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Chromium in food and drinking water Although Cr(VI) is generally believed to induce dG-DNA adducts, both bulky DNA adducts and oxidative damage at adenines and guanines were recently (Arakawa et al., 2012) detected in the p53 gene in Cr(VI) treated human lung cells. The analysis of the binding sites for the three major cellular Cr forms, namely Cr(III), Cr(VI) and Cr(V), suggested that Cr(VI) induction of lesions at dA and dG residues is likely to be through Cr(V) intermediates. Cr(III) binding sites were preferentially at dG sites whereas Cr(V) binding sites included both Cr(III) and Cr(VI) binding sites. The authors speculated that it is probable that Cr(VI) once reduced to Cr(V) is transferred to N7 of the dA to form a Cr(V)-dA adduct which is eventually converted to stable Cr(III)-dA. These Cr(VI) induced lesions could contribute to mutagenesis of the p53 gene that leads to lung carcinogenesis. Finally, Cr-DNA adducts have been also directly associated with the cytoxic effects of Cr (VI). NER deficient mammalian cells that are characterized by persistence of Cr-DNA adducts (see also Section on genotoxicity) showed increased apoptosis and clonogenic death by Cr(VI) (Reynolds et al., 2004). Another repair pathway, mismatch repair (MMR), is also involved in the toxicity of Cr(VI) adducts. Following exposure to Cr(VI), mouse and human cell lines defective in MMR showed higher survival and lower apoptosis when compared to MMR-proficient cells lines (Peterson-Roth et al., 2005). A significant induction of double-strand breaks (as detected by gamma-H2AX foci) was detected before apoptosis in MMR-proficient cells suggesting that the repair by MMR of bulky adducts formed by chromium leads to the formation of double-strand breaks (Salnikov and Zhitkovich, 2008). Mechanistic studies showed that Cr-DNA adducts lost their ability to block replication of Cr-modified plasmids in human colon cells lacking the MMR protein MLH1 (Peterson-Roth E et al, 2005). Reynolds et al. (2009) later showed that MMR complex MSH2-MSH6 (MutSalpha) effectively bound DNA containing ascorbate-Cr-DNA and cysteine-Cr-DNA cross-links. Conversely, binary Cr-DNA adducts were poor substrate for MSH2-MSH6 and their toxicity in cells was weak and MMR independent. The MMR complex MSH2 and MSH3 (MusSbeta) was shown to cooperate with MutSalpha in processing of Cr-DNA cross-links being essential for the induction of double-strand breaks, micronuclei and apoptosis in human cells by chromate. Conclusions It is clear that a key determinant for the genotoxic action of Cr(VI) is its intracellular reduction via Cr(V) to Cr(III). This reduction of Cr(VI) to Cr(III) is also important in an earlier phase of the mode of action since it is an important factor in the bioavailability of Cr(VI) upon oral intake, especially given the fact that bioavailability of Cr(III) may be more limited than that of Cr(VI) since Cr(III) can not easily pass cell membranes and enter cells. Only once absorbed, Cr(VI) is reduced to Cr(III) with formation of Cr-DNA adducts and other DNA damage resulting in mutagenesis, (MOA I in Figure 17) (McCarroll et al, 2010, OEHHA, 2011; Zhitkovich, 2011;). An additional MOA contribution to the DNA damage induced by Cr(VI) is the reduction of Cr(VI) resulting in production of Cr(V) that can result in formation of ROS upon reaction with hydrogen peroxide to generate hydroxyl radicals, ROS and oxidative stress (Bagchi D et al., 2002; Thompson et al., 2011 b), resulting in damage to DNA, and mutation (MOA II in Figure 17). Both modes of action can occur and contribute to the genotoxic effects of Cr(VI). Figure 17: Proposed mode of action for carcinogenicity of Cr(VI). EFSA Journal 2014;12(3):3595 110
7.5. Dose-response assessment Chromium in food and drinking water No human data could be identified to perform a dose-response assessment of chromium or any chromium species for oral exposure. Therefore, the CONTAM Panel considered the available data on neoplastic and non-neoplastic health effects in experimental animals for the evaluation of dose-response relationships separately for Cr(III) and Cr(VI) species. For Cr(III) no dose-response modelling was possible for the most reliable studies in experimental animals, since no effects were observed even at the highest dose tested, see Section 7.2.1. Although dose-response data were available on developmental and reproductive toxicity regarding the fertility of male and female mice, the CONTAM Panel noted their limitations (using only two dose groups) and since concerns were raised regarding the design, conduct and reporting of the data the CONTAM Panel concluded that these data could not be analysed by dose-response modelling. The data base for Cr(VI) allowed dose-response assessment of both, neoplastic and non-neoplastic effects in experimental animals. 7.5.1. Assessment of neoplastic effects of Cr(VI) The CONTAM Panel identified the neoplastic effects of Cr(VI) as the critical effects and identfied the data available from the 2-year studies on the carcinogenicity of sodium dichromate dihydrate in male and female F344/N rats and in male and female B6C3F1 mice (see Section 7.2.2.5) as suitable for dose-response evaluation. To this end, the CONTAM Panel applied the BMD approach to analyse the data on the incidence of neoplastic effects according to the guidance given in EFSA (2009c). Using the default BMR of 10 % extra risk for the incidence, the BMD 10 and its 95 % lower confidence limit BMDL 10 were calculated. For details see Appendix J. The dose-response data on squamous cell neoplastic lesions in the epithelium of the oral cavity in male and female rats were suitable for a BMD analysis. For each sex, the incidences of papilloma and of carcinoma were reported by the NTP separately both for oral mucosa and tongue. For the two sites of oral mucosa and tongue combined the joint incidence of papilloma or carcinoma combined) was reported (see Table 19) and the CONTAM Panel decided to perform a dose-response evaluation of the neoplastic activity of sodium dichromate dihydrate in the oral cavity in rats, a) for the incidence of papilloma or carcinoma in the oral cavity (oral mucosa or tongue) and b) for carcinoma in the oral mucosa only since the incidence in tongue only was very low. The incidences of the two endpoints exhibited a statistically significant dose-response relationship (poly-3 test for trend: p < 0.001), separately for both sexes. Since the dose ranges, the range of the observed carcinoma incidences and the shape of the dose-response were comparable in both sexes the CONTAM Panel investigated the possibility of a dose-response evaluation of males and females combined using the PROAST software (RIVM) which allows testing for differences between two dose-response curves of males and female. Table 21(A) presents the BMD/L 10 values for male and female rats, separately as well as combined, a) for the incidence of papilloma or carcinoma in oral cavity (mucosa or tongue) and b) for carcinoma in the oral mucosa, using the BMDS software BMDS 2.4 of US-EPA and PROAST (RIVM). Since there were no statistically significant differences between males and female, the CONTAM Panel derived from these data a BMDL 10 of 3.4 mg/kg b.w. per day for the incidence of papilloma or carcinoma in the oral cavity and a BMDL 10 of 3.6 mg/kg b.w. per day for carcinoma in oral mucosa only. The dose-response data on epithelial neoplastic lesions of the small intestine in male and female mice were also suitable for a BMD analysis. For each sex, the incidences of adenoma and of carcinoma were reported by the NTP separately for two sites, namely duodenum and jejunum, whereas the incidence of adenoma or carcinoma (combined) was reported for all three sites (i.e. duodenum, jejunum and ileum) combined (see Table 21(B)). Since the adenoma-carcinoma sequence is a well recognised pathway of carcinogenesis in different sections of the GI tract (e.g. Höhn, 1979; EFSA Journal 2014;12(3):3595 111
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