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ToxSci Advance Access published online on March 10, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh104
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received December 3, 2003; accepted February 5, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Risk Assessment

Existence of a Threshold for Induction of Aberrant Crypt Foci in the Rat Colon with Low Doses of 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine

S. Fukushima 1*, H. Wanibuchi 1, K. Morimura 1, S. Iwai 1, D. Nakae 2, H. Kishida 3, H. Tsuda 4, N. Uehara 4, K. Imaida 5, T. Shirai 6, M. Tatematsu 7, T. Tsukamoto 7, M. Hirose 8, and F. Furukawa 8

1 Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
2 Department of Pathology, Sasaki Institute, 2-2 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan
3 Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Sizyo-cho, Kashihara-shi, Nara 634-8521, Japan
4 Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
5 Department of Pathology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
6 Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
7 Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa, Nagoya 464-8681, Japan
8 Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

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


  Abstract

Until recently it has been generally considered that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. In the present study we show that a food derived, genotoxic hepatocarcinogen, 2-amino-1-methyl-6-phenolimidazo[4,5-b]pyridine (PhIP), does not induce aberrant crypt foci (ACF) as preneoplastic lesions at low dose (below 50 ppm) or 8-hydroxy-2'-deoxyguanosine (below 400 ppm) in the rat colon. Moreover PhIP-DNA adducts were not formed at the lowest dose (below 0.01 ppm). Thus, the dose required to initiate ACF is approximately 5000 times higher than that needed for adduct formation. The results imply a no-observed effect level (existence of a threshold) for colon carcinogenesis by a genotoxic carcinogen.

Key Words: PhIP, risk assessment, carcinogenicity threshold, PhIP carcinogenicity .


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