Effects of di-isononyl phthalate, di-2-ethylhexyl phthalate, and clofibrate in cynomolgus monkeys

The effects of the peroxisome proliferators di-isononyl phthalate (DINP) an d di-2-ethylhexyl phthalate (DEHP) were evaluated in young adult male cynom olgus monkeys after 14 days of treatment, with emphasis on detecting hepati c and other effects seen in rats and mice after treatment with high doses o f phthalates. Groups of 4 monkeys received DINP (500 mg/kg/day), DEHP (500 mg/kg/day), or vehicle (0.5% methyl cellulose, 10 ml/kg) by intragastric in tubation for 14 consecutive days. Clofibrate (250 mg/kg/day), a hypolipidem ic drug used for cholesterol reduction in human patients was used as a refe rence substance. None of the test substances had any effect on body weight or liver weights. Histopathological examination of tissues from these anima ls revealed no distinctive treatment-related effects in the liver, kidney, or testes. There were also no changes in any of the hepatic markers for per oxisomal proliferation, including peroxisomal beta-oxidation (PBOX) or repl icative DNA synthesis. Additionally, in situ dye transfer studies using fre sh liver slices revealed that DINP, DEHP, and clofibrate had no effect on g ap junctional intercellular communication (GJIC). None of the test substanc es produced any toxicologically important changes in urinalysis, hematology , or clinical chemistry; however, clofibrate produced some emesis, small in creases in serum triglyceride, decreased calcium, and decreased weights of testes/epididymides and thyroid/parathyroid. The toxicological significance of these small changes is questionable. The absence of observable hepatic effects in monkeys at doses that produce hepatic effects in rodents suggest s that DINP, DEHP, and clofibrate would also not elicit in primates other e ffects such as liver cancer. These data, along with results from in vitro h epatocyte studies, indicate that rodents are not good animal models for pre dicting the hepatic effects of phthalates in primates, including humans.