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Arsenic in Drinking Water (1999) / Chapter Skim
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7 Mechanisms of Toxicity
Pages 193-228

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From page 193...
... 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
From page 194...
... (1963) administered arsenic trioxide as a 0.01 % solution in drinking water or sodium arsenate by skin application (two
From page 195...
... (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)
From page 196...
... (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)
From page 197...
... . Relevance of Findings of Bioassays to Humans The findings of the rodent bioassays for inorganic arsenic are generally uniformly negative.
From page 198...
... (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.
From page 199...
... (1998) showed that arsenic exposure induced deletion mutations of human chromosome 11 in a human-hamster hybrid cell.
From page 200...
... . 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.
From page 201...
... 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.
From page 202...
... (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.
From page 203...
... 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.
From page 204...
... Either of those processes could result in a threshold dose response. Chromosomal aberrations are formed by errors in DNA repair of induced or endogenous DNA damage, errors in DNA replication on an altered template, or inhibition of enzymes, such as topoisomerases.
From page 205...
... Proteins involved in DNA repair that contain putative zinc fingers include the UVRA protein (Husain et al.
From page 206...
... It is conceivable that such instability could also be manifested by gross alterations in chromosomal structure, such as those observed in arsenic-exposed cells. However, if arsenic's effects on chromosomal aberrations is mediated by aberrant methylation, a sublinear dose response is likely to result for these effects at low exposure concentrations.
From page 207...
... 1979) have historically been linked to formation of stable arsenical complexes with the vicinal dithiols of the lipoic acid cofactor for the pyruvate dehydrogenase complex, but alterations in mitochondrial protein synthesis and inner-membrane structural integrity might also play an important role following in vivo exposures (Fowler et al.
From page 208...
... 1998) , indicating that this essential pathway is susceptible to arsenical disturbance.   The increased urinary excretion of carboxyl uroporphyrins VI, VII, and VIII and carboxyl coproporphyrin IV are the main measurable effects in experimental animal models following subchronic exposure to arsine gas (Fowler et al.
From page 209...
... FIGURE 7-2 Summary of statistical correlations between ultrastructural morphometric alterations in  mitochondrial substructure, respiratory function, mitochondrial heme pathway enzymes, and increased porphyrin excretion patterns in rats exposed to arsenate at 40 ppm in drinking water for 6 weeks. ALAS, delta-aminoleulinic acid synthetase; Vv, volume density; Sv,  surface density; RCR, respiratory control ratio; NAD, linked substrates such as pyruvate  and malate; P/O, phosphate-to-oxygen ratio. Source: Fowler et al. 1987. Reprinted with permission from the  Annals of the New York Academy of Sciences;  copyright 1987. Alterations in Cellular Gene Expression-Stress Protein Induction Exposure of cells to arsenicals either in vitro (Caltibiano et al.
From page 210...
... Given the capacity of arsenicals to produce oxidative stress, which includes induction of heme oxygenase, it is clear that reactive oxygen species, such as nitrate oxide and hydroxyl radicals, might play important roles in mediating the observed alterations in gene-expression patterns noted in many studies. Altered cytokine gene expression was recently reported in relation to the development of keratoses and might play a role in the development following chronic arsenical exposure (Germolec et al.
From page 211...
... Again, the doses of organic arsenicals (MMA and DMA) required for MT induction are one order higher than those of inorganic arsenicals (As(III)
From page 212...
... Arsine Gas Toxicity The toxicity of arsine gas (AsH 3 ) is directed primarily toward the red blood cells, producing hemolysis following acute, short-term, or prolonged exposure (Fowler et al.
From page 213...
... Other genotoxic responses that can be pertinent to the mode of action for arsenic carcinogenicity are comutagenicity, DNA methylation, oxidative stress, and cell proliferation; however, data on those genotoxic responses are insufficient to draw firm conclusions. The most plausible and generalized mode of action for arsenic carcinogenicity is that it induces structural and numerical chromosomal abnormalities without acting directly with DNA.
From page 214...
... ·      Oxidative stress produced by ROS formation results in the observed induction of the major stress protein families. ·      Intracellular production of ROS results in the inhibition of the heme biosynthetic pathway enzyme uroporphyrinogen decarboxylase.
From page 215...
... Other studies of less critical importance for characterizing risks but nonetheless needed to fill important data gaps include the following: — Studies to examine the relationships between ROS formation, oxidative stress, induction of the stress protein response and necrosis or apoptosis. — Studies to examine the relationships between arsenical-induced oxidative stress, DNA damage, induction of proto-oncogenes, inhibition of DNA mechanisms, and cancer.
From page 216...
... 1976. The intracellular effects of chronic arsenic exposure on renal proximal tubule cells.
From page 217...
... Natarajan.  1996.  Chromosomal aberrations in peripheral blood lymphocytes from native Andean women and children from northwestern Argentina exposed to arsenic in drinking water. Mutat.
From page 218...
... Malish, Toxicology Branch II, Review Section IV, Health Effects Division, to B Briscoe, Special Review and Reregistration Division, Health Effects Division.
From page 219...
... 1996. Urinary porphyrins and heme biosynthetic enzyme activities measured by HPLC in arsenic toxicity.
From page 220...
... 1998. Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species.
From page 221...
... 1985. The Reproductive Effects Assessment Group's report on the mutagenicity of inorganic arsenic.
From page 222...
... 1989. Heme oxygenase is the major 32-Kda stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.
From page 223...
... among individuals chronically exposed to arsenic in drinking water. Mutat.
From page 224...
... 1986. Inhibition of human excision DNA repair by inorganic arsenic and the co-mutagenic effect in V79 Chinese hamster cells.
From page 225...
... 1995. DNA-strand breaks induced by dimethylarsinic acid, a metabolite of inorganic arsenics, are strongly enhanced by superoxide anion radicals.
From page 226...
... 1992. Cancer risks fron arsenic in drinking water.
From page 227...
... 1991. Urinary porphyrin profiles as biomarkers of trace metal exposure and toxicity: Studies on urinary porphyrin excretion patterns in rats during prolonged exposure to methyl mercury.
From page 228...
... 1991. Cellular response to oxidative damage in lung induced by the administration of dimethylarsinic acid, a major metabolite of inorganic arsenics, in mice.


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