Overview

In general, a multivitamin/mineral (MVM) supplement is a dietary supplement that contains about 100% of the Daily Value (DV) of most vitamins and nutritionally essential minerals. However, there are no standardized definitions for MVMs, and the composition of marketed MVM products varies widely (e.g., some contain nonnutrient ingredients like herbs or phytochemicals) (1). No MVM supplement contains the DV for calcium, magnesium, potassium, and phosphorus since the resulting pill would be too bulky.

Similar to food labels, the DVs listed on supplement labels do not reflect the latest recommendations (i.e., the RDA and AI) from the Food and Nutrition Board (FNB) of the US Institute of Medicine; instead, most of the DVs are based on outdated recommendations made in 1968 (2). The DVs for vitamin A and biotin are considerably higher than the current FNB recommendations, but supplement manufacturers may include these vitamins at levels similar to the current recommendation and list that a tablet contains only a fraction of the DV. DVs of many micronutrients are significantly higher than the corresponding RDAs (Table 1). Several MVM products currently on the market are formulated specifically for young men, young women, older adults, or children since micronutrient (vitamins and nutritionally essential minerals) requirements differ by gender and life stage. For example, MVMs marketed to young women generally contain iron, while many of those marketed to men or postmenopausal women typically do not. This article discusses patterns of MVM use, the prevalence and consequences of micronutrient inadequacies, chronic disease prevention, and safety concerns of MVM supplementation in adults.

Table 1. Comparison between the Daily Values (DV) and the Dietary Reference Intakes (RDA or AI) for Adults
Micronutrient  DV  RDA or AI for Adult Males (amount/day)  RDA or AI for Adult Females (amount/day) 
Biotin  300 mcg  30 mcg  30 mcg 
Folate  400 mcg  400 mcga  400 mcga 
Niacin  20 mg  16 mgb  14 mgb 
Pantothenic Acid 10 mg  5 mg  5 mg 
Riboflavin 1.7 mg  1.3 mg  1.1 mg 
Thiamin 1.5 mg  1.2 mg  1.1 mg 
Vitamin A 5,000 IU  3,000 IUc  2,333 IUc 
Vitamin B6 2 mg  1.3-1.7 mg  1.3-1.5 mg 
Vitamin B12 6 mcg  2.4 mcgd  2.4 mcgd 
Vitamin C 60 mg  90 mg  75 mg 
Vitamin D 400 IU  600-800 IU  600-800 IU 
Vitamin E 30 IU  22.5-33 IUe  22.5-33 IUe 
Vitamin K 80 mcg  120 mcg  90 mcg 
Calcium 1,000 mg  1,000-1,200 mg  1,000-1,200 mg 
Chloride 3,400 mg  1,800-2,300 mg  1,800-2,300 mg 
Chromium 120 mcg  30-35 mcg  20-25 mcg 
Copper 2 mg  900 mcg  900 mcg 
Iodine 150 mcg  150 mcg  150 mcg 
Iron 18 mg  8 mg  8-18 mg 
Magnesium 400 mg  400-420 mg  310-320 mg 
Manganese 2 mg  2.3 mg  1.8 mg 
Molybdenum 75 mcg  45 mcg  45 mcg 
Phosphorus 1,000 mg  700 mg  700 mg 
Potassium 3,500 mg  4,700 mg  4,700 mg 
Selenium 70 mcg  55 mcg  55 mcg 
Zinc 15 mg  11 mg  8 mg 
Cholinef None established  550 mg  425 mg 

aDietary Folate Equivalents
bNE, niacin equivalent: 1 mg NE = 60 mg tryptophan = 1 mg niacin
cRetinol Activity Equivalents
dIntake for adults >50 years should be from supplements or fortified foods due to the age-related increase in food-bound malabsorption
e22.5 IU of natural-source α-tocopherol (d-α-tocopherol); 33 IU of synthetic α-tocopherol (dl-α-tocopherol)
fConsidered an essential nutrient, although not strictly a micronutrient

Abbreviations: DV, daily value; RDA, recommended dietary allowance; AI, adequate intake

Patterns of Use

Use of nutritional supplements is increasingly common in the United States, with MVMs being the most popular type of dietary supplement (3). A recent national survey found that one-third of Americans ages one year and older take a MVM supplement, which was defined as a supplement containing at least three vitamins and one mineral (4). Dietary supplement use was found to be generally more prevalent among females, non-Hispanic whites, older adults, and individuals with greater than a high-school education and less common among obese individuals (4). Other studies have reported similar trends in use (5-10). Additionally, a few studies have found that MVM users are more likely to have healthier diets (11, 12) or rate their health as excellent or very good (7, 10), suggesting that those who do not take MVMs may be the ones who would benefit the most from supplementation.

Prevalence and Consequences of Micronutrient Inadequacies

Despite MVM use being very common among some population groups, US national surveys indicate that select micronutrient inadequacies are relatively widespread. According to data from the National Health and Nutrition Examination Survey (NHANES), 93% of the US population do not meet the estimated average requirement (EAR) for vitamin E, 56% for magnesium, 44% for vitamin A, 31% for vitamin C, 14% for vitamin B6, and 12% for zinc (13). The EAR is used to establish the recommended dietary allowance (RDA), which is the higher of the two recommendations and should be used in dietary planning for individuals (14). Moreover, vitamin D deficiency is a major problem in the US and elsewhere; it has been estimated that 1 billion people in the world have either vitamin D deficiency or insufficiency (15).

Since more than one-third of American adults aged 20 years or older is considered overweight and another one-third is classified as obese (16), many Americans are exceeding energy (caloric) requirements but not meeting micronutrient recommendations, presumably due to excessive consumption of energy-rich, nutrient-poor foods. Data from NHANES found that energy-dense, nutrient-poor foods comprise 27% of daily caloric intake in the American diet, and alcohol constituted an additional 4% of daily caloric intake (17). This survey also found that higher intakes of energy-dense, nutrient-poor foods were associated with lower serum concentrations of several micronutrients, including vitamin A, folate, vitamin B12, vitamin C, and vitamin E (17). Select micronutrient deficiencies are common in other industrialized nations (18-20), and multiple micronutrient deficiencies, especially iron, vitamin A, zinc, and iodine, are prevalent in the developing world (21). Micronutrient deficiencies, affecting an estimated 2 billion people, contribute to infections and are associated with severe illness and death (22). Although not a comprehensive list, the following individuals may be at increased risk for micronutrient deficiencies (micronutrients of concern are noted in parentheses) (23-35):

  • Women of childbearing age (folate, vitamin D, iron)
  • Pregnant and lactating women (vitamin B6, folate, vitamin D, iron)
  • People who consume <1,200 cal/day (multiple micronutrients)
  • Obese individuals (multiple micronutrients)
  • Infants, children, and adolescents (vitamin D)
  • People with dark-colored skin (vitamin D)
  • Those who cover all exposed skin or using sunscreen whenever outside (vitamin D)
  • Older adults (vitamin B12, vitamin D, zinc)
  • Low socioeconomic status (multiple micronutrients)
  • Patients who have had bariatric surgery (multiple micronutrients)
  • Patients with fat malabsorption syndromes (fat-soluble vitamins A, D, E, and K)
  • Alcoholics (vitamin A, B vitamins)
  • Smokers (vitamins C and E)
  • Vegans and those with limited intake of animal products (vitamin B12, vitamin D, calcium)
  • People taking medications that interfere with the absorption and/or metabolism of certain micronutrients (e.g., proton pump inhibitors used to treat heartburn may impair vitamin B12 absorption (36); frequent aspirin use can lower vitamin C status (37)).
  • People whose diets are not adherent to the USDA food plate (formerly food pyramid)—the vast majority of Americans (multiple micronutrients)

Micronutrient inadequacies can increase susceptibility to illness and chronic disease. Deficiencies in select micronutrients can impair immunity, thereby increasing vulnerability to infectious disease (see the article on Immunity). Inadequate intake of certain micronutrients may increase risk for chronic diseases, such as cardiovascular disease, osteoporosis, and cancer (see the Disease Index), and may also be linked to cognitive dysfunction (see the article on Cognitive Function) (33, 34, 38). Moreover, certain micronutrient deficiencies during pregnancy can cause congenital anomalies (see the article on Micronutrient Needs During Pregnancy and Lactation). Dr. Bruce Ames, a prominent biochemist at the University of California, Berkeley, has hypothesized that when intakes are lower than the recommended levels, short-term requirements for micronutrients in metabolic reactions take precedence over long-term needs, thereby resulting in long-term, cumulative oxidative damage to macromolecules (DNA, RNA, proteins), declines in mitochondrial function, and accelerated cellular aging, increasing the risk of age-related diseases (33). In contrast, micronutrient intakes at the RDA would allow sufficient amounts for normal metabolism, and intakes of the RDA or higher may be needed for optimum health promotion and chronic disease prevention (33). Given the fact that many people are not meeting micronutrient intake recommendations, a daily multivitamin/mineral supplement would offer insurance that most micronutrient needs are met.

Chronic Disease Prevention

It is not known with certainty if taking a daily multivitamin/mineral supplement can reduce the risk of various chronic diseases. Several observational studies (prospective cohort studies and case-control studies) and randomized controlled trials (RCTs) have examined this question. In 2006, a National Institutes of Health (NIH) State-of-the-Science conference on MVMs and chronic disease prevention concluded that there was insufficient evidence to recommend in favor or against taking a MVM supplement (39). However, the panel limited their ‘evidence-based’ review to only long-term RCTs, ignoring the results of other epidemiological studies as well as the mechanistic and biochemical research that suggest an adequate supply of micronutrients is essential for optimal health (40). When used to evaluate the effects of nutrients, RCTs have a number of limitations (see below). Epidemiological studies published since the NIH conference have not provided a definitive answer to whether MVM use could help prevent chronic diseases. Recent systematic reviews or meta-analyses of epidemiological studies have found that MVM use was not associated with breast cancer (41) or prostate cancer (42). In addition, individual studies of MVM use and cardiovascular events or cardiovascular-related mortality are conflicting, with two finding a benefit (43, 44) and another reporting no association (45). Inconsistent findings in epidemiological studies may in part be due to wide variations in MVM supplement composition, dose, and duration of use.

Both observational studies and randomized controlled trials have inherent limitations. Observational studies—studies in which participants are simply observed over time (no experimental intervention or treatment is applied)—can only detect associations, not establish cause-and-effect relationships (46). Even though statisticians usually adjust for several confounding factors, residual confounding is always a concern with observational studies. Accurately measuring MVM use or compliance may also be problematic. Although not typically done, studies that measure micronutrient status in blood and correlate that with health outcomes are more reliable than those that measure supplement use by questionnaires or recall methods. Additionally, people who volunteer to be part of observational studies or RCTs are generally healthier than the average person (i.e., the "healthy enrollee effect," and similarly, people who take MVM supplements often have healthier dietary and lifestyle habits compared to those who don’t take MVMs (11, 12). While RCTs are considered the ‘gold standard’ to evaluate the effect of pharmaceutical drugs, they have a number of limitations and are not well-suited to study the effects of nutrients (46, 47). For example, trials of micronutrient supplementation compare low intakes (from diet) with higher intakes (from supplements) in subjects who have a lifelong intake of these micronutrients; by contrast, drug trials compare the absence of the drug with its presence in subjects who have not been exposed to this drug before. Therefore, the ‘placebo’ group in RCTs of micronutrient supplements is not a true placebo or ‘non-exposed’ group, in contrast to the placebo group in RCTs of drugs. Such a nutrient-free state in RCTs is not possible, and causing micronutrient deficiencies in the control group is unethical. Additionally, primary disease prevention trials using supplemental micronutrients are evaluated in healthy people, not diseased individuals, meaning that any effects of supplementation would be likely small and take years, perhaps decades, to be observed (46, 47). There are several other concerns with RCTs, such as selection of subjects, compliance during a long-term study, the need to recruit a large number of subjects, trial cost, and confounding with dietary intake of nutrients (40). Thus, for many reasons, it is not realistic that a long-term RCT would provide definitive results on whether MVMs are useful in chronic disease prevention. Short-term RCTs that assess DNA damage, inflammation, insulin sensitivity, lipid profile, blood pressure, immune function or other intermediary biomarkers or independent risk factors of chronic disease are more practical and may inform this question (40).

Safety

Although there is no consensus that MVM use by the general population benefits overall health or prevents chronic disease, such supplements are generally considered as safe in healthy individuals. Excessive intakes of select micronutrients can be unsafe, but amounts of micronutrients typically included in MVMs approximate or equal the DVs; for adults, the DV for most micronutrients is considerably lower than the tolerable upper intake level (UL)—the highest level of daily intake of a specific nutrient likely to pose no risk of adverse health effects in almost all individuals of a specified age (14). Intake from foods, fortified foods, and supplements should not exceed the UL for each micronutrient (48). In general, dosages of micronutrients included in MVMs are safe. Some supplements may provide excessive vitamin A or iron. For example, daily use of a MVM supplement can supply as much as 5,000 IU/day of vitamin A as retinol, an amount that has been associated with bone fractures in older adults. For this reason, the Linus Pauling Institute (LPI) recommends that adults take a MVM supplement that provides no more than 2,500 IU (750 mcg) of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 2,500 IU of additional vitamin A as β-carotene. Additionally, because excess preformed vitamin A (retinol) during pregnancy is known to cause birth defects and because a number of foods in the US are fortified with retinol, LPI recommends that pregnant women avoid a MVM or prenatal supplements that contain more than 5,000 IU (1,500 mcg) of vitamin A in the form of retinol. Moreover, children should not be given a MVM supplement that contains more retinol than the RDA for their age group (see the Table 1 in the article on vitamin A). Men and postmenopausal women are not at risk of iron deficiency, and excess iron from the diet and supplements can have adverse effects. Therefore, LPI recommends that men and postmenopausal women take a MVM supplement without iron. A number of MVMs formulated specifically for men or for those over 50 years of age do not contain iron. Concomitant use of certain supplements, such as a daily MVM and a daily B complex supplement, in addition to intake from fortified foods, may result in total intakes that exceed the UL for some micronutrients. Further, even though MVM supplements are safe for most people, individuals should discuss the use of all nutritional supplements with a competent healthcare professional. People taking pharmaceutical drugs to treat certain medical conditions need to be aware of any potential drug-nutrient interactions.

Another safety issue concerns the quality of commercially available MVM supplements. In 2007, the US Food and Drug Administration established standards of current good manufacturing practices (CGMPs), which ensure dietary supplements meet quality standards with respect to identity, purity, strength, and composition (49). All US and foreign companies were required to comply with the CGMPs by June 2010. In addition to these government regulations, at least three independent organizations evaluate the quality of dietary supplements on a fee basis: NSF International, US Pharmacopeia, and ConsumerLab.com. Supplement labels of approved products can bear the certification mark, verification mark, or seal of approval of these organizations. However, many products that are in full compliance do not carry such certification marks on their labels, and absence of a seal does not mean lack of adherence to CGMP or other regulations.

Conclusion

National surveys indicate that many Americans are not getting enough micronutrients from the diet, possibly increasing their risk for osteoporosis, some forms of cancer, and other chronic diseases. Marginal or subclinical micronutrient deficiencies have been linked to general fatigue (50), impaired immunity (51, 52), and adverse effects on cognition (53). Nutrition education campaigns have yet to convince people to make better food choices: the reality is that most Americans eat an energy-rich, nutrient-poor diet lacking in fruit and vegetables (54). Consequently, micronutrient inadequacies are widespread in the US and around the world. Given the facts that dietary habits are difficult to change and that some people cannot afford nutrient-rich fruit and vegetables, a daily multivitamin/mineral supplement is a sensible public health recommendation (55, 56). As part of its Rx for Health, the Linus Pauling Institute recommends a daily MVM supplement as nutritional insurance to meet micronutrient needs (see Supplements in the LPI Rx for Health). MVMs are a simple, inexpensive, and safe way to help fill nutritional gaps and improve micronutrient status. By definition, MVMs are “supplements” and should be used to complement a healthy diet (see Healthy Eating in the LPI Rx for Health). Eating a balanced diet is important to obtain other nutrients and phytochemicals that benefit health. While the specific consequences of chronic micronutrient inadequacies are difficult to document, it is prudent and affordable to ensure adequacy for health by taking a daily MVM supplement.


Authors and Reviewers

Written in August 2011 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2011 by:
Jeffrey Blumberg, Ph.D., F.A.C.N., F.A.S.N., C.N.S.
Director, Antioxidants Research Laboratory
Jean Mayer USDA Human Nutrition Research Center on Aging
Professor, Friedman School of Nutrition Science and Policy
Tufts University

This article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2011-2015   Linus Pauling Institute


References

1.  Yetley EA. Multivitamin and multimineral dietary supplements: definitions, characterization, bioavailability, and drug interactions. Am J Clin Nutr. 2007;85(1):269S-276S.  (PubMed)

2.  US Food and Drug Administration. US Department of Health & Human Services. 14. Appendix F: Calculate the percent daily value for the appropriate nutrients. http://www.fda.gov/Food/
GuidanceComplianceRegulatoryInformation/GuidanceDocuments/FoodLabelingNutrition/FoodLabelingGuide/ucm064928.htm. Accessed 8/23/11.

3.  Gahche J, Bailey R, Burt V, et al. Dietary Supplement Use Among U.S. Adults Has Increased Since NHANES III (1988-1994). NCHS Data Brief. 2011;(61):1-8.  (PubMed)

4.  Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr. 2011;141(2):261-266.  (PubMed)

5.  Satia-Abouta J, Kristal AR, Patterson RE, Littman AJ, Stratton KL, White E. Dietary supplement use and medical conditions: the VITAL study. Am J Prev Med. 2003;24(1):43-51.  (PubMed)

6.  Archer SL, Stamler J, Moag-Stahlberg A, et al. Association of dietary supplement use with specific micronutrient intakes among middle-aged American men and women: the INTERMAP Study. J Am Diet Assoc. 2005;105(7):1106-1114.  (PubMed)

7.  Sullivan KM, Ford ES, Azrak MF, Mokdad AH. Multivitamin use in pregnant and nonpregnant women: results from the Behavioral Risk Factor Surveillance System. Public Health Rep. 2009;124(3):384-390.  (PubMed)

8.  Park SY, Murphy SP, Martin CL, Kolonel LN. Nutrient intake from multivitamin/mineral supplements is similar among users from five ethnic groups: the Multiethnic Cohort Study. J Am Diet Assoc. 2008;108(3):529-533.  (PubMed)

9.  Shelton RC, Puleo E, Syngal S, Emmons KM. Multivitamin use among multi-ethnic, low-income adults. Cancer Causes Control. 2009;20(8):1271-1280.  (PubMed)

10.  Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999-2000. Am J Epidemiol. 2004;160(4):339-349.  (PubMed)

11.  Rock CL. Multivitamin-multimineral supplements: who uses them? Am J Clin Nutr. 2007;85(1):277S-279S.  (PubMed)

12.  Foote JA, Murphy SP, Wilkens LR, Hankin JH, Henderson BE, Kolonel LN. Factors associated with dietary supplement use among healthy adults of five ethnicities: the Multiethnic Cohort Study. Am J Epidemiol. 2003;157(10):888-897.  (PubMed)

13.  Moshfegh A, Goldman J, Cleveland L. 2005; What We Eat in America, NHANES 2001-2002: Usual nutrient intakes from food compared to dietary reference intakes. US Department of Agriculture, Agricultural Research Service. Available at: http://www.ars.usda.gov/Services/docs.htm?docid=13793.

14.  Food and Nutrition Board, Institute of Medicine. Summary. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academy Press; 2001:1-28.  (National Academy Press)

15.  Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.  (PubMed)

16.  Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303(3):235-241.  (PubMed)

17.  Kant AK. Consumption of energy-dense, nutrient-poor foods by adult Americans: nutritional and health implications. The third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2000;72(4):929-936.  (PubMed)

18.  Elmadfa I, Freisling H. Nutritional status in Europe: methods and results. Nutr Rev. 2009;67 Suppl 1:S130-134.  (PubMed)

19.  Taylor JP, Maclellan DL, van Til L, Sweet L. Widespread micronutrient inadequacies among adults in prince edward island. Can J Diet Pract Res. 2007;68(1):23-29.  (PubMed)

20.  Whatham A, Bartlett H, Eperjesi F, et al. Vitamin and mineral deficiencies in the developed world and their effect on the eye and vision. Ophthalmic Physiol Opt. 2008;28(1):1-12.  (PubMed)

21.  Muller O, Krawinkel M. Malnutrition and health in developing countries. CMAJ. 2005;173(3):279-286.  (PubMed)

22.  Food and Agriculture Organization of the United Nations. The state of food insecurity in the world 2004. Rome: Food and Agriculture Organization of the United Nations; 2004.  Available at: ftp://ftp.fao.org/docrep/fao/007/y5650e/y5650e00.pdf

23.  Malone M. Recommended nutritional supplements for bariatric surgery patients. Ann Pharmacother. 2008;42(12):1851-1858.  (PubMed)

24.  Halsted CH. Nutrition and alcoholic liver disease. Semin Liver Dis. 2004;24(3):289-304.  (PubMed)

25.  Craig WJ. Health effects of vegan diets. Am J Clin Nutr. 2009;89(5):1627S-1633S.  (PubMed)

26.  Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008;29(2 Suppl):S20-34; discussion S35-27.  (PubMed)

27.  Hollis BW. Vitamin D requirement during pregnancy and lactation. J Bone Miner Res. 2007;22 Suppl 2:V39-44.  (PubMed)

28.  Nead KG, Halterman JS, Kaczorowski JM, Auinger P, Weitzman M. Overweight children and adolescents: a risk group for iron deficiency. Pediatrics. 2004;114(1):104-108.  (PubMed)

29.  Parikh SJ, Edelman M, Uwaifo GI, et al. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 2004;89(3):1196-1199.  (PubMed)

30.  Glerup H, Mikkelsen K, Poulsen L, et al. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. J Intern Med. 2000;247(2):260-268.  (PubMed)

31.  Garcia OP, Long KZ, Rosado JL. Impact of micronutrient deficiencies on obesity. Nutr Rev. 2009;67(10):559-572.  (PubMed)

32.  Marra MV, Boyar AP. Position of the American Dietetic Association: nutrient supplementation. J Am Diet Assoc. 2009;109(12):2073-2085.  (PubMed)

33.  Ames BN. Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage. Proc Natl Acad Sci U S A. 2006;103(47):17589-17594.  (PubMed)

34.  Ames BN, Wakimoto P. Are vitamin and mineral deficiencies a major cancer risk? Nat Rev Cancer. 2002;2(9):694-704.  (PubMed)

35.  Stickel F, Hoehn B, Schuppan D, Seitz HK. Review article: Nutritional therapy in alcoholic liver disease. Aliment Pharmacol Ther. 2003;18(4):357-373.  (PubMed)

36.  Yang YX, Metz DC. Safety of proton pump inhibitor exposure. Gastroenterology. 2010;139(4):1115-1127.  (PubMed)

37.  Basu TK. Vitamin C-aspirin interactions. Int J Vitam Nutr Res Suppl. 1982;23:83-90.  (PubMed)

38.  Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest. 2005;115(12):3318-3325.  (PubMed)

39.  National Institutes of Health State-of-the-science conference statement: multivitamin/mineral supplements and chronic disease prevention. Ann Intern Med. 2006;145(5):364-371.  (PubMed)

40.  Ames BN, McCann JC, Stampfer MJ, Willett WC. Evidence-based decision making on micronutrients and chronic disease: long-term randomized controlled trials are not enough. Am J Clin Nutr. 2007;86(2):522-523; author reply 523-524.  (PubMed)

41.  Chan AL, Leung HW, Wang SF. Multivitamin supplement use and risk of breast cancer: a meta-analysis. Ann Pharmacother. 2011;45(4):476-484.  (PubMed)

42.  Stratton J, Godwin M. The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis. Fam Pract. 2011;28(3):243-252.  (PubMed)

43.  Rautiainen S, Akesson A, Levitan EB, Morgenstern R, Mittleman MA, Wolk A. Multivitamin use and the risk of myocardial infarction: a population-based cohort of Swedish women. Am J Clin Nutr. 2010;92(5):1251-1256.  (PubMed)

44.  Pocobelli G, Peters U, Kristal AR, White E. Use of supplements of multivitamins, vitamin C, and vitamin E in relation to mortality. Am J Epidemiol. 2009;170(4):472-483.  (PubMed)

45.  Neuhouser ML, Wassertheil-Smoller S, Thomson C, et al. Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts. Arch Intern Med. 2009;169(3):294-304.  (PubMed)

46.  Heaney RP. Nutrients, endpoints, and the problem of proof. J Nutr. 2008;138(9):1591-1595.  (PubMed)

47.  Blumberg J, Heaney RP, Huncharek M, et al. Evidence-based criteria in the nutritional context. Nutr Rev. 2010;68(8):478-484.  (PubMed)

48.  Mulholland CA, Benford DJ. What is known about the safety of multivitamin-multimineral supplements for the generally healthy population? Theoretical basis for harm. Am J Clin Nutr. 2007;85(1):318S-322S.  (PubMed)

49.  US Food and Drug Administration website. Dietary supplement current good manufacturing practices (CGMPs) and interim final rule (IFR) facts http://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/RegulationsLaws/ucm110858.htm. Accessed 8/23/11.

50.  Huskisson E, Maggini S, Ruf M. The role of vitamins and minerals in energy metabolism and well-being. J Int Med Res. 2007;35(3):277-289.  (PubMed)

51.  Ibs K-H, Rink L. Zinc. In: Hughes DA, Darlington LG, Bendich A,eds. Diet and human immune function. Totowa: Human Press Inc.; 2004:241-259.

52.  Bhaskaram P. Immunobiology of mild micronutrient deficiencies. Br J Nutr. 2001;85 Suppl 2:S75-80.  (PubMed)

53.  Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84(2):361-370.  (PubMed)

54.  Centers for Disease Control and Prevention. State indicator report on fruits and vegetables, 2009. http://www.fruitsandveggiesmatter.gov/indicatorreport. Accessed 8/23/11.

55.  Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002;287(23):3116-3126.  (PubMed)

56.  Fletcher RH, Fairfield KM. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002;287(23):3127-3129.  (PubMed)