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Abstract：
Limitations of regulatory in vivo developmental neurotoxicity (DNT) testing and assessment are well known, such as the 3Rs conflict, low throughput, high costs, high specific expertise needed and the lack of deeper mechanistic information. Moreover, the standard in vivo DNT data variability and in the experimental animal to human real life extrapolation is uncertain. Here, knowledge about these limitations and uncertainties is systematically summarized using a tabular OECD format. We also outline a hypothesis how alternative, fit-for-purpose Integrated Approaches to Testing and Assessment (IATAs) for DNT could improve current standard animal testing: Relative gains in 3Rs compliance, reduced costs, higher throughput, improved basic study design, higher standardization of testing and assessment and validation without 3Rs conflict, increasing the availability and reliability of DNT data. This could allow a more reliable comparative toxicity assessment over a larger proportion of chemicals within our global environment. The use of early, mechanistic, sensitive indicators for potential DNT could better support human safety assessment and mixture extrapolation. Using kinetic modelling ideally these could provide - eventually context dependent - at least the same level of human health protection. Such new approaches could also lead to a new mechanistic understanding for chemical safety, permitting determination of a dose that is likely not to trigger defined toxicity traits or pathways, rather than a dose not causing the current apical organism endpoints. The manuscript shall motivate and guide the development of new alternative methods for IATAs with diverse applications and support decision-making for their regulatory acceptance.
摘要：
调节体内发育神经毒性（DNT）测试和评估的局限性是众所周知的，比如3R冲突，低吞吐量，高成本,需要很高的专业知识，缺乏更深层次的机械信息。此外，标准的体内DNT数据变异性和在实验动物到人类现实生活中的外推是不确定的。这里,关于这些限制和不确定性的知识是使用表格经合组织格式系统地总结的。我们还概述了一个假设，适用于DNT的集成测试和评估方法（IATAs）可以改善当前的标准动物测试：3Rs合规性的相对收益，降低成本,更高的吞吐量，改进的基础研究设计，更高的测试、评估和验证标准化，没有3R冲突，提高DNT数据的可用性和可靠性。这可以对我们全球环境中更大比例的化学品进行更可靠的比较毒性评估。使用早期，机械学,潜在DNT的敏感指标可以更好地支持人体安全性评估和混合外推。理想情况下，使用动力学建模可以提供-最终取决于上下文-至少相同水平的人类健康保护。这种新方法也可能导致对化学品安全的新机械理解，允许确定可能不会触发定义的毒性特征或途径的剂量，而不是不引起当前顶端生物体终点的剂量。该手稿应激励和指导IATAs开发新的替代方法，并支持其监管接受的决策。
