Lack of initiation activity in rat liver of low doses of 2-amino-3,8- dimethylimidazo[4,5-f ]quinoxaline Shoji Fukushima a, * , Hideki Wanibuchi a , Keiichirou Morimura a , Min Wei a , Dai Nakae b , Yoichi Konishi c , Hiroyuki Tsuda d , Nobuo Takasuka d , Katsumi Imaida e , Tomoyuki Shirai f , Masae Tatematsu g , Tetsuya Tsukamoto g , Masao Hirose h , Fumio Furukawa h a Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan b Department of Pathology, Sasaki Institute, 2-2 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan c Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan d Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 1-1 Tsukiji 5 chome, Chuo-ku, Tokyo 104-0045, Japan e Department of Pathology, Kagawa Medical University, Takamatsu, Kagawa 761-0793, Japan f Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan g Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan h Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan Received 16 August 2002; received in revised form 15 October 2002; accepted 25 October 2002 Abstract It has been generally accepted that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged for cancer risk assessment in humans. Here we examined low dose carcinogenicity of a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx), using an in vivo medium-term bioassay to detect initiating activity for rat hepatocarcinogenesis. With MeIQx initiation at various doses followed by administration of phenobarbital, a well known hepatopromoter, no induction of glutathione S- transferase placental form-positive foci, assessed as preneoplastic lesions, was noted at doses of 0.001 –1 ppm. The results imply a no-observed effect level for hepatocarcinogenicity with this genotoxic agent. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: 2-Amino-3,8-dimethylimidazo[4,5-f ]quinoxaline; Phenobarbital; Risk assessment; Carcinogenicity threshold; Low dose carcinogenicity 1. Introduction There are many genotoxic carcinogens in our environment, but it is difficult to assess the actual impact of human exposure levels, which are generally very low. In fact, for carcinogenic risk assessment, it has been generally accepted that genotoxic carcino- gens have no threshold in exerting their carcinogenic potential [1,2]. Since most of the carcinogens are mutagenic, and seem to act through interaction with DNA to produce irreversible genetic changes in target organs, there is widespread acceptance of a linear 0304-3835/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. doi:10.1016/S0304-3835(02)00631-6 Cancer Letters 191 (2003) 35–40 www.elsevier.com/locate/canlet * Corresponding author. Tel.: þ81-6-6645-3735; fax: þ 81-6- 6646-3093. E-mail address: fukuchan@med.osaka-cu.ac.jp (S. Fukushima).