EU framework 6 project: predictive toxicology (PredTox)--overview and outcome.

Area of Science:

• Toxicology
• Biomarker Discovery
• Pharmacology

Background:

• The EU Framework 6 Predictive Toxicology (PredTox) project involved a consortium of pharmaceutical companies and universities.
• Assessing compound toxicity requires robust methodologies for mechanistic understanding and biomarker identification.

Purpose of the Study:

• To evaluate the integrated use of "omics" technologies and conventional toxicology in characterizing compound effects.
• To identify potential biomarkers and understand mechanisms of toxicity for liver and kidney damage.

Main Methods:

• Characterized effects of 16 test compounds using conventional toxicology and "omics" technologies (transcriptomics, proteomics, metabolomics).
• Focused analysis on liver hypertrophy, bile duct necrosis/cholestasis, and kidney proximal tubular damage.
• Integrated histopathological assessment with "omics" data for mechanistic investigations.

Main Results:

• Combined "omics" and conventional toxicology proved effective for mechanistic investigations and identifying putative biomarkers.
• Target organ transcriptomics, coupled with histopathology, was highly effective for generating mechanistic hypotheses.
• Targeted metabolite profiling (LC/GC-MS) was useful for investigating bile duct necrosis/cholestasis; proteomics and metabolomics supported other findings.

Conclusions:

• "Omics" technologies can significantly improve toxicologists' decision-making in exploratory studies.
• Hypothesis generation on mode of action and discovery of putative biomarkers are achievable outcomes of integrated "omics" analysis.
• Biomarker qualification, including identification, mechanistic anchoring, specificity, and sensitivity, remains a challenge.