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

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 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.

Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

“…Based on simulations using the model, terminal BPA elimination in rats, but not humans, was found to be strongly influenced by the enterohepatic recirculation of BPA glucuronide. The oral route blood kinetics in rats and the oral route plasma and urinary elimination kinetics in humans described by the model of Teeguarden et al (2005) were consistent with data reported by Pottenger et al (2000) and Volkel et al (2002) for BPA-treated rats and human volunteers, respectively. However, their model was based on single exposures to BPA and did not account for repeated exposures to humans, as actually occurs.…”

“…A few PBTK models have been developed for describing the toxicokinetics of BPA in rats (Shin et al 2004), pregnant mice (Kawamoto et al 2007), adult humans (Teeguarden et al 2005), and children < 2 years of age (Edginton and Ritter 2009). First, Shin et al (2004) developed a PBTK model involving vein, artery, lung, liver, spleen, kidneys, heart, testes, muscle, brain, adipose tissue, and small intestines for predicting tissue distribution and kinetics of BPA in rats.…”

“…In a model of oral route exposure to BPA in rats and humans, Teeguarden et al (2005) imposed restrictions on the concentration of unbound (free) BPA resulting from plasma protein binding and predicted the degree of ER binding that may occur in the rat uterus at different BPA doses. Based on simulations using the model, terminal BPA elimination in rats, but not humans, was found to be strongly influenced by the enterohepatic recirculation of BPA glucuronide.…”

NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

“…At radioactivity levels of 6-31 mg-eq/L (27-135 nM), plasma protein binding was reported at 95.4%. Additional studies reviewed by Teeguarden et al (2005) reported plasma protein binding of bisphenol A at B90-95%. An additional study by Kurebayashi et al (2003) compared metabolic patterns and excretion following exposure to a higher bisphenol A dose; that study is discussed in Section 2.1.2.3.…”

Structural Validation and Homology Modeling of Differentially Expressed Proteins in Rattus Norvergicus Induced by Bisphenol a and Probiotic Treatement.

“…Differences in the estrogenic activity of bisphenol A and reference estrogens may be due to differences in recruiting by the liganded receptor of co-regulatory proteins. BPA is thought to bind to plasma proteins in rodents, monkeys and humans [3]. Because pharmacokinetics are altered by protein binding, the potential uptake of BPA into other tissues, including estrogen-target tissues, may be affected.…”