New Evidence on Vitamin E Safety

An important review published in the American Journal of Clinical Nutrition in April, 2005 sheds new light on the safety of Vitamin E.

Statistical experts have already largely discredited the extremely poor meta-analysis announced last Fall by the medical journal Annals of Internal Medicine that re-analyzed only 19 studies on Vitamin E. The experts' overwhelmingly negative responses are posted on that journal's web site. Combining studies that did not use consistent forms or doses unfairly added variables while ignoring positive effects of the vitamin. The authors acknowledged that their findings do not apply to healthier populations and are not definitive.

The new review of Vitamin E published in the American Journal of Nutrition on April 1, 2005 states that after adjusting for variables in supplementation, the actual dose of Vitamin E that may have been slightly harmful to these seriously ill patients was statistically significant only at levels where patients took over 2,000 IU per day, well above the 400 IU suggested by the original Annals analysis.

A recent JAMA article on Vitamin E also used very sick patients but subjected positive data on Vitamin E's benefits to different, more stringent statistical methods than the equally skimpy negative data to produce a negative result and thereby tainting the study, which had been already been rejected by the journal Lancet a year earlier.

The national Institute of Medicine 's safe upper limit of 1,500 I.U. per day of natural Vitamin E is based on their own expert review of hundreds of well-designed studies.

The National Institutes of Health (NIH) supports the ongoing Selenium and Vitamin E Cancer Prevention Trial (SELECT), a multi-center, long-term, double-blind, randomized trial that includes 35,534 men age 55 and older taking 400 IU of vitamin E daily to verify earlier evidence of it preventing prostate cancer. NIH researchers carefully examined the data from these few negative reports and decided not to change their protocol, still believing that Vitamin E at this dose is unlikely to cause any harm to their patients.

This confirms the new American Journal of Nutrition review stating that there is no good evidence that levels of Vitamin E under 1,600 IU have been shown to increase health risks.

Two large observational studies (the Nurses' Health Study and the Health Professionals Follow-up Study) show that people taking Vitamin E supplements of 400 IU or more for at least two years had between 20-40% reduction in coronary heart disease. In the GISSI Prevention Trial of 11,000 heart attack survivors, Vitamin E reduced the number both of sudden deaths and deaths due to cardiovascular disease.

The scientific method of giving only one isolated nutrient has generated some brutal publicity for individual members of the antioxidant "family" because antioxidants function inter-dependently. For example, Beta-carotene has been cited in one study as putting smokers at greater risk of lung cancer, but a more thorough follow up analysis - looking at their diet plus other dietary supplements taken - revealed that the smokers' actual danger was due to low total antioxidant levels.

One caution is that people should not try to take a high dose of any one supplement without considering that it may increase our need for other nutrients. And elderly, sick people especially need a more holistic approach, rather than using a single nutrient in high doses as if it were a drug. Nutrients just don't work well in isolation from each other. Most people would benefit from taking a multiple vitamin and a Vitamin E supplement, and it would be even safer than just the Vitamin E alone.

There are also differences between natural and synthetic Vitamin E, with most studies using only the synthetic forms, which are composed of different-shaped molecules only half as effective as natural Vitamin E. Natural Vitamin E is called d-alpha tocopherol and synthetic Vitamin E is called dl-alpha tocopherol. It is known that alpha tocopherol can block absorption of gamma tocopherol, an important antioxidant. Vitamin E complexes with several forms of natural tocopherols, along with the related tocotrienols, are far better than just one kind of Vitamin E. The alpha forms have preferential absorption versus the other forms, for both tocopherols & tocotrienols, making it important to have the right balance so all can work together, as they do in healthy foods.

Vitamins are essential to health and life, but the average American gets only 1/3 of the recommended daily intake of Vitamin E, the amount that the Institute of Medicine determined to be needed by the average adult to prevent serious illnesses. People with serious heart diseases are more likely to take a Vitamin E supplement than the general population, but a single supplement may not work very quickly or effectively on these seriously ill people and should not be blamed for their illnesses without some more convincing science to back it up.

There is no published evidence that the average person taking a mixture of antioxidants is at greater risk of any disease, but plenty of studies show that people eating a variety of antioxidant nutrients receive some protection from various diseases. In the case of antioxidants, there is safety in numbers.

Neil E. Levin, CCN, DANLA

Saint Charles , Illinois

Neil E. Levin is a professional member of the International & American Associations of Clinical Nutritionists. He works as a nutrition educator, product formulator and Truth Advocate for the natural products industry.

Neil is a member of the Scientific Council of the national Clinical Nutrition Certification Board and has a Diplomate in Advanced Nutritional Laboratory Assessment. He is on the Board of Directors of the Mid-American Health Organization (MAHO). Neil has published numerous articles in magazines and newspapers, and has appeared on talk radio and television news programs.

Neil is also the President of Nutrition for Optimal Health Association, Inc. (www.nutrition4health.org), a not-for-profit nutrition education corporation based in Winnetka , Illinois .

Main References

  1. Margaret E. Wright , Susan T. Mayne, Rachael Z. Stolzenberg-Solomon, Zhaohai Li, Pirjo Pietinen, Philip R. Taylor, Jarmo Virtamo and Demetrius Albanes. American Journal of Epidemiology. July 2004. Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers.
  2. Edgar R. Miller, III, MD, PhD; Roberto Pastor-Barriuso, PhD; Darshan Dalal, MD, MPH; Rudolph A. Riemersma, PhD, FRCPE; Lawrence J. Appel, MD, MPH; and Eliseo Guallar, MD, DrPH. High-dose vitamin E supplementation may increase all-cause mortality, a dose response meta-analysis of randomized trials. Annals of Internal Medicine: Online: Nov. 10, 2004: Print: 4 January 2005 | Volume 142 Issue 1
  3. Satia-Abouta J, Kristal AR, Patterson RE, Littman AJ, Stratton KL, White E. Dietary supplement use and medical conditions. Am Journal Preventive Medicine 24:43-51, January 2003.
  4. Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003 Oct;133(10):3137-40.
  5. The Lewin Group, DaVanzo, J. et al. Improving Public Health, Reducing Health Care Costs: An Evidence-Based Study of Five Dietary Supplements. September 22, 2004.
  6. The Lewin Group, Al Dobson, Ph.D., et al. A Study of the Cost Effects of Daily Multivitamins for Older Adults. Prepared for: Wyeth Consumer Healthcare.
  7. Richer S, Stiles W, Statkute L et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75:216-30.
  8. John N Hathcock, Angelo Azzi, Jeffrey Blumberg, Tammy Bray, Annette Dickinson, Balz Frei, Ishwarlal Jialal, Carol S Johnston, Frank J Kelly, Klaus Kraemer, Lester Packer, Sampath Parthasarathy, Helmut Sies and Maret G Traber. REVIEW ARTICLE: Vitamins E and C are safe across a broad range of intakes. American Journal of Clinical Nutrition, Vol. 81, No. 4, 736-745, April 2005.

Additional References

Meeting of the American Association for Cancer Research, March 2004. (National Cancer Institute, the Fred Hutchinson Cancer Research Center in Seattle and the National Public Health Institute of Finland .)

Adachi H, Ishii N. Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. 2000 Jun;55(6):B280-5. PMID: 10843344

Agarwal MK, Agarwal ML, Athar M, Gupta S. Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle. 2004 Feb;3(2):205-11. PMID: 14712090

Anderson SL, Qiu J, Rubin BY. Tocotrienols induce IKBKAP expression: a possible therapy for familial dysautonomia. Biochem Biophys Res Commun. 2003 Jun 20;306(1):303-9. PMID: 12788105

Black TM, Wang P, Maeda N, Coleman RA. Palm tocotrienols protect ApoE +/- mice from diet-induced atheroma formation. J Nutr. 2000 Oct;130(10):2420-6. PMID: 11015467

Buring JE, Hennekens CH, for the Women's Health Study Research Group. The Women's Health Study: Rationale, background and summary of the study design. J Myocardial Ischemia 1992; 4:27-29 and 30-40.

Chao JT, Gapor A, Theriault A. Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion. J Nutr Sci Vitaminol ( Tokyo ). 2002 Oct;48(5):332-7. PMID: 12656204

Chatelain E, Boscoboinik DO, Bartoli GM, Kagan VE, Gey F, Packer L, Azzi A. 1993. Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim Biophys Acta 1176:83-89.

Stephan Christen, Alan A. Woodall, Mark K. Shigenaga, Peter T. Southwell-Keely, Mark W. Duncan, and Bruce N. Ames. -Tocopherol traps mutagenic electrophiles such as NOx and complements -tocopherol: Physiological implications PNAS 1997; 94: 3217-3222.

RV Cooney, AA Franke, PJ Harwood, V Hatch-Pigott, LJ Custer, and LJ Mordan. gamma-Tocopherol Detoxification of Nitrogen Dioxide: Superiority to alpha-Tocopherol. PNAS 1993; 90: 1771-1775.

Frazier AL, Li L, Cho E, Willett WC, Colditz GA. Adolescent diet and risk of breast cancer. Cancer Causes Control. 2004 Feb;15(1):73-82. PMID: 14970737

Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354:447-55.

Das S, Powell SR, Wang P, Divald A, Nesaretnam K, Tosaki A, Cordis GA, Maulik N, Das DK. CARDIOPROTECTION WITH PALM TOCOTRIENOL: ANTIOXIDANT ACTIVITY OF TOCOTRIENOL IS LINKED WITH ITS ABILITY TO STABILIZE PROTEASOMES. Am J Physiol Heart Circ Physiol. 2005 Feb 11; [Epub ahead of print] PMID: 15708953

Dial S, Eitenmiller RR. 1995. Tocopherols and tocotrienols in key foods in the U.S. diet. In: Ong ASH, Niki E, Packer L, eds. Nutrition, Lipids, Health, and Disease. Champaign , IL : AOCS Press. Pp. 327-342.

Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids (2000). Institute of Medicine

Guthrie N, Gapor A, Chambers AF, Carroll KK. Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination. J Nutr. 1997 Mar;127(3):544S-548S. PMID: 9082043

Halliwell B, Rafter J, Jenner A. Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not? Am J Clin Nutr. 2005 Jan;81(1 Suppl):268S-276S. Review. PMID: 15640490

Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. PMID: 11121464

Mark Houston, MD, MSc, FACP, FAHA. "Meta-Analysis, Metaphysics and Mythology": Scientific and Clinical Perspective on the Controversies Regarding Vitamin E for the Prevention and Treatment of Disease in Humans. Journal of the American Nutraceutical Association. JANA Vol. 8, No. 1, 2005

Ikeda I, Imasato Y, Sasaki E, Sugano M. Lymphatic transport of alpha-, gamma- and delta-tocotrienols and alpha-tocopherol in rats. Int J Vitam Nutr Res. 1996;66(3):217-21. PMID: 8899454

Inokuchi H, Hirokane H, Tsuzuki T, Nakagawa K, Igarashi M, Miyazawa T. Anti-angiogenic activity of tocotrienol. Biosci Biotechnol Biochem. 2003 Jul;67(7):1623-7. PMID: 12913317

Kamat JP, Sarma HD, Devasagayam TP, Nesaretnam K, Basiron Y. Tocotrienols from palm oil as effective inhibitors of protein oxidation and lipid peroxidation in rat liver microsomes. Mol Cell Biochem. 1997 May;170(1-2):131-7. PMID: 9144327

Kline K, Yu W, Sanders BG. Vitamin E and breast cancer. J Nutr. 2004 Dec;134(12 Suppl):3458S-3462S. Review. PMID: 15570054

Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ, Bell RA; The Insulin Resistance and Atherosclerosis Study (IRAS). Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care. 2002 Dec;25(12):2172-7. PMID: 12453956

McIntyre BS, Briski KP, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med. 2000 Sep;224(4):292-301. PMID: 10964265

McIntyre BS, Briski KP, Tirmenstein MA, Fariss MW, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on normal mouse mammary epithelial cells. Lipids. 2000 Feb;35(2):171-80. PMID: 10757548

Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett. 2003 Jan 30;337(1):56-60. PMID: 12524170

Montonen J, Knekt P, Jarvinen R, Reunanen A. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care. 2004 Feb;27(2):362-6. PMID: 14747214

Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT , Scherr PA. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. Am J Clin Nutr. 2005 Feb;81(2):508-14. PMID: 15699242

Nesaretnam K, Ambra R, Selvaduray KR, Radhakrishnan A, Reimann K, Razak G, Virgili F. Tocotrienol-rich fraction from palm oil affects gene expression in tumors resulting from MCF-7 cell inoculation in athymic mice. Lipids. 2004 May;39(5):459-67. PMID: 15506241

Nesaretnam K, Stephen R, Dils R, Darbre P. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Lipids. 1998 May;33(5):461-9. PMID: 9625593

Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A. Alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons. Neuropharmacology. 2004 Nov;47(6):904-15. PMID: 15527824

Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ. Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem. 1992 Oct 2;35(20):3595-606. PMID: 1433170

Qing Jiang, Ilan Elson-Schwab, Chantal Courtemanche, and Bruce N. Ames. -Tocopherol and its major metabolite, in contrast to -tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. PNAS 2000 97: 11494-11499; published online before print as 10.1073/pnas.200357097 Proceedings of the National Academy of Sciences.

Qing Jiang, Jeffrey Wong, Henrik Fyrst, Julie D. Saba, and Bruce N. Ames. -Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. PNAS 2004 101: 17825-17830; published online before print as 10.1073/pnas.0408340102

Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM, Elson CE. Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr. 1996 Feb;126(2):389-94. PMID: 8632210

Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993; 328:1450-6.

Rimm EB, Stampfer MJ. Antioxidants for vascular disease. Med Clin North Am 2000; 84:239-49.

Sakai M, Okabe M, Yamasaki M, Tachibana H, Yamada K. Induction of apoptosis by tocotrienol in rat hepatoma dRLh-84 cells. Anticancer Res. 2004 May-Jun;24(3a):1683-8. PMID: 15274341

Satia-Abouta J, Kristal AR, Patterson RE, Littman AJ, Stratton KL, White E. Am Journal Preventive Medicine 24:43-51, January 2003, Dietary supplement use and medical conditions.

Schaffer S, Muller WE, Eckert GP. Tocotrienols: constitutional effects in aging and disease. J Nutr. 2005 Feb;135(2):151-4. PMID: 15671205

Schwenke DC . Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer? J Nutr Biochem. 2002 Jan;13(1):2-20. PMID: 11834215

Shun MC, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K. Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr Cancer. 2004;48(1):95-105. PMID: 15203383

Soelaiman IN, Ahmad NS, Khalid BA. Palm oil tocotrienol mixture is better than alpha-tocopherol acetate in protecting bones against free-radical induced elevation of bone-resorbing cytokines. Asia Pac J Clin Nutr. 2004 Aug;13(Suppl):S111. PMID: 15294638

Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993; 328:1444-9.

Sylvester PW, McIntyre BS, Gapor A, Briski KP. Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase C(alpha) activation. Cell Prolif. 2001 Dec;34(6):347-57. PMID: 11736999

Sylvester PW, Shah SJ. Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells. Front Biosci. 2005 Jan 01;10:699-709. Print 2005 Jan 1. PMID: 15569611

Tanito M, Itoh N, Yoshida Y, Hayakawa M, Ohira A, Niki E. Distribution of tocopherols and tocotrienols to rat ocular tissues after topical ophthalmic administration. Lipids. 2004 May;39(5):469-74. PMID: 15506242

Stephanie J. Weinstein, M.S., Ph.D., and Demetrius Albanes, M.D., et al. Higher serum a-tocopherol and ?-tocopherol concentrations are associated with lower prostate cancer risk: Abstract No. 1096. 95th Annual Weinstein SJ, Wright ME, Pietinen P, King I, Tan C, Taylor PR, Virtamo J, Albanes D. Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study. J Natl Cancer Inst. 2005 Mar 2;97(5):396-9. PMID: 15741576

Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000; 342:154-60.

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