The decision-point approach for systematic carcinogen testing

Abstract

Advances in the understanding of the mechanisms of chemical carcinogenesis suggest new approaches to the practical aspects of the bioassay of carcinogens and regulatory impact, and to the determination of health risk. Chemical carcinogens have been classified into two main types on the basis of their specific properties: (1) genotoxic carcinogens; (2) agents operating by epigenetic mechanisms. Current concepts indicate that genotoxic carcinogens require distinct qualitative and quantitative types of analysis since their fundamental mechanisms of operation are different from those of epigenetic agents. A systematic ‘decision-point approach’ to carcinogen testing provides for distinction between genotoxic and epigenetic carcinogens. The first set of data points involves the following: (1) structure-activity relationships; (2) mutagenicity assays in prokaryotes; (3) mutagenicity assays in eukaryotes; (4) tests for induction of DNA repair in eukaryotes; (5) tests for sister chromatid exchange; (6) cell transformation. Not all of these have equal sensitivity, specificity and reliability. The sequence of in vitro tests permits preliminary decision making. As a second series, limited, relatively rapid, in vivo assays involve the following: (1) skin-tumour induction in mice, with and without promotion; (2) lung-tumour induction in mice; (3) breast-cancer induction in rats; (4) identification of early lesions in rodent liver. The data so obtained are considered for decision making and risk analysis. As a last step, a traditional chronic bioassay may be needed only when human exposure to the product is potentially high and/or continuous, or when the above phases of testing have yielded unsatisfactory or, in the case of epigenetic agents, negative results. More research is essential for the delineation of the effects of epigenetic agents, some of which are most important in the aetiology of human cancer.