Insights into in vitro biokinetics using Virtual Cell Based Assay simulations

Abstract

The Virtual Cell Based Assay (VCBA) is an in silico model that simulates the biokinetics of chemicals in in vitro test systems. VCBA simulations can indicate the degree to which the bioavailable concentration varies across chemicals and experimental conditions, thereby providing important contextual information for comparing the results of different in vitro toxicity experiments. The simulated results can also be used to support in vitro to in vivo extrapolation of toxicity data, especially when the VCBA is coupled to a physiologically based kinetic model.
In this work, we selected 83 chemicals previously tested for in vitro cytotoxicity with a neutral red uptake (NRU) assay and used the respective in vitro data to optimize a toxicity and effects model simulating the 3T3 BALB/c cell line in a 96-well microplate with 5% serum supplementation. We then used the optimized parameters to simulate alternative experimental conditions. The simulations show the impact of different physicochemical properties on chemical fate of this diverse group of chemicals and how the different partitioning (to protein, lipid, and plastic) and kinetic (evaporation and degradation) events are intrinsically connected. The results of VCBA simulations were interpreted with respect to the applicability domain of the different QSARs incorporated in the model and the underlying assumptions and uncertainties of the VCBA.