Mechanisms of multistep carcinogenesis: keys to developing in vitro approaches for assessing the carcinogenicity of chemicals.

The process of neoplastic development is a complex combination of genetic and non-genetic changes within a tissue. It is, therefore, not surprising that a number of mechanisms exist by which chemicals influence this process. In designing short-term tests to detect potential carcinogens, the major emphasis to date has been on genetic assays. This is justified on both theoretical and practical grounds. Substantial evidence exists to support the hypothesis that genetic damage increases the probability of tumour development. Mutational assays for gene mutations, clastogenicity and aneuploidy induction are therefore extremely important tests for carcinogens. Unfortunately, few assays exist for detecting chemicals that induce gene amplification, and thus, if these are carcinogens that specifically induce this type of genetic change, they may go undetected. Because of a variety of possible differences between a chemical's activity in vivo and in vitro, it is to be expected that chemicals that are mutagenic in vitro may not have a significant carcinogenic effect in vivo. However, the potential harm of these chemicals to man does exist and may be expressed under different conditions (e.g. species- or organ-specific carcinogenic effects) or as non-carcinogenic hazards.