Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models

Proença, Susana; Escher, Beate I.; Fischer, Fabian C.; Fisher, Ciarán; Grégoire, Sébastien; Hewitt, N.; Nicol, Beate; Paini, Alicia; Kramer, Nynke I.

doi:10.1016/j.tiv.2021.105133

Cited by 77 publications

(72 citation statements)

References 161 publications

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“…Effective in vitro concentrations in Molar were estimated by using the Virtual Cell Based Assay (VCBA) to simulate in vitro fate, as described in [ [53] , [54] , [55] ] and as reported in ‘Supplementary Materials and Methods (M&M)_VCBA’. These results showed that between 85%–96% of chemicals were available to the cells (either as free concentration in medium, or sequestered by cellular lipids) (Table SM4, in Supplementary M&M_VCBA).…”

Section: Methodsmentioning

confidence: 99%

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Herrmann

Carpi

Gyves

et al. 2021

Reproductive Toxicology

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Highlights Mixtures of similar MoA chemicals increased BDNF levels and neurite outgrowth. Mixtures of similar MoA chemicals decreased synapse formation and electrical activity. Synergistic effects on synaptogenesis features was predicted by mathematical modelling. Some of the DNT effects observed in hiPSC-neurons/astrocytes recapitulate ASD features. In vitro assays combined with mathematical modelling enable DNT testing of chemical mixtures.

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Section: Methodsmentioning

confidence: 99%

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Herrmann

Carpi

Gyves

et al. 2021

Reproductive Toxicology

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“…Another limitation of past QIVIVE studies was the use of applied or nominal in vitro concentrations only, that is, no consideration was made of the fate and distribution of the chemical in the reaction vessel. This could be a significant omission because the concentrations of chemical available for interaction with sub-cellular protein receptors and enzymes could be substantially lower than the nominal concentration (Tanneberger et al, 2010;Groothuis et al, 2015;Kramer et al, 2015;Proença et al, 2021). Chemicals have different properties, for instance highly lipophilic chemicals can interact with constituents of the reaction medium as well as reaction vessel geometry and composition.…”

Section: Introductionmentioning

confidence: 99%

“…Chemicals have different properties, for instance highly lipophilic chemicals can interact with constituents of the reaction medium as well as reaction vessel geometry and composition. For example, the chemical can migrate and bind to the plastic of the reaction vessel (Proença et al, 2019;Proença et al, 2021). To account for this one can set up in vitro distribution and fate measurements or use in silico tools to predict distribution.…”

Section: Introductionmentioning

confidence: 99%

Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

et al. 2022

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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).

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“…To use the results from the Neurosphere Assay in a risk assessment context, the calculated Point of Departure (PoD) values, in our case a benchmark concentration (BMC), need to be translated to an internal dose within the fetal brain. Therefore, reverse physiology-based kinetic modeling (PBK) and quantitative in vitro to in vivo extrapolations (qIVIVE) can be applied ( Basketter et al, 2012 ; Proença et al, 2021 ). One fundamental input to IVIVE is the determination of the free test compound concentration, which is defined as the concentration of the compound not bound to plastics, protein or lipid.…”

Section: Resultsmentioning

confidence: 99%

Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation

et al. 2022

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There is a call for a paradigm shift in developmental neurotoxicity (DNT) evaluation, which demands the implementation of faster, more cost-efficient, and human-relevant test systems than current in vivo guideline studies. Under the umbrella of the Organisation for Economic Co-operation and Development (OECD), a guidance document is currently being prepared that instructs on the regulatory use of a DNT in vitro battery (DNT IVB) for fit-for-purpose applications. One crucial issue for OECD application of methods is validation, which for new approach methods (NAMs) requires novel approaches. Here, mechanistic information previously identified in vivo, as well as reported neurodevelopmental adversities in response to disturbances on the cellular and tissue level, are of central importance. In this study, we scientifically validate the Neurosphere Assay, which is based on human primary neural progenitor cells (hNPCs) and an integral part of the DNT IVB. It assesses neurodevelopmental key events (KEs) like NPC proliferation (NPC1ab), radial glia cell migration (NPC2a), neuronal differentiation (NPC3), neurite outgrowth (NPC4), oligodendrocyte differentiation (NPC5), and thyroid hormone-dependent oligodendrocyte maturation (NPC6). In addition, we extend our work from the hNPCs to human induced pluripotent stem cell-derived NPCs (hiNPCs) for the NPC proliferation (iNPC1ab) and radial glia assays (iNPC2a). The validation process we report for the endpoints studied with the Neurosphere Assays is based on 1) describing the relevance of the respective endpoints for brain development, 2) the confirmation of the cell type-specific morphologies observed in vitro, 3) expressions of cell type-specific markers consistent with those morphologies, 4) appropriate anticipated responses to physiological pertinent signaling stimuli and 5) alterations in specific in vitro endpoints upon challenges with confirmed DNT compounds. With these strong mechanistic underpinnings, we posit that the Neurosphere Assay as an integral part of the DNT in vitro screening battery is well poised for DNT evaluation for regulatory purposes.

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Effective exposure of chemicals in in vitro cell systems: A review of chemical distribution models

Cited by 77 publications

References 161 publications

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Combining in vitro assays and mathematical modelling to study developmental neurotoxicity induced by chemical mixtures

Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

Scientific Validation of Human Neurosphere Assays for Developmental Neurotoxicity Evaluation

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