In order to replace the use of animals in toxicity testing, there is a need to predict human in vivo toxic doses from concentrations that cause adverse effects in in vitro test systems. The virtual cell based assay (VCBA) has been developed to simulate intracellular concentrations as a function of time, and can be used to interpret in vitro concentration-response curves. In this study we refine and extend the VCBA model by including additional target-organ cell models and by simulating the fate and effects of chemicals at the organelle level. In particular, we describe the extension of the original VCBA to simulate chemical fate in liver (HepaRG) cells and cardiomyocytes (ICell cardiomyocytes), and we explore the effects of chemicals at the mitochondrial level. This includes a comparison of: a) in vitro results on cell viability and mitochondrial membrane potential (mmp) from two cell models (HepaRG cells and ICell cardiomyocytes); and b) VCBA simulations, including the cell and mitochondrial compartment, simulating the mmp for both cell types. This proof of concept study illustrates how the relationship between mitochondrial disruption and cell toxicity can be simulated using the VCBA.

WORTH Andrew;  LOUISSE Jochem;  MACKO Peter;  SALA BENITO Jose';  PAINI Alicia; 

2017-10-16

PERGAMON-ELSEVIER SCIENCE LTD

JRC107374

0887-2333,   

https://doi.org/10.1016/j.tiv.2017.09.009,    https://publications.jrc.ec.europa.eu/repository/handle/JRC107374,   

10.1016/j.tiv.2017.09.009,