ArticlePloS one2019
Using the concordance of in vitro and in vivo data to evaluate extrapolation assumptions.
Article in PloS one, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed.
- Integrating mechanistic data to contextualize in vivo apical observations using the developmental neurotoxicity in vitro battery.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Extrapolation of in vitro effect concentrations to in vivo bioavailable concentrations using PBK modelling in humans for two classes of persistent and mobile compounds: triazoles and triazines.Archives of toxicology · 2026Article
- Extrapolation steps in quantitativeCurrent research in toxicology · 2026Review
- Cross-species comparisons of plasma binding and considerations for data evaluation.Toxicology in vitro : an international journal published in association with BIBRA · 2025Article
- Comparative Analysis of Chemical Distribution Models for Quantitative In Vitro to In Vivo Extrapolation.Toxics · 2025Article
- Incorporating new approach methods (NAMs) data in dose-response assessments: The future is now!Journal of toxicology and environmental health. Part B, Critical reviews · 2025Review
- Article
- Challenging the status quo: a framework for mechanistic and human-relevant cardiovascular safety screening.Frontiers in toxicology · 2024Review
- Development and validation of PBPK models for genistein and daidzein for use in a next-generation risk assessment.Frontiers in pharmacology · 2024Article
- Article
- New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.Environmental toxicology and chemistry · 2023Review
- HExpPredict:Environmental health perspectives · 2023Article
- Integrating distribution kinetics and toxicodynamics to assess repeat dose neurotoxicityFrontiers in pharmacology · 2023Article
- Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment.Archives of toxicology · 2022Article
- Exposure forecasting - ExpoCast - for data-poor chemicals in commerce and the environment.Journal of exposure science & environmental epidemiology · 2022Review
- Advances in computational methods along the exposure to toxicological response paradigm.Toxicology and applied pharmacology · 2022Article
- Comprehensive interpretation of in vitro micronucleus test results for 292 chemicals: from hazard identification to risk assessment application.Archives of toxicology · 2022Article
- IVIVE: Facilitating the Use ofToxics · 2022Review
- Predictive Performance of Next Generation Physiologically Based Kinetic (PBK) Model Predictions in Rats Based on In Vitro and In Silico Input Data.Toxicological sciences : an official journal of the Society of Toxicology · 2022Article
- Article
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Authors and funding
10 authors.
Funding
Abstract
Linking in vitro bioactivity and in vivo toxicity on a dose basis enables the use of high-throughput in vitro assays as an alternative to traditional animal studies. In this study, we evaluated assumptions in the use of a high-throughput, physiologically based toxicokinetic (PBTK) model to relate in vitro bioactivity and rat in vivo toxicity data. The fraction unbound in plasma (fup) and intrinsic hepatic clearance (Clint) were measured for rats (for 67 and 77 chemicals, respectively), combined with fup and Clint literature data for 97 chemicals, and incorporated in the PBTK model. Of these chemicals, 84 had corresponding in vitro ToxCast bioactivity data and in vivo toxicity data. For each possible comparison of in vitro and in vivo endpoint, the concordance between the in vivo and in vitro data was evaluated by a regression analysis. For a base set of assumptions, the PBTK results were more frequently better associated than either the results from a "random" model parameterization or direct comparison of the "untransformed" values of AC50 and dose (performed best in 51%, 28%, and 21% of cases, respectively). We also investigated several assumptions in the application of PBTK for IVIVE, including clearance and internal dose selection. One of the better assumptions sets-restrictive clearance and comparing free in vivo venous plasma concentration with free in vitro concentration-outperformed the random and untransformed results in 71% of the in vitro-in vivo endpoint comparisons. These results demonstrate that applying PBTK improves our ability to observe the association between in vitro bioactivity and in vivo toxicity data in general. This suggests that potency values from in vitro screening should be transformed using in vitro-in vivo extrapolation (IVIVE) to build potentially better machine learning and other statistical models for predicting in vivo toxicity in humans.
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