efsa-opinion-chromium-food-drinking-water

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Chromium in food and drinking water McConnell et al, 1986; Vogelstein et al., 1988; Spigelmann et al., 1994; and Dr. M. Iezzi 17 and Dr. M. Piantelli 17 , 2013, personal communication), the CONTAM Panel performed a dose-response evaluation for the neoplastic activity of sodium dichromate dihydrate in the small intestine in mice by considering both, a) the incidence of adenoma or carcinoma) and b) the incidence of carcinoma only at the three sites of duodenum, jejunum and ileum (combined). The incidence of adenoma or carcinoma and the incidence of carcinoma only exhibited a statistically significant dose-response relationship in both sexes (poly-3 test for trend for adenoma or carcinoma (p < 0.001) and for carcinoma in females (p < 0.001) and for carcinoma in males (p < 0.05) 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 performed also for the data of the small intestine a dose-response evaluation of males and females combined in the same way as described above for the oral cavity. Table 20(B) presents the BMD/L 10 values for male and female mice a) for the incidence of adenoma or carcinoma and b) for carcinoma only at all three sites of the small intestine investigated BMDS software BMDS 2.4 of US-EPA and PROAST (RIVM). Since there were no statistically significant differences between males and females, the CONTAM Panel derived for the incidence of adenoma or carcinoma combined a BMDL 10 of 1.0 mg/kg b.w. per day and for the incidence of carcinoma only at all sites a BMDL 10 of 3.8 mg/kg b.w. per day. Table 21: BMD analysis of the data on neoplastic effects observed in the 2-year-studies of the NTP (2007, 2008) on sodium dichromate dihydrate in male and female F344/N rats (A) and in male and female B6C3F1 mice (B). BMD 10 (mg/kg b.w. per day) (A) Dose-response analysis of the neoplastic changes in rat oral cavity Papilloma or carcinoma of the oral mucosa or tongue Male rat 1) 5.87 Female rat 1) 4.11 Male and female rats 2) 4.85 Carcinoma of the oral mucosa Male rat 1) 7.45 Female rat 1) 3.95 Male and female rats 2) 5.09 (B) Dose-response analysis of the neoplastic changes in mouse small intestine Adenoma or carcinoma in duodenum, jejunum and/or ileum Male mouse 1) 1.48 Female mouse 1) 1.15 Male and female mice 2) 1.53 Carcinoma in duodenum, jejunum and/or ileum Male mouse 1) 7.54 Female mouse 1) 6.63 Male and Female mice 2) 6.38 BMDL 10 (mg/kg b.w. per day) 1): using BMDS software for the analysis of single data sets 2): using PROAST software for the analysis of combined data. No statistical differences were observed in dose response relationship between the two sexes. 7.5.2. Assessment of non-neoplastic effects of Cr(VI) In order to assess the risk of non-neoplastic effect the CONTAM Panel considered dose-response data available from the 2-year NTP study on non-neoplastic lesions in liver, duodenum, mesenteric lymph nodes and pancreas and on haematological effects (NTP, 2008) (see Section 7.2.2.2 and Table 16). For the non-neoplastic lesions, considering the available data, the CONTAM Panel identified the occurrence of chronic inflammation of the liver in female rats, diffuse epithelial hyperplasia in the duodenum in male and female mice, histiocytic cellular infiltration in mesenteric lymph nodes in male 3.30 2.61 3.36 4.07 2.58 3.57 1.08 0.61 1.00 2.53 3.12 3.81 17 Immuno-Oncology Laboratory, Aging Research Center (CeSI), G.d'Annunzio University Foundation of Chieti-Pescara (Italy), EFSA Journal 2014;12(3):3595 112
Chromium in food and drinking water and female mice, histiocytic cellular infiltration in the liver in female mice and acinus, cytoplasmic alteration in pancreas in female mice as the most relevant endpoints for the risk assessment of Cr(VI) see also ADTSR (2012). A dose response analysis was therefore performed using the default BMR of 10 % extra risk for the incidence of the aforementioned non-neoplastic lesions, and the BMD 10 and its 95 % lower confidence limit BMDL 10 were calculated (see Appendix J.2 for details). The CONTAM Panel noted that several dose-response data were not suitable for a BMD analysis since the BMD/BMDL ratios and the range of the BMDL values of the acceptable models were larger than one order of magnitude such that a BMDL 10 value would either extrapolate orders of magnitude below the observed dose range or it would depend highly on the model chosen. Therefore no BMDL 10 values for some of these endpoints could be identified from these data according to guidance given by EFSA (2009). The BMDL 10 values for endpoints which could be evaluated varied from 0.27 mg Cr(VI)/kg b.w. per day for acinus, cytoplasmic alterations in pancreas to 0.011 mg Cr(VI)/kg b.w. per day for histiocytic cellular infiltration in liver in female mice. For male mice the BMD approach was only applicable to the data of diffuse epithelial hyperplasia in duodenum and resulted in a BMDL 10 of 0.11 mg Cr(VI)/kg b.w. per day (see Table 22). Table 22: BMD analysis of the data on non-neoplastic effects in the 2-year-studies of the NTP (2007, 2008) on sodium dichromate dihydrate in male and female F344/N rats and in male and female B6C3F1 mice. Presence or absence of lesions (i.e. a quantal effect) had been reported in the publications. For details see Appendix J2. Effect/ species/sex liver chronic inflammation female rats BMD 10 (mg/kg b.w. per day) No BMDL could be determined (a) BMDL 10 (mg/kg b.w. per day) histiocytic cellular infiltration in liver female mice 0.067 0.011 diffuse epithelial hyperplasia in duodenum male mice 0.14 0.11 female mice No BMDL could be determined (a) histiocytic cellular infiltration in mesenteric lymph node male mice female mice No BMDL could be determined (a) No BMDL could be determined (a) acinus, cytoplasmic alteration in pancreas female mice 0.61 0.26 (a): No BMDL could be determined since the BMD/BMDL ratios and the range of the BMDL values of the acceptable models were larger than one order of magnitude such that a BMDL 10 value would either extrapolate orders of magnitude below the observed dose range or it would depend highly on the model chosen. Regarding haematological effects the CONTAM Panel noted that several parameters measured in the 2-year NTP study on male rats at day 4, 22, and months 3, 6 and 12 exhibited a statistically significant change compared to controls and identified the effects on haematocrit, haemoglobin, MCV and MVH at day 22 after start of treatment with sodium dichromate dihydrate as critical effects, describing the haematotoxcity of Cr(VI), see also ADTSR (2012). The CONTAM Panel noted that the four data sets of means and standard errors available for the controls and each of the four dose groups can be modelled as continuous data. Using the default BMR of 5 %, in the absence of statistical or toxicological considerations supporting a deviation, the PROAST software was applied and the best fitting models of the nested Exponential and the Hill family was identified, respectively. The BMD/L values for the four haematological endpoints are listed in Table 23. The lowest BMDL 05 of 0.2 mg Cr(VI)/kg b.w. per day was calculated for decreased haematocrit in male rats. EFSA Journal 2014;12(3):3595 113
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