A clinical chemical atlas of xenobiotic toxicity for the Sprague–Dawley rat

Abstract

The Consortium for Metabonomic Toxicology (COMET) studies was 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), provide a more nuanced profile of organ-specific toxicity than consideration of individual parameters alone. 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.

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