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

项目 1：环境水平下人类多环芳烃的药代动力学、代谢和

• 批准号: 9058937
• 负责人: David E Williams
• 金额: $ 29.57万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-27 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9058937
• 关键词: Animals; Aromatic Polycyclic Hydrocarbons; Behavior; Benzo(a)pyrene; Biological Markers; Blood; CYP1A1 gene; CYP1B1 gene; Chemicals; Chrysenes; Code; Communities; Complex; Cytochrome P450; DNA; DNA Adduction; DNA Adducts; Data; Data Set; Diet; Dose; Drug Kinetics; Environment; Environmental Exposure; Environmental Pollution; Enzymes; Ethnic Origin; Evaluation; Exhibits; Exposure to; Family; Fishes; Food; General Population; Genes; Genetic; Genetic Polymorphism; Genotype; Glutathione S-Transferase; Haplotypes; Hazardous Substances; Health; Hour; Human; Human Volunteers; Indian reservation; Individual; Instruction; Laboratories; Lymphocyte; Malignant Neoplasms; Measures; Metabolic; Metabolic Activation; Metabolism; Modeling; Mus; Organ; Oxidoreductase; Parents; Phase; Play; Predisposition; Radioisotopes; Recruitment Activity; Relative (related person); Research Personnel; Risk; Risk Assessment; Role; Salmon; Sampling; Shipping; Ships; Smoke; Technology; Testing; Time; Toxic effect; Tribes; Urine; Work; accelerator mass spectrometry; adduct; base; benzo(a)pyrene-DNA adduct; carcinogenesis; clinical practice; detoxication; gene environment interaction; genetic variant; health data; human data; innovation; knowledge base; new technology; non-smoker; non-smoking; sulfotransferase; superfund site; uptake; volunteer

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.

项目摘要（参见说明）：项目 1 将分析典型致癌多环芳烃 (PAH)、苯并[a]芘 (BaP) 在环境相关暴露下人体中的药代动力学。目前，监管机构（EPA、FDA）以及 ATSDR 和 lARC 必须依靠高剂量动物研究来预测安全终生暴露水平。我们的总体假设是，以环境中遇到的水平给予人类的 BaP 将表现出可根据在小鼠中构建的 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。最终目标是探索性的，旨在根据共同的遗传多态性识别具有更大易感性的个体。人类志愿者服用的[14C]-BaP剂量将比美国非吸烟者的平均每日暴露剂量低一个数量级。加速器质谱 (AMS) 的使用允许化学和放射性同位素 (5 nCi) 的微剂量，并且仍然跟踪三天的血液和尿液水平。使用新开发的 AMS 技术使我们能够了解母体 BaP 以及单个代谢物的水平，这是一项重大进步，将有助于进行评估。 EPA 目前正在考虑使用相对效力因子 (RPF) 方法来评估 PAH 混合物的风险。我们将开展一项研究，根据鲑鱼中 PAH 的 RPF，将含有 10 倍 BaPeq 的 1-3 盎司熏鲑鱼与 [14C]- 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提供 RPF 方法的首次测试。最后，在探索性基因-环境相互作用研究中，将对表现出不同 BaP 代谢谱或 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，将通过提供关于人类暴露于环境水平的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的发展。