Dose Response for the Stimulation of Cell Division by Caffeic Acid in Forestomach and Kidney of the Male F344 Rat

Caffeic acid (CA, 3,4-dihydroxycinnainic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats and B6C3F1 mice. Based on its occurrence in coffee and numerous foods and using a linear interpolation for cancer incidence between dose 0 and 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could represent the main mechanism of carcinogenic action. The dose-response relationship for this effect was investigated in male F344 rats after 4-week feeding with CA at different dietary concentrations (0, 0.05, 0.14, 0.40, and 1.64%). Cells in S-phase of DNA replication were visualized by iminunohistochemical analysis of incorporated 5-bromo-2′-deoxyuridine (BrdU), 2 hr after intraperitoneal injection. In the forestomach, both the total number of epithelial cells per millimeter section length and the unit length labeling index of BrdU-positive cells (ULLI) were increased, about 2.5-fold, at 0.44) and 1.64%. The lowest concentration (0.05%) had no effect. At 0.14%, both variables were decreased by about one-third. In the kidney, the labeling index in proximal tubular cells also indicated a J-shaped (or U-shaped) dose response with a 1.8-fold increase at 1.64%. In the glandular stomach and in the liver, which are not target organs, no dose-related effect was seen. The data show a good correlation between the organ specificity for cancer induction and stimulation of cell division. With respect to the dose-response relationship and the corresponding extrapolation of the animal tumor data to a human cancer risk, a linear extrapolation appears not to be appropriate.