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

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2022
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Klose, Jördis
Pahl, Melanie
Bartmann, Kristina
Bendt, Farina
Fritsche, Ellen
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Cell biology and toxicology. Springer Science. 2022, 38(5), pp. 781-807. ISSN 0742-2091. eISSN 1573-6822. Available under: doi: 10.1007/s10565-021-09603-2
Zusammenfassung

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.

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570 Biowissenschaften, Biologie
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Developmental neurotoxicity, Flame retardants, Human cell–based testing battery, 3D in vitro model, New approach methodologies, Hazard assessment
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ISO 690KLOSE, Jördis, Melanie PAHL, Kristina BARTMANN, Farina BENDT, Jonathan BLUM, Xenia DOLDE, Anna-Katharina HOLZER, Katharina KOCH, Marcel LEIST, Ellen FRITSCHE, 2022. Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery. In: Cell biology and toxicology. Springer Science. 2022, 38(5), pp. 781-807. ISSN 0742-2091. eISSN 1573-6822. Available under: doi: 10.1007/s10565-021-09603-2
BibTex
@article{Klose2022-10Neuro-53705,
  year={2022},
  doi={10.1007/s10565-021-09603-2},
  title={Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery},
  number={5},
  volume={38},
  issn={0742-2091},
  journal={Cell biology and toxicology},
  pages={781--807},
  author={Klose, Jördis and Pahl, Melanie and Bartmann, Kristina and Bendt, Farina and Blum, Jonathan and Dolde, Xenia and Holzer, Anna-Katharina and Koch, Katharina and Leist, Marcel and Fritsche, Ellen}
}
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