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

点击翻译按钮获取中文摘要

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.