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Value of GST-P Positive Preneoplastic Hepatic Foci in Dose-Response Studies of Hepatocarcinogenesis: Evidence for Practical Thresholds with Both Genotoxic and Nongenotoxic Carcinogens. A Review of Recent Work

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, htsuda{at}gan2.ncc.go.jp

Shoji Fukushima

Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585

Hideki Wanibuchi

Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585

Kechirou Morimura

Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585

Dai Nakae

Department of Oncological Pathology, Cancer Center, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521

Katsumi Imaida

Department of Pathology, Nagoya City University Medical School, 1-Kawasumi, Mizuho-ku, Nagoya 467-8601

Masae Tatematsu

Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681

Masao Hirose

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501

Keiji Wakabayashi

Cancer Prevention Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan

Malcolm A. Moore

Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045

Recent low-dose carcinogenesis studies, including major group projects are reviewed. The prevailing paradigm is that carcinogens, particularly genotoxic compounds, have no threshold in exerting their potential for cancer induction. However, the nonthreshold hypothesis can be challenged for cancer risk assessment in humans. A recent very large-scale cooperative effort in Japan furthermore showed that the genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5- f ]quinoxaline, forms DNA adducts and 8-hydroxy-2'-deoxyguanosine at low doses, but does not induce glutathione S-transferase placental form (GST-P) positive foci as preneoplastic lesions in rat liver (10 ppm in diet). Moreover, very low doses of a N-nitroso compound, diethylnitrosamine (DEN), were also found not to significantly induce GST-P positive foci in rat liver (0.01 ppm in drinking water). Given the direct correlation between induction of the preneoplastic lesions in the short-term and carcinomas in the longer term with different carcinogens, the results imply a practical nonobserved effect level for hepatocarcinogenicity. Similar results were also observed with so-called nongenotoxic carcinogens such as phenobarbital (PB) and p,p'-dichlorodiphenyltrichloroethane (DDT), which do not exert positive effects on lesion development at very low doses. Furthermore, experiments with application of PB and DDT after treatment with DEN indicate that at very low doses (2 ppm in diet), they may even inhibit the development of GST-P positive foci. The data reviewed provide evidence that preneoplastic foci in the liver can be employed as end-point lesions in place of tumors and that exposure to very low levels of carcinogens, typical of those found in the human environment, does not necessarily present as a risk factor.

Key Words: Threshold • genotoxic • nongenotoxic • carcinogenicity • low dose • GST-P.

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Toxicologic Pathology, Vol. 31, No. 1, 80-86 (2003)
DOI: 10.1080/01926230390173879


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