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)

Project

Food and consumer protection

This project contributes to the research aim 'Food and consumer protection'. Which funding institutions are active for this aim? What are the sub-aims? Take a look:
Food and consumer protection

Project code: BfR-CHS-08-1334-169
Contract period: 01.07.2004 - 31.12.2007
Purpose of research: Applied research

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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