Dosimetry of human exposure to furan by monitoring exposure biomarkers

通过监测暴露生物标志物来测定人体接触呋喃的剂量

• 批准号: 423497382
• 负责人: Professorin Dr. Elke Richling
• 金额: --
• 依托单位: Fachrichtung Lebensmittelchemie / Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/423497382?language=en
• 关键词: Dosimetry; human; exposure; furan; monitoring

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.

呋喃是在食品热加工过程中由各种前体形成的；它的主要饮食来源是罐头食品和咖啡。呋喃在肝脏中通过细胞色素P450 - 1E2代谢成高活性和细胞毒性的代谢物顺-2-丁烯-1,4-dial （BDA）。Ames试验确定BDA是一种由呋喃代谢激活形成的遗传毒性中间体，随后的研究确定BDA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具有高度挥发性，因此食品中这些污染物的含量根据食品的制备方式以及制备和食用之间的时间间隔而有很大差异。1.） 因此，对人类膳食中呋喃/2-甲基呋喃暴露量进行准确的剂量测定，需要使用在食用前立即测定预制饭菜中这些化合物含量的方法。我们打算按照我们小组已经成功实施的设计，在人类志愿者中进行呋喃暴露的剂量反应研究。2.） 为了补充这项重复的基于饮食的暴露剂量测定实验，将测量尿液中呋喃和2-甲基呋喃代谢物的水平，以评估其作为暴露生物标志物的价值，目的是开发一种可靠的方法，通过反向剂量法评估饮食中的呋喃暴露。为此目的，将进行一项剂量反应研究，在这项研究中，志愿者将摄入含有呋喃的饮食，其水平相当于呋喃暴露的第95百分位数。研究人员将测量志愿者饮食中呋喃/2-甲基呋喃的摄入量，并将其与通过尿液排出的暴露相关代谢物水平进行比较。在初步研究中，我们已经鉴定、合成并表征了一种GSH-BDA环加合物，这种环加合物可以从人类尿液中排出，似乎是一种有希望的潜在暴露相关的人类生物标志物，在饮食呋喃暴露后形成于人类有机体中。此外，在随后的探索工作中，还确定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暴露相关的尿液代谢物。因此，我们预计我们的分析将产生尿液代谢物的概况，将澄清呋喃的代谢命运和毒性动力学。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（由重复饮食剂量法确定）与暴露相关生物标志物的尿输出，我们希望确定一种可靠的方法来评估内源性背景暴露的贡献，正如我们在丙烯酰胺的情况下成功地完成的那样。综上所述，这些研究将能够对考虑膳食摄取和潜在内源性背景形成的呋喃和2-甲基呋喃的人类总体暴露进行全面的风险评估。