Application of in vitro neurotoxicity testing for regulatory purposes:: Symposium III summary and research needs
Application of in vitro neurotoxicity testing for regulatory purposes:: Symposium III summary and research needs
复制标题
DOI：
10.1016/j.neuro.2008.02.008
复制
发表时间：
2008-05-01
期刊：
影响因子：
3.4
通讯作者：
Costa, Lucio G.
中科院分区：
文献类型：
--
作者：
Bal-Price, Anna K.;Sunol, Cristina;Costa, Lucio G.
神经毒性效应的预测是许多化合物毒理学特征的一个关键特征，因此是监管测试计划所要求的。目前，OECD和EC的神经毒性评价标准主要是基于体内试验，主要评价神经行为和神经病理学效应，成本高、耗时长，不适合筛选大量的化学品。此外，这种体内测试并不总是足够敏感，以预测人类神经毒性，往往不提供信息，促进监管决策过程。纳入替代试验（体外试验、计算建模、QSAR、分组、交叉读码等）在筛选策略将加快速度，其中化合物的知识和机制的数据是可用的，所获得的信息可用于在未来的体内研究，以促进神经毒性的预测的改进。REACH解决了欧洲化学品的一个关键问题，即缺乏公开的安全数据表。它概述了一项测试约30，000种现有物质的计划。目前，这些化学品的生产量超过1吨/年，而且缺乏关于人类健康和生态毒理学影响的基本数据。据估计，大约有390万只试验动物（包括260万只脊椎动物）（Hartung T，Bremer S，Casati S，Coecke S，Corvi R，Fortnaer S，et al. ECVAM's response to the changing political environment for alternatives：consequences of the European Union chemicals and cosmetics policies. ATLA 2003; 31：473-81）将是必要的，以满足REACH的要求，如果替代方法的开发和建立不被监管机构接受。为了在这一吨位范围内减少动物使用和试验成本，欧洲联盟委员会提倡使用替代方法。神经毒性试验在REACH法规中没有直接涉及，但是当基于器官特异性毒性研究观察到警报时，必须进行神经毒性评估。第11届国际神经毒理学协会会议提供了一个论坛，公开讨论和辩论在法规要求的背景下可能与神经毒性评估相关的体外试验策略的潜力。欧盟FP 6项目A-Cute-Tox作为预测人类急性全身毒性的可能体外试验策略的一个例子。其他专题介绍侧重于现有体外模型（细胞系和原代培养物）和神经元特异性终点的特性，特别强调电活动、代谢组学和泡状神经递质释放的调节，作为与体外神经毒性试验相关的可能神经元终点。最后，有人强调，在体外
Prediction of neurotoxic effects is a key feature in the toxicological profile of many compounds and therefore is required by regulatory testing schemes. Nowadays neurotoxicity assessment required by the OECD and EC test guidelines is based solely on in vivo testing, evaluating mainly effects on neurobehavior and neuropathology, which is expensive, time consuming and unsuitable for screening large number of chemicals. Additionally, such in vivo tests are not always sensitive enough to predict human neurotoxicity and often do not provide information that facilitates regulatory decision-making processes. Incorporation of alternative tests (in vitro testing, computational modelling, QSARs, grouping, read-across, etc.) in screening strategies would speed up the rate at which compound knowledge and mechanistic data are available and the information obtained could be used in the refinement of future in vivo studies to facilitate predictions of neurotoxicity.On 1st June 2007, the European Commission legislation concerning registration, evaluation and authorisation of chemicals (REACH) has entered into force. REACH addresses one of the key issues for chemicals in Europe, the lack of publicly available safety data sheets. It outlines a plan to test approximately 30,000 existing substances. These chemicals are currently produced in volumes greater than 1 ton/year and the essential data on the human health and ecotoxicological effects are lacking. It is estimated that approximately 3.9 million test animals (including 2.6 million vertebrates) (Hartung T, Bremer S, Casati S, Coecke S, Corvi R, Fortnaer S, et al. ECVAM's response to the changing political environment for alternatives: consequences of the European Union chemicals and cosmetics policies. ATLA 2003;31:473-81) would be necessary to fulfill the requirements of REACH if the development and establishment of alternative methods is not accepted by regulatory authorities. In an effort to reduce animal use and testing costs within this tonnage band, the European Commission has advocated the use of alternative approaches. Neurotoxicity testing is not directly addressed within REACH, however when alerts are observed based on organ specific toxicity studies then neurotoxicity assessment has to be performed.This session at the 11th International Neurotoxicology Association Meeting provided a forum to openly discuss and debate the potential of in vitro testing strategies that could be relevant for neurotoxicity evaluation in the context of regulatory requirements. The EU FP6 project A-Cute-Tox was presented as an example of a possible in vitro testing strategy for prediction of human acute systemic toxicity. Other presentations focused on the characterization of the available in vitro models (cell lines and primary culture) and neuronal specific endpoints, with a special emphasis on electrical activity, metabonomics and modulation of vesicular neurotransmitter release as possible neuronal endpoints relevant for in vitro neurotoxicity testing. Finally, it was underlined that in vitro