VIVD: Virtual in vitro distribution model for the mechanistic prediction of intracellular concentrations of chemicals in in vitro toxicity assays. (August 2019)

• Record Type: Journal Article
• Authors: Fisher, C.; Siméon, S.; Jamei, M.; Gardner, I.; Bois, Y.F.
• Is Part Of: Toxicology in vitro. Volume 58(2019)
• Page Start: 42
• Page End: 50
• Publication Date: 2019-08
• Subjects: In vitro assays -- IVIVE -- Biokinetics -- Toxicity; Φ membrane potential (mV) -- ΔUaw internal energy of phase change for air to water partitioning -- ΔUow internal energy of phase change for octanol to water partitioning -- [AP-] concentration of acidic phospholipids -- Cair concentration in the air in the headspace -- Ccell total intracellular concentration -- Cmedium, dissolved, u unbound, dissolved medium concentration -- Cnominal nominal test concentration in medium -- Cplastic concentration bound to plastic -- Celldiam. diameter of a single cell -- CoA certificate of Analysis -- F Faraday constant -- FBS fetal Bovine Serum -- fiw fractional cellular volume of intracellular water -- flyso fractional cellular volume of lysosome -- fmito fractional cellular volume of mitochondria -- fnl fractional cellular volume of neutral lipid -- fnp fractional cellular volume of neutral phospholipids -- fprotein fraction of FBS comprising albumin -- fnl, FBS fraction of FBS comprised of neutral lipid -- fprotein fraction of FBS comprising albumin -- fserum fraction of culture medium comprised of FBS -- fuFBS fraction unbound in FBS -- fuFBS, dilu fuFBS corrected for dilution in complete culture medium -- fui fraction unionised -- ITS integrated testing strategy -- IVIVE in vitro in vivo extrapolation -- K Kelvin -- KaAP acidic phospholipid association constant -- kair, u air to water partition coefficient -- kcell, u ratio of total cell concentration to unbound medium concentration -- kcell, uuuu ratio of the unbound, unionised concentration in the cell and the culture medium -- kH Henry's law constant -- KIW, uuuu ratio of the unbound, unionised concentration in the intracellular water cell and the specified organelle -- kplastic, u plastic to culture medium partition coefficient -- kprotein albumin to water partition coefficient -- PAH polycyclic aromatic hydrocarbons -- Pi partial pressure of the gas phase of the compound -- Pnl neutral lipid partition coefficient -- Pnp neutral phospholipid partition coefficient -- Pow octanol-water partition coefficient -- PSV partial specific volume -- Pvo:w olive oil-water partition coefficient -- R universal gas constant -- SAmedium plastic surface area of plastic culture vessel in contact with culture medium (m2) -- Systemdiam. diameter of culture system (mm) -- TAG triacylglyceride -- Tref reference temperature parameters are experimentally determined or predicted -- Tsys temperature of the cell culture system -- Vair volume of air in head space above culture medium (L) -- Vmedium volume of culture medium (μL) -- Vtotal cell total volume of cultured cells (L) -- Vwell volume of a culture vessel (μL) -- Y concentration ratio of ionised to unionised ionisable compound; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2018.12.017
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: In vitro toxicity testing routinely uses nominal treatment concentrations as the driver for measured toxicity endpoints. However, test compounds can bind to the plastic of culture vessels or interact with culture media components, such as lipids and albumin. Additionally, volatile compounds may partition into the air above culture media. These processes reduce the free concentrations of compound to which cells are exposed. Models predicting the freely dissolved concentrations by accounting for these interactions have been published. However, these have only been applied to neutral compounds or assume no differential ionisation of test compounds between the media and cell cytoplasm. Herein, we describe an in vitro distribution model, based on the Fick-Nernst Planck equation accounting for differential compound ionisation in culture medium and intracellular water. The model considers permeability of ionised and unionised species and accounts for membrane potential in the partitioning of ionised moieties. By accounting for lipid and protein binding in culture medium, binding to cell culture plastic, air-partitioning, and lipid binding in the cell, the model can predict chemical concentrations (free and total) in medium and cells. The model can improve in vitro in vivo extrapolation of toxicity endpoint by determining intracellular concentrations for translation to in vivo . Graphical abstract: Unlabelled Image Highlights: Published biokinetic models of in vitro fate do not account for ionisation of compounds. Our model incorporates differential ionisation, ion permeability, and membrane potential. Ionisation can significantly impact the prediction of intracellular concentrations. Differential ionisation also impacts subcellular distribution into organelles. Biokinetic modelling is critical to the in vitro to in vivo translation of toxicity.