College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea.
J Toxicol Environ Health A. 2010;73(21-22):1586-98. doi: 10.1080/15287394.2010.511584.
The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 μg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.
本研究旨在利用基于生理学的药代动力学（PBPK）模型预测人体血液和组织中经口服摄入双酚 A（BPA）的暴露情况。该模型经过改良，考虑了 BPA 的葡萄糖醛酸化、胆汁排泄和缓慢吸收，以描述口服摄入后观察到的 BPA 的第二个峰值。该开发模型充分描述了大鼠口服给药后 BPA 的第二个峰值和血液及各种组织中的浓度。一项前瞻性验证研究在大鼠中进一步支持了所提出的模型。为了外推至人类，预计每日口服 BPA 剂量为 0.237mg/70kg/d 或 0.0034mg/kg/d，可使平均稳态血液浓度达到 0.0055ng/ml（韩国孕妇血液中 BPA 的中位数浓度）。该剂量低于参考剂量（RfD，0.016mg/kg/d）和欧洲委员会确定的每日耐受摄入量（10μg/kg/d）。数据表明，肠肝循环可能具有重要的毒理学意义，因为该途径可能会增加 BPA 在人体内的暴露和终末半衰期。
