Core 3 - Biomarkers and Product Evaluation

摘要-核心003：生物标志物和产品评价核心 生物标志物和产品评估核心的目标是促进项目中提出的研究。 MARVEL通过提供关于暴露和生物效应的生物标志物的数据， 常用的电子烟产品。这些数据将使各个项目能够实现其特定目标。的 测量使用烟草制品的人的体液中的有毒物质和致癌物质代谢物是 客观评估这些产品暴露的公认方法。总尼古丁当量（TNE）， 尼古丁和六种尼古丁代谢物的总和占尼古丁剂量的>85%，这是一个公认的 尼古丁暴露的生物标志物。尼古丁代谢的主要途径是细胞色素P450 2A 6 （CYP 2A 6）催化的C-氧化，导致可替宁的形成。可替宁进一步代谢， 通过CYP 2A 6转化为3 '-羟基可替宁。血浆或唾液中的3 '-羟基可替宁与可替宁的比率（称为 NMR）是CYP 2A 6活性极好的表型测量，且可用于表征个体 尼古丁代谢的差异。尿中丙烯腈巯基尿酸，2-氰乙基- 与非吸烟者相比，吸烟者中的巯基尿酸（CEMA）高100至400多倍， 可用于区分可燃性和非可燃性烟草使用，具有灵敏度和特异性 > 99%。丙烯醛、巴豆醛和苯的巯基尿酸，3-羟丙基巯基尿酸 可以使用3-羟基-1-甲基丙基巯基尿酸（3 HPMA）、3-羟基-1-甲基丙基巯基尿酸（HMPMA）、S-苯基巯基尿酸（SPMA 量化香烟和电子烟使用者对挥发性有毒物质的暴露。氧化损伤可能是 用尿8-iso-PGF 2 α（一种F2-异前列腺素）和升高的PGE-M（一种前列腺素E2代谢产物）测量， 炎症的生物标志物。Vaping产品的流体成分和产生的气溶胶可能差异很大。 Core将分析实验室研究参与者的唾液样本中的可替宁和NMR。尿液样本 将分析参加实验室评估的参与者的TNE、巯基尿酸、8-iso-PGF 2 α 和PGE-M。核心还将确定电子液体成分和产生的气溶胶产量的最 在这项研究的参与者中大量使用电子烟。具体目标是：1）表征 队列研究中参与者尼古丁代谢和暴露的个体差异; 2）量化 暴露于烟草制品中发现的其他成分和氧化应激的全身指数， 基于实验室的评估的参与者的炎症; 3）表征电子液体中的有毒成分， 气雾剂核心是设在明尼苏达大学，提供国家的最先进的专业知识， 这些生物标志物的定量技术，以及电子烟的成分。大学 明尼苏达州被广泛认为是这项研究的主要学术中心之一。客观核查 产品特性、用户暴露和生物学效应是稳健性的关键组成部分， 研究烟草制品对健康的影响。

ABSTRACT – CORE 003: Biomarkers and Product Evaluation Core The goal of the Biomarkers and Product Evaluation Core is to facilitate the research proposed in Project MARVEL by providing data on biomarkers of exposure and biological effects as well as to characterize commonly used vaping products. These data will allow individual projects to achieve their Specific Aims. The measurement of toxicant and carcinogen metabolites in body fluids of people who use tobacco products is the accepted method for objective assessment of exposure to these products. Total nicotine equivalents (TNE), the sum of nicotine and six nicotine metabolites accounts for >85% of the nicotine dose, is a well-established biomarker of nicotine exposure. The primary pathway of nicotine metabolism is cytochrome P450 2A6 (CYP2A6)-catalyzed C-oxidation, which leads to the formation of cotinine. Cotinine is further metabolized, also by CYP2A6, to 3'-hydroxycotinine. The ratio of 3'-hydroxycotinine to cotinine in plasma or saliva (referred to as the NMR) is an excellent phenotypic measure of CYP2A6 activity, and may be used to characterize individual differences in nicotine metabolism. Urinary concentrations of the acrylonitrile mercapturic acid, 2-cyanoethyl- mercapturic acid (CEMA) is from 100 to more than 400 times higher in smokers compared to non-smokers and can be used to distinguish combustible from non-combustible tobacco use with sensitivity and specificity >99%. The mercapturic acids of acrolein, crotonaldehyde, and benzene, 3-hydroxypropyl-mercapturic acid (3HPMA), 3-hydroxy-1-methylpropylmercpturic acid (HMPMA), S-phenylmercapturic acid (SPMA) can be used to quantify exposure to volatile toxicants in cigarette and e-cigarette users. Oxidative damage can be measured with urinary 8-iso-PGF2α, an F2-isoprostane and elevated PGE-M, a prostaglandin-E2 metabolite is a biomarker of inflammation. Vaping products may vary widely in their fluid constituents and generated aerosol. The Core will analyze saliva samples from Lab Study participants for cotinine and the NMR. Urine samples from participants attending lab-based assessments will be analyzed for TNE, mercapturic acids, 8-iso-PGF2α and .PGE-M. The Core will also determine e-liquid constituents and generated aerosol yield of the most abundantly used e-cigarettes among the participants of this study. The Specific Aims are to: 1) Characterize individual differences in nicotine metabolism and exposure in participants in the cohort study; 2) Quantify exposure to other constituents found in tobacco products and systemic indices of oxidative stress and inflammation in participants of the lab-based assessments; 3) Characterize toxic constituents in e-liquids and aerosol. The Core is housed at the University of Minnesota which provides state-of-the-art expertise and technology for the quantitation of these biomarkers, and the constituents of e-cigarettes. The University of Minnesota is widely recognized as one of the leading academic centers for this research. Objective verification of product characteristics, user exposure, and biological effects is a critically important component of robust research on the health effects of tobacco products.