efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
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Chromium in <strong>food</strong> and <strong>drinking</strong> <strong>water</strong><br />
this figure to rodents to conclude that the reduction capacity of a 50 g mouse would be approximately<br />
0.4 mg/day (approximately 8 mg/kg/day). This value is greater than all of the male mouse doses and<br />
equivalent to the average daily dose of Cr(VI) in the high dose group of female mice in the 2-year<br />
carcinogenicity study by NTP. However, it should be noted that several lines of evidence suggest that<br />
Cr(VI) reduction is less efficient in rodents than in humans. Cr(VI) reduction is attenuated by raising<br />
the pH (see Section 1.1) and the pH of the gastric environment is higher in rodents than in humans<br />
(Kararli, 1995). Moreover, no post-meal peaks of gastric juice secretion occur in rodents, whereas this<br />
phenomenon provides the bulk of Cr(VI) reduction in humans. Unfortunately, experimental data are<br />
not available for Cr(VI) reduction by mouse gastric juice. The differential anatomy and functional<br />
properties of the stomach in rodents and in humans adds uncertainty to the use of tumor data in mice<br />
to estimate risk for humans.<br />
The relevance of oxidative damage for the mode of action and interpretation of genotoxicity<br />
data.<br />
Cr(VI) has been postulated to exert its genotoxic effects, at least in part, through the generation of<br />
oxygen radicals. In vitro studies indicate that in the reduction of Cr(VI) by cellular reductants, Cr(V)<br />
complexes are produced that react with hydrogen peroxide to generate hydroxyl radicals (reviewed in<br />
Bagchi D et al., Toxicology, 2002). This mechanism is consistent with results of in vitro mammalian<br />
cell studies showing a decrease in the Cr(VI)- induced DNA damage in the presence of a variety of<br />
oxygen radical scavengers, reducing agents, and metal chelators (Pattison et al., 2001; Cemeli et al.,<br />
2003; O’Brien et al., 2003) and dose-dependent increases in intracellular levels of reactive oxygen<br />
species such as hydrogen peroxide and superoxide anion radicals, as detected by electron spin<br />
resonance, in mouse epidermal cells exposed in vitro to Cr(VI) (Son et al., 2010). Similarly, in vivo<br />
studies showed reduction of the clastogenic potency when administration of radical scavengers<br />
occurred simultaneously with or prior to administration of Cr(VI) salts to rodents (Chorvatovičová et<br />
al., 1991, 1993; Sarkar et al., 1993). In the study by Wang et al. (2006) the increase in DNA damage<br />
as measured by the Comet assay in lymphocytes of mice administered by gavage with potassium<br />
dichromate was accompanied by increased ROS formation and apoptosis, but no lipid peroxidation, in<br />
the liver. No induction of oxidative DNA damage was reported in forestomach, glandular stomach and<br />
duodenum of SKH-1 mice administered Cr(VI) in <strong>drinking</strong> <strong>water</strong> (highest dose tested 20 mg Cr(VI)/L<br />
equivalent to 4.82 mg Cr(VI)/kg b.w. per day) (De Flora et al., 2008). Similarly, no significant<br />
increases in 8-hydroxy-2’-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, were<br />
detected in the oral mucosa or duodenum of female rats and mice dosed with Cr(VI) in the <strong>drinking</strong><br />
<strong>water</strong> (0.3-520 mg sodium dichromate dihydrate/L) for 90 days (Thompson et al., 2011a, 2012b).<br />
However, in this study significant decreases in the ratio of reduced/oxidized glutathione were reported<br />
in various tissues (oral mucosa, jejunum and duodenum) in both species. Whole genome microarray<br />
analysis (Kopec et al., 2012a, b) of duodenal epithelial samples identified changes in genes involved<br />
in oxidative stress response, cell cycle regulation, or lipid metabolism and species-specific in the<br />
number and functionality of upregulated genes (Kopec et al., 2012b).<br />
The relevance of Cr-DNA adducts for the mode of action and interpretation of genotoxicity data<br />
The ability to form stable complexes with many ligands and the presence of six coordination sites<br />
gives Cr(III) the opportunity to generate various DNA cross-links with other molecules. Ternary DNA<br />
cross-links formed by Cr(III)-mediated bridging of DNA with glutathione, cysteine, histidine or<br />
ascorbate represent the major form (approximately 50 %) of Cr-DNA adducts in Cr(VI)-exposed<br />
mammalian cells at non-toxic levels of exposure (Zhitkovich et al., 1995; Quievryn et al., 2002). All<br />
ternary DNA adducts are formed through the attachment of Cr(III) to DNA phosphates (Zhitkovich et<br />
al., 1996, Quievryn et al., 2002).<br />
EFSA Journal 2014;12(3):3595 107