Dosimetry of human exposure to furan by monitoring exposure biomarkers

• Applicant: Professorin Dr. Elke Richling
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Food Chemistry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423497382

• Final Report Year: 2023

Final Report Abstract

Furan and 2-Methylfuran (2-MF) are formed from various precursors during thermal processing of food; its major dietary sources are canned foods and coffee. Both are metabolized in the liver into the highly reactive and cytotoxic metabolites cis-2-buten-1,4-dial (BDA) and acetylacrolein (AcA) by cytochrome P450 2E1. Furan and 2-MF 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. Therefore, we performed an accurate dosimetry of human dietary furan/2-MF and conduct a dose response study of furan/2-MF exposure in human volunteers. We performed a human intervention study in a controlled environment for 11 days. After a furan/2-MF minimized diet, on days 4 and 8 the volunteers (10 male and 10 female) consumed 250 ml and 500 ml of coffee brew, respectively. Furan and 2-MF concentrations were additionally determined in the food (aliquots) consumed using an established headspace(hs)-SPME-GC-MS method. We were able to identify five main metabolites in the urine samples. Respectively, cis-2-buten-1,4-dial (BDA) derived urinary furan metabolites Lys-BDA, AcLys-BDA, and cyclic GSH-BDA as well as acetyl acrolein (AcA, 2-oxo-pent-2-enal) derived metabolites Lys-AcA and AcLys- AcA. These metabolites and their stable isotopically labeled analogues were synthesized and characterized by NMR and MS. Afterwards a stable isotope dilution analysis (SIDA) was established with UPLC- ESI-MS/MS and the urinary samples were analyzed. In the frame of our human intervention study, for two of three metabolites of furan (AcLys-BDA and Lys-BDA) as well as for the metabolites of 2-MF (AcLysAcA and LysAcA) the excretion kinetics showed similarities with two maxima (0-2 and 24-36 h) observed whereas for the glutathione adduct of BDA, GSH-BDA, revealed only one maximum at 1-4 h. Between men and women differences in the excretion kinetics could be observed as women excreted more metabolites than men. In conclusion, we established reliable biomarker to investigate furan and 2-MF exposure via urinary biomarkers.

Publications

• Detection and stability of BDA-lysine and -glutathione metabolites as urinary exposurebiomarkers for furan in humans. Naunyn Schmiedebergs Arch. Pharmacol. 393 (Suppl 1): S51.
  Kremer J.I.; Karlstetter D.; Klier C.; Rotermund J.; Thomas H.; Becker H.; Lang L.; Bakuradze T.; Eisenbrand G. & Richling E.
  
• Stable Isotope Dilution Analysis (SIDA) to Determine Metabolites of Furan and 2-Methylfuran in Human Urine Samples: A Pilot Study. Metabolites, 13(9), 1011.
  Kremer, Jonathan Isaak; Karlstetter, Dorothea; Kirsch, Verena; Bohlen, Daniel; Klier, Carina; Rotermund, Jan; Thomas, Hannah; Lang, Lukas; Becker, Hanna; Bakuradze, Tamara; Stegmüller, Simone & Richling, Elke
  
• Dosimetry of human exposure to furan and 2-methylfuran by monitoring urinary biomarkers. Food and Chemical Toxicology, 189, 114774.
  Bohlen, D.; Karlstetter, D.; Leidner, J.; Kremer, J.I.; Kirsch, V.; Eisenbrand, G.; Bakuradze, T.; Stegmüller, S. & Richling, E.