Di(2-ethylhexyl)phthalate but not phenobarbital promotes N-nitrosodiethylamine-initiated hepatocellular proliferative lesions after short-term exposure in male B6C3F1 mice.

The differential effects of short- or long-term exposure to the liver tumor promoters di(2-ethylhexyl)phthalate (DEHP) or phenobarbital (PB) were studied in male B6C3F1 mice. Mice were injected intraperitoneally (i.p.) at 4 weeks of age with N-nitrosodiethylamine (DEN) at a dosage of 80 mg/kg. At 5 weeks of age, the mice were fed diets containing PB or DEHP for periods of from 1 to 168 days and killed at 168 or 252 days. When DEHP was fed at a dietary level of 3000 ppm for 28, 84, or 168 days, or PB was fed in the water at 500 ppm for 168 days, there were significantly increased incidences of mice with focal hepatocellular proliferative lesions (FHPL) as compared with those in mice receiving DEN alone. There was no significant promotion of FHPL when DEHP was fed for 1 or 7 days or when PB was fed for 1, 7, 28, or 84 days. Thus, DEHP was an effective promoter after only 28, 84, or 168 days exposure whereas PB required 168 days of continuous exposure for a promotive effect to be evident.