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UTILIZATION OF A PBPK MODEL TO PREDICT THE DISTRIBUTION OF 2, 3, 7-8 TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN HUMANS DURING CRITICAL WINDOWS OF DEVELOPMENT
Citation:
Emond, C., M J. DeVito, AND L S. Birnbaum. UTILIZATION OF A PBPK MODEL TO PREDICT THE DISTRIBUTION OF 2, 3, 7-8 TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN HUMANS DURING CRITICAL WINDOWS OF DEVELOPMENT. Presented at Society of Toxicology 42nd Annual Meeting, Salt Lake City, Utah, March 9-13,2003.
Description:
Utilization of A PBPK model to predict the distribution of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) in humans during critical windows of development.
C Emond1, MJ DeVito2 and LS Birnbaum2
1National Research Council, US EPA, ORD, NHEERL, (ETD, PK), RTP, NC, 27711, USA 2 US EPA, ORD, NHEERL, ETD, PKB, RTP, NC, 27711, USA
TCDD is a ubiquitous environmental contaminant that induces a wide spectrum of toxic responses, including developmental toxicity. Some of these developmental effects have different critical windows of sensitivity. The utilization of a PBPK model to predict maternal to fetal transfer of TCDD can be important for improving human health risk assessments for the developmental effects of TCDD. While, PBPK models for TCDD have been published for different species including, rat, mice, fish and humans, no PBPK models have described the distribution of TCDD during pregnancy. The aim of this work was the development of a PBPK model to predict the distribution and accumulation of TCDD between maternal and fetal compartments in humans. Previously validated in the rat, this model consisted of 4 maternal compartments (liver, fat, placenta and, rest of the body) and 1 fetal compartment corresponding to the whole fetus. The model described Ah receptor binding, CYP1A2 induction and binding, and physiological alterations occurring during gestation. The model assumed the distribution of TCDD was diffusion limited for fat and liver. This model focused on oral exposure because dietary exposures represented over 95% of the daily intake of TCDD. Different exposure scenarios were examined including chronic exposure and chronic exposure with intermittent periods of high exposures (i.e. meals containing higher than average concentration of TCDD). This model assumed a background exposure prior to the gestation period. Initial testing of this model provided reasonable fits to human exposure data. This model may be a useful tool for use in risk assessments as well as for understanding basic pharmacokinetic and pharmacodynamic processes during development. Acknowledgments: This project was funded by in part by a cooperative agreement (CR 828790) with NRC, NAS and performed at US EPA RTP, NC, USA. (This abstract does not represent US EPA policy).