EVALUATION OF THE RODENT MICRONUCLEUS ASSAY IN THE SCREENING OF IARC CARCINOGENS (GROUPS 1, 2A AND 2B) - THE SUMMARY REPORT OF THE 6TH COLLABORATIVE STUDY BY CSGMT JEMS CENTER-DOT MMS/

To assess the correlation between micronucleus induction and human car cinogenicity, the rodent micronucleus assay was performed on known and potential human carcinogens in the 6th MMS/CSGMT collaborative study, Approximately 100 commercially available chemicals and chemical group s on which there was little or no micronucleus assay data were selecte d from IARC (International Agency for Research on Cancer) Groups 1 (hu man carcinogen), 2A (probable human carcinogen) and 2B (possible human carcinogen), As minimum requirements for the collaborative study, 5 m ale mice were treated by intraperitoneal injection or oral gavage once or twice with each chemical at three dose levels, and bone marrow and /or peripheral blood was analyzed. Five positives and 2 inconclusives out of 13 Group 1 chemicals, 7 positives and 5 inconclusives of 23 Gro up 2A chemicals, and 26 positives and 6 inconclusives of 67 Group 2B c hemicals were found. Such low positive rates were not surprising becau se of a test chemical selection bias, and we excluded well-known micro nucleus inducers, The overall evaluation of the rodent micronucleus as say was based on the present data combined with published data on the IARC carcinogens. After merging, the positive rates for Groups 1, 2A a nd 2B were 68.6, 54.5 and 45.6%, respectively. Structure-activity rela tionship analysis suggested that the micronucleus assay is more sensit ive to the genetic toxicity of some classes of chemicals. Those to whi ch it is sensitive consist of (1) aziridines and bis(2-chloroethyl) co mpounds; (2) alkyl sulfonate and sulfates; (3) acyl-type N-nitroso com pounds; (4) hydrazines; (5) aminobiphenyl and benzidine derivatives; a nd (6) azo compounds. Those to which it is less sensitive consist of ( 1) dialkyl type N-nitroso compounds; (2) silica and metals and their c ompounds; (3) aromatic amines without other functional groups; (4) hal ogenated compounds; and (5) steroids and other hormones. After incorpo ration of structure-activity relationship information, the positive ra tes of the rodent micronucleus assay became 90.5, 65.2 and 60.0% for I ARC Groups 1, 2A and 2B, respectively. Noteworthy was the tendency of the test to be more sensitive to those carcinogens with stronger evide nce human carcinogenicity.