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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

基本信息

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
项目类别：
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

项目摘要

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），来自不完全燃烧的碳（煤、柴油、汽车）