efsa-opinion-chromium-food-drinking-water

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).
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