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1 Chapter 1 : Dietary Supplements Linked to Higher Death Risk Medpage Today The U.S. infant mortality rate during was deaths per 1, live births.(8) Though the U.S. has the largest and most technologically powerful economy in the world, with a per capita GDP of $56,,(9) its infant mortality. Most attention so far has focused on how improvements in maternal nutrition can improve health outcomes for infants and young children. Adequate vitamin D and calcium nutrition throughout life may reduce the risk of osteoporosis, and calcium supplementation during pregnancy may reduce preeclampsia and low birth weight. To reduce neural tube defects, additional folic acid and possibly vitamin B12 need to be provided to non-deficient women before they know they are pregnant. This is best achieved by fortifying a staple food. It is unclear whether maternal vitamin A supplementation will lead to improved health outcomes for mother or child. Iron, iodine and zinc supplementation are widely needed for deficient women. Multimicronutrient supplementation MMS in place of the more common iron-folate supplements given in pregnancy in low-income countries may slightly increase birth weight, but its impact on neonatal mortality and other outcomes is unclear. More sustainable alternative approaches deserve greater research attention. Maternal nutrition, multimicronutrient supplementation, vitamins, minerals, low birth weight Introduction Nature has given women additional challenges in their role as the bearers and early nurturers of children-which in some sense act as sizable parasites. This places women more at nutritional risk, especially where fertility rates are high, as they tend to be in low-income countries. Some have suggested that maternal nutrition during gestation and breastfeeding may be involved [ 2 ]. This has led to speculation that treating women with multivitamin and mineral supplements during and after pregnancy might reduce this process of stunting in infants. Greiner suggested an alternative hypothesis, that early infant retardation in linear growth could to a great extent, be caused by the nearly universal lack of exclusive breastfeeding [ 3 ]. This is because in low income countries the foods and fluids given in the early months of life which always displace breast milk to a large extent, even if they are adequate in energy, lack the other nutrients needed for height growth. In wealthier settings, milk, infant formula or fortified baby foods are more commonly given, and nutritional stunting is not among the known health consequences of the failure to breast feed exclusively. Particularly important for height growth are proteins and minerals, levels of which vary quite little in breast milk, except for the soluble and often endemically deficient minerals iodine and selenium [ 4 ]. We know that suboptimal nutrient intakes among women can have an impact on health, including pregnancy outcomes, bone development, immune function, and, in the elderly, neurological function [ 5 ]. Ideally, this should be done by reviewing evaluations of public health programs. However, few such programs exist and evaluations of them are rare. Thus, the main focus here will be on intervention research that has been conducted during the past decade or so in women of about years of age. This kind of research has been conducted mainly in low-income settings. Some indirect interventions may have the greatest influence on maternal vitamin and mineral status such as delaying the first conception in young women, increased birth spacing, extending the period of paid maternity leave for working women, and better and earlier treatment of maternal infections. It has even been suggested that PMS may be a marker for inadequate calcium intake [ 8 ]. This appears to be due to correcting deficiency suboptimal calcium intake is common in women, even in rich countries rather than a pharmaceutical effect. Adequate vitamin D and calcium nutrition throughout the life-course appear to reduce the risk of osteoporosis [ 10 ]. So far there is no conclusive evidence that supplementation with any other nutrients has a beneficial impact on bone health [ 11 ]. Oral contraceptives and intensive breastfeeding [ 14 ] tend to reduce maternal iron losses during reproduction. Pregnancy and delivery are the source of the greatest iron losses and hemorrhaging during delivery is a major cause of maternal mortality, with women suffering from anemia at increased risk [ 15 ]. Iron supplementation during pregnancy can improve maternal iron status, but only if begun early enough and where adherence is high [ 16 ]. While deficiencies of several nutrients besides iron can cause anemia, and some nutrients like vitamin A are often linked to iron status, a recent review found no greater impact of a Page 1

2 multimicronutrient supplement on iron status than supplementing with iron alone [ 17 ]. Anemia increases the risk of preterm delivery and low birth weight LBW. But high maternal iron levels are associated with an increased risk of fetal growth restriction, preterm delivery, and preeclampsia. High iron levels cause oxidative stress and are also linked to gestational diabetes [ 18 ]. Thus in general, where infrastructure will allow it would probably be wiser to ensure that a pregnant woman is iron deficient before giving her iron supplementation during pregnancy, at least in large doses. Vitamin A Vitamin A policymaking has focused on providing large doses, either to young children or to women soon after delivery [ 19 ], actively reducing the attention given to alternative approaches [ 20 ]. Giving a dose larger than 10, IU, less than a two-day supply, at any other time to women in the reproductive age group is considered unethical, since higher doses may be associated with birth defects in women who do not yet know they are pregnant. While women do receive large doses soon after delivery in some countries, the purpose of this is to increase levels in their breast milk. A recent systematic analysis failed to find any other benefit [ 21 ]. Later trials within less vitamin A deficient populations in Bangladesh [ 23 ] and Ghana [ 24 ] failed to find any impact. Kirkwood argues that even the Nepal study provides inconclusive evidence, and thus, there is presently inadequate support for including low-dose vitamin-a supplementation for women in safe motherhood programs [ 25 ]. Results have been inconsistent for other supplements such as large doses of vitamin B6 and evening primrose oil. Zinc There is some evidence that zinc deficiency may be involved in some maternal mental health problems. Anorexia nervosa patients also improved more rapidly with zinc therapy [ 27 ]. Multivitamins In one study, the use of prenatal multivitamins was found to lead to easier pregnancies such as less morning sickness [ 8 ]. Health problems of the fetus or child linked to maternal nutrient deficiency Most vitamin and many mineral deficiencies in the mother, if serious enough, are likely to have any of a range of impacts on her offspring. But major attention must be placed on mortality, as well as birth defects and LBW, both major causes of infant morbidity and mortality. We begin with single nutrient interventions and then move to the major issue attracting research attention in recent years, multimicronutrient supplementation MMS of pregnant women. Single nutrients Birth defects Some studies have found a number of apparent benefits from taking prenatal vitamins, including reductions in heart, neural tube, and other birth defects [ 8 ]. However, the focus here will be on the outcome that has been most strongly confirmed and acted on, neural tube defects. Additional folic acid needs to be provided to women at the very beginning of pregnancy to reduce the incidence of neural tube defects recognizing that other birth defects may be affected as well. In particular, advising women to take prenatal supplements is ineffective [ 29 ]. This is partly because once a woman knows she is pregnant, the neural tube has already folded, and partly because, even with encouragement, too few women take them regularly enough. Thus impact can best be accomplished through mandatory fortification of a universally consumed food. While most staple food fortification has focused on wheat and to a lesser extent on maize, when rice is the staple food, it can be fortified at low cost with no impact on taste or appearance [ 30 ]. Recent research suggests that vitamin B12 deficiency may also be involved in the causation of neural tube defects [ 31 ]. Among other arguments for combining B12 with folate in fortification programs, there is some evidence that high folate combined with low B12 levels in pregnant women predisposes children to insulin resistance [ 32 ]. Infant morbidity A study in West Java found that zinc supplementation in pregnant mothers led to a decreased incidence of diarrhea but an increase in episodes of cough during the first six months of infancy. Prenatal zinc supplementation was also found to reduce infant diarrhea in Indonesia [ 33 ] and Peru [ 34 ]. Birthweight Even countries with high rates of low birthweight rarely have any defined programs to reduce it [ 35 ]. At the end of the s, there were no known interventions with single vitamins and minerals that would decrease rates of intrauterine growth retardation [ 36 ], but the lack of good research was noted by the investigators. Since then a great deal of additional research on this issue has been done. This effect may be due both to a prolongation of gestation and an increase in fetal growth. This same review found that the impact of magnesium supplementation during pregnancy may be even greater, but sample sizes so far have been slightly too small to be certain. The review found no significant impact of supplementation with other single nutrients on fetal Page 2

3 growth. However in deficient mothers, supplementation with iodine [ 38 ] and iron [ 39 ] can increase birthweight. For iodine, this is associated with neonatal survival [ 40 ] as well as IQ. One study found that zinc with routine iron-folate did not increase birthweight [ 41 ]. But among African American women with low levels of serum zinc at baseline, supplementation with 25 mg of zinc in women taking non-zinc containing prenatal MMS resulted in a g increase in birthweights [ 42 ]. Iron-folate supplementation during pregnancy has sometimes been found to improve a number of developmental outcomes in young children [ 43 ], and sometimes not [ 44 ]; also, zinc has not [ 45 ]. Multimicronutrient supplementation during pregnancy Birthweight During the past decade, the most extensive relevant research has involved supplementation of pregnant women with multimicronutrients, including a multi-site UNICEF study using approximately the recommended daily intakes of iron, folic acid, zinc, copper, selenium, iodine, and vitamins A, B1, B2, B3, B6, B12, C, D, and E. Note that this MMS did not include calcium or magnesium and used 30 mg of iron half the dose of what is often given in iron-folic acid supplements. However, a 60 mg dose is probably higher than necessary [ 46 ]. This research has focused on relatively large and "normal" populations, rather than on patients with clinical deficiencies. A Cochrane review of MMS during pregnancy in found that it worked better than placebo but not better than iron-folate supplementation to reduce LBW this is already commonly the standard of care and given to the control group in most studies [ 47 ]. In West Java, is supplement resulted in a non-significant 40 g increase birthweight compared to iron-folate supplementation [ 49 ]; as well as increases of 52 g in Burkina Faso [ 50 ]; 70 g in Pakistan [ 51 ]; and 67 g in Niger [ 52 ]. At age 2 years, children in B were about 2 cm taller and those in C were 1 cm taller than those in A [ 53 ]. A meta-analysis of 12 MMS trials found that the pooled estimate of increased birthweight was 24 g compared to supplementation iron-folate alone. However, there was an equally large increase in gestational age births that were excessively large [ 54 ]. It is possible that the levels of nutrients used in the MMS were too low. Among women for whom birth weights were available who had had fewer births and more education, one RDA, resulted in a 53 g increase in birth weight and two RDAs, a 95 g increase the latter was somewhat lower when potential confounders were adjusted for. There was no impact on the proportion born with LBWs or on mortality. A few such trials have also taken place in industrialized countries. A recent trial of women who commonly had micronutrient deficiencies in East London, UK, though rather seriously flawed about half the women did not complete the trial, suggested that MMS might reduce the incidence of small for gestational age deliveries [ 56 ]. Maternal vitamin C levels seemed particularly important for birth weight along with zinc for birth length. In the USA, one prospective study in a low-income city for over a decade which measured adherence to the prenatal vitamins prescribed to all participants found substantially lower rates of preterm delivery in women who used the supplements which contained 1 mg of folate, 25 mg zinc, 65 mg iron and mg of calcium [ 58 ]. However, there was no difference in the proportion that was small for gestational age. Height growth Shrimpton [ 59 ] argues that even modest reductions in LBW would substantially reduce stunting by two years of age. In France, maternal zinc supplementation alone was associated with birth length [ 57 ]. However, these studies appear to be exceptions. There was no effect of MMS on birth length in any of the 12 studies included in a meta-analysis and there was no overall impact when the data were combined [ 54 ]. Nor was such an impact seen in an MMS trial in Mexico, though in a per protocol analysis, the investigators noted that high adherence appeared more likely to lead to impact [ 60 ]. Young child morbidity Maternal supplementation with folic acid with or without iron and zinc reduced the risk of kidney dysfunction and, to a lesser extent, metabolic syndrome among children at y of age, however, MMS did not [ 61 ]. Similarly, in Pakistan [ 51 ], MMS increased the neonatal mortality rate from A meta-analysis found no impact of MMS on any type of mortality [ 64 ]. Intellectual and motor function in young children In Bangladesh, adding multiple micronutrients to food supplements for pregnant women led to better cognitive function in children at two years of age [ 65 ], although it failed to increase infant micronutrient levels, except for vitamin B12 [ 66 ]. In China, MMS increased raw scores in mental development at one year but not earlier, but it did not impact psychomotor development [ 67 ]. A study in Nepal found no such impact however [ 43 ]. Impacts on fetal Page 3

4 growth and on young child growth and development appear to be of small to moderate effect sizes. However, it is unclear whether there is an overall positive or negative impact on early infant mortality rates. Page 4

5 Chapter 2 : Vitamins and minerals for women: recent programs and intervention trials The intervention was a lipid-based nutritional supplement either without (LNS) or with additional vitamins and minerals (LNS-VM), beginning prior to ART initiation; supplement amounts were 30 g/day ( kcal) from recruitment until 2 weeks after starting ART and g/day (1, kcal) from weeks 2 to 6 after starting ART. Effect of maternal micronutrient supplementation on perinatal and neonatal mortality in randomized controlled trials in developing countries CI, confidence interval; HIV, human immunodeficiency virus; RR, relative risk. Discussion Our study is consistent with recent systematic reviews in showing that maternal micronutrient supplementation can reduce the risk of having an infant with low birth weight. We found that maternal educational level or gestational age at initiation of supplementation may have contributed to the heterogeneous effects on perinatal mortality. Several biological mechanisms can explain the beneficial effects of micronutrient supplementation on fetal growth. Women require more vitamins and minerals during pregnancy and supplements can improve their nutritional and haemoglobin status. Supplements also help improve and maintain functional immunity. Thus, micronutrient supplements can help maintain normal homocysteine levels. Many vitamins and minerals also play important roles in gene regulation as well as in cellular metabolism and fetal growth. In a trial in Burkina Faso, half of the perinatal deaths were due to prematurity. This led the researchers to conclude that an increase in perinatal mortality cannot be entirely due to the complications associated with delivering an infant too large for gestational age. We found that all trials that reported an adverse effect on perinatal mortality were conducted in poor rural settings where most mothers had no education. Maternal educational level is likely to be a proxy for unmeasured characteristics. Low maternal education may be a correlate of a greater likelihood of delivering at home, limited access to health facilities, limited availability of skilled birth attendants and maternal and newborn care of lesser quality. Furthermore, in most developing countries access to quality perinatal health care differs substantially between rural and urban areas. Large cluster randomized trials with a stepped wedge design may need to be conducted in rural settings to assess the safety and efficacy of micronutrient supplementation in the context of programmes for improving obstetric and postnatal care. In many parts of the developing world, enhancing access to obstetric care, improving postnatal care and empowering mothers through community health workers are essential measures for reducing perinatal and neonatal mortality. Thus, we are unable to assess whether a relationship exists or not between treatment effect and the timing of supplement initiation within trials. Alternatively, early supplementation could have altered metabolic regulation and led to complications during pregnancy and consequently to perinatal death. Another possibility is that micronutrient supplementation prevented early spontaneous abortion and allowed mothers to carry frail fetuses to much later stages of pregnancy, with a resulting spurious increase in the number of perinatal deaths. Minerals can interact with desoxyribonucleic acid DNA and disrupt ligand binding or protein function, or induce oxidative damage on embryotic tissue. Our study has several limitations. Factors that we did not examine, such as the prevalence of maternal infections, including malaria and hookworm, and dietary nutrient intake, may have accounted for the heterogeneity of effect estimates. As shown by a trial in Nepal, zinc can reduce the beneficial effects of iron supplements through biochemical interactions that are possibly influenced by whether or not supplements are taken with a meal. We were unable to verify the composition and dosage of the micronutrient supplements. Most trials used the RDA of each micronutrient, an amount considered sufficient to meet the requirements of most healthy individuals in industrialized countries. In developing countries pregnant women may require higher doses because of their poorer nutritional status and higher rates of infection. However, a recent trial found that multivitamin supplements containing the RDA of each component may be as effective as those containing multiple doses of the RDA in reducing the risk of adverse pregnancy outcomes among HIV-infected women. Although our study provides valuable insights into the heterogeneous effects of micronutrient supplements on perinatal mortality, more research is needed to explain why some trials found Page 5

6 multiple micronutrient supplementation to be associated with higher perinatal mortality. Few studies have examined the effects of micronutrient supplementation on long-term child health outcomes, such as child mortality, morbidity, growth and cognitive development. Micronutrient supplementation before pregnancy also warrants further research. Non-significant detrimental effects on perinatal mortality were reported in some trials conducted in poor rural settings. This suggests that in such settings supplements may need to be delivered in the context of programmes for improving obstetric and postnatal care. More research is needed to address the safety, efficacy and effective delivery of maternal micronutrient supplementation. Page 6

7 Chapter 3 : Vitamin and mineral supplement use and mortality in a US cohort. Related to reducing infant mortality and morbidity, what range of weight for infants decreases the mortality risk? 8lb and 13oz - 9lb and 14oz What is the listed weight that is associated with an infant mortality rate of? Point out that this observational study found an association between the use of multivitamins and several minerals and all-cause mortality in white, post-menopausal women. Note that the use of calcium and vitamin D was associated with a decreased risk when compared to nonuse. In postmenopausal women, the use of several common vitamin and mineral supplements was associated with an increased risk of death, researchers found. After adjustment for multiple potential confounders, use of multivitamins and vitamin B6, folic acid, iron, magnesium, zinc, and copper supplements was associated with greater all-cause mortality through 19 years of follow-up HRs 1. Use of a daily calcium supplement, on the other hand, was associated with a lower risk of death HR 0. The long-term impact of supplementation is unknown, however, and some studies have suggested a relationship between supplements and increased mortality. The mean age of the women at baseline in was The participants reported their use of supplements in,, and The percentage who reported using at least one supplement daily increased from The most commonly used supplements were calcium, multivitamins, vitamin C, and vitamin E. After adjustment for demographics, dietary and lifestyle factors, comorbidities, and use of hormone replacement therapy, the following supplements were associated with a greater risk of death during follow-up: After multivariate adjustment, use of calcium supplementation was associated with a lower risk of death HR 0. The absolute risk reduction was 3. To account for the multiple comparisons made, however, the researchers set a P value of less than 0. Only the increase associated with multivitamins, calcium, and copper remained significant using this threshold. In particular, the findings related to iron and calcium remained consistent when the analysis was restricted to follow-up from to, from to, and from to In addition, the mortality risk associated with iron supplementation increased in a dose-response fashion. However, we could find no evidence for such reverse causality. Added Redberg, "A better investment in health would be eating more fruits and vegetables, among other activities. Bjelakovic and Gluud reported that they had no conflicts of interest. Reviewed by Zalman S. Page 7

8 Chapter 4 : The Calcium to Magnesium Ratio- Effect on Mortality NHRI the infant mortality rate is the number of infant deaths per 1, live births in the first month of life false high caffeine consumption has been linked to an increase risk of miscarriages. However, numerous studies published over more than a decade have linked some supplements including vitamins E, C, D, A, and B, as well as selenium to no health benefits or even to adverse health effects. Recent studies with negative results, which drew media attention, include the following: In contrast, there are compelling cause and effect data linking the use of folic acid with consistent and significant reductions in fetal adverse pregnancy outcomes, demonstrating no beneficial effects of calcium and vitamin D supplements in improving bone strength and reducing fractures. These equivocal and conflicting findings on the effects of supplements on health outcomes have left consumers confused about their benefits and wary of the possible adverse effects of vitamin and mineral supplementation. The objectives of this session are to characterize the current state of the science as it relates to the impact of vitamin and mineral supplementation on human health, review the statutory and regulatory perspective of vitamin use from a safety perspective, assess the credibility of meta-analysis in the safety assessment of vitamins, and elicit the mechanisms of these interactionsâ pro-oxidant versus antioxidant effects and beneficial versus adverse effects. An association between diets containing fruits and vegetables and health has been noted since Hippocrates â BC â and in fact long before Bjelakovic and Gluud, It has been known for a long time that a diet that includes fruits and vegetables contains vitamins, minerals, and other bioactive nutrients. In recent years, we have isolated, purified, and by various manufacturing techniques made these vitamins, minerals, and other bioactive compounds available in the form of dietary supplements. This has resulted in a high rate of supplement use. Given such high supplement consumption, we are starting to see reports indicating that there might be some dangers associated with such levels of use. Two examples of these reports include the following: In, a large randomized controlled trial SELECT was halted after reporting that vitamin E and selenium resulted in an increase in incidence of prostate cancer Lippman et al. The Physician Health Study Gaziano et al. In contrast to studies that indicate possible adverse effects Brent and Oakley,, the Institute of Medicine IOM, report illustrated that the use of folic acid can reduce the incidence of malformation, i. In addition, another report Brannon et al. Macular degeneration is reduced in elderly people who were supplemented with vitamin C, E, beta-carotene, copper, and zinc supplements Huang et al. Therefore, there are conflicting reports in the literature, which has served as our motivation to organize this roundtable. The objectives of the present roundtable conference were to examine the current state of the science, review the statutory and regulatory aspects over supplements, access credibility of the research, and finally propose or elicit some potential mechanisms responsible for such diverse effects and to consider adverse versus beneficial effects for supplements, such as pro-oxidant versus antioxidant effects. Statutory and Regulatory Perspective T. Thurmond Vitamins and minerals are nutrients required by the body for normal growth and maintenance. Vitamin and mineral supplements can complement a regular diet but are not meant to be food substitutes because they cannot replicate all the nutrients in whole foods. Unfortunately, not all segments of the public are fully aware of the difference between foods and supplements. DSHEA places dietary supplements under a special category under foods, not drugs, and requires that they are labeled as dietary supplements. In order to be a dietary supplement ingredient, a substance must have one or a combination of the following: To be considered as an NDI, it must meet the previous definition and not have been sold in the United States prior to 15 October In addition, an NDI notice must be submitted to the FDA 75 days prior to introducing the supplement into interstate commerce. The NDI must contain information that demonstrates that the supplement is chemically pure and safe. Any claims made by a company for such supplements must be substantiated by adequate evidence showing that they are not false or misleading. It is the company that is responsible for the safety, quality, and labeling of their products. Starting in, the FDA began phasing in Page 8

9 current good manufacturing practices for producing dietary supplements. Second, the FDA also regulates vitamin and mineral supplements as direct food additives e. The manufacturer must submit complete chemistry and safety information for their product, which undergo a thorough assessment by FDA review scientists. The National Health and Nutrition Examination Survey NHANES, found that a third of the population took some form of vitamin or mineral supplement in the previous month, and a study of children and adolescents, conducted from to, also showed that a third took a dietary supplement in the previous month. It should be noted that both studies probably underestimate their use because of underreporting by the participants. There is substantial evidence Berdanier and Zempleni, demonstrating that the use of vitamin and mineral supplements can be beneficial, such as vitamin D and calcium can increase bone density in postmenopausal women, multivitamin supplements may be beneficial for human immunodeficiency virus and acquired immune deficiency syndrome patients, and taking multivitamins may reduce birth defects beyond that found for the use of folic acid by women of child-bearing age. Many people take a supplement, and many consume food that is enriched with vitamins and minerals. As noted previously, supplements are not essential for those consuming a healthy diet, and there is the possibility of over supplementation. There is little evidence that supplements are useful for the treatment of common cancers, cardiovascular disease CVD, or total mortality in postmenopausal women. There is, however, evidence that vitamin supplementation may enhance cancer cell survival in those undergoing cancer treatment Kristal and Lippman, and that supplementation with very high doses of beta-carotene and vitamin A may increase the risk of CVD in female smokers Omenn et al. The FDA does not ensure premarket safety of all multivitamin supplements, although there is a common public misconception that it does evaluate their safety prior to being marketed. In the paraphrased words of Paracelsus, dose makes the poison, which is true for all substances including vitamins and minerals. For example, there are dose-related acute toxicity issues with vitamin A at 25, international units IU per kilogram of body weight Berdanier and Zempleni, Symptoms of this severe acute toxicity can include headache, phobia and anoxia, skin-related lesions exfoliation, problems of long bones osteoporosis, and problems with closure of long bones in children. Toxicity may be manifested by hypercalcemia, muscle weakness, headache, and nausea. Longer term use may also produce constipation, cramps, polyuria, and polydipsia. There is also the possibility of dental decalcification and rebound scurvy in infants born to women consuming large concentrations of vitamin C and estrogen changes in women. Although calcium is essential, massive doses can promote atherosclerosis and other related problems. Acute high doses of iron can cause problems in iron storage in individuals with the genetic disease of hemachromatosis. Chronic massive higher concentration than the Dietary Reference Intake doses of iron in those genetically affected can cause iron being deposited in various internal organs. Other common symptoms of iron-related toxicity include hepatomegaly, skin pigmentation, joint diseases, and lethargy Berdanier and Zempleni, Although consumption of vitamin and mineral supplements is generally safe in moderation, in, over 69, calls were made to poison control centers for toxicity complaints relating to acute overdosing with vitamin or mineral supplements Poison Control Centers. Toxicity because of vitamin and mineral supplement ranked 15th among all the substances reported to poison control and seventh among all pediatric substances. Fortunately, no deaths were attributed to overdosing. Miller The findings of the meta-analysis of vitamin E supplementation and mortality were published in Miller et al. There have been numerous reports supporting the beneficial effects of vitamin E in CVDs. Vitamin E is a lipid soluble vitamin, which has been known to protect lipids from free-radical damage. In their model of atherosclerosis, circulating LDL crosses the endothelium layer, where oxidation by free-radical activity forms oxidized LDL. Oxidized LDL is picked up by receptors on macrophages and is accumulated in the intimal layer of arteries. According to the Steinberg model, LDL oxidation is obligatory for initiation of the early phase of atherosclerosis, and dietary antioxidants can prevent such damage. In vitro studies using isolated human LDL cholesterol show that antioxidants, such as beta-carotene and vitamin E supplementation, prevent the oxidation of LDL, as illustrated by indices, such as resultant decreased formation of conjugated dienes or malondialdehyde. In addition, studies from our Page 9

10 laboratory whereby subjects were supplemented with vitamin E, vitamin C, or both, for 2 months, resulted in reduced concentrations of urinary isoprostanes, which are markers of oxidative damage of arachidonic acid. These studies in total indicate, in principal, that supplementation in laboratory-based studies, with vitamin E for 2 months, can decrease oxidative stress. Going from laboratory-based studies to human epidemiological-based studies, it has been shown in multiple studies that there is a strong inverse association between serum or dietary intake of vitamin E and risk for atherosclerosis. Although such studies do not show cause and effect, they did provide strong justification for randomized trials. Subsequently, there have been numerous randomized trials completed, including hundreds of thousands of individuals. Thus, in total, this provided the incentive for meta-analysis. The inclusion criteria for meta-analysis was a randomized trial design, inclusion of a placebo group, more than 10 deaths in the trial, and a follow-up for more than 1 year; a dose-response analysis, as well. There were 19 randomized trials that included over, people and 12, deaths. Typical intake for vitamin E from food is 10 IU per day. Average age was 64 years, and the median length of follow-up was 4 years. Overall, there were more deaths in the vitamin E supplement group compared with the placebo group. At low doses of vitamin E and related to populations with vitamin E deficiency, vitamin E was associated with lower mortality. Based on current research findings, suggested reasons for increased mortality with high vitamin E supplementation include the following: Possible explanations for a lack of benefit of vitamin E are that natural vitamin E may be more important, need for studying combination of antioxidants, and perhaps the duration of trials are too short. Subsequently, the results from several additional trials have been published and have evaluated the consistency of new, independent evidence with findings. The pooled relative risk, 1. Based on recent CDC data, as people age, there is a tendency for increased use of vitamin E by the general population. However, there is no evidence from randomized trials that high dose vitamin E supplementation is beneficial; in fact, numerous long-term clinical trials and the meta-analysis report the opposite that there is an increased risk of mortality with higher doses. Bendich The objectives of this review were to present some basic information on beta-carotene, clinical data from beta-carotene trials, examples where lifestyle habits appear to increase risk factors, and highlight the paradox, i. Beta-carotene is one of a variety of some carotenoid compounds found in richly colored fruits and vegetables. Beta-carotene and four other carotenoids are classified as pro-vitamin A carotenoids. In theory, beta-carotene can be metabolically cleaved into two molecules of vitamin A Bendich, Beneficial examples of beta-carotene functions include antioxidant properties and specific immune cell functions, such as increasing natural killer cell activity. Beta-carotene is also associated with improved physiological functions, such as enhanced lung function Krinsky and Johnson, Beta-carotene was also an approved drug. Solatene was sold by Hoffman-LaRoche for use in an inherited disease of photosensitivity, erythropoetic protoporyphria. Epidemiological data have shown that in diets rich in beta-carotene, there is decreased incidence of cancer compared with those with normal diets. When people have less beta-carotene in their blood, there is an increased incidence of cancer. Additionally, smokers have consistently low serum levels of beta-carotene. Thus, based on these data, it has been suggested that beta-carotene should be helpful in preventing cancer. ATBC Cancer Prevention Study Group was a randomized placebo control study of approximately 30, male subjects of age 50â 69 years who were heavy smokers. There were four treatment groups: Subjects received their respective treatment for 5â 8 years. These subjects received 20 mg of beta-carotene in combination with 25, IU of retinol vitamin A for an average of 5 years. There was no significant increase in incidence of cancer, CVD, or total mortality. Whereas it has been suggested that a possible adverse effect of high levels of beta-carotene was on blood concentrations of vitamin E, Nierenberg et al. Primary prevention lung cancer clinical trials demonstrate a potential risk of increased lung cancer and overall mortality associated with beta-carotene supplementation for smokers or individuals exposed to asbestos. It is possible that treatment with beta-carotene in those studies was not long enough to show lung cancer prevention in high-risk people. The paradox is that whereas many dietary intake studies have shown an association of increased intake of beta-carotene with decreased risk of lung cancer, intervention studies with high-dose beta-carotene supplementation have shown an increased risk of lung Page 10

11 cancer in smokers and workers exposed to asbestos. Page 11