Quantitative analysis of hepatocellular lesions induced by di(2-ethylhexyl)phthalate in F-344 rats

Di(2-ethylhexyl)phthalate (DEHP), a peroxisome proliferator, has been shown to be a weak hepatocarcinogen in rats and mice. However, in previous studies no quantitative analysis of tumors was carried out. In the present study, F-344 male rats were given a diet containing 2% DEHP ad libitum for 108 wk. At necropsy livers were quantitatively analyzed for total tumor incidence and the number of lesions per liver after slicing the entire organ at 1- to 2-mm intervals. Neoplastic nodules and/or hepatocellular carcinomas were observed in 11 of 14 rats (78.5%). When evaluated according to the size, 57, 16, and 36% rats contained nodules ranging from 1 to 3, 3 to 5, and greater than 5 mm in size, respectively. The number of nodules per liver ranged from zero to four. These results indicate that DEHP induces tumors in a large number of animals at 2% dose levels. It is clear from this study that when a weak peroxisome proliferator is evaluated for carcinogenic effects, a complete and thorough gross examination of the liver is essential to obtain accurate tumor incidence.