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Journal article
Interlaboratory clinical chemistry parameter variation in seven-day acute hydrazine toxicity studies in the Sprague-Dawley rat
Archives of toxicology
2025
PMID: 41350941
Abstract
Clinical chemistry retains its position as a cornerstone of toxicological assessment, yet inter-laboratory variability in baseline values remains a challenge for the integration and interpretation of multisite datasets. This study leveraged a publicly available clinical chemistry database to assess the impact of inter-laboratory variability in response to hydrazine-induced steatosis. Seventeen clinical chemistry and physico-chemical parameters were evaluated in response to a single dose of hydrazine (at 30 mg/kg or 90 mg/kg) administered to Sprague-Dawley rats (n = 83) across five different pharmaceutical companies and compared with sham-dosed control animals. Hydrazine exposure produced a distinct and consistent biochemical signature at 48 h post-dose across the combined sample set from all laboratory sites, characterised by increased serum bilirubin and BUN and decreased serum protein concentrations, alongside atypical reductions in ALT and AST due to transaminase inhibition. Despite sizable inter-laboratory differences in response when considering single assays, multivariate analysis of the complete dataset was able to extract a core pathological response signature. Early changes at 24 h post-dose in AST, ALT, total protein, and calcium demonstrated strong predictive value for 48-h toxicity profiles (AUROC 0.98), underscoring the translational potential of early biomarkers. This study highlights both the robustness and contextual limitations of clinical chemistry data in toxicological studies. It underscores the importance of matched-control designs and multivariate approaches for multisite studies and advocates for the integration of early predictive modelling to optimise study design and align with the principles of the Replace, Reduce, and Refine initiative.
Details
- Title
- Interlaboratory clinical chemistry parameter variation in seven-day acute hydrazine toxicity studies in the Sprague-Dawley rat
- Authors/Creators
- Janonna Kadyrov - Murdoch UniversitySamuele Sala - Murdoch UniversityLucy Grigoroff - Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Perth, WA, AustraliaReika Masuda - Murdoch UniversitySamantha Lodge - Murdoch UniversityTimothy M Ebbels - Imperial College LondonMichael D Reily - Pfizer (United States)Donald Robertson - Pfizer (United States)Lois Lehman-McKeeman - Bristol-Myers Squibb (United States)John Shockcor - Formerly Drug Metabolism and Pharmacokinetics Section, Stine-Haskell Research Center, Dupont Pharmaceuticals Company, Newark, DE, USABruce D Car - Formerly Bristol-Myers-Squibb Company, Princeton, NJ, USACraig Thomas - Formerly Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46055, USAJohn C Lindon - Imperial College LondonJulien Wist - Chemistry Department, Universidad del Valle, Cali, 76001, Colombia. Julien.wist@murdoch.edu.auJeremy K Nicholson - Imperial College LondonElaine Holmes - Imperial College London
- Publication Details
- Archives of toxicology
- Publisher
- Springer Nature
- Number of pages
- 14
- Identifiers
- 991005836243607891
- Copyright
- © The Author(s) 2025
- Murdoch Affiliation
- Centre for Computational and Systems Medicine
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
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- Citation topics
- 2 Chemistry
- 2.211 Mass Spectrometry
- 2.211.990 Metabolomics
- Web Of Science research areas
- Toxicology
- ESI research areas
- Pharmacology & Toxicology