efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water
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7.5. Dose-response assessment<br />
Chromium in <strong>food</strong> and <strong>drinking</strong> <strong>water</strong><br />
No human data could be identified to perform a dose-response assessment of <strong>chromium</strong> or any<br />
<strong>chromium</strong> species for oral exposure.<br />
Therefore, the CONTAM Panel considered the available data on neoplastic and non-neoplastic health<br />
effects in experimental animals for the evaluation of dose-response relationships separately for Cr(III)<br />
and Cr(VI) species.<br />
For Cr(III) no dose-response modelling was possible for the most reliable studies in experimental<br />
animals, since no effects were observed even at the highest dose tested, see Section 7.2.1. Although<br />
dose-response data were available on developmental and reproductive toxicity regarding the fertility<br />
of male and female mice, the CONTAM Panel noted their limitations (using only two dose groups)<br />
and since concerns were raised regarding the design, conduct and reporting of the data the CONTAM<br />
Panel concluded that these data could not be analysed by dose-response modelling.<br />
The data base for Cr(VI) allowed dose-response assessment of both, neoplastic and non-neoplastic<br />
effects in experimental animals.<br />
7.5.1. Assessment of neoplastic effects of Cr(VI)<br />
The CONTAM Panel identified the neoplastic effects of Cr(VI) as the critical effects and identfied the<br />
data available from the 2-year studies on the carcinogenicity of sodium dichromate dihydrate in male<br />
and female F344/N rats and in male and female B6C3F1 mice (see Section 7.2.2.5) as suitable for<br />
dose-response evaluation. To this end, the CONTAM Panel applied the BMD approach to analyse the<br />
data on the incidence of neoplastic effects according to the guidance given in EFSA (2009c). Using<br />
the default BMR of 10 % extra risk for the incidence, the BMD 10 and its 95 % lower confidence limit<br />
BMDL 10 were calculated. For details see Appendix J.<br />
The dose-response data on squamous cell neoplastic lesions in the epithelium of the oral cavity in<br />
male and female rats were suitable for a BMD analysis. For each sex, the incidences of papilloma and<br />
of carcinoma were reported by the NTP separately both for oral mucosa and tongue. For the two sites<br />
of oral mucosa and tongue combined the joint incidence of papilloma or carcinoma combined) was<br />
reported (see Table 19) and the CONTAM Panel decided to perform a dose-response evaluation of the<br />
neoplastic activity of sodium dichromate dihydrate in the oral cavity in rats, a) for the incidence of<br />
papilloma or carcinoma in the oral cavity (oral mucosa or tongue) and b) for carcinoma in the oral<br />
mucosa only since the incidence in tongue only was very low. The incidences of the two endpoints<br />
exhibited a statistically significant dose-response relationship (poly-3 test for trend: p < 0.001),<br />
separately for both sexes. Since the dose ranges, the range of the observed carcinoma incidences and<br />
the shape of the dose-response were comparable in both sexes the CONTAM Panel investigated the<br />
possibility of a dose-response evaluation of males and females combined using the PROAST software<br />
(RIVM) which allows testing for differences between two dose-response curves of males and female.<br />
Table 21(A) presents the BMD/L 10 values for male and female rats, separately as well as combined, a)<br />
for the incidence of papilloma or carcinoma in oral cavity (mucosa or tongue) and b) for carcinoma in<br />
the oral mucosa, using the BMDS software BMDS 2.4 of US-EPA and PROAST (RIVM). Since there<br />
were no statistically significant differences between males and female, the CONTAM Panel derived<br />
from these data a BMDL 10 of 3.4 mg/kg b.w. per day for the incidence of papilloma or carcinoma in<br />
the oral cavity and a BMDL 10 of 3.6 mg/kg b.w. per day for carcinoma in oral mucosa only.<br />
The dose-response data on epithelial neoplastic lesions of the small intestine in male and female mice<br />
were also suitable for a BMD analysis. For each sex, the incidences of adenoma and of carcinoma<br />
were reported by the NTP separately for two sites, namely duodenum and jejunum, whereas the<br />
incidence of adenoma or carcinoma (combined) was reported for all three sites (i.e. duodenum,<br />
jejunum and ileum) combined (see Table 21(B)). Since the adenoma-carcinoma sequence is a well<br />
recognised pathway of carcinogenesis in different sections of the GI tract (e.g. Höhn, 1979;<br />
EFSA Journal 2014;12(3):3595 111