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4 SUMMARY AND CONCLU SION S The Committee' second assignment was to determine the feasibility of studying the quantitative value of short-term mutagenicity tests for prediction of carcinogenicity. Having reviewed this topic, the Committee does not believe that the Na tional Research Council should conduct a more detailed ~ tudy now . There is no doubt that short-term mutagenicity tests, such as the Ames Salmonella/microsome test, have been successful in identifying carcinogens. A substance that is found to be muta- genic in such a tes t is clearly a possible human carcinogen. This is attested by the very high fraction of known carcinogens that are positive in short-term mutagenicity tests arid by the large number of mutagens that were f ire t detected by short-term tests and later found to be positive in animal cancer tests. The difficulty lies in the question of whether such tests can be used for quantitative prediction of human carcinogenicity. The Committee believes that such tests may well have quanti- tative utility, but that it would be premature to make con- clusive statements now. Rather than calling for the judgment of a National Research Council study, the situation calls for more research and analys is of data. The relation between an initiating event, which may well be mutation, and the eventual development of a cancer is complex and is thought to involve multiple steps. Thus, the prediction of care inogenicity is more complex than the prediction of DNA damage iteel f . The activation systems used in short-term mutagenicity tests may not parallel those involved in human carcinogenesis, particularly those related to promotion and proliferation. Furthermore, some carcinogens are not detected in short-term mutagenicity tests. Until these discrepancies are resolved and more data have been analyzed, a National Research Council study will not be justified. This is not to say that we must wait for certainty; that would be the path to inac t ion. Bu t we be 1 ieve the t s tud ie s now in progres s may we provide much better information.. 27
Large studies have been started by Ames et al.50 and McCann_ al.S6~74 and by GENE-TOX. All involve analysis of large bodies of data, and a part-time National Research Council group would not have the facilities for such analysis. We believe that, if a National Research Council assessment is needed, the proper time to undertake it would be when the large analyses now going on are completed. In conclusion, the Committee on Chemical Environmental Mutagens thinks that it is not now feasible for the National Research Council to study the use of short-term mutagenicity tests for quantitative prediction of human carcinogenicity. Whereas the data are sufficient to establish a firm qualitative association, current models would require additional verifica- tion and study to make them sufficient for quantitative pre- diction. We recommend that the outcome of the several large projects that are in progress be awaited before consideration of a National Research Council study. * 28