Reducing uncertainty in dose-response assessments by incorporating Bayesian benchmark dose modeling and in vitro data on population variability

There are two primary sources of uncertainty in the interpretability of toxicity values, like the reference dose (RfD): estimates of the point of departure (POD) and the absence of chemical-specific human variability data. We hypothesize two solutions-employing Bayesian benchmark dose (BBMD) modeling to refine POD determination and combining high-throughput toxicokinetic modeling with population-based toxicodynamic in vitro data to characterize chemical-specific variability. These hypotheses were tested by deriving refined probabilistic estimates for human doses corresponding to a specific effect size (M) in the Ith population percentile (HD ) across 19 Superfund priority chemicals. HD values were further converted to biomonitoring equivalents in blood and urine for benchmarking against human data. Compared to deterministic default-based RfDs, HD values were generally more protective, particularly influenced by chemical-specific data on interindividual variability. Incorporating chemical-specific in vitro data improved precision in probabilistic RfDs, with a median 1.4-fold reduction in uncertainty variance. Comparison with US Environmental Protection Agency's Exposure Forecasting exposure predictions and biomonitoring data from the National Health and Nutrition Examination Survey identified chemicals with margins of exposure nearing or below one. Overall, to mitigate uncertainty in regulatory toxicity values and guide chemical risk management, BBMD modeling and chemical-specific population-based human in vitro data are essential.