The objective is to harness current techniques in order to identify the most probable, yet hitherto unsuspected, human carcinogens in Europe.
In the first part of the study two tasks will be undertaken. First, the hierarchical relationship between DNA
damage induced in rodents (comet assay) and mutation induction (lacZ mice) will be consolidated using recently
defined tissue-specific genotoxic carcinogens. These carcinogens will be selected to focus the experimental
evaluations in rodents on those tissues most often associated with chemically induced carcinogenesis in humans
(respiratory tract, skin, bladder). In parallel with these studies, environmental chemicals relevant to the EU
will be prioritised by chemical structure, known genetic toxicity and estimated levels of human exposure. This
will yield a priority list of 15 chemicals. The first Associated Partner will contribute to the process of
prioritisation over the first two years of the study using existing chemical lists/audits.
These priority chemicals will be evaluated in rodents using the comet assay to define their primary targets of
DNA reactivity. The nine most genotoxic of these compounds will be assessed for mutagenicity to lacZ
transgenic mice. Restriction site mutagenesis within the target lacZ gene will also be studied in key affected
tissues. Based on these data, a final group of six chemicals will be bioassayed for carcinogenicity over a period
of six months using hemisygous p53 mice. P53 genes derived from selected tumours will be sequenced to
determine the origin of their loss of function. Independent of these analyses, all bioassay tissues will be
conserved for possible future use.
If the study succeeds in its aims, six presumptive human carcinogens will be identified for confirmation in
subsequent human studies. Should the study fail, a re-appraisal of current approaches to the prediction of
possible human carcinogens will be required.
Funding SchemeCSC - Cost-sharing contracts
SA2 8PP Swansea
SK10 4TJ Macclesfield