COMPARATIVE ACTIVITY OF HUMAN CARCINOGENS AND NTP RODENT CARCINOGENS IN THE MOUSE BONE-MARROW MICRONUCLEUS ASSAY - AN INTEGRATIVE APPROACH TO GENETIC TOXICITY DATA ASSESSMENT

The mouse bone marrow micronucleus (MN) assay holds a key position in all schemes for detecting potential human carcinogens and mutagens. It ws therefore of concern when Shelby et al. reported that only 5 of 25 rodent carcinogens defined by the U.S. NTP were positive in the assay . Further, each of these positive responses was weak and indistinguish able from the 4 positive responses observed among the 24 NTP noncarcin ogens tested. To focus these findings, the activity in the MN assay of 26 human carcinogens, 6 reference rodent genotoxins, and the 9 NTP ch emicals positive in the MN assay have been displayed in a common forma t. This involved plotting the minimum positive dose level (expressed a s mu mole/kilogram) and the maximum fold-increase in micronucleated po lychromatic erythrocytes frequency observed at any dose level. By disp laying the high sensitivity of the micronucleus assay to the reference human and rodent genotoxins, this analysis emphasizes the weakness in the MN assay responses given by the NTP carcinogens reported by Shelb y et al. This, in turn, poses questions about the intrinsic hazard of this selection of NTP rodent carcinogens. Using fotemustine and vitami n C as models of a toxic and a nontoxic chemical known to be active in the MN assay, this analysis describes a method by which their relativ e potential human hazard can be distinguished (a synthetic, as opposed to an analytical approach to data assessment). The possibility that s ome weak responses observed in the MN assay at elevated dose levels ma y be stress induced is considered.