Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA.
Toxicol Lett. 2011 Dec 15;207(3):298-305. doi: 10.1016/j.toxlet.2011.09.020. Epub 2011 Sep 29.
Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure at levels largely below 1 μg/kg bw/d. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult and neonatal CD-1 mice by oral and subcutaneous (SC) injection routes. Deuterated BPA was used to avoid issues of background contamination. Significant inverse relationships were observed between postnatal age and measures of internal exposures (C(max)) to unconjugated BPA after oral administration. Phase II conjugation, area under the time-concentration curve (AUC), and elimination half-time of unconjugated BPA were also inversely related to age. In postnatal day (PND) 3 mice, the combination of under-developed Phase II metabolism, rapid absorption, and slow elimination kinetics led to equivalent internal exposures for unconjugated BPA from oral and SC routes; however, maturing metabolic capabilities in PND 10 and older mice, led to large and significant route effects. The significant inverse age-related developmental profiles from PND 3 through adulthood for unconjugated BPA internal exposure metrics from oral administration to CD-1 mice and Sprague-Dawley rats were remarkably similar; however, the developmental profile was quite different for neonatal rhesus monkeys in which small insignificant age-related differences were observed. These results suggest that an adverse effect from BPA observed in rodent models, attributable to exposure during a discrete time period of neonatal development, would be less likely for comparable neonatal primate dosing based on internal dosimetry. On the other hand in all adults of all species studied, including humans, a low oral dose of BPA produced similarly small internal exposures for the unconjugated form, reflecting the dominant effect of presystemic Phase II metabolism.
双酚 A（BPA）是一种重要的工业化学物质，用于制造聚碳酸酯塑料产品和环氧树脂基食品罐衬里。尿液中存在 BPA 代谢物的美国人超过 90%，年龄在 6-60 岁之间，这表明在很大程度上低于 1μg/kg bw/d 的水平下普遍存在和频繁暴露。本研究使用 LC/MS/MS 通过口服和皮下（SC）注射途径测量成年和新生 CD-1 小鼠血清中未结合（活性）和结合（非活性）BPA 的药代动力学。使用氘代 BPA 避免了背景污染问题。口服给药后，观察到未结合 BPA 的内部暴露（C(max)）与产后年龄之间存在显著的反比关系。Ⅱ相结合、时间浓度曲线下面积（AUC）和未结合 BPA 的消除半衰期也与年龄呈反比关系。在出生后第 3 天（PND3）的小鼠中，由于 II 相代谢发育不全、吸收迅速和消除动力学缓慢，导致口服和 SC 途径的未结合 BPA 具有等效的内部暴露；然而，在 PND10 及以上的小鼠中，成熟的代谢能力导致了大而显著的途径效应。从 PND3 到成年期，未结合 BPA 内部暴露指标的显著负相关发育曲线从口服给药到 CD-1 小鼠和 Sprague-Dawley 大鼠，在所有研究的物种中，包括人类，口服低剂量的 BPA 会产生类似的小的未结合形式的内部暴露，反映了预系统相 II 代谢的主导作用。
