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

多环芳烃（PAHs），来自碳的不完全燃烧（煤、柴油、汽车） 废气、木材烟雾等）是ATSDR关注的十大化学品之三。在啮齿动物模型中， 是强有力的肺部致癌物，并且有足够的流行病学证据也适用于人类。肺癌 是全球癌症死亡的第一大原因（2016年美国有160，000人）。诊断发生在晚期 强调需要预防。苯并[a]芘（BaP）是研究最广泛的PAH肺 致癌物，是1类已知人类致癌物（IARC）。目前EPA IRIS癌症风险斜率 BaP（终生暴露）的系数为7 mg/kg/天-1，假设线性范围为 啮齿动物肿瘤研究。与劳伦斯利弗莫尔国家实验室合作， ULPC-加速器质谱法（AMS）在低于平均剂量下进行人体ADME研究 每日膳食摄入量。我们的首要前提是：进行准确的PK分析和风险评估 人类是人类最好的模型。在FDA IND下进行，我们将进行3种新的 BaP研究为监管机构提供了一个独特的数据集， 对苯并（a）芘（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对 无烟美国成人。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.评估另一种多环芳烃菲的影响，这种物质通常存在于环境中的多环芳烃混合物中， 关于BaP的ADME。ADME的哪些组件受到影响？效果是相加的、抑制的还是 也许是协同效应答案对于风险评估和测试相对风险的假设至关重要。 大多数监管机构目前考虑的PAH混合物风险评估的效力因子方法 社. 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，在人类中的环境相关暴露水平为 BaP。影响是什么，是否涉及吸收、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，对于暴露于膳食中的健康人的化学预防， 化学致癌物在规定的环境相关剂量。

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.