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Chromium in food and drinking water Table 17: Developmental and reproductive toxicity studies with Cr(VI) compounds (continued). Study Doses in mg Cr(VI)/kg b.w. Species per day (a) 20-day (drinking water) Mice potassium dichromate, (treated F Sacrifice on GD 19 mated with 0, 52, 98, and 169 (e) untreated M) NOAEL LOAEL mg Cr(VI)/kg b.w. per day Maternal toxicity: 98 Maternal toxicity 169 Developmental toxicity: 52 Reference Junaid et al. (1996b) b.w.: body weight; NOAEL: no-observed-adverse-effect level; LOAEL: lowest-observed-adverse-effect level; GD: gestation day; M: male; F: female; PND: post natal day. (a): 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. (b): Data reported in the original publication; (c): Reproduction means effects on reproductive organs and spermatogenesis. Toxic effects observed in the study are reported in annex H6; (d): Conversion using the default correction factor for subacute/subchronic/chronic exposure via drinking water/feed from EFSA (2012c); (e): Conversion using drinking water/feed consumption data and average body weight reported in the publication; (f): Calculated applying allometric scaling using human data (70 kg b.w. and 2 L daily water consumption) and an exponent of 0.75. 7.2.2.4. Genotoxicity The mutagenic potential of Cr(VI) has been studied extensively and recently reviewed (ATSDR, 2012). Although study results vary depending on the test system, experimental conditions and type of Cr(VI) compounds tested, results of the assay systems used provide clear evidence for the mutagenic potential of Cr(VI) both in vitro and in vivo. Here, a brief summary of the literature and details only for the most relevant studies is provided. In vitro assays Bacteria and yeast Cr(VI) compounds have mostly tested positive for gene mutations in bacterial cells. Reverse mutations were observed after exposure to Cr(VI) compounds in multiple species and strains of Salmonella typhimurium and Escherichia coli able to detect a wide spectrum of DNA lesions, including oxidative damage and DNA crosslinks, and of mutations such as base pair substitutions and frame-shift mutations (Venitt and Levy, 1974; Nishioka, 1975; Bonatti et al., 1976; Petrilli and De Flora, 1977; Nakamuro et al., 1978; Kanematsu et al., 1980; Matsui, 1980; De Flora, 1981; Gentile et al., 1981; Venier et al., 1982; Bennicelli et al., 1983; Haworth et al., 1983; Singh, 1983; De Flora et al., 1984; Dunkel et al., 1984; Arlauskas et al., 1985; Kharab and Singh, 1985; Marzin and Phi, 1985; La Velle, 1986; Llagostera et al., 1986; Brams et al., 1987; Olivier and Marzin, 1987; Bronzetti and Galli, 1989; Zeiger et al., 1992; Le Curieux et al., 1993; Seo and Lee, 1993; Watanabe et al., 1998; Ryden et al., 2000; Yamamoto et al., 2002; Tagliari et al., 2004; NTP, 2007). Positive results were also found for forward mutations and mitotic gene conversion in yeast (Saccharomyces cerevisiae) (Sora et al., 1986; Vashishat and Vasudeva, 1987). EFSA Journal 2014;12(3):3595 90
Chromium in food and drinking water Mammalian cells Cr(VI) compounds are also mutagenic in mammalian cell lines. Potassium dichromate was reported to significantly increase mutation frequency at the HPRT locus in Chinese hamster cells AT3-2 and V79 (Paschin et al., 1983), and calcium chromate at the TK locus in mouse lymphoma cells L5178Y (McGregor et al., 1987). Clastogenic activity (micronuclei, chromosomal aberrations and sister chromatid exchanges) of Cr(VI) compounds (i.e. calcium chromate, chromic acid, potassium chromate, potassium dichromate, sodium chromate and sodium dichromate) was reported by several groups in cultured CHO cells (Levis and Majone, 1979; Bianchi et al., 1980; Koshi and Iwasaki, 1983; Seoane and Dulout, 1999), mouse mammary FM3A carcinoma cells (Umeda and Nishimura, 1979), human fibroblasts (MacRae et al., 1979; Seoane and Dulout, 2001; Wise et al., 2002, 2004; Holmes et al., 2006), human epithelial cells (Wise et al., 2006) and human lymphocytes (Nakamuro et al., 1978; Sarto et al., 1980; Gomez-Arroyo et al., 1981; Imreh and Radulescu, 1982; Stella et al., 1982). In general, metabolic activation is not required to detect the mutagenic/clastogenic effects observed in mammalian cells in culture indicating that Cr(VI) is a direct-acting mutagen. Repair processes have been shown to modulate Cr(VI)-induced mutagenicity. Reynolds et al. (2004) showed that human cells efficiently repair chromium−DNA adducts by nucleotide excision repair (NER) whereas NER-deficient XP-A, XP-C and XP-F cells were severely compromised in their ability to repair chromium-DNA lesions. Intracellular replication of Cr-modified plasmids demonstrated increased mutagenicity in cells with inactive NER (see also Mode of action). Brooks et al. (2008) showed that CHO cells deficient either in NER or base excision repair, grown under the standard ascorbate-deficient conditions, presented a lower HPRT mutation frequency than wild-type cells (Brooks et al., 2008). The CONTAM Panel noted that the results of the study may be opposite to what would be expected, and that the authors postulated that, in the absence of excision repair processes, DNA damage is channeled into an error-free system of DNA repair or damage tolerance. Morphological cell transformation has also been reported in BALB/3T3, Syrian hamster embryo, and the Rauscher leukemia virus-infected Fischer rat embryo cell lines and rat liver epithelial cells (DiPaolo and Casto, 1979; Dunkel et al., 1981; Briggs and Briggs, 1988). In vivo assays Cr(VI) compounds have tested positive for mutations in Drosophila melanogaster in several studies (Graf and Wurgler, 1996; Amrani et al., 1999; Spano et al., 2001; Kaya et al., 2002) where larvae were fed the test substance at the lowest effective concentration of 0.1 mM (Amrani et al., 1999). Positive genotoxicity was observed for Cr(VI) in numerous studies in rats and mice following administration of Cr(VI) compounds via the parenteral, intratracheal or inhalation route (Table H8, Appendix H). Contrasting data have been reported when Cr(VI) was admistered orally (summarised in Table 18 and described in details in Table H7, Appendix H). The three drinking water exposure positive studies include induction of mutations in a DNA deletion assay using C57BL/6Jpun/pun mice (Kirpnick-Sobol et al., 2006) and induction of chromosomal damage in two mouse strains (NTP, 2007). In the study by Kirpnick-Sobol et al. (2006) chromosome deletions were detected in the offspring of exposed pregnant females (lowest effective dose: 62.5 mg Cr(VI)/L). Statistically significant increases in micronuclei formation with a dose-response were observed in peripheral erythrocytes of am3-C57BL/6 mice (lowest effective dose: 43.6 mg Cr(VI)/L), equivocal results (nearly significant positive trend) in the B6C3F1 strain and no effects in BALB/c mice (NTP, 2007). Other studies have reported negative results in bone marrow or peripheral blood cells following oral exposure to Cr(VI) compounds (Mirsalis et al., 1996; Shindo et al., 1989; De Flora et al., 2006). Two studies compared the effects of the parenteral versus oral admistration route within the same experimental setting (Shindo et al., 1989; De Flora et al., 2006). In both cases genotoxicity was detected when the test item was administered i.p. and negative results were observed when administered orally in the drinking water or by gavage. In particular, in the study by Shindo et al (1989) potassium chromate administered to MS/Ae and CD-1 mice by i.p. injection induced the EFSA Journal 2014;12(3):3595 91
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