Initiative to improve genotoxicity assays and reduce animal use

A European collaborative project to improve the accuracy of the in vitro tests used to predict the cancer-causing potential or 'carcinogenicity' of compounds such as pharmaceutical medicines is being initiated by Covance, with funding from the NC3Rs and ECVAM.

A European collaborative project to improve the accuracy of the in vitro tests used to predict the cancer-causing potential or 'carcinogenicity' of compounds such as pharmaceutical medicines is being initiated by Covance, with funding from the NC3Rs and ECVAM. Improving the accuracy of these tests would lead to a significant reduction in the number of follow-up tests involving animals that were needed. 

The in vitro genetic toxicology tests used for regulatory purposes measure the formation of gene mutations and chromosomal changes following DNA damage induced by the compounds under test, and are used to predict the carcinogenic potential of such compounds in pharmaceuticals, agricultural chemicals and cosmetics. If a compound shows a positive result in these basic tests further in vitro mechanistic studies will most likely be performed, but in addition in vivo genotoxicity studies may be undertaken to assess the risk for humans. A recent analysis of nearly 1000 chemicals has highlighted the strikingly imprecise nature of genetic toxicology tests in predicting carcinogenicity.  When the standard in vitro genotoxicity tests were performed, at least 80% of compounds gave a false positive result.

The high false positive rate (low specificity) of the established in vitro tests means that an increased number of compounds are subjected to earlier and additional animal testing before the efficacy of the compound has been evaluated.  Many of these will be dropped from development in later efficacy trials. In some cases the positive in vitro genotoxicity results may trigger the conduct of 3-year carcinogenicity studies on compounds that would not otherwise be subjected to carcinogenicity testing. If there were more accurate, predictive in vitro tests for genotoxicity (i.e. less false positives) there would be a significant reduction in the number of animals used.  More accurate and reliable in vitro tests may ultimately mean there is less reliance on or need for data from in vivo genotoxicity and carcinogenicity tests.

The objective of the European project is to characterise existing mammalian cell systems for in vitro genotoxicity, such that more accurate tests may be selected and thus reduce unnecessary in vivo genotoxicity and carcinogenicity testing. To carry out this project, Covance is looking for post-doctoral scientists and technicians for a research project (up to 3 years), working in the Genetic and Molecular Toxicology Department of Covance Laboratories Limited in Harrogate, North Yorkshire, UK.

D. Kirkland, M. Aardema, L. Henderson, L. Müller (2005). Evaluation of the ability of a battery of 3 in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584: 1–256

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