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Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery |
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| Authors: | Klose Jördis Pahl Melanie Bartmann Kristina Bendt Farina Blum Jonathan Dolde Xenia Förster Nils Holzer Anna-Katharina Hübenthal Ulrike Keßel Hagen Eike Koch Katharina Masjosthusmann Stefan Schneider Sabine Stürzl Lynn-Christin Woeste Selina Rossi Andrea Covaci Adrian Behl Mamta Leist Marcel Tigges Julia Fritsche Ellen |
| Affiliation: | 1.IUF-Leibniz Research Institute for Environmental Medicine, Auf’m Hennekamp 50, 40225, Duesseldorf, NRW, Germany ;2.Department of Biology, University of Konstanz, Universit?tsstra?e 10, 78464, Konstanz, BW, Germany ;3.Faculty for Biology and Biotechnology, Bioinformatics Group, RUB – Ruhr University Bochum, Bochum, Germany ;4.Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium ;5.Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, 27709, USA ;6.Medical Faculty, Heinrich-Heine-University, Universit?tsstra?e 1, 40225, Duesseldorf, NRW, Germany ; |
| 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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