Vitamins E and C are safe across a broad range of intakes

¹ From the Council for Responsible Nutrition, Washington, DC (JNH and AD); the University of Bern, Bern, Switzerland (AA); Tufts University, Boston, MA (JB); Oregon State University, Corvallis, OR (TB, BF, and MGT); the University of California, Davis, Davis, CA (IJ); Arizona State University, Mesa, AZ (CSJ); King's College, London, United Kingdom (FJK); BASF, Ludwigshafen, Germany (KK); the University of Southern California, Los Angeles, CA (LP); Louisiana State University, Baton Rouge, LA (SP); and Heinrich Heine University, Dusseldorf, Germany (HS).

² Address reprint requests to JN Hathcock, Council for Responsible Nutrition, 1828 L Street, NW, Suite 900, Washington, DC 20036-5114. E-mail: jhathcock{at}crnusa.org.

ABSTRACT  
A robust database shows that dietary supplements of vitamins E and C are safe for the general population. Because these nutrients supply antioxidant and other functions for homeostasis and protection against free radical damage, supplementation has been intensively studied. Because of perceived benefits, many persons consume quantities of vitamins E and C well above the recommended dietary allowances. As safety guidance, tolerable upper intake levels have been established by the Food and Nutrition Board, Institute of Medicine, at 1000 mg for vitamin E and 2000 mg for vitamin C in adults. Many clinical trials with these vitamins have involved subjects with various diseases, and no consistent pattern of adverse effects has occurred at any intake. Numerous studies of vitamin C supplementation have provided no pattern of evidence to support concerns about safety other than occasional gastrointestinal upset or mild diarrhea resulting from the osmotic effects of unabsorbed quantities of vitamin C. Evidence of bleeding effects and other potential adverse effects of high vitamin E intakes in humans is not convincing. Evidence of adverse effects of vitamin C that result from its effects on iron absorption and metabolism has not been confirmed in clinical trials. Thus, we conclude from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts 1600 IU (1073 mg RRR--tocopherol or the molar equivalent of its esters) and that vitamin C supplements of 2000 mg/d are safe for most adults.

Key Words: Vitamin E • -tocopherol • tocopherol • vitamin C • ascorbic acid • risk assessment • safety • clinical trials

INTRODUCTION  
In the Western world, intakes of vitamins E and C are rarely low enough to cause overt deficiency diseases. Low intakes of these antioxidant micronutrients may, however, increase the risk of certain chronic diseases and accelerate several indicators of the aging process. These effects may be at least partly due to inadequate protection of tissues against oxidative damage from free radicals. Numerous studies suggest that supplements of vitamin E, vitamin C, or both may contribute, in many situations, to lowering the risk of specific chronic diseases such as Alzheimer disease, age-related macular degeneration, some types of cancer, cataracts, and ischemic heart disease (IHD). Because of much supporting evidence, the hypothesis that antioxidant activity may help decrease the risk of these diseases is viable, despite the fact that several clinical trials failed to find benefit (1–9). It is estimated that 70% of the US population uses dietary supplements at least occasionally, and 40% uses supplements on a regular basis (10, 11). The most commonly used supplements are multivitamins, vitamin C, vitamin E, and calcium.

DIETARY REFERENCE INTAKES FOR VITAMINS E AND C  
The Food and Nutrition Board (FNB) of the Institute of Medicine, a part of the US National Academies, has established a system of dietary reference intake (DRI) values for the US population that, for the first time, provides advice on the safety of the nutrients. "Safety" is defined as presenting no "unreasonable risk of illness or injury" or "a reasonable certainty of no harm," under labeled or ordinary conditions of use, as set forth in US laws and regulations for dietary supplements and food additives. The DRI system includes the estimated average requirement, the recommended dietary allowance (RDA) [or the acceptable intake for some nutrients], and the tolerable upper intake level (UL) (12). The RDA (or acceptable intake) represents the recommended daily intake for meeting normal nutritional needs and preventing clinical deficiency. Compared with the previous RDA, the new recommendations for vitamin E have been increased by 50% for men and by almost 100% for women. Similarly, the new recommendations for vitamin C have been increased by 25% for women and by 50% for men. The DRI values include a UL, which is the maximum amount considered safe (ie, likely to pose no risk) for healthy people when used daily for long periods. The RDA and UL values are based on exhaustive reviews of the scientific literature. RDA and UL values for vitamins E and C are shown in Table 1.

View this table:
TABLE 1. Recommended dietary allowance (RDA) and tolerable upper intake levels (UL) for vitamins E and C¹

 
Authoritative safety evaluations, including those by the FNB, the European Commission's Scientific Committee for Food (13) or its European Food Safety Authority (14) and the United Kingdom's Expert Group on Vitamins and Minerals (EVM; 15), have addressed the safety of vitamins C and E separately under the assumption that there will be little or no interaction of toxicologic importance.

VITAMIN E: THE EVIDENCE FOR SAFETY  
Several frequently cited literature reviews meticulously document the very consistent absence of adverse effects of vitamin E at intakes well above the RDA (16). The cited research included randomized, double-blind, placebo-controlled trials with large patient populations. Kappus and Diplock (17) similarly observed that many such scientifically reliable studies consistently showed no important adverse effects associated with vitamin E supplementation at intakes ranging up to 3200 IU/d. A recent meta-analysis that combined the results of 19 clinical trials of vitamin E supplementation for various diseases, including heart disease, end-stage renal failure, and Alzheimer disease, reported that adults who took supplements of 400 IU/d were 6% more likely to die of any cause than those who did not take vitamin E supplements (18). However, further breakdown of the risk by vitamin E dose and adjustment for other vitamin and mineral supplements found that the increased risk of death was significant only at a dose of 2000 IU/d, which is higher than the UL for adults. Furthermore, 3 other meta-analyses that combined the results of randomized controlled trials designed to evaluate the efficacy of vitamin E supplementation for the prevention or treatment of cardiovascular disease (CVD) found no evidence that vitamin E supplementation up to 800 IU/d significantly increased or decreased CVD mortality or all-cause mortality (19–21). At present, the evidence is not convincing that vitamin E supplementation up to the UL increases the risk of death due to CVD or other causes.

Few reports have cited any adverse effects of long-term use of vitamin E supplements at intakes up to many times the RDA. The evidence comes from many types of studies, ranging from observational studies of a few subjects to large, randomized, controlled intervention trials designed to ascertain whether there are beneficial effects on cancer, CVD, or other disorders. More than 20 published clinical trials involving 80 000 subjects have documented the safety of vitamin E supplements, as highlighted in Table 2.

View this table:
TABLE 2. Published safety observations for vitamin E supplementation¹

 
In a double-blind crossover study by Gillilan et al (22), 48 patients with stable angina documented by electrocardiography and angiography were randomly assigned to receive 1600 IU vitamin E/d for 6 mo either before or after a 2-mo placebo period. Although vitamin E did not appear to improve symptoms or exercise capacity in these patients with well-established heart disease, it proved entirely safe for them at that dose. There were no significant differences in symptomatic or laboratory indexes of heart disease in these patients between the active therapy and placebo periods.

Meydani et al (23) conducted an extensive 4-mo safety study of vitamin E (all-rac--tocopherol) at 60, 200, or 800 IU/d in 88 healthy elderly persons. None of the subjects reported any side effects. None showed any abnormalities on a wide array of laboratory tests, which included plasma proteins and lipids; glucose; lipoproteins, bilirubin, and other variables of liver, kidney, and metabolic function; red blood cell counts; bleeding time and other variables of coagulation; and a wide range of immune function indicators.

These findings from 2 small trials were corroborated by the larger Cambridge Heart Antioxidant Study, in which 2002 patients with symptomatic and angiographic CVD were randomly assigned to receive placebo or vitamin E at 400 or 800 IU/d (24). Over a median follow-up of 510 d, no significant adverse effects of vitamin E supplementation were reported among these patients. The slight numerical excesses of fatal myocardial infarction and total deaths with vitamin E treatment were not statistically significant. The rate of treatment discontinuation due to adverse effects—a common gauge of patient tolerance—was only 0.55% for the entire population and did not differ significantly between actively treated and control patients.

The Heart Outcomes Prevention Evaluation Study was an evaluation of the angiotensin-converting enzyme inhibitor ramipril, vitamin E given at 400 IU/d, or both in 9541 patients with multiple CVD risk factors (5). The Heart Outcomes Prevention Evaluation Study investigators concluded that vitamin E was "well tolerated" because the number of adverse events with the treatment was not significantly greater than that with the placebo over the mean follow-up of 4.5 y.

Chylack et al (6), Brown et al (35), and Cheung et al (39) tested the combination of simvastatin and niacin, with or without an antioxidant cocktail containing 800 IU vitamin E/d, against the cocktail alone or matching placebos in 160 patients with clinical IHD, low concentrations of HDL cholesterol, and healthy concentrations of LDL cholesterol. No adverse effects were observed in patients who received antioxidants alone, but there was an unexpected blunting of the favorable HDL-elevating response to simvastatin-niacin in those who received antioxidants with the drug treatments (39). The DATATOP clinical trial of 800 subjects for 8.2 y found no adverse effects of 2000 IU vitamin E/d (31). The data from this study support the safety of very high intakes of vitamin E over a long period.

The -Tocopherol, ß-Carotene Cancer Prevention Study (ATBC Study) raised a flag of caution (2). Among 29 133 male smokers in Finland, aged 50–69 y, supplementation with vitamin E at 50 mg/d (all-rac--tocopheryl acetate, and therefore 50 IU/d) for 5–8 y was associated with a 7.8% rate of death due to hemorrhagic stroke and with a 5.2% rate among those receiving placebo (66 cases in the vitamin group and 44 in the control group). In contrast, the vitamin E group had a significantly lower incidence of prostate cancer and significantly lower mortality due to ischemic stroke than did the placebo group. Ischemic stroke is more frequent than hemorrhagic stroke, and the overall stroke rate was lower in the vitamin E group than in the placebo group. However, statistical significance was not indicated for any of these apparent differences. The authors concluded only that the observation of higher hemorrhagic stroke mortality with vitamin E than with placebo required careful review. In a further evaluation, the researchers concluded that -tocopherol supplementation increased the risk of fatal hemorrhagic strokes but prevented cerebral infarction (3). In that study, there were, within 3 mo of the initial stroke diagnosis, 85 deaths due to subarachnoid hemorrhagic stroke; the number of such deaths in the vitamin E–supplemented group increased by 50%, for a total of 28 more deaths than in the placebo group. In contrast, there were 807 deaths due to cerebral infarction; the number of such deaths in the vitamin E–supplemented group decreased by 14%, for a total of 53 fewer deaths than in the placebo group. The overall net effects of vitamin E on the incidence of and mortality from total strokes were not significant.

A few reports other than the ATBC Study have suggested that bleeding complications may be associated with vitamin E supplementation. High intake of vitamin E can influence coagulation in some persons with drug-induced vitamin K deficiency, but most evidence suggests this effect does not occur in persons with adequate amounts of vitamin K, who represent well over half of the population (40–42). Moreover, a large trial of patients taking long-term warfarin who also took 800–1200 mg vitamin E/d showed no changes in coagulation variables that would suggest an increased risk of bleeding (43). A small clinical trial indicated that proteins induced by vitamin K absence–factor II, an accepted indicator of poor vitamin K status, increased with daily administration of 1000 IU RRR--tocopherol, but the clinical significance of this finding, if any, is not clear (44). Vitamin E may also affect coagulation through its actions on platelets. In addition, high vitamin E intakes inhibit protein kinase C and consequently limit the ability of platelets to clot (45). The platelet effects of vitamin E may produce health benefits.

Even the hemorrhagic-stroke mortality findings of the ATBC Study have not altered the prevailing consensus that vitamin E intake up to UL is safe, partly because that effect has not been seen in other trials using higher dosages and partly because the overall stroke risk was decreased. The Institute of Medicine report that delineated the DRI values for vitamins E and C stated that the "preliminary" ATBC Study findings were "not convincing" in the absence of corroboration in other large-scale clinical trials (12).

VITAMIN C: THE EVIDENCE FOR SAFETY  
The preponderance of scientific evidence, which has been thoroughly reviewed by several authors, shows consistently that vitamin C is safe at intakes of 2000 mg/d (1, 9, 46, 47). Several hypothesized adverse effects—including the hypotheses of adverse effects of increased oxalate and kidney stone formation, increased uric acid concentrations, excess iron absorption, reduced vitamin B-12 concentrations, systemic conditioning (induced scurvy), and prooxidant effects—were examined in detail and were found to have no substantive basis (12).

Although vitamin C supplementation may be less studied than vitamin E supplementation for the prevention for chronic disease, several clinical trials are relevant to its safety evaluation (Table 3). For example, in the Roche European American Cataract Trial (6), the Age-Related Eye Disease Study (34), and the simvastatin-niacin study of Brown et al (35), patients who received the vitamin cocktails also ingested vitamin C at doses of 750, 500, and 1000 mg/d, respectively. A combination of 800 IU vitamin E/d and 1000 mg vitamin C/d has been reported to attenuate the beneficial effects of a combined simivastatin-niacin treatment when measured as angiographic endpoints, but it had no significant effects on the treatment's clinical endpoints (6). The meaning of this observation with respect to the safety of vitamin E, vitamin C, or both in the presence or absence of simivastatin and niacin is not known.

View this table:
TABLE 3. Published safety observations for vitamin C supplementation¹

 
In the Medical Research Council and British Heart Foundation Heart Protection Study, 20 536 adults in the United Kingdom with IHD or other occlusive vascular disease or diabetes were randomly assigned to receive 250 mg vitamin C/d (along with vitamin E and ß-carotene) or placebo for 5 y (9). In this controlled trial with an unusually long follow-up, no clinically important safety issues arose.

Because vitamin C assists in the absorption of dietary iron, some research has focused on whether increased vitamin C intake inopportunely increases iron stores. The literature in general suggests that iron absorption does increase with rising vitamin C intake, especially at vitamin C intakes of 25 to 50 mg/d. Above that intake, vitamin C has little effect on iron uptake. Most published studies on the subject strongly indicate that vitamin C supplement doses up to 2000 mg/d do not increase body iron stores enough to produce any clinically significant adverse effects (9, 76). Cook et al (77) studied iron absorption in 17 healthy volunteers who received vitamin C at 2000 mg/d at meals for 16 wk; 9 subjects continued taking it for a total of 24 mo. Iron stores and effects were not enhanced by 2000 mg vitamin C/d, and subjects reported no instances of gastrointestinal upset or any other significant side effect.

Other evidence contradicts the few reports of adverse effects other than mild osmotic diarrhea associated with vitamin C supplementation, and collectively the other hypothesized adverse effects are of undetermined relevance (30, 78–80). Intakes of vitamin C well in excess of 2000 mg/d have sometimes been associated with gastrointestinal upset or skin rashes, but other evidence suggests that intakes up to 4000 mg/d are well tolerated in the general population.

Some case reports suggest that unusually high intakes of vitamin C, especially in persons who are given the vitamin intravenously or who have chronic renal failure, may be associated with the development of oxalate kidney stones (81). However, it is uncertain whether this risk occurs in the general population (78). An epidemiologic study found that the risk of kidney stones is significantly lower in men who consume 1500 mg vitamin C/d than in those who consume <250 mg vitamin C/d (82). Much evidence indicates that the "finding" of increased oxalate excretion in persons with high intakes of vitamin C actually is an analytic artifact resulting from a method that converts vitamin C in the test sample to oxalate during the analysis of the urine (83). Hoffer (84) commented, "[T]he idea that ingestion of ascorbic acid in large doses causes kidney stones has become established... by constant repetition this idea, based entirely on conjecture, has become enshrined as fact." Fortunately, the authoritative opinion of the FNB (12) has begun to replace the widely accepted misconception that vitamin C causes kidney stones. One study of young adults found an increase in oxalate excretion that remained in the normal range (48). No clinical significance of this observation has been established.

Increased uric acid concentrations have been observed in a few studies (12, 48, 49), but no increases were found in other studies that measured the plasma or urinary concentrations (or both) of uric acid (85–87). The health effects of the moderate increase in uric acid observed in a few studies but not in others are unknown (88) and are not an appropriate basis for a safety evaluation through risk assessment (12).

With respect to the new reference intakes for vitamin C, Frei and Traber (89) commented, "[T]here currently no consistent and compelling data for serious adverse health effects of vitamin C in humans, and a UL, therefore, cannot be established." Nonetheless, the Institute of Medicine considered the mild and transient diarrhea that can result from high intakes of vitamin C to fit the definition of a "hazard" under the protocol of the UL method, and it used related data to set a UL of 2000 mg/d.

An epidemiologic analysis of vitamin C intake found a correlation with increased risk of CVD mortality in postmenopausal women with diabetes (90). Vitamin C intake, including that from supplements, was unrelated to mortality due to CVD in subjects who were nondiabetic at baseline, and therefore the main findings apparently have no implications for healthy adults.

COMBINATIONS OF VITAMINS E AND C: THE EVIDENCE FOR SAFETY  
Several large or long-term clinical trials have employed combinations of vitamins E and C, sometimes with additional agents, as already discussed. For example, the combination of vitamins E and C used in the Antioxidant Supplementation in Atherosclerosis Prevention Study, the Roche European American Cataract Trial, the Age-Related Eye Disease Study, and the Medical Research Centre/British Heart Foundation trials, as well as the simvastatin-niacin study of Brown et al were already described for their antioxidant treatments (6, 34, 35, 38, 91). These studies support the safety of vitamin E and C in combination.

The data from the Women's Angiographic Vitamin and Estrogen Trial of 423 postmenopausal women treated with a combination of vitamins C and E, hormone replacement therapy, or both were interpreted by the authors as showing potential adverse effects from the combined supplement of 400 IU vitamin E and 500 mg vitamin C given twice daily (for totals of 800 IU and 1000 mg, respectively; 92). The design and execution of this trial, however, prevent any such conclusion; the trial focused on clinical endpoints that were beyond the statistical power of the study to detect. The methods exaggerated the potential adverse effects by assigning worst-case values to angiographic values when the values could not be obtained, and it did not correct for multiple comparisons, thereby biasing the results against the safety of the vitamins (93). Therefore, the Women's Angiographic Vitamin and Estrogen Trial does not contradict the conclusion that vitamins E and C, or their combination, are safe at these or higher intakes.

A recent meta-analysis concluded that there is no evidence that antioxidant supplements prevent gastrointestinal cancers but, instead, seem to increase overall mortality (94). The purpose of a meta-analysis is to apply statistical procedures that integrate the results of several independent studies considered to be "combinable," thereby increasing the statistical power (95). Thus, the clinical trials of selenium should not be combined with those of ß-carotene and vitamin E. Selenium trials have shown significant reductions in several, but not all, types of cancer. Two of the trials that included ß-carotene found significant increases in mortality that were linked to increases in lung cancer risk in populations of long-term heavy smokers, asbestos workers, or both. These 2 trials almost exclusively biased the meta-analysis toward unfavorable results, but only when the fixed-effects model rather than the more appropriate random-effects meta-analysis was applied. In contrast to the restricted fixed-effects analysis, the most highly aggregated meta-analysis showed a nonsignificant protective effect (relative risk: 0.96) when all trials, all treatments, and all types of cancer observed were considered.

MAXIMUM SAFE INTAKES OF VITAMINS E AND C  
The UL is defined by the FNB (96) as the highest daily nutrient intake that is likely to pose no risk of adverse health effects to almost all persons in the general population. The UL method is an adaptation of a general method in quantitative toxicology. It is similar to but has important differences from the acceptable daily intake method that is widely used to set regulatory limits for food additives and pesticide residues in foods. Both the UL and the acceptable daily intake involve identification of an intake that is a no-adverse-effect level (NOAEL) or a lowest-adverse-effect level (LOAEL), evaluation of uncertainty, and calculation of an intake that is expected to carry no significant risk of adverse effects, ie, the UL or acceptable daily intake. The UL and acceptable daily intake methods differ markedly in the way they address uncertainty. The UL method uses uncertainty factors (UFs) that are fully derived from the specific database for each substance under consideration. For derivation of a UL from human data, the FNB has utilized UFs that range from 1 to 5, with values of 1.5 to 2 being most common. When deriving the UL from animal data, higher uncertainty factors are used to account for the uncertainties in extrapolation between species.

The NOAEL (or LOAEL) data are selected on the basis of considerations of evidence of causality, relevance, and the quality and completeness of the database. The UL is calculated as

CONCLUSIONS  
Vitamin E and C dietary supplements are used widely in the United States and other industrialized countries. The fact that adverse effects are rarely reported for vitamins E and C at amounts higher than the RDA is testimony to the safety of such dietary supplementation up to the UL. Several literature reviews have concluded, on the basis of a survey of published evidence, that such intake does not cause adverse side effects or create other safety issues. The definitive FNB report on recommended RDA and UL values states that the upper limits were designed "to protect the most sensitive individuals in the general population." The UL is not intended to apply to the most sensitive persons in sensitive subpopulations, such as those with phenylketonuria or Wilson's disease but, instead, to apply to the healthy general population, including its normal range of variation. The recommendations are entirely based on the available scientific evidence; the main caveat is that healthy persons should not "routinely" take the vitamins in amounts higher than the UL. Beyond that, the recommendations support the consensus of published studies that vitamin E doses up to 1000 mg/d and vitamin C doses up to 2000 mg/d are safe for use by the general population. Many clinical trials show the safety of combinations of vitamins E and C at the amounts identified for their independent UL values.

ACKNOWLEDGMENTS  
JNH had the major responsibility for writing the manuscript; AD, AA, JB, TB, BF, IJ, CSJ, FJK, KK, LP, SP, HS, and MGT contributed to the writing and revision of the manuscript; and AD, AA, JB, TB, BF, IJ, CSJ, FJK, LP, and MGT contributed to the literature search and review. JNH and AD are employed by a vitamin and dietary supplement trade association; KK is employed by a manufacturer of bulk vitamin ingredients. None of the other authors had any personal or financial conflicts of interest.

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