Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Kelly Government Solutions, Durham, North Carolina 27709.
Toxicol Sci. 2019 Jan 1;167(1):6-14. doi: 10.1093/toxsci/kfy278.
The National Toxicology Program (NTP) receives requests to evaluate chemicals with potential to cause adverse health effects, including developmental neurotoxicity (DNT). Some recent requests have included classes of chemicals such as flame retardants, polycyclic aromatic compounds, perfluoroalkyl substances, and bisphenol A analogs with approximately 20-50 compounds per class, many of which include commercial mixtures. However, all the compounds within a class cannot be tested using traditional DNT animal testing guideline studies due to resource and time limitations. Hence, a rapid and biologically relevant screening approach is required to prioritize compounds for further in vivo testing. Because neurodevelopment is a complex process involving multiple distinct cellular processes, one assay will unlikely address the complexity. Hence, the NTP sought to characterize a battery of in vitro and alternative animal assays to quantify chemical effects on a variety of neurodevelopmental processes. A culmination of this effort resulted in a NTP-hosted collaborative project with approximately 40 participants spanning across domains of academia, industry, government, and regulatory agencies; collaborators presented data on cell-based assays and alternative animal models that was generated using a targeted set of compounds provided by the NTP. The NTP analyzed the assay results using benchmark concentration (BMC) modeling to be able to compare results across the divergent assays. The results were shared with the contributing researchers on a private web application during the workshop, and are now publicly available. This article highlights the overview and goals of the project, and describes the NTP's approach in creating the chemical library, development of NTPs data analysis strategy, and the structure of the web application. Finally, we discuss key issues with emphasis on the utility of this approach, and knowledge gaps that need to be addressed for its use in regulatory decision making.
国家毒理学计划（NTP）收到了评估具有潜在不良健康影响的化学物质的请求，包括发育神经毒性（DNT）。最近的一些请求包括阻燃剂、多环芳烃化合物、全氟烷基物质和双酚 A 类似物等类别的化学物质，每类约有 20-50 种化合物，其中许多包含商业混合物。然而，由于资源和时间限制，无法使用传统的 DNT 动物测试指南研究对一类中的所有化合物进行测试。因此，需要一种快速且与生物学相关的筛选方法来优先考虑进一步体内测试的化合物。由于神经发育是一个复杂的过程，涉及多个不同的细胞过程，一种测定方法不太可能解决复杂性。因此，NTP 试图描述一系列体外和替代动物测定方法，以量化化学物质对各种神经发育过程的影响。这项工作的成果是 NTP 主办的一个合作项目，大约有 40 名参与者来自学术界、工业界、政府和监管机构等领域；合作者提供了基于细胞的测定和替代动物模型的数据，这些数据是使用 NTP 提供的一组目标化合物生成的。NTP 使用基准浓度 (BMC) 建模分析了测定结果，以便能够比较不同测定方法的结果。在研讨会上，研究结果通过私人网络应用程序与做出贡献的研究人员共享，现在已经公开。本文重点介绍了该项目的概述和目标，并描述了 NTP 创建化学文库、制定 NTP 数据分析策略以及网络应用程序结构的方法。最后，我们讨论了关键问题，并强调了这种方法的实用性以及在监管决策中使用它需要解决的知识差距。
