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However, in mice phenobarbital occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with the potent carcinogen diethylnitrosamine. Both positive and negative effects of phenobarbital on hepatocytic proliferation and apoptosis, which are mechanistically involved in the promotion stage of hepatocarcinogenesis, have been described. These complex outcomes of phenobarbital treatment and their effects on hepatocarcinogenesis in mice raise serious issues regarding extrapolation of experimental data from laboratory animals to human risk assessment. 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