Project 2: Cross-Species Comparison of Transplacental Dosimetry PAHs

二苯并[a， 1]芘（DBP）是环境中存在的最具致癌性的多环芳烃（PAHs）之一，是有机材料燃烧和许多超级基金场址的副产品。这一提议的SBRP的合作者发表了第一个在怀孕期间暴露于DBP的小鼠后代中产生t细胞淋巴瘤的动物模型，t细胞淋巴瘤是儿童和年轻人的常见癌症。t细胞淋巴瘤模型提供了一个独特的机会来解决在推断人类经胎盘癌发生的潜在风险时的不确定性。在各种暴露条件下，可靠地预测化学物质（母体化合物或代谢物）活性形式的目标组织剂量是成功地从实验室条件推断到人类的必要先决条件。然而，目前还没有研究量化代谢激活与母体和胎儿/新生儿组织中DBP解毒和清除的其他潜在重要途径的相对贡献，这将有助于从动物模型到人类的靶组织剂量外推（胸腺中的DMA加合物）。事实上，重要的是物种、组织和发育阶段在清除能力上的差异

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.