High-throughput screening (HTS) assays may provide an efficient way to identify endocrine-active chemicals. However, nominal in vitro assay concentrations of a chemical may not accurately reflect the blood or tissue levels that cause in vivo effects because in vitro assays do not fully account for chemical pharmacokinetics. In this in vitro-to-in vivo extrapolation (IVIVE) study, we used metabolic clearance and plasma protein binding data with population-based pharmacokinetic (PK) models to quantitatively compare in vitro and in vivo dosimetry for reference chemicals estradiol and bisphenol A, and 230 environmental chemicals that potentially interact with the estrogen receptor (ER) pathway. We first determined the point-of-departure (POD) values from an HTS ER transactivation assay, BG1Luc HTS, and then estimated the daily oral equivalent doses (OEDs) in rats and humans that would result in a steady-state in vivo blood concentration equivalent to the POD values. Where available, we compared the OEDs to the lowest effective doses (LEDs) in rat uterotrophic assays and human exposure values. For all the chemicals with in vivo data, OEDs estimated from POD values were lower than the LEDs in rat uterotrophic assays, suggesting that BG1Luc HTS assay may provide a more conservative hazard estimate for use in risk assessment. Further, human exposure values were generally lower than OEDs estimated from the BG1Luc HTS assay across all environmental chemicals with reported exposure information. In cases where the human OEDs are orders of magnitude lower than the estimated exposures, chemical-induced toxicity appears unlikely. Our modeling approach highlights the importance of PK considerations in ranking endocrine-active chemicals based on in vitro HTS assays.
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