Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative to Extrapolation.

A computational workflow which integrates physiologically based kinetic (PBK) modelling; global sensitivity analysis (GSA), Approximate Bayesian Computation (ABC), Markov Chain Monte Carlo (MCMC) simulation and the Virtual Cell Based Assay (VCBA) for the estimation of the active, free concentration of chemical in the reaction medium was developed to facilitate quantitative to extrapolation (QIVIVE). The workflow was designed to estimate parameter and model uncertainty within a computationally efficient framework. The workflow was tested using a human PBK model for bisphenol A (BPA) and high throughput screening (HTS) concentration-response data, for estrogen and pregnane X receptor activation determined in human liver and kidney cell lines, from the ToxCast/Tox21 database. benchmark dose 10% lower confidence limits (BMDL) for oral uptake of BPA (ng/kg BW/day) were calculated from the dose-responses and compared to the human equivalent dose (HED) BMDL for relative kidney weight change in the mouse derived by European Food Safety Authority (EFSA). Three from four BMDL values calculated in this study were similar to the EFSA values whereas the fourth was much smaller. The derivation of an uncertainty factor (UF) to accommodate the uncertainties associated with measurements using human cell lines , extrapolated to , could be useful for the derivation of Health Based Guidance Values (HBGV).