Lack of cell proliferation activity in gastrointestinal organs in a subacute oral exposure of known tumor promoters in rats

Introduction We aimed to obtain the cell proliferation activity of tumor promoters in gastrointestinal (GI) organs following oral subacute incidental exposure to those promoters that do not target GI organs. Methods We conducted a 4-week repeated dose study using five-week-old Crl:CD(SD) rats (5 males/group), and selected sodium phenobarbital (PB) as a liver tumor promoter and 12-O-tetradecanoylphorbol-13-acetate (TPA) as a skin tumor promoter. Male rats were given PB (100; 300; and 900 μg/mL) or TPA (0.5; 1.5; and 4.5 μg/mL) orally in drinking water for 28 days. Histopathological examination and bromodeoxyuridine (BrdU) immunostaining were conducted to examine the cell proliferation activity in the target organ (liver or skin) and GI organs. Results There was no death, and no treatment-related changes in clinical signs, body weight, and food and water consumption in the TPA and PB treated groups by a 28-day treatment. While no macroscopic changes were observed in the treatment groups, hepatocellular hypertrophy (5/5) was found at ≥100 μg/mL of PB as a treatment-related histopathological finding. No significant changes in BrdU labeling indices were observed in any organ/tissue examined including skin, liver, and GI organs both in TPA and PB treated groups. Conclusions Within our study, subacute oral exposure to a sufficient amount of tumor promoters (target organ: liver or skin) as contaminants in foods was not associated with cell proliferation in the target and GI organs. This finding may be helpful in qualitatively determining the carcinogenic risk of unexpected food contamination of carcinogenic promoters.