Does rapid metabolism ensure negligible risk from bisphenol A?

Abstract

Background: Bisphenol A (BPA) risks are being evaluated by many regulatory bodies because exposure is widespread and the potential exists for toxicity at low doses.

Objective: We evaluated evidence that BPA is cleared more rapidly in humans than in rats in relation to BPA risk assessment.

Discussion: The European Food Safety Authority (EFSA) relied on pharmacokinetic evidence to conclude that rodent toxicity data are not directly relevant to human risk assessment. Further, the EFSA argues that rapid metabolism will result in negligible exposure during the perinatal period because of BPA glucuronidation in pregnant women or sulfation in newborns. These arguments fail to consider the deconjugation of BPA glucuronide in utero by beta-glucuronidase, an enzyme that is present in high concentrations in placenta and various other tissues. Further, arylsulfatase C, which reactivates endogenous sulfated estrogens, develops early in life and so may deconjugate BPA sulfate in newborns. Biomonitoring studies and laboratory experiments document free BPA in rat and human maternal, placental, and fetal tissues, indicating that human BPA exposure is not negligible. The pattern of these detections is consistent with deconjugation in the placenta, resulting in fetal exposure. The tolerable daily intake set by the EFSA (0.05 mg/kg/day) is well above effect levels reported in some animal studies.

Conclusion: This potential risk should not be dismissed on the basis of an uncertain pharmacokinetic argument. Rather, risk assessors need to decipher the BPA dose response and apply it to humans with comprehensive pharmacokinetic models that account for metabolite deconjugation.

Keywords: bisphenol A; endocrine disruption; fetus; glucuronidation; metabolism; neonate; β-glucuronidase.

Figure 1

Free BPA and ratio of conjugate to free BPA in rats from background exposure or after BPA dosing. ^aData from Takeuchi et al. (2004). ^bData from Domoradzki et al. (2003). ^cData from Takahashi and Oishi (2000).

Figure 2

Free BPA in humans from background exposure or after BPA dosing. ^aData from Takeuchi et al. (2002). ^bData from Schönfelder et al. (2002). ^cData from Yamada et al. (2002). ^dData from Völkel et al. (2002); LOD = 2.3 μg/L..