Assessing utility of thyroid in vitro screening assays through comparisons to observed impacts in vivo

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.