Comparative short-term effects of methyl tertiary butyl ether and unleaded gasoline vapor in female B6C3F1 mice.
PS-6 unleaded gasoline (UG) and methyl tert-butyl ether (MTBE), an UG additive, with long-term exposure at high concentrations increased liver tumors selectively in female mice. PS-6 UG is a liver tumor promoter in N-nitrosodiethylamine-initiated female mice and produces short-term effects potentially relevant to its tumor promoting ability. The new formulation of UG (91-01) and MTBE were evaluated for similar short-term effects in mouse liver. Mice were exposed to 7814 ppm MTBE, 2014 ppm 91-01 UG, or 2028 ppm PS-6 UG vapor for 3 or 21 days, 6 hr/day, 5 day/week. Relative liver weights increased and uterine weights decreased in MTBE-, 91-01 UG-, and PS-6 UG-exposed mice. Because the decrease in relative uterine weight is suggestive of hormonal modulation, we evaluated the effects of MTBE, 91-01 UG, and PS-6 UG in vivo on hepatic 17-beta estradiol metabolism in vitro. Gavage treatment with either blend of UG and with MTBE increased estrogen metabolism in isolated mouse hepatocytes. Hepatic microsomal P450 activity was assessed by 7-pentoxyresorufin-O-dealkylase (PROD) and 7-ethoxyresorufin-O-deethylase (EROD) activities. Similar increases in P450 content and PROD and EROD activities were observed in all exposed mice as compared to controls. No hepatoxicity was observed in any treatment group. The hepatic labeling index, as measured by the incorporation of 5-bromo-2'-deoxyuridine, was increased in all exposed mice at 3 days but not 21 days, indicating that MTBE and 91-01 UG are also hepatic mitogens. These data demonstrate that a newer blend of UG and the UG additive MTBE elicit short-term effects similar to those of PS-6 UG. Given that these effects are potentially related to tumor promotion and the general lack of genotoxic activity, MTBE and 91-01 UG may exhibit tumor promoting activity similar to that seen with PS-6 UG. Since the liver is under multihormonal control, the increase in hepatic estrogen metabolism and uterine effects supports a potential role for endocrine modulations in both MTBE-and UG-induced hepatocarcinogenesis.
Moser
G J
GJ
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Wong
B A
BA
Wolf
D C
DC
Moss
W R
WR
Goldsworthy
T L
TL
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005742:Gasoline / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008738:Methyl Ethers / Q000633:toxicity*; D051379:Mice; D018675:Toxicity Tests; D014599:Uterus / Q000187:drug effects*
D002273:Carcinogens; D004967:Estrogens; D005742:Gasoline; D008738:Methyl Ethers; C043243:methyl tert-butyl ether; D003577:Cytochrome P-450 Enzyme System; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1