Impact/Purpose:

The key issue that this research addresses is that EPA uses the linear multistage extrapolation model (LMS) to calculate the unit carcinogenic risks of PAHs. This model assumes that at low PAH exposure levels, the initial insults to DNA are linear and induce mutations and tumors in a linear fashion. Recent data suggests that this might not be valid at low PAH exposures. Since the default assumption of linearity is crucial to the use of the LMS model for PAH cancer risk assessment, the determination the shape of this curve is vital. The impact of a finding of non-linearity in the dose-response at environmental exposures would be a major change in the risk assessment process for this important class of Air Toxics. Furthermore, if the results with PAHs indicate a non-linear dose response at low exposures, these findings may affect the risk assessment of other genotoxic carcinogens. The techniques developed in this study will be the basis for future studies of mixtures and sensitive subpopulations.

Description:

We have previously characterized the administered dose tumor-response, stable DNA adduct-lung tumor response, and K-ras mutation profiles in tumors from strain A/J mice exposed i.p. to 6 PAHs including B[a]P . In summary, we demonstrated that: 1. The relationships between administered dose and tumors were curvilinear. 2. The PAH-DNA adduct profiles (adduction on guanine or adenine) and the induced mutations in Ki-ras oncogene in the lung tumors (mutations of guanine or adenine) were highly consistent. These results are in concert with many other studies of PAHs that demonstrate that mutations in the Ki-ras proto-oncogene are highly associated with lung tumors . However, the routes of metabolic activation, the specific DNA adducts that are formed, the repair or misrepair and its saturation, the misreplication of the lesions, and the induction of mutations all impinge on the final shape of the dose response curve at low exposures. The purpose of this research project is to determine the shape of the dose response curve of PAHs at low exposures, those to which people are exposed, using a relevant target tissue, lung, and an archetypal PAH. We propose to select B[a]P as the initial PAH to study, as B[a]P is the basis for EPA risk assessment activities for all PAHs. In addition, the results of this project may help to resolve the conflict in hypotheses of PAH carcinogenic mode of action at low exposures. To determine and explain the shape of the tumor dose-response curves, levels of stable and unstable PAH-DNA adduct levels, apurinic site levels, P450 induction, mutant frequencies, and gene expression data will be gathered. This information will provide the shape of the tumor dose response curve at low exposures, and by comparison of the individual response curves for the genotoxicity endpoints, identify the primary lesion(s) associated with the mutations and cancer.

Record Details: