ToxSci Advance Access originally published online on March 2, 2005
Toxicological Sciences 2005 85(2):823-838; doi:10.1093/toxsci/kfi135
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Evaluation of Oral and Intravenous Route Pharmacokinetics, Plasma Protein Binding, and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach
* Biological Monitoring and Modeling, Pacific Northwest National Laboratory, 902 Battelle Boulevard, P7-56, Richland, Washington 99352; Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Building 1803, Midland, Michigan 48674; ENVIRON International, 602 E Georgia Ave., Ruston, Louisiana 71270; U.S. EPA, Office of Research and Development, National Health Effects Research Laboratory, Experimental Toxicology Division, Pharmacokinetics Branch, U.S.E.P.A Mail Room, B143–01, Research Triangle Park, North Carolina 27711
Received October 28, 2004; accepted February 22, 2005
Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g., plasma protein binding, enterohepatic recirculation of the glucuronide [BPAG]) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated estrogen receptor (ER) binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous- and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats, but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor-mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.
Key Words: bisphenol A; PBPK model; endocrine; glucuronide; human; metabolism; pharmacokinetics; physiologically based pharmacokinetics; plasma protein binding; risk assessment.
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