Project 2: Cross-Species Comparison of Transplacental Dosimetry PAHs

二苯并[a，L]芘(DBP)是致癌活性最强的多环芳烃之一。 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地点。 提出的SBRP的合作者发布了第一个生产T细胞的动物模型 淋巴瘤，一种常见的儿童和年轻人的癌症，在接触DBP的小鼠的后代中 怀孕了。T细胞淋巴瘤模型提供了一个独特的机会来解决不确定因素 推断经胎盘致癌对人类的潜在风险。可靠地预测哪个目标 各种暴露下化学物质(母体化合物或代谢物)活性形式的组织剂量 条件是成功地从实验室条件外推到人类的必要前提。 然而，目前还没有研究量化代谢激活与其他因素的相对贡献 母体和胎儿/新生儿组织中DBP的潜在解毒和清除途径 这将有助于从动物模型推断目标组织剂量(胸腺中的DMA加合物) 人类。事实上，重要的物种、组织和发育阶段的清除能力的差异是 已知且必须加以说明。因此，这个项目的目标是开发定量的、依赖于剂量的 经胎盘DBP诱导的小鼠靶组织DMA加合物与改善机体功能的关系 推断人类暴露于DBP的相关致癌风险的生物学基础。至 要实现这一目标，关键是要确定和确定激活与解毒的相对比率 在老鼠和人类中的通路。提出了四个具体目标，包括：(1)确定剂量依赖性 DBP及其主要代谢物和DMA加合物的药代动力学和靶向组织剂量学 在小鼠经胎盘致癌模型中(2)测定比较代谢率 DBP在原代肝细胞和胸腺细胞中的激活(重点是CYP1B1)和解毒作用 (3)DBP超低剂量体内药代动力学测定及其关键 人类志愿者体内的代谢物；以及(4)开发第一个基于生理的药代动力学(PBPK) 能够识别和减少外推目标组织剂量的不确定性的DBP模型 DBP从小鼠到相关人类暴露的毒性代谢物。

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.