efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
Chromium in <strong>food</strong> and <strong>drinking</strong> <strong>water</strong><br />
Figure 15: Cysteine-Cr(III)-DNA cross-link structure as determined by analysis of crystal structure<br />
(de Meester et al., 1977; Madafiglio K et al., 1990)<br />
The information from several studies indicate that all cellular Cr-DNA adducts are ternary cross-links.<br />
Reductive metabolism of Cr(VI) in vitro usually generates a large number of binary Cr(III)-DNA<br />
adducts (Zhitkovich et al., 1996, 2000; Quievryn et al., 2002), but the presence of these DNA<br />
modifications in cells has not yet been established and is expected to be strongly inhibited due to the<br />
abundance of intracellular ligands capable of rapid coordination to Cr(III) prior to its binding to DNA.<br />
In cells in culture (human A549 cells) the restoration of physiological concentrations of ascorbic acid<br />
is required to detect ascorbate-Cr(III)-DNA adducts (Quievryn et al., 2002). The authors concluded<br />
that the availability of intracellular ascorbate for Cr(VI) reduction may be key to the amount of Crinduced<br />
DNA damage observed.<br />
DNA-protein cross-links (DPC) have also been detected in vitro during Cr(VI) reduction (Salnikow et<br />
al., 1992) as well as in various Cr(VI)-treated cells (Costa et al., 1996) and tissues in vivo (Hamilton,<br />
1986; Coogan et al., 1991b; Zhitkovich and Costa, 1992) as well as in vitro during Cr(VI) reduction<br />
(Salnikow et al., 1992). In particular, Coogan et al. (1991b) reported the induction of DPC in male<br />
Fischer 344 rat liver following 3-6 weeks of exposure via <strong>drinking</strong> <strong>water</strong> to potassium chromate at the<br />
lowest effective dose of 100 mg Cr(VI)/L. In contrast, no DPC were reported by De Flora et al. (2008)<br />
in forestomach, glandular stomach and duodenum cells of female SKH-1 hairless mice administerd<br />
with sodium dichromate dihydrate in <strong>drinking</strong> <strong>water</strong> at concentrations up to 20 mg Cr(VI)/L for<br />
9 months.<br />
Although DPC represent only a very small fraction of initially formed DNA adducts in cultured cells<br />
(about 0.1 % according to calculations by Zhitkovich group), DPC have been broadly utilized as a<br />
biomarker of Cr-exposure in human populations (Costa et al., 1993). However, it is important to note<br />
that the currently used methodologies do not allow differentiating between Cr(VI)-induced and other<br />
forms of DPC. Macfie et al. (2010) have recently proposed a three-step mechanism for Cr(VI)-induced<br />
DPC involving (i) reduction of Cr(VI) to Cr(III), (ii) Cr(III)-DNA binding and (iii) protein capture by<br />
DNA bound Cr(III).<br />
In vitro reduction of Cr(VI) by ascorbate (O’Brien et al., 2002; Bridge<strong>water</strong> et al., 1994) or cysteine<br />
(Zhitkovich et al., 2000) also produces a small number of Cr(III)-mediated interstrand DNA crosslinks.<br />
The most extensive DNA cross-linking was always observed under conditions of limited reducer<br />
concentrations. On the basis of the steric considerations and the fact that the yield of interstrand crosslinks<br />
had the exponential dose dependence, Zhitkovich et al (2000) proposed that Cr(III) oligomers,<br />
not monomeric Cr(III), are the cross-linking species.<br />
Mutagenic and cytotoxic properties of Cr adducts<br />
The fact that <strong>chromium</strong> binds preferentially to the N7 position of guanine on DNA was originally<br />
suggested by in vitro studies where DNA polymerases of different origin produced guanine-specific<br />
EFSA Journal 2014;12(3):3595 108