Upmeier A, Degen G H, Diel P, Michna H, Bolt H M
Institut für Arbeitsphysiologie an der Universität Dortmund, Germany.
Arch Toxicol. 2000 Oct;74(8):431-6. doi: 10.1007/s002040000144.
Bisphenol A [BPA; 2,2-bis-(4-hydroxyphenyl)-propane] is a monomer used in the manufacture of resins with a wide range of applications, e.g. plastic coatings in the food packaging industry. BPA has been shown to have a weak oestrogenic activity in vitro and in vivo. Despite its low oestrogenic potency there is concern that, as a consequence of slow clearance, BPA might reach biologically significant levels in humans and animals exposed to environmental levels. To address this concern, we assessed the kinetic behaviour of BPA in female DA/Han rats. Groups of female rats received 10 mg BPA/kg body weight intravenously or 10 or 100 mg BPA/kg body weight orally (by gavage). Blood samples were collected at different time-points and plasma was prepared. Free BPA in the samples was isolated by fluid-fluid extraction. BPA was measured by GC-MS which allowed the reliable determination of BPA concentrations as low as approximately 10 ng/ml plasma. Immediately after i.v. administration, the BPA plasma concentration was in the range of about 15 microg/ml and decreased rapidly within the first hour (to 700 ng/ml). The levels declined further (100 ng/ml at 2 h), and after 24 h the analytical detection limit was reached. BPA was detected in plasma as early as 10 min after gavage administration, indicating rapid initial uptake from the gastrointestinal tract. Absorption of BPA was variable. In animals receiving 10 mg/kg, maximal plasma levels were reached after 1.5 h (31 ng/ ml) and 6 h (40 ng/ml). In animals receiving 100 mg/kg, plasma levels reached maxima around 30 min (150 ng/ml) and 3 h (134 ng/ml) after administration. After 48 h BPA was at or below the detection limit in both dose groups. Fluctuations in the BPA plasma concentrations over time point to the possibility of enterohepatic recirculation and protracted absorption from the gastrointestinal tract. Using the area under the concentration-time curves (AUCs), low bioavailabilities of 16.4% and 5.6% were calculated for the 10 and 100 mg/kg dose groups, respectively. The toxicokinetic properties of BPA in DA/Han rats are in agreement with the hypothesis of a rapid first-pass elimination by the liver and efficient metabolic clearance of low oral doses. Only excessive doses may lead to bioaccumulation if detoxification pathways are saturated.
双酚A [BPA；2,2-双（4-羟基苯基）丙烷] 是一种用于制造具有广泛应用的树脂的单体，例如食品包装行业中的塑料涂层。已证明双酚A在体外和体内具有弱雌激素活性。尽管其雌激素效力较低，但人们担心，由于清除缓慢，双酚A在暴露于环境水平的人类和动物体内可能会达到具有生物学意义的水平。为了解决这一担忧，我们评估了双酚A在雌性DA/Han大鼠体内的动力学行为。将雌性大鼠分组，静脉注射10 mg双酚A/kg体重，或口服（通过灌胃）10或100 mg双酚A/kg体重。在不同时间点采集血样并制备血浆。通过液-液萃取分离样品中的游离双酚A。采用气相色谱-质谱联用仪（GC-MS）测定双酚A，其能够可靠地测定低至约10 ng/ml血浆的双酚A浓度。静脉注射后，双酚A的血浆浓度约为15 μg/ml，并在第一小时内迅速下降（至700 ng/ml）。浓度进一步下降（2小时时为100 ng/ml），24小时后达到分析检测限。灌胃给药后10分钟血浆中就检测到了双酚A，表明其能迅速从胃肠道吸收。双酚A的吸收情况存在差异。接受10 mg/kg剂量的动物，给药后1.5小时（31 ng/ml）和6小时（40 ng/ml）达到最大血浆浓度。接受100 mg/kg剂量的动物，给药后约30分钟（150 ng/ml）和3小时（134 ng/ml）达到血浆浓度最大值。48小时后，两个剂量组的双酚A浓度均降至或低于检测限。双酚A血浆浓度随时间的波动表明存在肝肠循环以及从胃肠道持续吸收的可能性。利用浓度-时间曲线下面积（AUC）计算得出，10和100 mg/kg剂量组的生物利用度分别为16.4%和5.6%，较低。双酚A在DA/Han大鼠体内的毒代动力学特性与肝脏快速首过消除以及低口服剂量有效代谢清除的假设一致。如果解毒途径饱和，则只有过量剂量才可能导致生物蓄积。
