Interpretation of thyroid-relevant bioactivity data for comparison to in vivo exposures: A prioritization approach for putative chemical inhibitors of in vitro deiodinase activity

Many ToxCast assay endpoints can be mapped to molecular initiating events (MIEs) within the thyroid adverse outcome pathway (AOP) network. Herein, we provide a framework for interpretation of thyroid-relevant bioactivity data across MIEs. As a proof-of-concept, we used ToxCast data on the inhibition of deiodinase (DIO) enzymes, which convert thyroid hormones between active and inactive forms, and identified substances most likely to inhibit DIO enzymes. Data from 4 relevant cell-free in vitro assays are available for > 2000 chemicals in single concentration screening and 327 chemicals in multi-concentration screening. We filtered to identify chemicals that demonstrated inhibition for each DIO enzyme less likely to be confounded by assay interference, refining the list of putatively active chemicals from 523 to 135. In vitro bioactivity data were then used to estimate administered equivalent doses (AEDs) using a novel high-throughput toxicokinetic (HTTK) model for in vitro to in vivo extrapolation (IVIVE) of dose. To consider potential thyroid-disrupting activity in an appropriate life-stage and dose context, we extended an existing human maternal-fetal HTTK model to allow for simulations involving the first trimester of pregnancy. For many chemicals, using modeled fetal tissue concentrations produced lower AED estimates than using modeled maternal plasma concentrations alone, at least partially due to conservative assumptions in our HTTK model of complete gestation. This extensible approach for MIE groups of thyroid-related bioactivity data from ToxCast may inform further screening or analyses for potential adverse outcomes during pregnancy and development.