efsa-opinion-chromium-food-drinking-water

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Chromium in food and drinking water Approximately 16 mg Cr(VI)-equivalents of reducing capacity per L of fed stomach contents (containing gastric secretions, saliva, water and food) was found for both species. The authors concluded that these findings support that, at the doses that caused cancer in the mouse small intestine (> 20 mg Cr(VI)/L in drinking water), the reducing capacity of stomach contents was likely exceeded. Taking all together the CONTAM Panel concluded that the absorption and tissue distribution of Cr(VI) depend strongly on the rate and extent of its reduction in the gastrointestinal tract but also on the ligands bound to Cr(VI) or the Cr(III) formed upon reduction of Cr(VI). The data available so far support that reduction along the gastrointestinal tract is efficient but that it cannot be excluded that even at low dose levels a small percentage of Cr(VI) escapes gastrointestinal reduction to Cr(III). Such a low fraction of Cr(VI) that would not be reduced may not be adequately detected in subsequent toxicokinetic studies if the majority of Cr(VI) would be reduced to Cr(III). The relevance of metabolism of Cr(VI) for the mode of action and interpretation of genotoxicity and carcinogenicity data Although the final product of Cr(VI) reduction is always Cr(III) the formation of specific intermediates and ternary Cr-DNA adducts is dependent on the nature of the reducing agent. The main intracellular biological reducers of Cr(VI) are low molecular weight thiols (glutathione and cysteine) and ascorbate. Studies on the reduction of Cr(VI) by extracts from rat lung, liver, or kidney have found that ascorbate accounted for at least 80 % of Cr(VI) metabolism in these target tissues (Standeven et al., 1991, 1992). Ascorbate is also the fastest reducer of Cr(VI) in the in vitro reactions (Quievryn et al., 2003). It should be noted that outside the cell ascorbate plays a protective-antioxidant role which contrasts with the pro-oxidative role inside the cells. Depending on the nature of the reducing agent and its concentration, this process can generate various amounts of unstable Cr(V) and Cr(IV) intermediates. Reductive reactions with ascorbate yield Cr(IV) as the first reaction intermediate when ascorbate is present in molar excess over Cr(VI) (Goodgame et al., 1987; Stearns et al., 1994; Dillon et al., 1997). The presence of Cr(V) was only detectable in reactions of Cr(VI) at nonphysiological conditions under conditions of limited ascorbate concentrations. It is of interest to note that there is approximately a 20-fold difference in the levels of ascorbic acid when comparing the in vivo cellular levels (about 1 mM) with those in cells in culture (about 50 µM) where the only source of ascorbic acid is the supplemented foetal bovine serum (Costa and Klein, 2006). Reduction of Cr(VI) can also be accomplished through non enzymatic reactions with cysteine and glutathione (O’Brien et al., 1992; Quievryn et al., 2003). However, in the target tissues of chromium toxicity such as lung, ascorbate is the primary reducer of Cr(VI). In mitochondria, the primary reductant of Cr(VI) appears to be NADPH leading to the formation of stable Cr(III) that effectively binds DNA (De Flora and Wetterhahn, 1989). In cell cultures, reduction of Cr(VI) is mainly facilitated by glutathione, which has been shown to produce a much higher concentration of oxidants than ascorbate (Wong et al., 2012). This difference in reduction processes may underlie the different types and amounts of DNA damage seen with Cr(VI) in vivo compared with in vitro exposure situations. The relative concentrations of Cr species and available reductants determine the rate and pathways involved in the reduction process, and, hence, the type and extent of DNA damage that may be produced. In the course of the Cr(VI) reduction many reactive oxygen species, including free radicals, such as the hydroxyl radical, singlet oxygen, superoxide anion, are formed. The final product of Cr(VI) reduction, Cr(III), forms stable adducts with macromolecules and other cellular constituents. The efficiency of the reduction processes as well as species-specific differences in metabolism should also be considered when interpreting carcinogenicity data. Stout et al. (2009) concluded that the induction of tumors in the small intestine of mice occurred at dose levels that did not exceed the estimated Cr(VI) reducing capacity for gastric juices in mice, based on the assumption of similar reduction capacity of humans versus rodents. Since the reduction capacity of human gastric juice has been estimated to be of 84-88 mg Cr(VI)/day (De Flora et al., 1997), Stout et al. (2009) extrapolated EFSA Journal 2014;12(3):3595 106
Chromium in food and drinking water this figure to rodents to conclude that the reduction capacity of a 50 g mouse would be approximately 0.4 mg/day (approximately 8 mg/kg/day). This value is greater than all of the male mouse doses and equivalent to the average daily dose of Cr(VI) in the high dose group of female mice in the 2-year carcinogenicity study by NTP. However, it should be noted that several lines of evidence suggest that Cr(VI) reduction is less efficient in rodents than in humans. Cr(VI) reduction is attenuated by raising the pH (see Section 1.1) and the pH of the gastric environment is higher in rodents than in humans (Kararli, 1995). Moreover, no post-meal peaks of gastric juice secretion occur in rodents, whereas this phenomenon provides the bulk of Cr(VI) reduction in humans. Unfortunately, experimental data are not available for Cr(VI) reduction by mouse gastric juice. The differential anatomy and functional properties of the stomach in rodents and in humans adds uncertainty to the use of tumor data in mice to estimate risk for humans. The relevance of oxidative damage for the mode of action and interpretation of genotoxicity data. Cr(VI) has been postulated to exert its genotoxic effects, at least in part, through the generation of oxygen radicals. In vitro studies indicate that in the reduction of Cr(VI) by cellular reductants, Cr(V) complexes are produced that react with hydrogen peroxide to generate hydroxyl radicals (reviewed in Bagchi D et al., Toxicology, 2002). This mechanism is consistent with results of in vitro mammalian cell studies showing a decrease in the Cr(VI)- induced DNA damage in the presence of a variety of oxygen radical scavengers, reducing agents, and metal chelators (Pattison et al., 2001; Cemeli et al., 2003; O’Brien et al., 2003) and dose-dependent increases in intracellular levels of reactive oxygen species such as hydrogen peroxide and superoxide anion radicals, as detected by electron spin resonance, in mouse epidermal cells exposed in vitro to Cr(VI) (Son et al., 2010). Similarly, in vivo studies showed reduction of the clastogenic potency when administration of radical scavengers occurred simultaneously with or prior to administration of Cr(VI) salts to rodents (Chorvatovičová et al., 1991, 1993; Sarkar et al., 1993). In the study by Wang et al. (2006) the increase in DNA damage as measured by the Comet assay in lymphocytes of mice administered by gavage with potassium dichromate was accompanied by increased ROS formation and apoptosis, but no lipid peroxidation, in the liver. No induction of oxidative DNA damage was reported in forestomach, glandular stomach and duodenum of SKH-1 mice administered Cr(VI) in drinking water (highest dose tested 20 mg Cr(VI)/L equivalent to 4.82 mg Cr(VI)/kg b.w. per day) (De Flora et al., 2008). Similarly, no significant increases in 8-hydroxy-2’-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, were detected in the oral mucosa or duodenum of female rats and mice dosed with Cr(VI) in the drinking water (0.3-520 mg sodium dichromate dihydrate/L) for 90 days (Thompson et al., 2011a, 2012b). However, in this study significant decreases in the ratio of reduced/oxidized glutathione were reported in various tissues (oral mucosa, jejunum and duodenum) in both species. Whole genome microarray analysis (Kopec et al., 2012a, b) of duodenal epithelial samples identified changes in genes involved in oxidative stress response, cell cycle regulation, or lipid metabolism and species-specific in the number and functionality of upregulated genes (Kopec et al., 2012b). The relevance of Cr-DNA adducts for the mode of action and interpretation of genotoxicity data The ability to form stable complexes with many ligands and the presence of six coordination sites gives Cr(III) the opportunity to generate various DNA cross-links with other molecules. Ternary DNA cross-links formed by Cr(III)-mediated bridging of DNA with glutathione, cysteine, histidine or ascorbate represent the major form (approximately 50 %) of Cr-DNA adducts in Cr(VI)-exposed mammalian cells at non-toxic levels of exposure (Zhitkovich et al., 1995; Quievryn et al., 2002). All ternary DNA adducts are formed through the attachment of Cr(III) to DNA phosphates (Zhitkovich et al., 1996, Quievryn et al., 2002). EFSA Journal 2014;12(3):3595 107
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EFSA Journal 2014;12(3):3595 SCIENT
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Chromium in food and drinking water
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