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ToxSci Advance Access published online on March 2, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi135
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Toxicological Sciences © The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 28, 2004
Accepted February 22, 2005

Biotransformation and Toxicokinetics

Evaluation of Oral and IntravenousRoute Pharmacokinetics, Plasma Protein Binding and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach

Justin G. Teeguarden 1*, John M. Waechter Jr.2, Harvey J. Clewell III3, Tammie R. Covington 3, and Hugh A. Barton 4

1 Biological Monitoring and Modeling, Pacific Northwest National Laboratory, 902 Battelle Boulevard, P7-56, Richland, WA 99352
2 Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Building 1803, Midland, MI 48674
3 ENVIRON International, 602 E Georgia Ave., Ruston, LA 71270
4 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, RTP NC, 27711

* To whom correspondence should be addressed.
Justin G. Teeguarden, E-mail: justin.teeguarden{at}pnl.gov


  Abstract

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 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.

Keywords: Bisphenol A; PBPK model; Endocrine; Human; Plasma Protein Binding; Biotransformation and Toxicokinetics - physiologically-based pharmacokinetics; Biomonitoring; Risk Assessment - biological modeling; Endocrine Toxicology - endocrine disruptors; Estrogen Receptor.
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