1. Chemical Carcinogenesis

This research line will focus on alternatives for animal testing with regard to chemical carcinogenesis. At present, (putative) human carcinogens are identified via testing of compounds in two chronic two-year rodent bioassays, namely with rats and mice. These testing methods all have severe ethical drawbacks in that they use numerous animals under stressful conditions, plus practical shortcomings because they are long lasting, insensitive, and expensive. On top of this, there is considerable scientific doubt on the reliability of the assay, since too many false positive results are observed; it is thought that these so-called rodent carcinogens are positive in the chronic bioassay due to the extremely high test doses applied, which are irrelevant for human risk assessment.

The primary goal is to identify a set of genomics effect markers that is able to test compounds for their carcinogenic potential, in that gene-expression fingerprints should be positive for chemical carcinogens while being able to discriminate between genotoxic and non-genotoxic (epigenetic) carcinogens, and should be negative for non-carcinogens. At the same time data can be used to study the underlying molecular mechanisms associated with chemical carcinogenesis.

Focus will be on alternatives for liver carcinogenicity in the rat, and for lymphoid carcinogenicity in the mouse, both being the most frequently observed cancers in these models. A parallelogram approach as described previously (animal in vivo – animal in vitro – human in vitro - human in vivo) will be applied.

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