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(见说明)：项目1将分析典型致癌多环芳烃(PAH)、苯并[a]芘(BaP)在环境相关暴露下在人体内的药代动力学。目前，监管机构(EPA、FDA)以及ATSDR和LARC必须依赖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，在环境中遇到的水平给予人类的BaP，将表现出从在小鼠身上构建的PBPK模型可预测的药代动力学。我们进一步假设，暴露于多环芳烃饮食混合物中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，并寻求根据共同的基因多态来确定具有更大易感性的个体。人类志愿者将被给予[14C]-BaP剂量，这个剂量比美国非吸烟者的平均日暴露剂量低一个数量级。加速器质谱仪(AMS)的使用允许化学和放射性同位素(5NCI)的微量剂量，并仍然跟踪三天的血液和尿液水平。使用新开发的AMS技术使我们能够获得父母BaP和个体代谢物的水平，这是一个重大进步，将有助于ASK评估。环保局目前正在考虑使用相对效力系数(RPF)方法对多环芳烃混合物进行风险评估。我们将进行一项研究，根据鲑鱼中多环芳烃的RPF，将1-3盎司含有10倍BaPeq的烟熏鲑鱼与[14C]-BaP联合给药。通过检查血液中的药代动力学、代谢物分布和共价DNA加合物，我们可以提供有史以来第一次在人类和环境相关水平上测试RPF方法。最后，在一项探索性的基因-环境相互作用研究中，将对表现出不同的BaP代谢物特征或BaP-DNA加合物水平的个体进行BaP代谢酶的等位基因变异的基因分型。这些研究具有很高的创新性和重要意义，将通过提供关于环境水平暴露的多环芳烃在人类体内的药代动力学行为的独特和强大的数据集，显着推动风险评估领域的发展。