More evidence that antioxidant “dangers” are exaggerated (especially beta-carotene)

More evidence that antioxidant “dangers” are exaggerated (especially beta-carotene) By Neil E. Levin, CCN, DANLA In a study published in 2006, cancer researchers tested daily supplementation of 400 IU of vitamins E as alpha-tocopherol along with 50,000 IU (39 mg) of beta-carotene on 540 head and neck cancer patients for three years after treatment with radiation therapies. Due to safety concerns in previous trials (which I have repeatedly criticized in previous writings, for various reasons), the beta-carotene component was discontinued during the trial. During a median 6 ½ years of follow up, 179 of the patients died. The researchers concluded that high-dose vitamin E supplementation could be harmful to cancer patients, with a 38% increased risk for death. 1 This study has been associated with the hyperbolic warnings against antioxidant use for cancer patients. The same group of researchers published a 2007 study looking at the same group of 540 cancer patients treated by radiation to see if the antioxidant vitamins reduced the toxicity of the treatments. This report investigated the dietary intake, supplementation and plasma levels of beta carotene in the patients to look for correlations in outcomes, specifically acute adverse effects of the radiation therapy and cancer recurrence. A higher beta carotene dietary intake was associated with 39% fewer severe acute adverse effects, and higher plasma levels with 27% fewer severe adverse effects, from the radiation treatments. The researchers reported that, “This study suggests that a higher usual dietary beta carotene intake can reduce the occurrence of severe adverse effects of radiation therapy and decrease local cancer recurrence.” 2 This conclusion is at odds with fears of beta-carotene toxicity that have been massively publicized over the past 14 years. Now, in 2008, we have heard again from this same group of researchers continuing to review the data from the same group of patients. It turns out that the large increase in mortality in the patient group given antioxidants - reported in the 2006 study – was basically limited to those patients who smoked during their radiation treatments. In fact, there was no significant mortality increase in patients who only smoked before or after the course of radiation treatment, or for non-smokers. 3 This new information tells us that the general cautions about antioxidants should be limited to certain narrow conditions or situations, such as active smokers during therapy. This is good information, since we know that 40% of cancer patients actually die of malnutrition; that plasma levels of antioxidants are a far better measure of antioxidant status than supplement intake prescriptions or dietary recall surveys; and that antioxidants are synergistic with inter-related functions and should not be given separately. Now we also can point to numerous benefits of antioxidants in clinical studies that have been far overshadowed by the over-hyped negative conclusions of a relative few prominent-but-flawed studies reported by prestigious institutions, sometimes with NIH funding. I agree with those critics who insist that it should be considered scientifically inappropriate to use the drug model for nutrient research, because the nutrients already exist in the diet and in the body and are clearly impacted by other nutrients; as well as other variables, some of which are quite well known. By contrast, in a drug study a new, foreign chemical is being tested which should not already be present in the diet or the body, making toxicity a bigger issue while eliminating many of the variables that are inappropriately ignored in sensational-but-flawed nutrient studies that get so much media attention and so many undeserved citations in scientific journals. I have previously written about the use of antioxidants for cancer patients, as have others, with the common conclusion that most such warnings are overblown and that much of the published science has been favorable regarding those combinations of factors. REFERENCES

• Bairati I, Meyer F, Jobin E, Gélinas M, Fortin A, Nabid A, Brochet F, Têtu B. Antioxidant vitamins supplementation and mortality: a randomized trial in head and neck cancer patients. Int J Cancer. 2006 Nov 1;119(9):2221-4. PMID: 16841333
• Meyer F, Bairati I, Jobin E, Gélinas M, Fortin A, Nabid A, Têtu B. Acute adverse effects of radiation therapy and local recurrence in relation to dietary and plasma beta carotene and alpha tocopherol in head and neck cancer patients. Nutr Cancer. 2007;59(1):29-35. PMID: 17927499
• Meyer F, Bairati I, Fortin A, Gélinas M, Nabid A, Brochet F, Têtu B. Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. 2008 Apr 1;122(7):1679-83. PMID: 18059031

Beta-carotene risks over-stated

Beta-carotene risks over-stated By Neil E. Levin, CCN, DANLA A recent journal article pointed out the widely-reported danger of smokers using beta-carotene, a natural source (provitamin) of vitamin A, as part of their multivitamins. 1 In this meta-analysis the researchers have neglected to consider pre-existing dietary and serum levels of this nutrient, making their claim to control by placebo inadequate to properly isolate this variable. In fact, this failure to determine the effects of beta-carotene at a dose-dependent plasma level – and by neglecting to measure total beta-carotene intake along with the relevant synergistic antioxidants associated with it, as opposed to simply measuring supplemental intake - raises serious questions about the validity of these results. 2 There is also legitimate scientific debate over the use of trans versus cis forms of this provitamin that may affect the way it is used in vivo that dispute whether all forms are equal, which most studies simply do not address (including this meta-analysis). 3 Regarding beta-carotene safety little has been satisfactorily resolved, and the negative studies have been vigorously disputed for these and other reasons. For example, researchers have previously noted in the Journal of the National Cancer Institute that beta-carotene has been shown to not affect the risk of oxidative DNA damage in male smokers, despite its reputation as an antioxidant. But neither did the provitamin A prove to cause oxidative DNA damage. 4 It has become apparent to numerous observers that simply measuring supplementation of beta-carotene is not a good predictor of serum levels or of risk, and that a low level of total antioxidant intake may be a more valid marker in this regard. In fact, the dietary level of several antioxidants has been shown to be an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A recent study reports, “This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.” 2 As the authors (Tanvetyanon, et al) of this current analysis have themselves noted, the Physicians Health Study compared the effects of taking 50 mg of supplemental beta-carotene (over 83,000 IU) every other day to a placebo in 22,071 US male physicians aged 40-84 and found no adverse health effects over a 12-year study period. 5 Likewise, the Women’s Health Study of 39,876 health professionals found no significant difference on lung cancer rates when looking at the effects of 50 mg of beta-carotene administered on alternate days over 2+ years plus a 4 year follow up period, using forms and dosing similar to the Physician’s Health Study to achieve very high serum levels of beta-carotene. 6 In a third study used in the current meta-analysis, The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (ATBC), an antioxidant study in Finland was halted early because of a widely reported small increase in cancer rates among male smokers taking beta-carotene that were only possibly linked to that nutrient. 7 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. This study continues to be widely cited and believed, despite the researchers’ own statements that the results were most likely due to chance. A later analysis published in July 2004 took another look at that same Finnish smokers study’s data, but now taking into account total antioxidant intake, which should have cleared away some of the scientific controversy over beta-carotene. The smokers’ risk of getting lung cancer was inversely associated with total antioxidants in the diet, with more total antioxidants resulting in fewer cancers. 8 In this study a composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: a combination of antioxidants lowered lung cancer risk in male smokers. Properly reviewed, beta-carotene was not the culprit; low antioxidant status was the more relevant factor affecting cancer rates, and supplementation with a single antioxidant supplement simply failed to create enough improvement to avert deaths related to oxidative factors. Perhaps the supplementation with beta-carotene was simply a case of “too little, too late”, rather than a root cause of a slightly higher lung cancer rate in those smokers. It is notable that Tanvetyanon et al included the ATBC study but failed to even reference the later Wright et al study that largely refuted the alleged harms of beta-carotene shown in ATBC, which were shown to be more likely due to low levels of total antioxidant intake than to excessive beta-carotene intake. This later review of ATBC should be a cautionary tale concerning the lack of proper controls in nutrient studies, especially as compounded by the use of meta-analysis, and should have alerted the current authors to that all-too-common mistake in nutrient study design. Indeed, another large study has noted that high carotenoid intake, confirmed by measures of plasma, was associated with lower mortality rates among the elderly over a ten year period. 9 This model measured results of consuming both supplements and foods, not solely supplement input, and when combined with plasma levels should therefore be regarded as a far more robust type of science for measuring vitamin effects than a meta-analysis of simply supplementation. As in the long-term Physicians Health Study, there was no observable risk of lung cancer noted in this report. The fourth study used in the current meta-analysis used very high doses of both beta-carotene (30 mg, equal to 50,000 IU) plus 25,000 IU of pre-formed vitamin A. 10 These amounts are extremely high; the Upper Limit for vitamin A is 10,000 IU, though there is none for beta-carotene because of its historic safety record. The amount of beta-carotene used in the eye vitamins were high only because the authors selected solely formulas designed for eye health that typically provide more beta-carotene than ordinary multivitamins. This distinction is not clear in their calling such formulas “multivitamins”, because that name is typically given to full-spectrum formulas containing a full range of the essential vitamins with minerals, not system-specific formulas like those sold for eye health. Such formulas have proved to be beneficial in maintaining eye health and the combination of antioxidants have been stronger antioxidants than beta-carotene, which is potentially a pro-oxidant at times and could thus be used more safely – and effectively - in combination with other antioxidants. 11 Most importantly, the authors have not shown why they assume that “multivitamin” use would be associated with the supposed risks of beta-carotene used singly, even if those risks for the solo provitamin are assumed to be true. Nor have they adequately demonstrated the alleged dangers of taking eye formula supplements, or even the danger of lung cancer rates increasing in those taking mixtures of beta-carotene combined with other antioxidant nutrients. In the case of multivitamins most studies have shown overwhelmingly positive effects, such as one report evidencing reduced infections in nursing homes with vitamins over placebo (73% vs. 43%; P < 0.001). Intervention was with a multivitamin containing beta-carotene. Infection-related absenteeism was higher in the placebo group than in the treatment group (57% vs. 21%; P < 0.001). Perhaps most importantly, 93% of participants with diabetes mellitus reported an infection versus only 17% of those receiving supplements (P < 0.001). 12 These huge reductions in potentially serious infections among our elderly citizens should be measured against the relatively slight and mostly theoretical risk of increased lung cancer rates associated with beta-carotene supplementation. A study reported in the Journal of the National Cancer Institute looked at death rates in a population given multivitamins or other nutrients. 13 After supplements were given for 5.25 years in the general population trial of 30,000 people, significant reductions in total [relative risk (RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium combined. The same researchers reported on a subgroup of 3,318 persons with esophageal Dysplasia (a precursor to esophageal cancer) that was given either a multiple vitamin-and-mineral supplement or a placebo for 6 years. In this portion of the trial, small reductions in total (RR 0.93) and cancer (RR = 0.96) mortality were observed but were not significant. In any case, no increase in cancer rates was noted in the group taking multivitamins; there was actually a possible small benefit in terms of reducing this risk. The participants getting the multivitamin took a daily beta-carotene capsule along with two multivitamin tablets. This was a group of subjects at high risk of getting throat cancer. 14-15 It is a leap of faith to assume that a single nutrient would have identical effects to a combination of nutrients without substantial supporting evidence, which is still lacking; confounded by conflicting evidence and multiplying variables in meta-analyses. Since nutrients are both synergistic and present in the diet, it is important to factor those known variables into a proper study design. All too often, researchers do not consider this fundamental difference between drug and nutrient research and unwittingly introduce extra variables that undermine their conclusions. 16 This current meta-analysis of 4 studies - only one of which unquestionably shows a slight increase in lung cancer risk but does not actually measure isolated beta-carotene risk; two others are well-designed and robust studies looking at serum levels of those taking a high dose of beta-carotene but show no increased risk in lung cancer rates, and the fourth has been largely shown to be moot by a later and more complete re-analysis of the data - does not support the hypothesis that beta-carotene increases rates of lung cancer and that multivitamins are therefore dangerous. Thus, there is no sound basis in the current review for suggesting that warning labels may be needed for multivitamins or eye health supplements containing beta-carotene along with other nutrients that have been shown in well-designed studies to help protect the eyesight – and independence - of our aging population. REFERENCES: Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008 Jul 1;113(1):150-7. PMID: 18429004 Valtueña S, et al. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. Eur J Clin Nutr. 2007 Jan;61(1):69-76. Epub 2006 Jul 12. PMID: 16835597 [Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.] Andreas Schieber, Reinhold Carle. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends in Food Science & Technology, Volume 16, Issue 9, September 2005, Pages 416-422 van Poppel G, Poulsen H, Loft S, Verhagen H. No influence of beta carotene on oxidative DNA damage in male smokers. J Natl Cancer Inst. 1995 Feb 15;87(4):310-1. PMID: 7707423 Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-9. PMID: 8602179 Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999 Dec 15;91(24):2102-6. PMID: 10601381 The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35. PMID: 8127329 Wright ME, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004 Jul 1;160(1):68-76. PMID: 15229119 Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr. 2005 Oct;82(4):879-86. PMID: 16210720 Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99. Review. PMID: 12950886 Liu BA, et al. Effect of multivitamin and mineral supplementation on episodes of infection in nursing home residents: a randomized, placebo-controlled study. J Am Geriatr Soc. 2007 Jan;55(1):35-42. Erratum in: J Am Geriatr Soc. 2007 Mar;55(3):478. PMID: 17233683 Blot WI, Li IY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993:8ı:1483-92 Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993 Sep 15;85(18):1492-8. PMID: 8360932 Blot WI, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1424S-1426S. PMID: 7495242

Science Sins and Media Mistakes

Science Sins and Media Mistakes What You Should Know About Dietary Supplement News Reporting By Neil E. Levin, CCN, DANLA Are male smokers taking beta-carotene really at increased risk of cancer? Are high dosages of Vitamin E really hazardous to your health? Is ephedra, an herb with demonstrated weight loss benefits, really a “killer” that merits its banned status by the U.S. Food and Drug Administration? Natural health remedies have a long history of promoting health and wellness, dating back thousands of years. But sloppy science and sensationalist health reporting by the news media make this increasingly hard to believe. And misleading and contradictory information about the safety of nutritional supplements may cause consumers to make poor health choices – or to avoid making any choices at all. The result: Many miss out on the myriad health benefits supplementation can bring about. Understanding the common sins of commission and omission on the part of science and the press arms the public with the ability to make better decisions – if not to apply a liberal grain of sea salt to what they’re reading and seeing. Beta Carotene: Myth vs. Fact There have been several instances where the reputation of a dietary supplement or herb has been tarnished due to poor science combined with the media’s inertia. The association of cancer risk with the use of the anti-oxidant beta-carotene is a prime example. In 1994, an antioxidant study being conducted in Finland was halted as a result of a report noting an increase in cancer rates among male smokers taking beta-carotene. Headlines roared: Beta-carotene connected with cancer risk. Doctors told patients to avoid this nutrient and sales dropped. Yet ten years later, the data was re-analyzed, this time taking into the account the smoker’s total antioxidant intake – not just beta-carotene. The results were clear: a combination of antioxidants – including beta-carotene – actually lowered lung cancer risk in male smokers. Supplementing beta-carotene to people with low antioxidant status was simply a matter of too little, too late. The antioxidant itself was not to blame; the lack of other antioxidants was. Science Sin: Poor science did not originally eliminate additional dietary antioxidants as variables or look at how antioxidants interact and support each other. Adding one antioxidant does not make up for the lack of others. Nutrients are not drugs, and supplementing a single nutrient is actually a model of a drug study, not a nutrient study. Media Mistake: Failing to fact check. In the original report, the researchers stated that the slightly increased risk was possibly due to chance and that there was no known mechanism as to how this could happen. Yet the news media and others, including a National Institute of Health (NIH) scientific panel, stubbornly continue to refer to beta-carotene as potentially harmful even though credible scientists actually revised those findings years ago and high blood levels of beta-carotene are shown to be consistently protective to populations at risk for cancer. Sloppy Science and Vitamin E One of the strongest examples of sloppy science is the controversy over Vitamin E. In 2004, warnings were issued by authors of a study published in Annals of Internal Medicine about taking 400 IU or more of Vitamin E per day. This warning was based on a “meta-analysis” report that was generated by statisticians who mathematically integrated the results collected from 19 individual studies, selected partly on the basis of at least ten deaths occurring - from any cause - in the course of each study. Sales of this essential vitamin dropped dramatically. This was a major national news event. But when leading antioxidant researchers re-reviewed the same individual datasets more carefully for the American Journal of Clinical Nutrition, they found that daily doses of Vitamin E up to 2,000 IU were actually safe in the same study populations. It seems that the Annals report did not properly segregate doses and forms, such as taking into account other supplements taken. Nor did it find a dose-dependent relationship between vitamin E and death risk, which is a normal toxicological rationale for determining risk. Apparently, it was simply sloppy work that was not able to be replicated using more accurate statistical models that properly accounted for more variables. Similarly, the Institute of Medicine sets the safe upper level of Vitamin E at 1,500 IU per day. And a recent SENECA study of 90,000 nurses showed a 30% to 40% lower incidence of heart disease among those who take in the highest amounts of Vitamin E from diet and supplements, indicating that the Annals report may have scared a lot of people from taking a life-saving essential vitamin. Science Sin: Mistaking unverified statistics for proven science. The straight mathematical integration of data from different selected scientific studies – and the interpretation of the results – were left largely to statisticians whose methods were heavily criticized in comments by other researchers published by the same journal. Consequently, apples were compared to oranges and the reputation of Vitamin E among consumers continues to feel the squeeze. The researchers have never adequately addressed the criticism or the reanalysis that produced vastly different results. Media Mistake: Making a mountain out of a molehill. The outcome of the original study was interpreted by the press to be more meaningful than it really was, as if one study negated all others, and no follow-up was done to report the reanalysis or to mention the myriad of studies showing the proven protective effects of vitamin E. To this day, journalists continue to cite the flawed report – even though Vitamin E has been proven safe and beneficial. Ephedra’s Bad Rap But it’s Ephedra – an herb most commonly used to assist with gentle weight loss and easing breathing difficulties – that will go down in history as the most pilloried dietary supplement ever. The FDA banned Ephedra in 2004 based on a series of unproven Adverse Event Reports (AERs.) AERs are by definition preliminary, unscreened and unverified reports of possible associations of a substance with a side effect. In banning Ephedra, the FDA said that evidence proving that the product has caused actual harm to someone is not required; all that is required is scientific evidence that supports the existence of some theoretical risk. Ironically, after closer examination of the claims, the FDA eliminated virtually all of the Ephedra AERs from consideration. It also admitted that a total ban on the herb would possibly prevent only one estimated death per year out of 3 billion doses taken by 20 million consumers. In comparison, about 100 out of 11 million people with true food allergies die each year. Yet tree nuts, fish and dairy (the most common food allergens) are still legal. Science Sin: Considering AERs to behard evidence. AERs are unverified and thus cannot be considered scientific evidence as proof of toxicity. Government and medical authorities falsely and cynically assumed that most dietary supplement AERs are true, while drugs that have received far more numerous AERs outlining severe side effects (including death) continue to be widely prescribed. More than 100 years of scientific studies were arbitrarily ignored by the FDA in ruling that ephedra had no benefits and no safe level of use; and the agency likewise ignored its own scientific panels that found no smoking gun. Supplements containing large doses of caffeine and other stimulants were lumped in as “ephedra-related” AERs because they also happened to contain ephedra; or more likely, synthetic ephedra alkaloids. Ironically, ephedrine alkaloids are still universally available as OTC drugs for allergies in doses considered too dangerous to sell in a dietary supplement label. However, they are usually sold behind the counter at pharmacies because of the risk of people making crystal meth from these drugs. Ironically, the ephedra herb is too dilute to economically make meth from. I assume that ephedra was axed as an innocent bystander in the drug war to avoid it competing with products which had to be locked up behind the counter. The coincidental timing of the supplement ban and access to the competing drug is very suspicious. Media Mistake: Not getting the whole story; scaring people unnecessarily. Journalists did not bother to research the whole story when it when it came to reporting on this controversial herb. The media made the all-too common assumption that press releases issued by researchers or governmental offices are true. With a little digging, the “real” story might have been reported. But the media was largely content to focus on the sensational “killer herb” rather than to investigate the facts and find out the truth. When controversy arises around dietary supplement or herb, an unproven AER is often at its root. AERs are intended to be an early warning system to allow experts to try to look for and hopefully isolate a dose-related cause and effect. But most, if not all, AERs involving dietary supplements actually involve a combination of substances and issues that include the supplement as well as prescription drugs or other substances along with pre-existing conditions. And many “adverse effects” attributed to supplements are known side effects of prescription drugs. It’s dubious that either science or the media will admit fault or repent. But with a little effort, consumers can get the most accurate and up-to-date information to ensure they can make informed and beneficial decisions when it comes to their most important asset: our families’ health.

Beta-carotene risks still unproven!

A recent journal article pointed out the widely-reported danger of smokers using beta-carotene, a natural source (provitamin) of vitamin A, as part of their multivitamins. 1 In this meta-analysis (as in common in such analyses) the researchers have neglected to consider pre-existing dietary and serum levels of this nutrient, making their claim to control by placebo inadequate to properly isolate this variable. In fact, this failure to determine the effects of beta-carotene at a dose-dependent plasma level – and by neglecting to measure total beta-carotene intake along with the relevant synergistic antioxidants associated with it, as opposed to simply measuring supplemental intake - raises serious questions about the validity of these results. 2 There is also legitimate scientific debate over the use of trans versus cis forms of this provitamin that may affect the way it is used by our bodies in vivo that dispute whether all forms are equal, which most studies simply do not address (including this meta-analysis). 3 Regarding beta-carotene safety little has been satisfactorily resolved, and the negative studies have been vigorously disputed for these and other reasons. For example, researchers have previously noted in the Journal of the National Cancer Institute that beta-carotene has been shown to not affect the risk of oxidative DNA damage in male smokers, despite its reputation as an antioxidant. But neither did the provitamin A prove to cause oxidative DNA damage. 4 It has become apparent to numerous observers that simply measuring supplementation of beta-carotene is not a good predictor of serum levels or of risk, and that a low level of total antioxidant intake may be a more valid marker in this regard. In fact, the dietary level of several antioxidants has been shown to be an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A recent study reports, "This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk." 2 As the authors (Tanvetyanon, et al) of this current analysis have themselves noted, the Physicians Health Study compared the effects of taking 50 mg of supplemental beta-carotene (over 83,000 IU) every other day to a placebo in 22,071 US male physicians aged 40-84 and found no adverse health effects over a 12-year study period. 5 Likewise, the Women’s Health Study of 39,876 health professionals found no significant difference on lung cancer rates when looking at the effects of 50 mg of beta-carotene administered on alternate days over 2+ years plus a 4-year follow up period, using forms and dosing similar to the Physician’s Health Study to achieve very high serum levels of beta-carotene. 6 In a third study used in the current meta-analysis, The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group (ATBC), an antioxidant study in Finland was halted early because of a widely reported small increase in cancer rates among male smokers taking beta-carotene that were only possibly linked to that nutrient. 7 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. This study continues to be widely cited and believed, despite the researchers’ own statements that the results were most likely due to chance. A later analysis published in July 2004 took another look at that same Finnish smokers study’s data, but now taking into account total antioxidant intake, which should have cleared away some of the scientific controversy over beta-carotene safety. The smokers’ risk of getting lung cancer was inversely associated with total antioxidants in the diet, with more total antioxidants resulting in fewer cancers. 8 In this study a composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: a combination of antioxidants lowered lung cancer risk in male smokers. Properly reviewed, beta-carotene was not the culprit; low antioxidant status was the more relevant factor affecting cancer rates, and supplementation with a single antioxidant supplement simply failed to create enough improvement to avert deaths related to oxidative factors. Perhaps the supplementation with beta-carotene was simply a case of "too little, too late", rather than a root cause of a slightly higher lung cancer rate in those smokers. It is notable that Tanvetyanon et al included the ATBC study but failed to even reference the later Wright et al study that largely refuted the alleged harms of beta-carotene shown in ATBC, which were shown to be more likely due to low levels of total antioxidant intake than to excessive beta-carotene intake. This later review of ATBC should be a cautionary tale concerning the lack of proper controls in nutrient studies, especially as compounded by the use of meta-analysis, and should have alerted the current authors to that all-too-common mistake in nutrient study design. Indeed, another large study has noted that high carotenoid intake, confirmed by measures of plasma, was associated with lower mortality rates among the elderly over a ten year period. 9 This model measured results of consuming both supplements and foods, not solely supplement input, and when combined with plasma levels should therefore be regarded as a far more robust type of science for measuring vitamin effects than a meta-analysis of simply supplementation. As in the long-term Physicians Health Study, there was no observable risk of lung cancer noted in this report. The fourth study used in the current meta-analysis used very high doses of both beta-carotene (30 mg, equal to 50,000 IU) plus 25,000 IU of pre-formed vitamin A. 10 These amounts are extremely high; the Upper Limit for vitamin A is 10,000 IU, though there is no official Upper Limit for beta-carotene because of its historic safety record. The amounts of beta-carotene used in the eye vitamins were high only because the authors selected solely formulas designed for eye health that typically provide more beta-carotene than ordinary multivitamins. This distinction is not clear in their calling such formulas "multivitamins", because that name is typically given to full-spectrum formulas containing a full range of the essential vitamins with minerals, not system-specific formulas like those sold for eye health. Such formulas have proved to be beneficial in maintaining eye health and the combination of antioxidants have been stronger antioxidants than beta-carotene, which is potentially a pro-oxidant at times and could thus be used more safely – and effectively - in combination with other antioxidants. 11 That being said, eye formulas with more milligrams of lutein than beta-carotene are probably better formulated than ones with very high beta-carotene because of their competition for absorption. Most importantly, the authors have not shown why they assume that "multivitamin" use would be associated with the supposed risks of beta-carotene used singly, even if those risks for the solo provitamin are assumed to be true. Nor have they adequately demonstrated the alleged dangers of taking eye formula supplements, or even the danger of lung cancer rates increasing in those taking mixtures of beta-carotene combined with other antioxidant nutrients. In the case of multivitamins most studies have shown overwhelmingly positive effects, such as one report evidencing reduced infections in nursing homes with vitamins over placebo (73% vs. 43%). Intervention was with a multivitamin containing beta-carotene. Infection-related absenteeism was higher in the placebo group than in the treatment group (57% vs. 21%). Perhaps most importantly, 93% of participants with diabetes mellitus reported an infection versus only 17% of those receiving supplements. 12 These huge reductions in potentially serious infections among our elderly citizens should be measured against the relatively slight and mostly theoretical risk of increased lung cancer rates associated with beta-carotene supplementation. A study reported in the Journal of the National Cancer Institute looked at death rates in a population given multivitamins or other nutrients. 13 After supplements were given for 5.25 years in the general population trial of 30,000 people, significant reductions in total [relative risk (RR) = 0.91] and cancer (RR = 0.87) mortality were observed in subjects receiving beta-carotene, alpha-tocopherol, and selenium combined. The same researchers reported on a subgroup of 3,318 persons with esophageal Dysplasia (a precursor to esophageal cancer) that was given either a multiple vitamin-and-mineral supplement or a placebo for 6 years. In this portion of the trial, small reductions in total (RR 0.93) and cancer (RR = 0.96) mortality were observed but were not significant. In any case, no increase in cancer rates was noted in the group taking multivitamins; there was actually a possible small benefit in terms of reducing this risk. The participants getting the multivitamin took a daily beta-carotene capsule along with two multivitamin tablets. This was a group of subjects at high risk of getting throat cancer. 14-15 It is a leap of faith to assume that a single nutrient would have identical effects to a combination of nutrients without substantial supporting evidence, which is still lacking; confounded by conflicting evidence and multiplying variables in meta-analyses. Since nutrients are both synergistic and present in the diet, it is important to factor those known variables into a proper study design. All too often, researchers do not consider this fundamental difference between drug and nutrient research and unwittingly introduce extra variables that undermine their conclusions. 16

This current meta-analysis of 4 studies - only one of which unquestionably shows a slight increase in lung cancer risk but does not actually measure isolated beta-carotene risk; two others are well-designed and robust studies looking at serum levels of those taking a high dose of beta-carotene but show no increased risk in lung cancer rates, and the fourth has been largely shown to be moot by a later and more complete re-analysis of the data - does not support the hypothesis that beta-carotene increases rates of lung cancer and that multivitamins are therefore dangerous. Thus, there is no sound basis in the current review for suggesting that warning labels may be needed for multivitamins or eye health supplements containing beta-carotene along with other nutrients that have been shown in well-designed studies to help protect the eyesight – and independence - of our aging population. REFERENCES:

1. Tanvetyanon T, Bepler G. Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands. Cancer. 2008 Jul 1;113(1):150-7. PMID: 18429004
2. Valtueña S, et al. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. Eur J Clin Nutr. 2007 Jan;61(1):69-76. Epub 2006 Jul 12. PMID: 16835597 [Supported by the European Community IST-2001–33204 'Healthy Market', the Italian Ministry of University and Research COFIN 2001 and the National Research Council CU01.00923.CT26 research projects.]
3. Andreas Schieber, Reinhold Carle. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends in Food Science & Technology, Volume 16, Issue 9, September 2005, Pages 416-422
4. van Poppel G, Poulsen H, Loft S, Verhagen H. No influence of beta carotene on oxidative DNA damage in male smokers. J Natl Cancer Inst. 1995 Feb 15;87(4):310-1. PMID: 7707423
5. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996 May 2;334(18):1145-9. PMID: 8602179
6. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999 Dec 15;91(24):2102-6. PMID: 10601381
7. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35. PMID: 8127329
8. Wright ME, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004 Jul 1;160(1):68-76. PMID: 15229119
9. Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr. 2005 Oct;82(4):879-86. PMID: 16210720
10. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150–1155.
11. Bartlett H, Eperjesi F. Age-related macular degeneration and nutritional supplementation: a review of randomised controlled trials. Ophthalmic Physiol Opt. 2003 Sep;23(5):383-99. Review. PMID: 12950886
12. Liu BA, et al. Effect of multivitamin and mineral supplementation on episodes of infection in nursing home residents: a randomized, placebo-controlled study. J Am Geriatr Soc. 2007 Jan;55(1):35-42. Erratum in: J Am Geriatr Soc. 2007 Mar;55(3):478. PMID: 17233683
13. Blot WI, Li IY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993:8ı:1483-92
14. Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993 Sep 15;85(18):1492-8. PMID: 8360932
15. Blot WI, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1424S-1426S. PMID: 7495242
16. Levin, N. Land of Confusion: How Poor Science and Misleading Media Coverage Create Public Confusion About How Dietary Supplements Affect Health. J App Nutr, Vol 55, No. 1, 2005 8-15

Antioxidant Confusion

Antioxidant Confusion By Neil E. Levin, CCN, DANLA Board certified clinical nutritionist with diplomate in advanced nutritional laboratory assessment March 2, 2007 A meta-analysis published in the medical journal JAMA this week reported that antioxidant vitamins do not extend life and may even increase death rates slightly. 1 These conclusions make no sense, based on the scientific record. A meta-analysis relies on a statistical model of existing science, and this model has severe limitations. Even the authors admit some of the basic problems inherent in this type of analysis. More importantly, the authors could not find a dose-dependent or cause-and-effect relationship between antioxidants and deaths (from all causes) of study participants. In other words, they couldn’t show that antioxidants actually caused any deaths or that there was risk at a particular dosage. Yet this questionable speculation received widespread publicity from the sensation-hungry media during “Sweeps Month”, dutifully spreading the lie that antioxidants are now worthless and dangerous. The researchers pooled 68 previously published trials but arbitrarily excluded all published studies that had no deaths reported from any cause. Indeed, 405 otherwise eligible studies were excluded solely for this reason, which if included would likely have dramatically changed the results and conclusion. The researchers did not disclose why they decided to exclude these. This is equivalent to playing a card game after removing all but 7 cards from the deck. (That wouldn’t be a fair game, would it?) They largely ignored the original outcome measures of the studies, many of which had shown positive results for antioxidants, to look only for deaths from any cause in a tiny segment of all published research. This arbitrary decision echoes a frequently cited complaint by scientists commenting to the journal Annals of Internal Medicine when the infamous Miller meta-analysis of vitamin E was released a few years ago, which led to a dramatic slowdown of vitamin E sales. 2 It is interesting that the Miller study’s negative conclusions about vitamin E safety have since been thoroughly debunked by a more rigorous analysis published in the American Journal of Clinical Nutrition by leading antioxidant experts. 3 It is even more interesting that the flawed Miller review was cited as a reference by the JAMA authors but the second, more thorough analysis of the same data by real nutrition experts was not. The lesson learned is that a flawed meta-analysis of nutrients by statisticians and physicians may not hold up to a more competent review done by actual experts in the field of nutrient interactions, though the initial report may have scared people and changed their behavior. Critical comments and corrections typically go ignored, uncited and unreported, in contrast with the sensational initial report. 4 I question both the selection of studies reviewed and the references cited in this meta-analysis. Obviously, excluding six times as many potentially eligible studies as were actually chosen solely because of a requirement that someone in the study population had to die unfairly magnifies negative results by dramatically reducing the pool of studies with potentially positive results and healthier populations. This negative shift is a result of limiting the combined patient population to those studies with at least one dying patient. This population shifts to those individuals who are more likely to be deficient in a variety of antioxidant substances and who are unlikely to respond to limited amounts of one or few supplemental antioxidants. The lack of additional supporting antioxidants may even sometimes increase the oxidative stress on the body. A review of antioxidant science noted, “These negative results…should not be taken as evidence that the free radical theory of aging is flawed. In fact, they prove merely that a complex organism like a human or rodent is unlikely to respond predictably to crude manipulations such as supplementation with one or a small number of compounds.” 1, 5, 6 This mirrors the JAMA authors’ admissions that “antioxidant supplements may show interdependency and may have effects only if given in combination,” and that their findings “should not be translated to potential effects of fruits or vegetables,” which are sources of numerous and varied antioxidant substances. 1 Previous studies have shown the folly of such a protocol. Some years ago an antioxidant study in Finland was halted early because of a widely reported increase in cancer rates among male smokers taking beta-carotene. 7 Headlines associated this supplement with cancer risk. Despite objections that the study was flawed, beta-carotene use dropped. A later analysis published in July 2004 took another look at that same Finnish smokers' study data, but now taking into account total antioxidant intake, which (should have) cleared away the scientific controversy. 8 A composite antioxidant index was generated for each of the 27,000 men over 14 years. The calculated amounts of carotenoids, flavonoids, Vitamin E, selenium and Vitamin C were compared to actual lung cancer rates, with a clear result: an increased intake of a combination of antioxidants lowered lung cancer risk in male smokers. Another large study has noted that high carotenoid intake, as confirmed by measures of blood levels, was associated with lower mortality rates among the elderly over a ten year period. 9 The dietary level of antioxidants is an independent predictor of plasma beta-carotene, especially in moderate alcohol drinkers. A more recent study reports, “This may explain, at least in part, the inverse relationship observed between plasma beta-carotene and risk of chronic diseases associated to high levels of oxidative stress (i.e., diabetes and CVD), as well as the failure of beta-carotene supplements alone in reducing such risk.” 10 In other words, we shouldn’t expect one or two supplemented antioxidants to compensate for a deficiency of total antioxidants in the diet. In fact, many of the protocols for supplementation in the included studies may have actually been of too low potency to achieve noticeable health benefits by remedying latent nutrient deficiencies in fragile patient populations. In other words: many of the interventions were too little, too late. Don’t blame the vitamins. The JAMA report admits that the study populations, the variety of antioxidants used, their potencies and the protocols for taking them were extremely variable, complicating their data with many uncompensated variables. Yet the authors actually claim that, “This increases the trustworthiness of our findings.” I don’t think so! One trial included gave only a single serving of antioxidants and then monitored participants for 3 months. Others used doses of as little as 10 IU of vitamin E (a low amount that is below the Daily Value) and 20 mcg of selenium 1 (an amount far below the 70 mcg DV and not anywhere near the 200+ mcg/day associated with lower cancer rates). 11, 12 I am not alone in these criticisms. Alexander Schauss, PhD, FACN has written, “The range of doses in the different trials they selected for the meta-analysis is dramatic. For example, vitamin A ranged from 1333 IU to 200,000 IU, and vitamin E from 10 IU to 1000 IU. The duration of the studies range from 28 days to 12 years. Nevertheless they were all lumped together.” An Associated Press article quoted other experts criticizing this meta-analysis: ‘Meir Stampfer, professor of nutrition and epidemiology at the Harvard School of Public Health, said the new analysis hasn't discouraged him from taking his vitamins. Stampfer said the studies were too diverse to pool together because they looked at various combinations and doses of antioxidants tested in different groups of people. The trials ranged from a three-month study of 109 elderly nursing home residents to a 12-year study of 22,071 male doctors. "This study does not advance our understanding, and could easily lead to misinterpretation of the data," said Stampfer, who was not connected to the new report.’ The AP report also quoted Donald Berry, chairman of the department of biostatistics at the University of Texas’ M.D. Anderson Cancer Center, stating that this expert also disagreed with the researchers' finding of an increased risk of dying. "There are so many choices you can make when you're doing these analyses," he said. A study of approximately 90,000 nurses suggested that the incidence of heart disease was 30% to 40% lower among nurses with the highest intake of vitamin E from diet and supplements. Researchers found that the apparent benefit was mainly associated with intake of vitamin E from dietary supplements. High vitamin E intake from food was not associated with significant cardiac risk reduction. 13 Levels of Vitamin E above 100 IU daily are associated with decreased risk of coronary heart disease and certain types of cancer, as well as enhancement of immune function. These increased vitamin E intakes are considerably above levels obtainable from diet alone. 14, 15, 16 In a report on the Women’s Health Study published in JAMA, subjects supplementing with vitamin E were reported to have a significant 24% reduction in cardiovascular deaths. 17 Have these previously published benefits of antioxidants miraculously vanished simply because some doctors manipulated a statistical model to elicit unreliable data with no solid basis? Many of the studies included were of patients with specific, serious medical conditions, including one of elderly nursing home patients measuring incidences of bacterial infections (contrasting with a 2004 study published in JAMA noted that, “we observed a protective effect of vitamin E supplementation on upper respiratory tract infections, particularly the common cold, that merits further investigation.” 18), patients with tumors removed from their colon/rectum (antioxidants are associated with apoptosis, a desirable change that leads to death of cancer cells 19, 20), patients with age-related macular degeneration (a condition associated with a deficiency of various antioxidants 21-24), patients with coronary heart disease (a condition related to oxidative damage 14-16), dialysis patients with a history of cardiovascular disease (a condition related to oxidative damage that is reduced by supplemental vitamin E 17), cataract patients (another condition related to oxidative damage 25), male cigarette smokers/present and former cigarette smokers/asbestos workers (all related to low levels of total antioxidants and high toxic load), as well as patients with alcoholic hepatitis, cirrhosis, lupus, heart failure, ALS, etc. This meta-analysis will not stand the test of time because of its many variables, flaws and the arbitrary structuring of its statistical model. When better studies exist, often supported by blood assays, that show higher serum antioxidant levels reduce actual death rates in large populations, then no arbitrary statistical model should be able to negate that robust science with a merely theoretical danger based on such preliminary, questionable criteria. All studies cited here were published in peer-reviewed scientific journals, but that does not make them all of equal quality. Remember my story of the meta-analysis on vitamin E that was refuted by a better meta-analysis, yet both were peer-reviewed? A meta-analysis has more validity if fewer variables are included and if the selection of studies included is not biased by a presumed conclusion. Were hundreds of studies without dying participants ineligible for this particular meta-analysis review simply because of a selection bias, with an intent to demonstrate the dangers of supplementation? These scientists should know better. I see their report as an ill-disguised partisan attack by medical special interests on dietary supplements, a smokescreen for those that don’t look at the quality and quantity of well-designed studies that do show the benefits of vitamins to protect health and prevent deaths. The Lewin Group has presented evidence that the use of antioxidants could save the vision and independence of many senior citizens, while saving the public billions of dollars in healthcare costs. 26 The Institute of Medicine, part of the National Institutes of Health, after reviewing hundreds of well-designed studies, has set safe upper limits for several antioxidants at levels far above the Daily Values. 27 Antioxidants are safe, and proven so in better studies than this one. REFERENCES: 1. Bjelakovic G, et.al. Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. JAMA 2007. 297(8):842-857 2. Miller ER 3rd, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4;142(1):37-46. Epub 2004 Nov 10. Summary for patients in: Ann Intern Med. 2005 Jan 4;142(1):I40. PMID: 15537682 3. Hathcock JN, et al. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. 2005 Apr;81(4):736-45. Review. PMID: 15817846 4. Levin, N. Land of Confusion: How Poor Science and Misleading Media Coverage Create Public Confusion About How Dietary Supplements Affect Health. J App Nutr, Vol 55, No. 1, 2005 8-15 5. Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998 Apr;78(2):547-81. Review. PMID: 9562038 6. BLOCK, G. Are clinical trials really the answer? Am. J. Clin. Nutr. 62, Suppl.: 15175-15205, 1995 7. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994 Apr 14;330(15):1029-35. http://content.nejm.org/cgi/content/full/330/15/1029?ijkey=bd47b716724d0dad4cad0fb19337308753658337 8. Wright ME, et al. Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers. July 2004 American Journal of Epidemiology http://aje.oupjournals.org/cgi/content/abstract/160/1/68?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&andorexacttitle=and&andorexacttitleabs=and&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;fulltext=beta+carotene&andorexactfulltext=and&searchid=1100534768534_1530&stored_search=&FIRSTINDEX=0&sortspec=relevance&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;fdate=7/1/2004&tdate=7/31/2004&journalcode=amjepid 9. Buijsse B, et al. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: The Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr 2005;82:879–886. 10. Brighenti F. The total antioxidant capacity of the diet is an independent predictor of plasma beta-carotene. European Journal of Clinical Nutrition (2007) 61, 69–76. 11. Clark LC, Marshall JR. Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia, Urology 57 (2001), pp. 185–187. 12. Duffield-Lillico, AJ, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial, Cancer Epidemiol. Biomarkers Prev. 11 (2002), pp. 630–639. 13. Stampfer MJ, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-9 14. Bauernfeind, J. Tocopherols in Foods. In: Vitamin E: A Comprehensive Treatise. Marcel Dekker, Inc., New York and Basel, pp. 99-167, 1980. 15. Horwitt, M.K. The Promotion of Vitamin E. J. Nutr. 116:1371-1377, 1986. 16. Weber, P., Bendich, A. and Machlin, L.J. Vitamin E and Human Health: Rationale for Determining Recommended Intake Levels. Nutrition 13:450-460, 1997. 17. I-Min Lee, MBBS, ScD; et al. Vitamin E in the Primary Prevention of Cardiovascular Disease and Cancer. The Women’s Health Study: A Randomized Controlled Trial. JAMA. 2005;294:56-65 18. Meydani SN, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA. 2004 Aug 18;292(7):828-36. Erratum in: JAMA. 2004 Sep 15;292(11):1305. PMID: 15315997 19. Narayanan BA. Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets. Curr Cancer Drug Targets. 2006 Dec;6(8):711-27. Review. PMID: 17168675 20. Valko M, et al. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44-84. Epub 2006 Aug 4. Review. PMID: 16978905 21. Chiu CJ, Taylor A. Nutritional antioxidants and age-related cataract and maculopathy. Exp Eye Res. 2007 Feb;84(2):229-45. Epub 2006 Jul 31. Review. PMID: 16879819 22. Moriarty-Craige SE, et al. Antioxidant supplements prevent oxidation of cysteine/cystine redox in patients with age-related macular degeneration. Am J Ophthalmol. 2005 Dec;140(6):1020-6. PMID: 16376645 23. Richer S, 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 Apr;75(4):216-30. PMID: 15117055 24. Koh HH, et al. Macular Pigment Optical Density in Early, Age-Related Maculopathy (ARM); Comparisons With Normals and Effects of a Lutein Supplement. Invest Ophthalmol Vis Sci 2002; 43:2562 25. Meyer CH, Sekundo W. Nutritional supplementation to prevent cataract formation. Dev Ophthalmol. 2005;38:103-19. Review. PMID: 15604620 26. DaVanzo JE, et al. An Evidence-Based Study of the Role of Dietary Supplements in Helping Seniors Maintain their Independence. The Lewin Group Inc. January 20, 2006 27. National Institutes of Health, Institute of Medicine, Office of Dietary Supplements. Vitamin E Fact Sheet

More evidence of vitamin E safety!

More evidence of vitamin E safety! According to a new study published in the American Journal of Clinical Nutrition1, male smokers in a study population who had the highest blood levels of vitamin E suffered significantly fewer deaths than comparable male smokers who had lower blood levels of this essential vitamin. Researchers from the National Cancer Institute at the National Institutes of Health teamed up with their counterparts in Finland to review the relationship of blood levels of vitamin E (alpha tocopherol) and all-cause mortality in male smokers age 50-69 in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The study included 29,092 men, with follow-ups continuing over a period of up to 19 years. For those in the groups with the highest blood levels of alpha-tocopherol, there was an 18% lower risk of deaths from all causes. Included in this figure are results relating to specific causes of death, including a 21% reduction in deaths from cancer, a 19% reduction in deaths from cardiovascular disease and a whopping 30% reduction in deaths from all other causes. The report reached this conclusion: “Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.” A non-reproduced meta-analysis6 warning of the largely theoretical dangers of taking vitamin E supplements has generated a lot of concern and a large decline in vitamin E usage, though this flies in the face of other, more rigorous studies showing that higher levels of serum vitamin E are associated with lower mortality numbers.1, 3-4, 7 These largely unsubstantiated warnings may be doing a disservice to figures showing that “93% of men and 96% of women in the United States do not consume the recommended daily amount of dietary vitamin E”.2, 5 In another study, ALS (amyotrophic lateral sclerosis) mortality was 62% lower among long-term users of vitamin E than among nonusers.8 Also, in a study of cancer patients done for the US Dept. of Health and Human Services, “Subgroup analysis did identify a statistically significant 9% reduction in all cause mortality” and “13% reduction in all-cancer mortality associated with supplemental vitamin E in combination with other micro-nutrients.”9 REFERENCES: Margaret E Wright, Karla A Lawson, Stephanie J Weinstein, Pirjo Pietinen, Philip R Taylor, Jarmo Virtamo and Demetrius Albanes. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. American Journal of Clinical Nutrition, Vol. 84, No. 5, 1200-1207, November 2006. (Researchers were from the Nutritional Epidemiology and the Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, and the Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, and the Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland) Maras JE, Bermudez OI, Qiao N, Bakun PJ, Boody-Alter EL, Tucker KL. Intake of alpha-tocopherol is limited among US adults. J Am Diet Assoc2004; 104 :567 –75. Traber MG. How much vitamin E? ... Just enough! Am J Clin Nutr. 2006 Nov;84(5):959-960. PMID: 17093143 Wright ME, Lawson KA, Weinstein SJ, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr2006; 84 :1200–7. Food and Nutrition Board, Institute of Medicine. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press, 2000. Edgar R. Miller, III, MD, PhD; et al. 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 John N Hathcock, et al. 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. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann Neurol. 2005 Jan;57(1):104-10. PMID: 15529299 Shekelle P, et al. Effect of the supplemental use of antioxidants vitamin C, vitamin E, and coenzyme Q10 for the prevention and treatment of cancer. Evid Rep Technol Assess (Summ). 2003 Oct;(75):1-3. Review. PMID: 15523748