Detection and analysis of hepatotoxic modes of action for the prediction of carcinogenic effects of chemicals in the subacute toxicity test (repeated dose 28-day oral toxicity study/ OECD TG 407)
Description:
Using a modified 28-day repeated-dose toxicity test based on OECD TG 407, rats were orally treated with different classes of hepatotoxic and carcinogenic model substances. A selection of 9 substances was established, which was grouped into categories genotoxic and non-genotoxic carcinogens plus hepatotoxic non-carcinogens. After 3, 7 and 28 days, liver tissue was subjected to histopathological and toxicogenomic analyses, using genomic and proteomic technologies. Based on these data, different modes and mechanisms of action could be assigned, which fit to the well known toxicological profiles and assigned categories of the used substances. Compared to the terminal time point after 28 days, data derived from earlier time points were shown to have only limited value for evaluation of mechanisms and detection of biomarker candidates related to chronic toxicity and cancerogenicity. As reported earlier, toxicogenomic and histopathologic data showed correlations, but were also useful to combine information, which could be used for comprehensive analysis and characterization of substance- and category-specific properties of test substances. Depending on successful development of publicly accessible databases and bioinformatic tools, which are essential for analysis and interpretation of toxicogenomic data, these methods could be integrated in the 28-day repeated-dose toxicity test (OECD TG 407). This way, long-term effects of substances could be assessed in a short-term study, and the number of long-term animal studies could be reduced. Present changes in the EU chemical’s legislation and envisaged support for ongoing research activities, offer favourable conditions for further development and implementation of this approach.
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Executive Institute:
BfR - Department 6: Chemicals Safety (BfR - CHS) Details of BfR - Department 6: Chemicals Safety
Parent institution:
Federal Institute for Risk Assessment (BfR) Details of (BfR) (Berlin)
Contract period:
01. 07. 2004 - 31. 12. 2007
Participating Institutions:
- German Cancer Research Center (DKFZ) Details of DKFZ
- Leibniz Institute for Molecular Pharmacology (FMP) Details of FMP
- Fraunhofer Institute of Toxicology and experiment ... (ITEM) Details of ITEM
- Merck KGaA Details of Merck KGaA
Funding Programme:
- BMELV / Core funding Details of BMELV / Core funding
Subject:
- Physiology of Nutrition
- Food Chemistry
- Toxicology
Purpose of research:
Applied research
Funding Institutions:
- Federal Ministry of Food, Agriculture and Consumer Protection (BMELV) Details of (BMELV)
Project Management Agency:
- Federal Ministry of Food, Agriculture and Consumer Protection (BMELV) Details of BMELV