Unleaded gasoline and estrogen: understanding liver cancer in female mice.

With many people pumping fuel at self-service stations daily, the potential for human exposure to the vapors of unleaded gasoline is high. A two-year cancer study found that inhalation exposure to high levels of unleaded gasoline vapor-much higher than that to which most people would be exposed-caused an increase of kidney tumors in male rats and liver tumors in female mice. What is the relevance of these findings for assessing human risk?

Previous work at the Chemical Industry Institute of Toxicology (CIIT) showed that the sensitivity of male rats to kidney tumors is the result of components of unleaded gasoline interacting with a kidney protein found in male rats, but not humans, and that humans are not at risk of kidney tumors from this mechanism. CIIT researchers wanted to understand the underlying mechanism for the special sensitivity of female mice to liver tumors caused by high levels of unleaded gasoline.

The exposures causing liver tumors in female mice also caused changes in the uterus, suggesting the increase in liver tumors might be related to changes in the sex hormone status. This led CIIT scientists to the hypothesis that high concentrations of unleaded gasoline inhibit the estrogen hormone activity in mice and that liver tumor promotion by unleaded gasoline is secondary to this effect. To evaluate this hypothesis, three studies were conducted.

In the first study, CIIT scientists demonstrated that exposure to high levels of unleaded gasoline increased liver tumor activity in female mice, above that produced solely by administration of a chemical known to cause liver tumors. The second study demonstrated that synthetic estrogen hormone inhibited liver tumor formation in female mice. This result in mice contrasts with findings that synthetic estrogen hormone appears to increase liver tumor formation in rats and humans. The third study demonstrated that exposure to high levels of unleaded gasoline decreased various biological activities of synthetic estrogen given to female mice. These results suggest that high-level exposures to unleaded gasoline produce an increase in liver tumors by interfering with estrogen hormone function in the mice. Collectively, these findings suggest that the association between exposure to unleaded gasoline and increased incidence of liver tumors is a high-dose phenomenon that may be unique to female mice. Such an association is unlikely to be observed in people at the low levels typically experienced.

The findings with unleaded gasoline also raise the possibility that the increased incidence of liver tumors observed in female mice given high levels of other chemicals may be produced by a similar mechanism. Future research at CIIT will address this issue, the importance of which is underscored by recognition that an increased incidence of liver tumors in female mice is one of the most frequent findings for a large number of chemicals whose cancer-causing potential has been tested in mice and rats. Mechanistic information on other chemicals such as that developed for unleaded gasoline would be useful in clarifying the relevance of the findings in female mice for assessing human cancer risks. (Sources: Standeven, A.M. and T.L. Goldsworthy (1993). "Promotion of neoplastic lesions and induction of CYP2B induced by unleaded gasoline vapors in female B6C3F1 mouse liver" Carcinogenesis 14:2137-2141. Standeven, A.M, D.C. Wolf, and T.L. Goldsworthy (1994), "Interactive effects of unleaded gasoline and estrogen on liver tumor promotion in female B6C3F1 mice" Cancer Research 54:1-7.)