, arsenic concentrations were increased in liver microsomes of the rabbits on the methyl-deficient diet (Vahter and Marafante 1987), a result similar to that seen in the marmoset monkeys (Vahter et al. 1982). Thus, nutritional factors might influence the subcellular distribution of arsenic. The methylation of arsenic appears to be affected by hepatic disease. Various liver diseases (i.e., alcoholic cirrhosis, chronic hepatitis, homochromatosis, postnecrotic cirrhosis, steatosis, and biliary cirrhosis) decreased the proportion of MMA (in relationship to the total urinary excretion of metabolites of inorganic arsenic) and increased the proportion of DMA in urine following injection of a single dose of sodium arsenite (Buchet et al. 1984; Geubel et al. 1988).  The overall effect was a more efficient methylation of the injected arsenic in individuals with liver disease than in healthy controls or controls with other types of diseases. The effect of the chelating agent 2,3-dimercapto-1-propanesulfonic acid (DMPS; 300 mg of Dimaval given by mouth after an overnight fast) on the urinary arsenic metabolite pattern was studied in people living in the Atacama desert in northeastern Chile, where the concentration of arsenic in drinking water is 600 µg/L (Aposhian et al. 1997). During the 2-hr period following administration, the content of metabolites of inorganic arsenic in urine consisted of 20-22% inorganic arsenic, 42% MMA, and 37-38% DMA. The usual range of MMA in human urine is 10-20% and that of DMA 60-80%. A similar increase in the percentage of MMA was found in the control subjects exposed to arsenic at 20 µg/L of drinking water. DMPS increased the total urinary arsenic excretion by about 5-6 times during the 6-hr period after administration. The mechanism for the increase in MMA excretion is not known. In vitro studies on arsenic methylation in rat-liver cytosol showed that chelating agents, such as DMSA and DMPS (0.05-0.5 mM), almost completely inhibit the methylation of inorganic arsenic to DMA (Buchet and Lauwerys 1985, 1988). Addition of DTT (dithiothreitol) and 2-mercaptoethanol of up to 0.5 mM  stimulated in vitro methylation, but resulted in inhibition at higher concentrations. Also, EDTA (1 mM) was shown to inhibit preferentially DMA formation from 74As-As(III) (carrier-free) in vitro (Styblo and Thomas 1997). Possibly, the administration of chelating agents results in an inhibition of the second step of the methylation of the inorganic arsenic released from tissues, giving rise to more MMA being excreted in the urine.

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Page 159 Transportation, Distribution, And Elimination In this section, the transportation of arsenic in blood, its distribution in tissues, and its elimination from the body are described. Transportation in Blood Absorbed arsenic is transported in the blood, mainly bound to sulfhydryl (SH) groups in proteins and low-molecular-weight compounds such as glutathione (GSH) and cysteine, to the organs in the body. Formation of complexes between trivalent arsenicals and GSH, probably mainly in the form of As(GS)3, has been demonstrated in water solutions (Scott et al. 1993; Delnomdedieu et al. 1994a), rabbit erythrocytes (Delnomdedieu et al. 1994b), and rat bile (Anundi et al. 1982). However, As(III) can be transferred easily from the As(GS)3 complex to binding sites of higher affinity. Recently, inorganic arsenic was reported to be the main form of arsenic bound to serum proteins in patients on continuous ambulatory peritoneal dialysis, and transferrin was the main carrier (Zhang et al. 1997, 1998a,b). Most of the arsenic in blood is rapidly cleared, following a three-exponential clearance curve (Mealey et al. 1959; Pomroy et al. 1980). The majority of arsenic in blood is cleared with a half-time of about 1 hr. The half-times of the second and third phases are about 30 and 200 hr, respectively. Experimental data on animals and data on patients with uremia indicate that the concentration of arsenic in red blood cells is severalfold that in plasma at low or background exposure concentrations but is close to onefold at increased blood concentrations (Lindgren et al. 1982; Versieck 1985; De Kimpe et al. 1993). The ratio between plasma and the red blood cells might also depend on the exposure form of arsenic; studies on rabbits found that As(III) is more easily taken up by erythrocytes than is As(V), MMA, or DMA (Delnomdedieu et al. 1995). Early studies on healthy individuals with no known exposure to arsenic indicate similar concentrations (about 2.5 µg/L) in plasma and whole blood (Heydorn 1970). People from the area in Taiwan with arsenic-rich water had about 15 µg/L in plasma and 22 µg/L in whole blood. Patients with blackfoot disease and their families had about 30 µg/L in plasma and 60 µg/L in whole blood (Heydorn 1970). Arsenic concentrations were found to be significantly higher in the serum and erythrocytes of chronic hemodialysis patients compared with controls (De Kimpe et al. 1993). Serum had a median arsenic concentration of 12 µg/L versus 0.38 µg/L in controls, and erythrocytes had a median of 9.5 µg/L

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Page 160 versus 3.2 µg/L in controls. A single hemodialysis treatment did not change the arsenic concentrations. In a similar study, Zhang et al. (1996) reported a mean total arsenic concentration of 5.1 µg/L in nonhemodialysis patients and 6.5 µg/L in hemodialysis patients, compared with 0.96 µg/L in a control group of healthy subjects. DMA and arsenobetaine (AsB) were the major arsenic species in serum, the mean values being about 1 µg/L for DMA and 3.5 µg/L for AsB. Serum concentrations of inorganic arsenic and MMA were below the detection limits. In the control group, serum arsenic concentrations were too low for speciation. Hemodialysis treatment removed 68% of total arsenic in serum and 16% in erythrocytes. The efficiency was similar for DMA and AsB. There are major species differences in the half-time of arsenic in blood. In the rat, arsenic is retained in the blood considerably longer than in other species because of the accumulation of DMA in the red blood cells, apparently bound to hemoglobin (Odanaka et al. 1980; Lerman and Clarkson 1983; Vahter 1983; Vahter et al. 1984). The accumulation of arsenic in the rat erythrocytes was first reported more than 50 years ago (Hunter et al. 1942), although at that time DMA was not known to be the main form of arsenic retained. Lanz and co-workers (1950) reported that the cat also had higher concentrations of arsenic in the blood than most other species, although not as high as the rat. Whether it is DMA that accumulates in the red blood cells of the cat is not known. Even though inorganic arsenic is not methylated in the chimpanzee, the clearance of arsenic from the plasma, following a single intravenous dose of 73 As-arsenate, was shown to be fast, with a half-time of about 1 hr (Vahter et al. 1995b). The elimination from red blood cells was slower, with a half-time of about 5 hr. Essentially, all 73 As in the plasma was ultrafiltrable, indicating a low degree of binding to high-molecular-weight proteins (above 25,000 daltons). Those findings indicate that the rate of clearance of arsenic from blood might be affected by factors other than methylation. Tissue Distribution In the body, As(III) is mainly bound to SH groups. In particular, As(III) forms high-affinity bonds with vicinal thiols, as demonstrated with lipoic acid and DMSA (Cullen and Reimer 1989; Delnomdedieu et al. 1993). Experimental animal studies found that the binding of arsenic is mainly to highmolecular-weight proteins in various tissues; however, arsenic is continuously released from most intracellular binding sites over time following exposure (Marafante et al. 1981; Vahter et al. 1982). Probably, As(III) is bound to

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Page 166 with a half-time of about 1 hr. The whole-body half-time of ingested arsenite is about 4 days, urine being the major excretory pathway. In humans, inorganic arsenic is methylated to MMA(V) and DMA(V), which are less reactive with tissue constituents, less acutely toxic, and more readily excreted in the urine than inorganic arsenic. The methylation involves addition of methyl groups from S-adenosylmethionine to arsenic in its trivalent oxidation state. A major part of absorbed pentavalent arsenic is reduced probably by GSH or cysteine. Thus, the tissue distribution, retention and toxicity of arsenic following exposure to moderate doses of arsenite and arsenate are similar. At very high doses, more arsenic is retained following exposure to arsenite than to arsenate. The liver is an important initial site of arsenic methylation, but most tissues seem to have methylating capacity. There are major differences in the biotransformation of inorganic arsenic between animal species and population groups. Most experimental animals methylate arsenic more efficiently and excrete less MMA in the urine than do humans. Some mammals (e.g., chimpanzee, marmoset monkey, and guinea pig) have been identified that do not methylate inorganic arsenic at all. Although the rat efficiently methylates arsenic, a major part of the DMA produced is retained in the erythrocytes. That response and the unusual biliary excretion of arsenic in the rat make it a less-suitable animal model for studies of arsenic disposition in humans. In people occupationally, experimentally, or environmentally exposed to inorganic arsenic, the urinary content of metabolites of inorganic arsenic generally consists of 10-30% inorganic arsenic, 10-20% MMA, and 55-75% DMA. Some groups of people who excrete only a few percent of MMA have been identified. That response, together with marked individual variations, can indicate a genetic polymorphism  in the arsenic methyltransferases. Experimental studies indicate that the methylation of arsenic might also be influenced by the arsenic species absorbed, by acute high-level exposures, as well as by nutritional factors and diseases. Animal studies have shown retention of arsenic in the skin, hair, squamous epithelium of the upper gastrointestinal tract, epididymis, thyroid, skeleton, and lens of the eye. Arsenite is the main form interacting with tissue constituents, except the skeleton. In human subjects, the hair and nails have the highest concentrations of arsenic (0.02-1 mg/kg of dry weight), and the skin and lungs have fairly high concentrations (0.01-1 mg/kg of dry weight). Data extrapolated from animal studies permit the development and validation of a suitable PB-PK model for inorganic arsenic for humans. Experimental animal studies show that both inorganic arsenic and the methylated metabolites pass the placenta. In humans exposed to arsenic via drinking water, arsenic concentration in cord blood was similar to that in

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Page 167 maternal blood. DMA was the main form of arsenic in plasma of mothers and newborns. The excretion of arsenic in human milk is low, and in areas with high arsenic concentrations in the water, an infant is less exposed to arsenic via breast feeding than via formula prepared from the water. Recommendations Because of interspecies differences in the amounts of various arsenic species excreted in the urine and the amounts of methyltransferases in tissues, extrapolation of animal data to humans is generally not possible. More human studies are needed, including research using human tissues, to answer some of the questions concerning the disposition and toxic effects of arsenic. Factors influencing methylation, tissue retention, and excretion of arsenic in humans (e.g., arsenic-binding proteins) also need to be investigated. Other studies of less critical importance but nonetheless needed to fill important data gaps include the following: —  Studies to determine whether the methylation of arsenic in vivo results in the formation of reactive intermediates that are distributed to tissues. —  Studies to identify the gene or genes for arsenic methyltransferases so that nucleotide probes can be used to examine the relationships between the polymorphism of arsenic methyltransferases and the phenotype (excretion of arsenic metabolites in urine), as well as between the polymorphism of arsenic methyltransferases and the signs and symptoms of arsenic toxicity. —  Studies on the bioavailability of inorganic arsenic in various types of food. —  Studies to examine fetal exposure to various arsenic metabolites during different stages of development. —  Studies using arsenic methyltransferase knock-out mice to determine whether methylation alters inorganic arsenite toxicology. References Anundi, I, J. Högberg, and M. Vahter. 1982. GSH release in bile as influenced by arsenite. FEBS Lett. 145:285-288. Aposhian, H.V. 1997. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu. Rev. Pharmacol. Toxicol. 37:397-419. Aposhian, H.V., R. Zakharyan, Y. Wu, S. Healy, and M.M. Aposhian. 1997.

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Page 168 Enzymatic methylation of arsenic compounds: II—An overview. Pp. 296321 in Arsenic: Exposure and Health Effects, C.O. Abernathy, R.L. Calderon, and W.R. Chappell, eds. London: Chapman & Hall. Bogdan, G.M., A. Sampayo-Reyes, and H.V. Aposhian. 1994. Arsenic binding proteins of mammalian systems: I. Isolation of three arsenite-binding proteins of rabbit liver. Toxicology 93:175-193. Buchet, J.P., and R. Lauwerys. 1985. Study of inorganic arsenic methylation by rat liver in vitro: Relevance for the interpretation of observations in man. Arch. Toxicol. 57:125-129. Buchet, J.P., and R. Lauwerys. 1988. Role ofthiols in the in vitro methylation of inorganic arsenic by rat liver cytosol.  Biochem. Pharmacol. 37:3149-3153. Buchet, J.P., R. Lauwerys, and H. Roels. 1981 a. Comparison of the urinary excretion of arsenic metabolites after a single dose of sodium arsenite, monomethylarsonate or dimethylarsinate in man. Int. Arch. Occup. Environ. Health 48:71-79. Buchet, J.P., R. Lauwerys, and H. Roels. 1981b. Urinary excretion of inorganic arsenic and its metabolites after repeated ingestion of sodium metaarsenite by volunteers. Int. Arch. Occup. Environ. Health 48:111-118. Buchet, J.P., A. Geubel, S. Pauwels, P. Mahieu, and R. Lauwerys. 1984. The influence of liver disease on the methylation of arsenite in humans. Arch. Toxicol. 55:151-154. Byrne, A.R., L. Kosta, M. Dermelj, and M. Tusek-Znidaric. 1983. Aspects of some trace elements in human milk. Pp. 21-35 in Trace Element Analytical Chemistry In Medicine And Biology, Vol. 2, P. Brätter and P. Schramel. Berlin: Walter de Gruyter. Challenger, F. 1945. Biological methylation. Chem. Rev. 36:315-361. Charbonneau, S.M., G.K.H. Tam, F. Bryce, Z. Zawidzka, and E. Sandi. 1979. Metabolism of orally administered inorganic arsenic in the dog. Toxicol. Lett. 3:107-114. Charbonneau, S.M., J.G. Hollins, G.K.H. Tam, F. Bryce, J.M. Ridgeway, and R.F. Willes. 1980. Whole-body retention, excretion and metabolism of [74As]arsenic acid in the hamster. Toxicol. Lett. 5:175-182. Concha, G., B. Nermell, and M. Vahter. 1998a. Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. Environ. Health Perspect. 106:355-359. Concha, G., G. Vogler, D. Lezeano, B. Nermell, and M. Vahter. 1998b. Exposure to  inorganic arsenic metabolites during  early human development. Toxicol. Sci. 44:185-190. Concha, G., G. Vogler, B. Nermell, and M. Vahter. 1998c. Low arsenic excretion in breast milk of native Andean women exposed to high levels of

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Page 176 Chemical speciation of arsenic in serum of uraemic patients. Analyst 123:13-17.