The Völkel et al. (2002
human dosing studies failed to detect free BPA () and so were interpreted by the EFSA (2008)
as supportive of rapid metabolic clearance and negligible exposure in adults as well as the fetus. However, numerous other studies have detected free BPA in both humans and rats, either associated with general background exposure or in experiments where rodents were dosed with BPA (). Free BPA was detected by a variety of methods and was found not only in adult blood but also in placental and fetal samples. Dekant and Volkel (2008)
argued that the detection of free BPA in such studies may result from background contamination from labware and indoor dust. Further, some free BPA may be formed by cleavage from the glucuronide present in the sample when readying the sample for analysis (Dekant and Volkel 2008
). However, many of the cited studies were aware of these potential artifacts and took steps to prevent false-positive detection of free BPA. Further, our review of the free BPA data derived from these studies suggests that this result is not artifactual. Quite the contrary, these data suggest patterns of occurrence that have important implications for BPA risk assessment.
includes studies in which free BPA was detected in rats dosed during pregnancy, demonstrating maternal serum BPA greater than fetal BPA in two studies (Domoradski et al. 2003
; Takahashi and Oishi 2000
). In a study in which placental BPA was also measured, the placenta had a higher BPA concentration than did the maternal or fetal compartments. This is consistent with human free BPA data collected in a biomonitoring study of pregnant women exposed to background sources of BPA (Schönfelder et al. 2002
). Once again, placenta had the highest concentration, followed by maternal and fetal compartments (). These trends have a plausible biological basis in that placenta has extensive β-glucuronidase activity (see above) and so may be an important site of metabolite deconjugation and resultant fetal exposure. Although peak fetal concentrations of free BPA were less than maternal concentrations in both rats and humans, a more detailed time course in rats indicated that cumulative free BPA exposure was actually greatest in the fetus [fetal area under the curve was 73% greater than maternal (Takahashi and Oishi 2000
)]. This may reflect ongoing deconjugation in placenta and fetus that prevents free BPA from declining as rapidly as in the maternal system. Also of note in this study was the finding of much higher concentrations of free BPA in liver and kidney compared with blood, again suggesting the importance of local tissue deconjugation and/or binding in determining free BPA dose. In this study, Takahashi and Oishi (2000)
used a very large dose (1 g/kg), so their results, although consistent with the others cited, should be repeated at more relevant doses.
Free BPA and ratio of conjugate to free BPA in rats from background exposure or after BPA dosing.
Free BPA in humans from background exposure or after BPA dosing.
Additional evidence of BPA deconjugation during gestation comes from rat data showing that the ratio of glucuronide to free BPA varies across maternal, placental, and fetal compartments (). Although Domoradzki et al. (2003)
reported no selective tissue affinity for BPA or its metabolite, their data show a continuous decrease in glucuronide to free BPA ratio across these compartments, suggesting a greater role for deconjugation in the placenta and fetus than in maternal blood.
The biological plausibility of the free BPA data is also supported by the difference between sexes in both rats and humans ( and ). Male rats exhibited greater free BPA than did females, consistent with decreased expression of the main BPA-glucuronidating enzyme [UDP-glucuronosyltransferase 2B1 (UGT2B1)] in male rat liver (Takeuchi et al. 2004
). The fact that this was also seen in humans () suggests that BPA metabolic fate is under hormonal control in both species. The sex differential appears to exist very early in human development, because free BPA was greater in male than female fetuses of women receiving BPA exposure from background sources (Schönfelder et al. 2002
The risk implications of free BPA detections need to be explored based upon dose–response assessment and suitable physiologically based pharmacokinetic (PBPK) modeling that can relate internal dose of free BPA to adverse effect. The existing PBPK models (Edginton and Ritter 2009
; Teeguarden et al. 2005
) have not considered the influence of local deconjugation reactions. In the only attempt to simulate free BPA concentrations, Teeguarden et al. (2005)
were not able to reproduce the free BPA results for rat plasma at the later time points (4 and 8 hr after dosing) even though their model included enterohepatic recirculation and plasma protein binding. There is a clear need to improve modeling efforts with respect to free BPA in maternal, fetal, and neonatal tissues across species, with metabolite deconjugation a potentially important element. Better calibration of the models against the database of free BPA detection () should be part of this effort. This may be facilitated by in vitro
studies that evaluate the conjugation–deconjugation activity of placenta and other human and rodent tissues. Such in vitro
data along with additional human volunteer studies evaluating BPA concentration after controlled exposures (e.g., Carwile et al. 2009
) will inform the degree of variability in human BPA pharmacokinetics. This is particularly uncertain given the small numbers of adult subjects that were involved in the detailed pharmacokinetic studies thus far reported (Völkel et al. 2002
; ). A PBPK model parameterized with empirical conjugation and deconjugation rate constants and calibrated for free BPA is needed to relate the dose response for toxic effects found in rodents to humans.