Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium

Kirman, C. R., Hays, S. M., Aylward, L. L., Suh, M., Harris, M. A., Thompson, C. M., Haws, L. C. and Proctor, D. M. (2012) Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium. Chemico-Biological Interactions, 200 1: 45-64. doi:10.1016/j.cbi.2012.08.016


Author Kirman, C. R.
Hays, S. M.
Aylward, L. L.
Suh, M.
Harris, M. A.
Thompson, C. M.
Haws, L. C.
Proctor, D. M.
Title Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium
Journal name Chemico-Biological Interactions   Check publisher's open access policy
ISSN 0009-2797
1872-7786
Publication date 2012-10-25
Year available 2012
Sub-type Article (original research)
DOI 10.1016/j.cbi.2012.08.016
Open Access Status DOI
Volume 200
Issue 1
Start page 45
End page 64
Total pages 20
Place of publication E Park, Shannon, Clare Ireland
Publisher Elsevier Ireland
Language eng
Formatted abstract
A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in rats and mice following long-term oral exposure. Model compartments were included for GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone, and a combined compartment for remaining tissues. 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 time-course 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. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats, consistent with small intestinal tumor formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma chromium ratios suggest that Cr(VI) entered portal circulation at drinking water concentrations equal to and greater than 60 mg/L in rodents. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. Overall, the PBPK model provides a good description of chromium toxicokinetics, with model predictions for tissue chromium within a factor of 3 for greater than 80% of measurements evaluated. The tissue data and PBPK model predictions indicate a concentration gradient in the small intestines (duodenum > jejunum > ileum), which will be useful for assessing the tumor response gradient observed in mouse small intestines in terms of target tissue dose. The rodent PBPK model presented here, when used in conjunction with a human PBPK model for Cr(VI), should provide a more robust characterization of species differences in toxicokinetic factors for assessing the potential risks associated with low-dose exposures of Cr(VI) in human populations.
Keyword Chromium
Gastrointestinal tract
Physiologically based model
Rodents
Toxicokinetics
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
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