Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology
Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology
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DOI：
10.1021/acs.est.6b06230
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发表时间：
2017-04-18
影响因子：
11.4
通讯作者：
Watanabe, Karen H.
中科院分区：
文献类型：
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作者：
Conolly, Rory B.;Ankley, Gerald T.;Watanabe, Karen H.
定量不良结局途径（qAOP）由一个或多个基于生物学的计算模型组成，描述了将分子起始事件（MIE）与不良结局联系起来的关键事件关系。一个qAOP提供定量，剂量反应，和时间过程的预测，可以支持监管决策：在这里，我们描述了qAOP的几个方面，包括（a）开发的动机，（B）技术考虑，（c）评估的信心，和（d）潜在的应用。qAOP用作这些点的说明性例子，描述了细胞色素P450 19A芳香酶（MIE）的抑制和黑头呆鱼（FHM; Pimephales promelas）种群水平下降之间的联系。qAOP由以下三个相关的计算模型组成：（a）雌性FHM中的下丘脑-垂体-性腺轴，其中芳香酶抑制降低睾酮向17 β-雌二醇（E2）的转化，从而减少E2依赖性卵黄蛋白原（VTG;蛋黄蛋白前体）合成，（B）VTG依赖性卵发育和产卵（繁殖力），以及（c）繁殖力依赖性种群轨迹。虽然开发的实施例qAQP是基于与FHM暴露于芳香酶抑制剂法倔唑的实验，我们还显示了如何毒性当量（TEQ）计算允许使用的qAOP预测的影响，另一个未经测试的芳香酶抑制剂，异菌脲。虽然qAOP的开发可能是资源密集型的，但所获得的定量预测以及基于TEQ的多种化学品的应用可能足以证明某些应用程序在监管决策中的成本合理。
A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose response, and time-course predictions that can support regulatory decision-making: Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications. The qAOP used as an illustrative example for these points describe the linkage between inhibition of cytochrome P450 19A aromatase (the MIE) and population-level decreases in the fathead minnow (FHM; Pimephales promelas). The qAOP consists of three linked computational models for the following: (a) the hypothalamic-pitutitary-gonadal axis in female FHMs, where aromatase inhibition decreases the conversion of testosterone to 17 beta-esttadiol (E2), thereby reducing E2-dependent vitellogenin (VTG; egg yolk protein precursor) synthesis, (b) VTG-dependent egg development and spawning (fecundity), and (c) fecundity-dependent population trajectory. While development of the example qAQP was based on experiments with FHMs exposed to the aromatase inhibitor fadrozole, we also show how a toxic equivalence (TEQ) calculation allows use of the qAOP to predict effects of another, untested aromatase inhibitor, iprodione. While qAOP development can be resource-intensive, the quantitative predictions obtained, and TEQ-based application-to multiple chemicals, may be sufficient to justify the cost for some, applications in regulatory decision-making.