EU Framework 6 Project: Predictive Toxicology (PredTox)-overview and outcome

Journal Article · Fri Apr 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.008· OSTI ID:21535276

Suter, Laura ^[1]; Schroeder, Susanne ^[2]; Meyer, Kirstin ^[3]; Gautier, Jean-Charles ^[4]; Amberg, Alexander ^[5]; Wendt, Maria; Gmuender, Hans ^[6]; Mally, Angela ^[7]; Boitier, Eric ^[4]; Ellinger-Ziegelbauer, Heidrun ^[8]; Matheis, Katja ^[9]; Pfannkuch, Friedlieb ^[1]

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1. Hoffmann-La Roche AG, Basel (Switzerland)
2. Nycomed GmbH, Barsbuettel (Germany)
3. Bayer Schering Pharma AG, Berlin (Germany)
4. Sanofi aventis R and D, Disposition, Safety and Animal Research, Vitry sur Seine (France)
5. Sanofi aventis R and D, Disposition, Safety and Animal Research, Frankfurt (Germany)
6. Genedata AG, Basel (Switzerland)
7. University of Wuerzburg, Institut fuer Toxikologie, Wuerzburg (Germany)
8. Bayer Schering Pharma AG, Wuppertal (Germany)
9. Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach (Germany)

In this publication, we report the outcome of the integrated EU Framework 6 Project: Predictive Toxicology (PredTox), including methodological aspects and overall conclusions. Specific details including data analysis and interpretation are reported in separate articles in this issue. The project, partly funded by the EU, was carried out by a consortium of 15 pharmaceutical companies, 2 SMEs, and 3 universities. The effects of 16 test compounds were characterized using conventional toxicological parameters and 'omics' technologies. The three major observed toxicities, liver hypertrophy, bile duct necrosis and/or cholestasis, and kidney proximal tubular damage were analyzed in detail. The combined approach of 'omics' and conventional toxicology proved a useful tool for mechanistic investigations and the identification of putative biomarkers. In our hands and in combination with histopathological assessment, target organ transcriptomics was the most prolific approach for the generation of mechanistic hypotheses. Proteomics approaches were relatively time-consuming and required careful standardization. NMR-based metabolomics detected metabolite changes accompanying histopathological findings, providing limited additional mechanistic information. Conversely, targeted metabolite profiling with LC/GC-MS was very useful for the investigation of bile duct necrosis/cholestasis. In general, both proteomics and metabolomics were supportive of other findings. Thus, the outcome of this program indicates that 'omics' technologies can help toxicologists to make better informed decisions during exploratory toxicological studies. The data support that hypothesis on mode of action and discovery of putative biomarkers are tangible outcomes of integrated 'omics' analysis. Qualification of biomarkers remains challenging, in particular in terms of identification, mechanistic anchoring, appropriate specificity, and sensitivity.

• OSTI ID: 21535276
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 2; Other Information: DOI: 10.1016/j.taap.2010.10.008; PII: S0041-008X(10)00386-8; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BILIARY TRACT
BIOLOGICAL MARKERS
DATA ANALYSIS
DRUGS
GAS CHROMATOGRAPHY
HANDS
HYPERTROPHY
HYPOTHESIS
KIDNEYS
LIVER
NECROSIS
NUCLEAR MAGNETIC RESONANCE
SENSITIVITY
SPECIFICITY
TOXICITY
ARMS
BODY
CHROMATOGRAPHY
DIGESTIVE SYSTEM
GLANDS
LIMBS
MAGNETIC RESONANCE
ORGANS
PATHOLOGICAL CHANGES
RESONANCE
SEPARATION PROCESSES