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3 Experimental Studies
Pages 75-132

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From page 75...
... 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.
From page 76...
... Oxidative stress can have numerous effects, including inhibition of heme-biosynthetic pathways and induction of major stress proteins. Although the role of arsenic-induced oxidative stress in mediating DNA damage is not clear, the intracellular production of reactive oxygen species
From page 77...
... The development ofthe analytical methods for the speciation of arsenic metabolites, as well as the advantages and disadvantages 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.
From page 78...
... 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.
From page 79...
... , but recent in vitro studies using rabbit liver cytoso! showed that the two steps in arsenic methylation to DMA are markedly inhibited by pyrogalloT (0.3 to 9 millimolar)
From page 80...
... 1999; NRC 1999~. Following exposure of mate rats to high concentrations of DMA in drinking water (100 mg/L, equivalent to 100,000 )
From page 81...
... (2000) reported a much higher rate of arsenic methylation in primary human hepatocytes compared with human keratinocytes and bronchial cells, and no methylation activity was detected in human urinary-bladder cells.
From page 82...
... 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)
From page 83...
... , the authors concluded that MMAV reductase was the rate-limiting enzyme for arsenite metabolism in the rabbit liver. However, it should be emphasized that, because of the species differences in arsenic methylation (see above)
From page 84...
... 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.
From page 85...
... 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)
From page 86...
... For a recent doctoral dissertation, which was also published as a conference proceeding, Ng (1999) administered AsV at 500 ~g/L in drinking water to 90 female C57BL/61 and 140 female metallothionein (MT)
From page 87...
... 2001) in which groups of mice were exposed to a range of arsenite concentrations in drinking water, an increase in AP-l DNA binding in bladder epithelial tissue was detected after ~ weeks of exposure to brining water containing 50,000 ,ug/L and 100,000 ,ug/L, but not after exposure to water containing arsenite at SOO ~g/L and 20,000 Go/.
From page 88...
... in drinking water to hairless mice that were concomitantly exposed to ultraviolet B radiation (2 kilojoules per square meter (kI/m2) twice weekly)
From page 89...
... Although these studies are of qualitative interest in demonstrating the carcinogenic potential of arsenic in rodents, the studies provide little useful quantitative information relevant to human risk assessment of arsenic following exposure via drinking water and cannot replace the current body of epidemiological data used for risk assessment.
From page 90...
... The copper content of the renal cortex increased from 10 Gig of wet weight to as high as 65 Gig of wet weight in a time- and concentration-dependent manner. Developmental Toxicity Studies One recent animal study has been published on the developmental toxicity resulting from repeated oral dosing with arsenic compounds.
From page 91...
... Studies that require arsenic concentrations greater than ~ O ,uM to produce a biological response in vitro are less likely to be relevant to the health effects related to chronic ingestion of arsenic in drinking water and have not been exhaustively reviewed. Relative Toxicity of Different Forms of Arsenic In the previous NRC report, it was stated that the pentavaTent methylated arsenic metabolites are much less mutagenic than the inorganic arsenicals (NRC 1999; p.
From page 92...
... 92 Ct so v ,% o Cal o v ._ 3 so .= v C)
From page 93...
... 93 Ct · _ rot Ct .
From page 94...
... 94 a, Cal A au U
From page 95...
... 9s 'e cd O c-]
From page 96...
... 96 a' an an U
From page 97...
... 97 Ct rat ~ _ ._.
From page 98...
... -40-transformed epithelial cell line derived from normal human urinary bladder cells, the investigators found that the trivalent methylated metabolites of arsenic were more cytotoxic than arsenite in all cell types (Styblo et al.
From page 99...
... , suggesting that oxidative stress might not have been responsible. In the comet assay, which examined the ability of arsenicals to induce DNA damage in cultured human Tymphocytes, MA and DMA~i were 77 and 386 times more potent, respectively, than arsenite.
From page 100...
... In a small study of subjects exposed to arsenic in drinking water in Finland, Maki-Paakkanen etal.
From page 101...
... As discussed in Chapters 2 and 4, there are species differences in response to the toxic and carcinogenic actions of arsenic, and it is also likely that there is interindividual variability in response. Mechanistic studies are helpful in identifying potential reasons for such variability in responses observed in viva, but great caution should be used in inferring relevance of a specific response to arsenic observed in vitro to humans exposed chronically at relatively low doses in drinking water.
From page 102...
... . Arsenite has been shown to inhibit the NF-KB signal transduction pathway that is important in transcriptional regulation of a variety of cellular pathways, including the inflammatory cytokines TNF-a and TL-8 (Rousse!
From page 103...
... that are frequently implicated in the promotion and progression of a variety of tumor types in experimental animal models and of some human tumors. However, which specific alterations in signal transduction pathways are actual targets that contribute to the development of arsenic-induced tumors in humans following chronic consumption of arsenic in drinking water remains uncertain.
From page 104...
... They found that cell proliferation in eight different cell lines were inhibited by As2O3, with ICsoS (the concentration that inhibits the response by 50%)
From page 105...
... (1999) studied the concentration of arsenic trioxide required to inhibit growth and induce apoptosis in oesophageal cancer cells in vitro.
From page 107...
... ~ 999~. Using a variety of specific modulators of oxidative stress and cell signaling, Chen et al.
From page 108...
... The arsenite-exposed HaCaT cells formed tumors when injected into nude mice, in contrast to the absence of tumor formation following injection of unexposed cells into nude mice. Induction of Oxidative Stress Prior to the 1999 NRC report, a great deal of research was conducted on the genotoxic and chromosomal effects of arsenic.
From page 109...
... 2000~. The results indicate that exogenous methylated arsenic species administered alone or synergistically in the presence of endogenous ascorbic acid can cause the release of iron from ferritin and an iron-dependent formation of reactive oxygen species.
From page 110...
... Arsenic was readily identified in four of five tumors classified as arsenic-related, but not in any of three cases of non-arsenic-related tumors. Those data provide further evidence that arsenic is capable of causing oxidative damage to DNA and suggest that this mechanism could contribute to the development of arsenic-related skin tumors in humans exposed to arsenic through drinking water.
From page 111...
... The kidney cell line was considerably more susceptible to cytotoxic effects of arsenic (ICE = 20 nM) than the human lung cell line, A549 cells (TCso = 400 nM)
From page 112...
... (2000) found a Tower percentage of pS3 expression in biopsies obtained from patients with a history of prior chronic ingestion of an arsenic-containing elixir compared with those with no known arsenic exposure and presumed UV-induced basalcell carcinoma (52.9% of 121 biopsies)
From page 113...
... , the releVance of these results to risk assessment of Tow concentrations of arsenic in drinking water is limited.
From page 114...
... . They also found that arsenic exposure activated the c-Jun/AP-1 transcription complex, which could explain some ofthe widespread changes in gene expression.
From page 115...
... Implications of Mode-of-Action Studies of Arsenic in Drinking Water to lIuman Carcinogenesis As described in this chapter, numerous recent studies have identified potential modes of action by which arsenic could increase cancer risk in human populations. Several recent in vivo animal studies have been completed, including one preliminary study that potentially demonstrated a significant carcinogenic response in mice to arsenic at 500 ppb (500 Egg)
From page 116...
... Human urinary bladder epithelium is one of the primary target tissues for arsenic carcinogenesis. Because this tissue is essentially bathed in urine that contains arsenic following ingestion of arsenic in the diet and drinking water, levels of biologically active forms of arsenic that appear in the urine following exposure to Tow-to-moderate doses in humans are particularly relevant to in vitro studies.
From page 117...
... Arsenite concentrations of 0.01-0.5 EM approximate the concentrations that might exist in human urine following ingestion of drinking water containing arsenic concentrations of 3-50 ppb, a range that is currently the focus of Tow- dose risk assessment.
From page 118...
... Thus, evidence is accumulating that relatively low concentrations of arsenic, potentially achievable through consumption of drinking water containing 10-50 ,ug/L of arsenic, can alter biochemical pathways relevant to carcinogenesis (gene expression, cell-cycle regulation, signal transduction, apoptosis, oxidative stress, and others)
From page 119...
... The aforementioned biological effects that might occur following exposure to arsenic are likely to exhibit a typical sigmoid dose-response relationship, characterized by a sublinear, linear, or supralinear shape, depending on where the dose range under consideration falls along the dose-response curve. An important and controversial issue is whether the existing mode-of-action data provide suitable evidence to demonstrate that arsenic acts as a thresholdtype carcinogen in humans exposed to arsenic in drinking water.
From page 120...
... There is increasing evidence for the presence of reactive amounts of trivalent methylated arsenic metabolites, especially MA, in tissues and urine following exposure to inorganic arsenic. Therefore, the methylation of inorganic arsenic is not entirely a detoxification process; the formation and distribution of the reduced metabolites might be associated with increased toxicity.
From page 121...
... · Although a threshold for carcinogenic activity for arsenic might conceivably exist in a given individual, interindividual variation in response and the variability in background exposure to arsenic via the diet and other sources within the human population complicates the determination of a no-effect level in a diverse human population, if such a level were to exist. RECOMMENDATIONS · Research should be conducted to determine in viva target-tissue concentrations of the various arsenic metabolites following ingestion of arsenic in drinking water.
From page 122...
... 1999. Dimethylarsinic acid effects on DNA damage and oxidative stress related biochemical parameters in B6C3F1 mice.
From page 123...
... 2000b. Antitumor effect of arsenic trioxide on mice experimental liver cancer [in Chinese]
From page 124...
... 2001. DNA damage in buccal epithelial cells from individuals chronically exposed to arsenic via drinking water in Inner Mongolia, China.
From page 125...
... 1996. Subchronic dispositional and toxicological effects of arsenate administered in drinking water to mice.
From page 126...
... 2000. Determination of monomethylarsonous acid, a key arsenic methylation intermediate, in human urine.
From page 127...
... 2000. NADH oxidase activation is involved in arsenite-induced oxidative DNA damage in human vascular smooth muscle cells.
From page 128...
... 1997. Micronuclei in exfoliated bladder cells among individuals chronically exposed to arsenic in drinking water.
From page 129...
... 1999. Arsenic trioxide and melarsoprol induce apoptosis in plasma cell lines and in plasma cells from myeloma patients.
From page 130...
... 1977. Airborne arsenic exposure and excretion ofmethylated arsenic compounds.
From page 131...
... 2000. Arsenic trioxide-mediated cytotoxicity and apoptosis in prostate and ovarian carcinoma cell lines.
From page 132...
... 1980. Arsenic metabolites in hair, blood and urine in workers exposed to arsenic trioxide.


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