Comparative activity of human carcinogens and NTP rodent carcinogens in the mouse bone marrow micronucleus assay: an integrative approach to genetic toxicity data assessment.

Abstract

The mouse bone marrow micronucleus (MN) assay holds a key position in all schemes for detecting potential human carcinogens and mutagens. It was 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 indistinguishable from the 4 positive responses observed among the 24 NTP noncarcinogens tested. To focus these findings, the activity in the MN assay of 26 human carcinogens, 6 reference rodent genotoxins, and the 9 NTP chemicals positive in the MN assay have been displayed in a common format. This involved plotting the minimum positive dose level (expressed as mumole/kilogram) and the maximum fold-increase in micronucleated polychromatic erythrocytes frequency observed at any dose level. By displaying 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 Shelby et al. This, in turn, poses questions about the intrinsic hazard of this selection of NTP rodent carcinogens. Using fotemustine and vitamin 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 relative potential human hazard can be distinguished (a synthetic, as opposed to an analytical approach to data assessment). The possibility that some weak responses observed in the MN assay at elevated dose levels may be stress induced is considered.Imagesp758-aFigure 1.

Estimating the extent of the health hazard posed by high-production volume chemicals.

“…The same is true for the other in vivo assay, the induction of SCEs in mice (Table 1). It should be noted that although the micronucleus assay is confirmatory when the Salmonella assay indicates the potential for mutagenicity, the micronucleus assay response can also be elicited by nongenotoxicants such as inhibitors of tubulin polymerization and of microtubular integrity, as well as by aneugens (59,60). This may explain the greater projected proportion of micronuclei inducers when compared to Salmonella mutagens.…”

Chemoprotective gene transfer II: multilineage in vivo protection of haemopoiesis against the effects of an antitumour agent by expression of a mutant human O6-alkylguanine-DNA alkyltransferase

“…Therefore we assessed the effects of hATPA/GA expression on the frequency of preleukaemic lesions in order to determine whether the gene therapy approach might also give rise to protection against iatrogenic tumours. As a direct assay for mutation frequency in human bone marrow progenitors does not yet exist, we used the mouse bone marrow micronucleus test, which serves as one of the 'industry standard' tests for the detection of carcinogens, including leukaemogens, 14 as a surrogate marker for mutation in the stem cell and progenitor compartments. Our observation that expression of hATPA/GA in around 50% of mouse bone marrow cells leads to significant protection against micronucleus formation in PCE whether O 6 -beG pretreatment is administered or not, strongly suggests that it may prove possible to provide protection against the mutagenic, and thus potential leukaemogenic, effects of O 6 -alkylating agents as well as the cytotoxicity of these drugs.…”