Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA; U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Toxicology and Ecology Division, Duluth, MN, 55804, USA.
U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Great Lakes Toxicology and Ecology Division, Duluth, MN, 55804, USA.
Regul Toxicol Pharmacol. 2023 Oct;144:105491. doi: 10.1016/j.yrtph.2023.105491. Epub 2023 Sep 4.
To better understand endocrine disruption, the U.S. Environmental Protection Agency's (USEPA) Endocrine Disruptor Screening Program (EDSP) utilizes a two-tiered approach to investigate the potential of a chemical to interact with the estrogen, androgen, or thyroid systems. As in vivo testing lacks the throughput to address data gaps on endocrine bioactivity for thousands of chemicals, in vitro high-throughput screening (HTS) methods are being developed to screen larger chemical libraries. The primary objective of this work was to investigate for how many of the 52 chemicals with weight-of-evidence (WoE) determinations from EDSP Tier 1 screening there are available in vitro HTS data supporting a thyroid impact. HTS data from the USEPA ToxCast program and the EDSP WoE were collected for this analysis. Considering the complexity of endocrine disruption and interpreting HTS data, concordance between in vitro activity and in vivo effects ranges from 58 to 78%. Based on this evaluation, we conclude that the current suite of HTS assays is beneficial for prioritizing chemicals for further inquiry; however, without a more detailed analysis, one cannot conclude whether HTS results are the primary mode-of-action. Furthermore, development of in vitro assays for additional thyroid-relevant molecular initiating events is required to effectively predict in vivo thyroid impacts.
为了更好地了解内分泌干扰，美国环境保护署（USEPA）的内分泌干扰物筛选计划（EDSP）采用了两阶段方法来研究化学物质与雌激素、雄激素或甲状腺系统相互作用的潜力。由于体内测试缺乏处理数千种化学物质内分泌生物活性数据空白的通量，因此正在开发体外高通量筛选（HTS）方法来筛选更大的化学库。这项工作的主要目的是调查 EDSP 第 1 阶段筛选中具有证据权重（WoE）确定的 52 种化学物质中有多少种具有支持甲状腺影响的体外 HTS 数据。为此分析收集了 USEPA ToxCast 计划和 EDSP WoE 的 HTS 数据。考虑到内分泌干扰的复杂性以及解释 HTS 数据的难度，体外活性与体内效应之间的一致性范围为 58%至 78%。基于此评估，我们得出结论，目前的 HTS 检测套件有助于优先考虑进一步研究的化学物质；然而，如果没有更详细的分析，就不能得出 HTS 结果是否是主要作用模式的结论。此外，需要开发额外的与甲状腺相关的分子起始事件的体外检测，以有效地预测体内甲状腺影响。
