LOSS OF TUMOR-PROMOTING ACTIVITY OF UNLEADED GASOLINE IN N-NITROSODIETHYLAMINE-INITIATED OVARIECTOMIZED B6C3F1 MOUSE-LIVER

Unleaded gasoline (UG) vapor (2056 ppm) increased the incidence of liv er tumors in a chronic bioassay and exhibited tumor-promoting activity in N-nitrosodiethylamine (DEN)initiated female mouse liver. Estrogen inhibited mouse liver tumor development and the hepatocarcinogenic and tumor-promoting dose of UG produced uterine changes suggestive of est rogen antagonism. To directly test the hypothesis that UG-induced tumo r-promoting ability is secondary to its interaction with the mouse liv er tumor inhibitor, estrogen, we compared the tumor-promoting ability of UG in ovariectomized (Ovex) mice with the hepatic tumor-promoting a bility of UG in intact mice. Ovaries were surgically removed at 4 week s of age, Exposure to wholly vaporized UG (2018 ppm) under bioassay an d tumor-promoting conditions began at 8 weeks of age. After 4 months o f exposure, UG increased relative liver weight and hepatic microsomal cytochrome P450 pentoxyresourfin-O-dealkylase and ethoxyresorufin-O-de ethylase activity to a similar extent in intact and Ovex mice. Non-foc al hepatocyte proliferation, as measured by the incorporation of bromo deoxyuridine, was not changed by UG exposure and was similar in all tr eatment groups. After 4 months of exposure to DEN-initiated mice, UG s ignificantly increased the volume fraction of liver occupied by foci ( three-fold) as compared to control intact mice. As expected, volume of foci was elevated in DEN/Ovex/control mice as compared to DEN/intact/ control mice. In DEN/Ovex mice UG did not significantly increase the f ocal volume fraction. Thus, the tumor promoting activity of UG, as dem onstrated by increased volume fraction of liver occupied by hepatic fo ci in intact mice, is greatly attenuated in Ovex mice. The volume frac tion data in Ovex mice support the hypothesis that the tumor promoting activity of UG is dependent upon the interaction of UG with ovarian h ormones. These data also indicate that hepatic microsomal cytochrome P 450 PROD and EROD induction, hepatomegaly and non-focal hepatic LI are not specific markers of hepatic tumor promoting activity of UG.