efsa-opinion-chromium-food-drinking-water

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Chromium in food and drinking water 149.8 ng/kg b.w. per day (maximum UB, infants). The 95 th percentile exposure ranged from 0.0 (minimum LB) to 148.7 ng/kg b.w. per day (maximum UB, ‘Toddlers’). An additional contribution to the exposure to Cr(VI) was considered from the water used to prepare certain foods (coffee, tea infusions, and infant dry and follow-on food mainly, but also some others such as instant soup, evaporated and dried milk, and dehydrated fruit juice). A worst-case scenario, with no reduction of the Cr(VI) present in water into Cr(III) when the foods are ingested immediately after their preparation, was assumed. This scenario led to an increase up to two-fold in the exposure levels to Cr(VI), in comparison to those estimated via the consumption of drinking water only. The CONTAM Panel concluded that the exposure via the diet likely represents the most important contribution to the overall exposure to Cr in the general population. Inhalation of Cr compounds present in particular in cigarette smoke may contribute to the overall exposure levels but the currently available information does not allow quantification of its relative contribution. Cr(III) compounds present low oral toxicity because they are poorly absorbed. Cr(III) compounds have the potential to react with DNA in acellular systems, however restricted cellular access limits or prevents genotoxicity. The CONTAM Panel decided to use the data from the chronic toxicity studies of the National Toxicology Programme (NTP) on chromium picolinate monohydrate to derive a health-based guidance value (HBGV) for the risk characterization of Cr(III). In the two year NTP chronic oral toxicity study in rats and mice, no carcinogenic or other adverse effects have been observed. The lowest no-observed-adverse-effect level (NOAEL) value derived from these studies amounted to 286 mg/kg b.w. per day in rats, which was the highest dose tested. Effects of Cr(III) on reproduction and developmental toxicity have been reported in some studies with the lowest lowestobserved-adverse-effect levels (LOAELs) in the order of 30 mg/kg b.w. per day, but the Panel noted that these studies had methodological limitations. In addition, no effects have been reported on reproductive organ weights, sperm parameters and oestrous cyclicity in subchronic dietary studies in rats or mice at the highest doses tested (506 mg/kg b.w. per day and 1090 mg/kg b.w. per day, respectively) (NTP studies). Taking these observations together, the Panel derived a Tolerable Daily Intake (TDI) of 300 µg Cr(III)/kg b.w. per day from the relevant NOAEL in the long-term rat NTP study of 286 mg/kg b.w. per day, applying a default uncertainty factor of 100 to account for species differences and human variability and an additional uncertainty factor of 10 to account for the absence of adequate data on reproductive and developmental toxicity. Under the assumption that all chromium in food is Cr(III), the CONTAM Panel noted that the mean dietary exposure levels across all age groups (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 of 300 µg Cr(III)/ kg b.w. per day. 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. Thus, also the dietary exposure of vegeterians 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 supplement intake. Considering the exposure via dietary supplement intake (13 g/kg b.w. per day and 22 g/kg b.w. per day, for typical and upper intake from fortified foods, PARNUTS and food supplements, respectively, for an adult of 70 kg b.w.) 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 below the TDI of 300 µg Cr(III)/ kg b.w. per day. After oral exposure, Cr(VI) has been shown to be carcinogenic in rats and mice of both sexes and genotoxic in some in vivo studies. The data available so far support that the reduction of Cr(VI) to Cr(III) along the gastrointestinal tract is efficient but it cannot be excluded that even at low dose levels a small percentage of Cr(VI) escapes gastrointestinal reduction to Cr(III). Once taken up in the cells, Cr(VI) is reduced to Cr(III) with formation of Cr-DNA adducts and production of oxidative stress (due to formation of reactive intermediates). Both modes of action can contribute to the genotoxicity and carcinogenicity of Cr(VI). EFSA Journal 2014;12(3):3595 4
Chromium in food and drinking water As recommended for substances which are both genotoxic and carcinogenic, the CONTAM Panel adopted a margin of exposure (MOE) approach for the risk characterisation of neoplastic effects of Cr(VI). To this end, lower 95 % confidence limit for a benchmark response of 10 % extra risk (BMDL 10 ) values were derived from the 2-year carcinogenicity study of the NTP investigating oral intake of Cr(VI) (as sodium dichromate dihydrate) via drinking water in male and female rats and mice. In this study increased incidence of tumours of the squamous epithelium of the oral cavity and of epithelial tissues of the small intestine was reported in male and female rats and mice, respectively. In a conservative approach, the CONTAM Panel selected a lowest BMDL 10 of 1.0 mg Cr(VI)/kg b.w. per day for combined adenomas and carcinomas of the small intestine in male and female mice as reference point (RP) for estimation of MOEs for neoplastic effects. The EFSA Scientific Committee has 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. The MOEs calculated for all age groups on the basis of the mean chronic exposure to Cr(VI) via consumption of drinking water indicated a low concern (MOE values > 10 000) for all age groups with the exception of infants at UB exposure estimates (maximum UB - minimum LB, 6 300 - 71 000). When considering the 95 th percentile exposure, MOE values below 10 000 were found at UB exposure estimates, particularly for ‘Infants’ (maximum UB - minimum LB, 3 100 - 21 000), ‘Toddlers’ (maximum UB - minimum LB, 4 200 - 62 000), and ‘Other children’ (maximum UB - minimum LB, 6 600 - 360 000). Similarly to the risk characterization carried out for all types of drinking water, in the case of exposure to Cr(VI) through the consumption of bottled water MOEs values below 10 000 were mainly found at UB estimates when considering the 95 th percentile exposure in the youngest populations (‘Infants’, ‘Toddlers’ and ‘Other children’). The CONTAM Panel noted that the MOE values calculated for exposure to Cr(VI) via consumption of all types of drinking water, as well as only bottled water were highly influenced by the high proportion of left-censored data. In addition, when interpreting the numerical values of the MOEs, it should be considered that they were calculated by using as RP the BMDL 10 for the combined incidence of adenomas and carcinomas in the mouse small intestine. Because of lack of in vivo data on the capacity and rate of reduction of Cr(VI) in the rodent and human gastrointestinal tract, there is a significant uncertainty associated with the use of tumour data in mice to estimate risk at doses of Cr(VI) relevant for human exposure. Based on the MOE values for neoplastic effects, the CONTAM Panel concluded that the current levels of exposure to Cr(VI) via the consumption of all types of drinking water or of bottled water only are of low concern from a public health point of view for the average consumers but there might be a potential concern for high consumers particularly in ‘Infants’, ‘Toddlers’ and ‘Other children’. The inclusion of the water used in the preparation of specific foods (coffee, tea infusions, and infant dry and follow-on food) led to an increase up to two-fold of the exposure to Cr(VI). However, the CONTAM Panel was not able to consider this additional contribution to the exposure to Cr(VI) when deriving MOEs since no reliable data to quantify Cr(VI) in food exist. 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. 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 Panel noted that the biological significance and cause of histiocytic cellular infiltration are unknown and therefore it cannot be considered 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 male mice was selected as the RP for the estimation of the MOE for non-neoplastic lesions in the intestine. In the case of haematological effects a BMDL 05 of 0.2 mg Cr(VI)/kg b.w. per day was EFSA Journal 2014;12(3):3595 5
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