efsa-opinion-chromium-food-drinking-water

16.04.2014 Views
Chromium in food and drinking water formation of micronuclei dose-dependently in both strains (lowest effective dose: 17.7 mg Cr(VI)/kg b.w.). In contrast, following p.o. administration, potassium dichromate chemical failed to induce micronuclei (highest dose tested: 113.1 mg Cr(VI)/kg). In the study by De Flora et al. (2006) sodium dichromate dihydrate and potassium dichromate were administered to BDF1 and Swiss mice of both genders either with the drinking water or in a single intragastric dose. No increase of the micronucleus frequency was observed in either bone marrow or peripheral blood erythrocytes following oral admistration (highest dose tested: 500 mg Cr(VI)/L for up to 210 consecutive days) whereas the same compounds induced a clastogenic damage following i.p. injection (lowest effective dose: 50 mg Cr(VI)/kg). In the same study pregnant mice were also treated up to a concentration of 10 mg Cr(VI)/L drinking water. No genotoxic effects were observed either in bone marrow of pregnant mice or in liver and peripheral blood of their fetuses. The observation of mutagenicity by Cr(VI) is of relevance in light of its tumorigenic effects (see Section 7.2.2.5). Cr(VI) was reported to be mutagenic in vivo following oral exposure (Kirpnick-Sobol et al., 2006) however, in this study a non standard assay (i.e. p(un) reversion assay in mice) was used. Cr (VI) was mutagenic in the transgenic lacI mice following intratracheal instillation of potassium dichromate (Chen et al., 2000). Interestingly, in this experimental system mutagenicity was inhibited by tissue GSH depletion by buthionine sulfoximine (BSO) before Cr(VI) treatment suggesting a role for GSH in the generation of mutagenic lesions. GSH-Cr-DNA adducts are mutagenic in mammalian cells in vitro (see mechanism of action) and these adducts might also play an important role in mutagenic responses in vivo. DNA damage as measured by the Comet assay has been observed in mice and rats in several tissues including stomach, colon, liver, kidney, bladder, brain and peripheral leukocytes (Devi et al., 2001; Sekihashi et al., 2001; Wang et al., 2006). In particular, a dose-dependent increase in DNA damage was observed in lymphocytes of mice admistered by gavage with potassium dichromate (Devi et al., 2001; Wang et al., 2006). Sekihashi et al. (2001) found DNA damage, in mouse stomach, colon, liver, kidney, bladder, lung and brain following administration by gavage of potassium dichromate. EFSA Journal 2014;12(3):3595 92

Chromium in food and drinking water Table 18: Test system/ Endpoint Summary of in vivo genotoxicity of Chromium (VI) – oral route. Female C57BL/ 6Jpun/pun mouse DNA deletions in 20-day-old offspring Compound Potassium dichromate Response (a) Dose (b) : mg Cr(VI)/kg b.w. per day Positive Reference Kirpnick-Sobol et al. 12.5 (c) (2006) Pregnant Swiss albino mouse Micronuclei in bone marrow cells from dams and liver and peripheral blood cells from fetuses BDF1 male mouse Micronuclei in bone marrow and peripheral blood cells BDF1 mouse (male and female) Swiss-Webster mouse Micronuclei in bone marrow cells Potassium dichromate Sodium dichromate dihydrate Potassium dichromate Sodium dichromate dihydrate Potassium dichromate Negative 1.8 (d) De Flora et al. (2006) Negative 6 (c) Negative F: 140 (c) M: 165 (c) Negative 3.6 (d) Mirsalis et al. (1996) B6C3F1 BALB/c am3-C57BL/6 male mouse Sodium dichromate dihydrate Equivocal 8.7 (c) (B6C3F1) Negative 8.7 (BALB/c) NTP (2007 ) Micronuclei in peripheral red blood cells B6C3F1 mouse Micronuclei in peripheral red blood cells BDF1 male mouse Micronuclei in bone marrow cells Male MS/Ae and CD-1 mouse Micronuclei in bone marrow cells Swiss albino mouse DNA damage Comet assay in leukocytes Swiss albino mouse DNA damage Comet assay in peripheral lymphocytes ddY mouse DNA damage Comet assay in cells from stomach, colon, liver, kidney, bladder, lung, brain and bone marrow Potassium dichromate Potassium chromate Potassium dichromate Potassium dichromate Potassium dichromate Positive 5.2 (c) (am3-C57BL/6) Negative 27.9 (c) NTP (2007) Negative 17.7 (c) De Flora et al. (2006) Negative 85.7 (c) Shindo et al. (1989) Negative up to acutely toxic doses Positive 0.21 (c) Devi et al. (2001) Positive 8.8 (c) Wang et al. (2006) Positive 85.7 (c) Sekihashi et al. (2001) (a): The lowest effective dose is indicated for positive results and the highest dose tested for negative results. (b): In the conversions from concentration to daily doses, the molecular weight (MW) of the anhydrous salts were used when no information on hydration number was available in the original publication. (c): Doses calculated using data from the original publication. (d): Doses calculated using the default correction factor for subacute/subchronic/chronic exposure via drinking water/feed from EFSA SC (2012). EFSA Journal 2014;12(3):3595 93

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