Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using...

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 in vitro concentration of chemical in the reaction medium was developed to facilitate quantitative in vitro to in vivo 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) in vitro concentration-response data, for estrogen and pregnane X receptor activation determined in human liver and kidney cell lines, from the ToxCast/Tox21 database. In vivo benchmark dose 10% lower confidence limits (BMDL₁₀) for oral uptake of BPA (ng/kg BW/day) were calculated from the in vivo dose-responses and compared to the human equivalent dose (HED) BMDL₁₀ for relative kidney weight change in the mouse derived by European Food Safety Authority (EFSA). Three from four in vivo BMDL₁₀ 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 in vitro, extrapolated to in vivo, could be useful for the derivation of Health Based Guidance Values (HBGV).