A Clinical Chemical Atlas of Xenobiotic Toxicity for the Sprague-Dawley Rat

The Consortium for Metabonomic Toxicology (COMET) studies were designed to model metabolic responses to organ- and mechanism-specific toxins to predict acute drug toxicity in rats. A range of clinical chemical parameters were measured in 7-day toxicology studies for 86 toxins eliciting a range of organ- and mechanism-specific effects. Additionally, 21 surgical or physiological stressors were evaluated to identify physiological or metabolic responses that might confound the interpretation of observed toxicity profiles. From these studies on a total of 3473 rats measured at six pharmaceutical companies, we provide a set of 12 serum and 5 urine physical and clinical chemistry parameters. Samples were collected at 24 h, 48 h and 168 h post-dose for each animal and are presented as a downloadable database file. We also summarise the main observations based on the group response at the level of the individual toxin. We demonstrate that correlations between parameters, such as serum bilirubin and aspartate aminotransferase (AST), to provide a more nuanced profile of organ-specific toxicity than consideration of individual parameters. In addition, we highlight the variability in the measured parameters across the dataset attributable to inter-laboratory differences, and the heterogeneity of metabolic responses to particular compounds or differences in temporal patterns of response. This clinical chemistry atlas of toxicity serves as a valuable reference tool for evaluating the potential toxicity of novel drug candidates.代谢组毒理学联盟（Consortium for Metabonomic Toxicology, COMET）所开展的研究，旨在针对器官特异性与作用机制特异性毒素的代谢应答进行建模，以预测大鼠的急性药物毒性。针对86种可引发多类器官特异性与作用机制特异性毒性效应的毒素，本研究在7天毒理学实验中测定了一系列临床化学指标。此外，本研究还评估了21种手术或生理应激原，以识别可能干扰毒性谱解读的生理或代谢应答。依托在六家制药公司开展、共计3473只大鼠参与的相关实验，本数据集提供了12项血清与5项尿液的物理及临床化学指标。每只实验动物均在给药后24小时、48小时及168小时采集样本，数据集以可下载数据库文件形式对外提供。本研究还基于单毒素水平的各组应答数据，对核心观测结果进行了总结。研究表明，相较于单一指标分析，血清胆红素与天冬氨酸转氨酶（AST）等指标间的相关性可提供更为精细的器官特异性毒性谱。此外，本研究还指出，数据集内测定指标的变异可归因于实验室间差异，同时也体现了不同化合物的代谢应答异质性，以及应答时间模式的差异。本毒性临床化学图谱可作为评估候选新药潜在毒性的重要参考工具。