DOSE-RESPONSE FOR THE STIMULATION OF CELL-DIVISION BY CAFFEIC ACID INFORESTOMACH AND KIDNEY OF THE MALE F344 RAT

Caffeic acid (CA, 3,4-dihydroxycinnamic acid), at 2% in the diet, had been shown to be carcinogenic in forestomach and kidney of F344 rats a nd B6C3F1 mice. Based on its occurrence in coffee and numerous foods a nd using a linear interpolation for cancer incidence between dose 0 an d 2%, the cancer risk in humans would be considerable. In both target organs, tumor formation was preceded by hyperplasia, which could repre sent the main mechanism of carcinogenic action. The dose-response rela tionship for this effect was investigated in male F344 rats after 4-we ek 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 immunohistochemical analysis of incorporated 5-bromo-2'-deoxyuridi ne (BrdU), 2 hr after intraperitoneal injection. In the forestomach, b oth 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 0.40 and 1.64%. The lowest concentratio n (0.05%) had no effect. At 0.14%, both variables were decreased by ab out one-third. In the kidney, the labeling index in proximal tubular c ells 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, whi ch are not target organs, no dose-related effect was seen. The data sh ow a good correlation between the organ specificity for cancer inducti on 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. (C) 1997 society of Toxicology.