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Chromium in food and drinking water Table 23: Result of the BMD analysis of haematological effects in male F/334 rat exposed to sodium dichromate dihydrate in drinking water for 22 days. Haematocrit PROAST Exponential PROAST Hill Haemoglobin PROAST Exponential PROAST Hill MCV PROAST Exponential PROAST Hill MCH PROAST Exponential PROAST Hill BMD 05 (mg/kg b.w. per day) 0.64 0.85 0.34 0.31 0.55 0.61 BMDL 05 (mg/kg b.w. per day) 0.53 0.33 0.62 0.49 BMD: benchmark dose; MCV: mean corpuscular volume; MCH: mean corpuscular haemoglobin; BMD: Benchmark dose; BMDL 05 : 95 % lower confidence limit of BMD. 0.21 0.74 0.27 0.23 0.41 0.50 7.6. Derivation of health-based guidance value(s)/margin of exposure The CONTAM Panel considered the critical effects of Cr(III) and Cr(VI) in order to derive healthbased guidance values (HBGV). Trivalent Chromium No carcinogenic or other adverse effects have been observed in the sub-chronic or long-term oral toxicity studies of Cr(III) in mice or rats. The relevant NOAELs derived from these studies corresponded to 506 and 286 mg Cr(III)/kg b.w. per day for the sub-chronic and long-term toxicity in the rat, respectively (NTP, 2010). No significant changes in reproductive organ weights in male or female animals, in sperm parameters, or in estrous cyclicity were reported in the sub-chronic oral toxicity studies on rats and mice at the highest doses tested (506 mg/kg b.w. per day and 1090 mg/kg b.w. per day, respectively) (NTP, 2010). However, the CONTAM Panel noted that in some other studies in rats or mice, reproductive or developmental toxicity by oral exposure to Cr(III) was reported. The lowest LOAELs for these effects were in the order of 30 mg/kg b.w. per day. The Panel noted that these studies have methodological limitations and were not designed for establishing reference doses. Taking together these observations the CONTAM Panel decided to use the relevant NOAEL in the long-term rat NTP study of 286 mg/kg b.w. per day as a RP for risk characterisation of Cr(III) and to apply, besides the standard uncertainty factor of 100, an additional factor of 10 to account for the absence of adequate data on reproductive and developmental toxicity. Therefore, the CONTAM Panel derived a tolerable daily intake (TDI) of 300 µg Cr(III)/ kg b.w per day. Hexavalent chromium Cr(VI) compounds are genotoxic. Cr(VI) is a human carcinogen by inhalation, and oral exposure via drinking water is associated with gastrointestinal system cancers in experimental animals. BMDL 10 values were derived from the animal carcinogenicity data (NTP, 2010). In this study increased incidence of tumours of the squamous epithelium of the oral cavity and of epithelial tissues of the small intestine were reported in male and female rats and mice, respectively. Since the adenomacarcinoma sequence is a well recognised pathway of carcinogenesis in the GI tract, in a conservative approach, the CONTAM Panel selected the BMDL 10 of 1.0 mg Cr(VI)/kg b.w. per day for combined adenomas or carcinomas of the small intestine in male and female mice as RP for the estimation of the margin of exposure (MOE) for neoplastic changes. After repeated oral administration of Cr(VI), in addition to the cancer effects, several toxic effects were identified in rats and mice including microcytic, hypochromic anaemia, and non-neoplastic lesions of the liver, duodenum, mesenteric and pancreatic lymph nodes and pancreas. The lowest EFSA Journal 2014;12(3):3595 114
Chromium in food and drinking water NOAEL for haematological effects from long-term toxicity studies in rats was 0.21 mg Cr(VI)/kg b.w. per day, whereas a NOAEL of 0.77 mg Cr(VI)/kg b.w. per day was identified in this species for liver toxicity, histiocytic cellular infiltration in mesenteric lymph nodes and in the duodenum. No NOAEL was established in the long-term toxicity mouse study for haematological effects, liver toxicity, hystiocytic cellular infiltration in mesenteric lymph nodes and hyperplasia in the duodenum observed at the lowest tested dose of 0.38 mg Cr(VI)/kg b.w. per day. The other toxic effects reported in repeated toxicity studies, including effects on fertility and development, appeared at higher doses. BMD analysis was performed on the suitable dose-response data for non-neoplastic effects. The BMDL 10 values of 0.27, 0.11 and 0.011 mg Cr(VI)/kg b.w. per day were calculated for non-neoplastic lesions in pancreas (acinus, cytoplasmic alteration), duodenum (diffuse epithelial hyperplasia) and liver (histiocytic infiltration), respectively. The CONTAM Panel noted that the biological significance and cause of histiocytic cellular infiltration are unknown and therefore it was not considered as a critical adverse effect. The BMDL 10 value of 0.11 mg Cr(VI)/kg b.w. per day for diffuse epithelial hyperplasia of the duodenum in female mice was selected as the RP for the estimation of the MOE for non-neoplastic lesions in the small intestine. In the case of haematological effects a BMDL 05 of 0.2 mg Cr(VI)/kg b.w. per day was calculated for decrease of haematocrit in male rats. The CONTAM Panel selected this value to be used as reference point for MOE estimation of hematotoxic effects of Cr(VI). 8. Risk characterisation Trivalent chromium The CONTAM Panel established a TDI of 300 µg /kg b.w. per day for Cr(III). Under the assumption that all chromium in food is Cr(III) (see Section 4.1) the mean dietary exposure across all age groups and surveys (minimum LB of 0.6 μg/kg b.w. per day and maximum UB of 5.9 μg/kg b.w. per day) as well as the 95 th percentile exposure (minimum LB of 1.1 μg/kg b.w. per day and maximum UB of 9.0 μg/kg b.w. per day) are well below the TDI. Therefore, the CONTAM Panel concluded that the current dietary exposure to Cr(III) does not raise concern from a public health point of view. Regarding the vegetarian population, although based on limited consumption data, the dietary exposure to Cr(III) seems to be similar to that estimated for the general population. Therefore, the dietary exposure of vegetarians is well below the TDI of 300 µg Cr(III)/ kg b.w. per day. A significant exposure to Cr(III) may occur via dietary supplemental intake. The combined exposure from supplemental intake in adults (i.e. from fortified foods, PARNUTS and food supplements) was estimated to be between 910 µg /day for a typical intake and 1540 µg /day for upper intake. Assuming a default value of 70 kg b.w. per adults, the exposure to Cr(III) from the upper supplemental intake would be 22 µg/kg b.w. per day. Considering this exposure and the maximum estimated contribution coming from the diet for adults (95 th percentile of 2.6 µg/kg b.w. per day), the total exposure remains well below the TDI of 300 µg Cr(III)/ kg b.w. per day. Hexavalent chromium Neoplastic effects As recommended for substances which are both genotoxic and carcinogenic (EFSA, 2005), the CONTAM Panel decided to adopt the MOE approach for the risk characterisation of neoplastic effects of Cr(VI), by using the BMDL 10 of 1.0 mg Cr(VI)/kg b.w. per day for the combined incidence of adenomas and carcinomas in the mouse small intestine as RP. The EFSA Scientific Committee concluded that, for substances that are both genotoxic and carcinogenic, an MOE of 10 000 or higher, based on a BMDL 10 from an animal study, is of low concern from a public health point of view (EFSA, 2005). In a conservative approach, the CONTAM Panel decided to consider all chromium in water intended for human consumption and natural mineral waters as Cr(VI) (see Section 4.1). The chronic exposure levels calculated across the different dietary surveys and age classes, ranged from 0.7 to 159.1 ng/kg b.w. per day (minimum LB - maximum UB) for mean consumption and from 2.8 to EFSA Journal 2014;12(3):3595 115
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EFSA Journal 2014;12(3):3595 SCIENT
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