Noga Maciej, Jurowski Kamil
Department of Regulatory and Forensic Toxicology, Institute of Medical Expertises in Łódź, Ul. Aleksandrowska 67/93, 91-205, Łódź, Poland.
Department of Toxicology, Faculty of Medicine, Medical College, Rzeszów University, Al. Mjr. W. Kopisto 2a, 35-959, Rzeszów, Poland.
Arch Toxicol. 2025 Jun 25. doi: 10.1007/s00204-025-04105-0.
Nitrogen mustards are potent alkylating agents originally developed as chemical warfare agents and later adapted for medical applications. Despite their well-documented toxicity, systematic studies on their acute toxicity profiles remain limited. Addressing this gap, the present study offers a comprehensive in silico evaluation of nitrogen mustards, employing both qualitative and quantitative computational models. Using advanced in silico tools, the toxicity of these compounds was assessed across multiple exposure routes, including oral, dermal, and inhalation pathways. Qualitative predictions conducted with STopTox, ADMETlab, and admetSAR consistently classified nitrogen mustards as highly toxic, particularly via inhalation and dermal exposure. Key toxicophores, such as ethylenimine moieties (-N(CH₂CH₂Cl)₂), were identified as primary contributors to their cytotoxicity and DNA alkylation potential. Quantitative analyses using TEST, ProTox-III, VEGA, QSAR Toolbox, and Percepta ACD/Labs revealed considerable variability in LD₅₀ and LC₅₀ estimates across different models. The LD₅₀ values confirmed the high toxicity potential of these compounds, with HN-2 emerging as the most hazardous, particularly in inhalation exposure scenarios. This study underscores the challenges associated with computational toxicity modeling, including inter-model variability and the dependence on structural analogs. Despite these limitations, in silico methodologies provide a rapid and cost-effective alternative to experimental toxicity assessments, helping to reduce reliance on in vivo testing. Further research should focus on refining predictive models, expanding training datasets, and integrating in vitro validation studies to enhance the accuracy of toxicity predictions. The findings highlight the critical role of computational toxicology in assessing chemical threats and developing mitigation strategies for nitrogen mustard exposure.
氮芥是强效烷化剂，最初作为化学战剂研发，后来被应用于医学领域。尽管其毒性已有充分记录，但关于它们急性毒性特征的系统性研究仍然有限。为填补这一空白，本研究利用定性和定量计算模型，对氮芥进行了全面的计算机模拟评估。使用先进的计算机模拟工具，评估了这些化合物在多种暴露途径下的毒性，包括口服、皮肤和吸入途径。使用STopTox、ADMETlab和admetSAR进行的定性预测一致将氮芥归类为剧毒物质，尤其是通过吸入和皮肤暴露途径。关键毒基团，如乙撑亚胺部分（-N(CH₂CH₂Cl)₂），被确定为其细胞毒性和DNA烷基化潜力的主要贡献因素。使用TEST、ProTox-III、VEGA、QSAR Toolbox和Percepta ACD/Labs进行的定量分析显示，不同模型的LD₅₀和LC₅₀估计值存在相当大的差异。LD₅₀值证实了这些化合物的高毒性潜力，其中HN-2被证明是最危险的，尤其是在吸入暴露情况下。本研究强调了与计算毒性建模相关的挑战，包括模型间的变异性以及对结构类似物的依赖性。尽管存在这些局限性，但计算机模拟方法为实验毒性评估提供了一种快速且经济高效的替代方案，有助于减少对体内测试的依赖。进一步的研究应集中在改进预测模型、扩大训练数据集以及整合体外验证研究，以提高毒性预测的准确性。这些发现突出了计算毒理学在评估化学威胁和制定氮芥暴露缓解策略中的关键作用。
