Lack of potential of low dose N-nitrosodimethylamine to induce preneoplastic lesions, glutathione S-transferase placental form-positive foci, in rat liver

Fukushima, Shoji; Wanibuchi, Hideki; Morimura, Keiichirou; Nakae, Dai; Tsuda, Hiroyuki; Imaida, Katsumi; Shirai, Tomoyuki; Tatematsu, Masae; Tsukamoto, Tetsuya; Hirose, Masao; Furukawa, Fumio

doi:10.1016/j.canlet.2004.08.035

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Volume 222, Issue 1 , Pages 11-15, 10 May 2005

Lack of potential of low dose N-nitrosodimethylamine to induce preneoplastic lesions, glutathione S-transferase placental form-positive foci, in rat liver

Shoji Fukushima
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
- Corresponding author. Tel.: +81 6 6645 3735; fax: +81 6 6646 3093.
Hideki Wanibuchi
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
Keiichirou Morimura
- Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan
Dai Nakae
- Department of Pathology, Sasaki Institute, Sasaki Foundation, 2-2 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan
Hiroyuki Tsuda
- Experimental Pathology and Chemotherapy Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
- Present address: Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
Katsumi Imaida
- Onco-Pathology, Department of Pathology and Host-Defence, Faculty of Medicine, Kagawa University, 1750 Ikenobe, Miki-cho, Kagawa 761-0793, Japan
Tomoyuki Shirai
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
Masao Hirose
- Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Fumio Furukawa
- Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan

Received 23 April 2004; received in revised form 19 August 2004; accepted 31 August 2004.

Abstract

Induction of liver lesions in male F344 rats by the genotoxic and carcinogenic N-nitrosodimethylamine (NDMA) was studied at a wide range of dose levels, i.e. from 0.001 to 10ppm, in drinking water for 16 weeks. Dose related and statistically significant increase of glutathione S-transferase placental form-positive foci, endpoint markers for hepatocarcinogenesis in rats, at 1 and 10ppm dose groups was obtained, but no increment in foci could be detected with the lower doses (0.001, 0.01, and 0.1ppm). This finding of a no-observed effect level supports our hypothesis that a threshold, at least in practical terms, exists in carcinogenesis proposed on the basis of extensive wide range dose-dependence studies of other genotoxic carcinogens.