Safety of High and Long-term Intake of Polyphenols

Polyphenols in Human Health and Disease

Volumn 1, Issue , 2013, Pages 747-756

  Nagasako Akazome, Yoko ^a  

^a Asahi Soft Drinks Co Ltd   (Japan)

Author keywords

Acute test; Animals; Clinical trials; Humans; Mutagenicity test; Polyphenol; Safety; Subcronic test; Toxicity

Indexed keywords

EID: 84902569454     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1016/B978-0-12-398456-2.00058-X     Document Type: Chapter

References (72)

1. National Food Research Institute. Apple, In: Food Encyclopaedia.National Food Research Institute, Ed., Asakura Publishing Co. Ltd.,Tokyo, Japan,2001; pp. 62-63.
2. Anonymous, Apple, Foodstuff in Season and Fruits of Four Seasons. Kodansha Ltd, Tokyo, Japan,2001; pp. 64-68.
3. Global Environment Monitoring System. Food Contamination Monitoring and Assessment Programme (GEMS/Food) Table 2 - GEMS/Food Consumption Cluster Diets, August 2006. URL: [accessed September 2012]. http://www.who.int/foodsafety/chem/gems/en/index2.html.
4. United States International Trade Commission. Apples, Industry and Trade Summary. Table 11, Fresh apples per capita consumption by selected countries, page 34. http://www.usitc.gov/publications/332/its_4.pdf.
5. Haslam E. Natural polyphenols (vegetable tannins) as drugs: possible modes of action. J Nat Prod 1996, 59(2):205-215.
6. Ohnishi-Kameyama M., Yanagida A., Kanda T., Nagata T. Identification of catechin oligomers from apple (Malus pumila cv. Fuji) in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and fast-atom bombardment mass spectrometry. Rapid Commun Mass Spectrom 1997, 11(1):31-36.
7. Nakano N., Nishiyama C., Tokura T., Nagasako-Akazome Y., Ohtake Y., Okumura K., et al. Procyanidin C1 from apple extracts inhibits FcεRI-mediated mast cell activation. Int Arch Allergy Immunol 2008, 147(3):213-221.
8. Enomoto T., Nagasako-Akazome Y., Kanda T., Ikeda M., Dake Y. Clinical effects of apple polyphenols on persistent allergic rhinitis: a randomized double-blind placebo-controlled parallel arm study. J Invest Allergol Clin Immunol 2006, 16(5):283-289.
9. Tokura T., Nakano N., Ito T., Matsuda H., Nagasako-Akazome Y., Kanda T., et al. Inhibitory effect of polyphenol-enriched apple extracts on mast cell degranulation in vitro targeting the binding between IgE and FcεRI. Biosci Biotechnol Biochem 2005, 69(10):974-977.
10. Akazome Y., Kametani N., Kanda T., Shimasaki H., Kobayashi S. Evaluation of safety of excessive intake and efficacy of long-term intake of beverages containing apple polyphenols. J Oleo Sci 2010, 59(6):321-338.
11. Akazome Y. Characteristics and physiological functions of polyphenols from apples. Biofactors 2004, 22(1-4):311-314.
12. Sunagawa T., Shimizu T., Kanda T., Tagashira M., Sami M., Shirasawa T. Procyanidins from apples (Malus pumila Mill.) extend the lifespan of Caenorhabditis elegans. Planta Med 2011, 77(2):122-127.
13. Toda T., Sunagawa T., Kanda T., Tagashira M., Shirasawa T., Shimizu T. Apple procyanidins suppress amyloid β-protein aggregation. Biochem Res Int 2011, 2011:784698.
14. Nishizuka T., Fujita Y., Sato Y., Nakano A., Kakino A., Ohshima S., et al. Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox. Proc Jpn Acad Ser B Phys Biol Sci 2011, 87(3):104-113.
15. Shoji T., Akazome Y., Kanda T., Ikeda M. The toxicology and safety of apple polyphenol extract. Food Chem Toxicol 2004, 42(6):959-967.
16. Ames B.N., McCann J., Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test. Mutat Res 1975, 31(6):347-364.
17. Food Safety Commission. Food safety information system, Food for Specified Health Use Safety Evaluation Report, "Polyphenol beverage." URL: [accessed September 2012]. http://www.fsc.go.jp/fsciis/evaluationDocument/show/kya20100118001.
18. Akazome Y., Kanda T., Ikeda H., Shimasaki H. Serum choresterol-lowering effect of apple polyphenols in healthy subjects. J Oleo Sci 2005, 54(3):143-151.
19. Akazome Y., Kanda T., Ohtake Y., Hashimoto H., Kametani N., Sato K., et al. Evaluation of safety of excessive intake and efficacy of long term intake of beverage containing polyphenols derived from apples. Japanese Pharm Ther 2005, 33(9):893-911.
20. Nagasako-Akazome Y., Kanda T., Ohtake Y., Shimasaki H., Kobayashi T. Apple polyphenols influence cholesterol metabolism in healthy subjects with relatively high body mass index. J Oleo Sci 2007, 56(8):417-428.
21. Lina B.A., Reus A.A., Hasselwander O., Bui Q., Tenning P.P. Safety evaluation of Evesse EPC, an apple polyphenol extract rich in flavan-3-ols. Food Chem Toxicol 2012, 50(8):2845-2853.
22. Blumenthal M. et al. Herbal medicine. Expanded Commission E Monographs. In Integrative Medicine Communications, Newton, 2000; pp. 193-195.
23. DeLyser DY, Kasper WJ Hopped beer. In: The Case for Cultivation, Econ. Botany 1994; pp. 166-170.
24. Neve R.A. Hops 1991, Chapman and Hall, London, pp. 25-29.
25. Kurumatni M., Fujita R., Kanda T., Ikeda M., Shoji A., Yanagida A., et al. Analysis of polyphenols from hop bract region using CCC. J Liq Chromatog Rel Technol 2005, 28(12-13):1971-1983.
26. Tanaka Y., Honma D., Tamura M., Yanagida A., Zhao P., Shoji T., et al. New chromanone and acylphloroglucinol glycosides from the bracts of hops. Phytochem Letts 2012, 5(3):514-518.
27. Yaegaki K., Tanaka T., Sato T., Murata T., Imai T., Tagashira M., et al. Hop polyphenols suppress production of water-insoluble glucan by Streptococcus mutans and dental plaque growth in vivo. J Clin Dent 2008, 19(2):74-78.
28. Kou Y., Inaba H., Kato T., Tagashira M., Honma D., Kanda T., et al. Inflammatory responses of gingival epithelial cells stimulated with Porphyromonas gingivalis vesicles are inhibited by hop-associated polyphenols. J Periodontol 2008, 79(1):174-180.
29. Shinada K., Tagashira M., Watanabe H., Sopapornamorn P., Kanayama A., Kanda T., et al. Hop bract polyphenols reduced three-day dental plaque regrowth. J Dent Res 2007, 86(9):848-851.
30. Inaba H., Tagashira M., Kanda T., Ohno T., Kawai S., Amano A. Apple- and hop-polyphenols protect periodontal ligament cells stimulated with enamel matrix derivative from Porphyromonas gingivalis. J Periodontol 2005, 76(12):2223-2229.
31. Yahiro K., Shirasaka D., Tagashira M., Wada A., Morinaga N., Kuroda F., et al. Inhibitory effects of polyphenols on gastric injury by Helicobacter pylori VacA toxin. Helicobacter 2005, 10(3):231-239.
32. Morinaga N., Iwamaru Y., Yahiro K., Tagashira M., Moss J., Noda M. Differential activities of plant polyphenols on the binding and internalization of cholera toxin in Vero cells. J Biol Chem 2005, 280(24):23303-23309.
33. Tagashira M., Uchiyama K., Yoshimura T., Shirota M., Uemitsu N. Inhibition by hop bract polyphenols of cellular adherence and water-insoluble glucan synthesis of Mutans streptococci. Biosci Biotechnol Biochem 1997, 61(2):332-335.
34. Kastenbaum M.A., Bowman K.O. Tables for determining the statistical significance of mutation frequencies. Mutat Res 1970, 9(5):527-549.
35. Schmid W. The micronucleus test. Mutat Res 1975, 31(1):9-15.
36. Nagasako-Akazome Y., Honma D., Tagashira M., Kanda T., Yasue M., Ohtake Y. Safety evaluation of polyphenols extracted from hop bracts. Food Chem Toxicol 2007, 45(8):1383-1392.
37. Tagashira M. Development of Poyphenol-rich Functional Foods 2007, CMC Publishing Co., Ltd, Tokyo, Japan, p. 255.
38. Fujii H., Sun B., Nishioka H., Hirose A., Aruoma O.I. Evaluation of the safety and toxicity of the oligomerized polyphenol Oligonol. Food Chem Toxicol 2007, 45(3):378-387.
39. Gao F., Ye H., Yu Y., Zhang T., Deng X. Lack of toxicological effect through mutagenicity test of polyphenol extracts from peanut shells. Food Chem 2011, 129(3):920-924.
40. Wang D., Xiao R., Hu X., Xu K., Hou Y., Zhong Y., et al. Comparative safety evaluation of Chinese Pu-erh green tea extract and Pu-erh black tea extract in Wistar rats. J Agric Food Chem 2010, 58(2):1350-1358.
41. Isbrucker R.A., Edwards J.A., Wolz E., Davidovich A., Bausch J. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 2: dermal, acute and short-term toxicity studies. Food Chem Toxicol 2006, 44(5):636-650.
42. Isbrucker R.A., Edwards J.A., Wolz E., Davidovich A., Bausch J. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 3: teratogenicity and reproductive toxicity studies in rats. Food Chem Toxicol 2006, 44(5):651-661.
43. Shen C.L., Chyu M.C., Pence B.C., Yeh J.K., Zhang Y., Felton C.K., et al. Green tea polyphenols supplementation and Tai Chi exercise for postmenopausal osteopenic women: Safety and quality of life report. BMC Complement Altern Med 2010, 10:76.
44. Jianming W. Progress in the study on the medical effects of Apocynum venetum (A. lancifolium). J Tradit Chin Med 1988, 8(1):34-36.
45. National Onion Association. Onions - Phytochemical and health properties. URL: [accessed September 2012]. http://onions-usa.org/img/site_specific/uploads/phytochemical_brochure.pdf#search='National+onion+association.+Onions+%E2%80%92Phytochemical+and+health+properties.
46. Food Safety Commission. Food safety information system. Food for specified health use safety evaluation report "Yang long tea level care." URL: [accessed September 2012]. http://www.fsc.go.jp/fsciis/evaluationDocument/show/kya20071024083.
47. Kajimoto O., Nakazawa Y., Kagawa T., Takahashi Y., Onizuka S., Nishibe M., et al. Effect of intake of the beverage containing yong long flavonoids on slightly elevated blood pressure levels in humans. Health Sciences 2005, 21:115-129.
48. Food Safety Commission. Food safety information system. Food for specified health use safety evaluation report "Otona dakara." URL: [accessed September 2012]. http://www.fsc.go.jp/fsciis/evaluationDocument/show/kya20101015577.
49. Tamano S., Hatahara Y., Sano M., Hagiwara A., Nakamura M., Washino T., et al. 13-week oral toxicity and 4-week recovery study of enzymatically modified isoquercitrin in F344/DuCrj rats. Jap J Food Chem Safety 2001, 8(3):161-167.
50. Salim E.I., Kaneko M., Wanibuchi H., Morimura K., Fukushima S. Lack of carcinogenicity of enzymatically modified isoquercitorin in F344/DuCrj rats. Food Chem Toxicol 2004, 42(12):1949-1969.
51. Yoshimura M., Mada T., Abe K., Ohta H., Kiso Y., Takehara K., et al. Body fat reducing effect and safety of the beverage containing polyphenols derived from Japanese Pagoda Tree (enzymatically modified isoquercitrin) in overweight and obese subjects. Japanese Pharmacol Ther 2008, 36(10):919-930.
52. Ishikura Y., Fujii W., Sakakibara H., Kitougo T., Katagiri Y., Oki M. Safety evaluation of excessive intake of the drink containing Japanese Pagoda Tree polyphenol (enzymatically modified isoquercitrin) in healthy adults include obesity persons. Japanese Pharmacol Ther 2008, 36:931-939.
53. 1 mice. J Toxicol Environ Health 1993, 38(1):89-101.
54. Yumoto T. Characteristics and applications of glucosyl hesperidin. Shoku To Kagaku 1999, 2:90-94.
55. Evaluation of the health aspects of hesperidin, naringin, and citrus bioflavonoid extracts as food ingredients. Life Sciences Research Offices, Federation of American Societies for Experimental Biology 1982; pp. 1-34.
56. Wollny H.-E., Arenz M., Hermann F. Salmonella typhimurium and Escherichia coli reverse mutation assay with α-glucosyl-hesperidin 1997, CCR, Cytotest Cell Research GEBH & Co. KG.
57. Food Safety Commission. Food safety information system. Food for specified health use safety evaluation report "Trigly tea." URL: [accessed September 2012]. http://www.fsc.go.jp/fsciis/evaluationDocument/show/kya20100118003.
58. Arcelin G. Acute oral toxicity study with α-glucosyl-hesperidin in rats 1997, RCC, Research & Consulting Company Ltd, pp. 1-25.
59. Pipp F., Krinke G.: α-Glucosyl-hesperidin: 4-week oral (feeding) dose range finding study in the rat, RCC Ltd Report, 2005; p. 1-182.
60. Sommer E., Flade D., Gretener P., Romeo L. α-Glucosyl-hesperidin: 13-week oral toxicity (feeding) study in the rat, RCC Ltd Report, 2005; pp. 1-348.
61. Arcelin G.α-Glucosyl-hesperidin: contact hypersensitivity in Albino Guinea pigs, maximization-test. RCC, Research & Consulting Company Ltd Report, 1998; pp. 1-49.
62. Nakagawa M., Ohgawara M., Matsumoto T., Andou R., Hori T., Koban H. Effect and safety of intake of the powder green tea containing glucosyl hesperidin on serum triglyceride levels in humans. J Nutr Food 2008, 11:15-28.
63. Yuasa M., Yasue M., Ohtake Y., Maitani R., Satoh K., Mitsuda H., et al. Efficacy and safety of intake of the beverage containing glucosyl hesperidin on serum triglyceride levels in humans. J Japanese Council for Adv Food Ingredients Res 2005, 8:125-143.
64. Meyer O.C. Safety and security of Daflon 500mg in venous insufficiency and in hemorrhoidal disease. Angiology 1994, 45(6 Pt 2):579-584.
65. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J Altern Complement Med 2003, 9(1):161-168.
66. Dadhaniya P., Patel C., Muchhara J., Bhadja N., Mathuria N., Vachhani K., et al. Safety assessment of a solid lipid curcumin particle preparation: acute and subchronic toxicity studies. Food Chem Toxicol 2011, 49(8):1834-1842.
67. D'Angelo S., Manna C., Migliardi V., Mazzoni O., Morrica P., Capasso G., et al. Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil. Drug Metab Dispos 2001, 29(11):1492-1498.
68. Gupta H., Pawar D., Riva A., Bombardelli E., Morazzoni P.A. randomized, double-blind, placebo-controlled trial to evaluate efficacy and tolerability of an optimized botanical combination in the management of patients with primary hypercholesterolemia and mixed dyslipidemia. Phytother Res 2012, 26(2):265-272.
69. Consumer Affairs Agency Food Labelling Division of Japan. Regulatory Systems of Health Claims in Japan. URL: [accessed September 2012]. http://www.caa.go.jp/en/pdf/syokuhin338.pdf.
70. Novel foods and novel food ingredients - Review of Regulation (EC) 258/97. URL: [accessed September 2012]. http://ec.europa.eu/food/food/biotechnology/novelfood/initiatives_en.htm.
71. U.S. Food and Drug Administration. Generally Recognized as Safe (GRAS). URL: [accessed September 2012]. http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/ucm2006850.htm.
72. U.S. Food and Drug Administration. New Dietary Ingredients in Dietary Supplements - Background for Industry. URL:. http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/ucm2006850.htm.