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Evidence-Based Complementary and Alternative Medicine
Volume 2012 (2012), Article ID 860542, 10 pages
http://dx.doi.org/10.1155/2012/860542
Review Article

Can Estragole in Fennel Seed Decoctions Really Be Considered a Danger for Human Health? A Fennel Safety Update

1Center for Integrative Medicine, Careggi and Department of Preclinical and Clinical Pharmacology, University Hospital of Florence and “M. Aiazzi Mancini”, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy
2Interuniversitary Centre of Molecular Medicine and Applied Biophysics (CIMMBA), Department of Pharmacology, University of Florence, 50139 Florence, Italy

Received 30 March 2012; Accepted 20 June 2012

Academic Editor: Cassandra Quave

Copyright © 2012 L. Gori et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Oktay, I. Gulcin, and O. I. Kufrevioglu, “Determination of in vitro antioxidant activity of fennel (Foeniculum vulgare) seed extracts,” LWT-Food Science and Technology, vol. 36, no. 2, pp. 263–271, 2003. View at Publisher · View at Google Scholar · View at Scopus
  2. N. Mimica-Dukić, S. Kujundžić, M. Soković, and M. Couladis, “Essential oil composition and antifungal activity of Foeniculum vulgare Mill. Obtained by different distillation conditions,” Phytotherapy Research, vol. 17, no. 4, pp. 368–371, 2003. View at Publisher · View at Google Scholar · View at Scopus
  3. R. Perry, K. Hunt, and E. Ernst, “Nutritional supplements and other complementary medicines for infantile colic: a systematic review,” Pediatrics, vol. 127, no. 4, pp. 720–733, 2011. View at Publisher · View at Google Scholar · View at Scopus
  4. V. Bruyas-Bertholon, A. Lachaux, J. P. Dubois, P. Fourneret, and L. Letrilliart, “Which treatments for infantile colics?” La Presse Médicale, vol. 41, no. 7-8, pp. e404–e410, 2012. View at Google Scholar
  5. D. W. Bristol, “NTP 3-month toxicity studies of estragole (CAS No. 140-67-0) administered by gavage to F344/N rats and B6C3F1 mice,” Toxicity Report Series, no. 82, pp. 1–111, 2011. View at Google Scholar · View at Scopus
  6. 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 282, 1-31, 2005.
  7. E. Miraldi, “Comparison of the essential oils from ten samples of fruits of different origin,” Flavour and Fragrance Journal, vol. 14, pp. 379–382, 1999. View at Google Scholar
  8. I. M. C. M. Rietjens, A. Punt, B. Schilter, G. Scholz, T. Delatour, and P. J. van Bladeren, “In silico methods for physiologically based biokinetic models describing bioactivation and detoxification of coumarin and estragole: implications for risk assessment,” Molecular Nutrition and Food Research, vol. 54, no. 2, pp. 195–207, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. N. Brand, “Foeniculum,” in Hagers Handbuch der Pharmazeutischen Praxis, H. Hager, R. Hänsel, K. Keller, H. Rimpler, and G. Schneider, Eds., vol. 5, pp. 156–181, Springer, Berlin, Germany, 1993. View at Google Scholar
  10. L. Toth, “Untersuchungen uber das atherische Ol von Foeniculum vulgare,” Planta Medica, vol. 15, pp. 371–389, 1967. View at Google Scholar
  11. K. Trenkle, “Recent studies on fennel (Foeniculum vulgare M.) 2. The volatile oil of the fruit, herbs and roots of fruit-bearing plants,” Pharmazie, vol. 27, no. 5, pp. 319–324, 1972. View at Google Scholar · View at Scopus
  12. J. Kunzemann and K. Herrmann, “Isolation and identification of flavon(ol)-O-glycosides in caraway (Carum carvi L.), fennel (Foeniculum vulgare Mill.), anise (Pimpinella anisum L.), and coriander (Coriandrum sativum L.), and of flavon-C-glycosides in anise—I. Phenolics of spices,” Zeitschrift für Lebensmittel-Untersuchung und -Forschung, vol. 164, no. 3, pp. 194–200, 1977. View at Publisher · View at Google Scholar · View at Scopus
  13. R. D. H. Murray, J. Mendez, and S. A. Brown, The Natural Coumarins. Occurrence, Chemistry, Biochemistry, Wiley-Interscience, John Wiley & Sons, Chichester, UK, 1982.
  14. A. R. Bilia, M. Fumarola, S. Gallori, G. Mazzi, and F. F. Vincieri, “Identification by HPLC-DAD and HPLC-MS analyses and quantification of constituents of fennel teas and decoctions,” Journal of Agricultural and Food Chemistry, vol. 48, no. 10, pp. 4734–4738, 2000. View at Publisher · View at Google Scholar · View at Scopus
  15. C. Tschiggerl and F. Bucar, “Volatile fraction of lavender and bitter fennel infusion extracts,” Natural Product Communications, vol. 5, no. 9, pp. 1431–1436, 2010. View at Google Scholar · View at Scopus
  16. F. C. Czygan and S. Fenchel, in Teedrogen, M. Wichtl, Ed., pp. 171–173, Wissenschaftliche Verlagsgesellschaft, Stuttgart, Germany, 2nd edition, 1989.
  17. O. Barazani, Y. Cohen, A. Fait et al., “Chemotypic differentiation in indigenous populations of Foeniculum vulgare var. vulgare in Israel,” Biochemical Systematics and Ecology, vol. 30, no. 8, pp. 721–731, 2002. View at Publisher · View at Google Scholar · View at Scopus
  18. M. G. Miguel, C. Cruz, L. Faleiro et al., “Foeniculum vulgare essential oils: chemical composition, antioxidant and antimicrobial activities,” Natural Product Communications, vol. 5, no. 2, pp. 319–328, 2010. View at Google Scholar · View at Scopus
  19. R. Piccaglia and M. Marotti, “Characterization of some Italian types of wild fennel (Foeniculum vulgare mill.),” Journal of Agricultural and Food Chemistry, vol. 49, no. 1, pp. 239–244, 2001. View at Publisher · View at Google Scholar · View at Scopus
  20. M. C. Díaz, M. S. Pérez-Coello, J. Esteban, and J. Sanz, “Comparison of the volatile composition of wild fennel samples (Foeniculum vulgare Mill.) from Central Spain,” Journal of Agricultural and Food Chemistry, vol. 54, no. 18, pp. 6814–6818, 2006. View at Publisher · View at Google Scholar · View at Scopus
  21. I. Telci, I. Demirtas, and A. Sahin, “Variation in plant properties and essential oil composition of sweet fennel (Foeniculum vulgare Mill.) fruits during stages of maturity,” Industrial Crops and Products, vol. 30, no. 1, pp. 126–130, 2009. View at Publisher · View at Google Scholar · View at Scopus
  22. Farmacopeia Portuguesa, Monografias do Funcho amargo e Doce, Fruto, Instituto Nacional de Farmacia e do Medicamento (INFARMED), Lisboa, Portugal, 8th edition, 1995.
  23. A. A. Shahat, A. Y. Ibrahim, S. F. Hendawy et al., “Chemical composition, antimicrobial and antioxidant activities of essential oils from organically cultivated fennel cultivars,” Molecules, vol. 16, no. 2, pp. 1366–1377, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. A. Zangouras, J. Caldwell, A. J. Hutt, and R. L. Smith, “Dose dependent conversion of estragole in the rat and mouse to the carcinogenic metabolite, 1′-hydroxyestragole,” Biochemical Pharmacology, vol. 30, no. 11, pp. 1383–1386, 1981. View at Publisher · View at Google Scholar · View at Scopus
  25. S. A. Sangster, J. Caldwell, and A. J. Hutt, “The metabolic disposition of [methoxy-14C]-labelled trans-anethole, estragole and p-propylanisole in human volunteers,” Xenobiotica, vol. 17, no. 10, pp. 1223–1232, 1987. View at Google Scholar · View at Scopus
  26. I. M. C. M. Rietjens, W. A. Huseiny, and M. G. Boersma, “Flavonoids and alkenylbenzenes: new concepts in bioactivation studies,” Chemico-Biological Interactions, vol. 192, no. 1-2, pp. 87–95, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Anthony, J. Caldwell, A. J. Gutt, and R. L. Smith, “Metabolism of estragole in rat and mouse and influence of dose size on excretion of the proximate carcinogen 1′-hydroxyestragole,” Food and Chemical Toxicology, vol. 25, no. 11, pp. 799–806, 1987. View at Google Scholar · View at Scopus
  28. W. Alhusainy, A. Paini, A. Punt et al., “Identification of nevadensin as an important herb-based constituent inhibiting estragole bioactivation and physiology-based biokinetic modeling of its possible in vivo effect,” Toxicology and Applied Pharmacology, vol. 245, no. 2, pp. 179–190, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. E. W. Boberg, E. C. Miller, and J. A. Miller, “Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1′-sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1′-hydroxysafrole in mouse liver,” Cancer Research, vol. 43, no. 11, pp. 5163–5173, 1983. View at Google Scholar · View at Scopus
  30. E. C. Miller, A. B. Swanson, and D. H. Phillips, “Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole,” Cancer Research, vol. 43, no. 3, pp. 1124–1134, 1983. View at Google Scholar · View at Scopus
  31. A. Paini, A. Punt, F. Viton et al., “A physiologically based biodynamic (PBBD) model for estragole DNA binding in rat liver based on in vitro kinetic data and estragole DNA adduct formation in primary hepatocytes,” Toxicology and Applied Pharmacology, vol. 245, no. 1, pp. 57–66, 2010. View at Publisher · View at Google Scholar · View at Scopus
  32. K. Randerath, R. E. Haglund, D. H. Phillips, and M. V. Reddy, “32P-post-labelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally-occurring alkenylbenzenes. I. Adult female CD-1 mice,” Carcinogenesis, vol. 5, no. 12, pp. 1613–1622, 1984. View at Google Scholar · View at Scopus
  33. A. Punt, T. Delatour, G. Scholz, B. Schilter, P. J. Van Bladeren, and I. M. C. M. Rietjens, “Tandem mass spectrometry analysis of N2-(trans-isoestragol- 3′-yl)-2′-deoxyguanosine as a strategy to study species differences in sulfotransferase conversion of the proximate carcinogen 1′- hydroxyestragole,” Chemical Research in Toxicology, vol. 20, no. 7, pp. 991–998, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. R. L. Smith, T. B. Adams, J. Doull et al., “Safety assessment of allylalkoxybenzene derivatives used as flavouring substances—methyl eugenol and estragole,” Food and Chemical Toxicology, vol. 40, no. 7, pp. 851–870, 2002. View at Publisher · View at Google Scholar · View at Scopus
  35. ESCF European Commission, “Opinion of the Scientific Commitee on Food on Estragole (1-allyl-4-methoxybenzene),” 2001.
  36. T. M. Guenthner and G. Luo, “Investigation of the role of the 2′,3′-epoxidation pathway in the bioactivation and genotoxicity of dietary allylbenzene analogs,” Toxicology, vol. 160, no. 1–3, pp. 47–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  37. W. G. Stillwell, M. J. Carman, L. Bell, and M. G. Horning, “The metabolism of safrole and 2′,3′ epoxysafrole in the rat and guinea pig,” Drug Metabolism and Disposition, vol. 2, no. 6, pp. 489–498, 1974. View at Google Scholar · View at Scopus
  38. E. Solheim and R. R. Scheline, “Metabolism of alkenebenzene derivatives in the rat. I. p Methoxyallylbenzene (estragole) and p methoxypropenylbenzene (anethole),” Xenobiotica, vol. 3, no. 8, pp. 493–510, 1973. View at Google Scholar · View at Scopus
  39. L. V. Iyer, M. N. Ho, W. M. Shinn et al., “Glucuronidation of 1′-hydroxyestragole (1′-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9,” Toxicological Sciences, vol. 73, no. 1, pp. 36–43, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. P. J. Czernik, J. M. Little, G. W. Barone, J. P. Raufman, and A. Radominska-Pya, “Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa,” Drug Metabolism and Disposition, vol. 28, no. 10, pp. 1210–1216, 2000. View at Google Scholar · View at Scopus
  41. C. P. Strassburg, N. Nguyen, M. P. Manns, and R. H. Tukey, “Polymorphic expression of the UDP-glucuronosyltransferase UGT1A gene locus in human gastric epithelium,” Molecular Pharmacology, vol. 54, no. 4, pp. 647–654, 1998. View at Google Scholar · View at Scopus
  42. N. R. Drinkwater, E. C. Miller, J. A. Miller, and H. C. Pitot, “Hepatocarcinogenicity of estragole (1 Allyl 4 methoxybenzene) and 1 Hydroxyestragole in the mouse and mutagenicity of 1′ acetoxyestragole in bacteria,” Journal of the National Cancer Institute, vol. 57, no. 6, pp. 1323–1331, 1976. View at Google Scholar · View at Scopus
  43. J. Caldwell and J. D. Sutton, “Influence of dose size on the disposition of trans-[methoxy-14C]anethole in human volunteers,” Food and Chemical Toxicology, vol. 26, no. 2, pp. 87–91, 1988. View at Google Scholar · View at Scopus
  44. D. Hoffmann, “Fennel fruit, estragole and the breast feeding mother,” http://www.herbcraft.org/hoffmannfennel.html.
  45. H. Özbek, S. Uǧraş, H. Dülger et al., “Hepatoprotective effect of Foeniculum vulgare essential oil,” Fitoterapia, vol. 74, no. 3, pp. 317–319, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. P. Tripathi, R. Tripathi, R. K. Patel, and S. S. Pancholi, “Investigation of antimutagenic potential of Foeniculum vulgare essential oil on cyclophosphamide induced genotoxicity and oxidative stress in mice,” Drug and Chemical Toxicology. In press.
  47. R. H. Mohamad, A. M. El-Bastawesy, M. G. Abdel-Monem et al., “Antioxidant and anticarcinogenic effects of methanolic extract and volatile oil of fennel seeds (Foeniculum vulgare),” Journal of Medicinal Food, vol. 14, pp. 986–1001, 2011. View at Google Scholar
  48. C. Martins, R. Cação, K. J. Cole et al., “Estragole: a weak direct-acting food-borne genotoxin and potential carcinogen,” Mutation Research, vol. 747, no. 1, pp. 86–92, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Muzolf-Panek, A. Gliszczyńska-Świgło, L. De Haan et al., “Role of catechin quinones in the induction of EpRE-mediated gene expression,” Chemical Research in Toxicology, vol. 21, no. 12, pp. 2352–2360, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. F. Firenzuoli, L. Gori, V. Mascherini, A. Vannacci, and M. Floridia, “Poster presentation. The safety of fennel tea: epigallocatechin gallate and phenolic compounds discovered in fennel tea inhibit estragole toxicity,” in Proceedings of the European Congress of Integrative Medicine, vol. 194, Berlin, Germany, 2011.
  51. W. Alhusainy, S. van den Berg, A. Paini et al., “Matrix modulation of the bioactivation of estragole by constituents of different alkenylbenzene-containing herbs and spices and physiologically-based biokinetic (PBBK) modeling of possible in vivo effects,” Toxicological Sciences. In press.
  52. J. E. Simmons, “Application of physiologically based pharmacokinetic modelling to combination toxicology,” Food and Chemical Toxicology, vol. 34, no. 11-12, pp. 1067–1073, 1996. View at Publisher · View at Google Scholar · View at Scopus
  53. Y. Y. Lee-Hilz, A. M. J. F. Boerboom, A. H. Westphal, W. J. H. Van Berkel, J. M. M. J. G. Aarts, and I. M. C. M. Rietjens, “Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression,” Chemical Research in Toxicology, vol. 19, no. 11, pp. 1499–1505, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. A. Raffo, S. Nicoli, and C. Leclercq, “Quantification of estragole in fennel herbal teas: implications on the assessment of dietary exposure to estragole,” Food and Chemical Toxicology, vol. 49, no. 2, pp. 370–375, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. AIRTUM (Italian Association of Cancer Registers) official database, March 2012.
  56. E. Dybing, J. O'Brien, A. G. Renwick, and T. Sanner, “Risk assessment of dietary exposures to compounds that are genotoxic and carcinogenic-an overview,” Toxicology Letters, vol. 180, no. 2, pp. 110–117, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. T. J. Key, N. E. Allen, E. A. Spencer, and R. C. Travis, “The effect of diet on risk of cancer,” The Lancet, vol. 360, no. 9336, pp. 861–868, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Barlow, A. G. Renwick, J. Kleiner et al., “Risk assessment of substances that are both genotoxic and carcinogenic. Report of an International Conference organized by EFSA and WHO with support of ILSI Europe,” Food and Chemical Toxicology, vol. 44, no. 10, pp. 1636–1650, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Peto, M. C. Pike, and L. Bernstein, “The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments,” Environmental Health Perspectives, vol. 58, pp. 1–8, 1984. View at Google Scholar · View at Scopus
  60. C. L. Galli, M. Marinovich, and M. Lotti, “Is the acceptable daily intake as presently used an axiom or a dogma?” Toxicology Letters, vol. 180, no. 2, pp. 93–99, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. L. D. Lehman-McKeeman, P. A. Rodriguez, R. Takigiku, D. Caudill, and M. L. Fey, “d-Limonen-induced male rat-specific nephrotoxicity: evaluation of the association between d-limonene and α(2u)-globulin,” Toxicology and Applied Pharmacology, vol. 99, no. 2, pp. 250–259, 1989. View at Google Scholar · View at Scopus
  62. P. Restani, P. Campagner, A. Fiecchi, P. Resmini, and C. L. Galli, “Identification of spinacine as the principal reaction product of γ-casein with formaldehyde in cheese,” Food and Chemical Toxicology, vol. 26, no. 5, pp. 441–446, 1988. View at Google Scholar · View at Scopus
  63. D. W. Gaylor, “Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens?” Regulatory Toxicology and Pharmacology, vol. 41, no. 2, pp. 128–133, 2005. View at Publisher · View at Google Scholar · View at Scopus