Unleaded
gasoline (UG), a nongenotoxic kidney
carcinogen in male, but not female, F344 rats or either sex of mice, and
2,2,4-trimethylpentane (
TMP), a representative nephrotoxic isoparaffinic component of UG, were tested for potential promoting and cocarcinogenic effects in a kidney initiation-promotion model. The promotion study was conducted with 305 male and 305 female F344 rats fed 170 ppm
N-ethyl-N-hydroxyethylnitrosamine in the
drinking water for 2 weeks and then inhalation exposed to 0, 10, 70, or 300 ppm UG or 50 ppm
TMP for 24 or 59 to 61 weeks. In a sequence reversal study, 390 male F344 rats were inhalation exposed to 0, 10, 70, or 300 ppm UG or 50 ppm
TMP for 24 weeks, followed by 170 ppm
N-ethyl-N-hydroxyethylnitrosamine in the
drinking water during weeks 28 to 30, and killed at weeks 65 to 67. Renal neoplastic lesions were classified as atypical cell foci (ACF) and renal cell
tumors (RCT). In the
hydrocarbon promotion study, dose related increases were observed in the incidence of ACF in male rats promoted with UG or 50 ppm
TMP for 24 or 60 weeks. A significant linear trend in the incidence of RCT was observed in male rats promoted with UG for 24 weeks. The incidence of ACF or RCT was not elevated in female rats promoted with UG or
TMP. In the sequence reversal study, a slight increase in ACF was demonstrated in male rats exposed to 300 ppm UG, whereas no increase in RCT was observed in any exposure group. It is concluded that UG and
TMP are promoters of ACF and RCT in male, but not female, rats under the conditions of this study. Data from related investigations suggest that the
tumor promoting potential of UG and
TMP results from reversible binding of metabolites to alpha 2u-globulin, which leads to decreased renal catabolism of this
protein, chronic lysosomal overload, cell death, and compensatory cell proliferation.