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Transgenic mice as alternatives in carcinogenicity testing: current status

Transgene muizen als alternatief voor de chronische carcinogeniteitstesten: huidige stand van zaken

Synopsis

The correct prediction of human risk after exposure to chemical and physical compounds has been a major challenge for a long time. For this, the lifetime bioassay using rats and mice is routinely used. However, over the years it has become clear that this assay has several drawbacks; for example large numbers of animals are used, the assays are slow, insensitive, and expensive. On top of this, there is considerable scientific doubt on the reliability of the assay, since too many false positive results (so-called rodent carcinogens) are observed. Therefore, there is an urgent need for alternative, more valid, carcinogenicity assays. One specific approach in finding alternatives is to use transgenic mice with modifications in genes involved in the development of cancer, thereby increasing their sensitivity for carcinogens. Several transgenic mouse models have now been generated and studied for their usefulness as replacements for the lifetime bioassay in carcinogenicity testing. Generally, the transgenic mouse models could reliably predict the carcinogenic potential of compounds, and importantly, the number of false positives was reduced significantly. For this, 3 to 4 fold less animals are used in an about 3 times shorter test period. As a result, also costs associated with performing these in vivo studies are reduced enormously. However, the transgenic models were not capable of identifying all known human carcinogens when applied as single assays. Using a short-term transgenic mouse assay in combination with a rat lifetime bioassay however, completely eliminated the occurrence of false-negatives, and moreover, increased the overall accuracy of detecting carcinogens and non-carcinogens enormously (85%) compared to using only the lifetime bioassay (69%). These marked advantages of transgenic mouse models have resulted in the fact that the FDA in the USA and the European CPMP now allow the use of transgenic mice in regulatory testing of pharmaceutical compounds as an alternative for a second lifetime bioassay, when a two-year bioassay with rats has been carried out. Nonetheless, a more extensive evaluation of transgenic mice, using newly developed models and more compounds with different modes of action needs to be carried out in the future.
 

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