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MECHANISTIC DESCRIPTION OF DOSE-DEPENDENT URINARY ELIMINATION OF PBDE-47 IN ADULT MICE USING A PHYSIOLOGICAL BASED PHARMACOKINETIC MODEL
Citation:
EMOND, C., D. STASKAL, AND L. S. BIRNBAUM. MECHANISTIC DESCRIPTION OF DOSE-DEPENDENT URINARY ELIMINATION OF PBDE-47 IN ADULT MICE USING A PHYSIOLOGICAL BASED PHARMACOKINETIC MODEL. Presented at Dioxin 2007, Tokyo, JAPAN, September 02 - 07, 2007.
Description:
Abstract Polybrominated diphenyl ethers (PBDEs) are used as additive flame-retardants. In North America, scientists have noted continuing increases in human body burdens. Our laboratory has previously described urinary elimination of parent compound in adult mice for at least 4 of the major BDE congeners measured in biota (i.e. BDEs 47, 99, 100, and 153). We have also demonstrated that urinary elimination saturates at high doses for BDE-47; however, this dose-dependent urinary elimination has not been observed in rats or immature mice. The objective of this study was to investigate the mechanism of BDE-47 urinary elimination in mice using a physiologically based pharmacokinetic model (PBPK). Specifically, we investigated two hypotheses: The first hypothesis investigated the extent to which mMUP drives the elimination of BDE-47and the second evaluated a disruption of glomerular filtration at high dose of PBDEs. To evaluate these hypotheses, we developed a PBPK model contained 6 compartments built and validated using data from rats and extrapolated to the mouse. At low doses, the model showed increased elimination as compared to higher doses, consistent with the experimental data. This work helps to explain the physiological observations of urinary transport in mice and should be considered when assessing human health risk.