Mutagenesis Advance Access published online on December 19, 2005
Mutagenesis, doi:10.1093/mutage/gei068
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1 Toxicological Research Center, Nitto Denko Corporation, 1-1-2, Shimohozumi, Ibaraki Osaka 567-8680, Japan
* To whom correspondence should be addressed. Micronucleus induction was studied for the DNA target clastogens mitomycin C (MMC) and 1-
Received May 24, 2005
Revised October 27, 2005
Accepted November 15, 2005
Original article
Practical threshold for micronucleated reticulocyte induction observed for low doses of mitomycin C, Ara-C and colchicine
Norihide Asano 1 *,
Dorothea K. Torous 2,
Carol R. Tometsko 2,
Stephen D. Dertinger 2,
Takeshi Morita 3,
and
Makoto Hayashi 4
2 Litron Laboratories, 200 Canal View Boulevard, Rochester, NY 14623, USA
3 Division of Safety Information on Drug, Food and Chemicals, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
4 Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Norihide Asano, E-mail: asanonri{at}nitto.co.jp
Abstract 
-D-arabinofuranosylcytosine (Ara-C), and also the non-DNA target aneugen colchicine (COL) in order to evaluate the dose-response relationship at very low dose levels. The acridine orange (AO) supravital staining method was used for microscopy and the anti-CD71-FITC based method was used for flow cytometric analysis. In the AO method, 2000 reticulocytes were analysed as commonly advised, but in the flow cytometric method, 2000, 20 000, 200 000 and 1 000 000 reticulocytes were analysed for each sample to increase the detecting power (i.e. sensitivity) of the assay. The present data show that increasing the number of cells scored increases the statistical power of the assay when the cell was considered as a statistical unit. Even so, statistically significant differences from respective vehicle controls were not observed at the lowest dose level for MMC and Ara-C, or the lower four dose levels for COL, even after one million cells were analysed. When the animal was considered as a statistical unit, only the top dose group for each chemical showed significant increase of micronucleated reticulocytes frequency. As non-linear dose-response curves were obtained for each of the three chemicals studied, these observations provide evidence for the existence of a practical threshold for the DNA target clastogens as well as the non-DNA target aneugen studied.
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