efsa-opinion-chromium-food-drinking-water

Chromium in food and drinking water
efficient detoxification by saliva, gastric juice and intestinal bacteria. De Flora (2000) also suggested
that the efficient uptake and reduction of Cr(VI) in red blood cells explains the lack of carcinogenicity
at sites remote from the portal of entry.
However, Zhitkovich (2005) noted that the analytical methods used to quantify the residual Cr(VI)
could have led to an overestimation of the reducing capacity of the biological systems studied by De
Flora and co-workers.
Reducing factors that contribute to the reduction of Cr(VI) to Cr(III) have been described in some
detail. Especially acidic environments with high organic content promote the reduction of Cr(VI) to
Cr(III). Vitamin C-rich products are particularly beneficial for the enhancement of gastric reduction of
Cr(VI) (Zhitkovich, 2011). Studies in tissue homogenates and biological fluids reveal that ascorbate is
the principal biological reducer of Cr(VI), accounting for 80-95 % of its metabolism (Suzuki and
Fukuda, 1990; Standeven and Wetterhahn, 1991, 1992; Zhitkovich, 2011). In vivo a combined activity
of ascorbate and low molecular weight thiols including especially glutathione (GSH) has been
reported to be responsible for > 95 % of Cr(VI) reduction (Zhitkovich, 2011).
Excretion
Upon administration of Cr(VI) by various routes, RBC chromium levels or the ratio of RBC to plasma
chromium either did not decline as rapidly or remained elevated for quite some time (Langård et al.,
1978; Sayato et al., 1980; Weber, 1983; Suzuki et al., 1984; Coogan et al., 1991a; Gao et al., 1993),
although the decrease in RBC chromium levels is apparently more rapid when Cr(VI) is administered
by oral route (Coogan et al., 1991a), likely reflecting the conversion to Cr(II) before the GI absorption.
The estimated half-time for whole-body chromium elimination is 22 days following administration of
Cr(VI) (WHO, 2000).
7.1.3. Physiologically-based kinetic (PBK) models
Physiologically based kinetic (PBK) models for chromium which incorporate absorption and
disposition schemes for Cr(VI) and Cr(III) throughout the body have been presented for rats
(O’Flaherty, 1996) and humans (O’Flaherty et al., 2001). The models account for most of the major
features of chromium kinetics, including differential absorption of Cr(VI) and Cr(III), rapid reduction
of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and
concentration-dependent urinary clearance. The human model was calibrated against blood and urine
chromium levels detected for a group of controlled studies in which adult human volunteers were
administered up to 10 mg/day of soluble inorganic salts of either Cr(III) or Cr(VI) (Kerger et al., 1996;
Paustenback et al., 1996; Finley et al., 1997). The model outcomes suggest that both Cr(III) and
Cr(VI) are poorly absorbed from the gastrointestinal tract. Chromium kinetics were predicted by the
model not to be dependent on the oxidation state of the administered chromium except in respect to
the amount absorbed. The fraction absorbed was suggested to be strongly dependent on the degree of
reduction of Cr(VI) to Cr(III) in the gastrointestinal tract, and thus on the amount and nature of the
stomach content at the time of ingestion of the Cr(VI). These human studies are described in more
detail in Section 7.4 (Mode of action).
Kirman et al. described a PBK model for rats and mice orally exposed to chromium (Kirman et al.,
2012). Data from ex vivo Cr(VI) reduction studies were used to characterize reduction of Cr(VI) in fed
rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue timecourse
data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water
for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. Clear species differences were
identified for chromium delivery to the target tissue (small intestines), with higher concentrations
achieved in mice than in rats, indicated by the authors to be consistent with small intestinal tumor
formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma
chromium ratios suggested that hexavalent chromium entered portal circulation at drinking water
concentrations equal to and greater than 60 mg/L in rodents. Species differences were described for
EFSA Journal 2014;12(3):3595 69