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Interpretation of thyroid-relevant bioactivity for comparison to in vivo exposures
Citation:
Truong, K., J. Wambaugh, R. Judson, AND K. Friedman. Interpretation of thyroid-relevant bioactivity for comparison to in vivo exposures. Society of Toxicology 62nd Annual Meeting and ToxExpo 2023, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.22714363
Impact/Purpose:
Poster presented to the Society of Toxicology 62nd Annual Meeting and ToxExpo March 2023. There are 92 thyroid-relevant assay endpoints from the ToxCast/Tox21 project that can be mapped to molecular initiating events (MIEs) within the thyroid adverse outcome pathway (AOP) network. However, a synthesis and interpretation of the data across MIEs and at the tissue level is currently lacking. We aimed to determine which substances have the most in vitro high-throughput screening support for the MIEs and for which exposures would yield potentially bioactive concentrations in vivo. This is work being conducted under CSS.405.1.1.
Description:
There are 92 thyroid-relevant assay endpoints from the ToxCast/Tox21 project that can be mapped to molecular initiating events (MIEs) within the thyroid adverse outcome pathway (AOP) network. However, a synthesis and interpretation of the data across MIEs and at the tissue level is currently lacking. We aimed to determine which substances have the most in vitro high-throughput screening support for the MIEs and for which exposures would yield potentially bioactive concentrations in vivo. One MIE group of interest is the inhibition of deiodinase (DIO) enzymes which are responsible for converting thyroid hormone between active and inactive forms. Data from 4 cell-free assays, each measuring inhibition of a different deiodinase enzyme, are available for >1800 chemicals in single concentration screening and 302 chemicals in multi-concentration screening. Applying a selectivity metric that compares 20% inhibitory concentrations with cytotoxic concentrations yielded 160 chemicals demonstrating selective inhibition of at least one DIO enzyme. We found through an enrichment analysis using ClassyFire structural descriptors that lipids are also enriched in the positive chemical space, particularly those used as surfactants. We considered surfactants to be false positives that likely interfered with the protein-based assay. Considering these two factors increased our confidence in a final list of 101 chemicals with bioactivity for at least one enzyme. Finally, the in vitro bioactivity data were used to predict administered equivalent doses (AEDs) using high-throughput toxicokinetic models for in vitro to in vivo extrapolation. These AEDs reflect the predicted steady-state plasma concentration from the most sensitive 95th percentile of the human population. These AEDs were then compared to predicted exposure levels in humans from the ExpoCast program to estimate margin of exposures (MOEs). Of the 66 chemicals with available MOEs, about 40% have MOEs below a factor of 1000, and 60% have MOEs above a factor of 1000, informing further prioritization of chemicals specific to the deiodinase MIE group. Future work will explore how internal doses in a maternal-fetal physiologically-based toxicokinetic model compare to bioactive concentrations from thyroid-related assay endpoints. This work suggests an extensible approach to other MIE groups of thyroid-related bioactivity data from ToxCast. A broad analysis of all ToxCast assays for MIEs in the thyroid AOP network may provide the weight of evidence necessary to connect MIEs to potential adverse outcomes in susceptible human populations. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Interpretation of thyroid-relevant bioactivity for comparison to in vivo exposures
SOT2023_TRUONG_DRAFT6_FINAL.PDF (PDF, NA pp, 677.022 KB, about PDF)