In vitro techniques for the assessment of neurotoxicity.
In vitro techniques for the assessment of neurotoxicity.
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评估神经毒性的体外技术。
DOI：
10.1289/ehp.98106s1131
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发表时间：
1998-02
影响因子：
10.4
通讯作者：
中科院分区：
文献类型：
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作者：
风险评估是一个过程，通常分为以下步骤：a）危害识别，B）剂量-反应评估，c）接触评估，d）风险定性。监管毒性研究通常旨在为前两个步骤提供数据。人类病例报告、环境研究和体外研究也可用于确定或进一步描述毒性危害。在本报告中，体外技术的优势和局限性进行了讨论，根据其有用性，以确定神经毒性危害，以及随后的剂量反应评估。由于神经系统的复杂性，单个细胞的多种功能，以及我们对神经毒性所涉及的生化过程的有限了解，目前尚不清楚任何体外系统将如何重现体内系统。因此，很难设计一种体外试验组合来代替体内试验系统。体外系统非常适合于在更孤立的背景下研究生物过程，并且已最成功地用于阐明毒性机制，鉴定神经毒性的靶细胞，并描绘神经毒物诱导的发育和复杂的细胞变化。生物化学和形态学终点均可使用，但许多使用的终点可通过药理作用以及毒性改变。因此，对于这些终点中的许多终点，很难或不可能设定一个标准来区分药理学作用和神经毒性作用。对于风险评估过程来说，这种区分是核心。因此，必须仔细选择用于确定化合物潜在神经毒性的终点，并评价其区分不良神经毒性作用和药理学作用的潜力。显然，对于体外神经毒性研究，可以使用的主要终点是通过特定神经毒性机制受到影响的终点。例如，体外系统可用于某些结构确定的化合物和毒性机制，如有机磷化合物和迟发性神经病，其靶细胞和参与神经毒性的生化过程是众所周知的。对于其他化合物和不同类型的神经毒性，首先需要确定毒性机制。一旦通过体内或体外方法鉴定，就可以开发一种系统来检测和评价所产生的体内神经毒性类型的预测能力。因此，体外试验在提供基本机械过程的信息方面具有最大的潜力，以便改进在整个动物中要解决的特定实验问题。
Risk assessment is a process often divided into the following steps: a) hazard identification, b) dose-response assessment, c) exposure assessment, and d) risk characterization. Regulatory toxicity studies usually are aimed at providing data for the first two steps. Human case reports, environmental research, and in vitro studies may also be used to identify or to further characterize a toxic hazard. In this report the strengths and limitations of in vitro techniques are discussed in light of their usefulness to identify neurotoxic hazards, as well as for the subsequent dose-response assessment. Because of the complexity of the nervous system, multiple functions of individual cells, and our limited knowledge of biochemical processes involved in neurotoxicity, it is not known how well any in vitro system would recapitulate the in vivo system. Thus, it would be difficult to design an in vitro test battery to replace in vivo test systems. In vitro systems are well suited to the study of biological processes in a more isolated context and have been most successfully used to elucidate mechanisms of toxicity, identify target cells of neurotoxicity, and delineate the development and intricate cellular changes induced by neurotoxicants. Both biochemical and morphological end points can be used, but many of the end points used can be altered by pharmacological actions as well as toxicity. Therefore, for many of these end points it is difficult or impossible to set a criterion that allows one to differentiate between a pharmacological and a neurotoxic effect. For the process of risk assessment such a discrimination is central. Therefore, end points used to determine potential neurotoxicity of a compound have to be carefully selected and evaluated with respect to their potential to discriminate between an adverse neurotoxic effect and a pharmacologic effect. It is obvious that for in vitro neurotoxicity studies the primary end points that can be used are those affected through specific mechanisms of neurotoxicity. For example, in vitro systems may be useful for certain structurally defined compounds and mechanisms of toxicity, such as organophosphorus compounds and delayed neuropathy, for which target cells and the biochemical processes involved in the neurotoxicity are well known. For other compounds and the different types of neurotoxicity, a mechanism of toxicity needs to be identified first. Once identified, by either in vivo or in vitro methods, a system can be developed to detect and to evaluate predictive ability for the type of in vivo neurotoxicity produced. Therefore, in vitro tests have their greatest potential in providing information on basic mechanistic processes in order to refine specific experimental questions to be addressed in the whole animal.