Project 1: PAHs in Humans at Environmental Levels Pharmacokinetics, Metabolism a

项目总结（见说明）：项目1将分析环境相关暴露条件下人体中典型致癌多环芳烃（PAH）、苯并[a]芘（BaP）的药代动力学。目前，管理机构（环境保护局、食品和药物管理局）以及美国毒物和疾病登记署和美国癌症研究所不得不依靠高剂量动物研究来预测安全的终生接触水平。我们的总体假设是，苯并（a）芘，在环境中遇到的水平给予人类，将表现出可从小鼠中构建的PBPK模型预测的药代动力学。我们进一步假设，暴露于PAH膳食混合物的人类的相对效力因子（RPF）将预测风险。最终的目的是探索性的，并试图根据共同的遗传多态性来识别具有更大易感性的个体。人类志愿者将被给予比美国非吸烟者平均每日暴露量低一个数量级的[14 C]-BaP剂量。加速器质谱法（AMS）的使用允许化学和放射性同位素（5 nCi）的微量给药，并且仍然跟踪血液和尿液水平三天。使用新开发的AMS技术使我们能够获得母体BaP以及单个代谢物的水平，这是一项重大进展，将有助于进行问评估。美国环保署目前正在考虑在多环芳烃混合物的风险评估中使用相对效力因子（RPF）方法。我们将进行一项研究，其中1-3盎司的熏鲑鱼含有10倍的BaPeq，基于鲑鱼中PAHs的RPF，将与[14 C]- BaP共同施用。通过检查血液中的药代动力学、代谢物谱和共价DNA加合物，我们可以在人类和环境相关水平上首次测试RPF方法。最后，在一项探索性基因-环境相互作用研究中，将对表现出不同BaP代谢物谱或BaP-DNA加合物水平的个体进行BaP代谢酶等位基因变体的基因分型。这些研究具有高度创新性和重要意义，将通过提供关于暴露于环境水平的人体中多环芳烃药代动力学行为的独特而强大的数据集，显着推进风险评估领域。

PROJECT SUMMARY (See instructions): Project 1 will analyze pharmacokinetics of the prototypical carcinogenic polycyclic aromatic hydrocarbon (PAH), benzo[a]pyrene (BaP) in humans at environmentally relevant exposures. Currently, regulatory agencies (EPA, FDA) and ATSDR and lARC have to rely on high-dose animal studies for predicting safe lifetime exposure levels. Our overall hypothesis is that BaP, given to humans at levels encountered in the environment, will exhibit pharmacokinetics predictable from PBPK models constructed in mice. We further hypothesize that the relative potency factor (RPF) for humans exposed to PAH dietary mixtures will be predictive of risk. The final aim is exploratory and seeks to identify individuals with greater susceptibility based on a common genetic polymorphism. Human volunteers will be administered a dose of [14C]-BaP an order of magnitude lower than the average daily exposure of a U.S. non-smoker. The use of accelerator mass spectrometry (AMS) allows for micro-dosing of both chemical and radioisotope (5 nCi) and still follow blood and urine levels for three days. Use of newly developed AMS technology permits us to access the levels of parent BaP as well as individual metabolites, a major advance that will contribute to ask assessment. The EPA is currently considering the use of a relative potency factor (RPF) approach in risk assessment for PAH mixtures. We will conduct a study in which 1-3 ounces of smoked salmon containing ten times the BaPeq, based on the RPF of the PAHs in the salmon, will be co-administered with the [14C]- BaP. By examining pharmacokinetics, metabolite profiles and covalent DNA adducts in blood, we can provide the first test ever of the RPF approach in humans and at environmentally relevant levels. Finally, individuals that exhibit distinct BaP metabolite profiles or levels of BaP-DNA adducts will be genotyped for allelic variants of BaP-metabolizing enzymes in an exploratory gene-environment interaction study. These studies are highly innovative and significant and will markedly advance the field of risk assessment by providing a unique and powerful dataset on pharmacokinetic behavior of PAHs in humans exposed at environmental levels.