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.

体内调节的局限性发育神经毒性 (DNT) 测试和评估是众所周知的，例如 3R 冲突、低通量、高成本、需要高专业知识以及缺乏更深层次的机制信息。此外，体内 DNT 数据的标准变异性和在实验动物中对人类现实生活的外推是不确定的。在这里，使用表格 OECD 格式系统地总结了有关这些限制和不确定性的知识。我们还概述了一个假设，用于 DNT 的替代的、适合目的的综合测试和评估方法 (IATA) 如何改进当前的标准动物测试：3Rs 合规性的相对收益、降低的成本、更高的吞吐量、改进的基础研究设计、更高的标准化没有 3R 冲突的测试、评估和验证，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。对潜在 DNT 使用早期、机械、敏感的指标可以更好地支持人类安全评估和混合物外推。理想地使用动力学模型，这些可以提供 - 最终取决于上下文 - 至少相同水平的人类健康保护。这种新方法还可能导致对化学安全性的新机制理解，允许确定可能不会触发确定的毒性特征或途径的剂量，而不是不会导致当前顶端生物终点的剂量。