Comparison of the Effects of Hexavalent Chromium in the Alimentary Canal of F344 Rats and B6C3F1 Mice Following Exposure in Drinking Water: Implications for Carcinogenic Modes of Action

Abstract

Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1–182 mg/l Cr(VI), administered as 0.3–520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well.

Oral Chromium Exposure and Toxicity

“…Although there was no neoplastic effect observed in this study due to the short duration of exposure, analysis of this study provided insights into potential mechanisms underlying Cr(VI)-induced tumor formation. First, the ratio of reduced-to-oxidized glutathione (GSH/GSSG), which is an indicator of oxidative stress, was decreased in both rats [57] and mice [46], suggesting Cr(VI) exposure caused oxidative stress in both species and also indicating that a substantial portion of Cr(VI) was not reduced in the GI tract.. While total Cr levels were comparable in the rat and mouse, the reduced GSH/GSSG ratio was only observed in rat oral mucosae and mouse duodenum, the sites that formed tumors in the NTP 2-yr study [46,57].…”

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

“…Therefore, adverse systemic effects of Cr(VI) are potentially due to (1) direct effects of Cr(VI) in the blood, or (2) secondary effects such as changes in blood redox or iron homeostasis. Exposure to Cr(VI) was shown previously to alter serum GSH/GSSG levels and ratios (Thompson, Proctor, et al, 2011; Thompson et al, 2012), as well as induce iron depletion (Suh et al, 2014). Because the Cr(VI) PBPK model (Kirman et al, 2017) can estimate the amount of Cr(VI) entering (i.e., fluxing) into the portal circulation from the gastrointestinal tract, this dose metric was used for effects of Cr(VI) manifested beyond the intestinal mucosa, whether by direct or indirect mechanisms.…”

“…Interestingly, we previously observed dose‐dependent decreases in the reduced/oxidized glutathione (GSH/GSSG) ratio (i.e., increased oxidation) in oral samples in F344 rats but not mice (Thompson et al, 2012). However, given the lack of gene expression changes in the oral mucosa (Thompson et al, 2016), the change in GSH/GSSG ratio may not have occurred in the oral mucosa tissue per se, but rather in the saliva or microbiota present in the oral cavity.…”

“…To inform the MOA and risk assessment of oral Cr(VI) exposure, a series of studies were conducted beginning with an overall proposed MOA (Thompson, Haws, Harris, Gatto, & Proctor, 2011), and subsequent 90‐day toxicity studies (Thompson, Proctor, et al, 2011; Thompson et al, 2012), transcriptomic analyses (Kopec et al, 2012; Kopec, Thompson, Kim, Forgacs, & Zacharewski, 2012; Rager et al, 2017), genotoxicity studies (O'Brien et al, 2013; Thompson, Seiter, et al, 2015; Thompson, Wolf, et al, 2015; Thompson, Young, et al, 2015; Thompson et al, 2017), as well as ex vivo gastric reduction studies and pharmacokinetic modeling (De Flora et al, 2016; Kirman et al, 2012; Kirman et al, 2013; Kirman et al, 2016; Proctor et al, 2012). Other genotoxicity studies were conducted in response to early drafts of the NTP 2‐year cancer bioassay (De Flora et al, 2006; De Flora et al, 2008).…”

Does the EU migration level of chromium VI in toys need to be lowered?

“…Animal studies showed relatively increased levels of chromium VI in the liver, kidney, and spleen, while RBC and plasma chromium levels were only modestly elevated after exposure to chromium VI (Costa, 1997;Thomann et al, 1994;Witmer et al, 1989;Collins et al, 2011;Witt et al, 2013). Thompson et al (2011Thompson et al ( , 2012 reported significant increases in total chromium concentrations in the oral cavity, glandular stomach, duodenum, jejunum, and ileum of rats and mice following 90 days of exposure to sodium dichromate dihydrate in drinking water. The half-life of chromium in various tissues of rats who are administered chromium VI was long and exceeded 20 days.…”