Theoretical and mathematical foundation of the Virtual Cell Based Assay – A review

Abstract

There is a need to interpret in vitro concentration-viability data in terms of the actual concentration that the cells are exposed to, rather than the nominal concentration applied to the test system. We have developed a process-based model to simulate the kinetics and dynamics of a chemical compound in cell-based in vitro assays. In the present paper we describe the mathematical equations governing this model as well as the parameters that are needed to run the model. The Virtual Cell Based Assay (VCBA) is an integrated model composed of: [1] a fate and transport model; [2] a cell partitioning model; [3] a cell growth and division model; [4] a toxicity and effects model; [5] the experimental set up. The purpose of the VCBA is to simulate the medium and intracellular concentrations, which can be used on its own to design and interpret in vitro experiments, and in combination with physiologically based kinetic (PBK) models to perform in vitro to in vivo extrapolation. The results can be used in chemical risk assessment to link an external dose to an internal effect or vice versa, using solely in vitro and in silico tools and thereby avoiding animal testing.

In vitro Models and On-Chip Systems: Biomaterial Interaction Studies With Tissues Generated Using Lung Epithelial and Liver Metabolic Cell Lines

“…This modeling approach is useful in the chemical risk assessment, when prioritization of chemical testing is important (Kramer et al, 2015 ; Bell et al, 2017 ). Whenever possible, in vitro studies were combined with in vivo studies in order to validate the proposed approach (Comenges et al, 2017 ).…”

“…Although in vitro assays are convenient to estimate toxic mechanisms, there are still some limitations of in vitro assays that make it impossible to completely replace in vivo studies (Comenges et al, 2017 ). These limitations mainly concern differences found between in vitro and in vivo experiments (false positives and negatives, large inter-assay variability, the low sensitivity etc.)…”

“…(Höfer et al, 2004 ; Lilienblum et al, 2008 ). Because of that, mathematical models that comprise the fate of a compound in the cell-based assay combined with a cell growth model are developed (Comenges et al, 2017 ). Virtual Cell Based Assay (VCBA) was developed from HTS laboratory data (Zaldívar et al, 2010 ; Zaldívar and Baraibar, 2011 ) with the aim to describe dynamic effects, since the kinetics is already described by PBK models (Sala Benito et al, 2017 ).…”

“…Virtual Cell Based Assay (VCBA) was developed from HTS laboratory data (Zaldívar et al, 2010 ; Zaldívar and Baraibar, 2011 ) with the aim to describe dynamic effects, since the kinetics is already described by PBK models (Sala Benito et al, 2017 ). The VCBA can be described as a process-based model or mathematical representation of an in vitro assay to simulate the effects and a fate of a chemical (Comenges et al, 2017 ). The VCBA model (Comenges et al, 2017 ; Sala Benito et al, 2017 ) consists of many parameters dependent on the physicochemical, experimental, as well as cell line characteristics, but can be divided into four sub models that describe: Fate and transport model, Cell partitioning model, Cell growth and division model, Cell dynamics including toxicity and effects model (Figure 3 ).…”

“…When it comes to toxicological studies, chemical of interest is often tested on the liver. In recent years, new in vitro and in silico technologies have enabled insight into toxic mechanisms in order to replace or reduce the use of animals in tissue examinations (Gubbels-van Hal et al, 2005 ; Jie et al, 2016 ; Comenges et al, 2017 ). This is done at the molecular level to understand how changes at lower levels influence higher levels of biological organization (e.g., tissue, organs, etc.…”