There are theoretical risks for isolated folic acid in high doses. But these supposed risks fly in the face of established science and are controversial, not at all conclusive. There is also confusion over the significance of the supposed risks of high dose isolated folic acid in test tube and animal studies which do not identify a danger for moderate level supplementation - or even higher dose supplementation if combined with multivitamins or vitamin B-12. In other words, if the theoretical risks do not reflect real world human activities and the way that people actually obtain essential vitamins from their diet, including supplementation, aren’t these improbable risks really irrelevant to us? On the other hand, these negative reports may stop people from taking essential vitamins in quite reasonable amounts even though they are known to promote human health. Published human clinical science has determined that folic acid can reduce birth defects and has been proven to do so. Clinical science has also found mechanisms by which folic acid can prevent cancers, as well as the theoretical possibility that very high doses given in isolation can stimulate colorectal cancers including prostate cancer. There is stronger evidence that taking B-12 or a multivitamin along with high folic acid actually reduces rates of prostate and colon cancers. For example, in one human clinical trial where food intake, blood and plasma levels of folic acid were considered, Multivitamin users had about 2/3 the risk of subsequent prostate cancer as Non-Multivitamin users; only the independent use of folic acid was considered a risk factor. The report concluded, “…on the whole, the biological and epidemiological evidence supports the potential for folate supplementation to prevent colorectal neoplasia in humans.” (Cole) This shows that single nutrient studies, especially if unpublished and not peer reviewed or subjected to subsequent comments by experts in the field, should not be given overinflated importance when they are merely preliminary studies that may conflict with more relevant published human clinical studies. In the case of such conflicts, the human clinicals should bear more weight and be seen as more convincing, especially those that mimic the full range of variables (nutrients) in the human diet. Folic acid itself is considered non-toxic. Also, “data from in vitro and in vivo studies indicate that folic acid is not genotoxic [damaging to genetic material]”. (UK Food Standards Agency) There have been reports of levels as high as 50,000 micrograms per day given with no signs of toxicity in humans. There are accepted problems associated with levels exceeding 5,000 micrograms a day, which resulted in a far more conservative Upper Limit of 1,000 micrograms daily being set. This effect has been demonstrated in patients suffering from pernicious anemia taken off of their successful medicine (vitamin B-12), which was replaced by 5,000 mcg/day of folic acid. The substitution of one vitamin for another was unsuccessful in treating pernicious anemia, but did mask some symptoms. This test – and a large safety margin - provided the rationale given for the current Upper Limit. But it does not logically imply danger to those who are not severely anemic and who obtain B-12 in adequate amounts. (Oakley) It is very uncommon for people to take folic acid singly in doses of thousands of micrograms daily, but this is the method which test tube and animal studies often use. Overemphasizing unproven cancer risks requires ignoring valid studies showing reductions of cancers by taking folic acid and multivitamins. Needlessly scaring people from taking their vitamins, which have in human clinical trials shown significant improvements in birth defect and cancer rates, is not helpful to our common goal of protecting public health. Neil E. Levin, CCN, DANLA QUOTES & REFERENCES: Dr. Gideon Koren, director of the Motherisk Program at the Hospital for Sick Children in Toronto , note that rates of birth defects such as spina bifida and cancers such as neuroblastoma have plummeted since folic acid supplementation was begun. He believes that the known benefits outweigh theoretical risks. "I think it is very important to remember that the scares about cancer are mostly from animal studies and laboratory studies, not from human experience," he says. "We are still awaiting to see such human experience." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech Health Canada recommends all women of childbearing age take 0.4 mg of folic acid a day, but says taking more than 1 mg a day of folic acid without the advice of a doctor is not recommended. "We continue to encourage all women who could become pregnant to take a daily supplement," the agency says on its website. "We caution against taking more than one multivitamin tablet a day, as excess amounts of certain vitamins can be toxic." http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20090417/folic_acid_090418/20090419?hub=SciTech “All women who could become pregnant should take a multivitamin containing 0.4 mg of Folic Acid every day. To help reduce the risk of NTDs, you should start taking the vitamin supplement at least three months before you get pregnant and continue through the first three months of your pregnancy. Talk to your health professional to find the supplement best for you…If you have had a previous pregnancy affected by an NTD or have a family history of this problem, see your doctor. You may be advised to take a higher dosage of Folic Acid. If you have diabetes, obesity or epilepsy, you may be at higher risk of having a baby with an NTD, and you should see your doctor before planning pregnancy… Do not take more than one daily dose of vitamin supplement as indicated on the product label. Increasing your dose of Folic Acid beyond 1 mg per day without the advice of a doctor is not recommended.” (Public Health Agency of Canada , 2/27/08; http://www.phac-aspc.gc.ca/fa-af/index-eng.php) The NIH’s Office of Dietary Supplement reports on the prevention of cancer with the use of supplemental folic acid as part of a multivitamin: “Over 88,000 women enrolled in the Nurses' Health Study who were free of cancer in 1980 were followed from 1980 through 1994. Researchers found that women ages 55 to 69 years in this study who took multivitamins containing folic acid for more than 15 years had a markedly lower risk of developing colon cancer.” (Giovannucci E, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 1998;129:517-24; http://ods.od.nih.gov/factsheets/folate.asp) Cole BF, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. Polyp Prevention Study Group. JAMA. 2007 Jun 6;297(21):2351-9. PMID: 17551129 Figueiredo JC, et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst. 2009 Mar 18;101(6):432-5. Epub 2009 Mar 10. PMID: 19276452 Folic Acid, CASRN: 59-30-3. NLM TOXNET Hazardous Substances Database accessed online 28 March, 2009. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@na+folic+acid Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. N Engl J Med. 2006 Apr 13;354(15):1567-77. Epub 2006 Mar 12. Erratum in: N Engl J Med. 2006 Aug 17;355(7):746. PMID: 16531613 Oakley GP Jr. When will we eliminate folic acid-preventable spina bifida? Epidemiology. 2007 May;18(3):367-8. PMID: 17435446 http://www.food.gov.uk/multimedia/pdfs/evm_folicacid.pdf
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: 7495242More 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
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 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.
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:
My letter criticizing their editorial in Annals of Internal Medicine was accepted and published online by that journal: http://www.annals.org/cgi/eletters/0000605-200708210-00177v1#21702 It is unfortunate that synergistic nutrients are tested individually, like drugs. This is a pharmaceutical practice, not human nutrition, and shouldn’t imply that comprehensive mixtures of nutrients (like a multivitamin) would have the same effects. I dispute that “randomized, controlled clinical trials have shown that ß-carotene and vitamin E supplements, which were widely believed to be safe, increase mortality and morbidity”. The choices, increasing variables, and manipulation by statistical models in meta-analyses are often questionable. In this report, prediabetic symptoms were not even considered as a variable. Buijsse noted that high carotenoid intake, confirmed by measures of blood levels, was associated with lower mortality rates among the elderly over a ten-year period, countering the claim that ß-carotene dangers are proven. The Miller meta-analysis, cited as proof of vitamin E’s dangers, was heavily criticized in published responses, and its conclusions were NOT replicated when the same data was re-analyzed (Hathcock). It should therefore not be cited as proof of the vitamin’s danger. Another meta-analysis cited (Bjelakovic) reported that antioxidant vitamins may increase death rates. But the authors did not determine a dose-dependent or cause-and-effect relationship between antioxidants and deaths (from all causes) of study participants. The researchers pooled 68 published trials, excluding 405 published studies with no deaths reported. Too wide a range of potencies (Vitamin A 1333 IU - 200,000 IU, vitamin E 10 IU to 1000 IU), and durations (28 days to 12 years) were lumped together. The statement, “No dietary supplement, including selenium, has proven useful so far for the prevention of cardiovascular disease or cancer in the general U.S. population,” is questionable. The Alpha-Tocopherol, Beta- Carotene Cancer Prevention (ATBC) Study published by the National Cancer Institute demonstrated a 32% reduction in prostate cancer incidence in response to daily alpha-tocopherol supplementation. The Women’s Health Study (JAMA) reported a significant 24% reduction in cardiovascular death with supplemental vitamin E. The NIH reports, “Taking a daily supplement containing 200 μg of selenium … significantly reduced the occurrence and death from total cancers. The incidence of prostate cancer, colorectal cancer, and lung cancer was notably lower in the group given selenium supplements.” Yet you suggest lowering consumption below the Daily Value (70 μg) used in multivitamins and far below the current upper limit. On the contrary, the Lewin Group reports that the use of antioxidants could save the vision and independence of many senior citizens, saving billions of dollars in healthcare costs. REFERENCES: 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 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. 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 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 Weinstein SJ, et al. Serum α -Tocopherol and γ-Tocopherol in Relation to Prostate Cancer Risk in a Prospective Study. J. Natl. Cancer Inst. 2005 97: 396-399; doi:10.1093/jnci/dji045
A reader of my nutrition blog wondered if I may be biased. That's a fair question. Actually, I believe that everyone has to deal with the issue of bias, and the Scientific Method is supposed to help us all overcome these biases by focusing on valid, reproduceable data. Unfortunately, some of us seem to be trying harder than others to fairly represent unbiased data. For one example, my letter published by the cancer journal CA, the Journal of the American Cancer Society http://caonline.amcancersoc.org/cgi/eletters/55/5/319#176 rebutted an article positing that antioxidants should be avoided during cancer therapies. However, none of the references provided in that article showed any evidence of risk! In my rebuttal, I catalogued a number of studies that used nutrients with drugs or radiation therapies, which showed no harmful effects and in some cases even enhanced anticancer effects. I also pointed out the 40% of cancer patients who die of malnutrition while under their doctors' care, much of which may be preventable if physicians actually follow evidence-based medicine instead of clinging to conventional therapies and theories. Click on the title of this article to see the original report and my response. I think that you'll find that I presented relevant published scientific reports to counter a biased opinion that was not even supported by the author's references. How did that crappy opinion even get published in a peer-reviewed journal in the first place?
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;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;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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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. 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