The drinking water community has been waiting patiently for results of toxicological studies that would help to clarify the mode of action (MOA) for chromium 6 (Cr-VI). The MOA is a key issue in assessing the risk presented by Cr-VI in drinking water.
The paper cited below appears to be the first of several to present results from this 90-day toxicology study. This paper discusses toxicokinetic, biochemical and pathological findings. Presumably future papers will discuss toxicogenomic findings. The authors state here:
“The 0.3 mg/L SDD [sodium dichromate dihydrate] group in this study (0.1 mg/L Cr(VI)) is equivalent to the current federal drinking water standard for total chromium, and at this exposure no appreciable increases in tissue chromium levels or adverse effects were observed. Notably, the chromium concentrations in the duodenum at day 91 in the three highest treatment groups are estimated to approach or exceed 1 mM – a tissue dose that is clearly toxic in in vitro assays. These findings suggest that the doses that caused cancer in mice in the NTP study are associated with cytotoxicity in target tissues. Further, the increases in plasma GSH and GSSG levels observed at the highest concentrations in this study might reflect systemic oxidative stress and/or toxicity. In this regard, it was previously suggested that the bodyweight decreases observed in the NTP (2008) 2-year bioassay (similar to those in the present study) indicate that the highest SDD concentration may have exceeded the maximum tolerated dose (Stern, 2010).
Toxicology buffs can click here for the full paper (open source). The full citation and abstract are below.
Thompson, C.M., D.M. Proctor, L.C. Haws, Hebert, S.D. Grimes, H.G. Shertzer, A.K. Kopec, J.G. Hixon, T.R. Zacharewski, and M.A. Harris. 2011. Investigation of the Mode of Action Underlying the Tumorigenic Response Induced in B6C3F1 Mice Exposed Orally to Hexavalent Chromium. Toxicol Sci. 2011 Jun 28.
Abstract (National Library of Medicine)
Chronic ingestion of high concentrations of hexavalent chromium [Cr(VI)] in drinking water induces intestinal tumors in mice. To investigate the mode of action (MOA) underlying these tumors, a 90-day drinking water study was conducted using similar exposure conditions as in a previous cancer bioassay, as well as lower (heretofore unexamined) drinking water concentrations.
Tissue samples were collected in mice exposed for 7 or 90 days, and subjected to histopathological, biochemical, toxicogenomic, and toxicokinetic analyses. Described herein are the results of toxicokinetic, biochemical and pathological findings. Following 90 days of exposure to 0.3-520 mg/L of sodium dichromate dihydrate (SDD), total chromium concentrations in the duodenum were significantly elevated at ≥ 14 mg/L. At these concentrations, significant decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed. Beginning at 60 mg/L, intestinal lesions were observed including villous cytoplasmic vacuolization. Atrophy, apoptosis, and crypt hyperplasia were evident at ≥ 170 mg/L. Protein carbonyls were elevated at concentrations ≥ 4 mg/L SDD, whereas oxidative DNA damage, as assessed by 8-hydroxydeoxyguanosine, was not increased in any treatment group. Significant decreases in the GSH/GSSG ratio and similar histopathological lesions as observed in the duodenum were also observed in the jejunum following 90 days of exposure. Cytokine levels (e.g. interleukin-1β) were generally depressed or unaltered at the termination of the study.
Overall, the data suggest that Cr(VI) in drinking water can induce oxidative stress, villous cytotoxicity, and crypt hyperplasia in the mouse intestine, and may underlie the MOA of intestinal carcinogenesis in mice.