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Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery

Klose, Jördis, Pahl, Melanie, Bartmann, Kristina, Bendt, Farina, Blum, Jonathan, Dolde, Xenia, Förster, Nils, Holzer, Anna-Katharina +13 more·2022·Cell Biology and Toxicology

Abstract

Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from <1 μM (5 FRs), 1<10 μM (7 FRs) to the >10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment. Graphical abstract

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Cited by

Sorted by citations

Authors
Klose, J., Pahl, M., Bartmann, K., Bendt, F., Blum, J., Dolde, X., Förster, N., Holzer, A.-K., Hübenthal, U., Keßel, H. E., Koch, K., Masjosthusmann, S., Schneider, S., Stürzl, L.-C., Woeste, S., Rossi, A., Covaci, A., Behl, M., Leist, M., Tigges, J., & Fritsche, E.
Venue
Cell Biology and Toxicology
Published
2021-05-10
Volume
38
Issue
5
Pages
781-807
ISSN
  • 0742-2091
  • 1573-6822
Cited by
42
References
2
Language
en
Funders
  • Forschungskommision of the medical faculty of the Heinrich-Heine-University (2016-53)
  • European Food Safety Authority (OC/EFSA/PRAS/2017/01)
  • CERST (233-1.08.03.03-121972/131 – 1.08.03.03 – 121972)
  • DFG Ursula M. Händel Tierschutzpreis to Ellen Fritsche (DFG FR 1392/6-1:)
  • European Union's Horizon 2020 research and innovation programme (681002, 825759)

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