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

中文翻译：

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使用人体 DNT 体外测试电池评估阻燃剂的神经发育毒性

由于其神经发育毒性，多溴二苯醚等阻燃剂 (FR) 已被禁止进入市场，取而代之的是替代性阻燃剂，如有机磷阻燃剂，这些阻燃剂大多具有未知的毒理学特征。为了研究它们的神经发育毒性，我们评估了几种 FR 的危害，包括已淘汰的多溴 FR 和有机磷 FR：2,2',4,4'-四溴二苯醚 (BDE-47)、2,2'、4,4'、 5-五溴二苯醚（BDE-99）、四溴双酚A、磷酸三苯酯、磷酸三（2-丁氧基乙基）酯及其代谢物磷酸双（2-丁氧基乙基）酯、磷酸异癸基二苯酯、异丙基磷酸三苯酯、磷酸三甲苯酯、三（1,3） -二氯-2-丙基)磷酸酯、叔丁基苯基二苯基磷酸酯、2-乙基己基二苯基磷酸酯、三(1-氯异丙基)磷酸酯，和磷酸三（2-氯乙基）酯。因此，我们使用了一种基于人体细胞的发育神经毒性 (DNT) 体外电池，涵盖了多种神经发育终点。根据电池中各自最敏感的基准浓度 (BMC)，效力从 <1 μM (5 FRs)、1<10 μM (7 FRs) 到 >10 μM 范围 (3 FRs)。使用 ToxPi 工具对数据进行的评估揭示了 (a) 与 BMC 和 (b) 与 ToxCast 数据相比的不同排名，这表明 ToxCast 分析无法很好地预测这些 FR 的 DNT 危害。将 DNT 体外电池 BMC 外推到人类通过母乳接触 FR 表明单个化合物的风险较低。然而，它引起了人们对现实生活中混合物暴露的潜在担忧，特别是当不同的化合物通过不同的作用模式聚集在共同的端点上时，例如本研究中的少突胶质细胞分化。这个使用 FRs 的案例研究表明，基于人体细胞的 DNT 体外电池是神经发育危害评估和风险评估中化合物优先级排序的一种有前途的方法。

图形概要