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© 1992 Oxford University Press

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Threshold dose dependence in phenobarbital promotion of rat hepatocarcinogenesis initiated by diethylnitrosamine

Akihiko Maekawa 1, Hiroshi Onodera, Hiroyuki Ogasawara, Yuko Matsushima, Kunitoshi Mitsumori and Yuzo Hayashi

Department of Pathology, Biological Safety Research Center, National Institute of Hygienic Sciences 1-18-1 Kamiyooga, Setagaya-ku, Tokyo 158, Japan

The dose—response of phenobarbitat (PB) promotion of hepatocarcinogenesis in rats was investigated. Male F344 rats were given 1, 4, 16, 75, 300 or 1200 p.p.m. PB solutions given ad libitum as their drinking water for 39 weeks following initiation with a single i.p. injection of diethylnitrosamine (DEN) (100 mg/kg). At week 40, the incidence of hepatic tumors was increased clearly in the DEN+PB groups given 300 p.p.m. PB or above, as compared to that in the group given DEN only. Linear dose—response curves for numbers and sizes of enzyme-altered hepatic foci ({gamma}-glutamyl-transpeptidase or placental glutathione S-transferase positive foci) were obtained in the dose range 16–1200 p.p.m. PB. The minimum promoting dose level of PB for enzyme-altered foci, estimated from dose—response curves by the Logit model, was calculated to be 15–23 p.p.m. Thus while dose dependence was demonstrated over a large range, a threshold was evident at low doses.


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