A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben
A case study on quantitative in vitro to in vivo extrapolation for environmental esters: Methyl-, propyl- and butylparaben
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DOI：
10.1016/j.tox.2015.03.010
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发表时间：
2015-06-05
期刊：
影响因子：
4.5
通讯作者：
Clewell, Harvey J.
中科院分区：
文献类型：
--
作者：
Campbell, Jerry L.;Yoon, Miyoung;Clewell, Harvey J.
据报告，对羟基苯甲酸酯是潜在的内分泌干扰物，广泛用于化妆品、食品和药品等消费项目。我们报告甲基，丙基和丁基对羟基苯甲酸酯的PBPK模型的发展。通过结合组织溶解度的QSAR和进入门户（包括肠和皮肤）以及主要代谢部位（肝脏）中水解的定量体外至体内外推（IVIVE），对模型进行参数化。总体而言，该模型提供了非常好的协议，在血液和尿液中的时间过程数据，从控制剂量的研究，在大鼠和人类，并证明了潜在的价值，定量IVIVE在扩大使用人类生物监测数据的安全性评估。通过比较体外雌激素活性试验的有效浓度与模型预测的游离尼泊金酯浓度（与NHANES（2009-2010年采集期）中报告的第95百分位尿液浓度相关），计算基于体外的累积安全范围（MOS）。成年女性的MOS计算值为108，而男性的MOS为444。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Parabens have been reported as potential endocrine disrupters and are widely used in consumer projects including cosmetics, foods and pharmaceuticals. We report on the development of a PBPK model for methyl-, propyl-, and butylparaben. The model was parameterized through a combination of QSAR for tissue solubility and quantitative in vitro to in vivo extrapolation (IVIVE) for hydrolysis in portals of entry including intestine and skin as well as in the primary site of metabolism, the liver. Overall, the model provided very good agreement with published time-course data in blood and urine from controlled dosing studies in rat and human, and demonstrates the potential value of quantitative IVIVE in expanding the use of human biomonitoring data in safety assessment. An in vitro based cumulative margin of safety (MOS) was calculated by comparing the effective concentrations from an in vitro assay of estrogenicity to the free paraben concentrations predicted by the model to be associated with the 95th percentile urine concentrations reported in NHANES (2009-2010 collection period). The calculated MOS for adult females was 108, whereas the MOS for males was 444. (C) 2015 Elsevier Ireland Ltd. All rights reserved.