More nonsense in vitamin research

More nonsense in vitamin research By Neil E. Levin, CCN, DANLA A report in Archives of Internal Medicine, an AMA journal, tells us that “the Women’s Health Initiative study provided convincing evidence that multivitamin use has little or no influence on the risk of common cancers, CVD, or total mortality in postmenopausal women.” [i] A closer look at that report reveals serious shortcomings in its references and logic, leading to questions about its validity. In spite of these defects, this report got extensive press coverage (“Study Says Multivitamins Not Effective”[ii]) to promote the view that multivitamins are worthless. Having read the report and reviewed its references, I have serious questions about its importance, which I can back up by reviewing some of its own references. First of all, on what basis do the authors base their assertion that this report was needed? Actually, on pretty flimsy grounds. They list two references to justify the belief that there is a common “belief that these preparations will prevent chronic diseases, such as cancer and cardiovascular disease (CVD)”, which this report claims to disprove. Their first reference (by the lead author of the current report) actually states that multivitamin nutrients have been effective and accepted in medical practice for the prevention of other conditions: “First, research findings published throughout the past 10–20 y have established that some supplements are very effective for disease prevention and their use has become a part of routine clinical practice [e.g., folic acid during the periconceptional period to reduce the risk of neural tube defects and iron to prevent or treat anemia during pregnancy].” This statement indirectly undermines the underlying argument in the current report that vitamins are worthless against chronic disease. This same reference directly undermines the current report by asserting that most people use multivitamins for general health, not for prevention of serious diseases as is claimed in the current report: “Multivitamins (with or without minerals), the supplements most commonly used by American women, are most likely to be used to maintain general good health.” While this reference mentions that most American women with cancer do take vitamins, it does not pretend to know why they do so. In fact, there is no assertion that people claim to take vitamins to prevent cancer and CVD, and this reference actually gives alternative reasons for that use by patients with those conditions. This reference, like the current study by the same lead author, is dismissive of a law (DSHEA) regulating dietary supplements; and while it decries this law as reducing regulation in some areas, it ignores significant increases in scrutiny that the same law establishes, which I will explore in a subsequent section. To me, for the lead author to twice publish reports focusing on perceived negatives in the law while ignoring its clear positives and other applicable laws that increase federal regulation - implies an agenda that goes beyond scientific inquiry. 1 [iii] [iv] [v] The second reference listed for justifying the report also does not provide the supposed justification. On the contrary, it states, “Generally, participants took multivitamins to feel better… Nearly half of participants reported that they take multivitamins because it is hard to eat a balanced diet.” [vi] An objective observer reading these two references finds that they do not provide the promised justification for testing their own assertion that people take multivitamins to prevent cancer and CVD. Obviously, the current authors have not provided adequate references to support their claimed hypothesis; their own references betray them. Next, the authors claim that dietary supplements are “an industry that is largely unregulated owing to the 1994 Dietary Supplement and Health Education Act [sic].” Two references are listed to defend this assertion. The first is the law itself, which actually creates clear new authority for federal regulation of supplement manufacturing, federal regulation of labels and health claims, federal regulation of new ingredients, making illegal any mislabeled or adulterated products, etc. A fair reading of this law, and of the subsequent regulations that have been written to enforce it, including the mandatory Good Manufacturing Practices currently being implemented, do not support the authors’ claim. [vii] [viii] The second reference given also fails to support its use as a justification for the belief that supplements are largely unregulated: “DS are regulated under food law, but with certain provisions that apply only to DS…Health claims have already been authorized for folic acid and calcium, but not for several others. In 1994, when the Dietary Supplement Health and Education Act (DSHEA) was passed, it expanded and clarified the definition of DS, specified additional requirements for safety and provided for four types of claims of nutritional support…Although S/F [affecting the structure and functions of the body] effects result from both foods and drugs, representation that a product will treat, cure, mitigate or diagnose a disease is reserved for drugs.” [ix] The current report also fails to note industry-supported legislation that now requires serious adverse events to be reported to the FDA’s MedWatch system, which serves as an early warning system for safety problems. [x] We have seen that the first two claims in the current report, namely that people take multivitamins to prevent certain chronic major diseases and that dietary supplements are largely unregulated, are not supported by the report’s own selected references. In other words, there is not any real justification provided to support the need for this particular report. How could the authors cite references that don’t really support their claims? How does this undermine their reasons for doing this study? Another problem is that the current authors rather arbitrarily ignore numerous FDA-approved health claims for dietary supplements in their argument against the use of multivitamins to prevent chronic diseases, including the benefits of calcium for osteoporosis, fiber to prevent coronary heart disease, soy protein to prevent coronary heart disease, plant sterol/stanol esters and risk of coronary heart disease, potassium and the risk of high blood pressure and stroke; claims that already have met the agency’s Significant Scientific Agreement (SSA) standard. [xi] Even more bizarrely, they ignore substantial scientific agreements that were mentioned in the lead author’s own previous publication (which is referenced by the current report) which identified an accepted use of “iron to prevent or treat anemia during pregnancy” and reported “at least 35 randomized-controlled trials have shown that supplemental calcium or calcium–vitamin D combinations increase bone mass and decrease fracture risk in adult females.” 6 Yet the current authors claim: “Despite the widespread use of supplements and the strong consumer beliefs about benefits, convincing scientific data to support efficacy are lacking. With the exception of recommending a folic acid–containing supplement to women of childbearing potential and advising avoidance the use of high-dose beta carotene supplements by smokers, current data are insufficient to formulate public health recommendations for dietary supplement use for otherwise healthy persons.” Also, the FDA has also approved a number of less definitive Qualified Health Claims (QHCs) including calcium and colon/rectal cancer & calcium and recurrent colon/rectal polyps, green tea and cancer, selenium and cancer, antioxidant vitamins & cancer, omega-3 fatty acids & coronary heart disease, B vitamins & vascular disease, phosphatidylserine & cognitive dysfunction and dementia, chromium picolinate & diabetes, calcium & hypertension, pregnancy-induced hypertension and preeclampsia. [xii] The FDA-Approved Health Claims and QHCs are the only disease claims authorized for dietary supplements in the United States, with all others prohibited under the supposedly deregulating DSHEA law. 7 Another reference mischaracterization is the authors’ statement that “One study of more than 1 million Americans reported no association of multivitamin use with total mortality, coronary heart disease mortality, or cancer mortality.” [xiii] If, in fact, one were to read the reference carefully, one might find a more contradictory and less definitive tone: “Because CPS-II collected information on vitamin supplement use only once, in 1982, our measurement of duration of use is imprecise, and we potentially misclassify people who changed their use of multivitamin during the 7-year follow-up. This is an important limitation and may explain why we did not find a reduced risk of colon cancer among women with long duration of multivitamin use, as was found in the Nurses’ Health Study, which had repeat assessments of multivitamin use.” The imprecise nature of this reference must be emphasized. The Cancer Prevention Study II (CPS-II), which relied on a single survey of multivitamin use to classify as users those who claimed to have taken a multivitamin of any strength at least once during the month preceding the survey, was likely to be more and more inaccurate over time, and wherein only about half of the people surveyed claimed to have taken their multivitamin supplement daily during the previous month, is not a strong reference because its weak design does not establish any definitive effects clearly attributed to multivitamins. 13 Contrast this with the admittedly more rigorous Nurses’ Health Study, showing benefits in those taking supplements that were validated by repeatedly assessing whether or not the subjects kept taking their vitamins. [xiv] While the current report has an 8-year follow up period, the Nurses’ Health Study reported significant benefits only after 15 years of multivitamin use, concluding that such “Long-term use of multivitamins may substantially reduce risk for colon cancer.” This is another indication that the current report’s authors have failed to design their study in such a way as to follow previous successes and avoid known shortcomings of previously published studies; surprisingly, not even the ones that they themselves have referenced or written. By looking at only half as much time as was previously shown to be effective, they have produced a far less rigorous and less convincing report. The incubation period of cancers and heart disease is often estimated to be many years. As the National Cancer Institute reports, “Prostate cancer often does not cause symptoms for many years.” [xv] Other sources confirm the lengthy breeding time of cancers. Mouth cancer has a ten-year incubation period. [xvi] Because “the “incubation period between HPV infection and development of invasive cervical cancer is long, prevention of cancer by a vaccination programme will not be obvious for 10 to 20 years.” [xvii] Asbestos dust can cause lung cancer some 10 to 30 years after exposure. [xviii] Cervical cancer “has a long incubation period, between three to 17 years.” [xix] Likewise, “the ‘incubation period’ between exposure to major coronary risk factors and the maximum effects on mortality may be 10 years or more.” [xx] In the current report, “stress multivitamins” [sic] consisting of B-Complex vitamins along with additional factors such as vitamin C or single minerals were classified as multivitamins, though they could lack essential vitamins A, D, and E, as well as most or all of the essential minerals. This is not a normal definition of a multivitamin formula. Stress formulas are normally considered B-Complex supplements that are fortified with one or more additional nutrients to help the body deal with stress, but not as a general all-in-one daily nutritional supplement. People tend to take stress supplements because they feel under stress, not as a general insurance against incomplete diets as multivitamins are taken. 3,6 While the percentage of subjects in this category is small, I question why they would be included as multivitamin users in the current report at all. Perhaps this design flaw betrays a lack of understanding of the topic being investigated, with a strangely unscientific willingness to throw too many doses and formulas in the supposedly controlled mix of variables. 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. [xxi] Interesting, the current report being reviewed also indicates that nonusers had a higher rate of diabetes treatment than multivitamin users; nonusers were treated at a rate of 5.2% while users ranged only from 2.7 to 3.5%. Nonusers also had slightly lower rates (81.4%) of mammograms compared with users (85.7 to 87.2%), which could imply greater rates of undetected breast cancer that may confound comparisons. 1 Another study reported in the Journal of the National Cancer Institute looked at death rates in a population given multivitamins or other nutrients. [xxii] 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. These nutrients are common in multivitamin formulas. 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, a trend towards small reductions in total (RR 0.93) and cancer (RR = 0.96) mortality were observed that did not reach statistical significance. 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. [xxiii],[xxiv] Another problem with the current study is that these are nutrients and there are several important yet uncontrolled variables preventing meaningful conclusions: * The same nutrients are found in people’s diet, confounding researchers more used to novel drug studies who may be unfamiliar with the need to control additional variables in nutrient study design * The variety of formulations and nutrients included prevent a meaningful comparison by individual or groups of vitamins or minerals, present or absent * The potency of various nutrients taken could vary from absent to very high; there is no dose-dependent data possible in this particular study design that lumped together a wide range of non-homogenous dietary supplements In conclusion, there are many basic omissions and errors in this report’s rationale and design that should have dramatically reduced its importance and avoided a media frenzy over its flimsy conclusions. Unfortunately, nutrient studies often lack adequate critical review and the researchers tend to jump to unsupported conclusions by ignoring important variables. In this case, one problem was the design of a study that was simply too short to show any benefits. Another is the absolute lack of control over potencies and nutrient content. Rather than blaming the vitamins, it was probably pre-existing conditions and supplemental intervention was too little, too late. This report’s authors seem to lack objectivity by referring to an industry that has had numerous new regulatory controls imposed as “unregulated”. They have also chosen to ignore numerous approved health claims for vitamins, as well as evidence of benefits for those suffering from diseases other than cancer and cardiovascular disease. Additionally, they have described unsubstantiated motives for why people take vitamins, designing a study that was too short and included too many uncontrolled variables to be definitive, thus undermining their entire project’s basis and conclusions. Nutrient studies are simply more complex than drug studies and require a much higher level of careful planning to ensure meaningful results and eliminate as many variables as possible. In this case, I fear that the current report failed to do this, in the process generating much heat but little light on the topic.

REFERENCES [i] Neuhouser ML, et al. Multivitamin Use and Risk of Cancer and Cardiovascular Disease in the Women's Health Initiative Cohorts. Arch Intern Med. 169(3), 294-304. FEB 9, 2009 [ii] WSAV-3 TV, NBC affiliate: http://www.wsav.com/sav/news/science/health_med_fit/article/study_says_multivitamins_not_effective/9446/ [iii] Neuhouser ML. Dietary supplement use by American women: challenges in assessing patterns of use, motives and costs. J Nutr. 2003 Jun;133(6):1992S-1996S. Review. PMID: 12771352 [iv] http://www.fda.gov/opacom/laws/pl109462.html [v] http://www.cfsan.fda.gov/~dms/ds-labl.html [vi] Neuhouser ML, Patterson RE, Levy L. Motivations for using vitamin and mineral supplements. J Am Diet Assoc. 1999 Jul;99(7):851-4. PMID: 10405685 [vii] Dietary Supplement and Health Education Act of 1994, Pub L No. 103-417, 103rd Cong (1994). [viii] http://www.cfsan.fda.gov/~dms/supplmnt.html [ix] Hathcock J. Dietary supplements: how they are used and regulated. J Nutr. 2001 Mar;131(3s):1114S-7S. Review. PMID: 11238828 [x] http://www.cfsan.fda.gov/~dms/ds-rept.html [xi] http://www.cfsan.fda.gov/~dms/flg-6c.html [xii] http://www.cfsan.fda.gov/~dms/qhc-sum.html [xiii] Watkins ML, Erickson JD, Thun MJ, Mulinare J, Heath CW Jr. Multivitamin use and mortality in a large prospective study. Am J Epidemiol. 2000 Jul 15;152(2):149-62. PMID: 10909952 [xiv] Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998 Oct 1;129(7):517-24. PMID: 9758570 [xv] National Cancer Institute: http://www.cancer.gov/cancertopics/factsheet/Detection/early-prostate [xvi] Mouth Cancer Foundation: http://www.rdoc.org.uk/chewing_tobacco_risk.html [xvii] Lowndes CM, Gill ON. Cervical cancer, human papillomavirus, and vaccination. BMJ. 2005 Oct 22;331(7522):915-6. No abstract available. Erratum in: BMJ. 2005 Nov 12;331(7525):1120. PMID: 16239668 [xviii] Ministry of Environment of the Republic of Korea: http://eng.me.go.kr/docs/sub2/policy_view.html?topmenu=C&cat=250&class=14 [xix] Indonesian Cancer Foundation: http://www.cvcradio.in/news/blogs/eye-on-indonesia/cervical-cancer-the-number-one-killer-of-indonesian-women [xx] Rose G. Incubation period of coronary heart disease. 1982. Int J Epidemiol. 2005 Apr;34(2):242-4. Epub 2005 Mar 11. PMID: 15764698 [xxi] 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 [xxii] 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 [xxiii] 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 [xxiv] 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

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&fulltext=beta+carotene&andorexactfulltext=and&searchid=1100534768534_1530&stored_search=&FIRSTINDEX=0&sortspec=relevance&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. 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