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 />
Approximately 16 mg Cr(VI)-equivalents of reducing capacity per L of fed stomach contents<br />
(containing gastric secretions, saliva, <strong>water</strong> and <strong>food</strong>) was found for both species. The authors<br />
concluded that these findings support that, at the doses that caused cancer in the mouse small intestine<br />
(> 20 mg Cr(VI)/L in <strong>drinking</strong> <strong>water</strong>), the reducing capacity of stomach contents was likely exceeded.<br />
Taking all together the CONTAM Panel concluded that the absorption and tissue distribution of<br />
Cr(VI) depend strongly on the rate and extent of its reduction in the gastrointestinal tract but also on<br />
the ligands bound to Cr(VI) or the Cr(III) formed upon reduction of Cr(VI). The data available so far<br />
support that reduction along the gastrointestinal tract is efficient but that it cannot be excluded that<br />
even at low dose levels a small percentage of Cr(VI) escapes gastrointestinal reduction to Cr(III). Such<br />
a low fraction of Cr(VI) that would not be reduced may not be adequately detected in subsequent<br />
toxicokinetic studies if the majority of Cr(VI) would be reduced to Cr(III).<br />
The relevance of metabolism of Cr(VI) for the mode of action and interpretation of genotoxicity<br />
and carcinogenicity data<br />
Although the final product of Cr(VI) reduction is always Cr(III) the formation of specific<br />
intermediates and ternary Cr-DNA adducts is dependent on the nature of the reducing agent. The<br />
main intracellular biological reducers of Cr(VI) are low molecular weight thiols (glutathione and<br />
cysteine) and ascorbate. Studies on the reduction of Cr(VI) by extracts from rat lung, liver, or kidney<br />
have found that ascorbate accounted for at least 80 % of Cr(VI) metabolism in these target tissues<br />
(Standeven et al., 1991, 1992). Ascorbate is also the fastest reducer of Cr(VI) in the in vitro reactions<br />
(Quievryn et al., 2003). It should be noted that outside the cell ascorbate plays a protective-antioxidant<br />
role which contrasts with the pro-oxidative role inside the cells.<br />
Depending on the nature of the reducing agent and its concentration, this process can generate various<br />
amounts of unstable Cr(V) and Cr(IV) intermediates. Reductive reactions with ascorbate yield Cr(IV)<br />
as the first reaction intermediate when ascorbate is present in molar excess over Cr(VI) (Goodgame et<br />
al., 1987; Stearns et al., 1994; Dillon et al., 1997). The presence of Cr(V) was only detectable in<br />
reactions of Cr(VI) at nonphysiological conditions under conditions of limited ascorbate<br />
concentrations. It is of interest to note that there is approximately a 20-fold difference in the levels of<br />
ascorbic acid when comparing the in vivo cellular levels (about 1 mM) with those in cells in culture<br />
(about 50 µM) where the only source of ascorbic acid is the supplemented foetal bovine serum (Costa<br />
and Klein, 2006).<br />
Reduction of Cr(VI) can also be accomplished through non enzymatic reactions with cysteine and<br />
glutathione (O’Brien et al., 1992; Quievryn et al., 2003). However, in the target tissues of <strong>chromium</strong><br />
toxicity such as lung, ascorbate is the primary reducer of Cr(VI). In mitochondria, the primary<br />
reductant of Cr(VI) appears to be NADPH leading to the formation of stable Cr(III) that effectively<br />
binds DNA (De Flora and Wetterhahn, 1989). In cell cultures, reduction of Cr(VI) is mainly facilitated<br />
by glutathione, which has been shown to produce a much higher concentration of oxidants than<br />
ascorbate (Wong et al., 2012).<br />
This difference in reduction processes may underlie the different types and amounts of DNA damage<br />
seen with Cr(VI) in vivo compared with in vitro exposure situations. The relative concentrations of Cr<br />
species and available reductants determine the rate and pathways involved in the reduction process,<br />
and, hence, the type and extent of DNA damage that may be produced. In the course of the Cr(VI)<br />
reduction many reactive oxygen species, including free radicals, such as the hydroxyl radical, singlet<br />
oxygen, superoxide anion, are formed. The final product of Cr(VI) reduction, Cr(III), forms stable<br />
adducts with macromolecules and other cellular constituents.<br />
The efficiency of the reduction processes as well as species-specific differences in metabolism should<br />
also be considered when interpreting carcinogenicity data. Stout et al. (2009) concluded that the<br />
induction of tumors in the small intestine of mice occurred at dose levels that did not exceed the<br />
estimated Cr(VI) reducing capacity for gastric juices in mice, based on the assumption of similar<br />
reduction capacity of humans versus rodents. Since the reduction capacity of human gastric juice has<br />
been estimated to be of 84-88 mg Cr(VI)/day (De Flora et al., 1997), Stout et al. (2009) extrapolated<br />
EFSA Journal 2014;12(3):3595 106