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

项目概述（见说明）：许多多环芳烃（PAH）污染物是致癌的，其中一些可以通过胎盘对后代产生影响。虽然反应性中间体的代谢激活是毒性所必需的，但在现实世界暴露条件下，人们对多环芳烃及其代谢物在人体中的药代动力学知之甚少。因此，我们在SRP中与癌症生物学家、化学家和毒理学家合作，开发了第一个基于生理的药代动力学（PBPK）模型，用于任何高分子量致癌性多环芳烃，能够在我们最初的资助周期中比较大鼠、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。该项目最初关注的是强效胎盘致癌物质二苯并[def，p]chrysene (DBC)，它会在怀孕期间暴露于单剂量小鼠的后代中产生t细胞淋巴瘤，这是儿童和年轻人的一种常见癌症。我们纳入了在超级基金站点中常见的原型多环芳烃，苯并[a]芘（BaP）的研究，因为它们的作用模式相似，这将使我们能够根据靶组织的内部剂量来比较效力。在这次更新中，我们将扩展我们的研究，以评估在发育、生长和成熟的每个阶段的关键代谢物的配置以及混合暴露的影响，以改善推断相关人类暴露致癌风险的基础。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、小鼠和人体组织中的体外代谢比较率以及混合暴露的影响；(2)重点开展BaP、DBC及其代谢物的体内药代动力学研究，以及混合物对大鼠和小鼠的影响；(3)确定与多环芳烃代谢有关的酶的功能活性与物种、组织和生命阶段的关系；(4)继续开发、评估和完善针对大鼠、小鼠和人类生命阶段的PBPK模型，为利益相关者提供定量工具，预测相关暴露对人类的风险。

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.