JMIR Publications

ABSTRACT

Background:

Environmental and occupational exposures to solvents may contribute to the development of several neurological diseases, however these chemicals are not systematically tested for their neurotoxic potency. This can partially be explained by the current OECD test guidelines relying on animal experiments that are expensive, laborious, and ethically debatable. Solvents have been shown to induce neurological conditions. It is therefore important to understand these risks in exposed workers as well as in the general population exposed to domestic products.

Objective:

We have two study aims: (1) provide regulatory agencies and industries with a strategy to rank solvents according to their neurotoxicity, and (2) demonstrate the use of toxicokinetic (TK) modelling 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 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 blood-brain barrier (BBB) and in vitro models for liver metabolism. Data are integrated in a TK model. Internal concentrations predicted with this TK model are compared to results from controlled in vivo human exposure experiments for model validation. The TK model is then used in reverse dosimetry to predict air concentrations leading to brain concentrations lower than the NOAECs determined in the hiPSCs-derived 3D brain model. These predictions will contribute to the protection of exposed workers and the general population with domestic exposures.

Results:

The project was funded by the Swiss Centre for Applied Human Toxicology (SCAHT) with a start date January 2021. The Human Ethical Committee approval was obtained in 2022. Zebrafish experiments and in vitro methods started February 2021 while recruitment of human volunteers started in 2022 after COVID-19 pandemic related restrictions were lifted. We anticipate that we will be able to provide a neurotoxicity testing strategy by 2026 as well as predicted air concentrations for six commonly used propylene glycol ethers based on toxicokinetic (TK) models incorporating liver metabolism, BBB leakage parameters, and brain toxicity.

Conclusions:

This study will be of high interest to regulatory agencies and chemical industries needing and seeking novel solutions to develop human chemical risk assessments. It will contribute to protect human health from the deleterious effects of environmental chemicals.