Dosimetry of human exposure to furan by monitoring exposure biomarkers

呋喃是在食品热加工过程中由各种前体形成的;其主要膳食来源是罐头食品和咖啡。呋喃在肝脏中通过细胞色素P450 1 E2代谢为高反应性和细胞毒性代谢产物顺式-2-丁烯-1，4-二醛（BDA）。艾姆斯试验将BDA鉴定为呋喃代谢活化形成的遗传毒性中间体，随后的研究确定其与细胞亲核试剂（如谷胱甘肽（GSH）和蛋白质）共价结合。呋喃及其衍生物，烷基呋喃，都是高度挥发性的，因此这些污染物在食品中的含量取决于食品的制备方式以及制备和消费之间的时间。1.）的人。因此，人类膳食呋喃/2-甲基呋喃暴露的准确剂量测定需要使用在食用前立即量化这些化合物在熟食中的水平的方法。我们打算在人类志愿者中进行呋喃暴露的剂量反应研究，遵循我们小组已经成功实施的设计。2.）的情况。为了补充这一重复的基于饮食的暴露剂量测定实验，将测量呋喃和2-甲基呋喃代谢物的尿液水平，以评估其作为暴露生物标志物的价值，目的是开发一种通过反向剂量测定评估饮食呋喃暴露的可靠方法。为此，将进行剂量反应研究，其中志愿者将食用含有呋喃的饮食，其水平相当于呋喃暴露的第95百分位数。将测量志愿者的饮食呋喃/2-甲基呋喃摄取量，并与尿液中排泄的呋喃相关代谢物水平进行比较。在试点研究中，我们已经确定，合成，并表征了GSH-BDA环加合物，该环加合物在人尿液中排泄，似乎是一种有前途的潜在的与呋喃饮食暴露后在人体内形成的人体生物标志物。此外，在随后的探索性工作中还鉴别出了另外两种候选代谢物。由于BDA具有多方面的化学反应性，它可以形成许多不同的呋喃脲相关的尿液代谢物。因此，预计我们的分析将产生尿液代谢产物谱，这将澄清呋喃的代谢命运和毒代动力学。我们不能排除呋喃和/或BDA可能通过各种生理前体和过程在人体内内源性产生的可能性，通过比较来自外源性来源的呋喃暴露（如通过重复的基于饮食的剂量测定法确定的）与尿排泄相关生物标志物的尿排出量，我们希望确定一种用于评估内源性背景暴露的贡献的可靠方法，就像我们在丙烯酰胺的情况下成功地做的那样。总之，这些研究将能够对人类摄入呋喃和2-甲基呋喃的总体风险进行全面评估，包括膳食摄入和潜在的内源性背景形成。

Furan is formed from various precursors during thermal processing of food; its major dietary sources are canned foods and coffee. Furan is metabolized into the highly reactive and cytotoxic metabolite cis-2-buten-1,4-dial (BDA) in the liver by cytochrome P450 1E2. Ames tests identified BDA as a genotoxic intermediate formed by metabolic activation of furan, and subsequent studies established that it binds covalently to cellular nucleophiles such as glutathione (GSH) and proteins. Both furan and its derivatives, the alkylfurans, are highly volatile, so levels of these contaminants in foodstuffs vary substantially depending on how the food was prepared and the time elapsed between preparation and consumption. 1.) Accurate dosimetry of human dietary furan/2-methylfuran exposure therefore requires the use of methods that quantify the levels of these compounds in prepared meals immediately before consumption. We intend to conduct a dose response study of furan exposure in human volunteers, following a design that has already been implemented successfully by our group. 2.) To complement this duplicate diet-based exposure dosimetry experiment, urinary levels of furan and 2-methylfuran metabolites will be measured to assess their value as exposure biomarkers, with the aim of developing a reliable method for assessing dietary furan exposure by reverse dosimetry. To this end, a dose response study will be performed in which volunteers will consume diets containing furan at levels corresponding to the 95th percentile of furan exposure. The volunteers’ dietary furan/2-methylfuran uptake will be measured and compared to the levels of exposure-related metabolites excreted in their urine. In pilot studies, we have identified, synthesized, and characterized a GSH–BDA cycloadduct that is excreted in human urine and appears to be a promising potential exposure-associated human biomarker formed in the human organism after dietary furan exposure. In addition, two further candidate metabolites were identified during later exploratory work. Because of BDA’s multifaceted chemical reactivity, it could form many different furan exposure-associated urinary metabolites. It is therefore expected that our analysis will yield a urinary metabolite profile that will clarify furan’s metabolic fate and toxicokinetics. We cannot exclude the possibility that furan and/or BDA may be generated endogenously within the human body via various physiological precursors and processes by comparing furan exposure from exogenous sources, as determined by duplicate diet-based dosimetry, to the urinary output of exposure-associated biomarkers, we hope to identify a reliable method for assessing the contribution of endogenous background exposure, as we did successfully in the case of acrylamide. Together, these studies will enable a holistic risk assessment of overall human exposure to furan and 2-methylfuran accounting for both dietary uptake and potential endogenous background formation.