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Experimental STudies This chapter discusses the effects of arsenic that have been observed in experimental studies. It begins with a summary of the experimental studies described in the 1999 report. Following that summary, toxicokinetic, animal toxicity, and mechanistic studies of arsenic, published since the previous NRC report was released, are discussed. This chapter does not provide a compre- hensive discussion of all the toxicologic mechanisms of arsenic. SUMMARY OF EXPERIMENTAL STUDIES DISCUSSED IN THE 1999 REPORT The previous NBC Subcommittee on Arsenic in Drinking Water reviewed the data on the toxicokinetics, animal toxicity studies, and mode of action of arsenic, focusing on the modes of action that might underlie the carcinogenic effects of arsenic (NRC 1999~. It concluded that inorganic arsenic is readily absorbed from the gastrointestinal tract in humans and it is mainly transported in the blood bound to sulfhydryl groups. At low-to-moderate doses, inorganic arsenic has a half-life in the body of about 4 days and is excreted primarily in the urine (NRC 19994. Humans and some animals methylate inorganic arsenic compounds to pentavalent monomethylarsonic acid (MMAV) and pentavalent dimethylarsinic acid (DMAV), which are less acutely toxic and readily ex- creted. At the time of the NRC 1999 report, there was little information on the 75

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76 ARSENIC INDR1rNKING WA TER: 2001 UPDA TE distribution and toxicity ofthe trivalent methylated metabolites (monomethyI- arsonous acid AMMAN and dimethylarsinous acid (DMA~. It was noted that the fractions of the various metabolites of arsenic in urine (inorganic arsenic, MMA, and DMA) vary markedly among humans, and the toxicoki- netics of arsenic varies considerably among animal species. It is not known in which animal species the toxicokinetics more closely resembles that in humans, and this uncertainty makes it difficult to extrapolate from animals to humans. The subcommittee concluded that the mechanisms or modes of action by which inorganic arsenic causes toxicity, including cancer, is not well estab- lished (NRC 1999~. The data available on the ability of inorganic arsenic to act as a cocarcinogen or a tumor promoter in rats and mice are conflicting, but studies conducted at very high doses indicate that DMA~ is not a tumor initia- tor but might act as a tumor promoter. Furthermore, inorganic arsenic and its metabolites have been shown to induce chromosomal alterations (aberrations, aneuploidy, and sister chromatic exchange) and large deletion mutations, but not point mutations. Data on other genotoxic responses that might indicate mode of action for arsenic were not sufficient for conclusions to be drawn. Therefore, the 1999 subcommittee concluded that "the most plausible and generalized mode of action for arsenic carcinogenicity is that it induces struc- tural and numerical chromosomal abnormalities without acting directly with DNA." The subcommittee also discussed other mechanisms, such as cell proliferation and oxidative stress. An indirect mechanism of mutagenicity suggests that the mostplausible shape ofthe carcinogenic dose-response curve is sublinear "at some point below the level at which a significant increase in tumors is observed tin the available epidemiological studies]." There was insufficient scientific evidence to identify the dose at which sublinearity might occur. Therefore, the subcommittee concluded that "because a specific mode (or modes) of action has not been identified at this time, it is prudent not to rule out the possibility of a linear response." The subcommittee further concluded that arsenicals inhibit some types of mitochondrial-respiratory function, leading to decreased cellular ATE produc- tion and increased production of hydrogen peroxide (H2O2) (NRC 1999~. Those effects could cause the formation of reactive oxygen species, resulting in oxidative stress. Oxidative stress can have numerous effects, including inhibition of heme-biosynthetic pathways and induction of major stress pro- teins. Although the role of arsenic-induced oxidative stress in mediating DNA damage is not clear, the intracellular production of reactive oxygen species

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EXPERIMENTAL STUDIES 77 might play an initiating role in the carcinogenic process by producing DNA damage. In the remainder ofthis chapter, more recent studies on the toxicoki- netics of arsenic will be discussed, followed by in vitro and in vivo studies that provide additional information on the mode of action of arsenic. TOXICOKINETICS Methylation of Arsenic . Arsenic can exist in methylated and inorganic forms as well as in different valence states (NRC 1999~. The form and valence state can affect the toxicity of arsenic; therefore, it is important to understand the metabolism and toxicokinetics of arsenic. As discussed in the 1999 NRC report, inorganic arsenic is believed to be methylated via sequential reduction of pentavalent arsenic to trivalent arsenic, followed by oxidative addition of a methyl group from S-adenosy~methionine (SAM) to the trivalent form (Figure 3-11. The main products of that methyla- tion, MMAV and DMAV, are readily excreted in the urine. More recent exper- iments have detected the presence of the reduced methylated forms EMMA and DMA~) in human urine.) The development ofthe analytical methods for the speciation of arsenic metabolites, as well as the advantages and disadvan- tages ofthese methods, were thoroughly discussed in the previous NRC report NRC 1999~. The reduced methylated forms and their toxicity are discussed later in this chapter. Further methylation of DMA to trimethylarsine is frequently seen in mi- croorganisms exposed to arsenite ARC 1999~. A smallpercentage of urinary arsenic as trimethylarsine oxide (TMAO) has been detected in mice, hamsters, and humans following exposure to DMA (for review, see Kenyon and Hughes 2001), but TMAO or demethylated products of DMA were not detected in the blood or tissues of mice exposed intravenously to DMA at a dose of 1 or 100 mg/kg (Hughes et al. 2000~. By contrast, TMAO has not been reported to be present in the urine of mammals exposed to inorganic arsenic. DMA foe by methylation of inorganic arsenic (Ash) and MMAi~has been shown to clear 'Because trivalent methylated forms of arsenic have been detected only recently, they often have not been specifically assayed for or discussed in most experiments. In those cases, the abbreviations MMA and DMA are used without indicating the valence state.

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78 ARSENIC IN DRINKING WA TER: 2001 UPDA TE rapidly from cells (Styblo et al. ~999a; Lin et al. 200~). That rapid clearance might prevent the accumulation of intracellular concentrations of DMA re- quired for further methylation to TMAO, explaining why TMAO is not de- tected following exposure to Astir. Nonenzyrnatic methylation of arsenic has been seen in vitro. Studies have demonstrated that methy~cobalam~n (a form of vitamin By) can mediate the nonenzymatic methylation of arsenite (Zakharyan and Aposhian 1999a), but whether that occurs in viva is not known. Glutathione (GSH), end possibly other thiols, can act es reducing agents in the methylation process (NRC 1999~. Recent in vitro studies indicate that dithiols (e.g., reduced lipoic acid) might be more active than GSH in providing the reduc- ing environment required for methylation by MA methyTtransferase (Zakharyan et al. 1999~. Thiol binding might also be involved in arsenic biotransformation. Trivalent arsenic metabolites are highly bound to cytosolic proteins in the cells (Styblo and Thomas 1997~. In in vitro studies, protein-bound inorganic arsenic and MMA were methylated to MMA and DMA, respectively. It has been proposed that arsenic is bound to a protein dithiol cofactor before the sequential methylation of arsenic (Thompson 1993; DeKimpe et al. 1999a). The exact sequence of events in arsenic biotransformation remains urdmown, but it seems clear that S-adenosy~me~ionine (SAM) is the main source of methyl H2AsO4- CH3+ 2e~ CH3+ 2e~ AsO33- CH3AsO32- Reductase Methyl- MMAV transferase 2e~ (CH3~2AsO2----------------> (CH3~2AsO Methyl- DMAV Reductase DMA~i transferase CH3ASo2 Reductase MMA~ FIGURE 3-1 Proposed chemical pathway for the methylation of inorganic arsenic in humans. The enzymes that have been proposed for the reduction and methylation reactions are indicated. Uncertainties regarding this pathway are discussed in the text.

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EXPERIMENTAL STUDIES 79 groups for the methylation of arsenic and that the methylation is dependent upon methyTtransferases. Studies have shown that SAM is required for arsenic methylation in various in vitro systems and that arsenic methylation in viva is decreased by specific inhibitors of SAM-dependent methylation and by low methionine intake ARC 1999~. Because of the importance of SAM in the methylation of arsenic, much research has been aimed at characterizing the methyTtransferases involved in SAM-dependent arsenic methylation. During recent years, arsenite and MMAi~ methyTtransferases from the liver of rabbits, hamsters, and rhesus monkeys have been purified and partially characterized (Wilt/fang et al. 1998; Za~aryan et al. 1999~. The Kin,, determined using Michaelis-Menten kinetics, for arsenite methyTtransferase for hamsters was ~ .79 x ~o-6 M and for MMA methy~transferase was 7.98 x 10- M. The MMA methy~transferase was higher than the arsenite methyTtransferase. Similar values were reported for rabbit methy~transferases, but the rhesus monkey had Knot values for MMA methyTtransferase of 3.5 X 10-6 M and for arsenite methy~transferase of S.5 x 10-6 M. Zakharyan et al. (1999) reported that the rabbit liver MMA methyTtransferase had higher affinity for MA than for MMAV. Furthermore, the Km for MMA~i methyTtransferase from Chang hu- man hepatocytes was not very different from that of rabbit liver. The exact structures ofthe arsenic methy~transferases have not been deter- mined (NRC ~ 999), but recent in vitro studies using rabbit liver cytoso! show- ed that the two steps in arsenic methylation to DMA are markedly inhibited by pyrogalloT (0.3 to 9 millimolar) (mM), a specific inhibitor of catechol-O- methyTtransferase (DeKimpe et al. ~ 999a). Those data suggest that the active sites of arsenite methyTtransferase and MMA methyTtransferase are similar to that of catechol-O-methy~transferase. Furthermore, trichIoromethiazide (TCM), an inhibitor of human microsomal thiopurine methyTtransferase, did not inhibit the formation of MMA but did inhibit the formation of DMA. in contrast, neither ofthose arsenic methylation steps was inhibited by an inhibi- tor of cytosolic thiopurine methy~transferase (p-anisic acid) or by an inhibitor of cytosine DMA methyTtransferase. ADMA methy~transferase, which would further methylate DMA forming TMAO, has not been reported to be present in mammalian cells. Styblo et al. (1 999b) reported that DMA was the only metabolite detected in rat or human hepatocytes incubated with DMAV or a glutathione complex of DMA~ (DMAi~-GS).

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80 ARSENIC IN DRINKING WA TER: 2001 UPDA TE Species Differences in the Methylation of Arsenic As discussed in the previous report, there is considerable variation in the methylation of inorganic arsenic among mammalian species (NRC 1999~. Rats, mice, and dogs show a very efficient methylation of arsenic to DMA. Rabbits and hamsters also methylate arsenic relatively efficiently. In most animals, the DMA that is formed is rapidly excreted in urine. However, in rats, most of the DMA that is formed accumulates in the red blood cells and tissues. Rats also appear to methylate administered DMA to TMAO more efficiently than other species (Kitchin et al. 1999; NRC 1999~. Following exposure of mate rats to high concentrations of DMA in drinking water (100 mg/L, equivalent to 100,000 )lg/~), about 10% of the urinary arsenic was present as TMAO (Yoshida et al. 1998~. Consistent with that marked variation in arsenic methylation efficiency seen among animal species (Vahter 1999b), the activity of methy~transferases differs markedly among the animals studied (Healy et al. ~ 999~. The variation in the activity of those enzymes probably underlies most of the cross-species variability in methylation ability (for review, see Healy et al. 1999; Vahter 1 999a). Guinea pigs and several types of non-human primates, including the chimpanzee, seem to be unable to methylate inorganic arsenic (Healy et al. 1999; Vahter ~ 999b), and no methyTtransferase activity was detected in those species (Healy et al. 1999~. Human arsenic methy~transferases were Tong thought to be very unstable, because activity could not be detected in human liver preparations (NRC ~ 999~. Recently, however, arsenic-methylation activity was detected in hu- man hepatocytes; MMA~imethy~transferase activity was detected in cultured Chang human hepatocytes (Zakharyan et al. 1999~. Incubation of primary human hepatocytes with arsenite yielded MMA and DMA, and incubation with EMMA' produced mainly DMA (Styblo et al. 1999a). Rat hepatocytes, however, methylated arsenic considerably faster than did human hepatocytes (Styblo et al. 1999a; Styblo et al. 2000~. In contrast to humans, most mammals do not excrete appreciable amounts of MMA in the urine. Recently, however, the Flemish Giant rabbit was found to excrete substantial amounts of MMA in urine (DeKimpe et al. ~ 999b), and MMA was formed in vitro after incubation of inorganic arsenic with rabbit- liver cytosol (DeKimpe et al. 1999a). No differences, however, were seen in the urinary pattern of arsenic me- tabolites in three strains of mice 24 hours (fur) after administration of an oral

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EXPERIMENTAL STUDIES 81 dose of arsenite (Hughes et al. 1999~. More than 95/O of the arsenic in urine (corresponding to 60%, 68%, and 69% ofthe administered dose in each ofthe three mouse strains) was in the form of DMA in all three mouse strains. As indicated above, the ability to excrete MMA and DMA in the urine varies among species. Because ofthis variation and other species differences in arsenic metabolism discussed in this section, extrapolation of data from studies in animals and animal cells to humans is difficult. Tissue Differences in the Methylation of Arsenic The liver appears to play the central role in arsenic methylation (NRC 1999), but in vitro studies using mate mouse cytosoT demonstrated that most tissues appear to be capable of methylating arsenic (Healy et al. ~998~. The highest activity of arsenite methyTtransferase was observed in the cytoso! from the testis, followed by cytosol from the kidney, liver, and lung. More recent data also point to the liver's important role. Styblo et al. (2000) reported a much higher rate of arsenic methylation in primary human hepatocytes com- pared with human keratinocytes and bronchial cells, and no methylation activ- ity was detected in human urinary-bladder cells. When proliferating human keratinocytes and bronchial epithelial cells were cultured in the presence of the relatively Tow arsenite concentration of 0.05 micromolar (EM) (approxi- mately 3.7 high), more than two-thirds of the cell-associated methylated arsenic consisted of MMA, most of which was retained intracellularly throughout a 24-hr incubation. Human keratinocytes cultured in the presence of ~ EM of methylarsine oxide, a putative substrate for MA methyI- transferase, did not produce any DMA. Recent studies indicate that EMMA' might be the most toxic intracellular form of arsenic in terms of oxidative stress, enzyme inhibition, and DNA `damage (see Mechanistic Data later in this chapter). It is noteworthy that cells from two tissues that are targets of arsenic-induced cancer (skin and lung) seem to have less efficient conversion of MMA to DMA at relevant concentrations of arsenite in culture that is, at concentrations similar to those that might occur in blood and possibly tissue following chronic ingestion of low-to-moderate concentrations of arsenic. However, more studies on this topic are needed before firm conclusions can be reached. The situation is even more complex in viva, where the extent of methyla- tion of inorganic arsenic to MMA and DMA is also influenced by the rate of

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82 ARSENIC IN DRINKING WATER: 2001 UPDATE cellular uptake of the inorganic arsenic in the various tissues. Tatum and Hood (1999) reported that the uptake and methylation of Asset by a kidney- epithelium-derived cell line, the NKR-52E cell line, were lower than those of primary rat hepatocytes or hepatoma-derived cell lines. Those data confirm previous findings that Astir is the main form of arsenic taken up by the liver (NRC 1999~. In the presence of phosphate-free media, the uptake and cytotoxicity of AsV in KB oral epidermoid carcinoma cells was greatly en- hanced (Huang and Lee ~996~. Cellular uptake and efflux of arsenic vary considerably among the differ- ent arsenic metabolites, and the variation affects the distribution of metabo- lites formed in the liver following absorption of arsenic compounds. In com- parison to the trivalent methylated forms of arsenic, exposure to the pentava- lent forms (MMAV or DMAV) results in very low tissue concentrations of MMA and DMA (Hughes and Kenyon 1998; NRC 1999~. That difference is probably because of a lower cellular uptake and accumulation of the pentava- lent forms than the trivalent forms. A lower uptake was confirmed in studies in rat and human hepatocytes that showed a several-fold higher cellular uptake of Astir and MA than of the corresponding pentavalent forms (Styblo et al. 1999a). In the presence of phosphate-free media, the uptake and cytotoxicity of AsV in KB oral carcinoma cells were greatly enhanced (Huang and Lee 1996~. Cellular efflux also appears to vary among the different forms of arsenic. Styblo et al. (1999a) demonstrated that DMA is the main excretory product in human and rat hepatocytes. Inhibition of the methylation of MMA to DMA by increasing arsenite concentrations in the medium resulted in the accumula- tion of MMA in the cells, indicating that MMA is not excreted as readily from liver cells as is DMA. Whether that same effect occurs in cells from other tissues is unknown. Induction of Arsenic Methy~transferases The inducibility of arsenic methyTtransferase has been investigated in mice. Arsenic methyTtransferase activity did not appear to be induced in mice exposed subchronicly to arsenic in the drinking water (25 or 2,500 Age) (Hughes and Thompson 1996; Healy et al. 1998~.

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EXPERIMENTAL STUDIES 83 Trivalent Methylated Arsenic Metabolites It is obvious from the proposed scheme of arsenic methylation (Figure 3- 1) that pentavalent methylated arsenic compounds can be reduced to trivalent methylated arsenic compounds EMMA and DMAi~. Although pentavalent arsenicals can be reduced directly, for example by glutathione (NRC ~ 999), recent studies indicate the involvement of arsenic reductases. Arsenate reduc- tase activity has been detected in human liver (Radabaugh and Aposhian 2000~. The enzyme has a molecular weight of about 72 kilodaltons (kI:)a), and it requires a thiol and a heat-stable cofactor for activity. It did not reduce MMAV, indicating the presence of two enzymes, arsenate reductase and MMAVreductase. MMAV reductase activity has been detected in rabbit liver (Zakharyan and Aposhian 1999b), hamster tissues (Sampayo-Reyes et al. 2000), and human liver (Zakharyan et al. 2001~. There is evidence that the human MMAV reduc- tase is identical to glutathione-s-transferase omega class A. The rabbit liver MMAV reductase was shown to reduce both DMAV and arsenate (AsV) (Zakharyan and Aposhian 1999b). The Kn~ values were 2.16 x i0-3 M with MMAV as the substrate, 20.9 x 10~3 M with DMAV as the substrate, and 109 X i0-3 M with arsenate as the substrate. ~en the Km for the rabbit liver MMAV reductase was compared with that ofthe As~ methyTtransferase (i.e., 5.5 x lo-6) and that of MMA~ methyTtransferase (i.e., 9.2 x lo-6), the authors concluded that MMAV reductase was the rate-limiting enzyme for arsenite metabolism in the rabbit liver. However, it should be emphasized that, be- cause of the species differences in arsenic methylation (see above), it is not known whether the rate-limiting step in the rabbit liver equates to the rate- limiting step in any particular human organ. It is not clear to what extent the DMA formed following exposure to inorganic arsenic is reduced to DMA~'~ by a specific DMAV reductase. The latter has not been well studied, but DMA~ was detected in the liver of ham- sters given arsenate (Sampayo-Reyes et al. 2000~. Tn addition, as mentioned previously, a small percentage of TMAO is found in the urine following expo- sure to DMA. The formation of TMAO would require the reduction of DMAV to DMAi~ before the addition of the third methyl group, indicating DMAV reductase activity. The activities of the arsenic reductases appear to vary markedly among tissues. In the male hamster, the highest activity was found in the brain, fol- lowed by the bladder, spleen, and liver; the Towest activity was found in the

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84 ARSENIC IN DRINKING WA TER. 2001 UPDA TE testis (Sampayo-Reyes et al. 2000~. Therefore, the tissues with high arsenic reductase activity seem to be different from those with high arsenic methyTtransferase activity (testis > kidney > liver > lung, as discussed previ- ously). Considering the marked species differences in the metabolism of arsenic, more data are needed on the tissue variation in arsenic metabolizing enzymes in various species. In particular, more data are needed on tissue variations in enzyme activities in humans. More data are also needed on sex differences, because most experiments have been performed in male animals. There is increasing evidence that the trivalent methylated arsenic metabo- lites (especially EMMA are released from the site of arsenic methylation. Aposhian et al. (2000a) reported that people in Romania exposed to arsenic in drinking water (28, 84, or 161 PAL) had MA in their urine at concentra- tions of 5 -7 ,ug/L, irrespective of their exposure. Mandal et al. (2001) re- ported the presence of both MMAi~ (2-5% of urinary arsenic) and DMA~ (5- 20% of urinary arsenic) in the urine of subjects chronically exposed to inor- ganic arsenic via drinking water (33-250 ,ug/~) in four villages in West Ben- gal, India. The concentrations of MMAi~i and DMAi~ in the four villages ranged from 3-30 ,ug/L and 8-64 vigil, respectively. The concentrations of both EMMA and DMA~ increased with increasing concentration of total arsenic in urine (i.e., the sum of metabolites). It should be noted that the concentrations oftrivaTent metabolites in the urine might have been underesti- mated, because the trivalent metabolites are easily oxidized (Le et al. 2000~. On the other hand, the trivalent metabolites are reported to be highly reactive; therefore, it is unlikely that urinary concentrations of the trivalent metabolites would be as high as MMAV and DMAV, which are much less reactive and readily excreted in urine. There are very few data on the tissue distribution of trivalent methylated arsenic metabolites following exposure to inorganic arsenic, and no data in humans. Bile-duct-canulated rats were injectedintravenously with arsenite or arsenate. Almost 10% ofthe injected dose (50 ~mol/kg) was excreted in the bile as MMAii~ and Astir (Gregus et al. 2000~. Rats excrete much more arsenic in the bile than other species; therefore, it is difficult to generalize those re- sults to other species. However, further support for the formation of trivalent methylated arsenic compounds in vivo following exposure to inorganic arsenic comes from experiments in hamsters. Both MMAiii and DMA~i were detected in the livers of hamsters treated with arsenite (Sampayo-Reyes et al. 2000~. Some ofthe trivaTentmethylated arsenic metabolites found in urine might be, in part, the result of reduction occurring in the kidneys and urinary blad-

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EXPERIMENTAL STUDIES 85 den It has been shown that arsenate is reabsorbed and reduced in the proximal renal tubuTi, after which Astir is excreted in the urine ARC 1999~. Also, as mentioned above, high MMAV reductase activity was found in the bladder of the hamster (Sampayo-Reyes et al.2000), indicating that reduction of MMA, and possibly also DMA, might occur in the urinary bladder. Administration of 300 mg ofthe chelating agent sodium 2,3-dimercapto- 1 - propane sulfonate (DMPS) to people exposed to arsenic in drinking water (568 ~ 58 vigil) in Inner Mongolia, China, markedly increased the urinary concentrations of inorganic arsenic (50-125,ug/L, on average) and MMA (50- 325 )lg/~), while the concentration of DMA decreased (240-125 ,ug/~) (Aposhian et al. 2000a; Le et al. 2000~. This study was the first to identify MMAi~ in urine as one of the arsenic metabolites. In vitro studies using par- tially purified rabbit liver MMAi~ methy~transferase showed that the MMAi~- DMPS complex did not serve as a substrate for the enzyme (Aposhian et al. 2000a). Therefore, the authors suggested that DMPS forms a stable complex with MA, which is excreted in urine. It should be noted that the amount of EMMA formed in tissues following exposure to inorganic arsenic is dependent upon the activity of arsenite methy~transferase, the enzyme that forms MMAV, and the presence of MMAV reductase, the enzyme that reduces MMAV to MA. It is also dependent on the presence and activity of MA methyTtransferase, the enzyme that further methylates EMMA to DMAV, which is readily excreted from cells (Styblo et al. 2000~. Inorganic Asiii and the reduced foes of the methylated arsenic metabo- lites EMMA and DMA~) are highly reactive and might contribute to the toxicity observed following exposure to inorganic arsenic (see Mechanisms of Toxicity). As discussed in the previous NBC report (NRC ~ 999) and by Styblo et al. (1997), trivalent inorganic and methylated arsenic metabolites have been shown to complex with GSH. Also, trivalent arsenicals are be- lieved to forte highly stable complexes with molecules containing vicinal thiols. In studies investigating the binding of Astir to proteins following expo- sure to arsenite in human lymphoblastoid cells, at least four 20-50 kDa pro- teins with arsenic affinity were isolated (Menzel et al. 1999~. Two of the proteins identified were tubulin and actin. This ability of arsenic to bind to functional groups (e.g., thiols) can result in the inhibition of certain enzymes (tin et al.2001) and is one possible mechanism underlying arsenic's toxicity. Reactions with sulfhydry] groups are also the basis for arsenic detoxification therapy (e.g., use of DMPS) (Aposhian et al. 2000a).

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122 ARSENIC IN DRINKING WA TER: 2001 UPDA TE REFERENCES Ahmad, S., W.L. Anderson, and K.T. Kitchin. 1999. Dimethylarsinic acid effects on DNA damage and oxidative stress related biochemical parameters in B6C3F1 mice. Cancer Lett. 139~2~: 129- 135. Ahmad, S., K.T. Kitchin, and W.R. Cullen. 2000. Arsenic species that cause release of iron from ferritin and generation of activated oxygen. Arch. Biochem. Biophys. 382~2~:195-202. Alemany, M., and J. Levin. 2000. The effects of arsenic trioxide (As203) on human megakaryocytic leukemia cell lines with a comparison of its effects on other cell lineages. Leuk. Lymphoma 38(1 -2~: 153- 163. Anundi, I., J. Hogberg, and M. Vahter. 1982. GSH release in bile as influenced by arsenite. FEES Lett. 145~2~:285-288. Aposhian, H.V., E.S. Gurzau, X.C. Le. A. Gurzau, S.M. Healy, X. Lu, M. Ma, L. Yip, R.A. Zakharyan, R.M. Maiorino, R.C. Dart, M.G. Tircus, D. Gonzalez-Ramirez, D.L. Morgan, D. Avram, and M.M. Aposhian. 2000b. Occurrence of mono- methylarsonous acid in urine of humans exposed to inorganic arsenic. Chem. Res. Toxicol. 13~8~:693-697. Aposhian, H.V., B. Zheng, M.M. Aposhian, X.C. Le. M.E. Cebrian, W. Cullen, R.A. Zakharyan, M. Ma, R.C. Dart, Z. Cheng, P. Andrewes, L. Yip, G.F. O'Malley, R.M. Maiorino, W. Van Voorhies, S.M. Healy, and A. Titcomb. 2000a. DMPS Arsenic challenge test. II. Modulation of arsenic species, including monomethylarsonous acid (MMA~), excreted in human urine. Toxicol. Appl. Pharmacol. 165~1~:74-83. ATSDR ~ Agency for Toxic Substances and Disease Registry). 2000. Toxicological Prof~le for Arsenic. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. ~ Online]. Available: http://www.atsdr. cdc.gov/toxprofiles/tp2.html [August 15, 20013. Barchowsky, A., R.R. Roussel, L.R. Klei, P.E. James, N. Ganju, K.R. Smith, and E.J. Dudek. 1999a. Low levels of arsenic trioxide stimulate proliferative signals in primary vascular cells without activating stress effector pathways. Toxicol. Appl. Pharmacol. 159~1):65-75. Barchowsky, A., L.R. Klei, E.J. Dudek, H.M. Swartz, and P.E. James. l999b. Stimulation of reactive oxygen, but not reactive nitrogen species, in vascular endothelial cells exposed to low levels of arsenite. Free Radic. Biol. Med.27~11- 12~: 1405-1412. Biggs, M.L., D.A. Kalman, L.E. Moore, C. Hopenhayn-Rich, M.T. Smith, and A.H. Smith. 1997. Relationship of urinary arsenic to intake estimates and abiornarker ofeffect,bladdercellrnicronuclei. Mutat.Res.386~3~:185-195. Boonchai, W., M. Walsh, M. Cummings, and G. Chenevix-Trench. 2000. Expression of p53 in arsenic-related and sporadic basal cell carcinoma. Arch. Dermatol. 136~2):195-198.

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124 ARSENIC IN DRINKING WATER: 2001 UPDATE Deaglio, S., D. Canella, G. Baj, A. Arnulfo, S. Waxman, and F. Malavasi. 2001. Evidence of an immunologic mechanismbehind the therapeutic effects of arsenic trioxide (As2O3) on myeloma cells. Leuk. Res. 25~3~:237-239. Farmer, J.G., and L.R. Johnson. 1990. Assessment of occupational exposure to inorganic arsenic based on urinary concentrations and speciation of arsenic. Br. J. Ind. Med. 47~5~:342-348. Fenaux, P., C. Chomienne,~ and L. Degos. 2001. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin. Hemotol. 38~1~: 13-25. Feng, Z., Y. Xia, D. Tian, K. Wu, M. Schmitt, R.K. Kwok, and J.L. Mumford. 2001. DNA damage in buccal epithelial cells from individuals chronically exposed to arsenic via drinking water in Inner Mongolia, China. Anticancer Res.21 (1A):51- 57. Foa, V., A. Colombi, M. Maroni, M. Buratti, and G. Calzaferri. 1984. The speciation of the chemical forms of arsenic in the biological monitoring of exposure to inorganic arsenic. Sci. Total Environ.34~3~:241-259. Forkner, C.E., and T.F. M. Scott. 1931. Arsenic as therapeutic agent in chronic myelogenous leukemia. J.A.M.A 97~1~:3-5. Germolec, D.R., J. Spalding, G.A. Boorman, J.L. Wilmer, T. Yoshida, P.P. Simeonova, A. Bruccoleri, F. Kayama, K. Gaido, R. Tennant, F. Burleson, W. Dong, R.W. Lang, and M.I. Luster. 1997. Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. Mutat. Res. 386(3):209-218. Germolec, D.R., J. Spalding, H.S. Yu, G.S. Chen, P.P. Simeonova, M.C. Humble, A. Bruccoleri, G.A. Boorman, J.F. Foley, T. Yoshida, and M.I. Luster. 1998. Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am. J. Pathol. 153~69: 1775-1785. Gregus, Z., A. Gyurasics, and I. Csanaky. 2000. Biliary and urinary excretion of inorganic arsenic: monomethylarsonous acid es amajorbiliarymetabolite inrats. Toxicol. Sci. 56~1~:18-25. Hakala, E., and L. Pyy. 1995. Assessment of exposure to inorganic arsenic by determining the arsenic species excreted in urine. Toxicol. Lett.77~1-3~:249-258. Hamadeh, H.K., M. Vargas, E. Lee, and D.B. Menzel. 1999. Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis. Biochem. Biophys. Res. Commun. 263~29:446-449. Hayashi, H., M. Kanisawa, K. Yamanaka, T. Ito, N. Udaka, H. Ohji, K. Okudela, S. Okada, and H. Kitamura. 1998. Dimethylarsinic acid, a main metabolite of inorganic arsenics, has tumorigenicity and progression effects in the pulmonary tumors of A/J mice. Cancer Lett. 125(1): 83-88. Healy, S.M., E.A. Casarez, F. Ayala-Fierro, and H. Aposhian. 1998. Enzymatic methylation of arsenic compounds. V. Arsenite methyltransferase activity in tissues of mice. Toxicol. Appl. Pharmacol. 148~1~:65-70. Healy, S.M., E. Wildfang, R.A. Zakharyan, and H.V. Aposhian. 1999. Diversity of inorganic arsenite biotransformation. Biol. Trace Elem. Res. 68~3~:249-266.

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EXPERIMENTAL STUDIES 125 Holson, J.F., D.G. Stump, K.J. Clevidence, J.F. Knapp, and C.H. Farr. 2000. Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats. Food Chem. Toxicol. 38~5~:459-466. Hsu, C.H., S.A. Yang, J.Y. Wang, H.S. Yu, and S.R. Lin. 1999. Mutation spectrum of pS3 gene in arsenic-related skin cancers from the blackfoot disease endemic area of Taiwan. Br. J. Cancer 80~7~: 1080-1086. Hu, Y., L. Su, and E.T. Snow. 1998. Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. Mutat. Res. 408~3~:203-218. Huang, R.N., and T.C. Lee. 1996. Cellular uptake oftrivalent arsenite and pentaval- ent arsenate in KB cells cultured in phosphate-free medium. Toxicol. Appl. Pharmacol. 136~2~: 243-249. Huang, C., W.Y. Ma, J. Li, A. Goranson, and Z. Dong. 1999a. Requirement of Erk, but not JNK, for arsenite-induced cell transformation. 274~21~: 14595-14601. J. Biol. Chem. Huang, C., W.Y. Ma, J. Li, and Z. Dong. l999b. Arsenic induces apoptosis through a c-dun NH2-terminal kinase-dependent, pS3-independent pathway. Cancer Res. 59~13~:3053-3058. Hughes, M.F., E.M. Kenyon, B.C. Edwards, C.T. Mitchell, and D.J. Thomas. 1999. Strain-dependent disposition of inorganic arsenic in the mouse. Toxicology 137~2~:95-108. Hughes, M.F., and E.M. Kenyon. 1998. Dose-dependent effects on the disposition of monomethylarsonic acid and dimethylarsinic acid in the mouse after intravenous administration. J. Toxicol. Environ. Health A. 53~2~:95-112. Hughes, M.F., and D.J. Thompson. 1996. Subchronic dispositional and toxicological effects of arsenate administered in drinking water to mice. J. Toxicol. Environ. Health 49~2~: 177-196. Hughes, M.F., L.M. Del Razo, and E.M. Kenyon. 2000. Dose-dependent effects on tissue distribution and metabolism of dimethylarsinic acid in the mouse after intravenous administration. Toxicology 143~2~:155-166. Hunder, G., J. Schaper, O. Ademuyiwa, and B. Elsenhans. 1999. Species differences in arsenic-mediated renal copper accumulation: a comparison between rats, mice and guinea pigs. Hum. Exp. Toxicol. 18~11~:699-705. Ishitsuka, K., S. Hanada, K. Uozumi, A. Utsunorniya, and T. Arima. 2000. Arsenic trioxide and the growth of human t-cell leukemia virus type i infected t-cell lines. Leuk. Lymphoma 37~5-69:649-655. Jiang, X.H., B. Chun-Yu Wong, S.T. Yuen, S.H. Jiang, C.H. Cho, K.C. Lai, M.C. Lin, H.F. Kung, and S.K. Lam. 2001. Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3. Int. J. Cancer 91~2~: 173-179. Kalman, D.A., J. Hughes, G. van Belle, T. Burbacher, D. Bolgiano, K. Coble, N.K. Mottet, and L. Polissar. 1990. The effect of variable environmental arsenic .~

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126 ARSENIC IN DRINKING WA TER: 2001 UPDATE contamination of urinary concentrations of arsenic species. Environ. Health Perspect. 89:145-151. Kaltreider, R.C., A.M. Davis, J.P. Lariviere, andJ.W. Hamilton. 2001. Arsenic alters the function of the glucocorticoid receptor as a transcription factor. Environ. Health Perspect. 109~3~:245-251. Kaltreider, R.C., C.A. Pesce, M.A. Ihnat, J.P. Lariviere, and J.W. Hamilton. 1999. Differential effects of arsenic (III) and chromium (VI) on nuclear transcription factor birding. Mol. Carcinog. 25~3~:219-229. Kapahi, P., T. Takahashi, G. Natoli, S.R. Adams, Y. Chen, R.Y. Tsien, and M. Karin. 2000. Inhibition of NF-kappa B activation by arsenite through reaction with a critical cysteine in the activation loop of Ikappa B kinase. J. Biol. Chem. 275(46):36062-36066. Kenyon, E.M., and M.F. Hughes. 2001. A concise review of the toxicity and carcinogenicityofdimethylarsinic acid. Toxicologyl60~1-3~:227-236. Kitchin, K.T., L.M. Del Razo, J.L. Brown, W.L. Anderson, and E.M. Kenyon. 1999. An integrated pharmacokinetic and pharmacodynarnic study of arsenite action. 1. Heme oxygenase induction in rats. Teratog. Carcinog. Mutagen. 19~6~:385- 402. - Kuo, T.T., S. Hu, S.K. Lo, and H.L. Chan. 1997. p53 expression and proliferative activity in Bowen's disease with or without chronic arsenic exposure. Hum. Pathol. 28~7~:786-790. Larochette, N., D. Decaudin, E. Jacotot, C. Brenner, I. Marzo, S.A. Susin, N. Zarnzami, Z. Xie, J. Reed, and G. Kroemer. 1999. Arsenite induces apoptosis via a direct effect on the mitochondrial permeability transition pore. Exp. Cell Res. 249~2~:413-421. Le. X.C., M. Ma, W.R. Cullen, H.V. Aposhian, X. Lu, and B. Zheng. 2000. Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine. Environ. Health Perspect. 108~119: 1015-1018. Li, D., K. Morimoto, T. Takeshita, and Y. Lu. 2001. Fonnanudopyrunidine-DNA glycosylase enhances arsenic-induced DNA s~aand breaks in PHA-stimulated and unstimulated human lymphocytes. Environ. Health Perspect. 109~5~:523-526. Li, Y.M., and J.D. Broome. 1999. Arsenic targets tubulins to induce apoptosis in myeloid leukemia cells. Cancer Res. 59~4~:776-780. Lin, S., W.R. Cullen, and D.J. Thomas. 1999. Methylarsenicals and arsinothiols are potent inhibitors of mouse liver thioredoxin reductase. Chem. Res. Toxicol. 12~10~:924-930. Lin, S., L.M. Del Razo, M. Styblo, C. Wang, W.R. Cullen, and D.J. Thomas. 2001. Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes. Chem. Res. Toxicol. 14~3~:305-311. Lin, T.H., and Y.L. Huang. 1995. Chemical speciation of arsenic in urine of patients with blackfoot disease. Biol. Trace Elem. Res. 48~3~:251-261.

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EXPERIMENTS ~ STUDIES 12 7 Liou, S.-H., J.C. Lung, Y.H. Chen, T. Yang, L.L. Hsieh, C.J. Chen, and T.N. Wu. 1999. Increased chromosome-type chromosome aberration frequencies as biomarkers of cancer risk in a blackfoot endemic area. Cancer Res.59~7~: 1481- 1484. Liu, J., M.B. Kadiiska, Y. Liu, T. Lu, W. Qu, and M.P. WaaLkes. 2001a. Stress- related gene expression in mice treated with inorganic arsenicals. Toxicol. Sci. 61~2~:314-320. Liu, J., H. Chen, D.S. Miller, J.E. Saavedra, L.K. Keefer, D.R. Johnson, C.D. Klaassen, and M.P. Waalkes. 200 lb. Overexpression of glutathione S-transfer- ase II and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. Mol. Pharmacol. 60~2~:302-309. Liu, J., Y. Liu, R.A. Coyer, W. Achanzar, and M.P. WaaLkes. 2000. Metallothionein- I/II null mice are more sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of chronic oral or injected inorganic arsenicals. Toxicol. Sci. 55~2~:460-467. Liu, S.X., M. Athar, I. Lippai, C. Waldren, and T.K. Hei. 2001. Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity. Proc. Natl. Acad. Sci. USA 98~4~: 1643-1648. Lu, T., J. Liu, E.L. LeCluyse, Y.S. Zhou, M.L. Cheng, and M.P. Waalkes. 2001. Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol. Sci. 59~1~:185-192. Lynn, S., J.R. Gurr, H.T. Lai, and K.Y. Jan. 2000. NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells. Circ. Res. 86:514-519. Lynn, S., J.N. Shiung, J.R. Gurr, andK.Y. Jan. 1998. Arsenite stimulates poly(ADP- ribosylation) by generation of nitric oxide. Free Radic. Biol. Med. 24~3~:442- 449. Machado, A.F., D.N. Hovland Jr., S. Pilafas, and M.D. Collins. 1999. Teratogenic response to arsenite during neurulation: relative sensitivities of C57BL/6J and SWV/Fnn mice and impact of the splotch allele. Toxicol. Sci. 51~1~:98-107. Maier, A., T.P. Dalton, and A. Puga. 2000. Disruption of dioxin-inducible phase I and phase II gene expression patterns by cadmium, chromium, and arsenic. Mol. Carcinog. 28~4~:225-235. Maki-Paal~anen, J., P. Kurttio, A. Paldy, and J. Pel~anen. 1998. Association between the clastogenic effect in peripheral lymphocytes and human exposure to arsenic through ~nking water. Environ. Mol. Mutagen.32~4~:301-313. Males, R.G., J.C. Nelson, and F.G. Herring. 1998. Vesicular membrane permeability of monomethylarsonic and dimethylarsinic acids. Biophys. Chem.70~1~:75-85. Mandal, B.K., Y. Ogra, and K.T. Suzuki. 2001. Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. Chem Res. Toxicol. 14~4~:371-378. Mass, M.J., and L. Wang. 1997. Arsenic alters cytosine methylation patters of the promoter of the tumor suppressor gene p53 in human lung cells: a model for a mechanism of carcinogenesis. Mutat. Res.386~3~:263-277.

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128 ARSENICIN DRINKING WATER: 2001 UPDATE Mass, M.J., A. Tennant, B.C. Roop, W.R. Cullen, M. Styblo, D.J. Thomas, and A.D. Kligerman. 2001. Methylated trivalent arsenic species are genotoxic. Chem. Res. Toxicol. 14~4~:355-361. Matsui, M., C. Nishigori, S. Toyokuni, J. Takada, M. Akaboshi, M. Ishikawa, S. Imamura, and Y. Miyachi. 1999. The role of oxidative DNA damage in human arsenic carcinogenesis: detection of 8-hydroxy-2'-deoxyguanosine in arsenic- relatedBowen'sdisease. J.Invest.Dermatol.113~1~:26-31. Menzel, D.B., H.K. Hamadeh, E. Lee, D.M. Meacher, V. Said, R.E. Rasmussen, H. Greene, and R.N. Roth. 1999. Arsenic binding proteins from human lymphoblastoid cells. Toxicol. Lett. 105~2~:89-101. Moore, L.E., A.H. Smith, C. Hopenhayn-Rich, M.L. Biggs, D.A. Kalman, and M.T. Smith. 1997. Micronuclei in exfoliated bladder cells among individuals chronically exposed to arsenic in drinking water. Cancer Epidemiol. Biomarkers Prev. 6~1~:31-36. Morikawa, T., H. Wanibuchi, K. Morimura, M. Ogawa, and S. Fukushima. 2000. Promotion of skin carcinogenesis by dimethylarsinic acid in keratin (K6~/ODC transgenic mice. Jpn. J. Cancer Res. 91~6~:579-581. Murgo, A.J. 2001. Clinical trials of arsenic trioxide in hematologic and solid tumors: overview of the National Cancer Institute Cooperative Research and Development Studies. Oncologist 6(suppl.2~:22-28. Namgung, U., and Z. Xia. 2001. Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kineses. Toxicol. Appl. Pharmacol. 174~2):130-138. Ng, J.C. 1999. Speciation, Bioavailability and Toxicology of Arsenic in the Environment. Ph. D. Thesis. University of Queensland, Australia. NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC: NationalAcademy Press. Osler, W. 1894. Principles and Practice of Medicine. New York: Appleton. Park, W.H., J.G. Seol, E.S. Kim, J.M. Hyun, C.W. Jung, C.C. Lee, B.K. Kim, and Y.Y. Lee. 2000. Arsenic trioxide-mediated growth inhibition in MC/CAR myeloma cells via cell cycle arrest in association with induction of cyclin- dependent kinase inhibitor, p21, and apoptosis. Cancer Res. 60~11~:3065-3071. Parrish, A.R., X.H. Zheng, K.D. Turney, H.S. Younis, and A.J. Gandolfi. 1999. Enhanced transcription factor DNA binding and gene expression induced by arsenite or arsenate in renal slices. Toxicol. Sci. 50~1~:98-105. Petrick, J.S., F. Ayala-Fierro, W.R. Cullen, D.E. Carter, and H.V. Aposhian. 2000. Monomethylarsonous acid (MMAii~) is more toxic than arsenite in Chang human hepatocytes. Toxicol. Appl. Pharmacol. 163~2~:203-207. Petrick, J.S., B. Jagadish, E.A. Mash, and H.V. Aposhian. 2001. Monometylarson- ous acid (MMA III) and arsenite: LD 50 in hamsters and in vitro inhibition of pyruvate dehydrogenase. Chem. Res. Toxicol. 14~6~:651-656. Porter, A.C., G.R. Fanger, and R.R. Vaillancourt. 1999. Signal transduction pathways regulated by arsenate and arsenite. Oncogene 18~54~:7794-7802.

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EXPERIMENTS ~ STUDIES 129 Puccetti, E., S. Guller, A. Orleth, N. Bruggenolte, D. Hoelzer, O.G. Ottmann, and M. Ruthardt. 2000. BCR-ABL mediates arsenic trioxide-induced apoptosis independently ofits aberrant kinase activity. Cancer Res. 60~13~:3409-3413. Radabaugh, T.R., and H.V. Aposhian. 2000. Enzymatic reduction of arsenic compounds in mammalian systems: reduction of arsenate to arsenite by human liver arsenate reductase. Chem. Res. Toxicol. 13~19:26-30. Ramirez, P., L.M. Del Razo, and M.E. Gonsebatt. 2000. Arsenite induces DNA-pro- tein crosslinks and cytokeratin expression in the WRL-68 human hepatic cell line. Carcinogenesis 21~4~:701-706. Romach, E.H., C.Q. Zhao, L.M. Del Razo, M.E. Cebrian, and M.P. Waalkes. 2000. Studies on the mechanisms of arsenic-induced self tolerance developed in liver epithelial cells through continuous low-level arsenite exposure. Toxicol. Sci. 54~2~:500-508. Rossman, T.G., and Z. Wang. 1999. Expression cloning for arsenite-resistance resultedinisolation of tumor suppressor fau cDNA: possible involvement ofthe ubiquitin system in arsenic carcinogenesis. Carcinogenesis 20~2~:311-316. Roussel, R.R., and A. Barchowsky. 2000. Arsenic inhibits NF-kappaB-mediated gene transcription by blocking IkappaB kinase activity and IkappaBalpha phosphorylation and degradation. Arch. Biochem. Biophys.377~19:204-212. Rousselot, P., S. Labaume, J.P. Marolleau, J. Larghero, M.H. Noguera, J.C. Brouet, and J.P. Fe~and. 1999. Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients. Cancer Res. 59~59: 1041-1048. Sampayo-Reyes, A., R.A. Zakharyan, S.M. Healy, and H.~. Aposhian. 2000. Monomethylarsonic acid reductase and monomethylarsonous acid in hamster tissue. Chem. Res. Toxicol. 13~11~:1181-1186. Santra, A., J. Das Gupta, B.K. De, B. Roy, and D.N.G. Mazumder. 1999. Hepatic manifestations in chronic arsenic toxicity. Indian J. Gastroenterol. 18~4~:152- 155. Santra, A., A. Maiti, S. Das, S. Lahin, S.K. Charkaborty, and D.N.G. Mazumder. 2000. Hepatic damage caused by chronic arsenic toxicity in experimental animals. J. Toxicol. Clin. Toxicol. 38~4~:395-405. Schroeder, M., and M.J. Mass. 1997. CpG methylation inactivates the ~anscriptional activity of the promoter of the human p53 tumor suppressor gene. Biochem. Biophys. Res. Commun. 235~23:403-406. Seol, J.G., W.H. Park, E.S. Kim, C.W. Jung, J.M. Hyun, B.K. Kim, and Y.Y. Lee. 1999. Effect of arsenic trioxide on cell cycle arrest in head and neck cancer cell line PCI-1. Biochem. Biophys. Res. Commun. 265~2~:400-404. Seol, J.G., W.H. Park, E.S. Kim, C.W. Jung, J.M. Hyun, Y.Y. Lee, and B.K. Kim. 2001. Potential role of caspase-3 and -9 in arsenic trioxide-mediated apoptosis in PCI-1 head and neck cancer cells. Int. J. Oncol. 18~2~:249-255. Shen, Z.Y., L.J. Tan, W.J. Cai, J. Shen, C. Chen, X.M. Tang, and M.H. Zheng. 1999. Arsenic trioxide induces apoptosis of oesophageal carcinoma in vitro. Int. J. Mol. Med. 4~1~:33-37.

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