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7
Mechanisms of Toxicity

In this chapter, the subcommittee summarizes what is known about the mechanisms of toxicity for arsenic. The chapter is divided into two major sections-cancer and noncancer effects. In the cancer section, the subcommittee summarizes results from in vivo and in vitro bioassays designed to investigate the role of arsenic and metabolites of arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as tumor promoters and initiators. That summary is followed by a discussion of the data on modes of action for arsenic-induced carcinogenesis and how those data can help delineate the slope of the dose-response curve at low exposure concentrations. In the noncancer section, the subcommittee summarizes what is known about the mechanisms of action leading to noncancer effects. The potential relationships between mechanisms of arsenic-induced cell injury or cell death and carcinogenic processes are discussed with particular attention to the inter-relationships between arsenic-induced formation of reactive oxygen species or oxidative stress and chromosomal damage in target-cell populations. The roles of other documented arsenic-induced cellular responses, such as alterations in the heme biosynthetic pathway, alterations in cellular gene expression, and inhibition of DNA-repair enzyme activities, are discussed as components of the broad spectrum of cellular responses to arsenic exposure.

Cancer Effects

Results from Bioassays
Inorganic Arsenic

In general, long-term studies on the carcinogenicity of arsenic in labora-



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Page 193 7 Mechanisms of Toxicity In this chapter, the subcommittee summarizes what is known about the mechanisms of toxicity for arsenic. The chapter is divided into two major sections-cancer and noncancer effects. In the cancer section, the subcommittee summarizes results from in vivo and in vitro bioassays designed to investigate the role of arsenic and metabolites of arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as tumor promoters and initiators. That summary is followed by a discussion of the data on modes of action for arsenic-induced carcinogenesis and how those data can help delineate the slope of the dose-response curve at low exposure concentrations. In the noncancer section, the subcommittee summarizes what is known about the mechanisms of action leading to noncancer effects. The potential relationships between mechanisms of arsenic-induced cell injury or cell death and carcinogenic processes are discussed with particular attention to the inter-relationships between arsenic-induced formation of reactive oxygen species or oxidative stress and chromosomal damage in target-cell populations. The roles of other documented arsenic-induced cellular responses, such as alterations in the heme biosynthetic pathway, alterations in cellular gene expression, and inhibition of DNA-repair enzyme activities, are discussed as components of the broad spectrum of cellular responses to arsenic exposure. Cancer Effects Results from Bioassays Inorganic Arsenic In general, long-term studies on the carcinogenicity of arsenic in labora-

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Page 194 tory animals have yielded negative results. In one of the more extensive studies, which was carried out by the FDA, rats were administered sodium arsenite at concentrations up to 250 ppm or sodium arsenate at concentrations up to 400 ppm in the diet for 2 years. No increases in tumors were observed (Byron et al. 1967). A similar negative finding was noted in beagles maintained on diets containing sodium arsenate or sodium arsenite at 5-125 ppm for 2 years; however, the high dose proved to be lethal (Byron et al. 1967). In another study, rats were administered lead arsenite at concentrations of 463 or 1,850 ppm (arsenic at approximately 400 ppm) or sodium arsenite at a concentration of 416 ppm in the diet (based on body weight and food consumption data, equivalent to approximately 18-20 mg/kg of body weight per day) for 29 months with some indication of toxicity, but no increase in tumorigenicity when compared with controls (Kroes et al. 1974). In a study of 20 Cynomolgus monkeys, arsenic was administered by mouth as sodium arsenate at a dose of 0.1 mg/kg per day, 5 days per week, for 15 years. None of the animals developed malignant tumors (Thorgeirsson et al. 1994). Animal studies on the carcinogenicity of arsenic administered via drinking water have also been conducted. In rats, sodium arsenite administered at a concentration of 5 mg/L for a lifetime did not cause an increase in tumors (Schroeder et al. 1968). The authors calculated that the concentration was equivalent to a dose of 0.38 mg/kg of body weight per day. Although some evidence of arsenic accumulation was found in the animals, it had no effect on survival (Schroeder et al. 1968). In a similar study, rats received sodium arsenate at a concentration of 5 mg/L (approximately 350 µg/kg of body weight per day) for a lifetime and had no indication of tumorigenicity (Kanisawa and Schroeder 1969). In a shorter study examining the effect of arsenic on mammary tumors, Schrauzer and Ishmael (1974) administered sodium arsenite to mice at 10 mg/L in drinking water for 16 weeks. The incidence of mammary tumors was lower in the tested animals (27%) than in the controls (82%). However, they found that arsenic increased the size of spontaneous mammary tumors. In a study, which has not yet been peer reviewed and is available only in abstract form, Ng et al. (1998) reported preliminary results indicating that the administration of sodium arsenate in drinking water (0.500 mg/L) to C57B1/6J and metallothionein knock-out mice for up to 26 months caused tumors of the gastrointestinal tract, lungs, liver, spleen, bone, skin, reproductive system, and eye. No tumors were observed in the control groups of the study. Several animal studies have examined the interaction of arsenic with other chemicals to determine if it might be acting as a promoter rather than as an initiator of tumors. Baroni et al. (1963) administered arsenic trioxide as a 0.01 % solution in drinking water or sodium arsenate by skin application (two

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Page 195 drops of a solution of 15.8 g/L twice weekly) to mice. Each of these treatments was tested in combination with skin application of croton oil (to test for promoting action), and after initiation with a single topical application of 7,12-dimethylbenz[a]anthracene or with administration of ethyl carbamate by intubation (to test for promoting action). There was no indication that either arsenic trioxide or sodium arsenate was acting as an initiator or promoter. Kroes et al. (1974) found that the administration of arsenic in the diet of rats (lead arsenate at 463 ppm or sodium arsenate at 416 ppm) for 29 months did not enhance the carcinogenicity of diethylnitrosamine (DENA) (5 µg per day administered by intubation 5 days per week). When three strains of mice were administered arsenic trioxide (0.01%) in their drinking water for 8 weeks and then subjected to topical application of methylcholanthrene, arsenic decreased the number of papillomas produced in CxC3H mice (Milner 1969). When arsenic trioxide was administered at 2 ppm in the drinking water of mice for a lifetime with or without selenium at 2 ppm, arsenic alone caused no increase in the incidence of mammary tumors, but some increase occurred in the growth and multiplicity of the tumors (Schrauzer et al. 1978). Selenium was protective in that the incidence of mammary tumors in the group given selenium alone was significantly lower than the control group. However, no protection was observed when selenium was administered with arsenic because the incidence of mammary tumors increased in the co-exposed group compared with the control group. Shirachi et al. (1983) administered sodium arsenite at a maximum tolerated dose of 160 ppm in drinking water to partially hepatectomized rats with or without a single dose of diethylnitrosamine (30 mg/kg of body weight intraperitoneally). Although 1 of 7 rats administered DENA without arsenic developed kidney tumors at the end of 25 weeks, 7 of 10 administered DENA with arsenic developed kidney tumors, suggesting that arsenic acted as a promoter. In a statistical reanalysis of the data, Smith et al. (1992) concluded that even in rats administered arsenic without DENA, liver and kidney tumors increased for all three forms of arsenic—arsenite, arsenate, and DMA. Starting with newborn mice, Laib and Moritz (1989) administered sodium arsenite (2 mg/kg per day) or sodium arsenate (20 mg/kg per day) 5 days per week for 3 weeks with or without DENA (2 mg/kg) and found an increase in ATPase-deficient foci in the livers of the mice given arsenite with DENA when compared with the mice given DENA alone or arsenate with DENA, suggesting a cocarcinogenic effect of the arsenite but not the arsenate. Monomethylarsonic Acid (MMA) In a study submitted to the EPA Office of Pesticides Program, male and

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Page 196 female Sprague-Dawley rats were fed MMA in the diet at concentrations of 0, 25, 50, 100, and 200 ppm for 2 years. There was an increase in thyroid tumors in the males but only at the highest dose (EPA 1981). In another report, when Fischer 344 (F344) rats were fed MMA at concentrations of 0, 50, 400, and 1,300 ppm (equivalent to 0, 3.2, 27, and 93 mg/g per day for the males and 0, 3.8, 33, and 101 mg/kg per day for the females) for 2 years, there was a suggestion of an increased incidence of parathyroid gland adenomas at 400 and 1,300 ppm in the male rats and in the females at 1,300 ppm, but the statistical significance depended upon the test used (EPA 1992a). Another study showed no evidence of carcinogenicity in male and female B6C3F1 mice fed MMA in the diet at concentrations of 0, 10, 50, 200, and 400 ppm (equivalent to 0, 1.8, 9.3, 38, and 83 mg/kg per day for the males and 0, 2.2, 12, 46, and 104 mg/kg per day for the females) for 2 years (EPA 1992b). Dimethylarsinic Acid (DMA) The arsenic metabolite DMA, which is the herbicide cacodylic acid, has been tested for its effects in vivo and in vitro. In studies on the tumorigenicity of DMA, Innes et al. (1969) found no evidence of tumorigenicity after administering DMA orally to two strains of mice at a daily dose of 46.4 mg/kg of body weight (maximum tolerated dose) for 18 months. In a study for EPA (1992c), male and female F344 rats were fed DMA at concentrations of 0, 2, 10, 40, and 100 ppm in the diet (equivalent to 0, 0.14, 0.73, 2.8, and 7.3 mg/kg per day for the males and 0, 0.16, 0.79, 3.2, and 8.0 mg/kg per day for the females) for 2 years. The results showed a carcinogenic response as evidenced by increases in transitional-cell papillomas and carcinomas at the highest dose in both sexes. In the bladder, urinary transitional-cell hyperplasia and vacuolar degeneration occurred in a doserelated manner at the concentrations of 40 and 100 ppm. The study was judged to be minimally acceptable by EPA (1992c, 1993). When male and female B6C3F1 mice were fed DMA at concentrations of 0, 8, 40, 200, and 500 ppm for 2 years, vacuolar degeneration of the urinary bladder transitional epithelium increased at 200 and 500 ppm in both sexes. There were no increases in urinary bladder tumors. This submitted study was judged by EPA to be inadequate because it was decided that higher doses of DMA could have been used (EPA 1991, 1992d). As reported in the Integrated Risk Information System (IRIS) of EPA, cacodylic acid (DMA) is classified as D—not classifiable as to human carcino-

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Page 197 genicity. The basis for this classification by the agency is that there are ''no human data and inadequate data in animals" (EPA 1998). In a complex study by Yamamoto et al. (1995), rats were administered DENA, N-methyl-N-nitrosourea, 1,2-dimethylhydrazine, N-butyl-N-(4hydroxybutyl)nitrosamine and N-bis(2-hydroxypropyl)nitrosamine and were given DMA in drinking water at concentrations of up to 400 ppm for 30 weeks. DMA alone was without effect, but in the five-carcinogen test group, it significantly enhanced the formation of tumors of the urinary bladder, kidney, liver, and thyroid gland and increased preneoplastic lesions in the liver. In a study by Yamanaka et al. (1996), DMA was administered at concentrations of 200 or 400 ppm in the drinking water of ddY mice for 25 weeks following initiation with 4-nitroquinoline 1-oxide (4NQO). DMA alone was without effect, but DMA at 400 ppm administered with 4NQO increased the number of lung tumors per animal when compared with 4NQO administered alone. In a further study, rats were administered N-(4-hydroxybutyl)nitrosamine for 4 weeks and then given DMA at 0, 2, 10, 25, 50, and 100 ppm in drinking water for 32 weeks (Wanibuchi et al. 1996). Again, no neoplastic lesions were observed in rats administered DMA alone. Urinary bladder tumors increased in rats given N-(4-hydroxybutyl)nitrosamine followed by DMA at 10 ppm or higher. The 5-bromo-2'-deoxyuridine labeling index also increased. Collectively, the studies suggest that DMA is not an initiator, but it might be a promoter. Yamanaka et al. (1989) found that DMA administered orally at 1,500 mg/kg caused DNA strand breaks in mouse lung. That dose is extremely high. In fact, it exceeds the LD50 (the lethal dose for 50% of the test animals) of 1,200 mg/kg of body weight in mice reported by other investigators (Kaise et al. 1989). Similarly, incubation of human lung cells (L-132) with 10 mM of DMA for 10 hr caused single-strand breaks (Tezuka et al. 1993). Cross-linking between DMA and nuclear proteins was also observed when L-132 was incubated with 10 mM of DMA (Yamanaka et al. 1993). The investigators have suggested that those effects might be related to the formation of active oxygen species (Yamanaka et al. 1991; Rin et al. 1995). Other investigators have shown that DMA in vitro at concentrations ranging from 62.5 to 250 mg/L induces tetraploids in Chinese hamster cells in a concentration-dependent manner (Endo et al. 1992). Relevance of Findings of Bioassays to Humans The findings of the rodent bioassays for inorganic arsenic are generally uniformly negative. Given the unquestionable oncogenic activity of inorganic

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Page 198 arsenic in humans, it would at first appear that these studies are of no value in helping to elucidate the carcinogenic mode of action of arsenic. However, in line with the evidence suggested in the sections that follow, such negative data may be supportive of a non-genotoxic mode of action. Certainly if arsenic were a direct and genotoxic carcinogen, one would expect to find positive results in at least one of these assays. The fact that there are species differences with rodents being resistant suggests that understanding the reason for this difference may shed some light on the mode of action. The very high doses of DMA used in animal bioassays in vivo bring into question whether the low arsenic concentrations in human exposures exert their tumor-promoting effects via the metabolite DMA. At low exposure concentrations, humans would not metabolize arsenic to DMA at the concentrations needed to promote the tumor production observed in the animal studies. Compared with inorganic arsenic, the DMA formed would also be expected to be excreted rapidly (see Chapter 5). In addition, as discussed below (see Mode of Action for Carcinogenicity), in vitro studies suggest that arsenite is orders of magnitude more potent than DMA in the induction of chromatid breaks and gaps in cultured human fibroblasts (Oya-Ohta et al. 1996). Recent studies by M.M. Moore et al. (1997) also compared the relative potentials of sodium arsenite, sodium arsenate, MMA, and DMA for mutagenic and clastogenic activities by using the L5178Y/TK+/- mouse lymphoma assay and found the organic arsenicals to be orders of magnitude less potent in producing genotoxicity. Mode of Action For the purposes of cancer risk assessment, it is important to distinguish between genotoxicity and mutagenicity when discussing mechanisms underlying the formation of tumors. Genotoxicity is the broader term that also encompasses cellular effects that are not themselves heritable. Those effects include DNA and protein adducts, sister chromatid exchanges (SCEs) and unscheduled DNA synthesis. In addition, abnormalities in DNA methylation, although not strictly a genotoxic effect, also could be included as a form of potentially reversible DNA modification. Mutagenicity specifically describes the production of changes in DNA that can be transmitted from generation to generation (for organisms and cells). Cancer is a genetic disease that requires the accumulation of mutations in several genes (most notably, oncogenes and tumor-suppressor genes) in a single cell to progress to a tumor. Thus, mutations, either directly or indirectly produced by a chemical, are the most pertinent indicator of the potential for carcinogenicity. The spectrum of

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Page 199 mutational classes, their frequencies, and their mechanisms of formation are all important in establishing the nature of the dose response for tumors induced by a particular chemical of interest at exposure concentrations below those for which tumor data can be obtained.  These various aspects of mutagenicity for arsenicals are discussed in this section in the context of arsenic-induced carcinogenicity. To characterize dose-response relationships, it is also appropriate to distinguish between mode of action and mechanism of action. It is much more feasible to establish a mode of action, because the only requirement is identifying the necessary (but not sufficient) steps whereby a particular agent causes tumor development. In contrast, the requirements for understanding the mechanism of action whereby an agent induces a tumor are identifying the necessary steps and characterizing their specific nature (e.g., the specific genes involved). Thus, considerable research efforts are required to move from a mode of action to a mechanism of action for tumor induction. The present state of knowledge for arsenic clearly necessitates that the mode of action be considered. Genotoxic Effects Induced by Arsenic Compounds Mutational Spectrum Genetic alterations induced in cells by chemicals can be of several different types. Broadly these are point mutations that involve alterations of a single base pair in the DNA, chromosomal alterations that include deletions within a chromosome arm, interchanges between two chromosomes and losses or gains of whole chromosomes (aneuploidy). Arsenic does not induce point mutations in bacterial or mammalian cells (Jacobson-Kram and Montalbano 1985). A recent report by M.M. Moore et al. (1997) showed that sodium arsenite and sodium arsenate induced mutations in L5178Y/TK+/- cells at concentrations of 1-2 µg/mL and 10-14 µg/mL, respectively. In contrast, the methylated metabolites MMA and DMA were mutagenic only at much higher concentrations, 2,500-5,000 µg/mL and almost 10,000 µg/mL, respectively. The organic arsenicals are much less mutagenic than the inorganic arsenicals. Of particular note for the present discussion, all four arsenicals induced deletion mutations and not point mutations at the TK locus. Hei et al. (1998) showed that arsenic exposure induced deletion mutations of human chromosome 11 in a human-hamster hybrid cell. Analysis at the molecular level showed that all mutants had lost one or more markers and that

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Page 200 the frequency of very large deletions increased with exposure concentration. Arsenicals produce a range of chromosomal alterations in mammalian cells in vitro, rodents in vivo, and humans exposed to relatively high concentrations of arsenic in drinking water. A discussion of many of these studies and their relevance to dose-response assessment can be found in Rudel et al. (1996) and in the comprehensive review by Rossman (1998). In vivo and in vitro studies of rodents and humans have reported chromosomal aberrations, including the induction of micronuclei (Larramendy et al. 1981; IARC 1987; Jha et al. 1992; Warner et al. 1994; Dulout et al. 1996; Gonsebatt et al. 1997; L.E. Moore et al. 1996, 1997). Arsenic-induced aneuploidy has also been demonstrated in vivo and in vitro in human lymphocytes and in exfoliated bladder cells but not consistently in buccal cells from exposed individuals (Gonsebatt et al. 1997; Warner et al. 1994; Vega et al. 1995; Dulout et al. 1996). SCEs have been induced in vitro, but evidence for their occurrence in exposed humans is equivocal (Nordenson et al. 1978; Larramendy et al. 1981; Lerda 1994; Rasmussen and Menzel 1997). The relative potency of arsenic compounds for clastogenicity in normal human fibroblasts in vitro is the following: (1) arsenite, (2) arsenate, and (3) DMA (Oya-Ohta et al. 1996). For example, more than 7 mM of DMA is required for clastogenicity, whereas only 0.8 µM of arsenite is needed to induce chromosomal alterations. Comutagenicity There are reports that arsenic potentiates the mutagenic effects of alkylating agents (Li and Rossman 1989a, 1991; Yang et al. 1992), UV radiation (Rossman 1981; Lee et al. 1985), X-rays and DNA cross-linking agents, 8-methoxypsoralen plus ultraviolet (UV) light and cis-platinum (Lee et al. 1986), and diepoxybutane (Wiencke and Yager 1992). Plasmid shuttle vector experiments indicated marked potentiation of point mutagenesis by short-wave UV at a concentration of 1 µM of sodium arsenite, an exposure that itself did not affect the cell viability of normal human fibroblasts (Wiencke et al. 1997); arsenic's effects were largely attributed to enhancement of small and large deletions and rearrangements. The enhancement of genotoxicity that has been observed for clastogenic effects and point mutations has not been found for induced SCEs. Arsenite (5 µM) was found to enhance by sixfold the neoplastic transformation of C3H/10T/1/2 cells by bovine papilloma virus (Kowalski et al. 1996). The role of these reported comutagenic effects on arsenic-induced carcinogenicity are as yet unclear given the somewhat artificial nature of the interac-

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Page 201 tions studied. Further discussion is provided below on the influence of these comutagenic effects on DNA repair. DNA Methylation Methylation changes in genes or their control regions could result in altered gene expression and perhaps carcinogenesis (Baylin et al. 1998). Further, nonmutagenic carcinogens, such as arsenic, could be carcinogenic via this mechanism (Costa 1995). In an initial study to test that hypothesis, Mass and Wang (1997) showed that exposure of human lung adenocarcinoma A549 cells to sodium arsenite (0.08-2 µM) or sodium arsenate (30-300 µM) produced dose-responsive hypermethylation within a 341-base-pair fragment of the promoter of p53. In contrast, DMA (2-2,000 µM) did not produce hypermethylation. Some data suggested that such hypermethylation might be a genomic change and not just a region-specific methylation change (Mass and Wang 1997). However, other explanations can be found for the phenomenon described including the possibility of selection of cells that were hypermethylated before arsenic exposure. Recently, Zhao et al. (1997) showed that chronic exposure to low concentrations of arsenic caused transformation of a rat liver epithelial cell line into one that was capable of causing tumors in nude mice. Hyperexpression of the metallothionein gene was also detected. The authors hypothesized that the methylation of arsenic by methyltransferases could cause a decrease in the Sadenosyl-methionine (SAM) available for methylation of DNA, leading to hypomethylation and a resultant aberrant gene express. They concluded that hypomethylation of DNA is a tenable epigenetic mechanisms for arsenic-induced carcinogenicity. Given that effects on cellular methylation status could have important consequences for gene expression patterns, levels of methylation donors in the diet could modulate the effects of arsenic on DNA metabolism. Oxidative Stress Some evidence supports the concept that arsenite induces oxidative stress in mammalian cells and that the induced oxidative damage can result in genotoxicity. For example, the concept is supported indirectly by the finding that adding superoxide dismutase to the culture medium reduces the frequency of arsenite-induced SCE in human lymphocytes (Nordenson and Beckman 1991). Similarly, vitamin E can protect human fibroblasts from arsenic

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Page 202 toxicity (Lee and Ho 1994). Arsenite can also increase the concentrations of a number of proteins that can protect against oxidative stress—e.g., metallothionein (Albores et al. 1992) and heme oxygenase (Keyse and Tyrrell 1989). Although those studies and other similar ones suggest that arsenic induces oxidative stress and results in genotoxicity, more direct evidence clearly needs to be provided. Recent studies by Hei et al. (1998) suggest that reactive oxygen species are involved in the formation of deletion mutations of human chromosome 11 in a human-hamster hybrid cell following arsenic treatment. The log-linear shape of the survival curve for these cells is noted to be supportive evidence for an effect of arsenic on DNA repair. This conclusion is supported, in part, by the data of Gurr et al. (1998), who showed that arsenic induced micronuclei in cells in vitro at concentrations above 10 µM. The induction of micronuclei was reduced by treatment with NO synthase inhibitors and superoxide dismutase, as well as calcium chelators and uric acid. An alternative explanation for arsenic's possible role in the induction of genotoxicity is that arsenic could affect the repair of endogenously produced oxidative DNA damage. However, without specific studies to address that hypothesis, it remains speculative. Cell Proliferation Sodium arsenite can increase the incorporation of 3H-thymidine into the DNA of human keratinocytes in vitro as well as increase cell number at low concentrations (0.001-0.002 µM) indicating increased cell proliferation. At higher concentrations, sodium arsenite was cytotoxic (Germolec et al. 1997). In support of arsenic-inducing cell proliferation, Germolec et al. (1997) showed that sodium arsenite induced increased mRNA transcripts of keratinocyte growth factors, including granulocyte macrophage-colony-stimulating factor (GM-CSF), transforming growth factor a (TGF-a), and the inflammatory cytokine tumor necrosis factor a (TNF-a) in primary human epidermal keratinocytes in vitro. In addition, c-myc expression, as an indicator of proliferation was increased. These effects on transcription were seen at sodium arsenite concentrations of 0.5-4 µM, with an approximately linear response over this range. While these data have the potential for providing input into the mode of action via the cell proliferation pathway, at this time they are observational rather than informative. Arsenicals can also cause cell proliferation in target organs in vivo, most likely as a regenerative response subsequent to induced toxicity. Oral administration of high concentrations of DMA to rats and mice after exposure to various genotoxic carcinogens caused increases in tumors in lung,

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Page 203 bladder, liver, kidney, and thyroid (Yamamoto et al. 1995; Wanibuchi et al. 1996; Yamanaka et al. 1996) (see the previous section Results from Bioassays). With that particular protocol, DMA is presumably acting as a promoting agent that would be supportive of a cell-proliferation effect. However, the specific experimental design can create some difficulties in interpretation. Arsenic-Induced Carcinogenicity and the Shape of Dose-Response Curve—A Mode-of-Action Approach The preceding section provides an overview of the various genotoxic effects of arsenicals in vitro and in vivo. The aim of this section is to discuss how some or all of those effects might be involved in arsenic-induced carcinogenicity, and further, how that information can provide information on the shape of the dose-response curve at low exposure concentrations. As discussed above, cancer is a genetic disease that requires the accumulation of a series of mutations in a single cell during the progression from a normal cell to a cancer cell. Those mutations can be point (gene) mutations, deletion mutations, other structural chromosomal alterations (e.g., inversions or rearrangement), or chromosomal numerical alterations (chromosomal losses or gains). On the basis of the mutagenicity profile for arsenicals discussed above, chromosomal alterations rather than point mutations are more likely to be involved in arsenic carcinogenicity. These chromosomal aberrations could feasibly be induced by direct or indirect interaction of arsenic with the DNA. Although the latter is much more likely to be based on available experimental evidence, direct interaction cannot be ruled out. Chromosomal structural alterations can arise via one of two basic pathways, direct interaction with DNA and indirect DNA effects. However, on the basis of the published data on mutational spectra for arsenic and the present discussion on other cellular responses to arsenic, arsenic-induced effects on cellular housekeeping processes are more likely to result ultimately in the formation of chromosomal alterations. Such indirect effects are predicted to lead to sublinear dose responses for chromosomal alterations, as supported by the experimental data reviewed by Rudel et al. (1996). Such a sublinear dose response is predicted for the less likely scenario of production of chromosomal aberrations following direct interaction of arsenic with DNA. This conclusion is based on the fact that the majority of structural chromosomal aberrations (with the possible exception of terminal deletions) require at least two independent events at the DNA level for their formation. Chromosomal alterations result from errors of DNA repair at the molecular level, or during DNA replication. The evidence in support of this hypothesis is

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Page 218 Reregistration Division.  Memorandum     008891.  Dec. 2.  U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, Washington, D.C. EPA  (U.S. Environmental Protection Agency).  1992a.  Review  of Toxicology Studies with Methanearsonic Acid/Methanearsonic Acid, Monosodium  to  Support Reregistration  of the Test Substance. Memorandum from S.L. Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to B. Briscoe, Special Review and Reregistration Division, Health Effects Division. Memorandum 009478. April. U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, Washington, D.C. EPA  (U.S. Environmental Protection Agency).  1992b.  Review  of Toxicology Studies with Methanearsonic Acid to Support Reregistration of the Test Substance. Memorandum from S.L. Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to B. Briscoe, Special Review and Reregistration Division, Health Effects Division. Memorandum 009382. March. U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, Washington, D.C. EPA  (U.S. Environmental Protection Agency).  1992c.  Review  of Toxicology Studies with Cacodylic Acid to Support Registration of Test Substance. Memorandum from S.L. Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to B. Briscoe, Special Review  and  Reregistration  Division, Health  Effects Division. Memorandum 009391. March. U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, Washington, D.C. EPA  (U.S. Environmental Protection Agency).  1992d.  Review  of Toxicology Study with Cacodylic Acid to Support Registration of Test Substance. Memorandum from S.L. Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to B. Briscoe, Special Review  and  Reregistration  Division, Health  Effects  Division. Memorandum 009775. October. U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1993. Cacodylic Acid: Registrant's Response to Agency's Review of Toxicology Data. Memorandum from S.L. Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to V. Dietrich, Product Manager, Registration Division.  Memorandum  010550.  September.  U.S. Environmental Protection Agency, Office of Prevention, Pesticides and Toxic Substances, Washington, D.C. EPA (U.S. Environmental Protection Agency). 1997. Report on the Expert Panel on Arsenic Carcinogenicity: Review and Workshop. Prepared by

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