Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods.
Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods.
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DOI：
10.1016/j.taap.2018.02.008
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发表时间：
2018-09-01
影响因子：
3.8
通讯作者：
Worth A
中科院分区：
文献类型：
--
作者：
Bal-Price A;Pistollato F;Sachana M;Bopp SK;Munn S;Worth A
目前，有可能诱发发育神经毒性（DNT）的化学品的鉴定是基于动物试验。由于在监管层面，DNT的系统性检测不是欧盟或美国化学法规安全性评估的标准要求，因此仅在基于化学结构活性关系或全身急性或重复剂量毒性研究中神经毒性证据触发的更高层次检测中进行DNT检测。然而，这些触发很少使用，此外，并不总是作为DNT的可靠指标，因为它们通常是基于成年啮齿动物的观察。因此，迫切需要开发替代方法，以可靠地支持识别DNT触发器，并更快速和更具成本效益地支持识别和表征具有DNT潜力的化学品。我们建议将来自体外研究的机制知识和数据纳入，以支持各种监管应用，包括：（a）识别潜在的DNT触发器，（B）初始化学筛选和优先级，（c）危害识别和表征，（d）化学生物分组，以及（e）评估化学混合物的暴露。理想情况下，目前可用的细胞神经元/神经胶质细胞来源于人类诱导多能干细胞（hiPSC）的模型应该被使用，因为它们允许评估化学品对关键神经发育过程的影响，通过复制人类大脑发育过程中的不同暴露窗口。来自hiPSC的一系列DNT体外测试方法可以产生有价值的机理数据，加速评估工业，农业和消费品中存在的数千种化合物，这些化合物缺乏DNT潜力的安全数据。目前在体内发育神经毒性（DNT）测试是不有效的，覆盖范围是稀疏的。体外机制数据可以支持各种监管应用。建议使用人诱导多能干细胞衍生的神经元模型进行DNT测试。DNT相关不良结局途径的进一步发展是迫切需要的。体外方法应包括在监管DNT测试中
Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential. We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential. Current in vivo developmental neurotoxicity (DNT) testing is not efficient and coverage is sparse. In vitro mechanistic data could support various regulatory applications. Human induced pluripotent stem cell-derived neuronal models are recommended for DNT testing. Further development of adverse outcome pathways relevant to DNT is urgently needed. In vitro approaches should be included in regulatory DNT testing
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DOI：
10.1186/1476-069x-7-50
发表时间：
2008-10-22
期刊：
Environmental health : a global access science source
影响因子：
--
作者：
Bjørling-Poulsen M;Andersen HR;Grandjean P
通讯作者：
Grandjean P
影响因子：
3.4
作者：
Bal-Price, Anna K.;Sunol, Cristina;Costa, Lucio G.
通讯作者：
Costa, Lucio G.
影响因子：
10.4
作者：
Coecke S;Goldberg AM;Allen S;Buzanska L;Calamandrei G;Crofton K;Hareng L;Hartung T;Knaut H;Honegger P;Jacobs M;Lein P;Li A;Mundy W;Owen D;Schneider S;Silbergeld E;Reum T;Trnovec T;Monnet-Tschudi F;Bal-Price A
通讯作者：
Bal-Price A
影响因子：
3.3
作者：
Aagaard, Alf;Brock, Theo;Van Der Linden, Ton
通讯作者：
Van Der Linden, Ton
影响因子：
6.1
作者：
Bal-Price, Anna;Crofton, Kevin M.;Fritsche, Ellen
通讯作者：
Fritsche, Ellen