Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery

This study compared the levels of cell proliferation and peroxisome prolife ration in rodent liver with tumor incidence, to provide more information on the relationship between these events following chronic exposure. Fischer 344 rats were treated with O, 100, 500, 2500, or 12,500 ppm DEHP, and B6C3F (1), mice were treated with 0, 100, 500, 1500, or 6000 ppm DEHP in the diet for up to 104 weeks. Additional groups of rats and mice received the highe st concentration for 78 weeks and then the control diet for an additional 2 6 weeks (recovery groups). Animals were terminated at weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA oxidation activity and higher liver-to-body weight ratios were observed for the 2500- and 12,500-p pm groups of rats, and for the 500-, 1500-, and 6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation activity was evident in th e recovery group, and relative liver weights were near control levels follo wing recovery. No hepatic cell proliferation was detected at Weeks 79 or 10 5 in either species although preliminary data indicated that cell prolifera tion did occur within the first 13 weeks of exposure. A significantly highe r incidence of hepatocellular tumors was only observed for the 2500- and 12 ,500-ppm group and its recovery group of rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group of mice. The tumor incidences were reduced for the recovery groups compared with the groups fed DEHP continuou sly for 104 weeks. The data indicate that high levels of peroxisome prolife ration and hepatomegaly are associated with DEHP hepatocarcinogenesis in ro dent liver, and that the tumorigenic process may be arrested by cessation o f DEHP treatment, suggesting that extended treatment with DEHP acts to prom ote tumor growth.