Dosimetry of human exposure to furan by monitoring exposure biomarkers

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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.