Novel strategy to assess the neurotoxicity of organic solvents such as glycol ethers. Protocol for combining in vitro and in silico methods with human-controlled exposure experiments

Background Chemicals are not required to be tested systematically for their neurotoxic potency, although they may contribute to the development of several neurological diseases. The absence of systematic testing may be partially explained by the current Organisation for Economic Co-operation and Development (OECD) Test Guidelines, which rely on animal experiments that are expensive, laborious, and ethically debatable. Therefore, it is important to understand the risks to exposed workers and the general population exposed to domestic products. In this study, we propose a strategy to test the neurotoxicity of solvents using the commonly used glycol ethers as a case study. Objective This study aims to provide a strategy that can be used by regulatory agencies and industries to rank solvents according to their neurotoxicity and demonstrate the use of toxicokinetic modeling to predict air concentrations of solvents that are below the no observed adverse effect concentrations (NOAECs) for human neurotoxicity determined in in vitro assays. Methods The proposed strategy focuses on a complex 3D in vitro brain model (BrainSpheres) derived from human-induced pluripotent stem cells (hiPSCs). This model is accompanied by in vivo, in vitro, and in silico models for the blood-brain barrier (BBB) and in vitro models for liver metabolism. The data are integrated into a toxicokinetic model. Internal concentrations predicted using this toxicokinetic model are compared with the results from in vivo human-controlled exposure experiments for model validation. The toxicokinetic model is then used in reverse dosimetry to predict air concentrations, leading to brain concentrations lower than the NOAECs determined in the hiPSC-derived 3D brain model. These predictions will contribute to the protection of exposed workers and the general population with domestic exposures. Results The Swiss Centre for Applied Human Toxicology funded the project, commencing in January 2021. The Human Ethics Committee approval was obtained on November 16, 2022. Zebrafish experiments and in vitro methods started in February 2021, whereas recruitment of human volunteers started in 2022 after the COVID-19 pandemic–related restrictions were lifted. We anticipate that we will be able to provide a neurotoxicity testing strategy by 2026 and predicted air concentrations for 6 commonly used propylene glycol ethers based on toxicokinetic models incorporating liver metabolism, BBB leakage parameters, and brain toxicity. Conclusions This study will be of great interest to regulatory agencies and chemical industries needing and seeking novel solutions to develop human chemical risk assessments. It will contribute to protecting human health from the deleterious effects of environmental chemicals. International Registered Report Identifier (IRRID) DERR1-10.2196/50300

Keywords

Subject (DDC)

500 - Naturwissenschaften und Mathematik

Project

Event

Exhibition start date

Exhibition end date

Conference start date

Conference end date

Date of the last check

ISBN

ISSN

1929-0748

Language

English

Created during FHNW affiliation

Yes

Strategic action fields FHNW

Publication status

Published

Review

Peer review of the complete publication

Open access category

Gold

License

Citation

Hopf, N. B., Suter-Dick, L., Huwyler, J., Borgatta, M., Hegg, L., Pamies, D., Paschoud, H., Puligilla, R. D., Reale, E., Werner, S., & Zurich, M.-G. (2024). Novel strategy to assess the neurotoxicity of organic solvents such as glycol ethers. Protocol for combining in vitro and in silico methods with human-controlled exposure experiments. JMIR Research Protocols, 13. https://doi.org/10.2196/50300

Full item page