Project 2: Cross-Species and Life StageComparisons of PAH Dosim (Corley)

项目摘要(见说明)：许多多环芳烃(PAH)超级基金现场的污染物是致癌的，其中一些可以通过胎盘在以后的生命中对后代产生影响。虽然毒性需要代谢活化为活性中间体，但人们对多环芳烃及其代谢物在真实暴露条件下在人体内的药代动力学知之甚少。因此，我们与癌症生物学家、化学家和毒物学家在这项SRP中合作，为任何高分子量致癌多环芳烃开发了第一个基于生理学的药代动力学(PBPK)模型，能够在我们最初的资金周期中比较大鼠、小鼠和人类在代谢激活和解毒过程中的物种、组织和生命阶段差异。该项目最初专注于一种有效的胎盘致癌物质二苯并[def，p]大黄素(DBC)，它会在怀孕期间单次注射的小鼠的后代中产生T细胞淋巴瘤，这是儿童和年轻人的一种常见癌症。我们包括了超级基金网站中常见的多环芳烃原型的研究，苯并[a]芘(BaP)，因为类似的作用模式将使我们能够比较基于目标组织内剂量的效力。在这次更新中，我们将扩展我们的研究，以评估关键代谢物在发育、生长和成熟的每个阶段的处置以及混合暴露的影响，以改善推断相关人类暴露的致癌风险的基础。为实现这一目标，提出了四个具体目标：(1)确定BaP、DBC及其主要代谢物在大鼠、小鼠和人类组织中的体外代谢率以及混合物暴露的影响；(2)对BaP、DBC和代谢物进行重点体内药代动力学研究以及混合物在大鼠和小鼠体内的影响；(3)确定对多环芳烃新陈代谢至关重要的酶的功能活性随物种、组织和生命阶段的变化；以及(4)继续发展、评估和完善大鼠、小鼠和人类特定生命阶段的PBPK模型，为利益攸关方提供量化工具，以预测相关暴露对人类造成的风险。

PROJECT SUMMARY (See instructions): Many polycyclic aromatic hydrocarbon (PAH) Superfund site contaminants are carcinogenic, some of which can cross the placenta to produce effects in offspring later in life. While metabolic activation to reactive intermediates is required for toxicity, little is known about the pharmacokinetics of PAHs and their metabolites in humans under real world exposure conditions. We therefore teamed with cancer biologists, chemists, and toxicologists in this SRP to develop the first physiologically based pharmacokinetic (PBPK) models for any high molecular weight carcinogenic PAHs capable of comparing species, tissue, and life stage differences in metabolic activation and detoxification processes in rats, mice and humans during our initial funding cycle. This project initially focused upon the potent transplacental carcinogen, dibenzo[def,p]chrysene (DBC) which produces T-cell lymphomas, a common cancer for children and young adults, in the offspring of mice exposed to a single dose during pregnancy. We included studies with the prototypic PAH commonly encountered in Superfund sites, benzo[a]pyrene (BaP), because of similar modes of action that will allow us to compare potencies based upon internal doses in target tissues. In this renewal, we will extend our studies to evaluate the disposition of key metabolites at each stage of development, growth, and maturation and the impact of mixture exposures to improve the basis for for extrapolating the risk of carcinogenesis to relevant human exposures. Four specific aims are proposed to achieve this goal: (1) determine the comparative rates of in vitro metabolism of BaP, DBC and their major metabolites in rat, mouse and human tissues and the impact of mixture exposures; (2) conduct focused in vivo pharmacokinetic studies with BaP, DBC and metabolites and impact of mixtures in rats and mice; (3) determine the functional activity of enzymes important to PAH metabolism as a function of species, tissue and life stage; and (4) continue to develop, evaluate and refine life stage-specific PBPK models for rats, mice and humans to provide stakeholders with quantitative tools for predicting risks to humans at relevant exposures.