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: 10306359
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306359
• 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; sealant; 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 (PAH)，来自碳的不完全燃烧（煤、柴油、汽车 废气、木材烟雾等）是 ATSDR 关注的 10 种最重要化学品中的 3 种。在啮齿动物模型中，PAH 是强效的肺癌致癌物，对于人类也有充足的流行病学证据。肺癌 是全球癌症死亡的第一大原因（2016 年美国有 160,000 人死亡）。诊断发生在晚期 强调预防的必要性。苯并[a]芘 (BaP)，是研究最广泛的肺多环芳烃 (PAH) 致癌物，是已知的 1 类人类致癌物 (IARC)。当前 EPA IRIS 癌症风险斜率 BaP（终生暴露）系数为 7 mg/kg/day-1，假设线性度超过几个数量级 啮齿动物肿瘤研究。我们可以与劳伦斯利弗莫尔国家实验室合作 ULPC 加速器质谱 (AMS) 以低于平均剂量进行人体 ADME 研究 每日饮食暴露。我们的首要前提是：准确的 PK 分析和风险评估 人类是人类最好的典范。根据 FDA IND 进行，我们将进行 3 项新颖的研究 BaP 的研究为负责提供最多信息的监管机构提供了独特的数据集 可以对 BaP (PAH) 暴露进行准确的风险评估。 1. 确定剂量 (50-250 ng) 在等于或低于平均每日暴露量的范围内的影响 不吸烟的美国成年人。利用 ULPC 与 AMS 接口确定剂量对代谢的影响 血浆和尿液中的分布（生物活性和解毒）。与我们的长期合作伙伴合作 太平洋西北国家实验室将这些数据纳入其 PBPK 和风险评估 模型。 2. 评估环境多环芳烃混合物中常见的另一种多环芳烃菲的影响， 关于 BaP 的 ADME。 ADME 的哪些组件受到影响？效果是累加性的、抑制性的还是 也许有协同作用？答案对于风险评估和测试相对假设至关重要 大多数监管机构目前考虑采用效力因子方法对 PAH 混合物进行风险评估 机构。 3.测试十字花科蔬菜/补充剂的化学预防潜力，在临床前有效 癌症模型和人群，在环境相关暴露水平下的人类 巴普。有什么影响？它是否涉及吸收、代谢和/或排泄的改变？ 这项研究将首次确定天然食品的功效、效力和机制， 与补充剂相比，对于接触膳食的健康人的化学预防作用 在规定的环境相关剂量下的化学致癌物质。

项目成果

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane.

源自葡糖油菜素的吲哚：通过吲哚-3-甲醇和 3,3-二吲哚基甲烷进行癌症化学预防。

• 发表时间: 2021
• 作者: Williams; David E
• 通讯作者: David E