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. 2025 Jun;99(6):2669-2681.
doi: 10.1007/s00204-025-04008-0. Epub 2025 May 6.

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

Janonna Kadyrov  1   2 , Samuele Sala  1   2 , Lucy Grigoroff  1   2 , Novia Minaee  1   2 , Reika Masuda  1   2 , Samantha Lodge  1   2 , Timothy M Ebbels  3 , Michael D Reily  4 , Donald Robertson  4 , Lois Lehman-McKeeman  5 , John Shockcor  6 , Bruce D Car  5 , Glenn H Cantor  5 , John C Lindon  7 , Jeremy K Nicholson  8   9   10 , Elaine Holmes  11   12   13 , Julien Wist  14   15   16   17
Affiliations

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

Janonna Kadyrov et al. Arch Toxicol. 2025 Jun.

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.

Keywords: Biofluid; COMET project; Clinical chemistry; Rats; Sprague–Dawley; Toxicity.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethical approval: All animal studies were conducted in accordance with the current guidelines for animal welfare (Guide for the Care and Use of Laboratory Animals, 1996) and the procedures used were reviewed and approved by the Institutional Animal Care and Use Committee in each company. Consent to participate: Not applicable. Consent for publication: All authors reviewed and approved the final manuscript.

Figures

Fig. 1
Fig. 1
Schematic of the experimental design for the Consortium for Metabonomic Toxicology - COMET project
Fig. 2
Fig. 2
Scatter plots of clinical chemistry parameters using samples taken 24 h post-dose. Control, low-dose and high-dose groups are represented as grey, black and red points, respectively. Background colour corresponds to the target organ of toxicity: control (grey), kidney (orange), liver (dark green), liver and kidney (pink), pancreas (purple) and testes (light green). Abbreviations: aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Fig. 3
Fig. 3
Spearman’s correlations between clinical chemistry parameters using all time points for control samples (a), and high-dose samples that were administered. Liver-targeting toxin (b), kidney-targeting toxin (c), liver and kidney-targeting toxin (d), pancreas-targeting toxin (e) and testicular-targeting toxin (f)
See this image and copyright information in PMC

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