Project 2: Cross-Species Comparison of Transplacental Dosimetry PAHs

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Dibenzo[a,l]pyrene (DBP) is one of the most potent carcinogenic polycyclic aromatic hydrocarbons (PAHs) present in the environment as a by-product of the burning of organic materials and at many Superfund sites. Collaborators on this proposed SBRP published the first animal model for the production of T-cell lymphomas, a common cancer for children and young adults, in offspring of mice exposed to DBP during pregnancy. The T-cell lymphoma model provides a unique opportunity to address uncertainties in extrapolating the potential risk to humans for transplacental carcinogenesis. Reliably predicting which target tissue doses of the active form of the chemical (parent compound or metabolite) under a variety of exposure conditions is a necessary prerequisite to successful extrapolations from laboratory conditions to humans. However, no studies currently exist that quantitate the relative contribution of metabolic activation with other potentially significant pathways for detoxification and clearance of DBP in maternal and fetal/neonatal tissues that would facilitate target tissue dose extrapolations (DMA adducts in the thymus) from the animal model to humans. In fact, important species, tissue, and stage of development differences in clearance capacities are known and must be accounted for. Therefore, the goal of this project is to develop quantitative, dose-dependent relationships for transplacental DBP-induced target tissue DMA adducts in mice to improve the biological basis for extrapolating the risk of carcinogenesis to relevant human exposures to DBP. To accomplish this goal, it is critical to identify and determine the relative rates of activation vs. detoxification pathways in mice and humans. Four specific aims are proposed and include: (1) determine the dose-dependent pharmacokinetics and target tissue dosimetry of DBP and its major metabolites and DMA adducts in the mouse model for transplacental carcinogenicity (2) determine the comparative rates of metabolic activation (with an emphasis on Cyp1b1) and detoxification of DBP in primary hepatocytes and thymocytes from mice vs. humans; (3) determine the in vivo ultra low dose pharmacokinetics of DBP and its key metabolites in human volunteers; and (4) develop the first physiologically based pharmacokinetic (PBPK) model for DBP capable of identifying and reducing the uncertainties in extrapolating target tissue doses of toxic metabolites of DBP from mice to relevant human exposures.