efsa-opinion-chromium-food-drinking-water
efsa-opinion-chromium-food-drinking-water efsa-opinion-chromium-food-drinking-water
Chromium in food and drinking water drinking water for 21 days (Anderson et al., 2002). Levels of chromium in the tissues increased linearly with dose below 80 ppm. Increased levels of chromium with dose were also observed in the liver and kidney of male and female mice (NTP, 2008). The WHO (2003) concluded that in animal studies after oral administration of different Cr(VI) compounds, chromium was found to accumulate mainly in liver, kidneys, spleen, and bone marrow, the distribution depending on the speciation. Autopsy data on humans both occupationally and nonoccupationally exposed showed the highest concentrations in lungs, followed by spleen, liver, and kidneys (Janus and Kranjc, 1990). The half-life of chromium in various tissues (other than plasma) of rats administered Cr(VI) exceeds 20 days (Weber, 1983). Rankov et al. (2010) reported a two generation study in white Wistar male rats exposed to drinking water containing 25, 50 or 75 mg Cr(VI)/L and one control group which received tap water. Results obtained revealed significant accumulation of chromium in genital organs and sexual accessory glands at all doses in comparison to controls, as well as increased chromium levels in genital organs (testis, epididymis) and sexual accessory glands (seminal vesicles, prostate, bulbo-urethral glands), in the F1 generation compared to the F0 generation. Stern (2010) compared the concentrations of total Cr retained in various tissues after 25 weeks of dosing, with either Cr(III) picolinate or sodium dichromate (NTP, 2008; 2010), and concluded that the concentrations of total Cr were 1.4-16.7 times larger for the rats ingesting Cr(VI), and 2.1-38.6 times larger for mice ingesting Cr(VI) despite a 1.8 and 2.8 times larger dose of Cr(III) in rats and mice, respectively. Metabolism Ingested Cr(VI) is efficiently reduced to trivalent chromium by the gastric juices (De Flora et al., 1987, 1997; Kerger et al., 1997; De Flora, 2000). De Flora (2000) estimated that saliva may reduce 0.7 to 2.1 mg of Cr(VI) per day and gastric juices have the capacity to reduce at least 80 to 84 mg of Cr(VI) per day. Saturation or exhaustion of the reducing capacity of saliva and gastric fluids upon high oral doses of Cr(VI) has been suggested to result in increased absorption, elevated blood levels and the appearance of toxicity that may not occur at lower doses. Gammelgaard et al. (1999) using an artificial gastric juice reported a half-life of Cr(VI) of 23 minutes. Proctor et al. (2012) performed ex vivo studies using stomach contents of rats and mice to quantify hexavalent chromium reduction rate and capacity for loading rates amounting to 1-400 mg Cr(VI)/L stomach contents, which are in the range of recent bioassays. Hexavalent chromium reduction followed mixed second-order kinetics, dependent on the concentrations of both Cr(VI) and the native reducing agents. Approximately 16 mg Cr(VI)-equivalents of reducing capacity per litre of fed stomach contents (containing gastric secretions, saliva, water and food) was found for both species. The second-order rate constants were 0.2 and 0.3 L mg /hour for mice and rats, respectively. The authors concluded that these findings support that, at the doses that caused cancer in the mouse small intestine (> 20 mg Cr(VI)/L in drinking water), the reducing capacity of stomach contents was likely exceeded. In the RBC, Cr(VI) is reduced to Cr(III) by glutathione (Petrilli and De Flora, 1978; Debetto and Luciani, 1988). By fitting the data on radiolabelled Cr(VI) levels in several tissues, such as lung, blood, liver, kidney, gastro intestinal (GI) tract, for the development of a physiologically-based kinetic (PBK) study of Cr kinetics in the rat, O’Flaherty (1996) assumed that hexavalent chromium is reduced to Cr(III) in all tissues. De Flora and collaborators (Petrilli and De Flora, 1982; De Flora et al., 1987, 1997; De Flora and Wetterhahn, 1989) performed a series of studies to evaluate the ability of various human physiological fluids and tissues to reduce or sequester Cr(VI). Based on these studies the overall Cr(VI) reducing or sequestering capacity of different human body compartment was evaluated. De Flora (2000) proposed that these reducing capacities account for the limited toxicity of Cr(VI) after oral ingestion due to EFSA Journal 2014;12(3):3595 68
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
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Chromium in <strong>food</strong> and <strong>drinking</strong> <strong>water</strong><br />
<strong>drinking</strong> <strong>water</strong> for 21 days (Anderson et al., 2002). Levels of <strong>chromium</strong> in the tissues increased<br />
linearly with dose below 80 ppm. Increased levels of <strong>chromium</strong> with dose were also observed in the<br />
liver and kidney of male and female mice (NTP, 2008).<br />
The WHO (2003) concluded that in animal studies after oral administration of different Cr(VI)<br />
compounds, <strong>chromium</strong> was found to accumulate mainly in liver, kidneys, spleen, and bone marrow,<br />
the distribution depending on the speciation. Autopsy data on humans both occupationally and nonoccupationally<br />
exposed showed the highest concentrations in lungs, followed by spleen, liver, and<br />
kidneys (Janus and Kranjc, 1990).<br />
The half-life of <strong>chromium</strong> in various tissues (other than plasma) of rats administered Cr(VI) exceeds<br />
20 days (Weber, 1983).<br />
Rankov et al. (2010) reported a two generation study in white Wistar male rats exposed to <strong>drinking</strong><br />
<strong>water</strong> containing 25, 50 or 75 mg Cr(VI)/L and one control group which received tap <strong>water</strong>. Results<br />
obtained revealed significant accumulation of <strong>chromium</strong> in genital organs and sexual accessory glands<br />
at all doses in comparison to controls, as well as increased <strong>chromium</strong> levels in genital organs (testis,<br />
epididymis) and sexual accessory glands (seminal vesicles, prostate, bulbo-urethral glands), in the F1<br />
generation compared to the F0 generation.<br />
Stern (2010) compared the concentrations of total Cr retained in various tissues after 25 weeks of<br />
dosing, with either Cr(III) picolinate or sodium dichromate (NTP, 2008; 2010), and concluded that the<br />
concentrations of total Cr were 1.4-16.7 times larger for the rats ingesting Cr(VI), and 2.1-38.6 times<br />
larger for mice ingesting Cr(VI) despite a 1.8 and 2.8 times larger dose of Cr(III) in rats and mice,<br />
respectively.<br />
Metabolism<br />
Ingested Cr(VI) is efficiently reduced to trivalent <strong>chromium</strong> by the gastric juices (De Flora et al.,<br />
1987, 1997; Kerger et al., 1997; De Flora, 2000). De Flora (2000) estimated that saliva may reduce<br />
0.7 to 2.1 mg of Cr(VI) per day and gastric juices have the capacity to reduce at least 80 to 84 mg of<br />
Cr(VI) per day. Saturation or exhaustion of the reducing capacity of saliva and gastric fluids upon<br />
high oral doses of Cr(VI) has been suggested to result in increased absorption, elevated blood levels<br />
and the appearance of toxicity that may not occur at lower doses. Gammelgaard et al. (1999) using an<br />
artificial gastric juice reported a half-life of Cr(VI) of 23 minutes.<br />
Proctor et al. (2012) performed ex vivo studies using stomach contents of rats and mice to quantify<br />
hexavalent <strong>chromium</strong> reduction rate and capacity for loading rates amounting to 1-400 mg Cr(VI)/L<br />
stomach contents, which are in the range of recent bioassays. Hexavalent <strong>chromium</strong> reduction<br />
followed mixed second-order kinetics, dependent on the concentrations of both Cr(VI) and the native<br />
reducing agents. Approximately 16 mg Cr(VI)-equivalents of reducing capacity per litre of fed<br />
stomach contents (containing gastric secretions, saliva, <strong>water</strong> and <strong>food</strong>) was found for both species.<br />
The second-order rate constants were 0.2 and 0.3 L mg /hour for mice and rats, respectively. The<br />
authors concluded that these findings support that, at the doses that caused cancer in the mouse small<br />
intestine (> 20 mg Cr(VI)/L in <strong>drinking</strong> <strong>water</strong>), the reducing capacity of stomach contents was likely<br />
exceeded.<br />
In the RBC, Cr(VI) is reduced to Cr(III) by glutathione (Petrilli and De Flora, 1978; Debetto and<br />
Luciani, 1988). By fitting the data on radiolabelled Cr(VI) levels in several tissues, such as lung,<br />
blood, liver, kidney, gastro intestinal (GI) tract, for the development of a physiologically-based kinetic<br />
(PBK) study of Cr kinetics in the rat, O’Flaherty (1996) assumed that hexavalent <strong>chromium</strong> is reduced<br />
to Cr(III) in all tissues.<br />
De Flora and collaborators (Petrilli and De Flora, 1982; De Flora et al., 1987, 1997; De Flora and<br />
Wetterhahn, 1989) performed a series of studies to evaluate the ability of various human physiological<br />
fluids and tissues to reduce or sequester Cr(VI). Based on these studies the overall Cr(VI) reducing or<br />
sequestering capacity of different human body compartment was evaluated. De Flora (2000) proposed<br />
that these reducing capacities account for the limited toxicity of Cr(VI) after oral ingestion due to<br />
EFSA Journal 2014;12(3):3595 68