High-throughput screening tools facilitate calculation of a combined exposure-bioactivity index for chemicals with endocrine activity
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States); US Environmental Protection Agency (EPA), Washington, DC (United States)
- Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States); US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States)
- US Environmental Protection Agency (EPA), Research Triangle Park, NC (United States)
High-throughput and computational tools provide a new opportunity to calculate combined bioactivity of exposure to diverse chemicals acting through a common mechanism. We used high throughput in vitro bioactivity data and exposure predictions from the U.S. EPA’s Toxicity and Exposure Forecaster (ToxCast and ExpoCast) to estimate combined estrogen receptor (ER) agonist activity of non-pharmaceutical chemical exposures for the general U.S. population. High-throughput toxicokinetic (HTTK) data provide conversion factors that relate bioactive concentrations measured in vitro (µM), to predicted population geometric mean exposure rates (mg/kg/day). These data were available for 22 chemicals with ER agonist activity and were estimated for other ER bioactive 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 in vitro potency and model certainty. Dose additivity was assumed in calculating a Combined Exposure-Bioactivity Index (CEBI), the sum of exposure/bioactivity ratios. Combined estrogen bioactivity was also calculated in terms of the percent maximum bioactivity of chemical mixtures in human plasma using a concentration-addition model. Estimated CEBIs vary greatly depending on assumptions used for exposure and bioactivity. In general, CEBI values were <1 when using median of the estimated general population chemical intake rates, while CEBI were ≥1 when using the upper 95th confidence bound for those same intake rates for all chemicals. Concentration-addition model predictions of mixture bioactivity yield comparable results. Based on current in vitro bioactivity data, HTTK methods, and exposure models, combined exposure scenarios sufficient to influence estrogen bioactivity in the general population cannot be ruled out. Future improvements in screening methods and computational models could reduce uncertainty and better inform the potential combined effects of estrogenic chemicals.
- Research Organization:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); USEPA
- Grant/Contract Number:
- SC0014664
- OSTI ID:
- 1904995
- Journal Information:
- Environment International, Vol. 137, Issue C; ISSN 0160-4120
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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