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Evidence of a Threshold-Effect for 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline Liver Carcinogenicity in F344/DuCrj Rats

¹ Developmental Research Laboratories, Shionogi & Co., Ltd. 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan
² Department of Pathology Osaka City University Medical School, 1-4-3 Asahi machi Abeno-ku Osaka 545-8585, Japan
³ Cancer Prevention Basic Research Project, National Cancer Center Research Institute 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
⁴ Japan Bioassay Research Center, Japan Industrial Safety & Health Association, 2445 Hirasawa, Hadano-shi, Kanagawa 257-0015, Japan

Correspondence: Address correspondence to: Shoji Fukushima, Director, MD, PhD, Japan Bioassay Research Center, Japan Industrial Safety & Health Association, 2445 Hirasawa, Hadano-shi, Kanagawa 257-0015, Japan; e-mail:s-fukushima{at}jisha.or.jp.

To estimate potential human risk of exposure to a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a 2-year carcinogenicity test was conducted using male F344 rats administered MeIQx-containing diet at doses of 0 (control), 0.001, 1, and 100 ppm. The lowest dose 0.001 ppm was established as equivalent to the daily intake of this carcinogen in humans (0.2 to 2.6 µg/man/day). Significant decreases of survival rate and body weight gain were observed in rats treated with 100 ppm MeIQx. Histopathological examination revealed significant induction of hepatocellular carcinomas, adenomas, and development of glutathione S-transferase placental form–positive foci with MeIQx at 100 ppm. Moreover, the incidences of Zymbal’s glands carcinoma, mammary fibroadenoma, and subcutaneous fibroma were found significantly increased in a 100 ppm MeIQx group. However, no significant induction of altered preneoplastic hepatocellular foci was observed in 0.001 and 1 ppm groups as compared to the controls. 8-Hydroxy-2’-deoxyguanosine levels in the rat liver DNA of the 100 ppm-treated group were not elevated, but MeIQx-DNA adduct formation increased as compared with the 1 ppm case, albeit without significance. No significant induction of any other neoplastic lesions related to the carcinogen administration was found in MeIQx-administered groups except for 100 ppm. These results imply that 1 ppm may be a no-effect level for MeIQx carcinogenesis.

Key Words: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline • MeIQx • heterocyclic amine • low dose carcinogenicity • threshold

Abbreviations: MeIQx, 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline • HCAs, heterocyclic amines • GST-P, positive foci, glutathione S-transferase placental positive foci • AHF, altered hepatocellular foci

This version was published on April 1, 2008

Toxicologic Pathology, Vol. 36, No. 3, 472-477 (2008)
DOI: 10.1177/0192623308315671


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