PROMOTION OF HEPATIC PRENEOPLASTIC LESIONS IN MALE B6C3F(1) MICE BY UNLEADED GASOLINE

In previous studies, unleaded gasoline (UG) vapor was found to be a li ver tumor promoter and hepatocarcinogen in female mice, bur UG was not a hepatocarcinogen in male mice. However, UG vapor had similar transi ent mitogenic effects in nonlesioned liver of both male and female mic e under the conditions of the cancer bioassay. We used an initiation-p romotion protocol to determine whether UG vapor acts as a liver tumor promoter in male mice and to examine proliferative effects that may be critical to tumor development. Twelve-day-old male B6C3F(1) mice were injected with N-nitrosodiethylamine (DEN; 5 mg/kg, intraperitoneally) or vehicle. Starting at 5-7 weeks of age, mice were exposed by inhala tion 6 hr/day, 5 days/week for 16 weeks to 0 or 2046 ppm of PS-6 blend UG. UG treatment caused a significant 2.3-fold increase in the number of macroscopic hepatic masses in DEN-initiated mice, whereas no macro scopic masses were observed in non-initiated mice. Altered hepatic foc i (AHF), which were predominantly basophilic in phenotype, were found almost exclusively in DEN-initiated mice. UC treatment significantly i ncreased both the mean volume (threefold) and the volume fraction (two fold) of the AHF without increasing the number of AHF per unit area. U G also induced hepatic pentoxyresorufin-O-dealkylase (PROD) activity, a marker of CYP2B, by more than 12-fold over control with or without D EN cotreatment. To study hepatocyte proliferative effects of UG, we tr eated mice with 5-bromo-2'-deoxyuridine (BrdU) via osmotic pump for 3 days before necropsy and measured hepatocyte BrdU labeling index (LI) in AHF and nonlesioned liver. UG did not significantly affect BrdU LI in nonlesioned liver. However, hepatocyte LI in AHF was about 30% high er in DEN/UG-treated mice relative to mice treated with DEN alone. The se data show that UG vapor promotes AHF in male mice and that liver tu mor promotion is associated with a selective increase in hepatocyte pr oliferation in AHF, UG acts as a liver tumor promoter in both male and female mice, and these findings contrast with the lack of hepatocarci nogenicity of UG in male mice in a cancer bioassay.