Short-term tests for defining mutagenic carcinogens

The results of short-term tests for mutagenicity were first included in the IARC Monographs in the mid-1970s on the basis of the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. The experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that the short-term tests were useful for predicting carcinogenicity. Although the correlations have become weaker over the past 20 years, and with them the predictive value of short-term tests, such tests still provide vital information for identifying and understanding mechanisms involved in carcinogenicity. The results of short-term tests compiled in the US Environmental Protection Agency-IARC Genetic Activity Profile database over the past 12 years are summarized and reviewed here in relation to the classification of agents for carcinogenicity within the system used at IARC. The role of the information from short-term tests in making overall classifications of specific compounds in recent Monographs is discussed. The usefulness of data on three genetic end-points, gene mutation, chromosomal aberrations and aneuploidy, and the criteria for mutagenicity and lack of mutagenicity based on a 'defining set' of test results are examined. Recommendations are made for assessing chemicals on the basis of the strength of the evidence from short-term tests, and the implications of this approach for identifying putative mutational mechanisms of carcinogenicity are discussed.