Benzo[a]pyrene Micro-dosing of Humans: A New Tool for Exposure, Risk Assessment and Prevention

人体苯并[a]芘微剂量：暴露、风险评估和预防的新工具

• 批准号: 10057385
• 负责人: David E Williams
• 金额: $ 46.02万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057385
• 关键词: ADME Study; Address; Adult; Aflatoxin B1; Aluminum; Aromatic Polycyclic Hydrocarbons; Automobile Exhaust; Benzo(a)pyrene; Blood; CYP11A1 gene; Cancer Etiology; Cancer Model; Carbon; Carcinogen exposure; Carcinogens; Cessation of life; Charge; Chemicals; Chemoprevention; Chemopreventive Agent; Coal; Coal Tar; Coke; Complex; Creosote; DNA Adduction; DNA Adducts; Data; Data Set; Detection; Diagnosis; Dietary intake; Dose; Drug Kinetics; Environmental Carcinogens; Environmental Pollutants; Epidemiology; Excretory function; Exhibits; Exposure to; Fire - disasters; Food; Gasoline; Gastrointestinal tract structure; General Population; Hour; Human; Individual; Ingestion; International Agency for Research on Cancer; Kinetics; Label; Laboratories; LacZ Genes; Lung; Malignant neoplasm of lung; Metabolism; Modeling; Mus; Mutation; Natural graphite; Oral; Pacific Northwest; Petroleum; Physiological; Plasma; Population; Prevention; Production; Risk; Risk Assessment; Risk Reduction; Rodent; Rodent Model; Site; Source; Technology; Testing; Time; Tissues; Tobacco smoke; Urine; Wood material; Work; absorption; accelerator mass spectrometry; anthropogenesis; base; cancer risk; carcinogenesis; chemical carcinogen; cruciferous vegetable; detoxication; dietary; dietary chemoprevention; diindolylmethane; exposed human population; forest; improved; metabolic profile; mortality; non-smoking; novel; pharmacokinetic model; phenanthrene; pollutant; pre-clinical; response; tool; transcriptomics; tumor; uptake; volcano; wood smoke

Polycyclic aromatic hydrocarbons (PAHs), from incomplete combustion of carbon (coal, diesel, auto exhaust, wood smoke, etc.) are 3 of top 10 chemicals of concern for ATSDR. In rodent models, PAHs are potent lung carcinogens and there is ample epidemiological evidence also for humans. Lung cancer is the #1 cause of cancer deaths worldwide (160,000 in U.S. for 2016). Diagnosis occurs in late stages emphasizing the need for prevention. Benzo[a]pyrene (BaP), the most widely-studied PAH lung carcinogen, is a class 1 known human carcinogen (IARC). The current EPA IRIS cancer risk slope factor for BaP (lifetime exposure) is 7 mg/kg/day-1, assuming linearity over orders of magnitude from rodent tumor studies. Collaborating with Lawrence Livermore National Laboratory we can employ ULPC-accelerator mass spectrometry (AMS) to conduct human ADME studies at doses below average daily dietary exposure. Our overarching premise is: for accurate PK analysis and risk assessment humans are the best model for humans. Conducted under an FDA IND, we will perform 3 novel studies with BaP providing a unique dataset for regulatory agencies charged with providing the most accurate risk assessment possible for BaP (PAH) exposure. 1. Determine the impact of dose (50-250 ng) over a range at or below average daily exposure for a non-smoking U.S. adult. Utilizing ULPC interfaced with AMS determine the impact of dose on metabolic profiles (bioactivation and detoxication) in plasma and urine. Working with our long-term collaborators at Pacific Northwest National Laboratory incorporate these data into their PBPK and risk assessment models. 2. Assess the impact of another PAH, phenanthrene, commonly found in environmental PAH mixtures, on the ADME of BaP. What components of ADME are impacted? Is the effect additive, inhibitory or perhaps synergistic? The answer is critical for risk assessment and testing assumptions of the Relative Potency Factor approach to risk assessment for PAH mixtures currently considered by most regulatory agencies. 3. Test the chemoprevention potential of cruciferous vegetables/supplement, effective in preclinical cancer models and human populations, in humans at environmentally relevant exposure levels of BaP. What is the impact and does it involves alterations in absorption, metabolism and/or excretion? This study will, for the first time, determine the efficacy, potency and mechanism of a whole food, compared to a supplement, with respect to chemoprevention in healthy humans exposed to a dietary chemical carcinogen at a defined environmentally relevant dose.

多环芳烃（PAHS），来自碳的不完全燃烧（煤，柴油，自动 排气，木烟等是ATSDR关注的十种化学物质中的3种。在啮齿动物模型中 是有效的肺癌，对于人类也有足够的流行病学证据。肺癌 是全球癌症死亡的第一名（2016年美国为160,000）。诊断发生在晚期 强调需要预防。苯并[a] pyrene（bap），最广泛研究的pah肺 致癌物是一种已知的人类致癌物（IARC）。当前的EPA IRIS癌症风险斜率 BAP（终生暴露）的因子为7 mg/kg/day-1，假设在数量级上线性 啮齿动物肿瘤研究。与劳伦斯·利弗莫尔国家实验室合作，我们可以雇用 ULPC加速器质谱法（AMS）以低于平均剂量进行人类ADME研究 每日饮食暴露。我们的总体前提是：用于准确的PK分析和风险评估 人类是人类的最佳典范。在FDA IND下进行，我们将执行3个小说 BAP的研究为负责提供最多的监管机构提供了独特的数据集 BAP（PAH）暴露的准确风险评估。 1。确定剂量（50-250 ng）在每日平均暴露范围内的影响 非吸烟的美国成年人。利用与AMS连接的ULPC确定剂量对代谢的影响 血浆和尿液中的特征（生物活化和解毒）。与我们的长期合作者合作 在太平洋西北国家实验室将这些数据纳入其PBPK和风险评估 型号。 2。评估在环境PAH混合物中通常发现的另一种PAH，菲的影响， 在bap的公平上。 ADME的哪些组成部分受到影响？效果是添加剂，抑制作用还是 也许是协同作用？答案对于相对的风险评估和测试假设至关重要 大多数监管目前考虑的PAH混合物的风险评估的效力因子方法 机构。 3。测试十字花科蔬菜/补充剂的化学预防潜力，有效 癌症模型和人类人口，在人类的环境相关暴露水平 bap。影响是什么，它涉及吸收，代谢和/或排泄的改变？ 这项研究将首次确定整个食物的功效，效力和机制， 与补充剂相比，关于健康人的化学预防，暴露于饮食 定义与环境相关的剂量的化学致癌物。