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ToxSci Advance Access published online on July 28, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh241
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received April 14, 2004
Accepted June 10, 2004

Carcinogenicity

No-Observed Effect Levels for Carcinogenicity and for in Vivo Mutagenicity of a Genotoxic Carcinogen

Manabu Hoshi 1, Keiichirou Morimura 2, Hideki Wanibuchi 2, Min Wei 2, Eriko Okochi 3, Toshikazu Ushijima 3, Kunio Takaoka 4, Shoji Fukushima 2*

1 Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Orthopaedic Surgery, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
2 Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
3 Carcinogenesis Division, National Cancer Center Research Institute, 1-1, Tsukiji, 5 chome, Chuo-ku, Tokyo 104-0045, Japan
4 Department of Orthopaedic Surgery, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan

* To whom correspondence should be addressed. E-mail: fukuchan{at}med.osaka-cu.ac.jp.


  Abstract

To elucidate the relationship between in vivo carcinogenic and mutagenic potentials of genotoxic carcinogens, low doses were tested in the livers of Big Blue transgenic rats with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). Male Big Blue rats were fed a diet containing 0.001, 0.01, 0.1, 1, 10, or 100 ppm of MeIQx for 16 weeks, and the frequencies of lacI mutants and GST-P positive foci in the liver were determined. The mutation frequencies significantly increased at doses of 10 and 100 ppm, and GST-P positive foci significantly increased at a dose of 100 ppm. However, no statistical increases in both frequencies were observed at lower doses. MeIQx most frequently induced G frameshifts, followed by G to T transversions. Thus, no-observed effect level (NOEL) was demonstrated for both carcinogenicity in terms of preneoplastic lesion induction and in vivo mutagenicity of MeIQx, and the NOEL for in vivo mutagenicity was lower than that for carcinogenicity.

Keywords: MeIQx; No-observed effect level; in vivo mutagenicity; carcinogenicity.
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