Genetic toxicology data in the evaluation of potential human environmentalcarcinogens

In 1969, the International Agency for Research on Cancer (IARC) initiated t he Monographs Programme to evaluate the carcinogenic risk of chemicals to h umans, Results from short-term mutagenicity tests were first included in th e IARC Monographs in the mid-1970s based on the observation that most carci nogens are also mutagens, although not all mutagens are carcinogens. Experi mental evidence at that time showed a strong correlation between mutagenici ty and carcinogenicity and indicated that short-term mutagenicity tests are useful for predicting carcinogenicity. Although the strength of these corr elations has diminished over the past 20 years with the identification of p utative nongenotoxic carcinogens, such tests provide vital information for identifying potential human carcinogens and understanding mechanisms of car cinogenesis. The short-term test results for agents compiled in the EPA/IAR C Genetic Activity Profile (GAP) database over nearly 15 years are summariz ed and reviewed here with regard to their IARC carcinogenicity classificati ons. The evidence of mutagenicity or nonmutagenicity based on a 'defining s et' of test results from three genetic endpoints (gene mutation, chromosoma l aberrations, and aneuploidy) is examined. Recommendations are made for as sessing chemicals based on the strength of evidence from short-term tests, and the implications of this approach in identifying mutational mechanisms of carcinogenesis are discussed. The role of short-term test data in influe ncing the overall classification of specific compounds in recent Monograph volumes is discussed, particularly with reference to studies in human popul ations. Ethylene oxide is cited as an example. (C) 1999 Elsevier Science B. V. All rights reserved.