Safety of Vitamin E

by | Feb 13, 2014 | Vitamin E, Vitamins

Written by Chrystal Moulton, Staff Writer. Very low toxicity of vitamin E seen in high supplementation given in clinical trials.

Vitamin E is a natural antioxidant found in eggs, nuts, vegetables oil, as well as other products. It is a fat-soluble vitamin that has approximately 8 different forms, the most common of which is D-alpha- tocopherol.(1) However, questions have been raised on the safety of vitamin E.

The US Food and Drug Administration classify Vitamin E (alpha-Tocopherol acetate) as GRAS meaning it is generally recognized as safe. [CFR 182.8890 & 182.8892] According to the Food and Nutrition Board, a recommended daily allowance (RDA) of vitamin E is  22.4IU for individuals 14 years of age and older. This means that they believe that 22.4 IU for both women and men is the average daily intake which adequately meets nutrient requirements in most healthy people (about 98%). Likewise, according to the Dietary Reference Intakes Report published by the Institute of Medicine, the RDA is 15mg (22.4IU) for both men and women.(1) However, various clinical trials have used doses substantially higher than the RDA for treatment with few side effects. What is evident in the literature is vitamin E toxicity is very low. See Table 1 below for details on a few double-blind placebo controlled human trials.

Table 1. Vitamin E: Double-blind Placebo Controlled Trials

Trials Subjects Dose Duration Side Effects
Tsai et al.(3) 202 healthy volunteers 600IU/d vitamin E 4 weeks ↓ T3,T4 (thyroid hormones) in those not taking steroidal contraceptives, ↑triglycerides in women
Stampfer et al.(4) 30 healthy volunteers 800IU/d vitamin E 16 weeks No side effects
Gillilan et al.(5) 52 cardiac patients 1600IU/d vitamin E 6 months 4% complaint of mild GI disturbance
Bierenbaum et al(6) 25 diabetic patients (crossover included) 2000IU/d vitamin E 6 weeks No side effects
de Gaetano et al.(7) 4495 cardiac patients 300mg/d vitamin E 3.6 years Hemorraghing in 0.3% of patients p<0.0008
Sacco et al(8) 1031 diabetic patients 300mg/d synthetic vitamin E ~3.6 years Hemorraghing in 0.2% of patients p<0.0007
Anderson et Reid(9) 36 cardiac patients 3200IU/d vitamin E 9 weeks 1 intestinal cramps, 3 diarrhea
Kitagawa et Mino(10) 19 healthy volunteers 900IU/d vitamin E 12 weeks No side effects

Each study utilized a different natural form of vitamin E except Sacco et al.

This is not to say that there are no side effects attributed to high doses of vitamin E. At doses between 1,600-3,000 mg/d with extended daily use individuals can experience intestinal cramps, diarrhea, impairment in coagulation, and creatinuria. Doses at this level are considered therapeutic doses and should be administered under the care of a health practitioner, especially in individuals already taking medication for pre-existing or chronic conditions who generally exhibit adverse side effects. It was stated, nonetheless, that intakes up to 720mg (1,073IU) of alpha-tocopherol/d is very well tolerated without side effects.(2) another important factor to take note of is the effect of the natural form of vitamin E (d-alpha-tocopherol) on  another form of vitamin E known as gamma-tocopherol. Actually gamma tocopherol is more prevalent in our diet than d-alpha-tocopherol.(11) However, supplementation with d-alpha-tocopherol has been shown to decrease gamma-tocopherol and delta-tocopherol levels. (12-14) It is not completely clear what role delta-tocopherol and gamma-tocopherol plays in the body, but studies on gamma-tocopherol have shown that it effectively reduces markers of oxidative stress and inflammation (15) as well as lower LDL cholesterol and prevent platelet aggregation.(16) gamma-Tocopherol is also necessary for excretion of nitrotyrosines.(15) Nitrotyrosines are part of a category of molecules known to damage cellular processes and play a role in the development of diabetes, inflammation, Alzheimer’s, Parkinson’s, and cardiovascular disease. (17,18) Further research of other forms of vitamin E including delta -tocopherol demonstrate significant cancer protective effects.(14,19-21) Nevertheless, research is still being done to determine the best balance of all forms of vitamin E for supplementation.

Essentially, it is important when taking any vitamin to consider one’s pre-existing conditions, medications, weight, and general physical health. Any variation in those factors will influence dose requirements for a particular vitamin. Consult your healthcare provider if you are uncertain. 

Posted February 13, 2014.

Chrystal Moulton BA, PMP, is a 2008 graduate of the University of Illinois at Chicago. She graduated with a bachelor’s in psychology with a focus on premedical studies and is a licensed project manager. She currently resides in Indianapolis, IN.

References:

  1. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. (2000) WashingtonDC. National Academies Press.
  2. H Kappus, AT Diplock. Tolerance and safety of vitamin E: a toxicological position report. Free Radic Biol Med. 1992;13(1):55-74.
  3. A.C. Tsai, J.J. Kelley, B. Peng, N. Cook. Study on the Effect of Megavitamin E Supplementation in Man. Am. J. Clin. Nutr., 31 (1978), pp. 831–837.
  4. M.J. Stampfer, W. Willet, W.P. Castelli, J.O. Taylor, J. Fine, C.H. Hennekens. Effect of Vitamin E on Lipids. Am. J. Clin. Pathol., 79 (Nr. 6) (1983), pp. 714–716.
  5. R.E. Gillilan, B. Mondell, J.R. Warbasse. Quantitative Evaluation of Vitamin E in the Treatment of Angina Pectoris. Am. Heart J., 93 (Nr. 4) (1977), pp. 444–449.
  6. M.L. Bierenbaum, F.J. Noonan, L.J. Machlin, S. Machlin, A. Stier, P.B. Watson, A.M. Naso, A.I. Fleischman. The Effect of Supplemental Vitamin E on Serum Parameters in Diabetics, Post Coronary and Normal Subjects. Nutr. Res. Int., 31 (Nr. 6) (1985), pp. 1171–1180
  7. De Gaetano G, Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89–95.
  8. M Sacco, et al. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care. 2003 Dec;26(12):3264-72.
  9. T.W. Anderson, D.B. Reid. A Double-Blind Trial of Vitamin E in Angina Pectoris. Am. J. Clin. Nutr., 27 (1974), pp. 1174–1178.
  10. M. Kitagawa, M. Mino. Effects of Elevated d-alpha (RRR)-Tocopherol Dosage in Man. J. Nutr. Sci. Vitaminol., 35 (1989), pp. 133–142
  11. Jiang Q, et al. gamma-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001 Dec;74(6):714-22.
  12. Handelman GJ, et al. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr. 1985 Jun;115(6):807-13.
  13. Baker H, et al. Comparison of plasma alpha and gamma tocopherol levels following chronic oral administration of either all-rac-alpha-tocopheryl acetate or RRR-alpha-tocopheryl acetate in normal adult male subjects. Am J Clin Nutr. 1986 Mar;43(3):382-7.
  14. 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.
  15. Devaraj S, et al. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med. 2008 Mar 15;44(6):1203-8.
  16. Singh I, et al. Effects of gamma-tocopherol supplementation on thrombotic risk factors. Asia Pac J Clin Nutr. 2007;16(3):422-8.
  17. Yeo WS, et al. Nitrosative protein tyrosine modifications: biochemistry and functional significance. BMB Rep. 2008 Mar 31;41(3):194-203.
  18. FeeneyMB, Schöneich C. Tyrosine modifications in aging. Antioxid Redox Signal. 2012 Dec 1;17(11):1571-9.
  19. Yang CS, Suh N. Cancer prevention by different forms of tocopherols. Top Curr Chem. 2013;329:21-33.
  20. Li GX, et al. δ-tocopherol is more active than α – or γ -tocopherol in inhibiting lung tumorigenesis in vivo. Cancer Prev Res (Phila). 2011 Mar;4(3):404-13.
  21. Guan F, et al. δ- and γ-tocopherols, but not α-tocopherol, inhibit colon carcinogenesis in azoxymethane-treated F344 rats. Cancer Prev Res (Phila). 2012 Apr;5(4):644-54.