Area-Under-the-Curve (AUC) As a Dose Metric for Promotional Responses Following 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Exposure. A. H. Kim, M. C. Kohn, and N. J. Walker; University of North Carolina at Chapel Hill, Laboratory of Computational Biology and Risk Analysis, and NIEHS
An underlying basis of risk assessment is that an equivalent risk for a certain dose metric exists that allows for extrapolation between species. To better understand the use of AUC as a dose metric for promotional responses following TCDD exposure, a novel study was designed using a newly revised physiologically-based pharmacokinetic model in the female Sprague-Dawley rat to obtain similar liver AUCs of TCDD by different patterns of exposure. In the first TCDD-treated group, rats received an administered average daily dose of 100 ng/kg/day TCDD in corn oil for the study duration of 15 weeks. In the second TCDD group, rats received a high peak dose averaging 1000 ng/kg/day for the first week followed by a lower TCDD administered dose of 23 ng/kg/day for the remainder of the study. Age-matched control rats received corn oil as a vehicle control. Altered hepatic foci (AHF) positive for the placental form of glutatione-S-transferase (PGST) enzyme were measured from representative lobes of the liver stained immunohistochemically for PGST expression. Volume fraction, expressed as a percentage, is considered to be the most stable measure of AHF. The median volume fraction was 0.045% in control rats and was significantly elevated in both TCDD treatment groups. However, the volume fraction of PGST-positive foci was significantly higher in the TCDD group given the high peak dose during the first week of TCDD treatment compared with the group receiving the same average daily dose over the study duration: 0.74% vs. 0.17%, respectively. This study also confirmed previous analyses that tissue burden of TCDD is not an appropriate dose metric for the promotional responses induced by TCDD following exposure. These findings suggest that the peak magnitude of TCDD in liver may play a significant role in additional to AUC in the induction of promotional responses by TCDD.
Go to . . .
2001 SRA Annual Meeting Table of Contents
2001 SRA Annual Meeting Author Index
Main Abstracts Menu Page
RiskWorld Home Page