Construction of A Short Term Test to Detect Carcinogens

Schiestl, Robert

Abstract

The long term objective of the proposed research is to develop a short term assay to detect mutagenic as well as nonmutagenic carcinogens. It has been estimated that about 70% to 90% of the new cases of cancer are linked to environmental carcinogens. A majority of these new cases might be preventable if the main risk and antirisk factors could be identified. At present environmental carcinogens are identified mainly based on long term animal bioassays. Long term animal bioassays are very costly and take 2 to 4 years to perform. Another problem with long term bioassays using whole vertebrate animals is the growing public concern with the suffering of laboratory animals. The solution to this problem would be in vitro tests which can partly replace or limit the number of the whole animal tests. Inexpensive and reliable short term tests are needed for large scale identification leading to removal of environmental carcinogens. However, about half of all carcinogens are not detected by currently used short term tests (so called nonmutagenic carcinogens). A system screening for intrachromosomal recombination (deletion, DEL assay) has been previously constructed in Saccharomyces cerevisiae. The DEL assay is readily inducible by a variety of nonmutagenic carcinogens which are not detectable by the Ames assay or by other short term tests. It is proposed to construct several different recombination systems in mammalian cells which are similar to the DEL recombination system in yeast. The inducibility of the DEL assay in mammalian cells with mutagenic and nonmutagenic carcinogens will be determined. If the DEL assay in mammalian cells turns out to be inducible by nonmutagenic carcinogens this assay would be usable as a short term test. In addition a positive result with the mammalian system would also enhance the usefulness of the yeast DEL assay. Use of these assays would reduce the number of animals used in toxicology studies.