94% of researchers rate our articles as excellent or good
Learn more about the work of our research integrity team to safeguard the quality of each article we publish.
Find out more
ORIGINAL RESEARCH article
Front. Toxicol.
Sec. Computational Toxicology and Informatics
Volume 7 - 2025 | doi: 10.3389/ftox.2025.1535112
Developing a predictive model for blood-brain-barrier permeability to explore relevance of in vitro neurotoxicity data for in vivo risk assessment
Provisionally accepted- 1University of Nevada, Reno, Reno, United States
- 2University of Rochester Medical Center, Rochester, New York, United States
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Despite recent rapid advancements in in vitro toxicology, its application to whole-body health outcomes remains limited. Incorporating factors like internal exposure, such as permeability across biomembranes, could improve its relevance. Notably, there is a lack of data and predictive models for blood-brain barrier (BBB) permeability, a proxy for the exposure of target organs to neurotoxicity. We developed a predictive model for BBB permeability to investigate whether it can strengthen the correlation between in vitro and in vivo neurotoxicity data. We collected permeability data from parallel artificial membrane permeability assays for brain membranes (PAMPA-BBB) for 106 compounds with varied physicochemical properties. This was utilized to develop an empirical model to expand the potential coverage of chemicals. A list of 23 chemicals with available in vivo and in vitro neurotoxicity data from EPA IRIS and ToxCast was curated to analyze the correlation in toxicity rankings with the Spearman correlation coefficient, with and without the consideration of permeability from our predictive model. The PAMPA-BBB predictive model showed promising results, with an R 2 of 0.71 (measured vs predicted permeabilities). Considering permeability did not improve the correlation between in vitro and in vivo neurotoxicity (0.01 vs -0.11). This weak correlation may stem from model uncertainty and the exclusion of other toxicokinetic processes, along with interspecies toxicodynamics differences. Our results indicate more detailed information on how neurotoxic substances behave inside the body is essential to better utilize the in vitro neurotoxicity data for predicting in vivo toxicity and assessing the risk to the central nervous system.
Keywords: blood-brain-barrier, Permeability, Neurotoxicity, in vitro, in vivo, Toxicokinetic
Received: 28 Nov 2024; Accepted: 07 Apr 2025.
Copyright: © 2025 Illa, Feng Earley, Li and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dingsheng Li, University of Nevada, Reno, Reno, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.