Table of Contents Author Guidelines Submit a Manuscript
Journal of Ophthalmology
Volume 2016, Article ID 3690140, 15 pages
http://dx.doi.org/10.1155/2016/3690140
Review Article

Zeaxanthin: Review of Toxicological Data and Acceptable Daily Intake

NIC-RD/HN Toxicology and Kinetics, DSM Nutritional Products Ltd., Wurmisweg 576, 4303 Kaiseraugst, Switzerland

Received 29 October 2015; Accepted 6 December 2015

Academic Editor: Joan E. Roberts

Copyright © 2016 James A. Edwards. 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. A. Perry, H. Rasmussen, and E. J. Johnson, “Xanthophyll (lutein, zeaxanthin) content in fruits, vegetables and corn and egg products,” Journal of Food Composition and Analysis, vol. 22, no. 1, pp. 9–15, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. O. Sommerburg, J. E. E. Keunen, A. C. Bird, and F. J. G. M. van Kuijk, “Fruits and vegetables that are sources for lutein and zeaxanthin: the macular pigment in human eyes,” British Journal of Ophthalmology, vol. 82, no. 8, pp. 907–910, 1998. View at Publisher · View at Google Scholar · View at Scopus
  3. F. Y. Mohamedshah, J. S. Douglass, M. M. Amann, and J. T. Heimbach, “Dietary intakes of lutein-zeaxanthin and total carotenoids among Americans age 50 and above,” The FASEB Journal, vol. 13, no. 4, part 1, abstract 441.17, p. A554, 1999. View at Google Scholar
  4. J. M. Seddon, U. A. Ajani, R. D. Sperduto et al., “Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration,” Journal of the American Medical Association, vol. 272, no. 18, pp. 1413–1420, 1994. View at Publisher · View at Google Scholar · View at Scopus
  5. G. I. Albert, U. Hoeller, J. Schierle, M. Neuringer, E. J. Johnson, and W. Schalch, “Metabolism of lutein and zeaxanthin in rhesus monkeys: identification of (3R,6′R)- and (3R,6′S)-3′-dehydro-lutein as common metabolites and comparison to humans,” Comparative Biochemistry and Physiology B: Biochemistry and Molecular Biology, vol. 151, no. 1, pp. 70–78, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. E. J. Johnson, M. Neuringer, R. M. Russell, W. Schalch, and D. M. Snodderly, “Nutritional manipulation of primate retinas. III. Effects of lutein or zeaxanthin supplementation on adipose tissue and retina of xanthophyll-free monkeys,” Investigative Ophthalmology and Visual Science, vol. 46, no. 2, pp. 692–702, 2005. View at Publisher · View at Google Scholar · View at Scopus
  7. W. Schalch, “Carotenoids in the retina—a review of their possible role in preventing or limiting damage caused by light and oxygen,” in Free Radicals and Aging, I. Emerit and B. Chance, Eds., vol. 62 of EXS, pp. 280–298, Birkhäuser, Basel, Switzerland, 1992. View at Publisher · View at Google Scholar
  8. W. Schalch, P. Dayhaw-Barker, and F. M. Barker, “The carotenoids of the human retina,” in Nutritional and Environmental Influences on the Eye, A. Taylor, Ed., pp. 215–250, CRC Press, Boca Raton, Fla, USA, 1999. View at Google Scholar
  9. JECFA, “Safety evaluation of certain food additives,” in Proceedings of the 63rd Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA '06), vol. 54 of International Programme on Chemical Safety, World Health Organization, World Health Organization, 2006.
  10. G. B. Arden and F. M. Barker, “Canthaxanthin and the eye: a critical ocular and toxicological assessment,” Journal of Toxicology. Cutaneous and Ocular Toxicology, vol. 10, pp. 115–155, 1991. View at Google Scholar
  11. R. Goralczyk, “Histological aspects of primate ocular toxicity with special emphasis on canthaxanthin-induced retinopathy in an animal model with cynomolgus monkeys,” in Towards New Horizons in Primate Toxicology, R. Korte and G. F. Weinbauer, Eds., pp. 159–174, Waxmann Münster, 2002. View at Google Scholar
  12. R. Goralczyk, F. M. Barker, S. Buser, H. Liechti, and J. Bausch, “Dose dependency of canthaxanthin crystals in monkey retina and spatial distribution of its metabolites,” Investigative Ophthalmology and Visual Science, vol. 41, no. 6, pp. 1513–1522, 2000. View at Google Scholar · View at Scopus
  13. R. Goralczyk, S. Buser, J. Bausch, W. Bee, U. Zühlke, and F. M. Barker, “Occurrence of birefringent retinal inclusions in cynomolgus monkeys after high doses of canthaxanthin,” Investigative Ophthalmology and Visual Science, vol. 38, no. 3, pp. 741–752, 1997. View at Google Scholar · View at Scopus
  14. E. Gocke, “Mutagenicity evaluation of zeaxanthin, Ro 01-9509/007 in the Salmonella/microsome assay (Ames test),” DSM Report B-0153207, 1987. View at Google Scholar
  15. E. Gocke, Decay of (3R, 3′R)-Zeaxanthin, Internal Communication, Hoffmann-La Roche, Basel, Switzerland, 1987.
  16. E. Gocke, “Ro 01-9509/007: bacterial reverse mutation test (Ames test),” DSM Report 1015664, 2004. View at Google Scholar
  17. R. Strobel, “Gene mutation assay in cultured mammalian cells with Ro 01 9509/007 (All-Trans-Zeaxanthin) (V79/HGPRT Test),” DSM Report B-0153078, 1986. View at Google Scholar
  18. R. Strobel, “Unscheduled DNA synthesis assay with the carotenoid Ro 01-9509/007 (all-trans-Zeaxanthin) using primary cultures of rat hepatocytes,” DSM Report B-0153081, 1987. View at Google Scholar
  19. R. Strobel and A. Bonhoff, “Chromosome analysis of human peripheral blood lymphocytes exposed in vitro to the carotenoid Ro 01-9509/007 (all-trans-(3R, 3′R) zeaxanthin) in the presence and absence of a rat liver activation system,” DSM Report B-0153083, 1987. View at Google Scholar
  20. F. Galandere, “Mutagenicity studies with Ro 01-9509 in mammalian systems, 1. The micronucleus test in the mouse,” DSM Report B-0090156, 1980. View at Google Scholar
  21. H. P. Baechtold, “Acute toxicity studies with zeaxanthin and its precursors,” Interoffice Memorandum 7100, Hoffmann-La Roche, Basel, Switzerland, 1977. View at Google Scholar
  22. G. Klecak and H. Geleick, “Determination of allergenicity of colorants used in products of the pharmaceutical, cosmetic and nutrition industries in Guinea pigs,” DSM Report B-0076538, 1977. View at Google Scholar
  23. M. Csato and G. Arcelin, “Ro 01-9509/000 (zeaxanthin): study of skin sensitization in albino Guinea pigs: maximization-test,” DSM Report B-0171910, 2000. View at Google Scholar
  24. M. Csato and G. Arcelin, “Primary eye irritation study in rabbits,” DSM Report B-0171911, 2000. View at Google Scholar
  25. R. Ettlin, A. Steiger, and H. Hummler, “Tolerance study with Ro 01-9509/007 (zeaxanthin as 10% water soluble beadlets) administered orally as a feed admixture to mice over 13 weeks,” DSM Report B-0093153, 1980. View at Google Scholar
  26. R. Ettlin, A. Steiger, and H. Hummler, “Tolerance study with Ro 01-9509/007 (zeaxanthin as 10% water soluble beadlets) administered orally as a feed admixture to rats over 13 weeks,” DSM Report B-0093152, 1980. View at Google Scholar
  27. S. Buser, “A 13-week toxicity study with Ro 01-9509/013 in the rat p.o. (feed admix),” DSM Report B-0105657, 1985. View at Google Scholar
  28. R. A. Ettlin, “13 Week tolerance study of Ro 01-9509/013 administered orally in capsules to dogs,” DSM Report B-0105639, 1985. View at Google Scholar
  29. A. Kistler, “Embryotoxicity and teratogenicity study in rats with oral administration (feed admix) of Ro 01-9509, zeaxanthin. Segment II-teratological study with postnatal evaluation,” DSM Report B-0104974, 1984. View at Google Scholar
  30. A. Kistler, “Embryotoxicity and teratogenicity study in rabbits with oral administration of Ro 01-9509, zeaxanthin. Segment II-teratological study,” DSM Report B-0104954, 1983. View at Google Scholar
  31. J. Edwards, S. Clode, J. Schierle, and N. Decker, “Zeaxanthin 10% WS beadlets (Ro 01 9509): two generation oral (dietary administration) reproduction toxicity study in the rat,” DSM Report No-2500072, 2006. View at Google Scholar
  32. S. Gradelet, P. Astorg, J. Leclerc, J. Chevalier, M.-F. Vernevaut, and M.-H. Siess, “Effects of canthaxanthin, astaxanthin, lycopene and lutein on liver xenobiotic-metabolizing enzymes in the rat,” Xenobiotica, vol. 26, no. 1, pp. 49–63, 1996. View at Publisher · View at Google Scholar · View at Scopus
  33. E. Wolz, H. Liechti, B. Notter, G. Oesterhelt, and A. Kistler, “Characterization of metabolites of astaxanthin in primary cultures of rat hepatocytes,” Drug Metabolism and Disposition, vol. 27, no. 4, pp. 456–462, 1999. View at Google Scholar · View at Scopus
  34. P. Astorg, S. Gradelet, J. Leclerc, and M.-H. Siess, “Effects of provitamin A or non-provitamin A carotenoids on liver xenobiotic-metabolizing enzymes in mice,” Nutrition and Cancer, vol. 27, no. 3, pp. 245–249, 1997. View at Publisher · View at Google Scholar · View at Scopus
  35. A. Kistler, H. Liechti, L. Pichard et al., “Metabolism and CYP-inducer properties of astaxanthin in man and primary human hepatocytes,” Archives of Toxicology, vol. 75, no. 11, pp. 665–675, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. EFSA ANS Panel, “Scientific opinion on the re-evaluation of lutein (E 161b) as a food additive,” EFSA Journal, vol. 8, no. 7, article 1678, 2010. View at Google Scholar
  37. EFSA NDA Panel, “Statement on the safety of synthetic zeaxanthin as an ingredient in food supplements,” EFSA Journal, vol. 10, no. 10, article 2891, 2012. View at Google Scholar
  38. D. Glatzle, J. Bausch, and F. Ringenbach, “Radioactivity in expired air during zeaxanthin balance studies compared to previous findings for canthaxanthin and astaxanthin with rats,” DSM Report B-0106789, 1999. View at Google Scholar
  39. J. Bausch, D. Glatzle, M. Bruchlen, and H. Liechti, “Zeaxanthin distribution study in rats,” DSM Report B 0106776, 1999. View at Google Scholar
  40. D. Glatzle, J. Bausch, S. Moalli, F. Ringenbach, and U. Matter, “Zeaxanthin balance studies,” DSM Report B-0106788, 1999. View at Google Scholar
  41. K.-Q. Hu, C. Liu, H. Ernst, N. I. Krinsky, R. M. Russell, and X.-D. Wang, “The biochemical characterization of ferret carotene-9′,10′-monooxygenase catalyzing cleavage of carotenoids in vitro and in vivo,” Journal of Biological Chemistry, vol. 281, no. 28, pp. 19327–19338, 2006. View at Publisher · View at Google Scholar · View at Scopus
  42. J. R. Mein, G. G. Dolnikowski, H. Ernst, R. M. Russell, and X.-D. Wang, “Enzymatic formation of apo-carotenoids from the xanthophyll carotenoids lutein, zeaxanthin and β-cryptoxanthin by ferret carotene-9′, 10′-monooxygenase,” Archives of Biochemistry and Biophysics, vol. 506, no. 1, pp. 109–121, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Hartmann, P. A. Thürmann, V. Spitzer, W. Schalch, B. Manner, and W. Cohn, “Plasma kinetics of zeaxanthin and 3′-dehydro-lutein after multiple oral doses of synthetic zeaxanthin,” The American Journal of Clinical Nutrition, vol. 79, no. 3, pp. 410–417, 2004. View at Google Scholar · View at Scopus
  44. F. Pfannkuch, E. Wolz, C. P. Aebischer, J. Schierle, B. Niggemann, and U. Zuhlke, “Ro 01-9509 (zeaxanthin 10%) and Ro 15-3971 (lutein 10%): combined 52-week oral (gavage) pilot toxicity study with two carotenoids in the cynomolgus monkey,” DSM Report and Subsequent Report Addenda B-0171423, 2000. View at Google Scholar
  45. F. Pfannkuch, “Ro 01-9509 (zeaxanthin 10%) and Ro 15-3971 (lutein 10%): combined 52-week oral (gavage) pilot toxicity study with two carotenoids in the cynomolgus monkey (Roche research report No.: B-0171423), comprehensive overview on eye examinations,” DSM Report 1004238, 2001. View at Google Scholar
  46. E. Zrenner, “Additional evaluation of electroretinography (ERG) and expert commentary,” Roche Addendum 12, 2000, Regulatory Document 1003501, 2000. View at Google Scholar
  47. R. Goralczyk, F. Barker, O. Froescheis et al., “Ocular safety of lutein and zeaxanthin in a long-term study in cynomolgous monkeys,” Investigative Ophthalmology & Visual Science, vol. 43, no. 12, p. 2546, 2002, ARVO Meeting Abstracts. View at Google Scholar
  48. R. Goralczyk, “Ro 01-9509 (zeaxanthin 10%) and Ro 15-3971 (lutein 10%): combined 52-week oral (gavage) pilot toxicity study with two carotenoids in the cynomolgus monkey, pathology report on eyes, amendment to final report no. 11,” DSM Report 1003526, 2000. View at Google Scholar
  49. O. Froescheis, B. Rossi, and J. Bausch, “Determination of lutein and zeaxanthin in retina and lens by HPLC,” Regulatory Document 1003501, Hoffmann-La Roche, 2000, Addendum No. 12, in Amendment to Final Report No. 1. View at Google Scholar
  50. F. Khachik, E. London, F. F. De Moura et al., “Chronic ingestion of (3R,3′R,6′R)-lutein and (3R,3′R)-zeaxanthin in the female rhesus macaque,” Investigative Ophthalmology & Visual Science, vol. 47, no. 12, pp. 5476–5486, 2006. View at Google Scholar
  51. ATBC Study Group, “The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers,” The New England Journal of Medicine, vol. 330, no. 15, pp. 1029–1035, 1994. View at Publisher · View at Google Scholar · View at Scopus
  52. G. S. Omenn, G. E. Goodman, M. D. Thornquist et al., “Chemoprevention of lung cancer: the beta-carotene and Retinol Efficacy Trial (CARET) in high-risk smokers and asbestos-exposed workers,” IARC Scientific Publications, vol. 136, pp. 67–85, 1996. View at Google Scholar
  53. C. Liu, X.-D. Wang, R. T. Bronson, D. E. Smith, N. I. Krinsky, and R. M. Russell, “Effects of physiological versus pharmacological β-carotene supplementation on cell proliferation and histopathological changes in the lungs of cigarette smoke-exposed ferrets,” Carcinogenesis, vol. 21, no. 12, pp. 2245–2253, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. C. Liu, R. T. Bronson, R. M. Russell, and X.-D. Wang, “β-Cryptoxanthin supplementation prevents cigarette smoke-induced lung inflammation, oxidative damage, and squamous metaplasia in ferrets,” Cancer Prevention Research, vol. 4, no. 8, pp. 1255–1266, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Männistö, S. A. Smith-Warner, D. Spiegelman et al., “Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies,” Cancer Epidemiology Biomarkers and Prevention, vol. 13, no. 1, pp. 40–48, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. R. A. Bone, J. T. Landrum, L. M. Friedes et al., “Distribution of lutein and zeaxanthin stereoisomers in the human retina,” Experimental Eye Research, vol. 64, no. 2, pp. 211–218, 1997. View at Publisher · View at Google Scholar · View at Scopus
  57. X. Xu, L. Zhang, B. Shao, X. Sun, C.-T. Ho, and S. Li, “Safety evaluation of meso-zeaxanthin,” Food Control, vol. 32, no. 2, pp. 678–686, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Sugiura, K. Ogawa, and M. Yano, “Absorption, storage and distribution of β-cryptoxanthin in rat after chronic administration of satsuma mandarin (Citrus unshiu MARC.) juice,” Biological and Pharmaceutical Bulletin, vol. 36, no. 1, pp. 147–151, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. R. Ravikrishnan, S. Rusia, G. Ilamurugan et al., “Safety assessment of lutein and zeaxanthin (Lutemax 2020): subchronic toxicity and mutagenicity studies,” Food and Chemical Toxicology, vol. 49, no. 11, pp. 2841–2848, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. K. B. Ravi, K. R. R. Reddy, J. Shankaranarayanan, J. V. Deshpande, V. Juturu, and M. G. Soni, “Safety evaluation of zeaxanthin concentrate (OmniXan): acute, subchronic toxicity and mutagenicity studies,” Food and Chemical Toxicology, vol. 72, pp. 30–39, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. EFSA ANS Panel, “Scientific opinion on the re-evaluation of canthaxanthin (E 161 g) as a food additive,” EFSA Journal, vol. 8, no. 10, article 1852, 2010. View at Google Scholar
  62. J. van de Kraats, M. J. Kanis, S. W. Genders, and D. van Norren, “Lutein and zeaxanthin measured separately in the living human retina with fundus reflectometry,” Investigative Ophthalmology and Visual Science, vol. 49, no. 12, pp. 5568–5573, 2008. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Forma, G. Carboni, B. J. Jennings, and A. Iannaccone, “Measures of macular function after dietary supplementation with zeaxanthin (Zx),” Investigative Ophthalmology & Visual Science, vol. 52, no. 6, p. 3637, 2011, ARVO Meeting Abstracts. View at Google Scholar
  64. G. Carboni, G. Forma, B. J. Jennings, and A. Lannaccone, “Effects of zeaxanthin (Zx) supplementation on macular pigment optical density (MPOD),” Investigative Ophthalmology & Visual Science, vol. 52, abstract 3622, 2011, ARVO Meeting Abstracts. View at Google Scholar
  65. EU Commission, “Commission implementing decision of 22 January 2013, authorising the placing on the market of synthetic zeaxanthin as a novel food ingredient under regulation (EC) No 258/97 of the European Parliament and of the Council,” Official Journal of the European Union, 24.1.2013, 2013.