Predicting human neurotoxicity of propylene glycol methyl ether (PGME) by implementing in vitro neurotoxicity results into toxicokinetic modelling

E Reale; J Sandstrom; M Culot; J Hechon; S Wellens; M Heymans; F Tschudi-Monnet; D Vernez; N B Hopf

doi:10.1016/j.scitotenv.2023.163767

Predicting human neurotoxicity of propylene glycol methyl ether (PGME) by implementing in vitro neurotoxicity results into toxicokinetic modelling

Sci Total Environ. 2023 Aug 15:886:163767. doi: 10.1016/j.scitotenv.2023.163767. Epub 2023 May 6.

Authors

E Reale¹, J Sandstrom², M Culot³, J Hechon⁴, S Wellens³, M Heymans³, F Tschudi-Monnet⁵, D Vernez¹, N B Hopf⁶

Affiliations

¹ Center for Primary Care and Public Health (Unisanté), Route de la Corniche 2, 1066 Epalinges-Lausanne, Switzerland.
² Swiss 3R Competence Centre, Hochschulstrasse 6, CH-3012 Bern, Switzerland; Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, CH-4055 Basel, Switzerland.
³ Univ. Artois, UR 2465, Laboratoire de la Barrière Hémato-Encéphalique (LBHE), F-62300 Lens, France.
⁴ Institut Universitaire de Santé au Travail (IST), Rue du Bugnon 19, 1005 Lausanne, Switzerland.
⁵ Swiss Centre for Applied Human Toxicology (SCAHT), University of Basel, Missionsstrasse 64, CH-4055 Basel, Switzerland.
⁶ Center for Primary Care and Public Health (Unisanté), Route de la Corniche 2, 1066 Epalinges-Lausanne, Switzerland. Electronic address: Nancy.Hopf@unisante.ch.

PMID: 37156387
DOI: 10.1016/j.scitotenv.2023.163767

Abstract

Although organic solvents have been associated with CNS toxicity, neurotoxicity testing is rarely a regulatory requirement. We propose a strategy to assess the potential neurotoxicity of organic solvents and predict solvent air concentrations that will not likely produce neurotoxicity in exposed individuals. The strategy integrated an in vitro neurotoxicity, an in vitro blood-brain barrier (BBB), and an in silico toxicokinetic (TK) model. We illustrated the concept with propylene glycol methyl ether (PGME), widely used in industrial and consumer products. The positive control was ethylene glycol methyl ether (EGME) and negative control propylene glycol butyl ether (PGBE), a supposedly non-neurotoxic glycol ether. PGME, PGBE, and EGME had high passive permeation across the BBB (permeability coefficients (P_e) 11.0 × 10^-3, 9.0 × 10^-3, and 6.0 × 10^-3 cm/min, respectively). PGBE was the most potent in in vitro repeated neurotoxicity assays. EGME's main metabolite, methoxyacetic acid (MAA) may be responsible for the neurotoxic effects reported in humans. No-observed adverse effect concentrations (NOAECs) for the neuronal biomarker were for PGME, PGBE, and EGME 10.2, 0.07, and 79.2 mM, respectively. All tested substances elicited a concentration-dependent increase in pro-inflammatory cytokine expressions. The TK model was used for in vitro-to-in vivo extrapolation from PGME NOAEC to corresponding air concentrations (684 ppm). In conclusion, we were able to predict air concentrations that would not likely result in neurotoxicity using our strategy. We confirmed that the Swiss PGME occupational exposure limit (100 ppm) will not likely produce immediate adverse effects on brain cells. However, we cannot exclude possible long-term neurodegenerative effects because inflammation was observed in vitro. Our simple TK model can be parameterized for other glycol ethers and used in parallel with in vitro data for systematically screening for neurotoxicity. If further developed, this approach could be adapted to predict brain neurotoxicity from exposure to organic solvents.

Keywords: 1-Methoxypropan-2-ol; CNS; Glycol ethers; IVIVE; PBPK; Solvent neurotoxicity.

MeSH terms

Ether*
Ethers / toxicity
Ethylene Glycols / metabolism
Ethylene Glycols / toxicity
Humans
Propylene Glycols* / metabolism
Propylene Glycols* / toxicity
Solvents
Toxicokinetics

Substances

propylene glycol methyl ether
Ether
Propylene Glycols
Ethers
ethylene glycol diethyl ether
Ethylene Glycols
Solvents