Hussien Yusuf, Dertinger Stephen D, Johnson George E
Instiutue of Life Sciences, Swansea University, Swansea, UK.
Litron Laboratories, Rochester, New York, USA.
Environ Mol Mutagen. 2025 Mar;66(3):122-133. doi: 10.1002/em.70003. Epub 2025 Mar 13.
In vitro genotoxicity has historically served a hazard identification role, with simple binary outcomes provided for each of several single endpoint assays. This will need to change, given: (i) efforts to curtail animal testing, (ii) the increased use of multiplexed in vitro assays and the ongoing development of NAMS, and (iii) the desire to holistically consider quantitative results from multiple biomarkers/endpoints that take potency into consideration. To help facilitate more quantitative analyses of multiple biomarkers and/or assay streams, we explored the combined use of PROAST and Toxicological Prioritization Index (ToxPi) software. As a proofofconcept, this investigation employed the MultiFlow DNA damage assay, focusing on γH2AX and p53 biomarkers at two time points, whereby 10 genotoxicants were evaluated in the presence and absence of rat liver S9 metabolic activation. Whereas PROAST was used to calculate BMD point estimates and confidence intervals (CIs), ToxPi synthesized the BMD results into visual, quantitative summaries conveying genotoxicity and metabolic properties. Our analyses suggest that ToxPi's data synthesis and visualization modules provide useful insights into compound response, chemical grouping, and genotoxic mechanisms. By integrating multiple data sources, we find that ToxPi offers a powerful complementary approach to traditional BMD CI graphs, particularly for the simultaneous analysis of multiple biomarkers, enhancing chemical potency analysis of complex datasets.
体外遗传毒性在历史上一直发挥着危害识别的作用，通过几种单一终点试验中的每一种提供简单的二元结果。鉴于以下几点，这种情况需要改变：（i）减少动物试验的努力；（ii）多重体外试验的使用增加以及新方法的不断发展；（iii）全面考虑多个生物标志物/终点的定量结果并考虑效力的愿望。为了有助于对多个生物标志物和/或试验流进行更定量的分析，我们探索了PROAST和毒理学优先指数（ToxPi）软件的联合使用。作为概念验证，本研究采用了多重流式DNA损伤试验，重点关注两个时间点的γH2AX和p53生物标志物，从而在有和没有大鼠肝脏S9代谢活化的情况下评估了10种遗传毒性物质。虽然PROAST用于计算基准剂量（BMD）点估计值和置信区间（CI），但ToxPi将BMD结果综合为直观的定量总结，传达遗传毒性和代谢特性。我们的分析表明，ToxPi的数据合成和可视化模块为化合物反应、化学分组和遗传毒性机制提供了有用的见解。通过整合多个数据源，我们发现ToxPi为传统的BMD CI图提供了一种强大的补充方法，特别是对于多个生物标志物的同时分析，增强了复杂数据集的化学效力分析。
