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Andrew M. Standeven, Douglas C. Wolf, and Thomas L. Goldsworthy

Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709 USA

Abstract

In previous studies, unleaded gasoline (UG) vapor was found to be a liver tumor promoter and hepatocarcinogen in female mice, but UG was not a hepatocarcinogen in male mice. However, UG vapor had similar transient mitogenic effects in nonlesioned liver of both male and female mice under the conditions of the cancer bioassay. We used an initiation-promotion 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 B6C3F₁ mice were injected with N-nitrosodiethylamine (DEN ; 5 mg/kg, intraperitoneally) or vehicle. Starting at 5-7 weeks of age, mice were exposed by inhalation 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 macroscopic masses were observed in noninitiated mice. Altered hepatic foci (AHF) , which were predominantly basophilic in phenotype, were found almost exclusively in DEN-initiated mice. UG treatment significantly increased both the mean volume (threefold) and the volume fraction (twofold) of the AHF without increasing the number of AHF per unit area. UG also induced hepatic pentoxyresorufin-O-dealkylase (PROD) activity, a marker of CYP2B, by more than 12-fold over control with or without DEN cotreatment. To study hepatocyte proliferative effects of UG, we treated 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% higher in DEN/UG-treated mice relative to mice treated with DEN alone. These data show that UG vapor promotes AHF in male mice and that liver tumor promotion is associated with a selective increase in hepatocyte proliferation in AHF. UG acts as a liver tumor promoter in both male and female mice, and these findings contrast with the lack of hepatocarcinogenicity of UG in male mice in a cancer bioassay. Key words: altered hepatic foci, cell proliferation, liver, gasoline, tumor promotion. Environ Health Perspect 103:696-700 (1995)

Address correspondence to T. L. Goldsworthy, CIIT, PO Box 12137, Research Triangle Park, NC 27709 USA. A.M. Standeven is currently at Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92713-9534 USA.

We thank the CIIT animal facility, inhalation, and histology staff for excellent technical assistance. This work was supported in part by the American Petroleum Institute and grant no. ES05599 from the NIEHS (to A.M.S.) .

Received 2 March 1995 ; accepted 12 May 1995.