Archives of Toxicology

, Volume 84, Issue 7, pp 563–578 | Cite as

Toxicity and carcinogenicity of furan in human diet

Genotoxicity and Carcinogenicity

Abstract

Furan is formed during commercial or domestic thermal treatment of food. The initial surveys of furan concentrations in heat-treated foods, published by European and US authorities, revealed the presence of relatively high furan levels in coffee, sauces, and soups. Importantly, furan is consistently found in commercial ready-to-eat baby foods. Furan induces hepatocellular tumors in rats and mice and bile duct tumors in rats with a high incidence. Epidemiological studies are not available. It is assumed that cis-2-butene-1,4-dial, the reactive metabolite of furan, is the causative agent leading to toxicity and carcinogenicity. Based on this data, furan is classified as a possible human carcinogen. The initial exposure estimates revealed a relatively small margin (~2,000) between human exposure and those furan doses, which induce liver tumors in experimental animals. As this may give rise for concern, in this review, the currently available toxicological and mechanistic data of furan are summarized and discussed with regard to its applicability in assessing the risk of furan in human diet.

Keywords

Furan Dietary exposure Carcinogenicity Mechanism of action Risk assessment 

References

  1. Appel KE, Bernauer U, Herbst U, Madle S, Schulte A, Richter-Reichhelm HB, Gundert-Remy U (2006) Kann für Formaldehyd eine „sichere” Konzentration abgeleitet werden?—Analyse der Daten zur krebserzeugenden Wirkung. Umweltmed Forsch Prax 11:347–361Google Scholar
  2. Becalski A, Seaman S (2005) Furan precursors in food: a model study and development of a simple headspace method for determination of furan. J AOAC Int 88:102–106PubMedGoogle Scholar
  3. Benamira M, Johnson K, Chaudhary A, Bruner K, Tibbetts C, Marnett LJ (1995) Induction of mutations by replication of malondialdehyde-modified M13 DNA in Escherichia coli: determination of the extent of DNA modification, genetic requirements for mutagenesis, and types of mutations induced. Carcinogenesis 16:93–99CrossRefPubMedGoogle Scholar
  4. Bianchi F, Careri M, Mangia A, Musci M (2006) Development and validation of a solid phase micro-extraction-gas chromatography-mass spectrometry method for the determination of furan in baby-food. J Chromatogr A 1102:268–272CrossRefPubMedGoogle Scholar
  5. Bolger MP, Tao SS-H, Dinovi M (2009) Hazards of dietary furan. In: Richard DRL, Stadler H (eds) Process-induced food toxicants. Wiley, New Jersey, pp 117–133Google Scholar
  6. Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E, Franceschi S, La Vecchia C (2007) Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 46:430–435CrossRefPubMedGoogle Scholar
  7. Burka LT, Washburn KD, Irwin RD (1991) Disposition of [14C]furan in the male F344 rat. J Toxicol Environ Health 34:245–257CrossRefPubMedGoogle Scholar
  8. Byrns MC, Predecki DP, Peterson LA (2002) Characterization of nucleoside adducts of cis-2-butene-1, 4-dial, a reactive metabolite of furan. Chem Res Toxicol 15:373–379CrossRefPubMedGoogle Scholar
  9. Byrns MC, Vu CC, Peterson LA (2004) The formation of substituted 1, N6-etheno-2′-deoxyadenosine and 1, N 2-etheno-2′-deoxyguanosine adducts by cis-2-butene-1, 4-dial, a reactive metabolite of furan. Chem Res Toxicol 17:1607–1613CrossRefPubMedGoogle Scholar
  10. Byrns MC, Vu CC, Neidigh JW, Abad JL, Jones RA, Peterson LA (2006) Detection of DNA adducts derived from the reactive metabolite of furan, cis-2-butene-1, 4-dial. Chem Res Toxicol 19:414–420CrossRefPubMedGoogle Scholar
  11. Carfagna MA, Held SD, Kedderis GL (1993) Furan-induced cytolethality in isolated rat hepatocytes: correspondence with in vivo dosimetry. Toxicol Appl Pharmacol 123:265–273CrossRefPubMedGoogle Scholar
  12. Cavin C, Holzhaeuser D, Scharf G, Constable A, Huber WW, Schilter B (2002) Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity. Food Chem Toxicol 40:1155–1163CrossRefPubMedGoogle Scholar
  13. Chen LJ, Hecht SS, Peterson LA (1995) Identification of cis-2-butene-1, 4-dial as a microsomal metabolite of furan. Chem Res Toxicol 8:903–906CrossRefPubMedGoogle Scholar
  14. Chen LJ, Hecht SS, Peterson LA (1997) Characterization of amino acid and glutathione adducts of cis-2-butene-1, 4-dial, a reactive metabolite of furan. Chem Res Toxicol 10:866–874CrossRefPubMedGoogle Scholar
  15. Chen T, Hickling K, Hamberger C, Mally A, Chipman K (2009) Modulation of hepatic gene expression and DNA methylation in furan treated Sprague-Dawley rats. Toxicol Lett 189S, 13 September 2009, 137 (Abstract A23)Google Scholar
  16. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867CrossRefPubMedGoogle Scholar
  17. Crews C, Castle L (2007) A review of the occurrence, formation and analysis of furan in heat-processed foods. Trends Food Sci Technol 18:365–372CrossRefGoogle Scholar
  18. Dinovi M, Mihalov J (2007) An updated exposure assessment for furan from the consumption of adult and baby foods. US food and drug administration (FDA). Available at: http://www.fda.gov/Food/FoodSafety/ FoodContaminantsAdulteration/Chemical Contami-nants/Furan/ucm110770.htm
  19. DONALD Studie (DOrtmund Nutritional and Anthropometric Longitudinally Designed Study) (1985) http://www.fke-do.de/content.php?seite=seiten/inhalt.php&details=559
  20. Durling LJ, Svensson K, Abramsson-Zetterberg L (2007) Furan is not genotoxic in the micronucleus assay in vivo or in vitro. Toxicol Lett 169:43–50CrossRefPubMedGoogle Scholar
  21. EFSA (European Food Safety Authority) (2004) Report of the scientific panel on contaminants in the food chain in furan in food (Question No. EFSA-Q-2004-109), Adopted on 7 December 2004. EFSA J 137:1–20Google Scholar
  22. EFSA (2005) Opinion of the Scientific Committee on a request from EFSA related to a harmonised approach for risk assessment of substances which are both genotoxic and carcinogenic. EFSA J 282:1–31Google Scholar
  23. EFSA (2009a) Technical report of EFSA prepared by Data Collection and Exposure Unit (DATEX) on “Monitoring of furan levels in food”. EFSA J 304:1–23Google Scholar
  24. EFSA (2009b) Scientific report submitted to EFSA by Arvid Fromberg, Sisse Fagt and Kit Granby DTU-National Food Institute on “Furan in heat processed food products including home-cooked food products and ready-to-eat products”. EFSA-Q-2009-00846 Accepted for publication on October 2009Google Scholar
  25. Elmore LW, Sirica AE (1991) Phenotypic characterization of metaplastic intestinal glands and ductular hepatocytes in cholangiofibrotic lesions rapidly induced in the caudate liver lobe of rats treated with furan. Cancer Res 51:5752–5759PubMedGoogle Scholar
  26. Elmore LW, Sirica AE (1993) “Intestinal-type” of adenocarcinoma preferentially induced in right/caudate liver lobes of rats treated with furan. Cancer Res 53:254–259PubMedGoogle Scholar
  27. Foureman P, Mason JM, Valencia R, Zimmering S (1994) Chemical mutagenesis testing in Drosophila. IX. Results of 50 coded compounds tested for the national toxicology program. Environ Mol Mutagen 23:51–63CrossRefPubMedGoogle Scholar
  28. Fransson-Steen R, Goldsworthy TL, Kedderis GL, Maronpot RR (1997) Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice. Toxicology 118:195–204CrossRefPubMedGoogle Scholar
  29. Gingipalli L, Dedon PC (2001) Reaction of cis- and trans-2-butene-1, 4-dial with 2′-deoxycytidine to form stable oxadiazabicyclooctaimine adducts. J Am Chem Soc 123:2664–2665CrossRefPubMedGoogle Scholar
  30. Goldmann T, Perisset A, Scanlan F, Stadler RH (2005) Rapid determination of furan in heated foodstuffs by isotope dilution solid phase micro-extraction-gas chromatography-mass spectrometry (SPME-GC-MS). Analyst 130:878–883CrossRefPubMedGoogle Scholar
  31. Hamberger C, Moro S, Malfatti M, Turteltaub K, Mally A, Dekant W (2009) Analysis of DNA binding of furan in rat liver by accelerator mass spectrometry. Toxicol Lett 189S, 13 September 2009, 229 (Abstract F06)Google Scholar
  32. Hasnip S, Crews C, Castle L (2006) Some factors affecting the formation of furan in heated foods. Food Addit Contam 23:219–227CrossRefPubMedGoogle Scholar
  33. Heppner CW, Schlatter JR (2007) Data requirements for risk assessment of furan in food. Food Addit Contam 24(Suppl 1):114–121CrossRefPubMedGoogle Scholar
  34. Higdon JV, Frei B (2006) Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr 46:101–123CrossRefPubMedGoogle Scholar
  35. IARC (International Agency for Research on Cancer) (1995) Monographs on the evaluation of carcinogenic risks to humans, volume 63. Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC, Lyon, pp 3194–3407Google Scholar
  36. Jackson MA, Lea I, Rashid A, Peddada SD, Dunnick JK (2006) Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors. Toxicol Sci 90:400–418CrossRefPubMedGoogle Scholar
  37. Johansson E, Reynolds S, Anderson M, Maronpot R (1997) Frequency of Ha-ras-1 gene mutations inversely correlated with furan dose in mouse liver tumors. Mol Carcinog 18:199–205CrossRefPubMedGoogle Scholar
  38. Jun HJ, Lee KG, Lee YK, Woo GJ, Park YS, Lee SJ (2008) Correlation of urinary furan with plasma gamma-glutamyltranspeptidase levels in healthy men and women. Food Chem Toxicol 46:1753–1759CrossRefPubMedGoogle Scholar
  39. Kedderis GL, Held SD (1996) Prediction of furan pharmacokinetics from hepatocyte studies: comparison of bioactivation and hepatic dosimetry in rats, mice, and humans. Toxicol Appl Pharmacol 140:124–130CrossRefPubMedGoogle Scholar
  40. Kedderis GL, Ploch SA (1999) The biochemical toxicology of furan. Chemical Industry Institute of Toxicology (CIIT) Activities 19:1–6Google Scholar
  41. Kedderis GL, Carfagna MA, Held SD, Batra R, Murphy JE, Gargas ML (1993) Kinetic analysis of furan biotransformation by F-344 rats in vivo and in vitro. Toxicol Appl Pharmacol 123:274–282CrossRefPubMedGoogle Scholar
  42. Kellert M, Brink A, Richter I, Schlatter J, Lutz WK (2008a) Tests for genotoxicity and mutagenicity of furan and its metabolite cis-2-butene-1, 4-dial in L5178Y tk ± mouse lymphoma cells. Mutat Res 657:127–132PubMedGoogle Scholar
  43. Kellert M, Wagner S, Lutz U, Lutz WK (2008b) Biomarkers of furan exposure by metabolic profiling of rat urine with liquid chromatography-tandem mass spectrometry and principal component analysis. Chem Res Toxicol 21:761–768CrossRefPubMedGoogle Scholar
  44. Kuballa T, Stier S, Strichow N (2005) Furan in kaffee und Kaffeegetränken. Deutsche Lebensmittel-Rundschau 101:229–235Google Scholar
  45. Kundu JK, Surh YJ (2008) Inflammation: gearing the journey to cancer. Mutat Res 659:15–30CrossRefPubMedGoogle Scholar
  46. Lachenmeier DW, Reusch H, Kuballa T (2009) Risk assessment of furan in commercially jarred baby foods, including insights into its occurrence and formation in freshly home-cooked foods for infants and young children. Food Addit Contam 26:776–785CrossRefGoogle Scholar
  47. Lee H, Bian SS, Chen YL (1994) Genotoxicity of 1, 3-dithiane and 1, 4-dithiane in the CHO/SCE assay and the Salmonella/microsomal test. Mutat Res 321:213–218CrossRefPubMedGoogle Scholar
  48. Leopardi P, Cordelli E, Villani P, Cremona TP, Conti L, De Luca G, Crebelli R (2009) Assessment of in vivo genotoxicity of the rodent carcinogen furan: evaluation of DNA damage and induction of micronuclei in mouse splenocytes. Mutagenesis [Published online ahead of print on October 22, 2009]Google Scholar
  49. Limacher A, Kerler J, Conde-Petit B, Blank I (2007) Formation of furan and methylfuran from ascorbic acid in model systems and food. Food Addit Contam 24(Suppl 1):122–135CrossRefPubMedGoogle Scholar
  50. Lu D, Sullivan MM, Phillips MB, Peterson LA (2009) Degraded protein adducts of cis-2-butene-1, 4-dial are urinary and hepatocyte metabolites of furan. Chem Res Toxicol 22:997–1007CrossRefPubMedGoogle Scholar
  51. Maga JA (1979) Furans in foods. CRC Crit Rev Food Sci Nutr 11:355–400CrossRefPubMedGoogle Scholar
  52. Marinari UM, Ferro M, Sciaba L, Finollo R, Bassi AM, Brambilla G (1984) DNA-damaging activity of biotic and xenobiotic aldehydes in Chinese hamster ovary cells. Cell Biochem Funct 2:243–248CrossRefPubMedGoogle Scholar
  53. McGregor DB, Brown A, Cattanach P, Edwards I, McBride D, Riach C, Caspary WJ (1988) Responses of the L5178Y tk+/tk− mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ Mol Mutagen 12:85–154PubMedGoogle Scholar
  54. McMurtry RJ, Mitchell JR (1977) Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes, including furosemide and cephaloridine. Toxicol Appl Pharmacol 42:285–300CrossRefPubMedGoogle Scholar
  55. Merk O, Speit G (1999) Detection of crosslinks with the comet assay in relationship to genotoxicity and cytotoxicity. Environ Mol Mutagen 33:167–172CrossRefPubMedGoogle Scholar
  56. Minko IG, Kozekov ID, Harris TM, Rizzo CJ, Lloyd RS, Stone MP (2009) Chemistry and biology of DNA containing 1, N(2)-deoxyguanosine adducts of the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol 22:759–778CrossRefPubMedGoogle Scholar
  57. Morehouse KM, Nyman PJ, McNeal TP, Dinovi MJ, Perfetti GA (2008) Survey of furan in heat processed foods by headspace gas chromatography/mass spectrometry and estimated adult exposure. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25:259–264PubMedGoogle Scholar
  58. Moriya M, Zhang W, Johnson F, Grollman AP (1994) Mutagenic potency of exocyclic DNA adducts: marked differences between Escherichia coli and simian kidney cells. Proc Natl Acad Sci USA 91:11899–11903CrossRefPubMedGoogle Scholar
  59. Moser GJ, Foley J, Burnett M, Goldsworthy TL, Maronpot R (2009) Furan-induced dose-response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Exp Toxicol Pathol 61:101–111CrossRefPubMedGoogle Scholar
  60. Mugford CA, Kedderis GL (1996) Furan-mediated DNA double strand breaks in isolated rat hepatocytes. Fundam Appl Toxicol 30(1, Part 2):128Google Scholar
  61. Mugford CA, Kedderis GL (1997) Role of bioactivation in the formation of furan-mediated DNA double strand breaks. Fundam Appl Toxicol 36(1, Part 2):56Google Scholar
  62. Mugford CA, Carfagna MA, Kedderis GL (1997) Furan-mediated uncoupling of hepatic oxidative phosphorylation in Fischer-344 rats: an early event in cell death. Toxicol Appl Pharmacol 144:1–11CrossRefPubMedGoogle Scholar
  63. NTP (National Toxicology Program) (1993) Toxicology and carcinogenesis studies of furan (CAS No. 110–00–9) in F344/N rats and B6C3F1 mice (gavage studies), NTP Technical Report No. 402. US Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NCGoogle Scholar
  64. Nyman PJ, Morehouse KM, McNeal TP, Perfetti GA, Diachenko GW (2006) Single-laboratory validation of a method for the determination of furan in foods by using static headspace sampling and gas chromatography/mass spectrometry. J AOAC Int 89:1417–1424PubMedGoogle Scholar
  65. Parmar D, Burka LT (1993) Studies on the interaction of furan with hepatic cytochrome P-450. J Biochem Toxicol 8:1–9CrossRefPubMedGoogle Scholar
  66. Perez LC, Yaylayan VA (2004) Origin and mechanistic pathways of formation of the parent furan: a food toxicant. J Agric Food Chem 52:6830–6836CrossRefGoogle Scholar
  67. Peterson LA (2006) Electrophilic intermediates produced by bioactivation of furan. Drug Metab Rev 38:615–626CrossRefPubMedGoogle Scholar
  68. Peterson LA, Naruko KC, Predecki DP (2000) A reactive metabolite of furan, cis-2-butene-1, 4-dial, is mutagenic in the Ames assay. Chem Res Toxicol 13:531–534CrossRefPubMedGoogle Scholar
  69. Peterson LA, Cummings ME, Vu CC, Matter BA (2005) Glutathione trapping to measure microsomal oxidation of furan to cis-2-butene-1, 4-dial. Drug Metab Dispos 33:1453–1458CrossRefPubMedGoogle Scholar
  70. Peterson LA, Cummings ME, Chan JY, Vu CC, Matter BA (2006) Identification of a cis-2-butene-1, 4-dial-derived glutathione conjugate in the urine of furan-treated rats. Chem Res Toxicol 19:1138–1141CrossRefPubMedGoogle Scholar
  71. Ploch SA, Kedderis GL (2001) Formation of DNA double-strand breaks in F-344 rat liver following in vivo exposure to furan. Toxicol Sci 60(1):154 Suppl.—The Toxicologist (Abstract 735)Google Scholar
  72. Ploch SA, Shearin L, Kedderis GL (1999) Formation and repair kinetics of furan-mediated DNA double-strand breaks in isolated rat hepatocytes. Toxicol Sci 48(1-S):123Google Scholar
  73. Reynolds SH, Stowers SJ, Patterson RM, Maronpot RR, Aaronson SA, Anderson MW (1987) Activated oncogenes in B6C3F1 mouse liver tumors: implications for risk assessment. Science 237:1309–1316CrossRefPubMedGoogle Scholar
  74. Roberts D, Crews C, Grundy H, Mills C, Matthews W (2008) Effect of consumer cooking on furan in convenience foods. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25:25–31PubMedGoogle Scholar
  75. Schulte A, Bernauer U, Madle S, Mielke H, Herbst U, Richter-Reichhelm HB, Appel KE, Gundert-Remy U (2006) Assessment of the Carcinogenicity of Formaldehyde (CAS No.50-00-0) BfR-Wissenschaft 02:1-156Google Scholar
  76. Shen J, Moy JA, Green MD, Guengerich FP, Baron J (1998) Immunohistochemical demonstration of ß-Naphthoflavone- inducible cytochrome P450 1A1/1A2 in rat intrahepatic biliary epithelial cells. Hepatology 27:1483–1491CrossRefPubMedGoogle Scholar
  77. Speit G, Frohler-Keller M, Schutz P, Neuss S (2008) Low sensitivity of the comet assay to detect acetaldehyde-induced genotoxicity. Mutat Res 657:93–97PubMedGoogle Scholar
  78. US Food and Drug Administration (2004) Exploratory data on furan in food. Individual Food Products. Available at: http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/ChemicalContaminants/Furan/ucm078439.htm
  79. US Food and Drug Administration (2005) Determination of furan in foods. Available at: http://www.fda.gov/Food/FoodSafety/FoodContaminantsAdulteration/ChemicalContaminants/Furan/ucm078400.htm
  80. Van Lancker F, Adams A, Owczarek A, De Meulenaer B, De Kimpe N (2009) Impact of various food ingredients on the retention of furan in foods. Mol Nutr Food Res 53:1505–1511CrossRefPubMedGoogle Scholar
  81. Vranova J, Ciesarova Z (2009) Furan in food. Czech J Food Sci 27:1–10Google Scholar
  82. Wiley RA, Traiger GJ, Baraban S, Gammal LM (1984) Toxicity-distribution relationships among 3-alkylfurans in mouse liver and kidney. Toxicol Appl Pharmacol 74:1–9CrossRefPubMedGoogle Scholar
  83. Wilson DM, Goldsworthy TL, Popp JA, Butterworth BE (1992) Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan. Environ Mol Mutagen 19:209–222CrossRefPubMedGoogle Scholar
  84. Yaylayan VA (2009) Precursors, formation and determination of furan in food. J für Verbraucherschutz und Lebensmittelsicherheit 1:5–9CrossRefGoogle Scholar
  85. Zoller O, Sager F, Reinhard H (2007) Furan in food: headspace method and product survey. Food Addit Contam 24(Suppl 1):91–107CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Unit of Food Toxicology, Department of Food SafetyFederal Institute for Risk AssessmentBerlinGermany

Personalised recommendations