Absence of γ-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male f-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator

Male F-344 rats were fed a diet containing 2% di-(2-ethylhexyl)phthalate (DEHP) for 95 weeks. Liver nodules and/or hepatocellular carcinomas (HCC) developed in 6/10 rats fed DEHP and none were found in controls (P<0.005 by x² test). All the nodules and HCC were negative for γ-glutamyl transpeptidase. In the non-tumorous portions of liver, the hepatocytes contained an increased number of peroxisomes and extensive accumulation of lipofuscin. By immunocyto-chemical analysis, the liver peroxisomes in rats treated chronically with DEHP had visually detectable decrease in the H₂O₂-degrading catalase and increase in H₂O₂-producing fatty acyl-CoA oxidase. These results show that higher dietary level of DEHP, which causes substantially greater degree of peroxisome proliferation than the 1.2% dietary level used in the National Toxicology Program bioassay (1982, Publication no. NTP-80-37, Tech. Report Series No. 217), can induce liver tumors in male rats.