Relating in Vitro Assays of Carcinogen-Induced Genotoxicity to Transformation of Diploid Human Fibroblasts

Abstract

As part of this EPA-sponsored discussion of the application of biological markers to carcinogen testing, we have been asked to consider some general aspects of the use of in vitro tests to quantitate the genotoxic effects of chemicals, as well as to describe some of our recent results on the transformation of diploid human fibroblasts by chemicals and radiation. The term genotoxicity is recent in origin and is used to designate the property of a chemical or radiation which results in damage to the genetic apparatus of a cell or virus. The fact that short term, in vitro assays designed to detect genotoxicity are commonly employed as a means of identifying potential cancer-causing agents indicates that it is now commonly assumed that DNA is the principal cellular target for carcinogenesis. That is the underlying basis, for example, of assays used to detect potential carcinogencity by screening chemicals for their mutagenic action in bacteria and for their ability to cause DNA damage and/or repair. This assumption does not necessarily underlie in vitro assays which use morphological transformation of mammalian cells as their end point for detecting carcinogens. However, as will be described, the induction of loss of anchorage dependence in diploid human fibroblasts, as well as in at least two other mammalian cell transformation systems, appears to be the result of a mutagenic event. Therefore, such assays can also be used to quantitate the genotoxicity of various environmental agents as well as their potential carcinogenicity.