Project 2: Cross-Species Comparison of Transplacental Dosimetry PAHs

二苯并[a，l]芘（DBP）是一种强致癌性多环芳烃（PAHs） 作为有机材料燃烧的副产品存在于环境中，并存在于许多超级基金场地。 SBRP的合作者发表了第一个生产T细胞的动物模型， 淋巴瘤，一种儿童和年轻人常见的癌症，在暴露于DBP的小鼠的后代中， 怀孕T细胞淋巴瘤模型提供了一个独特的机会，以解决不确定性， 推断经胎盘致癌对人类的潜在风险。可靠地预测出 在各种暴露条件下化学品活性形式（母体化合物或代谢物）的组织剂量 条件是从实验室条件成功外推到人类的必要先决条件。 然而，目前还没有研究定量代谢活化与其他代谢物的相对贡献。 母体和胎儿/新生儿组织中DBP解毒和清除的潜在重要途径 这将有助于从动物模型外推靶组织剂量（胸腺中的DMA加合物）， 人类事实上，重要的物种、组织和发育阶段在清除能力上的差异， 已知的，必须考虑的。因此，本项目的目标是开发定量的、剂量依赖的 经胎盘DBP诱导的小鼠靶组织DMA加合物与改善 将致癌风险外推至相关人体暴露于DBP的生物学基础。到 为了实现这一目标，识别和确定激活与解毒的相对速率至关重要 在小鼠和人类中的通路。提出了四个具体目标，包括：（1）确定剂量依赖性 DBP及其主要代谢产物和DMA加合物的药代动力学和靶组织剂量测定 在经胎盘致癌性的小鼠模型中（2）确定代谢的比较速率， 原代肝细胞和胸腺细胞中DBP的活化（重点是Cyp 1b 1）和解毒 （3）确定DBP的体内超低剂量药代动力学及其关键 在人类志愿者中的代谢物;和（4）开发第一个基于生理学的药代动力学（PBPK） DBP模型能够识别和减少外推靶组织剂量的不确定性， DBP的毒性代谢物从小鼠到相关的人体暴露。

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, dosedependent 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 dosedependent 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.