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High-throughput screening tools facilitate calculation of a combined exposure-bioactivity index for chemicals with endocrine activity
Citation:
Wegner, S., C. Pinto, C. Ring, AND J. Wambaugh. High-throughput screening tools facilitate calculation of a combined exposure-bioactivity index for chemicals with endocrine activity. ENVIRONMENT INTERNATIONAL. Elsevier B.V., Amsterdam, Netherlands, 137:105470, (2020). https://doi.org/10.1016/j.envint.2020.105470
Impact/Purpose:
We use ToxCast, ExpoCast, and HTTK to find that cumulative exposures sufficient to result in estrogen receptor bioactivity are within the range of uncertainty for EPA’s predictive models.
Description:
Background: High-throughput and computational tools provide a new opportunity to calculate cumulative bioactivity of exposure to diverse chemicals acting through a common mechanism. Objective: We used high throughput bioactivity data and exposure predictions from the U.S. EPA’s Toxicity and Exposure Forecaster (ToxCast and ExpoCast) to estimate cumulative estrogen receptor (ER) agonist activity of non-pharmaceutical chemical exposures for the general U.S. population. Methods: High throughput toxicokinetic (HTTK) data provide conversion factors that relate bioactive concentrations measured in vitro (µM), to predicted exposure rates (mg/kg/day). These data were available for 22 chemicals with ER agonist activity and were estimated for the remaining chemicals based on the geometric mean of HTTK values across chemicals. For each chemical, ER bioactivity across ToxCast assays was compared to predicted population geometric mean exposure at different levels of model certainty. Dose additivity was assumed in calculating a Cumulative Exposure-Bioactivity Index (CEBI), the sum of exposure/bioactivity ratios. Results: CEBIs are shown to span several orders of magnitude both greater (posing a risk) and lower than 1. The CEBI depends on how conservative the assumptions are about combining exposure and bioactivity. The assumptions reflect the potential variability across ToxCast assays and exposure model uncertainty. Concentration-addition model predictions of mixture bioactivity based on the same values yielded comparable results. Conclusions: Cumulative exposures sufficient to result in estrogen receptor bioactivity are within the range of uncertainty for EPA’s predictive models. Reducing model uncertainty will increase utility of this approach in regulatory programs such as the Endocrine Disruptor Screening Program (EDSP).
URLs/Downloads:
DOI: High-throughput screening tools facilitate calculation of a combined exposure-bioactivity index for chemicals with endocrine activity
https://pubmed.ncbi.nlm.nih.gov/32050122/