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Abstract: Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses. [Copyright &y& Elsevier]

The risk assessment of bisphenol A (BPA) on the development of offspring of humans is an important issue. There have been some reports on the fate of BPA in rodents, but information on the BPA level in fetal organs essential for the extrapolation to humans is inadequate. In the present study, we investigated the distribution pattern of 14C-BPA-derived radioactivity in fetal tissues following administration of 10 mg/kg 14C-BPA to the pregnant mice. The radioactivity was rapidly transferred through placenta and distributed to all fetal organs including reproductive organs and brains in a similar level. The concentration declined slowly compared with dams. Analysis of metabolites in fetuses showed that a fraction of BPA was unexpectedly large compared to the maternal blood. There was no clear effect of the fetal position in a uterus to influence the radioactivity concentration in whole fetuses. The dose dependence of pharmacokinetics should be recognized to extrapolate the pharmacokinetic result from animal experiments at high doses to humans at low doses. Similar experiments were conducted with an addition of two doses, 1 and 100 mg/kg, respectively. The pharmacokinetics seemed to be linear between 1 and 10 mg/kg, although at 100 mg/kg BPA was absorbed slowly and the radioactivity concentrations in fetuses were much higher than expected based on the linear dose dependence. Repeated doses were administered to pregnant mice since humans are exposed to BPA chronically. Radioactivity level in most of the fetal tissues on repeated administration was higher than single administration. [ABSTRACT FROM AUTHOR]